IP Library › Granted Patent US 7,776,862

Granted Patent B2

US 7,776,862 · App. 11/353,697 · Granted Aug 17, 2010

Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity

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Patent No.: US 7,776,862
App. No.: 11/353,697
Granted: Aug 17, 2010
Kind: B2

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Abstract

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: and the pharmaceutically acceptable salts, solvates and esters 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.

Claims (583)

1. A compound having the general structure shown in Formula 1:

or pharmaceutically acceptable salts, solvates or esters thereof wherein:

Z is N, C(R 29 ), or NO;

X is N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl or heterocyclenyl;

R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl, carboxamido, cyano, hydroxyl, urea, —N≡CH, ═NCN, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q CF 3 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —C(═S)N(H)alkyl, —N(H)—S(O) 2 -alkyl, —N(H)C(═O)N(H)-alkyl, —S(O) 2 alkyl, —S(O) 2 N(H)alkyl, —S(O) 2 N(alkyl) 2 , —S(O) 2 aryl, —C(═S)N(H)cycloalkyl, —C(═O)N(H)NH 2 , —C(═O)alkyl, -heteroaryl, heterocyclyl, and heterocyclenyl, fluorophenylmethylene, trifluoromethylphenylmethylene, cyanophenylmethylene, difluorophenylmethylene, bromophenylmethylene, chlorophenylmethylene, bromochlorophenylmethtlene, fluorochlorophenylmethylene, dichlorophenylmethylene, methoxylphenylmethylene, —CH 2 -cyclopropyl, cyclohexylmethylene, aminooxadiazoyl, 5-methyl-isoxazolyl, chloropyridyl, pyridylimethylene,

or alternatively when X is N, the N taken together with the R 1 and R 2 forms a heterocyclyl, heteroaryl or —N═C(NH 2 ) 2 ;

R 3 , R 4 , R 6 and R 29 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, —CN, CF 3 , haloalkyl, cycloalkyl, halogen, hydroxyalkyl, —N═CH—(R 31 ), —C(═O)N(R 30 ) 2 , —N(R 30 ) 2 , —OR 30 , —SO 2 (R 31 ), —N(R 30 )C(═O)N(R 30 ) 2 and —N(R 30 )C(═O)R 31 ;

R 7 and R 8 are the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxyl, —CN, alkoxy, alkylamino, —N(H)S(O) 2 alkyl and —N(H)C(═O)N(H)alkyl; or alternatively R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O—, —C═S—, —C═N(H)—, —C═N(alkyl)—, —C═N(Oalkyl)—, —C═N(OH)— or cycloalkyl;

the R 10 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO 2 H, hydroxyalkyl, —C(═O)N(R 30 ) 2 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —OR 30 , halogen, ═O, and —C(═O)R 31 ;

the R 11 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, hydroxyalkyl, carboxamide, CO 2 H, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —OR 30 , halogen, ═O, and —C(═O)R 31 ;

the R 12 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, —CN, —C(═O)N(R 30 ) 2 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , and —S(O 2 )R 31 ;

D is a five to nine membered cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms independently selected from O, S or N, wherein ring D is unsubstituted or optionally 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 H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —C(═NR 30 )NHR 30 , —C(═NOH)N(R 30 ) 2 , —C(═NOR 3 )N(R 30 ) 2 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 )SO 2 (R 31 ), —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —N(R 30 )S(O) 2 N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , —SR 30 , —SO 2 N(R 30 ) 2 , —SO 2 (R 31 ), —OSO 2 (R 31 ), and —OSi(R 30 ) 3 ; or alternatively two R 20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 R 21 moieties;

the R 21 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NSO 2 R 31 —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —C(═NR 30 )NHR 30 —C(═NOH)N(R 30 ) 2 —C(═NOR 31 )N(R 30 ) 2 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 )SO 2 (R 31 ), —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —N(R 30 )S(O) 2 N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , —SR 30 , —SO 2 N(R 30 ) 2 , —SO 2 (R 31 ), —OSO 2 (R 31 ), and —OSi(R 30 ) 3 ;

Y is selected from the group consisting of —(CR 13 R 13 ) r —, —CHR 13 C(═O)—, —(CHR 13 ) r O—, —(CHR 13 ) r N(R 30 )—, —C(═O)—, —C(═NR 30 )—, —C(═N—OR 30 )—, —CH(C(═O)NHR 30 )—, CH-heteroaryl-, —C(R 13 R 13 ) r C(R 13 )═C(R 13 )—, —(CHR 13 ) r C(═O)— and —(CHR 13 ) r N(H)C(═O)—;

the R 13 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, —CN, —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —(CHR 30 ) q OH, —(CHR 30 ) q OR 31 , —(CHR 30 ) q NH 2 , —(CH R 30 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —NH 2 , —N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —OH, OR 30 , —SO 2 N(R 30 ) 2 , and —SO 2 (R 31 );

the R 30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q Oalkylaryl, —(CH 2 ) q Oaryl, —(CH 2 ) q Oaralkyl, —(CH 2 ) q Ocycloalkyl, —(CH 2 ) q NH 2 , —(CH 2 ) q NHalkyl, —(CH 2 ) q N(alkyl) 2 , —(CH 2 ) q NHalkylaryl, —(CH 2 ) q NHaryl, —(CH 2 ) q NHaralkyl, —(CH 2 ) q NHcycloalkyl, —(CH 2 ) q C(═O)NHalkyl, —(CH 2 ) q C(═O)N(alkyl) 2 , —(CH 2 ) q C(═O)NHalkylaryl, —(CH 2 ) q C(═O)NHaryl, —(CH 2 ) q C(═O)NHaralkyl, —(CH 2 ) q C(═O)NHcycloalkyl, —(CH 2 ) q SO 2 alkyl, —(CH 2 ) q SO 2 alkylaryl, —(CH 2 ) q SO 2 aryl, —(CH 2 ) q SO 2 aralkyl, —(CH 2 ) q SO 2 cycloalkyl, —(CH 2 ) q NSO 2 alkyl, —(CH 2 ) q NSO 2 alkylaryl, —(CH 2 ) q NSO 2 aryl, —(CH 2 ) q NSO 2 aralkyl, —(CH 2 ) q NSO 2 cycloalkyl, —(CH 2 ) q SO 2 NHalkyl, —(CH 2 ) q SO 2 NHalkylaryl, —(CH 2 ) q SO 2 NHaryl, —(CH 2 ) q SO 2 NHaralkyl, —(CH 2 ) q SO 2 NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

the R 31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q Oalkylaryl, —(CH 2 ) q Oaryl, —(CH 2 ) q Oaralkyl, —(CH 2 ) q Ocycloalkyl, —(CH 2 ) q NH 2 , —(CH 2 ) q NHalkyl, —(CH 2 ) q N(alkyl) 2 , —(CH 2 ) q NHalkylaryl, —(CH 2 ) q NHaryl, —(CH 2 ) q NHaralkyl, —(CH 2 ) q NHcycloalkyl, —(CH 2 ) q C(═O)NHalkyl, —(CH 2 ) q C(═O)N(alkyl) 2 , —(CH 2 ) q C(═O)NHalkylaryl, —(CH 2 ) q C(═O)NHaryl, —(CH 2 ) q C(═O)NHaralkyl, —(CH 2 ) q C(═O)NHcycloalkyl, —(CH 2 ) q SO 2 alkyl, —(CH 2 ) q SO 2 alkylaryl, —(CH 2 ) q SO 2 aryl, —(CH 2 ) q SO 2 aralkyl, —(CH 2 ) q SO 2 cycloalkyl, —(CH 2 ) q NSO 2 alkyl, —(CH 2 ) q NSO 2 alkylaryl, —(CH 2 ) q NSO 2 aryl, —(CH 2 ) q NSO 2 aralkyl, —(CH 2 ) q NSO 2 cycloalkyl, —(CH 2 ) q SO 2 NHalkyl, —(CH 2 ) q SO 2 NHalkylaryl, —(CH 2 ) q SO 2 NHaryl, —(CH 2 ) q SO 2 NHaralkyl, —(CH 2 ) q SO 2 NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

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;

with the proviso that there are no two adjacent double bonds in any ring, and that when a nitrogen is substituted by two alkyl groups, said two alkyl groups may be optionally joined to each other to form a ring.

2. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkyl, aryl, amino, alkoxy, hydroxy, cycloalkyl, cycloalkenyl, arylalkyl, amidinyl, carboxamido, heteroaryl, heterocyclyl, heterocyclenyl, urea, —S(O) 2 alkyl, —S(O) 2 N(H)alkyl, —S(O) 2 N(alkyl) 2 , and —C(═S)N(H)cycloalkyl.

3. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkylaryl, aryl, heteroaryl, —(CH 2 ) q CF 3 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —(CH 2 ) q -amidinyl, cyclopropyl, cyclopropylhydroxyl, cyclobutyl, cyclobutylhydroxy, cyclopentyl, and cyclopentylhydroxy; and

q is an integer from 1 to 5.

4. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, —CH 3 , fluorophenylmethylene, trifluoromethylphenylmethylene, indanyl, cyanophenylmethylene, difluorophenylmethylene, bromophenylmethylene, chlorophenylmethylene, —CH 2 CH 2 O phenyl, cyclopentyl, bromochlorophenylmethylene, fluorochlorophenylmethylene, dichlorophenylmethylene, phenylmethylene, —(CH 2 ) 3 phenyl, —CH 2 CF 3 , methoxylphenylmethylene, —CH(CH 3 ) 2 , —C 2 H 5 , —CH 2 -cyclopropyl, —(CH 2 ) 2 CH 3 , cyclohexylmethylene, cyclohexyl, —CH 2 CH 2 SO 2 CH 3 , —CH 2 —CH 2 —NH 2 , —CH 2 CH 2 OCH 3 , cyclopropyl, isoxazolyl, oxadiazoyl, aminooxadiazoyl, —CH 2 CH 2 OH, —CH 2 CH 2 Ophenyl, —CH 2 CH 2 CH 3 , —NH 2 , —(CH 2 ) 2 NH 2 , pyrazolyl, 5-methyl-isoxazolyl, —CH 2 CH(OCH 2 CH 3 ) 2 , —OCH 3 , —NHC(═O)NH 2 , chloropyridyl, pyridylmethylene, —C(═O)NHcyclopropyl, —C(═O)N(H)C 2 H 5 , —C(═O)N(H)CH 2 CF 3 , —C(═O)N(H)C(CH 3 ) 3 , —C(═S)N(H)cyclopropyl, —C(═O)NH 2 , —C(═O)N(H)CH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —C(═O)CH 3 , —S(O) 2 (CH 2 ) 2 CH 3 , —C(═O)N(H)cyclohexyl, —C(═NH)NH 2 , —C(═O)N(H)NH 2 , —C(═O)N(H)CH(CH 3 ) 2 , thiazolyl, —C(═O)N(CH 3 ) 2 , —S(O) 2 CH 2 CF 3 , —S(O) 2 CF 3 , —CH 2 CH(OCH 2 CH 3 ) 2 ,

or when X is N, the N taken together with the R 1 and R 2 to which X is shown attached, forms an aziridine, an azetidine, a piperidine or

5. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, —CH 3 , —C 2 H 5 , difluorophenylmethylene, cyclopropyl, dichlorophenylmethylene, —CH(CH 3 ) 2 , cyclohexylmethylene, cyclohexyl, isoxazolyl, oxadiazoyl, aminooxadiazoyl, difluorophenyl, —CH 2 CH 2 OH, —CH 2 CH 2 N(CH 3 )) 2 , —C(═O)N(H)cyclopropyl, —C(═O)N(H)C 2 H 5 , —C(═O)N(H)CH 2 CF 3 , —C(═O)N(H)CH(CH 3 ) 2 , —C(═O)N(H)C(CH 3 ) 3 , —C(═S)N(H)cyclopropyl, —C(═O)NH 2 , —C(═O)N(H)CH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —C(═O)CH 3 , —S(O) 2 (CH 2 ) 2 CH 3 , —C(═O)N(H)cyclohexyl, —C(═NH)NH 2 , —C(═O)N(H)NH 2 , thiazolyl,

6. The compound according to claim 1 , wherein X is selected from the group consisting of N, O, —CH 3 , —CH 2 —, —CH, —CH 2 CH 3 , —CH 2 CN, —NH 2 , cyclopropyl,

7. The compound according to claim 6 , wherein X is N or O.

8. The compound according to claim 7 , wherein X is N.

9. The compound according to claim 1 , wherein Z is N or C(R 29 ).

10. The compound according to claim 9 , wherein Z is N.

11. The compound according to claim 9 , wherein Z is C(H), C(alkyl), C(halogen), C(CF 3 ) or C(N(R 30 ) 2 ).

12. The compound according to claim 11 , wherein Z is C(alkyl), C(F) or C(NH 2 ).

13. The compound according to claim 1 , wherein R 3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R 30 ) 2 , —OR 30 and —CF 3 .

14. The compound according to claim 1 , wherein 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 .

15. The compound according to claim 1 , wherein R 4 is selected from the group consisting of H, alkyl, hydroxyalkyl, halogen, OR 30 , or CF 3 .

16. The compound according to claim 1 , wherein 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.

17. The compound according to claim 16 , wherein R 6 is selected from the group consisting of H, —NH 2 , —CH 3 , —CN and —F.

18. The compound according to claim 1 , wherein R 7 and R 8 are the same or different, each being independently selected from the group consisting of H, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q N(H)-alkyl, —(CH 2 ) q N(H)—S(O) 2 alkyl, and —(CH 2 ) q N(H)—CO—N(H)alkyl; or alternatively R 7 and R 8 taken together with the carbon atoms to which they are shown attached is —C═O—, —C═N(OAlkyl)—, or —C═S—.

19. The compound according to claim 1 , wherein R 7 and R 8 are the same or different, each being independently selected from the group consisting of H, —CH 3 , and —OH; or alternatively R 7 and R 8 taken together with the carbon atom to which R 7 and R 8 are attached, is

20. The compound according to claim 1 , wherein R 7 and R 8 are each H; or alternatively R 7 and R 8 taken together with the carbon atom to which R 7 and R 8 are attached, is

21. The compound according to claim 1 , wherein R 10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl.

22. The compound according to claim 21 , wherein R 10 is selected from the group consisting of —CH 3 , —CH 2 CH 3 and —CH 2 CH 2 CH 3 , and m is 0-2.

23. The compound according to claim 1 , wherein R 11 is selected from the group consisting of H, alkyl, hydroxyalkyl and carbonyl.

24. The compound according to claim 23 , wherein R 11 is H or —CH 3 .

25. The compound according to claim 1 , wherein R 12 is selected from the group consisting of H, CN, —C(═O)N(R 30 ) 2 and alkyl.

26. The compound according to claim 25 , wherein R 12 is selected from the group consisting of H, —CH 3 , CN and —CH 2 CH 3 .

27. The compound according to claim 1 , wherein the ring atoms of ring D are independently C or N and substituted by independently selected 0-4 R 20 moieties.

28. The compound according to claim 1 , wherein ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by independently selected 0-4 R 20 moieties.

29. 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, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —N(R 30 )SO 2 N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , —SR 30 , —SO 2 N(R 30 ) 2 —SO 2 (R 31 ), —OSO 2 (R 31 ), and —OSi(R 30 ) 3 .

30. 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, alkyl, amino, halogen, CN, CH 3 , CF 3 , OCF 3 , —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 -C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , and —OSO 2 (R 31 ).

31. The compound according to claim 1 , wherein two R 20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R 21 moieties.

32. 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, —CN, —CH 3 , —CF 3 , —CH 2 OH, —CO 2 H, —CO 2 CH 3 , —NH 2 , —NHCH 3 , —OCF 3 , —OH, F, Cl, Br, —C(═NOH)NH 2 , —OCH 2 CH 2 S(O 2 )CH 3 , —C(═O)NH 2 ,

33. The compound according to claim 1 , wherein Y is selected from the group consisting of: —(CHR 13 ) r —, —(CR 13 R 13 ) r —, —C(═O)— and —CHR 13 C(═O)—.

34. The compound according to claim 1 , wherein Y is selected from the group consisting of: —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, and —C(═O)—.

35. The compound according to claim 1 , wherein m is 0-3.

36. The compound according to claim 1 , wherein n is 0-2.

37. The compound according to claim 1 , wherein q is 1, 2 or 3.

38. The compound according to claim 1 , wherein r is 1 or 2.

39. The compound according to claim 1 , wherein Z is N, C(H), C(alkyl), C(F) or C(NH 2 );

X is N;

R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkylaryl, aryl, heteroaryl, —(CH 2 ) q CF 3 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q —N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —(C H 2 ) q -amidinyl, cyclopropyl, cyclopropylhydroxyl, cyclobutyl, cyclobutylhydroxy, cyclopentyl, and cyclopentylhydroxy;

R 3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R 30 ) 2 , —OR 30 and —CF 3 ;

R 4 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, —N(R 30 ) 2 , —OR 30 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 7 and R 8 together with the carbon atom to which they are shown attached is selected from the group consisting of —C═O—, —C═S—, —C═N(H)—, —C═N(OH)—, and —C═N(Oalkyl)-;

R 10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl;

R 11 is selected from the group consisting of H, alkyl, hydroxyalkyl, and carbonyl;

R 12 is selected from the group consisting of H, CN, —C(═O)N(R 30 ) 2 and alkyl;

ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R 20 moieties;

the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH 3 , CF 3 , OCF 3 , —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 ,

and —OSO 2 (R 31 );

Y is selected from the group consisting of: —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, and —C(═O)—;

m is 0-2;

n is 0-2;

q is 1 or 2; and

r is 1 or 2.

40. The compound according to claim 1 , represented by structural Formula 2, Formula 3, Formula 4 or Formula 5:

or pharmaceutically acceptable salts, solvates or esters thereof, wherein:

R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, —CH 3 , fluorophenylmethylene, trifluoromethylphenylmethylene, indanyl, cyanophenylmethylene, difluorophenylmethylene, bromophenylmethylene, chlorophenylmethylene, —CH 2 CH 2 O phenyl, cyclopentyl, bromochlorophenylmethylene, fluorochlorophenylmethylene, dichlorophenylmethylene, phenylmethylene, —(CH 2 ) 3 phenyl, —CH 2 CF 3 , methoxylphenylmethylene, —CH(CH 3 ) 2 , —C 2 H 5 , —CH 2 -cyclopropyl, —(CH 2 ) 2 CH 3 , cyclohexylmethylene, cyclohexyl, —CH 2 CH 2 SO 2 CH 3 , —CH 2 —CH 2 -NH 2 , —CH 2 CH 2 OCH 3 , cyclopropyl, isoxazolyl, —CH 2 CH 2 OH, —CH 2 CH 2 O phenyl, —CH 2 CH 2 CH 3 , —NH 2 , —(CH 2 ) 2 NH 2 , pyrazolyl, 5-methyl-isoxazolyl, —CH 2 CH(OCH 2 CH 3 ) 2 , —OCH 3 , —NHC(═O)NH 2 , chloropyridyl, pyridylmethylene, —C(═O)NHcyclopropyl, —C(═O)N(H)C 2 H 5 , —C(═O)N(H)CH 2 CF 3 , —C(═O)N(H)C(CH 3 ) 3 , —C(═S)N(H)cyclopropyl, —C(═O)NH 2 , —C(═O)N(H)CH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —C(═O)CH 3 , —S(O) 2 (CH 2 ) 2 CH 3 , —C(═O)N(H)cyclohexyl, —C(═NH)NH 2 , —C(═O)N(H)NH 2 , —C(═O)N(H)CH(CH 3 ) 2 , thiazolyl, —C(═O)N(CH 3 ) 2 , —S(O) 2 CH 2 CF 3 , —S(O) 2 CF 3 , —CH 2 CH(OCH 2 CH 3 ) 2 ,

or when X is N, the N taken together with the R 1 and R 2 to which X is shown attached, forms an azetidine, a piperidine or

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 10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl;

R 11 is selected from the group consisting of H, alkyl, hydroxyalkyl and carbonyl;

R 13 is selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —(CHR 30 ) q OH, —(CHR 30 ) q OR 31 , —(CHR 30 ) q NH 2 , —(CHR 30 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 —N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —OR 30 , —SO 2 N(R 30 ) 2 , and —SO 2 (R 31 );

m, n, R 6 , R 7 , R 8 , R 20 , R 30 and R 31 are as defined in claim 1 .

41. The compound according to claim 1 , selected from the group consisting of:

Compound

No.

Compound Structure

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

or a pharmaceutically acceptable salts, solvates or esters thereof.

42. A compound selected from the group consisting of:

or pharmaceutically acceptable salt or ester thereof.

43. A compound selected from the group of compounds consisting of

or pharmaceutically acceptable salt, or ester thereof.

44. A compound according to claim 1 in purified form.

45. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt, or ester thereof, in combination with at least one pharmaceutically acceptable carrier.

46. The pharmaceutical composition of claim 45 , further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease.

47. A compound having the general structure shown in Formula 1:

or pharmaceutically acceptable salt thereof, wherein:

Z is N, C(R 29 ), or NO;

X is N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl or heterocyclenyl;

R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl, carboxamido, cyano, hydroxyl, urea, —N≡CH, ═NCN, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —C(═S)N(H)alkyl, —N(H)—S(O) 2 -alkyl, —N(H)C(═O)N(H)-alkyl, —S(O) 2 alkyl, —S(O) 2 N(H)alkyl, —S(O) 2 N(alkyl) 2 , —S(O) 2 aryl, —C(═S)N(H)cycloalkyl, —C(═O)N(H)NH 2 , —C(═O)alkyl, -heteroaryl, heterocyclyl, and heterocyclenyl; or alternatively when X is N, the N taken together with the R 1 and R 2 forms a heterocyclyl, heteroaryl or —N═C(NH 2 ) 2 ;

R 7 and R 8 are the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxyl, —CN, alkoxy, alkylamino, —N(H)S(O) 2 alkyl and —N(H)C(═O)N(H)alkyl; or alternatively R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O—, —C═S—,—C═N(H)—,—C═N(alkyl)—, —C═N(Oalkyl)—, —C═N(OH)— or cycloalkyl;

the R 10 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, —CO 2 H, hydroxyalkyl, —C(═O)N(R 30 ) 2 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —OR 30 , halogen, ═O, and —C(═O)R 31 ;

Y is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, and —C(═O)—;

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;

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

CHANGE OF NAME Recorded Aug 30, 2012

From: SCHERING CORPORATION

To: MERCK SHARP & DOHME CORP.

Reel/Frame 028884/0151 →