CXCR4 receptor antagonists
The compounds of formula (I) are antagonists of the CXCR4 receptor Wherein R 1 , X, Y and R 2 are as defined in the claims.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is selected from cyano, —COR 3 , and —CONR 3 R 4 ;
X is selected from radicals of formulae (A)-(F) inclusive, any of which being optionally substituted with one more substituents independently selected from halogen, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to R 1 and the bond marked ** is attached to Y;
Y is a radical of formula (L), which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to X and the bond marked ** is attached to R 2
and n is 1 or 2, and R 20 is hydrogen or C 1-4 -alkyl;
R 2 is selected from radicals of formulae (N)-(S) inclusive, any of which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to Y
and o and p are each independently 1 or 2, and W is O or NR 9 ;
R 3 is selected from hydrogen, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, C 6-10 -aryl-C 1-4 -alkyl, and heteroaryl-C 1-4 -alkyl, wherein
(i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, the C 6-10 -aryl-C 1-4 -alkyl, or the heteroaryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxy, cyano, C 1-4 -alkoxy, and NR 5A R 5B , and
(ii) the C 6-10 -aryl, the heteroaryl, the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl or the heteroaryl part of the heteroaryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 alkyl, —NR 4 C(O)—C 1-4 alkyl, —NR 4 C(O)O-fluoro-C 1-4 alkyl, —NR 4 C(O)-fluoro-C 1-4 alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)OR 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 alkyl;
R 4 , R 5A , and R 5B are each independently selected from hydrogen, C 1-4 -alkyl, and fluoro-C 1-4 -alkyl,
or
R 5A and R 5B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy,
or
R 3 and R 4 , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and
R 6 is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, and C 6-10 -aryl, wherein
(iii) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, or the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and
(iv) the C 6-10 -aryl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl;
R 7 is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, C 6-10 -aryl, and —NR 10A R 10B , wherein
(v) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and
(vi) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl;
R 8A , R 8B and R 9 are each independently selected from hydrogen, C 3-5 -cycloalkyl, C 1-6 -alkyl, and C 6-10 -aryl-C 1-4 -alkyl wherein any alkyl residue or cycloalkyl or C 6-10 -aryl ring system is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and C 1-4 -alkoxy,
or
R 8A and R 8B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring which is optionally fused to a C 6-10 -aryl or heteroaryl ring system, the 4- to 7-membered saturated heterocyclic ring or the C 6-10 -aryl or heteroaryl ring systems being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and
R 10A and R 10B are each independently selected from hydrogen and C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy,
or
R 10A and R 10B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy.
2. A compound of claim 1 , wherein R 1 is CONR 3 R 4 .
3. A compound of claim 2 , wherein R 4 is hydrogen or methyl.
4. A compound of claim 2 , wherein R 3 is tetrahydropyranyl, isopropylmethyl, tetrahydropyranylmethyl, imidazolylethyl, methoxyethyl, N-methylimidazolylmethyl, tetrahydrofuranylmethyl, 1-fluoroethyl, oxazolylmethyl, pyridylmethyl, 2,2-difluoromethyl, tetrahydrofuranyl, methyl, ethyl, n- or iso-propyl, n-sec-or tert-butyl, cyclopropyl, hydroxyethyl, cyanoethyl, phenyl, chlorophenyl, methoxyphenyl, methylphenyl, hydroxyphenyl, thiazoloylmethyl, indolyl, methoxypropyl, tetrahydroisoquinolinyl, furylmethyl, pyridylethyl, thiazolyl, or cyclopropylmethyl.
5. A compound of claim 2 , wherein R 3 is pyridyl optionally substituted with one or more substituents selected from halogen, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkyl.
6. A compound of claim 5 , where R 3 is 4-pyridyl optionally substituted with one or more methyl groups.
7. A compound of claim 1 , wherein X is formula (A).
8. A compound of claim 1 , wherein R 6 is C 1-6 -alkyl, C 1-6 fluoroalkyl, C 1-2 -alkoxy-C 1-4 alkyl, C 3-5 cycloalkyl, or C 3-5 fluorocycloalkyl.
9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is selected from cyano, —COR 3 , and —CONR 3 R 4 ;
X is selected from radicals of formulae (A)-(F) inclusive, any of which being optionally substituted with one more substituents independently selected from halogen, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to R 1 and the bond marked ** is attached to Y
Y is a radical of formula (L) which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to X and the bond marked ** is attached to R 2
and n is 1 or 2, and R 20 is hydrogen or C 1-4 -alkyl;
R 2 is selected from radicals of formulae (N)-(S) inclusive, any of which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to Y
and o and p are each independently 1 or 2, and W is O or NR 9 ;
R 3 is selected from hydrogen, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, C 6-10 -aryl-C 1-4 -alkyl, and heteroaryl-C 1-4 -alkyl, wherein
(i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, the C 6-10 -aryl-C 1-4 -alkyl, or the heteroaryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxy, cyano, C 1-4 -alkoxy and —NR 5A R 5B , and
(ii) the C 6-10 -aryl, the heteroaryl, the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl or the heteroaryl part of the heteroaryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 alkyl, —NR 4 C(O)—C 1-4 alkyl, —NR 4 C(O)O-fluoro-C 1-4 alkyl, —NR 4 C(O)-fluoro-C 1-4 alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 -C 1-4 alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 alkyl;
R 4 , R 5A and R 5B are each independently selected from hydrogen, C 1-4 -alkyl, and fluoro-C 1-4 -alkyl,
or
R 5A and R 5B together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy,
or
R 3 and R 4 , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and
R 6 is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, and C 6-10 -aryl, wherein
(iii) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, or the C 1-6 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and
(iv) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl;
R 7 is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, C 6-10 -aryl, and —NR 10A R 10B , wherein
(v) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the C 1-6 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and
(vi) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl;
R 8A , R 8B and R 9 are each independently selected from hydrogen, C 3-5 -cycloalkyl, C 1-6 -alkyl, and C 6-10 -aryl-C 1-4 -alkyl, wherein any alkyl residue or cycloalkyl or C 6-10 -aryl ring system is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and C 1-4 -alkoxy,
or
R 8A and R 8B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring which is optionally fused to a C 6-10 -aryl or heteroaryl ring system, the 4- to 7-membered saturated heterocyclic ring or the C 6-10 -aryl or heteroaryl ring systems being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and
R 10A and R 10B are each independently selected from hydrogen and C 1-6 -alkyl, wherein the C alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy,
or
R 10A and R 10B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and
a pharmaceutically acceptable carrier and/or excipient.
10. A pharmaceutical composition of claim 9 , wherein R 1 is CONR 3 R 4 .
11. A pharmaceutical composition of claim 10 , wherein R 4 is hydrogen or methyl.
12. A pharmaceutical composition of claim 10 , wherein R 3 is tetrahydropyranyl, isopropylmethyl, tetrahydropyranylmethyl, imidazolylethyl, methoxyethyl, N-methylimidazolylmethyl, tetrahydrofuranylmethyl, 1-fluoroethyl, oxazolylmethyl, pyridylmethyl, 2,2-difluoromethyl, tetrahydrofuranyl, methyl, ethyl, n- or iso-propyl, n-sec-or tert-butyl, cyclopropyl, hydroxyethyl, cyanoethyl, phenyl, chlorophenyl, methoxyphenyl, methylphenyl, hydroxyphenyl, thiazoloylmethyl, indolyl, methoxypropyl, tetrahydroisoquinolinyl, furylmethylpyridylethyl furylmethyl, pyridylethyl, thiazolyl, or cyclopropylmethyl.
13. A pharmaceutical composition of claim 9 , wherein R 3 is pyridyl optionally substituted with one or more substituents selected from halogen, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkyl.
14. A pharmaceutical composition of claim 10 , where R 3 is 4-pyridyl optionally substituted with one or more methyl groups.
15. A pharmaceutical composition of claim 9 , wherein X is formula (A).
16. A pharmaceutical composition of claim 9 , wherein R 6 is C 1-6 -alkyl, C 1-6 fluoroalkyl, C 1-2 -alkoxy-C 1-4 alkyl, C 3-5 cycloalkyl, C 3-5 fluorocycloalkyl, benzyl, alpha methyl-benzyl, and benzyl or alpha methyl-benzyl either of which being optionally ring-substituted by one or two substituents selected from halogen, C 1-4 -alkyl, and C 1-4 -alkoxy.