Prodrugs of fumarates and their use in treating various diseases

PRODRUGS OF FUMARATES AND THEIR USE IN TREATING VARIOUS DISEASES FIELD OF THE INVENTION

The present invention relates to various prodrugs of monomethyl fumarate. In particular, the present invention relates to derivatives of monomethyl fumarate which offer improved properties relative to dimethyl fumarate. The invention also relates to methods of treating various diseases.

BACKGROUND OF THE INVENTION

Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.

FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietzand Asadullah, Trends Mol Med 2605, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008,26,522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington’s disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; and Lehmann ct al., Arch Dermatol Res 2002,294,399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6.509,376, U.S. Pat. No. 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

1998/52549 and U.S. Pat. No. 6,436,992: Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006,13,604-610; and Schilling et al., Clin Experimental Immunology 2006,145,101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE-induccd genome damage (Hcidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034).

Fumaderm®, an enteric coated tablet containing a salt mixture of monoethyl fumarate and dimethyl fumarate (DMF) which is rapidly hydrolyzed to monomethyl fumarate, regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis. Fumaderm® is dosed TID with 1-2 grams/day administered for the treatment of psoriasis. Fumademi® exhibits a high degree of inlerpalienl variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Clin Expt'l Dermatology 2007,32,246-49; and Hoefnagel et al., Br J Dermatology 2003,149, 363-369). Side effects of current FAE therapy include gastrointestinal upset including nausea, vomiting, diarrhea and/or transient flushing of the skin.

Multiple sclerosis (MS) is an autoimmune disease with the autoimmune activity directed against central nervous system (CNS) antigens. The disease is characterized by inflammation in parts of the CNS, leading to the loss of the myelin sheathing around neuronal axons (gradual demyelination), axonal loss, and the eventual death of neurons, oligodendrocytes and glial cells.

Dimethyl fumarate (DMF) is the active component of the experimental therapeutic, BG-12, studied for the treatment of relapsing-remitting MS (RRMS). In a Phase lib RRMS study, BG-12 significantly reduced gadolinium-enhancing brain lesions. In preclinical studies, DMF administration has been shown to inhibit CNS inflammation in murine and rat EAE. It has also been found that DMF can inhibit astrogliosis and microglial activations associated with EAE. See, e.g., US Published Application No. 2012/0165404.

There are four major clinical types of MS: 1) relapsing-remitting MS (RRMS), cliaracterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery, periods between disease relapses characterized by a lack of disease progression; 2) secondary progressive MS (SPMS). characterized by initial relapsing remitting course followed by progression with or without occasional relapses, minor remissions, and plateaus; 3) primary progressive MS (PPMS), characterized by disease

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 progression from onset with occasional plateaus and temporary minor improvements allowed; and 4) progressive relapsing MS (PRMS), characterized by progressive disease onset, with clear acute relapses, with or without lull recovery; periods between relapses characterized by continuing progression.

Clinically, the illness most often presents as a relapsing-remitting disease and, to a lesser extent, as steady progression of neurological disability. Relapsing-remitting MS (RRMS) presents in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and recur, seemingly randomly over many years. Remission is often incomplete and as one attack follows another, a stepwise downward progression ensues with increasing permanent neurological deficit. The usual course of RRMS is characterized by repealed relapses associated, for the majority of patients, with the eventual onset of disease progression. The subsequent course of the disease is unpredictable, although most patients with a relapsing-remitting disease will eventually develop secondary progressive disease. In the relapsing-remitting phase, relapses alternate with periods of clinical inactivity and may or may not be marked by sequelae depending on the presence of neurological deficits between episodes. Periods between relapses during the relapsingremitting phase are clinically stable. On the other hand, patients with progressive MS exhibit a steady increase in deficits, as defined above and either from onset or after a period of episodes, but this designation does not preclude the further occurrence of new relapses.

Notwithstanding the above, dimethyl fumarate is also associated with significant drawbacks.

For example, dimethyl fumarate is known to cause side effects upon oral administration, such as flushing and gastrointestinal events including, nausea, diarrhea, and/or upper abdominal pain in subjects. See, e.g., Gold et al., N. Eng. J. Med., 2012, 367(12), 1098-1107. Dimethyl fumarate is dosed BID or TID with a total daily dose of about 480 mg to about 1 gram or more.

Further, in the use of a drug for long-term therapy it is desirable that the drug be formulated so that it is suitable for once- or twice-daily administration to aid patient compliance. A dosing frequency of once-daily or less is even more desirable.

Another problem with long-term therapy is tlie requirement of determining an optimum dose which can be tolerated by the patient. If such a dose is not determined this can lead to a diminution in the effectiveness of the drug being administered.

Accordingly, it is an object of the present invention to provide compounds and/or compositions which are suitable for long-term administration.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

It is a further object of the present invention to provide the use of a pharmaceutical active agent in a manner which enables one to achieve a tolerable steady state level for the drug in a subject being treated tlierewith.

Because of the disadvantages of dimethyl lumaratc described above, there continues to be a need to decrease the dosing frequency, reduce side-effects and/or improve the physicochemical properties associated with DMF. There remains, therefore, a real need in the treatment of neurological diseases, such as MS, for a product which retains the pharmacological advantages of DMF but overcomes its flaws in formulation and/or adverse effects upon administration. The present invention addresses these needs.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the hydrolysis of Compound 16 at pH 7.9, 25°C, showing vinylic region, as observed by NMR over 90 minutes.

Figure 2 depicts the hydrolysis of Compound 16 at pH 7.9, 25°C, showing vinylic region, as observed by NMR over 19 hours.

Figure 3 depicts the hydrolysis of Compound 16 at pH 7.9,25°C, showing aliphatic region, as observed by NMR over 19 hours.

Figure 4 depicts the hydrolysis of Reference Compound A at pH 7.9, 37°C, showing vinylic region, as observed by NMR over 15 hours.

Figure 5 depicts the hydrolysis of Reference Compound A at pl 17.9, 37°C, showing aliphatic region, as observed by NMR over 15 hours.

Figure 6 depicts a plot of weight loss vs time for Compound 14 and DMF.

Figure 7 depicts the unit cell for crystalline Compound 14.

SUMMARY OF THE INVENTION

This invention is directed to the surprising and unexpected discovery of novel prodrugs and related methods useful in the treatment of neurological diseases. The methods and compositions described herein comprise one or more prodrugs (e.g., aminoalkyl prodrugs) of monomethyl fumarate (MMF). The methods and compositions provide for a tlierapeutically effective amount of an active moiety in a subject for a time period of at least about 8 hours to at least about 24 hours.

More specifically, the compounds of the invention can be converted in vivo, upon oral administration, to monomethyl fumarate. Upon conversion, the active moiety (i.e., monomethyl fumarate) is effective in treating subjects suffering from a neurological disease.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

The present invention provides, in part, a compound of Formula (1), or a pharmaceutically acceptable sail, polymorph, hydrate, solvate or co-crystal thereof:

<img file="CA2906580C_D0001.tif" />

(1):

wherein:

Ri is unsubstituted Ci-Ce alkyl;

L_a is substituted or unsubstituted CrG, alkyl linker, substituted or unsubstituted C3Cio carbocycle, substituted or unsubstituted C₆-C|₀ aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S; and

R2 and R3 arc each, independently, H, substituted or unsubstituted ί\-(Λ> alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C₆-Cio aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S;

or alternatively, Ri and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6member rings and 1-4 heteroatoms selected from N, 0 and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S.The present invention also provides pharmaceutical compositions comprising one or more compounds of any of the formulae described herein and one or more pharmaceutically acceptable carriers.

The present invention also provides methods of treating a neurological disease hy administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the disease is treated.

The present invention also provides methods of treating multiple sclerosis by administering to a subject in need tliereof, a therapeutically effective amount of a compound

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated.

The present invention also provides methods of treating relapsing-reinitting multiple sclerosis (RRMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated.

The present invention also provides methods of treating secondary progressive multiple sclerosis (SPMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated.

The present invention also provides methods of treating primary progressive multiple sclerosis (PPMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated.

The present invention also provides methods of treating progressive relapsing multiple sclerosis (PRMS) by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the multiple sclerosis is treated.

The present invention also provides methods of treating Alzheimer’s disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, such that the Alzheimer's disease is treated.

The present invention also provides methods of treating cerebral palsy by administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the formulae described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal tliereof, such tliat the cerebral palsy is treated.

The present invention also provides compounds and compositions that enable improved oral, controlled- or sustained-release formulations. Specifically, dimethyl fumarate is administered twice or three times daily for the treatment of relapsing-remitting multiple sclerosis. In contrast, the compounds and compositions of the present invention may enable

CA 2906580 2017-03-16 formulations with a modified duration ol therapeutic efficacy for reducing relapse rales in subjects with multiple sclerosis, [or example, the present compounds and compositions provide therapeutically effective amounts of mononiethyl fumarate in subjects for at least about &lt;8 liours. at least about 11 hours, al least about 16 hours, al least about 20 hours or at 5 least about 24 liours.

I he present invention also pro\ ides compounds, compositions and methods which may result in decreased side effects upon administration to a subject relative to dimethyl lumaratc. For example, gastric irritation and Hushing arc known side cfi'ccts of oral administration of dimethyl fumarate in some subjects. The compounds, compositions and 10 methods of the present invention can be utilized in subjects that have experienced or are al risk of developing such side effects.

Hie present invention also provides for compounds and compositions which exhibit improved physical stability relative to dimethyl fumarate. Specifically, dimethyl fumarate is known in the art to undergo sublimation at ambient and elevated temperature conditions. The 15 compounds ol ihe invention possess greater physical stability than dimethyl fumarate under controlled conditions of temperature and relative humidity. Specifically, in one embodiment, the compounds ot the formulae described herein exhibit decreased sublimation relative to dimethyl fumarate.

Further, dimethyl fumarate is also known to be a contact irritant. See e.g., Material 20 Safety Data Sheet for DMI··. In one embiKlimcnt. flic compounds of the present invention exhibit reduced contact irritation relative to dimethyl fumarate. For example, the compounds ol the formulae described herein exhibit reduced contact initation relative to dimethyl fumarate.

he present invention also provides for compounds and compositions which exhibit 25 decreased food effect relative to dimethyl fumarate. The bioavailability of dimethyl fumarate is known in tlie art to be reduced wlien administered with food. Specifically, in one embodiment, die compounds of the formulae described herein exhibit decreased (bod effect relative to dimethyl fumarate.

Unless otlKrwi.se defined, all technical and scientific terms used herein have the same .50 meaning as commonly understood by one of ordinary skill in the art lo which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent lo those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

CA 2906580 2017-03-16

The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPIION DI· I III: INVENTION

I’he present invention provides novel compounds and methods of treating a neurological disease by administering a compound of Ibritiula (II. (lai. (lb). (II). (Ill), or IIV). synthetic methods for making a compound of Formula (I). (la). (Ib). (II). (Ill), or (IV). and pharmaceutical compositions containing a compound of Formula (1). (la), (lb). (11). (111), or (IV).

The present invention a Iso provides compounds and methods lor die treatment of psoriasis by administering to a subject in need thereof, a therapeutically effective amount of a compound oi Formula (1). (la). (Ib). (11). (Ill), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof.

The present invention provides, in part, metluxls for the treatment of a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound oi Formula (1). (la), (lb). (11). (Ill), οι (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal (hereof. The neurological disease can be multiple sclerosis. The present invention further provides the use of a compound of Formula (I), (lai. (lb). (ID. (ill), or (IV). or a pharmaceutically acceptable salt, polymorph. hydrate, solvate or co-crystal thereof, for the preparation of a medicament useful for the treatment of a neurological disease.

According to the present invention, a neurological disease is a disorder of the brain, spinal cord or nerves in a subject, in one embodiment. the neurological disease is characterized by demyelination, or degeneration of the myelin slieath. of the central net vous system. The myelin sliealh facilitates the transmission of nerve impulses through a nerve liber or axon. In another embodiment, the neurological disease is selected from the group consisting of multiple sclerosis. Alzlteimer’s disease, cerebral palsy, spinal cord injury. Amyotrophic lateral sclerosis (AI .S). stroke. Huntington’s disease. Parkinson's disease. &lt;»ptic neuritis. Devic disease, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy and adrenoniyeloneuropalhy, acute inflammatory demyelinating

CA 2906580 2017-03-16 polyneuropathy (AIDP). chronic inflammatory demyelinating polyneuropathy (C1DP). acute transverse myelitis, progressive multifocal leukoencephalopathy &lt;PML), acute disseminated encephalomyelitis (ADEM), and oilier hereditary disorders, such as leukodystrophies. Leber’s optic atrophy, and Charcot-Marie-Tooth disease. In some embodiments, the neurological disorder is an auto-immune disease. In one embodiment. the neurological disease is multiple sclerosis. In another embodiment, die neurological disease is stroke. In another embodiment, the neurological disease is Alzheimer's disease. In another embodiment, the neurologic.d disease is cerebral palsy. In another embodiment, the neurological disease is spinal cord injury. In another embodiment, tlie neurological disease is AI.S. In another embodiment, the neurological disease is Huntington’s disease. See, e.g.. US Patent No. 8.(117.826.

VV()2( 1)5/()99701 and WO2(X)4/()«268-l.

In a farther embodiment, die present invention provides nietlxids for the treatment of a disease or a symptom of a disease described herein by administering to a subject in need tlieieol. a therapeutically effective amount of a compiund of Formula (I). (la). (lb). (II). (III), or (IV). or a pharmaceutically acceptable sail, polymorph, hydrate, solvate or co-crystal thereof. The present invent ion farther provides tlie use of a compound of Formula ( I ). ( la). (Ib). (II). (Ill), or (IV). or a pharmaceutically acceptable sail, polymorph, hydialc. solvate or co-crysial thereof, for du* preparation of a medicament useful for the treatment of a disease or a symptom of a disease described herein.

In another embodiment, the present invention provides a compound of Formula ( I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-cryslal thereof, or a method for tlie treatment of a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (1). or a pharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof:

<img file="CA2906580C_D0002.tif" />

wherein;

Ri is unsubstiluled G-G, alkyl;

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

L_a is substituted or unsubstituted Ci-C&amp; alkyl linker, substituted or unsubstituted C3C_l0 carbocycle, substituted or unsubstituted C6-C_l0 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted hctcroaryl comprising one or two 5- or 6-mcmbcr rings and 1-4 heteroatoms selected from N, O and S; and

R2 and R3 are each, independently, H, substituted or unsubstituted Ci-Q alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted Ci-Ce alkynyl, substituted or unsubstituted Cô-Cio aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 14 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 14 heteroatoms selected from N, 0 and S;

or alternatively, R2 and R3, together with the nitrogen atom to which they arc attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6member rings and 14 heteroatoms selected from N, 0 and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, OandS.

In one aspect of the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

Ri is unsubstituted Cj-Ce alkyl;

L_â is unsubstituted Ci-Cô alkyl linker, unsubstituted C3-C10 caibocycle, unsubstituted C6-C10 aryl, unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted heteroaryl comprising one or two 5or 6-member rings and 1-4 heteroatoms selected from N, 0 and S; and

R2 and R3 are each, independently, H, Ci-Cé alkyl, C2-C6 alkenyl, C&amp;-Cio aryl, C3-C10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or heteroaryl comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S, wherein the alkyl, alkenyl, aryl, carbocycle, heterocycle, or heteroaryl groups may be optionally independently substituted one or more times with Ci-Ca-alkyl, OH, O(Ci-C4 alkyl), carbonyl, halo, NH2, N(H)(Ci-Cô alkyl), N(Cr C₆ alkyi)₂, SO4I. SO₂(Ci-C₆ alkyl), CHO, CO₂H, CO₂(C,-C₆ alkyl), or CN;

or alternatively, R₂ and R3, together with the nitrogen atom to which they arc attached, form a heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S; or a heterocycle comprising one or two 5- or 6-membei rings and 1-4 heteroatoms selected from N, 0 and S, wherein the heteroaryl or heterocycle may be

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 optionally substituted one or more times with Ci-C&amp; alkyl. CN, OH, halo, O(Ci-C&amp; alkyl), CHO, carbonyl, thione, NO, or NH₂.

In one embodiment of this aspect, at least one of Ri and R² is H.

In another embodiment of this aspect, L_a is (CI l·))?.

In another embodiment of Formula (I), R₂ and R3 together with the nitrogen to which they are attached form a heteroaryl, wherein the heteroaryl ring is a pyrrole ring, a pyrazole ring, an imidazole ring, a benzimidazole ring, a thiazole ring, a l//-l,2,4-triazole ring, a 1//1,2,3-triazole ring, a IW-tetrazole ring, a pyrimidinone ring, an indole ring, or a benzoisothiazole ring, wherein all of the rings may be optionally substituted one or more times with CG, alkyl, CN, OH, O(Ci-C6 alkyl), CHO, NO₂, or NH₂.

In still another embodiment of Formula (I), R₂ and R3 together with the nitrogen to which they arc attached form a heterocycle, wherein the heterocycle is a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2,5-dihydropyrrole ring, a 1,2-dihydropyridine ring, a piperazine ring, a succinimide ring, an isoindoline ring, a 2,5-dihydro-l //-tetrazole ring, an azetidine ring, a piperidine ring, a hexahydropyrimidine ring, a 2,3.3a,4,7,7a-hexahydro-l//4,7-epoxyisoindole ring, a 3,4-dihydroquinazoline ring, a 1,2,3,4-tetrahydroquinazoline ring, an oxazolidine ring, an oxazolidinone ring, an imidazolidinone ring, a 1,3-dihydro-2 IIimidazol-2-one ring, an imidizolidine thione ring, or an isothiazolidine ring, wherein all of the rings may be optionally substituted one or more limes with Cj-Ce alkyl, CO₂(Ci-C6 alkyl), Oil, (CIb)i-4OIl, O(Ci-C₆ alkyl), halo, NII->, (CIb)i₄NIb, (CIb)i-4NII(Ci-C4 alkyl), (Clb)i. 4N(Ci-C4alkyl)₂, carbonyl, or thione.

In one embodiment of Formula (I):

Ri is unsubstituted C1-C3 alkyl;

L_a is (CH₂)i^; and

R₂ and R3 are each, independently: H, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclohexyl, cyclohexenyl, phenyl, benzyl, benzodioxole, pyridinyl, (CH₂)₂N(CH3)₂, (CH₂)₃SO₂H, (CH₂)₂SO₂Me, CH₂CO₂H, ογ(0Η₂>£Ν, or alternatively, R₂ and R3, together with the nitrogen atom to which they are attached, form a morpholine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, or (CH₂)i.3N(Ci-C« alkyl)₂; an 8-oxa-3-azabicyclo[3.2.1]octane ring; a l,4-dioxa-8azaspiro[4.5]dccanc ring; a thiomorpholinc ring substituted one or more times with carbonyl or thione; a piperazine ring optionally substituted with C1-C4 alkyl, halo, (CH₂)₂OH, C1-C4 alkyl ester; a pyrrolidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a 2,5-dihydropyrrole ring optionally substituted one or more times with C1-C4 alkyl

CA 02906580 2015-09-1«

WO 2014/152494

PCT/IÎS2014/027401 or carbonyl; a succinimide ring optionally substituted one or more times with C1-C4 alkyl; a 3-azabicyclo[3.1.0]hexane-2,4-dione ring; a hexahydropyrimidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; a pyrrole ring optionally substituted one or more times with C1-C4 alkyl, halo, C(O)NH₂, or NCh; a pyrazole ring optionally substituted one or more times with C1-C4 alkyl, C(O)NH2, or NCh; an imidazole ring optionally substituted one or more times with C1-C4 alkyl or NO2; a l,3-dihydto-2H-imidazol-2-one ring; a benzimidazole ring; a thiazole ring;,an isoindoline ring substituted with carbonyl; a l/Z-letrazole ring; a 1// 2,5-dihydro-l//-lctrazole ring substituted with thione; a 1//-1,2,4-triazole ring; a 1//-1,2,3triazole ring; an azetidine ring substituted with carbonyl; an piperidine ring optionally substituted one or more limes with C1-C4 alkyl, carbonyl, halo, OH, or (CH2)i-4OH; a pyridinonc ring optionally substituted one or more times with C1-C4 alkyl, OH, or CN; a 1,2dihydropyridine ring substituted with carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidine ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more times with carbonyl; an indole ring; a 2,3,3a,4,7,7a-hexahydro-1//-4,7-epoxyisoindole ring optionally substituted one or more times with carbonyl; a 3,4-dihydroquinazoline ring substituted with carbonyl; 1,2,3,4tetrahydroquinazoline ring substituted one or more times with carbonyl; or a benzoisothiazole ring optionally substituted one or more times with carbonyl.

In another embodiment of Formula (I):

Ri is unsubstituted C1-C3 alkyl;

L_a is (CH₂)i-6; and

R₂ and R3 are each, independently: H, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclohexyl, phenyl, benzyl, benzodioxole, pyridinyl, (CfUbN/CHah. (C^hSCbH, (CH₂)₂SO2Me, CH2CO2H. or(CH₂)2CN;

or alternatively, R₂ and R3, together with the nitrogen atom to which they are attached, form a morpholine ring optionally substituted one or more times with C1-C4 alkyl, carbonyl, or (CH2)i.3N(Ci-C« alkyljj; an 8-oxa-3-azabicyclo[3.2.1]octane ring; a thiomorpholinc ring substituted one or more times with carbonyl or thione; a piperazine ring substituted with C1-C4 alkyl ester; a pyrrolidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a 2,5-diliydtopynole ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a succinimide ring optionally substituted one or more

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 times with C1-C4 alkyl; a 3-azabicyclo[3.1.0]hexane-2,4-dione ring; a hexahydropyrimidine ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an imidazole ring substituted with NO2; an isoindolinc ring substituted with carbonyl; an azctidinc ring substituted with carbonyl; an piperidine ring optionally substituted one or more times with C4-C4 alkyl, carbonyl, halo, OH, or (CHiji-iOH; a pyridinone ring optionally substituted one or more times with C1-C4 alkyl, OH, or CN; a pyrimidinone ring optionally substituted one or more times with C1-C4 alkyl; an oxazolidine ring optionally substituted one or more times with CiC4 alkyl: an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more limes with carbonyl; or a benzoiso thiazole ring optionally substituted one or more times with carbonyl.

In one aspect of the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

Ri is unsubstituted CrCe alkyl;

L is unsubstituted Ci-Ce alkyl linker, unsubstituted C3-C10 carbocycle, unsubstituted Cé-Cio aryl, unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or unsubstituted heteroaryl comprising one or two 5or 6-member rings and 1-4 heteroaloms selected from N, O and S; and or R2 and R3, together with the nitrogen atom to which they are attached, form a heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or a heterocycle comprising a 5-meinber ring and 1-3 heteroatoms selected from N, O and S, wherein the heteroaryl or heterocycle may be optionally substituted one or more times with Cj-Cc alkyl, CN, OH, halo, O(Ci-C« alkyl), CHO, carbonyl, thione, NO, or NIL.

In one embodiment of this aspect, at least one of R2 and R3 is H.

In another embodiment of this aspect, L_a is (CHih.

In still another embodiment of Formula (I), R? and R3 together with the nitrogen to which they are attached form a heterocycle, wherein the heterocycle is, a thiomorpholine ring, a pyrrolidine ring, a 2,5-dihydropyrrole ring, a 1,2-dihydropyridine ring, a piperazine ring, a succinimide ring, an isoindoline ring, a 2,5-dihydro-l//-tetrazole ring, an azetidine ring, a piperidine ring, a hcxahydropyrimidinc ring, a 2,3,3a,4,7,7a-hcxahydro-l W-4,7epoxyisoindole ring, a 3,4-dihydroquinazoline ring, a 1,2,3,4-tetrahydroquinazoline ring, an oxazolidine ring, an oxazolidinone ring, an imidazolidinone ring, a l,3-dihydro-2H-imidazol2-one ring, an imidizolidine thione ring, or an isothiazolidine ring, wherein all of the rings

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 may be optionally substituted one or more times with Ci-Cô alkyl, COj(Ci-Cô alkyl), OH, (CH₂)_MOH, O(C,-C₆ alkyl), halo, NH₂, (CH₂)_MNH₂, (CH₂),.₄NH(C₁-C₄ alkyl), (CH^. ₄N(Ci-C4alkyl)₂, carbonyl, or tliione.

In one embodiment of Formula (I):

Ri is unsubstituted C1-C3 alkyl;

L, is (CH₂)i^; and

R₂ and Rj, together with the nitrogen atom to which they are attached, form a morpholine ring substituted one or more times with Ci-C₄ alkyl, carbonyl, or (CH₂)i.₃N(CiC₄ alkyi)₂; an 8-oxa-3-azabicyclo[3.2.1]octane ring; a l,4-dioxa-8-azaspiro[4.5]decane ring; a thiomorpholine ring substituted one or more times with carbonyl or thione; a piperazine ring optionally substituted with Ci-C₄ alkyl, halo, (CH₂)₂OH, Ci-C₄ alkyl ester; a pyrrolidine ring optionally substituted one or more times with Ci-C₄ alkyl or carbonyl; a 2,5-dihydropyrrolc ring optionally substituted one or more times with Ci-C₄ alkyl or carbonyl; a succinimide ring optionally substituted one or more times with Ci-C₄ alkyl; a 3-azabicyclo[3.1.0]hexane-2,4dione ring; a hexahydropyrimidine ring optionally substituted one or more times with Ci-C₄alkyl or carbonyl; a pyrimidinone ring optionally substituted one or more times with Ci-C₄alkyl; a pyrrole ring optionally substituted one or more times with Ci-C₄ alkyl, halo, C(0)NH₂, or NO₂; a pyrazole ring optionally substituted one or more times with C4-C4 alkyl, C(0)NH₂, or NO/, an imidazole ring optionally substituted one or more limes willi C1-C4 alkyl or NO2; a l,3-dihydro-2II-imidazol-2-one ring; a benzimidazole ring; a thiazole ring;,an isoindoline ring substituted with carbonyl; a 1/7-tetrazole ring; a 1/7 2,5-dihydro-1/7-tetrazole ring substituted with thione; a 1//-1,2,4-triazole ring; a 177-1,2,3-triazole ring; an azetidine ring substituted with carbonyl; an piperidine ring optionally substituted one or more times with Ci-C₄ alkyl, carbonyl, halo, OH, or (CH₂)i-tOH; a pyridinone ring optionally substituted one or more times with C1-C4 alkyl, OH, or CN; a 1.2-dihydropyridine ring substituted with carbonyl; a pyrimidinone ring optionally substituted one or more times with CrC₄ alkyl; an oxazolidine ring optionally substituted one or more times with Ci-C₄ alkyl; an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times with C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more times with carbonyl; an indole ring; a 2,3,3a,4,7,7a-ltexahydro-l//-4,7-epoxyisoindole ring optionally substituted one or more times with carbonyl; a 3,4-dihydroquinazolinc ring substituted with carbonyl; 1,2,3,4-tetrahydroquinazoline ring substituted one or more times with carbonyl; or a benzoisothiazole ring optionally substituted one or more times with carbonyl.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

7

In some embodiments of Formula (I), at least one of R and R is H.

In other embodiments of Formula (I), L_d is (CH₂)₂.

In a particular embodiment of Formula (I):

Ri is methyl;

L_a is (CH₂>2; and

R₂ and R3, together with the nitrogen atom to which they are attached, form a succinimide ring.

In another embodiment of Formula (I):

Ri is methyl;

L_a is (CH₂)3; and

R₂ and Rj, together with the nitrogen atom to which they are attached, form a succinimide ring.

In still another embodiment of Formula (I):

Ri is methyl;

L_a is (CH₂)4; and

R₂ and Rj, together with the nitrogen atom to which they are attached, form a succinimide ring.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remilling multiple sclerosis (RRMS).

For example, the compound of Formula (I) is a compound listed in Table 1 herein.

For example, in the compound of Formula (I), Ri is methyl.

For example, in the compound of Formula (1), Ri is ethyl.

For example, in the compound of Formula (I), La is substituted or unsubstituted Ci-Q, alkyl linker.

For example, in the compound of Formula (I), La is substituted or unsubstituted C1-C3 alkyl linker.

For example, in the compound of Formula (I), La is substituted or unsubstituted C₂alkyl linker.

For example, in the compound of Formula (I), U is methyl substituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), La is di-methyl substituted or unsubstituted C₂ alkyl linker.

CA 02906580 2015-09-1«

WO 2014/152494 PCT/LS2014/027401

For example, in the compound of Formula (I), La is methyl or di-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (I), L, is unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), R₂ is substituted or unsubstituted C|-C₆alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted Cj-Q alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C1-C3 alkyl.

For example, in (he compound of Formula (I), R₂ is unsubstituted Ci-C₂ alkyl.

For example, in the compound of Formula (I), R₂ is C(O)OR_a-substituted Ci-Cô alkyl, wherein Ra is H or unsubstituted G G, alkyl.

For example, in the compound of Formula (I), R₂ is S(O)(O)Rb-subsliluled Ci-Cô alkyl, wherein Rt> is unsubstituted Ci-Co alkyl.

For example, in the compound of Formula (I), R₃ is H.

For example, in the compound of Formula (I), R₃ is substituted or unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (I), R₃ is unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (I), R₂ and R₃, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heleroaloms selected from N, 0 and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S.

For example, in the compound of Formula (I), R₂ and R₃, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S.

For example, in the compound of Formula (I), R₂ and R₃, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl. piperazinyl, or morpholinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together with the nitrogen atom to wliich tlrey are attached, form a substituted or unsubstituted piperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together with the nitrogen atom to which they are attached, form an unsubstituted piperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together with the nitrogen atom to which they are attached, form a halogen substituted piperidinyl ring.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a 4-halogen substituted piperidinyl ring.

For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they arc attached, form an unsubstituted morpholinyl ring.

For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a morpholino N-oxide ring.

For example, in the compound of Formula (I), Ri and R3, together with the nitrogen atom to which they are attached, form an unsubstituted pyrrolidinyl ring.

For example, in the compound of Formula (I), R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S.

For example, in the compound of Formula (I), R2 is substituted or unsubstituted Q>C10 aryl.

For example, in the compound of Formula (I), R2 is unsubstituted Cg-Cio aryl.

For example, in the compound of Formula (I), R? is unsubstituted phenyl.

For example, in the compound of Formula (I), R? is unsubstituted benzyl.

In another embodiment, the present invention provides a compound of Formula (la), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (la), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

<img file="CA2906580C_D0003.tif" />

(la);

wherein:

Ri is unsubstituted C| C_fi alkyl;

L_a is substituted or unsubstituted Ci-Cô alkyl linker, substituted or unsubstituted C3Cio carbocycle, substituted or unsubstituted Ce-Cio aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and

Ri is H, substituted or unsubstituted CpC₆ alkyl, substituted or unsubstituted Ci-C« alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted C₆-Cio aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 14 heteroatoms selected from N, O and S.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS).

For example, in the compound of Formula (la), Ri is methyl.

For example, in the compound of Formula (la), Ri is ethyl.

For example, in the compound of Formula (la), L_a is substituted or unsubstituted Cp C₆ alkyl linker.

For example, in the compound of Formula (la), L_a is substituted or unsubstituted Cp C3 alkyl linker.

For example, in the compound of Formula (la), L_a is substituted or unsubstituted Ci alkyl linker.

For example, in the compound of Formula (la), L_a is methyl substituted or unsubstituted C? alkyl linker.

For example, in the compound of Formula (la), L_a is di-methyl substituted or unsubstituted C2 alkyl linker.

For example, in the compound of Formula (la), L_a is methyl or di-methyl substituted Ci alkyl linker.

For example, in the compound of Formula (la), L_a is unsubstituted Ci alkyl linker.

For example, in the compound of Formula (la), R2 is substituted or unsubstituted Cp C₆ alkyl.

For example, in the compound of Formula (la), R2 is unsubstituted CpCé alkyl.

For example, in the compound of Formula (la), Ri is methyl.

For example, in the compound of Formula (la), R₂ is unsubstituted CpCs alkyl.

For example, in the compound of Formula (la), R2 is unsubstituted CpCî alkyl.

For example, in the compound of Formula (la), R2 is C(O)ORâ-substituted Ci-Cô alkyl, wherein R_a is H or unsubstituted CpC^ alkyl.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

For example, in the compound of Formula (la), R₂ is S(O)(O)Rb-substituted Ci-C&amp; alkyl, wherein R_b is unsubstituted Ci-C₆ alkyl.

In another embodiment, tire present invention provides a compound of Formula (lb), or a pharmaceutically acceptable polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (lb), or a pharmaceutically acceptable polymorph, hydrate, solvate or co-crystal thereof:

<img file="CA2906580C_D0004.tif" />

A‘ is a pharmaceutically acceptable anion:

Ri is unsubstituted Ci-Ce alkyl;

L_a is substituted or unsubstituted C|-C₆ alkyl linker, substituted or unsubstituted C3C10 carbocycle, substituted or unsubstituted Cô-Cio aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

R3' is substituted or unsubstituted Ci-Ce alkyl; and

R₂ and R3 arc each, independently, H, substituted or unsubstituted CrC&amp; alkyl, substituted or unsubstituted C₂-Cô alkenyl, substituted or unsubstituted C₂-Cô alkynyl, substituted or unsubstituted C₆-Cio aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S;

or alternatively, R₂ and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6member rings and 1-4 heteroatoms selected from N, 0 and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S.

For example, the neurological disease is multiple sclerosis.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS).

For example, in the compound of Formula (lb), Rj is methyl.

For example, in the compound of Formula (lb), Ri is ethyl.

For example, in the compound of Formula (lb), L_a is substituted or u nsubstituted CiQ alkyl linker.

For example, in the compound of Formula (lb), L_a is substituted or unsubstituted Cr C3 alkyl linker.

For example, in the compound of Formula (lb), L_a is substituted or unsubstituted C₂alkyl linker.

For example, in the compound of Formula (lb), L_a is methyl substituted or unsubstituted C2 alkyl linker.

For example, in the compound of Formula (lb), L_a is di-methyl substituted or unsubstituted C2 alkyl linker.

For example, in the compound of Formula (lb), L_a is methyl or di-methyl substituted Co alkyl linker.

For example, in the compound of Formula (lb), L_a is unsubstituted C2 alkyl linker.

For example, in the compound of Formula (lb), Ro is substituted or unsubstituted CiCô alkyl.

For example, in the compound of Formula (lb), Ro is unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (lb), Ro is unsubstituted C1-C3 alkyl.

For example, in the compound of Formula (lb), Ro is unsubstituted C1-C2 alkyl.

For example, in the compound of Formula (lb), R₂ is C(O)OR_a-substituted CrC’6 alkyl, wherein R_a is H or unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (lb), R2 is S(O)(O)Rb-substituted Q-Q alkyl, wherein R_b is unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (lb), R3 is H.

For example, in the compound of Formula (lb), R3 is substituted or unsubstituted CiCô alkyl.

For example, in the compound of Formula (lb), R3 is unsubstituted Ci-Ce alkyl.

For example, in the compound of Formula (lb), R₂ and R₃, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or a

CA 02906580 2015-09-1«

WO 2014/152494 PCT/LS2014/027401 substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (lb), R₂ and R3, together with tlie nitrogen atom to which they arc attached, form a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S.

For example, in the compound of Formula (lb), R₂ and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubsliluled piperidinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with the nitrogen atom to which they are attached, form an unsubstinited piperidinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with tlie nitrogen atom to which they are attached, form a halogen substituted piperidinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with the nitrogen atom to which they are attached, form a 4-halogen substituted piperidinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with the nitrogen atom to which they are attached, form an unsubsliluled morpholinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with the nitrogen atom to which they are attached, form an unsubstituted pyirolidinyl ring.

For example, in the compound of Formula (lb), R₂ and R3, together with tlie nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (lb), R₂ is substituted or unsubstituted (V Cio aryl.

For example, in the compound of Formula (lb), R₂ is unsubstituted Cô-Cio aryl.

For example, in the compound of Formula (lb), R₂ is unsubstituted phenyl.

For example, in the compound of Formula (lb), R₂ is unsubstituted benzyl.

For example, in the compound of Formula (lb), R3’ is unsubstituted CpCe alkyl.

For example, in the compound of Formula (lb), R₃’ is unsubstituted C1-C3 alkyl.

For example, in the compound of Formula (lb), R3’ is methyl.

In one embodiment, tlie present invention provides a compound of Formula (II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

<img file="CA2906580C_D0005.tif" />

wherein:

Ri is unsubstituted Ci-Cc alkyl;

R» and Rs are each, independently, H, substituted or unsubstituted Ci-Cô alkyl, substituted or unsubstituted C₂-C₆ alkenyl substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted Cô-Cio aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-ineniber rings and 1-4 heteroatoms selected from N, 0 and S;

Rô, R7, Rs and R9 are each, independently, H, substituted or unsubstituted CrC&amp; alkyl, substituted or unsubstituted C₂-Cô alkenyl, substituted or unsubstituted C₂-Cô alkynyl or C(0)0R_a; and

R_a is H or substituted or unsubstituted Ci-Cs alkyl.

In one embodiment of Formula (II),

Ri is methyl;

Ri and R₅ are each methyl; and

Rô, R7, Rs and Ro are each, independently, H or methyl

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS).

For example, in the compound of Formula (11), Ri is methyl.

For example, in the compound of Formula (II), Ri is ethyl.

For example, in the compound of Formula (II), R&lt; is substituted or unsubstituted CiCô alkyl.

For example, in the compound of Formula (II), R4 is unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (II), R4 is unsubstituted C1-C3 alkyl.

CA 02906580 2015-09-1«

WO 2014/152494 PCT/LS2014/027401

For example, in the compound of Formula (II), Rj is unsubstituted C1-C2 alkyl.

For example, in the compound of Formula (II), R4 is C(O)OR_a-substituted C_rC₆alkyl, wherein R_a is H or unsubstituted Cj-Cô alkyl.

For example, in the compound of Formula (Π), R» is S(O)(O)Rb-substitutcd Ci-Cô alkyl, wherein Rb is unsubstituted Ci-Cô alkyl.

For example, in the compound of Formula (II), R5 is H.

For example, in the compound of Formula (II), R5 is substituted or unsubstituted CiCô alkyl.

For example, in the compound of Formula (Π), R5 is unsubstituted Ci-Ce alkyl.

For example, in the compound of Formula (Π), R» is substituted or unsubstituted CeC10 aryl.

For example, in the compound of Formula (Π), R4 is unsubstituted C0-C10 aryl.

For example, in the compound of Formula (Π), R« is unsubstituted phenyl.

For example, in the compound of Formula (II), R« is unsubstituted benzyl.

For example, in the compound of Formula (Π), Rô R7, R« and R9 are each H.

For example, in the compound of Formula (II), Rr, is substituted or unsubstituted CiCô alkyl and R7, R$ and R9 are each II.

For example, in the compound of Formula (Π), Rô is unsubstituted Ci-Cô alkyl and R₇, Rs and R9 are each H.

For example, in the compound of Formula (II), Rs is substituted or unsubstituted CiCô alkyl and Rô, R7 and R9 are each H.

For example, in the compound of Formula (II), Rs is unsubstituted Ci-Cô alkyl and Rô, R₇ and R₉ are each H.

For example, in the compound of Formula (II), Rô and Rs are each, independently, substituted or unsubstituted Cj-Q alkyl and R7 and R9 are each H.

For example, in the compound of Formula (II), Rô and Rs are each, independently, unsubstituted Ci-Cô alkyl and R7 and R9 are each H.

For example, in the compound of Formula (II), Rô and R7 are each, independently, substituted or unsubstituted Ci-Cô alkyl and Rs and R9 are each H.

For example, in the compound of Formula (II), R$ and R7 are each, independently, unsubstituted Ci-C₆ alkyl and Rs and Ry arc each H.

For example, in the compound of Formula (II), Rs and R9 are each, independently, substituted or unsubstituted Ci-Cô alkyl and Rô and R7 are each H.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

For example, in the compound of Formula (II), Rs and Ry are each, independently, unsubstituted C_rC₆ alkyl and R&lt;, and R₇ are each H.

In one embodiment, the present invention provides a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

<img file="CA2906580C_D0006.tif" />

wherein:

Ri is unsubstituted Cj-Ce alkyl;

is selected from the group consisting of:

<img file="CA2906580C_D0007.tif" />

<img file="CA2906580C_D0008.tif" />

Xis N, 0, S, or SO?;

ZisCorN;

m is 0,1,2,, or 3;

n is 1 or 2;

wisO, 1,2 or 3;

t is 0,1,2,3,4,5,6,7,8,9, or 10;

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

R*, R/, Rs and R9 are each, independently, H, substituted or unsubstituted Ci-C&amp; alkyl, substituted or unsubstituted C₂-C(, alkenyl, substituted or unsubstituted C₂-C₆ alkynyl or C(O)OR_a; and

R_a is H or substituted or unsubstituted Ci-Q alkyl; and each Rio is, independently, H, halogen, substituted or unsubstituted Ci-Co alkyl, substituted or unsubstituted Ci-Q alkenyl, substituted or unsubstituted Ci-Q alkynyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 14 heteroatoms selected from N, O and S;

or, alternatively, two Rio’s attached to lire same carbon atom, together with the carbon atom to which they arc attached, form a carbonyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and I -4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S;

or, alternatively, two Rio’s attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstiluted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5or 6-member rings and 1-4 heteroatoms selected from N, 0 and S.

For example, tire neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiple sclerosis (RRMS).

For example, in the compound of Formula (III), Ri is methyl.

For example, in the compound of Formula (III), R! is ethyl.

For example, in the compound of Formula (III),

<img file="CA2906580C_D0009.tif" />

<img file="CA2906580C_D0010.tif" />

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<img file="CA2906580C_D0011.tif" />

For example, in the compound of Formula (III),

<img file="CA2906580C_D0012.tif" />

<img file="CA2906580C_D0013.tif" />

For example, in the compound of Formula (III),

<img file="CA2906580C_D0014.tif" />

<img file="CA2906580C_D0015.tif" />

For example, in the compound of Formula (III)

<img file="CA2906580C_D0016.tif" />

<img file="CA2906580C_D0017.tif" />

For example, in the compound of Formula (III), Rô is substituted or unsubsliluled CiCô alkyl and R7, Re and R9 are each II.

For example, in the compound of Formula (III), Rô is unsubstituted Cj-Cô alkyl and 10 R7, R$ and R9 are each H.

For example, in the compound of Formula (111), Rs is substituted or unsubstituted Cr C₆ alkyl and Rô, R7 and R₉ are each H.

For example, in the compound of Formula (III), Rs is unsubstituted Ci-Cô alkyl and Rô. R7 and R9 are each H.

For example, in the compound of Formula (III), Rô and Rs are each, independently, substituted or unsubstituted C1-C0 alkyl and R? and R9 are each H.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

For example, in the compound of Formula (III), Rô and R« are each, independently, unsubstituted C_rC₆ alkyl and R₇ and R₉ are each H.

For example, in the compound of Formula (III), Rs and R7 are each, independently, substituted or unsubstituted Ci-Cs alkyl and Rs and Ro arc each H.

For example, in the compound of Formula (III), R&amp; and R7 are each, independently, unsubstituted Ci-Q alkyl and Rg and R₉ are each H.

For example, in the compound of Formula (III), Rs and R₉ are each, independently, substituted or unsubstituted CpCe alkyl, and R(> and R₇ are each H.

For example, in the compound of Formula (ΙΠ), Rs and R₉ are each, independently, unsubstituted Ci-Cs alkyl, and R&amp; and R₇ are each H.

In one embodiment of Formula (III):

Ri is unsubstituted Ci-Cs alkyl;

<img file="CA2906580C_D0018.tif" />

<img file="CA2906580C_D0019.tif" />

m isO, 1,2,or3;

t is 2,4, or 6;

Rs, R7, Rs and R₉ are each, independently, H, unsubstituted Ci-Ce alkyl, or C(O)OR_a, wherein K, is H or unsubstituted Ci Q, alkyl; and two Rio’s attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl.

In another embodiment, the present invention provides a compound of Formula (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof, or a method for the treatment of a neurological disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

<img file="CA2906580C_D0020.tif" />

wherein:

Ri is unsubstituted G-Ce alkyl;

U is substituted or unsubstituted Ci-Ce alkyl linker;

R₂ and Rj are each, independently, H, substituted or unsubstituted acyl, NR14R15, C(S)Rn, C(S)SRh, C(S)NR)|R_I2, C(S)NRhNR|3Ri4. C(NR_n)NRi,R|₂, substituted or unsubstituted C₍-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-Cô alkynyl, substituted or unsubstituted G>-Go aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted hctcroaryl comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S;

R11 and Ri₂ are each, independently, H, substituted or unsubstituted Ci-C₆ alkyl, substituted or unsubstituted C>-C₆ alkenyL substituted or unsubstituted G-Q alkynyl. substituted or unsubstituted Cô-Go aryl, substituted or unsubstituted C3-G0 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, 0 and S;

R13 is H or substituted or unsubstituted G*C&amp; alkyl; and

Ri4 and R|5 are each, independently, H. substituted or unsubstituted acyl, substituted or unsubstituted G-Cô alkyl, substituted or unsubstituted G-Ce alkenyl, substituted or unsubstituted G-Ce alkynyl, substituted or unsubstituted CVGo aryl, substituted or unsubstituted G-Go carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, 0 and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1 -4 heteroatoms selected from N, O and S;

wherein at least one of R₂ and R3 is substituted or unsubstituted acyl, NR14R15, C(S)Rn, C(S)SR_U, C(S)NR_nR_I2, C(S)NR_nNRi3Ri4. or C(NRb)NRuRi₂.

In one embodiment of Formula (IV),

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

Ri is Ci-Cô alkyl;

L, is substituted or unsubstituted C1-C4 alkyl linker; and one of R₂ and R3 is CO₂(C|-C₆ alkyl),CO₂CH₂Ph, CO₂Pli, CO₂Py, pyridinyl-ALoxide ester, C(O)CH₂(imidazolc), C(S)NHPh, or C(NH)NH₂, wherein Ph or imidazole groups arc optionally substituted with NO2.

In another embodiment of Formula (IV),

Ri is C1-C4 alkyl;

L_a is substituted or unsubstituted C1-C4 alkyl linker; and

R2 and R3 are each, independently, II, methyl, ethyl, isopropyl, butyl, tert-butyl, cyclohexyl, cyclohexenyl, phenyl, benzyl, benzodioxole, pyridinyl, (CH2)2N(CH3)2, (CH2)3SO₂H, (CH₂)₂SO2Me, CHO, CH2CO2H, C(O)(CH₂)2CO2H, NO, C(O)NH2_;(CH₂)2CN, tert-butyl ester, benzyl ester, pyridinyl ester, pyridinyl-N-oxidc ester, C(0)CH₂(2-nitro-l//imidazol-l-yl), C(S)NHPh, C(NH)NH₂. ethyl substituted with carbonyl, propyl substituted with carbonyl, or phenyl ester substituted with NO₂, wherein the phenyl and benzyl groups can be optionally substituted one or more times with methyl, NH₂, NO₂. OH, or CHO;

wherein at least one of R₂ and R3 is substituted or unsubstituted acyl, NR14R15, C(S)Rn, C(S)SRn, C(S)NRnR_I2, C(S)NR_uNRi₃Ri4. or C(NRi₃)NR_ltRi₂.

In one embodiment of Formula (IV),

Ri is C_rC₆ alkyl;

L_â is (CI 12)1-4;

R₂ is H or C(O)Ci-Ce alkyl; and

R₃ is H or C(O)Ci-C₆ alkyl wherein at least one of R₂ and R, is C(O)Ci_ftalkyl.

For example, the compound is a compound listed in Table 1 herein.

Representative compounds of the present invention include compounds listed in Table 1 and in Table 2.

Table 1.

<td> 1</td><td> ho₂c^ HO₂C^N^Z</td><td> 0</td><td> ίχ,ΟΜβ 0</td>

<td> 2</td><td> 1 0¾</td><td> 0</td><td> i&lt;T)Me</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

<td> 3</td><td>¹ n</td>

<td> 4</td><td>_xl ₊ S 0 A’</td>

<td> 5</td><td> 0</td>

<td> 6</td><td> ^Α^ΑθΧ^γΟΜβ 0</td>

<td> 7</td><td> p 2 ^^N^\/^V^0Me 0</td>

<td> 8</td><td> H ft 0</td>

<td> 9</td><td> Z' 0</td>

<td> 10</td><td> Q,/) 2 χδχχ’^Ζ^Χ^ΧχΟΜβ 0</td>

<td> 11</td><td> 0¾^ 0 l^N^₀A^y)Me 0</td>

<td> 12</td><td> | S 0</td>

<td> 13</td><td> l^il i ? %Λ^χΝ_νχ-χ_σΑ_χί^&lt;_ζΟΜβ 0</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 14</td><td> çC 0</td><td> 0</td><td> x^OMe 0</td>

<td> 15</td><td colspan="3"> 0</td>

<td> 16</td><td></td><td> 0</td><td> iKJDMe 0</td>

<td> 17</td><td> ro °O.</td><td> 0</td><td> ^X^OMe 0</td>

<td> 18</td><td></td><td></td><td> x^OMe 0</td>

<td> 19</td><td> χ.</td><td> 'qA^</td><td> &lt;OMe 0</td>

<td> 20</td><td></td><td></td><td> kOMe 0</td>

<td> 21</td><td> K</td><td> 0 ^oAsj</td><td> ?X,OM0 0</td>

<td> 22</td><td> \-r^° yi_v0</td><td> 0</td><td> ^.OMe 0</td>

<td> 23</td><td> 0</td><td> 0</td><td> ^X^OMe 0</td>

<td> 24</td><td></td><td> 0</td><td> K^OMe</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

<td> 25</td><td> s ° 0</td>

<td> 26</td><td> 0% 0 ζχ,A^x^OMe ° ⁰ %</td>

<td> 27</td><td> o^⁰ 0 A^x^OMe I I</td>

<td> 28</td><td> 0 /(χ/Ν -^Χθ Asjjjj^OMe</td>

<td> 29</td><td>⁰ 1 2 X N zx A _OMe 0</td>

<td> 30</td><td> 0 k^N^^zx A^X^OMe γ 0 γ 0 0</td>

<td> 31</td><td> O 0^ 0 k^N^^zx^A^s. _OMe 0</td>

<td> 32</td><td> /o^] o ^X^N xz^zk^jX^OMe 0</td>

<td> 33</td><td> 0 ₍A_sX^N_Xx^₀A^_?iX_wz0Me 0</td>

<td> 34</td><td> ο'Ύ' 0 k^N^-^θΑ^^χ^ΟΜθ * O</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 35</td><td> 0 &lt;Ai s 1 1 JL ^?Xz^0Me '</td>

<td> 36</td><td> ηγ o n AzK,0Mc V J 0 o</td>

<td> 37</td><td> V zP f\ ⁰ Χζ-Ν^^ζχ If 0 0</td>

<td> 38</td><td>_z0 /l ⁰ \ -OMe 0</td>

<td> 39</td><td> ζ°Ύ° ⁰ VÀ ^ζχ Α^χ.ΟΜβ χζ' Χζ&lt; V Ο</td>

<td> 40</td><td> \/ ζΡ /^Ύ Ο ^HNy^A^Y°Me 0 0</td>

<td> 41</td><td>^Η U Æ^x^OMe X Ύ V/ '0' X/ Ο Ο</td>

<td> 42</td><td> /γ° ο ^ζχ &gt;x JL^x^-OMe 0 ο</td>

<td> 43</td><td> Ύ° ⁰ ΗΝ-^χχθΑ^χ^ΟΜε 0</td>

<td> 44</td><td> .J0 ι ⁰^χγ^Ν'^_οΑ^_γ°Μ_βο Ο</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 45</td><td> H U ΗΝχ,Ν.ζχ A zs. OMe 0 Ji nh₂ 0</td>

<td> 46</td><td> PhHN^S Y* 0 HN. _ζχ A .OMe 0 Q 0</td>

<td> 47</td><td> 1 u •γΟ^Ν^θΑ^γΟΜο 1 0 0</td>

<td> 48</td><td>^H u Χ^Ο^Ν^θΑ^γΟΜβ 1 0 0</td>

<td> 49</td><td> H « Π ..OMe 'sz- &gt;r o &gt;r O 0</td>

<td> 50</td><td> O·.®^ n » u 0 0</td>

<td> 51</td><td> H » U ^ΑγΝ^_Χχ_οΑ^_χ.°Μο 0 0</td>

<td> 52</td><td> Π H g Ο 0</td>

<td> 53</td><td> &lt;Ύ° ? k^N^x^Asÿjiis^OMe 0 Ο</td>

<td> 54</td><td> u γΝ^οΑ^γθΜθ 0 0</td>

<td> 55</td><td> r^° î γΝ^₀Α^ΟΜ« 0 0</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 56</td><td> A A &gt;^N^o^v^{ÜMc 0} 0</td>

<td> 57</td><td> \ .0 AY Π Vj\k Λ/Κ,ΟΜε M ⁰ Π 0 0</td>

<td> 58</td><td> H O^N^O 1 1 ⁰ Ax _I\L^ζχ Az^z^e 0</td>

<td> 59</td><td> x γ γ 0 . ζΧ_ΛA ^ζχ .OMe γ ο γ 1 0</td>

<td> 60</td><td> /γ» ⁰ ^x A .zxAL^x J3Me y 0</td>

<td> 61</td><td> CN o kzfk/xAzXzOMe y 0 γ OH 0</td>

<td> 62</td><td> H Il ⁰ JL^^OMe ^vZ Xz^ 'g' 0</td>

<td> 63</td><td> \_/γ ο '\Αχζ^_ΛΑ_&lt;ίί!^!'χΛ&gt;Μβ JT ο 0 0</td>

<td> 64</td><td> Λη ο ^ΗΝ\ζ-Ν^ζχ_ΛΑ_κ^_ίρχ^ΟΜβ s 0</td>

<td> 65</td><td> ''νΑ χ^χ Α-ίί^^θΜθ ff ⁰ π 0 0</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 66</td><td> Çç° ? 0</td>

<td> 67</td><td> Qr° î ΗΝγΝ_ν^_οΑ_χ&lt;{ί!&gt;γ.ΟΜβ 0 0</td>

<td> 68</td><td> N'NH 0 s o</td>

<td> 69</td><td> 'Ύ'' 0</td>

<td> 70</td><td> « U .zs. -N- .OMe ' 0 JJ 0</td>

<td> 71</td><td> H S \_yN_K/\_rtzk^\_yOMe ¹ 0</td>

<td> 72</td><td>⁰ Γ|Γ θ</td>

<td> 73</td><td> 1 U .IX^z^ -0-Jk ' ''X^ N ^x XOMe 1 O</td>

<td> 74</td><td> H n _rz^N_s^_oA_yiÿ*x^OMe X/ θ</td>

<td> 75</td><td> C^\ ⁰ν^Ν^/χθΑ^ί^χ^,ΟΜθ O</td>

<td> 76</td><td>^Η0&gt;Γ^Ν^ O z/^/xk ι 1 h ^{0 0} k.N_zx JL z#X^,OMe 0 Y o</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

<td> 77</td><td> 0 0 π o JI Y'^''^zOMe</td>

<td> 78</td><td> u H § HO^N^A^yOMe 0</td>

<td> 79</td><td> OH ^hoyV^{oh 0} 0</td>

<td> 80</td><td> Λη θ °s^^Nvx^₀Ai!i^!Sy^0Me-A o</td>

<td> 81</td><td> 1 ⁰ X Â '''ΧΓ'Ν'η ο k /Χ_ΛΑ&lt;^Χ^θΜθ ο γ 0</td>

<td> 82</td><td>^H&lt;YY ° k^«L ^ζχ,,Αζί^χ^ΟΜβ A ⁰ Π ' ' 0</td>

<td> 83</td><td> 1 u ^γΝ^οΑ^γΟΜθ k^N o</td>

<td> 84</td><td> Cl » U JLxÿX ^,OMc xz^O Y 0</td>

<td> 85</td><td>⁰ ^χ^Ν.^&gt;κ_ΛΑ^χ^θΜ6 rV '^ν^Λ*γ AsA o H₂N</td>

<td> 86</td><td> [^CN 0 ^?χ^Ν ^ζχ_λ A^x^OMe Cf 0</td>

<td> 87</td><td> Η π ΟγγΝχζ^θΑ^γθΜβ VM o</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 88</td><td> H H /x. AziK^OMe rT h₂nM ⁰</td>

<td> 89</td><td> Vl ^H u AAXA-^x^OMe ho o y 0</td>

<td> 90</td><td> ¢, A_ &lt;A_ZN. &gt;x A^X^OMe 0 ΊΓ 0</td>

<td> 91</td><td>^X°Y^L ^H JL 0</td>

<td> 92</td><td> 0 II —S=O S ⁰\^^Nxz^₀A^V^0Me°'o J</td>

<td> 93</td><td> O Ι,Ν χ/Χθ A^ÿjJ^x^zOMe Ο Ο</td>

<td> 94</td><td> Ο L.N _ζχ_Λ A xÿX .OMe ητ o y S O</td>

<td> 95</td><td> oV'i O _nA_sÿ^x_wz°^MeI I</td>

<td> 96</td><td> 0 k^Nxz^o'^^V'⁰¹'⁴⁶ S o</td>

<td> 97</td><td> 0 Η₂Ν_νΖ^._οΑ_&lt;^^γΟΜ_β 0</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 98</td><td> 1 1 u 0</td>

<td> 99</td><td> 1 u _/N_&gt;yx_oA_s^yOMc 1 0</td>

<td> 100</td><td> 1 u Λ/\„A/K_xOMe ^X Λ ⁰ Π ' ' 0</td>

<td> 101</td><td>¹ V U X^Nxz^₀^S^Y^0Me 0</td>

<td> 102</td><td>^H0'^^z^N^/X| o 0</td>

<td> 103</td><td>_NQi^zV'‘'^x^^Jls^Y⁰^e</td>

<td> 104</td><td> H N \ 0 o</td>

<td> 105</td><td> I U ^ΛΧ-Ν^χ-xζγ^χΟΜβ &lt;11 J 1 ο o</td>

<td> 106</td><td> N'NH 0 Y^Axy&gt;Me S 0</td>

<td> 107</td><td> /¾. 0 VN^z^_oA^yOMe 0</td>

<td> 108</td><td> /s&amp; O ^NyN_xx^_oA^y0Me ’ O</td>

<td> 109</td><td> O^_o'^Jl^Y^0Meo</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 110</td><td> fe/ 0</td>

<td> 111</td><td> /¾ ⁰ry^Nxz^₀^^Y°^MeXsss/ o</td>

<td> 112</td><td> /=tN 0 ^N VN 0</td>

<td> 113</td><td> /^NaN Π O</td>

<td> 114</td><td> nA 0 ^υ nh₂</td>

<td> 115</td><td> Nsn 0 ^NVNv^_oA^yOMe 0</td>

<td> 116</td><td> /=sN 0 O J 0</td>

<td> 117</td><td> Çk⁰ s HN^N___^θ&gt;&lt;^γ/ΟΜε o o</td>

<td> 118</td><td> Çk° N^N x^O^xUy^Y'°^Me 0</td>

<td> 119</td><td> ^ζΝχ/^θΑ^Χ^ΟΜβ O</td>

<td> 120</td><td>⁰ H ° θΛ,^Λγ-</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> 121</td><td> H U xk^H 0 u</td>

<td> 122</td><td> Λ ^h ϊ &lt;Ay^N&gt;^₀A^Xx^0Me S 0</td>

<td> 123</td><td> H U MeS^N-/x JC^iK^OMe Y ⁰ T S 0</td>

<td> 124</td><td> H H V /Νγ-ΝχΧ^θΑ^χ^ΟΜβ 0 0</td>

<td> 125</td><td> u Η H U Cfs ϊ</td>

<td> 126</td><td> /=¾ 0 ^HNy-^xx&gt;₎-^/^iX|X^0Me0 0</td>

<td> 127</td><td> o \=&amp; o</td>

<td> 128</td><td> H U 0 ⁰</td>

<td> 129</td><td>^H u &lt;Xx&lt;X^N. χχ A^^X^OMe Y η o ητ</td>

A' is a pharmaceutically acceptable anion.

Table 2.

<img file="CA2906580C_D0021.tif" />

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

<td> 131</td><td> O ⁰ Π O</td>

<td> 132</td><td> JO f\ ⁰ o O</td>

<td> 133</td><td> O H / N O y L O 0</td>

The present invention also provides pharmaceutical compositions comprising one or more compounds of Formula (I), (la), (lb), (11), (III), or (IV) and one or more pharmaceutically acceptable carriers.

In one embodiment, the pharmaceutical composition is a controlled release composition comprising a compound of Formula (I), (la), (lb), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers, wherein the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject. In another embodiment, the pharmaceutical composition is a controlled release composition comprising a compound of Formula (I), (la), (lb), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers, wherein the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject for at least about 8 hours to at least about 24 hours. In another embodiment, the pharmaceutical composition is a controlled release composition comprising a compound of Formula (I), (la), (lb), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers, wherein the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject for at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about 24 hours or longer. For example, at least about 18 hours. For example, at least about 12 hours. For example, greater than 12 hours. For example, al least about 16 hours. For example, al leasl aboul 20 hours. For example, at least about 24 hours.

CA 2906580 2017-03-16

In another embodiment, a compound of Formula (I). (la), (lb), (II). (Ill), or (IV) is efficiently converted lo (he active species, i.e.. monomelhyl fumarate, upon oral administration. For example, about 50 mole percent, about 55 mole percent, alxiut 60 mole percent, about 65 mole percent, about 70 mole percent, about 75 mole percent, about 80 mole 5 percent, about 85 mole percent, about 90 mole percent, or greater than 90 mole percent of the total dose of a compound of Formula (1). (la). (Ib). (II). (Ill), or (IV) administered is converted to nionomcthyl fumarate upon oral administration. In anollicr embodiment, a compound of Formula (1). (la), (lb). (II). (Ill), or (IV) is converted to the active species, i.e.. monomethyl fumarate, upon oral administration more efficiently (han dimethyl fumarate. In another embodiment, a compound of Formula (I). (la). (lb). (II). (Ill), or ( IV) is converted to (he active species, i.e., monomctliyl fumarate, upon oral administration more efficiently than one or more of the compounds described in I >S 8.148,414. For example, a compound of Formula (I), (la). (Ib), (Π), (III), or (IV) is essentially completely converted to the active species, i.e.. monomelhyl fumarate, upon oral administration.

In another embodiment, anyone of Compounds 1 - 133 is efficiently converted to (Ik active species, i.e.. monomethyl lumarate. upon oral administration. For example, about 50 percent, about 55 percent, about 60 percent, about 65 percent, about 70 percent, about 75 percent, about 80 percent, about 85 percent, about 90 percent. or greater than 90 percent of 20 the total dose of any one ol Compounds 1 133 administered is converted to nionomcthyl fumarate upon oral administration. In another embodiment, anyone of Compounds I - 133 is converted to the active species, i.e.. monomethy l fumarate, upon oral administration more efficiently (han dimethyl fumarate. In another embodiment, any one of Compounds I - 133 is converted to the active species, i.e.. nionomcthyl fumarate, upon oral administration more 25 efficiently than one or more of the compounds described in I 8.148.414. For example, any one of Compounds 1 - 133 is completely converted to the active species, i.e., monomelhyl lumarate. upon oral administration.

For a drug lo achieve its therapeutic effect, it is necessary to maintain tlx.· required level of blood or plasma concentration. Many drugs, including dimethyl fumarate, must he ->0 administered multiple times a day to maintain the required concentration. Furthermore, even with multiple administrations of such a drag per day. the blood or plasma concentrations of the active ingredient may still vary with time. i.e.. at certain time points between administrai ions there are higher concentrations of the active ingredient than at other times.

I hus. at certain time points of a 24-hour period, a patient may receive therapeutically

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 effective amounts of the active ingredient, while at other time points the concentration of the active ingredient in the blood may fall below therapeutic levels. Additional problems with such drugs include that multiple dosing a day often adversely affects patient compliance with the treatment. Therefore, it is desirable to have a drug dosage form wherein the active ingredient is delivered in such a controlled manner that a constant or substantially constant level of blood or plasma concentration of the active ingredient can be achieved by one or at most two dosing per day. Accordingly, the present invention provides controlled-release formulations as described below. In general, such formulations are known to those skilled in the art or are available using conventional methods.

As used herein, “controlled-release” means a dosage form in which the release of the active agent is controlled or modified over a period of lime. Controlled can mean, for example, sustained, delayed or pulscd-rclcasc at a particular time. For example, controlledrelease can mean that the release of the active ingredient is extended for longer than it would be in an immediate-release dosage form, i.e., at least over several hours.

As used herein, “immediate-release” means a dosage form in which greater than or equal to about 75% of the active ingredient is released within two hours, or, more specifically, within one hour, of administration. Immediate-release or controlled-release may also be characterized by their dissolution profiles.

Formulations may also be characterized by their pharmacokinetic parameters. As used herein, “pharmacokinetic parameters” describe the in vivo characteristics of the active ingredient over time, including for example plasma concentration of the active ingredient. As used herein, “Cnnx” means tlie measured concentration of the active ingredient in the plasma at the point of maximum concentration. “T_nui(” refers to the time at which the concentration of the active ingredient in the plasma is the highest. “AUC” is the area under the curve of a graph of the concentration of the active ingredient (typically plasma concentration) vs. time, measured from one time to another.

The controlled-release formulations provided herein provide desirable properties and advantages. For example, the formulations can be administered once daily, which is particularly desirable for the subjects described herein. The formulation can provide many (lierapeutic benefits that are not achieved with corresponding sltorter acting, or immediaterelease preparations. For example, the formulation can maintain lower, more steady plasma peak values, for example, Cnax, so as to reduce the incidence and severity of possible side effects.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

Sustained-release dosage forms release their active ingredient into the gastrointestinal tract of a patient over a sustained period of time following administration of the dosage form to the patient. Particular dosage forms include: (a) those in which the active ingredient is embedded in a matrix from which it is released by diffusion or erosion; (b) those in which the active ingredient is present in a core which is coated with a release ratecontrolling membrane; (c) those in which the active ingredient is present in a core provided with an outer coating impermeable to the active ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient; (d) those in which the active ingredient is released through a semi-permeable membrane, allowing the drug to diffuse across the membrane or through liquid filled pores within the membrane; and (e) those in which the active ingredient is present as an ion exchange complex.

It will be apparent to those skilled in the art that some of the above means of achieving sustained-release may be combined, for example a matrix containing the active compound may be formed into a multiparticulate and/or coated with an impermeable coating provided with an aperture.

Pulsed-release formulations release the active compound after a sustained period of time following administration of the dosage form to the patient. The release may then be in the form of immediate- or sustained-release. This delay may be achieved by releasing the drug at particular points in the gastro-intestinal tract or by releasing drug after a predetermined time. Pulsed-release formulations may be in the form of tablets or multiparticulates or a combination of both. Particular dosage forms include: (a) osmotic potential triggered release (see U.S. Pat. No. 3,952,741); (b) compression coated two layer tablets (see U.S. Pat. No. 5,464,633); (c) capsules containing an erodible plug (see U.S. Pat. No. 5,474,784); sigmoidal releasing pellets (referred to in U.S. Pat. No. 5,112,621); and (d) formulations coated with or containing pH-dependent polymers including shellac, phthalate derivatives, polyacrylic acid derivatives and crotonic acid copolymers.

Dual release formulations can combine the active ingredient in immediate release form with additional active ingredient in controlled-release form. For example, a bilayer tablet can be formed with one layer containing immediate release active ingredient and the otlier layer containing the active ingredient embedded in a matrix from which it is released by diffusion or erosion. Alternatively, one or more immediate release beads can be combined with one or more beads which are coated with a release rate-controlling membrane in a capsule to give a dual release formulation. Sustained release formulations in which the active ingredient is present in a core provided with an outer coating impermeable to the active

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401 ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient, can be coated with drug in immediate release form to give a dual release formulation. Dual release formulations can also combine drug in immediate release form with additional drug in pulsed release form. For example, a capsule containing an credible plug could liberate drug initially and, after a predetermined period of time, release additional drug in immediate- or sustained-release form.

In some embodiments, the dosage forms to be used can be provided as controlledrelease with respect to one or more active ingredients therein using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide lhe desired release profile in varying proportions. Suitable controlledrelease formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the present invention.

Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of additional amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from tlie body.

Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, concentration, or other physiological conditions or compounds.

Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may furtlier comprise one or more of a dispersing agent, wetting agent, suspending agent, and a preservative. Additional excipients, such as fillers, sweeteners, flavoring, or coloring agents, may also be included in these formulations.

A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared or packaged in the form of a discrete solid dose unit

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient. In one embodiment, a formulation of a pharmaceutical composition of the invention suitable for oral administration is coated with an enteric coat.

A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface-active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and al least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycollate. Known surface-active agents include, but are not limited to, sodium lauryl sulphate and poloxamers. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, com starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotically-controlled release tablets, optionally, with laser drilling. Tablets may further comprise a sweetener, a flavoring agent, a coloring agent, a preservative, or some combination of tliese in order to provide for pltarmaceutically elegant and palatable formulations.

Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin or HPMC. Such hard capsules comprise the active

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

As used herein, “alkyl”, “Ci, G- G, C4, G or Ce alkyl” or “CrG alkyl” is intended to include Ci, C₂, C3, C4, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or Ce branched saturated aliphatic hydrocarbon groups. For example, Ci-Cô alkyl is intended to include Ci, C₂, C3, C4, G and G alkyl groups. Examples of alkyl include, moielies having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pcntyl, or n-hcxyl.

In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., G-Cé for straight chain, C3-G for branclied chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

As used herein, “alkyl linker” is intended to include G, C₂, G, G, G, or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and G> G> C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, G-Cô alkyl linker is intended to include G, C₂, G, G, C5, and Ce alkyl linker groups. Examples of alkyl linker include, moielies having from one to six carbon atoms, such as, but not limited to, methyl (-CIL·-), ethyl (-CII2CII2-), n-propyl (-CH₂CH₂CH₂-), i-propyl (-CHCH₃CH₂-), n-butyl (-CH₂CH₂CH₂CH₂-), s-butyl (CHCH3CH₂CH₂-), i-butyl (-C(CH3)₂CH₂-), n-pentyl (-CH2CH₂CH₂CH₂CH₂-), s-pentyl (CHCH3CH2CH2CH2-) or n-hexyl K^CHîCHîCHîCUCH,-)· The term “substituted alkyl linker” refers to alkyl linkers having substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents do not alter the sp3hybridization of the carbon atom to which they are attached and include those listed below for “substituted alkyl.” “Heteroalkyl” groups are alkyl groups, as defined above, that have an oxygen, nitrogen, sulfur or phosphorous atom replacing one or more hydrocarbon backbone carbon atoms.

As used herein, the term “cycloalkyl”, “G, G. G. C₆, G or G cycloalkyl” or “G-G cycloalkyl” is intended to include hydrocarbon rings having from three to eight carbon atoms in their ring structure. In one embodiment, a cycloalkyl group lias five or six carbons in the ring structure.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

The term “substituted alkyl” refers to alkyl moieties having substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaniinocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heleroaronialic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)).

Unless the number of carbons is otherwise specified, “lower alkyl” includes an alkyl group, as defined above, having front one to six, or in another embodiment from one to four, carbon atoms in its backbone structure. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, two to six or of two to four carbon atoms.

“Aryl” includes groups with aromaticity, including “conjugated”, or multicyclic, systems with al least one aromatic ring. Examples include phenyl, benzyl, naphthyl, etc. “Ileteroaryl” groups are aryl groups, as defined above, having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics”. As used lierein, the tenu “heteroaryl” is intended to include a stable 5-, 6-, or 7-meinbered monocyclic or 7-, 8-, 9-, 10-, 11 - or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or Ιό heteroatonis, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatonis may optionally be oxidized (i.e., N—»0 and S(O)_P, where p=l or 2). It is to be noted that total number of S and O atoms in the heteroaryl is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiopliene, thiazole, isotliiazole, imidazole, triazoic, tctrazolc, pyrazolc, oxazole, isoxazolc, pyridine, pyrazine, pyridazinc, pyrimidine, and the like.

As used herein, “Ph” refers to phenyl, and “Py” refers to pyridinyl.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinolinc, naphthrydinc, indole, bcnzoturan, purinc, bcnzoluran, dcazapurinc, or indolizine.

In the case of multicyclic aromatic rings, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), although all of the rings may be aromatic (e.g., quinoline). The second ring can also be fused or bridged.

The aryl or heteroaryl aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heleroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).

As used lierein, “carbocycle” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. For example, a C3-C14 carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3,4,5,6,7,8,9,10,11,12,13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodccanc and [2.2.2]bicyclooctanc. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.

As used lierein, “heterocycle” includes any ring structure (saturated or partially unsaturated) which contains at least one ring hctcroatom (e.g., N, 0 or S). Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dilhiazinyl, dihydrofuro[2,3b]tctrahydroftiran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl. indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4oxadiazol5(4II)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pleridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl. pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl. 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofiiranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3thiadiazolyl, 1.2,4-thiadiazolyl, 12.5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl. 1,2,3triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

The term “substituted”, as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogen atoms on tlie atom arc replaced. Keto substituents arc not present on aromatic moictics. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term “acyl”, as used herein, includes moieties that contain the acyl radical (— C(O)-) or a carbonyl group. Substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulihydryl, alkyllhio, aryllhio, thiocarboxylatc. sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The description of the disclosure herein should be construed in congruity with the laws and principals of chemical bonding. For example, it may be necessary to remove a hydrogen atom in order accommodate a substituent at any given location. Furthermore, it is to be understood that definitions of the variables (i.e., “R groups”), as well as the bond locations of the generic formulae of the invention (e.g., Formulas I, la, lb, II III, and IV), will be consistent with the laws of chemical bonding known in the art. It is also to be understood that all of the compounds of the invention described above will further include bonds between adjacent atoms and/or hydrogens as required to satisfy the valence of each atom. That is, bonds and/or hydrogen atoms are added to provide the following number of total bonds to each of the following types of atoms: carbon: four bonds; nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds.

As used herein, a “subject in need thereof’ is a subject having a neurological disease. In one embodiment, a subject in need thereof has multiple sclerosis. A “subject includes a mammal. The mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or a pig. In one embodiment, the mammal is a human.

The present invention provides methods for the synthesis of the compounds of each of the formulae described herein. The present invention also provides detailed methods for the synthesis of various disclosed compounds of the present invention according to the following schemes and as shown in the Examples.

CA 2906580 2017-03-16

Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially ot. or consist of. tlie recited components. Similarly, where methods or processes arc described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of. the recited processing steps, lurtlier, it should he understood that die order ol steps or order lor performing certain actions is immaterial so long as the invention remains operable. Moreover. two or more steps or actions can be conducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety of functional groups; therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near tlie end of the overall process, all I tough it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, polymorph, hydrate, solvale or co-crystal thereof.

Compounds ol the present invention can be prepared in a variety of ways using commercially available starling materials, compounds known in tlie literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the ari. or which will be apparent to (he skilled artisan in light of lhe leachings herein. Standard synthetic methods and procedures for lhe preparation of organic molecules and functional group transformations and manipulations can be obtained from the 20 relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith. Μ B.. March. J.. March's Advanced Organic Chemistry Reactions. Mechanisms, and Structure. 5'¹' edition. John Wiley &amp; Sons: New York. 2001; and Greene, f. W.. Wuts. P. G M.. Protective Groups in Organic Synthesis, 3¹ edition, John Wiley &amp; Sons: New York, 1999, are useful and recognized

-- reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present invention.

( (impounds ot the present invention can be conveniently prepared by a variety of methods lamiliar to those skilled in lhe art. The compounds of this invention with each of lhe 30 iotmulae described herein may be prepared according to tlie following procedures from commercially available starting materials or starting materials which can be prepared using literature procedures. These procedures show the preparation of representative compoundsol this invention.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

EXPERIMENTAL

General Procedure 1

To a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5 equivalents) in DMF (25 ml per g of MMF) was added Hiinigs base (2.0 equivalents). The dark brown solution was stirred for 10 minutes, where turned into a brown suspension, before addition of the alcohol (1.0-1.5 equivalents). The reaction was stirred for 18 hours at room temperature. Water was added and the product extracted into ethyl acetate three times. The combined organic layers were washed with water three times, dried with magnesium sulphate, filtered and concentrated in vacuo at 45 °C to give the crude product. The crude product was purified by silica chromatography and in some cases further purified by trituration with diethyl ether to give the clean desired ester product. All alcohols were either commercially available or made following known literature procedures.

As an alternative to HBTU (A',MA.A''-Teiramethyl-(9-(lA/-benzotnazol-l-yl)uronium hexafluorophosphate), any one of the following coupling reagents can be used: EDCI/HOBt (/V-(3-dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride/hydroxybenzotriazole hydrate); COMU ((l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholinocarbenium hexafluorophosphate); TBTU (0-(benzotriazol-l-yl)-N,/V,N',Ntetramethyluronium tetrafluoroborate); TATU (0-(7-azabenzotriazole-l-yl)-l, 1,3,3telramelhyluronium tetrafluoroborate); Oxyma (ethyl (hydroxyimino)cyanoaceiate); PyBOP ((benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate); HOTT (5-(l-oxido2-pyridyl)-_iVW,.V'_&lt;.V-tetramethylthiuronium hexafluorophosphate); FDPP (pentafluorophenyl diphenylphosphinate); T3P (propylphosplionic anhydride); DMTMM (4-(4,6-dimethoxyl,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate); PyOxim ([ethyl cyano(hydroxyimino)acetato-0’]tri-l-pyrrolidinylphosphonium hexafluorophosphate); TSTU (/VJVJV',/V'-tetramethyl-O-(/V-succinimidyl)uronium tetrafluoroborate); TDBTU (0-(3,4dihydro-4-oxo-l,2,3-benzotriazrn-3-yl)-/V,/V,/V'A’-tetramethyluronium tetrafluoroborate); TPTU (0-(2-oxo-l(2//)pyridyl)-;V,AWW-tetranietliyluronium tetrafluoroborate); TOTU (O[(ethoxycarbonyl)cyanomethyle nami no]-Ν,Ν,Ν',Ν -tetramethyluron iu m tetrafluoroborate) ; IIDQ (isobutyl l,2-dihydro-2-isobutoxy-l-quinolinecarboxylate); or PyClU (chlorodipyrrolidinocarbenium hexafluorophospliate),

As an alternative to Hiinig’s base (diisopropylcthylaminc), anyone oi the following amine bases can be used: triethylamine; tributylamine; triphenylamine; pyridine; lutidine (2,6-dimethylpyridine); collidine (2,4,6-trimethylpyridine); imidazole; DMAP (4(dimethylamino)pyridine); DABCO (l,4-diazabicyclo|2.2.2]octane); DBU (1,8

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 diazabicyclo[5.4.0]undec-7-ene); DBN (l,5-diazabicyclo[4.3.0]non-5-ene); or proton sponge® (N, Ν,Ν',Ν -tetramethyl-1,8-naphthalenediamine).

General Procedure 2- Conversion of the Ester Product into the Hydrochloride Salt

To a mixture of the ester product in diethyl ether (25 ml per g) was added 2M HC1 in diethyl ether (1.5 equivalents). The mixture was stirred at room temperature for two hours. The solvent was decanted, more diethyl ether added and the solvent decanted again. The remaining mixture was then concentrated in vacuo at 45 °C and further dried in a vacuum oven at 55 °C for 18 hours to give the solid IIC1 salt.

General Procedure 3

To a 100 mL, onc-ncckcd, round-bottomed flask, fitted with a magnetic stirrer and nitrogen inlet/outlet, were added 11 mL of an MTBE solution containing freshly prepared mono-methyl lumaryl chloride (4.9 g, 33 mmol) and 50 mL of additional MTBE at 20 °C. The resulting yellow solution was cooled to &lt;20 °C with an ice water bath. Then, the alcohol, (33 mmol, 1 eq) was added dropwise, via syringe, over approximately 10 minutes. The reaction mixture was allowed to stir at &lt;20 °C for 10 minutes after which time the cooling bath was removed and the reaction was allowed to warm to 20 °C and stir at 20 °C temperature for 16 hours. The reaction was deemed complete by TLC after 16 hours al RT. The reaction mixture was filtered through a medium glass fritted funnel to collect the offwhite solids. The solids were dried in a vacuum oven at 25 °C overnight to afford the final product as an HC1 salt. All alcohols were either commercially available or made following known literature procedures.

General Procedure 4- Alkylation with an Appropriate Alkyl Mesylate

A mixture of monomethyl fumarate (MMF) (1.3 equivalent), the alkyl mesylate (1 equivalent), and potassium carbonate (1.5 equivalent) in acetonitrile (50 ml per g of MMF) was heated at reflux overnight. The mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic phase dried (MgSO.»). Filtration and removal of the solvent under reduced pressure gave the crude product wliich was purified in each case by silica chromatography.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

General Procedure 5- Alkylation with an Appropriate Alkyl Chloride

A mixture of monomethyl fumarate (MMF) (1.3 equivalent), the alkyl chloride (1 equivalent), and potassium carbonate (1.5 equivalent) in acetonitrile or dimetliylforniamide (50 ml per g of MMF) was heated at 20 to 65 ^UC overnight. The mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic phase dried (MgSO₄). Filtration and removal of the solvent under reduced pressure gave the crude product which was further purified by silica chromatography.

Chemical Analvsis/Procedurcs

The NMR spectra described herein were obtained with a Varian 400 MHz NMR spectrometer using standard techniques known in the art.

Examples

Example I (E)-2,2’-((2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)azanediyl)diacetic acid hydrochloride ω

<img file="CA2906580C_D0022.tif" />

co₂h o

To a solution of 2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)ethyl methyl fumarate (2.52 g, 6.2 mmol) in dioxane (25 ml) was added 2MIIC1 in dioxane (30 ml) and the mixture stirred for 90 hours. The precipitate was filtered, washed with diethyl ether and dried in a vacuum oven at 55 Ύ? for 18 hours to give (E)-2,2'-((2-((4-niethoxy-4-oxobut-2enoyl)oxy)ethyl)azanediyl)diacetic acid hydrochloride, a white solid (1.31 g, 65 %).

*H NMR (300 MHz, MeOD): δ 6.87 (2H, dd, J = 16.1 Hz); 4.46-4.53 (2H, m); 4.09 (4H, s); 3.79 (3H, s); 3.57-3.63 (2H, m). [M+H]⁺ = 290.12.

Methyl (2-(methvl(2-(methvlsulfonvl)ethyl)amino)ethvl) fumarate hydrochloride (2)

<img file="CA2906580C_D0023.tif" />

Methyl (2-(N-methylmethylsulfonamido)ethyl) fumarate 2 was synthesized following general procedure 1 and was converted to the HC1 salt methyl (2-(methyl(2(methylsulfonyl)ethyl)amino)ethyl) fumarate hydrochloride (procedure 2) (1.39 g, 95 %).

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 ‘11 NMR (400 MHz, DMSO): 8 11.51 (1H. m); 6.83 (2H, dd, J = 15.8 Hz); 4.48 (1H, bs); 3.24-3.90 (7H, m); 3.07 (3H, s); 2.78 (2H, bs). [M+H]⁺ = 294.09.

2-(dimcthylamino)propyl methyl tumaratc hydrochloride (3)

<img file="CA2906580C_D0024.tif" />

2-(dimelhylamino)propyl methyl fumarate 3 was synthesized following general procedure 1 and was converted to the HC1 salt: 2-(dimcthylamino)propyl methyl tumaratc hydrochloride (procedure 2) (329 mg, 92 %).

*H NMR (300 MHz, DMSO): 5 10.40 (1H. bs); 6.86 (2H, dd, J = 15.8 Hz); 4.25-4.46 (2H, m); 3.71 (3H, s); 3.34 (1H, s); 2.69 (6H s); 1.24 (3H, s). LM+H]⁺ = 216.14.

iE)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N.N.N-trimethylethanaminium iodide (4)

<img file="CA2906580C_D0025.tif" />

o

To a solution of 2-(dimethylamino)ethyl methyl fumarate 19 (760 mg, 3.7 mmol) in diethyl ether (20 ml) was added methyl iodide (246 μΐ, 3.9 mmol). The mixture was stirred at room temperature for 18 hours where a precipitate slowly formed. The mixture was filtered, washed with diethyl ether and dried in a vacuum oven al 55 °C for 18 hours to give (E)-2-((4methoxy-4-oxobut-2-enoyl)oxy)-N.N,N-trimethylethanaminium iodide, a white solid (1.15 g, 90%).

*H NMR (300 MHz, DMSO): δ 6.80 (2H, dd, J = 16.1 Hz); 4.56 (2H, bs); 3.66-3.75 (5H, m); 3.11 (9H, s). |M+HJ* = 216.14.

2-(4,4-difluoror>ir>eridin-l-vl)ethvl methyl fumarate hydrochloride (5)

<img file="CA2906580C_D0026.tif" />

o

2-(4,4-difluoropiperidin-l -yl)ethyl methyl fumarate 5 was synthesized following general procedure 1 and was converted to the HC1 salt: 2-(4,4-difluoropiperidin-l-yl)ethyl methyl fumarate hydrochloride (procedure 2) (780 mg, 87 %).

*H NMR (300 MHz, DMSO): δ 11.25 (1H. bs); 6.84 (2H, dd, J = 16.1 Hz); 4.50 (2H, bs); 3.35-4.00 (8H, m); 3.05-3.30 (2H. m); 2.20-2.45 (3H, s). fM+Hf = 278.16.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

1-(dimethylamino )propan-2-yl methyl fumarate hydrochloride (6)

<img file="CA2906580C_D0027.tif" />

o

1-(dimethylamino )propan-2-yl methyl fumarate 6 was synthesized following general procedure 1 and was converted to the HCI salt l-(dinielhylamino)propan-2-yl methyl fumarate hydrochloride (procedure 2) (690 mg, 72 %).

*H NMR (300 MHz, DMSO): δ 10.41 (1H, bs); 6.80 (2H, dd, J = 15.8 Hz); 5.18-5.33 (1H, m); 3.20-3.55 (2H, m); 3.72 (3H, s); 2.60-2.80 (7H, m); 1.18-1.28 (3H, m). [M+H]⁺ =

216.14.

Methyl (2-thiomorpholinoethyl) fumarate hydrochloride (7)

<img file="CA2906580C_D0028.tif" />

Methyl (2-thiomorpholinoethyl) fumarate 7 was synthesized following general procedure 1 and was converted to lhe HCI salt, methyl (2-thiomorpholinoethyl) fumarate hydrochloride (procedure 2) (623 mg, 93 %).

'Η NMR (300 MHz, DMSO): δ 11.03 (1H, bs); 6.83 (2H. dd, J = 15.6 Hz); 4.50 (2H, s); 3.00-3.80 (11H, m); 2.70-2.80 (2H, m). [M+H]⁺ = 216.14. [M+H]⁺ = 260.11.

Methyl (2-(phenvlamino)ethvl) fumarate hydrochloride (8)

<img file="CA2906580C_D0029.tif" />

Methyl (2-(phenylamino)ethyl) fumarate 8 was synthesized following general procedure 1 and was converted to the HCI salt methyl (2-(phenylamino)ethyl) fumarate hydrochloride (procedure 2) (1.80 g, quantitative).

*H NMR (300 MHz, DMSO): δ 6.50-6.80 (9H, m); 4.29 (2H, t, 4.4 Hz); 3.72 (3H, s);

3.45 (2H, t, J = 4.5 Hz). fM+H]⁺ = 250.13.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

2-(dimethylamino)-2-methylpropyl methyl fumarate hydrochloride (9)

<img file="CA2906580C_D0030.tif" />

2-(dimethylamino)-2-methylpropyl methyl fumarate 9 was synthesized following general procedure 1 and was converted to the HC1 salt, 2-(dimethylamino)-2-methylpropyl methyl fumarate hydrochloride (procedure 2) (883 mg, 76 %).

'H NMR (300 MHz, DMSO): 8 10.20 (1H, bs); 6.91 (2H, dd, J = 15.6 Hz); 4.29 (2H, s); 3.73 (3H, s); 2.57-2.80 (6H, m); 1.32 (6H, s). [M+Hf = 230.16.

Methyl (2-(methylsulfonyl)ethyl) fumarate (10)

Methyl (2-(methylsulfonyl)ethyl) fumarate 10 was synthesized following general procedure 1 and (1.01 g, 37 %).

*H NMR (400 MHz, CDClj): δ 6.88 (2H, dd, .1 = 16.0 Hz); 4.66 (2H, t, J = 5.8 Hz);

3.82 (3H, s); 3.38 (2H, t, J = 6.0 Hz); 2.99 (3H, s). fM+H]⁺ = 236.97.

2-(l.l-dioxidothiomoroholino)ethyl methyl fumarate hydrochloride (11)

<img file="CA2906580C_D0031.tif" />

o

2-(1,l-dioxidolhiomorpholino)elhyl methyl fumarate 11 was synthesized following general procedure 1 and was converted to the HC1 salt 2-(1,1-dioxidothiomorpholino)ethyl methyl fumarate hydrochloride (procedure 2) (1.33 g, 87 %).

Ή NMR (400 MHz, DMSO): 8 6.79 (2H, dd, J = 15.8 Hz); 4.34 (2H, bs); 3.72 (4H, s); 2.90-3.70 (11H, m). IM+HJ⁺ = 292.11.

Methyl (2-(methyl(r>henvl)amino)ethvl) fumarate hydrochloride (12)

<img file="CA2906580C_D0032.tif" />

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

Methyl (2-(methyl(phenyl)amino)ethyl) fumarate 12 was synthesized following general procedure 1 and was converted to the HCI salt methyl (2(mcthyl(phcnyl)amino)cthyl) fumarate hydrochloride (procedure 2) (1.76 g, 97 %).

'H NMR (400 MHz, DMSO): δ 6.72-7.40 (5H, m); 6.64 (2H. dd, J = 16.0 Hz); 4.27 (2H, s); 3.70 (5H, s); 2.97 (3H, s). [M+H]⁺ = 264.14.

2-(benzyl(methyl)amino)ethyl methyl fumarate hydrochloride (13)

2-(benzyl(methyl)amino)ethyl methyl fumarate 13 was synthesized following general procedure 1 and was converted to the HCI salt 2-(benzyl(methyl)amino)ethyl methyl fumarate hydrochloride (procedure 2) (2.70 g, 96 %).

*H NMR (400 MHz, DMSO): δ 10.65 (1H, bs); 7.39-7.60 (5H, m); 6.82 (2H, dd, J =

15.8 Hz); 4.20-4.60 (4H, m); 3.73 (3H, s); 3.27-3.50 (2H, m); 2.69 (3H, s). [Μ+ΗΓ = 278.16.

2-(2.5-dioxopynOlidin-l-yDcthyl methyl fumarate (14)

2-(2,5-dioxopyrrolidin-1 -yl)ethyl methyl fumarate 14 was synthesized following general procedure 1 (1.03 g, 35 %).

'H NMR (400 MHz, DMSO): δ 6.81 (2H, dd, J = 15.8 Hz); 4.36 (2H, t, J = 5.3 Hz);

3.84 (2H, l, J = 5.1 Hz); 3.80 (3H, s); 2.73 (4H, s). [M+H]⁺ = 256.07.

Methyl (2-(piperidin-l-yl)ethvl) fumarate hydrochloride (15)

HCI

Methyl (2-(piperidin-1 -yl)ethyl) fumarate hydrochloride 15 was synthesized following general procedure 3.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401 ‘11 NMR (400 MHz, DMS0-d6) δ 10.76 (s, 1H), 6.94 - 6.77 (m, 2H), 4.58 - 4.51 (m,

2H), 3.76 (s, 3H), 3.48 - 3.36 (m, 4H), 2.94 (dddd, J= 15.9,12.1,9.2,4.4 Hz, 2H), 1.91 1.64 (m, 5H), 1.37 (dtt, J= 16.4,11.3,4.9 Hz, 1H). [M+H]⁺ = 241.93.

Methyl (2-morpholinoethvl) fumarate hydrochloride (16)

<img file="CA2906580C_D0033.tif" />

Methyl (2-morpholinoethyl) fumarate hydrochloride 16 was synthesized following general procedure 3.

*11 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 6.92 (d, J = 15.9 Hz, 1H), 6.82 (d, J = 15.9 Hz, 1H), 4.60 - 4.52 (m, 2H), 4.00 - 3.77 (m, 6H), 3.76 (s, 3H), 3.22 - 3.04 (m, 4H). [M+H]⁺ = 244.00.

2-(l,4-dioxa-8-azaspiro[4.51decan-8-vl)ethvl methyl fumarate hydrochloride (17)

<img file="CA2906580C_D0034.tif" />

O

<img file="CA2906580C_D0035.tif" />

O

HCI

2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl methyl fumarate hydrochloride 17 was synthesized following general procedure 3.

*11 NMR (400 MHz, DMSO-d6) δ 11.26 (s, III), 6.91 (d, J= 15.9 Hz, 111), 6.82 (d, J = 15.9 Hz, 1H), 4.58 - 4.51 (m, 2H), 3.93 (s, 4H), 3.76 (s, 3H), 3.57 - 3.43 (m, 4H), 3.22 3.03 (in, 2H), 2.20 - 2.02 (in, 2H), 1.89 - 1.79 (in, 2H). [M+H]⁺ = 300.00.

Methvl (2-(Dyrrolidin-l-vl)ethvl) fumarate hydrochloride (18)

<img file="CA2906580C_D0036.tif" />

O

Methyl (2-(pyrrolidin-l -yl)ethyl) fumarate hydrochloride 18 was synthesized following general procedure 3.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 *H NMR (400 MHz, DMS0-d6) δ 11.12 (s, 1H), 6.94 (d, J= 15.8 Hz, 1H), 6.82 (d, J = 15.8 Hz. 1H), 4.53 - 4.46 (m, 2H), 3.76 (s, 3H), 3.61 - 3.45 (m, 4H), 3.11 - 2.94 (m, 2H), 2.06 - 1.79 (in. 4H). [M+H]⁺ = 228.46.

2-(dimethvlamino)ethvl methyl fumarate hydrochloride (19)

<img file="CA2906580C_D0037.tif" />

2-(dimethylamino)ethyi methyl fumarate hydrochloride 19 was synthesized following general procedure 3.

*H NMR (500 MHz, DMS0-d6) δ 10.87 (s, 1H), 6.93 (d, J= 15.9 Hz, 1H), 6.80 (d, J = 15.9 Hz, 1H), 4.53 - 4.45 (m, 2H), 3.75 (s, 3H), 3.44 - 3.38 (m, 2H), 2.77 (s, 5H). [M+H]⁺= 201.84.

2-(dicthylamino)cthyl methyl fumarate hydrochloride (20)

<img file="CA2906580C_D0038.tif" />

HCI

2-(diethylamino)ethyl methyl fumarate hydrochloride 20 was synthesized following general procedure 3.

'H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 6.90 (d, J= 15.8 Hz, 1H), 6.81 (d, J = 15.9 Hz. Ill), 4.56 - 4.48 (m, 211), 3.76 (s, 3Π), 3.48 - 3.38 (m, 211), 3.15 (qq, J=9.7,5.5, 4.9 Hz, 4H), 1.24 (t, J= 7.3 Hz, 6H). [M+H]⁺ = 230.59.

2-(3,3-difluoropyrrolidin-l-yl)ethyl methyl fumarate hydrochloride (21)

HCI

<img file="CA2906580C_D0039.tif" />

2-(3,3-Difluoropyrrolidin-l-yl)ethyl methyl fumarate 21 was synthesised from 2-(3,3difluoropyrrolidin-l-yl)ethanol following general procedure 1.

2-(3,3-difluoropyrrolidin-l-yl)ethyl methyl fumarate was converted to 2-(3,3difluoropyrrolidin-l-yl)elhyl methyl fumarate hydrochloride following general procedure 2 (0.55 g, 69 %).

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 *H NMR (300 MHz, DMSO); 8 6.79 (2H, d); 4.20-4.39 (2H, m), 3.81 (2H, t), 3.66 (3H, s), 3.53-3.65 (4H, m), 2.54 (2H, sep). m/z [M+H]⁺ = 264.14.

2-(bis(2-mcthoxycthyl)amino)cthyl methyl fumarate hydrochloride (24)

<img file="CA2906580C_D0040.tif" />

O-.

2-(Bis(2-methoxyethyl)amino)ethyl methyl fumarate 24 was synthesised from 2(bis(2-mcthoxycthyl)amino)cthanol following general procedure 1.

2-(Bis(2-methoxyethyl)amino)ethyl methyl fumarate was converted to 2-(bis(2methoxyethyl)amino)ethyl methyl fumarate hydrochloride following general procedure 2 (1.00 g, 27%).

'H NMR (300 MHz, DMSO); 8 12.84 (1H. br s), 6.90 (2H, d), 4.73 (2H, t), 3.92 (4H, t), 3.81 (3H, s), 3.62 (2H, br s), 3.51-3.36 (4H, m), 3.34 (6H, s). m/z [M+H]⁺ = 290.12.

2-(2.4-Dioxo-3-azabicyclo[3.1.01hexan-3-yl)ethyl methyl fumarate (22)

O

<img file="CA2906580C_D0041.tif" />

o

3-oxabicyclo[3.1.0]hexane-2,4-dione (1.0 g, 8-9 mmol) and ethanolamine (545 mg, 8.9 mmol) were heated neat at 200 °C for 2 hours. The crude reaction mixture was purified by silica chromatography (EtOAc) giving 3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexane2,4-dionc (1.06 g. 77%).

'H NMR (300 MHz, CDC1₃): 8 3.71 (2H, t), 3.56 (2H, t), 2.51 (2H, dd), 1.95 (1H, br s), 1.59-1.43 (2H, m).

<img file="CA2906580C_D0042.tif" />

2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)ethyl methyl fumarate 22 was synthesised from 3-(2-Hydroxyethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione following general procedure 1 (452 mg, 53 %).

*H NMR (300 MHz, CDClj): 8 6.81 (2H, d), 4.28 (2H, t), 3.80 (3H, s), 3.69 (2H, t),

2.48 (2H. dd), 1.59-1.49 (1H. m), 1.44-1.38 (1H, m). m/z |M+HJ⁺ = 268.11.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

2-(2,2-Dimethyl-5-oxopyrrolidin-l-vl)ethyl methyl fumarate (24)

<img file="CA2906580C_D0043.tif" />

Tert-butyl acrylate (19.7 mL, 134.8 mmol) was added dropwise over 10 minutes to a refluxing solution of 2-nitropropane and Triton B (40% in methanol) (440 pL) in ethanol (50 mL). The reaction was heated at reflux overnight. The reaction solvent was removed under reduced pressure giving a crude residue tliat was dissolved in etlianol (200 mL) and hydrogenated overnight (300 psi) using Raney nickel (approximately 15 g). The reaction was filtered through celite. The solvent was removed under reduced pressure giving tert-butyl 4amino-4-methylpentanoate (15.82 g, 63% yield).

*H NMR (300 MHz, CDC1₃): δ 2.26 (2H, t), 1.65 (2H, t), 1.43 (9H, s), 1.68 (6H, s).

<img file="CA2906580C_D0044.tif" />

To a solution of tert-butyl 4-amino-4-methylpentanoate (3.0 g, 16.04 mmol) in methanol (100 mL) was added chloroacetaldehyde (45% in fLO) (6.7 mL, 38.4 mmol) followed by acetic acid (2 mL, 35.0 mmol). After 1.5 hours sodium cyanoborohydride (1.51 g, 24.0 mmol) was added and the mixture stirred at room temperature for 3 hours. The reaction was partitioned between saturated aqueous sodium hydrogen carbonate (100 mL) and dichloromethane (300 mL). The organic phase was dried (MgSCh). Filtration and removal of the solvent under reduced pressure gave tert-butyl 4-((2-chloroethyl)amino)-4methylpentanoate (3.90 g, 98% yield).

*11 NMR (300 MHz, CDC1₃): δ 3.63 (211, t), 2.85 (211, t), 2.24 (211, t), 1.67 (211, t), 1,44 (9H,s), 1.07 (6H,s).

<img file="CA2906580C_D0045.tif" />

A mixture of tert-butyl 4-((2-chloroethyl)amino)-4-methylpentanoate (3.9 g, 15.7 mmol) and trifluoroacetic acid (27 mL) in dichloromethane (80 mL) were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in furtlrer dichlorometliane and concentrated again. This was repeated a further 3 times until the majority of the excess trifluoroacetic acid had been removed. The residue was dissolved in dichloromethane (500 mL) and N-(3-Dimethylaminopropyl)-N'

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 ethylcarbodiimide hydrochloride (4.61 g, 24.1 mmol), hydroxybenzotriazole hydrate (3.25 g, 24.1 mmol) and diisopropylethylamine (21 mL, 120 mmol) added. The mixture was stirred at room temperature overnight. Tire reaction was washed with water (300 mL) and dried (MgSO₄). Filtration and removal of the solvent under reduced pressure gave a crude residue that was purified by silica chromatography (heptane to ethyl acetate) giving 1-(2chloroethyl)-5,5-dimethylpyrrol idin-2-one (1.24 g, 44% yield).

'H NMR (300 MHz, CDC13): δ 3.61 (2H, t), 3.41 (2H, t), 2.38 (2H, t), 1.88 (2H, t),

1.24 (6H,s).

2-(2,2-Dimethyl-5-oxopyrrolidin-l-yl)ethyl methyl fumarate 24 was synthesised from l-(2-chloroelhyl)-5,5-dimelhylpyrrolidin-2-one following general procedure 5 (1.02 g, 41 %).

*H NMR (300 MHz, CDCh); 6.85 (2H, d), 4.33 (2H, t), 3.80 (3H, s), 3.41 (2H, t),

2.39 (2H, t), 1.88 (2H, t), 1.23 (6H, s). m/z [M+H]⁺ = 270.17.

(E)-4-(2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)morDholine4-oxide (26)

To a solution of methyl (2-morpholinoethyl) fumarate (1.1 g, 4.5 mmol) [synthesised from 4-(2-chloroethyl)morpholine following general procedure 5] in dichloromethane was added m-chloroperbenzoic acid (1.87 g, 5.4 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was diluted with water (25 mL) and washed with dichloromethane (3 x 50 mL). Tire aqueous phase was lyophilized giving (E)-4-(2-((4-methoxy-4-oxobut-2enoyl)oxy)ethyl)morpholine 4-oxide 26 (0.19 g, 16 %).

*H NMR (300 MHz, CDCh); 6.87 (1H, d), 6.81 (1H, d), 4.92-4.88 (2H, M), 4.44 (2H,

t), 3.78-3.73 (2H, m), 3.54-3.48 (2H, m), 3.34 (2H, t), 3.15 (2H, d). m/z [M-i-Hf = 260.2

2-(3.5-dioxomorpholino)ethyl methyl fumarate (27)

HO.

To a solution of diglycolic anhydride (2.0 g, 17 mmol) in pyridine (10 mL) was added elhanolamine (2.1 g, 34 mmol) and healed al reflux for 2 h. The volatiles were removed in

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 vacuo and the residue heated at 180 °C for 2 h and then 220 °C for 90 min. The reaction mixture was cooled and the residue purified on silica eluting with dichloromethane/ethyl acetate (4:1) giving 4-(2-hydroxyethyl)morpholine-3,5-dione (1.05 g, 38%).

*11 NMR (300 MHz, CDCh); 4.39 (4H, s), 4.02 (2H, t), 3.80 (2H, t).

2-(3,5-dioxomorpholino)ethyl methyl fumarate 27 was synthesised from 4-(2hydroxyethyl)morpholine-3,5-dione following general procedure 1 (0.82 g, 96%).

*H NMR (300 MHz, CDC1₃); 6.83 (1H, d), 6.75 (1H, d), 4.39-4.43 (6H, m), 4.12 (2H, t), 3.79 (3H, s).

2-(2^-dimelhylmorpholinoklhyl methyl fumarate hydrochloride (281

Cl

To a solution of 2.2-dimethylmorpholine (1.0 g, 8.7 mmol) in dichloromethane (35 mL) was added chloroacetaldehyde (50% in water, 1.65 mL, 13.0 mmol), followed by sodium triacetoxyborohydride (2.8 g, 13 .0 mmol). The reaction mixture was stirred for 90 min, diluted with 1 M aqueous sodium hydroxide (40 mL) and the organic phase separated. The aqueous phase was extracted with dichloromethane (2 x 30 mL) and the organic phases combined. After being dried over MgSO₄ the volatiles were removed in vacuo giving 4-(2chloroethyl)-2,2-dimethylmorpholine (1.45 g, 94%).

'H NMR (300 MHz, CDCh); 3.73 (2H ,dd), 3.55 (2H, t), 2.64 (2H, t), 2.43 (2H, dd),

2.25 (2H, s), 1.24 (6H,s).

HCI

2-(2,2-Dimethylmorpholino)ethyl methyl fumarate 28 was synthesised from 4-(2chloroethy 1)-2,2-dimethyl morpholine following general procedure 5 (0.71 g, 93%).

4-(2-chloroethyl)-2,2-dimethylmorpholine was converted to 4-(2-chloroethyl)-2,2dimethylmorpholine hydrochloride following general procedure 2 (0.69 g, 87 %).

'H NMR (300 MHz, CDCh); 6.85 (1H, d), 6.77 (1H, d), 4.52-4.47 (2H, m), 3.93-3.85 (2H, m), 3.70 (3H, s), 3.48-3.43 (2H, m), 3.32-3.00 (4H, m), 1.24 (6H, s). m/z. [M+H]⁺ =

272.2

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

2-(2,6-dimethylmorpholino)ethvl methyl fumarate hydrochloride (29)

<img file="CA2906580C_D0046.tif" />

To a solution of 2,6-diniethylmorpholine (1.0 g, 9.0 mmol) in dichloromethane (40 mL) was added chloroacctaldchydc (50% in water, 1.02 mL, 13.5 mmol) and acetic acid (0.75 mL, 13.5 mmol) followed by sodium triacetoxyborohydride (2.8 g, 13.5 mmol). The reaction mixture was stirred for 4 h, diluted with dichloromethane (20 ml.) and washed with saturated aqueous sodium hydrogen carbonate (30 mL). The organic phase separated, dried over M2SO4 the volatiles were removed in vacuo. The residue was further purified by silica chromatography eluting with heptanes/ethyl acetate (1:1) giving 4-(2-chloroethyl)-2,6dimethylmorpholine (0.44 g, 30%).

*H NMR (300 MHz, CDCI3); 3.75-3.62 (2H, m), 3.58 (2H, t), 2.65-2.79 (4H, m), 1.83 (2H, t), 1.15 (6H, d).

<img file="CA2906580C_D0047.tif" />

2-(2,6-dimethylmorpholino)ethyl methyl fumarate 29 was synthesised from 4-(2chloroethyl)-2,6-dimethylmorpholine following general procedure 5 (0.54 g, 71%). 2-(2,6-dimethylmorpholino)ethyl methyl fumarate was converted to 2-(2,6dimethylmorpholino)ethyl methyl fumarate hydrochloride following general procedure 2 (0.19 g, 64 %).

'H NMR (300 MHz, CTX1₃); 6.83 (1H, d), 6.75 (1H, d), 4.47-4.43 (2H, m), 3.93-3.82 (2H, m), 3.67 (3H, s), 3.46-3.40 (2H, m), 2.72 (2H, l), 1.10 (6H, d). m/z [M+H]⁺ = 272.2

Methyl (2-(3-oxomorpholino)ethvl) fumarate (30)

O

<img file="CA2906580C_D0048.tif" />

A mixture of potassium iert-butoxidc (5.9 g, 52.3 mmol) and toluene (50 mL) was heated at 75 °C for 30 min and then diethanolamine (5.0 g, 47.6 mmol) added. The reaction mixture was heated a further 30 min and then methyl chloroacetate (4.4 mL, 50.0 mmol)

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401 added. After a further 2 h heating the reaction was diluted with methanol (21 mL) and cooled to room temperature. The reaction mixture was filtered, washed with toluene and the mother liquor evaporated. The residue was further purified by silica flash column chromatography giving 4-(2-hydroxycthyl)morpholin-3-onc (0.65 g, 9%).

*H NMR (300 MHz, CDC1₃); 4.19 (2H, s), 3.89 (2H, t), 3.81 (2H, t), 3.57 (2H, t), 3.48 (2H, t), 2.89 (lH,s).

Methyl (2-(3-oxomorpholino)ethyl) fumarate 30 was synthesised from 4-(2hydroxyethyl)morpholin-3-one following general procedure 1 (0.71 g, 62%).

'H NMR (300 MHz, DMSO); 6.72 (2H, s), 4.28 (2H, t), 3.98 (2H, s), 3.77 (2H, I),

3.71 (3H, t), 3.59 (2H, t), 3.38 (2H, t). m/z [M+H]⁺ = 258.1

Methyl (2-(2-oxomorpholino)ethvl) fumarate hydrochloride (31)

Methyl (2-(2-oxomorpholino)ethyl) fumarate 31 was synthesised from 4-(2hydroxyethyl)morpholin-2-one following general procedure 1 (0.53 g, 34%).

Methyl (2-(2-oxomorpholino)ethyl) fumarate was converted to methyl (2-(2oxomorpholino)ethyl) fumarate hydrochloride following general procedure 2 (0.20 g, 34%).

*11 NMR (300 MHz, DMSO); 3.75 (211, s). 4.29-4.23 (411, m), 3.71 (311, s), 3.34 (211, s), 2.73 (2H, t), 2.68 (2H, t). m/z [M+H]⁺ = 258.15

2-(8-Oxa-3-azabicycloi3.2.11octan-3-yl)cthyl methyl fumarate hydrochloride (32)

O HCI

2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate 32 was synthesised from 3-(2-chloroethyl)-8-oxa-3-azabicyclo|3.2.1Joctane following general procedure 5 (0.25 g, 50%).

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate was converted to 2-(8-oxa-3azabicyclo[3.2.1]octan-3-yl)ethyl methyl fumarate hydrochloride following general procedure 2 (0.20 g, 73%).

*H NMR (300 MHz, D>O); 6.82 (1H, d), 6.75 (1H, d), 4.52-4.42 (4H, m), 3.69 (3H, s), 3.45-3.37 (4H, m), 3.26-3.19 (2H, m), 2.10-1.85 (4H, m). m/z [M+H]⁺ = 270.0

2-(2-((Dimethylamino)methyl)morpholino)ethyl methyl fumarate hydrochloride (33)

O HO

2-(2-((Dimelhylamino)melhyl)morpholino)elhyl methyl fumarate 33 was synthesised from 1-(4-(2-chloroethyl)morpholin-2-yl)-N,N-dimethyimethanamine following general procedure 5 (0.17 g, 16%).

2-(2-((Dimethylamino)methyl)niorpholino)ethyl methyl fumarate was converted to 2(2-((Dimethylamino)methyl)morpholino)ethyi methyl fumarate hydrochloride following general procedure 2 (0.17 g, 95%).

*H NMR (300 MHz, D₂O); 6.84 (1H, d), 6.77 (1H, d), 4.50-4.45 (2H. m), 4.21-4.06 (2H, m), 3.87-3.77 (1H, m), 3.68 (3H, s), 3.56-3.47 (2H, m), 3.25-3.09 (3H, m), 2.94 (1H, dd), 2.81 (6H, bs). m/z [M+H]⁺ = 301.2

2-((3S.5S)-3.5-DimethvlmorDholino)ethyl methyl lumarate hydrochloride (34) .0

2-((3S.5S)-3.5-Dimethylmorpholino)ethyl methyl fumarate 34 was synthesised from (3S,5S)-4-(2-chloroethyl)-3,5-dimethylmorpholine following general procedure 5 (0.11 g, 25%).

2-((3S.5S)-3.5-Dimethylmorpholino)ethyl methyl fumarate was converted to 2-((3S,5S)-3,5dimethylmorpholino)ethyl methyl fumarate hydrochloride following general procedure 2 (0.08 g, 68%).

'H NMR (300 MHz, D₂O); 7.15-7.00 (2H, m), 4.77-4.70 (2H, m), 4.20-4.08 (2H, m), 4.01-3.85 (8H, m), 3.68-3.58 (1H, m). m/z [M+H]⁺ = 272.3

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

2-(2.5-Dioxomorpholino)ethyl methyl fumarate (35)

<img file="CA2906580C_D0049.tif" />

2-(2,5-Dioxomorpholino)ethyl methyl fumarate 35 was synthesised from 4-(2hydroxyethyl)morpholine-2,5-dione following general procedure 1 (0.27 g, 65%). '11 NMR (300 MHz, DMSO); 6.75 (1H, d), 6.71 (1H, d), 4.72 (2H, s), 4.30 (2H, s), 4.26 (2H, t), 3.72 (3H, s), 3.60 (2H, t). m/z [M+H]⁺ = 272.2 (E)-Methvi 3-(4-methvl-2.5.7-trioxabicvclof2.2.2k>ctan-l-vl)acrvlate (130)

<img file="CA2906580C_D0050.tif" />

Methyl ((3-methyloxetan-3-yl)methyl) fumarate was synthesised from 3-methyl3oxetane methanol following general procedure 1 (0.86 g, 89%).

*11 NMR (300 MHz, CDCI₃); 6.88 (2H, s), 4.52 (2H, d), 4.40 (2H, d), 4.30 (2H, s), 3.82 (3H,s), 1.35 (3H,s).

<img file="CA2906580C_D0051.tif" />

To a solution of methyl ((3-methyloxetan-3-yl)iiiethyl) fumarate 130 (0.20 g, 0.93 mmol) in dichloromethane (5 mL) at 5 °C was added borontrifluoride diethyletherate (0.058 mL. 0.47 mmol). After 1 h a further portion of boronlrifluoride dielhylelherale (0.058 mL, 0.47 mmol) was added and the reaction mixture warmed to 20 °C over Ih. To the reaction mixture was added triethylamine (0.13 mL, 0.93 mmol) and then this was loaded directly onto a silica column. Tlie desired product was eluted with heptane/ethyl acetate (6:4) containing triethylamine (2.5% v/v) giving (E)-methyl 3-(4-methyl-2,5,7trioxabicyclo[2.2.2]octan-l-yl)acrylate (0.12 g, 60%).

'H NMR (300 MHz, CDCh); 6.66 (IH, d), 6.25 (IH, d), 3.97 (6H. s), 3.73 (3H, s), 0.84 (3H, s). m/z [M+Hf = 215.2

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<img file="CA2906580C_D0052.tif" />

Methyl prop-2-yn-l-yl fumarate (131)

Methyl prop-2-yn-l-yl fumarate 131 was synthesized from propargyl alcohol following general procedure 1 (0.51 g. 68%).

*H NMR (300 MHz, DMSO); 6.85-6.70 (2H, m), 4.81 (2H, d), 3.72 (3H, s), 3.60 ( 1H, t).

2-(l,3-Dioxoisoindolin-2-yl)ethyl methyl fumarate (36)

<img file="CA2906580C_D0053.tif" />

2-(l,3-Dioxoisoindolin-2-yl)ethyl methyl fumarate 36 was synthesised from 2-(2hydroxyethyl)isoindoline-l,3-dione following general procedure 1 (0.63 g, 79%).

*H NMR (300 MHz, McOD); 7.87-7.77 (4H, m), 6.74-6.73 (2H, m), 4.454.40 (2H, m), 4.01-3.96 (2H, m), 3.76 (3H, s). m/z [M+H]⁺ = 304.1

4-(2.5-Dioxopyrrolidin-l-yl)butyl methyl fumarate (132)

<img file="CA2906580C_D0054.tif" />

4-(2,5-Dioxopyrrolidin-l-yl)butyl methyl fumarate 132 was synthesised from 1-(4hydroxybutyl)pyrrolidine-2,5 -dione following general procedure 1 (0.77 g, 79%).

'H NMR (300 MHz, MeOD); 6.81-6.79 (2H, m), 4.20 (2H, t), 3.78 (3H, s), 3.50 (2H, t), 2.67 (4H, s), 1.71-1.62 (4H, m). m/z [M+H]⁺ = 284.2

2-(3,3-Dimethyl-2.5-dioxopyrrolidin-l-yl)ethyl methyl fumarate (36)

<img file="CA2906580C_D0055.tif" />

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

2-(3,3-Dimethyl-2,5-dioxopyrrolidin-l-yl)ethyl methyl fumarate 36 was synthesised from l-(2-hydroxyethyl)-3,3-dimethylpyrrolidine-2,5-dione following general procedure 1 (0.72 g, 74%).

‘11 NMR (300 MHz, CDCh); 6.83 (1H, d), 6.77 (1H, d), 4.38 (2H, t), 3.82 (1II. t),

3.80 (3H, s), 2.55 (2H, s), 1.31 (6H, s). mJz [M+H]* = 284.1

3-(2.5-Dioxopyrrolidin-l-yl)propyl methyl fumarate (133)

<img file="CA2906580C_D0056.tif" />

3-(2,5-Dioxopyrrolidin-l-yl)propyl methyl fumarate 133 was synthesised from 1-(3hydroxypropyl)pyrrolidine-2,5-dione following general procedure 1 (0.64 g, 69%).

'H NMR (300 MHz, McOD); 6.82 (2H, s), 4.17 (2H, t), 3.79 (3H, s), 3.59 (2H, t),

2.67 (4H, s), 1.95 (2H, dt). m/z [M+H]⁺ = 270.2

Methyl (2-(2-oxopvnrolidin-l-vl)ethvl) fumarate (38)

<img file="CA2906580C_D0057.tif" />

Methyl (2-(2-oxopyrrolidin-l-yl)ethyl) fumarate 38 was synthesised from 1-(2hydroxyethyl)pyrrolidin-2-one following general procedure 1 (0.68 g, 73%).

*H NMR (300 MHz, McOD); 6.85 (2H, s), 4.33 (2H, t), 3.80 (3H, s), 3.59 (2H, t),

3.46 (2H, t), 2.37 (2H, t), 2.03 (2H, dt). [M+H]* = 242.1

Methyl (2-(2-oxooxazolidin-3-yl)ethyl) fumarate (39)

<img file="CA2906580C_D0058.tif" />

Methyl (2-(2-oxooxazolidin-3-yl)ethyl) fumarate 39 was synthesised from 3-(2hydroxyethyl)oxazolidin-2-one following general procedure 1 (0.77 g, 92%).

'H NMR (300 MHz, MeOD); 6.82 (2H, s), 4.39-4.30 (4H, m), 3.78 (3H, s), 3.72-3.67 (2H, m), 3.58-3.54 (2H, m). m!z [M+H]* = 244.2

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

2-(4.4-Diniethvl-2.5-dioxoimidazolidin-l-vl')ethvl methyl fumarate (42)

<img file="CA2906580C_D0059.tif" />

2-(4,4-Dimethyl-2,5-dioxoimidazolidin-l-yl)ethyl methyl fumarate 42 was synthesised from 3-(2-hydroxyethyl)-5,5-dimethylimidazolidine-2,4-dione following general procedure 1 (0.33 g, 33%).

*H NMR (300 MHz, CDCh); 6.82 (2H, s), 5.50 (NH), 4.40 (2H, t), 3.86-3.76 (5H, m),

1.43 (6H, s). m/z [M+H]⁺ = 285.2

Methyl (2-(N-propionylpropionamido)ethyl) fumarate (42)

<img file="CA2906580C_D0060.tif" />

Methyl (2-propionamidoethyl) fumarate 41 was synthesised from N-(2hydroxyethyOpropionamide following general procedure 1 (1.7 g, 96%).

Ml NMR (300 MHz, CDC10; 6.87 (211, s), 4.29 (211, t), 3.81 (311, s), 3.58 (211, q), 2.21 (211, q),1.15(3H, t).

<img file="CA2906580C_D0061.tif" />

A mixture of methyl (2-propionamidoethyl) fumarate (1.7 g, 7.4 mmol), propionic anhydride (36 mL) and sodium propionate (1.0 g, 10.4 mmol) was heated at 150 °C for 16 h. The reaction was cooled, concentrated to l/3^r&lt;l volume and then loaded onto a silica column and eluted with 0-20% ethyl acetate/dichloromethane. The product containing fractions were combined, evaporated and re-purified by silica flash chromatography eluting with 10-50% ethyl acetate/heptanes giving methyl (2-(N-propionylpropionamido)ethyl) fumarate 42 (0.18 g, 21%).

*H NMR (300 MHz, CDC1₃); 6.83-6.82 (2H, m), 4.34 (2H, t), 4.01 (2H, t), 3.81 (3H, s), 2.75 (4H,q), 1.16 (6H, t).

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

2-((3R.4S)-3.4-Dimethyl-2.5-dioxopyrrolidin-l-yl)ethyl methyl fumarate (23)

<img file="CA2906580C_D0062.tif" />

Racemic 2-((3R,4S)-3,4-dimethyl-2,5-dioxopyrrolidin-l-yl)ethyl methyl fumarate 23 was synthesised from racemic (3R,4S)-l-(2-hydroxyethyl)-3,4-dimethylpyrrolidine-2,5-dione following general procedure 1 (0.54 g. 44%).

'll NMR (300 MHz, CDC1₃); 6.81-6.80 (211, m), 4.37 (211, t), 3.82 &lt;211, t), 3.80 (3IL s), 3.00-2.88 (2H, m), 1.25-1.18 (6H, m). m/z [M+H]⁺ = 284.2

2-Acetamidoethyl methyl fumarate (43)

<img file="CA2906580C_D0063.tif" />

2-Acetamidoethyl methyl fumarate was synthesised from N-(2hydroxyethyl)acetamide 43 following general procedure 1 (0.23 g, 70%).

‘H NMR (300 MHz, CDC1₃); 6.87 (2H, s), 5.80 (NH), 4.29 (2H, t), 3.81 (3H, s), 3.57 (2H, q), 2.00 (3H, s). m/z [M+H]* = 216.14

2-(N-Acetylacetamidolethyl methyl fumarate (44)

<img file="CA2906580C_D0064.tif" />

A mixture of 2-acctamidocthyl methyl iumaratc (0.62 g, 2.9 mmol), acetic anhydride (15 mL) and sodium acetate (0.33 g, 4.0 mmol) was heated at reflux for 20 h. The reaction mixture was evaporated and the residue suspended in dichloromethane. The supernatant was loaded onto a silica column and eluted with 0-205 ethyl acetate/dichloromethane giving 2-(NAcetylacetamido)ethyl methyl fumarate 44 (0.36 g, 48%).

'H NMR (300 MHz, CDCI3); 6.87 (1H, d), 6.82 (1H, d), 4.36 (2H,d), 4.00 (2H, d), 3.81 (3H, s), 2.44 (3H, s).

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

2-(to/-butoxvcarbonvl')amino')ethvl methyl fumarate (48)

<img file="CA2906580C_D0065.tif" />

To a suspension of monomethyl fumarate (MMF) (1.0 equivalent) in dichloromethane (11 mL per g of MMF) was added diisopropylethylamine (3 equivalents), 2-((/&lt;?r/butoxylcarbonyl)amino)ethanol (1.02 equivalents) and A/,jV,/V',A/-tetramethyl-O-(lWbenzotriazol-l-yl)uronium tetrafluoroborate (1.5 equivalents). The reaction was stirred for 118 hours at &lt;10 °C. The reaction was quenched with 1M hydrochloric acid (0.6 mL/niL of DCM). The organic layer was washed with 10% (w/w) aqueous sodium bicarbonate solution (0.6 mL/mL of DCM) followed by 37% (w/w) sodium chloride solution (0.6 mL/mL of DCM). The organic layer was dried over sodium sulfate, filtered to remove the drying agent, and the solution added to a silica plug (-6 g of silica eel/g of MMF) and the plug flushed with DCM until no more product eluted. -80% of the DCM was removed under reduced pressure at 30 °C after which time 25 mL of MTBE/g of MMF were added and the solution further concentrated at 30 °C until -10 mL/g of MMF remained. The resulting suspension was cooled to 5 °C for at least 1 hour and then tire resulting solids were collected by filtration to give the desired MMF ester prodrug. (3-8 g, 91 %).

'H NMR (400 MHz, DMS0-&lt;/«) δ 7.08 (t, J = 5.4 Hz, IH), 6.89 (d, J = 15.8 Hz, IH), 6.79 (d, J = 15.8 Hz, IH), 4.18 (t, .1 = 5.3 Hz, 2H), 3.81 (s, 3H), 3.28 (q, J = 5.4 Hz, 2H), 1.43 (s, 9H). m/z [M+H]+ = 274.3.

2-(2.5-dioxo-2.5-dihydro-l//-pyrrol-l-yl)ethyl methyl fumarate (55)

<img file="CA2906580C_D0066.tif" />

To a suspension of monomethyl fumarate (MMF) (1.0 equivalent) in dichloromethane (11 ml per g of MMF) was added diisopropylethylamine (3 equivalents), the desired alcohol (1.02 equivalents) and /V,/V,/V'_>iV'-tetraniethyl-0-(l//-henzotriaznl-1-yl)uroniuni tetrafluoroborate ( 1.5 equivalents). The reaction was stirred for 1-18 hours at <10 °C. The reaction was quenched with IM hydrochloric acid (0.6 mL/mL of DCM). The organic layer was washed with 10% (w/w) aqueous sodium bicarbonate solution (0.6 mL/mL of DCM) followed by 37% (w/w) sodium chloride solution (0.6 mL/mL of DCM). The organic layer was dried over sodium sulfate, Tillered to remove lhe drying agent, and lhe solution added to a silica plug (-6 g of silica gel/g of MMF) and the plug flushed with DCM until no more

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401 product eluted. -80% of the DCM was removed under reduced pressure at 30 °C after which time 25 mL of MTBE/g of MMF were added and the solution further concentrated at 30 °C until -10 mL/g of MMF remained. The resulting suspension was cooled to 5 °C for at least 1 hour and then the resulting solids were collected by filtration to give the desired MMF ester prodrug. (2.4 g, 67 %).

*H NMR (400 MHz, Chloroform-J) δ 6.82 (d, J = 2.8 Hz, 2H), 6.74 (s, 2H), 4.36 (t, J = 5.3 Hz, 2H), 3.86 (t, J = 5.3 Hz, 2H), 3.81 (s, 3H). m/z fM+H]+ = 254.2.

Reference Compound A

2-(diethvlamino)-2-oxoethvl methyl fumarate

<img file="CA2906580C_D0067.tif" />

2-(diethylamino)-2-oxoethyl methyl fumarate was synthesized following general procedure 3 and conformed to reported data in US Patent No. 8,148,414.

Example 2- Aqueous Chemical Stability of Several Compounds

Stock solutions of the compounds in acetonitrile or acetonitrile/methanol were prepared at 20 mg/mL and 20 pL, spiked into 3mL of buffer phosphate (lOOmM) and incubated at 37 °C. Aliquots (50 pL) were sampled at different time points and diluted 20 fold with ammonium formate (pH 3.5)/acetonitrile. The diluted samples were analyzed by HPLC. The peak areas corresponding to the compounds were plotted against time and the data were fitted to a first-order mono-exponential decay where the rate constant and the halflife were determined (Table 3). In some cases, in which the half life is too long (>360min), an estimated value of the half life is reported using the initial slope at low conversion (<10%).

Table 3.

<td> Compound</td><td> pH 8 (t min)</td>

<td> 1</td><td> 15</td>

<td> 4</td><td> 45</td>

<td> 5</td><td> 24</td>

<td> 6</td><td> 2.0</td>

<td> 7</td><td> 26.0</td>

<td> 8</td><td> 36.0</td>

<td> 9</td><td> 7.0</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

<td> Compound</td><td> pH 8 (t ‘A, min)</td>

<td> 10</td><td> 67.0</td>

<td> 11</td><td> &gt;240</td>

<td> 12</td><td> 396</td>

<td> 14</td><td> 144</td>

<td> 15</td><td> 3.0</td>

<td> 16</td><td> 20.0</td>

<td> 17</td><td> 11.0</td>

<td> 18</td><td> 5.0</td>

<td> 19</td><td> 6.0</td>

<td> 20</td><td> 5.0</td>

<td> Reference Compound A</td><td> 120</td>

Stock solutions of the compounds in acetonitrile or acetonitrile/MeOH were prepared at 0.05M. A 0.010 mL aliquot of the stock was spiked into 1 mL of 50 mM buffer phosphate pH 8 and incubated at 37 °C. Typically, aliquots (0.010 mL) were sampled at different time points and immediately injected in the HPLC with 1IV detection (211 nm). The peak areas corresponding to the compounds were plotted against time and the data were fitted to a firstorder mono-exponential decay where the rate constant and the half-life were determined from the slope (Tabic 4).

Table 4.

<td> Compound</td><td> pH 8 (t */2, min)</td>

<td> 1</td><td> 15</td>

<td> 4</td><td> 30</td>

<td> 5</td><td> 24</td>

<td> 6</td><td> 2</td>

<td> 19</td><td> 117</td>

<td> 22</td><td> 144</td>

<td> 23</td><td> 186</td>

<td> 26</td><td> 129</td>

<td> 27</td><td> 37</td>

<td> 28</td><td> &lt;10</td>

<td> 29</td><td> &lt;10</td>

<td> 30</td><td> 229</td>

<td> 31</td><td> 26</td>

<td> 32</td><td> 13</td>

<td> 33</td><td> 115</td>

<td> 35</td><td></td>

<td> 37</td><td> 182</td>

<td> 38</td><td> 201</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

<td> Compound</td><td> pH 8 (t */2, min)</td>

<td> 39</td><td> 183</td>

<td> 40</td><td> 203</td>

<td> 42</td><td> 158</td>

<td> 43</td><td> 177.5</td>

<td> 44</td><td> 145</td>

<td> 48</td><td> 220</td>

<td> 130</td><td> 1010</td>

<td> 131</td><td> 96</td>

<td> 133</td><td> 246</td>

Example 3- Evaluation of Aqueous Chemical Stability with NMR

The chemical hydrolysis was followed by dissolving the ester in phosphate buffered D>O (pH 7.9) in an NMR lube, healing the NMR lube to 37° C and periodically recording the spectra. These various species produced by hydrolysis of the dicstcrs were followed over time. See Figures 1-5.

Example 4- Delivery of MMF in Rats Upon Oral Administration of Prodrugs

Rats were obtained commercially and were pre-cannulated in the jugular vein. Animals were conscious at the time of the experiment. All animals were fasted overnight and until 4 hours post-dosing of a prodrug in the disclosure.

Blood samples (0.25 mL/sample) were collected from all animals at different timepoints up to 24 hours post-dose into tubes containing sodium fluoride/sodium EDTA. Samples were centrifuged to obtain plasma. Plasma samples were transferred to plain tubes and stored at or below -70° C prior to analysis.

To prepare analysis standards, 20 uL of rat plasma standard was quenched with 60 uL of internal standard. The sample tubes were vortexed for at least 1 min and (hen centrifuged at 3000 rpm for 10 min. 50 uL of supernatant was then transferred to 96-well plates containing 100 pL water for analysis by LC-MS-MS.

LC-MS/MS analysis was performed using an API 4000 equipped with HPLC and autosampler. The following HPLC column conditions were used: HPLC column: Waters Atlantis T3; flow rate 0.5 mL/min; run time 5 min; mobile phase A: 0.1% formic acid in waler; mobile phase B: 0.1% formic acid in acetonitrile (ACN); gradient: 98% A/2% B al 0.0 min; 98% A/2% B at 1 min; 5% A/95% B at 3 min; 5% A/95% B at 3.75 nun; 97% A/3% B at 4 min; and 98% A/2% B at 5.0 min. MMF was monitored in positive ion mode.

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

MMF, DMF or MMF prodrug was administered by oral gavage to groups of two to six adult male Sprague-Dawley rats (about 250 g). Animals were conscious at the time of the experiment. MMF, DMF or MMF prodrug was orally administered in an aqueous solution of 0.5% hydroxypropyl methyl cellulose (HPMC), 0.02% polysorbate 80, and 20 mM citrate buffer (pH 5), at a dose of 10 mg-equivalents MMF per kg body weight.

The percent absolute bioavailability (F%) of MMF was determined by comparing the area under the MMF concentration vs time curve (AUC) following oral administration of MMF, DMF or MMF prodrug with the AUC of the MMF concentration vs time curve following intravenous administration of MMF on a dose normalized basis.

The MMF prodrugs, when administered orally to rats at a dose of 10 mg/kg MMFequivalenls in the aqueous vehicle, exhibited an absolute oral bioavailabilily (relative to IV) ranging from about 3% to about 96% (See Tables 5 and 6). Tables 5 and 6 show data from two independent studies.

Table 5.

<td> Compound No.</td><td> Percent Absolute Bioavailabilily (F%)</td>

<td> MMF</td><td> 43%</td>

<td> DMF</td><td> 53%</td>

<td> 16</td><td> 60-82%</td>

<td> 4</td><td> 3%</td>

<td> 14</td><td> 96%</td>

<td> 10</td><td> 73%</td>

Table 6.

<td> Compound No.</td><td> Percent Absolute Bioavailability (F%)</td>

<td> MMF</td><td> 69.6</td>

<td> DMF</td><td> 69.6</td>

<td> 132</td><td> 60.3</td>

<td> 40</td><td> 70.4</td>

<td> 39</td><td> 91.4</td>

<td> 5</td><td> 81.1</td>

<td> 11</td><td> 71.4</td>

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

Example 5- Delivery of MMF in Dogs Upon Oral Administration of Prodrugs

Male Beagle dogs were obtained from the test facility's colony of non-native animals. All animals were fasted overnight prior to dose administration.

Oral doses were administered via oral gavage. The gavage tube was flushed with 10 mL of water prior to removal.

All animals were observed at dosing and at each scheduled collection. All abnormalities were recorded.

Blood samples were collected in Sodium Huoride/Na₂FDTA tubes and stored on wet ice until processed to plasma by centrifugation (300 rpm at 5oC) within 30 minutes of collection. All plasma samples were transferred into separate 96-well plates (matrix tubes) and stored al -80 °C until concentration analysis was performed via LC/MS/MS using an RGA 3 assay.

Extraction Procedure:

Note: Thawed test samples at 4*C. (Kept in ice while on bench).

1. Aliquoted 20uL of study sample, standard, and QC samples into labeled 96-well plate.

2. Added 120uL of appropriate internal standard solution (125ng/mL mouse embryo fibroblasts (MEF)) to each tube, except for the double blank to which 120uL of appropriate acelonilrile:FA (100:1) was added.

3. Sealed and vortexed for one minute.

4. Centrifuged at 3000 rpm for 10 minutes.

5. Transferred lOOuL of supernatant to a clean 96-well plate containing lOOuL water.

6. Sealed and vortexed gently for 2 minutes.

The percent absolute bioavailability (F%) of MMF was determined by comparing the area under the MMF concentration vs time curve (AUC) following oral administration of MMF prodrug with the AUC of the MMF concentration vs time curve following intravenous administration of MMF on a dose normalized basis.

The MMF prodrugs, when administered orally to dogs at a dose of 10 mg/kg MMFequivalents in the aqueous vehicle, exhibited an absolute oral bioavailability (relative to IV) ranging from about 31% to about 78% (See Table 7).

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LS2014/027401

Table?

<td> Compound No.</td><td> Percent Absolute Bioavailability (F%)</td>

<td> 16</td><td> 54%</td>

<td> 16 (capsule)</td><td> 54%</td>

<td> 14</td><td> 78%</td>

<td> 10</td><td> 31%</td>

Example 6- Physical Stability of the Instant Prodrugs and DMF in Crystalline Form

The physical stability of compounds of the present invention and DMF were measured via tliermogravimetric analysis (TGA). Figure 6 shows a plot of weight loss at 60 °C vs time for Compound 14 (12.15 mg), no change, and DMF (18.40 mg), ~100 % weight loss in less than 4 hours. These data indicate that DMF undergoes sublimation while Compound 14 is physically stable under similar conditions.

Example 7- Single Crystal X-ray Data for Compound 14

Compound 14 produced by the method described in Example 1 was analyzed. Figure 7 depicts the unit cell. The single crystal x-ray data are included below:

Single crystal data:

Empirical formula: Cl 1 Hl 3 N 06

Formula weight: 255.22

Temperature: 173(2) K

Wavelength: 1.54178 A

Space group: P-1

Unit cell dimensions: a = 6.07750(10) Â b = 7.96290(10) A c = 12.7850(2) Â op 84.9390(10)°.

β= 80.0440(10)°.

= 71.9690(10)°

Volume: 579.080(15) A3

Z: 2

Density (calculated): 1.464 Mg/m3

Absorption coefficient: 1.034 mm’’

F(000): 268

Crystal size: 0.37 x 0.15 x 0.15 mm3

Reflections collected: 8446

CA 02906580 2015-09-1«

WO 2014/152494

PCT/LÎS2014/027401

Independent reflections: 2229 [R(int) = 0.0249] Refinement method: Full-matrix least-squares on Goodness-of-fit on :1.049

Final R indices [I>2sigma(I)] Rl = 0.0317, wR2 = 0.0850

R indices (all data): R1 = 0.0334, wR2 = 0.0864

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: