US 2020/0138790 A1 · TRIAZOLONE COMPOUNDS AND USES THEREOF

Abstract

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.

A compound of Formula I

or a pharmaceutical 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 —(CH2)m—, —(CH2)m—O—(CH2)n—, —(CH2)m—NH—(CH2)n—, —(CH2)m—S(═O)o—(CH2)n—, optionally mono- or di-substituted with halogen, wherein m and n are independently 0, 1, 2, 3 or 4, and each o is independently 0, 1 or 2;
Y is O or S;
R1 and R2 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) CN,
(d) CF3,
(e) —C1-6alkyl,
(f) —C1-6alkyl-C(═O)OH,
(g) —O—(R7),
(h) —S(═O)oR7,
(i) —N(R7)(R8),
(j) —N(R7)—C(═O)—(R8),
(k) —N(R7)—C(═O)—O—(R8),
(l) —N(R7)S(═O)2(R8),
(m) —C3-6cycloalkyl,
(n) —C(═O)(R7),
(o) aryl,
(p) heteroaryl,
(q) —OC(═O)N(R7)(R8),
(r) —S(═O)2N(R7)(R8),
(s) —C(═O)N(R7)(R8), and
(t) —C(R7)(R8)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, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-6alkyl), —NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(═O)oC1-6alkyl, —S(═O)oC3-6cycloalkyl, and CN;
R3 is selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) CN,
(d) CF3,
(e) —C1-6alkyl,
(f) —C1-6alkyl-C(═O)OH,
(g) —O—(R7),
(h) —S(═O)oR7,
(i) —N(R7)(R8),
(j) —N(R7)—C(═O)—(R8),
(k) —N(R7)—C(═O)—O—(R8),
(l) —N(R7)S(═O)2(R8),
(m) —C3-6cycloalkyl,
(n) —C(═O)(R7),
(o) aryl,
(p) heteroaryl,
(q) —OC(═O)N(R7)(R8),
(r) —S(═O)2N(R7)(R8),
(s) —C(═O)N(R7)(R8),
(t) —C(R7)(R8)OH,
(u) —NHC(═O)—N(R7)(R8),
(v) —C3-6cycloalkyl-COOH,
(w) heterocycle, and
(x) —C1-6alkylC(═O)—N(R7)(R8),
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, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-6alkyl), —NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(═O)oC1-6alkyl, —S(═O)oC3-6cycloalkyl, hydroxyl and CN;
R4 and R4′ are each independently selected from the group consisting of:
(a) hydrogen,
(b) —N(R7)(R8),
(c) —N(R7)S(═O)2R8,
(d) —N(R7)—C(═O)R8,
(e) —N(R7)C(═O)OR8,
(f) —S(═O)oR7,
(g) —S(═O)2N(R7)(R8),
(h) —C(═O)R7,
(i) —C(═O)N(R7)(R8),
(j) —OC(═O)N(R7)(R8),
(k) —O—R7,
(l) —C(R7)(R8)OH,
(m) —C1-4alkyl-C(═O)NHS(═O)2R7,
(n) —C1-4alkyl-S(═O)2NHC(═O)R7,
(o) —C1-4alkyl-C(═O)—N(R7)(R8),
(p) —C1-4alkyl-N(R7)C(═O)(R8),
(q) —C1-4alkyl-N(R7) S(═O)2(R8),
(r) —C1-4alkyl-S(═O)2N(R7)(R8),
(s) —C1-4alkyl-N(R7)C(═O)O(R8)
(t) —C1-4alkyl-O—C(═O)N(R7)(R8)
(u) —C1-4alkyl-C(═O) (R7),
(v) —C1-4alkyl-C(R7)(R8) OH,
(w) —C1-4alkyl-O(R7),
(x) —C1-6alkyl-C(═O) OH,
(y) —C2-6alkenyl-C(═O)OH,
(z) —C3-6cycloalkyl-C(═O)OH,
(aa) —C3-6cycloalkyl-C(═O)NHS(═O)2R7,
(bb) —C3-6cycloalkyl-S(═O)2NHC(═O)R7,
(cc) —C3-6cycloalkyl-C(═O)—N(R7)(R8),
(dd) —C3-6cycloalkyl-N(R7)C(═O)(R8),
(ee) —C3-6cycloalkyl-N(R7)S(═O)2(R8),
(ff) —C3-6cycloalkyl-S(═O)2N(R7)(R8),
(gg) —C3-6cycloalkyl-N(R7)C(═O)O(R8),
(hh) —C3-6cycloalkyl-O—C(═O)N(R7)(R8),
(ii) —C3-6cycloalkyl-C(═O)(R7),
(jj) —C3-6cycloalkyl-C(R7)(R8)OH,
(kk) —C3-6cycloalkyl-O(R7),
(ll) —C(═O)OH,
(mm) aryl,
(nn) heteroaryl,
(oo) —C(═O)N(R7)S(═O)2(R8),
(pp) —S(═O)2N(R7)C(═O)(R8),
(qq) —NHS(═O)2N(R7)(R8),
(rr) —NHC(═O)N(R7)(R8),
(ss) —CH(OH)—C(═O)—N(R7)(R8),
(tt) —C(═O)—C(═O)—N(R7)(R8),
(uu) —C3-6cycloalkyl,
(w) —CF3,
(ww) —C1-6alkyl N(R7)(R8),
(xx) -heterocycle,
(yy) —C1-6alkyl,
(zz) halogen, and
(aaa) —O—C1-6alkyl-N(R7)(R8),
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 (z), (aa), (bb), (cc), (dd), (ee), (ff), (gg), (hh), (ii), (jj), (kk) and (uu), are optionally mono- or di-substituted with halogen, CN, aryl, C1-6alkyl, halo C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, or C3-6cycloalkoxy, 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, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-6alkyl), —NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(═O)oC1-6alkyl, —S(═O)oC3-6cycloalkyl, hydroxyl and CN, or
wherein R3 and R4 or R4 and R4′ 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 —C1-6alkyl-C(═O)OH, with the proviso that at least one of R3, R4 and R4′ is other than hydrogen;
R5 is selected from the group consisting of:
(a) hydrogen,
(b) —C1-6alkyl,
(c) —C1-4alkyl(R7),
(d) aryl,
(e) heteroaryl,
(f) —C3-6cycloalkyl,
(g) —C3-6cycloalkyl(R7),
(h) —C3-6cycloalkyl-O(R7),
(i) —C1-4alkyl-C3-6cycloalkyl,
(j) C1-6alkoxy, and
(k) C3-6cycloalkoxy,
wherein the alkyl portion of choices (b), (c), (i) and (j), the cycloalkyl portion of choices (f), (g), (h), (i) and (k) are optionally substituted with halogen or C1-4alkyl, 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, C1-6alkyl, CF3, C1-6alkoxy, halo C1-6alkyl, aryl, heteroaryl, C3-6cycloalkyl, C3-6cycloalkoxy, and CN;
R6 is selected from the group consisting of:
(a) hydrogen,
(b) —C1-6alkyl,
(c) —C1-6alkylaryl,
(d) —C1-6alkylheteroaryl,
(e) —S(═O)oC1-6alkyl(R7),
(f) —C(═O)C1-6alkyl(R7),
(g) —C3-6cycloalkyl,
(h) aryl,
(i) hetereoaryl,
(j) —C(═O)C3-6cycloalkyl(R7),
(k) —S(═O)oC3-6cycloalkyl(R7), and
(l) —C1-6alkyl(R7),
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 C1-4alkyl, 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, —CF3, C1-6alkyl, C1-6alkoxy, halo C4-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, aryl, heteroaryl, heterocycle optionally substituted with halogen, —NH(C1-6alkyl), —NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(═O)oC1-6alkyl, S(═O)oC3-6cycloalkyl, and CN;
R7 and R8 are each independently selected from the following:
(a) hydrogen,
(b) —C1-6alkyl,
(c) —C3-6cycloalkyl,
(d) -aryl,
(e) -heteroaryl,
(f) —C1-6alkylaryl,
(g) —C1-6alkylheteroaryl,
(h) —C(═O)C1-6alkyl,
(i) —S(═O)o-aryl,
(j) —C1-6alkyl-C1-6cycloalkyl, and
(k) CF3,
wherein the alkyl of choices (b), (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, —CF3, —NHC(═O)CH3, nitro, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-3alkyl), —NH(C3-6cycloalkyl), —N(C1-3alkyl)2, —N(C3-6cycloalkyl)2, —S(═O)oC1-4alkyl, S(═O)oC3-6cycloalkyl, aryl, heteroaryl, hydroxyl, and CN;
R9 and R10 are each independently selected from the following
(a) hydrogen,
(b) —C1-6alkyl,
(c) —C3-6cycloalkyl,
(d) halogen,
(e) —OC3-6cycloalkyl,
(f) CF3, and
(g) C1-6alkoxy,
wherein the alkyl portion of choice (b) and the cycloalkyl portion of choices (c) and (e), are each optionally mono-, di- or tri-substituted with halogen.

163 more elements

Triazolone compounds and uses thereof

Life of this patent

Triazolone compounds and uses thereof

Life of this patent

Abstract

Claims32