Substituted 2-(3,5-dichloro-4-(4-hydroxy-benzyl)phenoxy)acetamide derivatives

Abstract

The present application relates to compounds that are substituted derivatives of 2-(3,5-dichloro-4-(4-hydroxy-benzyl)phenoxy)acetamide and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising one or more of the compounds as an active ingredient, and methods of use thereof, which are useful for treating demyelinating diseases such as multiple sclerosis.

Description

SUBSTITUTED 2-(3,5-DICHLORO-4-(4-HYDROXY-BENZYL)PHENOXY)ACETAMIDE DERIVATIVESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 528,034, filed July 20, 2023, the entirety of which is incorporated by reference.FIELD

[0002] The present disclosure is directed to compounds useful for modulating thyroid hormone receptor-beta in the central nervous system (CNS), pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and the use of the compounds and salts thereof for preventing and / or treating demyelinating diseases, including but not limited to multiple sclerosis, in mammals and especially in humans.BACKGROUND

[0003] Multiple sclerosis (MS) arises when the immune system attacks myelin causing communication problems between the brain and the rest of the body. MS is characterized by both damage to the myelin sheath (demyelination) and a failure to repair the damaged myelin (remyelination). Without the protective myelin coating, messages traveling along nerve fibers maybe be slowed or stopped, and, over time, the axons and cell bodies of neurons can also become damaged. Remyelination is performed by nerve cells known as oligodendrocytes, which mature from oligodendrocyte progenitor cells (OPCs) in the central nervous system. While MS patients possess abundant OPCs, they fail to differentiate into oligodendrocytes and cannot help repairing damaged myelin. Thyroid hormone promotes the differentiation of OPCs into mature oligodendrocytes. These cells regenerate myelin to protect demyelinated neurons and restore neural conduction velocity to halt and potentially reverse the progressive course of MS.

[0004] Thyroid hormone is synthesized in the thyroid in response to thyroid stimulating hormone, and plays a critical role in growth, development, metabolism, and homeostasis. Thyroid hormone receptors (THRs), which mediate the biological activity of TH, belong to the nuclear hormone receptor superfamily and regulate the transcription of target genes. THRs have a ligand binding domain, a DNA binding domain, and an amino terminal domain. THR isoforms, THR-a and THR-f>, are encoded by distinct genes. THRs are expressed in most human tissues, however the distribution of specific THR isoforms varies. THR-a expression is prevalent in heart, brain, and bone, while THR- expression predominates in the liver, kidney, pituitary gland, and brain. Efforts have been directed to develop compounds selective for THR-0 that would be effective for treatment of metabolic and / or brain disorders without producing deleterious effects on heart and bone that would otherwise be mediated by THR-a.

[0005] Publications of patents and patent applications purporting to disclose THR agonists with selectivity towards THR- can be found, for instance in US 4,766,121, US 8,791,266 Bl, US 10,800,767 B2, US 11,203,587 B2, US 11,667,606 B2, and International Patent Publication No. WO2023 / 177667.However, the blood-brain barrier can be a substantial impediment to achieving therapeutic levels of THR agonists in the CNS to afford treatment of CNS disorders.

[0006] There remains a need to develop new THR agonists, that can be distributed into the brain to allow further improvement of tissue-targeted selectivity and efficacy for treatment of multiple sclerosis.SUMMARY

[0007] Provided herein are compounds, pharmaceutical compositions, and methods useful, inter alia, for preventing or treating a demyelinating disease, e.g., multiple sclerosis.

[0008] In one aspect, provided herein is a compound having Formula (II) or a pharmaceutically acceptable salt thereof:wherein R1and R2are each independently hydrogen or halo; R3is hydrogen or fluoro, with the proviso that each of R1and R2are hydrogen when R3is fluoro: R4, R\and R6are each independently hydrogen or methyl; and R7is hydrogen.

[0009] In some embodiments of the compound or pharmaceutical salt thereof of Formula (II), each of R4and R5is hydrogen. In some embodiments, one of R4and R3is hydrogen and the other of R4and R5is methyl.

[0010] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of 2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)acetamide; and2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide.

[0011] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is listed in Table ATABLE A

[0012] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is selected from the group consisting of (R)-2-(3,5-dichloro-4-((3',4'-difIuoro-6-hydroxy-[l,T-biphenylJ-3- yl)methyl)phenoxy)propanamide;(R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methy Ipropan amide ;(S)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,T-biphenyl]-3- yl)methyl)phenoxy)propanamide;(S)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropanamide;(R)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)propanamide;(R)-2-(3,5-dichloro-4-((3’-chloro-4'-fluoro-6-hydroxy- [1,1 ’-biphenyl] -3-yl)methyl)pheno xy)-N- methylpropan amide;(S)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,T-biphenyl]-3- yl)mcthyl)phcnoxy)propanamidc; and(S)-2-(3,5-dichloro-4-((3'-chloro-4’-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide.

[0013] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is listed in Table B.TABLE B

[0014] In one aspect, provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of2-(3,5-dichloro-4-((4'-fhioro-6-hydroxy-[l,T-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((4'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;(S)-2-(3,5-dichloro-4-((4'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)propanamide;(S)-2-(3,5-dichloro-4-((4'-fluoro-6-hydroxy-[l J'-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide;(R)-2-(3,5-dichloro-4-((4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)propanamide;(R)-2-(3,5-dichloro-4-((4'-fluoro-6-hydroxy- [ 1 , l'-biphenyl] -3-yl)methy l)phenoxy)-N - methylpropan amide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-3-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-3-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-2-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-2-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((3'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyrazin-2-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyrazin-2-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridazin-4-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridazin-4-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((6-hydroxy-2'-methyl-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((6-hydroxy-2'-methyl-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((3',5'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3',5'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((2'-chloro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2'-chloro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-3-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyrimidin-5-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-4-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-4-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((2'-chloro-5'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2'-chloro-5'-fluoro-6-hydroxy-fl,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyrimidin-4-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(pyrimidin-4-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(3-(2-fluoropyridin-4-yl)-4-hydroxybenzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(3-(2-fluoropyridin-4-yl)-4-hydroxybenzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((4'-chloro-3'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3'-fluoro-6-hydroxy-4'-methyl-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((4'-chloro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((6-hydroxy-4'-methyl-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((3'-chloro-4',5'-difluoro-6-hydroxy-[l,r-biphenylJ-3- yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3'-chloro-4\5'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((4'-chloro-3',5'-difluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((4'-chloro-3',5'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((2',4',5'-trifluoro-6-hydroxy-[l,l'-biphenyl]-3-yr)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2',4',5'-trifluoro-6-hydroxy-[l,l'-biphenyl]-3-yr)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((2',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;(S)-2-(3,5-dichloro-4-((2',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)propanamide;(S)-2-(3,5-dichloro-4-((2',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide;2-(3,5-dichloro-4-(3-(5-fluoropyridin-3-yl)-4-hydroxybenzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(3-(5-fluoropyridin-3-yl)-4-hydroxybenzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((2'-chloro-3'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2'-chloro-3'-fluoro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((3',4',5'-trifluoro-6-hydroxy-f l,l'-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3',4,,5,-trifluoro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(3-(2-chloropyridin-4-yl)-4-hydroxybenzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(3-(2-chloropyridin-4-yl)-4-hydroxybenzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N-methylacetamide;(S)-2-(3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)propanamide;(S)-2-(3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N-methylpropanamide;(R)-2-(3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)propan amide;(R)-2-(3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N-methylpropan amide;2-(3,5-dichloro-4-((6-hydroxy-[l,r-biphenyl]-3-yl)methyl)-2-methylphenoxy)acetamide;2-(3,5-dichloro-4-((6-hydroxy-[l,r-biphenyl]-3-yl)methyl)-2-methylphenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((4-fluoro-6-hydroxy-fl,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((4-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-5-(pyridin-4-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-5-(pyridin-4-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-((4,4l-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((4,4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((3',4,4'-trifluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3',4,4'-trifluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((4-chloro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((4-chloro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((2-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((2,4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2,4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((2'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((2'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yr)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(lH-pyrazol-3-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(lH-pyrazol-3-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(isothiazol-4-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(isothiazol-4-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(isothiazol-5-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(isothiazol-5-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(3-(l-cyclopropyl-lH-pyrazol-4-yl)-4-hydroxybenzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(3-(l-cyclopropyl-lH-pyrazol-4-yl)-4-hydroxybenzyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(isoxazol-4-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(isoxazol-4-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(lH-l,2,4-triazol-l-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(lH-l,2,4-triazol-l-yl)benzyl)phenoxy)-N-methylacetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(lH-imidazol-l-yl)benzyl)phenoxy)acetamide;2-(3,5-dichloro-4-(4-hydroxy-3-(lH-imidazol-l-yl)benzyl)phenoxy)-N-methylacetamide;(S)-2-(3,5-dichloro-4-((4'-chloro-6-hydroxy-[l,T-biphenyl]-3-yl)methyl)phenoxy)propanamide;(S)-2-(3,5-dichloro-4-((4'-chloro-6-hydroxy- [ 1 , I'-biphenyl] -3-yl)methyl)phenoxy)-N - methy Ipropan amide ;(R)-2-(3,5-dichloro-4-((4'-chloro-6-hydroxy-[l ,l'-biphenyl]-3-yl)methyl)phenoxy)propanamide; and(R)-2-(3,5-dichloro-4-((4'-chloro-6-hydroxy-[l,T-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropanamide.

[0015] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is listed in Table C.TABLE C

[0016] In one aspect, provided herein is a pharmaceutical composition comprising a compound or a pharmaceutical salt as provided herein, and a pharmaceutically acceptable excipient.

[0017] In one aspect, provided herein is a method of modulating a thyroid hormone receptorbeta in a cell, the method comprising contacting the cell with a compound or pharmaceutically acceptable salt as provided herein.

[0018] In one aspect, provided herein is a method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt as provided herein.DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 depicts plots of plasma concentration over time of parent P-15 and compound 1.(A) Plasma concentrations of P-15 following intravenous (IV) administration of 1.0 mg / kg ( -»•- ) and oral gavage (PO) administration of 5.0 mg / kg( ) of P-15. (B) Plasma concentrations of compound 1 () following IV administration of 1.0 mg / kg compound 1, and of compound 1 () and P-15 (~*~) following PO administration of 5.0 mg / kg compound 1.

[0020] FIG. 2 depicts bar graphs showing the brain-to-plasma ratio (BPR) and liver-to-plasma ratio (LPR) of P-15 at 0.25, 0.5 and 2 hours after administration of P-15 (FIG. 2A), and the BPR and LPR of compound 1 and P-15 at 0.25, 0.5 and 2 hours after administration of compound 1 (FIG. 2B).

[0021] FIG. 3 shows plasma concentrations over time for compound 2 ( ■ «■ ) and P-15 ( ) following IV administration of 1.0 mg / kg compound 2, and for compound 2 following PO administration of 5.0 mg / kg compound 2. a bar graph showing the brain-to-plasma ratio (BPR) and liver-to-plasma ratio d P-15 at 0.25, 0.5 and 2 hours after administration of compound 2. hows plasma concentrations over time for compound 3 ( *■**■ ) and P-61 ( ♦ ) on of 1.0 mg / kg compound 3, and for compound 3following PO administration of 5.0 mg / kg compound 3, which demonstrate the conversion of compound 3 to P-61 in vivo. Plasma concentrations of P-61 following administration of 1.0 mg / kg IV P-61 ( -*■■■ ) and 5.0 mg / kg PO P-61 (■■■♦■■■ ) are also shown.

[0024] FIG. 6 is a bar graph showing the brain-to-plasma ratio (BPR) and liver-to-plasma ratio (LPR) of compound 3 and P-61 at 0.25, 0.5 and 2 hours after IV administration of compound 3, and the BPR and LPR of P-61 at 0.25, 0.5 and 2 hours after IV administration of P-61.

[0025] FIG. 7 shows plasma concentrations over time of compound 9 and parent molecule P-55 demonstrating the conversion of compound 9 to P-55 in vivo.

[0026] FIG. 8 is a bar graph showing the brain-to-plasma ratio (BPR) and liver-to-plasma ratio(LPR) of compound 9 and P-55 at 0.25, 0.5, and 2 hours after IV administration of compound 9.DETAILED DESCRIPTION

[0027] Disclosed herein are amide-containing compounds which are converted in vivo to carboxy acid-containing parent molecules with selective thyroid hormone receptor-beta (THR- ) agonist activity. Moreover, the compounds disclosed herein have increased penetration into the brain, that is, they more easily cross the blood brain barrier, as compared to their respective carboxy acid-containing parent molecules.

[0028] In one aspect, provided herein is a compound having Formula (I) or a pharmaceutically acceptable salt thereof:whereinA isR1and R2are each independently hydrogen or halo;R3is hydrogen, chloro, or fluoro;R4, R5, R6, and R7are each independently hydrogen or methyl; andR8is hydrogen or chloro.

[0029] In one aspect, provided herein is a compound having Formula (II) or a pharmaceutically acceptable salt thereof:wherein R1and R2are each independently hydrogen or halo; R3is hydrogen or fluoro;R4, R and R6are each independently hydrogen or methyl; and R7is hydrogen.

[0030] In some embodiments of a compound having Formula (II) or a pharmaceutically acceptable salt thereof, R1and R2are each independently hydrogen or halo; R3is hydrogen or fluoro,with the proviso that each of R1and R2are hydrogen when R3is fluoro; R4, R5,and R6are each independently hydrogen or methyl; and R7is hydrogen.

[0031] In certain embodiments, provided herein is a compound having Formula (III) or a pharmaceutically acceptable salt thereof:wherein A, R3, R4, R5and R8are as defined above.

[0032] In certain embodiments, provided herein is a compound having Formula (IV) or a pharmaceutically acceptable salt thereof:wherein A, R3, R4, R5and R8are as defined above.

[0033] In some embodiments of the compound or pharmaceutical salt thereof of Formula (I),(II), (III) or (IV), each of R4and R5is hydrogen.

[0034] In some embodiments, the compound is selected from the group consisting of2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)acetamide;2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide;2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)mcthyl)phcnoxy)acctamidc; and2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylacetamide.

[0035] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is listed in Table ATABLE A

[0036] In some embodiments of the compound or pharmaceutical salt thereof of Formula (I),(II), (III) or (IV), one of R4and R5is hydrogen and the other of R4and R5is methyl.

[0037] In some embodiments, the compound is selected from the group consisting of(R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)propanamide;(R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide;(S)-2-(3,5-dichloro-4-((3’,4'-difluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)propanamide;(S)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide;(R)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)propanamide;(R)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide;(S)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl )methy l)phenoxy )propanamide; and(S)-2-(3,5-dichloro-4-((3'-chloro-4'-Iluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy)-N- methylpropan amide.

[0038] In some embodiments, provided herein is a compound or a pharmaceutical salt thereof, wherein the compound is listed in Table B.TABLE B

[0039] In one aspect, provided herein is a compound or a pharmaceutical salt thereof wherein the compound is listed in Table 1.TABLE 1

[0040] Compounds described in TABLE 1 are converted in vivo into carboxylic acid-containing parent molecules with selective THR- agonist activity. These parent molecules are described in table 1 of International Patent Publication No. WO2023 / 177667, which have the THR-a and THR- binding and selectivity index as described in table 2 of International Patent Publication No. WO2023 / 177667, which tables are incorporated herein by reference in their entireties.

[0041] In one aspect, provided herein is amide derivative of any carboxylic acid-containing compound listed in in table 1 of International Patent Publication No. WO2023 / 177667, which is incorporated herein by reference in its entirety.

[0042] Compounds provided herein are described with reference to both generic formulae and specific compounds. In addition, compounds of the present disclosure may exist in a number of different forms or derivatives, all within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, different crystal forms or polymorphs, and active metabolites.

[0043] The compounds of present disclosure can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. Thus, inventive compounds and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the present disclosure are enantiopure compounds. In certain embodiments, mixtures of enantiomers or diastereomers are provided.

[0044] The term “enantiomer” refers to two stereoisomers of a compound which are non- superimposable mirror images of one another. The term “diastereomer” refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.

[0045] As used herein, the term “isomers” includes any and all geometric isomers and stereoisomers. For example, “isomers” include cis- and trans-isomers, E- and Z- isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. For instance, a stereoisomer may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as “stereochemically enriched”.

[0046] Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer and may also be referred to as “optically enriched”. “Optically enriched”, as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0047] Compounds of the present disclosure can be formulated as or be in the form of pharmaceutically acceptable salts. Unless specified to the contrary, a compound provided herein includes pharmaceutically acceptable salts of such compound.

[0048] As used herein, the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the subjects being treated therewith.

[0049] As used herein, the term “pharmaceutically acceptable salt”, unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect.

[0050] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid,malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0051] Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

[0052] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous- alcohol solution containing the appropriate acid and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0053] Similarly, if the compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0054] It is also to be understood that the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystal or polymorphic forms), and the present disclosure is intended to encompass all such forms.

[0055] As used herein, the term “solvate” or “solvated form” refers to solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water withone molecule of the substance in which the water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopfopanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0056] As used herein, the terms “crystal form,” “crystalline form,” “polymorphic forms” and“polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

[0057] The present disclosure is also intended to include all isotopes of atoms in the compounds.Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to ‘H,2H,3H,nC,12C,13C,14C,14N,15N,16O,17O,18O,17F,19F,35C1, and37Cl. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon includes12C and13C.

[0058] As used herein, the term “halo” or “halogen” refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).

[0059] In one aspect, provided herein is a pharmaceutical composition comprising a compound having Formula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0060] A “pharmaceutical composition”, as used herein, is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), spray, ointment, paste, cream, lotion, gel, patch, inhalant, or suppository. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is a therapeutically effective amount and is varied according to the particular patient and treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, thepharmaceutical composition is formulated for oral administration. In some embodiments, the compound of the present disclosure is mixed under sterile conditions with a pharmaceutically acceptable excipient, and with any preservatives, buffers or propellants that are required.

[0061] As used herein, the term “pharmaceutically acceptable excipient” includes any solvent, dispersion medium, coating, antibacterial and antifungal agent, isotonic and absorption delaying agent and the like suitable for administration to a subject. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. The term “pharmaceutically acceptable excipient” also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent”.

[0062] The particular excipient, carrier, or diluent will depend upon the means and purpose for which a compound of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Acceptable excipients, diluents, and carriers, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The composition may also comprise one or more stabilizing agent, surfactant, wetting agent, lubricating agent, emulsifier, suspending agent, preservative, antioxidant, opaquing agent, glidants, processing aid, colorant, sweetener, perfuming agent, flavoring agent and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0063] The pharmaceutical compositions of compounds of the present disclosure can be formulated depending on the particular route of administration and dosage form.

[0064] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated for parenteral or oral administration. For example, the pharmaceutical compositions of the present disclosure may be formulated as solids, liquid solutions, emulsions or suspensions. In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated for pulmonary administration. For example, the pharmaceutical compositions of the present disclosure may be formulated as liquids or powders. In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration. In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder).

[0065] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

[0066] In some embodiments, the pharmaceutical composition of the present disclosure can be formulated in unit dosage form. As used herein, a “unit dosage form” is a composition containing an amount of a compound that is suitable for administration to a subject in a single dose, according to good medical practice. Such single or unit dosage form are contemplated to be administered once, twice, three times or more per day. In certain embodiments, the pharmaceutical compositions of the present disclosure can be formulated to contain 2.5 mg to 1,500 mg, 2.5 mg to 25 mg, 20 mg to 75 mg, 70 mg to 150 mg, 100 mg to 250 mg, 200 mg to 600 mg, 500 mg to 800 mg, or 750 mg to 1,500 mg of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, for example, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg,1,000 mg, or 1,500 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dose is administered once a day. In other embodiments, the unit dose is administered twice a day. In further embodiments, the unit dose is administered three times a day. In further embodiments, the unit dose is administered four times a day.

[0067] In some embodiments, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more additional active ingredients.

[0068] The skilled artisan will recognize that a variety of active ingredients may be combined with the compounds of the present disclosure. In some embodiments, the additional active ingredient of the pharmaceutical combination formulation or dosing regimen has complementary activities to the compounds of disclosure such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.

[0069] In certain embodiments, the pharmaceutical composition may comprise a compound of the present disclosure combined with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

[0070] A peripherally restricted moiety is one which poorly penetrates the blood brain barrier or is extruded rapidly from the brain. Without being limited to any theory or mechanism, it is believed that amide -containing compounds of the present disclosure are converted to carboxylic acid-containing parent molecules by FAAH, which is widely expressed in many tissues including the brain.

[0071] Peripherally restricted fatty acid amide hydrolase (FAAH) inhibitors are known in the art, and include, for instance, cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester (also known as URB937, CAS No.: 1357160-72-5); cyclohexylcarbamic acid 3'- carbamoyl-5- hydroxybiphenyl-3-yl ester; 5-(((4-(2-phenylethyl)piperidin-l-yl)carbonyl)oxy)nicotinic acid; and those described in WO 2012 / 015704 A2.

[0072] In one aspect, provided herein is a kit comprising a compound having Formula (I),Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof, in combination with a peripherally restricted FAAH inhibitor.

[0073] In one aspect, provided herein is a method of modulating activity of a thyroid hormone receptor-beta activity in a cell, the method comprising contacting a cell comprising a thyroid hormone receptor-beta with a compound having Formula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof as disclosed herein.

[0074] In one aspect, provided herein is a method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having Formula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a peripherally restricted FAAH inhibitor. The peripherally restricted FAAH inhibitor can, for example, be administered sequentially or concurrently with the compound havingFormula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof.

[0075] A “subject” includes a warm-blooded animal. In some embodiments, the warm-blooded animal is a human.

[0076] ‘Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder and / or reducing the severity of symptoms that will or are expected to develop.

[0077] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. “Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).

[0078] As used herein, the term “therapeutically effective amount” refers to an amount of a pharmaceutical agent which is sufficient to achieve a therapeutic effect. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0079] In some embodiments, the amount or dose per day of a compound having Formula (I),Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof administered to a subject in the method of treatment can be 2.5 mg to 1,500 mg, 2.5 mg to 25 mg, 20 mg to 75 mg, 70 mg to 150 mg, 100 mg to 250 mg, 200 mg to 600 mg, 500 mg to 800 mg, or 750 mg to 1,500 mg, for example, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1,000 mg, or 1,500 mg.

[0080] In some embodiments, a method of treating multiple sclerosis comprises administering to a subject having multiple sclerosis a combination of (i) a compound having Formula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or pharmaceutically acceptable salt thereof; and (ii) a peripherally restricted FAAH inhibitor. When a combination of active agents are administered to a subject, the two active agents can be administered in a simultaneous, separate or sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0081] In some embodiments, provided herein is a compound of Formula (I), Formula (II),Formula (III), Formula (IV), or as disclosed in TABLE 1, or a pharmaceutically acceptable salt thereof, for use in therapy, e.g., to treat multiple sclerosis. In some embodiments, there is provided a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or a pharmaceutically acceptable salt thereof for use as a medicament, e.g., to treat multiple sclerosis. In some embodiments, the compound Formula (I), Formula (II), Formula (III), Formula (IV), or as disclosed in TABLE 1, or a pharmaceutically acceptable salt thereof is to be administered to a subject having multiple sclerosis in combination with a peripherally restricted FAAH inhibitor.SYNTHESIS OF THE COMPOUNDS

[0082] Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the schemes are for better illustration and can be changed as appropriate.

[0083] The reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.

[0084] Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0085] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem.2004, 6(6), 874-883, which is incorporated herein by reference in its entirety), and normal phase silica chromatography.

[0086] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift (5) is given in the unit of parts per million (ppm). 'H-NMR spectra is recorded in CDCU, CD3OD or DMSO-de solutions (reported in ppm) on a Varian or Bruker instrument (400 MHz), using tetramethylsilane (TMS) as the reference standard (0.0 ppm).

[0087] MS measurement is carried out using Shimadzu 2010 Mass Spectrometer or Agilent6110A MSD or 1969A TOF mass spectrometer using electrospray, chemical and electron impact ionization methods from a range of instruments.

[0088] TLC measurement is carried out using Yantai Huanghai HSGF254 silica gel or Anhui Liang Chen Gui Yuan plates. The silica gel plates used for TLC are 0.15mm~0.2mm. The silica gel plates used for separating and purifying products by TLC are 0.4mm~0.5mm.

[0089] Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge (Waters).

[0090] The known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from commercial suppliers such as Aldrich Chemical Company, Adamas-beta, TCI or Accela ChemBio Co., Ltd, and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), dioxane and 1,1,2,2-tetrachloroethane were purchased from Aldrich in Sure seal bottles and used as received.

[0091] Unless otherwise specified, the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe.Glassware was oven dried and / or heat dried.

[0092] For illustrative purposes, the following shows general synthetic routes for preparing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0093] Starting materials and intermediates are either purchased or prepared using known procedures, or as otherwise illustrated. For example, compounds of Formula A can be prepared using the procedures described in the Examples in International Patent Application No. PCT / US2023 / 015193, which Examples are incorporated herein by reference in their entirety. As such, compounds of Formulas(I), (II), (III) and (IV) can be made according to general Scheme 1 and Scheme 2 shown below, wherein all substituents are as defined above unless indicated otherwise.Scheme 1Formula A Formula (III)

[0094] To a solution of a compound of Formula A (1 eq) in DMF is added HOBt (3 eq), EDCI(2 eq) and Et ;N (2 eq). The resulting mixture is stirred at 25 °C for 2 h before methylamine hydrochloride (3 eq) is added, then continued stirring at 25 °C for 16 h. The mixture is diluted with water, adjusted to pH~8 with aqueous 1.0 M HC1, and then extracted with EtOAc (x 2). The combined organic layers is washed with brine, dried over Na2SO i, filtered and concentrated. The residue is purified by flash silica gel chromatography to give a crude product, which can be purified by prep-HPLC to give a compound ofFormula (III).Scheme 2

[0095] To a solution of a compound of Formula A (1 eq) in DMF is added NH4CI (1.5 eq), HATU (1.5 eq), and DIEA (3 eq). The resulting mixture is stirred at 25 °C for 3 h. The mixture is diluted with water, adjusted to pH~8 with aqueous 1.0 M HO, and then extracted with EtOAc (x 2). The combined organic layers is washed with brine, dried over Na?SO4, filtered and concentrated. The residue is purified by flash silica gel chromatography to give a crude product, which can he purified by prep- HPLC to give a compound of Formula (IV).EXAMPLES

[0096] For the purpose of illustration, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the present disclosure. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare several other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are deemed to be within the scope of the present disclosure. For example, the synthesis of non-exemplified compounds according tothe present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and / or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.Example 1: 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy-phenyl]metIiyl]phenoxy]acetic acid (P-15)Preparation of (2,6-dichloro-4-triisopropylsilyloxy-phenyl)- (4-methoxyphenyl)methanol

[0097] To a solution of l-bromo-4-methoxy-benzene (1.20 g, 6.42 mmol, 0.80 mL, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 3.08 mL, 1.2 eq) at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h, and then 2,6-dichloro-4-triisopropylsilyloxy-benzaldehyde (2.01 g, 5.77 mmol, 0.9 eq) was added. The reaction mixture was stirred at 25 °C for 2 h, and then diluted with FLO (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over NaaSOi. filtered and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel chromatography (TSCO®: 40 g SEPAFLASH® Silica Flash Column, eluted with 0-10% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give (2,6-dichloro- 4-triisopropylsilyloxy-phenyl)-(4-methoxyphenyl)methanol (2.10 g, 71.9% yield) as a colorless oil.Preparation of [3,5-dichloro-4-[(4-methoxyphenyl)methyl]phenoxy]- triisopropyl-silane

[0098] To a solution of (2,6-dichloro-4-triisopropylsilyloxy-phenyl)-(4- mcthoxyphcnyl)mcthanol (1.10 g, 2.41 mmol, 1 eq) in DCM (20 mL) was added EtaSiH (842 mg, 7.24 mmol, 1.16 mL, 3 eq) and TFA (1.38 g, 12.05 mmol, 0.92 mL, 5 eq). The resulting mixture was stirred at 20 °C for 1 h, and then diluted with FLO (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with H2O (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SEPAFLASH® Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give [3,5-dichloro-4-[(4-methoxyphenyl)methyl]phenoxy]-triisopropyl-silane (900 mg, 2.05 mmol, 85% yield) as a light yellow oil.Preparation of [4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5-dichloro-phenoxy]-triisopropyl-silane

[0099] To a solution of [3,5-dichloro-4-[(4-methoxyphenyl)methyl]phenoxy]-triisopropyl-silane(700 mg, 1.59 mmol, 1 eq) in DMF (30 mL) was added NBS (340 mg, 1.91 mmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with H2O (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give [4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5- dichloro-phenoxy]-triisopropyl-silane (800 mg, 1.54 mmol, 97% yield) as a colorless oil.Preparation of 4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5-dichloro-phenol

[0100] To a solution of [4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5-dichloro-phenoxy]- triisopropyl-silane (800 mg, 1.54 mmol, 1 eq) in THF (10 mL) was added TBAF (1.0 M in THF, 2.31 mL, 1.5 eq). The resulting mixture was stirred at 20 °C for 1 h and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® Silica Flash Column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give 4-[(3-bromo-4-methoxy- phenyl)methyl]-3,5-dichloro-phenol (400 mg, 71.8% yield) as a light yellow oil.Preparation of ethyl 2-[4-[(3-bromo-4-methoxy-phenyl)mcthyl]-3,5-dichloro-phenoxy]acetate

[0101] To a solution of 4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5-dichloro-phenol (400 mg,1.10 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (305 mg, 2.21 mmol, 2 eq) and ethyl 2- bromoacetate (369 mg, 2.21 mmol, 2 eq). The mixture was stirred at 20 °C for 16 h, and then diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over NaiSOi, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give ethyl 2-[4-[(3-bromo-4-methoxy- phenyl)methyl]-3,5-dichloro-phenoxy]acetate (400 mg, 81.2% yield) as a light yellow oil.Preparation of ethyl ethyl 2-[4-[(3-bromo-4-hydroxy-phenyl)methyl]- 3,5- dichlorophenoxy ] acetate

[0102] To a solution of ethyl 2-[4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5-dichloro- phenoxy] cetate (300 nig, 0.67 mmol, 1 eq) in DCM (6 mL) was added BBr? (0.5 M in DCM, 2.68 mL, 2 eq) at -78 °C. The resulting mixture was stirred at 20 °C for 2 h, then diluted with water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® Silica Flash Column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 18 mL / min) to give ethyl 2-[4-[(3-bromo-4-hydroxy-phenyl)methyl]- 3,5-dichloro-phenoxy] acetate (150 mg, 51.6% yield) as a light yellow solid. LCMS (ESI) m / z, CnHisBrCTOi: calculated 431.95, found (M+H)+: 433.0.Preparation of 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy-phenyl]methyl]phenoxy]acetic acid (P-15)

[0103] To a mixture of ethyl 2-[4-[(3-bromo-4-hydroxy-phenyl)methyl]-3,5-dichloro-phenoxy] acetate (30 mg, 0.069 mmol, 1 eq) in dioxane (2 mL) and water (1 mL) were added (3,4- difluorophenyl)boronic acid (16.4 mg, 0.10 mmol, 1.5 eq), Pd(dppf)C12 (5.1 mg, 0.0069 mmol, 0.1 eq), Na2COs (22.0 mg, 0.21 mmol, 3 eq). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 16 h under N2 atmosphere. The mixture was diluted with water (15 mL), adjusted to pH~l with aqueous 1.0 M HO, and then extracted with EtOAc (15 mL x 4). The combined organic layers were washed with brine (15 mL), dried over Na-SO i. filtered and concentrated. The resulting residue was purified by prep-HPLC (column: VENUSIL ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 65%-95%, 9min) to give the compound (P-15) (26.9 mg, 88.7% yield) as a brown solid. LCMS (ESI) m / z, C21H1 / 1CI2F2O4: calculated 438.02, found (M+H)+: 439.0. 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.65 (s, 1H), 7.57-7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.30 (br s, 1H), 7.13 (s, 2H), 7.10 (d, J = 1.6 Hz, 1H), 6.93-6.91 (m, 1H), 6.87-6.85 (m, 1H), 4.78 (s, 2H), 4.12 (s, 2H).19F NMR (376 MHz, DMSO-d6) 8 (ppm) -139.45, -141.51.Example 2: 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetamide (1)

[0104] To a solution of 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (P-15) (70 mg, 0.16 mmol, 1 eq) in DMF (4 mL) was added NH4CI (12.79 mg, 0.24 mmol, 1.5 eq), HATU (90.89 mg, 0.24 mmol, 1.5 eq), and DIEA (61.79 mg, 0.48 mmol, 0.08 mL, 3 eq). The resulting mixture was stirred at 25 °C for 3 h. The mixture was diluted with water (20 mL), adjusted to pH~8 with aqueous 1.0 M HO, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na-SO i. filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SEPAFLASH® Silica Flash Column, eluted with 0-15% MeOH / DCM @ 35 mL / min). The residue was purified by prep-HPLC (HO condition; column: XTIMATE C18 150*40mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 45%-75%, lOmin) to give the title compound (1) (40.2 mg, 45.5% yield) as a white solid. LCMS (ESI) m / z, C21H15CI2F2NO3: calculated 437.04, found (M-H)’: 436.1. 'H NMR (400 MHz, DMSO-ds) 5 (ppm) 9.65 (br s, 1H), 7.59-7.43 (m, 4H), 7.30 (br s, 1H), 7.14-7.09 (m, 3H), 6.93-6.84 (m, 2H), 4.51 (s, 2H), 4.12 (s, 2H).19F NMR (376 MHz, DMSO-d6) 8 (ppm) -139.38 (s, IF), -141.44 (s, IF).Example 3: 2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,l'-biphenyl]-3-yl)methyl)phenoxy)-N-

[0105] To a solution of 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy] acetic acid (P-15) (250 mg, 0.57 mmol, 1 eq) in DMF (10 mL) was added HOBt (231 mg, 1.71 mmol, 3 eq) , EDCI (177 mg, 1.14 mmol, 2 eq) and EhN (115 mg, 1.14 mmol, 2 eq). The resulting mixture was stirred at 25 °C for 2 h before methylamine hydrochloride (115 mg, 1.71 mmol, 3 eq) was added, then continued stirring at 25 °C for 16 h. The mixture was diluted with water (20 mL), adjusted to pH~8 with aqueous 1.0 M HC1, and then extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SEPAFLASH® Silica Flash Column, eluted with 0-15% MeOH / DCM @ 35 mL / min) to give a crude product. The crude product was purified by prep-HPLC (HC1 condition; column: XTIMATE C18 150*40mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 45%-75%, lOmin) to give the title compound (2) (40.2 mg, 15.5% yield) as a white solid. LCMS (ESI) m / z, C22H17CI2F2NO3: calculated 451.06, found (M-H)’: 450.1. ’H NMR(400 MHz, DMSO-d6) 5 (ppm) 9.68 (br s, 1H), 8.09 (br s, 1H), 7.55-7.41 (m, 2H), 7.29 (br s, 1H), 7.15 (s, 2H), 7.09 (s, 1H), 6.93-6.84 (m, 2H), 4.54 (s, 2H), 4.12 (s, 2H), 2.65 (d, J = 4.4 Hz, 3H).19F NMR (376 MHz, DMSO-de) 5 ppm -139.42 (s, IF), -141.47 (s, IF).Example 4: (R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanoic acid (P-61)Preparation of ethyl (R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-methoxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanoate

[0106] To a solution of 3,5-dichloro-4-((3',4'-difluoro-6-methoxy-[Ll'-biphenyl]-3- yl)methyl)phenol (1.30 g, 3.29 mmol, 1 eq) in THF (25 m ) was added ethyl (S)-2-hydroxypropanoate (583 mg, 4.93 mmol, 1.5 eq), di-tert-butyl azodicarboxylate (1.14 g, 4.93 mmol, 1.5 eq) and PPI (1.29 g, 4.93 mmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SEPAFLASH® Silica Flash Column, eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give the title compound (1.29 g, 79.2% yield) as a white solid.Preparation of (R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanoic acid (P-61)

[0107] To a solution of ethyl (R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-methoxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanoate (1 .29 g, 2.60 mmol, 1 eq) in DCM (25 mL) was added BB (2 M in DCM, 7.8 mL, 6 eq) at -60 °C. The mixture was stirred at 20 °C for 2 h. H2O (10 mL) was added at 0 °C and the mixture was stirred at 25 °C for 10 min. The organic layer was separated, washed with brine (20 mL), dried over Na2SO i, filtered, and concentrated. The resulting residue was purified by prep-HPLC (FA condition; column: XTIMATE C18 150mm*40mm*10um; mobile phase: [water (0.225% FA)- ACN]; B%: 55%-85%, 7min) to give the compound (P-61) (391 mg, 33.2% yield) as a yellow solid. LCMS (ESI) m / z calculated for C22HI6C12F2O4452.04, found 451.1 (M-H)’. 'H NMR (400 MHz, CDjCN) 8 (ppm) 7.47-7.40 (m, 1H), 7.31-7.25 (m, 2H), 7.12-7.07 (m, 1H), 7.03-6.95 (m, 3H), 6.86-6.82 (m, 1H), 4.89-4.80 (m, 1H), 4.18 (s, 2H), 1.54 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, CD3CN) 8 (ppm) -140.75 (d, IF), -142.64 (d, IF).Example 5: (R)-2-(3,5-dichloro-4-((3',4'-difluoro-6-hydroxy-[l,r-biphenyl]-3-yl)methyl)phenoxy) propanamide (3)

[0108] To a solution of (2R)-2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]propanoic acid (P-61) (0.46 g, 1.01 mmol, 1 eq) in DMF (6 mL) was added NH4C1 (81.4 mg, 1.52 mmol, 1.5 eq , HATU (578mg, 1.52 mmol, 1.5 eq) and DIPEA (393 mg, 3.04 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated. The residue was purified by prep-HPLC (FA condition; column: XTIMATE C18 150mm*40mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 47%-77%, 7min) to give the title compound (3) (103 mg, 22% yield) as a white solid. LCMS (ESI) m / z calculated for C22H17Q2O3NF2: 451.06; found 450.1 (M- H)-. >H NMR (400 MHz, CD3CN) 6 (ppm) 7.48-7.39 (m, 1H), 7.32-7.24 (m, 2H), 7.10 (d, J = 2.0 Hz, 1H), 7.05-6.97 (m, 4H), 6.84 (d, J = 8.4 Hz, 1H), 6.59 (br s, 1H), 5.90 (br s, 1H), 4.72-4.63 (m, 1H), 4.19 (s, 2H), 1.48 (d, J = 6.4 Hz, 3H).1F NMR (376 MHz, CD3CN) 5 (ppm) -140.76 (d, IF), -142.64 (d, IF).Example 6: 2-[3,5-dichloro-4-[[3-(3-chloro-4-fluoro-phenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic add (P-18)

[0109] The title compound was prepared (26.4 mg, 48.9% yield, white solid) using the same procedure as in the preparation of Example 1, substituting (3,4-difluorophcnyl)boronic acid with (3- chloro-4-fluoro-phenyl)boronic acid. The crude residue was purified by pre-HPLC (column: VENUSIL ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 65%-95%, 9min). LCMS (ESI) m / z, C21H14CI3FO4: calculated 453.99, found (M+H)+: 455.0. 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.64 (s, 1H), 7.68-7.66 (m, 1H), 7.45-7.43 (m, 2H), 7.12 (s, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.891- 6.896 (d, J = 2.0 Hz, 1H), 6.86 (s, 1H), 4.77 (s, 2H), 4.11 (s, 2H).19F NMR (376 MHz, DMSO-d6) 5 (ppm) -119.28.Example 7: 2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)acetamide (7)

[0110] The title compound was prepared (45.2 mg, 43.4% yield, white solid) using the same procedure as in the preparation of Example 2, substituting 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4- hydroxy-phenyl]methyl]phenoxy]acetic acid (P-15) with 2-[3,5-dichloro-4-[[3-(3-chloro-4-fluoro- phenyl)-4-hydroxy-phenyl]methyl]phenoxy]acetic acid (P-18). The crude residue was purified by prep- HPLC (column: BOSTON PRIME Cl 8 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)- ACN]; B%: 55%-85%, 7min). LCMS (ESI) m / z, C2IHI5C13FNO3: calculated 453.01, found (M-H)': 452.1. 'H NMR (400 MHz, CD3CN) 6 (ppm) 7.63-7.61 (m, 1H), 7.44-7.40 (m, 1H), 7.29-7.24 (m, 1H), 7.09-7.07 (m, 3H), 7.04 (s, 1H), 7.01-6.99 (m, 1H), 6.85-6.83 (m, 1H), 6.68 (br s, 1H), 6.04 (br s, 1H), 4.44 (s, 2H), 4.20 (s, 2H).19F NMR (376 MHz, CD3CN) 8 (ppm) -120.26 (s, IF).Example 8: 2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)-N-methylacetamide (8)

[0111] The title compound was prepared (120.2 mg, 59% yield, white solid) using the same procedure as in the preparation of Example 3, substituting 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4- hydroxy-phenyl]methyl]phenoxy] acetic acid (P-15) with 2-[3,5-dichloro-4-[[3-(3-chloro-4-fluoro- phenyl)-4-hydroxy-phenyl]methyl]phenoxy]acetic acid (P-18). The crude residue was purified by prep- HPLC (HC1 condition; column: WELCH XTIMATE C18 150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, lOmin). LCMS (ESI) m / z, C22HI7C13FNO3: calculated 467.03, found (M-H) : 466.2. ’H NMR (400 MHz, DMSO-dg) 3 (ppm) 9.65 (br s, 1H), 8.08 (br s, 1H), 7.68-7.66 (m, 1H), 7.46-7.43 (m, 2H), 7.15 (s, 2H), 7.10 (br s, 1H), 6.90-6.85 (m, 2H), 4.54 (s, 2H), 4.12 (s, 2H), 2.66 (d, J = 4.0 Hz, 3H).19F NMR (376 MHz, DMSO-de) 3 ppm -119.26 (s, IF).Example 9: (R)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanoic acid (P-55)

[0112] The title compound (P-55) was prepared using the same procedure as in Example 4 for the preparation of P-61, substituting 3,5-dichloro-4-((3',4'-difluoro-6-methoxy-[l,T-biphenyl]-3- yl)methyl)phenol with 3,5-dichloro-4-[[3-(3-chloro-4-fluorophenyl)-4-methoxy-phenyl]methyl]phenol.Example 10: (R)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanamide (9)

[0113] To a solution of (R)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)mcthyl)phcnoxy)propanoic acid (P-55) (500 mg, 1.06 mmol, 1 eq) in DMF (5 ml) was added HATU (607 mg, 1.60 mmol, 1.5 eq), NH4CI (85 mg, 1.60 mmol, 1.5 eq) and DIPEA (550 mg, 4.26 mmol, 4 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum and purified by prep-HPLC (FA condition; column: XTIMATE C18 150*40mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 55%-85%, 7min) to give the title compound (96.3mg, 19.3% yield) as a light yellow solid. LCMS (ESI) m / z calculated for C22H17CI3FNO3: 467.03; found: 466.1(M-H) . ‘H NMR (400 MHz, CD3CN) 5 (ppm) 7.65-7.58 (m, 1H), 7.45-7.38 (m, 1H), 7.30-7.22 (m, 1H), 7.18-7.07 (m, 2H), 7.05-6.96 (m, 3H), 6.84 (d, J = 8.0 Hz, 1H), 6.61 (br s, 1H), 5.94 (br s, 1H), 4.73-4.59 (m, 1H), 4.18 (s, 2H), 1.48 (d, J = 6.4 Hz, 3H).19F NMR (376 MHz, CD3CN) 6 (ppm) -120.26 (s, IF).Example 11: (S)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanoic acid (P-54)

[0114] The title compound (P-54) was prepared using the same procedure as in Example 4 for the preparation of P-61 substituting (i) 3,5-dichloro-4-((3',4'-difluoro-6-methoxy-[l,r-biphenyl]-3- yl)methyl)phenol with 3,5-dichloro-4-[[3-(3-chloro-4-fluorophenyl)-4-methoxy-phenyl]methyl]phenol, and (ii) ethyl (S)-2-hydroxypropanoate with ethyl (R)-2-hydroxypropanoate.Example 12: (S)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,l'-biphenyl]-3- yl)methyl)phenoxy)propanamide (11)

[0115] To a solution of (S)-2-(3,5-dichloro-4-((3'-chloro-4'-fluoro-6-hydroxy-[l,r-biphenyl]-3- yl)methyl)phenoxy)propanoic acid (P-54) (500 mg, 1.06 mmol, 1 eq) in DMF (5 mL) was added HATU (607 mg, 1.60 mmol, 1.5 eq), NH4CI (85 mg, 1.60 mmol, 1.5 eq) and DIPEA (550 mg, 4.26 mmol, 4 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated and purified by prep- HPLC (FA condition; column: XTIMATE C18 150*40mm*10um; mobile phase: [water (0.225% FA)- ACN]; B%: 55%-85%, 7min) to give the title compound (107 mg, 21% yield) as a light yellow solid.LCMS (ESI) m / z calculated for C22H17CI3FNO3: 467.03, found 466.1 (M-H)’. 'H NMR (400 MHz, CD3CN) 5 (ppm) 7.74-7.60 (m, 1H), 7.53-7.38 (m, 1H), 7.35-7.22 (m, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.07-6.98 (m, 4H), 6.87 (d, J = 8.4 Hz, 1H), 6.61 (br s, 1H), 5.92 (br s, 1H), 4.78-4.60 (m, 1H), 4.22 (s, 2H), 1.51 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, CD3CN) 5 (ppm) -120.26 (s, IF).Example 13: THR-P Activity and Selectivity Index

[0116] Amide prodrug compounds as provided herein are converted in vivo into parent carboxylic acids with selective thyroid hormone receptor-beta (THR-P) agonist activity. Representative compounds are shown in TABEE 2 along with the structure, THR- activity (EC 50 value) and Selectivity Index (SI) (THR-a EC50 / THR-P EC50) of their respective parent molecules.

[0117] Materials and Methods'. THR-a and THR-P EC 50 values were determined using TR- FRET TR beta Coactivator Assay (THERMO SCIENTIFIC™, Cat. No. PV4686) and TR-FRET TR alpha Coactivator Assay (THERMO SCIENTIFIC™, Cat. No. PV4687) Kits as described in Example 60 of International Patent Application No. PCT / US2023 / 015193, which is incorporated herein by reference in its entirety. In brief, diluted test compounds were transferred into two 384-well plates in duplicate using an ECHO liquid handler. TR-FRET Coregulator Buffer C was prepared by diluting 1 M DTT to 5 mM DTT in buffer C and 10 pL of the buffer was dispensed to the each well of the assay plates. TR alpha, Fluorescein-SRC2-2 and Tb-anti-GST antibody were diluted and mixed to a concentration of 0.8 nM, 400 nM and 4 nM in TR-FRET Coregulatory Buffer C, respectively and 10 pL of the mixture was dispensed to each well of the assay plates. TR beta, Fluorescein-SRC2-2 and Tb anti-GST antibody were diluted and mixed to a concentration of 2.0 nM, 400 nM and 4 nM in TR-FRET Coregulatory Buffer C and 10 pL of the mixture was dispensed to the each well of another two assay plates. After incubation of the plates from the light at RT for 2 hours, signal measurement were performed on an ENVISION plate reader installed with a 340 nm laser, TRF D400 / D505 dual / Bias mirror, 520 / 25 nm filter and 495 / 10 nm filter. The terbium labeled anti-GST antibody was excited by laser and collected using the filters of TRF Emission 520 and TRF Emission 495, respectively. The TR-FRET ratio was calculated by dividing the emission signal at 520 nm for TR coactivator assay by the emission signal at 495 nm for TR coactivator assay. A binding curve was generated by plotting the emission ratio vs. the log [ligand]. To determine the EC50 value, the data was fitted using an equation for a sigmoidal dose response (variable slope), as provided by GRAPHPAD™ PRISM software. The equation was shown as below.Y=Bottom + (Top-Bottom) / (l+10A((LogEC50-X)*HillSlope))Note: X is the logarithm of conc ntr

[0118] TABLE 2 shown below shows theEC50) as determined for the parent THR-P agonist.TABLE 2Example 14: Compound 1 to P-15 Conversion and Pharmacokinetics

[0119] This example demonstrates that compound 1 converts to parent molecule P-15 in vivo, and that compound 1 has increased penetration into the brain as compared to P-15.

[0120] Materials and Methods

[0121] Test compounds were dosed to Sprague Dawley rats as an aqueous solution in containing low percentages of DMSO and / or solutol as a single dose via a 30-min intravenous infusion (IV; 1 mg / kg) or oral gavage (PO; 5 mg / kg) administration to rats. Blood (for preparation of plasma) were collected at collected at 0.083, 0.25, 0.5, 1, 2, 4, 7, 12, and 24 h post-dose. Target analyte was detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS) as described below.

[0122] To determine brain tissue-to-plasma and liver tissue-to-plasma ratio, test compounds were administered to Sprague-Dawley rats via a 30-min IV infusion at 3 mg / kg. At indicated time points blood samples were collected and following euthanasia, whole brains and livers were collected. Brain and liver tissues were homogenized with 10 volumes (w:v) of homogenizing solution (MeOH / 15 mM PBS (1 :2, v:v)) performed on wet ice, and aliquots (40 pL) were added to 96-well plates followed by 200 pL of acetonitrile containing fixed amount of internal standard 1 (IS 1 ). Mixtures were vortex-mixed for 10 min at 800 rpm and centrifuged for 15 min at 3220 x g, 4 °C, and 50 pL supernatant from each well was transferred to another clean 96-well plate, which was centrifuged for 5 min at 3220 x g, 4 °C. Supernatants were directly injected into the LC-MS / MS system to determine amounts of target analytes.

[0123] LC-MS / MS to determine amounts of target analytes in respective samples was performed using a triple-quadrupole mass spectrometer coupled with ultra-high performance liquid chromatographic system. Chromatographic separation of target analytes (e.g., compound 1 and P-15) were achieved via reverse-phased condition, followed by selective reaction monitoring (SRM) that is specific to each target analyte in negative ionization mode. Typical lower level of quantitation was 1.0 ng / mL in respective matrices. Tissue-to-plasma ratio was calculated based on the following formula:

[0124] In FIG. 1 through FIG. 8 data points in plasma concentration over time graphs and in bar graphs showing tissue-to-plasma ratios at various time points represent mean values ± standard deviation (N=3).

[0125] Results

[0126] Concentrations in Plasma: FIG. 1A shows the concentration of P-15 in rat plasma over time following 1.0 mg / kg IV administration ( -) and 5.0 mg / kg PO administration of P-15 ( ).Concentrations of compound 1 and P-15 were also determined in rat plasma following administration of compound 1 as shown in FIG. IB. FIG. IB demonstrates that compound 1 converts to P-15 in vivo.

[0127] Relative Amounts in Brain and Liver: Following administration of P-15 to rats, at 0.25,0.5 and 2 hours, plasma, liver and brain tissues were collected and the brain-to-plasma ratio (BPR) and liver-to-plasma ratio (LPR) for P-15 were determined. FIG. 2A shows that P-15 distributes predominantly to liver as compared to brain.

[0128] Following administration of compound 1, negligible amounts of compound 1 were found in brain or liver, however P-15 was detectable in both tissues (FIG. 2B). At 2 hours following administration, the relative amount of P-15 in brain was approximately 3-fold over that in liver.Example 15: Compound 2 to P-15 Conversion and Pharmacokinetics

[0129] This example demonstrates that compound 2 converts to parent molecule P-15 in vivo, and that compound 2 has increased penetration into the brain as compared to P-15.

[0130] Compound 2 was administered to rats and both (i) concentrations of compound 2 and P-15 in plasma over time and (ii) the BPR and LBR for of compound 2 and P-15 at indicated time points were determined by the following methods described in the previous example. Results are shown in FIG. 3 and FIG. 4, respectively.

[0131] FIG. 3 demonstrates that compound 2 converts to P-15 in vivo. FIG. 4 shows that following administration of compound 2, negligible amounts of compound 2 were found in brain or liver, however P-15 was detected in both tissues. At 2 hours following administration, the relative amount of P-15 in brain was roughly 2- to 3-fold over that in liver.Example 16: Compound 3 to P-61 Conversion and Pharmacokinetics

[0132] This example demonstrates that compound 3 converts to parent molecule P-61 in vivo, and that compound 3 has increased penetration into the brain as compared to P-61.

[0133] Following the methods described in Example 14 above, plasma concentrations over time of compound 3 and P-61, and tissue-to-plasma ratios at various time points of compound 3 and P-61, were determined as discussed below in connection with FIG. 5 and FIG. 6.

[0134] FIG. 5 shows plasma concentrations over time for compound 3 and P-61 as follows: () compound 3 following IV administration of 1.0 mg / kg compound 3;( ) P-61 following IV administration of 1.0 mg / kg compound 3; ( "** ' ) compound 3 following PO administration of 5.0 mg / kg compound 3; ( A ) P-61 following PO administration of 5.0 mg / kgcompound 3; () P-61 following IV administration of 1.0 mg / kg P-61; ( ■■♦■■■ ) P-61 following PO administration of 5.0 mg / kg P-61.

[0135] The distribution of compound 3 and P-61 to liver and brain following administration of compound 3 is shown in FIG. 6. These results demonstrate more P-61 is found in brain following administration of compound 3 than with administration of P-61, indicating that compound 3 has increased penetration into the brain as compared to parent molecule P-61.Example 17: Compound 9 to P-55 Conversion and Pharmacokinetics

[0136] This example demonstrates that compound 9 converts to parent molecule P-55 in vivo, and that compound 9 has increased penetration into the brain as compared to P-55.

[0137] Compound 9 was administered to rats and both (i) concentrations of compound 9 and P-55 in plasma over time and (ii) the BPR and LBR for of compound 9 and P-55 at indicated time points were determined by the following methods described in Example 14. Results are shown in FIG. 7 and FIG. 8, respectively.

[0138] FIG. 7 shows plasma concentrations over time for compound 9 and P-55 as follows: () compound 9 following IV administration of 1.0 mg / kg compound 9;( ) P-55 following IV administration of 1.0 mg / kg compound 9;) compound 9 following PO administration of 5.0 mg / kg compound 9; ( ■*•■• ) P-55 following PO administration of 5.0 mg / kg compound 9.

[0139] The distribution of compound 9 and P-55 to liver and brain tissues following administration of compound 9 is shown in FIG. 6.

[0140] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually to be incorporated by reference.

[0141] Although for purposes of clarity of understanding the foregoing embodiments are described in some detail by way of illustration and example, it will be readily apparent to those skilled in the art that certain changes and modifications may made thereto without departing from the spirit or scope of the appended claims. Only such limitations as appear in the appended claims should be placed on any claimed invention.

Claims

WHAT IS CLAIMED IS:

1. A compound having Formula (II) or a pharmaceutically acceptable salt thereof:whereinR1and R2arc each independently hydrogen or halo;R3is hydrogen or fluoro, with the proviso that each of R1and R2are hydrogen when R3is fluoro;R4, R5,and R6are each independently hydrogen or methyl; andR7is hydrogen.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein each ofR4and R5is hydrogen.The compound or pharmaceutically acceptable salt thereof of claim 2, wherein the compound selected from the group consisting of4. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein one of R4and R5is hydrogen and the other of R4and R5is methyl.

5. The compound or pharmaceutically acceptable salt thereof of claim 4, wherein the compound selected from the group consisting of6. A compound or a pharmaceutically acceptable salt thereof wherein the compound is selected from the group consisting of7. A pharmaceutical composition comprising the compound or pharmaceutical salt of any one of claims 1 to 6, and a pharmaceutically acceptable excipient.

8. A method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1 to 6.

9. The compound or pharmaceutically acceptable salt as claimed in any one of the claims 1 to 6 for use in the treatment of multiple sclerosis.

10. Use of the compound or pharmaceutically acceptable salt as claimed in any one of the claims 1 to 6, in the manufacture of a medicament for the treatment of multiple sclerosis.

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