Diphenyl-like Compound, Intermediate Thereof, Preparation Method Therefor, Pharmaceutical Composition Thereof And Uses Thereof

Abstract

The present invention provides a diphenyl-like compound, and intermediate thereof, a preparation method therefor, a pharmaceutical composition thereof and the uses thereof. According to the invention, the diphenyl-like compound has a significant inhibitory effect on PD-1 and/or PD-L1, and can effectively alleviate or treat related diseases such as cancer.

##STR00001##

Claims

1. A diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof: ##STR00134## wherein, ring A and ring B are independently aromatic ring or heteroaromatic ring; L.sup.1 is a chemical bond, alkynyl, —C(R.sup.5)═C(R.sup.6)— or —CR.sup.7R.sup.8—CR.sup.9R.sup.10—, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L.sup.2 is a chemical bond, alkynyl, —C(R.sup.5)═C(R.sup.6)— or —CR.sup.7R.sup.8—CR.sup.9R.sup.10—, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or absent; R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen, deuterium, halogen, cyano, or substituted or unsubstituted alkyl respectively; R.sup.1 and R.sup.2 are independently deuterium, halogen, cyano, or substituted or unsubstituted alkyl; each R.sup.3 and each R.sup.4 are independently hydrogen, deuterium, hydroxyl, —SR.sup.11, —NR.sup.12R.sup.13, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —CONH.sub.2, —COR.sup.14, —COOR.sup.15 or —OCOR.sup.16; R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl or —COR.sup.a, R.sup.a is hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy; R.sup.14, R.sup.15 and R.sup.16 are independently hydrogen, C.sub.1-C.sub.4 alkyl or substituted C.sub.1-C.sub.4 alkyl; among R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16, the substituted in the substituted C.sub.1-C.sub.4 alkyl refers to being substituted with one or more of C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl and substituted C.sub.1-C.sub.10 heteroaryl; substituents in the substituted cycloalkyl, the substituted heterocycloalkyl, the substituted aryl, the substituted heteroaryl in L.sup.1 and L.sup.2, the substituted alkyl in R.sup.1 and R.sup.2, the substituted alkyl or the substituted alkoxy in each R.sup.3 and each R.sup.4 are selected from one or more of halogen, cyano, C.sub.1-C.sub.4 alkyl, hydroxyl, ##STR00135## C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 carboxyl, C.sub.1-C.sub.4 ester group and C.sub.1-C.sub.4 amido; in ##STR00136## R.sup.17 and R.sup.18 are independently hydrogen, substituted or unsubstituted C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.6-C.sub.14 aryl, substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl, or substituted or unsubstituted C.sub.1-C.sub.4 alkoxy; or R.sup.17, R.sup.18 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5 to 7-membered heterocycle; in the heterocycle, heteroatom is N, or N and O, the number of heteroatom is 1 to 4; each R.sup.17 and each R.sup.18 are identical or different; substituents in the substituted C.sub.1-C.sub.4 alkyl, the substituted C.sub.6-C.sub.14 aryl, the substituted C.sub.3-C.sub.6 cycloalkyl, the substituted C.sub.1-C.sub.4 alkoxy and the substituted 5 to 7-membered heterocycle in R.sup.17 and R.sup.18 are selected from one or more of halogen, cyano, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl, hydroxyl, ##STR00137## C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 carboxyl, C.sub.1-C.sub.4 ester group and C.sub.1-C.sub.4 amido; in R.sup.17 and R.sup.18, when substituents in the substituted C.sub.1-C.sub.4 alkyl, the substituted C.sub.6-C.sub.14 aryl, the substituted C.sub.3-C.sub.6 cycloalkyl, the substituted C.sub.1-C.sub.4 alkoxy and the substituted 5 to 7-membered heterocycle are substituted C.sub.1-C.sub.4 alkyl, in the substituents, substituents in the substituted C.sub.1-C.sub.4 alkyl are selected from one or more of halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl, hydroxyl, ##STR00138## C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 carboxyl, C.sub.1-C.sub.4 ester group and C.sub.1-C.sub.4 amido; in ##STR00139## R.sup.a1 and R.sup.b1 are independently hydrogen, C.sub.1-C.sub.4 alkyl or ##STR00140## R.sup.a11 is C.sub.1-C.sub.4 alkyl; all the above C.sub.1-C.sub.10 heteroaryl refer to C.sub.1-C.sub.10 heteroaryl in which heteroatom is selected from N, O and S and the number of heteroatom is 1 to 4; substituents in all the above substituted C.sub.6-C.sub.14 aryl and substituted C.sub.1-C.sub.10 heteroaryl are selected from one or more of cyano, halogen, hydroxyl, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkoxy; when substituents are more than one, the substituents are identical or different; m is 1, 2 or 3; n is 1, 2 or 3.

2. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein the aromatic ring is C.sub.6-C.sub.20 aromatic ring, preferably C.sub.6-C.sub.14 aromatic ring, more preferably C.sub.6-C.sub.10 aromatic ring, most preferably benzene, naphthalene, tetrahydronaphthalene, 2,3-dihydroindene, diphenyl, phenanthrene, anthracene or acenaphthene; or, the heteroaromatic ring refers to C.sub.1-C.sub.10 heteroaromatic ring in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, preferably C.sub.1-C.sub.8 heteroaromatic ring in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, more preferably C.sub.1-C.sub.6 heteroaromatic ring in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, most preferably, acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoindoline, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole or dihydroquinoline; or, the cycloalkyl is C.sub.3-C.sub.20 cycloalkyl, preferably C.sub.3-C.sub.10 cycloalkyl, more preferably C.sub.3-C.sub.6 cycloalkyl, most preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl or cyclohexenyl; or, the heterocycloalkyl refers to C.sub.2-C.sub.10 non-aromatic ring in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, preferably C.sub.2-C.sub.8 heterocycloalkyl in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, further preferably C.sub.2-C.sub.6 heterocycloalkyl in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, most preferably, tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuryl, dihydroimidazolyl, indolinyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuryl, tetrahydrothiophenyl or N-oxides thereof; or, the aryl is C.sub.6-C.sub.20 aryl, preferably C.sub.6-C.sub.14 aryl, more preferably C.sub.6-C.sub.10 aryl, most preferably phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, xenyl, phenanthryl, anthryl or acenaphthyl, or, the heteroaryl refers to C.sub.1-C.sub.10 heteroaryl in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, further preferably C.sub.1-C.sub.8 heteroaryl in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, more preferably C.sub.1-C.sub.6 heteroaryl in which heteroatom is selected from O, N and S and the number of heteroatom is 1, 2, 3 or 4, most preferably, benzimidazolyl, benzofuryl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furyl, imidazolyl, indolinyl, indolyl, indazolyl, isobenzofuryl, isoindolinyl, isoquinolyl, isothiazolyl, isooxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiophenyl or triazolyl; or, the halogen is fluorine, chlorine, bromine or iodine; or, the alkyl refers to branched and linear saturated aliphatic hydrocarbonyl comprising 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, most preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl and various isomers thereof; or, the alkoxy represents cyclic or non-cyclic alkyl linked via oxygen bridge with the recited carbon atom number, preferably C.sub.1-C.sub.4 alkoxy, more preferably methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy; or, or the 5 to 7-membered heterocycle refers to 5 to 7-membered heterocycle in which heteroatom is selected from O, N and S, the number of heteroatom is 1, 2, 3 or 4 and the number of carbon atom is 1, 2, 3, 4, 5 or 6, preferably azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydroimidazolyl, indolinyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrotriazolyl or dihydroazetidinyl.

3. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein L.sup.1 is alkynyl, —C(R.sup.5)═C(R.sup.6)—, —CR.sup.7R.sup.8—CR.sup.9R.sup.10—, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, preferably alkynyl, —C(R.sup.5)═C(R.sup.6)— or —CR.sup.7R.sup.8—CR.sup.9R.sup.10—, more preferably —C(R.sup.5)═C(R.sup.6)—, most preferably —CH═CH—; or, L.sup.2 is alkynyl, —C(R.sup.5)═C(R.sup.6)—, —CR.sup.7R.sup.8—CR.sup.9R.sup.10—, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or absent, preferably alkynyl, —C(R.sup.5)═C(R.sup.6)—, —CR.sup.7R.sup.8—CR.sup.9R.sup.10— or absent, more preferably —C(R.sup.5)═C(R.sup.6)— or absent, most preferably —CH═CH— or absent; or, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen or deuterium respectively; or, R.sup.1 is halogen, cyano, substituted or unsubstituted alkyl, the alkyl is preferably C.sub.1-C.sub.4 alkyl, more preferably methyl; substituents in the substituted alkyl are preferably halogen or hydroxy; or, R.sup.2 is deuterium, halogen, cyano, substituted or unsubstituted alkyl, the alkyl is preferably C.sub.1-C.sub.4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, substituents in the substituted alkyl are preferably one or more of halogen, cyano, C.sub.1-C.sub.4 alkyl, hydroxyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 carboxyl, C.sub.1-C.sub.4 ester group and C.sub.1-C.sub.4 amido; or, R.sup.3 and R.sup.4 are independently deuterium, halogen, cyano, —SR.sup.11, —NR.sup.12R.sup.13, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; preferably are independently deuterium, halogen, cyano, —SR.sup.11, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

4. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein R.sup.1 and R.sup.2 are independently halogen, alkyl, or alkyl substituted with halogen; or, R.sup.3 and R.sup.4 are halogen; or, R.sup.3 and R.sup.4 are substituted or unsubstituted alkyl, substituents in the substituted alkyl are substituted with one or more of halogen, cyano, hydroxyl, ##STR00141## C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl, C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 carboxyl, preferably are substituted with one or more of halogen, ##STR00142## substituted C.sub.6-C.sub.14 aryl and substituted C.sub.1-C.sub.10 heteroaryl, when substituents are more than one, the substituents are identical or different, or, R.sup.3 and R.sup.4 are substituted or unsubstituted alkoxy, substituents in the substituted alkoxy are substituted with one or more of halogen, cyano, hydroxyl, ##STR00143## C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl and C.sub.1-C.sub.4 alkoxy, preferably are substituted with one or more of C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl and C.sub.1-C.sub.4 alkoxy, most preferably are substituted with C.sub.1-C.sub.4 alkoxy; when substituents are more than one, the substituents are identical or different.

5. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein R.sup.1 and R.sup.2 are independently halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkyl substituted with one or more of F, Cl, Br and I (for example, —CH.sub.2F, —CHF.sub.2 or —CF.sub.3); or, R.sup.3 and R.sup.4 are alkyl substituted with halogen, the alkyl substituted with halogen is C.sub.1-C.sub.4 alkyl preferably substituted with one or more of F, Cl, Br and I, preferably —CF.sub.3, or, R.sup.3 and R.sup.4 are alkyl substituted with ##STR00144## the alkyl substituted with ##STR00145## is preferably C.sub.1-C.sub.4 alkyl substituted with ##STR00146## the C.sub.1-C.sub.4 alkyl substituted with ##STR00147## is preferably ##STR00148## wherein, one of R.sup.17 and R.sup.18 is H, the other one is alkyl substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy and carboxyl, when R.sup.3 and R.sup.4 are alkyl substituted with ##STR00149## the alkyl substituted with ##STR00150## is preferably ##STR00151## ##STR00152## ##STR00153## or, R.sup.3 and R.sup.4 is alkyl substituted with substituted C.sub.6-C.sub.14 aryl, preferably ##STR00154## or, R.sup.3 and R.sup.4 is alkyl substituted with substituted C.sub.1-C.sub.10 heteroaryl, preferably ##STR00155## or, when R.sup.3 is substituted or unsubstituted alkyl, R.sup.3 is at meta-position or para-position of the atom linked with L.sup.1 on ring A; or, when R.sup.4 is substituted or unsubstituted alkyl, R.sup.4 is at meta-position or para-position of the atom linked with L.sup.2 on ring B; or, when R.sup.3 is substituted or unsubstituted alkyl, then 0, 1 or 2 additional substituents can be present on ring A, when 1 additional substituent is present, the additional substituent is at para-position, meta-position or ortho-position of the substituted or unsubstituted alkyl; or, when R.sup.4 is substituted or unsubstituted alkyl, then 0, 1 or 2 additional substituents can be present on ring B, when 1 additional substituent is present, the additional substituent is at para-position, meta-position or ortho-position of the substituted or unsubstituted alkyl; or, R.sup.3 and R.sup.4 are substituted or unsubstituted alkoxy, substituents in the substituted alkoxy are substituted with one or more of halogen, cyano, hydroxyl, ##STR00156## C.sub.6-C.sub.14 aryl, substituted C.sub.6-C.sub.14 aryl, C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl and C.sub.1-C.sub.4 alkoxy; preferably R.sup.3 and R.sup.4 are substituted alkoxy, substituents in the substituted alkoxy are substituted with one or more of C.sub.1-C.sub.10 heteroaryl, substituted C.sub.1-C.sub.10 heteroaryl and C.sub.1-C.sub.4 alkoxy, when substituents are more than one, the substituents are identical or different; the substituted alkoxy is preferably ##STR00157## or, when R.sup.3 is substituted or unsubstituted alkoxy, R.sup.3 is at ortho-position or meta-position of the atom linked with L.sup.1 on ring A; or, when R.sup.4 is substituted or unsubstituted alkoxy, R.sup.4 is at ortho-position or meta-position of the atom linked with L.sup.2 on ring B.

6. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein ##STR00158## are independently ##STR00159## wherein M.sup.1 and N.sup.1 are alkyl substituted with ##STR00160## or one of M.sup.1 and N.sup.1 is alkyl substituted with ##STR00161## the other one is substituted alkoxy; wherein the definitions of R.sup.17, R.sup.18, R.sup.3 and R.sup.4 are the same as defined in claim 1, n1 and m1 are independently 0, 1 or 2; preferably, M.sup.1 and N.sup.1 are ##STR00162## r one of M.sup.1 and N.sup.1 is ##STR00163## the other one is alkoxy substituted with one or more of C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.10 heteroaryl and substituted C.sub.1-C.sub.10 heteroaryl; R.sup.3 and R.sup.4 are hydrogen, halogen, alkyl, alkyl substituted with halogen, alkoxy or substituted alkoxy, substituents in the substituted alkoxy preferably are substituted with one or more of C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.10 heteroaryl and substituted C.sub.1-C.sub.10 heteroaryl; the definitions of R.sup.17 and R.sup.18 are the same as defined in claim 1; more preferably, M.sup.1 and N.sup.1 are ##STR00164## or one of M.sup.1 and N.sup.1 is ##STR00165## the other one is alkoxy substituted with C.sub.1-C.sub.4 alkoxy; R.sup.3 and R.sup.4 preferably are halogen, alkyl, alkyl substituted with halogen, alkoxy or alkoxy substituted with C.sub.1-C.sub.4 alkoxy; the definitions of R.sup.17 and R.sup.18 are the same as defined in claim 1.

7. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 6, wherein ##STR00166## wherein N.sup.1, R.sup.17 and R.sup.18 are the same as those defined in claim 6; or ##STR00167## wherein the definitions of M, R.sup.17 and R.sup.18 are the same as defined in claim 6.

8. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein ##STR00168## are independently ##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## are independently ##STR00177## ##STR00178## ##STR00179##

9. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein the diphenyl-like compound represented by general formula I is selected from any one compound of: ##STR00180## ##STR00181##

10. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 6, wherein the diphenyl-like compound represented by general formula I is a diphenyl-like compound represented by general formula I-A or II: ##STR00182## wherein, the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, M.sup.1, N.sup.1, R.sup.17 and R.sup.18 are the same as defined in claim 6, n1 is 0, 1 or 2, m1 is 0, 1 or 2.

11. A preparation method of the diphenyl-like compound represented by general formula I-A or II in claim 10, wherein in the compound represented by general formula I-A, when —NH— or —COOH is contained in M.sup.1 and N.sup.1, it is prepared by using a method comprising a step of: deprotecting a compound represented by general formula II-F as shown below, to obtain the diphenyl-like compound represented by general formula I-A, ##STR00183## wherein the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, M.sup.1 and N.sup.1 are the same as defined in claim 10, n1 is 0, 1 or 2, m1 is 0, 1 or 2, R.sup.IIF is a group containing amino or carboxyl protecting group corresponding to M.sup.1, R.sup.IIF1 is identical to N.sup.1; or R.sup.F is identical to M.sup.1, R.sup.IIF1 is a group containing amino or carboxyl protecting group corresponding to N.sup.1; or R.sup.IIF is a group containing amino or carboxyl protecting group corresponding to M.sup.1, R.sup.IIF1 is a group containing amino or carboxyl protecting group corresponding to N.sup.1; the preparation method of the diphenyl-like compound of general formula II employs any one method of: (1) method 1 comprising a step of: reacting a compound represented by general formula II-A with a compound II-A1 as shown below, to obtain the diphenyl-like compound represented by general formula II, ##STR00184## wherein the structure of the compound II-A1 is as follows: ##STR00185## or an acid salt thereof, the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.17 and R.sup.18 are the same as defined in claim 10, n1 is 0, 1 or 2, m1 is 0, 1 or 2; in this method, ##STR00186## in ring A and ring B are identical; (2) method 2 comprising a step of: reacting a compound represented by general formula II-B with a compound II-B1 as shown below, to obtain the diphenyl-like compound represented by general formula II, ##STR00187## wherein the structure of the compound II-B1 is as follows: ##STR00188## or an acid salt thereof, the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.17 and R.sup.18 are the same as defined in claim 10, n1 is 0, 1 or 2, m1 is 0, 1 or 2, M is halogen; in this method, ##STR00189## in ring A and ring B are identical; (3) method 3 comprising a step of: reacting a compound represented by general formula II-C with a compound II-C1 as shown below, to obtain the diphenyl-like compound represented by general formula II, ##STR00190## wherein the structure of the compound II-C1 is as follows: ##STR00191## or an acid salt thereof, the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.17 and R.sup.18 are the same as defined in claim 10, n1 is 0, 1 or 2, m1 is 0, 1 or 2; one of R.sup.IIC and R.sup.IIC1 is ##STR00192## the other one is ##STR00193## in this method, ##STR00194## in ring A and ring B are identical or different; (4) method 4 comprising a step of: reacting a compound represented by general formula II-D with a compound II-D1 as shown below, to obtain the diphenyl-like compound represented by general formula II, ##STR00195## wherein the structure of the compound II-D1 is as follows: ##STR00196## or an acid salt thereof, the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.17 and R.sup.18 are the same as defined in claim 10, n1 is 0, 1 or 2, m1 is 0, 1 or 2; one of R.sup.IID and R.sup.IID1 is ##STR00197## the other one is halogen, in this method, ##STR00198## in ring A and ring B are identical or different; (5) method 5 comprising a step of: deprotecting a compound represented by general formula II-E as shown below, to obtain the diphenyl-like compound represented by general formula II, R.sup.17 or R.sup.18 in the compound represented by general formula II containing carboxyl; ##STR00199## wherein the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.17 and R.sup.18 are the same as defined in claim 10, n1 is 0, 1 or 2, m1 is 0, 1 or 2, R.sup.IIE and R.sup.IIE1 are ##STR00200## each R.sup.17′ and each R.sup.18′ are identical or different, and at least one contains carboxyl protecting group, R.sup.17′ and R.sup.18′ free of carboxyl protecting group are the same as the corresponding R.sup.17 and R.sup.18 in general formula II respectively; in this method, ##STR00201## in ring A and ring B are identical or different.

12. A compound represented by general formula II-A, II-B, II-C, II-D, II-E and II-F: ##STR00202## the definitions of ring A, ring B, L.sup.1, L.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, M.sup.1, N.sup.1, R.sup.17 and R.sup.18 are the same as defined in claim 6, n1 is 0, 1 or 2, m1 is 0, 1 or 2; M is halogen, one of R.sup.IIC and R.sup.IIC1 is ##STR00203## the other one is ##STR00204## one of R.sup.IID and R.sup.IID1 is ##STR00205## the other one is halogen, R.sup.IIE and R.sup.IIE1 are ##STR00206## each R.sup.17′ and each R.sup.18′ are identical or different, and at least one contains carboxyl protecting group, R.sup.17′ and R.sup.18′ free of carboxyl protecting group are the same as the corresponding R.sup.17 and R.sup.18 in general formula II respectively; R.sup.IIF is a group containing amino or carboxyl protecting group corresponding to M.sup.1, R.sup.IIF1 is identical to N.sup.1; or R.sup.IIF is identical to M.sup.1, R.sup.IIF1 is a group containing amino or carboxyl protecting group corresponding to N.sup.1; or R.sup.IIF is a group containing amino or carboxyl protecting group corresponding to M.sup.1, R.sup.IIF1 is a group containing amino or carboxyl protecting group corresponding to N.sup.1.

13. A compound as shown below: ##STR00207## ##STR00208## ##STR00209##

14. A method of inhibiting PD-1 and/or PD-L1 in a subject in need thereof, comprising administering a therapeutically effective amount of the diphenyl-like compound of general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1 to the subject.

15. A method of preventing, alleviating or treating cancer, infection, autoimmune disease or related diseases thereof in a subject in need thereof, comprising administering a therapeutically effective amount of one or more of the diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor and prodrug thereof as defined in claim 1 to the subject, wherein the cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.

16. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor or prodrug thereof as defined in claim 1, and a pharmaceutically acceptable carrier and/or diluent.

17. The diphenyl-like compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, or prodrug thereof as defined in claim 1, wherein group ##STR00210## wherein the definitions of R.sup.1 and R.sup.2 are the same as defined in claim 1; group ##STR00211## is preferably ##STR00212##

Description

DETAILED DESCRIPTION OF THE EMBODIMENT

[0168] The present disclosure is further illustrated by way of examples below, but is not therefore limited to the scope of those examples. The experimental methods in the examples below of which the specific conditions are not indicated are selected according to the conventional methods and conditions, or according to the commodity instructions.

[0169] In the examples described below, room temperature refers to 10° C. to 30° C.; reflux refers to the refluxing temperature of a solvent; overnight refers to 8 to 24 hours, preferably 12 to 18 hours.

[0170] The structure of a compound is determined by nuclear magnetic reasonance (NMR) or mass spectrometry (MS), the nuclear magnetic reasonance spectra are obtained by Bruker Avance-500 instrument, using deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol and the like as solvent, and tetramethylsilane (TMS) as internal standard. The mass spectrum is obtained by liquid chromatography-mass spectrometry (LC-MS) Agilent Technologies 6110 with ESI ion source.

[0171] The microwave reaction is carried out in the Explorer automatic microwave synthesizer produced by CEM company, USA, the magnetron frequency is 2450 MHz and the continuous microwave output power is 300 W.

[0172] The instrument used for high performance liquid chromatography preparation is Gilson 281, and the used preparation column is Shimadazu Shim-Pack, PRC-ODS, 20×250 mm, 15 μm.

Example 1

2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-methylphenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-1-ethanol 1

[0173] ##STR00119##

[0174] Synthesis of Compound 1-f

[0175] At room temperature, to a solution of 2-bromo-6-chlorotoluene (15.67 g, 76.26 mmol) and pinacol ethenylborate (14.30 g, 91.51 mmol) in toluene (300 mL) were added bis(tri-tert-butylphosphine)palladium (2.73 g, 5.34 mmol) and triethylamine (61.74 g, 610.08 mmol), the reaction mixture was heated to 80° C., and reacted overnight with stirring under nitrogen. After the reaction was completed, the reaction mixture was diluted by adding ethyl acetate (100 mL), and washed with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 1-f (10.5 g, yield: 49.4%).

[0176] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.65-7.62 (d, J=18.5 Hz, 1H), 7.42-7.41 (d, J=7.5 Hz, 1H), 7.31-7.30 (d, J=7.5 Hz, 1H), 7.12-7.09 (t, 1H), 6.06-6.02 (d, J=18.0 Hz, 1H), 2.45 (s, 3H), 1.32 (s, 12H).

[0177] Synthesis of Compound 1-e

[0178] At room temperature, to a mixed solution of 3-bromo-4-trifluoromethyl benzaldehyde (4.16 g, 16.45 mmol) and compound 1-f (5.5 g, 19.74 mmol) in 1,4-dioxane (40 mL) and water (2 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (1.423 g, 1.645 mmol) and sodium carbonate (4.36 g, 41.13 mmol), the reaction mixture was heated to 80° C., and stirred under nitrogen for 16 hours. After the reaction was completed, the reaction mixture was diluted by adding ethyl acetate (50 mL), and washed with water (50 mL) and saturated brine (50 mL) successively. The resulting organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=40:1) to obtain compound 1-e (4.16 g, yield: 78%).

[0179] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 10.15 (s, 1H), 8.25 (s, 1H), 7.87 (s, 2H), 7.47-7.40 (m, 2H), 7.37-7.36 (d, J=7.0 Hz, 1H), 7.32-7.29 (m, 1H), 7.20-7.17 (m, 1H), 2.50 (s, 3H).

[0180] Synthesis of Compound 1-d

[0181] To a 100 milliliter of reaction flask were added compound 1-e (3.24 g, 10 mmol), bis(pinacolato)diboron (3.05 g, 12 mmol), tris(dibenzylideneacetone)dipalladium (458 mg, 0.5 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (952 mg, 2.0 mmol), potassium acetate (3.0 g, 112 mmol) and toluene (80 mL). The mixture was reacted at 90° C. under nitrogen protection for 16 hours. The mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=25:1) to obtain compound 1-d (3.06 g, yield: 82%).

[0182] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 10.15 (s, 1H), 8.28 (s, 1H), 7.85 (s, 2H), 7.73-7.76 (m, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.50 (d, J=18 Hz, 1H), 7.26-7.28 (m, 1H), 7.23 (d, J=7.5 Hz, 1H), 2.65 (s, 3H), 1.37 (s, 12H).

[0183] Synthesis of Compound 1-c

[0184] At room temperature, to a solution of compound 1-d (416.24 mg, 1.0 mmol) in tetrahydrofuran (20 mL) was added hydrogen peroxide (30%, 1 mL), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), and then washed with saturated sodium thiosulfate aqueous solution (20 mL) twice and saturated brine (20 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 1-c (220 mg, yield: 71.9%).

[0185] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.17 (s, 1H), 8.29 (s, 1H), 7.89 (s, 2H), 7.48-7.45 (d, J=16.0 Hz, 1H), 7.37-7.33 (m, 1H), 7.23-7.21 (d, J=7.5 Hz, 1H), 7.16-7.13 (t, 1H), 6.82-6.80 (d, J=8.0 Hz, 1H), 4.90 (s, 1H), 2.38 (s, 3H).

[0186] Synthesis of Compound 1-b

[0187] At room temperature, to a solution of compound 1-c (529 mg, 1.73 mmol) and phenylbis(trifluoromethanesulfonyl)imide (618 mg, 1.73 mmol) in acetone (20 mL) was added potassium carbonate (358 mg, 2.59 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), and then washed with saturated sodium thiosulfate aqueous solution (20 mL) twice and saturated brine (20 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=40:1 to 20:1) to obtain compound 1-b (391 mg, yield: 51.7%).

[0188] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.08 (s, 1H), 8.18 (s, 1H), 7.85-7.81 (m, 2H), 7.54-7.52 (d, J=7.5 Hz, 1H), 7.30 (s, 2H), 7.28-7.24 (m, 1H), 7.19-7.18 (m, 1H), 2.39 (t, 3H).

[0189] Synthesis of Compound 1-a

[0190] Under nitrogen protection, to a mixed solution of compound 1-b (391 mg, 0.892 mmol) and compound 1-d (445.4 mg, 1.070 mmol) in 1,4-dioxane (20 mL) and water (1 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (77.2 mg, 0.0892 mmol) and sodium carbonate (236.4 mg, 2.23 mmol). The reaction mixture was heated to 80° C., and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted by adding ethyl acetate solution (20 mL), and then washed with water (20 mL) three times and saturated brine (20 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel thin layer chromatography preparation plate (petroleum ether:ethyl acetate=10:1) to obtain compound 1-a (116 mg, yield: 22.5%).

[0191] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.07 (s, 2H), 8.22 (s, 2H), 7.80 (s, 4H), 7.57-7.55 (d, J=7.5 Hz, 2H), 7.46-7.43 (d, J=15.5 Hz, 2H), 7.36-7.31 (m, 2H), 7.26-7.21 (m, 2H), 7.08-7.07 (d, J=7.0 Hz, 2H), 2.11 (s, 6H).

[0192] Synthesis of Compound 1

[0193] At room temperature, to a mixed solution of compound 1-a (100 mg, 0.27 mmol) and aminoethanol (64.3 mg, 0.54 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added glacial acetic acid (32.4 mg, 0.54 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (84.8 mg, 1.35 mmol) was added and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), and then washed with water (20 mL) and saturated brine (20 mL) once respectively. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel thin layer chromatography preparation plate (dichloromethane:methanol=10:1) to obtain compound 1 (24 mg, yield: 18.9%). LC-MS (ESI): m/z=669.0 [M+H].sup.+.

[0194] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.15 (s, 2H), 7.84-7.83 (d, J=8.0 Hz, 2H), 7.67-7.59 (m, 6H), 7.41-7.33 (m, 4H), 7.14-7.13 (d, J=6.5 Hz, 2H), 4.41 (s, 4H), 3.88-3.86 (m, 4H), 3.25-3.23 (m, 4H), 2.20 (s, 6H).

Example 2

(2S)-3-hydroxy-2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-methylphenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-2-methylpropanoic Acid 2

[0195] ##STR00120##

[0196] Synthesis of Compound 2-e

[0197] At room temperature, to a mixed solution of compound 1-b (559 mg, 1.275 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (96.5 mg, 2.551 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), and then washed with water (20 mL) and saturated brine (20 mL) once respectively. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 2-e (517 mg, yield: 92.5%).

[0198] Synthesis of Compound 2-d

[0199] At room temperature, to a solution of compound 2-e (517 mg, 1.174 mmol) in dichloromethane (10 mL) were added thionyl chloride (698.4 mg, 5.87 mmol) and 2 drops of N,N-dimethylformamide, and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved with ethyl acetate (20 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL) twice, saturated brine (20 mL) once, and the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 2-d (500 mg, yield: 92.9%) which was directly used in the next reaction.

[0200] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.78 (s, 1H), 7.73-7.71 (d, J=8.0 Hz, 1H), 7.62-7.60 (d, J=8.0 Hz, 1H), 7.47-7.45 (d, J=8.0 Hz, 1H), 7.40-7.32 (m, 2H), 7.29-7.25 (m, 2H), 4.69 (s, 2H), 2.47 (m, 3H).

[0201] Synthesis of Compound 2-c

[0202] To a solution of compound 2-d (500 mg, 1.09 mmol) and (S)-2-methylserine methyl ester p-toluenesulfonate (332.8 mg, 1.09 mmol) in acetonitrile (20 mL) were added sodium iodide (32.7 mg, 0.218 mmol) and potassium carbonate (753.2 mg, 5.45 mmol), the reaction mixture was heated to 80° C. and stirred under nitrogen protection for 16 hours. The reaction mixture was cooled to room temperature, diluted by adding ethyl acetate (20 mL), and then washed with water (20 mL) and saturated sodium thiosulfate aqueous solution (20 mL) twice and saturated brine (20 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified through silica gel thin layer chromatography preparation plate (petroleum ether:ethyl acetate=5:1) to obtain compound 2-c (471 mg, yield: 77.7%).

[0203] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.74 (s, 1H), 7.68-7.67 (d, J=8.5 Hz, 1H), 7.61-7.60 (d, J=7.5 Hz, 1H), 7.44-7.42 (d, J=8.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.35-7.31 (t, 1H), 7.28-7.24 (m, 2H), 3.84-3.83 (d, J=2.0 Hz, 2H), 3.81 (s, 3H), 3.79-3.77 (d, J=11.0 Hz, 1H), 3.68-3.66 (d, J=11.0 Hz, 1H), 2.47 (s, 3H), 1.42 (s, 3H).

[0204] Synthesis of Compound 2-b

[0205] To a mixed solution of compound 2-c (471 mg, 0.848 mmol) and compound 1-d (423.3 mg, 1.017 mmol) in 1,4-dioxane (20 mL) and water (1 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (73.4 mg, 0.0848 mmol) and sodium carbonate (224.7 mg, 2.12 mmol), the reaction mixture was heated to 80° C. and stirred under nitrogen protection for 16 hours. The reaction mixture was cooled to room temperature, diluted by adding ethyl acetate solution (20 mL), and then washed with water (20 mL) three times and saturated brine (20 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel thin layer chromatography preparation plate (petroleum ether:ethyl acetate=1:1) to obtain compound 2-b (459 mg, yield: 77.9%). LC-MS (ESI): m/z=696.0 [M+H].sup.+.

[0206] Synthesis of Compound 2-a

[0207] At room temperature, to a mixed solution of compound 2-b (459 mg, 0.66 mmol) and aminoethanol (80.6 mg, 1.32 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added glacial acetic acid (79.3 mg, 1.32 mmol), the reaction mixture was stirred for 1 hour, then sodium cyanoborohydride (207.4 mg, 3.30 mmol) was added thereto and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), and then washed with water (20 mL) and saturated brine (20 mL) once respectively. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel thin layer chromatography preparation plate (dichloromethane:methanol=10:1) to obtain compound 2-a (32 mg, yield: 6.6%). LC-MS (ESI): m/z=741.0 [M+H].sup.+.

[0208] Synthesis of Compound 2

[0209] At room temperature, to a mixed solution of compound 2-a (100 mg, 0.27 mmol) in methanol (10 mL) and water (10 mL) was added sodium hydroxide (32.4 mg, 0.54 mmol), and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), and pH was adjusted to 4 to 5 using diluted hydrochloric acid (1.0 M), with white precipitate being separated out. The precipitate was filtered, and the filter cake was washed with water (5 mL), then dried in a vacuum to obtain compound 2 (30 mg, yield: 98%). LC-MS (ESI): m/z=727.0 [M+H].sup.+.

[0210] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.20-8.16 (d, J=19.0 Hz, 2H), 7.85-7.81 (m, 2H), 7.69-7.59 (m, 6H), 7.42-7.33 (m, 4H), 7.15-7.12 (m, 2H), 4.41 (s, 2H), 4.39-4.30 (m, 2H), 4.05-4.02 (d, J=12.5 Hz, 1H), 3.88-3.85 (m, 3H), 3.25-3.23 (m, 2H), 2.21-2.20 (d, J=4.0 Hz, 6H), 1.59 (s, 3H).

Example 3

(2S)-2-[({3-[(E)-2-(3-{3-[(E)-2-[5-({[(1S)-1-carboxyl-2-hydroxy-1-methylethyl]amino}methyl)-2-(trifluoromethyl)phenyl]ethenyl]-2-methylphenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-3-hydroxy-2-methylpropanoic Acid 3

[0211] ##STR00121##

[0212] Synthesis of Compound 3-c

[0213] At room temperature, to a mixed solution of compound 1-a (381 mg, 0.659 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (124.6 mg, 3.293 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), and then washed with water (20 mL) and saturated brine (20 mL) once respectively. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) to obtain compound 3-c (367 mg, yield: 96.3%).

[0214] Synthesis of Compound 3-b

[0215] At room temperature, to a solution of compound 3-b (367 mg, 0.63 mmol) in dichloromethane (20 mL) were added thionyl chloride (374.7 mg, 3.15 mmol) and 2 drops of N,N-dimethylformamide, and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved with ethyl acetate (20 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL) twice, saturated brine (20 mL) once, and the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 3-b (333 mg, yield: 85.4%) which was directly used in the next reaction.

[0216] Synthesis of Compound 3-a

[0217] To a solution of compound 3-b (333 mg, 0.538 mmol) and (S)-2-methylserine methyl ester p-toluenesulfonate (328.3 mg, 1.075 mmol) in acetonitrile (20 mL) were added potassium carbonate (743.6 mg, 5.38 mmol) and sodium iodide (40.3 mg, 0.269 mmol), the reaction mixture was heated to 80° C. and stirred under nitrogen protection for 16 hours. The reaction mixture was cooled to room temperature, diluted by adding ethyl acetate (20 mL), and then washed with water (20 mL) and saturated sodium thiosulfate aqueous solution (20 mL×2) and with saturated brine (20 mL) once. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified through silica gel thin layer chromatography preparation plate (dichloromethane:methanol=15:1) to obtain compound 3-a (360 mg, yield: 82.6%). LC-MS (ESI): m/z=813.0 [M+H].sup.+.

[0218] Synthesis of Compound 3

[0219] At room temperature, to a mixed solution of compound 3-a (360 mg, 0.443 mmol) in methanol (20 mL) and water (2 mL) was added sodium hydroxide (88.6 mg, 2.215 mmol), and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), and pH was adjusted to 4 to 5 using diluted hydrochloric acid (1.0 M), with white precipitate being separated out. The precipitate was filtered, and the filter cake was washed with water (5 mL), then dried in a vacuum to obtain compound 3 (264 mg, yield: 74.8%). LC-MS (ESI): m/z=785.0 [M+H].sup.+.

[0220] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.19 (s, 2H), 7.82-7.81 (d, J=8.5 Hz, 2H), 7.69-7.61 (m, 6H), 7.41-7.38 (m, 2H), 7.35-7.32 (m, 2H), 7.14-7.13 (d, J=7.5 Hz, 2H), 4.39-4.31 (m, 4H), 4.06-4.03 (d, J=12.5 Hz, 2H), 3.88-3.86 (d, J=12.5 Hz, 2H), 2.20 (s, 6H), 1.60 (s, 6H).

Example 4

2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-methoxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-chlorophenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-1-ethanol 4

[0221] ##STR00122## ##STR00123##

[0222] Synthesis of Compound 4-f

[0223] 3-bromo-4-trifluoromethylbenzaldehyde (4.0 g, 15.8 mmol) and ethene borate (2.92 g, 18.9 mmol) were dissolved in toluene (100 mL), and bis(tri-tert-butylphosphine)palladium (807 mg, 1.58 mmol) and triethylamine (4.78 g, 47.4 mmol) were added to the solution. The reaction mixture was stirred at 80° C. under nitrogen protection for 5 hours, and thin layer chromatography was used to monitor the complete reaction of the raw material. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50 to 10:1), to obtain brown viscous substance 4-f (300 mg, yield: 58%).

[0224] Synthesis of Compound 4-e

[0225] Compound 1-bromo-2-chloro-3-iodobenzene (2.0 g, 8.2 mmol) and compound 4-f (3.0 g, 9 mmol) were dissolved in a mixed solution of dioxane and water (50 mL/5 mL), tetrakis(triphenylphosphine) palladium (947 mg, 0.82 mmol) and sodium carbonate (2.60 g, 24.6 mmol) were added to the solution. The reaction mixture was stirred at 70° C. under nitrogen protection for 12 hours, and thin layer chromatography was used to monitor the complete reaction of the raw material. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=100 to 10:1), to obtain white solid 4-e (1.15 g, yield: 36%).

[0226] Synthesis of Compound 4-d

[0227] Compound 4-e (760 mg, 2.0 mmol) and 2-methoxyethylamine (450 mg, 6.0 mmol) were dissolved in a mixed solution of dichloromethane (30 ml) and MeOH (10 ml), glacial acetic acid (360 mg, 6.0 mmol) was added to the reaction mixture at ambient temperature, after the reaction mixture was stirred for 2 hours, sodium cyanoborohydride (152 mg, 4.0 mmol) was added to the reaction mixture, stirring was continued for 18 hours, and thin layer chromatography was used to monitor the complete reaction of the raw material. The reaction was concentrated under reduced pressure, the residue was dissolved in dichloromethane (80 mL), washed with water (50 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=20 to 5:1) to obtain brown solid 4-d (700 mg, yield: 78%).

[0228] .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 7.79 (s, 1H), 7.66-7.60 (m, 3H), 7.49 (s, 1H), 7.42-7.40 (m, 2H), 7.19 (t, J=6.0 Hz, 1H), 3.94 (s, 2H), 3.56 (t, J=4.0 Hz, 2H), 3.39 (s, 3H), 2.86 (t, J=4.0 Hz, 2H).

[0229] Synthesis of Compound 4-c

[0230] Compound 4-d (350 mg, 0.78 mmol) and di-tert-butyl dicarbonate (340 mg, 1.56 mmol) were dissolved in dichloromethane (30 ml), triethylamine (315.1 mg, 3.12 mmol) and 4-dimethylaminopyridine (9.5 mg, 0.078 mmol) were added successively, and the reaction mixture was stirred overnight at ambient temperature. The reaction system was diluted by adding dichloromethane (60 mL), then washed with water (50 ml) and saturated brine (40 ml) successively, and dried over anhydrous sodium sulfate. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=20 to 10:1), to obtain yellow oil 4-c (400 mg, yield: 93%).

[0231] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.69-7.60 (m, 4H), 7.50-7.46 (m, 1H), 7.48-7.42 (m, 1H), 7.32-7.27 (m, 1H), 7.19 (t, J=6.4 Hz, 1H), 4.62 (d, J=9.2 Hz, 2H), 3.57-3.40 (m, 4H), 3.34 (s, 3H), 1.54-1.39 (m, 9H).

[0232] Synthesis of Compound 4-b

[0233] Compound 4-c (165 mg, 0.3 mmol) and compound 1-d (137 mg, 0.33 mmol) were dissolved in a mixed solution of dioxane and water (40 mL/4 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (44 mg, 0.06 mmol) and sodium carbonate (127 mg, 1.2 mmol) were added to the solution. The reaction mixture was stirred at 85° C. under nitrogen protection for 12 hours. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=20 to 5:1), to obtain yellow solid 4-b (150 mg, yield: 66%).

[0234] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 10.17 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.76-7.65 (m, 4H), 7.60-7.34 (m, 6H), 7.25-7.18 (m, 3H), 4.62 (d, J=8.4 Hz, 2H), 3.56-3.39 (m, 4H), 3.33 (s, 3H), 2.24 (s, 3H), 1.45-1.39 (m, 9H).

[0235] Synthesis of Compound 4-a

[0236] Compound 4-b (130 mg, 0.17 mmol) and ethanolamine (52 mg, 0.85 mmol) were dissolved in a mixed solution of dichloromethane (10 mL) and methanol (3 mL), and 1 drop of glacial acetic acid was added to the reaction mixture. After the reaction mixture was stirred at room temperature for 2 hours, sodium cyanoborohydride (21 mg, 0.33 mmol) was added to the reaction mixture, and then the reaction was continued for 12 hours at room temperature. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (dichloromethane: methanol=20 to 10:1), to obtain yellow oil 4-a (130 mg, yield: 94%).

[0237] Synthesis of Compound 4

[0238] Compound 4-a (130 mg, 0.16 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (1 mL) was added dropwise, the temperature was kept at 30° C., and the reaction was stirred for 5 hours. The reaction was concentrated under reduced pressure, and the residue was purified through high performance liquid chromatography preparation to obtain white solid 4 (65 mg, yield: 58%). LC-MS (ESI): m/z=703.2[M-1].sup.+.

[0239] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.14 (d, J=4.8 Hz, 1H), 7.87-7.74 (m, 4H), 7.66-7.47 (m, 6H), 7.42-7.34 (m, 2H), 7.30 (d, J=10.6 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.40 (s, 2H), 4.39 (s, 2H), 3.87-3.85 (m, 2H), 3.71-3.69 (m, 2H), 3.43 (s, 3H), 3.33-3.30 (m, 2H), 3.24-3.22 (m, 2H), 2.23 (s, 3H).

Example 5

(2S)-3-hydroxy-2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-methoxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-chlorophenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-2-methylpropanoic Acid 5

[0240] ##STR00124##

[0241] Synthesis of Compound 5-a

[0242] Compound (S)-2-amino-3-hydroxy-2-methylpropanoic acid (72 mg, 0.60 mmol) was added to methanol (20 ml), stirred at room temperature, sodium hydroxide (24 mg, 0.6 mmol) aqueous solution (5 mL) was added slowly, and the reaction system gradually became clear. After being continuously stirred for 1 hour, a solution of compound 4-b (150 mg, 0.2 mmol) in THF (5 ml) was added to the reaction system. After completing the dropwise-addition, stirring was continued overnight. Sodium cyanoborohydride (25.2 mg, 0.4 mmol) was added to the system and stirred for 2 hours. The reaction was concentrated under reduced pressure, and the residue was washed with water (3 mL) to obtain crude product 5-a (160 mg). It was directly used for the next reaction. LC-MS (ESI): m/z=861[M+H].sup.+.

[0243] Synthesis of Compound 5

[0244] Compound 5-a (160 mg) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (1 mL) was added dropwise, and stirred at 30° C. for 5 hours. TCL was used to monitor the complete reaction of the raw material. The reaction was concentrated under reduced pressure, and the residue was purified through high performance liquid chromatography preparation to obtain white solid 5 (31 mg, yield: 20%). LC-MS (ESI): m/z=761.2[M+H].sup.+.

[0245] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.17 (s, 1H), 7.97 (s, 1H), 7.80-7.61 (m, 7H), 7.53-7.33 (m, 5H), 7.27 (d, J=6.0 Hz, 1H), 7.15 (d, J=5.6 Hz, 1H), 4.30-4.22 (q, 2H), 3.98-3.96 (m, 3H), 3.82 (d, J=9.6 Hz, 1H), 3.56 (t, J=4.4 Hz, 2H), 3.37 (s, 3H), 2.85 (t, J=4.4 Hz, 2H), 2.23 (s, 3H), 1.53 (s, 3H).

Example 6

(2S)-3-hydroxy-2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-chlorophenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-2-methylpropanoic Acid 6

[0246] ##STR00125## ##STR00126##

[0247] Synthesis of Compound 6-d

[0248] Compound 4-e (450 mg, 1.15 mmol) and 2-aminoethanol (211 mg, 3.47 mmol) were dissolved in a mixed solution of dichloromethane (30 mL) and methanol (10 mL), glacial acetic acid (0.1 mL) was added, the reaction mixture was stirred at room temperature for 2 hours, then sodium cyanoborohydride (114 mg, 2.30 mmol) was added, and the reaction was continued to be stirred for 18 hours after addition. The reaction was concentrated under reduced pressure, the residue was dissolved in dichloromethane (50 mL), washed with water (50 mL) and saturated brine (30 mL) successively, and dried over anhydrous sodium sulfate. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (methanol:ethyl acetate=1 to 20:100), to obtain white solid 6-d (430 mg, yield: 86%).

[0249] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.77 (s, 1H), 7.67-7.60 (m, 3H), 7.52-7.38 (m, 3H), 7.19 (t, J=6.4 Hz, 1H), 3.95 (s, 2H), 3.74 (t, J=4.0 Hz, 2H), 2.88 (t, J=4.0 Hz, 2H).

[0250] Synthesis of Compound 6-c

[0251] Compound 6-d (430 mg, 1.0 mmol) and di-tert-butyl dicarbonate (436 mg, 2.0 mmol) were dissolved in dichloromethane (40 mL), triethylamine (404 mg, 4.0 mmol) and 4-N,N-dimethylpyridine (122 mg, 1.0 mmol) were added successively, and the reaction mixture was stirred overnight at room temperature. The reaction system was diluted by adding dichloromethane (60 mL), then washed with water (50 mL) and saturated brine (30 mL) successively, and dried over anhydrous sodium sulfate. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50 to 15:1), to obtain yellow oil 6-c (100 mg, yield: 18%). LC-MS (ESI): m/z=536.0 [M+H].sup.+.

[0252] Synthesis of Compound 6-b

[0253] Compound 6-c (100 mg, 0.2 mmol) and 1-d (100 mg, 0.24 mmol) were dissolved in a mixed solution of dioxane and water (20 mL/2 mL), then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (29.2 mg, 0.04 mmol) and sodium carbonate (63.6 mg, 0.6 mmol) were added to the solution. The reaction mixture was stirred at 85° C. for 10 hours. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10 to 2:1), to obtain transparent oil 6-b (100 mg, yield: 66%). LC-MS (ESI): m/z=744.1[M+H].sup.+.

[0254] Synthesis of Compound 6-a

[0255] Compound (S)-2-amino-3-hydroxy-2-methylpropanoic acid (47.6 mg, 0.40 mmol) was added to methanol (10 ml), stirred at room temperature, sodium hydroxide (16 mg, 0.4 mmol) aqueous solution (3 ml) was added slowly, the reaction system gradually became clear, stirring was continued for 1 hour, and then a solution of 6-b (100 mg, 0.13 mmol) in THE (4 mL) was added slowly. After completing the dropwise-addition, stirring was continued overnight. Sodium cyanoborohydride (12.6 mg, 0.2 mmol) was added to the system and stirred for 2 hours. The reaction was concentrated under reduced pressure, and the resulting residue was washed with water (3 mL) to obtain crude product 6-a (160 mg). It was directly used for the next reaction. LC-MS (ESI): m/z=861.0[M+H].sup.+.

[0256] Synthesis of Compound 6

[0257] Compound 6-a (160 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added dropwise, and stirred at 30° C. for 5 hours. Thin layer chromatography was used to monitor the complete reaction of the raw material. The reaction was concentrated under reduced pressure, and the residue was purified through high performance liquid chromatography preparation to obtain white solid product 6 (9 mg, yield: 10%). LC-MS (ESI): m/z=374.2[M/2+H].sup.+.

[0258] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.17 (s, 1H), 8.13 (s, 1H), 7.87-7.74 (m, 4H), 7.67-7.63 (m, 4H), 7.55-7.34 (m, 4H), 7.30 (d, J=6.4 Hz, 1H), 7.1 (d, J=5.6 Hz, 1H), 4.42-4.38 (m, 4H), 4.10 (d, J=9.2 Hz, 1H), 3.90 (d, J=8.8 Hz, 1H), 3.87-3.85 (m, 2H), 3.24-3.22 (m, 2H), 2.23 (s, 3H), 1.64 (s, 3H).

Example 7

2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-chlorophenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-1-ethanol 7

[0259] ##STR00127##

[0260] Synthesis of Compound 7-a

[0261] Compound 6-b (168 mg, 0.2 mmol) and 2-aminoethanol (35 mg, 0.6 mmol) were dissolved in a mixed solution of dichloromethane (20 ml) and MeOH (5 ml), glacial acetic acid (0.1 mL) was added to the reaction mixture, stirred at room temperature for 2 hours, then sodium cyanoborohydride (25 mg, 0.4 mmol) was added, and the reaction was continued to be stirred for 18 hours after addition. The reaction was concentrated under reduced pressure, the residue was dissolved in dichloromethane (50 mL), washed with water (50 mL) and saturated brine (30 mL) successively, and dried over anhydrous sodium sulfate. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (methanol:ethyl acetate=1 to 20:100), to obtain colorless viscous substance 7-a (120 mg, yield: 67%). LC-MS (ESI): m/z=789.2[M+H].sup.+.

[0262] Synthesis of Compound 6

[0263] Compound 7-a (120 mg, 0.13 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added dropwise, and stirred at 30° C. for 5 hours. The reaction was concentrated under reduced pressure, and the resulting residue was purified through high performance liquid chromatography preparation to obtain white solid product 7 (40 mg, yield: 43%). LC-MS (ESI): m/z=689.3[M+H].sup.+.

[0264] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.98 (s, 1H), 7.96 (s, 1H), 7.76 (d, J=4.2 Hz, 1H), 7.72-7.31 (m, 8H), 7.53-7.33 (m, 5H), 7.27 (d, J=6.4 Hz, 1H), 7.13 (d, J 6.0 Hz, 1H), 3.93 (s, 4H), 3.72-3.70 (m, 4H), 2.79-2.70 (m, 4H), 2.22 (s, 3H).

Example 8

(2S)-3-hydroxy-2-[({3-[(E)-2-[3-(3-(E)-{2-[2-fluoro-5-(2-methoxyethoxy)phenyl]ethenyl}-2-methylphenyl)-2-methylphenyl]ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-2-methylpropanoic Acid 8

[0265] ##STR00128## ##STR00129##

[0266] Synthesis of Compound 8-g

[0267] At ambient temperature, to a solution of 3-bromo-4-fluorophenol (1.0 g, 5.24 mmol) and 1-bromo-2-methoxyethane (800 mg, 5.76 mmol) in DMF (20 mL) were added sodium iodide (157 mg, 1.05 mmol) and potassium carbonate (3.62 g, 26.2 mmol), and the reaction mixture was stirred overnight at 80° C. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, washed with water (100 mL) and saturated brine (100 mL). The resulting organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to obtain compound 8-g (1.263 g, yield: 96.9%).

[0268] .sup.1H NMR (500 MHz, CDCl3): δ 7.14-7.12 (1H, dd, J=0.0 Hz, J=0.5 Hz), 7.07-7.03 (1H, dd, J=0.5 Hz, J=9.5 Hz), 6.88-6.85 (1H, m), 4.10-4.08 (2H, m), 3.76-3.75 (2H, m), 3.47 (3H, s).

[0269] Synthesis of Compound 8-f

[0270] To a mixed solution of 8-g (1.263 g, 5.07 mmol) and 1-f (1.694 g, 6.08 mmol) in 1,4-dioxane (20 mL) and water (1 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (438 mg, 0.507 mmol) and sodium carbonate (1.344 g, 12.67 mmol), the reaction mixture was heated to 80° C. and reacted overnight with stirring under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column (PE:EA=50:1 to 10:1) to obtain 8-f (1.20 g, yield: 73.9%).

[0271] Synthesis of Compound 8-e

[0272] To a solution of 8-g (1.20 g, 3.74 mmol) and bis(pinacolato)diboron (1.14 g, 4.49 mmol) in toluene (20 mL) were added tris(dibenzylideneacetone)dipalladium (171 mg, 0.187 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (356.6 mg, 0.748 mmol) and potassium acetate (1.101 g, 11.22 mmol), the reaction mixture was heated to 90° C., and reacted overnight with stirring under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to obtain 8-e (336 mg, yield: 21.7%).

[0273] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.74-7.72 (d, J=0.5 Hz, 1H), 7.68-7.67 (d, J=0.5 Hz, 1H), 7.49-7.45 (d, J=6.0 Hz, 1H), 7.25-7.20 (m, 2H), 7.08-7.05 (d, J=16.5 Hz, 1H), 7.02-6.99 (t, J=9.0 Hz, 1H), 6.81-6.79 (m, 1H), 4.17-4.14 (m, 2H), 3.80-3.78 (m, 2H), 3.50 (s, 3H), 2.64 (3H, s), 1.39 (s, 12H).

[0274] Synthesis of Compound 8-d

[0275] To a solution of 8-e (336 mg, 0.815 mmol) and 1-b (297 mg, 0.679 mmol) in ethylene glycol dimethyl ether (10 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (58 mg, 0.068 mmol) and cesium fluoride (258 mg, 1.70 mmol), and the reaction mixture was stirred overnight at 80° C. under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=20:1 to 5:1) to obtain 8-d (100 mg, yield: 25.6%).

[0276] Synthesis of Compound 8-c

[0277] To a mixed solution of 8-d (100 mg, 0.174 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added sodium borohydride (13 mg, 0.348 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to obtain 8-c (80 mg, yield: 80%).

[0278] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.71 (s, 1H), 7.59-7.52 (m, 3H), 7.39-7.36 (d, J=16.0 Hz, 1H), 7.32 (s, 2H), 7.28-7.27 (d, J=8.0 Hz, 1H), 7.22-7.17 (m, 2H), 7.11-7.00 (m, 4H), 6.93-6.89 (t, J=9.0H, 1 Hz), 6.72-6.70 (m, 1H), 4.72 (s, 2H), 4.06-4.03 (m, 2H), 3.69-3.67 (m, 2H), 3.38 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H).

[0279] Synthesis of Compound 8-b

[0280] To a solution of 8-c (80 mg, 0.139 mmol) in dichloromethane (50 mL) was added thionyl chloride (82 mg, 0.694 mmol), and the reaction mixture was stirred overnight. After the completion of the reaction, the organic solvent was dried by spin drying, and the residue was further dried with an oil pump to obtain 8-b (82 mg, yield: 99%), which was directly used for the next reaction.

[0281] Synthesis of Compound 8-a

[0282] To a solution of 8-b (82 mg, 0.138 mmol) and (S)-2-methylserine methyl ester p-toluenesulfonate (84 mg, 0.28 mmol) in acetonitrile (10 mL) were added sodium iodide (10 mg, 0.068 mmol) and K.sub.2CO.sub.3 (191 mg, 1.38 mmol), and the reaction mixture was stirred overnight at 80° C. under nitrogen protection. After the completion of the reaction, the solvent was dried by spin drying, the residue was dissolved with ethyl acetate (100 mL) and washed with saturated sodium thiosulfate aqueous solution (100 mL×2) and saturated brine (100 mL×1). The resulting organic phase was dried over anhydrous sodium sulfate and dried by spin drying to obtain a crude compound, which was purified through preparation plate (petroleum ether:ethyl acetate=2:1) to obtain target compound 8-a (23 mg, yield: 24.2%). LC-MS (ESI): m/z=692.0 [M+H].sup.+.

[0283] Synthesis of Compound 8

[0284] To a mixed solution of 8-a (23 mg, 0.033 mmol) in methanol (10 mL) and water (1 mL) was added sodium hydroxide (6 mg, 0.15 mmol), and stirred overnight at room temperature. After the completion of the reaction, the solvent was dried by spin drying, the residue was diluted by adding water, then pH of the solution was adjusted to 4 to 5 using diluted hydrochloric acid (1 M), and a white solid was precipitated. The precipitate was filtered, and dried to obtain 8 (20 mg). LC-MS (ESI): m/z=678.0 [M+H].sup.+.

[0285] .sup.1H NMR (500 MHz, CD.sub.3OD): δ 8.22 (1H, s), 7.84-7.82 (d, J=8.5 Hz, 1H), 7.70-7.56 (m, 5H), 7.41-7.25 (m, 4H), 7.17-7.03 (m, 4H), 6.89-6.87 (m, 1H), 4.43 (s, 2H), 4.16-4.10 (m, 4H), 3.77-3.76 (m, 2H), 3.45 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 1.69 (s, 3H).

Example 9

2-({[(3-(E)-2-{3-[3-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-2-methylphenyl]-2-methylphenyl}ethenyl)-4-(trifluoromethyl)phenyl]methyl}amino)-1-ethanol 9

[0286] ##STR00130##

[0287] Synthesis of Compound 9-b

[0288] To a mixed solution of 3-formylphenylboric acid (1.0 g, 6.67 mmol) and 2,6-dibromotoluene (2.5 g, 10.0 mmol) in 1,4-dioxane (30 mL) and water (1.5 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (577 mg, 0.667 mmol) and sodium carbonate (1.768 g, 16.675 mmol), the reaction mixture was heated to 80° C. under nitrogen protection and stirred overnight. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to obtain target compound 9-b (1.106 g, yield: 60.1%).

[0289] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 10.0 (s, 1H), 7.83-7.81 (m, 1H), 7.73 (m, 1H), 7.55-7.47 (m, 3H), 7.11-7.09 (dd, J=1.0 Hz, J=7.5 Hz, 1H), 7.06-7.03 (t, J=8.0 Hz, 1H), 2.23 (s, 3H).

[0290] Synthesis of Compound 9-a

[0291] To a solution of 9-b (1.106 g, 4.02 mmol) and 1-d (2.00 g, 4.8 mmol) in ethylene glycol dimethyl ether (20 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (348 mg, 0.402 mmol) and cesium fluoride (1.527 g, 10.05 mmol), and the reaction mixture was stirred overnight at 80° C. under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to obtain 9-a (1.69 g, yield: 86.7%).

[0292] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 10.07 (s, 1H), 10.01 (s, 1H), 8.21 (s, 1H), 7.83-7.79 (m, 4H), 7.60-7.52 (m, 3H), 7.46-7.43 (d, J=15.5 Hz, 1H), 7.35-7.31 (m, 1H), 7.27-7.23 (m, 2H), 7.19-7.17 (m, 1H), 7.11-7.10 (m, 2H), 2.14 (s, 3H), 1.87 (s, 3H).

[0293] Synthesis of Compound 9

[0294] At ambient temperature, to a mixed solution of 9-a (100 mg, 0.206 mmol) and ethanolamine (25 mg, 0.41 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added glacial acetic acid (25 mg, 0.41 mmol), the reaction mixture was stirred for 1 hour, then sodium cyanoborohydride (63 mg, 1.0 mmol) was added thereto and stirred overnight at room temperature. The solvent was dried by spin drying, and the residue was purified through high performance liquid chromatography preparation to obtain target compound 9 (54 mg, yield: 45%). LC-MS (ESI): m/z=575.0 [M+H].sup.+.

[0295] .sup.1H NMR (500 MHz, CD.sub.3OD): δ 8.14 (s, 1H), 7.85-7.83 (d, J=8.0 Hz, 1H), 7.66-7.47 (m, 7H), 7.41-7.33 (m, 3H), 7.28-7.26 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.17-7.14 (m, 2H), 4.41 (s, 2H), 4.34 (s, 2H), 3.88-3.84 (m, 4H), 3.24-3.22 (m, 2H), 3.20-3.18 (m, 2H), 2.22 (s, 3H), 1.96 (s, 3H).

Example 10

2-({[(3-(E)-2-{3-[3-(5-{[(2-hydroxyethyl)amino]methyl}-2-fluoro-phenyl)-2-methylphenyl]-2-methylphenyl}ethenyl)-4-(trifluoromethyl)phenyl]methyl}amino)-1-ethanol

[0296] ##STR00131##

[0297] Synthesis of Compound 10-c

[0298] To a solution of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol) and bis(pinacolato)diboron (1.5 g, 5.91 mmol) in toluene (30 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (426 mg, 0.493 mmol) and potassium acetate (1.452 g, 14.79 mmol), and the reaction mixture was stirred overnight at 80° C. under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to obtain 10-c (1.1 g, yield: 90.2%).

[0299] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 10.00 (s, 1H), 8.32-8.31 (m, 1H), 8.04-8.01 (m, 1H), 7.22-7.19 (t, J=9.0 Hz, 1H), 1.40 (s, 12H).

[0300] Synthesis of Compound 10-b

[0301] To a mixed solution of 10-c (1.11 g, 4.439 mmol) and 2,6-dibromotoluene (1.664 g, 6.658 mmol) in 1,4-dioxane (30 mL) and water (1.5 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (384 mg, 0.444 mmol) and sodium carbonate (1.177 g, 11.1 mmol), the reaction mixture was heated to 80° C. and reacted overnight with stirring under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to obtain target compound 10-b (605 mg, yield: 46.5%).

[0302] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.94 (s, 1H), 7.89-7.85 (m, 1H), 7.74-7.73 (m, 1H), 7.58-7.56 (dd, J=2.0 Hz, J=7.5 Hz, 1H), 7.26-7.23 (t, J=9.0 Hz, 1H), 7.11-7.05 (m, 2H), 2.18 (s, 3H).

[0303] Synthesis of Compound 10-a

[0304] To a solution of 10-b (0.605 g, 2.064 mmol) and 1-d (1.031 g, 2.477 mmol) in ethylene glycol dimethyl ether (20 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (178.2 mg, 0.206 mmol) and cesium fluoride (784 mg, 5.16 mmol), and the reaction mixture was heated to 80° C. and reacted overnight with stirring under nitrogen protection. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=20:1 to 3:1) to obtain target compound 10-a (0.587 g, yield: 56.4%).

[0305] .sup.1H NMR (500 MHz, CDCl.sub.3): δ 10.08 (s, 1H), 9.96 (s, 1H), 8.21 (s, 1H), 7.88-7.80 (m, 4H), 7.56-7.55 (d, J=7.5 Hz, 1H), 7.46-7.43 (d, J=16.5 Hz, 1H), 7.35-7.31 (m, 1H), 7.29-7.23 (m, 3H), 7.16-7.11 (m, 3H), 2.13 (s, 3H), 1.82 (s, 3H).

[0306] Synthesis of Compound 10

[0307] To a mixed solution of 10-a (100 mg, 0.199 mmol) and ethanolamine (24.3 mg, 0.398 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added glacial acetic acid (23.9 mg, 0.398 mmol), the reaction mixture was stirred for 1 hour, then sodium cyanoborohydride (62.5 mg, 0.995 mmol) was added thereto and stirred overnight. After the completion of the reaction, the solvent was dried by spin drying, and the residue was purified through high performance liquid chromatography preparation to obtain target compound 10 (112 mg, yield: 95%). LC-MS (ESI): m/z=593.0 [M+H].sup.+.

[0308] .sup.1H NMR (500 MHz, CD.sub.3OD): δ8.15 (s, 1H), 7.84-7.83 (d, J=8.0 Hz, 1H), 7.67-7.55 (m, 5H), 7.41-7.27 (m, 5H), 7.22-7.15 (m, 2H), 4.41 (s, 2H), 4.32 (s, 2H), 3.88-3.84 (m, 4H), 3.24-3.19 (m, 4H), 2.22 (s, 3H), 1.89 (s, 3H).

Example 11

(2S)-2-[({3-[(E)-2-(3-{3-[5-({[(1S)-1-carboxyl-2-hydroxy-1-methylethyl]amino}methyl)-2-fluorophenyl]-2-methylphenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-3-hydroxy-2-methylpropanoic acid 11

[0309] ##STR00132##

[0310] Synthesis of Compound 11

[0311] (S)-2-methylserine (189.6 mg, 1.592 mmol) was suspended in methanol (5 mL), and a solution of sodium hydroxide (63.7 mg, 1.592 mmol) dissolved in 5 mL of water was added dropwise slowly. The reaction mixture was stirred until it was clear, then a solution of 10-a (100 mg, 0.199 mmol) in tetrahydrofuran (5 mL) was added, the reaction was stirred overnight, and then sodium borohydride (3 mg, 1.0 mmol) was added and the stirring was continued for half an hour. LC/MS was used to monitor the reaction process, after the completion of the reaction, the solvent was dried by spin drying, and the residue was purified through high performance liquid chromatography preparation to obtain compound 11 (48 mg, yield: 34.1%). LC-MS (ESI): m/z=709.0 [M+H].sup.+.

[0312] .sup.1H NMR (500 MHz, CD.sub.3OD): δ8.18 (s, 1H), 7.85-7.83 (d, J=8.5 Hz, 1H), 7.67-7.57 (m, 5H), 7.42-7.29 (m, 5H), 7.22-7.16 (m, 2H), 4.44-4.38 (dd, J=12.5 Hz, J=4.5 Hz, 2H), 4.37-4.31 (dd, J=13.0 Hz, J=4.5 Hz, 2H), 4.15-4.10 (t, J=12.0 Hz, 2H), 3.94-3.90 (m, 2H), 2.22 (s, 3H), 1.91 (s, 3H), 1.68 (s, 3H), 1.66 (s, 3H).

Example 12

2-[({3-[(E)-2-(3-{3-[(E)-2-(5-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)phenyl)ethenyl]-2-(fluoromethyl)phenyl}-2-methylphenyl)ethenyl]-4-(trifluoromethyl)phenyl}methyl)amino]-1-ethanol 12

[0313] ##STR00133##

[0314] Synthesis of Compound 12-b

[0315] 2,6-Dibromobenzyl alcohol (2.40 g, 9.06 mmol) was suspended in dry dichloromethane (60 mL), diethylaminosulfur trifluoride (1.90 mg, 11.8 mmol) was added dropwise at −78° C. slowly, and then continued to be stirred at −78° C. for 1 hour after the addition. TLC was used to monitor the completion of reaction. The reaction mixture was added slowly into saturated sodium bicarbonate aqueous solution (150 mL), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phase was combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (eluent: petroleum ether) to obtain white solid product 12-b (1.86 g, yield: 78%).

[0316] Synthesis of Compound 12-a

[0317] To 100 mL of three-necked flask were added 12-b (268 mg, 1.0 mmol), 4-f (391 mg, 1.2 mmol), 1-d (541 mg, 1.3 mmol), cesium fluoride (600 mg, 4.0 mmol), potassium phosphate (848 mg, 4.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (120 mg, 0.16 mmol) and toluene (25 mL). The reaction mixture was reacted under nitrogen protection with stirring at 80° C. for 6 hours. The reaction was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 8:1) to obtain yellowish solid 12-a (306 mg, yield: 44%).

[0318] Synthesis of Compound 12

[0319] To a solution of 12-a (150 mg, 0.25 mmol) in dichloromethane (10 mL) were added ethanolamine (61 mg, 1.0 mmol), methanol (10 mL), and glacial acetic acid (20 mg, 0.34 mmol). The reaction mixture was stirred for 1 hour, and then sodium cyanoborohydride (63 mg, 1.0 mmol) was added. After the addition, the stirring was continued for 16 hours. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified through silica gel column chromatography (dichloromethane:7N solution of ammonia in methanol=15:1) to obtain off-white solid 12 (54 mg, yield: 31%). LC-MS (ESI): m/z=687 [M+H].sup.+.

[0320] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.98 (s, 1H), 7.97 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.69-7.72 (m, 3H), 7.61-7.65 (m, 2H), 7.52-7.57 (m, 2H), 7.45 to 7.48 (m, 2H), 7.37 to 7.42 (m, 1H), 7.31 to 7.35 (m, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 5.36 to 5.45 (m, 1H), 5.24 to 5.33 (m, 1H), 3.93 (s, 2H), 3.92 (s, 2H), 3.71 (d, J=5.2 Hz, 4H), 2.76-2.79 (m, 4H), 2.19 (s, 3H).

Effect Examples

[0321] The binding ability of the compounds of the present disclosure to PD-1/PD-L1 was detected using Homogeneous Time-Resolved Fluorescence (HTRF) binding test.

[0322] The purchased kit (CisBio, #64CUS000C-1) contained the reagents needed for experiments, such as PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer and Detection Buffer.

Steps of Experiment

[0323] 1. The compound was prepared with 100% DMSO to 10 concentrations with a concentration gradient of 3 times.

[0324] 2. A solution of the compound in DMSO was added into Dilute Buffer, mixed uniformly, and then transferred into 96-well plate.

[0325] 3. PD-L1 was diluted with Dilute Buffer, and then added into the above 96-well plate.

[0326] 4. PD-1 was diluted with Dilute Buffer, and then added into the above 96-well plate and incubated at room temperature for 30 minutes.

[0327] 5. A part of anti-tag1-Eu and a part of Anti-tag2-XL665 were added into Detection Buffer, mixed uniformly and then transferred into the above 96-well plate.

[0328] 6. The mixed solution in this 96-well plate was incubated at room temperature for 1 hour to 24 hours.

[0329] 7. HTRF values were read with Envision.

Experimental Results

[0330] The biological activity of the compounds of the present disclosure was determined by the above test, and the tested results are shown as below (Table 1):

TABLE-US-00001 TABLE 1 IC.sub.50 values of some compounds of the present disclosure binding to PD-1/PD-L1 Compounds IC.sub.50 (μM) Compounds IC.sub.50 (μM) 1 0.0061 2 0.0044 3 0.0032 4 0.0043 5 0.0023 6 0.0028 7 0.0026 8 0.510 9 0.0075 10 0.014 11 0.0087 12 0.0047