Maytansinoid derivatives, conjugates thereof, and methods of use

1 . A compound of Formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

A is arylene or heteroarylene;

L is a linker;

BA is a binding agent; and

k is an integer from one to ten.

2 . A compound of Formula II

or a pharmaceutically acceptable salt or stereoisomer thereof,

in A is a divalent radical of benzene, pyridine, naphthalene, or quinolone.

3 . A compound of Formula P1

wherein A is a divalent radical of benzene, pyridine, naphthalene, or quinolone; and RL is a reactive linker.

4 . A compound of Formula PPII

wherein A is a divalent radical of benzene, naphthalene, or quinolone.

5 . The compound of claim 4 , wherein

A is

R 1 , independently at each occurrence, is selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro,

 and azido;

R A is alkyl;

n is an integer from zero to four.

6 . The compound of claim 5 , wherein R 1 , independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl.

7 . The compound of claim 4 , wherein the compound of Formula PPII is a compound of Formula PP5A1

wherein

R 1 , independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl; and

n is an integer from zero to four.

8 . The compound of claim 4 , wherein the compound is selected from

9 . A method of preparing a compound of Formula I

comprising contacting a compound of P1

with a binding agent under conjugation conditions, wherein

A is a divalent radical of benzene, pyridine, naphthalene, or quinolone;

L is a linker;

BA is a binding agent;

k is an integer from one to ten; and

RL is a reactive linker.

10 . The method of claim 9 , wherein:

A is

R 1 , independently at each occurrence, is selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro,

and azido;

R A is alkyl; and

n is an integer from zero to four.

11 . The method of claim 10 , wherein

R 1 , independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl; and

n is an integer from zero to four.

12 . The method of claim 9 , wherein

the compound of Formula P1 is prepared by contacting a compound of Formula II

with a RL,

RL is a reactive linker; and

the compound of Formula II is prepared by contacting a compound of Formula PP5A with a suitable reducing agent

wherein

R 1 , independently at each occurrence, is selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro,

 and azido;

R A is alkyl;

n is an integer from zero to four; and

the suitable reducing agent is selected from a metal, a metal foil, a metal powder, dust of a metal, a metal amalgam, or metal filings.

13 . A method of making a compound of Formula II

wherein

A is a divalent radical of benzene, pyridine, naphthalene, or quinolone comprising:

(a) contacting a compound of Formula P2

with a compound of Formula PP6

under Lewis acid synthesis conditions to form a compound of Formula PPII

 and

(b) reducing the compound of Formula PPII by contacting the compound of Formula PPII with a reducing agent to form the compound of Formula II.

14 . The method of claim 13 wherein

A is

R 1 , independently at each occurrence, is selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro,

 and azido;

R A is alkyl;

n is an integer from zero to four.

15 . The method of claim 13 , wherein R 1 , independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl.

16 . A method of making a compound of Formula PPII, comprising contacting a compound of Formula P2 with a compound of Formula PP6 under Lewis acid synthesis conditions

wherein A is a divalent radical of benzene, naphthalene, or quinolone.

17 . The method of claim 16 , wherein

A is

R 1 , independently at each occurrence, is selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro,

 and azido;

R A is alkyl;

n is an integer from zero to four.

18 . The method of claim 16 , wherein R 1 , independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl.