Substituted pyrido[3,4-b]indoles for the treatment of cartilage disorders

1. A compound of formula I

or a pharmaceutically acceptable salt thereof,

wherein:

A is selected from the group consisting of phenyl and a monocyclic or bicyclic, 5-membered to 10-membered, aromatic heterocyclic group,

wherein the aromatic heterocyclic group comprises 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 20 ), O and S, and is bonded via a ring carbon atom, and

wherein the phenyl and the aromatic heterocyclic group are unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a direct bond or a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members selected from the group consisting of N(R 25 ), O and S(O) m , and the other chain members are identical or different groups C(R 26 )(R 27 );

G is selected from the group consisting of hydrogen, halogen, (C1-C4)-alkyl, cyano and R 30 ;

R 1 , R 3 , R 4 and R 6 are independently selected from the group consisting of hydrogen, halogen and (C 1 -C 4 )-alkyl;

R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—C(O)—;

R 5 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O—, cyano, R 7 —O—C(O)— and R 8 —N(R 9 )—C(O)—;

R 7 , R 8 , R 9 , R 20 , R 22 , R 25 , R 31 , R 33 , R 34 and R 40 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl;

R 10 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl and (C 3 -C 7 )-cycloalkyl,

wherein the (C 1 -C 6 )-alkyl group is unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group consisting of (C 3 -C 7 )-cycloalkyl, Het, cyano and (C 1 -C 4 )-alkyl-O—, and

wherein each (C 3 -C 7 )-cycloalkyl group is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;

R 21 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and cyano, or two groups R 21 attached to adjacent ring carbon atoms in group A are taken together with the carbon atoms to which they are attached to form a 5-membered to 7-membered mono-unsaturated ring comprising 0, 1 or 2 identical or different hetero ring members selected from the group consisting of N(R 22 ), O and S(O) m , and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;

R 26 and R 27 are independently selected from the group consisting of hydrogen, fluorine, (C 1 -C 4 )-alkyl and hydroxy, and in one or two groups C(R 26 )(R 27 ), the substituents R 26 and R 27 attached to the same carbon atom are optionally taken together to form oxo;

R 30 is a monocyclic or bicyclic, 3-membered to 10-membered ring, which is saturated or unsaturated and comprises 0, 1, 2 or 3 identical or different hetero ring members selected from the group consisting of N, N(R 31 ), O and S(O) m , and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 32 ;

R 32 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, hydroxy, oxo, (C 1 -C 4 )-alkyl-O—, cyano, R 33 —N(R 34 )— and Het; and

m is selected from the group consisting of 0, 1 and 2, wherein all numbers m are independent of each other and are identical or different;

wherein Het is a monocyclic, 4-membered to 7-membered, saturated heterocyclic group comprising 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 40 ), O and S(O) m , and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl; and

wherein each alkyl group, independently of any other substituents which can be present on an alkyl group, is optionally substituted by one or more fluorine substituents,

provided that the compound of formula I is not 8-phenyl-9H-pyrido[3,4-b]indole.

2. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is selected from the group consisting of phenyl and a monocyclic, 5-membered or 6-membered, aromatic heterocyclic group,

wherein the aromatic heterocyclic group comprises 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 20 ), O and S, and is bonded via a ring carbon atom, and

wherein the phenyl and the aromatic heterocyclic group are unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a direct bond or a chain consisting of 1 to 4 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members selected from the group consisting of N(R 25 ), O and S(O) m , and the other chain members are identical or different groups C(R 26 )(R 27 );

G is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and R 30 ;

R 1 , R 3 , R 4 and R 6 are independently selected from the group consisting of hydrogen, halogen and (C 1 -C 3 )-alkyl;

R 2 is selected from the group consisting of hydrogen, halogen and (C 1 -C 3 )-alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and cyano;

R 10 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl,

wherein the (C 1 -C 6 )-alkyl group is unsubstituted or substituted by 1 substituent selected from the group consisting of (C 3 -C 7 )-cycloalkyl, Het, cyano and (C 1 -C 4 )-alkyl-O—, and

wherein each (C 3 -C 7 )-cycloalkyl group is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;

R 20 , R 22 , R 25 , R 31 and R 40 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl;

R 21 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and cyano,

or two groups R 21 attached to adjacent ring carbon atoms in group A are taken together with the carbon atoms to which they are attached to form a 5-membered or 6-membered mono-unsaturated ring comprising 0, 1 or 2 identical or different hetero ring members selected from the group consisting of N(R 22 ), O and S(O) m , and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;

R 26 and R 27 are independently selected from the group consisting of hydrogen, fluorine, (C 1 -C 3 )-alkyl and hydroxy, and in one group C(R 26 )(R 27 ), the substituents R 26 and R 27 attached to the same carbon atom together are optionally taken together to form oxo;

R 30 is a monocyclic or bicyclic, 3-membered to 10-membered ring, which is saturated or unsaturated and comprises 0, 1, 2 or 3 identical or different hetero ring members selected from the group consisting of N, N(R 31 ), O and S(O) m , and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 32 ;

R 32 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, hydroxy, oxo, (C 1 -C 4 )-alkyl-O— and cyano; and

m is selected from the group consisting of 0, 1 and 2, wherein all numbers m are independent of each other and can be identical or different;

wherein Het is a monocyclic, 4-membered to 6-membered, saturated heterocyclic group comprising 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 40 ) and O, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl; and

wherein each alkyl group, independently of any other substituents which can be present on an alkyl group, is optionally substituted by one or more fluorine substituents.

3. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is selected from the group consisting of phenyl and a monocyclic, 5-membered or 6-membered, aromatic heterocyclic group,

wherein the aromatic heterocyclic group comprises 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 20 ), O and S, and is bonded via a ring carbon atom, and

wherein the phenyl and the aromatic heterocyclic group are unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a direct bond or a chain consisting of 1 to 4 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members selected from the group consisting of N(R 25 ) and O, and the other chain members are identical or different groups C(R 26 )(R 27 );

G is selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl and R 30 ;

R 1 and R 4 are independently selected from the group consisting of hydrogen, halogen and (C 1 -C 3 )-alkyl;

R 2 is selected from the group consisting of hydrogen, halogen and (C 1 -C 3 )-alkyl;

R 3 and R 6 are independently selected from the group consisting of hydrogen, halogen and C 1 -alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and cyano;

R 10 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl,

wherein the (C 1 -C 6 )-alkyl group is unsubstituted or substituted by 1 substituent selected from the group consisting of (C 3 -C 7 )-cycloalkyl, Het, cyano and (C 1 -C 4 )-alkyl-O—, and

wherein each (C 3 -C 7 )-cycloalkyl is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;

R 20 , R 22 , R 25 , R 31 and R 40 are independently selected from the group consisting of hydrogen and (C 1 -C 4 )-alkyl;

R 21 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and cyano,

or two groups R 21 attached to adjacent ring carbon atoms in group A are taken together with the carbon atoms to which they are attached to form a 5-membered or 6-membered mono-unsaturated ring comprising 0, 1 or 2 identical or different hetero ring members selected from the group consisting of N(R 22 ) and O, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents selected from the group consisting of fluorine and C 1 -alkyl;

R 26 and R 27 are independently selected from the group consisting of hydrogen, fluorine, (C 1 -C 3 )-alkyl and hydroxy, and in one group C(R 26 )(R 27 ), the substituents R 26 and R 27 attached to the same carbon atom are optionally taken together to form oxo;

R 30 is a monocyclic or bicyclic, 3-membered to 10-membered ring, which is saturated or aromatic and comprises 0, 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 31 ), O and S(O) m , and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 32 ;

R 32 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, hydroxy, oxo and (C 1 -C 4 )-alkyl-O—; and

m is selected from the group consisting of 0, 1 and 2, wherein all numbers m are independent of each other and can be identical or different;

wherein Het is a monocyclic, 4-membered to 6-membered, saturated heterocyclic group comprising 1 hetero ring member selected from the group consisting of N(R 40 ) and O, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 3 )-alkyl; and

wherein each alkyl group, independently of any other substituents which can be present on an alkyl group, is optionally substituted by one or more fluorine substituents.

4. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is selected from the group consisting of phenyl and a monocyclic, 5-membered or 6-membered, aromatic heterocyclic group,

wherein the aromatic heterocyclic group comprises 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 20 ) and S, and is bonded via a ring carbon atom, and

wherein the phenyl and the heterocyclic group are unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain members are identical or different hetero chain members selected from the group consisting of N(R 25 ) and O, and the other chain members are identical or different groups C(R 26 )(R 27 );

G is selected from the group consisting of hydrogen and R 30 ;

R 1 and R 4 are independently selected from the group consisting of hydrogen, halogen and (C 1 -C 2 )-alkyl;

R 2 is selected from the group consisting of hydrogen, halogen and (C 1 -C 2 )-alkyl;

R 3 and R 6 are independently selected from the group consisting of hydrogen, halogen and C 1 -alkyl;

R 5 is selected from the group consisting of hydrogen, halogen and (C 1 -C 2 )-alkyl;

R 10 is selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -05)-cycloalkyl,

wherein the (C 1 -C 4 )-alkyl group is unsubstituted or substituted by 1 substituent selected from the group consisting of (C 3 -C 5 )-cycloalkyl and Het, and

wherein each (C 3 -C 5 )-cycloalkyl group is unsubstituted or substituted by one or more identical or different substituents (C 1 -C 2 )-alkyl;

R 20 , R 25 and R 31 are independently selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl;

R 21 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and cyano;

R 26 and R 27 are independently selected from the group consisting of hydrogen, fluorine, C 1 -alkyl and hydroxy, and in one group C(R 26 )(R 27 ), the substituents R 26 and R 27 attached to the same carbon atom are optionally taken together to form oxo;

R 30 is a monocyclic 3-membered to 6-membered or bicyclic 9-membered to 10-membered ring, which is saturated or aromatic and comprises 0, 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 31 ) and O, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 32 ; and

R 32 is selected from the group consisting of halogen, (C 1 -C 3 )-alkyl, hydroxy and oxo;

wherein Het is a monocyclic, 4-membered or 5-membered, saturated heterocyclic group comprising 1 hetero ring member which is 0, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents (C 1 -C 3 )-alkyl; and

wherein each alkyl group, independently of any other substituents which can be present on an alkyl group, is optionally substituted by one or more fluorine substituents.

5. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is selected from the group consisting of phenyl, pyrazolyl and pyridinyl, each of which is unsubstituted or substituted on ring carbon atoms by one or more identical of different substituents R 21 ;

E is a direct bond or a chain consisting of 1 to 3 chain members of which 0 or 1 chain member is a hetero chain member which is O, and the other chain members are identical or different groups C(R 26 )(R 27 );

G is selected from the group consisting of hydrogen and R 30 ;

R 1 and R 4 are independently selected from the group consisting of hydrogen, halogen and C 1 -alkyl;

R 2 is selected from the group consisting of hydrogen, halogen and C 1 -alkyl;

R 3 and R 6 are each hydrogen;

R 5 is selected from the group consisting of halogen and (C 1 -C 2 )-alkyl;

R 10 is selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 5 )-cycloalkyl,

wherein the (C 1 -C 4 )-alkyl group is unsubstituted or substituted by 1 substituent selected from the group consisting of (C 3 -C 5 )-cycloalkyl and Het;

R 21 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and cyano;

R 26 and R 27 are independently selected from the group consisting of hydrogen, fluorine and C 1 -alkyl;

R 30 is a monocyclic, 3-membered to 6-membered ring, which is saturated or aromatic and comprises 0, 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 31 ) and O, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 32 ;

R 31 is selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl; and

R 32 is selected from the group consisting of halogen and (C 1 -C 3 )-alkyl;

wherein Het is a monocyclic, 4-membered or 5-membered, saturated heterocyclic group comprising 1 hetero ring member which is O, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents (C 1 -C 3 )-alkyl; and

wherein each alkyl group, independently of any other substituents which can be present on an alkyl group, is optionally substituted by one or more fluorine substituents.

6. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl, which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a direct bond; and

G is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and cyano.

7. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl, which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members selected from the group consisting of N(R 25 ), O and S(O) m , and the other chain members are identical or different groups C(R 26 )(R 27 ); and

G is R 30 .

8. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic, 5-membered to 10-membered, aromatic heterocyclic group comprising 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 20 ), O and S, and is bonded via a ring carbon atom, and which is unsubstituted or substituted on ring carbon atoms by one or more identical of different substituents R 21 ;

E is a direct bond; and

G is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and cyano.

9. The compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic, 5-membered to 10-membered, aromatic heterocyclic group comprising 1 or 2 identical or different hetero ring members selected from the group consisting of N, N(R 20 ), O and S, and is bonded via a ring carbon atom, and which is unsubstituted or substituted on ring carbon atoms by one or more identical or different substituents R 21 ;

E is a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members selected from the group consisting of N(R 25 ), O and S(O) m , and the other chain members are identical or different groups C(R 26 )(R 27 ); and

G is R 30 .

10. The compound of formula I according to claim 1 , which is selected from the group consisting of:

6-Bromo-9-ethyl-1-methyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-9H-pyrido[3,4-b]indole;

6-Chloro-1,5-dimethyl-8-[4-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-9H-pyrido[3,4-b]indole;

2-(4-[6-Chloro-9-(2,2,2-trifluoroethyl)-9H-pyrido[3,4-b]indol-8-yl]pyrazol-1-yl)ethanol;

6-Chloro-1-methyl-8-[4-(2-pyrazol-1-ylethoxy)-phenyl]-9H-pyrido[3,4-b]indole;

6-Bromo-9-ethyl-1,3-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-pyrido[3,4-b]indole;

6-Chloro-8-(4-methoxy-phenyl)-1,9-dimethyl-9H-pyrido[3,4-b]indole;

6-Chloro-8-(4-methoxy-phenyl)-1,5-dimethyl-9H-pyrido[3,4-b]indole;

8-(4-Methoxy-phenyl)-1-methyl-9H-pyrido[3,4-b]indole-6-carbonitrile;

6-Chloro-1-methyl-8-[4-(1-methyl-1H-imidazol-2-ylmethoxy)-phenyl]-9H-pyrido[3,4-b]indole;

6-Chloro-1,5-dimethyl-8-[4-(2-pyrazol-1-yl-ethoxy)-phenyl]-9H-pyrido[3,4-b]pyridine;

6-Chloro-9-cyclopropylmethyl-8-(2,6-dichloro-pyridin-3-yl)-9H-pyrido[3,4-b]indole;

6-Chloro-8-(2,6-dichloro-pyridin-3-yl)-9-ethyl-9H-pyrido[3,4-b]indole;

8-(2,6-Dichloro-pyridin-3-yl)-1,6-dimethyl-9H-pyrido[3,4-b]indole;

6-Chloro-9-ethyl-1-methyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-9H-pyrido[3,4-b]indole;

6-Chloro-8-(4-chloro-phenyl)-9-ethyl-1-methyl-9H-pyrido[3,4-b]indole;

6-Chloro-8-(4-methoxy-phenyl)-1-methyl-9H-pyrido[3,4-b]indole;

6-Chloro-8-chroman-6-yl-1-methyl-9H-pyrido[3,4-b]indole;

6-Chloro-8-[4-(2-imidazol-1-yl-ethoxy)-phenyl]-1-methyl-9H-pyrido[3,4-b]indole;

6-Bromo-9-ethyl-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-pyrido[3,4-b]indole;

4-(6-Chloro-1-methyl-9H-pyrido[3,4-b]indol-8-yl)-pyridin-2-ylamine;

6-Chloro-1-methyl-8-[4-(1-methyl-pyrrolidin-3-ylmethoxy)-phenyl]-9H-pyrido[3,4-b]indole;

6-Chloro-9-ethyl-1-methyl-8-[4-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-9H-pyrido[3,4-b]indole;

6-Bromo-9-ethyl-1-methyl-8-[4-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-9H-pyrido[3,4-b]indole; and

6-Chloro-9-cyclopropylmethyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-9H-pyrido[3,4-b]indole,

or a pharmaceutically acceptable salt thereof.

11. A process for preparing the compound of formula I according to claim 1 , comprising:

reacting a compound of formula II with a compound of formula III, wherein:

A, E, G, le to R 6 and R 10 in the compounds of formulae II and III are defined as in the compound of formula I, or functional groups are present in protected form or in the form of a precursor group;

X in the compound of formula II is a leaving group; and

each Y in the compound of formula III is independently hydrogen or (C 1 -C 4 )-alkyl,

or two groups Y are taken together with the —O—B—O— moiety to which they are attached to form a saturated 5-membered or 6-membered ring comprising 2 or 3 carbon atoms as ring atoms in addition to the —O—B—O— moiety, and is unsubstituted or substituted by one or more (C 1 -C 4 )-alkyl substituents,

to form the compound of formula I.

12. A pharmaceutical composition comprising the compound of formula I according claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.