Substituted pyrimidines as CCR2 Receptor Antagonists and Uses Thereof in medicines.

摘要

2. New antagonists of CCR2 (the second receptor of CC chemotherapy) and the drugs used to provide treatment for diseases, especially for lung diseases such as asthma and chronic diseases. 1. Characteristic 1: Compound conforming to formula (1),Where R1 is - l1-r7, a can selected between one or a set of selected connections or groups between C1-2 tar and C1-2 alquenileno C1-2, including from - or--C (O) - and -NH- in the chain and which is optionally substituted with a group selected from -OH, -NH2, -C1-3alkyl, O-C1-6alkyl and -CN, wherein R7 is a ring selected from -C3-8cycloalkyl, -C3-8 heterocyclyl, -C5-10 -aryl, and -C5-10 heteroaryl, wherein the R7 ring is optionally substituted with one or more groups selected from -CF3, -O -CF3, -CN and -halogen, or in which the R7 ring is optionally substituted with one or more groups selected from -C 1-6 alkyl, -O-C 1-6 alkyl, -C5-10 aryl, -C5 heteroaryl- 10, -C3-8cycloalkyl, -C3-8 heterocyclyl, -C 1-6 alkenyl and -C 1-6 alkynyl,One or more groups selected from - Oh, NH2, c1-3, or - tar C1-6, CN, CF3, ocf3, halogen y = O can be selected to replace, or the R7 ring can be selectively replaced in two adjacent atoms in the ring, so as to form an attachment ring with one or more selected groups Between C1-6, C1-6, alquenileno c2-6 and C4-6, one or two heteroatoms selected from n, O and s can be selected to replace one or two carbon centers, while one or more groups selected from - Oh, NH2, c1-3, C1-6, CN, CF3 and ocf3 can replace two carbon centers,Halogen y = O; R2 is selected from - h-halogen-cn - or - c1-4-tar-hc-4-hc-ch2-c: ch-cf3-ocf3-ocf2h and - ocfh2; R3 is selected from - h-methyl-ethyl-propyl-i-propyl-propyl-cyclopropyl-cyclopropyl-och3 and - CN; R4 and R5 are selected from two electrons, respectively, -H and a group selected from - c1-6-nh2-cycloquilo c3-8-heterosexual c3-8-arilo c5-10-heterosexual c5-10 and y-c (o) - n (r8r8),where R8 and R8 'are independently selected from -H and -C1-6 alkyl, and in which R4 and R5, if they are different from an electron pair or are -H, they are optionally substituted independently with one or more groups selected from -halogen, -OH, -CF3, -CN, -C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 3-8 cycloalkyl, -O-C 3-8 heterocyclyl, -O-C 5-10 aryl, -O-C5-10 heteroaryl, -C0-6-CN alkylene, -C0-4 alkylene-C1-4 alkyl, -C0-4 -C-alkylene-C3-8 cycloalkyl, -C0-4-O-C3-heterocyclyl -8, -C0-4-O-C6-10 -alkyl, -C0-4 -O-C5-10 -alkylene, -C0-4-Q-C0-4-N-alkyl (R9R9 '),-C0-4-N (R10) alkylene -Q-C1-4 alkyl, -C0-4-N-alkylene (R10) -Q-C3-8 cycloalkyl, -C0-4-N-alkylene (R10) -Q-heterocyclyl C3-8, -C0-4-N alkylene (R10) -Q-C5-10 aryl, -C0-4-N-alkylene (R10) -Q-C5-10 heteroaryl, -C0-4-QN alkylene (R11R11 ' ),-alquileno C0-4-N (R12) -Q-N (R13R13)-C0-4-R14 alkylene, -C0-4-Q-C1-6 alkyl, -C0-4-Q-C3-8 alkylene, -C0-4-Q-C3-8 heterocyclyl, -C0 alkylene -4-Q-C5-10 aryl, -C0-4-Q-C5-1o-heteroaryl, C0-4-OQN-alkylene (R15R15 ') and -C0-4-N (R16) -QO- (R17-alkylene ),If you are already registered, please log in first.Among them, R12 and R16 are independently selected from - h-c1-6 and - ring 12 quilo C3-6, among which R9, r9'r10, R11 and R11 ',R13, R13 ',R15 and R15 are selected from - H, C1-6 and - ring 12 quilo C3-6 or R9 and R9, respectively.R11 and R11 ',R13 and R13 ',R15 and R15 'are added together to form a group of c2-6 tar, wherein R14 and R17 are independently selected from - H, C1-6 tar, arilo c5-10, heterosexual c5-10, ring-chemical C3-8 and - acyclic-c3-8, respectively. In the ring, the - acyclic-c3-8 can selectively include nitrogen and / or SO2, In this case, R14 and R17 can be selected by one or more from - Oh, - OC3, - CF3, - ocf3, - CN, - halogen, - tar C1-4, = or y-so2, C1-4, or L2 from - nh-y-n (C1-4 tar) when R4 and / or R5 are an independent structural group - l2-r18,wherein R18 is selected from -C5-10 aryl, -C5-10 heteroaryl, -C3-8 cycloalkyl and -C3-8 heterocyclyl, in which R18 is optionally substituted with one or more groups selected from halogen, -CF3, -OCF3, -CN, -OH, -O-C 1-4 alkyl, -C 1-6 alkyl, -NH-C (O) -C 1-6 alkyl, -N (C 1-4 alkyl) -C (O) - C 1-6 alkyl, -C (O) -C 1-6 alkyl, -S (O) 2-C 1-6 alkyl, -NH-S (O) 2-C 1-6 alkyl, -N (C 1-4 alkyl) -S (O) 2-C1-6 alkyl and -C (O) -O-C1-6 alkyl, and in which R4, R5 and R18 are optionally further substituted with C3-8 spirocycloalkyl or C3-8 spiro-heterocyclyl such that together with R4, R5 and / or R18 a spirocycle is formed,In this spiral isocyclopropene C3-8, one or more groups selected from nitrogen can be optionally included, - C (o) -,-So2-y-n (so2-c1-4) - or R4, R5 and R18 in the ring can also be replaced by one or more groups. One or more spiral rings or accessories are selected from C1-6 tar, c2-6 and C4-6, One or two carbon centers can be replaced by one or two heteroatoms selected from n, O and s, one or more groups of ring atoms or two adjacent atoms in the ring can be selected from - oh-nh2-c1-3 tar or c1-6-tar-cn-cf3-ocf3 and halogen in the ring. R6 selected from - H, C1-4, oh, or - C1-4,-Halogen, CN, CF3 and ocf3: select a in a simple link,-CH2...- that is...-S-Y-NHN is 1, 2 or 3, Z is C or N, and is in the form of an acid salt containing a pharmaceutically acceptable acid.