Benzamide, heteroarylamide and reverse amides
View Patent ↗The present invention relates to novel to P2X 7 inhibitors of formula I and to processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy. The active compounds of the present invention are potent inhibitors of P2X 7 and as such are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
1. A compound of the formula
wherein A is —(C═O)NH— or —NH(C═O)—;
X, Y and Z are ═(CR 6 )—, ═(CR 7 )—, and ═(CR 8 )—;
R 1 is
wherein R 0 is hydrogen, R 10 is hydrogen
q is an integer one or two;
s is an integer from one to three;
R 2 is chloro, bromo, (C 1 –C 4 )alkyl, —CF 3 or —CN;
R 3 is selected from the group consisting of (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s , (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )—; (C 1 –C 10 )heterocyclyl-(CR 11 R 12 ) s — and (C 1 –C 10 )heteroaryl-(CR 11 R 12 ) s —; wherein each of said R 3 group members (C 1 –C 10 )heteracyclyl(CR 11 R 12 ) s — and (C 1 –C 10 )heteroaryl(CR 11 R 12 ) s — contain one to three heteroatoms independently selected from —O— and —S(O) n —; wherein each of said R 3 group members (C 3 –C 12 )cycloalkyl(CR 11 R 12 ) s —, (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )—, (C 1 –C 10 )heterocyclyl(CR 11 R 12 ) s — and (C 1 –C 10 )heteroaryl(CR 11 R 12 ) s — may optionally be substituted on any ring carbon atom able to support an additional substituent, by one to four substituents per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, (C 1 –C 4 )alkyl-(C═O)—, (C 6 –C 10 )aryl, [(C 6 –C 10 )aryl] 2 —CH—, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, benzyl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein said R 3 group members (C 3 –C 12 )cycloalkyl(CR 11 R 12 ) s — and (C 1 –C 10 )heterocyclyl(CR 11 R 12 ) s — may also optionally be substituted by oxo; wherein each of the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl anywhere on said R 3 substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-NH—, [(C 1 –C 4 )alkyl] 2 —N—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl—(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—;
R 6 , R 7 and R 8 are each hydrogen;
R 11 and R 12 are each independently selected from the group consisting of hydrogen, fluoro, cyano, hydroxyl, CF 3 , CF 3 O—, (C 1 –C 6 )alkyl, (C 3 –C 8 )cycloalkyl, (C 1 –C 6 )alkyloxy, (C 3 –C 8 )cycloalkyloxy, phenyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl; wherein said (C 1 –C 6 )alkyl, (C 3 –C 8 )cycloalkyl, (C 1 –C 6 )alkyloxy, (C 3 –C 8 )cycloalkyloxy phenyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl may optionally be substituted by one to three substituents independently selected from chloro, fluoro, cyano, hydroxyl, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, or (C 1 –C 4 )alkyl-(C═O)—,
with the proviso that when said R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s —; R 1 and R 2 are each hydrogen; and s is one or two; then said (C 3 –C 12 )cycloalkyl must be other than optionally substituted adamantyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein A is —(C═O)NH—.
3. A compound according to claim 1 , wherein A is —NH(C═O)—.
4. A compound according to claim 2 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — wherein R 11 and R 12 is are each independently hydrogen or (C 1 –C 4 )alkyl.
5. A compound according to claim 2 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — wherein at least one of R 11 and R 12 is other than hydrogen or (C 1 –C 4 )alkyl.
6. A compound according to claim 2 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s —; optionally substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, oxo, —CO 2 —(C 1 –C 4 )alkyl, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
7. A compound according to claim 2 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — optionally substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —CN, (C 1 –C 4 )alkyl and (C 1 –C 4 )alkoxy.
8. A compound according to claim 2 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — optionally substituted by at least one substituent selected from the group consisting of (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )hereroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein each of the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 12 )hereroaryl and (C 1 –C 10 )heterocyclyl anywhere on said (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) 2 — substituents may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, —CO 2 —(C 1 –C 4 )alkyl, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
9. A compound according to claim 2 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — optionally substituted by at least one spiro substituent selected from the group consisting of (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein each of the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl spiro substituent on said (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, —CO 2 —(C 1 –C 4 )alkyl, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
10. A compound according to claim 2 , wherein R 3 is (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )—; wherein R 11 and R 12 )are each independently hydrogen or (C 1 –C 4 )alkyl.
11. A compound according to claim 2 , wherein R 3 is (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )—; wherein R 11 and R 12 are each independently selected from the group consisting of hydrogen and (C 1 –C 4 )alkyl and wherein each of R 11 and R 12 of the CR 11 R 12 directly attached to group A are hydrogen; and wherein said (C 6 –C 10 )aryl of said (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )— group member is substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, oxo, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, benzyloxy and (C 1 –C 4 )alkyl-(C═O)—.
12. A compound according to claim 2 , wherein R 3 is (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )—; wherein R 11 and R 12 are each independently selected from the group consisting of hydrogen and (C 1 –C 4 )alkyl; and wherein said (C 6 –C 10 )aryl of said (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )— group member is substituted by one to three substituents independently selected from the group consisting of hydrogen, halo, —CN, (C 1 –C 4 )alkyl, benzyloxy and (C 1 –C 4 )alkoxy.
13. A compound according to claim 2 , wherein R 3 is (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )—; wherein R 11 and R 12 are each independently selected from the group consisting of hydrogen and (C 1 –C 4 )alkyl; and wherein said (C 6 –C 10 )aryl of said (C 6 –C 10 )aryl-(CR 11 R 12 ) q —(CH 2 )— group member is substituted by at least one substituent selected from the group consisting of (C 1 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )hereroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein each of the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl substituents may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, benzyloxy and (C 1 –C 4 )alkyl-(C═O)—.
14. A compound according to claim 2 , wherein R 3 is (C 1 –C 10 )heteroaryl-(CR 11 R 12 ) s — optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 6 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 6 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
15. A compound according to claim 2 , wherein R 3 is (C 1 –C 10 )heteroaryl-(CR 11 R 12 ) s — optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
16. A compound according to claim 2 , wherein R 3 is (C 1 –C 10 )heteroaryl-(CR 11 R 12 ) s — optionally substituted on at least one carbon atom able to support an additional substituent by a substituent selected from the group consisting of (C 6 –C 10 )aryl, (C 3 C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O— substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
17. A compound according to claim 2 , wherein R 3 is (C 1 –C 10 )heterocyclyl-(CR 11 R 12 ) s — optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, oxo, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
18. A compound according to claim 2 , wherein R 3 (C 1 –C 10 )heterocyclyl-(CR 11 R 12 ) s — optionally substituted on any carbon atom able to support an additional substituent by one to three substituents per ring independently selected from the group consisting of halo, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, oxo, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
19. A compound according to claim 2 , wherein R 3 is (C 1 –C 10 )heterocyclyl-(CR 11 R 12 ) s — optionally substituted on at least one carbon atom able to support an additional substituent by a substituent selected from the group consisting of (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 5 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O— substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
20. A compound according to claim 2 , wherein R 3 is (C 1 –C 10 )heterocyclyl-(CR 11 R 12 ) s — optionally substituted on at least one carbon atom able to support an additional substituent by a spiro substituent selected from the group consisting of (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O— spiro substituents may optionally be substituted on any ring carbon atom by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—.
21. A compound according to claim 1 , wherein R 2 is chloro or bromo.
22. A compound according to claim 1 , wherein R 2 is chloro.
23. A compound according to claim 1 , wherein R 2 is (C 1 –C 4 )alkyl or —CN.
24. A compound according to claim 1 , wherein R 2 is hydroxy.
25. A compound according to claim 1 wherein said compound of formula I has the formula
wherein R 3 is (C 6 –C 10 )aryl-(CR 11 R 12 ) q —CH 2 —; wherein said (C 6 –C 10 )aryl may optionally be substituted by one to two substituents independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, (C 1 –C 4 )alkyl-(C═O)—, (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein each of the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl substituents may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, (C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, and (C 1 –C 4 )alkyl-(C═O)—
or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 1 wherein said compound of formula I has the formula
wherein R 3 is optionally substituted (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — wherein R 11 and R 12 are each independently hydrogen or (C 1 –C 4 )alkyl or wherein at least one of R 11 and R 12 is other than hydrogen or (C 1 –C 4 )alkyl; wherein said (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s — may optionally be substituted on any ring carbon atom able to support an additional substituent, by one to four substituents per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, (C 1 –C 4 )alkyl-(C═O)—, (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )hereroaryl, (C 1 –C 10 )heterocyclyl, (C 6 –C 10 )aryl-O—, (C 3 –C 8 )cycloalkyl-O—, (C 1 –C 10 )heteroaryl-O— and (C 1 –C 10 )heterocyclyl-O—; wherein each of the aforesaid (C 6 –C 10 )aryl, (C 3 –C 8 )cycloalkyl, (C 1 –C 10 )heteroaryl and (C 1 –C 10 )heterocyclyl substituents may optionally be substituted by one to three moieties per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, and (C 1 –C 4 )alkyl-S—.
27. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(2-fluoro-phenyl)-ethyl]-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2,2-diphenyl-ethyl)-benzamide;
N-[2-(2-Chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzamide;
N-[2-(2-Benzyloxy-phenyl)-ethyl]-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-phenyl-cyclohexylmethyl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-p-tolyl-cyclohexylmethyl)-benzamide;
2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5(4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; and
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(2-trifluoromethyl-phenyl)-ethyl]-benzamide; and pharmaceutically acceptable salts thereof.
28. A method for treating rheumatoid arthritis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition for the treatment of rheumatoid arthritis in a mammal which comprises an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
30. The method of claim 28 , wherein said mammal is a human.
31. The pharmaceutical composition of claim 29 , wherein said mammal is a human.
32. A compound having the formula
wherein R 3 is a C 7 cycloalkyl-(CR 11 R 12 ) s — substituted by one hydroxyl group on any ring carbon atom able to support an additional substituent;
wherein R 11 and R 12 are each hydrogen;
wherein s is one;
wherein R 2 is chloro; and
wherein R 10 is hydrogen.
33. A method for treating rheumatoid arthritis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound according to claim 27 .
34. A compound according to claim 1 , wherein R 3 is (C 3 –C 12 )cycloalkyl-(CR 11 R 12 ) s —;
wherein said R 3 group (C 3 –C 12 )cycloalkyl(CR 11 R 12 ) s — may optionally be substituted on any ring carbon atom able to support an additional substituent, by one to four substituents per ring, independently selected from the group consisting of halo, hydroxy, —CN, (C 1 –C 10 )alkyl, (C 1 –C 4 )alkoxy, —CF 3 , CF 3 O—, C 1 –C 4 )alkyl-S—, (C 1 –C 4 )alkyl-(S═O)—, (C 1 –C 4 )alkyl-(SO 2 )—, (C 1 –C 4 )alkyl-O—(C═O)—, formyl, (C 1 –C 4 )alkyl-(C═O)—, and (C 6 –C 10 )aryl;
wherein R 11 and R 12 are each hydrogen;
wherein s is one; and
wherein R 2 is chloro.
35. A pharmaceutical composition which comprises a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
36. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(4-phenyl-butyl)-benzamide;
2-Chloro-N-[2-(4-chloro-phenyl)-ethyl-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-phenethyl-benzamide;
N-[2-(4-Bromo-phenyl)-ethyl]-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(3-fluoro-phenyl)-ethyl-benzamide;
2-Chloro-N-[2-(2,6-dichloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(3-methoxy-phenyl)-ethyl]-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(2-ethoxy-phenyl)-ethyl]-benzamide;
N-(2-(5-Bromo-2-methoxy-phenyl)-ethyl)-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; and
2-Chloro-N-(2-(3-chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; and pharmaceutically acceptable salts thereof.
37. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
2-Chloro-N-(2-(2,4-dichloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4triazin-2-yl)-N-[2-(4-fluoro-phenyl)-ethyl-benzamide;
2-Chloro-N-cyclohexylmethyl-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-N-(2-(3,4-dichloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2-phenyl-propyl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2-thiophen-2-yl-ethyl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(5-hydroxy-1,3,3-trimethyl-cyclohexylmethyl)-benzamide;
N-Bicyclo[2.2.1 ]hept-2-ylmethyl-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4-]triazin-2-yl)-benzamide;
3-{[2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoylamino]-methyl}-cyclohexanecarboxylic acid methyl ester; and
N-Bicyclo[2.2.1.]hept-2-ylmethyl-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-1,2,4]triazin-yl)-benzamide; and pharmaceutically acceptable salts thereof.
38. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2-m-tolyl-ethyl)-benzamide;
2-Chloro-N-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(3-fluoro-phenyl)-2-hydroxy-ethyl]-benzamide;
3-{2-[2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoylamino]-ethyl}-benzoic acid methyl ester;
2-Chloro-N-(6,6-dimethyl-bicyclo[3.1.1]-hept-2-ylmethyl)-5-(3,5-dioxo4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2-hydroxy-2-phenyl-ethyl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-isochroman-1-ylmethyl-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(3-methylsulfanyl-phenyl)-ethyl]-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(2-methoxy-2-phenyl-ethyl)-benzamide; and
2-Chloro-N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; and pharmaceutically acceptable salts thereof.
39. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-[2-(2-methoxy-phenyl)-ethyl]-benzamide;
N-[2-(2-Bromo-4-methoxy-phenyl)-ethyl]-2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-phenyl-cyclopentylmethyl)-benzamide;
5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(4-phenyl-tetrahydro-pyran-4-ylmethyl)-2-trifluoromethyl-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(4-phenyl-tetrahydro-pyran-4-ylmethyl)-benzamide;
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-tricyclo[4.3.1.1 3.8 ]undec-1-ylmethyl-benzamide;
2-Chloro-N-[2-(4-chloro-phenyl)-propyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide; and
2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cyclohexylmethyl)-benzamide; and pharmaceutically acceptable salts thereof.
40. A compound according to claim 1 , wherein said compound is 2-Chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide, and pharmaceutically acceptable salts thereof.