Granted Patent E1

US 50,594 · App. 18/093,145 · Granted Sep 23, 2025

Inventors: Andreas Gollner (Vienna, AT); Joachim Broeker (Moedling, AT); Nina Kerres (Vienna, AT); Christiane Kofink (Perchtoldsdorf, AT); Juergen Ramharter (Vienna, AT); Harald Weinstabl (Vienna, AT); Annika Gille (Ulm, DE); Stefan Goepper (Biberach an der Riss, DE); Manuel Henry (Schemmerhofen, DE); Guenther Huchler (Hochdorf, DE)

Assignee: Boehringer Ingelheim International GmbH

C07D487/22A61K31/4162A61K31/437A61K31/4545A61K31/5377A61K45/06A61P35/00C07D209/02C07D471/22

Abstract

Claims (65)

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.

Assignments (1)

Priority Claims (1)

Continuity (3)

References Cited (230)