Prodrugs of fumarates and their use in treating various deseases.

(54) Title: DRUG PROMARKETS AND THEIR USE IN THE TREATMENT OF DIFFERENT DISEASES. (54) Title: PRODRUGS OF FUMARATES AND THEIR USE IN TREATING VARIOUS DESEASES.

(57) Summary

The present invention provides the compounds of formula (I), and their pharmaceutically acceptable salts.

(57) Abstract

The present invention provides compounds of formula (I), and pharmaceutical compositions thereof.

ΙΜΡΙ £

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PATENT TITLE No. 356368

Owner (s): ALKERMES PHARMA IRELAND LIMITED

Address: Coñnaught House 1 Burlington Road, Dublln, IRELAND

Denomination:

Classification:

Inventor (s):

DRUGS OF DRUGS AND THEIR USE IN THE TREATMENT OF DIFFERENT DISEASES.

CIP: C07C219 / 08; A61K31 / 221; pC7C22q / 12; C07C229 / 16; C07C309 / 18

CPC: CO7C219 / 08? A61K31 / 225; 'C07¿22í9 / ^ 6; C07C233 / 18; C07C233 / 91;

C07C317 / 18; C07C317 / 28; 0070207 /) 6: C07D207 / 40; C07D209 / 52;

C07D211 / 06; CO7D2 £ 1Z3 £ O0¡ ^ 95 / O88; C07Í049J / 113

TARij-K Á. ZEIDAN ;, SQpT *

ANDREW WYNN; CARLQSN ^

Number:

MX / a / 2015/011897

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-, ν · Λ \

K-St · s • C ^^ JOPHéR ^. HENCKEN; THOMAS «4,

Country:

US US

Validity: Twenty years

Expiration Date: 14 ngaizgde 2034 Issue Date: 2§ * $ e „p | Éiyo

The patent of referencst ^ LKKga with fundame ^ "B ^ jMt¿jlos''l⁰, H fqpc || iWfe °

In accordance with article MJP'Ú the LeyWfc Ftopiedl ^ ndíStHSSíWfliftilnte pátmpfc as of the date of present ^^ ¿ete «3licidad inteen &amp; BieBato these? SLUSÍ? f pfe &amp; nijsúi ri based^{* 1} injpc ^ la ^ articulas'. · ........... v '„:

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thematic:

Number:

61 / 782,445 61 / 9ÍÍ365

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Who subscribes to this title is »(Official Gazette of the Federation (EE € LF :)»

25/01/2006, 06/05/2009,06/01 /2010,’^®^

Regulations of the Mexican Institute of articles 1, 3, 4, 5, section V, subsection a),

12/27/1999, amended on 10/10/2002, 07/29/20 *

Deputy Generals, Coordinator, Directors DiVf ^ fotóf # s_t^ Departmental and other subordinates of the Mexican Institute of 04/08/2004 and 09/13/2007).

reformed the

0, ^ 8 / 065¾) ^ ¾¾) 1 2 ítoflad ladustaal “fracdSM ^ iiinüabaa ^ Íal f stgti s DIVf

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59 ^ 59 dejjaíeyde fd ^ fcílMtUndustrial.

jjnyvigjSalfrde velr * áBejÚ extendable, counted to iBWramener vtoenftsRs rights.

i *. ¹ ’*

6 ° fraCC¡ones lll y'TRbis ^ of the Industrial Property Law 994, jfe / 1 affSÉfc 26/12 / MV, 999, 01/26/2004, 06/16/2005,

Y2012Í) atfáculoe1 3fr «tQ ij &amp; so a). 4th and 12th sections I and lll of * WorrnaíegÍ0l / iwro0awe / 07/2004, 07/28/2004 and 09/07/2007);

ite ^ lMexrcano of Industrial Property (DOF Agreement that delegates powers to the Directors is, Divisional Deputy Directors. Coordinators F. 12/15/1999, amended on 02/04/2000, 07/29/2004,

<img file="MX356368B_D0005.tif" />

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THE DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

<img file="MX356368B_D0006.tif" />

Onginal Chain;

NAHANNY MARISOL CANAL REYES | 00001000000403252793 | Trlbutar¡a Administration Service | 1695 || MX / 2018/43777 | MX / a / 2015/011897 | PCT patent title | 1220 | RRGO | Page (s) | jkeT3oVxy + bLlxUvYJZN0Vuav1 E =

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<img file="MX356368B_D0007.tif" />

MX / 2018/43777

3S6368

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DRUG DRUGS AND THEIR USE IN ...

DIFFERENT ILLNESSES - = RELATED REQUESTS

This application claims the priority of the United States provisional patent application with number 61 / 782,445, filed on March 14, 2013, and the United States provisional patent applications with number 61 / 934,365, filed on March 31, 2013. January 2014, the content of which has been incorporated in full in this document by reference.

FIELD OF THE INVENTION

The present invention relates to various monomethyl fumarate prodrugs. In particular, the present invention relates to monomethyl fumarate derivatives that offer improved properties over dlmetllo fumarate. The invention also relates to methods of treating different diseases.

BACKGROUND OF THE INVENTION

Fumaric acid esters (FAE) are licensed in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and their use has been proposed in the treatment of a wide range Immune, autoimmune and inflammatory diseases and ailments.

The use of AEDs and other fumaric acid derivatives has been proposed to treat a wide variety of diseases and conditions involving

IMPIAS.

immunological, autoimmune, and / or Th'ftáOíerioSS ^ K ^ endo processes of psoriasis (Joshi and Strebel, document WO 1993240858; on the patent'tfe ~ los

United States 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111 (1),

43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary disease (Joshi et al, WO 2005/023241 and US 2007/0027076); heart failure including left ventricular failure, 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, retinopathy pigmentosa, and encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, US Patent No. 6,509,376 , U.S. Patent No. 6,858,750, and U.S. Patent No. 7,157,423); transplant (Joshi and Strebel, WO 2002/055063, US 2006/0205659, United States Patent No. 6,359,003, United States Patent No. 6,509,376, and United States Patent No. 7,157 .423; and in Lehmann et al. Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Patent No.

6,509,376, U.S. Patent No. 7,157,423, and US Document

2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, document

WO 1998/52549 and in US Patent No. 6,436,992; Went and

Lieberburg, US 2008/0089896; Schimrigk et al., EurJ Neurology 2006,

13, 604-610; and in Schilling et al., Clin Experimental Ii

rL

<img file="MX356368B_D0009.tif" />

1oi107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); age-induced genomic damage (Heidland, WO 2005/027899;

inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (NUsson et al, WO 2006/037342 and Nilsson and MuUer, WO 2007/042034).

Fumaderm®, an enteric-coated tablet containing a mixture of monoethyl fumarate and diethyl fumarate (DMF) salts that rapidly hydrolyzes to monoethyl fumarate, considered to be the main bioactive metabolite, was licensed in Germany in 1994 for treatment of psoriasis. Fumaderm® is dosed three times a day, administering 1-2 grams / day for the treatment of psoriasis. Fumaderm® shows a high degree of variability between patients in regards to the absorption of the drug and the food reduces bioavailability in a significant way. Absorption is believed to occur in the small intestine, and peak levels are reached

5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Cl / n Expt'l Dermatology 2007, 32, 246-49; and in Hoefnagel et al, Br J Dermatology 2003, 149, 363-369 ). Side effects of current AED treatments include gastrointestinal problems including nausea, vomiting, diarrhea and / or transient skin irritation.

Multiple sclerosis (MS) is an autoimmune condition where autoimmune activity is directed against central nervous system (CNS) antigens. The

IMPI disease is characterized by inflammation of the country ^^^. S ^ jq

INDUSTRIAL

<img file="MX356368B_D0010.tif" />

in the loss of the myelin sheaths that surround the neuronal axons (gradual demyelination), axonal loss, and the eventual death of neurons, oligodendrocytes, and glial cells.

Dimethyl fumarate (DMF) is the therapeutic principle of the experimental drug BG-12, studied for the treatment of relapsing-remitting MS (RRMS). In a Phase IIb RRMS study, BG-12 significantly reduced gadolinium-enhanced brain injury. In preclinical studies, DMF administration has been shown to inhibit CNS inflammation in murine and rat EAE. DMF has also been found to inhibit astrogliosis and microglial activations associated with EAE. See, for example, US patent application published number 2012/0165404.

There are four main clinical types of MS: 1) MS with relapse-remission (RRMS), characterized by clearly defined relapses with complete recovery or with sequelae or residual deficit after recovery; periods between relapses of the disease characterized by a lack of evolution of the disease; 2) Secondary progressive MS (SPMS), characterized by an initial course of remission with relapse followed by evolution with or without occasional relapses, minor remissions, and plateaus; 3) primary progressive MS (PPMS), characterized by an evolution of the disease from the beginning with occasional plateaus and minor temporary improvements allowed; and 4) MS with

<img file="MX356368B_D0011.tif" />

IMPI

1NSTIT1JTO MEXICANO j progressive relapse (PRMS, for its acronym in ^ e ^^^ Mrs progressive disease with acute relapses niaras. With or without nn-a complete rooupcrpción, periods between relapses characterized by a continuous progression.

From a clinical point of view, the disease very often presents as a relapse-remission disease and, to a lesser extent, as a continued progression of neurological disability. Relapsing-remitting MS (RRMS) occurs in the form of recurrent attacks of focal and multifocal neurological dysfunction. Attacks can take place, remit, and recur, spreading randomly over many years. Remission 10 is frequently incomplete and one attack follows another, a progressive staggered loss leads to a permanent increasing neurological deficit. The usual course of RRMS is characterized by repeated relapses in most patients, with the eventual onset of disease progression. The subsequent course of the disease is unpredictable, although most patients with relapsing-remitting disease will eventually develop secondary progressive disease. In the relapse-remission phase, alternate relapses with periods of clinical inactivity that may or may not be marked by sequelae depending on the presence of neuronal deficits between episodes. The periods between relapses, during the relapse phase20 remissions, are clinically stable. On the other hand, patients with progressive MS show a stationary increase in deficits, as defined above, either from the beginning or after a period of episodes, but this designation does not prevent the further appearance of new relapses.

Understanding the above, dimethyl fumarate JaJ ^^ Já ^^ pS ^ jcon

KSTITU'rn MEXICANO

OF THE. PROPERTY C significant drawbacks. Industrial — For example, diniéttlo fumarate OCaWfíeT is known to have secondary effects after oral administration, such as irritation and gastrointestinal events including nausea, diarrhea, and / or upper abdominal pain in subjects. See, for example, Gold et al, N. Eng. J. Med., 2012, 367 (12), 10981107. Dalmetl fumarate is dosed twice daily or three times daily, with a total daily dose of about 480 mg to about 1 gram or more.

Furthermore, in the use of a drug for long-term treatment it is desirable that the drug be formulated in a manner that is suitable for administration once or twice a day to aid patient compliance. A dosing frequency of once a day is even more desirable.

Another problem with long-term treatment is the requirement to determine an optimal dose that the patient can tolerate. IF said dose is not determined, this may lead to a decrease in the efficacy of the administered drug.

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

It is a further object of the present invention to provide the use of a pharmaceutical active ingredient in a manner that enables a tolerable steady state level to be achieved for the drug with which the subject is treated.

MFI «STinrR: MEXICANO

Due to the disadvantages of dlmetlItf ^ J ^ TOeRlt ^^ was fumarate, there is still a need to decrease the fr^Qriionüla dt do^and¡Ficanión. minor side effects and / or improve the physicochemical properties associated with DMF. Therefore, there continues to be a real need in the treatment of neurological disorders, such as MS, for a product that maintains the pharmacological advantages of DMF but overcomes its drawbacks of formulation and / or adverse effects after its administration. The present invention addresses these needs.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 graphically depicts the hydrolysis of Compound 16 at pH

7.9, 25 ° C, showing the vinyl ruler, as observed by NMR for 90 minutes.

Figure 2 graphically depicts the hydrolysis of Compound 16 at pH

7.9, 25 ° C, showing the vinyl region, as observed by NMR for 19 hours.

Figure 3 graphically depicts the hydrolysis of Compound 16 at pH

7.9, 25 ° C, showing the allphalic ruler, as observed by NMR for 19 hours.

Figure 4 graphically depicts the hydrolysis of Compound 20 reference A at pH 7.9, 37 ° C, showing the vinyl ruler, as observed by NMR for 15 hours.

Figure 5 graphically depicts the hydrolysis of Reference Compound A at pH 7.9, 37 ° C, showing the allphatic rule, as seen (3.3.

by NMR for 15 hours.

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

Figure 6 graphically depicts the loss of pean cnn pI time for Compound 14 and DMF.

Figure 7 graphically depicts the unit crystal cell for Compound 14.

SUMMARY OF THE INVENTION

The present 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 (eg, aminoalkyl prodrugs) of monomethyl fumarate (MMF). The methods and compositions provide a therapeutically effective amount of an active moiety in a subject for a period of time of at least about 8 hours to at least about 24 hours.

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

The present invention provides, in part, a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

<img file="MX356368B_D0012.tif" />

O ^^Lto,

NOT

IMPI

INSTITUTO MEXICANO DS LA PROPIEDAD INDUSTWAL

<img file="MX356368B_D0013.tif" />

where:

R-ι is Ci-C alkyl₆ not substituted;

L_to is a Ci-C alkyl linker₆ substituted or unsubstituted; carbocycle C₃5 C₁₀ substituted or unsubstituted, aryl C₆-C₁₀ substituted or unsubstituted, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 14 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; and

R2 and R3 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, C2-C alkenyl.₆ substituted or unsubstituted, C2-C alkynyl₆ substituted or unsubstituted, aryl C₆-Ci₀ substituted or unsubstituted, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl which it comprises one or two 5- or 6-membered rings and 14 heteroatoms selected from N, O 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

<img file="MX356368B_D0014.tif" />

5- or 6-membered rings and 1-4 selected heteroatoms_te &lt;nfre N; Oy &lt;O a

OE PROPERTY C '/

INDUSTRIAL 'substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S. The present invention also provides pharmaceutical compositions comprising one or more compounds of any of the described formulas herein and one or more pharmaceutically acceptable carriers.

The present invention also provides methods of treating a neurological disease, administering to a subject in need a therapeutically effective amount of a compound of any of the formulas described herein, or a salt, polymorph, hydrate, solvate, or co-cr It is pharmaceutically acceptable in the same way that said disease is treated.

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

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

MEXICAN INSTITUTE

The present invention also provides me ^ oáW ^ feraiít ^ iíáB ^ ja Secondary Progressive Multiple Sclerosis (SPMS) by administering to a subject χμΐ £. It is required by a therapeutically effective amount of a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof such that multiple sclerosis is treated.

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

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

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

IMPI

<img file="MX356368B_D0015.tif" />

Alzheimer's.

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

The present invention also provides compounds and compositions that allow for improved oral, controlled or sustained release formulations. Specifically, dimethyl fumarate is administered two or three times a day for the treatment of relapsed-remission multiple sclerosis. On the contrary, the compounds and compositions of the present invention can allow formulations with a modified duration of their therapeutic efficacy to reduce relapse rates in subjects with multiple sclerosis. For example, the present compounds and compositions provide therapeutically effective amounts of monomethyl fumarate in subjects for at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 20 hours, or at least about 24 hours.

The present invention also provides compounds, compositions, and methods that can result in a decrease in side effects upon administration to a subject relative to dimethyl fumarate. For example, gastric irritation and skin irritation are known side effects of oral administration of dimethyl fumarate in

IMPI

ΙΝίΤΓΠΠΌ MEXICAN Dt LA PÍOPIfcPAL?

<img file="MX356368B_D0016.tif" />

some subjects. Compounds, compositions and méWéfó'á¹· Of the present invention may be used in subjects who have had or are in danger of experiencing such side effects.

The present invention also provides compounds and compositions that show improved physical stability with respect to dimethyl fumarate. Specifically, dimethyl fumarate is known to be known in the art for undergoing sublimation under ambient and elevated temperature conditions. The compounds of the invention have greater physical stability than dimethyl fumarate under controlled conditions of temperature and relative humidity. Specifically, in one embodiment, the compounds of the formulas described herein show less sublimation with respect to dimethyl fumarate.

In addition, dimethyl fumarate is also known to be a contact irritant, See, eg, DMF Safety Data Sheet. In one embodiment, the compounds of the present invention show reduced contact irritation compared to dimethyl fumarate. For example, the compounds of the formulas described herein show reduced contact irritation compared to dimethyl fumarate.

The present invention also provides compounds and compositions that show less effect of the food with respect to dimethyl fumarate. The bioavailability of dimethyl fumarate is known to be reduced when administered together with food. Specifically, in one embodiment, the compounds of the formulas described herein show a lower feed effect relative to the fumarate of

FROM THE PROPERTY 'NDV5TJUAL

<img file="MX356368B_D0017.tif" />

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by a person ordinarily skilled in the art to which the present invention belongs. In the specification, singular forms include plurals unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. It is not accepted that the references cited herein belong to the prior art of the claimed invention. In case of conflict, the present descriptive memory, including the definitions, will have preeminence. Furthermore, 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 from the claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds and methods for treating a neurological disease by administering a compound of Formula (I), (la), (Ib), (II), (III), or (IV), synthetic methods for prepare a compound of Formula (I), (la), (Ib), (II), (III), or (IV), and pharmaceutical compositions containing a compound of Formula (I), (la), (Ib) , (II), (III), or (IV).

ΪΜΡΙ

<img file="MX356368B_D0018.tif" />

I,. .,. ,.,.^W5T1J1T^C lissican,.

The present invention also provides compound ^ and p ^ jetqjgi ^, treatment of psoriasis by administering to a subject-g · <=> in nenfiftphta a therapeutically effective amount of a compound of Formula (I), (la), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

The present invention provides, in part, methods of treating a neurological disease by administering to a subject in need a therapeutically effective amount of a compound of Formula (I), (la), (Ib), (II), (III), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof. The neurological disease may be multiple sclerosis. The present invention further provides the use of a compound of Formula (I), (la), (Ib), (II), (III), or (IV), or a salt, polymorph, hydrate, solvate, or co-crystal pharmaceutically acceptable thereof in the preparation of a medicament useful for the treatment of a neurological disease.

In accordance with the present invention, a neurological disease is a disorder of the brain, spine, or nerves of a subject. In one embodiment, the neurological disease is characterized by a demyelination, or degeneration of the myelin sheath, of the central nervous system. The myelin sheath facilitates the transmission of nerve impulses through a nerve fiber or axon. In another embodiment, neurological disease is selected from the group consisting of multiple sclerosis, Alzheimer's disease, cerebral palsy, spinal cord injury, amyotrophic lateral sclerosis (ALS), stroke, Huntington's disease, Parkinson's disease, optic neuritis Devic's disease

<img file="MX356368B_D0019.tif" />

<img file="MX356368B_D0020.tif" />

Transverse myelitis, disseminated encephalomyelitis agEtdán / B / JKéf anos and adrenomyeloneuropathy, Acute inflammatory demyelinating polyneuropathy (AIDP), Chronic inflammatory demyelinating polyneuropathy (CIDP), Acute myelitis, progressive multifocal leukoencephalopathy (PML), Acute encephalitis (encephalomyelitis and other hereditary disorders, such as leukodystrophies, Leber's optic atrophy, and Charcot-Marle-Tooth disease. In some embodiments, the neurological disorder is an autoimmune disease. In one embodiment, the neurological disease is multiple sclerosis. In another embodiment, the neurological disorder is stroke. In another embodiment, the neurological disorder is Alzheimer's disease. In another embodiment, the neurological disorder is cerebral palsy. In another embodiment, the neurological disease is injury to the spine. In another embodiment, the neurological disease is ALS. In another embodiment, the neurological disorder is Huntington's disease. See, eg, US Patent No. 8,007,826, W02005 / 099701 and W02004 / 082684, which have been incorporated by reference in their entirety.

In a further embodiment, the present invention provides methods for treating a disease or symptom of a disease described herein by administering to a subject in need a therapeutically effective amount of a compound of Formula (I), (la) , (Ib), (II), (lll), or (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof. The present invention further provides the use of a compound of Formula (I), (la), (Ib), (II), (lll), or (IV), or a salt, polymorph, hydrate, solvate or co17

<img file="MX356368B_D0021.tif" />

IMPI

INSTTTMTO MEXICAM. '

Dt LA HUWJAl '_ __ pharmaceutically acceptable crystal thereof, for I ^^ Vé'paraciÓnde a medicament useful for the treatment of an enitíllllédád or a symptom or 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-crystal thereof or a method of treating a neurological disease by administering to a subject in need an amount therapeutically effective compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

R₂

<img file="MX356368B_D0022.tif" />

Rl (i);

where;

Ríes Ci-C alkyl₆ not substituted;

L_to is a Ci-C alkyl linker₆ substituted or unsubstituted; substituted or unsubstituted C3C10 carbocycle, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 14 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl which it comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; and

<img file="MX356368B_D0023.tif" />

ΛΡ1

MEXICANI INSTITUTE

R2 and R3 are each, independently, H, substituted ^ SS ^ s alkynyl, substituted or unsubstituted C2-C6 alkenyl, unsubstituted or substituted alqttwite-C ^ Cb, substituted or unsubstituted C6-C10 aryl, C3-C10 carbocycle substituted or unsubstituted, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered 5-rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 14 heteroatoms selected from N, O 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 10 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S.

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

Ríes Ci-C alkyl₆ not substituted;

L_to is a Ci-C alkyl linker₆ unsubstituted, unsubstituted C3-C10 carbocycle, unsubstituted C6-C10 aryl, unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 20 1-4 heteroatoms selected from N, O and S; and

R₂ and R3 are each, independently, H, Ci-C alkyl₆, alkenyl C₂C₆, aryl C₆-Cio, C3-C10 carbocycle, heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl

<img file="MX356368B_D0024.tif" />

Atoms comprising one or two 5 or 6 m rings selected from N, O and S, where the aigniin aigiianiin aryl, carbocieip, heterocycle, or heteroaryl groups may be optionally independently substituted one or more times with C1-C3 alkyl, OH, O (C1-C4 alkyl), carbonyl, halo,

-NH₂, N (H) (Ci-C alkyl₆), N (Ci-C alkyl₆) 2, SO₂H, SO₂(Ci-C alkyl₆), CHO,

CO₂H, CO₂(Ci-C alkyl₆), or CN;

or alternatively R₂ and R₃, together with the nitrogen atom to which they are attached, form a heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; or a heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, where the heteroaryl or heterocycle may optionally be substituted one or more times with Ci-C alkyl₆, CN, OH, halo, O (Οι-Οβ alkyl), CHO, carbonyl, thione, NO or NH₂.

In one embodiment of this aspect, at least one of Ri and R₂ it's H.

In another embodiment of this aspect. L_to is (CH₂)₂.

In another embodiment of Formula (I), R₂ and R₃ together with the nitrogen atom to which they are attached they form a heteroaryl, where the heteroaryl ring is a pyrrole ring, a pyrazole ring, an imidazole ring, a benzimidazole ring, a thiazole ring, a ring of 1 / 7-1,2,4-triazole, a 1H20 1,2,3-triazole ring, a 1H-tetrazole ring, a pyrimidinone ring, an indole ring, or a benzoisothiazole ring, where all rings can be optionally substituted one or more times with CiC alkyl₆, CN, OH, O (alkyl Ο-ι-Οθ), CHO,

NOT₂, or NH₂.

In yet another embodiment of Formula (I), R₂ and

IMPI

INDUSTRIAL nitrogen to which they are attached form a heterocycle, where the heterocycle is a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2,5-dihydropyridine ring, a 1,2-dihydropyridine ring, a piperazine, a succinimide ring, an isoindoline ring, a 2,5-dihydro-1/7-tetrazole ring, an azetidine ring, a piperidine ring, a hexahydropyrimidine ring, a 2,3,3a ring , 4,7,7a-hexahydro-1 / - / - 4,7-epoxyisoindole, 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 / - / - imidazol-2-one, an imidizolidine thione ring, or an isothiazolidine ring, where all rings can be optionally substituted one or more times with Ci-C alkyl₆, CO₂(Ci-C alkyl₆), OH, (CH₂) i-4OH, O (alkyl C C₆), halo, -NH₂, (CH₂) i.₄NH₂, (CH₂)_MNH (C1-C4 alkyl) (CH₂)₁.₄NH (alkyl C_rC₄)₂, carbonyl, or tione.

In one embodiment of Formula (I),

Ries C1-C3 unsubstituted alkyl;

L_to is (CH₂) i.₆. and

R₂ and R₃ they are each independently: H, methyl, ethyl, isopropyl, butyl, tere-butyl, cyclohexyl, cyclohexenyl, phenyl, benzyl, benzodioxol, pyridinyl, (CH₂)₂N (CH₃)₂, (CH₂)₃SW₂H, (CH₂)₂SW₂Me, 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 by Ci-C alkyl₄, carbonyl, or (CH₂) i.₃N (Ci-C alkyl₄)₂; a ring of n 8-oxa-321

IMPI

<img file="MX356368B_D0025.tif" />

azabicyclo [3.2.1] octane; a ring of 1,4-d¡oxa-8-azaspirc5 / f4í5Idéfcáód) q¡> ring of

INDUSTRIAL thiomorpholine 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 by C1-C4 alkyl or carbonyl; a 2,5-dihydroplrrol ring optionally substituted one or more times by C1-C4 alkyl or carbonyl; a succinimide ring optionally substituted one or more times by C1-C4 alkyl, a 3azabicyclo [3.1.0] hexane-2,4-done ring; a hexahldroplrlmldin ring optionally substituted one or more times by C1-C4 alkyl or carbonyl; a pyrimidone ring optionally substituted one or more times by alkyl a pyrrole ring optionally substituted one or more times by alkyl CrC4, halo, C (O) NH₂, or not₂; a pyrazole ring optionally substituted one or more times by C1-C4 alkyl, C (O) NH₂, or not₂; an imidazole ring optionally substituted one or more times by C1-C4 alkyl or NO₂; a 1,3-d¡h¡dro-2 / - / - im¡dazol-2one ring; a benzimidazole ring; a thiazole ring; a carbonyl-substituted isoindollna ring; a 1 / - / - tetrazole ring; a thione substituted 1H 2,5-dihydro-1 Htetrazole ring; a 1 / - / - 1,2,4-triazole ring; a 1 / 7-1,2,3triazole ring; a carbonyl-substituted n-azetidine ring; a piperidine ring optionally substituted one or more times by C1-C4 alkyl, carbonyl, halo, OH, or (CH₂) i_₄OH; a pyridinone ring optionally substituted one or more times by C1-C4 alkyl, OH, or CN; a carbonyl-substituted 1,2-dihldroplridine ring; a pyrimidone ring optionally substituted one or more times by C-iC4 alkyl, an oxazolidine ring optionally substituted one or more times by alkyl

<img file="MX356368B_D0026.tif" />

optionally one or more times per 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 / - / 5 4,7-epoxyindole ring optionally substituted one or more times with carbonyl; a carbonyl-substituted 3,4-dihydroquinazoline ring; a 1,2,3,4-tetrahydroquinazoline ring substituted one or more times with carbonyl; a benzoisothiazole ring optionally substituted one or more times with carbonyl;

In another embodiment of Formula (I):

Ries C1-C3 unsubstituted alkyl;

L_to is (CH₂) i-₆. and

R₂ and R3 are each independently: H, methyl, ethyl, isopropyl, butyl, tere-butyl, cyclohexyl, phenyl, benzyl, benzodioxol, pyridinyl, (CH₂)₂N (CH₃)₂, (CH₂)₃SW₂H, (CH₂)₂SW₂Me, 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 by C1-C4 alkyl, carbonyl, or (CH₂) i_₃N (Ci-C alkyl₄)2; an n 8-oxa-3azabicyclo [3.2.1] octane ring; a thiomorpholine 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 by C1-C4 alkyl or carbonyl; a 2,5-dihydropyrrole ring optionally substituted one or more times by C / -C4 alkyl or carbonyl; a succinimide ring optionally substituted one or more times by C1-C4 alkyl, a 3-azabicyclo [3.1.0] hexane-2,423 ring

IMPI

MEXICAN INSTmrrO DE LA MOHEDAL · INDUSTRIAL

<img file="MX356368B_D0027.tif" />

diona; a hexahydropyrimidine ring optionally substituted one or more times by C1-C4 alkyl or carbonyl; a pyrimidone ring optionally substituted one or more times by C1-C4 alkyl, a NO-substituted imidazole ring₂; a carbonyl-substituted isoindoline ring; a 5-carbonyl-substituted n-azetidine ring; a piperidine ring optionally substituted one or more times by C1-C4 alkyl, carbonyl, halo, OH, or (CH₂) i-4OH; a pyridinone ring optionally substituted one or more times by C1-C4 alkyl, OH, or CN; a pyrimidone ring optionally substituted one or more times by C1-C4 alkyl, an oxazolidine ring optionally substituted one or more times by C1-C4 alkyl, an oxazolidinone ring; an imidazolidinone ring optionally substituted one or more times by C1-C4 alkyl or carbonyl; an imidizolidine thione ring; an isothiazolidine ring optionally substituted one or more times with carbonyl; a benzoisothiazole 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.

Ríes Ci-C alkyl₆ not substituted;

L_to is an unsubstituted C1-C6 alkyl linker, unsubstituted C3-C10 carbocycle, unsubstituted Ce-Cio aryl, unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and

1-4 heteroatoms selected from N, O, and S; i r₂ and R₃, together with the nitrogen atom to which they are attached, form a heteroaryl comprising one or two 5- or 6-membered rings and 1-4

ΙΜΡΪ heteroatoms selected from N, O and S; or a hetec ^^^^ u ^^ ompíóndó'ón

INDUSTRIAL '5-membered ring and 1-3 heteroatoms selected from N, O and S, where the heteroaryl or heterocycle may be optionally substituted one or more times with C1-C6 alkyl, CN, OH, halo, O (alkyl Οι-Οβ ), CHO, carbonllo, tiona, NO o

NH₂.

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

In another embodiment of this aspect. L_to is (CH₂)₂.

In yet another embodiment of Formula (I), R₂ and R3 together with the nitrogen atom to which they are attached form a heterocycle, where the heterocycle is, a thiomorpholine ring, a plrrolldlna ring, a 2,5-dihldroplrrol ring, a 1,2-dlhldroplridlna ring, a piperazine ring, a succlnlmlda ring, a solndollna ring, a 2,5-dlhldro-1H-tetrazole ring, an azetidine ring, a piperidine ring, a hexahldropyrimidine ring, a 2.3 ring, 3a, 4,7,7a-hexahldro1 / - / - 4,7-epoxüsoindole, a 3,4-dhrodolinol ring, a 1,2,3,415 tetrahydroqulnazoline ring, an oxazolldlno ring, an oxazolldlnone ring, a midazolldlnone ring, a 1,3- ring dlhldro-2H-lm¡dazol-2-one, an imidizolidine thione ring, or an isotlazolldine ring, where all rings may be optionally substituted one or more times with Ci-C alkyl₆, C0₂(some CrC₆), OH, (CH₂)_MOH, O (some CrC₆), halo, -NH₂, (CH₂)_MNH₂, (CH₂) i20 ₄NH (C1-C4 alkyl) (CH₂) i „₄NH (alkyl CrC ^, carbonyl, or thione.

In one embodiment of Formula (I):

Ries C1-C3 unsubstituted alkyl;

L_to is (CH ^ ve and

INSTIT ΓΥ} A4 l · 'V .'í' * J ki Vr - *** I

<img file="MX356368B_D0028.tif" />

' ^atitai '^^>^^s:^CANi·¹ '^ <- Γ'.,., ^ - γ · Ν

R2 and R3, together with the nitrogen atom to which they are located, morpholine ring substituted one or more times ρηι - * «'ΐΐι ρ i¡hr, r_4l r »arhnn¡ | o._o ^ (CH₂) i-3N (alkyl Ci-C₄)₂; an n 8-oxa-3-azabylcycle [3.2.1] octane ring; a 1,4-doxa-8-azaspiro [4.5] decane ring; a thiomorpholine ring substituted one or more times with carbonyl or tlone; 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 by Ci-C alkyl₄ or carbonyl; a 2,5-dlhydropyrrole ring optionally substituted one or more times by Ci-C alkyl₄ or carbonyl; a succinimide ring optionally substituted one or more times by Ci-C alkyl₄, a 3-azabicyclo [3.1.0] hexane-2,4-done ring; a hexahydropyrimidine ring optionally substituted one or more times by Ci-C alkyl₄ or carbonyl; a pllmldone ring optionally substituted one or more times by Ci-C alkyl₄, a pyrrole ring optionally substituted one or more times by Ci-C alkyl₄, halo, C (O) NH₂, or not₂; a pyrazole ring optionally substituted one or more times by Ci-C alkyl₄, C (O) NH2, or NO2; an ildazole ring optionally substituted one or more times by Ci-C alkyl₄ or not₂; a ring

1,3-d¡h¡dro-2 / - / - lmidazol-2-one; a benzimidazole ring; a tlazol ring; a carbonyl-substituted soldering ring; a 1W-tetrazole ring; a tlone-substituted / - / - 2,5-hydro-1H-tetrazole ring; a 1 / - / - 1,2,4-triazole ring; a 1H-1,2,3-trlazole ring; a carbonyl-substituted n-azetldine ring; a plperldine ring optionally substituted one or more times by Ci-C alkyl₄, carbonyl, halo, OH, or (CH₂) -i-4OH; a plrldinone ring optionally substituted one or more times by Ci-C alkyl₄, OH, or CN; a carbonyl-substituted 1,2-dihydroplrldine ring; a ring of pirlmldona sus ^ j ^^ Jg ^ aL ^ níé-jjn, ao

Say LA FFOFÍBOAO '' i '' '· .-- · -'., '- \ / INDUSTRIAL more times by C1-C4 alkyl, an oxazolidine ring optionally substituted one or more times by C1-C4 alkyl, a ring of oxazolidinone; an imidazolidinone ring optionally substituted one or more times by 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-epoxyindole ring optionally substituted one or more times with carbonyl; a carbonyl-substituted 3,4-dhhydroquinoline ring; a 1,2,3,4-tetrahydroquinazoline ring substituted one or more times with carbonyl; a benzolsotlazole ring optionally substituted one or more times with carbonyl;

In some embodiments of Formula (I), at least one of R₂ and R3 is H. In other embodiments of Formula (I), L_to is (CH₂)₂.

In a particular embodiment of Formula (I):

R1 is methyl;

L_to 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):

R1 is methyl;

L_to is (CH₃)₂; and

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

In yet another embodiment of Formula (I):

IMPI ifcjí-m-xrrr * MCXlCANO

<img file="MX356368B_D0029.tif" />

Ri is methyl;

L_to is (CH₄)₂; and

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

For example, neurological disease is multiple sclerosis.

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

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

For example, in the compound of Formula (I), R1 is methyl.

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

For example, in the compound of Formula (I), L_to is an alkyl linker

Ci-C₆ substituted or unsubstituted.

For example, in the compound of Formula (I), L_to is an alkyl linker

C1-C3 substituted or unsubstituted.

For example, in the compound of Formula (I), L_to is a C-alkyl linker₂ substituted or unsubstituted.

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

For example, in the compound of Formula (I), L_to it is dimethyl with an alkyl linker C₂ substituted or unsubstituted.

For example, in the compound of Formula (I), L_to it is methyl or dimethyl with a substituted C2 alkyl linker. -TO

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

C₆ unsubstituted,

For example, in the compound of Formula (I), R_to it is substituted or unsubstituted Cg-Ce alkyl.

<td>By</td><td>example,</td><td>in</td><td>the</td><td>compound</td><td>of</td><td>Formula</td><td>(I).</td><td>R₂is</td><td>I rent</td><td>C1-C6</td><td>not</td>

<td>substituted;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>By</td><td>example,</td><td>in</td><td>the</td><td>compound</td><td>of</td><td>Formula</td><td>(I).</td><td>R₂is</td><td>I rent</td><td>Ci-C₃</td><td>not</td>

<td>substituted;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>By</td><td>example,</td><td>in</td><td>the</td><td>compound</td><td>of</td><td>Formula</td><td>(I).</td><td>R₂is</td><td>I rent</td><td>Ci-C₂</td><td>not</td>

substituted;

For example, in the compound of Formula (I), R₂ is C1-C2 alkyl substituted with C (O) OR_to, where R_to it is H or C1-C2 alkyl.

For example, in the compound of Formula (I), R₂ is CrC alkyl₂ substituted with S (O) (O) Rb, where Rb is a Ci-C alkyl₆,

For example, in the compound of Formula (I), R₃ it's H.

For example, in the compound of Formula (I), R₃ is CrC alkyl₆ substituted or unsubstituted.

For example, in the compound of Formula (I), R₃it is unsubstituted C1-C6 alkyl;

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

<img file="MX356368B_D0030.tif" />

selected from N, O and S, or a substitute heterocycle ^^^^ usgjwa ^ we comprises one or two 5- or 6-membered rings v 1-4 heteroatoms selected from N, O 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-membered rings and 1-4 heteroatoms selected from N, O 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 which they 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.

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, along with the atom of

<img file="MX356368B_D0031.tif" />

nitrogen to which they are attached form a morphoini ring

For example, in the compound of Formula (I), P ^ and Ro, jurrtu ei'in 11 "nitrogen to which they are attached, form a morpholino N-oxide 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 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-membered rings and 1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (I), R₂ is aril C₆-Ci₀ substituted or unsubstituted.

For example, in the compound of Formula (I), R₂ is aril C₆-Cio not substituted.

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

For example, in the compound of Formula (I), R₂ it 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 of treating a neurological disease by administering to a subject in need a therapeutically effective amount of a compound of Formula (la) , or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

<img file="MX356368B_D0032.tif" />

where:

Ries C1-C6 unsubstituted alkyl;

L_to it is a substituted or unsubstituted C1-C6 alkyl linker; carbocycle C₃5 C10 substituted or unsubstituted, aryl C₆-Ci₀ substituted or unsubstituted, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 14 heteroatoms selected from

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

R₂ is H, substituted or unsubstituted C1-C6 alkyl, C alkenyl₂-C₆ substituted or unsubstituted, alkynyl C₂-C6 substituted or unsubstituted, aryl C₆-Ci₀ substituted or unsubstituted, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl which it comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

For example, neurological disease is multiple sclerosis.

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

For example, in the compound of Formula (la), Ai - ^ unitilol Γ '&lt;

MEXICAN INSTITUTE b-, ·· -,

DS THE PROPERTY 'i. ,

INDUSTRIAL *

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

For example, in the compound of Formula (la), L_to is an alkyl linker

C1-C6 substituted or unsubstituted.

For example, in the compound of Formula (la), L_to is an alkyl linker

C1-C3 substituted or unsubstituted.

For example, in the compound of Formula (la), L_to is a C-alkyl linker₂ substituted or unsubstituted.

For example, in the compound of Formula (la), L_to is methyl with an alkyl linker C₂ substituted or unsubstituted.

For example, in the compound of Formula (la), L_to it is dlmetllo with an alkyl linker C₂ substituted or unsubstituted.

For example, in the compound of Formula (la), L_to is methyl or dimethyl with an alkyl linker C₂ replaced.

For example, in the compound of Formula (la), L_to is an alkyl linker

Ce not substituted,

For example, in the compound of Formula (la), R_to is Ci-C alkyl₆ substituted or unsubstituted.

For example, in the compound of Formula (la), R₂it is unsubstituted C1-C6 alkyl;

For example, in the compound of Formula (la), R₂ it is methyl.

For example, in the compound of Formula (la), R₂it is unsubstituted C1-C3 alkyl;

For example, in the compound of Formula i

<img file="MX356368B_D0033.tif" />

not substituted;

For example, in the compound of Formula (la), R₂ is Ci-C alkyl₂ replaced with C (O) OR_to, where R_to is H or Ci-C alkyl₂.

For example, in the compound of Formula (la), R₂ is Ci-C alkyl₂ replaced with S (O) (O) R_b, where R_b is a Ci-C alkyl₆,

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

(Ib)

A 'is a pharmaceutically acceptable anion;

Ries C1-C6 unsubstituted alkyl;

L_to it is a substituted or unsubstituted C1-C6 alkyl linker; substituted or unsubstituted C3C10 carbocycle, substituted or unsubstituted C6-C10 aryl, heterocycle

<img file="MX356368B_D0034.tif" />

χ> <

substituted or unsubstituted which comprises one or two "5Í £ riB" a.

heteroatoms selected from N, O and S, or substituted-o, jn-substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;

R₃'is Ci-C alkyl₆ substituted or unsubstituted; and

R₂ and R3 are each, independently, H, substituted or unsubstituted C ^ -Ce alkyl, alkenyl Ο₂-Οθ substituted or unsubstituted, alkynyl C₂-C6 substituted or unsubstituted, aryl C₆-Ci₀ substituted or unsubstituted, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl which it comprises one or two 5- or 6-membered rings and 14 heteroatoms selected from N, O 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 6-membered rings and 1-4 heteroatoms selected from N, O and S, or a substituted heterocycle or unsubstituted comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

For example, neurological disease is multiple sclerosis.

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

For example, in the compound of Formula (Ib), R1 is methyl.

For example, in the compound of Formula (Ib), R1 is ethyl.

For example, in the compound of Formula (Ib), L_to is an alkyl linker

INSTlTVrrO MEXICANO DELA PROFIf.OAD INOU5TMJAJL

<img file="MX356368B_D0035.tif" />

Ci-C₆ substituted or unsubstituted.

For example, in the compound of Formula (lh) i _Q gg a nnhTiHnr Hn-aiqniin

C1-C3 substituted or unsubstituted.

For example, in the compound of Formula (Ib), L_to is an alkyl linker

C₂ substituted or unsubstituted.

For example, in the compound of Formula (Ib), L_to is an alkyl linker

C₂ substituted or not substituted with methyl.

For example, in the compound of Formula (Ib), L_to is an alkyl linker

C₂ substituted or unsubstituted with dimethyl.

For example, in the compound of Formula (Ib), L_to is an alkyl linker

C₂ substituted or not substituted with methyl or dimethyl.

For example, in the compound of Formula (Ib), L_to is a C-alkyl linker₂ not replaced.

For example, in the compound of Formula (Ib), R₂ is a Ci-C-alkyl₆ substituted or unsubstituted.

For example, in the compound of Formula (Ib), R₂ it is an unsubstituted Ο-ι-Οθ alkyl.

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

For example, in the compound of Formula (Ib), R₂ it is unsubstituted C1-C2 alkyl.

For example, in the compound of Formula (Ib), R₂ is a C1-C6 alkyl substituted with C (O) OR_to, where R_to is H or Ci-C alkyl₆ replaced.

ρ I

Λ Á ζ - -ρΙΝΠΤΓΙΠΧ! ML'XVAN .. υ · 7 &lt;-7--1

For example, in the compound of Formula (Ib), R¿^to, ^ í ^ alfeuifoSC substituted with S (O) (O) Rb, where Rb is Ci-C alkyl₆ replace it

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

For example, in the compound of Formula (Ib), R₃ is a Ci-C alkyl₆ substituted or unsubstituted.

For example, in the compound of Formula (Ib), R₃ it is unsubstituted C1-C6 alkyl.

For example, in the compound of Formula (Ib), 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-membered rings and 1-4 heteroatoms selected from N, O and S, or a substituted or unsubstituted heterocycle substituted comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (Ib), 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-membered rings and 1-4 heteroatoms selected from N, O and S.

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

MEXICAN INSTITUTE: ¹ //

OF THE PROPERTY ,/

INDUSTRIAL * ^j

IMPI replaced.

For example, in the compound of Formula (Ib), Rg.y.Rg, .jurito. £ Qn. To the nitrogen atom to which they are attached, form an unsubstituted piperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R3, together with the nitrogen atom 5 to which they are attached, form a halogen-substituted piperidinyl ring.

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

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

For example, in the compound of Formula (Ib), R₂ and R₃, together with the nitrogen atom 15 to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (Ib), R₂ is aril C₆-Cio substituted or unsubstituted.

For example, in the compound of Formula (Ib), R₂ it is unsubstituted C6-C10 aryl.

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

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

IMPIOS

MEXICAN INSTITUTE ⁵

For example, in the compound of Formula (Ib ^^ ses ^ alqíJtte ^ S ^ Ce unsubstituted. ---------

For example, in the compound of Formula (Ib), R₃is Ci-C alkyl₃ not replaced.

For example, in the compound of Formula (Ib), R₃'is methyl.

In one embodiment, the present invention provides a compound of

Formula (II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof or a method of treating a neurological disease by administering to a subject in need a therapeutically effective amount of a compound of Formula (II) , or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

<img file="MX356368B_D0036.tif" />

(Π):

where:

Ríes Ci-C alkyl₆ not substituted;

R₄ and R₅ are each, independently, H, substituted or unsubstituted C1-C6 alkyl, C alkenyl₂-C₆ substituted or unsubstituted, alkynyl C₂-C₆ substituted or unsubstituted, aryl C₆-Ci₀ substituted or unsubstituted, carbocycle C₃-Substituted or unsubstituted cyo, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5-ring or 6 members and 120

IMPI MEXICAN INDUSTRIAL PROPERTY RIST

<img file="MX356368B_D0037.tif" />

heteroatoms selected from N, O and S;

R₆, R7, Re, and R9 are each, independantitemérifé, H, substituted or unsubstituted alkyl'Όϊ-Οβ, substituted or unsubstituted C2-C6 alkenyl, C2-C6 alkynyl or C (O) OR_to; and

R_to it is H or substituted or unsubstituted C1-C6 alkyl.

In one embodiment of Formula (II),

R1 is methyl;

R₄ and R5 are each methyl; and

R₆, R7, Re and R9 are each, independently, H, or methyl.

For example, neurological disease is multiple sclerosis.

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

For example, in the compound of Formula (II), R1 is methyl.

For example, in the compound of Formula (II), R1 is ethyl.

For example, in the compound of Formula (II), R₄ it is substituted or unsubstituted C1-C6 alkyl.

For example, in the compound of Formula (II), R₄it is unsubstituted C1-C6 alkyl.

For example, in the compound of Formula (II), R₄it is unsubstituted C1-C3 alkyl.

For example, in the compound of Formula (II), R₄it is unsubstituted C1-C2 alkyl.

For example, in the compound of Formula (II), R₄ is Ci-C alkyl₂ replaced

IMPIOS

MEXICAN INST ITUTO

OF THE PROPERTY ...

INDUSTRIAL with C (O) OR_to, where R_to is H or Ci-C alkyl₂.

For example, in the compound of Formula (II), R₄ is Ci-C alkyl₂ replaced with S (O) (O) Rb, where R_b is a Ci-C alkyl₆,

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

For example, in the compound of Formula (II), R₅ it is substituted or unsubstituted Ο-ι-Οβ alkyl.

For example, in the compound of Formula (II), R₅is alkyl C_rC6 unsubstituted;

For example, in the compound of Formula (II), R₄ is aril C₆-Ci₀ substituted or unsubstituted.

For example, in the compound of Formula (II), R₄ it is unsubstituted C6-C10 aryl.

For example, in the compound of Formula (II), R₄ it is unsubstituted phenyl.

For example, in the compound of Formula (II), R₄ it is unsubstituted benzyl. For example, in the compound of Formula (II), R₆, R7, Rs and R9 are each H.

For example, in the compound of Formula (II), R6 is C1-C6 alkyl and R7 substituted or unsubstituted, Re and Rg are each H.

For example, in the compound of Formula (II), R₆ is CiC alkyl₆ and R7 unsubstituted, Re and R9 are each H.

For example, in the compound of Formula (II), Rs is C1-C6 alkyl and R6 substituted or unsubstituted, R₇ and R9 are each H.

For example, in the compound of Formula (II), Rs is C1-C6 alkyl and R6 is not

IMPIOS

IWSriTUTO MEXICANO -C - 'A

OELA PROPERTY replaced, R₇ and Rg are each H.

For example, in the compound of Formula (il), R_c And p₀independently, C1-C6 alkyl and R7 and substituted or unsubstituted Rg are each H.

For example, in the compound of Formula (II), R₆ and R₈ are each, independently, Ci-C alkyl₆ and R₇ and unsubstituted Rg are each H.

For example, in the compound of Formula (II), R6 and R7 are each, independently, C1-C6 alkyl and R₈ and substituted or unsubstituted R9 are each H.

For example, in the compound of Formula (II), R₆ and R₇ are each, independently, C1-C6 alkyl and Re and unsubstituted Rg are each H.

For example, in the compound of Formula (II), R₈ and Rg are each, independently, C1-C6 alkyl and R6 and substituted or unsubstituted R7 are each H.

For example, in the compound of Formula (II), R₈ and Rg are each, independently, C1-C6 alkyl and R₈ and R7 unsubstituted 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 of treating a neurological disease by administering to a subject in need a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

<img file="MX356368B_D0038.tif" />

where:

Ries C1-C6 unsubstituted alkyl;

<img file="MX356368B_D0039.tif" />

is selected from the group consisting of:

X is N, O, S, or SO₂;

Z is C or N;

m is 0, 1, 2 or 3;

n is 1 or 2;

w is 0, 1, 2 or 3;

tesO, 1, 2, 3,4, 5, 6,7, 8, 9, or 10;

IMPI

MEXICAN INSTITUTE · '? IM PROPERTY

INDUSTRIAL

<img file="MX356368B_D0040.tif" />

R6, R7, Re and R9 are each, independently, H, Ci-C alkyl₆ substituted or unsubstituted, alkenyl C₂-C₆ substituted or unsubstituted, alkynyl C₂-C₆or C (O) OR_to; and

R_to is H or substituted or unsubstituted C-C6 alkyl; and each R_1st is, independently, H, halogen, alkyl CiC₆ substituted or unsubstituted, alkenyl C₂-C6 substituted or unsubstituted, C-alkynyl₂-Substituted or unsubstituted C6, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl substituted comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;

or alternatively two R₁₀ attached to the same carbon atom together with the carbon atom to which they are attached, they form a carbonyl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S;

or alternatively two R10s attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1 -4 heteroatoms selected from N, O and S, or unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 14 heteroatoms selected from N, O and S.

ΪΜΡΙ

I'kJC-'T-fT'l! ··,> »í r · _» », ->, V, .-, —Ζ _____. - · »

For example, neurological disease is sclerosis ^

For example, neurological disease as multiple relapsed-remission fisclfirosis (RRMS).

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

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

For example, in the compound of Formula (III)

<img file="MX356368B_D0041.tif" />

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

<img file="MX356368B_D0042.tif" />

' is

<img file="MX356368B_D0043.tif" />

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

<img file="MX356368B_D0044.tif" />

IMPI

Mexican Institute of Industrial Property

<img file="MX356368B_D0045.tif" />

<img file="MX356368B_D0046.tif" />

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

<img file="MX356368B_D0047.tif" />

For example, in the compound of Formula (lll), R6 is substituted or unsubstituted C1-C6 alkyl and R7, Rs and R9 are each H.

For example, in the compound of Formula (lll), R6 is C1-C6 alkyl and R7 unsubstituted, Rs and R9 are each H.

For example, in the compound of Formula (lll), Rs is C1-C6 alkyl and R6 substituted or unsubstituted, R7 and Rg are each H.

For example, in the compound of Formula (lll), Rs is alkyl Ο-ι-ilo and R6 unsubstituted, R₇ and R₉ they are each H.

<img file="MX356368B_D0048.tif" />

For example, in the compound of Formula (III), Re and Rs are each, independently, Ci-C alkyl₆ and R7 and substituted or unsubstituted Rg are each H.

For example, in the compound of Formula (III), Re and Re are each, independently, Ci-C alkyl₆ and unsubstituted and R₇ and Rg are each of them

H.

For example, in the compound of Formula (III), Re and R7 are each, independently, Ci-C alkyl₆ and Rs and R9 substituted or unsubstituted are each H.

For example, in the compound of Formula (III), Re and R7 are each, independently, Ci-Ce and unsubstituted alkyl and R₈ and Rg are each of them

H.

For example, in the compound of Formula (III), Re and Rg are each, independently, substituted or unsubstituted C1-C6 alkyl, and Re and R7 are each H.

For example, in the compound of Formula (III), Re and Rg are each, independently, unsubstituted C1-C6 alkyl, and R₆ and R7 are each of them

H.

In one embodiment of Formula (III),

Ríes Ci-C alkyl₆ not substituted;

N

IMPI

ΙΝΣΤ1ΤΙ (ΤΟ M t X ¡CANO OT LA M>. INDUiTÜlAL PIETY

<img file="MX356368B_D0049.tif" />

is selected from the group consisting of

<img file="MX356368B_D0050.tif" />

t is 2, 4, or 6;

R₆, R7, Re and R9 are each, independently, H, unsubstituted C1-C6 alkyl, or C (O) OR_to, where R_to it is H or unsubstituted C1-C2 alkyl; and two R10s 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 of treating a neurological disease by administering to a subject in need a therapeutically effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof.

R₂

N

To go₃

<img file="MX356368B_D0051.tif" />

where:

Ries Ci-Cg unsubstituted alkyl;

L_to it is a substituted or unsubstituted C1-C6 alkyl linker;

R₂ and R3 are each, independently, H, substituted or unsubstituted acllo, NR14R15, C (S) Rn, C (S) SRn, C (S) NRhRi₂, C (S) NRnNRi3Ri₄, C (NRi3) NRiiRi₂, substituted or unsubstituted C1-C6 alkyl, C alkenyl₂-Ce substituted or unsubstituted, alkynyl C₂-Substituted or unsubstituted C6, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;

R11 and Ri₂ are each, independently, H, substituted or unsubstituted C1-C6 alkyl, C alkenyl₂-C6 substituted or unsubstituted, C-alkynyl₂-C₆ substituted or unsubstituted, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;

Ri3 is H or Ci-C alkyl₆ substituted or not substituted8 ^^ ñw.sDAj ¹ '* ΐνηιιιτηι ^ vj

INDUSTRIAL

Ru and R-I5 are each, independently, H, substituted or unsubstituted acyl, Ci-C alkyl₆ substituted or unsubstituted, alkenyl C₂-C₆ substituted or unsubstituted, alkynyl C₂-C₆ substituted or unsubstituted, aryl C₆-Ci₀ substituted or unsubstituted, carbocycle C₃-Ci₀ substituted or unsubstituted, substituted or unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-ring members and 1-4 heteroatoms selected from N, O, and S;

where at least one of R₂ and R₃ is substituted or unsubstituted acyl, NR14R15,

C (S) Rn, C (S) SRn, C (S) NRnR₁₂, C (S) NRnNR₁₃R₁₄, or C (NR₁₃) NRnR₁₂.

In one embodiment of Formula (IV),

Ríes Ci-Cs alkyl;

L_to it is a substituted or unsubstituted C1-C4 alkyl linker; and one of R₂ and R₃ is CO₂(some Οι-Οβ), CO₂CH₂Ph, CO₂Ph, CO₂Py, ester of

Ν-pyridine oxide, C (O) CH₂(imidazole), C (S) NHPh, or C (NH) NH₂, where the Ph or Imidazole groups are optionally substituted by NO₂.

In another embodiment of Formula (IV),

Ries C1-C4 alkyl;

L_to it is a substituted or unsubstituted C1-C4 alkyl linker; and

R₂ and R₃ are each, independently, H, methyl, ethyl, Isopropyl, butyl, tere-butyl, cyclohexyl, cyclohexenllo, phenyl, benzyl, benzodloxol, pyridinyl, (CH₂)₂N (CH₃)₂, (CH₂)₃SW₂H, (CH₂)₂SW₂Me, CHO, CH₂CO₂H, C (O) (CH₂) 2CO₂H

IV X Λ

MEXICAN INSTITUTE \ '' 's¿ 3 \ _ _ _ _ ~ DE LA PROPIEDAD „f .'¿J

NO C (O) NH₂, (CH₂)₂CN, tert-butyl ester, benzyl ester, ester ^ d ^ pyridine mf ^ - ^ N-oxide pyridinyl ether, C (O) CH₂(2-nitro-1H-imidazole - ^^ l) TCtS) WⁱtPhrOtNH> NH₂-, carbonyl-substituted ethyl, carbonyl-substituted propyl, or NO-substituted phenyl ester₂, where the phenyl and benzyl groups can be optionally substituted one or more times with methyl, -NH₂, NOT₂, OH, or CHO;

where at least one of R₂ and R3 is substituted or unsubstituted acyl, NR14R15,

C (S) Rn, C (S) SRn, C (S) NRnRi2, C (S) NRnNR₁₃Ri4, or C (NR₁₃) NRhR₁₂.

In one embodiment of Formula (IV),

Ríes alkyl Οι-Οθ;

L_to is (CH₂) i.₄;

R₂ is H or C (O) Ci-C6 alkyl, and R3 is H or C (O) Ci-C6 alkyl, where at least one of R₂ and R₃ is C (O) Ci-C alkyl₆.

For example, the compound is a related compound in Table 1 herein. Representative compounds of the present invention include the compounds listed in Table 1 and Table 2.

IMPIOUS

Table 1.

ΙΚΪΠΤ · / Γ0 MEXICAN

FROM THE FKOt'lEOAD &lt;· .., ...! INNULSTRLAL - ~

<td> 1</td><td>—77: 7 .; HO₂CN Μ θ</td>

<td> 2</td><td>i ⁰ \₅/ \ zN 0-¾ ° S</td>

<td> 3</td><td>x N, γχ ^ θJL ^^ XflzOMe OR</td>

<td> 4</td><td>IO ^ Νζ ^ θΛ ^^ ΟΜβ OR TO'</td>

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

<td> 6</td><td>_x.N ^_zzJs.Q ^_s^^ s ^ .OMe</td>

<td> 7</td><td>S ^ | 0 k ^ N ^ x ^^ Jk ^ s ^ OMe</td>

<td> 8</td><td>HU</td>

<td> 9</td><td>OR</td>

<td rowspan="2"> 10</td><td>ο. ο V '"JSSSSS &gt; Si ^ z * XQJk ^ s&gt; 3Me</td>

<td>Ό ..........................</td>

<td> 11</td><td>N_{% ii&gt; z}x ^ qjS_s&gt; ^ íx_&lt;^_zX3 Μ θ 0</td>

<td> 12</td><td>OR? 0</td>

<td> 13</td><td>You ^ Ñ_x^₀X_&lt;JÉ ^ 0Me</td>

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

<td> 15</td><td>Cx N</td>

<td> 16</td><td>^I23i^|X ^ Q ^ Yes! ^ Y^OMe 0</td>

<td> 17</td><td>Okh ° I * —N ^ / x_orJLz¿&gt; x ^ OMe 0</td>

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

<img file="MX356368B_D0052.tif" />

<img file="MX356368B_D0053.tif" />

<img file="MX356368B_D0054.tif" />

<td> 28</td><td>--wgTiTUTn MLXjCAy&gt; —ui— -,</td>

<td> 29</td><td>oA 0 xk.N ^_or^Jl^ Y^OMe 0</td>

<td> 30</td><td>O ^ i 0</td>

<td> 31</td><td>OR "TO, ₀ ^^Ν^ χ₀Λ ^ γ ° Μ^β</td>

<td> 32</td><td>OR</td>

<td> 33</td><td>θ (Αχ ^ Νχ ^ .θΛ ^ .ΟΜβ z ^ \ O</td>

<td> 34</td><td>(&lt;And or * γΝχΧ ·.₀Ά ^ γ ° Μ · or</td>

<td> 35</td><td> 0 _ORK ψ. ^ Λ ^ γ^0Μβ</td>

<td> 36</td><td>O o</td>

<img file="MX356368B_D0055.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 37</td><td>or 0</td>

<td> 38</td><td> 0</td>

<td> 39</td><td>ί »Ύ ° W 0</td>

<td> 40</td><td>X^or t "ΜχΧ-γΛ ^ ν-⁰· 0 or</td>

<td> 41</td><td>H and Νζ ^ φΛχ ^ γΟΜ⁵O o</td>

<td> 42</td><td>0 ^ Ν ^, Λ ^ γΟΜ »oo</td>

<td> 43</td><td>0 ΗΝ ^ χ ^ θΛ ^ γΟΜβ 0</td>

<td> 44</td><td>O ° o ^ γ^Ν'^-_οΛ ^ γΟΗ_β 0 0</td>

<td> 45</td><td>Η 8 ΗΝ ^ Ν ^^ θΧ ^ -OMe νη₂ 0</td>

<td> 46</td><td>-PhUM-C-inSTRUTO MEXICANO yz -r-η PhHN ^ S θ^HN^^ o '^Jl^ y^OMe</td>

<td> 47</td><td>I oo</td>

<td> 48</td><td>I oo</td>

<td> 49</td><td>^H 8 ^ΙΜγ^ΝχΧ&gt;, Χ_ί^ γ&gt; Μ « O 0</td>

<td> 50</td><td>w £ 2) n ^h i 0 0</td>

<td> 51</td><td>ΟγΝ ^^ θΛ ^ γΟΜβ 0 OR</td>

<td> 52</td><td></td>

<td> 53</td><td>° N xX '^ Q JU ^ s ^ OMe 0 0</td>

<td> 54</td><td></td>

<td> 55</td><td> -_Λ-tHgrtWFO i-, ... &gt; 0 DS IA PKOTOOAU v - 2i + FI ~~ AND 0 INDUSTRIAL ---------- ν ^_οΛ ^ γθ «·</td>

<td> 56</td><td></td>

<td> 57</td><td>&gt; y ° 0 0 0</td>

<td> 58</td><td>O ^ N ^ O ₀</td>

<td> 59</td><td>W °? k &amp; z-N -s ^ z— '0</td>

<td> 60</td><td>CC ^ oA ^ ™ ® 0</td>

<td> 61</td><td>CN Υ ^ Υ ° 0 OH O</td>

<td> 62</td><td>θ ^ Ν · ^⁰ or ^^₀λ ^ γΟΜ_βOR</td>

; ΙΜΡϊ

<td rowspan="2"> 63</td><td>-7 ·· ..... V --- PB LA FEOWBPAP- rf, 0 INDUSTRIAL »</td>

<td>or 0</td>

<td> 64</td><td>^ΗΝγ'Ν ^ χχ_οΛ ^ γ0Μ_βS o</td>

<td> 65</td><td>^&lt;^ Χ ^₀Λ ^ γΟΜβ</td>

<td> 66</td><td>Όγ ° 0 Ν ^ Ν_χΧ-χ_οΛ_{&gt; &lt;ίί}γΟΜβ</td>

<td> 67</td><td>Qy&gt; o^ΗΝγ^Ν^^χο-^Α^ γ^ΟΜθoo</td>

<td> 68</td><td>N-NH or Y ^ ok ^ Y⁰s 0</td>

<td> 69</td><td>- γ ^ θΑ ^ γΟΜβ IO</td>

<td> 70</td><td>H ft or</td>

<td> 71</td><td>H H 'O</td>

<img file="MX356368B_D0056.tif" />

IMPÍ

MEXICAN INSTITUTE οε la mgredao industrial

<td> 72</td><td>⁰L¿Z 'yOMf. ---- _</td>

<td> 73</td><td>1st Χ^Ν^^ Ν ^^ ° γ ^ Α₀Μβ • 0</td>

<td> 74</td><td>Η ΐ 0-^Ν^ ο^Λ^ γ^ΟΜβ</td>

<td> 75</td><td>C ^ x, --- cA ^ Y °^I 0</td>

<td> 76</td><td>^ηο&gt; ^^ ν — Ί 9 0</td>

<td> 77</td><td>0 0 ^ Β^χχχ° Υ^ζΐ^^ζ^^ΟΜ·</td>

<td> 78</td><td>Ηο-Ο ^ θΧ ^ γΟΜ · OR</td>

<td> 79</td><td>oh^h° yS ^^{oh 0}ηο ·· ^^ν-^_οΧ ^ Υ^ομ' 0</td>

<td> 80</td><td>Q Α °</td>

cr?

IMPIOS

<td> 81</td><td>-: - Λ-BvyftTUTO MEXICANO — 05 ' Yes OF THE reOPifcPW V;. · B.-_; · or. / \ J II INDUSTWAI. 0</td>

<td> 82</td><td>ΗθγΧ ^ o</td>

<td> 83</td><td>I °</td>

<td> 84</td><td>OR</td>

<td> 85</td><td></td>

<td> 86</td><td>Q ^ C ^₀- ^ Y °^I</td>

<td> 87</td><td>ςς / —Αγ '</td>

<td> 88</td><td>Η₂Ν '^ζ*^{ΪΙ! 5ιΖ}^ °</td>

<td> 89</td><td>hoXXj ^ -A ^ y⁰· 0</td>

ΙΜΡΠ “·· Λ, Α or» '

<td> 90</td><td>----- H4 £ L £ IÍIAi-,^Ι^ Λ ^ Ν_Χζ^_οΛ ^ γΟΜβ 0</td>

<td> 91</td><td>Η₂Ν^Λ^-^Ν^ Ο^Λ^°^ΜβOR</td>

<td> 92</td><td>0 II —S = O S 0 \ »- **** s_vz Ν Μ β θ *% 8</td>

<td> 93</td><td>^δ~ Ί fí ^^N^^xcr^s^ 'Y °^I</td>

<td> 94</td><td>S '^xj 0 ίγΝ ^_οΛ ^ γΟ «β</td>

<td> 95</td><td>οΛ ^ | η 1_Ν ^^_οΑ ^^ γΟΜβ 0 or</td>

<td> 96</td><td>0 « 0 = í /&gt; o k ^ N ^^₀X ^ Xj /&gt; Me</td>

<td> 97</td><td>OR HjN ^^^ qA ^ jííS * ^ 0</td>

<td> 98</td><td>OR</td>

<img file="MX356368B_D0057.tif" />

IMPI

MEXICAN INSTITUTE OF PROPERTY

<td rowspan="2"> 99</td><td>---- tPPU3TRtAL- · * ^_χΝ</td>

<td>IO</td>

<td> 100</td><td>I ° χ-Ν - ^^ χθΧ ^^ 'χ ^, ΟΜβ' ​​'O</td>

<td> 101</td><td>I \ / θ χ^Ν^ ο '^Λ^ γ^θΜβor</td>

<td> 102</td><td>^-------or Ι ^ Ν ^ χ ^_οΑ_&lt;ί_!^ γΟΜβ OR</td>

<td> 103</td><td>\ sssí OO</td>

<td> 104</td><td>^ ΟγΝ ^ χ ^_οΑ ^ γΟΜβ</td>

<td> 105</td><td>I θ ^ γΟγΝ ^ χ ^ θΧ ^ γΟΜβ io O</td>

<td> 106</td><td>JN-NH or</td>

<td> 107</td><td>ys &amp; δ 'VN ^^ X ^^ OMe OR</td>

<td> 108</td><td>/ 5η θ</td>

ΐΜΡΙβΙ!

ΙΝΈΤΓΤ^{, Γ}ΓΡ iNrUSTWAL

<td> 109</td><td>Q ^ J, you -----—- 0</td>

<td> 110</td><td> ' 0</td>

<td> 111</td><td>ζ ^ Ν ^_οΛ ^ γο_Μβ</td>

<td> 112</td><td>Q 0</td>

<td> 113</td><td>/ * N 0 VÑ ^ x ^_orX¿ * ^ 0Me 0</td>

<td> 114</td><td>/ = aa O V. Ν &lt;Aih₂ °</td>

<td> 115</td><td>ΝβΜ O^Ν^ Ν ^^_οΛ ^ γΟΜβ</td>

<td> 116</td><td>/ = SN 0 ^ Ν ^^_οΛ ^ γ, 0Μβ OR</td>

<td> 117</td><td>0ύ ° p HN · γ'Ν ^ _ / ^._οoo</td>

IMPI θ-Λ

<td> 118</td><td>INDUSTRIAL 9r or „ NN Μθ</td>

<td> 119</td><td>or k ^ Ns ^ z ^_or-TO_s2^ A ^ -OMe OR</td>

<td> 120</td><td>δ ~ o | 0-^JI'p-^N^ O-^J,^ Y^OMe</td>

<td> 121</td><td>H 2 ΟγΝγΝ_{χ /}χ₀Λ_&lt;ίίί =&gt; γΟΜβ ¿R</td>

<td> 122</td><td>Okjx ^^_orX ^ \ ^ OMe SW</td>

<td> 123</td><td>HU MeS N S 0</td>

<td> 124</td><td>Η H j¡ χ-^Ν γ^Ν ^_orA ^ OMe OO</td>

<td> 125</td><td>MHH n</td>

<td> 126</td><td>'p-Αμγ *</td>

______to go

MEXICAN INSTITUTE

<td> 127</td><td>5 INDÚSTWAL</td>

<td> 128</td><td>^H 8 o °</td>

<td> 129</td><td>^H 8 ^orV'V^N'^^°^xW^ V °^IV</td>

A 'is a pharmaceutically acceptable anion.

<img file="MX356368B_D0058.tif" />

The present invention also provides pharmaceutical compositions.

MEXICAN INSTITUTE -j

OE THE PROPERTY>

comprising one or more compounds of Formula (I), (la), (Ib), W7 ^ ITI), or * (lV) and one or more pharmaceutically acceptable carriers -............ · ^ '

In one embodiment, the pharmaceutical formulation is a controlled release composition comprising a compound of Formula (I), (la), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers , where the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject. In another embodiment, the pharmaceutical formulation is a controlled release composition comprising a compound of Formula (I), (la), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers , where the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject for from at least about 8 hours to at least about 24 hours. In another embodiment, the pharmaceutical formulation is a controlled release composition comprising a compound of Formula (I), (la), (Ib), (II), (III), or (IV) and one or more pharmaceutically acceptable carriers , where the controlled release composition provides a therapeutically effective amount of monomethyl fumarate to a subject for at least about 8 hours, at least about about about about about

<td> 10</td><td>hours,</td><td>to the</td><td>less</td>

<td> 13</td><td>hours,</td><td>to the</td><td>less</td>

<td> 15</td><td>hours,</td><td>to the</td><td>less</td>

<td> 17</td><td>hours,</td><td>to the</td><td>less</td>

<td> 19</td><td>hours,</td><td>to the</td><td>less</td>

approximately approximately approximately approximately approximately

<td> 12</td><td>hours,</td><td>to the</td><td>less</td>

<td> 14</td><td>hours,</td><td>to the</td><td>less</td>

<td> 16</td><td>hours,</td><td>to the</td><td>less</td>

<td> 18</td><td>hours,</td><td>to the</td><td>less</td>

<td> 20</td><td>hours,</td><td>to the</td><td>less</td>

ίΝΪΤΓΠΓΓΟ MEXICAN PROPERTY

INDUSTRIAL approximately 21 hours, at least approximately 22 hours, at least approximately 23 hours or at least approximately 24 hours or more. For example, at least about 18 hours. For example, at least about 12 hours. For example, more than 12 hours. For example, at least about 16 hours. For example, at least about 20 hours. For example, at least about 24 hours.

In another embodiment, a compound of Formula (I), (la), (Ib), (II), (III), or (IV) is effectively converted into the active ingredients, i.e. monomethyl fumarate, after administration oral. For example, about 50 mole percent, about 55 mole percent, about 60 mole percent, about 65 mole percent, about 70 mole percent, about 75 mole percent , about 80 mole percent, about 85 mole percent, about 90 mole percent, or more than 90 mole percent of the total dose of a compound of Formula (I), (la), (Ib), (II), (III), or (IV) administered is converted to monomethyl fumarate after oral administration. In another embodiment, a compound of Formula (I), (la), (Ib), (II), (III), or (IV) is converted to the active ingredients, i.e. monomethyl fumarate, after oral administration more effectively than dimethyl fumarate. In another embodiment, a compound of Formula (I), (la), (Ib), (II), (III), or (IV) is converted to the active ingredients, i.e. monomethyl fumarate, after oral administration more effectively than one or more of the compounds described in US 8,148,414. For example, a compound of Formula (I), (la), (Ib), (II), (III), or (IV) is

PISTa Mexican Institute> 'Í ^;¡ And it essentially becomes the principles ^ a © Svo® £ éfegée # * ^ monometllo fumarate, after oral administration. US 8,148.d1 <1 - is expressly incorporated herein by reference.

In another embodiment, any one of Compounds 1-133 is effectively converted into the active ingredients, i.e. monometllo fumarate, after 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 , approximately 90 percent, or more than percent of the total administered dose of any one of the Compounds

1-133 is converted to monometllo fumarate after oral administration. In another embodiment, any one of Compounds 1-133 is converted to the active ingredients, i.e. monometllo fumarate, after oral administration more effectively than dimethyl fumarate. In another embodiment, any one of Compounds 1-133 is converted to the active ingredients, i.e. monometllo fumarate, after oral administration more effectively than one or more of the compounds described in US 8,148,414. For example, any one of Compounds 1-133 is fully converted to the active ingredients, i.e. monometllo fumarate, after oral administration.

For a drug to achieve its therapeutic effect, it must maintain the necessary level of concentration in blood or plasma. Many drugs, including dimethyl fumarate, must be administered several times to the IMTiSel Mexican Institute - _ ···· - g and day to maintain the required concentration. In addition, daily administrations of this drug continue to vary concentrations of the active ingredient in blood or plasma, that is, at certain times between administrations higher concentrations of the active ingredient occur than at other times. Thus, at certain time points in a 24-hour period, a patient can receive therapeutically effective amounts of the active ingredient, while at other time points, the concentration of the active ingredient in the blood may be below therapeutic levels. Additional problems with such drugs include that various dosages throughout the day negatively affect patient compliance with treatment. Therefore, it is desirable to have a pharmaceutical form of a drug where the active ingredient is supplied in a controlled way that allows a constant or substantially constant level of concentration in the blood or plasma of the active ingredient to be maintained with one or at most two doses. daily. Accordingly, the present invention provides controlled release formulations as described below. In general, such formulations are known to those of skill in the art or available using conventional methods.

As used herein, controlled release means a pharmaceutical form where the release of the active ingredient is controlled or modified over a period of time. Controlled can mean, for example, a sustained, delayed or pulsed release over a particular period of time. For example, controlled release can mean that release from the beginning

<img file="MX356368B_D0059.tif" />

Active extends for longer than immediate release did, that is, at least for several hours. Such r.nmn rn ihwh »» · this document, Immediate release means a pharmaceutical form where an amount equal to or greater than approximately 75% of the active ingredient is released within two hours, or, more specifically, within a period of one hour, from the administration. Immediate release or controlled release are also characterized by their dissolution profiles.

The formulations are also characterized by their pharmacokinetic parameters. As used herein, pharmacokinetic parameters describe the in vivo characteristics of the active ingredient over time, including for example the plasma concentration of the active ingredient. As used herein, C_max means the measured concentration of the active substance in the plasma at the point of maximum concentration. T_max refers to the time when the concentration of the active substance in the plasma is greatest. ABC is the area under the curve of a graph of the concentration of the active ingredient (usually the plasma concentration) vs. time, measured from one moment to another.

The controlled release formulations provided herein provide desirable properties and benefits. For example, the formulations can be administered once a day, which is especially desirable for the subjects described herein. The formulation can provide many therapeutic benefits that are not achieved with the corresponding shorter-acting preparations, or with the "μ-titre:". Immediate release preparations. For example, the formulation can^HeeManterief lower peak plasma values ​​more stationary, for example, 'C ^ ax / d ^ ormaque reduce the incidence and severity of possible side effects.

The sustained release dosage forms release their active ingredient into the gastrointestinal tract of a patient for an extended period of time after administration of the dosage form to the patient. Particular dosage forms include: (a) those with the active ingredient included in a matrix from which it is released by diffusion or erosion; (b) those that have the active ingredient present in a nucleus that is coated with a speed control membrane; (c) those with the active ingredient present in a core provided with an outer waterproof coating for the active ingredient, the outer shell having an opening (which is perforated) to release the active ingredient; (d) those in which the active ingredient is released through a semipermeable membrane, allowing the drug to diffuse through the membrane or through liquid-filled pores inside the membrane; and (e) those that have the active principle present in a lomeo exchange complex.

It will be apparent to those skilled in the art that part of the above means to achieve a sustained release can be combined, for example, a matrix containing the active ingredient can be formed into a multiparticulate and / or coated with a waterproof coating provided with a opening.

Pulsed release formulations release the active substance after a

IMPI

INSTITI * TO MEXICANO Say LA fRC PIEDAD w »wim« WAU sustained period of time after administration of the form ^ Wmac &amp; otrca to the patient. Release may then occur in the form of an immediate or sustained release *. This delay can be achieved by releasing the drug at specific points in the gastrointestinal tract or releasing the drug after a predetermined time. The pulsed release formulations can be in the form of tablets or multiparticulates or a combination of both. Particular dosage forms include: (a) release triggered by an osmotic potential (see US Patent No. 3,952,741); (b) compression-coated two-layer tablets (see US Patent No. 5,464,633); (c) capsules containing an erodible plug (see US Patent No. 5,474,784); sigmoldal release agglomerates (cited in US Patent No. 5,112,621); and (d) formulations coated or containing pH-dependent polymers including shellac, phthalate derivatives, polyacrylic acid derivatives and crotonic acid polymers.

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 a layer containing an immediate release active ingredient and the other layer containing the active ingredient included 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 that are coated with a rate-controlling membrane in a capsule to obtain a

ΙΜΡΪ /?

MEXIfANQ INSTITUTE! TO.

double release formula. The formulations of release ^ g ^ gdst ^ o ^^ the active ingredient is present in a core provided with an outer waterproof coating for the active ingredient, the outer shell having an opening (which is perforated) to release the active ingredient, can be coat an immediate-release form of the drug with 5 to form a dual-release formulation. Dual-release formulations can also combine drug in an immediate-release form with additional drug in a pulsed-release form. For example, a capsule containing an erodible plug could release drug initially and, after a predetermined period of time, release additional drug in an immediate or sustained release form.

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

IMPI

INSTITU IO Mt / ICANO Ut THE PROPERTY

INDUSTUUAI

<img file="MX356368B_D0060.tif" />

Most release formulations control-oothan dioogenated to initially release an amount of drug that rapidly produces the desired therapeutic effect, and to gradually and continuously release additional amounts of drug to maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug metabolized and excreted by the body.

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

Powdery or granular formulations of a pharmaceutical preparation of the present invention can be prepared using known methods. Said formulations can be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension by adding an aqueous or oily vehicle to the above. Each of these formulations may further comprise one or more of a dispersing agent, wetting agent, suspending agent, and a preservative. Additional excipients, such as fillers, sweeteners, flavors, or coloring agents, may also be present, may also be included in such formulations.

A formulation of a pharmaceutical composition of the invention suitable for oral administration can be prepared or packaged in the form of a

ΙΜΡΪΟ>

¡NSTlTlfTO MEXICANO γΤ '·' /> I heard THE PROPERTY '-' '' discrete solid unit dose including, but not limited to, LWicc ^ riiVtt ^ .tjna 'sura or soft capsule, a seal, a thick pill, or tma · pill¹ para-ehupar, 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 coating.

A tablet comprising the active ingredient, for example, can be prepared by compression or molding of the active ingredient, optionally with one or more additional ingredients. Tablets can be prepared by compression in a suitable device, the active ingredient being in a fluid form such as a powder or granule preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surfactant , and a dispersing agent. Molded tablets can be prepared by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least enough liquid to wet the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets comprise, 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 glycolate. Known surfactants include, but are not limited to, sodium lauryl sulfate and poloxamers. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose,

IMPIDO

MEXICAN INSTITUTE / X / microcrystalline cellulose, calcium phosphate, hydrogen phosphate, sodium, sodium chloride. Granulating and disintegrating agents jcQXKMJdos-jeeiuyeftrpei '^ Sfn limitation, cornstarch and alginic acid. Known binding agents include, but are not limited to, gelatin, gum arabic, pregelatinized corn starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

The tablets may be uncoated 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 stearate can be used to coat tablets. In addition, by way of example, tablets can be coated using the methods described in US Patent Nos. N^ros

4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets, optionally, with laser perforation. The tablets may further include a sweetener, a flavoring agent, a coloring agent, a preservative, or some combination of these to provide pharmaceutically elegant and tasty formulations.

Hard capsules comprising the active ingredient can be manufactured using a physiologically degradable composition, such as gel or HPMC. Such hard capsules comprise the active ingredient, and further comprise other ingredients, including, for example, such an inert solid diluent.

IMPI

INSTITUT O MEXICANO - - 'V &lt;as calcium carbonate, calcium phosphate, or kaolin. ““ “· ££

Soft gelatin capsules that nnmprgnrlgn pI prinripin artivn qp can manufacture using a physiologically degradable composition, such as gelatin. Said soft capsules comprise the active principle that can be mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil.

As used herein, alkyl, alkyl Ci, C is intended to₂, C₃, C₄, C₅ or C₆ or Ci-C alkyl₆ include saturated aliphatic hydrocarbon groups Ci, C₂, C3, C₄, C5 or C₆ straight-chain (linear) and saturated aliphatic hydrocarbon groups C₃, C₄, C₅ or C₆ branched chain. For example, C1-C6 alkyl is intended to include Ci, C alkyl groups₂, C₃, C₄, C5 and Οθ. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, tbutyl, n-pentyl, s-pentyl, or n-hexyl.

In certain embodiments, a straight or branched chain alkyl has six or fewer carbon atoms (eg, C1-C6 for a straight chain, C3-C6 for a branched chain), and in another embodiment, a straight chain or branched has four or fewer carbon atoms.

As used herein, the alkyl linker is intended to include C1, C saturated aliphatic hydrocarbon groups₂, C₃, C_4l C_5l or C₆ straight chain (linear) and saturated aliphatic hydrocarbon groups C₃, C₄, C5, or branched chain Cs. For example, Ci-Ce alkyl linker is intended to include C1, C alkyl linker groups₂, C₃, C₄, C₅, and C₆. Examples of ί Μ ΡΙ

INSTI TUTO MEXICANO 'ÍTc-A.-fy;

alkyl linker include moieties having one to such as, but not limited to, methyl (-CH₂-), ^Qtil (-ΠΗ ,, Γ.Η ^ -χ n-prnpil fCH₂CH₂CH₂-), i-propil (-CHCH₃CH₂-), n-butyl (-CH₂CH₂CH₂CH₂-), s-butyl (CHCH₃CH₂CH₂-), i-butyl (-C (CH₃)₂Oh₂-), n-pentyl (-CH₂CH₂CH₂CH₂CH₂-), s-pentil (5 CHCH₃CH₂CH₂CH₂-) or n-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₂-). The term "substituted alkyl linker" refers to alkyl linkers having substituents that substitute one or more hydrogen atoms for one or more carbon atoms of the hydrocarbon backbone. Such substituents do not alter the sp3 hybridization 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 substituting for one or more carbon atoms in the hydrocarbon backbone.

As used herein, the term "cycloalkyl, cycloalkyl C₃, C₄, C₅, C₆, C₇ o Cs is intended to include hydrocarbon rings having three to eight carbon atoms in its ring structure. In one embodiment, a cycloalkyl group has five or six carbon atoms in the ring structure.

The term "substituted alkyl" refers to alkyl moieties having substituents that substitute one or more hydrogen atoms for one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,

IMPIIO

<img file="MX356368B_D0061.tif" />

alkoxycarbéfií! NDü alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, amylamino, arylcarbonylamino). , imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylate it, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, for example, with the substituents described above. An alkylaryl moiety or an aralkyl moiety is an aryl-substituted alkyl (eg, phenylmethyl (benzyl)).

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

Aryl includes groups with aromaticity, including conjugated, or multicyclic, systems with at least one aromatic ring. Examples include phenyl, benzyl, naphthyl, etc. Heteroalkyl groups are aryl groups, as defined above, having one to four heteroatoms in the ring structure, and aryl or heteroaromatic heterocycles may also be determined. As used herein, the term heteroaryl is intended to include a stable 5-, 6-, or 7-membered monocyclic ring

<img file="MX356368B_D0062.tif" />

or a 7, 8, 9 bicyclic aromatic heterocyclic ring, consisting of carbon atoms and one or more heteroatoms-for example 1 n 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, selected independently among the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom can be substituted or unsubstituted (ie, N or NR where R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (ie, N—> 0 and S (0) p, where p = 1 or 2). It should be noted that the total number of S and O atoms in heteroaryl is not more than

1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

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

In addition, the terms "aryl" and "heteroaryl" include multicyclic aryl and heteroaryl groups, eg, tricyclic, bicyclic, eg, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzolmldazole, benzotlofen, methylenedioxyphenyl, quinoline, isoquinoline, naphthrothin, , purine, benzofuran, deazapurine, or idolizine.

In the case of multicyclic aromatic rings, only one of the rings has to be aromatic (for example, 2,3-dihydroindole), although all rings can be aromatic (for example, quinoline), the second ring can also fuse or form a bridge.

The aryl or heteroaryl aromatic ring can

INDUSTRIAL more positions of the ring with the substituents mentioned as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl , arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, amino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfate, , sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylate it, or an aromatic or heteroaromatic moiety. Aryl groups can also fuse or bridge with alicyclic or heterocyclic rings, which are not aromatic, such that they form a multicyclic system (eg tetralin, methylenedioxyphenyl).

As used herein, carbocycle or carbocyclic ring is intended to include any stable monocyclic, bicyclic, or tricyclic ring having the specified number of carbon atoms, 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,

ΙΡΙ

INSTITíl'IO MEXICANO cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, clclohepfefn ©, cretotypyl, cycloheptenyl, adamantyl, cyclooctyl, chloclotenyl, —eieloctedienyl, fluoro; phenyl, naphthlo, ndanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0] bcyclooctane, [4.3.0] bicyclononane, [4.4.0] blclclodecane, and [2.2.2 ] b-cyclooctane. A bridge-shaped ring is produced when one or more than two non-adjacent carbon atoms are attached. In one embodiment, the bridged rings have one or two carbon atoms. It should be noted that a bridged ring always converts a monocyclic ring to a tricyclic ring. When a ring bridges, the listed substituents for the ring may also be present on the bridge. Fused rings (eg naphthyl, tetrahydronaphthyl) and spiro are also included.

As used herein, "heterocycle" includes any ring structure (saturated or partially unsaturated) that contains at least one ring heteroatom (eg, N, O, or S). Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, plperldine, plperazine, and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, carlzollozyl, benzyl, benzoyl, l-benzyl, l-benzylzyl, , chromenyl, cinolinyl, decahldroqulnollnllo, 2H, 6 / - / - 1,5,2-dltlazlnllo, dihldrofuro [2,3-b] tetrahydrofuran, furanyl, furazanil,

IMPI

MEXICAN PROPERTY INSTITUTE imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl / '^ iñUoHnil, indolizinyl, indolyl, 3H-indolyl, isatinolinyl, isobenzofuranyl, isochromonyl, isoindazolyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindanyl, isoindynyl , morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,

1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4 oxadiazol-5 (4H) -one, oxazolidinyl, oxazolyl, oxindolyl , pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, pyridinyl, pyrazyl, pyrazyl, pyrazyl, pyrazyl, pyrazyl, pyrazyl, , pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2Hpyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4 / - / - quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6Λ7-1,2,5-thiadia 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, triantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 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 of the designated atom is substituted with a selection from the indicated groups, provided that the normal valence of the designated atom is not exceeded, and that the substitution of a stable compound as a result. When a substituent is keto (ie = 0), then the 2 hydrogen atoms in the atom are substituted. Keto substituents are not present on aromatic moieties. The doubles

IMP

INSTrrUTU MEXICAN »» ··. &lt;. · Ring bonds, as used in the present document. Stable Compound and Stable Structure Indicate a compound that is solid enough to survive isolation in a useful degree of purity from a reaction mixture, and formulation in an effective therapeutic agent.

The term "acyl, as used herein, includes moieties containing the acyl radical (-C (O) -) or a carbonyl group. Substituted acyl includes acyl groups where one or more of the hydrogen atoms are substituted by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonylloxy, carboxylate, alkylcarbonyllo, arylcarbonyl, alkoxycarbonyl, , dlalqullamlnocarbonllo, alkylthiocarbonllo, alkoxy, phosphate, phosphonate, phosphinate, amino (Including alkyllamyl, dlalkylamine, arllamlno, dlarllamlno and alqullarllamlno), acllamlno (Including alkylcarbonllamlno, arllcarbonllamlno, carbamoílo and ureldo), amldlno, mino, sulfhldrilo, alkylthio, sulfur, trio, sulfate, alqullsulflnllo, sulfate, alqullsulflnllo alkylate it, or an aromatic or heteroaromatic residue.

The description of the memory of the present document must be taken in accordance with the laws and principles of chemical bonding. For example, it may be necessary to remove a hydrogen atom to accommodate a substitute at a given location. Furthermore, it should be understood that the definitions of the variables, i.e. groups R), as well as the locations of

IMPI 2 ??

INSTITUTO MEXICANO rc IA PROPIEDAD the links of the generic formulas of the invention (for example, Formulas I, la, Ib, II, lll, and IV), will be consistent with the chemical bond laws known in the art. It will also be understood that all of the compounds of the invention described above will further include bonds between adjacent atoms and / or hydrogens as necessary to satisfy the valence of each atom. That is, the 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: four bonds; oxygen: two bonds; and sulfur: two-six bonds.

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

The present invention provides methods for the synthesis of the compounds of each of the formulas described herein. The present invention provides detailed methods for the synthesis of various disclosed compounds of the present invention according to the following schemes shown in the examples.

Throughout the description, where the compositions are described as having, including, or comprising specific components, it is contemplated that the compositions also consist essentially of, or consist of, the

<img file="MX356368B_D0063.tif" />

Λ * Χ components listed. Similarly, where Tos^Dm ^ ¡^ §¿o describe having, including, or understanding stages of prnr.Acn ocpo ^ ¡f¡r>_Sq processes also consist essentially of, or consist of, the listed processing steps. Furthermore, it should be understood that the order of steps 5 or the order for carrying out certain actions is immaterial as long as the invention remains operable. Furthermore, two or more stages or actions can be carried out 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 the end of the overall process, although it may be desirable in certain cases to further convert the compound to a salt, polymorph, hydrate, solvate, or co-crystal thereof.

The compounds of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, using standard synthetic methods and procedures known to those skilled in the art, or which will be apparent to the skilled technician in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and transformations and manipulations of functional groups can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, such classic texts

<img file="MX356368B_D0064.tif" />

like Smith, Μ. B., March, J., March's Advanced Orgg

Mechanisms, and Structure, 5^to edition, John Wiley &amp; Sons, New York, 2001; and Greene, TW, Wuts, P. G M., Protective Groups in Organic Synthesis, 3^to edition, John Wiley &amp; Sons, New York, 1999, which has been Incorporated by reference herein, are useful and well-known organic synthesis textbooks known to those of skill in the art. The following descriptions of the synthetic methods are designed to illustrate, but not to limit, the general procedures for the preparation of the compounds of the present invention.

The compounds of the present invention can be conveniently prepared by a variety of methods familiar to one skilled in the art. The compounds of the present invention of each of the formulas described herein can be prepared according to the following procedures from commercially available starting materials or starting materials that can be prepared using procedures outlined in the literature. These procedures demonstrate the preparation of representative compounds of the present invention.

EXPERIMENTAL PART

General procedure 1

Hiinigs base (2.0 equivalents) was added to a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5 equivalents) in DMF (25 ml per g of MMF). The dark brown solution was stirred for 10 minutes, and became a brown suspension, before the addition of the alcohol

MEXICAN INSTITUTE

DK LA MONEDAD '

INDUSTRIAL.

(1.0-1.5 equivalents). The reaction was stirred rinrgnto ia hnroe ot ^^ pe ^ far⁰environment. Water was added, and the product was extracted into ethyl acetate three times. The organic layer combination was washed three times with water, dried with magnesium sulfate, filtered, and concentrated in vacuo at 45 ° C to obtain the crude product. The crude product was purified by chromatography on silica gel and, in some cases, further purified by trituration with diethyl ether to obtain the desired clean ester product. All alcohols were either commercially available or prepared following procedures known in the literature.

As an alternative to HBTU (A /, A /, A / 'hexafluorophosphate, A / -tetramethyl (1 / - / benzotriazole-1-l) uronic acid), one of the following can be used coupling reagents: EDCI / HOBt (N- (3-dimethylamine no propyl) -N'ethylcarbodiimide hydrochloride / hydroxybenzotriazole hydrate); COMU ((1-cyano-2-ethoxy-2-oxoetll¡denam¡nooxy) hemetofluorophosphate) dimethyllamno-morpholino-carbenium); TBTU (O- (benzotriazol-1-yl) - / \ /, A /, A / ', / V'-tetramethyluronon tetrafluoroborate); TATU (O- (7-azabenzotriazole-1-l) -1,1,3,3-tetramethyluronium tetrafluoroborate); oxime ((hydroxymino) ethyl cyanoacetate); PyBOP ((benzotriazol-1-loxy) tripyrrolidinephosphonium hexafluorophosphate); HOTT (5- (1-oxide-2-pyridyl) hexafluorophosphate Λ /, Λ /, Λ / ', Λ /' - tetramethyltluronium); FDPP (pentafluorophenyl dlfenllfosflnato); T3P (propylphosphonic anhydride); DMTMM (4- (4,6-d-methoxy-l, 3,5-triaz-2-yl) -4-methylmorpholin) tetrafluoroborate); PyOxim ([cyan (hydroxy-amino) acetate-O² tri-1-pyrrolidinylphosphonium ethylloxafluorophosphate); TSTU (A /, A /, / V ', / V-tetramethyl O- (N-succinimidyl) uronic tetrafluoroborate); TDBTU (O- (3,489 tetrafluoroborate

IMPI

DE pK PR d¡h¡dro-4-oxo-l, 2,3-benzotr¡az¡n-3-¡l) -W, / V, A / ', / V-tetramet¡luiOniO7F

MEXICAN INSTITUTE OF PROPERTY liirnnirWDUSTRiAL

<img file="MX356368B_D0065.tif" />

TU (O- (2-oxo-1 (2H) p¡r¡d¡l) tetrafluoroborate) - / V, / V, / \ /²/ W^,,-ltíliai iiettluíUltíDT-TOTU (tetrafluoroborate 0 - [(ethoxycarbonyl) cyanomethyleneam] - / V, MA / ', A / tetramethyluronium); IIDQ (1,2-d¡h¡dro-2-lsobutox¡-1-quolin, nocarboxylate of sobutyl);

or PyCIU (chlorodlpyrrolidinocarbenium hexafluorophosphate),

As an alternative to the Hünlg base (düsopropylethylamine), any one of the following expanded bases can be used: trletllamlna; 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-dayzabyl [5.4.0] undec-7-ene); DBN (1,5-diazabicycle [4.3.0] non-5-ene); or proton sponge® (A /, A /, A / ', / V-tetramethyl-1,8-naphthalenediam).

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 HCI in diethyl ether (1.5 equivalents). The mixture was stirred at room temperature for two hours. The solvent was decanted, more diethyl ether was added, and the solvent was 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 obtain the solid HCI salt.

General procedure 3

To a 100 mL single-neck round bottom flask equipped with a magnetic stirrer and nitrogen inlet / pan 11 mL of a freshly prepared monomethyl fumarate chloride-containing MTBE solution (4.9 g, 33 mmol) were added. ) and 50 ml more of MTBE at 20 ° C. The resulting yellow solution was cooled to &lt;20 ° C in a

<img file="MX356368B_D0066.tif" />

OF THE INDUSTRIAL PRnv'E'JAD

<img file="MX356368B_D0067.tif" />

<img file="MX356368B_D0068.tif" />

(33 mmol, 1 equiv.) Was added dropwise, via syringe, over approximately 10 minutes. The reaction mixture was allowed to stir at &lt;20 ° C for 10 minutes. At the end of time, the cooling bath was removed and the reaction was allowed to warm to 20 ° C and allowed to stir at a temperature of 20 ° C for 16 hours. The reaction was considered complete according to

TLC after 16 hours at RT. The reaction mixture was filtered through a sintered glass funnel with a plate to collect the cream-colored solid. The solid was dried in a vacuum oven at 25 ° C overnight to obtain the final product as an HCI salt. All alcohols were either commercially available or prepared following procedures known in the literature.

General procedure 4 - Alkylation with a suitable alkyl mesylate

A mixture of monomethyl fumarate (MMF) (1.3 equivalents), alkyl mesylate (1 equivalent), and potassium carbonate (1.5 equivalents) in acetonitrile (50 ml per g of MMF) was heated under reflux for the night. The mixture was partitioned between ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was dried (MgSCL). Filtration and removal of solvent under reduced pressure provided the crude product, which was each purified by chromatography on silica gel.

General procedure 5 - Alkylation with a suitable alkyl chloride

A mixture of monomethyl fumarate (MMF) (1.3 equivalents), alkyl chloride (1 equivalent), and potassium carbonate (1.5 equivalents) in acetonitrile or dimethylformamide (50 ml per g of MMF) was heated to 20 to 65 ° C

IMPIOS

MEXICAN INSTITUTE during the night. The mixture was partitioned between ^ Kfc ^ SÜháhSSÉ acetate saturated aqueous sodium hydrogen carbonate and the organic phase was dried (MgSCU). Filtration and removal of the solvent under reduced pressure provided the crude product, which was further purified by chromatography on silica gel.

Chemical analysis / procedures

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

Examples

Example 1

Acid_Hydrochloride_ (E) -2.2 '- ((2 - ((4-methoxy-4-oxobut-2enoyl) oxy) ethyl) azanodiyl) diacetic (1) ^₂n _Q_HQ co₂ho

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

<img file="MX356368B_D0069.tif" />

NMR ¹H (300 MHz, MeOD): δ 6.87 (2H, dd, J = 1 oe INDUSTRJA PROPERTY i.

4.09 (4H, s); 3.79 (3H, s); 3.57-3.63 (2H, m). [M + Hf = 290.12.

(2- (Methyl (2- (Methyl sulfonyl) et) l) amine) ethyl) methyl fumarate hydrochloride (2)

<img file="MX356368B_D0070.tif" />

He has

(2- (N-Methylmethylsulfonamido) ethyl) methyl fumarate 2 was synthesized following general procedure 1 and converted to the HCI salt of (2- (methyl (2- (methylsulfonyl)) hydrochloride etl) amine) etl) methyl fumarate (procedure 2) (1.39 g, 95%). ~

NMR ¹H (400 MHz, DMSO): δ 11.51 (1H, m); 6.83 (2H, dd, J = 15.8 Hz);

4.48 (1H, brs); 3.24-3.90 (7H, m); 3.07 (3H, s); 2.78 (2H, brs). [M + H]⁺ = 294,09.

2- (Dimethylamino) propylmethyl fumarate hydrochloride (3)

<img file="MX356368B_D0071.tif" />

He has

2- (Dimethylamine) propylmethyl fumarate 3 was synthesized following general procedure 1 and converted to the HCI salt of: 2- (dimethylamine) fumarate hydrochloride propylmethyl (procedure 2) (329 mg, 92%).

NMR ¹H (300 MHz, DMSO): δ 10.40 (1H, brs); 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). [M + H]⁺ = 216,14.

(E) -2 iodide - ((4-methoxy-4-oxobut-2-ene¡l) ox¡) -N, NN-trimethyllatamine (4) ~ l °

<img file="MX356368B_D0072.tif" />

INSTITí / rC .wüLAnu, ·. ·

To a solution of 2- (dimethylamino) et fumarate^AND) Wtt0u ^ 9 ^ -60 ^ -mg,

3.7 mmol) in diethyl ether (20 ml) motil iodide (2d6 µΙ, 3, Q-mmel) was added: - The mixture was stirred at room temperature for 18 hours; a precipitate slowly formed. The mixture was filtered, washed with diethyl ether and dried in a vacuum oven at 55 ° C for 18 hours to obtain (E) -2 - ((4-methoxy-4-oxobut-2-eneyl) iodide) oxy) -N, N, N-trimethylethanamine, a white solid (1.15 g, 90

%)·

NMR ¹H (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 + Hf = 216.14.

2- (4,4-Difluoropiper¡din-1-methyl ethyl fumarate hydrochloride (5)

HCI

2- (4,4-Difluoropyridine-1-yl) ethyl methyl fumarate 5 was synthesized following general procedure 1 and converted to the HCI salt of: 2- (4,4-fumarate hydrochloride -dfluoropyridin-1-yl) ethyl methyl (procedure 2) (780 mg, 87

%)·

NMR ¹H (300 MHz, DMSO): δ 11.25 (1H, brs); 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). [M + H]⁺ = 278,16.

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

I MPI / sINDUSTRIAL

<img file="MX356368B_D0073.tif" />

1- (Dimethylamino) propan-2-yl methyl fumarate general procedure 1 and was converted to the HCI salt of 1- (dimethylamino) propan-2-y fumarate hydrochloride l methyl (procedure 2) (690 mg, 72%).

NMR ¹H (300 MHz, DMSO): δ 10.41 (1H, brs); 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 (7) n HCI hydrochloride

The methyl (2-thomorpholinoethyl) fumarate hydrochloride 7 was synthesized 10 following general procedure 1 and converted to the HCI salt, methyl (2-tlomorpholinoethyl) fumarate (procedure 2) ( 623 mg, 93%).

NMR ¹H (300 MHz, DMSO): δ 11.03 (1H, brs); 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 + Hf = 216.14. [M + Hf = 260.11.

Methyl (2- (phenylamino) ethyl) fumarate hydrochloride (8)

HCI

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

NMR ¹H (300 MHz, DMSO): δ 6.50-6.80 (9H, m); 4.29 (2H, t, 4.4Hz); 3.72 (3H, s); 3.45 (2H, t, J = 4.5 Hz). [M + Hf = 250.13.

<img file="MX356368B_D0074.tif" />

.'JíL-mi »UVJ IIIVIV 1 '

2- (dimethylamine)? 2-mafifáfl fumarate hydrochloride

<img file="MX356368B_D0075.tif" />

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

NMR ¹H (300 MHz, DMSO): δ 10.20 (1H, brs); 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.

(2- (Methylsulfonyl) etl) methyl fumarate (10)

<img file="MX356368B_D0076.tif" />

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

NMR ¹H (400 MHz, CDCI₃): δ 6.88 (2H, dd, J = 16.0 Hz); 4.66 (2H, t, J = 5.8 Hz); 3.82 (3H, s); 3.38 (2H, t, J = 6.0Hz); 2.99 (3H, s). [M + Hf = 236.97.

2- (1,1-Doxydotomomorphol) ethylmethyl fumarate hydrochloride (11) or

^HCI °

2- (1,1-Dioxydothiomorpholine) ethyl fumarate 11 was synthesized following general procedure 1 and converted to the HCl salt of 2- (1,1-dioxldotomomorfol fumarate hydrochloride). No) ethyl (procedure 2) (1.33 g, 87%).

NMR ¹H (400 MHz, DMSO): δ 6.79 (2H, dd, J = 15.8 Hz); 4.34 (2H, brs);

IMPI faith?

MEXICAN INSTITUTE fz— 'J DE LA PROPIEDAD - - · industrial —3.72 (4Η, s); 2.90-3.70 (11H, m). [M + Hf = 292.11.

Matiln M9.V (2- (methyl (phenyl) amino) ethyl) fumarate hydrochloride

<img file="MX356368B_D0077.tif" />

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

NMR ¹H (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) ethylmethyl methyl fumarate hydrochloride (13)

<img file="MX356368B_D0078.tif" />

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

NMR ¹H (400 MHz, DMSO): δ 10.65 (1H, brs); 7.39-7.60 (5H, m); 6.82 (2H, 15 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).

[M + Hf = 278.16.

2- (2.5-Dioxopyrroled-1-l) ethal fumarate (14) fumarate

<img file="MX356368B_D0079.tif" />

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

ΙΜΡΪβ ^ Ι * ........ ~

NMR Ή (400 MHz, DMSO): δ 6.81 (2H, dd, J = 15, »^^ indust:

Hz); 3.84 (2H, t, J = 5.1 Hz); 3.80 (3H, s); 2.73 (4H, s). [M + Hf = 256.07. Methyl (2- (piperidin-1-Ethyl) fumarate hydrochloride (15)

<img file="MX356368B_D0080.tif" />

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

NMR ¹H (400 MHz, DMSO-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 + Hf = 241.93.

Methyl (2-morpholinoethyl) fumarate (16) hydrochloride or

^hci

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

NMR ¹H 1H (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 6.92 (d, J = 15.9 Hz, 1H), 15 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 + Hf = 244.00.

2- (1,4-Dioxa-8-azaspiro [4.5ldecan-8-ll) etlmetyllo (17) fumarate hydrochloride ^hci or

<img file="MX356368B_D0081.tif" />

INATlTuTO MEXICANO.

OF PROPERTY C j. i

2- (1,4-Dioxa-8-az᧠^ íi ^ 4.5ÍdecaTí-'8il) ethylmethyl 17 fumarate hydrochloride was synthesized following the general procedure or. ——

NMR ¹H (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 6.91 (d, J = 15.9 Hz, 1H), 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 (m, 2H), 2.20 - 2.02 (m, 2H), 1.89 - 1.79 (m, 2H). [M + Hf =

300,00.

Methyl (2- (pyrrolidin-1-ethyl) fumarate (18) hydrochloride

<img file="MX356368B_D0082.tif" />

or

Methyl (2- (pyrrolidin-1-yl) ethyl) fumarate 18 hydrochloride was synthesized 10 following general procedure 3.

NMR ¹H (400 MHz, DMSO-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 (m, 4H). [M + H]⁺ = 228,46.

2- (Dimethylamine) ethyl methyl fumarate hydrochloride (19) ^HCI⁰

2- (Dimethylamine) ethylmethyl fumarate hydrochloride 19 was synthesized following general procedure 3.

NMR ¹H (500 MHz, DMSO-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 • IMPI • n (diethylamino) ethylmelite (20) wsTrrvTo Mexican fumarate hydrochloride BE THE INDUSTRIAL PROPERTY

<img file="MX356368B_D0083.tif" />

Ο '^ ο' ^ Αγ⁰', ^HCI

2- (Diethylamino) ethylmethyl fumarate hydrochloride 20 was synthesized following general procedure 3.

NMR ¹H (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 6.90 (d, J = 15.8 Hz, 1H),

6.81 (d, J = 15.9 Hz, 1H), 4.56 - 4.48 (m, 2H), 3.76 (s, 3H), 3.48 - 3.38 (m, 2H) , 3.15 (cc, J = 9.7, 5.5, 4.9 Hz, 4H), 1.24 (t, J = 7.3 Hz, 6H). [M + Hf = 230.59.

2- (3,3-Difluoropyrroled-1-yl) ethyl methyl fumarate hydrochloride (21)

<img file="MX356368B_D0084.tif" />

2- (3,3-Dfluoropyrrolidin-1-yl) ethylmethyl fumarate 21 was synthesized from 2- (3,3-difluoropyrrolidin-1-yl) ethanol following general procedure 1.

2- (3,3-Difluoropyrrolidin-1-yl) ethylmethyl fumarate was converted to 2- (3,3-difluoropyrrolidin-1-yl) ethylmethyl fumarate hydrochloride following general procedure 2 (0.55 g, 69%).

NMR ¹H (300 MHz, DMSO); δ 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 + Hf = 264.14.

2- (Bis (2-methoxy-ethyl) amino) ethylmethyl (24) fumarate hydrochloride or

<img file="MX356368B_D0085.tif" />

2- (Bis (2-methoxyethyl) amino) ethylmethyl fumarate 24 was synthesized from

100

IMPI

ΙΝΓΓΤΠΤΤΟ MEXICAN

Ct LA HtüPÍEOAP and

2- (bis (2-methoxyethyl) amino) ethanol following the general procedure 2- (Bis (2-methoxyethyl) amino) ethylmethyl was converted to fumarate hydrochloride of

2- (bis (2-methoxyetll) amine) etylmethyl following general procedure 2 (1.00 g,

%).

NMR ¹H (300 MHz, DMSO); δ 12.84 (1H, brs), 6.90 (2H, d), 4.73 (2H, t),

3.92 (4H, t), 3.81 (3H, s), 3.62 (2H, brs), 3.51-3.36 (4H, m), 3.34 (6H, s). m / z [M + Hf = 290.12.

2- (2,4-Dioxo-3-azab¡c¡clo3.1.01 hexan-3-¡l) ethyl methyl fumarate (22)

<img file="MX356368B_D0086.tif" />

Oh

3-oxablclclo [3.1.0] hexane-2,4-done (1.0 g, 8.9 mmol) and ethanolamine (545 mg, 8.9 mmol) were purely heated at 200 ° C for 2 hours. The crude reaction mixture was purified by chromatography on silica gel (EtOAc) obtaining the 3- (2-hydroxyethyl) -3-azab-cycle [3.1.0] hexane-2,4-d¡ one (1.06 g, 77%).

NMR ¹H (300 MHz, CDCI₃): δ 3.71 (2H, t), 3.56 (2H, t), 2.51 (2H, dd), 1.95 (1H, sa), 1.59-1.43 (2H, m ).

or

<img file="MX356368B_D0087.tif" />

2- (2,4-Dioxo-3-azabylcyl [3.1.0] hexan-3-yl) ethyl methyl 22 fumarate was synthesized from 3- (2-hydroxyethyl) - 3-azabicyclo [3.1.0] hexane-2,4-dlone following general procedure 1 (452 ​​mg, 53%).

101

<img file="MX356368B_D0088.tif" />

NMR ¹H (300 MHz, CDCI₃): δ 6.81 (2H, d), 4.28 (2H, t), 2.48 (2H, dd), 1.59-1.49 (1H, m), 1.44-1.38 (1H, m) m / z [Μ ± Η] ί - == - 26β,

2- (2,2-Dimethyl-5-oxopyrrrolidin-1-l) fumarate (24) ⁰ i

<img file="MX356368B_D0089.tif" />

Tere-Butyl Acrylate (19.7 ml, 134.8 mmol) was added dropwise over minutes to a solution heated to reflux temperature of 2-n -tropropane and Triton B (40% in methanol) (440 µΙ) in ethanol (50 ml). The reaction was heated to reflux temperature overnight. The reaction solvent was removed under reduced pressure, yielding a crude residue which was dissolved in ethanol (200 ml) and hydrogenated overnight (300 psl, 2.07 MPa) using Raney nickel (approximately 15 g). The reaction was filtered through cellte. The solvent was removed under reduced pressure to provide tert-butyl 4-amlno-4-methylpentanoate (15.82 g, 63% yield).

NMR ¹H (300 MHz, CDCI3): δ 2.26 (2H, t), 1.65 (2H, t), 1.43 (9H, s), 1.68 (6H, s).

Chloroacetaldehyde (45% H) was added to a solution of tere-butyl 4-amlno-4-methyl-pentanoate (3.0 g, 16.04 mmol) in methanol (100 ml).₂O) (6.7 ml, 38.4 mmol) followed by acetic acid (2 ml, 35.0 mmol). After 1.5 hours sodium clanoborohydride (1.51 g, 24.0 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction was divided between a

102

<img file="MX356368B_D0090.tif" />

Ini II 1 U Η 'ΜΓ.Αι · -ζ> i'- * /' · '.

saturated aqueous solution of hydrogen carbonate fWOtl) * and dichloromethane (300 ml). The organic phase was dried- (MgSQ4). Filtration ~ and -removal of the solvent under reduced pressure provided tere-butyl 4 - ((2-chloroethyl) amino) 4-methylpentanoate (3.90 g, 98% yield).

NMR ¹H (300 MHz, CDCI₃): δ 3.63 (2H, t), 2.85 (2H, t), 2.24 (2H, t), 1.67 (2H, t), 1.44 (9H, s), 1, 07 (6H, s).

ci

A mixture of tere-butyl 4 - ((2-chloroethyl) amino) -4-methylpentanoate (3.9 g,

15.7 mmol) and trifluoroacetic acid (27 ml) in dichloromethane (80 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in more dichloromethane and concentrated again. This was repeated 3 more times until most of the excess trifluoroacetic acid was removed. The residue was dissolved in dichloromethane (500 ml) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (4.61 g, 24.1 mmol), N-hydroxybenzotriazole hydrate (3.25 g, 24.1 mmol) and diisopropylethylamine (21 ml, 120 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was washed with water (300 ml) and dried (MgSO₄). Filtration and removal of the solvent under reduced pressure provided a crude residue which was purified by chromatography on silica gel (heptane to ethyl acetate) obtaining 1- (2-chloroethyl) -5,5-dimethylpyrrolidin2-one (1.24 g , 44% yield).

103

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MEXICAN INSTITUTE OF PROPERTY

NMR ¹H (300 MHz, CDCI₃); δ 3.61 (2H, t), 3.41 (2HfO8 (2H, t), 1.24 (6H, s). ——

<img file="MX356368B_D0091.tif" />

, 1,88

2- (2,2-D-Methyl-5-oxopyrrol-din-1-l) ethyl methyl 24 fumarate was synthesized from 1 - (2-chloroethyl) -5,5- dimethylpyrrolidin-2-one following general procedure 5 (1.02 g, 41%).

NMR ¹H (300 MHz, CDCI₃); 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 + Hf = 270.17.

4-oxide of (E) -4- (2 - ((4-methoxy, 4-oxobut-2-ene, Dox,) etl) morpholine (26)

<img file="MX356368B_D0092.tif" />

To a solution of methyl (2-morpholinyethyl) fumarate (1.1 g, 4.5 mmol) [synthesized from 4- (2-chloroethyl) morpholine following general procedure 5] in dichloromethane m-Chloroperbenzoic acid (1.87 g, 5.4 mmol) was added to the reaction mixture and stirred for 1 h. The reaction mixture was diluted with water (25 ml) and washed with dichloromethane (3 x 50 ml). The aqueous phase was lyophilized to give 4-oxide of (E) -4- (2 - ((4-methoxy-4-oxobut-2-ene-l) oxi) ethyl) morpholine 26 (0.19 g, 16%).

NMR ¹H (300 MHz, CDCI₃); 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 + Hf = 260.2.

104

<img file="MX356368B_D0093.tif" />

2- (3,5-D-oxomorpholino) ethylmethyl fumarate (27

------ .......

₀A / °

To a solution of glycolic anhydride (2.0g, 17mmol) in pyridine (10ml) was added ethanolamine (2.1g, 34mmol) and heated at reflux temperature for 2h. The volatile compounds were removed in vacuo and the residue was heated at 180 ° C for 2 h and then at 220 ° C for 90 min. The reaction mixture was cooled and the residue was purified on silica gel eluting with dichloromethane / ethyl acetate (4: 1) obtaining 4- (2-hydroxyethyl) morpholine-3,5dione (1.05 g, 38%). NMR¹H (300 MHz, CDCI₃); 4.39 (4H, s), 4.02 (2H, t), 3.80 (2H, t).

2- (3,5-Dioxomorpholino) ethylmethyl fumarate 27 was synthesized from 4 (2-hydroxyethyl) morpholine-3,5-dione following general procedure 1 (0.82 g, 96

%)·

NMR ¹H (300 MHz, CDCI₃); 6.83 (1H, d), 6.75 (1H, d), 4.39-4.43 (6H, m), 4.12 (2H, t), 3.79 (3H, s).

2- (2) fumarate hydrochloride₁2-Methylmorpholino) etylmetyl (28)

To a solution of 2,2-dimethylforfoline (1.0 g, 8.7 mmol) in dichloromethane

105

<img file="MX356368B_D0094.tif" />

(35 ml) Chloroacetaldehyde (50% in water, 1.65 ml, 13.0 mmolf, followed by sodium triacetoxyborohydride (2.8 g, 13.0 mmol) was added. The reaction mixture was stirred for 90 min, diluted with a 1M aqueous solution of sodium hydroxide (40 ml) and the organic phase was separated The aqueous phase was extracted with 5 dichloromethane (2 x 30 ml) and the organic phases were combined. After drying with MgSO4, the volatiles were removed in vacuo to give 4- (2-chloroethyl) 2,2-dimethylmorpholine (1.45 g, 94%).

NMR ¹H (300 MHz, CDCI₃); 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-Dimethylmorpholine) ethylmethyl fumarate 28 was synthesized from 4 (2-chloroethyl) -2,2-dimethylmorpholine following general procedure 5 (0.71 g, 93%). 4- (2-Chloroethyl) -2,2-dimethylmorpholine was converted to 4- (2-chloroethyl) -2,2-dimethylmorpholine hydrochloride following general procedure 2 (0.69 g, 87%).

NMR ¹H (300 MHz, CDCI₃); 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 + Hf = 272.2.

2- (2,6-Dimethylmorpholino) ethyl methyl fumarate hydrochloride (29)

To a solution of 2,6-dimethylforfoline (1.0 g, 9.0 mmol) in dichloromethane

106

IMPI (40 ml) chloroacetaldehyde (50% in water, 1.0 ^ · ^^

INDUSTRIAL

<img file="MX356368B_D0095.tif" />

acetic (0.75 ml, 13.5 mmol) followed by sodium triacetoxyborohydride (2.8 g, 13.5 mmol). The reaction mixture was stirred for 4 hours, diluted with dichloromethane (20 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (30 ml). The organic phase was separated, dried with MgSO₄ and the volatile compounds were removed in vacuo. The residue was further purified by chromatography on silica gel eluting with heptanes / ethyl acetate (1: 1) to give 4- (2-chloroethyl) -2,6-dimethylmorpholine (0.44 g,

%).

NMR ¹H (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).

or lyO

2- (2,6-Dimethylmorpholine) ethylmethyl fumarate 29 was synthesized from 4 (2-chloroethyl) -2,6-dimethylmorpholine following general procedure 5 (0.54 g, 71

%). 2- (2,6-Dimethylmorpholine) ethylmethyl fumarate was converted to 2- (2,6-dimethylmorpholine) ethylmethyl fumarate hydrochloride following general procedure 2 (0.19g, 64%).

NMR ¹H (300 MHz, CDCI₃); 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, t), 1.10 (6H, d). m / z [M + Hf = 272.2.

Methyl (2- (3-Oxomorpholino) ethyl) fumarate (30)

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INSTITUTO MEXICa no DE LA FRÜP1EDAD

INDUSTRIAL

<img file="MX356368B_D0096.tif" />

HO

<img file="MX356368B_D0097.tif" />

A mixture of potassium tert-butoxide (5.9 g, 52.3 mmol) and toluene (50 ml) was heated at 75 ° C for 30 min and then dletanolamine (5.0 g, 47.6 mmol) was added . The reaction mixture was heated for an additional 30 min, and then methyl chloroacetate (4.4 ml, 50.0 mmol) was added.

After an additional 2 hr 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 was evaporated. The residue was further purified by flash chromatography on silica gel to give 4- (210-hydroxy-ethyl) morpholine-3-one (0.65 g, 9%).

NMR ¹H (300 MHz, CDCI₃); 4.19 (2H, s), 3.89 (2H, t), 3.81 (2H, t), 3.57 (2H,

t), 3.48 (2H, t), 2.89 (1H, s).

Methyl (2- (3-oxomorfollno) etll) fumarate 30 was synthesized from 4- (215 hydroxyethyl) morpholin-3-one following general procedure 1 (0.71 g, 62%).

NMR ¹H (300 MHz, DMSO); 6.72 (2H, s), 4.28 (2H, t), 3.98 (2H, s), 3.77 (2H, t), 3.71 (3H, t), 3.59 (2H , t), 3.38 (2H, t). m / z [M + Hf = 258.1.

Methyl (2- (2-oxomorpholine) etl) hydrochloride (31)

108

IMPIOS

<img file="MX356368B_D0098.tif" />

Methyl (2- (2-oxomorpholino) etl) fumarate 31 is * §8i ^ 1 ^^cE $l | baittu7 hydroxyethyl) morpholin-2-one following general procedure 1 (0.53 g, 34%). Methyl (2- (2-oxomorpholin) etl) fumarate was converted to methyl (2- (2-oxomorpholino) etl) fumarate following general procedure 2 (0.20g,

34 %).

NMR ¹H (300 MHz, DMSO); 3.75 (2H, s), 4.29-4.23 (4H, m), 3.71 (3H, s), 3.34 (2H, s), 2.73 (2H, t), 2 , 68 (2H, t). m / z [M + Hf = 258.15.

2- (8-Oxa-3-azabylyl [3.2.noctan-3-l) ethylmethyl fumarate hydrochloride

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

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

NMR ¹H (300 MHz, D₂OR); 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 + Hf =

270,0.

2- (2 - ((Dimethyl) methyl) morpholine) etylmetllo fumarate hydrochloride

133)

109 I

HCI 'N ^

INSTITUTO MEXICANl) OF THE PROPERTY

INDUSTRIAL v - &lt;

2- (2 - ((dimethylamino) methyl) morpholino) ethyl methyl 33 fumarate was synthesized from 1- (4- (2-chloroethyl) morpholin-2-¡ l) -N, Ndimethylmethanamine following general procedure 5 (0.17 g, 16%).

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

NMR ¹H (300 MHz, D₂OR); 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 10 (3H, m), 2.94 (1H, dd), 2.81 (6H, brs), m / z [M + Hf = 301.2.

2 - ((3S, 5S) -3.5-dimethylmorpholino) ethylmethalochloride (34) or

<img file="MX356368B_D0099.tif" />

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

The 2 - ((3S, 5S) -3,5-dimethylmorpholine) ethyl fumarate was converted to the 2 - ((3S, 5S) -3,5-dimethylmorpholine) ethanol hydrochloride. lmethyl following general procedure 2 (0.08 g, 68%).

NMR ¹H (300 MHz, D₂OR); 7.15-7.00 (2H, m), 4.77-4.70 (2H, m), 4.20-4.08 20 (2H, m), 4.01-3.85 (8H, m), 3.68-3.58 (1H, m). m / z [M + Hf = 272.3.

2- (2,5-D-oxomorpholine) ethyl methyl fumarate (35)

110

IMPO

MEXICAN INSTITUTE £ »E LA PROPISOáO ^l.

TWUJhXIAL ⁰ V o

2- (2,5-Dioxomorpholine) ethylmethyl fumarate 35 was synthesized from 4 (2-hydroxyethel) morpholine-2,5-done following the general procedure 1 (0.27g, 65%). NMR¹H (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 + Hf = 272.2.

(E) -Methyl-3- (4-methyl-2,5,7-trioxabicyl (2.2.2) octan-1-! Dacrylate (130)

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

NMR ¹H (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).

or

To a solution of methyl ((3-methyloxetan-3-yl) methyl) fumarate 130 (0.20 g, 0.93 mmol) in dichloromethane (5 ml) at 5 ° C was added boron trifluoride diethyl etherate (0.058 mi, 0.47 mmol). After 1 h an additional portion of boron trifluoride diethyl etherate (0.058 ml, 0.47 mmol) was added and the reaction mixture was heated at 20 ° C for 1 h. Triethylamine (0.13 ml, 0.93 mmol) was added to the reaction mixture, and then it was directly loaded into a

111

IMPí @ Hí

IC5ΤΓΠΠΌ MEXICANO DE LA PROPIÉPAD silica gel column. The desired product was eluted with h^Ntriethylamine-containing (2.5% v / v) epphane / acetycyl ethyl (6: 4) yielding (E) -3- (4-methyl ^ 2, X77 trloxablclclo [2.2.2] octan-1 -ll) acrylate methyl (0.12 g, 60%).

NMR ¹H (300 MHz, CDCI₃); 6.66 (1H, d), 6.25 (1H, d), 3.97 (6H, s), 3.73 5 (3H, s), 0.84 (3H, s). m / z [M + Hf = 215.2.

Prop-2-in-1-yl methyl fumarate (131) or

Methyl prop-2-ln-1-II fumarate 131 was synthesized from propargyl alcohol following general procedure 1 (0.51 g, 68%).

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

3.60 (1H, t).

2- (1,3-dxoxo, solndol-n-2-l), fumarate (36)

<img file="MX356368B_D0100.tif" />

The 2- (1,3-dioxolsol-n-2-ll) etyll-fumarate 36 fumarate was synthesized from 15 2- (2-hldroxl, etl), solndolin- 1,3-dlone following general procedure 1 (0.63 g,

%).

NMR ¹H (300 MHz, MeOD); 7.87-7.77 (4H, m), 6.74-6.73 (2H, m), 4.45-4.40 (2H, m), 4.01-3.96 (2H, m ), 3.76 (3H, s). m / z [M + Hf = 304.1.

4- (2,5-Dioxoplrrol¡d¡n-1-¡l) butylomethalo fumarate (132)

112

<img file="MX356368B_D0101.tif" />

ρ o.

<img file="MX356368B_D0102.tif" />

, ο

O me

4- (2,5-Dioxopyrrolin-1-yl) butylmethyl fumarate 132 was synthesized from 1- (4-hydroxybutyl) pyrrolidine-2,5-dione following general procedure 1 ( 0.77 g, 79%).

NMR ¹H (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-1-l) ethylmethyl fumarate (36)

<img file="MX356368B_D0103.tif" />

2- (3,3-Dimethyl-2,5-dioxopyrrolin-1-yl) ethylmethyl fumarate 36 was synthesized from 1- (2-hydroxyethyl) -3,3-dimethylpyrrolidine-2, 5-dione following general procedure 1 (0.72 g, 74%).

NMR ¹H (300 MHz, CDCI₃); 6.83 (1H, d), 6.77 (1H, d), 4.38 (2H, t), 3.82 (1H, t), 3.80 (3H, s), 2.55 (2H , s), 1.31 (6H, s). m / z [M + Hf = 284.1.

3- (2.5-D-oxopyrrolid-n-1-l) fumarate fumarate (133)

<img file="MX356368B_D0104.tif" />

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

113

MEXICAN INSTITUTE - - \ property

IMPIDO

ΙΝβΤΙΤ

NMR ¹H (300 MHz, MeOD); 6.82 (2H, s), 4.17 (2H, t), 3j t), 2.67 (4H, s), 1.95 (2H, dt). m / z [M + Hf = 270.2.

(2- (2-Oxop¡rrol¡d¡n-1-Dethyl) methyl fumarate (38)

or.

OMe

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

NMR ¹H (300 MHz, MeOD); 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 + Hf = 242.1 (2- (2-oxooxazolidin-3-yl) et¡D methyl fumarate (39) or

<img file="MX356368B_D0105.tif" />

Methyl (2- (2-oxooxazolid-3-l) etl) fumarate 39 was synthesized from

3- (2-hydroxyethyl) oxazolidine-2-one following general procedure 1 (0.77 g, 92

%)·

NMR ¹H (300 MHz, MeOD); 6.82 (2H, s), 4.39-4.30 (4H, m), 3.78 (3H, s), 15 3.72-3.67 (2H, m), 3.58-3 , 54 (2H, m). m / z [M + Hf = 244.2.

2- (4,4-Dimethyl-2.5-doxyimidazolidin-1-deetylmethyl fumarate (42) or

<img file="MX356368B_D0106.tif" />

2- (4,4-Dimethyl-2.5-doxoxo-midazole-d-n-1-yl) ethyl methyl fumarate 42 is

114

<img file="MX356368B_D0107.tif" />

synthesized from 3- (2-hydroxyethyl) -5,5-dimethylimidazolidi general procedure 1 (0.33 g, 33%).

NMR ¹H (300 MHz, CDCI₃); 6.82 (2H, s), 5.50 (NH), 4.40 (2H, t), 3.86-3.76 (5H, m), 1.43 (6H, s). m / z [M + Hf = 285.2.

(2- (N-propionylpropyl) etl) methyl fumarate (42)

<img file="MX356368B_D0108.tif" />

Methyl (2-proplonamidoethyl) fumarate 41 was synthesized from N- (2-hydroxyethyl) propionamide following general procedure 1 (1.7g, 96%).

NMR ¹H (300 MHz, CDCI₃); 6.87 (2H, s), 4.29 (2H, t), 3.81 (3H, s), 3.58 (2H, C), 2.21 (2H, c), 1.15 (3H , t).

<img file="MX356368B_D0109.tif" />

N— 'OMe

A mixture of methyl (2-proplonamldoetll) fumarate (1.7g, 7.4mmol), proplonyl anhydride (36ml) and sodium proplonate (1.0g, 10.4mmol) was heated to

150 ° C for 16 h. The reaction was cooled, concentrated to 1/3 volume, and then loaded onto a column of silica gel and eluted with 0-20% ethyl acetate / dichloromethane. Fractions containing product were combined, evaporated and re-purified by flash silica gel chromatography eluting with 10-50% ethyl acetate / heptanes to give

115

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INSTm m 'méxicano * BE LA HLOFIEC-AO el (2- (N-prop¡on¡lprop¡onam¡do) etíl) methyl fumarate 4 ^ (0, .18 ς ^ ΦΜί /).

NMR ¹H (300 MHz, CDCI₃); 6.83-6.82 (2H, m), 4.34 (2II, t), 4, Q1- (21-trT);

<img file="MX356368B_D0110.tif" />

3.81 (3H, s), 2.75 (4H, c), 1.16 (6H, t).

2 - ((3R.4S) -3,4-dimethyl-2.5-d-oxopyrol-din-1-l) ethal fumarate (23) or

<img file="MX356368B_D0111.tif" />

or

Racemic 2 - ((3R, 4S) -3,4-d-methyl-2,5-d-oxopyrolidin-1-yl) ethylmethyl fumarate 23 was synthesized from (3R, 4S) -1- (2-hydroxyethyl) - 3,4dmethylprolrolid-2,5-done racemic following general procedure 1 (0.54g, 44%).

NMR ¹H (300 MHz, CDCI₃); 6.81-6.80 (2H, m), 4.37 (2H, t), 3.82 (2H, t),

3.80 (3H, s), 3.00-2.88 (2H, m), 1.25-1.18 (6H, m). m / z [M + Hf = 284.2.

2-Acetamidoethylmethyl fumarate (43)

<img file="MX356368B_D0112.tif" />

<img file="MX356368B_D0113.tif" />

OMe

2-Acetamidoethylmethyl fumarate was synthesized from N- (215 hldroxletyl) acetamide 43 following general procedure 1 (0.23g, 70%).

NMR ¹H (300 MHz, CDCI₃); 6.87 (2H, s), 5.80 (NH), 4.29 (2H, t), 3.81 (3H, s), 3.57 (2H, c), 2.00 (3H, s ). m / z [M + Hf = 216.14.

2- (N-Acetylacetate) fumarate etylmethyl (44)

116 or

<img file="MX356368B_D0114.tif" />

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<img file="MX356368B_D0115.tif" />

A mixture of 2-acetamidoethylmethyl fumarate (0.62g, 2.9mmol), acetic anhydride (15ml) and sodium acetate (0.33g, 4.0mmol) was heated at reflux temperature for 20h. . The reaction mixture was evaporated and the residue was suspended in dichloromethane. The supernatant was loaded onto a silica gel column and eluted with 0-20% ethyl acetate / dichloromethane to give 2- (N-acetylacetamido) ethylmethyl fumarate 44 (0.36g, 48%).

NMR ¹H (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).

2 - ((tert-Butoxycarbonyl) amino) ethyl methyl fumarate (48)

<img file="MX356368B_D0116.tif" />

oo

To a suspension of monomethyl fumarate (MMF) (1.0 equivalent) in dichloromethane (11 ml per g of MMF) was added diisopropylethylamine (3 equivalents), 2-f (ferc-butoxycarbonyl) amino) ethanol (1.02 equivalents) ) and A /, A /, / V ', A /' - tetramethyl O- (1 / - / - benzotriazol-1-yl) uronic tetrafluoroborate (1.5 equivalents). The reaction was stirred for 1-18 hours at &lt;10 ° C. The reaction was quenched with 1M hydrochloric acid (0.6 ml / ml DCM). The organic layer was washed with a 10% (w / w) aqueous sodium bicarbonate solution (0.6 ml / ml DCM) followed by a 37% (w / w) sodium chloride solution (0, 6 ml / ml of

DCM). The organic layer was dried with sodium sulfate, filtered to remove the

117

<img file="MX356368B_D0117.tif" />

desiccant agent, and the solution was added to a tap I of silica / g of MMF) and the stopper was washed with DCM until qua no oo eiluyú ni¿rs piudüCto. -80% of the DCM was removed under reduced pressure at 30 ° C, at which time 25 ml of MTBE / g of MMF was added and the solution was concentrated adlclonally to

30 ° C until -10ml / g MMF remained. The resulting suspension was cooled to ° C for at least 1 hour and then the resulting solid was collected by filtration to obtain the desired MMF ester prodrug. (3.8g, 91%).

NMR ¹H (400 MHz, DMSO-cfe) δ 7.08 (t, J = 5.4 Hz, 1H), 6.89 (d, J = 15.8

Hz, 1H), 6.79 (d, J = 15.8 Hz, 1H), 4.18 (t, J = 5.3 Hz, 2H), 3.81 (s, 3H), 3.28 ( c, J = 5.4 Hz, 2H), 1.43 (s, 9H). m / z [M + Hf = 274.3.

2- (2,5-Dioxo-2,5-dihydro-1 / - / - prolol-1-l) ethylmethyl fumarate (55)

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 A /, tetrafluoroborate /, / V ', / V-tetramethyl-O- (1H-benzotriazole-1-l) uronium (1.5 equivalents). The reaction was stirred for 1-18 hours at &lt;10 ° C. The reaction was quenched with 1M hydrochloric acid (0.6 ml / ml DCM). The organic layer was washed with a 10% (w / w) aqueous sodium bicarbonate solution (0.6 ml / ml DCM) followed by a 37% (w / w) sodium chloride solution (0, 6 ml / ml DCM). The organic layer was dried with sodium sulfate, filtered to remove the drying agent, and the solution was

118 fMP '' i σιτυτο mexican ^ζ· Added to a silica plug (~ -6 g of silica gel / g of ta ^ SfeSé washed with DCM until no more product eluted. -80% of DCM ae-olimino-under reduced pressure at 30 ° C, at which time 25 ml of MTBE / g of MMF was added and the solution was further concentrated at 30 ° C until -10 ml / g of

MMF. The resulting suspension was cooled to 5 ° C for at least 1 hour and then the resulting solid was collected by filtration to obtain the desired MMF ester prodrug. (2.4g, 67%).

NMR ¹H (400 MHz, chloroform-d) 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 [M + H]⁺ = 254,2.

Reference compound A

2- (Diethylamine) -2-oxoethylmethyl fumarate> ⁰

2- (Diethylamino) -2-oxoethylmethyl fumarate was synthesized following the general procedure 3 and according to the data indicated in the patent of the

United States No. 8,148,414.

Example 2- Chemical stability of various compounds in water

Stock solutions of the compounds were prepared in acetonitrile or in acetonitrile / methanol at 20 mg / ml and 20 µΙ, introduced into 3 ml of phosphate buffer (100 mM) and incubated at 37 ° C. Aliquots (50 µΙ) were taken at different time points, and diluted 20 times with ammonium formate (pH 3.5) / acetonitrile.

Diluted samples were analyzed by HPLC. Peak areas

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XA '' '- ^ ¾ corresponding to the compounds were plotted at time, and the data were fitted to a first order monoexponential disappearance reaction. The rate constant and half-life were determined (Table 3). In some cases, where the half-life is too long (> 360 min), an estimated half-life value was reported using the initial slope at low conversion (<10%).

Table 3.

<td>Compound</td><td>pH 8 (t^{1 / z}, 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>

<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>

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<td>Compound</td><td>-_- HOTlTUrQ M pH 8 (t^{1 / z}, min) ““ ¿S</td><td>XiCANO r &lt; ) P1EDAÜ Vj-Xz- ÍU USTRIAL</td>

<td rowspan="2"> 18</td><td>an</td><td></td>

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

<td> 19</td><td> 6,0</td><td></td>

<td> 20</td><td> 5,0</td><td></td>

<td>Compound</td><td> 120</td><td></td>

<td>reference to</td><td></td><td></td>

Stock solutions of the compounds were prepared in acetonitrile or in acetonitrile / MeOH at 0.05 M. A 0.010 ml aliquot of the stock solution was ¹⁰ It was introduced into 1 ml of 50 mM phosphate buffer pH 8 and incubated at 37 ° C. Normally, aliquots (0.010 ml) were taken at different time points and immediately injected into the HPLC kit with UV detection (211 nm). The peak areas corresponding to the compounds were plotted against time, and the data were fitted to a first order monoexponential disappearance reaction. The speed constant and the half-life were determined from the slope (Table 4).

Table 4.

<td>Compound</td><td>pH 8 (t^1/2, 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>

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<td>Compound</td><td>pH 8 (t^1/2, min)</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>

<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>

MEXICAN INSTITUTE OF THE FFOriEDAt) 1NPU3T5UAL

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<img file="MX356368B_D0118.tif" />

<td>Compound</td><td>pH 8 (t^1/2, min)</td>

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

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

Example 3- Evaluation of chemical stability in water by NMR

Chemical hydrolysis was followed by dissolution of the ester in D₂Or phosphate buffered (pH 7.9) in an NMR tube, heating the NMR tube to 37 ° C and periodic recording of the spectrum. A temporary monitoring of these different species produced by hydrolysis of the diesters was carried out. See Figures

1-5.

Example 4- Delivery of MMF in rats after oral administration of prodrugs

Rats were obtained commercially and precannulated into the jugular vein. Animals were conscious at the time of the experiment. All animals fasted overnight and up to 4 hours after dosing of a prodrug of the disclosure.

Blood samples (0.25 ml / sample) were taken from all animals at different time points up to 24 hours after dosing in tubes containing sodium fluoride / sodium EDTA. The samples were centrifuged to obtain the plasma. Plasma samples were transferred to new tubes and stored at or below -70 ° C prior to analysis.

To prepare the assay standards, 20 ul of rat plasma standard were inoculated with 60 ul of Internal standard. Sample tubes were vortexed

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for at least 1 min and then centrifuged at 30OtTr ^ ím^r^ ráhté ^ rfn¡n.

ul of supernatant were then transferred to 90 'ppenTg ^^ qúT plates containing 10 µΙ of water for analysis by MS-MS.

The analysis by CM-EM-EM was carried out with an API instrument

4000 Provided with HPLC and automatic sampler. The following column conditions were used for HPLC: column HPLC: Waters Atlantis T3; flow rate 0.5 ml / mln; analysis time 5 min .; Mobile phase A: 0.1% formic acid in water; mobile phase B: 0.1% formic acid in acetonitrile (ACN); gradient: 98% A / 2% B at 0.0 min; 98% A / 2% B at 1 min; 5% A / 95% B at 3 min; 5% A / 95% B a

3.75 min; 97% A / 3% B at 4 min; and 98% A / 2% B at 5.0 min. MMF was controlled in positive ion mode.

MMF, DMF or MMF prodrug were administered by oral gavage to groups of two to six adult male Sprague-Dawley rats (approximately 250 g). Animals were conscious at the time of the experiment. MMF,

DMF or MMF prodrug was administered orally in an aqueous solution of 0.5% hldroxlpropylmethylcellulose (HPMC), 0.02% polysorbate 80, and 20 mM citrate buffer (pH 5), at a dose of 10 mg-equlvalent MMF per kg of body weight.

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

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The MMF prodrugs, when administered ^^^ f ^ axTfiía ^^ a dose of 10 mg / kg MMF-equivalents in the aqueous vehicle showed. absolute oral bioavailability (relative to IV) between 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>Bioavailability absolute percentage (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>Bioavailability absolute percentage (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>

125 to go

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<td> 39</td><td>_nc the pi- 91.4 ^{! N1}</td><td>• USTR1AL -</td>

<td> 5</td><td> 81,1 ~~</td><td rowspan="2"></td>

<td> 11</td><td> 71,4</td>

⁵ Example 5- Supply of MMF in dogs after oral administration of prodrugs

Male Beagle dogs were obtained from the colony of non-native animals in the animal house. All animals fasted overnight before administration of the dose.

Oral doses were administered by gastric tube. The gastric tube was washed with 10 ml of water before its removal.

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

Blood samples were collected in Sodium Fluoride / Na2EDTA tubes and stored on wet ice until the plasma was processed by centrifugation (300 rpm at 5 ° C) within 30 minutes of collection. All plasma samples were transferred to separate 96-well plates (matrix tubes) and stored at -80 ° C until assayed for concentration by LC / MS / MS with an RGA 3 assay.

Extraction procedure:

Note: Thaw samples at 4 ° C. (Keep on ice on the poyata).

126 neither

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one. Take an aliquot of 20 to 20 ul of studied / labeled sample 96-well plates.

2. Add 120 ul of the appropriate internal standard solution (125 ng / ml mouse embryofibroblasts (MEF)) to each tube, except for the double blank, to which 120 ul of the appropriate acetonitrile: FA (100: 1) was added.

3. Sealing and vortization for one minute.

Four. Spin at 3000 rpm for 10 minutes.

5. Transfer 100 ul of supernatant to a clean 96-well plate containing 100 ul of water.

6. Sealed and smooth vortization for 2 minutes.

The absolute percentage bioavailability (F%) of MMF was determined by comparing the area under the MMF concentration curve vs. time (AB) after oral administration of the MMF drug with the AUC of the concentration curve of

MMF vs. time after intravenous administration of MMF based on a standard dose.

MMF prodrugs, when administered orally to dogs at a dose of 10 mg / kg MMF-equivalents in the aqueous vehicle, showed absolute oral bioavailability (relative to IV) between about 31% to about 78% (See Table 7).

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<img file="MX356368B_D0119.tif" />

Table 7

<td>Compound No.</td><td>Bioavailability absolute percentage (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>

¹θ Example 6 - Physical stability of the present prodrugs and DMF in crystalline form

The physical stability of the compounds of the present invention and DMF was measured by thermogravimetric analysis (TGA). Figure 6 graphically represents weight loss over time at 60 ° C for Compound 14¹⁵ (12.15 mg). unchanged, and DMF (18.40 mg), -100% weight loss in less than hours. These data indicate that DMF undergoes sublimation, while Compound 14 is physically stable under similar conditions.

Example 7- X-ray data for a single crystal of Compound 14

Compound 14 produced by the method described in Example was analyzed.

one. Figure 7 graphically represents the unit cell. X-ray data for a single crystal is included below. Details of an individual crystal:

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Empirical formula: C11 H13 N 06 Weight formula: (255.22) Temperature, 173 (2) K Wavelength: 1.54178 A Space group: P-1

Unit cell dimensions:

a = 6.07750 (10) A b = 7.96290 (10) A c = 12.7850 (2) A Volume: 579.080 (15) A³Z: 2

Density (calculated): 1,464 Mg / m³Absorption coefficient: 1,034 mm¹ a = 84.9390 (10) °. β = 80.0440 (10) °.

γ = 71.9690 (10) °.

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INSTITUTO MEXICANO OSLA INDUSTRIAL PROPERTY

<img file="MX356368B_D0120.tif" />

F (000): 268

Glass size: 0.37 x 0.15 x 0.15 mm³

Reflections collected: 8446

Independent reflections: 2229 [R (int) = 0.0249]

Refining method: Full least squares matrix for F²Goodness of fit in F²: 1,049 final R indices [l> 2sigma (l) j Rl = 0.0317, wR2 = 0.0850 R indices (all data): Rl = 0.0334, wR2 = 0.0864

129