Splicing modulator antibody-drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-11945807-B2
Application number	US-202217661909-A
Country	US
Kind code	B2
Filing date	May 3, 2022
Priority date	Jun 1, 2018
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

Linker-drug compounds and antibody-drug conjugates that bind to human oncology targets are disclosed. The linker-drug compounds and antibody-drug conjugates comprise a splicing modulator drug moiety. The disclosure further relates to methods and compositions for use in the treatment of neoplastic disorders by administering the antibody-drug conjugates provided herein. In an embodiment, the splicing modulator comprises a pladienolide or a pladienolide derivative.

First claim

The invention claimed is:

1. A compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and -CD 3 ;
R 3 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, and —O—C(═O)—(C 1 -C 6 alkyl) groups;
R 4 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 6 alkyl) groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups; and
R 10 is chosen from 3 to 10 membered carbocycles and 3 to 10 membered heterocycles, each of which is substituted with 0 to 3 R a ,
wherein each R 8 is independently chosen from halogens, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 )alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylhydroxy groups,
S(═O) w -(4 to 7 membered heterocycles) wherein w is 1 or 2, 4 to 7 membered carbocycles, hydroxyl groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups,
wherein each R a is independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, -NR 15 R 16 , C 1 -C 6 alkyl groups, —(C═O)—(C 1 -C 6 alkyl) groups, -(C═O)—(C 1 -C 6 alkyl)-(C 3 -C 10 heterocyclyl) groups, —S(═O) w -(C 3 -C 8 heterocyclyl) groups wherein w is 0, 1, or 2, and C 1 -C 6 alkylcarboxylic acid groups; and

R 15 and R 16 are each independently chosen from hydrogen, R 17 , —C(═O)-R 17 , and —C(═O)—O-R 17 , wherein R 17 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups;
wherein R 1 , R 3 , R 4 , R 15 , R 16 , and R 17 are each independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 alkyl) groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, C 1 -C 6 alkylhydroxy groups, C 1 -C 6 alkylalkoxy groups, benzyl groups, and C 3 -C 8 heterocyclyl groups.

2. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

3. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

4. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

5. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

6. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

7. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

8. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

9. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

10. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

11. The compound of claim 1 , wherein the compound is chosen from a compound of formula

and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A method of treating a subject having or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

14. The method of claim 13 , wherein the neoplastic disorder is a leukemia, a lymphoma, or a myeloma.

15. The method of claim 14 , wherein the myeloma is multiple myeloma.

16. A method of reducing or inhibiting growth of a tumor in a subject having or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

17. A compound of Formula (VIII-A):

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is absent or is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and -CD 3 ;
R 3 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, and —O—C(═O)—(C 1 -C 6 alkyl) groups;
R 4 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 6 alkyl) groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups; and
R 10 is chosen from 3 to 10 membered carbocycles and 3 to 10 membered heterocycles, each of which is substituted with 0 to 3 R 8 ,
wherein each R a is independently chosen from halogens, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 )alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylhydroxy groups, -S(═O)w-(4 to 7 membered heterocycles) wherein w is 1 or 2, 4 to 7 membered carbocycles, hydroxyl groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups,
wherein each R 8 is independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, -NR 15 R 16 , C 1 -C 6 alkyl groups, -(C═O)—(C 1 -C 6 alkyl) groups, -(C═O)—(C 1 -C 6 alkyl)(C 3 -C 10 heterocyclyl groups), -S(═O) w -(C 3 -C 8 heterocyclyl) groups wherein w is 0, 1, or 2, and C 1 -C 6 alkylcarboxylic acid groups, each of which is substituted with 0, 1, or 2 groups independently chosen from halogens, hydroxyl groups, -NR 15 R 16 , and C 1 -

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Pazolli Ermira
• Buonamici Silvia
• Samarakoon Thiwanka
• Prajapati Sudeep
• Fishkin Nathan
• Palacino James
• Seiler Michael
• Zhu Ping
• Cook Andrew
• Smith Peter
• Liu Xiang
• Ellery Shelby
• Reynolds Dominic
• Yu Lihua
• Wu Zhenhua
• Peng Shouyong
• Calandra Nicholas
• Sheehan Megan
• Xiao Yonghong

Classifications

• G01N33/575

  for cancer · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6851 Primary

  the antibody targeting a determinant of a tumour cell · CPC title