JPWO2021148500A5 - - Google Patents

Claims (29)

Formula I:
(wherein X ¹ and X ² are of formula Ia:
independently selected from the group, Q is
where Q ^X is such that Q is an amino acid residue, a dipeptide residue, a tripeptide residue or a tetrapeptide residue;
a=0-5, b1=0-16, b2=0-16, where at least b1 or b2=0;
Y is H or F;
c1 is 0 to 5;
c2 is 0 to 5;
X ³ is -CH ₂ - or -C(=O)-;
X ⁴ is ^X3 - (CH ₂ ) _d1 - (C ₂ H ₄ O) _e - (CH ₂ ) _d2 - ^GL , where d1 is from 0 to 5 and d2 is from 0 to 5. Yes, e is 0 to 16;
^GL is a linker for connecting to the ligand unit)
A compound with Q is
(a) an amino acid residue selected from Phe, Lys, Val, Ala, Cit, Leu, He, Arg, and Trp; or (b) ^NH -Phe-Lys- ^C=O ,
^NH -Val-Ala- ^C=O ,
^NH -Val-Lys- ^C=O ,
^NH -Ala-Lys- ^C=O ,
^NH -Val-Cit- ^C=O ,
^NH -Phe-Cit- ^C=O ,
^NH -Leu-Cit- ^C=O ,
^NH -Ile-Cit- ^C=O ,
^NH -Phe-Arg- ^C=O ,
^NH -Trp-Cit- ^C=O , and
a dipeptide residue selected from ^NH -Gly-Val- ^C=O ; or (c) ^NH -Glu-Val-Ala- ^C=O ,
^NH -Glu-Val-Cit- ^C=O ,
^NH -αGlu-Val-Ala- ^C=O , and
or (d) a tripeptide residue selected from ^NH -αGlu-Val-Cit- ^C=O ; or (d) ^NH -Gly-Gly-Phe-Gly ^C=O ; and
The compound according to claim 1, which is a tetrapeptide residue selected from ^NH -Gly-Phe-Gly-Gly ^C=O . a is,
(a) 0-3; or (b) 0 or 1; or (c) 0
The compound according to claim 1 or claim 2, which is b1 is
(a) 0-8; or (b) 0; or (c) 2; or (d) 3; or (e) 4; or (f) 5; or (g) 8
The compound according to any one of claims 1 to 3, which is b2 is
(a) 0-8; or (b) 0; or (c) 2; or (d) 3; or (e) 4; or (f) 5; or (g) 8
The compound according to any one of claims 1 to 3, which is A compound according to any one of claims 1 to 5, wherein Y is H. A compound according to any one of claims 1 to 6, wherein X ¹ and X ² are the same. c1 is
(a) 0-3;
(b) 1 or 2; or (c) 2
The compound according to any one of claims 1 to 7, which is c2 is
(a) 0-3;
(b) 1 or 2; or (c) 2
The compound according to any one of claims 1 to 8, which is A compound according to any one of claims 1 to 9, wherein c1 and c2 are the same. A compound according to any one of claims 1 to 10, wherein X ³ is -C(=O)-. d1 is
(a) 0-3;
(b) 1 or 2; or (c) 2
The compound according to any one of claims 1 to 11, which is d2 is
(a) 0-3;
(b) 1 or 2; or (c) 2; or (d) 0
A compound according to any one of claims 1 to 12, which is e is,
(a) 0-8;
(b) 0;
(c)2;
(d) 4; or (e) 8
A compound according to any one of claims 1 to 13, which is The compound according to any one of claims 1 to 11, wherein d1+d2 is 2 and e is 0. Each a is 0, each b1 is 0, each b2 is 2, c1 is 2, c2=2, X3=-C(=O)-, and d1 is 2, d2 is 0, and e is 0. ^GL is
A compound according to any one of claims 1 to 16, selected from: in which Ar represents a C _5-6 arylene group and X represents C _1-4 alkyl. 18. A compound according to claim 17, wherein G ^L is selected from G ^L1-1 and G ^L1-2 . Formula IV:
L-( ^DL ) _p (IV)
(wherein L is a ligand unit and D ^L is a formula III:
^a drug linker unit ^{which is} of ^the formula:
^GLL is a linker connecting the ligand unit;
p is an integer from 1 to 20)
or a pharmaceutically acceptable salt or solvate thereof. ^GLL is
Complex according to claim 19, selected from: wherein Ar represents a C _5-6 arylene group and X represents C _1-4 alkyl. 21. The conjugate of claim 20, wherein G ^LL is selected from G ^LL1-1 and G ^LL1-2 . A conjugate according to claim 19 or 20, wherein the ligand unit is an antibody or an active fragment thereof. 23. The conjugate of claim 22, wherein p is an integer from 1 to about 10. 24. The mixture of conjugates of claim 22 or 23, wherein the average drug loading per antibody in the mixture of antibody drug conjugates is about 2 to about 20. A pharmaceutical composition comprising a complex or mixture according to any one of claims 19 to 24 and a pharmaceutically acceptable excipient, carrier or additive. 26. A pharmaceutical composition according to claim 25 for the treatment of a proliferative disease in a subject. 27. The pharmaceutical composition according to claim 26, wherein the disease is cancer. A medicament for medical treatment, comprising a complex or mixture according to any one of claims 19 to 24 or a pharmaceutical composition according to claim 25. 29. A medicament according to claim 28 , wherein the medical treatment is for treating cancer.