LIGAND-DRUG CONJUGATE OF EXATECAN ANALOGUE, AND MEDICAL USE THEREOF
Provided herein are compounds having formulas (I) or (VII): or pharmaceutically acceptable salts, tautomers, isotopologues, stereoisomers, or prodrugs thereof, wherein the substituents are as described herein; ligand-drug conjugates and pharmaceutically acceptable salts or solvates thereof, wherein the ligand-drug conjugate comprises a residue of the compound provided here; and methods of treating cancer thereof.
1 . (canceled)
2 . A compound of formula (II):
or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, or prodrug thereof, wherein
A is CR 1 R 2 or N—R 1 ;
B is a bond, —C(═O)—, —C(═O)O—, or —OC(═O)—;
each of R 1 and R 2 is, independently, H or C 1-4 alkyl;
each of R 3 and R 4 is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxyl; or R 3 and R 4 , together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
each of R 5 and R 6 is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxyl;
n is 1, 2, 3, 4, or 5; and
when R 3 is methyl and R 4 is F, A-B is not —NH—C(═O)—.
3 . The compound of claim 2 , wherein A is CH 2 and B is a bond.
4 . The compound of claim 3 , wherein R 5 and R 6 are hydrogen and n is 1, 2, or 3.
5 . The compound of claim 4 , wherein R 3 is methyl and R 4 is F.
6 . The compound of claim 5 , wherein the compound is
7 . The compound of claim 4 , wherein R 3 and R 4 , together with the atoms to which they are attached, form an unsubstituted or substituted dioxole ring.
8 . The compound of claim 7 , wherein the compound is
9 . The compound of claim 2 , wherein R 3 is methyl, R 4 is F, A is N(CH 3 ), and B is a bond.
10 . (canceled)
11 . The compound of claim 9 , wherein the compound is
12 . The compound of claim 2 , wherein R 3 is methyl, R 4 is F, A is NH, and B is —C(═O)O—.
13 . (canceled)
14 . The compound of claim 12 , wherein the compound is
15 . (canceled)
16 . The compound of claim 2 , wherein the compound is
17 . (canceled)
18 . (canceled)
19 . The compound of claim 2 , wherein R 3 and R 4 , together with the atoms to which they are attached, form unsubstituted or substituted heterocyclyl.
20 . The compound of claim 19 , wherein R 3 and R 4 , together with the atoms to which they are attached, form an unsubstituted or substituted dioxole ring, and B is —C(═O)—.
21 . The compound of claim 20 , wherein the compound is
22 . The compound of claim 2 , wherein the compound is a compound of formula (III):
or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, or prodrug thereof,
wherein R 3 and R 4 together are not methyl and F, respectively.
23 . The compound of claim 22 , wherein the compound is
24 - 30 . (canceled)
31 . The compound of claim 22 , wherein R 3 and R 4 , together with the atoms to which they are attached, form unsubstituted or substituted heterocyclyl.
32 . The compound of claim 31 , wherein R 3 and R 4 , together with the atoms to which they are attached, form an unsubstituted or substituted dioxole ring.
33 . The compound of claim 32 , wherein the compound is
34 . (canceled)
35 . The compound of claim 2 , wherein the compound is
36 . (canceled)
37 . (canceled)
38 . A ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate comprises a residue of the compound of claim 2 .
39 . (canceled)
40 . The ligand-drug conjugate of claim 38 , wherein the ligand is an antibody selected from patritumab, cofetuzumab, trastuzumab, ifinatamab, and mAb10.
41 . A compound of formula (VII):
or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer, or prodrug thereof, wherein
each of R 7 and R 8 is, independently, hydrogen or substituted or unsubstituted alkyl; or R 7 and R 8 , together with the nitrogen atom to which they are attached, form unsubstituted or substituted heterocyclyl or unsubstituted or substituted heteroaryl.
42 . The compound of claim 41 , wherein the compound is
43 . A ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate comprises a residue of the compound of claim 41 .
44 - 48 . (canceled)
49 . An antibody or antigen binding fragment thereof that specifically binds human HER3, comprising:
(i) a heavy chain variable region that comprises the amino acid sequence of SEQ ID NO: 1; and
(ii) a light chain variable region that comprises the amino acid sequence of SEQ ID NO: 2.
50 - 54 . (canceled)
55 . The compound of claim 2 , wherein A is N—R 1 ; B is —C(═O)O—; R 1 , R 5 , and R 6 are each hydrogen; R 3 and R 4 , together with the atoms to which they are attached, form an unsubstituted or substituted dioxole ring; and n is 2.
56 . The compound of claim 20 , wherein A is N—R 1 ; R 1 is H; and —C(R 5 )(R 6 ) m —OH is —C(CH 3 )(F)—CH 2 —OH.