N1-cyclic amine-N5-substituted phenyl biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same

A method of preparing a compound of Formula 1, comprising:

• reacting a compound of Formula 2 with dicyanoamide in an organic solvent to obtain a compound of Formula 3;
• and
• reacting the compound of Formula 3 with a compound of Formula 4 in water, an organic solvent or a mixture thereof to obtain the compound of Formula 1:
• wherein R1 and R2 are taken together with nitrogen to which they are attached to form 3- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy and C1-6alkyl;
• n is an integer ranging from 2 to 5;
• each R3 is unsubstituted or substituted and is independently selected from the group consisting of halogen, unsubstituted hydroxy, substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, unsubstituted or substituted C1-6alkylthio, unsubstituted or substituted amino, unsubstituted or substituted amide, unsubstituted or substituted sulfonamide, nitro, unsubstituted or substituted heteroaryl, cyano, sulfonic acid and unsubstituted or substituted sulfamoyl,
• wherein the substituted R3 has at least one substituent selected from the group consisting of halogen, hydroxy and C1-6alkyl.

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:

• wherein R1 and R2 are taken together with nitrogen to which they are attached to form 3- to 8-membered heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl and aziridinyl, wherein the heterocycloalkyl is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy and C1-6alkyl;
• n is 1;
• each R3 is unsubstituted or substituted and is independently selected from the group consisting of unsubstituted hydroxy, substituted C1-6alkyl, substituted C1-6alkoxy, unsubstituted or substituted C1-6alkylthio, unsubstituted or substituted amino, unsubstituted or substituted amide, unsubstituted or substituted sulfonamide, nitro, unsubstituted or substituted heteroaryl, cyano, sulfonic acid and unsubstituted or substituted sulfamoyl, and
• wherein the substituted R3 has at least one substituent selected from the group consisting of halogen, hydroxy and C1-6alkyl.

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:

• wherein R1 and R2 are taken together with nitrogen to which they are attached to form morpholinyl unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy and C1-6alkyl;
• n is 1;
• each R3 is unsubstituted or substituted and is independently selected from the group consisting of halogen, unsubstituted hydroxy, unsubstituted or substituted C1-6alkoxy, unsubstituted or substituted C1-6alkylthio, unsubstituted or substituted amino, unsubstituted or substituted amide, unsubstituted or substituted sulfonamide, nitro, unsubstituted or substituted heteroaryl, cyano, sulfonic acid and unsubstituted or substituted sulfamoyl,
• wherein the substituted R3 has at least one substituent selected from the group consisting of halogen, hydroxy and C1-6alkyl.