JPWO2020200880A5

JPWO2020200880A5 -

Info

Publication number: JPWO2020200880A5
Application number: JP2021557758A
Authority: JP
Publication date: 2022-08-24
Anticipated expiration: 2040-03-23

Claims

Formula I:

[wherein ^RL is a linker attached to an antibody or antigen-binding fragment of an antibody, which is:
(ia):

(In the formula,
Q is:

(where Q ^X is such that Q is an amino acid residue, a dipeptide residue, a tripeptide residue, or a tetrapeptide residue, and the superscript labels ^{C (=O)} and ^NH are represents the group to which the atom is attached );
X is:

(wherein a = 0-5, b1 = 0-16, b2 = 0-16, c1 = 0 or 1, c2 = 0 or 1, d = 0-5, where at least b1 or b2 = 0 , at least c1 or c2=0);
^GL is a linker attached to the antibody or antigen-binding fragment of the antibody,

(wherein Ar represents a C _5-6 arylene group and X′ represents a C _1-4 alkyl) ;
(ib):

(wherein R ^L1 and R ^L2 are independently selected from H and methyl, or together with the carbon atoms to which they are attached form a cyclopropylene or cyclobutylene group;
e is 0 or 1 )
selected from ]
or a salt or solvate thereof.

R ^L is of Formula Ia and Q is:
(a) is an amino acid residue selected from Phe, Lys, Val, Ala, Cit, Leu, Ile, 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
is 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 2 -αGlu-Val-Ala- ^C═O , and
is a tripeptide residue selected from ^NH 2 -αGlu-Val-Cit- ^C=O ; or
(d)
^NH -Gly-Gly-Phe-Gly ^C=O ; and
a tetrapeptide residue selected from ^NH 2 -Gly-Phe-Gly-Gly ^C═O ;
(where ^NH- represents the N-terminus of the residue and ^-C=O represents the C- terminus of the residue)
A compound according to claim 1 .

a is:
(a) 0 to 3; or (b) 0 or 1; or (c) 0 , and
Optionally, b1 is:
(a) is between 0 and 8; or
(b) is 0; or
(c) is 2; or
(d) is 3; or
(e) is 4; or
(f) is 5; or
(g) is 8, and
Optionally, b2 is:
(a) is between 0 and 8; or
(b) is 0; or
(c) is 2; or
(d) is 3; or
(e) is 4; or
(f) is 5; or
(g) is 8;
A compound according to claim 2 .

(i) c1 is:
(a) is 0; or (b) is 1;
(ii) c2 is:
(a) is 0; or (b) is 1;
wherein at least one of c1 and c2 is 0 , and
Optionally, d is:
(a) is between 0 and 3; or
(b) is 1 or 2; or
(c) is 2; or
(d) is 5;
4. A compound according to claim 2 or 3 .

(a) whether a is 0, b1 is 0, c1 is 1, c2 is 0, d is 2, and b2 is 0, 2, 3, 4, 5, or 8; or (b) a is 1, b2 is 0, c1 is 0, c2 is 0, d is 0, and b1 is 0, 2, 3, 4, 5, or 8 or (c) a is 0, b1 is 0, c1 is 0, c2 is 0, d is 1, b2 is 0, 2, 3, 4, 5, or or (d) b1 is 0, b2 is 0, c1 is 0, c2 is 0, one of a and d is 0, and of a and d is 1 or 5; or (e) a is 1, b2 is 0, c1 is 0, c2 is 1, d is 2, b1 is 0, 2, is 3, 4, 5, or 8;
A compound according to any one of claims 2-4 .

A compound according to any one of claims 1 to 5 , wherein ^GL is selected from ^GL1-1 and ^GL1-2 .

R ^L is of Formula Ib, and;
(a) R ^L1 and R ^L2 are both H; or (b) R ^L1 is H and R ^L2 is methyl; or (c) R ^L1 and R ^L2 are both methyl or (d) R ^L1 and R ^L2 together with the carbon atom to which they are attached form a cyclopropylene group; or (e) R ^L1 and R ^L2 are 2. The compound of claim 1, which together with the remaining carbon atoms form a cyclobutylene group.

1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide)-N-((S)-1-(((S)-1-((( S)-9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7 ] indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-3,6,9,12 , 15,18,21,24-octaoxaheptacosane-27-amide.

(S)-2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetamido)-N-((S)-1-(((S)-9-ethyl-9-hydroxy -10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline -4-yl)amino)-1-oxopropan-2-yl)-3-methylbutanamide, the compound of claim 1.

N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-2,3,9,10,13,15-hexahydro -1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)- 3-methyl-1-oxobutan-2-yl)-4,7,10,13,16-pentaoxanonadeca-18-ynamide, the compound of claim 1;

Formula IV:
L-(D ^L ) _p (IV)
[wherein L is a ligand unit and D ^L is a compound of formula III:

(where R ^LL is
(ia′):

(wherein Q and X are as defined in any one of claims 1 to 5 , ^GLL is a linker connected to the ligand unit ,

(wherein Ar represents a C _5-6 arylene group and X′ represents a C _1-4 alkyl) ; and (ib′):

wherein R ^L1 and R ^L2 are as defined in either claim 1 or claim 7 is a linker connected to said Ligand unit. is a linker unit;
p is an integer from 1 to 20 ; and
Said Ligand unit is an antibody or an active fragment thereof ]
or a pharmaceutically acceptable salt or solvate thereof.

The conjugate of claim 11 , wherein G ^LL is selected from G ^LL1-1 and G ^LL1-2 .

Q is a dipeptide residue, ^ＮＨNH -Val-Ala- ^Ｃ＝ＯC=O , a is 0, b1 is 0, c1 is 1, c2 is 0, d is 2, b2 is 8, G ^ＬＬLL is G ^{ＬＬ１－１LL1-1} and ^ＮＨNH - represents the N-terminus of the residue, - ^Ｃ＝ＯC=O A conjugate according to claim 11, wherein is a dipeptide residue, representing the C-terminus of the residue.

The conjugate according to any one of claims 11-13, wherein the drug loading (p) of the drug (D) relative to the antibody (Ab) is an integer of 1-10 .

A pharmaceutical composition comprising a conjugate according to any one of claims 11 to 14 and a pharmaceutically acceptable diluent, carrier or excipient.

16. A pharmaceutical composition according to claim 15 for use in treating cancer in a subject.

Formula VI:

A compound having [Q is as defined in either claim 1 or 2 ].