Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors

Patent metadata

Field	Value
Publication number	US-9499563-B2
Application number	US-201414306614-A
Country	US
Kind code	B2
Filing date	Jun 17, 2014
Priority date	May 15, 2009
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present invention relates to a series of compounds having antiviral activity, more specifically HIV (Human Immunodeficiency Virus) replication inhibiting properties. The invention also relates to methods for the preparation of such compounds, as well as to novel intermediates useful in one or more steps of such syntheses. The invention also relates to pharmaceutical compositions comprising an effective amount of such compounds as active ingredients. This invention further relates to the use of such compounds as medicines or in the manufacture of a medicament useful for the treatment of animals suffering from viral infections, in particular HIV infection. This invention further relates to methods for the treatment of viral infections in animals by the administration of a therapeutic amount of such compounds, optionally combined with one or more other drugs having anti-viral activity.

First claim

The invention claimed is:

1. A compound according to formula (B),

wherein,
each dotted line represents an optional double bond whereby maximally two non-adjacent dotted lines can form a double bond;
n is selected from 0, 1, or 2;
m is selected from 0, 1, 2, 3, 4, 5, or 6;
R′ is independently selected from alkyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl;
wherein in the alkyl moiety of said alkyl, arylalkyl, or heterocycle-alkyl, one or more —CH 3 or —CH 2 — is optionally replaced by one or more NH 2 , —NH—, —O—, or —S—, respectively;
and wherein said alkyl, aryl, heterocycle, arylalkyl or heterocycle-alkyl can be unsubstituted or substituted with one or more Z 1 ;

R 2a is independently selected from hydrogen, alkyl, alkynyl, arylalkyl, or heterocycle-alkyl and R 2b is independently selected from alkyl, alkynyl, arylalkyl, or heterocycle-alkyl;
wherein in the alkyl moiety of said alkyl, arylalkyl, or heterocycle-alkyl, one or more —CH 3 or —CH 2 — is optionally replaced by one or more NH 2 , —NH—, —O—, or —S—, respectively;
and wherein said alkyl, alkynyl, arylalkyl, or heterocycle-alkyl can be unsubstituted or substituted with one or more Z′;

R 3 is independently selected from —COOH or —COOZ 2 ;
R 4 is independently selected from hydroxyl or alkyl;
wherein in said alkyl, one or more —CH 3 or —CH 2 — is optionally replaced by one or more —NH 2 , —NH—, —O—, or —S—, respectively;
and wherein said alkyl can be unsubstituted or substituted with one or more Z 1 ;

each Z 1 is independently selected from hydrogen, halogen, —OZ 2 , —SZ 2 , —S(O)Z 3 , —S(O) 2 Z 3 , —SO 2 NZ 4 Z 5 , trifluoromethyl, nitro, —NZ 4 Z 5 , —NZ 2 S(O) 2 Z 3 , cyano, —COOZ 2 , —C(O)NZ 4 Z 5 , —C(O)Z 3 , alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl;
and wherein in the alkyl, alkenyl or alkynyl moiety of said alkyl, alkenyl, alkynyl, arylalkyl, or heterocycle-alkyl, one or more —CH 3 , —CH 2 —, —CH═ or ≡CH is optionally replaced by one or more —NH 2 , —NH—, —O—, —S—, —N═ or ≡N, respectively; or

two Z 1 on the same carbon atom can be taken together to form a 5, 6 or 7-membered spiro-cycloalkyl or a saturated spiro-heterocycle together with the (4, 5, 6, 7 or 8-membered unsaturated) ring they are attached to; or
two Z 1 on adjacent atoms can be taken together to form a 5, 6 or 7-membered cycloalkyl, aryl or heterocycle fused to the (4, 5, 6, 7, or 8-membered unsaturated) ring they are attached to;
each Z 2 is independently selected from hydrogen, alkyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl; and
wherein in said alkyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl, one or more —CH 3 , —CH 2 —, or —CH═ is optionally replaced by one or more —NH 2 , —NH—, —O—, —S—, or —N═, respectively; and
wherein said alkyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can be unsubstituted or substituted with alkyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF 3 , cyano, nitro, —COOH or NH 2 ;

each Z 3 is independently selected from hydroxyl, alkyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl; and
wherein in said alkyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl, one or more —CH 3 , —CH 2 —, or —CH═ is optionally replaced by one or more —NH 2 , —NH—, —O—, —S—, or —N═, respectively; and
wherein said alkyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF 3 , cyano, nitro, —COOH or NH 2 ;

each Z 4 or Z 5 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl; and
wherein in said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl, one or more —CH 3 , —CH 2 —, —CH═ or ≡CH is optionally replaced by one or more —NH 2 , —NH—, —O—, —S, —N═ or ≡N respectively; and
wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF 3 , cyano, nitro, —COOH or NH 2 ; and
wherein Z 4 and Z 5 , respectively, can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF 3 , cyano, nitro, —COOH or —NH 2 ;

and a stereoisomer, tautomer, solvate, hydrate, salt, or pharmaceutically acceptable salt of any thereof.

2. The compound according to claim 1 ,
wherein,
each Z 1 is independently selected from hydrogen, halogen, —OZ 2 , —SZ 2 , trifluoromethyl, —NZ 4 Z 5 , —C(O)Z 3 , alkyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl;
and wherein said alkyl arylalkyl or heterocycle-alkyl, optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms O, S and N;
and wherein said alkyl, aryl, heterocycle, arylalkyl, or heterocycle-alkyl can be unsubstituted or substituted with alkyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF 3 , cyano, nitro, —COOH or NH 2 ; or

two Z 1 on the same carbon atom can be taken together to form a spiro-carbocycle or a saturated spiro-heterocycle together with the 4, 5, 6, 7 or 8-membered unsaturated ring they are attached to; or
two Z 1 on adjacent atoms can be taken together to form a fused ring system together with the 4, 5, 6, 7 or 8-membered unsaturated ring they are attached to;
wherein, Z 1 , Z 2 , and Z 3 are as defined in claim 1 .

3. The compound according to claim 1 , wherein R 3 is —COOH.

4. The compound according to claim 1 , wherein R 1 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or substituted with one or more Z 1 ;
wherein, Z 1 is as defined in claim 1 .

5. The compound according to claim 1 , wherein R 2a is hydrogen, and R 2b is selected from alkyl, alkynyl, arylalkyl, or heterocycle-alkyl;
wherein said alkyl, alkynyl, arylalkyl, or heterocycle-alkyl optionally includes one or more heteroatoms, said heteroatoms in the alkyl or alkynyl moiety being selected from the atoms O, S and N; and
wherein said alkyl, alkynyl, arylalkyl, or heterocycle-alkyl can be unsubstituted or substituted with one or more Z 1 ;
wherein, Z 1 is as defined in claim 1 .

6. A compound selected from the group consisting of:
Methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4, 5]thieno [2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro [1]benzothieno [2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-p-tolylbenzo [4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno [2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;
Methyl [2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Assignees

• Univ Leuven Kath

Inventors

• Bardiot Dorothée
• Chaltin Patrick
• Christ Frauke
• Debyser Zeger
• De Maeyer Marc
• Marchand Arnaud
• Marchand Damien
• Voet Arnout

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/18

  for HIV · CPC title

• C07D495/20 Primary

  Spiro-condensed systems · CPC title

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title