WO2008016700A2

WO2008016700A2 - N-oxide compounds for therapeutics uses

Info

Publication number: WO2008016700A2
Application number: PCT/US2007/017300
Authority: WO
Inventors: Alfred M. Ajami
Original assignee: Xanthus Pharmaceuticals, Inc.
Priority date: 2006-08-02
Filing date: 2007-08-02
Publication date: 2008-02-07
Also published as: WO2008016700A3

Abstract

Compounds of formula (I) and a method of treating a patient suffering from certain inflammatory disorders, demyelinating disorders, FLT3-mediated disorders, CSF-1R-mediated disorders, cancers and leukemias, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Definitions for the variables are provided herein.

Description

N-OXIDE COMPOUNDS FOR THERAPEUTIC USES

RELATED APPLICATIONS

This application claims the benefit of Provisional Application No. 60/835,063, filed August 2, 2006. The entire teachings of the above application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

There is a need for new pharmaceutically acceptable therapies for an inflammatory disorder, a demyelinating disorder, a FLT3-mediated disorder, a cancer, a leukemia or a CSF-I R-mediated disorder in a patient.

SUMMARY OF THE INVENTION

The present invention is directed to a class of novel compounds that can be used for treatment of an inflammatory disorder, a demyelinating disorder, a FLT3 -mediated disorder, a cancer, a leukemia or a CSF-I R-mediated disorder in a patient.

In one embodiment, the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(J)

In one embodiment of formula (I), R is R^x, or R and R⁴ or, alternatively, R and R⁵ taken together with their intervening carbon atoms form a 5, 6 or 7 member, optionally substituted, cycloalkyl or non-aromatic optionally substitued heterocycle containing one or two oxygens and optionally substituted with methyl or hydroxy 1. In another embodiment of formula (I), R is a hydrolysable group. In yet another embodiment of formula (I), R, alone or taken together with R⁴, or alternatively R⁵, and their intervening carbon atoms is a phenol isosteric group. The remainder of the variables in formula (I) take the following values:

R^x is -H, an optionally substituted alkyl, hydroxyl, alkoxy group, or a halogen;

R² is -H₃ an optionally substituted Cl-ClO alkyl or an optionally substituted aryl, an optionally substituted aralkyl or an optionally substituted heteroaryl;

R³ is a group represented by a structural formula

n is an integer from 1 to 5;

R^a and R^b, each independently are hydrogen or an optionally substituted alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a non- aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, provided that the heterocycle comprises no more than one ring nitrogen atom;

R⁴, R⁵ and R⁶, are each independently -H, -OH, a halogen or an optionally substituted C1-C6 alkoxy; or R⁵ and R⁶ taken together with their intervening carbon atoms, form a 5, 6 or 7 member, optionally substitited cycloalkyl or non-aromatic heterocycle. In another embodiment, the present invention is a method of treating a patient suffering from a demyelinating disorder, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is a method of treating a patient suffering from an inflammatory disorder, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention is a pharmaceutical composition, comprising a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

In another embodiment, the present invention is the use a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a medicament useful for treating a patient suffering from a cancer.

In another embodiment, the present invention is the use a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a medicament useful for treating a patient suffering from a demyelinating disorder.

In another embodiment, the present invention is the use a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a medicament useful for treating a patient suffering from an inflammatory disorder.

DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that administration of certain indazole compounds can be used to treat an inflammatory disorder, a demyelinating disorder, a FLT3- mediated disorder, a cancer, a leukemia or a CSF-lR-mediated disorder in a patient. Accordingly, in one embodiment, the present invention is a compound of formula (I) below or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a method of treating certain types of cancer, or an inflammatory disorder, or a demyelinating disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

(I) Values and preferred values for the variables in formula (I) are provided in the following paragraphs.

In one embodiment, R is either R^x or taken together with R⁴ or, alternatively, R⁵ and their intervening carbon atoms form a 5, 6 or 7 member, optionally substituted, cycloalkyl or non-aromatic heterocycle containing one or two oxygens and optionally substituted with methyl or hydroxyl. Preferably, R is R^x, wherein R^x is -H, an optionally substituted alkyl, hydroxyl, alkoxy group, a halogen. More preferably, R^x is -F, -OH or -OCH₃.

In another embodimnent, R is a hydrolysable group. Preferably, R is selected from groups (II) - (VII):

(II); / (-THTTIV); ■ Π (IVVY); (V);

(VI); (VII); A^» (VIII); and

In another embodiment, R, alone or taken together with R⁴, or alternatively R⁵, and their intervening carbon atoitns is a phenol isosteric group. Preferably, the phenol isosteric group is selected from:

R¹⁷ HH ^c

(XVI);

R is -H, an optionally substituted Cl-ClO alkyl or an optionally substituted aryl, an optionally substituted aralkyl, or an optionally substituted heteroaryl. Preferably, R² is -H or an optionally substituted Cl-ClO alkyl. More preferably, R² is -H, C1-C4 alkyl or C1-C4 haloalkyl. Even more preferably, R² is a -H or a C1-C4 alkyl. Yet more preferably, R² is -H , methyl or ethyl.

R³ is

wherein R^a and R^b, each independently are hydrogen or an optionally substituted alkyl, or R^a and R , taken together with the nitrogen to which they are attached, form a non- aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, provided that the heterocycle comprises no more than one ring nitrogen atom. Preferably, R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R , taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy. More preferably, R^a and R^b, is each independently a hydrogen or a C1-C3 alkyl, or, taken together with the nitrogen to which they are attached, form group R^y selected form a group consisting of

wherein Q² is CH₂, S or O. Preferably, R^a and R^b, taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring. Even more preferably, R^B and R^b are independently each a -H or an alkyl optionally substituted with a C1-C4 hydroxyalkyl. Yet more preferably, R^a and R^b are each independently a C1-C3 alkyl. Preferably, R^a and R^b are identical and are methyl or ethyl. R⁴, R⁵ and R⁶, are each independently -H, -OH, a halogen or an optionally substituted C1-C6 alkoxy, or R⁵ and R⁶ taken together with their intervening carbon atoms, form a 5, 6 or 7 member, optionally substitited cycloalkyl or non-aromatic heterocycle. Preferably, R⁴, R⁵ and R⁶ are each independently -H, -OH, CI-C4 alkyl or C1-C4 haloalkyl, or R⁵ and R⁶ taken together are methylenedioxy. More preferably, R⁴ is -H, and R⁵ and R⁶ are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or taken together are methylenedioxy. n is an integer from 1 to 5. Preferably, n is 2 or 3. R⁷ and R⁸ are independently each H, optionally substituted C1-C6 alkyl, optionally substituted aryl or optionally substituted aralkyl. Preferably, R⁷ and R⁸ are independently each H, optionally substituted C1-C6 alkyl or phenyl or benzyl, each optionally substituted with one or more hydroxyl, C1-C3 alkoxy, amino, alkylamino, halogen, haloalkyl or haloalkoxy groups. More preferably, R⁷ and R⁸ are each independently H, methyl or ethyl.

R⁹ is carboxyl, carboxamide optionally N-substituted or N, N '-di substituted with C1-C4 alkyl, C1-C6 alkanoyl, C1-C6 carbalkoxy, or optionally substituted aroyl. Preferably, R⁹ is carboxyl, carboxamide optionally N-substituted or N₅N '-di substituted with a C1-C4 alkyl, C1-C4 alkanoyl, or C1-C4 carbalkoxy. More preferably, R⁹ is a Cl-C4 alkanoyl.

R¹⁰ is H, optionally substituted C1-C6 alkyl or optionally substituted aryl or optionally substituted aralkyl. Preferably, R¹⁰ (formula (V) and, independently, in formula (VII)) is H or C1-C4 alkyl, phenyl, or benzyl, each optionally substituted with one or more hydroxyl, C1-C3 alkoxy, amino, alkylamino, halogen, haloalkyl or haloalkoxy groups. More preferably, each R¹⁰ (formula (V), and, independently, formula (VII)) is independently an H, or C1-C4 alkyl. R^u and R¹² are independently each H, optionally substituted C1-C6 alkyl or, taken together with the atom to which they are attached, form an optionally substituted non-aromatic heterocycle. Preferably, R¹¹ and R¹² (formula (IV)) are independently each a H, methyl or ethyl or, taken together with the nitrogen atom to which they are attached form non-aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, and optionally substituted at any one or more ring nitrogen atoms with C1-C4 alkyl or C1-C4 alkyl substituted with -NR^cR^d, wherein R^c and R^d are individually H, methyl or ethyl. More preferably, in formula (IV), NR¹¹R¹² is N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl or N-piperazinyl, optionally N'-substituted or N',N'-disubstituted with Cl -C4 alkyl or Cl -C4 alkyl substituted with -NR^cR^d, wherein R^c and R^d are individually H, methyl or ethyl.

R¹³ and R¹⁴ are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkanoyl, or optionally substituted aroyl, or, taken together with the atom to which they are attached, form an optionally substituted heteroaryl or non-aromatic optionally substituted heterocycle.

R¹⁶ is optionally substituted C1-C6 alkyl, optionally substituted aryl or aralkyl, C1-C6 alkanoyl, or optionally substituted aroyl. Preferably, R¹⁶ (formula (V)) is a Cl - C6 alkanoyl, optionally substituted with -OH, -SH, halogen, cyano, nitro, amino, -COOH, a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl, or -(CH₂)_q-C(O)OH, wherein q is an integer from 1 to 6. More preferably, R¹⁶ (formula (V)) is a branched C3-C6 alkanoyl.

R¹⁷ is H, C1-C6 alkyl, C1-C6 alkoxyalkyl, optionally substituted aryl or aralkyl or heteroaryl, optionally substituted aryloxy, aralkyloxy or heteroaryloxy, Q is O or S, and Z is CH or N . Preferably, R¹⁷ is H, optionally substituted C 1 -C6 alkyl, or C 1 -C6 alkoxyalkyl, or. phenyl, benzyl, phenyloxy or benzyloxy each optionally substituted with halogen, -NO₂, -NH₂, -COOH, C1-C3 alkyl, C1-C3 carbalkoxy, C1-C3 a alkoxy group, CI-C3 haloalkyl or C1-C3 haloalkoxy. More preferably, R¹⁷ is H, C1-C4 alkyl, or phenyl, each optionally substituted with one or more halogen atoms, -NO₂, -NH₂, -COOH, C 1 -C3 alkyl, C 1 -C3 carbalkoxy, C 1 -C3 a alkoxy group, C 1 -C3 haloalkyl or C1-C3 haloalkoxy. Even more preferably, R¹⁷ is H, C1-C4 haloalkyl or phenyl, each optionally substituted with one or more halogen atoms or C1-C3 haloalkyls. Yet more preferably, R¹⁷ is H, trifluoromethyl or phenyl substituted with one or more trifiuoromethyls. R²¹ is optionally substituted Cl-ClO alkyl, or an optionally substituted aryl or aralkyl or, R²¹ and R²² taken together with their intervening atoms form a 5-7 membered non-aromatic heterocycle. Preferably, either R²¹ is optionally substituted Cl-ClO alkyl, phenyl, or benzyl, each optionally substituted with a halogen, -NO₂, -NH₂, -COOH, alkyl, C1-C3 carbalkoxy, C1-C3 alkoxy group, C1-C3 haloalkyl or Cl- C3 haloalkoxy, or R²¹ and R²², taken together with their intervening atoms, form a 5 or 6 membered non-aromatic heterocycle.

R²² and R²³ are each independently -H, or a optionally substituted C1-C6 alkyl, provided that R²² and R²³ are not simultaneously hydrogens. Preferably, R²² and R²³ are each independently -H, or a C1-C3 alkyl. R¹⁰⁰ is optionally substituted C1-C6 alkyl or optionally substituted aryl or optionally substituted aralkyl. Preferably, R¹⁰⁰ (formula (III)) is a C1-C4 alkyl.

R¹⁰¹ is H, optionally substituted C1-C6 alkyl or optionally substituted aryl or optionally substituted aralkyl. Preferably, R¹⁰¹ is H or C1-C4 alkyl. More preferably, R¹⁰¹ (formula (VI)) is H, methyl or ethyl. R¹⁰⁷ is optionally substituted C1-C6 alkyl, optionally substituted aryl or aralkyl, or a non-aromatic heterocycle, optionally substituted at one or more substitutable carbon atoms with methyl, hydroxyl, or methoxy, and optionally N'-substituted at any substitutable nitrogen atom with C1-C4 alkyl or C1-C4 alkyl substituted with -NR^cR^d. Preferably, R¹⁰⁷ (formula (IX)) is C1-C6 alkyl optionally substituted with -OH, -SH, halogen, cyano, nitro, amino, -COOH, a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl, or -(CH₂VC(O)OH. More preferably, R¹⁰⁷ (formula (IX)) is C1-C6 alkyl or C1-C6 carboxyalkyl.

Q¹ is O or NH.

Preferably, the group of formula (VI) is represented by structural formulas (Via) or (VIb):

wherein Y is a halogen, -NO₂, -NH₂, -COOH, alkyl, C1-C3 carbalkoxy, C1-C3 alkoxy group, C1-C3 haloalkyl or C1-C3 haloalkoxy. Ring A is a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, oxy, or methoxy, and optionally substituted at any one or more ring nitrogen atoms with C1-C4 alkyl or C1-C4 alkyl substituted with -NR^cR^d, wherein R^c and R^d are individually H, methyl or ethyl. Preferably, ring A in formula (VIb) is selected from:

and

In one embodiment of the compound of formula (I), R is a hydrolyzable group selected from groups (II) - (VII); and R³ is

wherein n is an integer from 1 to 5, and R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy. Values and preferred values for the remainder of the variables are as described for formula (I). In another embodiment of the compound of formula (I), R is a hydrolyzable group selected from groups (II) - (VII); R³ is

wherein n is an integer from 1 to 5, and R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy;

R² is -H, C1-C4 alkyl or C1-C4 haloalkyl; and

R⁴, R⁵ and R⁶ are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R⁵ and R⁶ taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).

In another embodiment of the compound of formula (I), R is a hydrolyzable group selected from groups (II) - (VII);

R³ is

wherein either n is 2 or 3 and R^a and R^b, is each independently a hydrogen or a C1-C3 alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form group R^y selected form a group consisting of.

wherein Q² is CH₂, S or O;

R² is -H, C1-C4 alkyl or C1-C4 haloalkyl; and

R⁴, R⁵ arid R⁶ are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R⁵ and R⁶ taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).

R³ is

wherein either n is 2 or 3 and R^a and R >b , is each independently a hydrogen or a C1-C3 aallkkyyll,, oorr RR^aa a anndd RR^bb,, ttaakkeenn ttooggeetthheerr wwiitthh tthhee nniitrogen to which they are attached, form group R^y selected form a group consisting of

wherein Q² is CH₂, S or O; and

R² -H , methyl or ethyl, R⁴, R⁵ and are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, and R⁶ is -H, -OH or methyl or ethyl. Values and preferred values for the remainder of the variables are as described for formula (I).

In one embodiment of the compound of formula (I), R is a phenol isosteric group is selected from groups (X) - (XXIII):

^OH (X);

(XII);

(XIII);

(XVIII); l^' (XlX);

(XX); (XXI);

(XXII); and

(XXIII); and R³ is

wherein n is an integer from 1 to 5, and R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy. Values and preferred values for the remainder of the variables are as described for formula (I).

In another embodiment of the compound of formula (I), R is a phenol isosteric group is selected from groups (X) - (XXIII); R³ is

R² is -H, C1-C4 alkyl or C1-C4 haloalkyl; and

R⁴, R⁵ and R⁶ are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R⁵ and R⁶ taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I). In another embodiment of the compound of formula (I), R is a phenol isosteric group is selected from groups (X) - (XXIII);

R³ is

wherein either n is 2 or 3 and R^a and R^b, is each independently a hydrogen or a C1-C3 alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form group R^y selected form a group consisting of

wherein Q² is CH₂, S or O;

R² is -H, C1-C4 alkyl or C1-C4 haloalkyl; and

R⁴, R⁵ and R⁶ are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R⁵ and R taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).

In another embodiment of the compound of formula (I), R is a phenol isosteric group is selected from groups (X) - (XXIII);

R³ is

wherein Q² is CH₂, S or O; and

In one embodiment of the compound of formula (I), R is R^x as defined above for formula (I); and

R³ is

wherein n is an integer from 1 to 5, and R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy. Values and preferred values for the remainder of the variables are as described for formula (I). In another embodiment of the compound of formula (I), R is R";

R³ is

wherein n is an integer from 1 to 5, and R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy; R² is -H, C1-C4 alkyl or C1-C4 haloalkyl; and R⁴, R⁵ and R⁶ are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, or R⁵ and R⁶ taken together are methylenedioxy. Values and preferred values for the remainder of the variables are as described for formula (I).

In another embodiment of the compound of formula (I), R is R^x;

R³ is

wherein Q² is CH₂, S or O;

R² is -H, C1-C4 alkyl or C1-C4 haloalkyl; and

In another embodiment of the compound of formula (I), R is R^x;

R³ is

wherein Q² is CH₂, S or O; and

R² -H , methyl or ethyl, R⁴, R⁵ and are each independently -H, -OH, C1-C4 alkyl or C1-C4 haloalkyl, and R⁶ is -H, -OH or methyl or ethyl. Values and preferred values for the remainder of the variables are as described for formula (I). In one preferred embodiment, the compound of formula (I) is represented by structural formula (XXX):

In one embodiment of the compound of formula (XXX). Values and preferred values for the variables are as described above for formula (I). Preferably, R is -F, -OH or -OCH₃ and the remainder of the variables take the values and preferred values defined above in formula (I).

More preferably, R is -F, -OH or -OCH₃, n is 2 or 3, and values and preferred values for R², R^a and R^b are as defined for formula (I). Even more preferably, R is -F, -OH or -OCH₃, n is 2 or 3, and R² is a -H or a C1-C4 alkyl. Values and preferred values for R^a and R^b are as defined for formula (I).

Yet more preferably, R is -F, -OH or -OCH₃, n is 2 or 3, and R² is a -H or a Cl- C4 alkyl, and R^a and R^b are each independently a C1-C3 alkyl.. Alternatively, R is -F, -OH or -OCH₃, n is 2 or 3, R² is a -H or a Cl -C4 alkyl, and R^a and R^b are independently each a -H or an alkyl optionally substituted with a C1-C4 hydroxyalkyl.

In one preferred embodiment, R is -F, -OH or -OCH₃, R^a and R^b are identical and are methyl or ethyl, or taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring; n is 2 or 3; R² is a hydrogen or a C1-C4 alkyl. In another embodiment of the compound of formula (XXX), n is 2 or 3. The remainder of the variables take the values and preferred values defined above in formula (I).

In another embodiment of the compound of formula (XXX), R² is a -H or a Cl- C4 alkyl. The remainder of the variables take the values and preferred values defined above in formula (I).

In another embodiment of the compound of formula (XXX), R^a and R^b are each independently a C1-C3 alkyl. The remainder of the variables take the values and preferred values defined above in formula (I).

In another embodiment of the compound of formula (XXX), R^a and R^b are independently each a -H or an alkyl optionally substituted with a C1-C4 hydroxyalkyl. The remainder of the variables take the values and preferred values defined above in formula (I).

In another embodiment of the compound of formula (XXX), R is -F, -OH or -OCH3, R^a and R^b are identical and are methyl or ethyl, or taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring; n is 2 or 3; R² is a hydrogen or a C1-C4 alkyl. The remainder of the variables take the values and preferred values defined above in formula (I).

Examples of compounds of formula (I) include:

The term "alkyl", as used herein, unless otherwise indicated, includes straight or branched saturated monovalent hydrocarbon radicals, typically Cl-ClO, preferably Cl- C6. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl. Suitable substituents for a substituted alkyl include -OH, -SH, halogen, cyano, nitro, amino, -COOH, a C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl.

The term "cycloalkyl", as used herein, is a non-aromatic saturated carbocyclic moieties, typically C3-C8. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Suitable substituents for a cycloalkyl are defined above for an alkyl.

The term "haloalkyl", as used herein, includes an alkyl substituted with one or more F, Cl, Br, or I, wherein alkyl is defined above.

The terms "alkoxy", as used herein, means an "alkyl-O-" group, wherein alkyl, is defined above.

The term "alkanoyl", as used herein, means an "alkyl-C(O)-" group, wherein alkyl is defined above.

The term "haloalkoxy", as used herein, means "haloalkyl-O-", wherein haloalkyl is defined above. The term "aryl", as used herein, refers to a carbocyclic aromatic group.

Examples of aryl groups include, but are not limited to phenyl and naphthyl.

The term "heteroaryl", as used herein, refers to aromatic groups containing one or more heteroatoms (O, S, or N). A heteroaryl group can be monocyclic or polycyclic, e.g. a monocyclic heteroaryl ring fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofiiranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, fiiropyridinyl, pyrolopyrimidinyl, and azaindolyl.

The term "non-aromatic heterocycle" refers to non-aromatic carbocyclic ring systems typically having four to eight members, preferably five to six, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Non aromatic heteroccyles can be optionally unsaturated. Examples of non- aromatic heterocyclic rings include 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl, [l,3]-dioxalanyl, [l,3]-dithiolanyl, [1,3]- dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3- moφholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrorolidinyl, 1-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N- substituted diazolonyl, and 1-pthalimidinyl. The heteroaryl or non-aromatic heterocyclic groups may be C-attached or N- attached (where such is possible). For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).

Suitable substituents for an aryl, a heteroaryl, or a non-aromatic heterocyclic group are those that do not substantially interfere with the pharmaceutical activity of the disclosed compound. One or more substituents can be present, which can be identical or different. Examples of suitable substituents for a substitutable carbon atom in aryl, heteroaryl or a non-aromatic heterocyclic group include -OH, halogen (-F, -Cl, -Br, and -I), -R', haloalkyl, -OR', -CH₂R', -CH₂OR', -CH₂CH₂OR', -CH₂OC(O)R', -O-COR', -COR', -SR', -SCH₂R', - CH₂SR', -SOR', -SO₂R', -CN, -NO₂, -COOH, -SO₃H, -NH₂, -NHR', -N(R')₂, -COOR', -CH₂COOR', -CH₂CH₂COOR', -CHO, -CONH₂, -CONHR', -CON(R')2, -NHCOR', -NR' COR', -NHCONH₂, -NHCONR'H, -NHCON(R'>2, -NR⁵CONH₂, -NR'CONR'H, -NR'CON(R')₂, -C(=NH)-NH₂, -C(=NH)-NHR', -C(=NH)-N(R')_2ϊ -C(=NR')-NH₂, -C(=NR')-NHR', -C(=NR')-N(R')₂, -NH-C(=NH)-NH_2j -NH-C(=NH)-NHR', -NH-CC=NH)-NCR')2_S -NH-CC=NR' )-NH₂, -NH-CC=NR')-NHR', -NH-CC=NR')-NCR')₂, -NR⁹H-CC=NH)-NH₂, -NR'-CC=NH)-NHR', -NR'-CC=NH)-NCR')₂, -NR'-C(=NR')-NH₂, -NR'-C(=NR')-NHR\

-SO₂NH₂, -SO₂NHR', -SO₂NR'₂, -SH, -SOkR' (k is 0, 1 or 2) and -NH-CC=NH)-NH₂. Each R' is independently an alkyl group. Oxo CC=O) and thio CC=S) are also suitable substituents for a non-aromatic heterocycle.

Suitable substituents on the nitrogen of a non-aromatic heterocyclic group or a heteroaryl group include -R", -N(TV)₂, -CCO)R", -CO₂ R", -C(O)C(O)R", -C(O)CH₂ C(O)R", -SO₂R", -SO₂ N(R")₂, -C(=S)NCR")₂, -C(=NH)-N(R")₂, and -NR" SO₂R". R" is hydrogen, an alkyl or alkoxy group.

Synthesis of the Compounds of the Invention

Compounds of formula CI) can be synthesized according to a variety of synthetic schemes from precursors disclosed in U.S. Pat. Nos. 5,231,100 and 6,229,015, incorporated herein by reference in their entirety. One example of such a scheme is shown below:

H₂N(CHi)_nNRaRb

THFZNH₂-NH,, Ni;

OR

Pd/C «nd H2 /aqu∞ul HCVETOH

(S 1-4) (S 1.3)

(Scheme I).

As used herein, the "activated alkanoic acylating agent" is defined within the references cited. For example: alkyl nitriles are reacted with HCl in methanol or ethanol to give the corresponding acetimidate ester hydrochlorides, R-CN going to R- C(OMe)=NH+ Cl-, where R is an alkyl. This acetimidate reacts with the amine in compound (S 1.3) and cyclized to the methyl or ethyl or other alkylimidazole, again per the cited articles.

The end product of Scheme I is further converted into the amine oxide (N ->O) by oxidation of tertiary amines or pyridine analogs with hydrogen peroxide (H2O2) or peracids like metachlorperbenzoic acid (mCPBA). Representative preparative procedures for these transformations have been described in detail by J. C Craig and K.K. Purushothaman, J. Org. Chem. 35: 1721-1722, 1970; J Subik et al., Antimicrob. Agents Chemother. 12: 139-146, 1977; and B.M. Choudary, J. Molecular Catal. A: Chemical, 217:81-85, 2004. The relevant teachings of these publications are incorporated herein by reference. Disorders Treatable by the Compounds of the Invention

It has now been discovered, that compounds of formula (I) can be used to treat an inflammatory disorder, a demyelinating disorder, a FLT3 -mediated disorder, a cancer, a leukemia or a CSF-lR-mediated disorder in a patient. The term "patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans. The terms "treat" or "treating" include any treatment, including, but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or preventing or slowing the appearance of symptoms and progression of the named disorder or condition.

/. Cancers

In one embodiment, the present invention is a method of treating a patient suffering from a cancer. The method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is a method of treating a subject suffering from a cancer. As used herein, the term "cancer" refers to the uncontrolled growth of abnormal cells that have mutated from normal tissues. A cancerous tumor (malignancy) is of potentially unlimited growth and expands locally by invasion and systemically by metastasis. Examples of cancers that can be treated by the compounds of the present invention include: breast cancer, colorectal cancer, non-small cell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck, hepatocellular, thyroid, multidrug-resistant leukemia, lymphoma, multiple myeloma, esophageal, large bowel, pancreatic, mesothelioma, carcinoma (e.g. adenocarcinoma, including esophageal adenocarcinoma), sarcoma (e.g. spindle cell sarcoma, liposarcoma, leiomyosarcoma, abdominal leiomyosarcoma, sclerosing epithelioid sarcoma) and melanoma (e.g. metastatic malignant melanoma). In one embodiment, the patient can be treated for bone metastases. Treatment of subtypes of the aforementioned cancers is also included. Subtypes are described in the following paragraphs. "Treating a subject suffering from cancer" includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components).

"Treating a bone metastases", as used herein, refers to reducing (partially or completely) the size of the bone metastases, slowing the growth of the metastases relative to the absence of treatment and reducing the extent of further spread of the cancer. "Treating a bone metastases" also includes pain reduction, decreased incidents of fractures, relief of spinal cord compression, control of hypercalcaemia, and/or restoration of normal blood cell counts.

"Breast cancer" includes, but is not limited to, ductal carcinoma, lobular carcinoma, inflammatory carcinoma, medullary carcinoma, colloid or mucinous carcinoma, papillary carcinoma, tubular carinoma, triple negative breast cancer, inflammatory breast cancer, metaplastic carcinoma, Paget's disease, and Phyllodes tumor.

As used herein "ovarian cancer", is cancer of the ovaries or fallopian tubes, including cancers of germ cells, stromal cells, and epithelial cells. Examples of ovarian cancers include but are not limited to:

Epithelial Ovarian Tumors, which include but are not limited to, serous adenomas, mucinous adenomas, and Brenner tumors, tumors of low malignant potential (LMP tumors), borderline epithelial ovarian cancer, epithelial ovarian cancers, carcinomas and undifferentiated epithelial ovarian carcinomas; Germ Cell tumors which include but are not limited to, teratoma, dysgerminoma, endodermal sinus tumor, and choriocarcinoma; and

Stromal tumors, which include but are not limited to, granulosa cell tumors, granulosa-theca tumors, and Sertoli-Leydig cell tumors.

"Renal cancer" or "kidney cancer", as used herein, includes but is not limited to, transitional cell cancer (TCC) of the renal pelvis, Wilms Tumour and renal cell cancer. Renal cell cancer is also called renal adenocarcinoma or hypernephroma. In renal cell cancer, the cancerous cells are found in the lining of the tubules (the smallest tubes inside the nephrons that help filter the blood and make urine).

There are several types of renal cell cancer including but not limited to clear cell, chromophilic, chromophobe, oncocytic, collecting duct and sarcomatoid.

Renal cancer also includes cancers containing more than one of the cell types described above.

As used herein, "melanoma" is a type of skin cancer that occurs in the cells that color the skin, called melanocytes. Types of melanoma include but are not limited to: Cutaneous melanoma, superficially spreading melanoma, nodular malignant melanoma, lentiginous malignant melanoma, acral lentiginous melanoma, demoplastic malignant melanomas, giant melanocyte nevus, amelanotic malignant melanoma, acral lentiginous melanoma unusual melanoma variants, including mucosal malignant melanoma and ocular malignant melanoma. "Sarcomas", as used herein, include but are not limited to, fibrosarcomas from fibrous body tissues, leiomyosarcomas and rhabdomyosarcomas from muscle tissues, liposarcomas from fat, synovial sarcomas, angiosarcomas from blood vessels, MPNST - malignant peripheral nerve sheath tumours (PNSTs), GIST - gastrointestinal stromal sarcoma, osteosarcoma, myosarcoma, chondrosarcoma, bile duct sarcoma, brain sarcoma, breast sarcoma, soft tissue sarcoma, uterine sarcoma, endocardial sarcoma, stromal sarcomas from supporting tissues (endometrial stromal sarcoma), granuloytic, histiolytic, hemangioendothelial, Kupffer-cell, neurogenic, round-cell, reticulum cell, spindle cell, Kaposi's sarcoma of the skin, Ewing's sarcomas and PNETs. In certain embodiments, the sarcoma is leiomyosarcoma or liposarcoma. "Thyroid cancer", as used herein, includes but is not limited to, papillary and/or mixed papillary/follicular, follicular and/or Hurthle cell, lymphoma, medullary, anaplastic and combinations thereof.

The term "head and neck cancer" as used herein, encompasses tumors that occur in several areas of the head and neck region, including the nasal passages, sinuses, mouth, throat, larynx (voice box), swallowing passages, salivary glands, and skin cancers that develop on the scalp, face, or neck may also be considered head and neck cancers. These cancers include but are not limited to squamous cell carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, lymphoma, adenocarcinoma, esthesioneuroblastoma, tumors of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, cancers of the oral cavity (including all the various parts of the mouth: the lips; the lining inside the lips and cheeks (the buccal mucosa); the bottom of the mouth; the front of the tongue; the front part of the top of the mouth (the hard palate); the gums; and the area behind the wisdom teeth (the retromolar trigone)), tumors of the oropharynx, hypopharyngeal tumors, laryngeal cancer and salivary gland cancer (including malignant salivary gland tumor).

As used herein "hepatocellular cancer" or "liver cancer" includes but is not limited to: hepatocellular carcinoma (also sometimes called hepatoma or HCC) "carcinoma", fibrolamellar HCC, cholangiocarcinoma, angiosarcoma (also be called haemangio sarcoma) and hepatoblastoma. As used herein, "non-small cell lung cancer" includes, squamous cell carcinoma, adenocarcinoma and undifferentiated non-small cell lung cancer (undeveloped cancer cells are known as undifferentiated cells) and large cell carcinoma.

"Colorectal cancer" as used herein, includes any type of colon or rectal cancer, including but not limited to, adenoscarcinoma, sarcoma, melanoma, stromal, carcinoid, and lymphoma.

2. Inflammatory conditions

In one embodiment, the present invention is a method of treating a patient suffering from an inflammatory condition. The method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof. The condition can be systemic lupus, inflammatory bowl disease, psoriasis, Crohn's disease, rheumatoid arthritis, sarcoid, Alzheimer's disease, insulin dependent diabetes mellitus, atherosclerosis, asthma, spinal cord injury, stroke, a chronic inflammatory demyelinating neuropathy, multiple sclerosis, a congenital metabolic disorder, a neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, a hereditary demyelinating condition, a prion-induced demyelination, encephalitis-induced demyelination.

Examples of chronic inflammatory demyelinating neuropathies include:

Chronic Immune Demyelinating Polyneuropathy (CIDP); multifocal CIDP; multifocal motor neuropathy (MMN); anti-MAG Syndrome (Neuropathy with IgM binding to Myelin-Associated Glycoprotein); GALOP Syndrome (Gait disorder Autoantibody Late-age Onset Polyneuropathy); anti-sulfatide antibody syndrome; anti-GM2 gangliosides antibody syndrome; POEMS syndrome (Polyneuropathy Organomegaly Endocrinopathy or Edema M-protein Skin changes); perineuritis; and IgM anti-GDlb ganglioside antibody syndrome.

3. Demyelinating conditions In another embodiment, the present invention is a method of treatment of a patient suffering from a demyelinating condition. The method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, a "demyelinating condition" is a condition that destroys, breaks the integrity of or damages a myelin sheath. As used herein, the term "myelin sheath" refers to an insulating layer surrounding vertebrate peripheral neurons, that increases the speed of conduction and formed by Schwann cells in the peripheral or by oligodendrocytes in the central nervous system. Such condition can be multiple sclerosis, a congenital metabolic disorder, a neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, a hereditary demyelination condition, a prion-induced demyelination, encephalitis-induced demyelination, a spinal cord injury, Alzheimer's disease as well as chronic inflammatory demyelinating neuropathies, examples of which are given above. In one embodiment, the condition is multiple sclerosis. The method comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a method of promoting remyelination of nerve cells in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I). The patient can be suffering from any of the demyelinating conditions listed above. In another embodiment, the present invention is a method of preventing demyelination and promoting remyelination in a patient in need thereof, comprising administering a combination of a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof, and an anti-inflammatory agent as described below. In another embodiment, the present invention is a method of reversing paralysis in a subject in need thereof with a demyelinating disease, comprising administering to the subject a compound in an amount sufficient to inhibit lymphocyte infiltration of immune cells in the spinal cord to promote remyelination of nerve cells in the spinal cord and thereby treating paralysis in said subject, wherein the compound is of formula formula (I) or a pharmaceutically acceptable salt thereof.

4. FLT3-Mediated Disorders

In one embodiment, the present invention is a method of treating a patient suffering from an acute myeloid leukemia characterized by a FLT3 mutation. The method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, the term "FLT3 -mediated disorder" is a disorder in which one or more symptoms can be inhibited, alleviated, reduced or whose onset can be delayed by inhibiting completely or partially the FLT3 protein kinase. The terms "treat" or "treating", when used with reference to a FLT3 -mediated condition, include any treatment, including, but not limited to, alleviating symptoms, eliminating the causation of the symptoms associated with a FLT3-mediated condition either on a temporary or permanent basis, or preventing or slowing the appearance of symptoms and progression of the named disorder or condition. As used herein the term "therapeutically effective amount", when used with reference to a FLT3-mediated condition, is the amount of a compound disclosed herein that will achieve a partial or total inhibition or delay of the progression of a FLT3- mediated disorder in a patient. FLT3-mediated disorders and conditions include axonal degeneration, acute transverse myelitis, amyotrophic lateral sclerosis, infantile spinal muscular atrophy, juvenile spinal muscular atrophy, Creutzfeldt- Jakob disease, subacute sclerosing panencephalitis, organ rejection, bone marrow transplant rejection, non-myeloablative bone marrow transplant rejection, ankylosing spondylitis, aplastic anemia, Behcet's disease, graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia,

Wegener's granulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia purpura, and Myasthenia gravis.

FLT3 (Fms-like tyrosine kinase; other names include CDl 35, FLK2 (Fetal liver kinase 2), STKl (Stem cell kinase I)) is a class III receptor tyrosine kinase (RTK) structurally related to the receptors for platelet derived growth factor (PDGF), colony stimulating factor 1 (CSFl), and KIT ligand (KL). These RTKs contain five immunoglobulin-like domains in the extracellular region and an intracelular tyrosine kinase domain split in two by a specific hydrophilic insertion (kinase insert). FLT3, closely related to PDGF receptors and c-Kit is, however, not inhibited by the small molecule inhibitors of PDGF and c-Kit; (G Del Zotto et al., J. Biol. Regulators Homeostatic Agents 15: 103-106, 2001).

5. Leukemias

In one embodiment, the compounds of the present invention, for example the compounds of formula (I), can be used to treat certain leukemias, including FLT3- mediated leukemias.

Leukemias are selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). In one embodiment, the present inevtnion is a method of treating a patient suffering from a hairy cell leukemia (HCL). As used herein, the term "leukemia" is a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms. Acute lymphocytic leukemia (also known as Acute Lymphoblastic Leukemia, or ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older.

Acute myelogenous leukemia (also known as Acute Myeloid Leukemia, or AML) occurs more commonly in adults than in children. This type of leukemia was previously called acute nonlymphocytic leukemia. Chronic lymphocytic leukemia (CLL) most often affects adults over the age of

55. It sometimes occurs in younger adults, but it almost never affects children.

Chronic myelogenous leukemia (CML) occurs mainly in adults. A very small number of children also develop this disease.

Hairy Cell Leukemia (HCL) leukemia is an incurable, indolent blood disorder in which mutated, partly matured B cells accumulate in the bone marrow. Its name is derived from the shape of the cells, which look like they are covered with short, fine, hair-shaped projections. Unlike any other leukemia, HCL is characterized by low white blood cell counts.

6. CSF-I R-mediated disorders

In one embodiment, the present invention is a method of treating a CSF-IR- mediated condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Colony Stimulating Factor -1 Receptor (CSF-IR) signaling play an important role in the etiology of the disorders and conditions described above is well known and is described, for example in Simoncic et al, Mol.Cel. Biol., Vol. 26, No. 11 (2006), pp. 41-49-4160.; Yang et al., Ann. Rheum. Dis. (2006); 65, pp. 1671-1672; Irving et al, The FASEB J., Vol. 20 (2006): pp.E1315-E1326; Irving et al, The FASEB J., Vol. 20 (2006), pp. 1921-1923; Heinonen et al, PNAS (2006), vol. 103, no. 8, pp. 2776-2781; Conway et al, PNAS (2006), vol. 102, no. 44, pp. 16078-16083; Himes et al, The J. Immunol. (2006), 176: 2219-2228; Pixley et al, Trends in Cell Biol. (2004), Vol. 14, No. 11, pp.628-638; U.S. Pat. App. Pub. No. 2006/0094081; U.S. Pat. App. Pub. No. 2006/0189623; U.S. Pat. App. Pub. No. 2006/0148812; U.S. Pat. App. Pub. No. 2006/0100201; U.S. Pat. 5,714,493; U.S. RE37,650. The relevant portions of all of these publications are incorporated herein by reference.

CSF-lR-mediated disorders include cardiovascular disease (e.g. artherial sclerosis), diseases with an inflammatory component including glomerulonephritis, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain, osteoporosis, Paget's disease, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone, uterine cancer, stomach cancer, hairy cell leukemia, Sjogren's syndrom, or uveitis. The disorders include cancers such as osteolytic sarcoma, myeloma, and tumor metastasis to bone, uterine cancer, stomach cancer, hairy cell leukemia.

Modes of Administration The term "therapeutically effective amount" means an amount of the compound, which is effective in treating the named disorder or condition. In certain embodiments, therapeutically effective amount means an amount sufficient to effect remyelination of nerve cells in a patient.

In treating a patient afflicted with a conditions described above, all of the disclosed compounds can be administered in any form or mode which makes the compound bioavailable in therapeutically effective amounts. For example, compounds of formula (I) can be administered in a form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the present invention. "Pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (I). Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids.

Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p- toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2- hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points. "Pharmaceutically acceptable basic addition salts" means non-toxic organic or inorganic basic addition salts of the compounds of formula (I). Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline. The selection of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

Compounds of the present invention can be administered by a number of routes including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermal Iy, intranasally, rectally, topically, and the like. One skilled in the art of preparing formulations can determine the proper form and mode of administration depending upon the particular characteristics of the compound selected for the condition or disease to be treated, the stage of the disease, the condition of the patient and other relevant circumstances. For example, see Remington's Pharmaceutical Sciences, 18^th Edition, Mack Publishing Co. (1990), incorporated herein by reference. The disclosed compounds are administered by any suitable route, including, for example, orally in capsules, suspensions or tablets.

Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.

Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials.

The compound of formula (I) of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifϊers and stabilizers.

In the embodiments in which the compounds of the invention are used to treat cancer, the dosage range at which the disclosed compounds, for example, compounds of formula (I), including the above-mentioned examples thereof, exhibit their ability to act therapeutically can vary depending upon the severity of the condition, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally, the compounds described herein will exhibit their therapeutic activities at dosages of between about 0.1 mg/m² free base equivalent per square meter of body surface area/single dose to about 1000 mg/m² free base equivalent per square meter of body surface area/single dose. These dosages can be administered, for exaple, once per week, once every other week, once every third week or once per week for three out of every four weeks. Alternatively, when used to treat cancer, the disclosed compounds can be administered daily (typically orally). Daily dose of administration of the compounds of the present invention can be repeated, in one embodiment, for one week. In other embodiments, daily dose can be repeated for one month to six months; for six months to one year; for one year to five years; and for five years to ten years. Representative total daily doses would include those in the range of 10-2000 mg. The total daily dose can be divided into equal doses and administered twice daily, thrice daily, or four times daily. In other embodiments, the length of the treatment by repeated administration is determined by a physician.

When used to treat other indications, the dosage range at which the disclosed compounds of formula (I) exhibit their ability to act therapeutically can vary depending upon the severity of the condition, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally, the inventive compounds of the invention will exhibit their therapeutic activities at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day. For example, the dosage can be 0.1-100 mg/kg per every other day or per week.

Combination Therapies The compounds used in the present invention can be administered alone or in combination with one or more other pharmaceutically active agents that are effective against the inflammatory condition and/or the demyelating disorder being treated. As used herein, the term "combination" with reference to pharmaceutically active agents and the term "co-administering" and "co-administration" refer to administering more than one pharmaceutically active agent to a patient during one treatment cycle and not necessarily simultaneous or in a mixture.

In one embodiment, the compounds of the present invention are administered in combination with an anti-inflammatory agent. The anti -inflammatory agent can be adrenocorticotropic hormone, a corticosteroid, an interferon, glatiramer acetate, or a non-steroidal anti-inflammatory drug (NSAID).

Examples of suitable anti-inflammatory agents include corticosteroid such as prednisone, methylprednisolone, dexamethasone Cortisol, cortisone, fludrocortisone, prednisolone, 6α-methylprednisolone, triamcinolone, or betamethasone.

. Other examples of suitable anti-inflammatory agents include NSAIDs such as aminoarylcarboxylic acid derivatives (e.g., Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid), arylacetic acid derivatives (e.g., Acematicin, Alclofenac, Amfenac, Bufexamac, Caprofen, Cinmetacin, Clopirac, Diclofenac, Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozic Acid, Fenoprofen, Fentiazac, Flubiprofen, Glucametacin, Ibufenac, Ibuprofen, Indomethacin, Isofezolac, Isoxepac, Ketoprofen, Lonazolac, Metiazinic Acid, Naproxen, Oxametacine, Proglumrtacin, Sulindac, Tenidap, Tiramide, Tolectin, Tolmetin, Zomax and Zomepirac), arylbutyric acid ferivatives (e.g., Bumadizon, Butibufen, Fenbufen and Xenbucin) arylcarboxylic acids (e.g., Clidanac, Ketorolac and Tinoridine), arylproprionic acid derivatives (e.g., Alminoprofen, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Naproxen, Oxaprozin, Piketoprofen, Piroprofen, Pranoprofen, Protinizinic Acid, Suprofen and Tiaprofenic Acid), pyrazoles (e.g., Difenamizole and Epirizole), pyrazolones (e.g., Apazone, Benzpiperylon, Feprazone, Mofebutazone, Morazone, Oxyphenbutazone, Phenylbutazone, Pipebuzone, Propyphenazone, Ramifenazone, Suxibuzone and Thiazolinobutazone), salicyclic acid derivatives (e.g., Acetaminosalol, 5-Aminosalicylic Acid, Aspirin, Benorylate, Biphenyl Aspirin, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Flufenisal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, Lysine Acetylsalicylate, Mesalamine, Morpholine Salicylate, 1-Naphthyl Sallicylate, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, Phenyl Salicylate, 2-Phosphonoxybenzoic Acid, Salacetamide, Salicylamide O-Acetic Acid, Salicylic Acid, Salicyloyl Salicylic Acid, Salicylsulfuric Acid, Salsalate and Sulfasalazine), thiazinecarboxamides (e.g., Droxicam, Isoxicam, Piroxicam and Tenoxicam), e-Acetamidocaproic Acid, S-Adenosylmethionine, 3- Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine, Bucolome, Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Ketorolac, Meclofenamic Acid, Mefenamic Acid, Nabumetone, Nimesulide, Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime, Piroxicam, Proquazone, Tenidap and a COX-2 inhibitor (e.g., Rofecoxib, Valdecoxib and Celecoxib). Further examples of anti-inflammatory agents include aspirin, a sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine, a para-aminophenol derivatives, an indole, an indene acetic acid, a heteroaryl acetic acid, an anthranilic acid, an enolic acid, an alkanones, a diaryl- substituted furanone, a diaryl-substituted pyrajzoles, an indole acetic acids, or a sulfonanilide.

In some embodiments, the compounds of the present invention can be administered in combination with immunotherapeutic agents such as interferons and anti-integrin blocking antibodies like natalizumab.

Examples of agents suitable for treating demyelinating disorders include Pirfenidone, Epalrestat, Nefazodone hydrochloride, Memantine hydrochloride, Mitoxantrone hydrochloride, Mitozantrone hydrochloride, Thalidomide, Roquinimex, Venlafaxine hydrochloride, Intaxel, Paclitaxel, recombinant human nerve growth factor; nerve growth factor, ibudilast, Cladribine, Beraprost sodium, Levacecarnine hydrochloride; Acetyl-L-carnitine hydrochloride; Levocamitine acetyl hydrochloride, Droxidopa, interferon alfa, natural interferon alpha, human lymphoblastoid interferon, interferon beta- Ib, interferon beta-Ser, Alemtuzumab, Mycophenolate mofetil, Zoledronic acid monohydrate, Adapalene, Eliprodil, Donepezil hydrochloride, Dexanabinol, Dexanabinone, Xaliproden hydrochloride, interferon alfa-n3, lipoic acid, thioctic acid, Teriflunomide, Atorvastatin, Pymadin, 4-Aminopyridine, Fampridine, Fidarestat, Priliximab, Pixantrone maleate, Dacliximab, Daclizumab, Glatiramer acetate, Rituximab, Fingolimod hydrochloride, interferon beta- Ia, Natalizumab, Abatacept, Temsirolimus, Lenercept, Ruboxistaurin mesilate hydrate, Dextromethorphan/quinidine sulfate, Capsaicin, Dimethylfumarate or Dronabinol/cannabidiol. In some embodiments, the compounds of the present invention can be administered in combination with one or more other pharmaceutically active agents that are effective against multiple sclerosis. Examples of such agents include the interferons (interferon beta 1-a, beta 1-b, and alpha), glatiramer acetate or corticosteroids such as methylprednisolone and prednisone as well as chemotherapeutic agents such as mitoxantrone, methotrexate, azathioprine, cladribine cyclophosphamide, cyclosporine and tysabri.

Further examples of pharmaceutically active agents that are effective against multiple sclerosis and are suitable to be administered in combination with compounds of the present invention include compounds of the following structural formulae:

Further examples of pharmaceutical agents that can be co-administered with the compounds of formula (I) include: T-cell receptor (TCR) Vβ6 CDR2 peptide vaccine consisting of TCR Vβ6, amino acid sequence 39-58, Leu - GIy - GIn - GIy - Pro - GIu - Phe - Leu - Thr - Tyr - Phe - GIn - Asn - GIu - Ala - GIn - Leu - GIu - Lys - Ser (SEQ ID NO:1);

Myelin basic protein immunogen peptide, aminoacid sequence 75-95, Lys - Ser - His - GIy - Arg - Thr - GIn - Asp - GIu - Asn - Pro - VaI - VaI - His - Phe - Phe - Lys - Asn - He - VaI - Thr (SEQ ID NO:2);

Tiplimotide, myelin basic protein immunogen vaccine peptide, aminoacid sequence 83-99, D - Ala - lys - pro - val - val - his - leu - phe - ala - asp - ile - val - thr - pro - arg - thr - pro, (SEQ ID NO:3);

Myelin basic protein immunogen peptide, aminoacid sequence 82-98, Asp - glu - asp - pro - val - val - his - phe - phe - lys - asp - ile - val - thr - pro - arg - thr, (SEQ ID NO:4);

Adrenocorticotropic hormone (ACTH), Ser - Tyr - Ser - met - glu - his - phe - arg - try - gly - lys - pro - val - gly - lys- lys - arg - arg - pro - val - lys - val - tyr- pro - asp - gly - ala - glu - asp - glu - leu - ala - glu - ala - phe - pro - leu - glut - phe, (SEQ ID NO:5).

Further examples of pharmaceutically active agents that are effective against multiple sclerosis and are suitable to be administered in combination with compounds of the present invention include:

3-4 diaminopyridine; ABT-874; Actos® (pioglitazone); ALCAR (acetyl-L- carnitine); Alpha lipoic acid; AndroGel® (testosterone gel); combination of trimethoprim and vitamin C; combination of azithromycin and rifampin; minocycline; donezepil HCL; Avandia® (rosiglitazone maleate; combination of IFN beta- Ia) and acetaminophen, ibuprofen or prednisone; combination of Avonex® (interferon beta- Ia) + CellCept® (mycophenolate mofetil); combination of Avonex® (interferon beta- Ia) and Copaxone® (glatiramer acetate); combination of Avonex® (interferon beta- Ia) and doxycycline; combination of Avonex® (interferon beta-1 a) and EMLA (lidocaine and prilocaine) anesthetic cream; Avonex® (interferon beta- Ia) and estrogen and progesterone; combination of Avonex® (interferon beta-la) + Fludara® (fludarabine phosphate); combination of Avonex® (interferon beta- Ia) and methotrexate and leucovorin rescue; combination of Avonex® (interferon beta- Ia) and methotrexate and methylprednisolone; combination of Avonex® (interferon beta- Ia) and Novantrone® (mitoxantrone); combination of Avonex® (interferon beta- Ia) and Prozac® (fluoxetine); combination of Avonex® (interferon beta- Ia) and Topamax® (topiramate); combination of Avonex® (interferon beta- Ia) and Zocor® (simvastatin); AVP-923 (dextromethorphan/quinidine); combination of Betaseron® (interferon beta- 1 b) and Imuran® (azathioprine); combination of Betaseron® (interferon beta- 1 b) and Copaxone® (glatiramer acetate); combination of BHT-3009-01 and Lipitor® (atorvastatin); Bone marrow/peripheral stem cell transplant; CellCept® (mycophenolate mofetil); combination of CellCept® (mycophenolate mofetil) and Avonex® (interferon beta- Ia); Oral cladribine; CNTO 1275 (monoclonal antibody); combination of Copaxone® (glatiramer acetate) and Antibiotic therapy (minocycline); combination of Copaxone® (glatiramer acetate) and Novantrone® (mitoxantrone); combination of Copaxone® (glatiramer acetate) and prednisone; combination of Copaxone® (glatiramer acetate) and Proventil® (albuterol); Cyclophosphamide; Daclizumab; Deskar® (pirfenidone); Estriol; Fumaric acid esters; Gabitril® (tiagabine HCL); Ginkgo biloba; IDEC- 131 (anti-CD40L or anti-CD 154); the combination of Immunoglobulin and methylprednisolone; Inosine; Interferon tau; Lamictal® (lamotrigine); Lexapro® (escitalopram); Lipitor® (atorvastatin); combination of Lipitor® (atorvastatin) and Rebif® (interferon beta-1 a); combination of Lymphocytapheresis (removal of immune cells), Imuran® (azathioprine) and prednisone; MBP8298; Methylprednisolone; combination of Methylprednisolone and Avonex (interferon beta-la); Modiodal (modafinil); NBI-5788 (altered peptide ligand); combination of Novantrone® (mitoxantrone for injection concentrate) and Avonex® (Interferon beta-la) or Copaxone® (glatiramer acetate); Omega-3 Fatty Acid Supplementation; Pixantrone (BBR 2778); combination of Provigil® (modafinil) and Avonex® (interferon beta- Ia); Rapamune® (sirolimus); RG2077; Rituxan® (rituximab); Rolipram (phosphodiesterase- 4 inhibitor); SAIK-MS (laquinimod, ABR-215062); T cell vaccination; Teriflunomide; Tetrahydrocannabinol; Tetrahydrocannabinol (dronabinol); Thalamic stimulation; combination of Tysabri® (natalizumab) and Avonex® (interferon beta- Ia); combination of Tysabri® (natalizumab) and Copaxone® (glatiramer acetate); and Viagra® (sildafenil citrate).

Further examples of pharmaceutically active agents that are effective against multiple sclerosis and are suitable to be administered in combination with compounds of the present invention include compounds listed in FIG. 14. Additionally, Copaxone (Glatiramer) can be orally co-administered with the compounds of the present invention.

In other embodiments, pharmaceutically active agents that are effective against multiple sclerosis and are suitable to be administered in combination with compounds of the present invention include compounds include: Mylinax, an oral formulation of cladrlbine used in leukaemia treatment, developed by Serono/Ivex; Teriflunomide, a metabolite of Arava, an oral immunosuppressant, developed by Sanofl-Aventis; FTY 720, an oral immunomodulator (Sphingosine-1 -phosphate receptor agonist), developed by Novartis; MBP 8298, a synthetic myelin basis protein designed to reduce the emergence of antibodies directed against the myelin, developed by Bio MS Medical; an orphan drug 4-aminopyridline (4-AP)₅ a potassium channel blocker, developed by Acorda; Gamunex, an intravenous immunoglobulin formulation, developed by Bayer; BG- 12 fumarate, a second generation oral futnarate, developed by Biogen Idec/Fumapharm; Temsirolimus, a T-lymphocytes proliferation blocker, developed by Wyeth; E-2007, an AMPA receptor agonist, developed by Eisal; Campath, a humanized antibody directed against CD52, developed by Genzyme; Neuro Vax, a vaccine, developed by Immune Response; Zocor, a statin, developed by Merck; NBI 5788, a myelin-mimicking peptide ligand, developed by Neurocrine; Tauferon, Interferon tau, developed by Pepgen; Zenapax, a humanized anti-CD25 immunosuppressive antibody, developed by Protein Design; a combination of MS-IET and EMZ 701, a methyl donator, developed by Transition Therapeutics; Laquinlmod, an oral formulation of a derivative of linomide, developed by Active Biotech/Teva; deskar pirfenidone, a TNF- alpha inhibitor, developed by Mamac; ATL-1102, a second generation antisense inhibitor targeting VLA4, developed by Antisense Therapeutics.

In some embodiments, compounds of formula (A) can be administered in combination with antivascular agents, in particular agents inhibiting the growth factor receptors, Epidermal Growth Factor Receptor (EGFR), Vascular Epidermal Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR). Examples of such agents include, Iressa, Tarceva, Erbitux, Pelitinib, AEE-788, CP-547632, CP- 547623, Tykerb (GW-2016), INCB-7839, ARRY-334543, BMS-599626, BIBW-2992, Falnidamol, AG1517, E-7080, KRN-951 , GFKI-258, BAY-579352, CP-7055, CEP- 5214, Sutent, Macugen, Nexavar, Neovastat, Vatalanib succinate, GW-78603413,

Lucentis, Teavigo, AG-13958, AMG-706, Axitinib, ABT-869, Evizon, Aplidin, NM-3, PI-88, Coprexa, AZD-2171, XL-189, XL-880, XL-820, XL-647, ZK-CDK, VEGFTrap, OSI-930, Avastin, Revlimid, Endostar, Linomide, Xinlay, SU-668, BIBF-1 120, BMS- 5826624, BMS-540215. In some embodiments, compounds of formula (I) can be administered in combination with agents that affect T-cell homing, extravastion and transmigration. Examples of such agents include, FTY-720PKI-166, PTK-787, SU-11248.

In some embodiments, compounds of formula (I) can be administered in combination with agents inhibiting VLA-4. Examples of such agents include, Tysabri, Bio-1211. HMR-1031, SB-683698, RBx-4638,RO-0272441, RBx-7796,SB-683699, DW-908e, AJM-300, and PS-460644.

In certain embodiments, the compound of formula (I) can be administered alone or in combination with an anti -cancer agent.

As used herein, the term "combination" with reference to pharmaceutically active agents and the term "co-administering" and "co-administration" refer to administering more than one pharmaceutically active agent to a patient during one treatment cycle and not necessarily simultaneous or in a mixture.

Anti-cancer agents that can be employed in combination with the compounds of the invention include Taxol™ (also referred to as "paclitaxel", and compounds that have the basic taxane skeleton), Adriamycin, Dactinomycin, Bleomycin, Vinblastine,

Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin

II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl ; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin and zorubicin hydrochloride. Other anti-cancer drugs that can be employed in combination with the compounds described herein include: 20-epi-l,25 dihydroxy vitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing moφhogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;

BCR/ ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5- azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocaπnycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefiir; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol,

4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6- benzyl guanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfϊnosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins;

UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred anti-cancer drugs are 5-fluorouracil and leucovorin.

Other chemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones. The invention is illustrated by the following examples, which are not intended to be limiting in any way.

EXEMPLIFICATION

Example I: Synthesis of imidazoacridinone dialkylamino N-oxides With reference to structural formula (XXX), reproduced below, the following example of the compounds of the present invention were synthetized:

(1) The compound of structural formula (XXXa)

(XXXa)

Compound (XXXa) was prepared from the precursor imidazoacridinone as follows: a solution of m-chloroperbenzoic acid (1 18 mg, 0.685 mmol, 1.2eq) was dissolved in chloroform (5 ml), and added dropwise to a stirred solution of the precursor (200 mg, 0.571 mmol, leq) in a mixture of chloroform /methanol (5 ml / 1 ml) at 0-5⁰C. Stirring was continued 24h, during which time the mixture was allowed to equilibrate with room temperature. The solvent was removed by rotary evaporation and flash chromatography on silica gel with chloroform/methanol 2:3 v/v and 0.05 ml of triethylamine afforded 210 mg (90%) of the N-oxide product, with 98% purity by HPLC. ¹H NMR (DMSO) δ 1.45t, 6H, CH₃CH₂NO), δ 3.7-4.0 (m, 6H₃ CH₂NO), δ 4.1t, 2H, CH₂NH), δ 7.20-8.20 (m, 5H, H ar), δ 8.40s, IH, CH=N).

(2) The compound of structural formula (XXXb)

(XXXb)

Compound (XXXb) was prepared from the precursor imidazoacridinone as follows: a solution of m-chloroperbenzoic acid (110 mg, 0.637 mmol, 1.2eq) was dissolved in chloroform (5 ml) and added dropwise to a stirred solution of the precursor (200 mg, 0.548 mmol, leq) in chloroform (5 ml) at 0-5⁰C. Stirring was continued 24h, during which time the mixture was allowed to equilibrate with room temperature. The solvent was removed by rotary evaporation and flash chromatography on silica gel with chloroform/methanol 2:3 v/v and 0.05 ml of triethylamine afforded 210 mg (90%) of the N-oxide product, with 97% purity by HPLC. ¹H NMR (DMSO) δ 1.43t, 6H,

CH₃CH₂NO)₅ 6 3.88s, 3H, CH₃O), δ 3.9-4.1(m, 6H, CH₂NO), δ 4.2t, 2H, CH₂NH, δ 7.20-8.20(m, 5H, H ar), δ 8.40s, IH, CH=N).

(3) The compound of structural formula (XXXc)

O

(XXXc)

Compound (XXXc) was prepared from the precursor imidazoacridinone as follows: a solution of m-chloroperbenzoic acid (123 mg, 0.714 mmol, 1.2eq) was dissolved in chloroform (5 ml) and added dropwise to a stirred solution of the precursor (200 mg, 0.595 mmol, leq) in chloroform (5 ml) at 0-5⁰C. Stirring was continued 24h, during which time the mixture was allowed to equilibrate with room temperature. The solvent was removed by rotary evaporation and flash chromatography on silica gel with chloroform/methanol 2:3 v/v and 0.05 ml of triethylamine afforded 209 mg (91%) of the N-oxide product, with 98% purity by HPLC. ¹H NMR (DMSO) δ 2.1 Om, 2H, CH₂CH₂CH₂), δ 3.4 (m, 2H, CH₂NO), δ 3.6 (s, 6H, CH₃NO), δ 3.9t, 2H, δ CH₂NH), 6.90-8.30(m, 5H, H ar), δ 8.50s, IH, CH=N).

EXAMPLE 2: Imidazoacridinone N-oxides are cytotoxic to cancer cells and the cytotoxicity increases under hypoxic conditions.

Three human leukemia cell lines were used to test the amine oxide compounds of this invention. They were chosen to be representative of cancer cells which may be grown under normoxic and also under hypoxic conditions, the latter to simulate the conditions prevailing in solid tumor cancers. The three cell lines, obtained from the American Type Culture Collection and grown as recommended, included the so called RS4(11) lymphoblastic translocation mutant, the so called myelomonocytic MV4(11) translocation mutant, and HL-60, an immortalized promyelocyte leukemia line that differentiates to either granulocytes or monocytes. This latter leukemia cell may be considered also to serve as a model for the precursor cell lineage from which inflammatory cells are also derived These cells were each seeded at a 10⁵ cells/ml and grown for 24 hours. Thereafter the cells were treated with appropriate drug concentrations which spanned a relevant IC₅₀ curve (T = 0). The cells were counted on at T = 0, 24, 48, and 72 hours and cell viability was compared to the control wells. Each well was prepared in duplicate. Cytotoxicity was determined with an MTS assay. At T = 48 h, an aliquot from each well was transferred in triplicate to a 96-well plate and allowed to grow for 24 h. At T = 72 h, MTS solution was added to each well; the samples were monitored over the next 2-5 h for color formation at 490 run. (MTS cell proliferation assay: CellTiter 96 Aqueous non-radioactive cell proliferation assay (Promega cat#G5421). The resulting dose response curves were fitted to the four parameter Hill equation, a sigmoid saturation viability inhibition function, and the median lethality effect, or LC50 as the percent change in viability from control. For normoxic conditions, the cells were grown in air containing 5% CO₂. For hypoxic conditions, the cells were grown for 24 hrs under normoxic conditions prior to test compound exposure and thereafter under nitrogen containing 2% O₂ and 5% CO₂.

The results are shown in TABLE 1, and are particularly noteworthy with respect to the effect of hypoxia.

TABLE 1: Imidazoacridinones are lethal to cancer cells and the lethality increases under hypoxic conditions

These results indicate that the N-oxides derivatives of imidazoacridinones are marginally cytotoxic to cancer cells initially at much higher levels than commonly found to be therapeutically useful in the case of standard cytotoxic chemotherapeutic drugs. But, more importantly, the results also show that the cytotoxicity of imidazoacridinone N-oxides increases by more than 10-50 fold, i.e. the LC₅0 values drop to lower levels, when hypoxic conditions prevail. This is a significant finding and novel finding for this genus of compounds. It is a desirable feature for cancer drugs with an improved safety profile to show differential cytotoxicity between normal cells and cancer cells. Cancer cells have been shown to undergo abnormal metabolism associated with the over production of metabolites triggered by reactive oxygen species and the concomitant increased titers of bioreducing factors, such as NADH and NADPH. Under these conditions, cancer cells are known to reduce tertiary amine N-oxides back to their parent alkylamines and thereby generate, in a manner selective to their own hypoxic conditions, a more active chemotherapeutic species. Bioreductive activation is a generally accepted phenomenon that accompanies the peculiar features of cancer cell biology and permits these cell types to be targeted selectively in the presence of normal cells. • .

EXAMPLE 3: Imidazoacridinone N-oxides Alleviate the Symptoms of Collagen Antibody Induced Arthritis in the Mouse, an Animal Model of Rheumatoid Arthritis and Autoimmune Disease

Rheumatoid Arthritis (RA) is an autoimmune disorder characterized by the chronic erosive inflammation in joints leading to the destruction of cartilage and bones mediated by autoreactive inflammatory cells, such as macrophages. One of the biochemical hallmarks of the disease, especially in connection macrophages, is the generation of hypervalent oxygen species similar to those which accumulate during periods of cellular hypoxia and free radical stress. Overproduction of biological reductant species are also generated as part of the cellular erosive process in part to provide electronic mass balance to over production of oxygen radicals. It follows from these circumstance that an effective treatment might be targeted at the causative autoreactive cells by taking advantage of the bioreductive phenomenology as a means of pro-drug activation. Any agents that are not activated by bioreduction, as would be the case in normal tissues, should prove less intrinsically harmful.

Several disease modifying antirheumatic drugs (DMARDS) are used in the treatment of RA. Currently, the two most important DMARDS are inhibitors of tumor necrosis factor α (TNF-α) and methotrexate (MTX). One method for demonstrating the utility of a pharmaceutical compound for the treatment of various conditions associated with RA is its ability to inhibit the induction of arthritis by collagen monoclonal antibodies (mABs) in mice.

Collagen-induced Arthritis (CIA) is an experimental autoimmune disease that can be elicited in susceptible strains of rodents (rat and mouse) and nonhuman primates by immunization with type II collagen, the major constituent protein of articular cartilage. CIA manifests as swelling and erythema in the limbs of the mouse. This model of autoimmunity shares several clinical and pathological features with rheumatoid arthritis (RA) and has become the most widely studied model of RA. CIA in the mouse model was first described by Courtenay et al. in 1980 (Courtnay, J.S., Dallman, M.J., Dayman, A.D., Martin A., and Mosedale, B. (1980) Immunisation against heterologous type II collagen induces arthritis in mice. Nature 283, 666-668). Like RA, susceptibility to CIA is regulated by the class II molecules of the major histocompatibility complex (MHC), indicating the crucial role played by T cells.

Methods Groups of 3 BALB/c strain mice, 6-7 weeks of age, were used for the induction of arthritis by monoclonal antibodies (mABs) raised against type II collagen, plus lipopolysaccharide (LPS). A combination of 4 different mABs (D8, FlO, DI-2G and A2) totaling 4 mg/mouse was administered to the animal intravenously on day 0, followed by intravenous challenge with 25 mg/mouse of LPS 72 hours later (day 3). From day 3, test substance, selected from among the imidazoacridinone N-oxides listed in Example I, and vehicle were each administered orally once daily for 3 consecutive days. For each animal, volumes of both hind paws were measured using a plethysmometer with water cell (12 mm diameter) on Days 0, 5, 7, 10, and 14. Percent inhibition of increase in volume induced by mABs + LPS was calculated by the following formula:

Inhibition (%): [1 - (Tn - T0)/(Cn- CO)] x 100%

Where: CO (Cn): volume of day 0 (day n) in vehicle control

TO (Tn): volume of day 0 (day n) in test compound-treated group

Reduction of edema in the hind paws by 30% or more is considered significant.

Results

To monitor the onset of CIA, the volume of the two hind paws of mAB treated mice were measured. In the control (vehicle) treated animals the paws quickly became inflamed with a 42-55% increase in volume on day 5, the maximum volume of 87-83% was observed on day 10 and persisted until day 14, whereupon the swelling began to subside. As shown in TABLE 2, the imidazoacridinone N-oxides tested reduced the hind paw edema score by more than 30% over control. The difference in means by paired t-test and in medians by non-parametric Mann- Whitney rank-sums all show p values lower than 0.01.

TABLE 2: Efficacy of imidazoacridinone N-oxides in treatment of collagen antibody induced arthritis

Conclusion

Imidazoacridinone N-oxides demonstrated anti-arthritic activity in the mouse CIA model, with significant anti-inflammatory activity on day 10 and day 14. These findings are relevant in the context of autoimmune disease in general because they exemplify the efficacy of the imidazoacridinone N-oxide compounds of this invention via an unexpected mechanism, e.g. bioreductive activation that targets macrophages and other autoreactive cells involved in the degenerative phases of disease. The collagen antibody model of rheumatoid arthritis is significant because it by-passes the primary inflammatory insult of antigen presentation. Classical anti -inflammatories like the corticosteroids and anti-folates like methotrexate alleviate the consequence of autoimmune inflammatory diseases by suppressing the primary events of inflammatory cell activation and recruitment. The antibody induced model generates the symptoms of disease that present in the later stages of the autoimmune response, after activated cells become invasive into cartilage, having extravasated and transmigrated.

Methotrexate, a benchmark therapeutic agent, has been shown to yield diminishing benefit in antibody induced models, which are intrinsically less dependent on T-cell activation than on their trafficking and migratory properties. The work of Lange et al. can be cited in this context {Annals of Rheumatoid Disease 64:599-605, 2005). By contrast, the novel imidazoacridinone N-oxides described here appear fully active. The results presented in this example are especially relevant to the treatment of human subjects, because the therapeutic effect was obtained by oral administration. In the era of injectable biologies, such as blocking antibodies, the addition of an effective, non-immunosuppressive therapy via the oral route is particularly desirable. A further and novel therapeutic benefit of the imidazoacridinone N-oxide genus emerges from the observation that they show marginal cytotoxicity until activated under conditions prevalent in tissues with hypoxic disease. This property can be expected to significantly lessen side effects, which otherwise would accrue from collateral damage to normal tissues.

Example 4: Efficacies of Representative Compounds of the Invention Efficacies a compound of formula (A)

and of a compound of formula (B)

have been tested by determining EC50 and ElOOO values according to the following protocol.

The terms "IC50" and "EC50" are used interchangeably. As used herein, "EC50" refers to nMolar concentration at median percent inhibition determined by dose respose (DR) assay. As used herein, the term "ElOOO" refers to percent inhibition at 1000 nMolar determined by assay. EC50 was calculated based on dose response curve was fitted to 4 parameter Hill equation.

Testing of the compounds described in this invention was carried out using the SelectScreen™ platform from Invitrogen, Inc. (Carlsbad, CA, USA) and the details of its performance are readily viewed via the web by linking to: http://www.invitrogen.com/downloads/SelectScrn Brochure.pdf.

Briefly the approach is based on treating each specific kinase with a unique substrate and optical reporter system in the presence of ATP at 100 micromolar. In controls, the substrate is phosphorylated and a baseline optimal response is recorded. Compounds were initially tested at 1000 nanomolar concentrations and the % inhibition of enzyme activity determined (ElOOO). The compounds were then re-tested by adding graded amounts of putative inhibitor which were added in 5 separate increments to generate a dose response curve. The latter is obtained by fitting to a 4 parameter Hill equation, a sigmoid saturation equation. The concentration which causes 50% enzyme inhibition (EC50) was then calculated from the dose response equation.

An effective level of inhibition in the low nanomolar range is considered to qualify the test compound as potential drug or targeting agent against the specific kinase that it has inhibited. The EC_5O value is, therefore, a measure of potency. Another important feature is specificity. It is considered a desirable property when claiming efficacy to determine how many kinases are inhibited by the same molecule. The fewer number inhibited points toward specificity; the greater to inhibitory promiscuity. For the compounds of this invention, the experimental condition were as follows. The 2X FLT3/Tyr 02 peptide mixture was prepared in 50 mM HEPES pH 7.5, 0.01 BRIJ-35, 1OmM MgC12, ImM EGTA. The final 10 uL kinase reaction consists of 0.6-76.0 ng FLT3 and 2 uM Tyr 02 peptide in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM Mg C12, 1 mM EGTA. After 1 hour kinase reaction incubation, 5 uL of a 1 :64 dilution of development reagent A was added.

The measurements indicate that compound (A) exhibisted EC50 of 49 nM and ElOOO of 94%, while compound (B) exhibited EC50 of 77 nM and ElOOO of 91%.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of following formula or a pharmaceutically acceptable salt thereof:

wherein:

R is -OH or -OCH₃; R² is -H or a C1-C4 alkyl; n is an integer from 1 to 5; and

R^a and R^b, each independently are hydrogen or an optionally substituted alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a non-aromatic heterocycle, optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy, provided that the heterocycle comprises no more than one ring nitrogen atom.

2. The compounds of Claim 1 , wherein n is 2 or 3.

3. The compound of Claim 2, wherein R" and R^b are each independently a C1-C3 alkyl.

4. The compound of Claim 1 wherein R^a and R^b, each independently are hydrogen or an alkyl, or R^a and R^b, taken together with the nitrogen to which they are attached, form a 5-7 membered non-aromatic heterocycle optionally substituted at one or more substitutable ring carbon atoms with methyl, hydroxyl, or methoxy.

5. The compound of Claim 1 wherein R^a and R^b, is each independently a hydrogen or a C1-C3 alkyl, or, taken together with the nitrogen to which they are attached, form group R^y selected form a group consisting of

wherein Q² is CH₂, S or O.

6. The compound of Claim 1 , wherein R is -OH or -OCH₃, R^a and R^b are identical and are methyl or ethyl, or taken together with the nitrogen atom to which they are attached, form an N-oxo morpholino ring; n is 2 or 3; R² is a hydrogen or a Cl-C4 alkyl.

7. The compound of Claim 6, wherein R is -OH,

8. The compounds of Claim 1 , represented by the following formulas:

or a pharmaceutically acceptable salt thereof.

9. The compound of Claim 1 wherein the comound is represented by a structural formula selected from:

or a pharmaceutically acceptable salt thereof.

10. A method of treating an inflammatory disorder, a demyelinating disorder, a FLT3-mediated disorder, a cancer, a leukemia or a CSF-lR-mediated disorder in a patient, comprising administering to said patient a therapeutically effective amount of a compound of any one of Claims 1-9.

11. The method of Claim 10, wherein the disorder is a cancer selected from brest cancer, colorectal cancer, non-small cell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck, hepatocellular, thyroid, multidrug-resistant leukemia, lymphoma, multiple myeloma, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma.

12. The method of Claim 11 , wherein the patient is being treated for bone metastases.

13. The method of Claim 10, wherein the disorder is an inflammatory disorder selected from systemic lupus, inflammatory bowl disease, psoriasis, Crohn's disease, rheumatoid arthritis, sarcoid, Alzheimer's disease, insulin dependent diabetes mellitus, atherosclerosis, asthma, spinal cord injury, stroke, a chronic inflammatory demyelinating neuropathy, multiple sclerosis, a congenital metabolic disorder, a neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, a hereditary demyelinating condition, a prion-induced demyelination, and encephalitis- induced demyelination.

14. The method of Claim 10, wherein the disorder is a demyelinating condition selected from multiple sclerosis, a congenital metabolic disorder, a neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, a hereditary demyelination condition, a prion-induced demyelination, encephalitis-induced demyelination, a spinal cord injury, Alzheimer's disease, Chronic Immune Demyelinating Polyneuropathy (CIDP); multifocal CEDP; multifocal motor neuropathy (MMN); anti-MAG Syndrome (Neuropathy with IgM binding to Myelin- Associated Glycoprotein); GALOP Syndrome (Gait disorder Autoantibody Late-age Onset Polyneuropathy); anti- sulfatide antibody syndrome; anti-GM2 gangliosides antibody syndrome; POEMS syndrome (Polyneuropathy Organomegaly Endocrinopathy or Edema M-protein Skin changes); perineuritis; and IgM anti-GDlb ganglioside antibody syndrome.

15. The method of Claim 10, wherein the disorder is a FLT3-mediated disorder selected from axonal degeneration, acute transverse myelitis, amyotrophic lateral sclerosis, infantile spinal muscular atrophy, juvenile spinal muscular atrophy, Creutzfeldt- Jakob disease, subacute sclerosing panencephalitis, organ rejection, bone marrow transplant rejection, non-myeloablative bone marrow transplant rejection, ankylosing spondylitis, aplastic anemia, Behcet's disease, graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia, Wegener's granulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia purpura, and Myasthenia gravis.

16. The method of Claim 10, wherein the disorder is a CSF-I R-mediated disorder selected from a cardiovascular disease, diseases with an inflammatory component including glomerulonephritis, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain, osteoporosis, Paget's disease, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone, uterine cancer, stomach . cancer, hairy cell leukemia, Sjogren's syndrom, uveitis, osteolytic sarcoma, uterine cancer, and stomach cancer.

17. The method of Claim 10, wherein one or more additional pharmaceutical agents is co-administered with a compound of formula (I).

18. A pharmaceutical composition comprising: i) the compound of any one of Claims 1-10 or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier or diluent.