Cytotoxic and anti-mitotic compounds, and methods of using the same

Patent metadata

Field	Value
Publication number	US-9879086-B2
Application number	US-201514857733-A
Country	US
Kind code	B2
Filing date	Sep 17, 2015
Priority date	Sep 17, 2014
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

Compounds having cytotoxic and/or anti-mitotic activity are disclosed. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed. Also disclosed are compositions having the structure: (T)-(L)-(D), wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound having cytotoxic and/or anti-mitotic activity.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from: amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, amino-heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from aryl, aryl-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, carboxyl, carboxamide, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl, guanidino, halo, C 1 -C 6 haloalkyl, heterocyclyl, heterocyclyl-C 1 -C 6 alkyl, hydroxyl, and thio; or
R 1 is R a R b NCH(R c )—;
R a is selected from: H and C 1 -C 6 alkyl;
R b is C 1 -C 6 alkyl; and
R c is R d —C(CH 3 ) 2 —; and
R d is selected from: H, aryl, C 3 -C 7 cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: C 1 -C 4 acylthio, C 2 -C 4 alkenyl, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 alkyloxy, amino, amino-C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-C 1 -C 4 alkyl, and thio, wherein C 2 -C 4 alkenyl, C 1 -C 4 alkylamino and C 1 -C 4 alkyloxy are further optionally substituted with one substituent selected from C 1 -C 4 alkylaryl, hydroxyl, and thio; or
R b and R c taken together with the atoms to which they are each bonded form a heterocyclyldiyl;
R 2 is selected from: C 2 -C 6 alkyl, aryl, aryl-C 1 -C 6 alkyl, C 4 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl, heteroaryl, heteroaryl-C 1 -C 6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, amino, amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C 1 -C 6 haloacyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-C 1 -C 6 alkyl; and
X is absent.

2. The compound of claim 1 , wherein R 1 is selected from: amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, amino-heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halo.

3. The compound of claim 1 , wherein R 1 is selected from: 1-(dimethylamino)-2-methylpropyl, 2-methyl-1-(methylamino)propyl, 1-aminocyclopentyl, 1-aminocyclopropyl, 4-aminophenyl, 2-aminopropan-2-yl, 1-aminocyclohexyl, 3-aminooxetan-3-yl, 2-(methylamino)propan-2-yl, 1-amino-2-methylpropan-2-yl, 2-methylpyrrolidin-2-yl, 2-amino-3-methylbutan-2-yl, 2-aminobutan-2-yl, 2-methyl-1-(methylamino)propan-2-yl, 1-methylpiperidin-2-yl, 3-fluoropyrrolidin-3-yl, 1,2-dimethylpyrrolidin-2-yl, and 2-(dimethylamino)propan-2-yl.

4. The compound of claim 1 , wherein R 1 is 1-(dimethylamino)-2-methylpropyl.

5. The compound of claim 1 , wherein R 1 is 2-methyl-1-(methylamino)propyl.

6. The compound of claim 1 , wherein R 1 is (R)-1-(dimethylamino)-2-methylpropyl.

7. The compound of claim 1 , wherein R 1 is (R)-2-methyl-1-(methylamino)propyl.

8. The compound of claim 1 , wherein R 2 is selected from: C 2 -C 6 alkyl, aryl, aryl-C 1 -C 6 alkyl, C 4 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl, heteroaryl, heteroaryl-C 1 -C 6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, tert-butyl, carboxamide, carboxyl, chloro, cyano, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, thio, thiomethyl, trifluoromethoxy, and trifluoromethyl.

9. The compound of claim 1 , wherein R 2 is selected from: 5,6,7,8-tetrahydronaphthalen-1-yl, benzyl, cyclohexyl, ethyl, hexan-2-yl, naphthalen-2-yl, piperidin-1-yl, phenyl, propyl, pyridin-3-yl, and thien-2-yl, each optionally substituted with one or more substituents selected from: 1-aminocyclopropyl, 4-aminophenyl, amino, aminomethyl, bromo, tert-butyl, carboxamide, carboxyl, chloro, cyano, ethyl, fluoro, hydroxy, isopropyl, methoxy, methyl, nitro, phenyl, thio, thiomethyl, trifluoromethoxy, and trifluoromethyl.

10. The compound of claim 1 , wherein R 2 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 3-cyanophenyl, 2-nitrophenyl, 4-methoxy-2-nitrophenyl, 4-aminocarbonyl-2-nitrophenyl, 4-methoxyphenyl, phenyl, 2-fluorobenzyl, piperidin-1-yl, o-tolyl, 4-bromophenyl, naphthalen-2-yl, 4-methoxycarbonylphenyl, 2-(trifluoromethyl)benzyl, hexan-2-yl, 2-methoxyethyl, cyclopentylmethyl, cyclohexyl, pyridin-3-ylmethyl, 4-carboxyphenyl, 3-aminophenyl, pyridin-3-yl, thien-2-yl, 4-hydroxyphenyl, 4-(1-aminocyclopropyl)benzyl, 4-(1-aminocyclopropyl)phenyl, 2-methylbenzyl, 4-nitrobenzyl, 4-chlorobenzyl, phenethyl, 4-bromobenzyl, 4-cyanobenzyl, 3-nitrobenzyl, 4-tert-butylbenzyl, 2-nitrobenzyl, 4-nitrophenethyl, 2-chloro-3-methoxycarbonylphenyl, 2-aminophenyl, [1,1′-biphenyl]-4-yl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-fluorobenzyl, 3-(trifluoromethyl)benzyl, 3-(trifluoromethoxy)benzyl, 3,4-dichlorobenzyl, 2-cyanobenzyl, 3-chlorobenzyl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl, and 4-amino-3-(trifluoromethyl)phenyl.

11. The compound of claim 1 , wherein R 2 is selected from: aryl and aryl-C 1 -C 6 alkyl, each optionally substituted with one or more substituents selected from:
amino and amino-C 1 -C 6 alkyl.

12. The compound of claim 1 , wherein R 2 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, and benzyl.

13. The compound of claim 1 , wherein R 2 is 4-aminobenzyl.

14. The compound of claim 1 , wherein R 2 is 4-(aminomethyl)benzyl.

15. The compound of claim 1 , wherein R 2 is 4-(aminomethyl)phenyl.

16. The compound of claim 1 , wherein R 2 is 4-aminophenyl.

17. The compound of claim 1 , wherein R 2 is benzyl.

18. The compound of claim 1 , of Formula Ia:

or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is selected from: C 2 -C 6 alkyl, aryl, aryl-C 1 -C 6 alkyl, C 4 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl, heteroaryl, heteroaryl-C 1 -C 6 alkyl, and heterocyclyl, each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, amino, amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, aryl, carboxamide, carboxyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, hydroxyl, nitro, thio, and thio-C 1 -C 6 alkyl; and
R 4 and R 5 are each independently selected from: H and C 1 -C 6 alkyl.

19. The compound of claim 1 , of Formula Ia:

or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, benzyl, 3-mercaptopropyl, 2-mercaptoethyl, 4-(mercaptomethyl)phenyl, p-tolyl, 2,4,6-trimethylphenyl, 4-(trifluoromethoxy)phenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl

Assignees

• Zymeworks Inc

Inventors

• Winters Geoffrey C
• Rich James R
• Garnett Graham Albert Edwin
• Mandel Alexander Laurence
• Hsieh Tom Han Hsiao
• Bourque Elyse Marie Josée
• Barnscher Stuart Daniel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• H10W90/00

  Package configurations · CPC title

• C07K5/0205 Primary

  containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title