Aryl pladienolides for the treatment of neoplastic disorders
The present disclosure provides novel pladienolide compounds according to Formula I: pharmaceutical compositions containing such compounds, and methods for using the compounds as therapeutic agents. These compounds may be useful in the treatment of cancer, particularly cancers in which agents that target the spliceosome and mutations therein are known to be useful. Also provided herein are methods of treating cancers by administering at least one compound disclosed herein and at least one additional therapy.
1 . A method for treating a subject having a neoplastic disorder or a subject suspected of having a neoplastic disorder, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of at least one compound of the following formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is:
wherein R 1 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 3 -C 8 cycloalkyl group, a hydroxy-C 1 -C 6 alkyl group, N(CH 3 ) 2 , and a methoxy-C 1 -C 6 alkyl group;
R 2 is hydrogen, a C 1 -C 6 alkyl group, or an OR 10 group;
R 3 is hydrogen, a C 1 -C 6 alkyl group, or an OR 10 group;
R 4 is hydrogen, a C 1 -C 6 alkyl group, or an OR 10 group;
R 5 is hydrogen, a C 1 -C 6 alkyl group, or an OR 10 group;
R 6 is hydrogen, a C 1 -C 6 alkyl group, or an OR 10 group;
R 7 is hydrogen, a C 1 -C 6 alkyl group, or an OR 10 group;
V is —CH 2 — or —NR 9 —;
W is a 3- to 8-membered carbocyclyl group or a 3- to 10-membered heterocyclyl group, wherein the 3- to 8-membered carbocyclyl group or the 3- to 10-membered heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, NR 8 R 9 , a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a methoxy-C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, and a C 3 -C 5 cycloalkyl group;
each R 8 is independently hydrogen or a C 1 -C 6 alkyl group;
each R 9 is independently hydrogen or a C 1 -C 6 alkyl group;
each R 10 is independently hydrogen, a C 1 -C 6 alkyl group, a C 1 -C 6 aminoalkyl group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkylcarboxylic acid group, a C 3 -C 8 cycloalkyl group, a benzyl group, a C 3 -C 8 heterocyclyl group, a CH 2 —C 3 -C 8 heterocyclyl group, a C(O)—C 3 -C 8 heterocyclyl group, an acyl group, a hydroxy-C 1 -C 6 alkyl group, a methoxy-C 1 -C 6 alkyl group, CD 3 , or C(O)—NR 11 R 12 ;
each R 11 is independently hydrogen, a C 1 -C 6 alkyl group, a C 1 -C 6 aminoalkyl group, a C 1 -C 6 alkylamino group, a C 3 -C 8 cycloalkyl group, or a C 3 -C 8 heterocyclyl group;
each R 12 is independently hydrogen, a C 1 -C 6 alkyl group, a C 1 -C 6 aminoalkyl group, a C 1 -C 6 alkylamino group, a C 3 -C 8 cycloalkyl group, or a C 3 -C 8 heterocyclyl group;
L 1 is a bond, —O—, —C(O)—, —C(O)—O—, —NR 13 —C(O)—, —C(O)—NR 13 —, —NR 13 —S(O) 2 —, —S(O) 2 —NR 13 —, —S(O) 2 —, or —NR 13 —;
X is a bond, a 3- to 8-membered carbocyclyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered carbocyclyl group or the 3- to 8-membered heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a methoxy-C 1 -C 6 alkyl group, an S(O) 2 —C 1 -C 6 alkyl group, and NR 14 R 15 ;
L 2 is a bond, —O—, —C(O)—, —C(O)—O—, —NR 13 —C(O)—, —C(O)—NR 13 —, —NR 13 —S(O) 2 —, —S(O) 2 —NR 13 —, —S(O) 2 —, or —NR 13 —;
Y is hydrogen, a 3- to 8-membered carbocyclyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered carbocyclyl group or the 3- to 8-membered heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a methoxy-C 1 -C 6 alkyl group, a S(O) 2 —C 1 -C 6 alkyl group, and NR 14 R 15 ;
each R 13 is independently hydrogen or a C 1 -C 6 alkyl group;
each R 14 is independently hydrogen or a C 1 -C 6 alkyl group;
each R 15 is independently hydrogen or a C 1 -C 6 alkyl group;
n 1 is 0, 1, 2, 3, or 4;
n 2 is 0, 1, 2, 3, or 4;
n 3 is 0, 1, 2, 3, or 4; and
n 4 is 0, 1, 2, 3, or 4;
wherein administration of the therapeutically effective amount of the at least one compound or pharmaceutically acceptable salt thereof to the subject in need thereof:
(i) induces at least one neoantigen; or
(ii) induces a T-cell response; or
(iii) induces at least one neoantigen and a T-cell response.
2 . The method of claim 1 , wherein the neoplastic disorder is a solid tumor selected from the group consisting of breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer.
3 . The method of claim 1 , wherein the neoplastic disorder is a hematological malignancy selected from the group consisting of a B-cell malignancy, a leukemia, a lymphoma, and a myeloma.
4 . The method of claim 1 , wherein the amount of the at least one compound administered is reduced relative to a standard dosage of the at least one compound, due to the induction of at least one neoantigen and/or the induction of the T-cell response.
5 . The method of claim 4 , wherein the administered amount of the at least one compound is reduced by at least 10% relative to a standard dosage of the at least one compound.
6 . The method of claim 5 , wherein the at least one compound is administered at least 10% less frequently, relative to a standard dosing regimen of the at least one compound.
7 . The method of claim 1 , wherein R 1 is
and wherein R 1 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and a C 1 -C 6 alkyl group.
8 . The method of claim 1 , wherein R 1 is
and wherein R 1 is optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkyl groups.
9 . The method of claim 1 , wherein R 1 is unsubstituted
10 . The method of claim 1 , wherein R 2 is hydrogen and R 3 is methyl.
11 . The method of claim 1 , wherein R 4 is hydrogen and R 5 is OH.
12 . The method of claim 1 , wherein R 6 is hydrogen and R 7 is methyl.
13 . The method of claim 1 , wherein R 8 is methyl.
14 . The method of claim 1 , wherein V is —CH 2 —.
15 . The method of claim 1 , wherein W is a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, or an imidazopyridine ring, wherein the benzene ring, the pyridine ring, the benzimidazole ring, the benzotriazole ring, the indazole ring, the 1,2,3,6-tetrahydropyridine ring, or the imidazopyridine ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, NR 8 R 9 , a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a methoxy-C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, and a C 3 -C 5 cycloalkyl group.
16 . The method of claim 1 , wherein W is a benzene ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and a C 1 -C 6 alkyl group.
17 . The method of claim 1 , wherein X is a bond or a 3- to 8-membered carbocyclyl or heterocyclyl group and Y is a 3- to 8-membered carbocyclyl or heterocyclyl group, wherein the 3- to 8-membered carbocyclyl or heterocyclyl group of X and Y are independently selected from the group consisting of
wherein the 3- to 8-membered carbocyclyl or heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a methoxy-C 1 -C 6 alkyl group, an S(O) 2 —C 1 -C 6 alkyl group, and NR 14 R 15 .
18 . The method of claim 1 , wherein Y is hydrogen and X is a 3- to 8-membered carbocyclyl or heterocyclyl group selected from the group consisting of
wherein the 3- to 8-membered carbocyclyl or heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a methoxy-C 1 -C 6 alkyl group, an S(O) 2 —C 1 -C 6 alkyl group, and NR 14 R 15 .
19 . The method of claim 1 , wherein Y is hydrogen and X is a bond.
20 . The method of claim 1 , further comprising administering at least one additional therapy.
21 . A method for treating a subject having a neoplastic disorder or a subject suspected of having a neoplastic disorder, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of at least one compound of selected from the group consisting of:
or a pharmaceutically acceptable salt thereof,
wherein administration of the therapeutically effective amount of the at least one compound or pharmaceutically acceptable salt thereof to the subject in need thereof:
(i) induces at least one neoantigen; or
(ii) induces a T-cell response; or
(iii) induces at least one neoantigen and a T-cell response.
22 . The method of claim 21 , wherein the neoplastic disorder is a solid tumor selected from the group consisting of breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer.
23 . The method of claim 21 , wherein the neoplastic disorder is a hematological malignancy selected from the group consisting of a B-cell malignancy, a leukemia, a lymphoma, and a myeloma.