Fused phenyl amido heterocyclic compounds
View Patent ↗The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A is (4-12)-membered heterocyclyl; Ring B is a fused benzene ring selected from the group consisting of: Ring A, ring B, ring C, R 1 , R 1a , R 2 , R 3 , R 4 , L 2 , n, t, w, and z are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a condition that is mediated by the modulation of glucokinase, the method comprising administering to a mammal an effective amount of a compound of formula (I).
1. The compound of the formula
or a pharmaceutically acceptable salt thereof;
wherein L 1 is —O—, —NR 5 —, or —S—;
Ring A is (4-12)-membered heterocyclyl;
each of R 1 , R 1a , and R 4 are independently selected from H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 5 , —(C═O)—O—R 5 , —O—(C═O)—R 5 , —NR 5 (C═O)—R 7 , —(C═O)—NR 5 R 6 , —NR 5 R 6 , —NR 5 OR 6 , —S(O) k NR 5 R 6 , —S(O) j (C 1 -C 6 )alkyl, —O—SO 2 —R 5 , —NR 5 —S(O) k , —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), —(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q (C═)(CR 5 R 6 ) v (C 6 -C 10 )aryl, —(CR 5 R 6 ) q (C═O)(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) v O(CR 5 R 6 ) q (C 6 -C 10 )aryl, —(CR 5 R 6 ) v O(CR 5 R 6 ) q (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q S(O) j (CR 5 R 6 ) v (C 6 -C 10 )aryl, and —(CR 5 R 6 ) q S(O) j (CR 5 R 6 ) v (4-10-membered heterocyclyl;
L 2 is >C═O, >C═O—O—, —O—C═O—, —O—C═O—O, —O—C═O—NR 5 —, —NR 5 —(C═O)—, —NR 5 —(C═O)—O—, —NR 5 —(C═O)—NR 6 , —(C═O)—NR 5 —, —O—, —NR 5 —, —S(O) j —, —NR 5 SO 2 —, —SO 2 NR 5 —, —(C═O)NR 5 SO 2 —, —SO 2 NR 5 (C═O)—, or —CR 5 R 6 ;
R 2 is H, (C 1 -C 6 )alkyl, —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), or —(CR 5 R 6 ) v (4-12)-membered heterocyclyl;
R 3 is H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 5 , —(C═O)—O—R 5 , —O—(C═O)—R 5 , —NR 5 (C═O)—R 7 , —(C═O)—NR 5 R 6 , —NR 5 R 6 , —NR 5 OR 6 , —S(O) k NR 5 R 6 , —S(O) j (C 1 -C 6 )alkyl, —O—SO 2 —R 5 , —NR 5 —S(O) k , —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), —(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q (C═O)(CR 5 R 6 ) v (C 6 -C 10 )aryl, —(CR 5 R 6 ) q (C═O)(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) v O(CR 5 R 6 ) q (C 6 -C 10 )aryl, —(CR 5 R 6 ) v O(CR 5 R 6 ) q (4-10 membered heterocyclyl, —(CR 5 R 6 ) q S(O) j (CR 5 R 6 ) v (C 6 -C 10 )aryl, or —(CR 5 R 6 ) q S(O) j (CR 5 R 6 ) v (4-10)-membered heterocyclyl;
each of R 5 , R 6 and R 7 are independently selected from H, (C 1 -C 6 )alkyl, —(CR 8 R 9 ) v (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 8 -C 10 )aryl, and —(CR 8 R 9 ) p (4-10)-membered heterocyclyl;
any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently optionally substituted with 1 to 3 R 11 substituents each independently selected from halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, —O—R 12 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—R 12 , —(C═O)—O—R 8 , —(C═O)—O—R 12 , —O—(C═O)—R 8 , —O—(C═O)—R 12 , —NR 8 (C═O)—R 10 , —(C═O)—NR 8 R 9 , —(C═O)—NR 8 R 12 , —NR 8 R 9 , —NR 8 R 12 , —NR 8 OR 9 , —NR 8 OR 12 , —S(O) k NR 8 R 9 , —S(O) k NR 8 R 12 , —S(O) j (C 1 -C 6 )alkyl, —S(O) j R 12 , —O—SO 2 —R 8 , —O—SO 2 —R 12 , —NR 8 —S(O) k , —NR 12 —S(O) k , —(CR 8 R 9 ) v (3-10)-membered cycloalkyl, —(CR 8 R 9 ) v (C 6 -C 10 aryl), —(CR 8 R 9 ) v (4-10)-membered heterocyclyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) v (C 6 -C 10 )aryl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) v (4-10)-membered heterocyclyl, —(CR 8 R 9 ) v O(CR 8 R 9 ) q (C 6 -C 10 )aryl, —(CR 8 R 9 ) v O(CR 8 R 9 ) q (4-10)-membered heterocyclyl, —(CR 8 R 9 ) q S(O) j (CR 8 R 9 ) v (C 6 -C 10 )aryl, and —(CR 8 R 9 ) q S(O) j (CR 8 R 9 ) v (4-10)-membered heterocyclyl;
any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl of the foregoing R 11 are independently optionally substituted with 1 to 3 R 13 substituents each independently selected from halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, (CH 2 ) v OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—R 12 , —(C═O)—O—R 8 , —(C═O)—O—R 12 , —O—(C═O)—R 8 , —O—(C═O)—R 12 , —NR 8 (C═O)—R 10 , —(C═O)—NR 8 R 9 , —NR 8 R 9 , and —NR 8 R 12 ;
any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 and R 12 are independently optionally substituted with (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—O—R 8 , —(C═O)—NR 8 R 9 , —(CR 8 R 9 ) v (3-10)-membered cycloalkyl, —(CR 8 R 9 ) v (C 6 -C 10 aryl), —(CR 8 R 9 ) v (4-10)-membered heterocyclyl, —(CR 8 R 9 ) q (C═O)(CR 8 R 9 ) v (C 6 -C 10 )aryl, or —(CR r R 9 ) q (C═O)(CR 8 R 9 ) v (4-10)-membered heterocyclyl;
each R 8 , R 9 , and R 10 are independently H or (C 1 -C 6 )alkyl;
R 12 is —(CR 8 R 9 ) v (3-10)-membered cycloalkyl, —(CR 8 R 9 ) v (C 6 -C 10 aryl), or —(CR 8 R 9 ) v (4-10)-membered heterocyclyl;
p, q, and v are each independently 0, 1, 2, 3, 4, or 5;
w, n and j are each independently 0, 1, or 2;
k is 1 or 2; and
t and z are each independently 1, 2, 3, or 4;
with the proviso that when
Ring A is pyridin-2-yl or thiazol-2-yl;
L 1 is —O—;
L 2 is —O—; and
R 2 is (C 1 -C 6 )alkyl, —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), or —(CR 5 R 6 ) v (4-12)-membered heterocyclyl; then
R 2 is further substituted by R 11 substituents each independently selected from —SO 2 —(C 1 -C 6 )alkyl, —S(O) j R 12 , —S(O) k NR 8 R 9 , —S(O) k NR 8 R 12 , —(C═O)—R 12 , —(C═O)—NR 8 R 9 , or —(C═O)—NR 8 R 12 .
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said Ring A is selected from the group consisting of oxadiazolyl, triazolyl, pyrrolyl, oxazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, pyridinylcyclohexyl, and naphthyridinyl.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein Ring A is pyrazinyl;
R 3 is (C 1 -C 6 )alkyl and n is 1.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R 1 is H and R 4 is (C 1 -C 4 )alkyl.
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein L 1 is —O—; and L 2 is —O—.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 2 is pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl and wherein R 2 is substituted with a —(C═O)—NR 8 R 9 .
7. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.