IMMUNOMODULATORS, COMPOSITIONS AND METHODS THEREOF
20210040118 ยท 2021-02-11
Inventors
- Yiqian Wang (Beijing, CN)
- Bang FU (Beijing, CN)
- Yao ZHANG (Beijing, CN)
- Xiangyong Liu (Beijing, CN)
- Jiabing Wang (Beijing, CN)
- Lieming Ding (Hangzhou, CN)
Cpc classification
A61P31/00
HUMAN NECESSITIES
C07D277/56
CHEMISTRY; METALLURGY
C07D271/10
CHEMISTRY; METALLURGY
C07D285/12
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
C07D263/34
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D271/10
CHEMISTRY; METALLURGY
C07D277/56
CHEMISTRY; METALLURGY
C07D285/12
CHEMISTRY; METALLURGY
Abstract
The present invention relates to compounds of Formula I, methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.
##STR00001##
Claims
1. A compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, ##STR00248## wherein, Q and Q are each independently selected from absent, C(O) or C(R.sub.2).sub.2; R.sub.1 and R.sub.10 are each independently selected from H, halogen, CN, or C.sub.1-8alkyl; R.sub.2 and R.sub.20 are each independently selected from H, or C.sub.1-8alkyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; or R.sub.10 and R.sub.20 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; R.sub.3 and R.sub.4 are each independently selected from heterocyclic ring or heteroaryl ring optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O, wherein the heterocyclic ring or heteroaryl ring is monocyclic or bicyclic, optionally substituted with C.sub.1-8alkyl, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pCONR.sub.30R.sub.40, (CH.sub.2).sub.pOH, (CH.sub.2).sub.p-heterocyclyl, C.sub.3-7cycloalkyl, C.sub.3-7heterocyclyl, or (CH.sub.2).sub.pNR.sub.30R.sub.40, wherein C.sub.1-8alkyl, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pCONR.sub.30R.sub.40, (CH.sub.2).sub.pOH, (CH.sub.2).sub.p-heterocyclyl, C.sub.3-7cycloalkyl, C.sub.3-7heterocyclyl, or (CH.sub.2).sub.pNR.sub.30R.sub.40 is optionally substituted with C.sub.1-8alkyl, halogen, OH, CN, COOH, or NR.sub.30R.sub.40; R.sub.30 and R.sub.40 are each independently selected from H, C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.3-7heterocyclyl; or R.sub.30 and R.sub.40 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; R.sub.21 and R.sub.21 are each independently selected from halogen, CN, OH, COOH, or C.sub.1-8alkyl; s and p are each independently selected from 0, 1, 2 or 3.
2. The compound of claim 1, wherein Q and Q are each independently selected from absent, C(O) or CH.sub.2; or s and p are each independently selected from 0 or 1; or R.sub.1 and R.sub.10 are each independently selected from H, methyl, F or Cl; or R.sub.2 and R.sub.20 are each independently selected from H or methyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5-member heterocyclic ring; or R.sub.10 and R.sub.20 together with the atoms to which they are attached form a 5-member heterocyclic ring; or R.sub.21 and R.sub.21 are each independently selected from CH.sub.3, F, Cl or CN.
3-8. (canceled)
9. The compound of claim 1, wherein R.sub.3 and R.sub.4 are each independently selected from ##STR00249## which is each unsubstituted or substituted with at least one substituent selected from C.sub.1-6alkyl, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pCONR.sub.30R.sub.40, (CH.sub.2).sub.pOH, (CH.sub.2).sub.p-heterocyclyl, C.sub.3-7cycloalkyl, C.sub.3-7heterocyclyl, or (CH.sub.2).sub.pNR.sub.30R.sub.40, wherein C.sub.1-6alkyl, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pNH.sub.2, (CH.sub.2).sub.pCONR.sub.30R.sub.40, (CH.sub.2).sub.pOH, (CH.sub.2).sub.p-heterocyclyl, C.sub.3-7cycloalkyl, C.sub.3-7heterocyclyl, or (CH.sub.2).sub.pNR.sub.30R.sub.40 is optionally substituted with C.sub.1-8alkyl, halogen, OH, CN, COOH, or NR.sub.30R.sub.40; R.sub.30 and R.sub.40 are each independently selected from H, C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.3-7heterocyclyl; or R.sub.30 and R.sub.40 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring.
10. The compound of claim 9, wherein, R.sub.30 and R.sub.40 are each independently selected from H, or C.sub.1-3alkyl; or R.sub.3 and R.sub.4 are each independently selected from ##STR00250##
11. (canceled)
12. The compound of claim 1, wherein R.sub.3 and R.sub.4 are each independently selected from ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262##
13. The compound of claim 1, wherein the compound is of Formula II: ##STR00263## wherein, R.sub.1 and R.sub.10 are each independently selected from H, halogen, CN, or C.sub.1-8 alkyl; R.sub.2 and R.sub.20 are each independently selected from H, or C.sub.1-8 alkyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; or R.sub.10 and R.sub.20 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; Q and Q are each independently selected from absent, C(O) or C(R.sub.2).sub.2; X, Y, Z, X, Y or Z is independently selected from N, S, O or C; R.sub.5, R.sub.6, R.sub.5 and R.sub.6 are each independently selected from (CH.sub.2).sub.pNR.sub.30R.sub.40, (CH.sub.2).sub.m-cycloalkyl, (CH.sub.2).sub.m-heterocyclyl, C.sub.1-8alkyl, wherein (CH.sub.2).sub.pNR.sub.30R.sub.40, (CH.sub.2).sub.m-heterocyclyl, C.sub.1-8alkyl are each unsubstituted or substituted with at least one substituent selected from C.sub.1-8alkyl, COOH, NH.sub.2, (CH.sub.2).sub.m-hydroxyl, or CN; or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 6- to 7-member heterocyclic ring comprising 1, 2 or 3 hetero atoms independently selected from N, O or S, the heterocyclic ring being unsubstituted or substituted with at least one substituent selected from C.sub.1-8alkyl, (CH.sub.2).sub.m-carboxyl, (CH.sub.2).sub.m-hydroxyl, (CH.sub.2).sub.m-heterocyclyl, (CH.sub.2).sub.m-aryl, (CH.sub.2).sub.m-amido, (CH.sub.2).sub.mCN, (CH.sub.2).sub.mCF.sub.3, (CH.sub.2).sub.mCHF.sub.2, (CH.sub.2).sub.mCH.sub.2F, or (CH.sub.2).sub.mNH.sub.2; or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 6- to 7-member heterocyclic ring comprising 1, 2 or 3 hetero atoms independently selected from N, O or S, the heterocyclic ring being unsubstituted or substituted with at least one substituent selected from C.sub.1-8alkyl, (CH.sub.2).sub.m-carboxyl, (CH.sub.2).sub.m-hydroxyl, (CH.sub.2).sub.m-heterocyclyl, (CH.sub.2).sub.m-aryl, (CH.sub.2).sub.m-amido, (CH.sub.2).sub.mCN, (CH.sub.2).sub.mCF.sub.3, (CH.sub.2).sub.mCHF.sub.2, (CH.sub.2).sub.mCH.sub.2F, or (CH.sub.2).sub.mNH.sub.2; R.sub.30 and R.sub.40 are each independently selected from H, C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.3-7heterocyclyl; or R.sub.30 and R.sub.40 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; R.sub.21 and R.sub.21 are each independently selected from halogen, CN, OH, COOH, or C.sub.1-8alkyl; p, s, and m are each independently selected from 0, 1, 2 or 3; is a single bond or a double bond.
14. The compound of claim 13, wherein R.sub.1 and R.sub.10 are independently selected from H, methyl, F or Cl; or R.sub.2 and R.sub.20 are independently selected from H or methyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5-member heterocyclic ring; or R.sub.10 and R.sub.20 together with the atoms to which they are attached form a 5-member heterocyclic ring; or R.sub.21 and R.sub.21 are each independently selected from CH.sub.3, F, Cl or CN; or X and X are each independently selected from O, S or N; or Y and Y are each independently selected from C, S or N; or Z and Z are each independently selected from C, or N; or R.sub.5 and R.sub.5 are each independently selected from CH.sub.3, ##STR00264## or R.sub.6 and R.sub.6 are each independently selected from absent, H or methyl.
15-23. (canceled)
24. The compound of claim 1, the compound is of Formula III: ##STR00265## wherein, R.sub.1 and R.sub.10 are each independently selected from H, halogen, CN, or C.sub.1-8alkyl; R.sub.2 and R.sub.20 are each independently selected from H, or C.sub.1-8alkyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; or R.sub.10 and R.sub.20 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; Q and Q are each independently selected from absent, C(O) or C(R.sub.2).sub.2; Ring A and Ring A are independently a 5-6 membered aromatic heterocyclic ring, which is each unsubstituted or substituted with at least one substituent selected from C.sub.1-8alkyl, halogen, OH, or CN; Ring B and Ring B are independently a 5-7 membered heterocyclic ring, which is each unsubstituted or substituted with at least one substituent selected from C.sub.1-8alkyl, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pCONR.sub.30R.sub.40, (CH.sub.2).sub.pOH, (CH.sub.2).sub.p-heterocyclyl, C.sub.3-7cycloalkyl, C.sub.3-7heterocyclyl, or (CH.sub.2).sub.pNR.sub.30R.sub.40, wherein C.sub.1-8alkyl, (CH.sub.2).sub.pCOOH, (CH.sub.2).sub.pCONR.sub.30R.sub.40, (CH.sub.2).sub.pOH, (CH.sub.2).sub.p-heterocyclyl, C.sub.3-7cycloalkyl, C.sub.3-7heterocyclyl, or (CH.sub.2).sub.pNR.sub.30R.sub.40 is optionally substituted with C.sub.1-8alkyl halogen, OH, CN, COOH, or NR.sub.30R.sub.40; R.sub.30 and R.sub.40 are each independently selected from H, C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.3-7heterocyclyl; or R.sub.30 and R.sub.40 together with the atoms to which they are attached form a 5- to 6-member heterocyclic ring; R.sub.21 and R.sub.21 are each independently selected from halogen, CN, OH, COOH, or C.sub.1-8alkyl; p and s are each independently selected from 0, 1, 2 or 3.
25. The compound of claim 24, wherein R.sub.1 and R.sub.10 are independently selected from H, methyl, F or Cl; or R.sub.2 and R.sub.20 are independently selected from H or methyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5-membered heterocyclic ring; or R.sub.10 and R.sub.20 together with the atoms to which they are attached form a 5-membered heterocyclic ring; or R.sub.21 and R.sub.21 are each independently selected from CH.sub.3, F, Cl or CN; or s and p are each independently selected from 0 or 1; or ##STR00266## and are each independently selected from ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276##
26-31. (canceled)
32. The compound of claim 1, wherein Q and Q are the same, R.sub.1 and R.sub.10 are the same, R.sub.2 and R.sub.20 are the same, R.sub.3 and R.sub.4 are the same, R.sub.21 and R.sub.21 are the same.
33. The compound of claim 1, wherein the compound is 1) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 2) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 3) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxamide); 4) 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetic acid; 5) N-(2,2-dimethyl-3-(N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1-biphenyl]-3-yl)-N-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide; 6) 2-((8-((3-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)quinolin-3-yl)amino)ethan-1-ol; 7) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(((2-hydroxyethyl)amino)methyl)thiazole-2-carboxamide); 8) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide); 9) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-((S)-1-aminoethyl)-1,3,4-oxadiazole-2-carboxamide); 10) N-(2,2-dimethyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 11) N-(3-(6-aminobenzo[d]thiazole-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 12) N-(3-(5-amino-1H-benzo[d]imidazole-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 13) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-2-carboxamide); 14) N-(2,2-dimethyl-3-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-2-carboxamide; 15) N-(2,2-dimethyl-3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 16)(2S,2'S)-1,1-((1S,1'S)-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(1,3,4-oxadiazole-5,2-diyl))bis(ethane-1,1-diyl))bis(piperidine-2-carboxylic acid); 17)(2S,2'S)-1,1-((1S,1'S)-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(1,3,4-thiadiazole-5,2-diyl))bis(ethane-1,1-diyl))bis(piperidine-2-carboxylic acid); 18) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(aminomethyl)-1,3,4-oxadiazole-2-carboxamide); 19) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(1-aminoethyl)-1,3,4-oxadiazole-2-carboxamide); 20) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(aminomethyl)-1,3,4-thiadiazole-2-carboxamide); 21) N-(3-(6-amino-N-methylbenzo[d]thiazole-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)-N-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 22) N3-((6-aminobenzo[d]thiazol-2-yl)methyl)-N3,N3,2,2-tetramethyl-N3-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methyl)-[1,1-biphenyl]-3,3-diamine; 23) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(N-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 24) N3,N3,2,2-tetramethyl-N3,N3-bis((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methyl)-[1,1-biphenyl]-3,3-diamine; 25)2,2-dimethyl-N3,N3-bis((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methyl)-[1,1-biphenyl]-3,3-diamine; 26) N3,N3-bis((5-(1-aminocyclobutyl)-1,3,4-thiadiazol-2-yl)methyl)-2,2-dimethyl-[1,1-biphenyl]-3,3-diamine; 27) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(1-aminocyclobutyl)-1,3,4-thiadiazole-2-carboxamide); 28) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4-methyl-5-(pyrrolidin-1-ylmethyl)thiazole-2-carboxamide); 29) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(pyrrolidin-1-ylmethyl)thiazole-2-carboxamide); 30) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-carboxamide); 31) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-((S)-1-aminoethyl)-1,3,4-thiadiazole-2-carboxamide); 32) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide); 33)[4,4-biindoline]-1,1-diylbis((6,7-dihydro-4H-512-thiazolo[5,4-c]pyridin-2-yl)methanone); 34) N-(2,2-dimethyl-3-(N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1-biphenyl]-3-yl)-N-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide; 35) N-(2,2-dimethyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide; 36) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(7-(1-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide); 37) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(guanidinomethyl)-1,3,4-thiadiazole-2-carboxamide); 38) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(1-guanidinocyclobutyl)-1,3,4-thiadiazole-2-carboxamide); 39) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxamide); 40) N,N-(2,2-dicyano-[1,1-biphenyl]-3,3-diyl)bis(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide); 41) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(pyrrolidin-2-yl)-1,3,4-oxadiazole-2-carboxamide); 42) N-(2,2-dimethyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide; 43) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 44) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 45) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(1-hydroxypropan-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 46) 1,1-bis((6,7-dihydro-4H-512-thiazolo[5,4-c]pyridin-2-yl)methyl)-4,4-biindoline; 47)1,1-bis(1-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)ethyl)-4,4-biindoline; 48) N,N-(2-chloro-2-methylbiphenyl-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 49) N,N-(2-chloro-2-methylbiphenyl-3,3-diyl)bis(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 50) N-(2-chloro-2-methyl-3-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)biphenyl-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 51) N,N-(2,2-dimethylbiphenyl-3,3-diyl)bis(5-((2-hydroxyethylamino)methyl)-4-methylthiazole-2-carboxamide); 52) (2S,2'S)-1,1-(2,2-(2,2-dimethylbiphenyl-3,3-diyl)bis(azanediyl)bis(oxomethylene)bis(4-methylthiazole-5,2-diyl))bis(methylene)dipiperidine-2-carboxylic acid; 53) (2S,2'S)-2,2-(2,2-(2,2-dimethylbiphenyl-3,3-diyl)bis(azanediyl)bis(oxomethylene)bis(4-methylthiazole-5,2-diyl))bis(methylene)bis(azanediyl)bis(2-(tetrahydro-2H-pyran-4-yl)acetic acid); 54) (2S,2'S)-1,1-(2,2-(2-chloro-2-methylbiphenyl-3,3-diyl)bis(azanediyl)bis(oxomethylene)bis(4-methylthiazole-5,2-diyl))bis(methylene)dipiperidine-2-carboxylic acid; 55) (2S,2'S)-2,2-(2,2-(2-chloro-2-methylbiphenyl-3,3-diyl)bis(azanediyl)bis(oxomethylene)bis(4-methylthiazole-5,2-diyl))bis(methylene)bis(azanediyl)bis(2-(tetrahydro-2H-pyran-4-yl)acetic acid); 56)(2S,2'S)-1,1-(2,2-(4,4-biindoline-1,1-diylbis(oxomethylene))bis(4-methylthiazole-5,2-diyl))bis(methylene)dipiperidine-2-carboxylic acid; 57)(2S,2'S)-2,2-(2,2-(4,4-biindoline-1,1-diylbis(oxomethylene))bis(4-methylthiazole-5,2-diyl))bis(methylene)bis(azanediyl)bis(2-(tetrahydro-2H-pyran-4-yl)acetic acid); 58)(S)-1-((2-(3-(1-(5-(((S)-2-carboxypiperidin-1-yl)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)-2-methylphenylcarbamoyl)-4-methylthiazol-5-yl)methyl)piperidine-2-carboxylic acid; 59)(S)-2-((2-(3-(1-(5-(((S)-carboxy(tetrahydro-2H-pyran-4-yl)methylamino)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)-2-methylphenylcarbamoyl)-4-methylthiazol-5-yl)methylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid; 60)(S)-1-((2-(3-(1-(5-(((S)-2-carboxypiperidin-1-yl)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)-2-chlorophenylcarbamoyl)-4-methylthiazol-5-yl)methyl)piperidine-2-carboxylic acid; 61)(S)-2-((2-(3-(1-(5-(((S)-carboxy(tetrahydro-2H-pyran-4-yl)methylamino)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)-2-chlorophenylcarbamoyl)-4-methylthiazol-5-yl)methylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid; 62)(S)-1-((2-(3-(1-(5-(((S)-2-carboxypiperidin-1-yl)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)phenylcarbamoyl)-4-methylthiazol-5-yl)methyl)piperidine-2-carboxylic acid; 63)(S)-2-((2-(3-(1-(5-(((S)-carboxy(tetrahydro-2H-pyran-4-yl)methylamino)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)phenylcarbamoyl)-4-methylthiazol-5-yl)methylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid; 64) N,N-(2,2-dimethylbiphenyl-3,3-diyl)bis(3-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-carboxamide); 65)2,2-((((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetic acid; 66) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(5-(((2-hydroxyethyl)amino)methyl)thiazole-2-carboxamide); 67)(2S,2'S,4R,4R)-1,1-(((((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(thiazole-2,5-diyl))bis(methylene))bis(4-hydroxypyrrolidine-2-carboxylic acid); 68) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(5-(((2,2,2-trifluoroethyl)amino)methyl)thiazole-2-carboxamide); 69) ((2-((3-(5-((((S)-1-carboxy-2-methylpropyl)amino)methyl)thiazole-2-carboxamido)-2,2-dichloro-[1,1-biphenyl]-3-yl)carbamoyl)thiazol-5-yl)methyl)-L-valine; 70) [4,4-biindoline]-1,1-diylbis((5-(((2-hydroxyethyl)amino)methyl)thiazol-2-yl)methanone); 71) (2S,2'S)-2,2-((((((2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(thiazole-2,5-diyl))bis(methylene))bis(azanediyl))bis(2-(tetrahydro-2H-pyran-4-yl)acetic acid); 72) (S)-1-((2-((3-(1-(5-(((S)-2-carboxypiperidin-1-yl)methyl)thiazole-2-carbonyl)indolin-4-yl)-2-methylphenyl)carbamoyl)thiazol-5-yl)methyl)piperidine-2-carboxylic acid; 73) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(((2-hydroxyethyl)amino)methyl)-1,3,4-thiadiazole-2-carboxamide); 74) N,N-(2,2-dicyano-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 75) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(3,4-dichlorobenzyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 76) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(3-hydroxy-2,2-dimethylpropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 77) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 78)4,4-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))dibutyric acid; 79)2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))dipropionic acid; 80) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(cyanomethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 81) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(3-morpholinopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 82) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 83) [4,4-biindoline]-1,1-diylbis((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 84) [4,4-biindoline]-1,1-diylbis((5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 85) [4,4-biindoline]-1,1-diylbis((5-(2,2-difluoroethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 86)2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetamide; 87)[4,4-biindoline]-1,1-diylbis((5-(2-fluoroethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 88)[4,4-biindoline]-1,1-diylbis((5-(oxetan-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 89) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 90) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(5-(2-amino-2-oxoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 91) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 92) N,N-(2,2-dichloro-[1,1-biphenyl]-3,3-diyl)bis(5-(oxetan-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 93) N,N-(5,5-dichloro-2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 94) N,N-(2,2,4,4-tetramethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 95) N-(5-fluoro-2-methyl-3-(1-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)indolin-4-yl)phenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 96) N,N-(5,5-difluoro-2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide); 97) N-(2,2-dichloro-3-(5-(((2-hydroxyethyl)amino)methyl)thiazole-2-carboxamido)-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide; 98) N-(2,2-dichloro-3-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)thiazole-2-carboxamide; 99) (5-(((2-hydroxyethyl)amino)methyl)thiazol-2-yl)(1-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-[4,4-biindolin]-1-yl)methanone; 100) (1-(3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)-[4,4-biindolin]-1-yl)(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone; 101) N-(2-chloro-3-(1-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)indolin-4-yl)phenyl)-5-(((2-hydroxyethyl)amino)methyl)thiazole-2-carboxamide; 102) dimethyl 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetate; 103) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetic acid; 104) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetamide; 105) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(N-methylacetamide); 106) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(N,N-dimethylacetamide); 107) 2-(2-(1-(5-(2-amino-2-oxoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-[4,4-biindoline]-1-carbonyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)acetic acid; 108) 2-(2-(1-(5-(2-(methylamino)-2-oxoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-[4,4-biindoline]-1-carbonyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)acetic acid; 109) 2-(2-(1-(5-(2-(dimethylamino)-2-oxoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-[4,4-biindoline]-1-carbonyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)acetic acid; 110) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d]thiazole-2,9-diyl))diacetic acid; 111) 2-(2-(1-(9-(2-amino-2-oxoethyl)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d]thiazole-2-carbonyl)-[4,4-biindoline]-1-carbonyl)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d]thiazol-9-yl)acetic acid; 112) [4,4-biindoline]-1,1-diylbis((5-((dimethylamino)methyl)thiazol-2-yl)methanone); 113) [4,4-biindoline]-1,1-diylbis((5-((methylamino)methyl)thiazol-2-yl)methanone); 114) N-(3-(1-(5-((dimethylamino)methyl)-4-methylthiazole-2-carbonyl)indolin-4-yl)phenyl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)thiazole-2-carboxamide; 115) (5-((dimethylamino)methyl)-4-methylthiazol-2-yl)(1-(5-(((2-hydroxyethyl)(methyl)amino)methyl)thiazole-2-carbonyl)-[4,4-biindolin]-1-yl)methanone; 116) [4,4-biindoline]-1,1-diylbis((5-(((2-hydroxyethyl)(methyl)amino)methyl)thiazol-2-yl)methanone); 117) N,N-((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5 (4H)-diyl))bis(ethane-2,1-diyl))dimethanesulfonamide; 118) N,N-((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5 (4H)-diyl))bis(ethane-2,1-diyl))bis(N-methylmethanesulfonamide); 119) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[4,5-c]pyridine-2,5(4H)-diyl))diacetic acid; 120) [4,4-biindoline]-1,1-diylbis((5-(2-(2-hydroxyethoxy)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 121) ((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(propane-3,1-diyl))diboronic acid; 122) tetramethyl ((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(propane-3,1-diyl))diboronate; 123) dimethyl ((2-(1-(5-((dimethoxyphosphoryl)methyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-[4,4-biindoline]-1-carbonyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)phosphonate; 124) dimethyl (2-(2-(1-(5-(2-(dimethoxyphosphoryl)ethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-[4,4-biindoline]-1-carbonyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethyl)phosphonate; 125) [4,4-biindoline]-1,1-diylbis((5-((2H-tetrazol-5-yl)methyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone); 126) N,N-((([4,4-biindoline]-1,1-dicarbonyl)bis(5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[d]thiazole-2,9-diyl))bis(ethane-2,1-diyl))dimethanesulfonamide; 127) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(N-(methylsulfonyl)propanamide); 128) 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(2-methyl-N-(methylsulfonyl)propanamide); 129) 1,1-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(N-(methylsulfonyl)cyclopropane-1-carboxamide); 130) dimethyl ((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(ethane-2,1-diyl))dicarbamate; 131) dimethyl (((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(cyclopropane-1,1-diyl))bis(methylene))dicarbamate; 132) dimethyl (((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(methylene))bis(cyclopropane-1,1-diyl))dicarbamate; 133) 1,1-((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine2,5(4H)-diyl))bis(ethane-2,1-diyl))bis(thiourea); 134) 1,1-((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(ethane-2,1-diyl))diurea; 135) dimethyl 2,2-(((([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))diacetate; 136) [4,4-biindoline]-1,1-diylbis((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl) methanone); 137) (5-((12-azanyl)methyl)-1H-1,2,4-triazol-3-yl)(1-(5-(aminomethyl)-1H-1,2,4-triazole-3-carbonyl)-[4,4-biindolin]-1-yl)methanone; 138) 2,2-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))diacetic acid; 139) ((8-((3-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2-di methyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine; 140) 2,2-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))dipropionic acid; 141) (S)-4-(((8-((3-((3-(((carboxymethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid; 142) 2,2-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(3-methylbutanoic acid); 143) (3S,3'S)-4,4-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(3-hydroxybutanoic acid); 144) 2,2-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))diacetamide; 145) 2,2-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(N,N-dimethylacetamide); 146) 2-(((8-((2,2-dimethyl-3-((3-(((2,2,2-trifluoroethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)-N,N-dimethylacetamide; 147) 2-(((8-((2,2-dimethyl-3-((3-(((2-(methylamino)-2-oxoethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)-N-(2-hydroxyethyl)-N-methylacetamide; 148) ((8-((3-((3-(((2-(dimethylamino)-2-oxoethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine; 149) ((8-((3-((3-(azetidin-1-ylmethyl)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine; 150) 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azetidin-3-ol); 151) 2,2-dimethyl-N3,N3-bis(3-(morpholinomethyl)-1,7-naphthyridin-8-yl)-[1,1-biphenyl]-3,3-diamine; 152) N,N-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(ethane-2,1-diyl))diacetamide; 153) N3,N3-bis(3-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)-2,2-dimethyl-[1,1-biphenyl]-3,3-diamine; 154) (S)-((8-((3-((3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)glycine; 155) 1,1-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(piperidine-2-carboxylic acid); 156) 2-(((8-((2,2-dimethyl-3-((3-(((2,2,2-trifluoroethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)ethan-1-ol; 157) (1S,1'S)-1,1-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(methylene))bis(azanediyl))bis(cyclopropane-1,1-diyl))bis(ethan-1-ol); 158) dimethyl ((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))bis(m ethylene))bis(azanediyl))bis(ethane-2,1-diyl))dicarbamate; 159) 2-(2-(4-(3-((3-(((2-((methoxycarbonyl)amino)ethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)indoline-1-carbonyl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridin-5 (4H)-yl)acetic acid; 160) ((8-((3-(1-(5-(carboxymethyl)-3a,4,5,6,7,7a-hexahydrothiazolo[5,4-c]pyridine-2-carbonyl)indolin-4-yl)-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)glycine; 161) 3-(2-(4-(3-((3-(((carboxymethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)indoline-1-carbonyl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)propanoic acid; 162) 3-(2-(4-(3-((3-(((2-hydroxyethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-m ethylphenyl)indoline-1-carbonyl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)propanoic acid; 163) ((8-((3-(1-(5-(carboxymethyl)-3a,4,5,6,7,7a-hexahydrothiazolo[5,4-c]pyridine-2-carbonyl)indolin-4-yl)-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methyl)alanine; 164) 2-(2-(4-(3-((3-(((2-amino-2-oxoethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)indoline-1-carbonyl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)acetic acid; 165) 2-(2-(4-(3-((3-(((2-(dimethylamino)-2-oxoethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)indoline-1-carbonyl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)acetic acid; 166) 2-(2-(4-(3-((3-(((2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)indoline-1-carbonyl)-3a,6,7,7a-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)acetic acid; 167) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide); 168) dimethyl ((2S,2'S)-(([4,4-biindoline]-1,1-dicarbonyl)bis(7,8-dihydro-1,6-naphthyridine-2,6(5H)-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; 169) dimethyl ((2S,2'S)-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(7,8-dihydro-1,6-naphthyridine-2,6(5H)-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; 170) ethyl 2-(2-((2,2-dimethyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate; 171) 2-((3-(6,6-dimethyl-5,6,7,8-tetrahydro-614-1,6-naphthyridin-7-ylium-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)carbamoyl)-6,6-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-6-ium chloride; 172) di-tert-butyl 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(7,8-dihydro-1,6-naphthyridine-2,6(5H)-diyl))diacetate; 173) 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(7,8-dihydro-1,6-naphthyridine-2,6(5H)-diyl))diacetic acid; 174) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide); 175) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide); 176) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(6-(2-morpholinoethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide); 177) diethyl (2-(2-((3-(((6-(2-(diethoxyphosphoryl)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)methyl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl)phosphonate; 178) 2-(2-((2,2-dimethyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetic acid; 179) diethyl 2,2-((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(pyrazine-5,2-diyl))bis(ethane-1,1-diyl))bis(azanediyl))diacetate; 180) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(1-(methylamino)ethyl)pyrazine-2-carboxamide); 181) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-(1-((2-hydroxyethyl)amino)ethyl)pyrazine-2-carboxamide); 182) 6-acetyl-N-(2,2-dimethyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide; 183) N-(3-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide; 184) bis((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) 2,2-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate); 185) N-(2,2-dimethyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide; 186) N-(2,2-dimethyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamido)-[1,1-biphenyl]-3-yl)-6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide; 187) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(6-(2,2-difluoroethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide); 188) N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-carboxamide); 189) [4,4-biindoline]-1,1-diylbis((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)methanone); or 190) 2,2-((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(7,8-dihydropyrido[4,3-d]pyrimidine-2,6(5H)-diyl))diacetic acid.
34. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
35. A method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof.
36. A method of treating a disease associated with inhibition of PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof.
37. The method of claim 36, wherein the disease is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, renal cancer, prostate cancer, ovarian cancer or breast cancer.
38. A method of enhancing, stimulating and/or increasing the immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof.
39. Use of the compound of claim 1 for the preparation of a medicament.
40. The use of claim 39, wherein the medicament is used for the treatment or prevention of cancer.
41. The use of claim 40, wherein the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, renal cancer, prostate cancer, ovarian cancer or breast cancer; or the medicament is used as an inhibitor of PD-1/PD-L1 interaction.
42. (canceled)
43. Use of the pharmaceutical composition of claim 12 for the preparation of a medicament.
Description
EXAMPLES
[0323] Experimental procedures for compounds of the invention are provided below. Open Access Preparative LCMS Purification of some of the compounds prepared was performed on Waters mass directed fractionation systems. The basic equipment setup, protocols and control software for the operation of these systems have been described in detail in literature. See, e.g., Blom, Two-Pump At Column Dilution Configuration for Preparative LC-MS, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blom et al, Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification, J. Combi. Chem., 2003, 5, 670-83; and Blom et al., Preparative LC-MS Purification: Improved Compound Specific Method Optimization, J. Combi. Chem., 2004, 6, 874-883.
[0324] The following abbreviations have been used in the examples: [0325] Boc: t-butyloxycarbonyl; [0326] BSA: Bovine serum album; [0327] DCM: Dichloromethane; [0328] DIEA: Diisopropylethylamine; [0329] DMF: N, N-Dimethylformarmide; [0330] DMSO: Dimethyl sulfoxide; [0331] Et.sub.2O: Ethyl ether; [0332] EtOAc: Ethyl acetate; [0333] h or hrs: hour or hours; [0334] HATU:O-(7-azabenzotrizol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate; [0335] HTRF: Homogeneous Time Resolved Fluorescence [0336] MeCN: Methyl cyanide; [0337] min: minute; [0338] Pd(dppf)Cl.CH.sub.2Cl.sub.2:1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex [0339] t or r.t.: room temperature; [0340] TFA: trifluoroacetic acid; [0341] THF: Tetrahydrofuran.
Example 1 Synthesis of Compound 1
N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide)
[0342] ##STR00031##
Step 1: Preparation of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (M1)
[0343] ##STR00032##
[0344] A mixture of 3-bromo-2-methylaniline (4.000 g), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (6.550 g) and potassium acetate (4.220 g) in 1,4-dioxane (44.8 mL) and DMSO (9.0 mL) was purged with nitrogen for 10 min. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium DCM adduct (0.527 g) was added, the mixture was purged for another 5 min then was heated at reflux for 2 h. The mixture was cooled and filtered through Celite. The solids were washed with EtOAc, and the combined filtrates were washed with water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a gradient from 20:1 to 85:15). 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (compound M) as a light yellow waxy solid (4.400 g, 88%).
[0345] .sup.1H NMR (400 MHz, chloroform-d) 7.21 (1H, dd, J=7.3, 1.0 Hz), 7.02 (1H, t, J=7.7 Hz), 6.75 (1H, dd, J=7.8, 1.0 Hz), 3.54 (2H, br. s.), 2.37 (3H, s), 1.34 (12H, s). Mass spectrum m/z 233.3, 234.3, 235.3 (M+H)+.
Step 2: Preparation of 2,2-dimethyl-[1,1-biphenyl]-3,3-diamine (M2)
[0346] ##STR00033##
[0347] A mixture of 3-bromo-2-methylaniline (1.000 g), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.270 g) and potassium acetate (850 mg) in 1,4-dioxane (15 mL) and water (2.0 mL) was purged with nitrogen for 10 min. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium DCM adduct (20 mg) was added, the mixture was purged for another 5 min then was heated at reflux for 2.7 h. The mixture was cooled and filtered through Celite. The solids were washed with EtOAc, and the combined filtrates were washed with water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a gradient from 10:1 to 85:15). 2,2-dimethyl-[1,1-biphenyl]-3,3-diamine (compound M2) as a light yellow waxy solid (900 mg, 79%).
Step 3: Preparation of di-tert-butyl 2,2-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) (M3)
[0348] ##STR00034##
[0349] To a solution of 2,2-dimethyl-[1,1-biphenyl]-3,3-diamine (100 mg) in dry dicloromethane was added HATU (300 mg) and DIEA (232 mg), A solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (282 mg) in dicloromethane was added slowly and stirred at 40 C. for 4 hrs and then at room temperature overnight. Reaction mass was then concentrated and purified by column chromatography to afford the di-tert-butyl 2,2-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(carbonyl))bis(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) (compound M3) as a light yellow solid (250 mg).
Step 4: Preparation of N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide) (Compound 1)
[0350] ##STR00035##
[0351] To a solution of 2,2-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis (carbonyl))-bis(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) (200 mg) in dicloromethane was added TFA (5 mL), and stirred at 40 C. for hrs. Reaction mass was then concentrated and washed by n-hexane to afford the N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide) (compound 1) as a light yellow solid (125 mg).
Example 2 Synthesis of Compound 2
[0352] ##STR00036##
[0353] Prepare the compound M2 as described for Example 1.
[0354] Then, to a solution of 2,2-dimethyl-[1,1-biphenyl]-3,3-diamine (100 mg, 0.45 mmol) in dry dichloromethane was added HATU (300 mg) and DIEA (232 mg). A solution of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (232 mg) in dicloromethane was added slowly and stirred at 40 C. for 4 hrs and then at room temperature overnight. Reaction mass was then concentrated and purified by column chromatography to afford the N,N-(2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide) (Compound 2) as a light yellow solid (180 mg).
Example 3 Synthesis of Compound 3
Step 1: Preparation of tert-butyl (S)-2-(2-(2-ethoxy-2-oxoacetyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate (M3)
[0355] ##STR00037##
[0356] To a solution of Boc-L-proline (2.150 g) and ethyl 2-hydrazinyl-2-oxoacetate (1.980 g) in dry DMF was added DIPEA (2.600 g). HATU (5.700 g) was added in small portions at room temperature. The mixture was stirred for 2 h at the same temperature. DMF was evaporated under reduced pressure. The residue was purified directly by RP-column (mobile phase: MeCN:water=30:70) to afford tert-butyl (S)-2-(2-(2-ethoxy-2-oxoacetyl)hydrazine-2-carbonyl)pyrrolidine-1-carboxylate as a white solid (2.420 g).
Step 2: Preparation of ethyl (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxylate (M33)
[0357] ##STR00038##
[0358] To a solution of tert-butyl (S)-2-(2-(2-ethoxy-2-oxoacetyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate (2.310 g) in THF was added Lawesson reagent (3.400 g). The resulting mixture was heated to reflux for 2 h. The reaction was quenched by saturate Na.sub.2CO.sub.3 solution and extracted by EtOAc for 3 times. The combined organic phase was washed with water and brine then dried over Na.sub.2SO.sub.4. The resulting solution was concentrated and purified by silicagel (eluting with hexane-EtOAc using a gradient from 10:1 to 7:1) to afford ethyl (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxylate as a light yellow solid (1.610 g).
Step 3: Preparation of (S)-5(1-((tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxylic acid (M333)
[0359] ##STR00039##
[0360] To a solution of ethyl (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxylate (1.610 g) in THF/water=1:1 (20 mL) was added LiOH (0.860 g). The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched by 2M HCl and the PH value was adjusted to 4-5. Water and THF was evaporated out. The resulted solid was purified by RP-column (mobile phase: MeCN:water using a gradient from 10:90 to 30:70) to afford (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxylic acid as a white solid (0.900 g).
Step 4: Preparation of Compound 3
[0361] ##STR00040##
[0362] Prepare the compound M2 as described for Example 1.
[0363] Then, to a solution of 2,2-dimethyl-[,1-biphenyl]-3,3-diamine (100 mg, 0.45 mmol) in dry dichloromethane was added HATU (300 mg) and DIEA (232 mg), A solution of (S)-5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxylic acid (312 mg) in dicloromethane was added slowly and stirred at 40 C. for 4 hrs and then at room temperature overnight. Reaction mass was then concentrated and purified by column chromatography to afford the Boc-protected intermediate (180 mg).
[0364] The above Boc-protected intermediate was dissolved in DCM 5 mL. TFA (1 mL) was added slowly at room temperature. The mixture could be stirred at room temperature for 2 h. The reaction was quenched by 10% Na.sub.2CO.sub.3 solution and extracted by DCM for 3 times. The combined organic layers was dried over Na.sub.2SO.sub.4. Na.sub.2SO.sub.4 was filtered out. The resulting solution was concentrated under reduced pressure to afford N,N-(2,2-dimethyl-[,1-biphenyl]-3,3-diyl)bis(5-((S)-pyrrolidin-2-yl)-1,3,4-thiadiazole-2-carboxamide) (compound 3) as a white solid (89 mg).
[0365] Prepare the following examples (shown in Table 1) essentially as described for Example 1, 2, or 3 using the corresponding starting materials.
TABLE-US-00001 TABLE 1 Physical Data EX (MS) No. Chemical Name Structure (M + H).sup.+ 1 N,N-(2,2-dimethyl-[1,1- biphenyl]- 3,3-diyl)bis(4,5,6,7- tetrahydrothiazolo[5,4- c]pyridine-2- carboxamide)
Example 33 Synthesis of Compound 33
[0366] ##STR00073##
Step 1: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (33-1)
[0367] A mixture of 4-bromoindoline (1.000 g.), 4,4,4,4, 5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (2.550 g) and potassium acetate (2.220 g) in 1,4-dioxane (14.8 mL) and DMSO (1.0 mL) was purged with nitrogen for 10 min. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium DCM adduct (0.127 g) was added, the mixture was purged for another 5 min then was heated at reflux for 2 h. The mixture was cooled and filtered through Celite. The solids were washed with EtOAc, and the combined filtrates were washed with water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a gradient from 20:1 to 85:15). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (compound 2-1) as a light yellow waxy solid (1.400 g).
Step 2: Preparation of 4,4-biindoline (33-2)
[0368] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (1.000 g), 4-bromoindoline (0.700 g) and potassium acetate (350 mg) in 1,4-dioxane (15 mL) and water (2.0 mL) was purged with nitrogen for 10 min. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium DCM (20 mg) was added, the mixture was purged for another 5 min then was heated at reflux for 2.7 h. The mixture was cooled and filtered through Celite. The solids were washed with EtOAc, and the combined filtrates were washed with water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a gradient from 10:1 to 85:15). 4,4-biindoline (700 mg).
Step 3: Preparation of 2-4 di-tert-butyl 2,2-([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) (33-3)
[0369] To a solution of 4,4-biindoline (100 mg) in dry dicloromethane was added HATU (300 mg) and DTEA (240 mg), A solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (293 mg) in dicloromethane was added slowly and stirred at 40 C. for 4 hrs and then at room temperature overnight. Reaction mass was then concentrated and purified by column chromatography to afford the di-tert-butyl 2,2-([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) (compound 33-3) as a light yellow solid (130 mg).
Step 4: Preparation of [4,4-biindoline]-1,1-diylbis((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone) (33)
[0370] To a solution of di-tert-butyl 2,2-([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) (compound 33-3) (200 mg) in dicloromethane was added TFA (5 mL), and stirred at 40 C. for 5 hrs. Reaction mass was then concentrated and washed by n-hexane to afford the [4,4-biindoline]-1,1-diylbis((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methanone) (compound 33) as a light yellow solid (125 mg).
Example 34 Synthesis of Compound 34
[0371] ##STR00074##
Step 1: Preparation of tert-butyl 2-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylat (34-2)
[0372] In a 100 ml round bottom flask, was placed compound 1 (197 mg) and 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (200 mg), HATU (322 mg), DMF (5 mL), DIPEA (274 mg), the reaction was stirred for 2 hrs at r.t.
[0373] To the above mixture, H.sub.2O (10 mL) was added, EA (15 mL) extract for 3 times, the organic phase was combined, washed with saturated NaCl(aq), dried with Na.sub.2SO.sub.4, concentrated, purified with flash chromatographic column (hexane/EA, EA=0-15%), 287 mg product was obtained with a little yellow solid.
Step 2: Preparation of tert-butyl 2-((3-bromo-2-methylphenyl)carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (34-4)
[0374] In a 100 mL round bottom flask, was placed compound 34-3 (153 mg) and 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (200 mg), HATU (341 mg), DIPEA (290 mg), DMF (5 mL), stirred overnight at 40 C. Concentrated, the result mixture was purified with a flash chromatographic column (hexane/EA, EA=15%), 462 mg product was obtained with a yellow solid.
Step 3: Preparation of tert-butyl 2-((3-(7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (34-5)
[0375] In a 100 mL round bottom flask was placed 2 (200 mg) and 4 (134 mg), Pd(dppf)Cl.CH.sub.2Cl.sub.2 (25 mg), K.sub.2CO.sub.3 (85 mg), dioxane (10 mL), H.sub.2O (1 mL), with a N.sub.2 atmosphere, stirred for 2 hrs at 80 C. Cooled down, concentrated, purified with flash chromatographic column (DCM/MeOH, MeOH=0-5%), 57 mg product was obtained with a little yellow solid.
Step 4: Preparation of tert-butyl 2-((3-(7-(tert-butoxycarbonyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-2,2-dimethyl-[1,1-biphenyl]-3-yl)(methyl)carbamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (34-6)
[0376] In a 100 mL round bottom flash was placed 5 (50 mg), THF (2 mL), was added NaH (8 mg) at 0 C., stirred for 30 min, then CH.sub.3I (24 mg) was added, stirred for another 30 min at r.t. Quenced with H.sub.2O (5 mL), extracted with EA (15 mL*3), the organic phase was combined, dried with Na.sub.2SO.sub.4, concentrated, purified with a flash chromatographic column (DCM/MeOH, MeOH=0-10%), 80 mg product was obtained with a yellow solid.
Step 5: N-(2,2-dimethyl-3-(N-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamido)-[1,1-biphenyl]-3-yl)-N-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (34)
[0377] In a 50 mL round bottom flask was placed 6 (80 mg), TFA (3 mL) and DCM (9 mL), stirred for 1 h at r.t. Concentrated, diluted with H.sub.2O (0 mL), adjusted pH=7-8 with NaHCO.sub.3(aq), extracted with DCM (15 mL*3), the organic phase was combined and washed with saturated NaCl(aq), dried with Na.sub.2SO.sub.4, concentrated, the result product was washed with Et.sub.2O (10 mL), 18 mg pure product was obtained with a red solid.
[0378] In some Examples, some of examples are used as a starting material, which undergoes the corresponding reaction with other material, such as methyl 2-bromoacetate. For example, preparing the following Example 102 and 103 using Example 33 as a starting material, which is describing for Example 102 and 103.
Example 102 and 103 Synthesis of Compound 102 and 103
[0379] ##STR00075##
Step 1: dimethyl 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetate (102)
[0380] To a solution of [4,4-biindoline]-1,1-diylbis((6,7-dihydro-4H-512-thiazolo[5,4-c]pyridin-2-yl)methanone) (50 mg) in DMF (2 mL) was added K.sub.2CO.sub.3 (60 mg), methyl 2-chloroacetate (50 mg), potassium iodide (5 mg), and stirred at 80 C. for 10 hrs. Reaction was add H.sub.2O (20 mL) and extracted by EtOAc for 3 times. The combined organic phase was washed with water and brine (30 mL*5) then dried over Na.sub.2SO.sub.4. The resulting solution was concentrated, the resulted solid was purified by Column chromatography to get the dimethyl 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetate (compound 102) as a light yellow solid (35 mg).
Step 2: 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetic acid (103)
[0381] To a solution of dimethyl 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetate (compound 2-6) (30 mg) in THF:CH.sub.3OH=1:1 (15 mL) was added LiOH (10 mg) and H.sub.2O (2 mL), and stirred at 25 C. for 2 hrs. The reaction was quenched by 1M HCl and the PH value was adjusted to 4-5. Water and THF was evaporated out. The resulted solid was purified by RP-column (mobile phase: MeCN:water using a gradient from 10:90 to 30:70) to afford 2,2-(([4,4-biindoline]-1,1-dicarbonyl)bis(6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-diyl))diacetic acid (compound 110)(20 mg).
[0382] Prepare the following examples (shown in Table 2) essentially as described for Example 1, 33, 34, 102 or 103 using the corresponding starting materials. For example, prepare the following Example 44 (shown in Table 2) essentially as described for Example 1 using
##STR00076##
instead of
##STR00077##
and other starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
TABLE-US-00002 TABLE 2 Physical Data (MS) NO. Chemical Name Structure (M + H).sup.+ 33 [4,4-biindoline]-1,1-diylbis((6,7- dihydro-4H-5l2-thiazolo[5,4-c]pyridin- 2-yl)methanone)
[0383] The present invention also exemplarily provides a method of preparing other compounds, for example, compound 6.
Example 6 Synthesis of Compound 6
Step 1: Preparing of 8-chloro-3-vinyl-1,7-naphthyridine
[0384] ##STR00183##
[0385] To a solution of 3-bromo-8-chloro-1,7-naphthyridine (2.43 g) in toluene (30 mL), EtOH (10 mL), and 10% Na.sub.2CO.sub.3 aq. (10 mL) Pd(dppf)Cl.sub.2.DCM (420 mg) was added. 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.1 g) was added dropwise under N.sub.2 protection. The mixture was allowed to stir at 100 C. for 16 h. The reaction was quenched by H.sub.2O (50 mL) and extracted by EtOAc for 3 times. Organic layer was combined and washed with brine. The resulting solution was concentrated and purified by silicagel (eluting with hexane-EtOAc using a gradient from 8:1 to 5:1) to afford 8-chloro-3-vinyl-1,7-naphthyridine (1.1 g) as a brown solid.
Step 2: Preparing of (8-chloro-1,7-naphthyridin-3-yl)methanol
[0386] ##STR00184##
[0387] To a solution of 8-chloro-3-vinyl-1,7-naphthyridine (380 mg) in 1,4-dioxane (20 mL) and water (20 mL) Os.sub.4 (0.9 mL, 4% in water) was added and stirred for 30 min at room temperature. NaIO.sub.4 (4.0 g) was added in small portions at the same temperature. After stirring for 3 h, the reaction was quenched with saturated Na.sub.2S.sub.2O.sub.3 solution. The mixture was extracted with DCM (40 mL) for 3 times. Organic layer was combined and dried over Na.sub.2SO.sub.4. The resulting solution was concentrated to afford 8-chloro-1,7-naphthyridine-3-carbaldehyde as a crude product which can be used directly in next step.
[0388] The above aldehyde was dissolved in 20 mL MeOH. NaBH.sub.4 (400 mg) was added in one portion. The resulting mixture was stirred for 2 h at room temperature then quenched by water (30 mL). The mixture was extracted with DCM (20 mL) for 3 times and the organic phase was dried over Na.sub.2SO.sub.4. The resulting solution was concentrated and purified by silicagel (eluting with hexane-EtOAc using a gradient from 4:1 to 2:1) to afford (8-chloro-1,7-naphthyridin-3-yl)methanol (50 mg) as a brown solid.
Step 3: Preparing of (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol
[0389] ##STR00185##
[0390] To a microwave reaction vial were added 3-bromo-2-methylaniline (370 mg), (8-chloro-1,7-naphthyridin-3-yl)methanol (98 mg), LiHMDS (1.0 M in THF, 4.0 mL) and THF (3.5 mL). The vial was capped and the reaction mixture was heated at 60 C. for 4 h. It was diluted with 20 mL of water and then extracted with DCM (20 mL*2). The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified directly by RP-column (mobile phase: MeCN:water=30:70) to afford (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (73 mg) as a black solid.
Step 4: Preparing of (8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1,7-naphthyridin-3-yl)methanol
[0391] ##STR00186##
[0392] To a microwave reaction vial were added (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (68 mg), Bis(pinacolato)diboron (120 mg), Pd(dppf)Cl.sub.2.DCM (10 mg), KOAc (102 mg), and 1,4-dioxane (3.0 mL). The vial was capped and the reaction mixture was heated at 100 C. for 2 h. It was diluted with 20 mL of water and then extracted with DCM (20 mL*2). The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified silicagel (eluting with hexane-EtOAc using a gradient from 4:1 to 2:1) to afford (8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1,7-naphthyridin-3-yl)methanol (50 mg) as a brown solid.
Step 5: Preparing of (((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))dimethanol
[0393] ##STR00187##
[0394] To a solution of (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (50 mg), (8-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1,7-naphthyridin-3-yl)methanol (50 mg) in toluene (3 mL), EtOH (1 mL), and 10% Na.sub.2CO.sub.3 aq. (1 mL), Pd(dppf)Cl.sub.2.DCM (10 mg) was added under N.sub.2 protection. The mixture was allowed to stir at 100 C. for 16 h. The reaction was quenched by H.sub.2O (20 mL) and extracted by DCM for 3 times. Organic layer was combined and washed with brine. The resulting solution was concentrated and purified by silicagel (eluting with DCM-MeOH using a gradient from 15:1 to 8:1) to afford (((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))dimethanol (40 mg) as a brown semi-solid.
Step 6: Preparing of 2-(((8-(3-((3-(2-hydroxyethyl)amino)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)ethan-1-ol
[0395] ##STR00188##
[0396] To a solution of (((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(azanediyl))bis(1,7-naphthyridine-8,3-diyl))dimethanol, TEA (100 mg) in DCM (5.0 mL). MsCl (80 mg) was added dropwise at 0 C. The reaction was allowed to stir at room temperature for 90 min. The resulting mixture was concentrated under vacuo and redissolved by THF (3 mL). Ethanolamine was added then the reaction was continued to stir at room temperature for another 2 h unstill above methanesulfonate was consumed. The residue was concentrated and purified directly by RP-column (mobile phase: MeCN:water=10:90 with 0.1% HCl) to afford 2-(((8-((3-((3-((2-hydroxyethyl)amino)-1,7-naphthyridin-8-yl)amino)-2,2-dimethyl-[1,1-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)amino)ethan-1-ol (17 mg) as an off-white solid.
Example 167 Synthesis of Compound 167
[0397] ##STR00189##
[0398] SM1(1.00 g), SM5(1.79 g), HATU (4.1 g), DMF (15 mL), and DIPEA (2.08 g) was placed in a 100 mL round bottom flask and stirred for 2 h at r.t. Monitored by TLC till the SM1 consumed. Ice water (25 mL) was added, and extracted with EA (20 mL*3), the organic phase was washed by saturated NaCl(aq) (20 mL*3) and dried with anhydrous Na.sub.2SO.sub.4, and concentrated. Purified with silica column (hexane/EA=5/1) to give the desired product with off-white solid.
[0399] The compound 167 was synthesized with M167 according to the method described above.
[0400] Prepare the following examples (shown in Table 3) essentially as described for Example 6 using the corresponding starting materials.
TABLE-US-00003 TABLE 3 Physical Data (MS) NO. Chemical Name Structure (M + H)+ 138 2,2-(((((2,2-dimethyl-[1,1-biphenyl]- 3,3-diyl)bis(azanediyl))bis(1,7- naphthyridine-8,3- diyl))bis(methylene))bis(azanediyl)) diacetic acid
Example 191 Synthesis of Comparative Example 1
N-(2-methyl-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
[0401] ##STR00243##
Step 1: Preparation of 2-methyl-[1,1-biphenyl]-3-amine (M11)
[0402] ##STR00244##
[0403] A mixture of 3-bromo-2-methylaniline (1.000 g), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (1.320 g) and Potassium carbonate (1.480 g) in 1,4-dioxane (14.8 mL) and water (1.0 mL) was purged with nitrogen for 10 min. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium DCM adduct (27 mg) was added, the mixture was purged for another 5 min then was heated at reflux for 1.5 hrs. The mixture was cooled and filtered through Celite. The solids were washed with EtOAc, and the combined filtrates were washed with water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a gradient from 20:1 to 25:1). 2-methyl-[1,1-biphenyl]-3-amine (compound M1) as a light yellow waxy solid (950 mg).
Step 2: Preparation of tert-butyl 2-((2-methyl-[1,1-biphenyl]-3-yl)carbamoyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (M22)
[0404] ##STR00245##
[0405] To a solution of 2-methyl-[1,1-biphenyl]-3-amine (850 mg) in dry dicloromethane was added HATU (2.180 g) and DIEA (1.750 g). A solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid (1.450 g) in dicloromethane was added slowly and stirred at 40 C. for 4 hrs and then at room temperature overnight. Reaction mass was then concentrated and purified by column chromatography to afford the tert-butyl 2-((2-methyl-[1,1-biphenyl]-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (compound M22) as a light yellow solid (1.450 g).
Step 3: Preparation of N-(2-methyl-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Comparative Example 1)
[0406] ##STR00246##
[0407] To a solution of tert-butyl 2-((2-methyl-[1,1-biphenyl]-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (800 mg) in dicloromethane was added TFA (5 mL), and stirred at 40 C. for hrs. Reaction mass was then concentrated and washed by n-hexane to afford the N-(2-methyl-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Comparative Example 1) as a light yellow solid (540 mg).
Example 192 Synthesis of Comparative Example 2
N-(2-methyl-[1,1-biphenyl]-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
[0408] ##STR00247##
[0409] Prepare the above comparative example essentially as described for Example 34 using the corresponding intermediates.
[0410] Resolved Fluorescence (HTRF) Binding Assay
[0411] The assays were conducted in a standard black 384-well polystyrene plate with a final volume of 20 L. Inhibitors were first serially diluted in DMSO and then added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assays were carried out at 25 C. in the PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from AcroBiosy stems (PD1-H5229). Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay buffer and 10 L was added to the plate well. Plates were centrifuged and proteins were preincubated with inhibitors for 40 min. The incubation was followed by the addition of 0 L of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to SureLight-Allophycocyanin (APC, PerkinElmer-AD0059H). After centrifugation, the plate was incubated at 25 C. for 60 min. Before reading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Final concentrations in the assay were 3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG and 20 nM anti-His-Allophycocyanin. IC.sub.50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
[0412] Compounds of the present disclosure, as exemplified in the Examples, showed IC.sub.50 values in the following ranges: * stands for IC.sub.50-25 nM; ** stands for 25 nM<IC.sub.50100 nM; *** stands for 100 nM<IC.sub.50200 nM; **** stands for IC.sub.50>200 nM.
[0413] Data obtained for the Example compounds using the PD-1/PD-L1 homogenous time-resolved fluorescence (HTRF) binding assay described in Example A is provided in Table 4.
TABLE-US-00004 TABLE 4 EX No. IC.sub.50 EX No. IC.sub.50 Com. EX. No. 1 212 Com. EX. No. 2 130.7 1 0.48 84 ** 2 0.74 85 ** 3 * 86 * 4 * 87 * 5 *** 88 * 6 * 89 * 7 * 90 * 8 * 91 * 9 * 92 * 10 * 93 * 11 *** 94 * 12 ** 95 * 13 ** 96 * 14 * 97 * 15 * 98 * 16 * 99 * 17 * 100 * 18 ** 101 * 19 ** 102 * 20 * 103 0.37 21 *** 104 * 22 **** 105 * 23 *** 106 * 24 *** 107 * 25 ** 108 * 26 ** 109 * 27 3.13 110 * 28 * 111 * 29 * 112 * 30 * 113 * 31 * 114 * 32 18.1 115 * 33 0.21 116 * 34 * 117 * 35 * 118 * 36 * 119 * 37 * 120 * 38 * 121 * 39 * 122 * 40 * 123 * 41 * 124 * 42 * 125 * 43 * 126 * 44 0.62 127 * 45 * 128 ** 46 * 129 ** 47 * 130 * 48 * 131 ** 49 * 132 ** 50 * 133 * 51 * 134 * 52 * 135 * 53 * 136 *** 54 * 137 *** 55 * 138 * 56 * 139 * 57 * 140 * 58 * 141 * 59 * 142 * 60 * 143 * 61 * 144 * 62 * 145 * 63 * 146 * 64 * 147 * 65 * 148 * 66 * 149 * 67 * 150 * 68 * 151 * 69 * 152 * 70 * 153 * 71 * 154 * 72 * 155 * 73 * 156 * 74 * 157 * 75 *** 158 * 76 * 159 * 77 ** 160 * 78 * 161 * 79 * 162 * 80 * 163 * 81 * 164 * 82 * 165 * 83 * 166 * 167 * 179 ** 168 * 180 * 169 * 181 * 170 * 182 * 171 * 183 * 172 *** 184 **** 173 * 185 * 174 * 186 * 175 * 187 ** 176 ** 188 *