Spirohydantoin compounds and their use as selective androgen receptor modulators

1 . A compound of formula (I-1) in free form or in pharmaceutically acceptable salt form

in which

X is O or N(R 8 );

Y is CH 2 , C(═NH), C(═O), C(═S) or C(H)(OR 9 );

Z is O or S;

R 1 is C 1 -C 3 alkyl;

R 2 is halogen;

A is selected from:

a 4-membered saturated ring which contains zero or one O atom, which ring is unsubstituted or substituted once or twice with R A ; or

a 5-membered saturated or unsaturated non-aromatic ring which contains zero or one O atom, which ring is unsubstituted or substituted once or twice with R A ;

R A is, for each occurrence, independently selected from hydroxy, halogen, C 1 -C 3 alkyl, hydroxyC 1 -C 3 alkyl, or two R A at the same carbon atom form an oxo group

R 8 is C1-C 6 alkyl optionally substituted with cyano, hydroxy-C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl wherein the alkoxy portion is optionally substituted with cyano or halogen or

R 8 is —(CH 2 ) n —B;

n is 1 or 2;

B is a 5- to 6-membered aromatic or non-aromatic ring which comprises 0, 1, 2, 3, or 4 heteroatoms selected from N, O or S, which ring is unsubstituted or substituted once or twice with R B ;

R B is, for each occurrence, independently selected from halo, cyano, C 1 -C 6 alkyl; and

R 9 is hydrogen or C 1 -C 3 alkyl.

2 . A compound of formula (I) in free form or in pharmaceutically acceptable salt form

in which

X is O or N(R 8 );

Y is CH 2 , C(═NH), C(═O), C(═S) or C(H)(OR 9 );

Z is O or S;

R 1 is C 1 -C 3 alkyl;

R 2 is halogen;

R 3 is cyano;

R 4 and R 5 are independently selected from hydrogen, hydroxy or halogen; or R 4 and R 5 together form an oxo group;

R 6 and R 7 are independently selected from hydrogen, hydroxy, or halogen; or R 6 and R 7 together form an oxo group; or

R 4 and R 6 together form a bond and R 5 and R 7 are each hydrogen;

R 8 is C 1 -C 3 alkyl, C 1 -C 6 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl; and

R 9 is hydrogen or C 1 -C 3 alkyl.

3 . A compound of claim 2 which is a compound of formula (Ia) in free form or in pharmaceutically acceptable salt form

in which

X is O or N(R 8 );

Y is CH 2 , C(═NH), C(═O), C(═S) or C(H)(OR 9 );

Z is O or S;

R 2 is halogen;

R 3 is cyano;

R 4 is hydrogen, hydroxy or halogen;

R 8 is C 1 -C 3 alkyl, C 1 -C 6 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl; and

R 9 is hydrogen or C 1 -C 3 alkyl.

4 . A compound of claim 2 which is a compound of formula (Ib) in free form or in pharmaceutically acceptable salt form

in which X is O or N(R 8 );

Y is CH 2 , C(═NH), C(═O), C(═S) or C(H)(OR 9 );

Z is O or S;

R 2 is halogen;

R 3 is cyano;

R 4 is hydrogen, hydroxy or halogen;

R 8 is C 1 -C 3 alkyl, C 1 -C 6 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl; and

R 9 is hydrogen or C 1 -C 3 alkyl.

5 . A compound of claim 2 which is a compound of formula (Ic) in free form or in pharmaceutically acceptable salt form

in which X is O or N(R 8 );

Y is CH 2 , C(═NH), C(═O), C(═S) or C(H)(OR 9 );

Z is O or S;

R 2 is halogen;

R 3 is cyano;

R 4 is hydrogen, hydroxy or halogen;

R 8 is C 1 -C 3 alkyl, C 1 -C 6 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl; and

R 9 is hydrogen or C 1 -C 3 alkyl.

6 . A compound of claim 2 which is a compound of formula (Id) in free form or in pharmaceutically acceptable salt form

in which X is O or N(R 8 );

Y is CH 2 , C(═NH), C(═O), C(═S) or C(H)(OR 9 );

Z is O or S;

R 2 is halogen;

R 3 is cyano;

R 4 is hydrogen, hydroxy or halogen;

R 8 is C 1 -C 3 alkyl, C 1 -C 6 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl; and

R 9 is hydrogen or C 1 -C 3 alkyl.

7 . A compound according to claim 1 in free form or in pharmaceutically acceptable salt form,

in which X is —N(CH 3 ), Y is —(C═O), and Z is O.

8 . A compound according to claim 1 in free form or in pharmaceutically acceptable salt form,

in which R 1 is methyl and R 2 is chloro.

9 . A compound according to claim 1 in free form or in pharmaceutically acceptable salt form which is selected from

2-chloro-4-(6-hydroxy-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-methyl-2,4,6-trioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(4,6-dihydroxy-1-methyl-2-oxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-ethyl-6-hydroxy-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(6-fluoro-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]non-6-en-3-yl)benzonitrile;

2-chloro-4-(6-hydroxy-1-methyl-2-oxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(1-(2-methoxyethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-ethyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(6-hydroxy-2,4-dioxo-1-oxa-3-azaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(6-hydroxy-4-methoxy-2-oxo-1-oxa-3-azaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(2-oxo-1-oxa-3-azaspiro[4.4]non-6-en-3-yl)benzonitrile;

2-chloro-4-(7-hydroxy-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(7-fluoro-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-methyl-2,4,7-trioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(7,7-difluoro-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(6-(hydroxymethyl)-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1,6-dimethyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methyl benzonitrile;

2-chloro-4-(4-imino-1-methyl-2-oxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(4-cyanobenzyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-((5-methyl isoxazol-3-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(2,4-dioxo-1-(2-(pyridin-4-yl)ethyl)-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(2,4-dioxo-1-(pyridin-2-ylmethyl)-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(2,4-dioxo-1-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-((6-methyl pyridin-3-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-3-methyl-4-(1-((5-methyloxazol-2-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(1-((5-(hydroxymethyl)oxazol-2-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-(oxazol-5-ylmethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-3-methyl-4-(1-((2-methyloxazol-5-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(1-(2-fluoroethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methyl benzonitrile;

2-chloro-4-(1-(5-cyanopentyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(2-(2-fluoroethoxy)ethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(2-(cyanomethoxy)ethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(3-cyanopropyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methyl benzonitrile;

2-chloro-4-(1-isobutyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(4-cyanobutyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(2-hydroxyethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(2-cyanoethyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-4-(1-(3-fluoropropyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile;

2-chloro-3-methyl-4-(1-methyl-2,4-dioxo-7-oxa-1,3-diazaspiro[4.4]nonan-3-yl)benzonitrile;

2-chloro-4-(2,4-dioxo-1-((tetrahydrofuran-3-yl)methyl)-1,3-diazaspiro[4.4]nonan-3-yl)-3-methylbenzonitrile; and

2-chloro-3-methyl-4-(5-methyl-6,8-dioxo-5,7-diazaspiro[3.4]octan-7-yl)benzonitrile.

10 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in free form or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carriers.

11 . A combination comprising a therapeutically effective amount of a compound according to claim 1 in free form or in pharmaceutically acceptable salt form and one or more therapeutically active co-agents.

12 . (canceled)

13 . (canceled)

14 . A method of treating a disorder or disease selected from muscle wasting diseases, osteoporosis, sarcopenia, frailty, and cancer cachexia, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 in free form or in pharmaceutically acceptable salt form.

15 . A compound according to claim 2 in free form or in pharmaceutically acceptable salt form,

in which X is —N(CH 3 ), Y is —(C═O), and Z is O.

16 . A compound according to claim 2 in free form or in pharmaceutically acceptable salt form,

in which R 1 is methyl and R 2 is chloro.

17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 2 in free form or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carriers.

18 . A combination comprising a therapeutically effective amount of a compound according to claim 2 in free form or in pharmaceutically acceptable salt form and one or more therapeutically active co-agents.