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US-12622905-B2 - Aryl pladienolides for the treatment of neoplastic disorders

US12622905B2US 12622905 B2US12622905 B2US 12622905B2US-12622905-B2

Abstract

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.

Inventors

  • Andrew Cook
  • Jason T. LOWE
  • JAMES PALACINO
  • Dominic Reynolds
  • Cheng Zhong
  • RYAN BRAWN
  • SHELBY ELLERY
  • Thiwanka Samarakoon
  • Xiang Liu
  • Sudeep Prajapati
  • MEGAN SHEEHAN

Assignees

  • EISAI R&D MANAGEMENT CO., LTD.

Dates

Publication Date
20260512
Application Date
20230307

Claims (20)

  1. 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. 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. 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. 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. 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. 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. 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. 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. 9 . The method of claim 1 , wherein R 1 is unsubstituted
  10. 10 . The method of claim 1 , wherein R 2 is hydrogen and R 3 is methyl.
  11. 11 . The method of claim 1 , wherein R 4 is hydrogen and R 5 is OH.
  12. 12 . The method of claim 1 , wherein R 6 is hydrogen and R 7 is methyl.
  13. 13 . The method of claim 1 , wherein R 8 is methyl.
  14. 14 . The method of claim 1 , wherein V is —CH 2 —.
  15. 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. 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. 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. 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. 19 . The method of claim 1 , wherein Y is hydrogen and X is a bond.
  20. 20 . The method of claim 1 , further comprising administering at least one additional therapy.

Description

The present application is a division of application Ser. No. 17/046,528, filed Oct. 9, 2020, which is a national stage filing under 35 U.S.C. § 371 of International Application No. PCT/US2019/026992, filed on Apr. 11, 2019, which claims the benefit of priority to U.S. Provisional Application No. 62/656,865 filed Apr. 12, 2018; U.S. Provisional Application No. 62/679,658 filed Jun. 1, 2018; U.S. Provisional Application No. 62/814,824 filed Mar. 6, 2019; and U.S. Provisional Application No. 62/814,828 filed Mar. 6, 2019, all of which are incorporated herein by reference. STATEMENT REGARDING SEQUENCE LISTING The sequence listing associated with this application is provided in xml format and is hereby incorporated by reference in its entirety into the specification. The name of the xml file containing the sequence listing is 080610036.xml; the file is 83,919 bytes; was created on Mar. 1, 2023 and is being submitted via Patent Center with the filing of this application. Disclosed herein are novel organic compounds and pharmaceutical compositions containing such compounds. 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. These compounds may also be useful in treating cancer when administered in combination with at least one additional therapy. In eukaryote organisms, newly synthesized messenger RNAs typically have multiple introns, which are excised to provide the mature mRNA. The spliceosome is a multisubunit complex that accomplishes this task. The spliceosome consists of five small nuclear RNAs (snRNAs; U1-6) in combination with a variety of proteins. Mutations in spliceosome genes have been found in various types of cancers. For example, mutations in the splicing factor 3B subunit 1 (SF3B1) of the spliceosome exist in a number of cancers and comprise a target for anticancer agents. Such cancers include, but are not limited to, myelodysplastic syndrome (MDS), leukemia such as chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), and solid tumors such as breast cancer and uveal melanoma. Compounds isolated from the bacteria Streptomyces platensis (Sakai, Takashi; Sameshima, Tomohiro; Matsufuji, Motoko; Kawamura, Naoto; Dobashi, Kazuyuki; Mizui, Yoshiharu. Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107. I. Taxonomy, Fermentation, Isolation and Screening. The Journal of Antibiotics. 2004, Vol. 57, No. 3.), termed pladienolides and discovered while screening for inhibitors of the vascular endothelial growth factor (VEGF) promoter, inhibit expression of a reporter gene controlled by human VEGF promoter, which inhibition is known to be a useful mechanism of action for anticancer agents. These compounds also inhibit proliferation of U251 human glioma cells in vitro. The most potent of these compounds, Pladienolide B, inhibits VEGF-promoted gene expression with an IC50 of 1.8 nM, and inhibits glioma cell proliferation with an IC50 of 3.5 nM. The structure of pladienolide B is known, (Sakai, Takashi; Sameshima, Tomohiro; Matsufuji, Motoko; Kawamura, Naoto; Dobashi, Kazuyuki; Mizui, Yoshiharu. Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107. II. Physico-chemical Properties and Structure Elucidation. The Journal of Antibiotics. Vol. 57, No. 3. (2004)) and pladienolide B is known to target the SF3b spliceosome to inhibit splicing and alter the pattern of gene expression (Kotake et al., “Splicing factor SF3b as a target of the antitumor natural product pladienolide”, Nature Chemical Biology 2007, 3, 570-575). Certain pladienolide B compounds, as well as other pladienolide compounds, are likewise known, as disclosed the following patent applications: WO 2002/060890; WO 2004/011459; WO 2004/011661; WO 2004/050890; WO 2005/052152; WO 2006/009276; WO 2008/126918; and WO 2015/175594. For example, a pladienolide compound, (8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide, also known as E7107, is a semisynthetic derivative of the natural product pladienolide D, and the results of its Phase I study have been reported. As another example, the pladienolide pyridine compound (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((R,2E,4E)-6-(pyridin-2-yl)hepta-2,4-dien-2-yl)oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate (also named “(2S,3S,4E,6S,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((2E,4E,6R)-6-(pyridin-2-yl)hepta-2,4-dien-2-yl)oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate”), also known as H3B-8800, has received orphan drug designation for the treatment of certain hematological cancers. However, additional agents useful in the treatment of cancer, particularly cancers in which agents that target the spliceosome and mutations therein are known to be useful, are needed.