# US 10,246,467 B2 · Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-p53 inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,246,467 B2
- Document ID: US10246467B2
- Status: Granted
- Kind: B2
- Application number: 15/503,754
- Filed: 2015-08-20
- Published: 2017-08-31
- Granted: 2019-04-02
- Earliest claimed: 2014-08-21
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Juergen Ramharter; Joachim Broeker; Annika Gille; Andreas Gollner; Manuel Henry; Nina Kerres; Harald Weinstabl
- Web page: https://patentgrep.com/patent/US10246467B2

## CPC

- C07D 498/20: Spiro-condensed systems
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/5365: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/20: Spiro-condensed systems
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 487/10: Spiro-condensed systems
- C07D 487/20: Spiro-condensed systems
- C07D 498/22: in which the condensed system contains four or more hetero rings
- C08K 3/18: Oxygen-containing compounds, e.g. metal carbonyls
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08K: Use of inorganic or non-macromolecular organic substances as compounding ingredients (paints, inks, varnishes, dyes, polishes, adhesives C09)

## Abstract

The present invention encompasses compounds of formula (I) wherein the groups R1 to R7, A, V, W, X, Y, n, r and q are defined in claim 1, their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions which contain compounds of this kind, their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases, and synthetic intermediates.

## Claims

### Claim 1

A compound of formula (I)
wherein
R1 is a group, optionally substituted by one or more, identical or different Rb1 and/or Rc1, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rb1 is independently selected from among —ORc1, —NRc1Rc1, halogen, —CN, —C(O)Rc1, —C(O)ORc1, —C(O)NRc1Rc1, —S(O)2Rc1, —S(O)2NRc1Rc1, —NHC(O)Rc1 and —N(C1-4alkyl)C(O)Rc1;
each Rc1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd1 and/or Re1, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rd1 is independently selected from among, —ORe1, NRe1Re1 halogen, —CN,
C(O)Re1, —C(O)ORe1, —C(O)NRe1Re1, S(O)2Re1, —S(O)2NRe1Re1, —NHC(O)Re1 and —N(C1-4alkyl)C(O)Re1;
each Re1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rf1 and/or Rg1, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rf1 is independently selected from among —ORg1, —NRg1Rg1, halogen, —CN, —C(O)Rg1, —C(O)ORg1, —C(O)NRg1Rg1, —S(O)2Rg1, —S(O)2NRg1Rg1, —NHC(O)Rg1 and —N(C1-4alkyl)C(O)Rg1;
each Rg1 is independently selected from among hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
R2 and R3, each independently, is selected from among hydrogen, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein this C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl is optionally substituted by one or more, identical or different Rb2 and/or Rc2;
each Rb2 is independently selected from among —ORc2, —NRc2Rc2, halogen, —CN, —C(O)Rc2, —C(O)ORc2, —C(O)NRc2Rc2, —S(O)2Rc2, —S(O)2NRc2Rc2, —NHC(O)Rc2 and —N(C1-4alkyl)C(O)Rc2;
each Rc2 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd2 and/or Re2, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C4-6cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rd2 is independently selected from among —ORe2, —NRe2Re2, halogen, —CN, —C(O)Re2, —C(O)ORe2, —C(O)NRe2Re2, —S(O)2Re2, —S(O)2NRe2Re2, —NHC(O)Re2 and —N(C1-4alkyl)C(O)Re2;
each Re2 independently of one another denotes hydrogen or a group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C4-6cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
A is selected from among phenyl and 5-6 membered heteroaryl;
each R4 is independently selected from among Ra4 and Rb4;
each Ra4 independently of one another is a group, optionally substituted by one or more, identical or different Rb4 and/or Rc4, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rb4 is independently selected from among —ORc4, —NRc4Rc4, halogen, —CN, —C(O)Rc4, —C(O)ORc4, —C(O)NRc4Rc4, —C(O)NRg4ORc4, —S(O)2Rc4, —S(O)2NRc4Rc4, —NHSO2Rc4, —N(C1-4alkyl)SO2Rc4, —NHC(O)Rc4 and —N(C1-4alkyl)C(O)Rc4;
each Rc4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd4 and/or Re4, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rd4 is independently selected from among —ORe4, —NRe4Re4, halogen, —CN, —C(O)Re4, —C(O)ORe4, —C(O)NRe4Re4, —C(O)NRg4ORe4, —S(O)2Re4, —S(O)2NRe4Re4, —NHC(O)Re4 and —N(C1-4alkyl)C(O)Re4;
each Re4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rf4 and/or Rg4, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rf4 is independently selected from among —ORg4, —NRg4Rg4, halogen, —CN, —C(O)Rg4, —C(O)ORg4, —C(O)NRg4Rg4, —C(O)NRg4ORg4, —S(O)2Rg4, —S(O)2NRg4Rg4, —NHC(O)Rg4 and —N(C1-4alkyl)C(O)Rg4;
each Rg4 is independently selected from among hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
r denotes the number 0, 1, 2 or 3
R5 and R6, each independently, is selected from among hydrogen, C1-4alkyl and C1-4haloalkyl;
n denotes the number 0;
each R7 is independently selected from among halogen, C1-4alkyl, —CN, C1-4haloalkyl, —OC1-4alkyl and —OC1-4haloalkyl;
q denotes the number 0, 1, 2 or 3;
W, X and Y is each independently selected from —N═ and —CH═
with the proviso that the hydrogen in each —CH═ may be replaced by a substituent R7 if present and that a maximum of two of W, X and Y can be —N═;
V is oxygen or sulfur;
or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 of formula (Ia)
or a salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein
R1 is a group, optionally substituted by one or more, identical or different Rb1 and/or Rc1, selected from among C1-6alkyl, C2-6alkenyl, C1-6haloalkyl and C3-7cycloalkyl;
each Rb1 is independently selected from among —ORc1, —NRc1Rc1, halogen, —CN, —C(O)Rc1, —C(O)ORc1, —C(O)NRc1Rc1, —S(O)2Rc1, —S(O)2NRc1Rc1, —NHC(O)Rc1 and —N(C1-4alkyl)C(O)Rc1;
each Rc1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different Rd1 and/or Re1, selected from among C1-6alkyl, C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rd1 is independently selected from among —ORe1, —NRe1Re1, halogen, —CN, —C(O)Rc1, —C(O)ORc1, —C(O)NRc1Rc1, —S(O)2Rc1, —S(O)2NRc1Rc1, —NHC(O)Rc1 and —N(C1-4alkyl)C(O)Rc1;
each Rc1 independently of one another is selected from among hydrogen, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
or a salt thereof.

### Claim 4 (depends on 1)

The compound according claim 1, wherein
one of R2 and R3 is hydrogen and the other is selected from among phenyl and 5-6 membered heteroaryl, wherein this phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different Rb2 and/or Rc2;
each Rb2 is independently selected from among —ORc2, —NRc2Rc2, halogen, —CN, —C(O)Rc2, —C(O)ORc2, —C(O)NRc2Rc2, —S(O)2NRc2Rc2, —NHC(O)Rc2 and —N(C1-4alkyl)C(O)Rc2;
each Rc2 independently of one another denotes hydrogen or a group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C4-6cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocyclyl;
or a salt thereof.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein
one of R2 and R3 is hydrogen and the other is selected from among phenyl and pyridyl, wherein this phenyl and pyridyl is optionally substituted by one or more, identical or different substituents selected from among —OC1-6alkyl, halogen, C1-6alkyl and C1-6haloalkyl;
or a salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
R3 is hydrogen;
or a salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein
A is selected from among phenyl and 5-6 membered heteroaryl;
each R4 is independently selected from among Ra4 and Rb4;
each Ra4 independently of one another is a group, optionally substituted by one or more, identical or different Rb4 and/or Rc4, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each Rb4 is independently selected from among —ORc4, —NRc4Rc4, halogen, —CN, —C(O)Rc4, —C(O)ORc4, —C(O)NRc4Rc4, —C(O)NRg4ORc4, —S(O)2Rc4, —S(O)2NRc4Rc4, —NHSO2Rc4, —N(C1-4alkyl)SO2Rc4, —NHC(O)Rc4 and —N(C1-4alkyl)C(O)Rc4;
each Rc4 independently of one another is selected from among hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, C4-7cycloalkenyl, C6-10aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
r denotes the number 0, 1, 2 or 3;
or a salt thereof.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein
A is selected from among phenyl and pyridyl;
each R4 is independently selected from among Ra4 and Rb4;
each Ra4 independently of one another is C1-6alkyl optionally substituted by one or more, identical or different Rb4;
each Rb4 is independently selected from among —ORc4, —NRc4Rc4, halogen, —CN, —C(O)Rc4, —C(O)ORc4, —C(O)NRc4Rc4, —C(O)NRg4ORc4, —S(O)2Rc4, —S(O)2NRc4Rc4, —NHSO2Rc4, —N(C1-4alkyl)SO2Rc4, —NHC(O)Rc4 and —N(C1-4alkyl)C(O)Rc4;
each Rc4 independently of one another is selected from among hydrogen and C1-6alkyl;
r denotes the number 0, 1, 2 or 3;
or a salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R5 and R6 is hydrogen;
n denotes the number 0;
or a salt thereof.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein each R7 independently is halogen and q is 1 or 2;
or a salt thereof.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein
V is oxygen;
or a salt thereof.

### Claim 12

A compound selected from the group consisting of
or a salt thereof.

### Claim 13 (depends on 1)

A method for the treatment of a disease and/or condition wherein the inhibition of the interaction between MDM2 and p53 is of therapeutic benefit comprising administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a human being, wherein said disease and/or condition is acute myeloid leukaemia (AML), prostate cancer or lung cancer.

### Claim 14 (depends on 1)

A method for the treatment of cancer comprising administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a human being, wherein said cancer is acute myeloid leukaemia (AML), prostate cancer or lung cancer.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

A method for the chiral separation of compounds (I) according to claim 1 comprising precipitating a salt of one enantiomer formed with a chiral base, from a solution or suspension of compounds (I) in a solvent.

### Claim 17 (depends on 16)

The method of claim 16, wherein the chiral base is selected from the group consisting of (R)- and (S)-1,2,3,4-tetrahydronaphthyl-1-amine and the solvent is iso-propyl acetate.