Macro label for interaction of restricted protection / protection, scheduled death protection 1 (PD-1) / PD-1 (PD-L1) and PD-L1 / CD80

摘要

Macrocyclic peptides that inhibit the interaction of PD-1 / PD-L1 and PD-L1 / CD80 proteins, thus contributing to the improvement of various diseases, including cancer and infectious diseases. 1. Claim 1: a compound characterized by formula (1),Or a pharmaceutically acceptable salt, wherein: A is selected from the link, or a formula group compound (2);Wavy line *" refers to the connection point with carbide group, "wavy line" refers to the connection point with nitrogen atom; Z is 0, 1 or 2; W is 1 or 2; n is 0 or 1; m is 1 or 2; m 'is 0 or 1; P is 0, 1 or 2; r739e is selected from hydrogen, amine, hydrogen Xi and methyl; R183088 and r183099 are independent of hydrogen and methyl; r761111 is selected from hydrogen y-c (o) nhr18310;Where r8310 is selected from the hydrogen gas, - chr18311; (o) nh8322;-CHR¹⁷C (O) NHCHR¹⁸C (O) NH₂ and -CHR¹⁷C (O) NHCHR¹⁸C (O) NHCH₂C (O) NH₂;e. In R1 831111b, hydrogen and - ch8322oh are selected, and in R1 831222, hydrogen and methyl are selected; in r7515e, a side chain of hydrogen or natural amino acid is selected; wave line * "represents the connection point with carbon group", "wave line" represents the connection point of nitrogen atom; r758080;R75848,R688a,R83055,R750404 and r8319 are hydrogen; r74919;R74977,Rʲ and Rᵏ are each independently selected from hydrogen and methyl; R¹⁰ is indolylC₁₋₃alkyl, where the indolyl part is optionally substituted with a group selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, (C₁₋₆alkyl) S (O) ₂NHC (O) C₁₋₃alkyl , arylS (O) ₂NHC (O) C₁₋₃alkyl, arylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, C₃₋₆cycloalkylS (O) ₂NHC (O) C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkyl (O) ₂NHC (O) C₁₋₃alkyl, heteroarylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, -NRᵖRq, (NRᵖRq) C₁₋₃alkyl and tetrazolylC₁₋₃alkyl,or with two selected groups of C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, C₁₋₃alkyl, (C₁₋₆alkyl) S (O) ₂NHC (O) C₁₋₃alkyl, arylS (O) ₂NHC (O) C₁ ₋₃alkyl, arylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS (O) ₂NHC (O) C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkyl (O) ₂NHC (O ) C₁₋₃alkyl, halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl, heteroarylS (O) ₂NHC (O) C₁₋₃alkyl, heteroarylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq) C₁ Qualkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl,wherein phenyl is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; or R¹⁰ is azaindolylC₁₋₃alkyl, wherein the azaindolyl part of azaindolylC₁₋₃alkyl is substituted with 1 or 2 different groups independently selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, (C₁₋₆alkyl ) S (O) ₂NHC (O) C₁₋₃alkyl, arylS (O) ₂NHC (O) C₁₋₃alkyl, arylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, CycloalkylS (O) ₂NHC (O) C₁₋₃alkyl,C₃₋₆cycloalkylC₁₋₃alkylS (O) HCNHC (O) C₁₋₃alkyl, halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl, heteroarylS (O) ₂NHC (O) C₁₋₃alkyl, heteroarylC₁₋₃alkyl (O) ₂NHC (O) C₁₋ ₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq) C₁₋₃alkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl, wherein phenyl is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; or R¹⁰ is - (CH₂) ₙQ ’is a saturated or unsaturated fused 5,6 ring system containing 1, 2, 3 or 4 nitrogen atoms, where the ring system is optionally substituted with 1,2 or 3 groups selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, C₁₋₃alkyl, (C₁₋₆alkyl) S (O) ₂NHC (O) C₁₋₃alkyl, arylS (O) ₂NHC (O) C₁ ₋₃alkyl, arylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS (O) ₂NHC (O) C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkyl (O) ₂NHC (O ) C₁₋₃alkyl, halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl, heteroarylS (O) ₂NHC (O) C₁₋₃alkyl, heteroarylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq) C₁ Qualkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl,wherein phenyl is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; as long as Q ’is not azaindolyl or indolyl; or R¹⁰ is - (CH₂) ₙZ ’,where n is 1-3 and Z 'is a saturated or unsaturated fused ring system 6,6 containing 1, 2, 3 or 4 nitrogen atoms, where the ring system is optionally substituted with 1, 2 or 3 selected groups of C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, C₁₋₃alkyl, (C₁₋₆alkyl) S (O) ₂NHC (O) C₁₋₃alkyl, arylS (O) ₂NHC (O) C₁₋₃alkyl, arylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS (O) ₂NHC (O) C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkyl (O) NHC (O) C₁₋ ₃alkyl, halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl,heteroarylS (O) ₂NHC (O) C₁₋₃alkyl, heteroarylC₁₋₃alkylS (O) ₂NHC (O) C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq) C₁₋₃alkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl, where phenyl it is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; Rᵖ and Rq are independently selected from hydrogen and C₁₋₆ alkyl; R¹³ is selected from a natural amino acid side chain, a non-natural amino acid side chain and - (C (R¹⁷ᵃ) ₂) ₂-X-R³⁰;-C (R) C (O) N (R) C (R) -X -R-C (R) C (O) N (R) C (R) -X-R-1:1:1:1:1:1, in which 1 atom has 1:1:1:1:1 atomic energy, in which 1 atom is selected from carbon and oxygen. In these atomic chains, the atomic chain can contain 1, 2, 3 or 4 selected NHC (o) nh-y groups. -C (o) NH embedded; in the chain, 1 to 6 target groups independent of - co8322jh, - C (o) nh832222 are substituted;-CH C (O) NH y - (CH) CO HX es una cadena de 1 a 172 tomos en donde los tomos se seleccionan de carbono y ox geno y en donde la cadena puede contener 1 2 3 4 grupos seleccionados de -NHC ( wherein Rʷ and Rˣ are independently selected from hydrogen and C₁₋₆alkyl, provided that when X is carbon, R³⁰ is not -CH₃;R es -CO H -C (O) NR R-CH8323,a. Alexa-5-sdp and biocina; r831181; 749191 are not screened based on hydrogen, c83218331; pitch-ch8322; oh-ch8322; - c8322; - (ch832222) c8322;; co8322; h; r18311811 is not screened based on hydrogen, c8332323;(CH) N- (CH) NH-X-R3 1,- (CH) CO H -CH OH CH CC CCH y - (CH) -triazolil-X-Rwhere z is 1-6, and R³⁵ is selected from -CO₂H, -C (O) NRʷRˣ,Ch8323,Biota -, 2-fluoroiridina - (ch832222) C (o) or - Vitamin E - (C (o) or - Vitamin E; and a formula compound (3) if at least 1 r831111 is non hydrogen -, ch8323o-ch8322;]R2,R3,R830808,R83099,R8310,R8311th,R8322,R8313,R1 and R1 2 are selected independently of one natural amino acid transverse chain and one unnatural amino acid transverse chain, or form a ring corresponding to the next R group, as described below; r74979 and r750303 can respectively form a ring related to the next R group, as well as the corresponding atoms; a. One or four separate groups selected from azeidina, pirrolidina, morpolina, piperina, piperazina and tetrahydroendosulfan; in these groups, each ring can be selected to be replaced by one to four selected groups independent of aminobenzene, cyanogen, methyl, halogen and hydrogen Xi; r7495es metro, or r7495y R2;They are combined with atoms to form a selected Azerbaijani, pyridine, pyridine, morphine, pyridine, pyridine and tetrahydrothiazole ring, in which each ring can be selectively replaced by one to four target groups without aminobenzene, cyanogen, methyl, halogen and hydrogen; r7496es hydrogen or methyl, or r7496y r83088;Combined with atoms, they can form a selected Azerbaijani, pyridine, pyridine, morphine, pyridine, pyridine and tetrahydrothiazole ring; in this ring, one to four target groups free of aminobenzene, cyanogen, methyl, halogen, hydroxy and phenyl can be selected to replace each ring; r7501es hydrogen or methyl, or r7501y; R8311th,When combined with atoms, they can form a selected Azerbaijani, pyridine, pyridine, morphine, pyridine, pyridine and tetrahydroendosulfan ring; in this ring, each ring can be replaced by a specific group of one to four non amines, optionally with halo, benzene and cyanogens. Cyclohexane, methyl, halogenated, hydroxy, isoquinolyloxy are quinolinoxy and tetramethylbenzene which are replaced by a methoxi group and selectively by a halogenated cluster; pyridine and pyridine ring are selectively fused with a cyclohexane, phenyl or indolea group; RL is methyl, or RL and R1 square,They combine with atoms to form a selected Azerbaijani pyridine pyridine ring in which each ring is replaced by one to four selected groups, regardless of aminobenzene, cyanogen, formic acid, halogen and hydroxyl group.