USRE50594EActiveUtility
Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors
Est. expiryOct 9, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Andreas GollnerJoachim BroekerNina KerresChristiane KofinkJuergen RamharterHarald WeinstablAnnika GilleStefan GoepperManuel HenryGuenther Huchler
A61K 45/06A61K 31/5377A61K 31/4545A61K 31/437A61K 31/4162A61P 35/00C07D 209/02C07D 471/22A61P 31/00A61K 31/438A61P 29/00A61P 37/00A61P 43/00A61P 37/06A61P 39/00A61P 19/08A61P 15/00A61P 17/06A61P 17/00A61P 33/00A61P 31/10A61P 31/04A61P 19/02A61P 13/12A61P 25/28A61P 1/00A61P 35/02C07D 487/22
78
PatentIndex Score
0
Cited by
231
References
15
Claims
Abstract
The present invention encompasses intermediates for preparing compounds of formula (I) wherein the groups R 1 to R 4 , R 7 , A, D, E, F, 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
exact text as granted — not AI-modifiedThe invention claimed is:
1. Intermediate of formula B-20
R 2 and R 3 , each independently, is selected from among hydrogen, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl is optionally substituted by one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from among —OR c2 , —NR c2 R c2 , halogen, —CN, —C(O)R c2 , —C(O)OR c2 , —C(O)NR c2 R c2 , —S(O) 2 R c2 , —S(O) 2 NR c2 R c2 , —NHC(O)R c2 , —N(C 1-4 alkyl)C(O)R c2 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
each R c2 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d2 and/or R e2 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d2 is independently selected from among —OR e2 , —NR e2 R e2 , halogen, —CN, —C(O)R e2 , —C(O)OR e2 , —C(O)NR e2 R e2 , —S(O) 2 R e2 , —S(O) 2 NR e2 R e2 , —NHC(O)R e2 , —N(C 1-4 alkyl)C(O)R e2 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
each R e2 independently of one another denotes hydrogen or a group selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
A is selected from among phenyl and 5-6 membered heteroaryl;
each R 4 is independently selected from among R a4 and R b4 ;
each R a4 independently of one another is a group, optionally substituted by one or more, identical or different R b4 and/or R c4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R b4 is independently selected from among —OR c4 , —NR c4 R c4 , halogen, —CN, —C(O)R c4 , —C(O)OR c4 , —C(O)NR c4 R c4 , —C(O)NR g4 OR c4 , —S(O) 2 R c4 , —S(O) 2 NR c4 R c4 , —NHSO 2 R c4 , —N(C 1-4 alkyl)SO 2 R c4 , —NHC(O)R c4 and —N(C 1-4 alkyl)C(O)R c4 ;
each R c4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d4 and/or R e4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d4 is independently selected from among —OR e4 , —NR e4 R e4 , halogen, —CN, —C(O)R e4 , —C(O)OR e4 , —C(O)NR e4 R e4 , —C(O)NR g4 OR e4 , —S(O) 2 R e4 , —S(O) 2 NR e4 R e4 , —NHC(O)R e4 and —N(C 1-4 alkyl)C(O)R e4 ;
each R e4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f4 and/or R g4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R f4 is independently selected from among —OR g4 , —NR g4 R g4 , halogen, —CN, —C(O)R g4 , —C(O)OR g4 , —C(O)NR g4 R g4 , —C(O)NR g4 OR g4 , —S(O) 2 R g4 , —S(O) 2 NR g4 R g4 , —NHC(O)R g4 and —N(C 1-4 alkyl)C(O)R g4 ;
each R g4 is independently selected from among hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
r denotes the number 0, 1, 2 or 3;
each R 7 is independently selected from among halogen, C 1-4 alkyl, —CN, C 1-4 haloalkyl, —OC 1-4 alkyl and —OC 1-4 haloalkyl;
q denotes the number 0, 1, 2 or 3;
V is oxygen or sulfur; and
wherein W, X and Y is each independently selected from —N═ and —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 if present and wherein a maximum of two of W, X and Y can be —N═,
or a salt thereof.
2. A method for synthesizing an intermediate of formula B-20
comprising reacting a compound B-2
with an imine B-19
wherein R 2 , R 3 , R 4 , R 7 , A, V, r and q are as defined in claim 1 , and wherein W, X and Y is each independently selected from —N═ and —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 if present and wherein a maximum of two of W, X and Y can be —N═.
3. A compound of formula (I)
wherein R 1 is a group, optionally substituted by one or more, identical or different R b1 and/or R c1 , selected from among C 1-6 alkyl, C 2-6 alkenyl and C 1-6 haloalkyl;
each R b1 is independently selected from among —OR c1 and —S(O) 2 R c1 ;
each R c1 independently of one another is a group, optionally substituted by one or more, identical or different R d1 and/or R e1 , selected from among C 1-6 alkyl, C 3-7 cycloalkyl and phenyl;
each R d1 is independently selected from among —OR e1 , —CN and halogen;
each R e1 independently of one another is C 1-6 alkyl or C 1-6 alkyl-O—C 1-6 alkyl;
one of R 2 and R 3 is hydrogen and the other is selected from among phenyl, thienyl and pyridyl, wherein said phenyl, thienyl and pyridyl is optionally substituted by one or more, identical or different substituents selected from among —OC 1-6 alkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
A is selected from among phenyl and 5-6 membered heteroaryl if F is carbon or
A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;
each R 4 is independently selected from among R a4 and R b4 ;
each R a4 independently of one another is a group, optionally substituted by one or more, identical or different R b4 and/or R c4 , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;
each R b4 is independently selected from among —OR c4 , —NR c4 R c4 , halogen, —C(O)R c4 , —C(O)OR c4 , —C(O)NR c4 R c4 , —C(O)NR g4 OR c4 , —S(O) 2 R c4 , and —NHC(O)R c4 ;
each R c4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d4 and/or R e4 , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;
each R d4 is independently selected from among —OR e4 , —NR e4 R e4 and —S(O) 2 R e4 ;
each R e4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f4 and/or R g4 , selected from among C 1-6 alkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;
each R f4 is independently —OR g4 ;
each R g4 is independently selected from among hydrogen and C 1-6 alkyl;
r denotes the number 0, 1, 2 or 3;
n denotes the number 1 or 2;
each R 7 is independently halogen or —CN;
q denotes the number 1 or 2;
W, X and Y is each —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 ;
V is oxygen;
D is nitrogen, E is carbon and F is carbon; or
D is carbon, E is nitrogen and F is carbon; or
D is carbon, E is carbon and F is nitrogen;
or a salt thereof.
4. The compound according to claim 3 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 4 and a pharmaceutically acceptable carrier.
6. A compound of formula Ib-159 or a pharmaceutically acceptable salt thereof
7. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 6 and a pharmaceutically acceptable carrier.
8. A compound of formula Ib-160 or a pharmaceutically acceptable salt thereof
9. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 8 and a pharmaceutically acceptable carrier.
10. A compound of formula Ib-190 or a pharmaceutically acceptable salt thereof
11. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 10 and a pharmaceutically acceptable carrier.
12. A compound of formula Ib-210 or a pharmaceutically acceptable salt thereof
13. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 12 and a pharmaceutically acceptable carrier.
14. A compound of formula Ib-240 or a pharmaceutically acceptable salt thereof
15. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 14 and a pharmaceutically acceptable carrier.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.