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1.4 - substituted piperazine compounds with CXCR3 antagonist activity, which includes a Pharmaceutical Composition and its use in the treatment of diseases mediated by the chemokine receptor CXCR3
1.4 - substituted piperazine compounds with CXCR3 antagonist activity, which includes a Pharmaceutical Composition and its use in the treatment of diseases mediated by the chemokine receptor CXCR3
The present application describes a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs 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 the formula (1) or a salt, solvate or ester acceptable for pharmaceutical use thereof. Its use is also described to treat chemokine-mediated diseases, such as palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example (s) includes,SoAutoimmune diseases (e.g., non limiting) include (n),Rheumatoid arthritis multiple sclerosisRejection of migration (for example, non limiting) includes (n),No aloe, no zenoinjerto,Infectious diseases (for example)Tuberculosis leprosyFixed drug rashes, delayed skin hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula (1). Claim 1: A compound having the general structure shown in formula (1) or a salt, solvate or ester acceptable for pharmaceutical use thereof, wherein: G is -C ° N or a compound of formula (2);X is N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl or heterocyclynyl; Z is N or NO; R¹ and R² are independently absent or present, and if present, each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, -alkylamino, amidinyl, carboxamido, cyano, hydroxyl, urea, -NCH, = NCN, - (CH₂) qOH, - (CH₂) qOR³¹,- (CH) qNH- (CH) qNHR(CH) qN (R)- (CH) qC (3DO) NHR- (CH) qSO R- (CH) qNHSO R- (CH) qSO NHR-C (= S) N (H) alkyl, -N (H) -S (O) ₂-alkyl, -N (H) C (= O) N (H) -alkyl, -S (O) ₂- alkyl, -S (O) ₂N (H) alkyl, -S (O) ₂N (alkyl) ₂,-S (O) -arilo -C (3DS) N (H) cicloalquilo -C (3DO) N (H) NH-C (= O) tar, - C (= O) arilo, - C (= O) ISO tar, hetero, isocyclic propene and isocyclic propene; or when x is n, N absorbed together with R1 and R * forms a kind of cyclopropyl, isocyclic propene, isocyclic propene o-n = C (nh832222) 83222;Part of R3,R83099 and r8310a may be the same or different, and they are independently selected from a group consisting of H, lease, lease, aralquilo, (= O) lessor,, CN and cf832323 respectively;OCF83223,Halide, cyclopentanediol, halogen, hydroxy-n = ch - (R3 1),-C (3DO) N (R)-N (R)-NSO₂R³¹,-OR³⁰,-SO (R)-SO₂NHR³⁰,-N (R) C (3DO) N (R) y -N (R) C (3DO) RR831181 and r831222 are the same or different. They are selected independently from a group consisting of H, asphalt, rental, heterogeneous, hydroxy CN, alcox-n (R3 833044) and r8322;-They are============N (o-asphalt)The ratio of n (O H) or cyclopropyl; R 1.83044 can be equal or different, which can be selected from a separate group consisting of H, tar, cyclopentanediol, arilo, isopropyl, isopropyl, isopropyl, rental, arilalquilo, co8322; h, hydroxyl, alcoxi, hydroxil-n (R 3.83044) and 832222, respectively;-C (3DO) N (R)- (CH) qOH - (CH) qOR- (CH) qNHR- (CH) qN (R)-OR³⁰,1. Halogen, y-c (= O) R3 1;or where two portions R¹⁰ together in the same atom form = O; the portions R¹¹ may be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclynyl, alkylaryl, arylalkyl, hydroxyalkyl, hydroxyl, alkoxy, carboxamide, -N (R³⁰) ₂,CO H - (CH) qOH - (CH) qOR- (CH) qNHR- (CH) qN (R)-OR³⁰,1. Halogen, y-c (= O) R3 1;O in which two R1 ions form in the same carbon atom = O; R2 from h, tar, halogen-cn, cf8322; h, cf.83323;-C (3DO) N (R)- (CH) qOH - (CH) qOR- (CH) qNHR- (CH) qN (R)y -S (O) RD is a cyclopentadiene ring composed of 3 to 9 members, a cyclopentadiene ring composed of 3 to 9 members, or an arilo, heterosexual, isomerized or isomerized ring composed of 5 to 8 members, consisting of 0-4 nonatomic or partially independent components of N, O, s and so83222;where ring D is unsubstituted or optionally substituted with 1-5 portions R²⁰ independently selected; the portions R²⁰ may be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, -alkylamino, -alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl-,-C (= O) -O-alkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, cyano, cycloalkyl, cycloalkenyl, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyloxyl, hydrocyclyloxy, hydrocyclyloxy, cyclocyclyloxy, heterocyclyloxy, cyl , nitro, trifluoromethoxy, - (CH₂) qOH, - (CH₂) qOR³¹,- (CH) qNH- (CH) qNHR- (CH) qN (R)- (CH) qC (3DO) NHR- (CH) qSO R- (CH) qNHSO R- (CH) qSO NHR- (CH) qSO NHR-Asphalt C (R3 1) 8322; or 3 1,-C (3DO) R-C (3DO) N (R)-C (3DNR) NHR-C (3DNOH) N (R)-C (3DNOR) N (R)-C (3DO) OR-N (R)-N (R) C (3DO) R-NHC (3DO) N (R)-N (R) C (3DO) OR-N (R) C (3DNCN) N (R)-N (R) C (3DO) N (R) SO (R)-N (R) C (3DO) N (R)-N (R) SO (R)-N (R) S (O) N (R)-OR³⁰,-OC (3DO) N (R)-SR³⁰,-SO N (R)-SO (R)OSO (R)y -OSi (R)or alternatively two R²⁰ portions are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, or heteroaryl or heteroaryl ring where said aryl, cycloalkyl, heterocyclyl, heterocyclynyl, or five or six membered heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 portions R²¹;R2 ion 1 can be the same or different, each of which can be a group independent of H, asphalt, dinitrile, taxi, asphalt, taxi, alchemy, alchemy, asphalt, - alchemy, - C (= O) - or - asphalt, amide, aralquillo, aralquenilo, aralcoxi, aralcoxicarbonilo, aralquiltio, arilo. Ciano, cycloquilo, cycloquilo, cycloquenilo, guanidinil, halogen, halogen, isopar, heterogeneous, isomerization, isomerization, isomerization, Narcissus, hydroxamato, nitro, trifluorometoxi, - (CH 8322222) qoh, - (CH 832222) QOR 1,- (CH) qNH- (CH) qNHR- (CH) qN (R)- (CH) qC (O) NHR- (CH) qSO R- (CH) qNHSO R- (CH) qSO NHR-Asphalt C (R3 1) 8322; or 3 1,-C (3DO) R-C (3DO) N (R)-C (3DNR) NHR-C (3DNOH) N (R)-C (3DNOR) N (R)-C (3DO) OR-N (R)-N (R) C (3DO) R-NHC (3DO) N (R)-N (R) C (3DO) OR-N (R) C (3DNCN) N (R)-N (R) C (3DO) N (R) SO (R)-N (R) C (3DO) N (R)-N (R) SO (R)-N (R) S (O) N (R)-OR³⁰,-OC (3DO) N (R)-SR³⁰,-SO N (R)-SO (R)-OSO (R)y -OSi (R)And from - (CR * 3 R1 m3) 6911 -,-CHR C (3DO) -- (CHR) O-- (CHR) N (R) --C (=O)-C (3DNR) --C (3DN-OR) --CH (C (3DO) NHR) -Cross dressing-C (R1 m3) 6911; (R1 m3) = C (R1 m3) -,- (CHR) C (3DO) - y - (CHR) N (H) C (3DO) -Or a substitute, which is cyclopentadiene, isopropene or isopropene, in which cyclopentadiene, isopropene or isopropene are combined with ring D; r1:3 parts can be the same or different, and each part is independent of a group composed of H, asphalt, rental, cyclopentadiene, alcoxi and arilo, Heterosexual, heterosexual, heterosexual, isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl-C (3DO) N (R)- (CHR) qOH - (CHR) qOR- (CHR) qNH- (CHR) qNHR- (CH) qC (3DO) NHR- (CH) qSO R- (CH) qNSO R- (CH) qSO NHR-NH832222,-N (R)-N (R) C (3DO) N (R)-N (R) SO (R) -OH OR-SO N (R)y -SO (R)the R³⁰ portions may be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, - (CH₂) qOH, - (CH₂) qO-alkyl, - (CH₂ ) q-alkylaryl, - (CH # x2
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