Triazolone compounds and uses thereof
The invention disclosed herein is directed to compounds of Formula I and pharmaceutically acceptable salts thereof, which are useful in the treatment of prostate, breast, colon, pancreatic, human chronic lymphocytic leukemia, melanoma and other cancers. The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. The invention disclosed herein is also directed to methods of treating prostate, breast, ovarian, liver, kidney, colon, pancreatic, human chronic lymphocytic leukemia, melanoma and other cancers. The invention disclosed herein is further directed to methods of treating prostate, breast, colon, pancreatic, chronic lymphocytic leukemia, melanoma and other cancers comprising administration of a therapeutically effective amount of a selective PPARα antagonist. The compounds and pharmaceutical compositions of the invention are also useful in the treatment of viral infections, such as HCV infections and HIV infections.
1. A method for treating cancer comprising administering a therapeutically effective amount of a compound of Formula I and an anti-cancer agent to a mammal in need thereof:
or a pharmaceutically acceptable salt thereof wherein:
A1 is phenyl or a 6-membered heteroaromatic ring having 1, 2 or 3 N in the heteroaromatic ring;
A2 is selected from A2a or A2b
wherein A2a is phenyl or a 6 membered heteroaromatic ring having 1, 2 or 3 N in the heteroaromatic ring, and
A2b is a 5 membered heteroaromatic ring having 1, 2 or 3 heteroatoms independently selected from O, S and N;
X is selected from the group consisting of —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 , —(CH 2 ) m —O—(CH 2 ) n —, optionally mono- or di-substituted with halogen, wherein m and n are independently 0, 1, 2, 3 or 4, with the proviso that m+n is 2, 3, or 4;
Y is O;
R 1 and R 2 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) CN,
(d) CF 3 ,
(e) —C 1-6 alkyl,
(f) —C 1-6 alkyl-C(═O)OH,
(g) —O—(R 7 ),
(h) —S(═O) o R 7 ,
(i) —N(R 7 )(R 8 ),
(j) —N(R 7 )—C(═O)—(R 8 ),
(k) —N(R 7 )—C(═O)—O—(R 8 ),
(l) —N(R 7 )S(═O) 2 (R 8 ),
(m) —C 3-6 cycloalkyl,
(n) —C(═O)(R 7 ),
(o) aryl,
(p) heteroaryl,
(q) —OC(═O)N(R 7 )(R 8 ),
(r) —S(═O) 2 N(R 7 )(R 8 ),
(s) —C(═O)N(R 7 )(R 8 ), and
(t) —C(R 7 )(R 8 )OH,
wherein the alkyl portion of choices (e) and (f), and the cycloalkyl portion of choice (m) are optionally substituted with halogen, and
wherein the aryl of choice (o) and the heteroaryl of choice (p) are optionally mono- or di-substituted with substituents selected from halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cyc loalkyl) 2 , —S(═O) o C 1-6 alkyl, —S(═O) o C 3-6 cycloalkyl, and CN; each o is independently 0, 1, or 2;
R 3 is selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) CN,
(d) CF 3 ,
(e) —C 1-6 alkyl,
(f) —C 1-6 alkyl-C(═O)OH,
(g) —O—(R 7 ),
(h) —S(═O) o R 7 ,
(i) —N(R 7 )(R 8 ),
(j) —N(R 7 )—C(═O)—(R 8 ),
(k) —N(R 7 )—C(═O)—O—(R 8 ),
(l) —N(R 7 )S(═O) 2 (R 8 ),
(m) —C 3-6 cycloalkyl,
(n) —C(═O)(R 7 ),
(o) aryl,
(p) heteroaryl,
(q) —OC(═O)N(R 7 )(R 8 ),
(r) —S(═O) 2 N(R 7 )(R 8 ),
(s) —C(═O)N(R 7 )(R 8 ),
(t) —C(R 7 )(R 8 )OH,
(u) —NHC(═O)—N(R 7 )(R 8 ),
(v) —C 3-6 cycloalkyl-COOH,
(w) heterocycle, and
(x) —C 1-6 alkylC(═O)—N(R 7 )(R 8 ),
wherein the alkyl portion of choices (e), (f) and (x), and the cycloalkyl portion of choices (m) and (v) are optionally substituted with halogen or hydroxyl, and
wherein the aryl of choice (o), the heteroaryl of choice (p), and the heterocycle of choice (w) are optionally mono- or di-substituted with substituents selected from halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , —S(═O) o C 1-6 alkyl, —S(═O) o C 3-6 cycloalkyl, hydroxyl and CN;
R 4 and R 4′ are each independently selected from the group consisting of:
(a) hydrogen,
(b) —N(R 7 )(R 8 ),
(c) —N(R 7 )S(═O) 2 R 8 ,
(d) —N(R 7 )—C(═O)R 8 ,
(e) —N(R 7 )C(═O)OR 8 ,
(f) —S(═O) o R 7 ,
(g) —S(═O) 2 N(R 7 )(R 8 ),
(h) —C(═O)R 7 ,
(i) —C(═O)N(R 7 )(R 8 ),
(j) —OC(═O)N(R 7 )(R 8 ),
(k) —O—R 7 ,
(l) —C(R 7 )(R 8 )OH,
(m) —C 1-4 alkyl-C(═O)NHS(═O) 2 R 7 ,
(n) —C 1-4 alkyl-S(═O) 2 NHC(═O)R 7 ,
(o) —C 1-4 alkyl-C(═O)—N(R 7 )(R 8 ),
(p) —C 1-4 alkyl-N(R 7 )C(═O)(R 8 ),
(q) —C 1-4 alkyl-N(R 7 ) S(═O) 2 (R 8 ),
(r) —C 1-4 alkyl-S(═O) 2 N(R 7 )(R 8 ),
(s) —C 1-4 alkyl-N(R 7 )C(═O)O(R 8 )
(t) —C 1-4 alkyl-O—C(═O)N(R 7 )(R 8 )
(u) —C 1-4 alkyl-C(═O) (R 7 ),
(v) —C 1-4 alkyl-C(R 7 )(R 8 ) OH,
(w) —C 1-4 alkyl-O(R 7 ),
(x) —C 1-6 alkyl-C(═O) OH,
(y) —C 2-6 alkenyl-C(═O)OH,
(z) —C 3-6 cycloalkyl-C(═O)OH,
(aa) —C 3-6 cycloalkyl-C(═O)NHS(═O) 2 R 7 ,
(bb) —C 3-6 cycloalkyl-S(═O) 2 NHC(═O)R 7 ,
(cc) —C 3-6 cycloalkyl-C(═O)—N(R 7 )(R 8 ),
(dd) —C 3-6 cycloalkyl-N(R 7 ) C(═O)(R 8 ),
(ee) —C 3-6 cycloalkyl-N(R 7 )S(═O) 2 (R 8 ),
(ff) —C 3-6 cycloalkyl-S(═O) 2 N(R 7 )(R 8 ),
(gg) —C 3-6 cycloalkyl-N(R 7 )C(═O)O(R 8 ),
(hh) —C 3-6 cycloalkyl-O—C(═O)N(R 7 )(R 8 ),
(ii) —C 3-6 cycloalkyl-C(═O)(R 7 ),
(jj) —C 3-6 cycloalkyl-C(R 7 )(R 8 )OH,
(kk) —C 3-6 cycloalkyl-O(R 7 ),
(ll) —C(═O)OH,
(mm) aryl,
(nn) heteroaryl,
(oo) —C(═O)N(R 7 )S(═O) 2 (R 8 ),
(pp) —S(═O) 2 N(R 7 )C(═O)(R 8 ),
(qq) —NHS(═O) 2 N(R 7 )(R 8 ),
(rr) —NHC(═O)N(R 7 )(R 8 ),
(ss) —CH(OH)—C(═O)—N(R 7 )(R 8 ),
(tt) —C(═O)—C(═O)—N(R 7 )(R 8 ),
(uu) —C 3-6 cycloalkyl,
(w) —CF 3 ,
(ww) —C 1-6 alkyl N(R 7 )(R 8 ),
(xx) -heterocycle,
(yy) —C 1-6 alkyl,
(zz) halogen, and
(aaa) —O—C 1-6 alkyl-N(R 7 )(R 8 ),
wherein the alkyl portion of choices (m), (n), (o), (p), q), (r), (s), (t), (u), (v), (w), (x), (ww), (yy) and (aaa), the alkenyl portion of choice (y), and the cycloalkyl portion of choices (aa), (bb), (cc), (dd), (cc), (gg), (hh), (ii), (jj), (kk) and (uu), are optionally mono- or di-substituted with halogen, CN, aryl, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkoxy, and
wherein the aryl of choice (mm), the heteroaryl of choice (nn), and the heterocycle of choice (xx) are optionally mono- or di-substituted with substituents selected from halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —(C 3-6 cycloalkyl) 2 , —S(═O) o C 3-6 cycloalkyl, hydroxyl and CN, or
wherein R 3 and R 4 or R 4 and R 4′ are joined together to form a 5- or 6-membered heterocyclic ring, said ring having one heteroatom selected from O and N, wherein said ring is optionally substituted with —C(═O)OH, or —C 1-6 alkyl-C(═O)OH, with the proviso that at least one of R 3 , R 4 and R 4′ is other than hydrogen;
R 5 is selected from the group consisting of:
(a) hydrogen,
(b) —C 1-6 alkyl,
(c) —C 1-4 alkyl(R 7 ),
(d) aryl,
(e) heteroaryl,
(f) —C 3-6 cycloalkyl,
(g) —C 3-6 cycloalkyl(R 7 ),
(h) —C 3-6 cycloalkyl-O(R 7 ),
(i) —C 1-4 alkyl-C 3-6 cycloalkyl,
(j) C 1-6 alkoxy, and
(k) C 3-6 cycloalkoxy,
wherein the alkyl portion of choices (h), (c), (i) and (j), the cycloalkyl portion of choices (f), (g), (h), (i) and (k) are optionally substituted with halogen or C 1-4 alkyl, and
wherein the aryl of choice (d) and the heteroaryl of choice (e), are optionally mono- or di-substituted with substituents selected from halogen, nitro, C 1-6 alkyl, CF 3 , C 1-6 alkoxy, halo C 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, and CN;
R 6 is selected from the group consisting of:
(a) hydrogen,
(b) —C 1-6 alkyl,
(c) —C 1-6 alkylaryl,
(d) —C 1-6 alkylheteroaryl,
(e) —S(═O) o C 1-6 alkyl(R 7 ),
(f) —C(═O)C 1-6 alkyl(R 7 ),
(g) —C 3-6 cycloalkyl,
(h) aryl,
(i) heteroaryl,
(j) —C(═O)C 3-6 cycloalkyl(R 7 ),
(k) —S(═O) o C 3-6 cycloalkyl(R 7 ), and
(l) —C 1-6 alkyl(R 7 ),
wherein the alkyl portion of choices (b), (c), (d), (e), (f), and (l) and the cycloalkyl portion of choices (g), (j), and (k), are optionally substituted with halogen or C 1-4 alkyl, and
wherein the aryl portion of choices (c) and (h), and the heteroaryl portion of choices (d) and (i), are optionally mono- or di-substituted with substituents selected from halogen, nitro, —CF 3 , C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, aryl, heteroaryl, heterocycle optionally substituted with halogen, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl) —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , —S(═O) o C 1-6 alkyl, S(═O) o C 3-6 cycloalkyl, and CN;
R 7 and R 8 are each independently selected from the following:
(a) hydrogen,
(b) —C 1-6 alkyl,
(c) —C 3-6 cycloalkyl,
(d) -aryl,
(e) -heteroaryl,
(f) —C 1-6 alkylaryl,
(g) —C 1-6 alkylheteroaryl,
(h) —C(═O)C 1-6 alkyl,
(i) —S(═O) o -aryl,
(j) —C 1-6 alkyl-C 3-6 cycloalkyl, and
(k) CF 3 ,
wherein the alkyl of choices (h), (f), (g), (h), and (j), and the cycloalkyl of choices (c) and (j), are each optionally mono-, di- or tri-substituted with halogen, and
wherein the aryl portion of choices (d), (f) and (i), and the heteroaryl portion of choices (e) and (g), are each optionally mono- or di-substituted with substituents selected from halogen, —C(═O)OH, —CF 3 , —NHC(═O)CH 3 , nitro, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, —NH(C 1-3 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-3 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , —S(═O) o C 1-4 alkyl, S(═O) o C 3-6 cycloalkyl, aryl, heteroaryl, hydroxyl, and CN;
R 9 and R 10 are each independently selected from the following
(a) hydrogen,
(b) —C 1-6 alkyl,
(c) —C 3-6 cycloalkyl,
(d) halogen,
(e) —OC 3-6 cycloalkyl,
(f) CF 3 , and
(g) C 1-6 alkoxy,
wherein the alkyl portion of choice (b) and the cycloalkyl portion of choices and (e), are each optionally mono-, di- or tri-substituted with halogen;
wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, liver cancer, kidney cancer, colon cancer, pancreatic caner, human chronic lymphocytic leukemia, and melanoma.
2. The method according to claim 1 , wherein X is —CH 2 CH 2 CH 2 — or —CF 2 CH 2 CH 2 —.
3. The method according to claim 1 , wherein A1 is phenyl.
4. The method according to claim 1 , wherein:
R 1 and R 2 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) CN,
(d) CF 3 ,
(e) —C 1-6 alkyl,
(f) —O—(R 7 ),
(g) —C 3-6 cycloalkyl, and
(h) —N(R 7 )(R 8 ),
wherein the alkyl portion of choice (e) and the cycloalkyl portion of choice (g) are optionally substituted with halogen.
5. The method according to claim 4 , wherein R 1 and R 2 are each hydrogen.
6. The method according to claim 1 , wherein A2 is A2a and A2a is substituted phenyl, substituted pyrimidine, substituted pyrazine, or substituted pyridine.
7. The method according to claim 1 , wherein:
R 3 is selected from the group consisting of:
(a) hydrogen,
(b) —O—(R 7 ),
(c) —N(R 7 )S(═O) 2 (R 8 ), and
(d) —C 1-6 alkyl,
wherein the alkyl portion of choice (d) is optionally substituted with halogen or hydroxyl.
8. The method according to claim 1 , wherein:
R 4 and R 4′ are each independently selected from the group consisting of:
(a) hydrogen,
(b) —O—(R 7 ),
(c) —C(R 7 )(R 8 )OH,
(d) —C 1-6 alkyl-C(═O)OH,
(e) —C 3-6 cycloalkyl-C(═O)OH,
(f) —C(═O)OH,
(g) C 3-6 cycloalkyl,
(h) CF 3 ,
(i) heterocycle,
(j) —C 1-6 alkyl, and
(k) halogen,
wherein the alkyl portion of choices (d) and (j), and the cycloalkyl portion of choice (g) are optionally mono- or di-substituted with halogen, CN, aryl, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkoxy, and
wherein the heterocycle of choice (i) is optionally mono- or di-substituted with substituents selected from halogen, hydroxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , —S(═O) o C 1-6 alkyl, —S(═O) o C 3-6 cycloalkyl, and CN.
9. The method according to claim 1 , wherein:
R 5 is selected from the group consisting of:
(a) hydrogen,
(b) —C 1-6 alkyl, and
(c) —C 1-4 alkyl(R 7 ),
wherein the alkyl portion of choices (b) and (c) is optionally substituted with halogen or C 1-4 alkyl.
10. The method according to claim 1 , wherein:
R 6 is selected from the group consisting of:
(a) —C 1-6 alkylaryl,
(b) —C 1-6 alkylheteroaryl, and
(c) —C 1-6 alkyl(R 7 ),
wherein the alkyl portion of choices (a), (b), and (c) is optionally substituted with halogen or C 1-4 alkyl, and
wherein the aryl portion of choice (a), and the heteroaryl portion of choice (b) are optionally mono- or di-substituted with substituents selected from the group consisting of halogen, nitro, —CF 3 , C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyoxy, aryl, heteroaryl, heterocycle optionally substituted with halogen, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , and CN.
11. The method according to claim 1 , wherein:
R 9 and R 10 are each independently
(a) hydrogen,
(b) —C 1-6 alkyl,
(c) halogen,
(d) CF 3 , and
(e) C 1-6 alkoxy,
wherein the alkyl portion of choice (b) is optionally mono-, di-, or tri-substituted with halogen.
12. The method according to claim 1 , wherein:
A2 is A2a, and A2a is a substituted phenyl, substituted pyrimidine, substituted pyrazine, or substituted pyridine;
R 1 and R 2 are each independently selected from:
(a) hydrogen,
(b) halogen,
(c) —CF 3 ,
(d) —C 1-6 alkyl, and
(e) —O—(R 7 ),
wherein the alkyl portion of choice (d) is optionally substituted with halogen;
R 3 is selected from the group consisting of:
(a) hydrogen,
(b) —O—(R 7 ),
(c) —N(R 7 )S(═O) 2 (R 8 ), and
(d) —C 1-6 alkyl,
wherein the alkyl portion of choice (d) is optionally substituted with halogen or hydroxyl;
R 4 and R 4′ are each independently selected from the group consisting of:
(a) hydrogen,
(b) —N(R 7 )S(═O) 2 R 8 ,
(c) —N(R 7 )—C(═O)R 8 ,
(d) —O—(R 7 ),
(e) —C(R 7 )(R 8 )OH,
(f) —C 1-4 alkyl-S(═O) 2 NHC(═O)R 7 ,
(g) —C 1-4 alkyl-N(R 7 ) S(═O) 2 (R 8 ),
(h) —C 1-4 alkyl-S(═O) 2 N(R 7 )(R 8 ),
(i) —C 1-4 alkyl-O(R 7 ),
(j) —C 1-6 alkyl-C(═O)OH,
(k) —C 3-6 cycloalkyl-C(═O)OH,
(l) —C 3-6 cycloalkyl-N(R 7 )S(═O) 2 (R 8 ),
(m) —C 3-6 cycloalkyl-S(═O) 2 N(R 7 )(R 8 ),
(n) —C 3-6 cycloalkyl-O(R 7 ),
(o) —C(═O)OH,
(p) —C(═O)N(R 7 )S(═O) 2 (R 8 ),
(q) —S(═O) 2 N(R 7 )C(═O)(R 8 ),
(r) —NHS(═O) 2 N(R 7 )(R 8 ),
(s) —C 3-6 cycloalkyl,
(t) CF 3 ,
(u) heterocycle,
(v) —C 1-6 alkyl, and
(w) halogen,
wherein the alkyl portion of choices (f), (g), (h), (i), (j), and (v), and the cycloalkyl portion of choices (k), (l), (m), (n), and (s), are optionally mono- or di-substituted with halogen, CN, aryl, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkoxy, and
wherein the heterocycle of choice (u) is optionally mono- or di-substituted with substituents selected from halogen, hydroxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , —S(═O) o C 1-6 alkyl, —S(═O) o C 3-6 cycloalkyl and CN;
R 5 is selected from the group consisting of:
(a) hydrogen,
(h) —C 1-6 alkyl, and
(c) —C 1-4 alkyl(R 7 ),
wherein the alkyl portion of choices (b) and (c) is optionally substituted with halogen or C 1-4 alkyl;
R 6 is selected from the group consisting of:
(a) —C 1-6 alkylaryl,
(b) —C 1-6 alkylheteroaryl, and
(c) —C 1-6 alkyl(R 7 ),
wherein the alkyl portion of choices (a), (b), and (c) is optionally substituted with halogen or C 1-4 alkyl, and
wherein the aryl portion of choice (a), and the heteroaryl portion of choice (b), are optionally mono- or di-substituted with substituents selected from halogen, nitro, —CF 3 , C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, aryl, heteroaryl, heterocycle optionally substituted with halogen, —NH(C 1-6 alkyl), —NH(C 3-6 cycloalkyl), —N(C 1-6 alkyl) 2 , —N(C 3-6 cycloalkyl) 2 , —S(═O) o C 1-6 alkyl, —S(═O) o C 3-6 cycloalkyl, and CN.
13. The method according to claim 1 , wherein the compound is a compound of Formula 1a:
or a pharmaceutically acceptable salt thereof.
14. The method according to claim 1 , wherein the compound is a compound of Formula 1b:
or a pharmaceutically acceptable salt thereof.
15. The method according to claim 1 , wherein the compound has the structure:
16. The method according to claim 1 , wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, liver cancer, kidney cancer, colon cancer, and pancreatic cancer.
17. The method according to claim 1 , wherein the cancer is liver cancer.
18. The method according to claim 1 , wherein the anti-cancer agent is a monoclonal antibody.
19. The method according to claim 1 , wherein the anti-cancer agent is imatinib, gefitinib, erlotinib, sorafenib, or sunitinib.