Benzamide derivatives and their use as glucokinase activating agents

A compound of Formula (I), or a salt thereof:

• wherein:
• R2 is methoxymethyl;
• R2 is selected from —C(O)NR4R5, —SO2NR4R5, and —S(O)pR4;
• HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S;
• which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R6;
• R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
• R4 is selected from hydrogen and (1-4C)alkyl;
• R5 is hydrogen or (1-4C)alkyl;
• R6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
• HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
• p is independently at each occurrence 0, 1, or 2;
• m is 0 or 1;
• and
• n is 0, 1, or 2;
• provided that when m is 0, then n is 1 or 2.

A compound of Formula (I) or a salt, pro-drug, or solvate thereof:

• wherein:
• R1 is methoxymethyl;
• R2 is selected from —C(O)—HET-3 and —SO2—HET-3;
• HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S;
• which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R6;
• R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
• R6 is independently selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl;
• HET-3 is selected from morpholino, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl;
• m is 1 and R2 is in the para position relative to the ether linkage;
• and
• n is 0, 1, or 2.

A compound of Formula (I), or a salt thereof:

• wherein:
• R2 is methoxymethyl;
• R2 is selected from —C(O)NR41R51, —SO2NR41R51, and —S(O)pR41;
• HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S;
• which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R6;
• HET-2 is a 4-, 5-, or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein a —CH2— group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to a S(O) or S(O)2 group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R7;
• R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
• R41 is selected from (1-4C)alkyl substituted with 1 or 2 substituents independently selected from HET-2, —OR5, —SO2R5, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R7), and —C(O)NR5R5;
• (3-6C)cycloalkyl (optionally substituted with 1 group selected from R7);
• and HET-2;
• R51 is hydrogen or (1-4C)alkyl;
• R4 is selected from (1-4C)alkyl optionally substituted with 1 or 2 substituents independently selected from HET-2, —OR5, —SO2R5, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R7), and —C(O)NR5R5;
• (3-6C)cycloalkyl (optionally substituted with 1 group selected from R7);
• and HET-2;
• R5 is hydrogen or (1-4C)alkyl;
• or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3;
• R6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
• R7 is selected from —OR5, (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR4R5, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O)pR5;
• HET-3 is an N-linked, 4-, 5-, or 6-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms independently selected from O, N, and S, wherein a —CH2— group can optionally be replaced by a —C(O)— and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)2 group;
• which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R8;
• or
• HET-3 is an N-linked, 7-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom independently selected from O, S, and N, wherein a —CH2— group can optionally be replaced by a —C(O)— group and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O)2 group;
• which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R8;
• or
• HET-3 is an N-linked, 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom wherein a —CH2— group can optionally be replaced by a —C(O)—;
• which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R3;
• R8 is selected from —OR5, (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR4R5, (1-4C)alkylamino, di(1-4C)alkylamino, HET-3 (wherein said ring is unsubstituted), (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O)pR5;
• HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
• p is independently at each occurrence 0, 1, or 2;
• m is 1 and R2 is in the para position relative to the ether linkage;
• and
• n is 0, 1, or 2.

A compound of the Formula (I), or a salt, pro-drug, or solvate thereof:

• wherein:
• R1 is methoxymethyl;
• R2 is HET-2;
• HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N, and S;
• which ring is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R6;
• HET-2 is a 4-, 5-, or 6-membered, C- or N-linked heterocyclyl ring containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein a —CH2— group can optionally be replaced by a —C(O)—, and wherein a sulphur atom in the heterocyclic ring may optionally be oxidised to an S(O) or S(O)2 group, which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R7;
• R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy, and cyano;
• R4 is selected from hydrogen;
• (1-4C)alkyl optionally substituted with 1 or 2 substituents independently selected from HET-2, —OR5, —SO2R5, (3-6C)cycloalkyl (optionally substituted with 1 group selected from R7), and —C(O)NR5R5;
• (3-6C)cycloalkyl (optionally substituted with 1 group selected from R7);
• and HET-2;
• R5 is hydrogen or (1-4C)alkyl;
• or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclyl ring system as defined by HET-3;
• R6 is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl, and HET-4;
• R7 is selected from —OR5, (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR4R5, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O)pR5;
• HET-3 is an N-linked, 4-, 5-, or 6-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms independently selected from O, N, and S, wherein a —CH2— group can optionally be replaced by a —C(O)— and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)2 group;
• which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R8;
• or
• HET-3 is an N-linked, 7-membered, saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further heteroatom independently selected from O, S, and N, wherein a —CH2— group can optionally be replaced by a —C(O)— group and wherein a sulphur atom in the ring may optionally be oxidised to an S(O) or S(O)2 group;
• which ring is optionally substituted on an available carbon or nitrogen atom by 1 or 2 substituents independently selected from R8;
• or
• HET-3 is an N-linked, 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom, wherein a —CH2— group can optionally be replaced by a —C(O)—;
• which ring is optionally substituted on an available carbon or nitrogen atom by 1 substituent selected from hydroxy and R3;
• R8 is selected from —OR5, (1-4C)alkyl, —C(O)(1-4C)alkyl, —C(O)NR4R5, (1-4C)alkylamino, di(1-4C)alkylamino, HET-3 wherein said ring is unsubstituted, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O)pR5;
• HET-4 is a 5- or 6-membered, C- or N-linked unsubstituted heteroaryl ring containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S;
• p is independently at each occurrence 0, 1, or 2;
• m is 1 and R2 is in the para position relative to the ether linkage;
• and
• n is 0, 1, or 2.