Compounds for the treatment of inflammatory disorders and microbial diseases

A method of treating a disorder associated with UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I):

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• A is selected from the group consisting of:
• d is 0 to 4;
• J is selected from the group consisting of O, S, and NR5;
• E is selected from the group consisting of:
• O, S, and NR5;
• T is O or S;
• R1 and R2 are the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl;
• or alternatively R1 and R2, taken together with the N to which R1 and R2 are shown attached, represent a 4-8 membered heterocyclic ring having 1-3 heteroatoms including said N, said heterocyclic ring being optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, heteroaryl and 4-8 membered heterocyclic ring can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R70 moieties below;
• R10 is selected from the group consisting of H, alkyl, and fluoroalkyl;
• R20 is selected from the group consisting of H, alkyl, and fluoroalkyl;
• R30 is H or alkyl, or alternatively R30 and R40 taken together with the N to which R40 is shown attached to in Formula I, are joined to form a 4-7 membered heterocylic ring, wherein said heterocylic ring is unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R70 moieties below;
• R40 is H or alkyl;
• R50 is H or alkyl;
• W is —(CR132)n—, wherein n is 0 to 5 or a covalent bond, or alternatively two R13 groups can fuse to form a 3-8 membered cycloalkyl, wherein said 3-8 membered cycloalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R6 moieties below;
• X is absent or present, and if present X is selected from the group consisting of a covalent bond, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R70 moieties below;
• Y is absent or present, and if present Y is selected from the group consisting of a covalent bond, —[C(R6)2]n— wherein n is 1 or 2, —O—, —S—, —NR1—, —SOv— wherein v is 1 to 2, —SOn(CR62)p— wherein n is 1 or 2 and p is 1 to 4, —O(CR62)q— or —(CR62)qO— wherein q is 1 to 4, —N(R7)S(O)n— or —S(O)nN(R7)—;
• wherein n is 1 or 2, and —N(R7)C(O)— or —C(O)N(R7)—;
• Z is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cycloalkyl, heterocyclyl, aryl, and heteroaryl being optionally fused with aryl, heterocyclyl, heteroaryl or cycloalky;
• wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R70 moieties below;
• R5 is selected from the group consisting of hydrogen, alkyl, and alkylaryl;
• each R6 is the same or different and is independently selected from the group consisting of hydrogen, halogen, —SR15, —S(O)qR15 wherein q is 1 to 2, alkyl, cycloalkyl, heterocyclyl, alkoxyl, hydroxy, nitro, cyano, amino, alkenyl, alkynyl, arylalkyl, aminocarbonyl, alkylcarbonyl, and alkoxycarbonyl;
• each R7 is the same or different and is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, alkenyl, alkynyl, arylalkyl, alkylcarbonyl, and alkoxycarbonyl, wherein each of the aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R70 moieties below;
• R13 is the same or different and is independently selected from the group consisting of hydrogen, halogen, —OH, —OR14, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylaryl, alkylamino, and alkylcarbonyl;
• R14 is alkyl;
• each R70 is a substituent for H where indicated and is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —CF3, —OCF3, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)qN(R15)(R16) wherein q is 1 to 2, —C(═NOR15)R16, —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R17)S(O)2N(R16)(R15), N(R17)S(O)N(R16)(R15), —N(R17)C(O)N(R16)(R15), —CH2—N(R17)C(O)N(R16)(R15), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, and —S(O)qR15 wherein q is 1 to 2;
• and wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl are independently unsubstituted or substituted by 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —N(R15)(R16), —C(O)OR15, —C(O)N(R15)(R16), and —N(R15)S(O)R16;
• and
• each R15, R16 and R17 are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or alternatively R15 and R16 taken together with the N to which they are shown attached, are joined to form a 4-8 membered heterocylic ring, wherein said 4-8 membered cycloalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R75 moieties below;
• each R75 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl, and wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl are independently unsubstituted or substituted by 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, —CF3, —CN, —OR19, —N(R19)2, —C(O)OR19, —C(O)N(R19)2, and —N(R19)S(O)R19;
• and
• each R19 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.