Method for the sysnthesis of compounds of formula I and their uses thereof

A method for treating acute and/or chronic inflammation, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating vascular permeability, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating nephropathy, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating atherosclerosis, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating retinopathy, which comprises administering to a subject in need thereof a therapeutically effective amount of compound of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating Alzheimer's disease, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating erectile dysfunction, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method for treating tumor invasion and/or metastasis, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising at least one moiety of the formula

• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R9, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)m—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of the formula —Y—C1-6-alkyl-NR7R8.

A method of treating RAGE mediated diseases, the method comprising administering to a subject in need thereof, a therapeutically effective amount of

• at least one compound comprising at least one moiety of the formula
• wherein L1 is a C1-C4 alkyl group and L2 is a direct bond, and Aryl1 and Aryl2 are aryl, wherein each of Aryl1 and Aryl2 are substituted by at least one lipophilic group selected from the group consisting of
• a) —Y—C1-6 alkyl;
• b) —Y-aryl;
• c) —Y—C-1-6 alkylaryl;
• d) —Y—C1-6-alkyl-NR7R8;
• e) —Y—C1-6-alkyl-W—R20;
• wherein
• Y and W are, independently selected from the group consisting of —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, —O—CO—,
• f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl;
• wherein
• R18 and R19 are independently selected from the group consisting of aryl, C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkoxy, and C1-C6 alkoxyaryl;
• R20 is selected from the group consisting of aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, and C1-C6 alkylaryl;
• and wherein R7 and R8 may be taken together to form a ring having the formula —(CH2)n—X—(CH2)n— bonded to the nitrogen atom to which R7 and R8 are attached, wherein m and n are, independently, 1, 2, 3, or 4;
• X is selected from the group consisting of —CH2—, —O—, —S—, —S(O2)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —O—C(O)—, —NHSO2NH—,
• or a pharmaceutically acceptable salt thereof,
• wherein at least one of Aryl1 and Aryl2 is substituted with a lipophilic group of
• the formula —Y—C1-6-alkyl-NR7R8;
• in combination with one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.