IP Library › Granted Patent US 9,475,775

Granted Patent B2

US 9,475,775 · App. 15/061,105 · Granted Oct 25, 2016

Benzazepine dicarboxamide compounds

Inventors: Sabine Hoves (Habach, DE); Lisha Wang (Riehen, CH); Hongying Yun (Shanghai, CN); Weixing Zhang (Shanghai, CN); Wei Zhu (Shanghai, CN)

Assignee: Hoffmann-La Roche Inc.

C07D223/16 C07D401/12 C07D403/12 C07D413/12 C07D417/12

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Quick Facts

Patent No.: US 9,475,775
App. No.: 15/061,105
Granted: Oct 25, 2016
Kind: B2

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Abstract

This invention relates to novel benzazepine dicarboxamide compounds of the formula wherein R 1 to R 4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.

Claims (148)

1. A compound of the formula

wherein

R 1 is C 3-7 -alkyl or C 3-7 -cycloalkyl;

R 2 is selected from the group consisting of C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, C 2-7 -alkenyl, C 3-7 -alkinyl, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, halogen-C 1-7 -alkyl, C 3-7 -cycloalkyl-C 1-7 -alkyl and phenyl-C 1-7 -alkyl, wherein phenyl is unsubstituted or substituted by amino-C 1-7 -alkyl;

R 3 is hydrogen;

R 4 is selected from the group consisting of

phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkyl-amino-C 1-7 -alkyl, di-C 1-7 -alkyl-amino-C 1-7 -alkyl, amino-C 2-7 -alkenyl, C 1-7 -alkyl-amino-C 2-7 -alkenyl, di-C 1-7 -alkyl-amino-C 2-7 -alkenyl, amino-C 2-7 -alkinyl, C 1-7 -alkyl-amino-C 2-7 -alkinyl, di-C 1-7 -alkyl-amino-C 2-7 -alkinyl, benzyloxycarbonylamino-C 1-7 -alkyl, amino-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl, heterocyclylcarbonyl and phenyl-C 1-7 -alkyl, wherein phenyl is unsubstituted or substituted by C 1-7 -alkoxy or amino-C 1-7 -alkyl, and

heteroaryl, said heteroaryl being a 5- or 6-membered aromatic ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or substituted by one or two groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkyl-amino-C 1-7 -alkyl, di-C 1-7 -alkyl-amino-C 1-7 -alkyl, amino-C 2-7 -alkenyl, C 1-7 -alkyl-amino-C 2-7 -alkenyl, di-C 1-7 -alkyl-amino-C 2-7 -alkenyl, amino-C 2-7 -alkinyl, C 1-7 -alkyl-amino-C 2-7 -alkinyl, di-C 1-7 -alkyl-amino-C 2-7 -alkinyl, benzyloxycarbonylamino-C 1-7 -alkyl, amino-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl, heterocyclylcarbonyl and phenyl-C 1-7 -alkyl, wherein phenyl is unsubstituted or substituted by C 1-7 -alkoxy or amino-C 1-7 -alkyl,

or a pharmaceutically acceptable salt thereof.

2. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-7 -alkyl.

3. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl or butyl.

4. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of C 1-7 -alkyl, C 3-7 -alkinyl, halogen-C 1-7 -alkyl, C 3-7 -cycloalkyl-C 1-7 -alkyl and hydroxy-C 1-7 -alkyl.

5. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-7 -alkyl.

6. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being unsubstituted or substituted by one or two groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, hydroxy-C 1-7 -alkyl, C 1-7 -alkyl-amino-C 1-7 -alkyl, di-C 1-7 -alkyl-amino-C 1-7 -alkyl, amino-C 2-7 -alkenyl, C 1-7 -alkyl-amino-C 2-7 -alkenyl, di-C 1-7 -alkyl-amino-C 2-7 -alkenyl, C 1-7 -alkyl-amino-C 2-7 -alkinyl, di-C 1-7 -alkyl-amino-C 2-7 -alkinyl, benzyloxycarbonylamino-C 1-7 -alkyl, amino-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl, heterocyclylcarbonyl and phenyl-C 1-7 -alkyl, wherein phenyl is unsubstituted or substituted by C 1-7 -alkoxy or amino-C 1-7 -alkyl.

7. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O or S and being substituted by one or two groups selected from the group consisting of C 1-7 -alkyl, halogen, C 1-7 -alkoxy, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, di-C 1-7 -alkyl-amino-C 1-7 -alkyl, amino-C 2-7 -alkenyl, amino-C 2-7 -alkinyl, benzyloxycarbonylamino-C 1-7 -alkyl, amino-C 1-7 -alkoxy and phenyl-C 1-7 -alkyl, wherein phenyl is unsubstituted or substituted by C 1-7 -alkoxy or amino-C 1-7 -alkyl.

8. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- or 6-membered heteroaryl ring is selected from the group consisting of imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl and pyrimidinyl.

9. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the 6-membered heteroaryl ring is pyridyl.

10. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkyl-amino-C 1-7 -alkyl, di-C 1-7 -alkyl-amino-C 1-7 -alkyl, amino-C 2-7 -alkenyl, C 1-7 -alkyl-amino-C 2-7 -alkenyl, di-C 1-7 -alkyl-amino-C 2-7 -alkenyl, amino-C 2-7 -alkinyl, C 1-7 -alkyl-amino-C 2-7 -alkinyl, di-C 1-7 -alkyl-amino-C 2-7 -alkinyl, benzyloxycarbonylamino-C 1-7 -alkyl, amino-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl, heterocyclylcarbonyl and phenyl-C 1-7 -alkyl, wherein phenyl is unsubstituted or substituted by C 1-7 -alkoxy or amino-C 1-7 -alkyl.

11. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, said phenyl being unsubstituted or substituted by one or two groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, amino-C 1-7 -alkyl, amino-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl and heterocyclylcarbonyl.

12. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl substituted by one group selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, amino-C 1-7 -alkyl, amino-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkoxy, amino-C 1-7 -alkoxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, C 1-7 -alkylsulfonyl and heterocyclylcarbonyl.

13. A compound of the formula I according to claim 1 , wherein

R 1 is C 3-7 -alkyl or C 3-7 -cycloalkyl;

R 2 is selected from the group consisting of C 1-7 -alkyl, C 2-7 -alkenyl, C 3-7 -alkinyl, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkoxy-C 1-7 -alkoxy-C 1-7 -alkyl, halogen-C 1-7 -alkyl and C 3-7 -cycloalkyl-C 1-7 -alkyl;

R 3 is hydrogen;

R 4 is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

14. A compound selected from the group consisting of

2-amino-N4,N4-dipropyl-N8-(3-pyridyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-pyrimidin-5-yl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-(4-pyridyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-phenyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[6-(aminomethyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(hydroxymethyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[6-(hydroxymethyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3-methylsulfonylphenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-thiazol-5-yl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(4-chlorophenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-thiazol-2-yl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3-methylimidazol-4-yl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(4-fluorophenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(m-tolyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-[3-(pyrrolidine-1-carbonyl)phenyl]-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-[5-(pyrrolidine-1-carbonyl)-3-pyridyl]-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(5-methyl-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3-fluorophenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(5-fluoro-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(2-methyl-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(6-methyl-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3,5-dimethylphenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[4-(aminomethyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[4-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-(3-hydroxypropyl)-N8-(m-tolyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(o-tolyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-(p-tolyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3-ethylphenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3-methoxyphenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-[3-(trifluoromethyl)phenyl]-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(3-chlorophenyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(aminomethyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dipropyl-N8-pyridazin-4-yl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(6-ethoxy-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(aminomethyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(1-methylpyrazol-3-yl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-oxazol-2-yl-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-(3-hydroxypropyl)-N4-propyl-N8-(3-pyridyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(5-methoxy-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(m-tolyl)-N4-propyl-N4-prop-2-ynyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4,N4-dibutyl-N8-(m-tolyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(aminomethyl)-5-methyl-phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(5-ethoxy-3-pyridyl)-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-[2-(2-aminoethoxy)ethoxy]phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(5-aminopentoxy)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-[2-(2-aminoethoxy)ethoxymethyl]phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(3-aminoprop-1-ynyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-N8-(m-tolyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(3-aminopropyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-(m-tolyl)-N4-propyl-N4-(3,3,3-trifluoropropyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-[(E)-3-aminoprop-1-enyl]-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide, and

2-amino-N4-(cyclopropylmethyl)-N8-(m-tolyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide,

or a pharmaceutically acceptable salt thereof.

15. A compound selected from the group consisting of

2-amino-N8-[3-(2-aminoethyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-isobutyl-N8-(m-tolyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-[3-(3-aminopropoxy)propyl]-N8-(m-tolyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[4-(5-aminopentyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-[[4-(aminomethyl)phenyl]methyl]-N8-(m-tolyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[4-(3-aminopropyl)phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(2-aminoethyl)-4-fluoro-phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[3-(2-aminoethyl)-5-chloro-phenyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-butyl-N4-(2-hydroxyethyl)-N8-(m-tolyl)-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(2-aminoethoxy)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

benzyl-N-[[5-[[2-amino-4-(dipropylcarbamoyl)-3H-1-benzazepine-8-carbonyl]amino]-3-pyridyl]methyl]carbamate,

2-amino-N8-[5-[(E)-3-aminoprop-1-enyl]-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(2-phenylethyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-[2-(4-methoxyphenyl)ethyl]-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-[2-[4-(aminomethyl)phenyl]ethyl]-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(5-aminopentyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-[2-(3-methoxyphenyl)ethyl]-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(6-aminohexyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[6-(3-aminopropyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-(4-aminobutyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[6-(4-aminobutyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N8-[5-[(dimethylamino)methyl]-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

2-amino-N4-(cyclopropylmethyl)-N8-(5-ethoxy-3-pyridyl)-N4-propyl-3H-1-benzazepine-4,8-dicarboxamide, and

2-amino-N8-[5-(2-aminoethyl)-3-pyridyl]-N4,N4-dipropyl-3H-1-benzazepine-4,8-dicarboxamide,

or a pharmaceutically acceptable salt thereof.

16. A compound selected from the group consisting of