Ciclobuten - 1.2 - dionas 3.4 - di substituted and its Salts as CXC - chemokine receptor ligands, Pharmaceutical compositions and the use thereof for the manufacture of a medicament

摘要

Cyclohexane-1,2-diazo-3,4-distitude, including a formula compound (1) and its salts (such as sodium or calcium) or an acceptable solution for drug use, selected from formula group (2)The rings in group A are replaced by 1-6 substitution rings, which are selected from R9 group and formula group respectively (3),One or two rings in group A are replaced by 1-6, and each ring is independently selected from group R9; formula group (4),a. The phenyl ring of group A is replaced by 1 to 3 substitutes, each of which is selected independently from group R9; and formula group (5);In a group of N values of 0-6, P values of 1-5, x values of O, NH or s, Z values of 1-3, B is selected from a group of n (6),wherein R2 is selected from the group consisting of: hydrogen, OH, -C (O) OH, -SH, -SO2NR13R14, -NHC (O) R13, -NHSO2NR13R14, -NHSO2R13, -NR13R14, -C (O) NR13R14, -C (O) NHOR13, -C (O) NR13OH, -S (O) 2OH, -OC (O) R13, a substituted or unsubstituted heterocyclic acid functional group and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents in said substituted heterocyclic acidic functional group, each substituent being independently selected from the group consisting of R9 groups; each R3 and R4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, OH, -CF3, -OCF3, -NO2, -C (O) R13, -C (O) OR13, -C ( O) NHR17,-C (O) NR13R14 -SOtNR13R14 -SOtR13 -C (O) NR13OR14 -NHC (O) R17 arilo no sustituido o sustituido heteroarilo no sustituido o sustituido -P (3DO) R31R31 -C (3DNR30) NR13R14 y -C (3DNOR13) -Sotnr13r14, - C (o) nr13 or14, cyanogen, unreplaced or replaced arilo and unreplaced or replaced alien arilo, where there are 1-6 substitutes, the substitutes are independent of R9; In the presence of one to six alternatives, each alternative in the variant group being replaced is selected independently of the R9 group; while each R7 and R8 is selected independently of the following categories: H, unreplaced or substituted tar, unreplaced or substituted arilo, unreplaced or substituted heterogeneous East Africa, Not replaced or replacedThere are no substitutes or replacements for heteromorphic love, no substitutes or replacements for cyclomequine, no substitutes or replacements for cyclomequine tequila (co2r13), conr13r14, asphalt, alquinio and cyclomequinyl; in the case of one or more substitutes for R7 and R8, each substitute is selected independently of its group. From (a) halogen (b) - C F 3 (c) - cor13 (d) - R13 (E) - nr13 (f) - NO2 (g) CN (H) - so2or13 (f) - if (lease) 3, each asphalt is independently selected, (J) - if (arilo) 3, each asphalt is independently selected, (k) ((R13) 2r14si, each R13 is independently selected, (L) - co2r13 (m) - C (o) n13r14,n) -SO2NR13R14, o) -SO2R13, p) -OC (O) R13, q) -OC (O) NR13R14, r) -NR13C (O) R14, and s) -NR13CO2R14; R8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R9 is independently selected from the group consisting of: a) R13, b) halogen, c) -CF3, d) -COR13, e) -OR13, f) -NR13R14, g) -NO2, h) -CN, i) -SO2R13, j) -SO2NR13R14, k) -NR13COR14, l) -CONR13R14, m) -NR13CO2R14, n) -CO2R13, o) tetrazol-5-yl, p) alkyl substituted with one or more (eg one) groups -OH (eg - (CH2) qOH, where q is 1-6, usually 1 to 2, and preferably 1),q) alkyl substituted with one or more (eg one) -NR13R14 groups, (eg - (CH2) qNR13R14, where q is 1-6, usually 1 to 2, and preferably 1),(c) Pops, including POPs; R13 is h, R14 is asphalt, such as methyl;Each R10 and R11 is independent of the choice of hydrogen, tar (for example, a mixture). C1-6, such as methyl,halogen, -CF3, -OCF3, -NR13R14, -NR13C (O) NR13R14, -OH, -C (O) OR13, -SH, -SOtNR13R14, -SO2R13, -NHC (O) R13, -NHSO2NR13R14, -NHSO2R13, -C (O) NR13R14, -OC (O) R13 and cyano; R12 is selected from the group consisting of: hydrogen, -C (O) OR13, unsubstituted or substituted aryl group, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, non-substituted cycloalkylalkyl substituted or substituted and unsubstituted or substituted heteroarylalkyl, wherein there are 1 to 6 substituents in the substituted R12 groups and each substituent is independently selected from the group consisting of R9 groups;Each R13 and R14 type waste selection consists of hydrogen, unreplaced or replaced tar, unreplaced or replaced arilo, unreplaced or replaced heteromorph, unreplaced or replaced heteromorph, unreplaced or replaced cyclododecane, unreplaced or replaced cyclododecane, unreplaced or replaced cyclododecylquine, There are 1 to 6 substitutes in these R13 and R14 groups, each of which is selected without belonging to the following groups:fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, -N (R40) 2, -C (O) OR15, -C (O) NR15R16, -S (O) tNR15R16, -C (O) R15, -SO2R15, provided R15 is not H, halogen and -NHC (O) NR15R16; or R13 and R14 taken together with the nitrogen to which they are attached in the groups -NR13R14, -C (O) NR13R14, -SO2NR13R14, -OC (O) NR13R14, -CONR13R14, -NR13C (O) NR13R14, -SOtNR13R14, - NHSO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing an additional heteroatom selected from the group consisting of: O, S, and NR18,wherein there are 1 to 3 substituents in the R13 and R14 cyclic groups and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino , -C (O) OR15, -C (O) NR15R16, -S (O) tNR15R16, -C (O) R15, -SO2R15, provided that R15 is not H, -NHC (O) NR15R16, -NHC (O ) OR15, halogen and a heterocycloalkenyl group; each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R17 is selected from the group consisting of: -SO2alkyl, -SO2aryl,-So2cycloquilo y-so2 heterosexual; R18 is selected from the following categories: H, asphalt, arilo, heterosexual, - C (o) R19, - so2r19, y-c (o) nr19, y-c (o) nr19; each R19 and R20 is selected from the following categories respectively: asphalt, arilo and heterosexual; R30 is selected from the following categories: asphalt, cyclopropyl-cn, - NO2, or so2r19, provided that: R15 is non-H; each R31 shall be selected separately from the following categories: unreplaced or replaced asphalt, unreplaced or replaced asphalt, unreplaced or replaced non-n-propene and unreplaced or replaced cyclopropyl compounds;In the case of one to six of these R31 alternatives, each alternative shall be selected independently of the R9 alternative category; each R40 shall be selected independently of the h, tar and cyclopentadiene alternative category; t is 0, 1 or 2; 2. Pharmaceutical ingredients and the use of these compounds to manufacture drugs for the treatment of acute and chronic inflammatory disorders and cancer and other chemical mediating diseases;