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CN-121991029-A - Biphenyl compound and application thereof

CN121991029ACN 121991029 ACN121991029 ACN 121991029ACN-121991029-A

Abstract

The invention discloses a biphenyl compound and application thereof. The invention provides a biphenyl compound shown as a formula I or a formula II, pharmaceutically acceptable salts thereof, solvates thereof or solvates of pharmaceutically acceptable salts thereof. The biphenyl compounds have an inhibiting effect on PD-1/PD-L1 combination, and can be used for treating or diagnosing related diseases such as tumors and the like.

Inventors

  • WANG YUGUANG
  • CAI SENLIN
  • FENG ZHENHUA
  • ZHAO QIANG

Assignees

  • 上海再极医药科技有限公司

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241101

Claims (17)

  1. 1. A biphenyl compound shown in formula I or formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; ; R 1 is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with one or more R a ; Each R a is independently deuterium, halogen, hydroxy, amino, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-or-COOH-; L 1 is: (i) A single bond or- (CH 2 ) n -; (ii) - (CH 2 ) m -, wherein 1,2, 3,4 or 5 non-adjacent CH 2 are independently replaced by-Y 1 -, each Y 1 is independently-O-, C (O) -, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-; Or (iii) - (CH 2 ) p -, wherein 1 CH 2 is replaced by-Y 2 -, and the other 0,1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by-Y 3 -, each Y 3 is independently-O-, C (O) -, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-, Y 2 is a 5-7 membered carbocyclic ring or a 5-12 membered heterocyclic ring, wherein the number of heteroatoms is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; l 1 is unsubstituted or 1,2 or 3H contained in L 1 are each independently substituted with R 2 ; n, m and p are each independently 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13 or 14; Each R 2 is independently C 1 -C 4 alkyl or-L 3 -R 3 ; L 3 is: (i) -(CH 2 ) j -; Or (ii) - (CH 2 ) k -, wherein 1, 2, 3, or 4 non-adjacent CH 2 are independently replaced by-Y 4 -, each Y 4 is independently-O-, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-; l 3 is unsubstituted or 1,2 or 3H contained in L 3 are each independently substituted with R 4 ; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R 3 is hydrogen, C 6 -C 10 aryl or C 6 -C 10 aryl substituted with one or more R b ; each R 4 is independently C 1 -C 4 alkyl; each R b is independently C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with one or more R c ; Each R c is independently deuterium, halogen, hydroxy, amino, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-or-COOH-; l 2 is a radionuclide-containing group.
  2. 2. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein the biphenyl compound of formula I or formula II satisfies one or more of the following conditions: (1) In R 1 、R a and R c , the halogen is F, cl, br or I; (2) In R 1 、R a 、R 2 、R 4 、R b and R c , the C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more R a , and C 1 -C 4 alkyl in C 1 -C 4 alkyl substituted with one or more R c are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (3) When Y 2 is a 5-7 membered carbocycle, the 5-7 membered carbocycle is a 5-7 membered saturated carbocycle, preferably For example For another example ; (4) When Y 2 is a 5-12 membered heterocycle, the 5-12 membered heterocycle is a monocyclic or bicyclic ring, the bicyclic ring is a parallel ring, a spiro ring or a bridged ring, preferably a spiro ring; (5) When Y 2 is a 5-12 membered heterocycle, the 5-12 membered heterocycle is a 5-7 membered heterocycle or an 8-12 membered heterocycle; (6) When Y 2 is a 5-12 membered heterocycle, the 5-12 membered heterocycle is a 5-7 membered heterocycle, the 5-7 membered heterocycle is For example ; And (7) when Y 2 is a 5-12 membered heterocycle, said 5-12 membered heterocycle is an 8-12 membered heterocycle, said 8-12 membered heterocycle is a bicyclic ring, preferably a spiro ring, for example 、 Or (b) 。
  3. 3. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of pharmaceutically acceptable salt thereof according to claim 1, wherein the biphenyl compound of formula I or formula II satisfies one of the following schemes one and two: Scheme one: L 1 is: (ii) - (CH 2 ) m -, wherein 1,2, 3,4 or 5 non-adjacent CH 2 are independently replaced by-Y 1 -, each Y 1 is independently-O-, C (O) -, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-; Or (iii) - (CH 2 ) p -, wherein 1 CH 2 is replaced by-Y 2 -, and the other 0,1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by-Y 3 -, each Y 3 is independently-O-, C (O) -, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-, Y 2 is a 5-7 membered carbocyclic ring or a 5-12 membered heterocyclic ring, wherein the number of heteroatoms is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L 1 is unsubstituted or 1H contained in L 1 is substituted with R 2 ; m and p are each independently 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R 2 is-L 3 -R 3 ; L 3 is- (CH 2 ) k ) -in which 1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by-Y 4 -, each Y 4 is independently-C (O) NH-; l 3 is unsubstituted; k is 7, 8 or 9; R 3 is C 6 -C 10 aryl substituted with one or more R b , each R b is independently C 1 -C 4 alkyl; Scheme II, wherein L 1 is -O(CH 2 ) n1 -、-O(CH 2 ) n1 NH-、-O(CH 2 ) n1 O(CH 2 ) m1 -、-O(CH 2 ) n1 NH(CH 2 ) n2 O(CH 2 ) m1 、-O(CH 2 ) n1 NHC(O)(CH 2 ) m1 、-O(CH 2 ) n1 O(CH 2 ) m1 NH-、-O(CH 2 ) n1 O(CH 2 ) n2 O(CH 2 ) m1 NH-、-O(CH 2 ) n1 O(CH 2 ) n2 O(CH 2 ) m1 -、-O(CH 2 ) n1 OC(O)(CH 2 ) m1 -、-O(CH 2 )n 1 Y 2 -C(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 Y 2 -、-O(CH 2 ) n1 O(CH 2 ) n2 -NHC(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 O(CH 2 ) n2 -NHC(O)-(CH 2 ) m1 NH-、-O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NHC(O)-(CH 2 ) m1 NH- or -O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NH-C(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 -;, and the oxygen atom end is connected with a benzene ring; preferably, L 1 is -O(CH 2 ) n1 -、-O(CH 2 ) n1 NH-、-O(CH 2 ) n1 O(CH 2 ) m1 -、-O(CH 2 ) n1 O(CH 2 ) m1 NH-、O(CH 2 ) n1 O(CH 2 ) n2 O(CH 2 ) m1 NH-、-O(CH 2 ) n1 O(CH 2 ) n2 O(CH 2 ) m1 -、-O(CH 2 )n 1 Y 2 -C(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 Y 2 -、-O(CH 2 ) n1 O(CH 2 ) n2 -NHC(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 O(CH 2 ) n2 -NHC(O)-(CH 2 ) m1 NH-、-O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NHC(O)-(CH 2 ) m1 NH- or -O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NH-C(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 -; wherein the oxygen atom terminal is attached to a benzene ring; More preferably, L 1 is -O(CH 2 ) n1 O(CH 2 ) m1 -、-O(CH 2 )n 1 Y 2 -C(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NH-C(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 O(CH 2 ) n2 -NHC(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 -、-O(CH 2 ) n1 O(CH 2 ) n2 O(CH 2 ) m1 - or-O (CH 2 ) n1 -; Each n1, each n2, each n3, and each m1 is independently 1,2,3, 4, 5, or 6; L 1 is unsubstituted or one H in L 1 is substituted by R 2 ; preferably, n1 is 1, 2 or 5, n2 is 1 or 2, n3 is 1 or 2, and m1 is 1 or 2.
  4. 4. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof, as claimed in claim 1 or 3, wherein the biphenyl compound of formula I or formula II satisfies one or more of the following conditions: (1) R 1 is C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more R a , each R a is independently halogen; (2) Y 2 is a 5-7 membered saturated carbocycle, a 5-7 membered monocyclic heterocycloalkyl or an 8-12 membered bicyclic heterocycloalkyl, e.g 、 、 、 Or (b) ; (3) R 3 is phenyl or phenyl substituted with one or more R b ; (4) In R b , the C 1 -C 4 alkyl is methyl or ethyl; And (5) R 2 is 。
  5. 5. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein L 2 consists of a radionuclide-containing ion and a chelating group.
  6. 6. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof, as claimed in claim 5, wherein the biphenyl compound of formula I or formula II satisfies one or more of the following conditions: (1) The radionuclide is a radionuclide capable of releasing alpha rays, beta rays or gamma rays, preferably a radionuclide capable of releasing alpha rays; (2) The radionuclide is Mn、At、Ac、Pb、Th、Tb、Ra、Bi、F、K、Sc、Ti、Cr、Co、Fe、Ni、Ge、As、Se、Br、Rb、Ru、Pd、Rh、Ag、Sb、Sn、Pr、Pm、Eu、Gr、Dy、Ho、Yb、Os、Pt、Ir、Hg、Au、Lu、Y、I、Re、Ce、Sm、La、Cu、Zr、Sr、In、Tl、Ga、Nb、Mo、Tc、Te、Er、Gd、Hf、Ta、Po、Rn、Pa、U、Np、Pu、Am、Cm、Bk、Cf、Es、Fm、Md、No、Lr、Rf、Sg、Hs、Mt、Rg or Nh, preferably Mn、At、Ac、Pb、Th、Tb、Ra、Bi、F、K、Sc、Ti、Cr、Co、Fe、Ni、Ge、As、Se、Br、Rb、Ru、Pd、Rh、Ag、Sb、Sn、Pr、Pm、Eu、Gr、Dy、Ho、Yb、Os、Pt、Ir、Hg、Au、Y、I、Re、Ce、Sm、La、Cu、Zr、Sr、In、Tl、Ga、Nb、Mo、Tc、Te、Er、Gd、Hf、Ta、Po、Rn、Pa、U、Np、Pu、Am、Cm、Bk、Cf、Es、Fm、Md、No、Lr、Rf、Sg、Hs、Mt、Rg or Nh, more preferably Ac, pb or Ra, and even more preferably Ac or Pb; (3) The radionuclide is 51 Mn、 52 Mn、 43 K、 43 Sc、 44 Sc、 46 Sc、 47 Sc、 48 Sc、 49 Sc、 44 Ti、 51 Ti、 51 Cr、 57 Co、 58 Co、 59 Fe、 61 Fe、 63 Ni、 65 Ni、 66 Ni、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 71 Ge、 72 As、 72 Se、 75 Br、 76 Br、 77 As、 77 Br、 81 Rb、 86 Y、 88 Y、 90 Y、 89 Zr、 89 Sr、 94m Tc、 99m Tc、 97 Ru、 100 Pd、 101m Rh、 105 Rh、 103 Pd、 109 Pd、 111 Ag、 111 In、 113 In、 119 Sb、 121 Sn、 142 Pr、 143 Pr、 149 Pm、 149 Tb、 152 Tb、 155 Tb、 161 Tb、 151 Eu、 153 Eu、 169 Eu、 159 Gr、 165 Dy、 166 Ho、 175 Yb、 186 Re、 188 Re、 189 Re、 191 Os、 193 Pt、 194 Ir、 197 Hg、 198 Au、 199 Au、 211 At、 203 Pb、 212 Pb、 225 Ac、 226 Th、 227 Th、 223 Ra、 224 Ra、 212 Bi、 213 Bi、 18 F、 177 Lu、 134 Ce、 153 Sm、 132 La、 135 La、 139 La、 140 La、 124 I、 125 I、 123 I、 131 I、 201 Tl、 95 Nb、 99 Mo、 132 Te、 182 Hf、 210 Po,, preferably 51 Mn、 52 Mn、 43 K、 43 Sc、 44 Sc、 46 Sc、 47 Sc、 48 Sc、 49 Sc、 44 Ti、 51 Ti、 51 Cr、 57 Co、 58 Co、 59 Fe、 61 Fe、 63 Ni、 65 Ni、 66 Ni、 64 Cu、 67 Cu、 71 Ge、 72 As、 72 Se、 75 Br、 76 Br、 77 As、 77 Br、 81 Rb、 86 Y、 88 Y、 90 Y、 89 Zr、 89 Sr、 94m Tc、 99m Tc、 97 Ru、 100 Pd、 101m Rh、 105 Rh、 103 Pd、 109 Pd、 111 Ag、 111 In、 113 In、 119 Sb、 121 Sn、 142 Pr、 143 Pr、 149 Pm、 149 Tb、 152 Tb、 155 Tb、 161 Tb、 151 Eu、 153 Eu、 169 Eu、 159 Gr、 165 Dy、 166 Ho、 175 Yb、 186 Re、 188 Re、 189 Re、 191 Os、 193 Pt、 194 Ir、 197 Hg、 198 Au、 199 Au、 211 At、 203 Pb、 212 Pb、 225 Ac、 226 Th、 227 Th、 223 Ra、 224 Ra、 212 Bi、 213 Bi、 18 F、 134 Ce、 153 Sm、 132 La、 135 La、 139 La、 140 La、 124 I、 125 I、 123 I、 131 I、 201 Tl、 95 Nb、 99 Mo、 132 Te、 182 Hf、 210 Po,, more preferably 225 Ac、 203 Pb、 212 Pb、 223 Ra or 224 Ra, and even more preferably 225 Ac、 203 Pb or 212 Pb; (4) The valence of the radionuclide ion is monovalent, divalent, trivalent or tetravalent, such as divalent, trivalent or tetravalent; (5) The ions of the radionuclide are ions of radioactive metals or ions of radioactive non-metals, preferably ions of radioactive metals; Preferably, the ion of the radioactive metal is 44 Ti 4+ 、 51 Cr 3+ 、 59 Fe 2+ 、 63 Ni 2+ 、 177 Lu 3+ 、 68 Ga 3+ 、 47 Sc 3+ 、 57 Co 2 + 、 58 Co 2+ 、 71 Ge 4+ 、 81 Rb + 、 90 Y 4+ 、 225 Ac 3+ 、 212 Pb 2+ 、 203 Pb 2+ 、 223 Ra 3+ 、 224 Ra 3+ 、 67 Cu 2+ 、 161 Tb 3+ 、 213 Bi 3+ 、 212 Bi 3+ 、 89 Zr 4+ 、 99 Mo 3+ 、 111 In 3+ 、 113 In 3+ 、 153 Eu 3+ 、 186 Re 3+ 、 188 Re 3+ 、 153 Sm 3+ 、 134 Ce 3+ 、 132 La 3+ 、 135 La 3+ 、 139 La 3+ 、 140 La 3+ 、 99m Tc 4+ 、 201 Tl 3+ 、 226 Th 4+ or 227 Th 4+ , preferably 44 Ti 4+ 、 51 Cr 3+ 、 59 Fe 2+ 、 63 Ni 2+ 、 47 Sc 3+ 、 57 Co 2 + 、 58 Co 2+ 、 71 Ge 4+ 、 81 Rb + 、 90 Y 4+ 、 225 Ac 3+ 、 212 Pb 2+ 、 203 Pb 2+ 、 223 Ra 3+ 、 224 Ra 3+ 、 67 Cu 2+ 、 161 Tb 3+ 、 213 Bi 3+ 、 212 Bi 3+ 、 89 Zr 4+ 、 99 Mo 3+ 、 111 In 3+ 、 113 In 3+ 、 153 Eu 3+ 、 186 Re 3+ 、 188 Re 3+ 、 153 Sm 3+ 、 134 Ce 3+ 、 132 La 3+ 、 135 La 3+ 、 139 La 3+ 、 140 La 3+ 、 99m Tc 4+ 、 201 Tl 3+ 、 226 Th 4+ or 227 Th 4+ , more preferably 225 Ac 3+ 、 212 Pb 2+ 、 203 Pb 2+ 、 223 Ra 3+ or 224 Ra 3+ , still more preferably 225 Ac 3+ 、 212 Pb 2+ or 203 Pb 2+ ; preferably, the radioactive nonmetallic ion is [ Al 18 F] 2+ ; And (6) the chelating group is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) Wherein the a-terminus is linked to L 1 , preferably the chelating group is 、 、 、 、 、 、 Or (b) More preferably Or (b) 。
  7. 7. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof, as claimed in claim 1, wherein the biphenyl compound of formula I or formula II satisfies one or both of the following conditions: (1) L 1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) Wherein the b-terminal is connected with benzene ring; Preferably, L 1 is 、 、 、 、 、 、 、 、 、 、 Or (b) Wherein the b-terminal is connected with benzene ring; and (2) L 2 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) Preferably, L 2 is Or (b) 。
  8. 8. The biphenyl compound of formula I or formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein the biphenyl compound of formula I or formula II satisfies one of the following schemes one, two, and three: Scheme one: L 2 consists of ions containing a radionuclide and a chelating group, wherein the radionuclide is 225 Ac、 203 Pb or 212 Pb; the chelating group is 、 、 、 、 、 、 Or (b) ; Scheme II: a biphenyl compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; ; R 1 is C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more R a , each R a is independently halogen; L 1 is -O(CH 2 ) n1 O(CH 2 ) m1 -、-O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NH-C(O)-(CH 2 ) n3 -NHC(O)-(CH 2 ) m1 - or -O(CH 2 ) n1 -NHC(O)-Y 2 -(CH 2 ) n2 -NHC(O)-(CH 2 ) m1 NH-;Y 2 is a 5-7 membered saturated carbocyclic ring, each n1, each n2, each n3 and each m1 is independently 1 or 2; Preferably, L 1 is 、 Or (b) Wherein the b-terminal is connected with benzene ring; L 2 consists of an ion containing a radionuclide and a chelating group, wherein the radionuclide is 225 Ac; the chelating group is Or (b) ; Scheme III: A biphenyl compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; ; L 1 is-O (CH 2 )n 1 Y 2 -C(O)-(CH 2 ) m1 -or-O (CH 2 ) n1 Y 2 -;Y 2 is a 5-7 membered heterocycloalkyl; each n1 and each m1 are each independently 1 or 2; Preferably, L 1 is Or (b) Wherein the b-terminal is connected with benzene ring; L 2 consists of an ion containing a radionuclide and a chelating group, wherein the radionuclide is 225 Ac; the chelating group is Or (b) 。
  9. 9. The biphenyl compound of formula I or formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof according to claim 1, wherein the biphenyl compound of formula I is selected from any one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) ; The compound shown in the formula II is selected from any one of the following structures: 、 、 、 、 、 Or (b) 。
  10. 10. A biphenyl compound shown in formula III or formula IV, pharmaceutically acceptable salt thereof, solvate thereof or solvate of pharmaceutically acceptable salt thereof, ; Wherein, the L 4 is a group containing a non-radionuclide, preferably L 4 is composed of ions containing a non-radionuclide and a chelating group; The chelating group, R 1 and L 1 are as defined in any one of claims 1 to 9.
  11. 11. The biphenyl compound of formula III or formula IV, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof, as claimed in claim 10, wherein the biphenyl compound of formula III or formula IV satisfies one or more of the following conditions: (1) The nonradionuclide is Mn、At、Ac、Pb、Th、Tb、Ra、Bi、F、K、Sc、Ti、Cr、Co、Fe、Ni、Ge、As、Se、Br、Rb、Ru、Pd、Rh、Ag、Sb、Sn、Pr、Pm、Eu、Gr、Dy、Ho、Yb、Os、Pt、Ir、Hg、Au、Lu、Y、I、Re、Ce、Sm、La、Cu、Zr、Sr、In、Tl、Ga、Nb、Mo、Tc、Te、Er、Gd、Hf、Ta、Po、Rn、Pa、U、Np、Pu、Am、Cm、Bk、Cf、Es、Fm、Md、No、Lr、Rf、Sg、Hs、Mt、Rg or Nh, preferably Mn、At、Ac、Pb、Th、Tb、Ra、Bi、F、K、Sc、Ti、Cr、Co、Fe、Ni、Ge、As、Se、Br、Rb、Ru、Pd、Rh、Ag、Sb、Sn、Pr、Pm、Eu、Gr、Dy、Ho、Yb、Os、Pt、Ir、Hg、Au、Y、I、Re、Ce、Sm、La、Cu、Zr、Sr、In、Tl、Nb、Mo、Tc、Te、Er、Gd、Hf、Ta、Po、Rn、Pa、U、Np、Pu、Am、Cm、Bk、Cf、Es、Fm、Md、No、Lr、Rf、Sg、Hs、Mt、Rg or Nh, more preferably Ac, pb or Ra, even more preferably Ac or Pb; (2) The ion of the non-radionuclide is Ti 4+ 、Cr 3+ 、Fe 2+ 、Ni 2+ 、Lu 3+ 、Ga 3+ 、Sc 3+ 、Co 2+ 、Ge 4+ 、Rb + 、Y 4+ 、Ac 3+ 、Pb 2+ 、Ra 3+ 、Cu 2+ 、Tb 3+ 、Bi 3+ 、Zr 4+ 、Mo 3+ 、In 3+ 、Eu 3+ 、 1 Re 3+ 、Sm 3+ 、Ce 3+ 、La 3+ 、Tc 4+ 、Tl 3+ or Th 4+ , preferably Ti 4+ 、Cr 3+ 、Fe 2+ 、Ni 2+ 、Sc 3+ 、Co 2+ 、Ge 4+ 、Rb + 、Y 4+ 、Ac 3+ 、Pb 2+ 、Ra 3+ 、Cu 2+ 、Tb 3+ 、Bi 3+ 、Zr 4+ 、Mo 3+ 、In 3+ 、Eu 3+ 、 1 Re 3+ 、Sm 3+ 、Ce 3+ 、La 3+ 、Tc 4+ 、Tl 3+ or Th 4+ , more preferably Ac 3+ 、Pb 2+ or Ra 3+ , and further preferably Ac 3+ or Pb 2+ ; and (3) L 4 is 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  12. 12. The biphenyl compound of formula III or formula IV, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of pharmaceutically acceptable salt thereof according to claim 10, wherein the biphenyl compound of formula III or formula IV has any one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  13. 13. A pharmaceutical composition comprising a substance a and a pharmaceutical adjuvant, wherein the substance a is a substance B, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and the substance B is a biphenyl compound of formula I or formula II according to any one of claims 1 to 9 or a biphenyl compound of formula III or formula IV according to any one of claims 10 to 12.
  14. 14. Use of a biphenyl compound of formula I or formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9 in the manufacture of a medicament; the medicine is used for treating tumors or diagnosing tumors; Preferably, when the drug is a drug for treating tumor, the radionuclide in the biphenyl compound shown in formula I or formula II is a radionuclide ion for treatment, such as 225 Ac 3+ 、 212 Pb 2+ 、 203 Pb 2+ or 224 Ra 3+ ; preferably, when the drug is a drug for diagnosing tumor, the radionuclide in the biphenyl compound shown in formula I or formula II is radionuclide ion for diagnosis.
  15. 15. Use of a biphenyl compound of formula III or formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 10-12 in the manufacture of a medicament for the treatment and/or prophylaxis of a tumour.
  16. 16. The use according to claim 14 or 15, wherein the tumor is a PD-1/PD-L1 associated or mediated tumor, such as colorectal, prostate, lung, gastric, cervical, ovarian, breast, pancreatic, liver, bladder, renal, bone, melanoma, glioma, glioblastoma or leukemia, and such as colorectal, lung or prostate cancer.
  17. 17. A method of treating a tumor comprising administering to a tumor patient a therapeutically effective amount of a biphenyl compound of formula I or formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-9; preferably, the radionuclide in the biphenyl compound shown in the formula I or the formula II is radionuclide ion for treatment, such as 225 Ac 3+ 、 212 Pb 2+ 、 203 Pb 2+ or 224 Ra 3+ ; preferably, the tumor is a PD-1/PD-L1-associated or mediated tumor, such as colorectal cancer, prostate cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, renal cancer, bone cancer, melanoma, glioma, glioblastoma or leukemia, and further such as colorectal cancer, lung cancer or prostate cancer.

Description

Biphenyl compound and application thereof Technical Field The invention relates to a biphenyl compound and application thereof. Background Radionuclide-conjugated drugs (Radioactive Drug Conjugates, RDCs) refer to a special class of drugs containing radionuclides for medical diagnosis and treatment, and generally consist of a radioisotope in combination with a molecular reagent specifically targeted to a specific organ and tissue, wherein the molecular reagent functions to deliver the radioisotope to the specific organ, tissue or cell. After a patient takes a radiopharmaceutical orally or by injection, radiation emitted from a radioisotope contained in the radiopharmaceutical for diagnosis and treatment of a particular disease is detected by PET or SPECT. The radiopharmaceuticals can reflect pathological genes, molecules, metabolism and functional states by utilizing the biological characteristics of the marked carrier, can be used for more early and specific insight into the information of the disease molecular level, and can also be used for accurately killing tumors by utilizing the radiation energy of the radionuclide. In recent years, with the successful marketing of two heavy-duty therapeutic radiopharmaceuticals Lutathera and Pluvicto of North, and the increasing availability/union of biomedical bulk to radiopharmaceutical businesses or product lines, radiopharmaceutical research has received increased attention from businesses both abroad and abroad. Radionuclide-coupled drugs are classified into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals according to clinical use. In radiopharmaceuticals currently in the clinical research and marketing stage, the main research targets are focused on PSMA, SSTR, FAP, CAIX, and the like. At present, no small-molecule radionuclide coupling medicine based on PD-1/PD-L1 targets is marketed in the prior art, so that the development of a radiopharmaceutical with strong targeting for treatment or diagnosis and treatment integration has great significance in bringing more new treatment choices for more patients. Disclosure of Invention The invention provides a biphenyl compound with a brand new structure and application thereof, wherein the biphenyl compound has an inhibition effect on PD-1/PD-L1 combination and can be used for treating or diagnosing related diseases such as tumors and the like. The invention provides a biphenyl compound shown as a formula I or a formula II, pharmaceutically acceptable salts thereof, solvates thereof or solvates of pharmaceutically acceptable salts thereof; ; R 1 is hydrogen, halogen, C 1-C4 alkyl or C 1-C4 alkyl substituted with one or more R a; Each R a is independently deuterium, halogen, hydroxy, amino, C 1-C4 alkyl, C 1-C4 alkyl-O-or-COOH-; L 1 is (I) A single bond or- (CH 2)n -; (ii) - (CH 2)m -, wherein 1, 2, 3,4 or 5 non-adjacent CH 2 are independently replaced by-Y 1 -, each Y 1 is independently-O-, C (O) -, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-, or (Iii) - (CH 2)p -, wherein 1 CH 2 is replaced by-Y 2 -, and the other 0,1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by-Y 3 -, each Y 3 is independently-O-, C (O) -, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-, Y 2 is a 5-7 membered carbocyclic ring or a 5-12 membered heterocyclic ring, wherein the number of heteroatoms is 1,2, 3 or 4, and each heteroatom is independently selected from N, O and S; l 1 is unsubstituted or 1,2 or 3H contained in L 1 are each independently substituted with R 2; n, m and p are each independently 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13 or 14; Each R 2 is independently C 1-C4 alkyl or-L 3-R3; l 3 is (I) - (CH 2)j -; or (Ii) - (CH 2)k -, wherein 1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by-Y 4 -, each Y 4 is independently-O-, -C (O) O-, -NH-, -C (O) NH-, or-NHC (O) NH-; l 3 is unsubstituted or 1,2 or 3H contained in L 3 are each independently substituted with R 4; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R 3 is hydrogen, C 6-C10 aryl or C 6-C10 aryl substituted with one or more R b; each R 4 is independently C 1-C4 alkyl; each R b is independently C 1-C4 alkyl or C 1-C4 alkyl substituted with one or more R c; Each R c is independently deuterium, halogen, hydroxy, amino, C 1-C4 alkyl, C 1-C4 alkyl-O-or-COOH-; l 2 is a radionuclide-containing group. In some embodiments, R 1 is C 1-C4 alkyl or C 1-C4 alkyl substituted with one or more R a, each R a is independently halogen. In some embodiments, in R 1、Ra and R c, the halogen is F, cl, br, or I. In some embodiments, in R 1、Ra、R2、R4、Rb and R c, the C 1-C4 alkyl, C 1-C4 alkyl substituted with one or more R a, and C 1-C4 alkyl in C 1-C4 alkyl substituted with one or more R c are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, L 1 is (Ii) - (CH 2)m -, wherein 1, 2, 3,4 or 5 non-adjacent CH 2 are independently replaced by-Y 1 -, each Y 1 is independ