MDM2 inhibitor and a platinum compound for cancer treatment

Patent metadata

Field	Value
Publication number	US-11850239-B2
Application number	US-202017127131-A
Country	US
Kind code	B2
Filing date	Dec 18, 2020
Priority date	Dec 19, 2019
Publication date	Dec 26, 2023
Grant date	Dec 26, 2023

Abstract

Provided herein is a method of treating, preventing, or alleviating one or more symptoms of a disorder, disease, or condition mediated by an MDM2 with an MDM2 inhibitor, e.g., a compound of Formula (I), and a platinum compound. Also provided herein is a method of inhibiting the growth of a cell with an MDM2 inhibitor and a platinum compound.

First claim

What is claimed is:

1. A method of treating, or alleviating one or more symptoms of a disorder, disease, or condition mediated by an MDM2 or an MDM2/p53 interaction in a subject, comprising administering to the subject a therapeutically effective amount of an MDM2 inhibitor and a therapeutically effective amount of a platinum compound; wherein the MDM2 inhibitor is a compound of Formula (I):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

ring B is C 3-10 cycloalkyl or heterocyclyl;
R 1 is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, —NR 1b R 1c , or —OR 1a ;
n is an integer of 0, 1, or 2;
R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, fluoro, chloro, methyl, or trifluoromethyl;
R 6 is

 wherein each R 1f is independently —C(═O)OR 1a , —C(═O)NR 1b R 1c , —C(═O)NHSO 2 CH 3 ;
R 1d and R 1c are each independently hydrogen, halo, C 1-6 alkyl, or —OR 1a ; or R 1d and R 1e together with the carbon to which they are attached form C 3-10 cycloalkyl or heterocyclyl; and
each R 1a , R 1b , and R 1c is independently hydrogen or C 1-6 alkyl;
wherein each alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) deuterium, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(O)SR a , —C(NR a )NR b R c , —C(S)R a , —C(S)OR a , —C(S)NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(O)SR a , —OC(═NR a )NR b R c , —OC(S)R a , —OC(S)OR a , —OC(S)NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(O)SR d , —NR a C(═NR d )NR b R c , —NR a C(S)R d , —NR a C(S)OR d , —NR a C(S)NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) deuterium, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(O)SR e , —C(NR e )NR f R g , —C(S)R e , —C(S)OR e , —C(S)NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(O)SR e , —OC(═NR e )NR f R g , —OC(S)R e , —OC(S)OR e , —OC(S)NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(O)SR f , —NR e C(═NR h )NR f R g , —NR e C(S)R h , —NR e C(S)OR f , —NR e C(S)NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

2. The method of claim 1 , wherein the disorder, disease, or condition is cancer.

3. The method of claim 2 , wherein the cancer is solid cancer.

4. The method of claim 3 , wherein the cancer is salivary gland cancer.

5. The method of claim 4 , wherein the salivary gland cancer is mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, carcinoma ex pleomorphic adenoma, squamous cell carcinoma, or adenocarcinoma.

6. The method of claim 2 , wherein the cancer has a functional p53 or a wild-type p53; or wherein the cancer is metastatic, refractory, relapsed, or drug-resistant.

7. The method of claim 1 , wherein the MDM2 inhibitor is:
3-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro-[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[1.1.1]pentane-1-carboxylic acid A1;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro-[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A2;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-4,4-difluoro-2″-oxodispiro-[cyclo-hexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicycle-[2.2.2]octane-1-carboxylic acid A3;
(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-((methylsulfonyl)-carbamoyl)-bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide A4;
4-((1r,3′R,4R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-4-hydroxy-4-methyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)-bicyclo[2.2.2]octane-1-carboxylic acid A5;
4-((1s,3′R,4R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-4-hydroxy-4-methyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)-bicyclo[2.2.2]octane-1-carboxylic acid A6;
(3′R,4′S,5′R)—N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-methyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide A7;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro-[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A8;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-methyl-2″-oxodispiro-[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)-bicyclo[2.2.2]octane-1-carboxylic acid A9;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-3,3-dimethyl-2″-oxodispiro[cyclobutane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A10;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′,3,3-trimethyl-2″-oxodispiro[cyclobutane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A11;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-pyrrolo[3,2-c]pyridine]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A12;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-methyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-pyrrolo[3,2-c]pyridine]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A13;
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-3,3-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclobutane-1,2′-pyrrolidine-3′,3″-pyrrolo[3,2-c]pyridine]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid A14; or
4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′,3,3-trimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclobutane-1,2′-pyrrolidine-3′

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Ascentage Pharma Group Corp Ltd

Inventors

• Zhai Yifan
• Yang Dajun

Classifications

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/282

  Platinum compounds · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K31/555 Primary

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title

• A61K33/243

  Platinum; Compounds thereof · CPC title