Heterocyclic substituted pyridine 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, xenograft 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:
Z is N, NO, or NOH;
G is selected from the group consisting of:
wherein is a single bond or double bond, R 8 and R 9 are optional substituents, and two independent R 9 substituents may be substituted on the same ring carbon when the valency so permits;
R 3 is selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , cyclopropyl, —F, —Cl, —OCH 3 , —OCF 3 , and —CF 3 ;
R 5 is selected from the group consisting of H, alkyl, halogen, and CF 3 ;
R 6 is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, —CN, —N(R 30 ) 2 , —OR 30 , —N═CH-alkyl, and —NR 30 C(═O)alkyl;
R 8 is H;
R 9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, —C(═O)N(H)R 30 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —N(H)R 30 , and —N(R 30 ) 2 ;
R 10 is selected from the group consisting of H, alkyl, aralkyl, and hydroxyalkyl, or wherein two R 10 taken together with the carbon atom to which both are attached is >C═O;
the R 11 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, and hydroxyalkyl, wherein two R 11 taken together with the carbon atom to which both are attached form >C═O;
R 12 is selected from the group consisting of H, CN, —C(═O)N(R 30 ) 2 and alkyl;
D is selected from the group consisting of
L is CH or N;
the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CH 3 , CF 3 , OCF 3 , —(CH 2 ) q OR 31 , and —(CH 2 ) q NHR 31 ,
Y is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, —C(═O)— and —CH(CO 2 alkyl)-;
the R 30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, aralkyl, cycloalkyl, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q NH 2 , —(CH 2 ) q NHalkyl, —(CH 2 ) q N(alkyl) 2 , —(CH 2 ) q NHaralkyl, —(CH 2 ) q C(═O)NHalkyl, —(CH 2 ) q C(═O)N(alkyl) 2 , —(CH 2 ) q C(═O)NHaralkyl, —(CH 2 ) q SO 2 alkyl, and —(CH 2 ), q SO 2 NHalkyl;
the R 31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, aralkyl, cycloalkyl, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q NH 2 , —(CH 2 ) q NHalkyl, —(CH 2 ) q N(alkyl) 2 , —(CH 2 ) q NHaralkyl, —(CH 2 ) q C(═O)NHalkyl, —(CH 2 ) q C(═O)N(alkyl) 2 , —(CH 2 ) q C(═O)NHaralkyl, —(CH 2 ) q SO 2 alkyl, and —(CH 2 ) q ,SO 2 NHalkyl;
m is 0 to 4;
n is 0 to 4;
p is 1 to 5; and
each q can be the same or different, each being 1 or 2.
2. The compound according to claim 1 , wherein Z is N or NO.
3. The compound of claim 1 , wherein G is
4. The compound of claim 1 , wherein G is
5. The compound according to claim 1 , wherein R 6 is selected from the group consisting of H, —NH 2 , —CH 3 , —CN and —F.
6. The compound according to claim 1 , wherein the R 9 moieties can be the same or different, each being independently selected from the group consisting of H, cyclopropyl, —CH 3 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —C(═O)NH 2 , —C(═O)N(H)CH 2 CH 2 OH, —C(═O)N(H)-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —N(H)CH 2 CH 3 , —N(H)CH(CH 3 ) 2 , —N(H)CH 2 CH 2 CH 3 , —N(H)CH 2 CH 2 OH, —N(H)CH 2 CH 2 NH 2 , and —N(H)CH 2 CH 2 SO 2 CH 3 .
7. The compound according to claim 1 , wherein the R 9 moieties can be the same or different, each being independently selected from the group consisting of H, —CH 2 CH 2 NH 2 , —NH 2 , —NHCH 3 , —N(H)CH 2 CH 3 , —N(H)CH(CH 3 ) 2 , —N(H)CH 2 CH 2 CH 3 , and —N(H)CH 2 CH 2 OH.
8. The compound according to claim 1 , wherein R 10 is selected from the group consisting of —CH 3 , —CH 2 CH 3 and —CH 2 CH 2 CH 3 , or wherein two R 10 taken together with the carbon atom to which both are attached form >C═O, and m is 0-2.
9. The compound according to claim 1 , wherein R 11 is H or —CH 3 .
10. The compound according to claim 1 , wherein R 12 is selected from the group consisting of H, —CH 3 , CN and —CH 2 CH 3 .
11. The compound according to claim 1 , wherein the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, —CH 3 , —CF 3 , —CO 2 H, —CO 2 CH 3 , —NH 2 , —NHCH 3 , —OCF 3 , —OH, F, Cl, and Br.
12. The compound according to claim 1 , wherein m is 0-2.
13. The compound according to claim 1 , wherein n is 0-2.
14. The compound according to claim 1 , wherein Z is N;
R 9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, —C(═O)N(H)R 30 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , and —N(H)R 30 ;
m is 0-2; and
n is 0-2.
15. The compound according to claim 14 , wherein ring G is
16. The compound according to claim 1 , wherein said compound is represented by any one of structural Formulae 2, 3, 4, 5, and 7:
or a pharmaceutically acceptable salt thereof, wherein:
p is 1-5;
in Formula 4 is a single bond or a double bond; and
m, L, R 3 , R 5 , R 6 R 8 , R 9 , R 10 , R 20 and Y are as defined in claim 1 .
17. The compound according to claim 16 , wherein in Formulae 2, 3, 4, 5, or 7, R 9 moieties are the same or different, each being independently selected from the group consisting of H, cyclopropyl, —CH 3 , —CH 2 CH 3 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —C(═O)NH 2 , —C(═O)N(H)CH 2 CH 2 OH, —C(═O)N(H)-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —N(H)CH 2 CH 3 , —N(H)CH(CH 3 ) 2 , —N(H)CH 2 CH 2 CH 3 , —N(H)CH 2 CH 2 OH, —N(H)CH 2 CH 2 NH 2 , and —N(H)CH 2 CH 2 SO 2 CH 3 .
18. The compound according to claim 16 , wherein in Formulae 2, 3, 4, 5, or 7, the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, —CH 3 , —CF 3 , —CO 2 H, —CO 2 CH 3 , —NH 2 , —NHCH 3 , —OCF 3 , —OH, F, CI, Br, —OCH 2 CH 2 S(O 2 )CH 3 , and —C(═O)NH 2 .
19. The compound according to claim 16 , wherein in Formulae 2, 3, 4, 5, or 7, L is CH.
20. The compound according to claim 16 , wherein in Formulae 2, 3, 4, 5, or 7, L is N.
21. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt, in combination with at least one pharmaceutically acceptable carrier.