Urea and thiourea derivatives
The present application discloses compounds of formula (I) wherein X is ═O, ═S, ═NH, ═NOH and ═NO-Me; A is —C(═O)—, —S(═O) 2 —, —C(═S)— and P(═O)(R 5 )—; B is, —O—, —(CH 2 ) 3-6 —, and O—(CH 2 ) 2-5 —; D is, —O—, —CR 7 R 8 — and —NR 9 ; m is 0-12, n is 0-12, m+n is 1-20; p is 0-4; R 1 is opt. sub. heteroaryl; and pharmaceutically acceptable salts thereof, and prodrugs thereof. The application also discloses the compound for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT), e.g. inflammatory and tissue repair disorders; dermatosis; autoimmune diseases, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telengiectasia.
1. A compound of the formula (I)
wherein
X is selected from ═O and ═S;
A is selected from —C(═O)— and —S(═O) 2 —;
B is selected from —(CH 2 ) 3-6 —, —O—, and —O—(CH 2 ) 2-5 —;
D is selected from a single bond —O—, and —NR 9 , wherein R 9 is selected from hydrogen, optionally substituted C 1-12 -alkyl, optionally substituted C 1-12 -alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
m is an integer of 2-8 and n is 0;
p is an integer of 0-2;
R 1 is selected from optionally substituted heteroaryl;
R 2 is selected from hydrogen, optionally substituted C 3-12 -cycloalkyl, —[CH 2 CH 2 O] 1-10 -(optionally substituted C 1-6 -alkyl), CH 2 ) 0-2 -(optionally substituted aryl), —(CH 2 ) 0-2 -(optionally substituted heteroaryl) and —(CH 2 ) 0-2 -(optionally substituted heterocyclyl); and
R 3 is selected from optionally substituted C 3-12 -cycloalkyl, —[CH 2 CH 2 O] 1-10 -(optionally substituted C 1-6 -alkyl), optionally substituted C 1-12 -alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
R 4 is independently selected from hydrogen, optionally substituted C 3-12 -cycloalkyl, —(CH 2 ) 0-2 -(optionally substituted aryl), —(CH 2 ) 0-2 -(optionally substituted heteroaryl) and —(CH 2 ) 0-2 -(optionally substituted heterocyclyl); and
R 4* is hydrogen;
with the provisos that R 1 is not optionally substituted thiazol-2-yl when p is 0;
and with the proviso that the compound is not phenyl-NH—C(═O)—(CH 2 ) 5 —NH—C(═S)—NH-(4-pyridyl);
and pharmaceutically acceptable salts thereof, and prodrugs thereof.
2. The compound according to claim 1 , wherein B is —O—.
3. The compound according to claim 1 , wherein D is a single bond.
4. The compound according to claim 1 , wherein B is selected from —(CH 2 ) 3-6 — and —O—(CH 2 ) 2-5 —.
5. The compound according to claim 4 , wherein A is —S(═O) 2 —.
6. The compound according to claim 1 , wherein R 1 is selected from optionally substituted pyridin-4-yl, optionally substituted pyrimidin-4-yl, optionally substituted 1,2,4-triazin-3-yl, optionally substituted isoxazol-4-yl, optionally substituted pyrazin-2-yl, and optionally substituted picolyl.
7. The compound according to claim 1 , wherein p is 0 and R 1 is pyridine-4-yl.
8. The compound according to claim 1 , which is selected from compounds 1001-1101:
Com-
pound
Structure
1001.
1002.
1003.
1004.
1005.
1006.
1007.
1008.
1009.
1010.
1011.
1012.
1013.
1014.
1015.
1016.
1017.
1018.
1019.
1020.
1021.
1022.
1023.
1024.
1025.
1026.
1027.
1028.
1029.
1030.
1031.
1032.
1033.
1034.
1035.
1036.
1037.
1038.
1039.
1040.
1041.
1042.
1043.
1044.
1045.
1046.
1047.
1048.
1049.
1050.
1051.
1052.
1053.
1054.
1055.
1056.
1057.
1058.
1059.
1060.
1061.
1062.
1063.
1064.
1065.
1066.
1067.
1068.
1069.
1070.
1071.
1072.
1073.
1074.
1075.
1076.
1077.
1078.
1079.
1080.
1081.
1082.
1083.
1084.
1085.
1086.
1087.
1088.
1089.
1090.
1091.
1092.
1093.
1094.
1095.
1096.
1097.
1098.
1099.
1100.
1101.