IP Library › Granted Patent US 9,096,579

Granted Patent B2

US 9,096,579 · App. 13/864,394 · Granted Aug 4, 2015

Amino-indolyl-substituted imidazolyl-pyrimidines and their use as medicaments

Inventors: Georg Dahmann (Warthausen-Birkenhard, DE); Horst Dollinger (Schemmerhofen, DE); Christian Gnamm (Biberach an der Riss, DE); Dennis Fiegen (Biberach an der Riss, DE); Matthias Hoffmann (Mittelbiberach, DE); Jasna Klicic (Biberach an der Riss, DE); David James Lamb (Mittelbiberach, DE); Andreas Schnapp (Biberach an der Riss, DE)

Assignee: Boehringer Ingelheim International GmbH

C07D403/14 A61K31/506 A61K31/5377 A61K31/5386 A61K31/541 A61K31/55 A61K31/551 A61K31/553 A61K45/06 C07D209/42 C07D401/14 C07D403/06 C07D405/14 C07D409/14 C07D413/14 C07D417/14 C07D471/04 C07D487/04 C07D487/10 C07D498/04 C07D498/10 C07D513/04

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Quick Facts

Patent No.: US 9,096,579
App. No.: 13/864,394
Granted: Aug 4, 2015
Kind: B2

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Abstract

The invention relates to new amino-indole-substituted imidazolyl-pyrimidines of formula 1 wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined as in claim 1 and pharmaceutically acceptable salts thereof and the use of these compounds for the preparation of a medicament for treating a disease selected from asthma, COPD, rheumatoid arthritis, specific lymphomas and specific diseases of the nervous system.

Claims (127)

1. A compound of formula 1

wherein

R 1 is selected from the group consisting of hydrogen, C 1-6 -alkyl and C 1-6 -haloalkyl;

R 2 is selected from the group consisting of hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, —(C 1-3 -alkylene)-O—(C 1-3 -alkyl) and three-, four-, five- or six-membered cycloalkyl, wherein this cycloalkyl may optionally be substituted by halogen;

R 3 is selected from the group consisting of hydrogen, C 1-6 -alkyl, halogen, —O—C 1-6 -alkyl, three-, four-, five- or six-membered cycloalkyl, —S—(C 1-3 -alkylene)-A, —S-A and -A,

with A being a group selected from the group consisting of —CO—N(C 1-3 -alkyl) 2 , —CO—NH(C 1-3 -alkyl), —CO—NH 2 , five- or six-membered heteroaryl comprising 1, 2 or 3 heteroatoms each independently selected from S, O or N and five-, six- or seven-membered heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from S, O or N,

wherein A may optionally be further substituted by one, two or three groups each independently selected from —C 1-3 -alkyl, halogen, -oxo, —OH or C 1-3 -haloalkyl;

R 4 is selected from the group consisting of hydrogen, -halogen, SH, —OH, —NH 2 , —CO—Y, —CO—N(CH 3 )—Y, —CO—N(CH 3 )(C 1-5 -alkylene)-Y, —CO—N(ethyl)(C 1-5 -alkylene)-Y, —CO—N(ethyl)-Y, —CS—Y, —CS—N(CH 3 )—Y, —CS—N(CH 3 )—(C 1-3 -alkylene)-Y, —C 1-6 -alkyl, —C 1-3 -haloalkyl, —CO—NH—Y, —CO—NH—C 1-6 -alkylene-Y, —CO—N(CH 3 )—(C 2-3 -alkylene)-O—(C 1-3 -alkyl), —NH 2 , —C 1-6 -alkylene-L, —SO 2 -phenyl, —SO 2 —(C 1-3 -alkyl), —CO—N(C 1-4 -alkyl) 2 and —CO—N(C 2-4 -alkylene-O—C 1-3 -alkyl) 2 ,

or wherein R 4 is a five- or six-membered heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, wherein said heteroaromatic group on any atom available for substitution may optionally be further substituted by one, two or three groups each independently selected from —C 1-3 -alkyl halogen or C 1-3 -haloalkyl,

with Y being a group selected from the group consisting of —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —C 1-6 -alkylene-N(CH 3 ) 2 , —O—C 1-3 -alkyl, —C 1-3 -haloalkyl, —OH, —N(ethyl) 2 and —C 1-5 -alkinyl,

or with Y being a group selected from the group consisting of a four-, five-, six- or seven-membered monocyclic fully saturated or partially unsaturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, a five- or six-membered monocyclic heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, —C 6-10 -aryl, and C 3-6 -cycloalkyl,

or with Y being a 8- to 11-membered bicyclic annellated fully saturated, partially unsaturated or aromatic heterocycle comprising 1, 2, 3 or 4 heteroatoms each independently from each other selected from N, S or O,

or with Y being an 8- to 11-membered bicyclic fully saturated spiro-heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, with the proviso that this spiro-heterocycle comprises at least one N-atom and that this heterocycle is directly attached to the molecule via this N-atom,

or with Y being a six- or seven-membered fully saturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, which is bridged by an additional C 1-3 -alkylene-unit,

whereby each Y may optionally be substituted by one, two or three groups Z each independently from each other selected from the group consisting of halogen, -oxo, OH, —CN, —C 1-5 -alkyl, —C 1-5 -alkanol, —O—C 1-3 -alkyl, a four-, five-, six- or seven-membered fully saturated or partially unsaturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, a fully saturated or partially unsaturated C 3-6 -cycloalkyl, a five- to six-membered heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, —CO—(C 1-3 -alkyl), —CHO, —CO-L, —C 1-3 -alkylene-CO-L, —C 1-4 -alkylene-O—C 1-3 -alkyl, —N(CH 3 ) 2 and —N(ethyl) 2 ,

whereby each group Z may optionally be further substituted by one, two or three groups T each independently selected from the group consisting of -oxo, OH, halogen, —C 1-3 -alkyl, —O—C 1-3 -alkyl, —N(methyl) 2 , —N(ethyl) 2 , 5- to 6-membered fully saturated, partially unsaturated or aromatic heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S, a C 3-6 -cycloalkyl and —CN,

wherein each group T may also optionally be substituted by a group selected from the group consisting of C 1-3 -alkyl, halogen, OH, oxo and —O—C 1-3 -alkyl,

whereby L denotes a 5- or 6-membered fully saturated or partially unsaturated heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S, where the heterocycle may optionally be substituted by one, two or three groups independently selected from methyl, halogen, OH or -oxo;

R 5 is selected from the group consisting of hydrogen, C 1-6 -alkyl, C 1-3 -haloalkyl and —(C 1-4 -alkylene)-O—(C 1-3 -alkyl);

or a pharmaceutically acceptable salt thereof.

2. The compound of formula 1 according to claim 1 , wherein

R 4 is selected from the group consisting of

—CO—Y, —CO—N(CH 3 )—Y, —CO—N(CH 3 )(C 1-5 -alkylene)-Y, —CO—N(ethyl)(C 1-5 -alkylene)-Y, —CO—NH—Y and —CO—NH—C 1-6 -alkylene-Y, or

R 4 is a five- or six-membered heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, wherein said heteroaromatic group on any atom available for substitution may optionally be further substituted by one, two or three groups each independently selected from —C 1-3 -alkyl halogen or C 1-3 -haloalkyl,

with Y being a group selected from the group consisting of —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —C 1-6 -alkylene-N(CH 3 ) 2 , —O—C 1-3 -alkyl, —C 1-3 -haloalkyl, —OH and —C 1-5 -alkinyl,

or with Y being a group selected from the group consisting of a four-, five-, six- or seven-membered monocyclic fully saturated or partially unsaturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O; a five- or six-membered monocyclic heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, —C 6-10 -aryl and a C 3-6 -cycloalkyl,

or with Y being a 8-, 9-, 10- or 11-membered bicyclic annellated fully saturated, partially unsaturated or aromatic heterocycle comprising 1, 2, 3 or 4 heteroatoms each independently from each other selected from N, S or O,

or with Y being an 8-, 9-, 10- or 11-membered bicyclic fully saturated spiro-heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, with the proviso that this spiro-heterocycle comprises at least one N-atom and that this heterocycle is directly attached to the molecule via this N-atom,

whereby each Y may optionally be substituted by one, two or three groups Z each independently from each other selected from the group consisting of —F, —Cl, —Br, —I, -oxo, OH, —CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, —C 1-5 -alkanol, —O—CH 3 , —O-ethyl, —O-(n-propyl), —O-isopropyl, a four-, five-, six- or seven-membered fully saturated or partially unsaturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, a fully saturated or partially unsaturated C 3-6 -cycloalkyl, a five- to six-membered heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, —CO-methyl, —CO-ethyl, —CO-propyl, —CHO, —CO-L, —C 1-3 -alkylene-CO-L, —C 1-4 -alkylene-O—C 1-3 -alkyl, —N(CH 3 ) 2 and —N(ethyl) 2 ,

whereby each group Z may optionally be further substituted by one, two or three groups T each independently selected from the group consisting of -oxo, OH, halogen, methyl, ethyl, n-propyl, isopropyl, —O-methyl, —O-ethyl, —O-(n-propyl), —O-(isopropyl), —N(methyl) 2 , —N(ethyl) 2 , 5- to 6-membered fully saturated, partially unsaturated or aromatic heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S, a C 3-6 -cycloalkyl and —CN,

whereby L denotes a 5- or 6-membered fully saturated or partially unsaturated heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S, which said heterocycle may optionally be substituted by one, two or three groups independently selected from methyl, halogen, OH or —oxo;

or a pharmaceutically acceptable salt thereof.

3. The compound of formula 1 according to claim 1 , wherein

R 1 is selected from the group consisting of hydrogen and methyl;

or a pharmaceutically acceptable salt thereof.

4. The compound of formula 1 according to claim 1 , wherein

R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, -methylene-O-methyl, and -ethylene-O-methyl;

or a pharmaceutically acceptable salt thereof.

5. The compound of formula 1 according to claim 4 , wherein

R 2 is selected from the group consisting of methyl, isopropyl, isobutyl, cyclopropyl, and -ethylene-O-methyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of formula 1 according to claim 3 , wherein

R 1 is hydrogen;

and or a pharmaceutically acceptable salt thereof.

7. The compound of formula 1 according to claim 1 , wherein

R 2 is methyl, isopropyl or cyclopropyl;

or a pharmaceutically acceptable salt thereof.

8. The compound of formula 1 according to claim 7 , wherein

R 2 is methyl;

or a pharmaceutically acceptable salt thereof.

9. The compound of formula 1 according to claim 1 , wherein

R 3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, —F, —Cl, —Br, —O-methyl, —O-ethyl, —O-(n-propyl), —O-(isopropyl), cyclopropyl, —S-methylene-A, and -A,

with A being a group selected from the group consisting of —CO—N(CH 3 ) 2 , —CO—NH(CH 3 ), and five- or six-membered heteroaryl comprising 1, 2 or 3 heteroatoms each independently selected from S, O or N;

wherein A may optionally be further substituted by one, two or three groups each independently selected from methyl, ethyl, propyl or isopropyl;

or a pharmaceutically acceptable salt thereof.

10. The compound of formula 1 according to claim 1 , wherein

R 3 is selected from —Cl or methyl;

or a pharmaceutically acceptable salt thereof.

11. The compound of formula 1 according to claim 1 , wherein

R 5 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -methylene-O-methyl and -ethylene-O-methyl;

or a pharmaceutically acceptable salt thereof.

12. The compound of formula 1 according to claim 11 , wherein

R 5 is selected from the group consisting of hydrogen, methyl, isobutyl and -ethylene-O-methyl;

or a pharmaceutically acceptable salt thereof.

13. The compound of formula 1 according claim 1 , wherein

R 5 is hydrogen;

or a pharmaceutically acceptable salt thereof.

14. The compound of formula 1 according to claim 1 , wherein

R 4 is selected from the group consisting of —CO—Y, —CO—N(CH 3 )—Y, —CO—N(CH 3 )(C 1-5 -alkylene)-Y, —CO—N(ethyl)(C 1-5 -alkylene)-Y, —CO—NH—Y and —CO—NH—C 1-6 -alkylene-Y, or

with Y being a group selected from the group consisting of —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —C 1-6 alkylene-N(CH 3 ) 2 , —O-methyl, —O-ethyl, —O-n-propyl, —O-isopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, —C 1-3 -haloalkyl, —OH and

—CH 2 ≡CH 3 ,

or with Y being a group selected from the group consisting of a four-, five-, six- or seven-membered monocyclic fully saturated or partially unsaturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O; a five- or six-membered monocyclic heteroaromatic group comprising 1, 2 or 3 heteroatoms each independently selected from N, S and O, —C 6-10 -aryl or a C 3-6 -cycloalkyl,

whereby each group Z may optionally be further substituted by one, two or three groups T each independently selected from the group consisting of -oxo, OH, halogen, methyl, ethyl, n-propyl, isopropyl, —O-methyl, —O-ethyl, —O-(n-propyl), —O-(isopropyl), —N(methyl) 2 , —N(ethyl) 2 , C 3-6 -cycloalkyl, —CN, 5- to 6-membered fully saturated, partially unsaturated or aromatic heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S,

whereby L denotes a 5- or 6-membered fully saturated or partially unsaturated heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S, wherein the heterocycle may optionally be substituted by one, two or three groups independently selected from methyl, —Cl, —Br, —F, —OH or -oxo;

or a pharmaceutically acceptable salt thereof.

15. The compound of formula 1 according to claim 14 , wherein

R 4 is selected from the group consisting of —CO—N(CH 3 )—Y and —CO—N(CH 3 )(C 1-5 -alkylene)-Y,

with Y being a group selected from the group consisting of —NH(CH 3 ), —N(CH 3 ) 2 , —O-methyl, —CF 3 , methyl, ethyl, and OH,

or with Y being a six- or seven-membered fully saturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, which is bridged by an additional —CH 2 -unit,

whereby each group Z may optionally be further substituted by one, two or three groups T each independently selected from the group consisting of -oxo, OH, halogen, methyl, ethyl, n-propyl, isopropyl, —O-methyl, —O-ethyl, —O-(n-propyl), —O-(isopropyl), —N(methyl) 2 , —N(ethyl) 2 , C 3-6 -cycloalkyl, —CN, 5- to 6-membered fully saturated, partially unsaturated or aromatic heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S,

or a pharmaceutically acceptable salt thereof.

16. The compound of formula 1 according claim 14 , wherein

R 4 is selected from the group consisting of —CO—NH—Y and —CO—NH—C 1-6 -alkylene-Y,

with Y being a group selected from the group consisting of —NH(CH 3 ), —N(CH 3 ) 2 , —O-methyl, —CF 3 , methyl, ethyl and —OH,

or with Y being a six- or seven-membered fully saturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, which is bridged by an additional —CH 2 -unit,

whereby each group Z may optionally be further substituted by one, two or three groups T each independently selected from the group consisting of -oxo, OH, halogen, methyl, ethyl, n-propyl, isopropyl, —O-methyl, —O-ethyl, —O-(n-propyl), —O-(isopropyl), —N(methyl) 2 , —N(ethyl) 2 , C 3-6 -cycloalkyl, —CN, 5- to 6-membered fully saturated, partially unsaturated or aromatic heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S,

or a pharmaceutically acceptable salt thereof.

17. The compound of formula 1 according to claim 1 , wherein

R 4 is —CO—Y,

with Y being a group selected from the group consisting of —NH(CH 3 ), —N(CH 3 ) 2 , —O-methyl, —CF 3 , methyl, ethyl and —OH,

or with Y being a six- or seven-membered fully saturated heterocycle comprising 1, 2 or 3 heteroatoms each independently selected from N, S or O, which is bridged by an additional —CH 2 -unit,

whereby each group Z may optionally be further substituted by one, two or three groups T each independently selected from the group consisting of -oxo, OH, halogen, methyl, ethyl, n-propyl, isopropyl, —O-methyl, —O-ethyl, —O-(n-propyl), —O-(isopropyl), —N(methyl) 2 , —N(ethyl) 2 , C 3-6 -cycloalkyl, —CN, 5- to 6-membered fully saturated, partially unsaturated or aromatic heterocycle comprising 1 or 2 heteroatoms each independently selected from N, O or S,

or a pharmaceutically acceptable salt thereof.

18. The compound of formula 1 according to claim 1 , wherein

or a pharmaceutically acceptable salt thereof.

19. The compound of formula 1 according to claim 1 , wherein

R 4 is an oxadiazole group that may optionally be substituted by one, two or three groups each independently selected from methyl, ethyl, F, Cl, or —CF 3 ;

or a pharmaceutically acceptable salt thereof.

20. The compound of formula 1 according to claim 1 , selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical formulation comprising a compound of formula 1 according to claim 1 , or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical formulation of claim 21 , in further combination with an active substance selected from anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors, CRTH2-antagonists, HMG-CoA reductase inhibitors or combinations thereof.

23. A method for treating a disease selected from asthma, COPD, rheumatoid arthritis, allergic rhinitis, adult respiratory distress syndrome, bronchitis, idiopathic thrombocytopenic purpura, and lupus erythematodes, comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 1 .

24. The method according to claim 23 , wherein the disease is selected from asthma, COPD, allergic rhinitis and rheumatoid arthritis.

25. The method according to claim 24 , wherein the disease is asthma.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2013

From: DAHMANN, GEORG; DOLLINGER, HORST; GNAMM, CHRISTIAN; FIEGEN, DENNIS; HOFFMANN, MATTHIAS; KLICIC, JASNA; LAMB, DAVID JAMES; SCHNAPP, ANDREAS

To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Reel/Frame 031150/0530 →

Priority Claims (1)

EP 12164861 · Apr 20, 2012 · regional

Continuity (1)

Related Publication 20130281430A1 · Oct 24, 2013