Hemiasterlin derivatives for conjugation and therapy

Patent metadata

Field	Value
Publication number	US-2016257709-A1
Application number	US-201615011388-A
Country	US
Kind code	A1
Filing date	Jan 29, 2016
Priority date	Jan 30, 2015
Publication date	Sep 8, 2016
Grant date	—

Abstract

Provided herein are hemiasterlin derivatives, conjugates thereof, compositions comprising the derivatives or conjugates thereof, methods of producing the derivatives and conjugates thereof, and methods of using the derivatives, conjugates, and compositions for the treatment of cell proliferation. The derivatives, conjugates, and compositions are useful in methods of treatment and prevention of cell proliferation and cancer, methods of detection of cell proliferation and cancer, and methods of diagnosis of cell proliferation and cancer. In an embodiment, the hemiasterlin derivatives are according to Formula 1000:

or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Ar, L, W 1 , W 4 , W 5 , SG, and R are as described herein.

First claim

1 . A compound according to Formula 1000:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
Ar is a divalent five- or six-membered, substituted or unsubstituted, monocyclic aryl or heteroaryl ring or a divalent eight-, nine- or ten-membered, substituted or unsubstituted, fused bicyclic aryl or heteroaryl ring;
L is absent or —CH 2 —;

W 1 , W 2 , W 3 , W 4 , W 5 are each independently a single bond, absent, or a divalent attaching group;
EG is absent or an eliminator group;
each RT is a release trigger group, in the backbone of Formula 1000 or bonded to EG, wherein each RT is optional;
RT 1 is a release trigger group, or a cleavable linker, or RT 1 is absent;
HP is a single bond, absent, or a divalent hydrophilic group;
HP 1 is a single bond, absent, a divalent hydrophilic group, or

where R HP is a monovalent hydrophilic group;
SG is a single bond, absent, or a divalent spacer group; and

R is hydrogen, a terminal conjugating group, or a divalent residue of a terminal conjugating group;
or, in the alternative, W 1 , W 2 , W 3 , W 4 , W 5 , EG, RT, HP, SG, and R combine to form —H.

2 . The compound of claim 1 according to Formula I:

or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein EG is an eliminator group; or, in the alternative, W 1 , W 2 , W 3 , W 4 , W 5 , EG, RT, HP, SG, and R combine to form —H.

3 . The compound of claim 1 according to Formula 1001 or 1002:

or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein
RT 1 is a release trigger group or a cleavable linker;
RT is a release trigger group bonded to EG; and RT is optional;
R is hydrogen or a terminal conjugating group.

4 - 8 . (canceled)

9 . The compound of claim 2 , wherein R is:

—N 3 , or —SH;
wherein R 201 is lower alkyl.

10 . The compound of claim 9 , wherein R 201 is methyl, ethyl, or propyl.

11 . (canceled)

12 . (canceled)

13 . The compound of claim 9 , wherein EG is:

wherein each R EG is independently selected from the group consisting of hydrogen, alkyl, biphenyl, —CF 3 , —NO 2 , —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)— and dialkylaminoC(O)—.

14 . The compound of claim 13 , wherein RT comprises a residue of a natural or non-natural amino acid or a residue of a sugar.

15 . The compound of claim 13 , wherein RT is:

16 . (canceled)

17 . The compound of claim 3 , wherein RT 1 is absent;

valine-alanine; valine-glutamic acid; alanine-phenyl alanine; phenylalanine-lysine; phenylalanine-homolysine; glycine-glycine-glycine;

where aa is a natural or non-natural amino acid residue; or

where the

ring is a 4-7 membered heterocyclic ring comprising 3-6 carbon atoms.

18 . The compound of claim 15 , wherein SG comprises C 1 -C 10 alkylene, C 4 -C 6 alkylene, —C(O)—, or a combination thereof.

19 . The compound of claim 13 , wherein SG is:

20 . (canceled)

21 . The compound of claim 13 , wherein HP is:

wherein m is an integer from 1 to 12.

22 . The compound of claim 17 , wherein HP 1 is absent or

where R HP is

wherein R is —H or —CH 3 and m is an integer from 1 to 12 or R HP is —C 1 -C 6 -alkylene-S(O) 3 − .

23 . The compound of claim 1 , wherein W 1 , W 2 , W 3 , W 4 , and W 5 are each independently a single bond, absent, or comprise —C(O)—, —O—, —C(O)NH—, —C(O)NH-alkyl-, —OC(O)NH—, —SC(O)NH—, —NH—, —NH-alkyl-, —N(CH 3 )CH 2 CH 2 N(CH 3 )—, —S—, —S—S—, —OCH 2 CH 2 O—, or a combination thereof.

24 . The compound of claim 2 where W 1 , W 2 , W 3 , W 4 , and W 5 are independently absent or a bond; or a pharmaceutically acceptable salt, solvate, or tautomer thereof.

25 . (canceled)

26 . The compound of claim 13 , wherein Ar is a divalent six-membered, substituted or unsubstituted, monocyclic aryl or monocyclic heteroaryl ring.

27 . (canceled)

28 . The compound of claim 13 , wherein Ar is a divalent nine-membered, substituted or unsubstituted, fused bicyclic heteroaryl ring.

29 . (canceled)

30 . The compound of claim 1 , wherein L is absent.

31 . (canceled)

32 . The compound of claim 2 , wherein W 1 , W 2 , W 3 , W 4 , W 5 , EG, RT, HP, SG, and R combine to form —H.

33 . The compound of claim 1 , according to any of the following Formulas:

or a pharmaceutically acceptable salt, solvate, or tautomer thereof.

34 . A conjugate comprising the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or tautomer thereof, linked to a second compound.

35 . The conjugate of claim 34 according to Formula (E1):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
COMP is a residue of a second compound;
Ar is a divalent five- or six-membered, substituted or unsubstituted, monocyclic aryl or heteroaryl ring or a divalent eight-, nine- or ten-membered, substituted or unsubstituted, fused bicyclic aryl or heteroaryl ring;
L is absent or —CH 2 —;

Assignees

• Sutro Biopharma Inc

Inventors

• Kline Toni
• Yin Qun
• Bajjuri Krishna

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C07K5/06078

  and aromatic or cycloaliphatic · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title