NOVEL 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, Alzheimers 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, ═S, ═NH, ═NOH and ═NO-Me;
A is selected from —C(═O)—, —S(═O) 2 —, —C(═S)— and —P(═O)(R 5 )—, wherein R 5 is selected from C 1-6 -alkyl, C 1-6 -alkoxy and hydroxy;
B is selected from a single bond, —(CH 2 ) 3-6 —, —O—, and —O—(CH 2 ) 2-5 —;
D is selected from a single bond, —O—, —CR 7 R 8 — and —NR 9 , wherein R 7 , R 8 and R 9 are independently 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 0-12 and n is an integer of 0-12, wherein the sum m+n is 1-20;
p is an integer of 0-4;
R 1 is selected from optionally substituted heteroaryl;
R 2 is selected from hydrogen, optionally substituted C 1-12 -alkyl, 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; and R 3 is selected from optionally substituted C 1-12 -alkyl, 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; or R 2 and R 3 together with the intervening atoms (i.e. —N—B—) form an optionally substituted N-containing heterocyclic or heteroaromatic ring;
each of R 4 and R 4 * is independently selected from hydrogen, optionally substituted C 1-12 -alkyl and optionally substituted C 1-12 -alkenyl;
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 X is selected from ═O and ═S.
3 . The compound according to claim 1 , wherein B is —O—.
4 . The compound according to claim 1 , wherein A is selected from —S(═O) 2 — and —C(═O).
5 . The compound according to claim 2 , wherein D is a single bond.
6 . The compound according to claim 1 , wherein B is selected from —(CH 2 ) 3-6 — and —O—(CH 2 ) 2-5 —.
7 . The compound according to claim 6 , wherein A is —S(═O) 2 —.
8 . The compound according to claim 1 , wherein D is selected from a single bond, —O—, and —NR 9 .
9 . 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.
10 . The compound according to claim 1 , wherein p is 0-2.
11 . The compound according to claim 10 , wherein p is 0 and R 1 is pyridine-4-yl.
12 . The compound according to claim 1 , wherein m is an integer of 0-10 and n is an integer of 0-10, wherein the sum m+n is 1-12.
13 . The compound according to claim 12 , wherein m is an integer of 2-8 and n is 0.
14 . The compound according to claim 1 , wherein at least one of R 2 and R 3 includes a carbocyclic ring, heterocyclic ring or a heteroaromatic ring, or R 2 and R 3 together with the intervening atoms form an optionally substituted N-containing heterocyclic or heteroaromatic ring.
15 . The compound according to claim 14 , wherein R 2 and R 3 together with the intervening atoms form an optionally substituted N,O-containing heterocyclic or heteroaromatic ring.
16 . The compound according to claim 1 , wherein
X is selected from ═O and ═S;
A is selected from —C(═O)— and —S(═O) 2 —;
B is selected from —O—, —(CH 2 ) 3-6 — and —O—(CH 2 ) 2-5 —;
D is selected from a single bond, —O—, and —NR 9 ;
m is an integer of 2-8 and n is 0;
p is an integer of 0-2;
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);
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 selected from hydrogen, optionally substituted C 3-12 -cycloalkyl, —(CH 2 )O 2 -(optionally substituted aryl), —(CH 2 ) 0-2 -(optionally substituted heteroaryl) and —(CH 2 ) 0-2 -(optionally substituted heterocyclyl); and
R 4 * is hydrogen.
17 . The compound according to claim 1 , which is selected from compounds 1001-1101:
Compound
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.
1030.
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.
18 - 20 . (canceled)
21 . A method of inhibiting the enzymatic activity of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound as defined in claim 1 .
22 . A method of treating a disease or condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound as defined in claim 1 .
23 . The method according to claim 22 , wherein the compound is administered in combination with a DNA damaging agent.
24 . The method according to claim 22 , wherein said disease or condition is one or more selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, asthma, COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis, fibrotic diseases, dermatosis, psoriasis, atopic dermatitis, ultra-violet induced skin damage, autoimmune diseases, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue rejection, organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, breast cancer, prostate cancer, lung cancer, colon cancer, cervix cancer, ovary cancer, skin cancer, CNS cancer, bladder cancer, pancreas cancer, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection, Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telangiectasia.