WO2017120355A1

WO2017120355A1 - Dihydroquinolines and uses thereof

Info

Publication number: WO2017120355A1
Application number: PCT/US2017/012358
Authority: WO
Inventors: Eliezer Falb; Victor Piryatinsky; Dvorah Daily; Haifeng Yin; Guoqiang TIAN; Xingnan JIAO; Zhicheng ZHU; Yingjie Li; Lijun LEI; Junsheng Yang; Jinzhong CHEN; Shougang HU
Original assignee: Teva Pharmaceutical Industries Ltd; Teva Pharmaceuticals USA Inc
Current assignee: Teva Pharmaceutical Industries Ltd; Teva Pharmaceuticals USA Inc
Priority date: 2016-01-06
Filing date: 2017-01-05
Publication date: 2017-07-13
Anticipated expiration: 2018-07-06

Abstract

The present invention provides a compound or a pharmaceutically acceptable salt or ester thereof. The present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier. The present invention also provides a method of treating a subject afflicted with multiple sclerosis comprising administering to the subject an amount of the compound of the present invention.

Description

DIHYD OQUINOLI ES AND USES THEREOF

This application claims priority of U.S. Provisional Application No. 62/275,621, filed January 6, 2016, the contents of which are hereby incorporated by reference.

Throughout this application, various publications are referred to by first author and year of publication. Full citations for these publications are presented in a References section immediately before the claims. Disclosures of the documents and publications referred to herein are hereby incorporated in their entireties by reference into this application.

Background

Multiple Sclerosis (MS) is a neurological disease affecting more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on subjects and their families, friends and bodies responsible for health care (EMEA Guideline, 2006) . A clinically isolated syndrome (CIS) is a single monosymptomatic attack suggestive of MS, such as optic neuritis, brain stem symptoms, and partial myelitis. Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis (CDMS) . Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Third Edition, 1999) . Among them, relapsing-remitting multiple sclerosis (RRMS) is the most common form at the time of initial diagnosis. Many subjects with RRMS have an initial relapsing-remitting course for 5-15 years, which then advances into the secondary progressive MS (SPMS) disease course. There are currently a number of disease-modifying medications approved for use in relapsing MS (RMS), which includes RRMS and SPMS (The Disease Modifying Drug Brochure, 2006) . These include interferon beta 1-a (Avonex® and Rebif®) , interferon beta 1-b (Betaseron®) , glatiramer acetate (Copaxone®) , mitoxantrone (Novantrone®) , natalizumab (Tysabri®) and Fingolimod (Gilenya®) . Immunosuppressants or cytotoxic agents are used in some subjects after failure of conventional therapies. However, the relationship between changes of the immune response induced by these agents and the clinical efficacy in MS is far from settled (EMEA Guideline, 2006) .

Other therapeutic approaches include symptomatic treatment which refers to all therapies applied to improve the symptoms caused by the disease (EMEA Guideline, 2006) and treatment of acute relapses with corticosteroids. While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects.

Laquinimod (TV-5600) is a synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005; Comi et al 2008). Laquinimod and its sodium salt form are described, for example, in U.S. Patent No. 6,077,851. The mechanism of action of laquinimod is not fully understood.

Animal studies show it causes a Thl (T helper 1 cell, produces pro- inflammatory cytokines) to Th2 (T helper 2 cell, produces antiinflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Bruck, 2011) . Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010) . Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain- derived neurotrophic factor (BDNF) (Runstrom, 2006; Briick, 2011) .

Laquinimod showed a favorable safety and tolerability profile in two phase III trials (Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO Results) . Brief Description of the Drawings

Fig. 1: Activity of compounds in MOG EAE Study.

Fig. 2: Mean plasma concentration-time profiles of prodrug 53 and parent drug after IV and PO dose of prodrug 53 in male SD rats. Fig. 3: Mean plasma concentration-time profiles of prodrug 5 and parent drug after IV and PO dose of prodrug 5 in male SD rats.

Fig. 4 : Mean plasma concentration-time profiles of prodrug 69 and parent drug after IV and PO dose of prodrug 69 in male SD rats.

Fig. 5: Mean plasma concentration-time profiles of prodrug 54 and parent drug after IV and PO dose of prodrug 54 in male SD rats.

Summary of the Invention

The present invention provides compound having the structure:

wherein

a is absent of present and when present is a bond,

wherein when a is present, then X is O, β is absent and χ is present ;

β is absent or present and when present is a bond,

wherein when β is present, then a and χ are absent;

χ is absent or present and when present is a bond,

wherein when χ is present, then X is O, a is present and β is absent ;

X is O, OH, CI, Br, O-Ri, 0-C(0)-R₂, 0-C(0)-OR₃, O-C (0) -NR4R5, 0-CH₂-OR₆, O-SO2-R7, 0-S0₂-NR₈R₉, O-P (0) (OR10) 2, O-L- ( laquinimod residue), O-L- ( fingolimod residue), O-L- ( cilomilast residue) or O-L- ( D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C2-C12 alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl , alkyl-COOH, alkyl-SCH₃, alkyl-C0₂- alkyl, alkyl-NHC (0) -aryl , alkyl-NHC (O) -heteroaryl, alkyl

alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine) , alkyl-C (0)- (dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue), alkyl-C (0) -( amino acid residue), alkyl-NH- ( amino acid residue) or -CH ( alkyl-OAc) ₂ ;

R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane;

R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R.4 and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;

R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C(O)- heteroalkyl, C0₂-alkyl, C (0) -heterocycloalkyl , C (0) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) (alkyl) 2, C (O) NH-alkyl- N(CH₃) (Boc), C0₂-alkyl-N (CH₃) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue) ;

R7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

Rs and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and

Each Rio is, independently, H or alkyl;

Y is absent or present and when present is H, CI or alkyl-SCH3,- Z is aryl, heteroaryl or cycloalkyl-aryl ,

wherein when X is OH, then is Z is heteroaryl or cycloalkyl-aryl; or a pharmaceutically acceptable salt or ester thereof. also provides compound having the structure:

wherein

δ and ε are absent or present and when present are bonds,

φ and γ are absent or present and when present are bonds,

wherein when δ and ε are present, then φ and γ are absent and when φ and γ are present, then δ and ε are absent;

R11 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and

R12 is H, alkyl, alkenyl, alkynyl,- aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof.

In present invention further provides a compound having the structure:

wherein

η and ι are absent or present and when present are bonds,

φ is absent or present and when present is a bond,

wherein when η and ι are present, then φ is absent and

when φ is present, then η and t are absent;

Cb is H, OH, alkyl, alkenyl or alkynyl; and

Q is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof.

Detailed Description of the Invention

The present invention provides compound having the structure:

wherein

a is absent of present and when present is a bond,

wherein when a is present, then X is O, β is absent and χ is present;

β is absent or present and when present is a bond,

wherein when β is present, then a and χ are absent;

χ is absent or present and when present is a bond,

wherein when χ is present, then X is O, a is present and β is absent;

X is O, OH, CI, Br, O-Ri, 0-C(0)-R₂, 0-C(0)-OR₃, O-C (0) -NR4R5, 0-CH₂-OR₆ 0-S0₂-R7, 0-S0₂-NR₈R₉, O-P (0) (OR10) 2, O-L- ( laquinimod residue), O-L- (fingolimod residue), O-L- ( cilomilast residue) or O-L- ( D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C₂-C₁₂ alkyl, alkenyl, alkynyl, hydroxyalkyl , aminoalkyl, alkylaryl, heterocycloalkyl , alkyl-COOH, alkyl-SCH₃, alkyl-C0₂- alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl , alkyl-C (0) NH- alkyl-NH-alkyl, alkyl-C (O) - (N-methylethanolamine ) , alkyl-C (0)- (dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue), alkyl-C (O) - (amino acid residue), alkyl-NH- ( amino acid residue) or -CH ( alkyl-OAc) ₂ ;

R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C0₂-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane;

R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; FU and R₅ are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;

R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C(O)- heteroalkyl, C0₂-alkyl, C (O) -heterocycloalkyl, C (0) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (O) N (alkyl) ₂, C (0) H-alkyl- N(CH₃)(Boc), C0₂-alkyl-N (CH₃) (Boc) , or C (O) -piperazine-C (O) - (amino acid residue) ;

R_? is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

■ Rg and Rg are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl;

Y is absent or present and when present is H, CI or alkyl-SCH₃;

Z is aryl, heteroaryl or cycloalkyl-aryl,

wherein when X is OH, then is Z is heteroaryl or cycloalkyl-aryl; or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, Z is heteroaryl or cycloalkyl-aryl. , a compound having the structure:

wherein X is CI, Br, O-Ri, 0-C(0)-R₂, 0-C(0)-OR₃, O-C (0) -NR4R5, 0-CH₂- OR₆, 0-S0₂-R₇, 0-S0₂-NR₈R9, O-P (0) (OR10) 2,· O-L- (laquinimod residue), 0-L- (fingolimod residue), 0-L- (cilomilast residue) or 0-L- ( D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C₂-Ci₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH₃, alkyl-C0₂- alkyl, alkyl-NHC (0) -aryl , alkyl-NHC (0) -heteroaryl, alkyl-C (0) H- alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine ) , alkyl-C (O)- (dimethylaminoethanol ) , amino acid residue, alkyl- (amino acid residue), alkyl-C (O) -( amino acid residue), alkyl-NH- ( amino acid residue) or -CH (alkyl-OAc) ₂;

R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (O) -NH-indane ;

F.3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;

R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(0) -alkyl, C(0)- heteroalkyl, C0₂-alkyl, C (0) -heterocycloalkyl, C (0) H-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) N (alkyl) 2, C (0) NH-alkyl- N(CH₃) (Boc), C0₂-alkyl-N (CH₃) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue);

Rv is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

Ra and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl; and

Z is aryl, heteroaryl or cycloalkyl-aryl ; or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, Z is

one embodiment, a compound having the structure

wherein X is CI, Br, O-Ri, 0-C(0)-R_2/ 0-C(0)-OR₃, O-C (0) -NR4R5 , 0-CH₂- OR₆, O-SO2-R7, 0-S0₂-NR₈R₉, O-P (0) (OR10) 2, O-L- (laquinimod residue), O-L- (fingolimod residue) , O-L- (cilomilast residue) or O-L- ( D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C₂-C₁₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH₃, alkyl-C0₂- alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl , alkyl-C (0) H- alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine ) , alkyl-C (0)-

(dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue) , alkyl-C (0) - (amino acid residue), alkyl-NH- ( amino acid residue) or -CH (alkyl-OAc) ₂;

R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C0₂~alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane ;

R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R₄ and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;

R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(0) -alkyl, C(O)- heteroalkyl, C0₂-alkyl, C (0) -heterocycloalkyl, C (O) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) (alkyl) ₂, C (0) NH-alkyl- N(CH₃) (Boc), C0₂-alkyl-N (CH₃) (Boc) , or C (O) -piperazine-C (0) - (amino acid residue) ;

R₇ is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

Rs and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl,

or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, A is O-Ri,

wherein Ri is C₂-C₁₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH₃, alkyl-C0₂-alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl, alkyl-C (0) H-alkyl-NH- alkyl, alkyl-C (0) - (N-methylethanolamine) , alkyl-C (0)- (dimethylaminoethanol ) , (amino acid residue), alkyl- (amino acid residue) , alkyl-C (0) - (amino acid residue), alkyl-NH- (amino acid residue) or -CH (alkyl-OAc) ₂ - In some embodiments, Ri is isopropyl, allyl, -CH ( CH3-OAC ) 2 , -CH2CH2CH2OH ,

-CH2CH2CH2NH2 , - CH2CO2CH2CH3 , -CH2CO2H,

In some embodiments, A is 0-C(0)-R2.

wherein R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane . H₃,

In some embodiments, A is 0-C(0)-OR3, wherein R₄ is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl.

In some embodiments, R3 is methyl, isobutyl, t-butyl or p-nitrophenyl .

In some embodiments, A is O-C (0) -NR4R5, wherein R,j and R₅ are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or

heteroaryl.

In some embodiments, wherein R4 and R5 are each H, methyl, ethyl or - CH2CH2NHCH3 . In some embodiments, A is O-CH2-OR6, wherein R₆ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C (0) -heteroalkyl, C0₂-alkyl, C(O)- heterocycloalkyl, C (0) H-alkyl-heterocycloalkyl, C(0)NH-aryl,

C(0)N(alkyl)₂, C (O) NH-alkyl-N (C¾) (Boc) , C0₂-alkyl-N (CH₃) (Boc) , or C (O) -piperazine-C (0) - (amino acid residue).

In some embodiments, R6 is methyl, butyl, -C(0)0CH3,

C(0)CH₂CH₃, -CH₂CH₂OCH₂CH₃, -C (0) CH (CH₂CH₂CH₃) 2, -CH₂CH₂ (phenyl ) ,

In some embodiments, A is 0-S0₂-R7 wherein R7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl.

In some embodiments, R7 is methyl or p-methylphenyl.

In some embodiments, A is 0-S0₂-NRaR9, wherein Re and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl .

In some embodiments, Re is methyl or ethyl; and Rg is methyl or ethyl; or R₈ and Rg combine to form a morpholino. In some embodiments, A is O-P(O) (ORio)2, wherein each Rio is, independently, H or alkyl.

In some embodiments, each Ri₀ is ethyl.

In some embodiments, A is O-L- ( laquinimod residue). In some embodiments, A is O-L- ( fingolimod residue). 23 In some embodiments, A is O-L- (cilomilast residue) . In some embodiments, A is O-L- ( D-glucose residue).

In some embodiments, L is present.

In some embodiments, L is absent.

In some embodiments, L is an alkyl, alkyl-C(O), alkyl-NH, alkyl-O, alkyl-C(O) or C (0) -phenyl-C (0) .

In some embodiments, L is an

In one embodiment, a compound having the structure

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment, a compound having the structure:

or a pharmaceutically acceptable salt or ester thereof.

or a pharmaceutically acceptable salt or ester thereof.

re:

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment, a compound having the structure:

or a pharmaceutically acceptable salt or ester thereof. having the structure:

or a pharmaceutically acceptable salt or ester thereof.

cture:

or a pharmaceutically acceptable salt or ester thereof.

ent, a compound having the structure:

or a pharmaceutically acceptable salt or ester thereof. one embodiment, a compound having the structure

or a pharmaceutically acceptable salt or ester thereof.

ent, a compound having the structure:

or a pharmaceutically acceptable salt or ester thereof. In one embodiment, a compound having the structure:

wherein Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, Z is

In one embodiment, a compound having the structure:

or a pharmaceutically acceptable salt or ester ther In one embodiment, a compound having the structure:

wherein Z is heteroaryl or cycloalkyl-aryl,

or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, Z is

In one embodiment, a compound having the structure:

or a pharmaceutically acceptable salt or ester thereof. , a compound having the structure:

wherein

Y is H, CI or alkyl-SCH₃; and

Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, Z is

In one embodiment, a compound having the structure:

or a pharmaceutically acceptable salt or ester thereof. also provides compound having the structure:

wherein δ and ε are absent or present and when present are bonds,

φ and γ are absent or present and when present are bonds,

Rii is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and

Ri₂ is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof. In one embodiment, a compound having the structure:

wherein

Qi is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and

Q₂ is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, Qi is H , alkyl or aryl; and Q₂ is H, alkyl or aryl .

In some embodiments, Qi is H , CH3 or phenyl; and Q2 is H , C¾ or phenyl. ture:

or a pharmaceutically acceptable salt or ester thereof. present invention further provides a compound having the structure:

wherein

η and ι are absent or present and when present are bonds,

φ is absent or present and when present is a bond,

wherein when η and ι are present, then φ is absent and

when φ is present, then η and ι are absent;

Q3' is H, OH, alkyl, alkenyl or alkynyl; and

Q4 is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof. o embodiment, a compound having the structure

wherein

b is H, OH, alkyl, alkenyl or alkynyl; and

Q4 is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof-. In some embodiments, Q3 is H or OH; and Q4 is H or OH. one embodiment, a compound having the structure

or a pharmaceutically acceptable salt or ester thereof.

In one embodiment, a compound having the structure:

wherein X is ORi,

wherein Ri is hydroxyalkyl ; and

Z is aryl, heteroaryl or cycloalkyl-aryl, or a pharmaceutically acceptable salt or ester the

In some embodiments, Ri is C₁-C6 hydroxyalkyl.

In some embodiments, Z is phenyl.

In one embodiment, a compound having the structure

wherein X is O-C (0) -NR4R5,

wherein R, and R5 are each an alkyl; and

Z is aryl, heteroaryl or cycloalkyl-aryl, or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, R4 is Ci-Cs alkyl; and R4 is C1-C6 alkyl In some embodiments, R₄ is methyl; and R is ethyl.

In some embodiments, Z is phenyl.

In one embodiment, a compound having the structure:

wherein X is 0-CH₂-OR₆,

wherein ]¾ is C (0) N (alkyl ) 2 or C (0) cycloheteroalkyl; and

In some embodiments, R6 is C (0) N ( alkyl ) 2, wherein the alkyl is Ci-Ce alkyl.

In some embodiments, R.6 is C (O) cycloheteroalkyl, wherein the cycloheteroalkyl is a morpholinyl. In some embodiments, Z is phenyl. having the structure:

or a pharmaceutically acceptable salt or ester thereof.

The present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier. The present invention also provides a method of treating subject afflicted with multiple sclerosis comprising administering to the subject an amount of the compound of the present invention.

In some embodiments, a pharmaceutically acceptable salt or ester of any of the compounds disclosed herein.

In some embodiments, the multiple sclerosis is relapsing multiple sclerosis or relapsing-remitting multiple sclerosis.

In some embodiments, the amount of the compound is effective to reduce a symptom of multiple sclerosis in the subject.

In some embodiments, the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.

In one embodiment, the use of the compound for the preparation of a medicament for the treatment of multiple sclerosis.

In one embodiment, the use of the compound for the treatment of multiple sclerosis .

In one embodiment, the compound of the present invention for use in treating a subject afflicted with multiple sclerosis. The present invention also provides a pharmaceutical composition comprising an amount of the compound of the present invention for use in treating a subject afflicted with multiple sclerosis. The present invention also provides a method of treating a subject afflicted with Crohn's disease comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with rheumatoid arthritis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with lupus nephritis or active lupus nephritis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with insulin-dependent diabetes mellitus (IDDM) comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with systemic lupus erythematosus (SLE) comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with inflammatory bowel disease (IBD) comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with psoriasis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method of treating a subject afflicted with inflammatory respiratory disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method of treating a subject afflicted with atherosclerosis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method of treating a subject afflicted with ocular inflammatory disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method of treating a subject suffering from stroke comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subj ect .

The present invention also provides a method of treating a subject afflicted with Alzheimer's disease comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method of treating a subject afflicted with BDNF-related disease comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject. The present invention also provides a method of treating a subject afflicted with GABA related disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method of treating a subject afflicted with CB1 receptor related disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.

The present invention also provides a method for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject, the method comprising administering to the subject the compound of the present invention so as to thereby reduce or inhibit progression of the level of fatigue in the multiple sclerosis subject.

The present invention also provides a method of treating a subject afflicted with glaucoma or suffering from retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or of reducing retinal ganglion cell loss, retinal ganglion cell damage or intraocular pressure in a subject, comprising administering to the subject an amount of the compound of the present invention to reduce retinal an ion cell loss or damage, or reduce intraocular pressure in the subject.

The present invention provides a method for in vivo delivery of laquinimod to a subject, the method comprising administering to the subject a compound of the present invention so as to thereby deliver laquinimod to the subject.

In some embodiments, the subject is afflicted with multiple sclerosis.

In some embodiments, the multiple sclerosis is relapsing multiple sclerosis or relapsing-remitting multiple sclerosis. In some embodiments, the in vivo delivery of laquinimod to a subject is effective to reduce a symptom of multiple sclerosis in the subject.

In some embodiments, the subject is afflicted with Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin- dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage,' or elevated intraocular pressure

In some embodiments, the in vivo delivery of laquinimod to a subject is effective to reduce a symptom of the Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CBl receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure in the subject. In some embodiments, the amount of the compound is effective to decrease or inhibit reduction of brain volume in the subject.

In some embodiments, the amount of the compound is effective to decrease or inhibit reduction of brain volume.

In some embodiments, the brain volume is measured by percent brain volume change (PBVC) .

In some embodiments, the amount of the compound is effective to increase time to confirmed disease progression.

In some embodiments, time to confirmed disease progression is increased by 20-60%.

In some embodiments, the amount of the compound is effective to decrease abnormalities observed in whole Brain MTR histogram.

In some embodiments, the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) score, or is assessed by the time to confirmed disease progression as measured by EDSS score.

In some embodiments, the subject had an EDSS score of 0-5.5 at baseline, an EDSS score of 1.5-4.5 at baseline or an EDSS score of 5.5 or greater at baseline.

In some embodiments, the confirmed disease progression is a 1 point or a 0.5 point increase of the EDSS score. In some embodiments, impaired mobility is assessed by the Timed-25 Foot Walk test, the 12-Itern Multiple Sclerosis Walking Scale (MSWS-12) self- report questionnaire, the Ambulation Index (AI), the Six-Minute Walk (6MW) Test or the Lower Extremity Manual Muscle Test (LEMMT) Test.

In some embodiments, the amount of the compound is effective to reduce cognitive impairment.

In some embodiments, cognitive impairment is assessed by the Symbol Digit Modalities Test (SDMT) score.

In some embodiments, general health status is assessed by the EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) .

In some embodiments, functional status is measured by the subject's Short-Form General Health survey (SF-36) Subject Reported Questionnaire score . In some embodiments, quality of life is assessed by SF-36, EQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) .

In some embodiments, the subject's SF-36 mental component summary score (MSC) is improved.

In some embodiments, the subject's SF-36 physical component summary sore (PSC) is improved.

In some embodiments, fatigue is assessed by the EQ5D, the subject's Modified Fatigue Impact Scale (MFIS) score or the French valid versions of the Fatigue Impact Scale (EMIF-SEP) score. In some embodiments, symptom severity on work is measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire .

In some embodiments, the compound is administered via oral administration. In some embodiments, the compound is administered by inj ection .

In some embodiments, the further comprising administration of nonsteroidal anti-inflammatory drugs (NSAIDs) , salicylates, slow-acting drugs, gold compounds, hydroxychloroquine, sulfasalazine, combinations of slow-acting drugs, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies.

In some embodiments, the subject is a human patient.

The present invention provides the use of the compound of the present invention for the preparation of a medicament for treating multiple sclerosis .

The present invention provides the use of the compound of the present invention for treating multiple sclerosis.

The present invention provides the use of the compound of the present invention for the preparation of a medicament for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject. The present invention provides the use of the compound of the present invention for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF- related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.

The compound of the present invention for use in treating multiple sclerosis .

The compound of the present invention for use in treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CBl receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.

A pharmaceutical composition comprising the compound of the present invention for use in treating multiple sclerosis.

A pharmaceutical composition comprising the compound of the present invention for use in treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.

The present invention provides the use of the compound of the present invention for the preparation of a medicament for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.

The present invention provides the use of the compound of the present invention for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF- related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject. The present invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of the compound of the present invention and a pharmaceutically acceptable carrier and b) instructions for us of the pharmaceutical composition to treat a subject afflicted with multiple sclerosis, Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus { IDDM) , systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.

The subject invention also provides a process of preparing a medicament prepared for treating a subject afflicted with multiple sclerosis, Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure using an amount of the compound of the present invention, comprising 1) obtaining a pharmaceutical composition comprising an amount of the compound of the present invention and a pharmaceutically acceptable carrier, and 2) packaging the pharmaceutical composition to make the medicament.

Use of laquinimod for treatment of various conditions, and the corresponding dosages and regimens, are described in U.S. Patent No. 6,077,851 (multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke, and Alzheimer's disease), U.S. Application Publication No. 2011- 0027219 (Crohn's disease, colitis), U.S. Application Publication No. 2010-0322900 (Relapsing-remitting multiple sclerosis), U.S. Application Publication No. 2011-0034508 (brain-derived neurotrophic factor (BDNF) - related diseases), U.S. Application Publication No. 2011-0218179 (active lupus nephritis), U.S. Application Publication No. 2011-0218203 (rheumatoid arthritis), U.S. Application Publication No. 2011-0217295 (active lupus arthritis), U.S. Application Publication No. 2012-0142730 (reducing fatigue, improving quality of life, and providing neuroprotection in MS patients), U.S. Application Publication No. 2014- 0045886 (GABA-mediated disorders), U.S. Application Publication No. 2014-0045887 (cannabinoid receptor type 1 (cbl) mediated disorders), U.S. Application Publication No.2015-0141458 (glaucoma), each of which is hereby incorporated by reference in its entireties into this application. The compounds of the present inventions are useful in treating each of the above conditions.

As used herein, a "BDNF-related disease" is a disease in which a patient suffering from the disease has BDNF serum levels which are lower than those of a corresponding healthy individual and/or a disease in which the elevation of BDNF in a patient suffering from the disease can be associated with amelioration of the disease or of symptoms thereof.

This application also provides for a method for treating a human subject suffering from a BDNF-related disease selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, depressive disorders, anxiety disorders, retinitis pigmentosa, erectile dysfunction, memory disorders, Rett syndrome, Alzheimer's disease, bipolar disorder and acute mania comprising administering an amount of the compound of the present invention in an amount effective to treat the human subject. As used herein, a "CBl receptor related disorder" is a disorder in which a patient suffering from the disorder has defective CB1 receptor function. Such disorders include, but are not limited to, attention- deficit/hyperactivity disorder (ADHD), Huntington's Disease, mood disorders, schizophrenia, bipolar disorder and stroke.

This application also provides for a method for treating a human subject suffering from a GABA related disorder which includes, but is not limited to, schizophrenia, epilepsy (seizures) , spasticity, stiff-person syndrome (SPS) , premenstrual dysphoric disorder, drug addiction, fertility disorder insomnia, spinocerebellar degeneration, or neuro- Behcet's syndrome.

A "pharmaceutically acceptable carrier" refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.

The compound of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit can be in a form suitable for oral administration. The compound can be administered alone but is generally mixed with a pharmaceutically acceptable carrier, and co-administered in the form of a tablet or capsule, liposome, or as an agglomerated powder. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.

The following delivery systems, which employ a number of routinely used pharmaceutical carriers, may be used but are only representative of the many possible systems envisioned for administering compositions in accordance with the invention.

Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's) .

Other injectable drug delivery systems include solutions, suspensions, gels. Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch) , diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc). Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone .

Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).

Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid) .

Dermal delivery systems include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions , liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone ) . In one embodiment, the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.

Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine) , preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti- caking agents, coating agents, and chelating agents (e.g., EDTA) . Specific examples of the techniques, pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Patent No. 7, 589, 208, PCT International Application Publication Nos . WO 2005/074899, WO 2007/047863, and 2007/146248.

General techniques and compositions for making dosage forms useful in the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979) ; Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976) ; Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995) ; Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds) .; Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds) . These references in their entireties are hereby incorporated by reference into this application. As used herein, an "amount" or "dose" of the compound as measured in milligrams refers to the milligrams of compound present in a preparation, regardless of the form of the preparation. A "dose of 0.6 mg" means the amount of compound in a preparation is 0.6 mg, regardless of the form of the preparation. Thus, when in the form of a. salt, e.g. a sodium salt, the weight of the salt form necessary to provide a dose of 0.6 mg would be greater than 0.6 mg due to the presence of the additional salt ion . As used herein, a "unit dose", "unit doses" and "unit dosage form ( s ) " mean a single drug administration entity/entities.

As used herein, "about" in 'the context of a numerical value or range means ±10% of the numerical value or range recited or claimed.

As used herein, a pharmaceutical composition is "stable" when the composition preserves the physical stability/integrity and/or chemical stability/integrity of the active pharmaceutical ingredient during storage. Furthermore, "stable pharmaceutical composition" is characterized by its level of degradation products not exceeding 5% at 40°C/75%RH after 6 months or 3% at 55°C/75% RH after two weeks, compared to their level in time zero.

As used herein, "effective" when referring to an amount of the compound refers to the quantity of the compound that is sufficient to yield a desired therapeutic response. Efficacy can be measured by an improvement of a symptom of multiple sclerosis. Such symptoms can include a MRI- monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, time to confirmed disease progression, time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, visual function, fatigue, impaired mobility, cognitive impairment, brain volume, abnormalities observed in whole Brain MTR histogram, general health status, functional status, quality of life, and/or symptom severity on work.

In an embodiment, an effective amount is an amount that is sufficient to decrease or inhibit reduction of brain volume (optionally brain volume is measured by percent brain volume change (PBVC)), increase time to confirmed disease progression (e.g., by 20-60% or at least 50%), decrease abnormalities observed in whole Brain MTR histogram, decrease the accumulation of physical disability (optionally measured by Kurtzke Expanded Disability Status Scale (EDSS) score, e.g., wherein the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (EDSS) score), improve impaired mobility (optionally assessed by the Timed-25 Foot Walk test, the 12-Item Multiple Sclerosis Walking Scale ( SWS-12) self-report questionnaire, the Ambulation Index (AI), the Six- Minute Walk (6MW) Test, or the Lower Extremity Manual Muscle Test (LEMMT) Test) , reduce cognitive impairment (optionally assessed by the Symbol Digit Modalities Test (SDMT) score) , improve general health (optionally assessed by the EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) ) , improve functional status (optionally measured by the subject's Short-Form General Health survey (SF-36) Subject Reported Questionnaire score), improve quality of life (optinally assessed by SF-36, EQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) ) , improve the subject's SF-36 mental component summary score (MSC) and/or SF-36 physical component summary sore (PSC), reduce level of fatigue (optionally assessed by the EQ5D, the subject's Modified Fatigue Impact Scale (MFIS) score or the French valid versions of the Fatigue Impact Scale (EMIF-SEP) score) , or improve symptom severity on work (optionally measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire) .

"Administering to the subject" or "administering to the (human) patient" means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition. The administration can be periodic administration. As used herein, "periodic administration" means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.

"Treating" as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., Relapsing MS (RMS), or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder. "Treating" as applied to patients presenting CIS can mean delaying the onset of clinically definite multiple sclerosis (CDMS) , delaying the progression to CDMS, reducing the risk of conversion to CDMS, or reducing the frequency of relapse in a patient who experienced a first clinical episode consistent with multiple sclerosis and who has a high risk of developing CDMS.

"Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.

A "symptom" associated with MS or RMS includes any clinical or laboratory manifestation associated with MS or RMS and is not limited to what the subject can feel or observe.

Multiple sclerosis is a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurologic symptoms and signs, usually with remission and exacerbations.

As used herein, "a subject afflicted with multiple sclerosis" includes a subject who has been clinically diagnosed to have multiple sclerosis or relapsing multiple sclerosis (RMS) , which includes relapsing-remitting multiple sclerosis (RRMS) and Secondary Progressive multiple sclerosis (SPMS), or is a subject presenting a clinically isolated syndrome (CIS) .

As used herein, a subject at "baseline" is as subject prior to administration of the compound.

A "patient at risk of developing MS" (i.e. clinically definite MS) as used herein is a patient presenting any of the known risk factors for MS. The known risk factors for MS include any one of a clinically isolated syndrome (CIS) , a single attack suggestive of MS without a lesion, the presence of a lesion (in any of the CNS, PNS, or myelin sheath) without a clinical attack, environmental factors (geographical location, climate, diet, toxins, sunlight) , genetics (variation of genes encoding HLA-DRBl, IL7R-alpha and IL2R-alpha) , and immunological components (viral infection such as by Epstein-Barr virus, high avidity CD4⁺ T cells, CD8⁺ T cells, anti-NF-L, anti-CSF 114 (Glc) ) .

"Clinically isolated syndrome (CIS)" as used herein refers to 1) a single clinical attack (used interchangeably herein with "first clinical event" and "first demyelinating event") suggestive of MS, which, for example, presents as an episode of optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence) , bowel problems (including constipation and loss of bowel control) , impotence, diminished sexual arousal, loss of sensation, sensitivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning, and 2) at least one lesion suggestive of MS. In a specific example, CIS diagnosis would be based on a single clinical attack and at least 2 lesions suggestive of MS measuring 6 mm or more in diameter.

"Relapse Rate" is the number of confirmed relapses per unit time. "Annualized relapse rate" is the mean value of the number of confirmed relapses of each patient multiplied by 365 and divided by the number of days that patient is on the study drug.

"Expanded Disability Status Scale" or "EDSS" is a rating system that is frequently used for classifying and standardizing the condition of people with multiple sclerosis. The score ranges from 0.0 representing a normal neurological exam to 10.0 representing death due to MS. The score is based upon neurological testing and examination of functional systems (FS) , which are areas of the central nervous system which control bodily functions. The functional systems are: Pyramidal (ability to walk), Cerebellar (coordination) , Brain stem (speech and swallowing) , Sensory (touch and pain) , Bowel and bladder functions, Visual, Mental, and Other (includes any other neurological findings due to MS) (Kurtzke JF, 1983) .

A "confirmed progression" of EDSS, or "confirmed disease progression" as measured by EDSS score is defined as a 1 point increase from baseline EDSS if baseline EDSS was between 0 and 5.0, or a 0.5 point increase if baseline EDSS was 5.5. In order to be considered a confirmed progression, the change (either 1 point or 0.5 points) must be sustained for at least 3 months. In addition, confirmation of progression cannot be made during a relapse.

"Adverse event" or "AE" means any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign including an abnormal laboratory finding, symptom, or diseases temporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product.

"Gd-enhancing lesion" refers to lesions that result from a breakdown of the blood-brain barrier, which appear in contrast studies using gandolinium contrast agents. Gandolinium enhancement provides information as to the age of a lesion, as Gd-enhancing lesions typically occur within a six week period of lesion formation.

"Magnetization Transfer Imaging" or "MTI" is based on the magnetization interaction (through dipolar and/or chemical exchange) between bulk water protons and macromolecular protons. By applying an off resonance radio frequency pulse to the macromolecular protons, the saturation of these protons is then transferred to the bulk water protons. The result is a decrease in signal (the net magnetization of visible protons is reduced) , depending on the magnitude of MT between tissue macromolecules and bulk water. "MT" or "Magnetization Transfer" refers to the transfer of longitudinal magnetization from the hydrogen nuclei of water that have restricted motion to the hydrogen nuclei of water that moves with many degrees of freedom. With MTI, the presence or absence of macromolecules (e.g. in membranes or brain tissue) can be seen (Mehta, 1996; Grossman, 1994) .

"Magnetization Resonance Spectroscopy" or "MRS" is a specialized technique associated with magnetic resonance imaging (MRI) . MRS is used to measure the levels of different metabolites in body tissues. The MR signal _\ produces a spectrum of resonances that correspond to different molecular arrangements of the isotope being "excited". This signature is used to diagnose .^certain metabolic disorders, especially those affecting the brain, (Rosen, 2007) as well as to provide information on tumor metabolism (Golder, 2007) .

As used herein "mobility" refers to any ability relating to walking, walking speed, gait, strength of leg muscles, leg function and the ability to move with or without assistance. Mobility can be evaluated by one or more of several tests including but not limited to Ambulation Index, Time 25 foot walk, Six-Minute Walk (6MW) , Lower Extremity Manual Muscle Test (LEMMT) and EDSS. Mobility can also be reported by the subject, for example by questionnaires, including but not limited to 12- Item Multiple Sclerosis Walking Scale (MSWS-12) . Impaired Mobility refers to any impairment, difficulty or disability relating to mobility.

"Tl-weighted MRI image" refers to an MR-image that emphasizes Tl contrast by which lesions may be visualized. Abnormal areas in a Tl-weighted MRI image are "hypointense" and appear as dark spots. These spots are generally older lesions. "T2-weighted MRI image" refers to an MR-image that emphasizes T2 contrast by which lesions may be visualized. T2 lesions represent new inflammatory activity .

The "Six-Minute Walk (6MW) Test" is a commonly used test developed to assess exercise capacity in patients with COPD (Guyatt, 1985) . It has been used also to measure mobility in multiple sclerosis patients (Clinical Trials Website) . The "Timed-25 Foot Walk" or "T25-FW" is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. The score for the T25-FW is the average of the two completed trials. This score can be used individually or used as part of the MSFC composite score (National MS Society Website) .

One of the central symptoms of multiple sclerosis is fatigue. Fatigue can be measured by several tests including but not limited to decrease of French valid versions of the Fatigue Impact Scale (EMIF-SEP) score, and European Quality of Life (EuroQoL) Questionnaire (EQ5D) . Other tests, including but not limited to Clinician Global Impression of Change (CGIC) and Subject Global Impression (SGI), as well as EQ-5D, can be used to evaluate the general health status and quality of life of MS patients .

"Ambulation Index" or ^,ΑΙ" is a rating scale developed by Hauser et al. to assess mobility by evaluating the time and degree of assistance required to walk 25 feet. Scores range from 0 (asymptomatic and fully active) to 10 (bedridden) . The patient is asked to walk a marked 25-foot course as quickly and safely as possible. The examiner records the time and type of assistance (e.g., cane, walker, crutches) needed. (Hauser, 1983) .

"EQ-5D" is a standardized questionnaire instrument for use as a measure of health outcome applicable to a range of health conditions and treatments. It provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care as well as population health surveys. EQ-5D was developed by the "EuroQoL" Group which comprises a network of international, multilingual, multidisciplinary researchers, originally from seven centers in England, Finland, the Netherlands, Norway and Sweden. The EQ-5D questionnaire is in the public domain and can be obtained from EuroQoL.

"SF-36" is a multi-purpose, short-form health survey with 36 questions which yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index. It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. The survey is developed by and can be obtained from QualityMetric, Inc. of Providence, RI .

The compounds used in the method of the present invention may be in a salt form. As used herein, a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide , hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate , and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19) .

As used herein, the term "amino acid residue" refers to an amino acid molecule that has lost an "OH" or "H" by becoming covalently bonded to

)

another molecule. Each remaining OH or NH₂ of the amino acid may be substituted with a protecting group. Examples of amino acid residues are shown below:

As used herein, the term "laquinimod residue" refers to a laquinimod molecule that has lost an "H" by becoming covalently bonded to another molecule. An example of a laquinimod residue is shown below:

As used herein, the term "fingolimod residue" refers ^'to a fingolimod molecule that has lost an "H" by becoming covalently bonded to another molecule. Example of fingolimod residues are shown below:

As used herein, the term "cilomilast residue" refers to a fingolimod molecule that has lost an "OH" or "H" by becoming covalently bonded to another molecule. Examples of cilomilast residues are shown below:

As used herein, the term "D-glucose residue" refers to a D-glucose molecule that has lost an "OH" or "H" by becoming covalently bonded to another molecule. An example of a D-glucose residue is shown below:

As used herein, "chemical linker" is any organic moiety that links a compound with another compound or drug. The chemical linker can both react with groups on the other compound or drug to link the structures together. It is known in the art how to prepare suitable linkers with suitable groups and react linkers with groups to be linked, as well as to functionalize both the linkers and groups to be linked to cause the desired linkage to occur. The chemical linker may be cleavable non- cleavable or releasable linker. The cleavable linker of the conjugate can be cleaved from the compound by, for example, enzymatic cleavage in vivo, to release the compound of the present invention. The ADC may bind to a cell and become internalized prior to the drug being enzymatically released from the antibody to become activated inside the cell. Examples of the chemical linker include, but are not limited to, alkyl linkers, aminoalkyl linkers, terephthalate linkers, peptide linkers, self- immolative linkers, disulfide linkers, thioether linkers, hydrazine linkers, maleimide linkers, hydrophilic linkers or other linkers that are generally known in the art. The chemical linker may also link the compound with a drug.

The term "cleaveable linker" is intended to mean a moiety that is unstable in vivo. The linker allows for activation of the therapeutic agent by cleaving the agent from the rest of the conjugate. The linker may be cleaved in vivo by the biological environment. The cleavage may come from any process without limitation, e.g., enzymatic, reductive, pH, etc. The cleaveable group may be selected so that activation occurs at the desired site of action, which can be a site in or near the target cells or organs.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, Ci-C_n as in "Ci-C_n alkyl" is defined to include groups having 1, 2 , n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C20 alkyl, C2-C20 alkyl, C3-C20 alkyl, C4- C20 alkyl and so on. An embodiment can be C1-C30 alkyl, C2-C30 alkyl, C3- C30 alkyl, C4-C30 alkyl and so on. "Alkoxy" represents an alkyl group as described above attached through an oxygen bridge. "Hydroxyalkyl" includes an alkyl where at least one hydrogen is replaced with an -OH. "Aminoyalkyl" includes an alkyl where at least one hydrogen is replaced with a primary, secondary or tertiary amine or an secondary or tertiary amine is contained within the alkyl chain.

The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present. Thus, C2-C_n alkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon- carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a Ce alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl . As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is .indicated. An embodiment can be C2-C12 alkenyl, C3-C₁₂ alkenyl, C2-C20 alkenyl, C3-C20 alkenyl, C2-C30 alkenyl, or C3-C30 alkenyl. The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2~C_n alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2~C_n alkynyl . An embodiment can be C2-C12 alkynyl or C3-C12 alkynyl, C2-C20 alkynyl, C3-C20 alkynyl, C2- C30 alkynyl, or C3-C30 alkynyl.

As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having at least 1 heteroatom within the chain or branch. As used herein, "cycloalkyl" includes cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) . As used herein, "heterocycloalkyl" is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of 0, N and S, and includes bicyclic groups.. "Heterocycl" includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl , morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl , tetrahydrothiophenyl , 4- mehtylpiperazinyl and the like. If the heterocycle contains nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl , indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. The substituted aryls included in this invention include substitution at any suitable position with amines, substituted amines, alkylamines, hydroxys and alkylhydroxys , wherein the "alkyl" portion of the alkylamines and alkylhydroxys is a C2-C_n alkyl as defined hereinabove. The substituted amines may be substituted with alkyl, alkenyl, alkynl, or aryl groups as hereinabove defined.

The term "alkylaryl" refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an "alkylaryl" group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl ) , p-trifluoromethylbenzyl ( 4-trifluoromethyl- phenylmethyl) , 1-phenylethyl , 2-phenylethyl , 3-phenylpropyl, 2- phenylpropyl and the like.

The term "heteroaryl" as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include but are not limited to phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6- membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from 0, N or S . Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl , benzoxazolyl , carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl , isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl , tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1, 4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl , dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl , dihydroisothiazolyl, dihydrooxadiazolyl , dihydrooxazolyl, dihydropyrazinyl , dihydropyrazolyl , dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl , dihydrothiadiazolyl , dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl , dihydroazetidinyl , methylenedioxybenzoyl, tetrahydrofuranyl , tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline . In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. The alkyl, alkenyl, alkynyl, and aryl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise. For example, a (C₁-C6) alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on. In the compounds of the present invention, alkyl, alkenyl, and alkynyl groups can be further substituted by replacing one or more hydrogen atoms by non-hydrogen groups described herein to the extent possible. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl .

The term "substituted" as used herein means that a given structure has a substituent which can be an alkyl, alkenyl, or aryl group as defined above. The term shall be deemed to include multiple degrees of substitution by a named substitutent . Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

Examples of substituent groups include the functional groups described above, and halogens (i.e., F, CI, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n- propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4- trifluoromethylphenylmethoxy) ; heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p- toluenesulfonyl ; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl ; cyano; amino groups, such as amino, methylamino, dimethylamino , ethylamino, and diethylamino ; and carboxyl . Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

In the compounds of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise. In the compounds of the present invention, alkyl, heteroalkyl, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl .

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The compounds used in the method of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5^th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience ) 5^th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds. The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided · by the invention. For example, "0.1-2.5mg/day" includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day. Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

Experimental Details

5-chloro-N-ethyl-4-methoxy-l-methYl-2-oxo-N-phenyl-l ,2-dihydroquinoline-3- carboxamide , 1.

To a mixture of Laquinimod (356 mg, 1 mmol) , PPh3 (786 mg, 3 mmol), MeOH (192 mg, 6 mmol) in 25 mL THF at 0 °C . , was added drop .wise DIAD (606 mg, 3 mmol) and the mixture was stirred at rt for 6h., after which NaHCCb (saturated, aqueous, 10 mL) was added and the reaction was extracted with EtOAc (10 mL*3) . The organic layer was dried over a2S0 , filtered and concentrated. The crude was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH₄HC0₃) , B: MeCN) to afford 1 (200 mg, 54 % yield) as a white solid. ^XH-NMR (400 MHz, CDC1₃) : 57.366-7.328 (m, 3 H) , 7.216-7.143 (m, 5 H) , 4.088-4.063 (m, 1 H),4.028 (s, 3 H) , 3.849-3.822 (m, 1 H) , 3.558 (s, 3 H) , 1.284-1.255 (t, 3H) ; LCMS (ESI) calc'd for (C₂₀H₁₉CIN₂O₃) [M+H]⁺,371.12; found, 371.2.

5-chloro-N-ethyl-4-isobutoxy-l-methyl-2-oxo-N-phenyl-l , 2- dihydroquinoline-3-carboxamide , 2.

To a mixture of Laquinimod (200 mg, 0.56 mmol, 1 eq. ) , PPh₃ (440 mg, 3 eq.) , 2-methylpropan-l-ol (248 mg, 6 eq.) in 25 mL THF at 0°C, was added drop wise DIAD (340 mg, 3 eq.) . The mixture was stirred at room temperature for 6 hrs . The reaction mixture was quenched with NaHCC>3

(saturated, aqueous, 10 mL) and extracted with AcOEt (20 mL>3) . The organic layer was dried over Na2SC>4, filtered and concentrated. The crude product was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH4HCO3) , B: MeCN) to afford 2 (40mg, 17%) as a white solid. ¹H-NMR

(CDCI₃, 500 MHz) : 57.39-7.35 (3H, m) , 7.25-7.16 (5H, m) , 4.06-4.01 (2H, m) , 3.95-3.76 (2H, m) , 3.58 (3H, s), 2.31-2.28 (1H, m) , 1.30-1.25 (3H, m) , 1.19-1.17 (3H, m) , 1.06-1.03 (3H, m) ; Mass (ESI+) : calculated as 412.1, found 412.9 ([M+H]⁺) .

2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) propane-1 , 3-diyl Diacetate, 3

Pyridine, DCU_t RT, 24 hrs.

Preparation of 2-hydroxypropane-l , 3-diyl diacetate: To a solution of propane-1, 2, 3-triol (5 g, 54 mmol) and Pyridine (13 g, 162 mmol) in DCM (50 mL) was stirred at 0°C, then acetic anhydride (11 g, 108 mmol) was added drop wise. The reaction mixture was stirred at RT for 24h, and then washed with 1M HC1, NaHCOa and brine. The organic layer was dried over a2S04, filtered and concentrated. The crude as a colorless oil was purified by column chromatography to afford the desired product 2- hydroxypropane-1, 3-diyl diacetate (4 g, 42 % yield) as colorless oil; To a mixture of Laquinxmod (200 mg, 0.56 mmol), PP t3 (440 mg, 1.68 mmol) , 2-hydroxypropane-l, 3-diyl diacetate (198 mg, 1.12 mmol) in 20 mL THF at 0°C was added drop wise DIAD (340 mg, 1.68 mmol) and the mixture was stirred at rt for 6h. Then NaHCC>3 (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL*3) . The organic layer was dried over Na₂SC>4, filtered and concentrated. The crude was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH₄HC0₃) , B: MeCN) to afford 3 (100 mg, 35 % yield) as a white solid. ¹H-NMR (400 MHz, CDC1₃) : 57.286-7.248 (m, 3 H) , 7.146-7.073 (m, 5 H) , 5.092-5.082 (m, 1 H) , .525- 4.493 (m, 1 H) , 4.442-4.419 (m, 1 H) , 4.345-4.321 (m, 1 H) , 4.288-4.278 (m, 1 H) , 3.914-3.869 (m, 2 H) , 3.506 (s, 3 H) , 2.003 (s, 3 H) , 1.688 (s, 3 H) , 1.213-1.185 (t, 3 H) ; LCMS (ESI) calc'd for ( C26H27CIN2O7 ) [M+H]⁺,515.16; found, 515.2

4- (allyloxy) -5-chloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l ,2- dihydroquinoline-3-carboxamide, 4.

Laquinxmod (212 mg, 0.6 mmol) and 3-bromoprop-l-ene (363 mg, 3.0 mmol) was dissolved in acetonitrile (15 mL) and the mixture stirred at ambient temperature. Potassium carbonate (276 mg, 2.0 mmol) was added to the mixture. It was heated under reflux overnight, then diluted with water (50 mL) and dichloromethane (150 mL) . The dichloromethane layer was washed with brine (30 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2 : 1 ) to provide 4 as white solid (40 mg, yield 17%) . ¹H-NMR (300 MHz, CDC1₃) : δ 7.402-7.348 (m, 3 H) , 7.292-7.167 (m, 5 H) , 6.298-6.140 (m, 1 H) , 5.575 (d, 1 H) , 5.352 (d, 1 H) , 4.741- 4.694 (m, 2 H) , 4.182-4.123 (m, 1 H) , 3.813-3.774 (m, 1 H) , 3.593 (s, 3 H) , 1.298-1.250 (t, 3 H) ; LCMS (ESI) calc'd for (C₂₂ H₂iClN₂0₃) [M+H]⁺, 397.13; found, 397.01.

5-chloro-N-ethyl-4- (3-hydroxypropoxy) -1-methyl-2-oxo-N-phenyl- dihydroquinoline-3-carboxamide , 5.

S

Laquinimod (1.09 g, 3.0 mmol) , propane-1 , 3-diol (760 mg, 10.0 mmol) and triphenylphosphine (1.56 g, 6.0 mmol) were dissolved in tetrahydrofuran (45 mL) and the solution stirred at ambient temperature. DEAD (1.02 g, 6.0 mmol) was added to the mixture dropwise. The mixture was stirred overnight, and the solvent was removed under vacuum. The residue was diluted with water (30 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (20 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 5 (1.0 g, yield 81%) as white solid. ¹H-NMR (300 MHz, CDC1₃) : δ 7.423-7.350 (m, 3 H) , 7.335-7.172 (m, 5 H) , 4.354-4.26 (m, 2 H) , 4.129-4.037 (m, 2 H) , 3.961-3.868 (m, 2 H) , 3.564 (s, 3 H) , 2.161-2.067 (m, 2 H) , 1.276-1.252 (t, 3 H) ; LCMS (ESI) calc'd for (C₂₂H₂₃C1N₂0₄ ) [M+H]+, 415.14; found, 414.89.

4- (2-aminoethoxy) -5-chloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l ,2- dihydroquinoline-3-carboxamide , 6.

Laquinimod (1.09 g, 3.0 mmol) , tert-butyl 2-hydroxyethylcarbamate (480 mg, 3.0 mmol) and triphenylphosphine (1.56 g, 6.0 mmol) were dissolved in THF (45 mL) at ambient temperature. DEAD (1.02 g, 6.0 mmol) was added drop wise into the mixture. The mixture was stirred at ambient temperature overnight, then concentrate to dryness under vacuum. The residue was diluted with water (20 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (20 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide the t-Boc protected derivative of 1 (1.2 g, yield 81%) as a white solid. The tert-Boc protection of the latter compound (250 mg, 0.5 mmol) was removed in dichloromethane (5 mL) using trifluoroacetic acid (5 mL) . The mixture was stirred 0.5 hour at ambient temperature, and then concentrated to dryness on rotavapor. The residue was treated with ethyl ether (5 mL) to give 6 as a white solid (220 mg, yield 88%) . ¹H-NMR (300MHz, CDC1₃) : δ 7.395-7.321 (m, 3 H) , 7.269-7.153 (m, 5 H) , 4.449-4.434 (m, 1 H) , 4.291-4.269 (m, 1 H) , 4.048-4.003 (m, 1 H) , 3.899-3.876 (m, 1 H) , 3.554 (s, 3 H) , 3.299-3.189 (m, 2 H) , 1.271-1.223 (t, 3 H) ; LCMS (ESI) calc'd for ( C21H22CIN3O3 ) [M+H]+, 400.13; found, 400.28.

4- (3-aminopropoxy) -5-chloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l , 2 dihydroquinoline-3-carboxamide , 7.

Laquinimod (1.09 g, 3.0 mmol), N-Boc-3-aminopropanol (525 mg, 3.0 mmol) and triphenylphosphine (1.56 g, 6.0 mmol) were dissolved in tetrahydrofuran (45 mL) at ambient temperature. DEAD (1.02 g, 6.0 mmol) was added drop wise to the mixture. The mixture was stirred overnight, then concentrated to dryness under vacuum. The residue was partitioned between water (30 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (30 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide the t-Boc protected derivative of 7 (1.2 g, yield 78%, 1H-NMR) as a white solid. The tert- Boc protection of the latter compound (250 mg, 0.5 mmol) was removed in dichloromethane (5 mL) using trifluoroacetic acid (5 mL) . The mixture was stirred 0.5 hour at ambient temperature, and then concentrated to dryness on rotavapor. The residue was treated with ethyl ether (5 mL) to give 7 as a white solid (210 mg, yield 84%) . ¹H-NMR (300 MHz , CDC1₃) : δ 7.401-7.117 (m, 8 H) , 4.346-4.310 (m, 1 H) , 4.200-4.135 (m, 1 H) , 4.012-3.933 (m, 2 H) , 3.554 (s, 3 H) , 3.321-3.280 (m, 2 H) , 1.260-1.212 (t, 3 H) ; LCMS (ESI) calc'd for ( C22H24 CIN3O3 ) [M+H]+, 414.16; found, 414.39.

5-c loro-N-ethyl-l-methyl-4- (2-morp olinoethoxy) -2-oxo-N-phenyl-l , 2- dihydroquinoline-3-carboxamide , 8 .

Laquinimod (1.09 g, 3.0 mmol), 2-morpholinoethanol (393 mg, 3.0 mmol) and triphenylphosphine (1.56 g, 6.0 mmol) were dissolved in tetrahydrofuran (45 mL) at ambient temperature. DEAD (1.02 g, 6.0 mmol) was added drop wise to the solution. The mixture was stirred overnight at ambient temperature, and the solvent was removed under vacuum. The residue was partitioned between water (20 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (20 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column ( dichloromethane/ethanol=10 : 1 ) to provide 8 (0.71g, yield 51%) as a white solid. ^-NMRPOO MHz, CDC1₃) : δ 1.27 ( t, 3H) , 2.60 (br s, 4 H) , 2.90 (br s, 2H) , 3.56 (s, 3H) , 3.75 (s, 4H) , 3.94 (m, 2H) , 4.35 (t, 2H) , 7.21{m, 5H) ; 7.41 (m, 3H) ; LCMS (ESI) calc' d for (C22H28CIN3O4) [M+H]+, 470.18; found, 470.40.

Eethyl 2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) acetate , 9.

Laquinimod (212 mg, 0.6 mmol) was dissolved in acetonitrile (15 mL) at ambient temperature. Ethyl 2-bromoacetate (330 mg, 2.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added to the solution. The mixture was heated under reflux overnight, then diluted with water (50 mL) and dichloromethane (150 mL) . The organic layer was separated and washed with brine (50 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 9 (168 mg, yield 63%) as a white solid. ¹H-NMR (300 MHz, CDCI3) : δ 7.493-7.346 (m, 3 H) , 7.265- 7.156 (m, 5 H) , 4.857-4.722 (q, 2 H) , .4.339- .268 (q, 2H) , 4.039-3.994 (m, 1 H), 3.839-3.765 (m, 1 H) , 3.567 (s, 1 H) , 1.357-1.278 (t, 3 H) , 1.267-1.219 (t, 3 H) ; LCMS (ESI) calc'd for (C₂3H23C1N₂0₅ ) [M+H]⁺, 443.14; found, 443.12. 2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) acetic acid, 10.

The compound ethyl 2- (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2- oxo-1, 2-dihydroquinolin-4-yloxy) acetate, 9 (442 mg, 1.0 mmol) was dissolved in lOmL tetrahydrofuran and lOmL water, and stirred at ambient temperature. Then NaOH (400 mg, 10 mmol) was added. The mixture was stirred at ambient temperature for lh, then tetrahydrofuran was removed, and the pH of the mixture was adjusted with IN HCl to pH=4 and extracted with ethyl acetate (20 mix 3) . The organic phase was combined, dried and concentrated to dryness on rotavapor to give 10 as a white solid (403 mg, 97%,) . ¹H-NMR (300 MHz, CDC1₃) : δ 7.484-7.372 (m, 3 H) , 7.285-7.188 (m, 5 H) , 4.951-4.787 (q, 2 H) , 4.180-4.055 (m, 1 H) , 3.903-3.791 (m, 1 H) , 3.576 (s, 3 H) , 1.306-1.248 (t, 3 H) ; LCMS (ESI) calc'd for (C21H19CIN2O5) [M+H]+, 415.11; found, 412.99. 5-chloro-N-ethyl-l-methyl-4- (2- (nicotinamido) et oxy) -2-oxo-N-phenyl- 1 , 2-

6 (200 mg, 0.5 mmol), nicotinic acid (123 mg, 1.0 mmol), EDCI (197 mg, 1.0 mmol) and HOBT (135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) at ambient temperature. Triethylamine (202 mg, 2.0 mmol) was added, and the mixture was stirred overnight after which it was washed with water (5 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 11 (210 mg, 83%) as a white solid. ¹H-NMR (300 MHz , CDC1₃) : δ 9.076 (s, 1 H) , 8.716 (d, 1 H) , 8.267 (d, 1 H) , 7.433-7.070 (m, 9 H) , 4.680-4.560 (m, 1 H) , 4.251 (m, 1 H) , 4.124- 4.079 (m, 1 H) , 3.817-3.691 (m, 3 H) , 3.349 (s, 3 H) , 1.185-1.102 (t, 3 H) ; LCMS (ESI) calc'd for (C27 H25C1N404) [M+H]+, 505.16; found, 505.34.

5-chloro-N-ethyl-l-methyl-4- (2- (nicotinamide)) ethoxy) -2-oxo-N-phenyl- 1 , 2-dihydroquinoline-3-carboxamide , 12.

A solution of 7 (207 mg, 0.5 mmol) , nicotinic acid (123 mg, 1.0 mmol) , EDCI (197 mg, 1.0 mmol) and HOBT (135 mg, 1.0 mmol) in dichloromethane (20 mL) was stirred at ambient temperature, and triethylamine (202 mg, 2.0 mmol) was added. The mixture was stirred overnight. It was washed with water (10 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 12 (204 mg, yield 80%) as a white solid. ¹H-NMR (300 MHz, CDCl₃) : δ 9.076 (s, 1 H) , 8.716 (d, 1 H) , 8.267 (d, 1 H) , 7.433-7.070 (m, 9 H) , 4.680-4.560 (m, 1 H) , 4.251 (m, 1 H)^' , 4.124-4.079 (m, 1 H) , 3.817-3.691 (m, 3 H) , 3.349 (s, 3 H) , 1.185-1.102 (t, 3 H) ; LCMS (ESI) calc'd for (C₂₇ H25CIN4O4) [M+H]+, 505.16; found, 505.34. methyl 3- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1 -methyl-2-oxo-l ,2- dihydroquinolin-4-yloxy) propanoate, 13.

Laquinimod (1.09 g, 3.0 imtiol) , methyl 3-hydroxypropanoate (312 mg, 3.0 mmol) and triphenylphosphine (1.56 g, 6.0 mmol) were dissolved in tetrahydrofuran (45 mL) at ambient temperature. DEAD (1.02 g, 6.0 mmol) was added drop wise to the mixture. The mixture was stirred at ambient temperature overnight, then concentrated to dryness under vacuum. The residue was diluted with water (20 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (20 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 13 (560 mg, yield 42%, 1H-NMR) as a white solid. ¹H-NMR (300 MHz, CDC13) : δ 7.369-7.115 (m, 8 H) , 4.563-4.520 (m, 2 H) , 4.064-3.877 (m, 2 H) , 3.753 (s, 3 H) , 3.560 (s, 3 H) , 2.942-2.898 (m, 2 H) , 1.291-1.221 (t, 3 H) ; LCMS (ESI) calc'd for (C23H23CIN2O5) [M+H]⁺, 443.14; found, 443.07.

5-chloro-N-ethyl-l-methyl-4- (2- ( (2- (methylamino) ethyl) amino) -2- oxoethoxy) -2-oxo-N-phenyl-l , 2-dihydroquinoline-3-carboxamide , 14.

Nl-Boc-Nl-methylethylenediamine (87 mg, 0.5 mmol), 10 (207 mg, 0.5 mmol), EDCI (197 mg, 1.0 mml) and HOBT (135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) at ambient temperature, and to the solution was added triethylamine (202 mg, 2.0 mmol) . The mixture was stirred overnight at ambient temperature after which it was washed with water (5 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide the Boc protected 14 (204 mg, 71%, 1H-NMR) as a white solid. The latter compound (204 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) , trifluoroacetic acid (5 mL) was added and the mixture was stirred for 0.5 hour at ambient temperature. Solvent was removed under vacuum, and the residue was treated with ether (15 mL) to give 14 as a white solid (186 mg, yield 91%, 1H-NMR) . ¹H-N R (300 MHz, CDC13) : 57.444-7.389 (m, 3 H) , 7.292-7.202 (m, 5 H) , 4.728-4.632 (dd, 2 H) , 4.004-3.919 (m, 2 H) , 3.608 (s, 3 H) , 3.566-3.533 (m, 2 H) , 2.905- 2.868 (m, 2 H) , 2.539 (s, 3 H) , 1.313-1.242 (m, 3 H) ; LCMS (ESI) calc'd for (C24H27CIN4O4) [M+H]⁺, 471.18; found, 471.34.

4,4'- (ethane-1 , 2-diylbis (oxy) )bis (5-chloro-N-ethyl-l-methyl-2-oxo-N- phenyl-1 , 2-dihydroquinoline-3-carboxamide) , 15.

A mixture of 5-chloro-N-ethyl-4-hydroxy-l-methyl-2-oxo-N-phenyl-l, 2- dihydroquinoline-3-carboxamide, Laq. (5.0 g, 14.0 mmol) in POCI3 (50 mL) was heated at 80 °C for 1.5 h and then concentrated. The residue was poured into cool Na₂C0₃ solution (100 mL, 2.0 M) and the mixture was extracted with DCM (100 mL x 2) . The organic layers were combined, washed with brine (100 mL) , dried over a2S04 and concentrated. The residue was recrystallized from DCM/PE (400 mL, 1/3) to afford 4 , S-Dichloro-N-ethyl- l-methyl^-oxo-N-phenyl-l , 2-dihydroquinoline-3-carboxamide, 77 as a yellow solid (3.3 g) . The mother liquid was concentrated and purified by flash chromatography to afford another portion of 77 (1.0 g) . ¹H NMR confirmed its structure. To a mixture of 77 (400 mg, 1.07 mmol) and ethane-1, 2-diol (30 mg, 0.48 mmol) in THF (8 mL) was added NaH (43 mg, 60% in mineral oil, 1.07 mmol) under nitrogen at 0°C. The mixture was then stirred at room temperature for 2d. Another portion of 77 (200 mg, 0.54 mmol) and NaH (22 mg, 60% in mineral oil, 0.54 mmol) was added. The mixture was heated to 60 °C overnight and then cooled. Water (20 mL) was added to quench the reaction and the mixture was extracted with DCM (20 mL x 2) . The organic layers were combined, washed with Na₂CC>3 (IN, 20 mL) , dried and concentrated. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, from 100/1 to 40/1) to afford 15 as a light yellow solid (240 mg, 20%) . ^-NMR (300 MHz, CDC13) : δ 7.480-7.126 (m, 16 H) , 4.734-4.677 (m, 4 H) , 4.071-3.917 (m, 4 H) , 3.585-3.574 (m, 6 H) , 1.318-1.248 (dt, 6 H) ; LCMS (ESI) calc'd for (C₄oH36Cl2N₄06), [M+H]⁺, 739.21; found, 739.31.

5-chloro-N-ethyl-4- (2- ( (l-hydroxy-2- (hydroxymethyl) -4- (4- octylphenyl) butan-2-yl) amino) -2-oxoethoxy) -l-methyl-2-oxo-N-phenyl- -dihydroquinoline-3-carboxamide, 16.

2-Amino-2- ( 4-octylphenethyl) propane-1 , 3-diol (172 mg, 0.5 mmol), 10 (207 mg, 0.5 mmol), EDCI (197 mg, 1.0) and HOBT(135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) at ambient temperature. Triethylamine (202 mg, 2.0 mmol) was added, and the mixture was stirred overnight. It was then washed with water (10 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (dichloromethane/ethanol=10 : 1 ) ) to provide 16 (yield 90 mg, 26%) as a white solid; ¾ NMR (300 MHz, CDC1₃) : δ 7.4374- 7.353 (m, 3.H), 7.235-7.066 (m, 9 H) , 4.657 (s, 1 H) , 4.025-3.896 (m, 4 H) , 3.795-3.758 (m, 2 H) , 3.567 (s, 3 H) , 2.645-2.527 (m, 3 H) , 2.039- 2.021 (m, 2 H), 1.901-1.576 (m, 4 H) , 1.265-1.139 (m, 12 H) , 0.893-0.849 (m, 3 H) ; LCMS (ESI) calc'd for (C40H5OCIN3O6) [M+H]+, 704.35; found, 704.40. (S) -5-chloro-4- (2- (2 , 6-diaminohexanamido) ethoxy) -N-ethyl-l-methyl-2- oxo-N-phenyl-1 , 2-dihydroquinoline-3-carboxamide , 17.

To a solution of Laq. (1.07 g, 3 mmol) in THF (30 mL) was added tert- butyl 2-hydroxyethylcarbamate (0.48 g, 3 mmol), PPh3 (1.57 g, 6 mmol) and DEAD (1.04 g, 6 mmol), the mixture was stirred overnight at room temperature. Most of solvent was removed under reduced pressure, the residue was treated with DCM (100 mL) and water (100 mL) , the organic phase was separated, dried and concentrated to give crude Mitsunobu product. The latter product was dissolved in DCM (15 mL) , TFA (15 mL) was added and the mixture was stirred for 1 h at room temperature. Then sodium bicarbonate (10%) aqueous solution was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with DCM (15 mL x 2), and the organic phase combined, dried, concentrated and purified by flash chromatography to give the primary amine (600 mg, 50 % yield for two steps) . To a solution of the primary amine (290 mg, 0.73 mmol) in DCM (20 mL) was added di-Boc protected Lys (380 mg, 1.10 mmol), EDCI (285 mg, 1.46 mmol), HOBT (300 mg, 2.20 mmol) and TEA (368 mg, 3.65 mmol). The mixture was stirred overnight, water (20 mL) was added, the organic phase was separated and washed with water (20 mL x 2), the organic phase was dried, concentrated and purified by flash chromatography to give the amide (108 mg, 20% yield) . The latter was dissolved (108 mg, 0.15 mmol) in DCM (5 mL) , TFA (5 mL) was added and the mixture was stirred for Ih. NaHCC aqueous solution (sat) was added to quench the reaction, the organic phase separated, the aqueous phase was extracted with DCM (15 mL x 2) and the organic phase combined, dried, concentrated to give 17 (40 mg, 51 % yield) . ¹H-NMR (300 MHz, CDC13) : δ 8.0 (m, 1 H) , 7.0-7.5 (m, 8 H) , 4.6 (m, 3 H) , 4.3 (m, 1 H) , 4.2 (m, 1 H) , 4.1 (m, 1 H) , 3.9 (m, 2 H) , 3.7 (m, 2 H) , 3.4 (s, 3 H) , 3.3 (m, 1 H) , 2.7 (m, 1 H) , 2.4 (m, 8 H) , 1.7 (m, 1 H) , 1.1-1.6 (m, 12 H) ; LCMS (ESI) calc'd for (C27H34CIN5O4 ) [M+H]⁺, 528.24; found, 528.33.

(R) -5-chloro-4- ( (5, 9-diamino-4-oxononyl) oxy) -N-ethy1-1-methyl-2-oxo-N- phenyl-1, 2-dihydroquinoline-3-carboxamide, 18.

To a solution of Laq. (1.07 g, 3 mmol) in THF (30 mL) was added tert- butyl 3-hydroxypropylcarbamate (0.53 g, 3 mmol), PPI 3 (1.57 g, 6 mmol) and DEAD (1.04 g, 6 mmol) and the mixture was stirred overnight. Most of solvent was removed under reduced pressure, the residue was treated with DCM (100 mL) and water (100 mL) , the organic phase was separated, dried and concentrated to give the crude Mitsunobu product (3 g) . The crude compound (3 g) was dissolved in DCM (15 mL) , TFA (15 mL) was added and the mixture was stirred for 1 h at room temperature, sodium bicarbonate (10%) aqueous solution was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with DCM (15 mL x 2) and the organic phase combined, dried, concentrated and purified by flash chromatography to give the corresponding primary amine (700 mg, 56 % yield for two steps) . To a solution of primary amine (300 mg, 0.73 mmol) in DCM (20 mL) was added di-Boc protected Lys (380 mg, 1.10 mmol), EDCI (285 mg, 1.46 mmol), HOBT (300 mg, 2.20 mmol) and TEA (368 mg, 3.65 mmol), the mixture was stirred overnight, water (20 mL) was added, the organic phase was separated and washed with water (20 mL x 2), the organic phase was dried, concentrated and purified by flash chromatography to the amide (100 mg, 18% yield) . To a solution of the latter amide (100 mg, 0.13 mmol) in DCM (5 mL) was added TFA (5 mL) , the mixture was stirred for lh, most of solvent was evaporated under reduced pressure, the residue was treated with ether (2 mL) and acetonitrile (2 mL), concentrated to give 18 (100 mg) . ^!fi-NMR (300 MHz, DMSO) : δ 8.574 (s, 1 H) , 8.193 (s, 2 H) , 7.801 (s, 2 H) , 7.548-7.459 (m, 3 H) , 7.321- 7.205 (m, 5 H) , 4.181 (m, 1 H) , 4.064 (m, 1 H) , 3.861-3.691 (m, 4 H) , 3.523 (s, 3 H), 2.775 (m, 2 H) , 2.081-2.008 (m, 2 H) , 1.745-1.724 (m, 2 H) , 1.562 (m, 2 H) , 1.354 (m, 2 H) , 1.153-1.105 (m, 3 H) ; LCMS (ESI) calc'd for (C30H37CIF3N5O6) [M+H]⁺, 542.25; found, 542.35.

5-chloro-N-ethyl-4- (2- ( (2-hydroxyethyl) (methyl) amino) -2-oxoethoxy) -1- methyl-2-oxo-N-phenyl-l , 2-dihydroquinoline -3-carboxamide , 19.

10 (103 mg, 0.25 mmol), 2- (methylamino ) ethanol (37 mg, 0.5 mmol), EDCI (197 mg, 1.0 mmol) and HOBt (135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) at ambient temperature. To the solution was added triethylamine (202 mg, 2.0 mmol) . The mixture was stirred overnight at ambient temperature. It was washed with water (5 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 19 (30 mg, yield 25%) as a white solid; (300MHz, CDC1₃) δ 7.560- 7.476 (m, 2 H) , 7.412-7.346 (m, 1 H) , 7.286-7.157 (m, 5 H) , 5.104-4.930 (m, 2 H) ;3.953-3.870 (m, 3 H) , 3.779-, 3.616 (m, 1 H) , 3.562 (s, 3 H) , 3.256 (m, 2 H) , 3.069 (s, 3 H) , 1.263-1.215 (t, 3 H) ; LCMS (ESI) calc' d for (C₂₄H₂₆C1N₃0₅) [M+H]+, 472.16; found, 472.21.

N6- (2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) acetyl) -L-lysine , 20.

To a solution of compound 10 (300 mg, 0.73 mmol) in DCM (20 mL) was added N-Boc-Lys- -Bu ester (263 mg, 0.87 mmol), EDCI (285 mg, 1.46 mmol), HOBT (300 mg, 2.20 mmol) and TEA (368 mg, 3.65 mmol) . The mixture was stirred overnight, water (20 mL) was added, the organic phase was separated and washed with water (20 mL x 2) , the organic phase was collected, dried, concentrated and purified by flash chromatography to give the corresponding amide (350 mg, 69% yield) , which was dissolved (350 mg, 0.50 mmol) in DCM (5 mL) . TFA was added (5 mL) , the mixture was stirred for 2h., after which most of solvent evaporated under reduced pressure, the residue was treated with ether (2 mL) and acetonitrile (2 mL) , to give a suspension from which 20 was collected by filtration (200 mg, 63% yield) as a white solid; ¹H-NMR (300 MHz, CD30D) : δ 7.563-7.243 (m, 8 H) , 4.698-4.682 (m, 2 H) , 4.153-3.983 (m, 2 H) , 3.840 (m, 1 H) , 3.605 (s, 3 H) , 3.425-3.317 (m, 2 H) , 2.050-1.900 (m, 2 H) , 1.697-1.511 (m, 4 H) , 1.278-1.173 (m, 3 H) , LCMS (ESI) calc'd for (C29H32CIF3N4O8) [M+H]⁺, 543.19; found, 543.29.

(S) -2-amino-3- (4- (2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2- oxo-1 , 2-dihydroquinolin-4-yl) oxy) acetoxy) phenyl) propanoic acid, 21.

10 (207 mg, 0.5 mmol) , Boc-Tyr-0- tBu (170 mg, 0.5 mmol) and EDCI (197 mg, 1.0) were dissolved in dichloromethane (20 mL) at ambient temperature. To the solution was added DMAP (244 mg, 2.0 mmol) . The mixture was stirred overnight at ambient temperature. It was washed with water (5 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide the Boc-O-tBu protected 21 (103 mg, yield 28%) as a white solid. The latter compound (103 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL) . Trifluoroacetic acid (5 mL) was added, and the mixture was stirred for 0.5 hour at ambient temperature. Solvent was removed under vacuum, and the residue was treated with ether (15 mL) to give 21 as a white solid (60 mg, yield 65%); (300 MHz, CD₃OD) : δ 7.551-7.104 (m, 12 H) , 5.209 (d, 1 H) , 4.973 (d, 1 H) , 3.939-3.862 (m, 2 H) , 3.597 (s, 3 H) , 3.139-3.070 (m, 1 H) , 1.210-1.162 (t, 3 H) ; LCMS (ESI) calc'd for ( C32H29CI F3N3O7 ) [ -H] - , 576.15; found, 576.20.

O- (2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) acetyl) -L-serine, 22.

10 (207 mg, 0.5 mmol), Boc-Ser-OH (205 mg, 1.0 mmol) and EDCI (197 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) . DMAP (244 mg, 2.0 mmol) was added. The mixture was stirred at ambient temperature overnight. It was washed with water (10 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified by prep-HPLC to provide the Boc protected 22 (36 mg, yield 12%) as a white solid. The latter compound (36 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL) , and trifluoroacetic acid (5 mL) was added. The mixture was stirred for 0.5 hour at ambient temperature. Solvent was removed on rotavapor, and the residue was treated with ethyl ether to give 22 as a white solid (24 mg, yield 68%) . ^XH-NMR (300 MHz, CD30D) : δ 7.514-7.410 (m, 4 H) , 7.318-7.194 (m, 4 H) , 5.034-5.011 (m, 1 H) , 4.843- 4.717 (m, 3 H) , 4.463 (m, 1 H) , 3.932-3.868 (m, 2 H) , 3.591 (s, 3 H) , 1.259-1.200 (m, 3 H) ; LCMS (ESI) calc'd for (C24H2₄CIN3O7 ) [M+H]+, 502.14; found, 502.14.

2- (dime hylamino) ethyl-2- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1- methyl-2-oxo-l , 2-dihydroquinolin-4-yl) oxy) acetate , 23.

10 (207 mg, 0.5 mmol), 2- (dimethylamino) ethanol (180 mg, 2.0 mmol) and EDCI (197 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) . DMAP (244 mg, 2.0 mmol) was added. The mixture was stirred at ambient temperature overnight. It was washed with water (10 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified by prep-HPLC to provide 23 (40 mg, yield 14%) as a white solid; ^!H- MR (300 MHz, CD₃OD) : δ 7.525-7.403 (m, 5 H) , 7.331-7.219 (m, 3 H) , 5.078 (d, 1 H) , 4.785 (d, 1 H) , 4.618-4.602 (m, 2 H) , 3.901-3.874 (m, 2 H) , 3.590 (s, 3 H) , 3.590-3.547 (m, 2 H) , 3.002-2.960 (m, 6 H) , 1.244-1.196 (t, 3 H) ; LCMS (ESI) calc'd for (C25H28CIN₃O₅) [M+H]+, 485.18; found, 486.14.

3- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) propyl (Is , 4s) -4-cyano-4- (3- (cyclopentyloxy) -

4-methoxyphenyl) cyclohexane-l-carboxylate , 24.

5 (207 mg, 0.5 mmol) , cilomilast (170 mg, 0.5 mmol) and EDCI (197 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) . DMAP (244 mg, 2.0 mmol) was added. The mixture was stirred at ambient temperature overnight. It was washed with water (10 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified by prep-TLC (petroleum ether: ethyl acetate=l:l) to provide 24 (100 mg, yield 27%) as a white solid. ^-NMR (300 MHz, CDC1₃) : δ 1.24 (m, 4H) , 1.63-2.61 (m, 18H) , 3.81-4.05 (m, 2H) , 3.56 (s, 3H) , 3.89 (s, 3H) , 4.28 (m, 2H) , 4.40 (m, 2H) , 4.80 (s, 1H) , 6.84 (m, 1H) , 6.96 (m, 2H) , 7.15- 7.26 (m, 4H) , 7.31-7.38 (m, 4H) ; LCMS (ESI) calc'd for (C42H46CIN3O7) [M+H] +, 740.31; found, 740.24.

3- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy)propyl (Is , 4s) -4-cyano-4- (3- (cyclopentyloxy) -

4-methoxyphenyl) cyclohexane-l-carboxylate , 25.

7 (207 mg, 0.5 mmol), cilomilast (170 mg, 0.5 mmol), EDCI (197 mg, 1.0 mmol) and HOBt (135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) . Triethylamine (202 mg, 2.0 mmol) was added. The mixture was stirred at ambient temperature overnight. It was then washed with water (10 mL) , and dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified by prep-TLC (petroleum ether: ethyl acetate=l:l) to provide 25 (75 mg, 20%) as a white solid. -Ή-NMR (300 MHz, CDC1₃) : δ 1.24 (m, 4H) , 1.63-2.53 (m, 18H) , 3.20 (m, 1H) , 3.57 (s, 3H) , 3.70-3.82 (m, 2H) , 3.86 (s, 3H) , 4.05-4.30 (m, 3H) , 4.80 (m, 1H) , 6.89 (m, 1H) , 6.98 (m, 2H) , 7.19-7.28 (m, 4H) , 7.32-7.41 (m, 4H) ; LCMS (ESI) calc'd for (C₄2H7C1 40₆) [M+H]\ 739.33; found, 739.12. 5-chloro-4- (2- ( (Is , s) -4-cyano-4- (3- (cyclopentyloxy) -4- methoxyphenyl) cyclohexane-l-carboxamido) ethoxy) -N-ethyl-1-methyl-2- oxo-N-phenyl-1 , 2-dihydroquinoline-3-carboxamide , 26.

6 (200 mg, 0.5 mmol) , cilomilast (170 mg, 0.5 mirtol) , EDCI (197 mg, 1.0 mmol) and HOBt (135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) . Triethylamine (202 mg, 2.0 mmol) was added, then the mixture was stirred at ambient temperature overnight. It was washed with water (10 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified by prep-TLC (petroleum ether: ethyl acetate=l:l) to provide 26 (50 mg, yield 14%,) as white solid. ^- MR (300 MHz, CDC1₃) : δ 1.27 (m, 4H) , 1.63-2.30 (m, 18H) , 3.40 (m, 1H) , 3.55(s, 3H) , 3.75(m, 2H) 3.85(s, 3H) , 4.28 (m, 2H) , 4.55 (m, 1H) , 4.80 (m, 1H) , 6.83(m, 1H) , 6.98(m, 2H) , 7.16-7.26(m, 4H) , 7.32-7.38(m, 4H) , 7.80 (m 1H) ; LCMS (ESI) calc'd for (C₄₁H₄5CIN4O6) [M+H] ⁺ , 725.31; found, ^"725.10.

(3R, 4S , 5R, 6R) -2,3, 5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-4- yl 3- ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) propanoate , 27.

A solution of D-Glucose (10 g, 56.0 mmol) , dry acetone (500 mL) and iodine (700 mg) was heated under reflux for 6 hours. It was cooled to room temperature and slowly quenched with an aqueous sodium thiosulfate (0.5 M) solution until complete discoloration. After evaporation of the solvent, the solution was extracted with dichloromethane (3 x 100 mL) . The combined extract was washed with water (100 mL) , dried over anhydrous sodium sulfate and concentrated to dryness on rotavapor. The residue was re-crystallized from hot hexane to give the protected Glucose derivative as a white solid (11.6 g, 80% yield) . ¹H-NMR confirmed its structure. To a solution of 10 (318 mg, 0.77 mmol), EDCI (697 mg, 3.5 mmol) and DMAP (188 mg, 1.5 mmol) in dichloromethane (50 mL) was added the protected Glucose derivative (200 mg, 0.77 mmol) at 0 °C. The mixture was stirred overnight at ambient temperature, then quenched with water (20 mL) and diluted with dichloromethane (50 mL) . The organic layer was separated and dried over sodium sulfate. It was concentrated to dryness under reduced pressure. The residue was purified on silica gel column to give the protected Glucose derivative of Laq. (200 mg, 40% yield) . ¹H-NMR and UPLC-MS confirmed its structure. To a solution of the latter compound (120 mg, 183 mmol) in propan-2-ol (3 ml) was added concentrated aqueous HC1 (3 ml) at .0 °C. The reaction mixture was stirred 30 min, then concentrated to dryness to give 27 (100 mg) as a white solid. ¹H-NMR, (300 MHz, MeOD) δ 7.27-7.34 (m, 7H) , 7.07-7.05 (m, 6H) , 5.25-5.50 (m, 2H) , 5.11-5.12(d, J = 5.1 Hz, 1H) , 4.91-5.05 (m, 1H) , 4.85-4.92 (m, 2H) , 4.61-4.80 (m, 2H) , 4.51-4.59 (d, 1H) , 3.6-3.9 (m, 9H) , 3.41-3.58 (m, 7H) , 3.21-3.48 (m, 4H) , 1.05-1.20 (m, 7H) ; DEPT135, HSQC and LC-MS confirmed its structure; LCMS (ESI) calc'd for (C27H29CIN2O10) [M+H]⁺, 577.15; found, 577.08.

5-chloro-N-ethyl-l-methyl-4- ( (methylthio) oxy) -2-oxo-N-phenyl-l , 2- dihydroquinoline-3-carboxamide , 28.

Laquinimod (212 mg, 0.6 mmol) was dissolved in DMF (15 mL) at ambient temperature. Chlorome hyl methyl sulfide (61 mg, 0.6 mmol) and triethylamine (200 mg, 2.0 mmol) were added to the mixture. The mixture was stirred overnight at ambient temperature, then diluted with water (30 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (20 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 28 (103 mg, yield 41%) as a white solid. ¹H-NMR (300 MHz, CDCI3) : δ 7.412-7.357 (m, 3 H) , 7.284-7.171 (m, 5 H) , 5.360 (d, 1 H) , 5.268 (d, 1 H) , 4.0173-3.944 (m, 2 H) , 3.583 (s, 3 H) , 2.457 (s, 3 H) , 1.295-1.248 (t, 3 H) ; LCMS (ESI) calc'd for ( C21H21CIN2O3S ) [M+H]+, 417.10; found, 417.90. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l ,2- dihydroquinolin-4-yl acetate, 29.

5-chloro-N-ethyl-4-hydroxy-l-methyl-2-oxo-N-phenyl-l, 2- dihydroquinoline-3-carboxamide (Laq. 356 mg, 1 mmol, 1 eq. ) in 10 mL anhydrous THF, was added acetic anhydride (122 mg, 1.2 eq.) and DIPEA (208 mg, 1.5 eq.) . The mixture was stirred at 40 0°C overnight. The mixture was washed with saturated NaHCCh solution (10ml), dried over MgSC and evaporated to dryness. The residue was stirred in lOmL ethyl acetate and filtered to give product as a white solid (200mg, 50.3 %). ¾-NMR (DMSO-de, 500 MHz): δ 7.73-7.20 (8H, m) , 3.94-3.90 (0.8 H, m) , 3.74 (0.4 H, s) , 3.70-3.66 (1.2 H, m) , 3.55 (2.6 H, s), 2.39 (3H, s), 1.14 (2.5 H, t, J = 7.5 Hz), 0.92 (0.5H, t, J = 7.5 Hz) . Mass (ESI+) : calculated as 398.1, found 399.1 ([M+H]⁺.

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl propionate, 30. _v

To a solution of 5-chloro-IV-ethyl-4-hydroxy-l-methyl-2-oxo-W-phenyl- 1 , 2-dihydroquinoline-3-carboxamide (Laq., 356 mg, 1 mmol, 1 eq.) in 10 mL anhydrous THF, was added propionyl chloride (110 mg, 1.2 eq.) and DIPEA (208 mg, 1.5 eq. ) . The mixture was stirred at 40°C overnight. The mixture was washed with saturated NaHCOa solution (10ml), dried over MgS0 and evaporated to dryness. The residue was stirred in ethyl acetate (10 mL) and filtered to give 30 as a white solid (270 mg, 65.5 %); ¹H- NMR (DMSO-de, 500 MHz) : δ 7.73-7.21 (8H, m) , 3.91-3.88 (0.9 H, m) , 3.74 (0.4 H, s), 3.72-3.69 (0.8 H, m) , 3.62-3.57 (0.3 H, m) , 3.55 (2.6 H, s) , 2.73-2.69 (2H, m) , 1.21-1.11 (5.5H, m) , 0.92 (0.5H, t, J = 7.5 Hz); Mass (ESI+) : calculated as 412.1, found 413.1 [M+H]⁺. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl ethyl oxalate, 31.

To a solution of Laquinimod (0.25 g, 0.7 mmol) and triethylamine (0.14 g, 1.4 mmol) in dichloromethane (10 mL) was added ethyl 2-chloro-2- oxoacetate (0.1 g, 0.75 mmol) . The mixture was stirred 3 hours, then diluted with dichloromethane (25 mL) . It was washed with water (3 x 50 mL) , dried over sodium sulfate and concentrated to dryness under vacuum. The residue was treated with ether (4 mL) to give 31 (200 mg, yield 63%,) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.471-7 ,416 (m, 3 H) , 7.311-7.208 (m, 5 H) , 4.547-4.475 (q, 2H) , 4.148-4.079 (m, 1H) , 3.822- 3.728 (m, 1H) , 3.613 (s, 3H) , 1.513-1.447 (t, 3H) , 1.282-1.235 (t, 3H) LCMS (ESI) calc'd for (C23H21CI 2O6) [M+H]+, 457.11; found, 457.40.

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl pivalate, 32.

Laquinimod (356 mg, 1.0 mmol) was dissolved in dichloromethane (25 ml) at ambient temperature. Boc anhydride (327 mg, 1.5 mmol) and DMAP (37 mg, 0.3 mmol) were added to the mixture. The mixture was stirred overnight, and then diluted with water (30 mL) . It was extracted with dichloromethane (2 ^χ 40 ml) . The combined organic layer was washed with brine (30 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 32 (60 mg, yield 13%) as white solid. ¹H-NMR (300 MHz, CDC13) : δ 7.460-7.407 (m, 3 H) , 7.379-7.159 (m, 5 H) , 4.219-4.150 (m, 1 H) , 3.755-3.642 (m, 1 H) , 3.576 (s, 3 H) , 1.677 (m, 9 H) , 1.329-1.218 (t, 3 H) ; LCMS (ESI) calc'd for (C₂₄ H25CIN2O5 ) 456.92 [M+H]⁺, found, 457.15.

5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 ,2- dihydroquinolin-4-yl 2-propylpentanoate , 33.

Laquinimod (178 mg, 0.5 mmol), 2-propylpentanoic acid (144 mg, 1.0 mmol) and EDCI (197 mg, 1.0) were dissolved in dichloromethane (20 mL) at ambient temperature. DMAP (244 mg, 2.0 mmol) was added, and the mixture was stirred overnight. It was washed with water (5 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 33 (50 mg, yield 21%) as a white solid. ^:H-NMR (300 MHz, CDC1₃) : δ 7.416-7.351 (m, 3 H) , 7.285-7.176 (m, 5 H) , 4.350-4.310 (m, 1 H) ,

4.042-3.804 (m, 2 H) , 3.574 (s, 3 H) , 1.742-1.452 (m, 8 H) , 1.277-1.217 (m, 3 H) , 1.072-0.935 (m, 6 H) ; LCMS (ESI) calc'd for ( C27H31CIN2O4 ) [M+H]⁺, 483.21; found, 483.12. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl (S) -2-acetoxypropanoate, 34.

To the solution of (S) -2-acetoxypropanoic acid (2.0 g, 15 mmol) in dichloromethane (20 mL) was added DCC (1.56 g, 7.58 mmol) . The mixture was stirred for 0.5 hour. DMAP (0.345 g, 2.8 mmol) and Laq. (0.5 g, 1.4 mmol) were added. The mixture was stirred for 3 hours. The precipitates were removed by filtration, and the filtrate was washed with IN aqueous HC1 solution (15 mL) and saturated aqueous NaHC03 solution (15 mL) . It was dried over sodium sulfate and concentrated to dryness to give 34 (270 mg, 41%) as a white solid; 1H-NMR (300 MHz, CDC13) : 57.466-7.331 (m, 3 H) , 7.240-7.186 (m, 5 H) , 5.769-5.731 (m, 1H) , 3.998-3.893 (m, 2H) , 3.553 (s, 3H) , 2.239 (s, 3H) , 1.768-1.716 (t, 3H) , 1.274-1.198 (t, 3H) ; LCMS (ESI) calc'd for (C24H23CIN2O6) [M+H]⁺, 471.12; found, 471.23.

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dih droquinolin-4-yl L-phenylalaninate , 35.

To a mixture of L-Phe (3.3 g, 20 mmol), NaOH (960 mg, 24 mmol) in 40 mL dioxane and 40 mL H2O at 0°C, B0C2O (5.2 g, 24 mmol) was added dropwise. The mixture was stirred at rt for 12h. The reaction mixture was extracted with EtOAc (40 mL) . The aqueous layer was adjust the pH to 3 with 1M HC1, then extracted with EtOAc (40 mL* 3) . The organic layer was washed with brine and dried over a2S04, filtered and concentrated to afford (S) -2- (tert-butoxycarbonylamino) -3-phenylpropanoic acid (Boc-L-Phe, 5 g, 94 % yield) as a colorless oil. To a mixture of Laq. (356 mg, 1 mmol) , Boc-L-Phe (398 mg, 1.5 mmol), DMAP (183 mg, 1.5 mmol) in 20 mL DCM at 0°C, was added EDCI (360 mg, 2 mmol) . The mixture was stirred at rt for 4h. NaHC0₃ (10 mL) was added and the reaction mixture extracted with EtOAc (10 mL*3) . The organic layer was dried over a₂S0 , filtered .and concentrated. The crude was purified by column chromatography to afford (S) -5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl 2- (tert-butoxycarbonylamino) -3-phenylpropanoate (200 mg, 33 %) as a white solid. To a solution of the latter compound (200 mg, 0.33 mmol) in DCM (4 mL) was added TFA (1 mL) and the mixture was stirred at rt for 30 min. The mixture was adjusted to pH 9 with NaHCCh, extracted with EtOAc (10 mL x 3) . The organic layer was dried over Na₂S0₄, filtered and concentrated. The crude was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH4HCO3) , B: MeCN) to afford 35 (90 mg, 53 % yield) as a white solid. ¹H-NMR (400 MHz, CDC1₃) : 57.426-7.301 (m, 4 H) , 7.244-6.835 (m, 8 H) , 6.458-6.445 (d, J=5 Hz, 1 H),4.65 (s, 1 H), 3.935-3.914 (m, 2 H) , 3.788-3.492 (m, 4 H) , 3.373 (s, 3 H) , 2.986-2.939 (t, 1 H) , 1.169-1.118 (m, 3 H) . LCMS (ESI) calc' d for (C₂₈H2₆CI ₃O₄) [M+H]⁺,504.17; found, 504.2

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l ,2- dihydroquinolin-4-yl L-valinate, 36.

To a mixture of Laq. (712 mg, 2 mmol), N-Boc-Val (868 mg, 4 mmol), DMAP (976 mg, 8 mmol) in 50 mL DCM at 0°C, EDCI (Ig, 6 mmol) was added. The mixture was stirred at rt for 12h. The reaction mixture was added NaHC03 (10 mL) and extracted with AcOEt (10 mL*3) . The organic layer was dried over Na₂SC>4, filtered and concentrated. The crude was purified by column chromatography to afford the desired product (S) -5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2-dihydroquinolin-4-yl 2- (tert-but oxycarbonylamino) -3-methylbutanoate (Laq- Boc Val, 0.5 g, 54

% yield) as a white solid. The latter product (200 mg, 0.36 mmol) was dissolved in a solution of TFA (2 mL) and DCM (8 itiL) and was stirred at rt for 30 min. The mixture was adjusted to pH 9 with NaHC03, extracted with EtOAc (10 mL*3) . The organic layer was dried over Na2SO<i, filtered and concentrated. The crude was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH₄HC0₃) , B: MeCN) to afford 36 (80 mg, 50 % yield) as a white solid. ^-NMR (400 MHz, CDC1₃) : 57.579-7.331 (m, 1 H) , 7.138-6.739 (m, 7 H) , 4.636-4.387( m, 1 H) , 4.032-3.316 (m, 5 H) , 2.432- 2.327 (m, 1 H) , 1.375-0.723 (m, 9 H) . LCMS (ESI) calc'd for ( C24H26CI 3O4 ) [M+H]⁺, 456.17; found, 456.2. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl diethyl phosphate, 37.

To a solution of Laquinimod (0.4 g, 1.1 mmol) in the THF (10 mL) were added dropwise at the same time a solution of diethyl phosphorochloridate (5.8 g, 33.7 mmol) in THF (10 mL) and a solution (10 mL) of DABCO (3.78 g, 33.7 mmol) in THF (10 mL) . The mixture was. stirred overnight and then diluted with dichloromethane (200 mL) . The dichloromethane extract was washed with IN HC1 (2 x 80 mL) , saturated NaHC0₃ (3 x 80 mL) and brine (100 mL) . It was dried over sodium sulfate and concentrated to dryness on rotavapor. The residue was treated with ether (50 mL) to give 37 (385 mg, 70%) as a white solid. ^XH-NMR (300 MHz, CDC1₃) : 57.404-7.341 (m, 3 H) , 7.284-7.170 (m, 5 H) , 4.357-4.219 (m, 4H) , 4.157-3.770 (m, 2H) , 3.624 (s, 3H), 1.468-1.417 (t, 3H) , 1.312-1.249 (m, 6H) ; LCMS (ESI) calc'd for (C₂₃H2₆CIN₂O6P) [M+H]+, 493.12; found, 493.08. 5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 ,2- dih droquinolin-4-yl 5-morpholinopentanoate, 38.

5-Morpholinopentanoic acid (1 g, 5.3 mmol) was dissolved in thionyl chloride (30 mL) . The mixture was refluxed for 3 hours. Removal of solvent under reduced pressure gave crude aceyl chloride (1.1 g) as a white solid, which was used in the next step without further purification. To a solution of Laquinimod (0.5 g, 1.4 mmol) and triethylamine (1.2 mL, 8.4 mmol) in dichloromethane (15 mL) was added the crude aceyl chloride (0.83 g, 4.2 mmol) . The mixture was stirred 3 hours, and then diluted with dichloromethane (40 mL) . It was washed with water (3 x 20 mL) , dried over sodium sulfate and concentrated to dryness on rotavapor. The residue was titrated with ether (7 mL) to give 38 (160 mg, 21%) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.438-7.337 (m, 3 H) , 7.258-7.197 (m, 5 H) , 4.153-4.084 (m, 1H) , 3.825 (b, 4H) , 3.571 (s, 3H), 2.763-2.714 (m, 2H) , 2.495 (b, 2H) , 1.890-1.817 (m, 2H) , 1.686- 1.615 (m, 2H) , 1.283-1.225 (t, 3H) ; LCMS (ESI) calc'd for (C28H32CIN3O5) [M+H]⁺, 526.20; found, 526.15.

5-chloro-3- (ethyl (phenyl) carbamoyl) -1-m thyl-2-oxo-1 , 2- dihydroquinolin-4-yl- ( ) -4- ( (2 , 3-dihydro-lH-inden-l-yl) amino) -4- oxobutanoate , 39.

To the solution of 4-methoxy-4-oxobutanoic acid (411 mg, 2.81 mmol) in 10 mL of DCM was added HATU (1.42 g, 3.76 mmole), the mixture was stirred at RT for 0.5 h, then ( ) -2 , 3-dihydro-lH-inden-l-amine (250 mg, 1.87 mmol) and DIPEA (1.21 g, 9.39 mmol) were added, the mixture was stirred at RT for 3 h, the reaction mixture washed with water and brine, organic phase was dried over Na2SC>4, and after removal of the solvent the amide was obtained as a light yellow solid (425 mg, yield 87%) . The latter (425 mg, 1.63 mmol) was hydrolyzed with 5N aq. LiOH (1.6mL, 8.13 mmole) in MeOH (10 mL) with stirring at RT for 2 h, after which time the mixture was adjusted to pH 2 with^'4N HC1, extracted with EtOAc (20 mL*2), washed with water and brine and dried over Na2SC> . Removal of the solvent, gave a light yellow solid of the carboxylic acid (300 mg, yield 84%) . The latter (294 mg, 1.26 mmol) was coupled with Laq. (300 mg, 0.84 mmol) in 1, 2-Dichloroethane (15 ml) using DCC (226 mg, 1.09 mmol) and DMAP (103 mg, 0.84 mmol) at 60°C with stirring overnight. After cooling the mixture was purified by silica gel chromatography (EA:PE-2:1) to give 39 (34 mg, 7.3%) as a white solid. ¹H-NMR (500 MHz, Actone-d₆) : δ 7.55-7.10 ( m, 13.4 H),5.47 (m, 1 H) , 3.95 (m, 0.9 H) , 3.84 (m, 1.4 H) , 3.60 (s, 2.8 H) , 3.2-2.79(m, 3.2 H),2.80 (s, 1.5 H) , 2.70 (m, 2.1 H),2.50 (m, 1 H) , 1.86 (m, 1 H),1.30 (s, 2 H),1.21 (m, 2.8 H) , 1.02 (m, 1 H) .

5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 ,2- dihydroquinolin-4-yl- (Is , 4s) -4-cyano-4- (3- (cyclopentyloxy) -4- methoxyphenyl) cyclohexane-l-carboxylate, 40.

Laquinimod (178 mg, 0.5 mmol), cilomilast (170 mg, 0.5 mmol), and EDCI (197 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) . DMAP (244 mg, 2.0 mmol) was added. The mixture was stirred at ambient temperature overnight. It was washed with water (10 mL) , dried over sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified by prep-TLC (petroleum ether: ethyl acetate=l:l) to provide 40 (49 mg, yield 14%,) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : δ 1.24 (m, 3H) , 1.63- 2.30 (m, 17H) , 3.50(s, 3H) , 3.80(s, 3H) , 3.95-4.05 (m, 2H) , 4.80 (m, 1H) , 6.87(m, 1H) , 7.00 (m, 2H) , 7.16-7.33 (m, 4H) , 7.35-7.43(m, 4H) . LCMS (ESI) calc'd for ( C39H40CIN3O6 ) [M+H]⁺, 682.27; found, 682.13.

Bis (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) terephthalate , 41.

Laquinimod (106 mg, 0.3 mmol) was dissolved in dichloromethane (25 ml) at ambient temperature. Terephthaloylchloride (61 mg, 0.3 mmol) and triethylamine (90 mg, 0.9 mmol) were added to the mixture. Reaction mixture was stirred overnight, and then diluted with water (25 mL) . It was extracted with dichloromethane (2 * 30 ml) . The combined organic layer was washed with brine (25 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 41 (60 mg, yield 24%) as a white solid. ^JH-NMR (300 MHz, CDCI₃) : δ 8.444-8.422 (m, 3 H) , 7.489-7.226 (m, 17 H) , 4.077-4.031 (m, 2 H) , 3.767-3.502 (m, 8 H) , 1.159-1.112 (m, 6 H) ; LCMS (ESI) calc'd for (C46H36CI2N O8) [M+H]⁺, 843.20; found, 843.06. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l ,2- dihydroquinolin-4-yl methanesulfonate , 42.

Laquinimod (212 mg, 0.6 mmol) was dissolved in dichloromethane (15 mL) at ambient temperature. Methanesulfonyl chloride (228 mg, 2.0 mmol) and triethylamine (200 mg, 2.0 mmol) were added to the mixture. The mixture was stirred overnight at ambient temperature, and then partitioned between water (30 mL) and dichloromethane (50 mL) . The organic layer was washed with brine (20 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 42 (100 mg, yield 38%) as a white solid. ¹H-N R (300 MHz, CDC1₃) : δ 7.363-7.358 (m, 2 H) , 7.335- 7.332 (m, 2 H) , 7.284-7.199 (m, 4 H) , 4.012-3.940 (q, 2 H) , 3.648 (s, 3 H) , 3.406 (s, 3 H) , 1.322-1.255 (t, 3 H) ; LCMS (ESI) calc'd for (C₂oHi₉ClN₂0₅S) [M+H]⁺, 435.08; found, 436.88. 5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 , 2- dihydroquinolin-4-yl 4-methylbenzenesulfonate, 43.

Laquinimod (212 mg, 0.6 mmol) was dissolved in acetonitrile (15 mL) and the solution stirred at ambient temperature. TsCI (380 mg, 2.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added to the mixture. The mixture was heated under reflux overnight, and then partitioned between water (50 mL) and dichloromethane (150 mL) . The dichloromethane layer was washed with brine (30 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 43 (102 mg, yield 33%) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : δ 7.890-7.801 (m, 2 H) , 7.493-7.350 (m, 4 H) , 7.285-7.124 (m, 6 H) , 3.897-3.787 (dd, 2 H) , 3.620 (s, 3 H) , 2.492 (s, 3 H) , 1.172-1.097 (t, 3 H) ; LCMS (ESI) calc'd for ( C26H23CIN2O5 S ) [M+H]⁺, 511.11; found, 511.05.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l ,2- dihydroquinolin-4-yl) oxy) methyl acetate , 44.

Chloromethyl chloroformate (512 mg, 4 mmol) was added to a mixture of Et₃N (808 mg, 8 mmol) in 5 mL MeOH at 0°C.The mixture was stirred at RT for lh. after which time it was concentrated to afford the chloromethyl methyl carbonate (400 mg, 81 % yield) as colorless oil. Next, a mixture of Laq. (180 mg, 0.5 mmol), chloromethyl methyl carbonate (124 mg, 1 mmol) and CS₂CO3 (326 mg, 1 mmol) in 5 mL DMF was stirred at 45°C for 12h. and then water (10 mL) was added and the mixture extracted with AcOEt (10 mL*3) . The organic layer was dried over Na2SC>4, filtered and concentrated and the crude product was purified by flash column chromatography (mobile phase: A: water (10 mmol NH4HCO3) , B: MeOH) to afford 44 (90 mg, 40% yield) as a white solid. ¾-NMR (400 MHz, CDCI3) : 57.374-7.325 (m, 3 H) , 7.209-7.139 (m, 5 H) , 5.897-5.884 (d, J=5 Hz, 1 H) , 5.672-5.660 (d, J=5 Hz, 1 H) , 3.973-3.873 (m, 2 H) , 3.865(s, 3 H) , 3.575 (s, 3 H) , 1.254-1.225 (t, 3 H) ; LCMS (ESI) calc'd for (C22H21CIN2O6) [M+H]⁺, 445.12; found, 445.2.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl propionate, 45.

To a stirred mixture of DMF (15mL) and potassium propionate (4.5g, 40 mmol) is added bromochloromethane (105 g, 0.8 mol, 20 equivalents) and the mixture is kept at 30°C for 50 hours. The reaction mixture is washed with water, dried, and distilled at atmospheric pressure to give propionic acid chloromethyl ester (lg, 28 % yield) which was used (488 mg, 4 mmol) in the next step with Laq. (356mg, 1 mol) and TEA (600 mg, 6 mol) in DCM (20 mL) at 30°C stirred for 2 days. Then solvent was removed under reduce press and the crude product was purified by preparative-TLC (EA/DCM=1/1) to give 45 (150 mg, 34% yield) as a white solid. ¹H-NMR (400 MHz, CDC13) : 57.34-7.32 (m, 3 H) , 7.21-7.12 (m, 5 H) , 5.94 (d, J=5 Hz, 1 H) , 5.53 (d, J=5 Hz, 1 H) , 3.88 (m, 2 H) , 3.59 (s, 3 H) , 2.46 (m, 2 H) , 1.21 (t, 3 H) , 1.17 (t, 3 H) ; LCMS (ESI) calc'd for (C22H21C1N206) [M+H]+, 445.12; found, 445.2.

5-chloro-N-ethyl-4- (methoxymetjioxy) -1-methy1-2-oxo-N-phenyl-1 , 2- dihydroquinoline-3-carboxamide , 46.

Laquinimod (212 mg, 0.6 mmol) was dissolved in DMF (15 mL) at ambient temperature. Chloromethyl methyl ether (48 mg, 0.6 mmol) and triethylamine (200 mg, 2.0 mmol) were added to the mixture. The mixture was stirred overnight at ambient temperature, and then diluted with water (20 mL) and dichloromethane (50 mL) . The organic layer was separated washed with brine (20 mL) , dried with sodium sulfate, filtered and filtrate was concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 46 (69 mg, 29% yield) as a white solid. ^i-N R (300 MHz, CDC1₃) : δ 7.461-7.344 (m, 3 H) , 7.284-7.172 (m, 5 H) , 5.346 (d, 1 H) , 5.296 (d, 1 H) , 4.058-3.888 (m, 2 H) , 3.712 (s, 3 H) , 3.585 (s, 3 H) , 1.334-1.244 (t, 3 H) ; LCMS (ESI ) calc'd for (C21H21CIN2O4 ) [M+H]⁺, 401.13; found, 401.09.

4- (butoxymethoxy) -5-chloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l ,2- dihydroquinoline-3-carboxamide 4-oxobutanoate, 47.

To the solution of Laquinimod (400 mg, 1.12 mmol) in the dichloromethane (10 mL) were added triethylamine (226 mg, 2.24 mmol) and butyl chloromethyl ether (205 mg, 1.6 mmol) . The mixture was stirred overnight, and then diluted with dichloromethane (40 mL) . It was washed with saturated aqueous NaHC0₃ solution (15 mL) , the organic layer dried over sodium sulfate, filtered and filtrate was concentrated to dryness under vacuum. The residue was treated with ether (10 mL) to give 47 (130 mg, 27% yield) as a white solid. ¹H-NMR (300 MHz, CDCI₃) : 57.392-7.361 (m, 3 H) , 7.261-7.161 (m, 5 H) , 5.407-5.357 (m, 1H) , 3.921-3.866 (m, 4H) , 3.579 (s, 3H), 1.710-1.577 (m, 2H) , 1.450-1.425 (m, 2H) , 1.291-1.261 (t, 3H) , 0.990-0.941 (t, 3H) ; LCMS calc'd for ( C24H27CIN2O4 ) [Μ+ΗΓ, 443.17; found, 443.18. 5-chloro-4- ( (2-ethoxyethoxy) methoxy) -N-ethyl-1-methyl-2-oxo-N-phenyl- -dihydroquinoline-3-carboxamide, 48.

To a solution of 2-ethoxyethanol (5 g, 55.6 miriol) in the DME (50 mL) were added NaH (2.44 g, 61.1 mmol) and Nal (8.33 ^< g, 55.6 mmol) at 0°C. The mixture was stirred for 0.5 hr. and chloromethyl methylsulfane (5.36 g, 55.6 mmol) was added and stirring continued overnight at room temperature. The mixture was quenched with ice water (50 mL) , extracted with ether (2x100 mL) and the organic solvent was combined, dried, filtered and concentrated to give ( (2-e hoxyethoxy) methyl) (methyl) sulfane (5.6 g, 67% yield) as an oil. To a solution of the latter compound (2.0 g, 13.3 mmol) in DCM (30 ml) was added drop wise S0C1₂ (1.5 g, 13.3 mmol) solution in the DCM (30 mL) and the mixture was stirred for 0.5 hr. at room temperature after which solvent was removed to give 1- (chloromethoxy) -2-ethoxyethane (1.87 g, 100%) as an oil. To a solution of Laq. (450 mg, 1.26 mmol) in the DMF (5 mL) were added TEA (255 mg, 2.53 mmol) and 1- ( chloromethoxy) -2-ethoxyethane (263 mg, 1.90 mmol) . The mixture was stirred overnight and then diluted with DCM (150 mL) , washed with saturated NaHCC>3, and the DCM layer was dried and concentrated to leave a residue which upon treatment with ether gave 48 (240 mg, 41.6% yield) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.438-7.317 (m, 3 H) , 7.232-7.144 (m, 5 H) , 5.434-5.345 (m, 2H) , 4.054-3.895 (m, 4H) , 3.759- 3.618 (m, 2H) , 3.659 (s, 3H) , 1.261-1.089 (m, 6H) ; LCMS calc' d for (C₂₄H₂₇CIN₂O₅) [M+H] + , 459.16; found, 459.10.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl 2-propylpentanoate, 49.

A mixture of 2-propylpentanoyl chloride (5 g, 31 mmol), paraformaldehyde (1.15 g, 38 mmol) and ZnCl2 (50 mg, 0.38 mmol) was heated for 3 hours at 70 °C. after which time reaction mixture was cooled to room temperature and diluted with dichloromethane (50 mL) . The mixture was filtered, and the filtrate was concentrated to dryness under vacuum and the residue was purified on silica gel column to give chloromethyl 2-propylpentanoate (2.6 g, yield 44%) as an oil which was reacted (650 mg, 3.4 mmol) in the next step with Laquinimod (400 mg, 1.12 mmol) in DMF (5 mL) with triethylamine (340 mg, 3.4 mmol) . The mixture was stirred overnight, and then diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was treated with ether (10 mL) to give 49 (164 mg, 29% yield) as a white solid. ^-NMR (300 MHz, CDC1₃) : 57.370-7.285 (m, 3 H) , 7.242-7.162 (m, 5 H) , 5.914-5.856 (m, 2H) , 4.066-3.914 (m, 2H) , 3.604 (s, 3H) , 2.496-2.433 (m, 1H) , 1.662-1.280 (m, 11H) , 0.897-0.890 (m, 6H) ; LCMS (ESI) calc' d for (C₂8H33C1 ₂0₅) [M+H]⁺, 513.21; found, 513.29. 5-chloro-N-ethyl-l-methyl-2-oxo-4- (phenethoxymethoxy) -N-phenyl-1 ,2- dihydroquinoline-3-carboxamide , 50.

To a solution of 2-phenylethanol (10 g, 82 mmol) in D E (50 mL) were added NaH (1.8 g, 45 mmol) and Nal (12 g, 82 mmol) at 0°C and the mixture was stirred for 0.5 hr. Chloromethyl methylsulfane (7.9 g, 82 mmol) was added and the mixture was stirred for 3 hrs at room temperature and then quenched with ice water (50 mL) and extracted with ether (2x100 mL) . The organic phase was combined, dried, filtered and concentrated and the residue was purified by chromatography column to give methyl (phenethoxymethyl) sulfane (2.2 g, 14.8%) as an oil which was used (2.23 g, 12.25 mmol) in the next step in DCM (40 mL) with drop wise addition of S0C1_Z (1.65 g, 12.25 mmol) solution in the DCM (30 mL) . The mixture was stirred for 0.5 hr at room temperature, and then the solvent was removed to give (2- (chloromethoxy) ethyl) benzene (2.5 g, 100%) as an oil. The latter (145 mg, 0.82 mmol) was added into a solution of Lag. (200 mg, 0.56 mmol) in DMF (5 mL) and TEA (115 mg, 1.12 mmol) and the mixture was stirred overnight, and then diluted with DCM (30 mL) , washed with saturated NaHCCh, and the DCM layer was dried, filtered and concentrated. The residue was treated with ether to give 50 (70 mg, 25.5%) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.317-7.240 (m, 3 H) , 7.216-7.140 (m, 5 H) , 5.372-5.315 (m, 2H) , 4.120-3.846 (m, 4H) , 3.659 (s, 3H) , 3.030-2.980 (m, 2H) , 1.199-1.181 (t, 3H) ; LCMS calc'd for ( C28H27CIN2O4 ) [M+H]⁺, 491.17; found, 491.07. 2- ( ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methoxy) ethyl acetate , 51.

To a 250 mL flask equipped with mechanical stirrer was added ZnCl2 (1 g, 6.8 mmol) and 1 , 3-dioxolane (50 g, 0.67 mol) . The mixture was stirred for 0.5 hour at ambient temperature, and then acetyl chloride (64 g, 0.81 mol) was added drop wise over 1 hour. The reaction mixture was then heated for 1 hour at 80 °C, and cooled to room temperature and stirred overnight. Distillation of the crude afforded 2- (chloromethoxy) ethyl acetate (75 g, yield 73%) . The latter (275 mg, 1.7 mmol) was added into a sol-ution of Laquinimod (400 mg, 1.12 mmol) in dichloromethane (15 mL) and triethylamine (340 mg, 3.4 mmol) and the mixture was stirred overnight, and then diluted with dichloromethane (40 mL) . The mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified on silica gel column to give 51 (284 mg, 54% yield) as a white solid. ¾-NMR (300 MHz, CDC1₃) : 67.442-7.332 (m, 3 H) , 7.238-7.153 (m, 5 H) , 5.416-5.342 (m, 2H) , 4.342-4.316 (m, 2H) , 4.141-3.882 (m, 4H) , 3.564 (s, 3H) , 2.044 (s, 3H) , 1.270-1.222 (t, 3H) ; LCMS (ESI) calc'd for ( C2₄H2₅CI 2O6 ) [M+H]⁺, 473.14; found, 473.15. ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl 4-methylpiperazine-l-carboxylate ,

To a solution of 1-methylpiperazine (0.5 g, 5 mmol) in dichloromethane (10 mL) was added slowly chloromethyl chloroformate (0.7 g, 5.4 mmol) at 0°C. The mixture was stirred 0.5 hour, and then diluted with dichloromethane (25 mL) and washed with IN HC1 (15 mL) , dried over sodium sulfate, filtered and concentrated to give chloromethyl 4- methylpiperazine-l-carboxylate (0.4 g, 42 % yield) as a colorless oil which was stirred (0.4 g, 2 mmol) with Laquinimod (0.5 g, 1.4 mmol) in D F (10 mL) and triethylamine (0.45 mL) overnight, and then diluted with ether (50 mL) and washed with water (3 x 50 mL) , dried over sodium sulfate, filtered and concentrated to dryness on rotavapor to leave a residue which was treated with ether (5 mL) to give 52 (120 mg, 17% yield) as white solid. ^JH-NMR (300 MHz, CDC1₃) : δ 7.402-7.352 (m, 3 H) , 7.247-7.156 (m, 5 H) , 5.992 (d, 1H) , 5.701 _.(d, 1H) , 3.96 (q, 2H) , 3.618 (s, 3H) , 3.590-3.543 (b, 4H) , 2.471-2.347 (b, 4H) , 1.662 (s, 3H) , 1.253- 1.229 (t, 3H) LCMS (ESI) calc' d for (C₂₆H2₉CI ₄O₅ ) [M+H]⁺, 513.18; found, 513.49.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl morpholine-4-carboxylate, 53.

To a solution of morpholine (0.67 g, 7.75 mmol) in dichloromethane (20 mL) at 0°C was added chloromethyl chloroformate (0.5 g, 3.88 mmol) and the mixture was stirred for 2 hours, and then diluted with dichloromethane (30 mL) and washed with IN HC1 (45 mL) and brine (50 mL) , dried over sodium sulfate, filtered and concentrated to dryness to give chloromethyl morpholine-4-carboxylate (0.58 g, 83 % yield) as a yellow oil which was added (0.26 g, 1.46 mmol) into a solution of Laquinimod (0.4 g, 1.12 mmol) and triethylamine (0.23 g, 2.3' mmol) in DMF (15 mL) and stirred overnight after which time the mixture was diluted with dichloromethane (40 mL) washed with water (3 x 50 mL) , dried over sodium sulfate and concentrated- to dryness on rotavapor to leave a residue which was treated with ether (10 mL) to give 53 (370 mg, 66% yield) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.456-7.341 (m, 3 H) , 7.285-7.157 (m, 5 H) , 6.021 (d, 1H) , 5.641 (d, 1H) , 3.980-3.908 (m, 2H) , 3.775 (b, 4H) , 3.621 (s, 3H) , 3.589 (b, 4H) , 1.273-1.225 (t, 3H) ; LCMS (ESI) calc'd for (C25H26CI 3O6) [M+H]+, 500.15; found, 500.20.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo- dih dro uinolin-4- l) ox ) methyl dimethylcarbamate, 54

chloromethyl carbonochloridate (256 mg, 2 mmol) was added drop wise into a mixture of dimethylamine (in 2-Methyl-THF, lmL) and Et3N (202 mg, 2mmol) in THF (5 mL) at 0°C and the resulting mixture was stirred at RT for 2 hours after which the mixture was diluted with EtOAc and washed twice with water. The organic phase was separated, dried (Na2SOi) , filtered, and concentrated to give a residue (200 mg, 73 % yield) which was stirred (137 mg, 1 mmol) with Laq. (180 mg, 0.5 mmol) and CS₂CO₃ (652 mg, 2 mmol) in DMF (5 mL) at 45°C for 12h. after which time water was added (10 mL) and the mixture extracted with EtOAc (3 x 10 mL) . The organic layer, separated and dried over Na2S0 , filtered and concentrated. The crude was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH₄HCO3) , B: MeCN) to afford 54 (80 mg, 35 % yield) as a white solid. ¹H-NMR (400 MHz, CDC1₃) : 57.363-7.337 (m, 3 H) , 7.214- 7.140 (m, 5 H) , 5.941-5.929 (d, J=5 Hz, 1 H) , 5.664-5.652 (d, J=5 Hz, 1 H), 3.929-3.901 (m, 2 H) , 3.605 (s, 3 H) , 2.968 (s, 3 H) , 2.879 (s, 3 H) , 1.250-1.222 (t, 3 H) ; LCMS (ESI) calc'd for (C23H24CIN3O5) [M+H]⁺, 458.15; found, 45.8.2 ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 ,2- dihydroquinolin-4-yl) oxy) methyl piperazine-l-carboxylate, 55.

To a solution of N-Boc-piperazine (0.5 g, 2.7 mmol) and triethylamine (0.81 g, 7.2 mmol) in dichloromethane (10 mL) was added chloromethyl chloroformate (0.42 g, 3.23 mmol) at 0°C. The mixture was stirred for 1 hr. and diluted with dichloromethane (30 mL) , washed with IN HC1 (10 mL) and saturated NaHCC (10 mL) , the dichloromethane layer was dried, filtered and concentrated to give 1- (tert-butyl) 4- (chloromethyl) piperazine-1 , 4-dicarboxylate (0.51 g, 68% yield) as a yellow oil which was further reacted (0.47 g, 1.68 mmol) with Laquinimod (0.5 g, 1.4 mmol) and triethylamine (0.42 g, 4.2 mmol) in DMF (10 mL) . The mixture was stirred overnight, and then diluted with dichloromethane (40 mL) . The dichloromethane layer was washed with water (3 x 20 mL) , dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was treated with ether (5 mL) to give Boc protected 55 (0.3 g, yield 36%) as a white solid which was stirred (0.2 g, 0.33 mmol) in trifluoroacetic acid (3 mL) and dichloromethane (5 mL) for 3 hours at rt., and then concentrated to dryness to leave a residue which was dissolved in dichloromethane (60 mL) and the solution washed with saturated aqueous NaHCC^ solution and then dried, filtered and concentrated to give 55 (145 mg, 87% yield) as a white solid. ¹H-N R (300 MHz, CDC1₃) : 57.447-7.351 (m, 3 H) , 7.236-7.128 (m, 5 H) , 6.006 (d, 1H) , 5.701 (d, 1H) , 3.978-3.906 (m, 2H) , 3.614 (s, 3H) , 3.506 (m, 4H) , 2.922 (m, 4H) , 1.271-1.223 (t, 3H) ; LCMS (ESI) calc' d for (C25H27CIN₄O5) [M+H]⁺, 499.17; found, 499.25.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl (2-morpholinoethyl) carbamate , 56.

To a solution of 2-morpholinoethanamine (1 g, 7.6 mmol) and chloromethyl carbonochloridate (1 g, 7.6 mmol) in DCM (20 mL) was added Et3 (2 mL, 11 mmol) at 0°C, and the mixture was stirred for lh at room temperature, then water (40 mL) was added to quench the reaction, phases were separated and most of DCM evaporated, the aqueous phase was extracted with EtOAc (2 x 50 mL) , the organic phase was combined and washed with brine (50 mL) , dried, filtered and concentrated to give chloromethyl (2- morpholinoethyl) carbamate (300 mg, 17% yield) as a yellow oil which was dissolved (300 mg, 1.36 mmol) in DMF (5 mL) and reacted with Laq. (356 mg, lmmol) in the presence of TEA (0.4 mL, 3 mmol), with stirring overnight at room temperature, then treated with EtOAc (20 mL) and water (20 mL) , the organic phase separated and washed with brine (10 mL) , dried, filtered and concentrated and the residue purified by flash chromatography to give 56 (60 mg, 11% yield) as a colorless oil. ¾-NMR (300 MHz, CDCI3) : δ 7.402-7.333 (m, 3 H) , 7.284-7.151 (m, 5 H) , 6.018 (d, 1 H) , 5.406 (d, 1 H) , 3.927-3.876 (q, 2 H) , 3.766-3.718 (m, 4 H) , 3.612 (s, 3 H), 3.379-3.351 (m, 2 H) , 2.585-2.520 (m, 6 H) , 1.264-1.216

(t, 3 H) ; LCMS (ESI) calc'd for (C₂₇ H₃iClN₄0₆) [M+H]⁺, 543.20; found, 543.02.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl nicotinate , 57.

Nicotinic acid (2.46 g, 20 mmol) , NaHC0₃ (3.16 g, 40 mmol) and BuNCl (0.1 g) were stirred in water (50 mL) and dichloromethane (50 mL) . The mixture was stirred at ambient temperature, and a solution of chloromethyl sulfochloridate (4.95 g, 30 mmol) in dichloromethane (20 mL) was added drop wise and stirred for 2 hours. The organic layer was washed with water (2 ^χ 30 mL) , and saturated aqueous sodium carbonate solution (30 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor to give chloromethyl nicotinate (2.5 g, 73% yield) as a yellow oil (171 mg, 1.0 mmol) which was stirred with Laquinimod (178 mg, 0.5 mmol) in DMF (15 mL) , and triethylamine (202 mg, 2.0 mmol) overnight at 50 °C, and then diluted in ethyl acetate (150 mL) . The organic layer was washed with water (3 ^χ 50 mL) , dried with sodium sulfate, filtered and concentrated to dryness on rotavapor to give a residue which was purified on silica gel column (petroleum ether: ethyl acetate=l:l) to provide 57 (55 mg, yield 23%) as a white solid. ¹H-NMR (300 MHz, DMSOd₆) : δ 9.063 (s, 1 H) , 8.854-8.838 (m, 1 H) , 8.297-8.264 (m, 1 H) , 7.612- 7.495 (m, 4 H) , 7.349-7.200 (m, 5 H) , 6.137 (d, 1 H) , 5.862 (d, 1 H) , 3.712-3.689 (m, 2 H) , 3.567 (s, 3 H) , 11.087-1.040 (t, 3 H) ; LCMS (ESI) calc'd for ( C26H22CIN3O5 ) [M+H]⁺, 492.13; found, 493.58. ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 ,2- dihydroquinolin-4-yl) oxy) methyl 1-methyl-pyridinum-3-carboxylate , 58.

To a solution of 57 (245 mg, 0.5 mmol) in tetrahydrofuran (15 mL) was added iodomethane (700 mg, 5 mmol) and the mixture was stirred overnight at ambient temperature, and then filtered. The cake was washed with tetrahydrofuran (30 mL) to give 58 (105 mg, yield 42%) as a yellow solid. ¹H-NMR (300MHz, DMSOd₆):5 9.596 (s, 1 H) , 9.227 (d, 1 H), 9.010 (d, 1 H) , 8.345-8.297 (m, 1 H) , 7.603-7.532 (m, 2 H) , 7.356-7.206 (m, 6 H) , 6.214 (d, 1 H), 5.805 (d, 1 H) , 4.458 (s, 3 H) , 3.739-3.568 (m, 2 H) , 3.349 (s, 3 H) , 1.076-1.028 (t, 3 H) ; LCMS (ESI) calc'd for ( C27H25CIN3O5 ) [M+H]⁺, 507.97; found, 506.18.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl (R) - (2 , 3-dihydro-lH-inden-l- yl) carbamate , 59.

To a solution of chloromethyl carbonochloridate (485 mg, 3.76 mmol) in DCM (15 mL) was added (R) -2, 3-dihydro-lH-inden-l-amine (500 mg, 3.76 mmol) and TEA (759 mg, 7.52 mmol) at -10°C and the mixture was stirred at 0°C for 3 h. The solution was washed with saturated NaHC03 and the organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE: EA=3:1) to afford compound chloromethyl (R) - (2 , 3-dihydro-lH-inden-l- yl)carbamate (600 mg, 71%) as a white solid. ¾ NMR (500 MHz, CDC1₃) : δ 7.31 (d, J = 7.0 Hz, 1H) , 7.26-7.20 (m, 3H) , 5.79 (s, 2H) , 5.26 (q, J = 7.5 Hz, 1H) , 3.02-2.96 (m, 1H) , 2.90-2.83 (m, 1H) , 2.65-2.58 (m, 1H) , 1.89-1.82 (m, 1H) . To a solution of Laq. (870 mg, 2.44 mmol) in DMF (15 mL) was added NaH (60% in oil, 293 mg, 7.32 mmol) at 0°C and the solution was stirred at 0°C for 1 h. and then, chloromethyl (R) - (2, 3-dihydro-lH- inden-l-yl) carbamate (550 mg, 2.44 mmol) and KI (406 mg, 2.44 mmol) were added and the mixture was stirred at rt . for 4 h. after which water (20 mL) and EtOAc (40 mL) were added and the organic phase was separated, washed with water (30 mL x 2), dried over anhydrous Na₂SC>₄ and concentrated under reduced pressure to give a residue which was purified by prep-HPLC to afford 59 (220 mg, 17%) as a white solid. ^JH NMR (500 MHz, CDC1₃) : δ 7.64-7.33 (m, 4H) , 7.24-7.13 (m, 8H) , 6.09-6.03 (m, 1H) , 5.53-5.42 (m, 2H) , 5.25-5.20 (m, 1H) , 3.99-3.84 (m, 2H) , 3.62-3.58 (m, 3H) , 3.03-2.98 (m, 1H) , 2.88-2.84 (m, 1H) , 2.63-2.58 (m, 1H) , 2.06-1.85 (m, 1H) , 1.26-1.18 (m, 3H) .

( (5-chloro-r3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl (2- (methylamino) ethyl) carbonate,

To a solution of tert-butyl (2-hydroxyethyl) (methyl) carbamate (1.3 g, 7.5 mmol) and triethylamine (2.3 g, 22.5 mmol) in dichloromethane (40 mL) was added chloromethyl carbonochloridate (964.5 mg, 7.5 mmol) drop wise at 0°C and the resulting solution was stirred for 10 min. TLC (DCM: MeOH= 10: 1) showed full consumption of SM and formation of a new product. DCM evaporated to give the crude product as a white solid (2g, 100%), which was used in the next step without further purification in a mixture of DMF (50mL) Laq. (1 g, 3 mmol) and Cs₂C0₃ (2.4 g, 7.5 mmol), with stirring at 45^°C overnight, after which it was diluted with DC (200 mL) and washed with water (100 mL ^χ 3) . The organic layer was dried over a2S0₄, filtered and concentrated under vacuum to give the crude product, which was purified by flash chromatography on silica (ethyl acetate in petroleum ether: 0% to 50%) to give Boc-60 (500 mg, 30% yield) as a colorless oil which was dissolved in DCM (20 mL) and upon drop wise addition of TFA (5 mL) and stirring at room temperature for 2 hrs . and monitoring the reaction by LCMS/TLC to allow the evaporation of the solvent under vacuum to give the crude product, which was purified by Prep-HPLC (Mobile phase; A: water (10 mmol NH₄HC0₃) , B: MeCN) to afford 60 as a white solid (98.1 mg, 25%) . ¹H-NMR (CDC1₃, 500 MHz) : δ 10.10- 9.90 (1H, s), 7.46-7.18 (8H, m) , 5.70-5.69 (1H, d, J = 7.0 Hz), 5.57- 5.56 (1H, d, J = 7.5 Hz), 4.75-4.65 (1H, m) , 4.48-4.41 (1H, m) , 3.89- 3.87 (2H, m) , 3.66 (3H, s) , 3.48-3.25 (2H, m) , 2.80 (3H, s), 1.26 (3H, t, J = 7.0 Hz) . The signals splitted into couples peaks, which might be due to regio-isomer or rotary chilarity. The peak of chloroform residue was overlaped with aromatic protons of 60. LCMS (ESI) calc'd for ( C₂₄H₂6CIN₃O6 ) 487.15; found, 488.2 ([M+H]⁺). tert-butyl (2- ( ( ( ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo- 1 , 2-dihydroquinolin-4-yl) oxy) methoxy) carbonyl) amino) ethyl) (methyl) , carbamate, 61.

Nl-methylethane-l , 2-diamine (1.48g, 20 mmol) was dissolved in acetonitrile (50 ml) at ambient temperature. Boc anhydride (2.18g, 10 mmol) and triethylamine (2.02 g, 20 mmol) were added to the mixture which was stirred for 3 hours and then concentrated to dryness on a rotavapor. The residue was purified on silica gel column

: 1 ) to provide tert-butyl (2-aminoethyl) (methyl) carbamate (l.lg, 63% yield) as a colorless oil which was dissolved (870 mg, 5.0 mmol) in DCM (50 ml), trimethylamine (2.02g, 20 mmol) was added and the solution was stirred at 0°C in an ice-water bath. Chloromethylchloroformate (635 mg, 5.0 mmol) was added drop-wise over 10 minutes, and the mixture was allowed to warm to room temperature and stirred for another 2 hours after which DCM was removed on rotavapor, and the residue was purified on silica gel column (petroleum ether: ethyl acetate = 4:1) to provide tert-butyl (2- (( (chloromethoxy) carbonyl) amino) ethyl) (methyl) carbamate (1.03 g, 77% yield) as a colorless oil which was dissolved (266 mg, 1.0 mmol) in dichloromethane (15 ml) and Laquinimod (178 mg, 0.5 mmol) and triethylamine (202 mg, 2 mmol) were added and the mixture was stirred 2 days at ambient temperature. It was diluted with ethyl acetate (150ml) and washed with water (3 x50ml) . The combined organic extract was dried over sodium sulfate, filtered and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 61 (60 mg, 22%) as a white solid. ^XH-NMR (300MHz, CDC1₃) : δ 7.445-7.345 (m, 3 H) , 7.227-7.121 (m, 5 H) , 5.441-5.390 (m, 2 H) , 3.949-3.879 (m, 2 H) , 3.760 (s, 3 H) , 3.486-3.392 (m, 4 H) , 2.905 (s, 3 H) , 1.448 (m, 9 H) , 1.289-1.216 (t, 3 H) ; LCMS (ESI) calc' d for (C29H35CIN4O7) [M+H]⁺, 587.23; found, 587.29. tert-butyl- (2- ( ( ( ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo- 1 , 2-dihydroquinolin-4-yl) oxy) methoxy) carbonyl) oxy) ethyl)

(methyl) carbamate , 62.

To a solution of N-Boc-N-methyl-2-aminoethanol (0.5 g, 2.9 mmol) and pyridine (0.35 g, 4.4 mmol) in dichloromethane (10 mL) was added chloromethyl chloroformate (0.4 g, 3.1 mmol) at 0°C. The mixture was stirred for 2 hours, and then diluted with dichloromethane (25 mL) and washed with IN HC1 (15 mL) and saturated NaHCC (15 mL) , dried over sodium sulfate, filtered and concentrated to dryness to give fcert-butyl (2- ( ( (chloromethoxy) carbonyl) oxy) ethyl) (methyl) carbamate (0.5 g, 65 % ) as a colorless oil which was further reacted (0.5 g, 1.86 mmol) with Laquinimod (0.5 g, 1.4 mmol) and triethylamine (0.38 g, 3.7 mmol) in DMF (10 mL) with stirring overnight, and then diluted with dichloromethane (40 mL) , washed with water (3x50 mL) , the dichloromethane layer was dried and concentrated to give a solid which was washed with ether (6 mL) to give 62 (110 mg, 13%) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.457- 7.372 (m, 3 H) , 7.283-7.161 (m, 5 H) , 5.926-5.905 (d, 1H) , 5.724-5.905 (d, 1H), 4.356 (b, 2H) , 4.015-3.769 (m, 2H) , 3.599 (s, 3H) , 3.566 (b,

2H) , 2.828 (s, 3H) , 1.449 (s, 9H) , 1.288-1.240 (t, 3H) ; LCMS (ESI) calc' d for (C29H₃₄CIN3O8) [M+H] ⁺, 588.20 ; found, 588.26. N6- (4- ( ( ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l ,2- dihydroquinolin-4-yl) oxy) methoxy) carbonyl) piperazine-1- carbonyl) lysine , 63.

To a solution of L-Boc-Lys-OtBu (200 mg, 0.66 mmol) in dichloromethane (30 mL) was added CDI (330 mg, 1.98 mmol) and the mixture was stirred 0.5 hour at ambient temperature, when TLC showed consumption of SM the mixture was washed with water (2 x 30 mL) , dried over sodium sulfate and concentrated (to ~ 10 mL) and 55 (55, 200 mg, 0.4 mmol) and DMAP (98 mg, 0.8 mmol) were added and the mixture was stirred overnight and then washed with 1 N HC1 solution (5 mL) and saturated NaHC0₃ solution (5 mL) , dried over sodium sulfate, filtered and concentrated to dryness to give O- terfc-Bu-N-Boc 63 (250 mg, 76%) as a white solid which was dissolved (250 mg, 0.3 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (2 ml.) . The mixture was stirred for 2 hours, and then concentrated to dryness under vacuum. The residue was treated with ether (5 mL) to give 63 (200 mg, 86%) as a white solid. ¹H-N R (300 MHz, DMSO-d₆) : δ 8.19(b, 4H) , 7.56(m, 3H) , 7.27 (m, 6H) , 6.57 (m, 1H) , 5.88 (m, 1H) , 5.60 (m, 1H) , 3.80-2.95 (m, 13H) , 1.41-1.13 (m, 9H) ; LCMS calc'd for (C32H39CIN6O8) [M+H]⁺, 671.25; found, 671.62.

( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methyl 4- (N2 ,N6-diacetyllysyl) iperaz carboxylate , 64.

To a solution of L-N₀, N_DAc-Lys-OH (100 mg, 0.43 mmol) , 55 (100 mg, 0.2 mmol) and HATU (200 mg, 0.52 mmol) in DMF (5 mL) was added DIPEA (125 mg, 0.96 mmol) . The mixture was stirred for 2 hours, and then diluted with dichloromethane (80 mL) , washed with IN HC1 solution (10 mL) and with saturated NaHC0₃ solution (10 mL) . The dichloromethane layer was dried over sodium sulfate, filtered and concentrated to dryness and the residue was purified on silica gel column to give 65 (110 mg, 78%) as a white solid. ^!HNMR (300 MHz, CDC1₃) : δ 7.51 (m, 8H) , 6.56 (br s, 1H) , 6.13 (m, 2H), 5.61 (m, 1H) , 4.91 (m, 1H) , 3.98-3.24 (m, 16H) , 1.2.17- 1.13 (m, 15H) ; LCMS calc'd for (CssH^ClNeOs) [M+H] ⁺, 11.28 ; found 711.34.

N^D- (4- ( ( ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl) oxy) methoxy) carbonyl) piperazine-1- carbonyl) arginine , 65.

To a solution of L-Boc-Arg-OtBu (800 mg, 2.4 iranol) and triethylamine (260 mg, 2.6 mmol) in dichloromethane (15 mL) at 0°C was added a solution of 4-nitrophenyl chloroformate (517 mg, 2.6 mmol) in dichloromethane (10 mL) and the mixture was stirred for 1 hour, and then 55 (500 mg, 1.0 mmol) and triethylamine (0.8 g, 7.9 mmol) were added. The mixture was stirred overnight, then washed with IN HC1 solution (5 mL) and saturated NaHCCh solution (5 mL) , dried over sodium sulfate, filtered and concentrated to dryness under vacuum and the residue was purified on silica gel column to give N-Boc, O- fcerfc-Bu 65 (230 mg, 27%) as a white solid which was dissolved (230 mg, 0.27 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) . The mixture was stirred for 2 hours. Solvent was removed under vacuum, and the residue was treated with ether (5 mL) to give 65 (180 mg, 86%) as a white solid. ¹H-NMR (300 MHz, DMSO_d6) : 57.548-7.334 (m, 3 H) , 7.237-7.187 (m, 5 H) , 5.904 (m, 1H) , 5.557 (m, 1H) , 3.881-3.812 (m, 3H) , 3.562 (s, 3H) , 3.560-3.2.239 (m, 12 H) , 1.785-1.495 (m, 4H) , 1.140-1.075 (t, 3H) ; LCMS (ESI) calc'd for (C₃₂H₃₉CI ₈O8) [M+H] + , 699.26; found, 699.23. ( (5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l ,2- dihydroquinolin-4-yl) oxy) methyl- (S) -4- (3- (4-acetoxyphenyl) -2- aminopropanoyl) piperazine-l-carboxylate , 66.

To a solution of L-Boc- (4-Ac-Tyr) -OH (340 mg, 1.0 mmol) , 55 (400 mg, 0.8 mmol) and HATU (400 mg, 1.0 mmol) in DMF (10 mL) was added DIPEA (310 mg, 2.3 mmol) . The mixture was stirred for 1 hour, then diluted with dichloromethane (80 mL) and washed with IN HC1 solution (10 mL) and saturated NaHCC solution (10 mL) . The dichloromethane layer was dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified on silica gel column to give N-Boc 66 (0.4 g, 63%) as a white solid of which 200 mg (0.25 mmol) were dissolved in DCM (6 mL) and trifluoroacetic acid (3 mL) was added and the mixture was stirred for 2 hours and then concentrated to dryness under vacuum. The residue was treated with ether (10 mL) to give 66 (140 mg, 86%,) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) : δ 8.34 (b, 2H) , 7.69-7.11 (m, 12H) , 5.89-5.45 (m, 2H) , 4.70 (b, 3H) , 3.78-2.72 (m, 11H) , 2.26 (s, 3H) , 1.13 (m, 3H) ; LCMS calc'd for (C₃6H_3BC1 ₅0B) [M+H] ⁺, 704.24 ; found 704.27.

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl me hylcarbamate, 67.

To the solution of Laq. ^~ (250 mg, 0.7 mmol) in 10 mL anhydrous THF, was added methylcarbamic chloride (98 mg, 1.05 mmole) and DIPEA (181 mg, 1.40 mmole) , the mixture was stirred at RT overnight, then filtered, solvent evaporated and the crude product was purified by prep-HPLC to afford compound 67 (94.8 mg, 33%) as a white solid. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4- l-methyl (2- (methylaminoethyl) carbamate 68

To a solution of Nl , N2-dimethylethane-l , 2-diamine (4.4 g, 50 mmol) and Et₃N (12 g, 119 mmol) in DCM (100 mL) was added Boc₂0 (12 g, 55 mmol) drop-wise at 0°C and the mixture was stirred at RT for 12h. and then water (50 mL) were added and the mixture was extracted with DCM (50 mL x 3) . The organic layer was dried over a2S04, filtered and concentrated and the crude was purified by column chromatography to afford tert-butyl methyl (2- (methylamino) ethyl) carbamate (3.4 g, 30 % yield) as a colorless oil which was dissolved (940 mg, 5 mmol) in DCM (20 mL) . Bis (trichloromethyl ) carbonate ( "Triphosgen" , 739.5 mg, 2.5 mmol) and DIPEA (1.3 g, 10 mmol) were added at 0°C and the mixture was stirred at RT for 12h. and then concentrated to give a residue which was purified by column chromatography to afford the desired tert-butyl (2- ( (chlorocarbonyl) (methyl) amino) ethyl) (methyl) carbamate (0.6 g, 49 % yield) as a colorless oil which was dissolved (500 mg, 2 mmol) in Pyridine (10 mL) and stirred with Laq. (500 mg, 1.4 mmol) at 40°C for 12h. after which the mixture was diluted with EA, and the resulting solution was washed twice with water. The extracts were dried (Na2SC>4) , filtered, and concentrated and the crude product was purified by column chromatography to afford N-Boc 68 (0.4 g, 48 % yield) as a white solid (0.7 mmol) which was dissolved in TFA (2 mL) and DCM (8 mL) and the mixture was stirred at RT for 30 min. after which the pH of the mixture was adjusted with NaHCC to pH 9, extracted with EtOAc (50 mL x 3) and the organic layer was dried over a₂SO_¾, filtered and concentrated and the crude was purified by preparative HPLC (Mobile phase; A: water (10 mmol NH4HCO3) , B: MeCN) to afford 68 (140 mg, 42 % yield) as a white solid. ¹H-NMR (500 MHz, CDCla) : 57.55-7.15 (m, 8 H) , 4.14-2.74 (m, 17 H) , 1.23-1.14 (m, 3 H) ; LCMS (ESI) calc'd for ( C24H27CIN4O4 ) [M+H]⁺, 471.18; found, 471.2. 5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 , 2^

dihydroquinolin-4-yl ethyl (methyl) carbamate , 69.

Laquinimod (212 mg, 0.6 mmol) was dissolved in acetonitrile (15 mL) and ethyl (methyl) carbamic chloride (240 mg, 2.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added and the mixture was stirred under reflux overnight, and then diluted with water (50 mL) and dichloromethane (150 mL) . The dichloromethane layer was washed with brine (20 mL) , dried with sodium sulfate, filtered and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=2:l) to provide 69 (68 mg, 26%) as a white solid. ¹H-NMR (300 MHz, CDCI3) : δ 7.522-7.196 (m, 8 H) , 4.1-4.3 (m, 1 H) , 3.9-4.1 (m, 1 H) , 3.8 (s, 1 H) , 3.6 (s, 1 H) , 3.2 (s, 2 H) , 3.0-3.2 (m, 2 H) , 1.1-1.4 (m, 6 H) ; LCMS (ESI) calc'd for (C23H24CIN3O4) [M+H]⁺, 442.15; found, 441.86. 5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl methyl carbonate, 70.

To a solution of Laq. (356 mg, 1 mmol) in anhydrous DMF (10 mL) , was added methyl chloroformate (188 mg, 2.0 mmol) and DIPEA (268 mg, 2.0 mmol) . The mixture was stirred at 40°C overnight and quenched with saturated NaHCC (10 ml) and water (50 mL) , then filtered and the solid was washed with water (20 mL) and dried under vacuum to give 70 as a white solid (100 mg, 24.2 %) . ¹H-NMR (CDC1₃, 500 MHz): δ 7.75-7.74 (0.3H, m) , 7.64-7.60 (0.8H, m) > 7.57-7.55 (0.8H, m) , 7.51-7.48 (0.5H, m) , 7.39- 7.36 (1H, m) , 7.30-7.27 (2H, m) , 7.23-7.20 (2.4H, m) , 3.90-3.85 (3.8H, m) , 3.74-3.68 (1.4H, m) , 3.56 (2.8H, s), 1.13 (2.5H, t, J = 7.0 Hz), 0.93 (0.5H, t, J = 7.0Hz). Mass (ESI+) : calculated as 414.1, found 415.2 ( [M+H]+) .

5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 , 2- dih droquinolin-4-yl isobutyl carbonate, 71.

Laquinmod (106 mg, 0.3 mmol) was dissolved in dichloromethane (15 ml) at ambient temperature. Isobutyl chloroformate (80 mg, 0.6 mmol) and triethylamine (60 mg, 0.6 mmol) were added to the mixture which was stirred overnight, and then quenched with water (30 mL) . The mixture was extracted with dichloromethane (2 ^χ 30 ml) and the combined organic layer was washed with brine (20 mL) , dried with sodium sulfate, filtered and concentrated to dryness on rotavapor. The residue was purified on silica gel column (petroleum ether: ethyl acetate=3:l) to provide 71 (60 mg, yield 35%) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : δ 7.443-7.357 (m, 3 H) , 7.285-7.194 (m, 5 H) , 4.16-4.052 (m, 4 H) , 3.590 (s, 3 H) , 2.114- 2.069 (m, 1 H) , 1.305-1.257 (t, 3 H) , 0.982-0.949 (m, 6 H) ; LCMS (ESI) calc'd for (C24H2₅CIN2O5 ) [M+H]⁺ 457.15; found, 457.48.

5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 ,2- dihydroquinolin-4-yl (4-nitrophenyl) carbonate, 72.

Laquinimod (356mg, 1.0 mmol) was dissolved in dichloromethane (25 ml) at ambient temperature. 4-Nitrophenyl chloroformate (300 mg, 1.5 mmol) and triethylamine (300 mg, 3.0 mmol) were added to the mixture which was stirred overnight, and then quenched with water (30 mL) and extracted with dichloromethane (2 ^χ 40 ml) . The combined organic layer was washed with brine (30 mL) , dried with sodium sulfate, filtered and concentrated to dryness on rotavapor to leave a residue which was purified on silica gel column (petroleum ether: ethyl acetate=3:l) to provide 72 (160 mg, yield 32%,) as a white solid. ^!H- MR (300 MHz, CDC1₃) : δ 8.348-8.318 (m, 2 H) , 7.572-7.542 (m, 3 H) , 7.492-7.378 (m, 2 H) , 7.321-7.225 (m, 5 H) , 4.182-4.137 (m, 1 H) , 3.844-3.775 (m, 1 H) , 3.598 (s, 3 H) , 1.342-1.295 (t, 3 H) ; LCMS (ESI) calc'd for ( C26H20CIN3O7 ) [M+H]⁺, 522.11; found, 522.03.

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl dimethylsulfamate , 73.

To a solution of Laquinimod (0.5 g, 1.4 mmol), triethylamine (0.43 g, 4.2 mmol) and 4-dimethylaminopyridine (0.1 g, 0.84 mmol) in dichloromethane (8 mL) was added dimethylsulfamoyl chloride (0.8 g, 5.6 mmol) and the mixture was stirred overnight, then diluted with dichloromethane (40 mL) washed with water (4 x 20 mL) , dried over sodium sulfate, filtered and concentrated to dryness on rotavapor to leave a residue which was treated with ether (8 mL) to give 73 (180 mg, yield 28%,) as a white solid. ^- MR (300 MHz, CDC1₃) : 57.453-7.337 (m, 3 H) , 7.258-7.197 (m, 5 H) , 4.165-3.799 (m, 2H) , 3.632 (s, 3H) , 3.098 (s, 6H) , 1.287-1.225 (t, 3H) ; LCMS (ESI) calc' d for (C21H22CIN3O5S) [M+H]⁺, 464.10; found, 464.03.

5-chloro-3- (ethyl (phenyl) carbamoyl) -1-methyl-2-oxo-1 , 2- dihydroquinolin-4-yl diethylsulfamate , 74.

To the solution of Laquinimod (0.5 g, 1.4 mmol), triethylamine (0.43 g, 4.2 mmol) and D AP (0.1 g, 0.84 mmol) in the dichloromethane (20 mL) was added diethylsulfamoyl chloride (0.96 g, 5.6 mmol) and the mixture was stirred overnight, and then diluted with dichloromethane (40 mL) and washed with water (4 x 20 mL) , the organic phase was separated, dried over sodium sulfate, filtered and concentrated to dryness under vacuum and the residue was purified on silica gel column to give 74 (124 mg, 18%) as a white solid. ¹H-NMR (300 MHz, CDC1₃) : 57.450-7.337 (m, 3 H) , 7.255-7.197 (m, 5 H) , 4.142-3.801 (m, 2H) , 3.619 (s, 3H) , 3.596-3.395 (m, 4H), 1.291-1.225 (m, 9H) ; LCMS (ESI) calc'd for ( C23H26CI 3OSS ) [M+H]⁺, 492.13; found, 492.69.

5-chloro-3- (ethyl (phenyl) carbamoyl) -l-methyl-2-oxo-l , 2- dihydroquinolin-4-yl morpholine-4-sulfonate , 75.

To a solution of Laquinimod (1.0 g, 2.8 mmol) in acetonitrile (50 mL) were added K₂CO₃ (2.0 g, 14.5 mmol) and morpholine- -sulfonyl chloride

(3 g, 16.2 mmol) and the mixture was heated under reflux for 5 hours, and then diluted with dichloromethane (70 mL) and washed with water (2 x 30 mL) . The organic phase separated, dried over sodium sulfate, filtered and concentrated to dryness under vacuum to give a residue which was purified on silica gel column to give 75 (140 mg, yield 10%,) as a white solid. ¹H-NMR (300 MHz, CDC13) : 57.4.50-7.351 (m, 3 H) , 7.239- 7.128 (m, 5 H) , 4.185-3.847 (m, 2H) , 3.779-3.456 (m, 6H) , 3.614 (s, 3H) , 3.506 (m, 2H) , 1.290-1.242 (t, 3H) ; LCMS (ESI) calc'd for ( C₂₃H₂₄CIN₃O₆S )

[M+H]⁺, 506.11; found, 506.21.

5-chloro-N-ethyl-4-hydroxy-l-methyl-2-oxo-N- (pyridin-4-yl) -1 ,2- dihydroquinoline-3-carboxamide , 76.

To a solution of pyridin-4-amine (2.6 g, 28 mmol) and Et3N (6 g, 60 mmol) in CH₃CN (50 mL) was added dropwise EtOAc (2.5 g, 28 mmol). The mixture was stirred at RT for 2h. and then NaHC03 (20 mL) was added and the mixture extracted with EtOAc (50 mL x 3) . The organic layer was dried over a2S0 , filtered and concentrated to afford N- (pyridin-4- yl) acetamide (2.9 g, 96 % yield) as a white solid. The latter compound (2.7 g, 20 mmol) was reduced with LiAlH₄ (1.5 g, 40 mmol) in THF (100 mL) by stirring the mixture at RT for 2h. after which the mixture was quenched with water and filtered. The filtrate was concentrated to afford N- ethylpyridin-4-amine (2.0 g, 80 % yield) as a white solid. Next, to a mixture of 1 g (8.18 mmol) of the latter solid, 5-chloro-4-hydroxy-l- methyl-2-oxo-l , 2-dihydroquinoline-3-carboxylic acid (2 g, 7.9 mmol) and Et₃N (1.8 g, 18 mmol) in DCM (100 mL) was added S0C1₂ (1.2 g, 10 mmol) at 0°C. and the mixture was stirred at RT for 12h. after which time it was quenched with water (50 mL) and extracted with DCM (50 mL x 3) . The organic layer was dried over Na2SC> , filtered and concentrated and the crude product was purified by column chromatography and pre-HPLC to afford the desired product 76 (43 mg, 1.4 % yield) as a white solid. ¹H- NMR (500 MHz, DMSO) : 58.316-8.311 (d, 2 H) , 7.34-6.90(m, 5 H) , 5.24-5.21 (br, 1 H) , 3.80(s, 2 H) , 3.43-3.16 (m, 3 H) , 1.08-1.07 (m, 3 H) . LC S (ESI) calc'd for (CisHieCl aOs) [M+H] ⁺, 358.10 ; found, 358.2.

4 , 5-dichloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l , 2-dihydroquinoline-3- carboxamide, 77.

Laq. (5.0 g, 14.0 mmol) was heated at 80°C in P0C1₃ (50 mL) for 1.5 h and then concentrated. The residue was poured into cool Na₂CC>3 (100 mL, 2.0 M) and the mixture was extracted with DCM (100 mL x 2). The organic layer was combined, washed with brine (100 mL) , dried over Na₂SC>4 filtered and concentrated and the residue was recrystallized from DCM/PE (400 mL, 1/3) to afford 77 as a yellow solid (3.3 g, 63%) . The mother liquid was concentrated and purified by flash chromatography to afford another portion of 79 (1.0 g, 19%) . *HNMR (300 MHz, CDC1₃) : δ 7.40-7.50 (m, 3H) , 7.24-7.30 (m, 5H) , 3.97 (m, 2H) , 3.61 (s, 3H) , 1.30 (t, 3H) ; LCMS (ESI) calc'd for (C₁9H16CI₂N2O2) [M+H]⁺, 375.06; found, 375.67.

4-bromo-5-chloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l , 2-dihydroquinoline- 3-carboxamide, 78.

To a mixture of Laq. (240mg, 0.67 mmol) in toluene (15ml) was added PBr₅ (900 mg, 2.1 mmol) at 0°C, the resulting mixture was stirred for 3 h at 100°C, then concentrated and re-dissolved in EtOAc (30 mL) , washed with sat. NaHC0₃ (aqueous, 30 mL) and the organic phase was separated, dried over sodium sulfate, filtered and concentrated and the residue purified by chromatography to give 78 (200 mg, 71% yield) as a white solid. ^XH- N R (300 MHz, CDC1₃) : δ 7.48-7.54 (m, 3H) , 7.17-7.37 (m, 5H) , 3.96 (m, 2H) , 3.60 (s, 3H), 1.27 (t, 3H) ; LCMS (ESI) calc'd for (C₁₉Hi6BrCl ₂02) [M+H]⁺, 419.01; found, 418.98.

3 , 5-dichloro-N-ethyl-l-met yl-2 , 4-dioxo-N-phenyl-l ,2,3,4- tetrahydroquinoline-3-carboxamide , 79.

A mixture of Laq. (2.0 g, 5.6 mmol), NCS (0.92 g, 7.3 mmol) and Benzoyl peroxide (0.08 g, 0.33 mmol) in CC1₄ (80 mL) was heated at 80°C under nitrogen for 2 h and then cooled. The reaction was quenched with NaHS03 (10%, 100 mL) and the mixture was extracted with DCM (100 mL x 2) . The organic layer was combined, washed with NaHCC (150 mL) and brine (150 mL) , dried over Na₂S04 filtered and concentrated. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, from 5/1 to 2/1) to afford 79 as a yellow solid (1.71 g, 73%). ¾ NMR (300 MHz, CDC1₃) : δ

7.22 (m, 1H) , 7.14 (m, 3H) , 7.02 (m, 3H) 6.84 (m, 1H) , 3.94 (q, 1H) ,

3.75 (q, 1H) , 1.23 (t, 3H) .

5-chloro-N-ethyl-l-methyl-3- ( (methylthio) methyl) -2 , 4-dioxo-N-phenyl- 1,2,3, 4-tetrahydroquinoline-3-carboxamide , 80.

To a solution of Laq (200 mg, 0.56 mmol) in DMF (5ml) was added t-BuOK (93 mg, 0.84 mmol) and chloromethyl methyl sulfide (80 mg, 0.84 mmol), the resulting mixture was stirred overnight at ambient temperature. The mixture was diluted with ethyl acetate (40 mL) and brine (30 mL) . The organic phase was separated, dried over sodium sulfate, concentrated and purified by chromatography to give 80 (100 mg, 43%) as a white solid. ¾-NMR - (300 MHz, CDC1₃) : δ 6.88-7.32 (m, 6H) , 6.77 (m, 2H) , 3.76 (m, 2H) , 3.56 (m, 2H) , 3.24 (s, 3H) , 1.89 (s, 3H) , 1.14 (t, 3H) ; LCMS (ESI) calc'd for ( C2₁H₂₁CIN₂O₃S ) [M+H]⁺, 417.1; found, 416.7.

7-chloro-N-ethyl-3-methyl-2-oxo-N-phenyl-3 , 7b-dihydrooxireno [2 , 3- c] quinoline-la (2H) -carboxamide , 81.

A solution of 3, 5-dichloro-N-ethyl-l-methyl-2 , 4-dioxo-N-phenyl-l, 2, 3, 4- tetrahydroquinoline-3-carboxamide, 79 (1.71 g, 4.4 mmol) in ethanol (20 mL) was cooled to -78°C. NaB¾ (0.33 g, 8.8 mmol) was added in three portions. After complete addition, the mixture was stirred at the same temperature for 1.5 h and then the cooling bath was removed. The reaction was warmed to room temperature and stirred for further 1 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2) . The organic phase was combined, dried, filtered and concentrated and the residue was purified by flash chromatography (petroleum ether/ ethyl acetate, from 10/1 to 4/1) to afford 81 as a 'white solid (0.79 g, 50%) . ^XH NMR (300 MHz, CDC1₃) : δ 7.277-6.973 (m, 8 H) , 4.763 (s, 1 H) , 4.124- 4.036 (m, 1 H) , 3.704-3.696 (m, 1 H) , 3.308 (s, 3 H) , 1.236-1.157

H) / LCMS (ESI) calc'd^'for (Ci₉ Hi₇ClN₂0₃) [ +H]⁺, 357.10; found, 357

(3aR, 9bR) -9-chloro-N-ethyl-2 , 2 , 5-trimethyl-4-oxo-N-phenyl-5 , 9b- dihydro- [1 , 3] dioxolo- [4 , 5-c] quinoline-3a (4H) -carboxamide, 82.

A solution of 83 (214 mg, 0.6 rnmol) in acetone (5 mL) was cooled to 0°C and BF3.Et₂0 (0.04 mL, 0.3 mmol) in acetone (1 mL) was added drop-wise. The reaction was stirred at the same temperature for 0.5 h and warmed to room temperature. After stirred for 2 h, the reaction mixture was poured into icy saturated NaHC0₃ (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 2 ) . The organic phase was combined, washed with brine (40 mL) , dried, filtered and concentrated. The residue was purified by flash chromatography (petroleum ether/ ethyl acetate, from 10/1 to 5/1) . The product thus obtained was further purified by preparative HPLC to afford 82 (65 mg, 26%) and 84 (13 mg, 6%) as white solids. ^JH NMR and X-Ray analysis confirmed their structure. ^XH-NMR (300 MHz, CDC1₃) for 82: δ 7.291-7.285 (m, 5 H) , 7.173-7.147 (m, 2 H) , 6.956- 6.928 (m, 1 H) , 5.496 (s, 1 H) , 3.910-3.810 (m, 1 H) , 3.610-3.460 (m, 1 H) , 3.423 (s, 3 H) , 1.207 (m, 3 H) , 1.104 (m, 3 H) , 0.950 (m, 3 H) ; LCMS (ESI) calc'd for (C22H23CIN₂O ) [M+Na]⁺, 437.12; found, 437.23. ^XH- NMR (300 MHz, CDCI₃) for 84 : δ 7.285-7.263 (m, 3 H) , 7.125-7.097 (m, 1 H) , 7.040-7.013 (m, 1 H) , 6.979-6.928 (m, 1 H) , 6.633-6.607 (m, 1 H) , 4.918-4.909 (m, 1 H) , 4.809 (s, 1 H) , 4.340-4.221 (m, 1 H) , 4.108-3.990 (m, 1 H) , 3.203 (s, 3 H) , 1.433-1.385 (t, 3 H) ; LCMS (ESI) calc'd for (C19 H17CIN₂O3) [M+H]⁺, 357.10; found, 357.18.

(2S , 3aS , 9bS) -9-chloro-N-ethyl-5-methyl-4-oxo-N, 2-diphenyl-5 , 9b- di ydro- [1 , 3] dioxolo [4 , 5-c] quinoline-3a (4H) -carboxamide, 83 & (6aR,12bS)-l-chloro-8-ethy1- 6a-hydroxy-5-methyl-8 , 12b- dihydrodibenzo [c,f] [2 , 7] naphthyridine-6 , 7 (5H , 6aH) -dione , 84.

A solution of 81 (354 mg, 1.0 mmol) in benzaldehyde (5 mL) was cooled to 0°C. To this solution was added drop wise a solution of BF₃*Et20 (0.06 mL, 0.5 mmol) in benzaldehyde (1 mL) . The reaction was allowed to warm to ambient temperature slowly. After 20 minutes, the reaction mixture was poured into icy saturated NaHC03 (20 mL) . The mixture was extracted with ethyl acetate (2 x 20 mL) and the organic layer was combined, washed with brine (40 mL) , dried filtered and concentrated and the residue was purified by flash chromatography (petroleum ether/ethyl acetate=10/l to 5/1) . The product thus obtained was further purified by preparative HPLC to afford 83 (63 mg) and 84 as white solids. ¹H NMR for 83 (300 MHz, CDCI₃) : δ 7.404-7.079 (m, 12 H) , 6.924-6.896 (m, 1 H) , 5.585 (s, 1 H) , 5.114 (s, 1 H), 3.896-3.796 (m, 1 H) , 3,659-3.510 (m, 1 H) , 3.392 (s, 3 H) , 1.211-1.139 (m, 3 H) ; LCMS (ESI) calc' d for (C26H23CIN2O4 ) [M+Na]⁺, 485.12; found, 485.13. l-chloro-8-ethyl-5-methyldibenzo [c,f] [2 , 7] naphthyridine-6 , 7 (5H, 8H) - dione , 85.

A flask charged with 4 , 5-dichloro-N-ethyl-l-methyl-2-oxo-N-phenyl-l , 2- dihydroquinoline-3-carboxamide, (77, 400 mg, 1.07 mmol), KOAc (209 mg, 2.13 mmol), PPh₃ (56 mg, 0.22 mmol) and Pd(OAc)₂ (24 mg, 0.11 mmol) was exchanged with nitrogen for 15 min and DMF (20 mL) was added. The mixture was stirred at 110°C for 5 h. and then cooled to room temperature, filtered and the cake was washed with ethyl acetate (50 mL) . The filtrate and elution were combined, washed with NaHCC (50 mL x 2), dried over Na₂S0₄ filtered and concentrated. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1/1 then DCM/methanol , 30/1) to afford 85 as a yellow solid (150 mg) . ^-NMR (300 MHz, CDC1₃) : δ 7.585-7.514 (m, 3 H) , 7.458-7.164 (m, 4 H) , 4.578-4.510 (m, 1 H ) , 4.366-4.322 (m, 1 H ) , 3.705 (s, 3 H) , 1.479-1.402 (t, 3 H) ; LCMS (ESI) calc'd for ( C₁₉H₁₅CIN2O₂ ) [M+H]⁺, 339.09; found, 341.00. 5-chloro-N-ethyl-4-hydroxy-l-methyl-N- (4- (3-

(methylsulfonyl) henyl) cyclohexyl) -2-oxo-l ,2-dihydroquinoline-3- carboxamide , 86.

Preparation of 1 , 4-dioxaspiro [4.5] dec-7-en-8-yl trifluoro- methanesulfonate (86a). To a stirred solution of 1,4- dioxaspiro [4.5] decan-8-one (2.4 g, 15.38 iranol) , 1 , 1 , 1-trifluoro-N- phenyl-N- ( (trifluoromethyl) sulfonyl) methanesulfonamide (7.14 g, 20 mmol) in THF (40 mL) was added 0.5M potassium bis-trimethylslylamide in tolune (40.0 mL, 0.5 M, 20 mmol) under N₂ atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 4 hrs before warmed to room temperature. The mixture was quenched with water and extracted with ether (200 mL x 3) . The combined organic layer was dried over Na2S04 , filtered and purified by chromatography (silica gel, ethyl acetate in petroleum ether, 2% to 8%) to give 1 , -dioxaspiro [4.5] dec-7-en-8-yl trifluoromethanesulfonate (86a, 3.2 g, 46%) as a clear oil. LCMS (ESI) calc'd for (C₉H₁₁F₃O₅S) [M+H]⁺, 289.7. Preparation of 4 , 4 , 5 , 5-tetramethyl-2- (3- (methylsulfonyl) phenyl) -1 , 3 , 2- dioxaborolane (86b). To a solution of l-bromo-3- (methylsulfonyl) benzene

(1.175 g, 5 mmol) in 1,4-dixone (30 mL) was added Bis (pinacolato) diboron (4,4,4' ,4' ,5,5,5' , 5 ' -octamethyl-2 , 2 · -bi (1 , 3 , 2-dioxaborolane , 1.27 g, 5 mmol), KOAc (980 mg, 10 mmol) followed by [1 , 1 ' -Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf ) 2CI2 200 mg, 0.27 mmol) under 2 atmosphere. The resulting mixture was stirred at 80°C for 10 hrs. after which it was cooled and filtered. The filtrate was diluted with water and extracted with ethyl acetate (20 mL 3) . The combined organic layers were dried over Na2S04 filtered and concentrated in vacuum. The residue was purified by combi-flash chromatography (silica gel, ethyl acetate in petroleum ether, 5% to 25%) to give 4 , 4 , 5 , 5-tetramethyl-2- (3- (methylsulfonyl) phenyl) -1 , 3 , 2-dioxaborolane (86b, 490 mg, 33%) as a light yellow solid. Preparation of 8- (3- (methylsulfonyl) phenyl) -1 , 4-dioxaspiro [ .5] dec-7- ene (86c) . To a solution of 86a (1.72 g, 6 mmol) and 86b (564 mg, 2 mmol) in acetonitrile (30 mL) was added aq. NaHCC (4.2 mL, IN) followed by Bis (triphenylphosphxne) palladium (II) dichlorxde (Pd (PPh3) ₂CI2 , 200 mg, 0.2 mmol) at room temperature under 2 protection. The resulting mixture wa s stirred at 70°C for 12 hrs. and then cooled and filtered. The filtrate was diluted with water and extracted with ethyl acetate (20 mL * 3) . The combined organic layer was dried over Nas S Ozi , filtered and concentrated in vacuum and the residue was purified by combi-flash ( silica gel, ethyl acetate in petroleum ether, 5% to 25%) to give 86c (400 mg, 67%) as a colorless oil. ^- MR (500 MHz, CDC1₃) : 57.84 (t, J =1.5 Hz, 1 H) , 7.10 (d, J = 7.5Hz, 1 H) , 7.65(d, J = 8 Hz, 1 H) , 7.47 (t, J =8 Hz, 1 H) , 6.05-6.03(m, 1 H) , 7.32-7.27 (m, 2 H) , 3.90 (s, 4 H) , 3.02 (s, 3 H) , 2.52 (s, 2 H), 2.36 (s, 2 H) , 1.82 (t, J =7 Hz, 2 H) . Preparation of 8- (3- (methylsulfonyl) phenyl) -1 , -dioxaspiro [4.5] decane (86d) . A mixture of 86c (400 mg, 1.35 mmol) and Pd/C (80 mg, 5%) in EtOH (10 mL) was purged with ¾ and stirred at room temperature for 12 hrs . then filtered and the filtrate concentrated in vacuum to give 86d (357 mg, 90%) as a white solid.

Preparation of 4- (3- (methylsulfonyl) phenyl) cyclohexan-l-one , (86e) .

A mixture of 86d (357 mg, 1.20 mmol) in THF (6 mL) , water (3 mL) and H₂SO₄ (1.5 mL) was stirred at room temperature for 1.5 hrs. The reaction was diluted with brine and extracted with ethyl acetate (20 mL ^χ 3) . The combined organic layers were dried over a2S0 filtered and concentrated in vacuum to give 86e (280 mg, 92%) as a white solid.

Preparation of N-ethyl-4- (3- (methylsul onyl) phenyl) cyclohexan-l-amine (86 ) . To a solution of 86e (280 mg, 1.12 mmol) in acetonitrile (10 mL) was added ethanamine hydrochloride (205 mg, 2.54), acetic acid (O.lmL) and NaBH(OAc)3 (538 mg, 2.54 mmol). The mixture was stirred at 25°C for 12 hrs. after which it was diluted with sat.NaHCC>3 and extracted with 10% MeOH in CH2CI2 (50 mL ^χ 3) . The combined organic layer washed with brine, dried over Na2SC>4 filtered and concentrated in vacuum. The residue was purified by combi-flash (water in acetonitrile , 5% to 52%) to give 86f (226 mg, 72%) as an orange oil.

Preparation of 5-chloro-N-ethyl-4-hydroxy-l-methyl-N- (4- (3- (methylsulfonyl) phenyl) cyclohexyl) -2-oxo-l , 2-dihydroquinoline-3-carboxamide , 86. To a solution of 86f (226 mg, 0.80 mmol) and 5-chloro-4~hydroxy-l- me hyl-2-oxo-l , 2-dihydroquinoline-3-carboxylic acid (204 mg, 0.80 mmol) in DCM (10 mL) was added triethylamine (240 mg, 2.4 mmol). The mixture was cooled in an ice bath, and S0C1₂ (113.2 mg, 0.96 mmol) was added drop wise over 10 minutes. The mixture was stirred at 0°C for 3 hrs . and then concentrated in vacuum. The residue was purified by prep-HPLC (water in acetonitrile ,5 to 72%) to give 86 (102 mg, 29%) as a white solid. ¾- N R (500 MHz, CDCl₃) : 57.94 (s, 0.3 H) , 7.79 (0.3 H, d, J = 8.0 Hz), 7.74(s, 1.3 H), 7.67 (d, J =7.5 Hz, 0.3 H), 7.79 (t, J =7.5Hz, 0.3 H) , 7.50-7.46 (m, 2.4 H) , 7.32-7.27 (m, 2 H) , 3.70 (s, 0.8 H) , 3.67 (s, 2 H), 3.52 (s, 1.3 H), 3.31 (s, 0.5 H) , 3.07 (s, 0.9 H) , 3.03 (s, 2.0 H) , 2.60 (t, J =11.5 Hz, 0.7 H) , 2.33 (d, J =14 Hz, 0.6 H) , 2.12 (br, 1 H),1.98 (d, J =12.5 Hz, 1.5 H) , 1.97-1.67 (m, 3 H) , 1.54-1.53 (m, 1.4 H), 1.37-1.27 (m, 2.6 H) , 1.14 (t, J =6.5 Hz, 1 H) . LCMS (ESI) calc'd for (C26H29CIN2O5S) [M+H]⁺, 517.2; found: 517.2.

Example 1. Pharmacological test

Experimental Autoimmune Encephalomyelitis (EAE) is an Experimental Model (mostly used with rodents) of the human CNS demyelinating diseases, including MS.

Doses of prodrugs were adjusted to ~5 mg/kg laquinimod dose equivalent based on AUCs of free laquinimod (released from prodrug, see Table 1) exposure :

Table 1.

Healthy, nulliparous, non-pregnant female mice of the C57BL/6 strain were obtained from Harlan Animal Breeding Center, Jerusalem, Israel. The body weights of the animals were recorded on the day of delivery. The animals weighed 17-20 g on arrival, and were approximately 9 weeks of age. The mice were allocated to the following treatment groups (15 mice/group, see Table 2) :

Table 2.

After drug administration scoring of EAE clinical signs was initiated from the 10^th day post-EAE induction and was continued daily for 30 days. The clinical profiles of the treatment groups are presented graphically in Figure 1. Results of the study indicate that following administration of equivalent dose all 4 tested compounds demonstrated disease inhibition activity higher than laquinimod at 5 mg/kg. Example 2. Chemical stability in FaSSGF (Fasted-State Simulated Gastric Fluid) and FaSSIF (Fasted State Simulated Intestinal Fluid)

Compounds 54 and 69 (10 μΜ) were incubated in duplicates for 0, 5, 15, 30, 45, 60 min at 37°C in presence of FaSSGF and FaSSIF buffer and analyzed by LC/MS . Results are summarized in Table 3.

Conclusion: The results showed that 54 and 69 were stable in simulated gastric and intestinal fluid. Example 3. Microsomal stability

Compounds (1 μΜ) were evaluated for microsomal stability using human and rat liver microsomes. Compounds were incubated in duplicates for 0, 5, 15, 30, 45 min (for 54) or for 0, 5, 10, 15, 30, 40 min (for 5, 53, 69) at 37°C in presence of rat and human liver micosomes with final protein concentration of 0.5 mg/mL. Samples were analyzed for pro-drug and parent drug by LC-MS . Results are summarized in Table 4.

Conclusion: A similar metabolic rate was observed for 5, 53 and 69 in rat and human microsomes with a half-life between 10 min to 19 min. A higher metabolic rate was observed for 6d compared to other pro-drugs, with a half-life of 2min and 4min for rat and human microsomes, respectively .

Plasma stability:

Plasma stability of 54 and 69 was evaluated in the presence of mouse, rat, dog, monkey and human plasma. Compounds (2 μΜ) were incubated in presence of plasma in duplicates for 0, 5, 15, 30, 45 and 60 min at 37 °C. Procaine and Benfluorex were used as reference compounds. Results are summarized in Table 5.

Conclusion: 54 and 69 were stable in rat, mouse, dog, monkey and human plasma .

Example 4 : Caco-2 permeability assay

Compounds (10 μ ) were incubated in Caco-2 cell lines in HBSS buffer, pH 7.4 for 90min (for 54) or for 120min (for 5, 53, 69) at 37°C. Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) . Each determination was, performed in duplicate. The co-dosed lucifer yellow flux was also measured for each monolayer to ensure no damage was inflicted to the cell monolayers during the flux period. All samples were assayed for the dosed prodrug and the expected parent drug by LC-MS/MS. The results are summarized in Table 6.

Data interpretation:

Permeability classification - (P_apP A-B) < 1.0 x 10^~s cm/s : Low; (Papp A- B) > 1.0 x 10^~6 cm/s: High; Significant Efflux - Efflux ratio > 2.0 and (Papp B-A) > 1.0 x 10^~6 cm/s

Conclusion: All pro-drugs showed high permeability through Caco-2 monolayers, with no significant efflux. Very low levels of parent drug were detected for all pro-drugs under these conditions (except for 69, where no parent drug could be detected) .

Example 5 : Pharmacokinetics of prodrug compounds and parent drug in plasma following IV or oral administration of prodrug compounds to male SD rats

Three rats were administered IV (lmg/kg) or PO (3mg/kg for 53, 5 and 69 or 5mg/kg for 54) . Plasma was collected at pre-dose and at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hr after IV and PO dosing and analyzed for pro- drug and parent drug by LC-MS.MS.

PK parameters are summarized in Tables 7, 8, 9 and 10 for 53, 5, 69 and 54, respectively. The PK profiles of prodrug and parent drug following a single PO administration of 53, 5, 69 and 54 to rats are presented in Figures 1 to 4, respectively. The PK parameters of the prodrugs and parent drug showed oral bioavailability of the prodrugs (F between 3.18 to 25.8%) with a rapid prodrug to parent drug conversion following administration of the prodrugs to rats.

Example 6. Administration of Compounds 5, 53, 54 or 69

Administration of compound 5, 53, 54 or 69 to a subject afflicted with multiple sclerosis provides increased efficacy in treating the patient than when laquinimod is administered (at the same dose) . The compound also provides efficacy in treating the patient without undue adverse side effects.

The compound therapy provides a clinically meaningful advantage and is more effective in treating the patient than when laquinimod is administered (at the same dose) in the following manners:

1. The compound is more effective in reducing the decrease in brain volume (determined by the percent brain volume change (PBVC)), in multiple sclerosis patients; The compound is more effective in increasing the time to confirmed disease progression (CDP) , in multiple sclerosis patients, where CDP is defined as a sustained increase in EDSS of >1 point from Baseline for at least 3 months. Progression cannot be confirmed during a relapse;

The compound is more effective in reducing abnormalities observed in whole Brain MTR histogram, in multiple sclerosis patients during;

The compound is more effective in reducing the number of confirmed relapses and therefore the relapse rate, in multiple sclerosis patients ;

The compound is also more effective in reducing the accumulation of physical disability in multiple sclerosis patients, as measured by the time to confirmed progression of EDSS;

The compound is more effective in reducing MRI-monitored disease activity in multiple sclerosis patients, as measured by the cumulative number of Tl Gd-enhancing lesions on Tl-weighted images, the cumulative number new Tl hypointense lesions, the cumulative number of new T2 lesions, the cumulative number of new Tl hypointense lesions on Tl-weight images (black holes) , the number of active (new T2 or GdE-Tl) lesions, presence or absence of GdE lesions, change in total volume of Tl Gd-enhancing lesions, change in total volume of T2 lesions, and/or cortical thickness;

The compound is more effective in reducing brain atrophy in multiple sclerosis patients;

The compound is more effective in reducing the frequency of relapses, the frequency of clinical exacerbation, and the risk for confirmed progression in multiple sclerosis patients;

The compound is more effective in increasing the time to confirmed relapse in multiple sclerosis patients; 10. The compound is more effective in improving the general health status (as assessed by the EuroQoL (EQ5D) questionnaire) , symptom severity on work (as assessed by the work productivity and activities impairment General Health (WPAI-GH) questionnaire) and quality of life, in multiple sclerosis patients; and/or

11. The compound is more effective in decreasing cerebral dysfunction/cognitive impairment (as assessed by Symbol Digit Modalities Test (SDMT) ) , in multiple sclerosis patients during the double blind study period. Example 7. Laquinimod Prodrugs

As demonstrated in the data contained herein compounds 5, 53, 54 or 69 are converted to laquinimod in vivo. The analogues of 5, 53, 54 or 69 contained herein are also converted to laquinimod in vivo and act as prodrugs of laquinimod. An amount of any one of the analogues of 5, 53, 54 or 69 contained herein is administered to a subject afflicted with multiple sclerosis. The amount of the compound is effective to treat the subj ect .

Discussion

Disclosed herein is a method for treating a subject, e.g., a human patient, afflicted with multiple sclerosis, e.g., relapsing multiple sclerosis or presenting a CIS, using the compound of the present invention which provides a more efficacious treatment than laquinimod. The use of laquinimod for multiple sclerosis had been previously suggested in, e.g., U.S. Patent No. 6,077,851. However, the prodrugs contained herein are particularly effective for the treatment of a subject afflicted with MS or presenting a CIS as compared to laquinimod.

Refrences

Briick (2011) "Insight into the mechanism of laquinimod action." J Neurol Sci. 2011 Jul 15;306(l-2) :173-9.

Cohen, J.A. and Rudick, R. A. (2007) Multiple Sclerosis Therapeutics, 3rd Edition, CRC Press.

Comi et al . (2007) LAQ/5062 Study Group. "The Effect of Two Doses of Laquinimod on MRI-Monitored Disease Activity in Patients with Relapsing- Remitting Multiple Sclerosis: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study", Presented at: 59th Annual Meeting of the American Academy of Neurology; April 28-May 5, 2007; Boston, MA. De Rosbo NK, Ben-Nun A. (1999) Experimental autoimmune encephalomyelitis induced by various antigens of the central nervous system: overview and relevance to multiple sclerosis. In: Shoenfeld Y, ed. The Decade of Autoimmunity. The Netherlands: Elsevier Science, 169-77. EMEA Guideline on Clinical Investigation of Medicinal Products for the Treatment of Multiple Sclerosis (CPMP/E P/561/98 Rev. 1, Nove.2006).

Gurevich et al . (2010) "Laquinimod suppress antigen presentation in relapsing-remitting multiple sclerosis: in vitro high-throughput gene expression study" (J Neuroimmunol . 2010 Apr 15; 221 (1-2) : 87-94. Epub 2010 Mar 27.

Guyatt et al . (1985) "The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure", Can Med Assoc J., 132:919-823.

Kurtzke JF, (1983) "Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)", Neurology 33 (11) : 1444-1452. Polman et al., (2005) "Diagnostic criteria for multiple sclerosis : _.2005 revisions to the McDonald Criteria", Annals of Neurology, Volume 58 Issue 6, Pages 840-846. Polman et al., (2005) "Treatment with laquinimod reduces development of active MRI lesions in relapsing MS", Neurology. 64:987-991.

Runstrom et al. (2006) "Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-β k.o. and wild type mice" Journal of Neuroimmunology, 173 (2006) : 69- 78.

Sandberg-Wollheim et al. (2005) "48-week open safety study with high- dose oral laquinimod in patients", Mult Scler. 11:S154 (Abstract).

Teva Press Release dated August 1, 2011, entitled "Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment" . U.S. Patent No. 6,077,851, issued Jun 20, 2000 (Bjork et al) .

Yang et al . , (2004) "Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Thl/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats", J. Neuroimmunol . 156:3-9.

Claims

What is claimed is :

1. A compound having the structure

wherein

a is absent of present and when present is a bond,

wherein when a is present, then X is 0, β is absent and χ is present ;

β is absent or present and when present is a bond,

wherein when β is present, then a and χ are absent;

χ is absent or present and when present is a bond,

wherein when χ is present, then X is 0, a is present and β is absent ;

X is O, OH, CI, Br, O-Ri, 0-C(0)-R₂, 0-C(0)-0R₃, 0-C (0) -NR4R5, 0-CH₂-OR₆, O-SO₂-R7, 0-S0₂-NR₈R9, O-P (0) (OR10) 2, O-L- (laquinimod residue) , 0-L- (fingolimod residue), 0-L- (cilomilast residue) or 0-L- (D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C₂-C₁₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH₃, alkyl-C0₂- alkyl, alkyl-NHC (O) -aryl , alkyl-NHC (0) -heteroaryl, alkyl-C (0) NH- alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine ) , alkyl-C (0)- (dimethylaminoethanol ) , amino acid residue, alkyl- (amino acid residue), alkyl-C (0) - (amino acid residue), alkyl-NH- (amino acid residue) or -CH (alkyl-OAc) ₂;

R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C0?-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane;

R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₄ and R5 are each, independently, H , alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;

Re is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(0) -alkyl, C(O)- heteroalkyl, C0₂-alkyl, C (0) -heterocycloalkyl, C (0) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) (alkyl) ₂, C (0) NH-alkyl- N(CH₃) (Boc), C0₂-alkyl-N (CH₃) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue) ;

R7 is H , alkyl, alkenyl, alkynyl, aryl or heteroaryl;

Rg and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and

Each Rio is, independently, H or alkyl;

Y is absent or present and when present is H, CI or alkyl-SCH₃;

Z is aryl, heteroaryl or cycloalkyl-aryl ,

wherein when X is OH, then is Z is heteroaryl or cycloalkyl-aryl; or a pharmaceutically acceptable salt or ester thereof. 2. The compound of claim 1 having the structure:

wherein X is CI , Br, O-Ri , 0-C(0)-R₂, 0-C(0)-0R₃, 0-C (0) -NR4R5, 0-CH₂- 0R₆, 0-S0₂-R₇ , 0-S0₂-NR₈R9, 0- P (0) ( OR10 ) 2 , 0-L- ( laquinimod residue), 0-L- (fingolimod residue), 0-L- (cilomilast residue) or 0-L- (D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C₂ -Ci₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH , alkyl-SCH₃ , alkyl-C0₂- alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl, alkyl-C (0) NH- alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine) , alkyl- C (0)- (dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue), alkyl-C (O) -( amino acid residue), alkyl-NH- ( amino acid residue) or -CH (alkyl-OAc) ₂;

R₃ is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C(O)- heteroalkyl, C0₂-alkyl, C (0) -heterocycloalkyl, C (0) H-alkyl- heterocycloalkyl, C(0)NH-aryl, C (O) N (alkyl) 2, C (0) NH-alkyl- N(CH₃) (Boc), C0₂-alkyl-N (CH₃) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue) ;

R₇ is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

RB and Rg are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl; and

Z is aryl, heteroaryl or cycloalkyl-aryl ; or a pharmaceutically acceptable salt or ester thereof. ein Z is

4. The compound of claim 3 having the structure:

wherein X is Cl, Br, O-Ri, 0-C(0)-R_2/ 0-C (0) -OR3, 0-C (0) -NR4R5, 0-CH₂- 0R₆, 0-S0₂-RT, 0-S0₂-NR₈Rg, O-P (0) (OR₁₀) 2, 0-L- (laquinimod residue), 0-L- (fingolimod residue) , O-L- ( cilomilast residue) or O-L- ( D-glucose residue) ,

wherein

L is present or absent and when present is a chemical linker; Ri is C₂-C₁₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH₃, alkyl-C0₂- alkyl, alkyl-NHC (O) -aryl, alkyl-NHC ( 0 ) -heteroaryl , alkyl-C (O) NH- alkyl-NH-alkyl, alkyl-C ( 0 ) - (N-methylethanolamine ) , alkyl-C (O)- (dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue) , alkyl-C (O) -( amino acid residue), alkyl-NH- ( amino acid residue) or -CH (alkyl-OAc) 2;

R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C0?-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C ( 0 ) -NH-indane ;

R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C( 0 ) -alkyl, C( 0 ) - heteroalkyl, C0₂-alkyl, C (O) -heterocycloalkyl, C (O) NH-alkyl- heterocycloalkyl, C( 0)NH-aryl, C ( 0 ) (alkyl) 2, C (O) NH-alkyl- N(CH₃) (Boc), C0₂-alkyl-N (CH₃) (Boc) , or C ( 0 ) -piperazine-C (O) - (amino acid residue) ;

R7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

or a pharmaceutically acceptable salt or ester thereof.

5 . The compound of claim 4 , wherein A is O-Ri ,

wherein Ri is C₂-C₁₂ alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, · alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH₃, alkyl-C0₂-alkyl, alkyl-NHC (O) -aryl, alkyl-NHC ( 0 ) -heteroaryl, alkyl-C ( 0 ) NH-alkyl-NH- alkyl, alkyl-C ( 0 ) - (N-methylethanolamine ) , alkyl-C ( 0 ) - (dimethylaminoethanol ) , (amino acid residue), alkyl- (amino acid residue), alkyl-C (0) - (amino acid residue), alkyl-NH- ( amino acid residue) or -CH (alkyl-OAc) 2 ·

6. The compound of claim 5, wherein Ri is isopropyl, allyl, -CH( CH3^~ OAc)₂, -CH2C -CH2CH2CH2NH2 , -CH2CO2CH2CH3 , -CH2CO2H ,

7. The compound of claim 4, wherein A is 0-C(0)-R2.

wherein R₂ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (O) -NH-indane . , -CH₂CH₃, -C0₂CH₂CH₃,

9. The compound of claim 4, wherein A is 0-C(0)-0R3, wherein R4 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl.

10. The compound of claim 9, wherein R3 is methyl, isobutyl, fc-butyl or p-nitrophenyl .

11. The compound of claim 10, wherein A is O-C (O) -NR4R5, wherein R₄ and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl.

12. The compound of claim 11, wherein R& and R₅ are each H, methyl, ethyl or -CH₂CH₂NHCH₃. 13. The compound of claim 4, wherein A is O-CH2-OR6, wherein R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl , aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C (0) -heteroalkyl, C0₂- alkyl, C (0) -heterocycloalkyl, C (0) H-alkyl-heterocycloalkyl , C(0)NH- aryl, C (O) N (alkyl) 2, C (0) H-alkyl-N (CH₃) (Boc) , C0₂-alkyl- (CH₃) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue).

14. The compound of claim 13, wherein R₆ is methyl, butyl, -C(0)0CH3, - -CH2CH2OCH2CH3 , -C(0)CH(CH₂CH2CH₃ ) 2 , -CH₂CH₂ (phenyl ) ,

15. The compound of claim 4, wherein A is O-SO2-R7 wherein R7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl.

16. The compound of claim 4, wherein A is O-SC^-NRsRg, wherein Rs and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or

heteroaryl, or combine to form a heterocycloalkyl.

17. The compound of claim 4, wherein A is 0-P(0) (ORio)₂, wherein each Rio is, independently, H or alkyl. 18. The compound of claim 4, wherein A is O-L- ( laquinimod residue), O- L- (fingolimod residue), A is O-L- ( cilomilast residue), O-L- ( cilomilast residue) or O-L- (D-glucose residue) .

19. The compound of claim 18, wherein L is absent.

20. The compound of 19, wherein L is an alkyl, alkyl-C(O), alkyl-NH, alkyl-O, alkyl-C(O) or C (0) -phenyl-C (0) .

22. The compound of claim 1 having the structure:

WO 2017/120355 PCT/US2017/012358

or a pharmaceutically acceptable salt or ester thereof. 23. The compound of claim 1 having the structure:

wherein Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof; or having th structure :

wherein Z is heteroaryl or cycloalkyl-aryl, or a pharmaceutically acceptable salt or ester thereof; or having th structure :

wherein

Y is H, CI or alkyl-SCH₃; and

or a pharmaceutically acceptable salt or ester thereof. the structure:

wherein

δ and ε are absent or present and when present are bonds, φ and γ are absent or present and when present are bonds,

wherein when δ and ε are present, then φ and γ are absent and when φ and are present, then δ and ε are absent;

Rii is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and

Ri2 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl,. or a pharmaceutically acceptable salt or ester thereof. 26. The compound of claim 28 having the structure

wherein

Qi is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and Q.2 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof. re:

or a pharmaceutically acceptable salt or ester thereof.

2 A compound having the structure:

wherein

η and ι are absent or present and when present are bonds, φ is absent or present and when present is a bond,

wherein when η and ι are present, then φ is absent and when φ is present, then η and ι are absent;

Q3 is H, OH, alkyl, alkenyl or alkynyl; and

Qi is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof.

29. The compound of claim 28 having the structure:

or a pharmaceutically acceptable salt or ester thereof. 30. The compound of claim 1 having the structure:

wherein X is ORi,

wherein Ri is hydroxyalkyl ; and

Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof; or having the structure :

wherein X is O-C (O) -NR4R5,

wherein R and R5 are each an alkyl; and

Z is aryl, heteroaryl or cycloalkyl-aryl, or a pharmaceutically acceptable salt or ester thereof; or having the structure :

wherein X is 0-CH₂-OR₆,

wherein R6 is C (0) ( alkyl ) 2 or C (0) cycloheteroalkyl ; and

Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof; or having the structure .

or a pharmaceutically acceptable salt or ester thereof.

32. A pharmaceutical composition comprising a compound of any one of claims 1-31 and a pharmaceutically acceptable carrier.

33. A method of treating a subject afflicted with multiple sclerosis, relapsing multiple sclerosis or relapsing-remitting multiple sclerosis comprising administering to the subject an amount of the compound of any one of claims 1-31 so as to thereby treat the subject.

34. The method of claim 33, wherein the amount of the compound is effective to reduce a symptom of multiple sclerosis in the subject. 35. A method of treating a subject afflicted with Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, systemic lupus erythematosus (SLE) , insulin-dependent diabetes mellitus (IDDM) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder or a CBl receptor comprising administering to the subject an amount of the compound of any one of claims 1-31 so as to thereby treat the subject.

36. A method for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject, the method comprising administering to the subject the compound of any one of claims 1-31 so as to thereby reduce or inhibit progression of the level of fatigue in the multiple sclerosis subject so as to thereby reduce or inhibit the level of fatigue in the multiple sclerosis subject.

37. A method of treating a subject afflicted with glaucoma or suffering from retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or of reducing retinal ganglion cell loss, retinal ganglion cell damage or intraocular pressure in a subject, comprising administering to the subject an amount of the compound of any one of claims 1-31 to reduce retinal an ion cell loss or damage, or reduce intraocular pressure in the subject.

38. A method for in vivo delivery of laquinimod to a subject, the method comprising administering to the subject a compound of any one of claims 1-31 so as to thereby deliver laquinimod to the subject.

39. The method of claim 38, wherein the subject is afflicted with multiple sclerosis, relapsing multiple sclerosis or relapsing-remitting multiple sclerosis.

40. The method of claim 39, wherein the in vivo delivery of laquinimod to a subject is effective to reduce a symptom of the multiple sclerosis, relapsing multiple sclerosis or relapsing-remitting multiple sclerosis in the subject.

41. The method of claim 34 or 40, wherein the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work .

42. The method of claim 38, wherein the subject is afflicted with Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure; and wherein the in vivo delivery of laquinimod to a subject is effective to reduce a symptom of the Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure in the subject.