IP Library › Granted Patent US 7,868,006

Granted Patent B2

US 7,868,006 · App. 11/353,641 · Granted Jan 11, 2011

Heterocyclic substituted piperazines with CXCR3 antagonist activity

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Patent No.: US 7,868,006
App. No.: 11/353,641
Granted: Jan 11, 2011
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: or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various moieties are defined herein. 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 (301)

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

or a pharmaceutically acceptable salt thereof, wherein:

G is selected from the group consisting of:

wherein is a single bond or double bond;

R 3 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, and halogen;

R 6 is selected from the group consisting of H, alkyl, halogen, —N(R 30 ) 2 , and —NR 30 C(═O)alkyl;

the R 8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(═O)-aryl-halogen, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , (CH 2 ) q C(═O)OR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 2 R 31 , or —(CH 2 ) q SO 2 NHR 31 ;

the R 9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, —CF 3 , alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl, —C(═O)OR 30 , —C(═O)N(R 30 ) 2 , —C(═O)N(H)CH 2 CF 3 , —C(═S)N(R 30 ) 2 , —C(═O)alkyl, —C(CH 3 ) 2 OH, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —CH 2 N(H)C(═O)CF 3 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —N(R 30 ) 2 , —N(H)-cyclopropyl-CH 3 , —N(R 30 )S(O 2 )R 31 , —N(R 30 )C(═O)N(R 30 ) 2 , —OR 30 , —SO 2 (R 31 ), —SO 2 N(R 30 ) 2 , ═O and ═S;

R 10 is alkyl;

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, carboxamide, CO 2 H, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —OR 30 , halogen, ═O , and —C(═O)R 31 ;

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 and —S(O 2 )R 31 ;

ring D is selected from the group consisting of phenyl, pyridyl, thienyl and pyrimidinyl, 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, 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 C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 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 ), —OSi(R 30 ) 3 ,

or alternatively two R 20 moieties are linked together to form a five or six membered aryl or cycloalkyl, ring wherein said five or six membered aryl or cycloalkyl 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, 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 C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 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 —, —C(═O)—, and —(CHR 13 ) r 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, —CN, —CO 2 H, —C(═O)OR 31 , —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 N(H)SO 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, -cycloalkylalkyl, 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)O-alkyl, —(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 N(H)SO 2 alkyl, —(CH 2 ) q N(H)SO 2 alkylaryl, —(CH 2 ) q N(H)SO 2 aryl, —(CH 2 ) q N(H)SO 2 aralkyl, —(CH 2 ) q N(H)SO 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 N(H)SO 2 alkyl, —(CH 2 ) q N(H)SO 2 alkylaryl, —(CH 2 ) q N(H)SO 2 aryl , —(CH 2 ) q NSO 2 aralkyl, —(CH 2 ) q N(H)SO 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;

wherein said aryl of R 8 , R 9 , R 11 , R 13 , R 20 , R 21 , R 30 , and R 31 is independently an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms;

wherein said heteroaryl of R 8 , R 9 , R 11 , R 13 , R 21 , R 30 , and R 31 is an aromatic monocyclic or multicyclic ring system comprising from 5 to 14 ring atoms wherein one or more of the ring atoms of the heteroaryl is nitrogen, oxygen, or sulfur;

wherein said heterocyclyl of R 8 , R 9 , R 11 , R 13 , R 21 ,R 30 , and R 31 is a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, wherein one or more of the ring atoms of the heterocyclyl is nitrogen, oxygen, or sulfur;

wherein said heterocyclenyl of R 11 , R 13 , R 21 , R 30 , and R 31 is a non-aromatic monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, wherein one or more of the ring atoms of the heterocyclenyl is nitrogen, oxygen, or sulfur, and wherein the heterocyclenyl contains at least one carbon-carbon double bond or carbon-nitrogen double bond;

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 G represents a dihydroimidazole, imidazole, dihydrooxadiazole, oxadiazole, or triazole ring.

3. The compound according to claim 1 , wherein R 3 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , cyclopropyl, —Cl, and CF 3 .

4. The compound according to claim 1 , wherein R 6 is selected from the group consisting of H, —NH 2 , —NHC(═O)CH 3 , —CH 3 , and —F.

5. The compound according to claim 1 , wherein R 8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , and —C(═O)-aryl-halogen.

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, alkyl, cycloalkyl, —C(═O)N(H)R 30 , —C(═O)OR 30 , —C(═O)alkyl, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —N(H)R 30 , —N(H)S(O 2 )R 31 , —N(H)C(═O)NH(R 30 ), —OR 30 , —SO 2 (R 31 ), and —SO 2 N(H)R 30 .

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, —OH, cyclopropyl, —CF 3 , —CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —C(═O)OCH 3 , —C(═O)OCH 2 CH 3 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NHSO 2 CH 3 , —CH 2 CH 2 SO 2 CH 3 , —C(═O)NH 2 , —C(═O)N(H)CH 2 CH 2 OH, —CH 2 N(H)C(═O)CF 3 , —C(═O)N(H)-cyclopropyl, —C(═O)N(H)CH 2 CF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —N(H)CH 2 CH 3 , —N(H)-cyclopropyl-CH 3 , —N(H)CH(CH 3 ) 2 , —N(H)CH 2 CH 2 CH 3 , —N(H)CH 2 C(═O)OCH 3 , —N(H)CH 2 C(═O)OCH 2 CH 3 , —N(H)CH 2 C(═O)NH-cyclopropyl, —N(H)CH 2 CH 2 OH, —N(H)CH 2 CH 2 NH 2 , —N(H)CH 2 CH 2 NHSO 2 CH 3 , —N(H)CH 2 CH 2 SO 2 CH 3 , —N(H)C(═O)N(H)CH 2 CH 3 , —N(H)CH 2 C(═O)NH 2 , —OCH 3 , —N(CH 2 CH 3 )S(═O) 2 -phenyl-alkyl, —N(H)S(═O) 2 -alkyl, ═S and ═O.

8. The compound according to claim 7 , wherein the R 9 moieties can be the same or different, each being independently selected from the group consisting of H, —OH, —CF 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, —C(═O)OCH 3 , —C(═O)OCH 2 CH 3 , —CH 2 CH 2 OH, —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 , —N(H)-cyclopropyl-CH 3 , —N(H)CH 2 C(═O)OCH 3 , —N(H)CH 2 C(═O)OCH 2 CH 3 , —N(H)CH 2 C(═O)NHCH 3 , —N(H)CH 2 C(═O)NH-cyclopropyl, —N(H)CH 2 CH 2 OH, —N(CH 2 CH 3 )S(═O) 2 -phenyl-alkyl, and —N(H)S(═O) 2 -alkyl.

9. The compound according to claim 1 , wherein R 10 is selected from the group consisting of —CH 3 , and —CH 2 CH 3 , and m is 0-2.

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

11. The compound according to claim 10 , wherein R 11 is H or —CH 3 .

12. 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.

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

14. The compound according to claim 1 , wherein ring D is substituted with 0-4 R 20 moieties.

15. 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, hydroxyalkyl, 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 N(H)SO 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 .

16. 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, cycloalkyl, 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 N(H)SO 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 , —N(R 30 )SO 2 (R 31 ), —OR 30 , —OC(═O)N(R 30 ) 2 , and —OSO 2 (R 31 ).

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

18. 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 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, —CF 3 , —CH 2 OH, —CH 2 —S(═O) 2 CH 3 , —C(═O)H, —CO 2 H, —CO 2 CH 3 , —NH 2 , —N(H)CH 3 , —N(H)S(═O) 2 CH 3 , —OCF 3 , —OH, F, Cl, Br, —C(═NOH)NH 2 , —OCH 2 CH 2 S(O 2 )CH 3 , —C(═O)NH 2 ,

19. The compound according to claim 1 , wherein 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, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy.

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

21. The compound according to claim 1 , wherein m is 0-2.

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

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

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

25. The compound according to claim 1 , wherein

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 , —C(═O)OR 30 , —C(═O)alkyl, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —N(H)R 30 , —N(H)S(O 2 )R 31 , —N(H)C(═O)NH(R 30 ), —OR 30 , —SO 2 (R 31 ), and —SO 2 N(H)R 30 ;

R 11 is selected from the group consisting of: H, alkyl, and ═O;

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

ring D is substituted with 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, cycloalkyl, 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 N(H)SO 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 , —N(R 30 )SO 2 (R 31 ), —OR 30 , —OC(═O)N(R 30 ) 2 ,

and —OSO 2 (R 31 );or alternatively, two R 20 moieties are linked together to form a five or six membered aryl or cycloalkyl, ring wherein said five or six membered aryl or cycloalkyl ring is fused to ring D and the fused ring is optionally substituted with 0 to 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, cyano, cycloalkyl, formyl, halogen, haloalkyl, hydroxyalkyl, nitro, and trifluoromethoxy;

Y is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, —CH(CH 2 OCH 2 -phenyl)-, —C(═O)—, and —CH[(C═O)O-alkyl]-;

m is 0-2;

n is 0-2; and

q is 1 or 2.

26. A compound according to claim 1 , wherein Formula 1 is represented by one of structural Formulae 2-10:

or a pharmaceutically acceptable salt thereof, wherein:

the R 8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , and —C(═O)-aryl-halogen;

the R 9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, —CF 3 , —C(═O)N(H)R 30 , —C(═O)OR 30 , —C(═O)alkyl, —(CH 2 ) q OH, —C(CH 3 ) 2 OH, —CH 2 N(H)C(═O)CF 3 , —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —N(H)R 30 , —N(H)S(O 2 )R 31 , —N(H)C(═O)NH(R 30 ), —OR 30 , —SO 2 (R 31 ), and —SO 2 N(H)R 30 ;

L is C or N;

in Formula 4 is a single bond or a double bond;

X in formula 9 is S;

p is 0 to 4; and

m, n, q, R 10 , R 11 , R 12 , R 20 and Y are as defined in claim 1 .

27. The compound according to claim 26 , wherein R 9 moieties are the same or different, each being independently selected from the group consisting of H, —OH, cyclopropyl, —CF 3 , —CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —C(═O)OCH 3 , —C(═O)OCH 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, —CH 2 N(H)C(═O)CF 3 , —C(═O)N(H)-cyclopropyl, —C(═O)N(H)CH 2 CF 3 , —NH 2 , —NHCH 3 , —N(H)CH 2 CH 3 , —N(H)-cyclopropyl-CH 3 , —N(H)CH(CH 3 ) 2 , —N(H)CH 2 CH 2 CH 3 , —N(H)CH 2 C(═O)OCH 3 , —N(H)CH 2 C(═O)OCH 2 CH 3 , —N(H)CH 2 C(═O)NH-cyclopropyl, —N(H)CH 2 CH 2 OH, —N(H)CH 2 CH 2 NH 2 , —N(H)CH 2 CH 2 NHSO 2 CH 3 , —N(H)CH 2 CH 2 SO 2 CH 3 , —N(H)C(═O)N(H)CH 2 CH 3 , —OCH 3 , and —N(H)S(═O) 2 -alkyl.

28. The compound according to claim 26 , wherein R 11 is selected from the group consisting of: of H, alkyl, and ═O.

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

30. The compound according to claim 26 , wherein R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, 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 N(H)SO 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 , —N(R 30 )SO 2 (R 31 ), —OR 30 , —OC(═O)N(R 30 ) 2 ,

and —OSO 2 (R 31 );or alternatively, two R 20 moieties are linked together to form a five or six membered aryl or cycloalkyl ring wherein said five or six membered aryl or cycloalkyl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R 21 moieties;

31. The compound according to claim 30 , wherein the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , cyclopropyl, —CF 3 , —CH 2 OH, —CH 2 —S(═O) 2 CH 3 , —C(═O)H, —CO 2 H, —CO 2 CH 3 , —NH 2 , —N(H)CH 3 , —N(H)S(═O) 2 CH 3 , —OCF 3 , —OH, F, Cl, Br, —OCH 2 CH 2 S(O 2 )CH 3 , —C(═O)NH 2 ,

or alternatively, two R 20 moieties are linked together to form a five or six membered aryl or cycloalkyl ring wherein said five or six membered aryl or cycloalkyl 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 26 , wherein L is carbon.

33. The compound according to claim 26 , wherein L is nitrogen.

34. The compound according to claim 26 , wherein Y is selected from the group consisting of: —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, —CH(CH 2 OCH 2 -phenyl)-, —C(═O)—, and —CH[(C═O)O-alkyl]-.

35. The compound according to claim 26 , wherein R 3 is selected from the group consisting of alkyl, cycloalkyl, halogen, and —CF 3 ;

R 6 is selected from the group consisting of H, alkyl, halogen, —N(R 30 ) 2 , and —NR 30 C(═O)alkyl,;

the 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 , —C(═O)OR 30 , —C(═O)alkyl, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —N(H)R 30 , —N(H)S(O 2 )R 31 , —N(H)C(═O)NH(R 30 ), —OR 30 , —SO 2 (R 31 ), and —SO 2 N(H)R 30 ;

R 10 is alkyl;

Y is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —CH(CH 2 OH)—, —CH(CH 2 OCH 2 -phenyl)-, —C(═O)—, and —CH[(C═O)O-alkyl]-;

m is 0-2;

n is 0-2; and

q is 1 or 2.

36. The compound of claim 1 selected from the group consisting of:

Compound

Number

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

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

or a pharmaceutically acceptable salt thereof.

37. The compound according to claim 36 , selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

38. A compound of the formula

or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 38 , wherein said salt is a mesylate salt.

40. 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.

41. The pharmaceutical composition of claim 40 , further comprising at least one additional agent, drug, medicament, antibody and/or inhibitor for treating a CXCR3 chemokine receptor mediated disease.

42. A pharmaceutical composition comprising at least one compound of claim 36 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising at least one compound of claim 38 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.

44. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignments (4)

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 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 7, 2006