Heteroarilalcanoico acid Derivatives, Pharmaceutical compositions and the use of these derivatives for the manufacture of medicaments for inhibiting or antagonizing the alfavbeta3 selectively and alfavbeta5 INTEGRINS

摘要

a. Isoacrylic acid derivatives, including a compound containing a formula (1) or a pharmaceutically acceptable formula salt, wherein: a ring is a single ring with 4-8 members or a double ring with 7-12 members, consisting of 1 to 4 heteroatoms selected from the O, n or s groups; It can be saturated or unsaturated, or unsaturated or unsaturated, and can be replaced by one or more substitutes selected from the group, such as asphalt, halotar, arilo, heterogeneous, halogenated, alcohy, amino, hydroxy, hydroxy, hydroxy, hydroxy group, sulfurized bitter, aminobenzene, taxi, arilamino, asphalt, alkylamide, amino acid, ester, acrylamine, acrylamine, acrylamine, acrylammonium Tar powdera. Sulfur amide, alkenylhydrazide, methyldioxy, ethyldioxy, tar, carbohydrate, cyanogen and - (CH2) mcor, where m is 0-2, R is hydroxy, propyl, tar or amino; however, when Y4 is h in the formula, a ring does not necessarily have to be oxazol, and its side chain contains X - and is connected with carbon 2, as shown in the formula (2);A1 is a single ring cycle composed of 5 to 9 members or 7 to 14 members of formula (3), which contains at least one nitrogen atom, optionally one to four heteroatoms selected from O, N, s, SO2 or co groups; optionally saturated or unsaturated; a. Alternatively, it can be replaced by one or more rk, selected from the group of hydrogen Xi, alcoxi, hydrocoxi, hydrogen sulfide, halogenated tar, cyanogen, aminobenzene, leasing Mino, halogenation, acid lamino, ammonium sulfate and cor with R as hydroxyl, Alcoy, alcoxi, hydrocarbon or amino group; The remaining formulations (3) include the following aperiodic ring systems (4),(5) Or (6) uranium containing at least one nitrogen atom, wherein Za is h, tar, alcoxi, hydroxi, amino, rental mine, diklamina, carboxilo, alcoxibonilo, hydroxilquilo, halogeno or brine tar, and R1 is h, tar, alcoxidiquilo, acilo, brine tar or alcoxyl. More specifically, some examples include Pyridylamine, Pyridylamine, morphine Pyridylamine, tetrahydrazine, oxazolilamino, thiazolidine, Pyridylamine, quinoline, isoquinol, tetrahydroquinol, Pyridylamine, benzidine, Pyridylamine or quinolona; foreign body of formula (7) a (33),For heterocycles of pyridine derivatives, X4 and X5 substitutes are mainly class h, asphalt, bulk tar, rental, oxygen rental, halotar, hydrogen sulfide, halogen, aminobenzene, alcoxi, alcohole, hydroxi, cyanogen or acilamino; Among the current alternatives, X4 and X5 may be methyl, thyroid, amine, methylene amine, trifluoromethyl acyl, trimethylamine, hydroxy, chlorine, bromine, fluorine and cyanogen; X6 may be the preferred alternative for H, tar, halogen, alcox and halotar,Pyridine ring can be combined with 4-8 ring, optionally saturated or unsaturated; examples of these ring systems include tetrahydrazine, quinoline, tetrahydroquinol, azaquin, morphine pyridine, pyridan, etc.; single ring systems, such as pyridan, thiazole, oxazol, etc. Pyrazoles and the like may contain an alternative amine or may be leased anywhere in the ring; in the present alternative form, when the Z1 formulation (1) is co or SO2, the a1-z2 link (1) in the formulation preferably includes the following heterocyclic derived ring systems: pyridine, pyridan, thiazole, oxazol, benzodiazepine,imidazopiridina y similares otros heterociclos preferidos para Z1-Z2 de la presente incluyen los representados por las formulas (34) a (42) y en las que X4 es como se define en lo anterior o A1 es un resto de formula (43) en donde R2 and R7 together form a heterocycle consisting of 4-12 members of dinitrobenzene substitutes, which can optionally be replaced by one or more substitutes selected from the group of low tar, sulfur, rental, hydroxy, ethyl, propyl, halogen, phenyl, amino, amino, amino or methyl ester; Or R2 and R7 together form a heterocycle composed of 4-12 members, including one or more heteroatoms selected from O, N, or with R7 together form a heteroaromatic ring composed of 5 members, combined with an arilo or heterocyclic ring; R7 (not used with R2) and R8 are independently selected. In group H, there were people,Aralquilo, amino, rental, hydroxi, alcoxi, arilamino, amido, acalkanonilo, alcocino, ariloxi, ariloxicarbona, halocalcocino, halocalcycloxicarbonanilo, pollutibonilo, aritimocobonilo, aciloximethoxicarbonilo, cyclo, cyclop, bicyclo, arilo, acilo, benzoilo; o N7 and R8 together, They form a single or double ring ring ring containing 4-12 mono nitrobenzene members, optionally replaced by one or more lower tar substitutes selected from carbohydrate, arilo, or hydroxy derivatives, wherein the optional ring contains a heteroatom selected from the O, N, and s groups.R5 is selected from H and asphalt group; or A1 is a remaining formula (44), wherein Y2 is selected from asphalt, cyclophosphate, bicycle, single cycle heteromorphic, single cycle cycle cycle group; Z1 is selected from CH2, O, NH, Co, s, so, CH (OH) and SO2 group; Z2 is an optional c2-5 can. Or more heterogeneous atoms selected from O, s and N groups; otherwise, Z1 and Z2 may also contain a group of carbon box, sulfur, sulfonamide, acylpyridan, starch, tar or acilo; in these substances, the carbon and nitrogen atoms of z1-z2 may be replaced by asphalt, alcox, hydrogen sulfide and tar,In addition, z1-z2 may contain an arilo or heterosexual ring, which is replaced by RC, It can contain 1-3 heteroatoms selected from O, N and s groups; X from contains - CHRE, NRF, O -.- yes.-SO2...Y-CO...Where re is h, low pressure tar, alcoxi, cycloquilo, alcohydro, hydroxi, tar, alquenilo, haloaquilo, tioalquilo or arilo; where re is hydroxyl, the optional hydrogen Xi group can form a pigment with a chain carboxyl acid function; RF is selected from the h, tar and arilo groups, 1. Bencilo and halotars; and from (CH2) P -, CHRG -, NRG -, andRG and SO2 companies, where RG is selected from h, asphalt, halo tar, alcohy, tar, arilo, heterogeneous, aralquilo, hidroxi, alcoxi and carboxalquilo groups; P is 0 or 1; alternatively, the X-Y group may contain a portion selected from ACIO, asphalt, sulfuryl, amine, ether, thioether groups, 1. Carbon boxamido, sulfonamido, aminosulfonilo and olefinas; Y3 and Y4 are independent of class h, asphalt, halogen, halogen, arilo, aralquilo, isopropyl isopropyl compound, isopropyl, alquenos, hydroxalquilo and aspha1. The tar chain can be linear or separable, and can selectively contain one or more heteroatoms selected from the N, O and s groups, and can also contain one sulfur, sulfonamide, nitro, anthrax, kaboahicks or kabushillo group; Arilo ring and heteromorphic ring may be single ring or double ring, optionally containing 1-5 heteroatom, ring may be saturated or unsaturated, or unsaturated or unsaturated, such ring can be replaced by one or more RC, provided that when Y3 or Y4 is h, Y5 can be C or N, otherwise Y5 is C.Y3 and Y4 together form a single ring (45) equation b ring, which consists of 3 to 8 members, or 7 to 11 members, optionally including one or more double ring links, or one or more heteromorphic atoms or functional groups selected from O, NRG, s, Co or SO2, One or more substitutes can be selected to replace it, and selected from the group of asphalt, halogenated, halogenated, propoxy, asphalt, asphalt, tar, sulfur amide, hydrogen carbide and carboxalquilo; or X and Y3 can be made into a C-type single ring (460) with 3-8 members or a double cycle system with 8-11 members,The selection includes one or more double-sided links, optionally one or more heteroatoms or a functional group selected from O, NRG, s, Co or SO2, and is optionally replaced by one or more substitutes selected from tar, halogenated, cyanogen, carboxalcoxi, alcoxi, tar, arilo, aralquilo groups, 1. Isopropyl, halo, hydroxy or oxy; Rb is x2-rh, X2 is selected from the group consisting of O, s and Nrj, in which RH and RJ are selected independent of the group consisting of H, tar, arilo, aralquilo, ACIO and alcoxidiquilo;1. Pharmaceutical compounds containing formula compounds (1) and drugs using these derivatives to selectively inhibit or resist avb3 or avb5 complex;