US 11,666,557 B2
Triazolone compounds and uses thereof
Nicholas Simon Stock, Encinitas, CA (US); Austin Chih-Yu Chen, San Marcos, CA (US); Yalda Mostofi Bravo, San Diego, CA (US); Jason Duarte Jacintho, San Diego, CA (US); Jill Melissa Baccei, Poway, CA (US); Brian Andrew Stearns, Encinitas, CA (US); and Ryan Christopher Clark, San Diego, CA (US)
Assigned to TEMPEST THERAPEUTICS, INC., Brisbane, CA (US)
Filed by Tempest Therapeutics, Inc., Brisbane, CA (US)
Filed on Dec. 20, 2019, as Appl. No. 16/722,773.
Application 16/722,773 is a continuation of application No. 15/590,766, filed on May 9, 2017, granted, now 10,568,871.
Application 15/590,766 is a continuation of application No. 14/654,225, granted, now 9,676,754, issued on Jun. 13, 2017, previously published as PCT/US2013/074197, filed on Dec. 10, 2013.
Claims priority of provisional application 61/739,906, filed on Dec. 20, 2012.
Prior Publication US 2020/0138790 A1, May 7, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/4196 (2006.01); A61K 31/41 (2006.01); A61K 31/4439 (2006.01); A61K 31/506 (2006.01); C07D 401/10 (2006.01); C07D 401/06 (2006.01); C07D 403/10 (2006.01); C07D 403/06 (2006.01); C07D 249/12 (2006.01); A61P 35/00 (2006.01); A61P 35/02 (2006.01)
CPC A61K 31/4196 (2013.01) [A61K 31/41 (2013.01); A61K 31/4439 (2013.01); A61K 31/506 (2013.01); A61P 35/00 (2018.01); A61P 35/02 (2018.01); C07D 249/12 (2013.01); C07D 401/06 (2013.01); C07D 401/10 (2013.01); C07D 403/06 (2013.01); C07D 403/10 (2013.01)] 19 Claims
 
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:

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
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)2—, —(CH2)3—, —(CH2)4, —(CH2)m—O—(CH2)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;
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(C3-6cyc loalkyl)2, —S(═O)oC1-6alkyl, —S(═O)oC3-6cycloalkyl, and CN; each o is independently 0, 1, or 2;
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, C1-6 alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-6alkyl), —NH(C3-6 cycloalkyl), —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 (aa), (bb), (cc), (dd), (cc), (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(C3-6 cycloalkyl), —N(C1-6alkyl)2, —(C3-6cycloalkyl)2, —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) —C1-4 alkyl(R7),
(d) aryl,
(e) heteroaryl,
(f) —C3-6cycloalkyl,
(g) —C3-6cycloalkyl(R7),
(h) —C3-6cycloalkyl-O(R7),
(i) —C1-4 alkyl-C3-6cycloalkyl,
(j) C1-6alkoxy, and
(k) C3-6cycloalkoxy,
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 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) heteroaryl,
(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 C1-6alkyl, 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) —C1-6 alkyl-C3-6cycloalkyl, and
(k) CF3,
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, —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 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.