Treatment of inflammatory conditions and autoimmune diseases with glucose uptake inhibitors

A method of treating an autoimmune disease or an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound the formula I:

• wherein:
• R1 is selected from the group consisting of aryl, —(CH2)y—NR13R14, —X—R12, —(CH2)y—C(═O)NR13R14, —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-cycloalkyl, —(CH2)y—O—C(═O)—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —(CH2)y—S(═O)2NR13R14, —O—(CH2)y—S(═O)2NR13R14, —NH—S(═O)2—X—R1, —NH—(CH2)y—NR13R14, —O—(CH2)y-heteroaryl, —O—C(═O)—(CH2)y—NR13R14, and —O—(CH2)z—NR13R14;
• R12 is selected from the group consisting of C1-C10 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, aryl, —(C1-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cyano, and C1-C3 perfluoro alkyl;
• R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —SO2-alkyl, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, —SO2-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
• X is selected from a covalent bond, O, and C1-C6 alkyl;
• R15 is selected from the group consisting of H, C1-C8 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O-(aryl), —(C1-C6 alkyl)-C(═O)NR16R17, —O—(CH2)x—CO2R18, —O—(CH2)x—C(═O)NR16R17, —(C1-C6 alkyl)—CO2R18, and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
• R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
• or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
• R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
• x is selected from 1 to 6;
• y is selected from 0 to 6;
• z is selected from 2 to 6;
• each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
• n is selected from 0 to 4;
• R3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, —(CH2)a—NR33R34, —Y—R32, —O—(CH2)a—CO2R32, —O—(CH2)a—C(═O)NR33R34, —O—(CH2)a-heteroaryl, —O—(CH2)a-cycloalkyl, —O—C(═O)—(CH2)a—NR33R34, —O—(CH2)c—NR33R34, —NH—C(═O)—(CH2)a—NR33R34, —NH—C(═O)—Y—R35, —NH—C(═O)—(CH2)a—NR33R34;
• R32 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR36R37, —(C1-C6 alkyl)-C(═O)NR36R37, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• R33 and R34 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR36R37, —(C1-C6 alkyl)-C(═O)NR36R37, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• or R33 and R34 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• Y is selected from a covalent bond, O, NH, and C1-C6 alkyl;
• R35 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR36R37, —CO2R38, —O—(CH2)b—CO2R38, and —C(═O)NR36R37,
• R36 and R37 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• or R36 and R37 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• R38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR36R37, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
• R4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, —(CH2)a—NR43R44, —Z—R42, —O—(CH2)a—CO2R42, —O—(CH2)a—C(═O)NR43R44, —O—(CH2)a-heteroaryl, —O—(CH2)a-cycloalkyl, —O—C(═O)—(CH2)a—NR43R44, —O—(CH2)c—NR43R44, —NH—C(═O)—(CH2)a—NR43R44, —NH—C(═O)—Z—R45, —NH—C(═O)—(CH2)a—NR43R44;
• R42 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• R43 and R44 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• or R43 and R44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• Z is selected from a covalent bond, O, NH, and C1-C6 alkyl;
• R45 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —CO2R48, —O—(CH2)b—CO2R48, and —C(═O)NR46R47;
• R46 and R47 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
• R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
• each a is independently selected from 0 to 6;
• each b is independently selected from 0 to 6;
• each c is independently selected from 2 to 6;
• R5 is selected from the group consisting of H and C1-C6 alkyl;
• R6 is selected from the group of formula (IA) and (IB):
• wherein
• Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
• Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
• R7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
• and
• m is 0 to 2.