Heterocyclic substituted piperazine compounds with CXCR3 antagonist activity
View Patent ↗The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: or a pharmaceutically acceptable salt, solvate or ester thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, zenograft rejection), infectious diseases (e.g., tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.
1. A compound having the general structure shown in Formula 1:
or a pharmaceutically acceptable salt thereof wherein:
G is —C≡N or
X is N;
Z is N, or NO;
R 1 and R 2 are independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, and hydroxyalkyl;
or alternatively, the N taken together with the R 1 and R 2 forms —N═C(NH 2 ) 2 ,
R 3 , R 5 and R 6 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, CF 3 , OCF 3 , haloalkyl, halogen, —N(R 30 ) 2 and —OR 30 ;
R 7 and R 6 are the same or different, each being independently selected from the group consisting of H, and alkyl; or alternatively R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O;
the R 10 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, hydroxyl, —N(R 30 ) 2 , —OR 30 , and halogen; or wherein two R 10 moieties together on the same carbon atom form —C═O;
the R 11 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, hydroxyl, —N(R 30 ) 2 , —OR 30 , and halogen; or wherein two R 11 moieties together on the same carbon atom form —C═O;
R 12 is selected from the group consisting of H, alkyl, haloalkyl and CF 3 ;
D is a phenyl, which is unsubstituted or substituted with 1-5 independently selected R 20 moieties;
the R 20 moieties can be the same or different, each being independently selected from the group consisting of alkyl, cyano, halogen, haloalkyl, haloalkoxy, —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —N(R 30 ) 2 , OR 30 , —SO 2 N(R 30 ) 2 , and —SO 2 (R 31 );
Y is selected from the group consisting of —(CR 13 R 13 ) r —, —CHR 13 C(═O)—, and —C(═O)—;
the R 13 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, and alkoxy;
the R 30 moieties can be the same or different, each being independently selected from the group consisting of H and alkyl;
the R 31 moieties are independently alkyl;
m is 0 to 4;
n is 0 to 4;
each q can be the same or different, each being independently selected from 1 to 5; and
r is 1 to 4;
wherein:
“alkyl” refers to C 1 -C 6 alkyl;
“cycloalkyl” refers to C 3 -C 10 cycloalkyl; and
“aryl” refers to C 6 -C 10 aryl.
2. The compound according to claim 1 , wherein G is —C≡N.
3. The compound according to claim 1 , wherein G is
4. The compound according to claim 3 , wherein R 1 and R 2 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, and cycloalkyl.
5. The compound according to claim 3 , wherein R 1 and R 2 are independently selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OH, and cyclopropyl.
6. The compound according to claim 1 , wherein R 3 is selected from the group consisting of H, alkyl, alkoxy, halogen, and haloalkyl.
7. The compound according to claim 1 , wherein R 3 is selected from the group consisting of —H, —CH 3 , OCH 3 , —Cl and —CF 3 .
8. The compound according to claim 1 , wherein R 5 is selected from the group consisting of H, alkyl, —OR 30 , —N(R 30 ) 2 , and halogen.
9. The compound according to claim 1 , wherein R 5 is selected from the group consisting of H, CH 3 , OH, NH 2 , and F.
10. The compound according to claim 8 , wherein R 5 is H.
11. The compound according to claim 1 , wherein R 6 is selected from the group consisting of H, alkyl, —OR 30 , —N(R 30 ) 2 , and halogen.
12. The compound according to claim 1 , wherein R 6 is selected from the group consisting of H and alkyl.
13. The compound according to claim 1 , wherein R 6 is selected from the group consisting of H, CH 3 , OH , NH 2 , and F.
14. The compound according to claim 1 , wherein R 6 is selected from the group consisting of —H and —CH 3 .
15. The compound according to claim 3 , wherein R 7 and R 8 are both H, or R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O.
16. The compound according to claim 1 , wherein R 10 is independently selected from the group consisting of alkyl, hydroxyl, and alkoxy, or wherein two R 10 moieties together on the same carbon atom form —C═O, and m is 1-2.
17. The compound according to claim 16 , wherein R 10 is alkyl, and m is 1-2.
18. The compound according to claim 17 , wherein R 10 is selected from the group consisting of —CH 3 and —CH 2 CH 3 .
19. The compound according to claim 1 , wherein R 11 is selected from the group consisting of H, alkyl, alkoxy, and hydroxyl, or wherein two R 11 moieties together on the same carbon atom form —C═O; and n is 1-2.
20. The compound according to claim 19 , wherein R 11 is H, and n is 1.
21. The compound according to claim 1 , wherein R 12 is selected from the group consisting of H, alkyl, and haloalkyl.
22. The compound according to claim 1 , wherein R 12 is selected from the group consisting of H, CH 3 , and CF 3 .
23. The compound according to claim 22 , wherein R 12 is H.
24. The compound according to claim 1 , wherein Y is selected from the group consisting of: —(CHR 13 ) r — and —C(═O)—.
25. The compound according to claim 1 , wherein Y is selected from the group consisting of: —CH 2 — and —C(═O)—.
26. The compound according to claim 1 , wherein D is a phenyl optionally substituted with 1-2 R 20 moieties selected independently from the group consisting of halogen, —OR 30 , alkyl, —N(R 30 ) 2 , haloalkyl, cyano, —SO 2 (R 31 ), —SO 2 N(R 30 ) 2 , and haloalkoxy.
27. The compound according to claim 1 , wherein D is a phenyl optionally substituted with 1-2 R 20 moieties selected independently from the group consisting of halogen, hydroxyl, alkyl, alkoxy, aminoalkyl, haloalkyl, cyano, sulfonylalkyl, sulfonylamino and haloalkoxy.
28. The compound according to claim 27 , wherein D is a phenyl optionally substituted with 1-2 R 20 moieties selected independently from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.
29. The compound according to claim 1 , wherein D is phenyl, substituted with 1-2 moieties selected independently from the group consisting of alkyl, alkoxy, —Cl, —F, and trifluoromethoxy.
30. The compound according to claim 1 , wherein:
G is
R 1 and R 2 are independently selected from the group consisting of H, alkyl, aryl and cycloalkyl;
R 3 , R 5 , and R 6 are independently selected from the group consisting of —H, alkyl, haloalkyl, amino, aminoalkyl, alkoxy, CF 3 , halogen, or hydroxyl;
R 10 and R 11 are independently selected from the group consisting of H, alkyl, —N(R 30 ) 2 , halogen, or hydroxyl or wherein two R 10 or R 11 moieties together on the same carbon atom form —C═O; and
m and n are independently an integer from 1 to 4.
31. The compound according to claim 1 , wherein:
Z is N;
G is
X is N;
R 1 and R 2 are independently selected from the group consisting of H, alkyl, and cycloalkyl;
R 3 , R 5 , and R 6 are independently selected from the group consisting of —H, alkyl, haloalkyl, amino, aminoalkyl, alkoxy, CF 3 , halogen, and hydroxyl;
R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O; and
m and n are independently an integer from 1 to 4.
32. The compound according to claim 1 , wherein:
Z is N;
G is
X is N;
R 1 and R 2 are independently selected from the group consisting of H, alkyl, and cycloalkyl;
R 3 , R 5 , and R 6 are independently selected from the group consisting of —H, alkyl, haloalkyl, amino, aminoalkyl, alkoxy, CF 3 , halogen, and hydroxyl;
R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O;
R 10 , R 11 are independently selected from the group consisting of H, alkyl, amino, aminoalkyl, halogen, or hydroxyl or wherein two R 10 or R 11 moieties together on the same carbon atom form —C═O; and
m and n are independently an integer from 1 to 4.
33. The compound according to claim 1 , wherein:
Z is N;
G is
X is N;
R 1 and R 2 are independently selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , cyclopropyl and alkyl;
R 3 , R 5 , R 6 is independently selected from the group consisting of H, —CH 3 , —F, —Cl, —OH, —OCH 3 , —OCF 3 , NH 2 , SO 2 CH 3 , and —CF 3 ;
R 7 and R 8 are both H, or R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O;
R 10 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , and hydroxyl, or two R 10 moieties together on the same carbon atom form ═O, and m is 1-2;
R 11 is selected from the group consisting of H and hydroxyl or two R 11 moieties together on the same carbon atom form —C═O, and n is 1;
R 12 is selected from the group consisting of H and CF 3 ;
Y is selected from the group consisting of —CH 2 — and —C(═O)—; and
D is a phenyl, wherein ring D is substituted with 1-2 moieties selected independently from the group consisting of —Cl, —CH 3 , —F, —OH, OCH 3 , OCF 3 , NH 2 , NH(CH 3 ) 2 , SO 2 CH 3 , SO 2 NH 2 , and trifluoromethyl.
34. The compound according to claim 33 , wherein:
Z is N;
G is
X is N;
R 1 and R 2 are independently selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , cyclopropyl and alkyl;
R 3 , R 5 , R 6 is independently selected from the group consisting of H, —CH 3 , —F, —Cl, —OH, —OCH 3 , —OCF 3 , SO 2 CH 3 , and —CF 3 ;
R 7 and R 8 are both H, or R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O;
R 10 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , and hydroxyl, or two R 10 moieties together on the same carbon atom form —C═O, and m is 1-2;
R 11 is selected from the group consisting of H and hydroxyl or two R 11 moieties together on the same carbon atom form —C═O, and n is 1;
R 12 is selected from the group consisting of H and CF 3 ;
Y is selected from the group consisting of —CH 2 — and —C(═O)—; and
D is a phenyl, wherein ring D is substituted with 1-2 moieties selected independently from the group consisting of —Cl, —CH 3 , —F, —OH, NH 2 , SO 2 CH 3 , and trifluoromethoxy.
35. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
36. A compound according to claim 1 , in optically pure form.
37. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37 , further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease.
39. A pharmaceutical composition comprising at least one compound of claim 35 , or a pharmaceutically acceptable salt, in combination with at least one pharmaceutically acceptable carrier.
40. The pharmaceutical composition of claim 39 , further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease.