Inhibitors of IAP

Patent metadata

Field	Value
Publication number	US-9586991-B2
Application number	US-201514974140-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Jan 3, 2012
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

Novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies and have the general formula I:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described herein.

First claim

We claim:

1. A method for preparing a compound of formula I

wherein
Ph is phenyl;
R 1 is C 3-7 cycloalkyl;
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently in each occurrence H or C 1-6 alkyl; or
a pharmaceutically acceptable salt thereof;

which comprises:
coupling an amine-protected amino acid residue and deprotecting it according to the following Scheme 1:

or by a substitution reaction according to Scheme 3:

wherein the A ring is the oxazole-phenylthiazole group shown in formula (I), Pr is a carboxy-protecting group, Br is bromine and DMF is dimethylformamide.

2. The method of claim 1 wherein the compound prepared is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide (Ia) or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 wherein R 2 -R 6 are each independently H or methyl.

4. The method of claim 1 wherein R 1 is cyclohexyl.

5. The method of claim 3 wherein R 1 is cyclohexyl.

6. The method of claim 3 wherein one of R 2 and R 3 is H and the other is methyl; or R 4 is methyl; or R 5 and R 6 are each H.

7. The method of claim 1 , wherein the amino acid residue is provided on a solid phase support.

8. The method of claim 1 , wherein, when R 2 or R 3 are substituents other than H, the method further comprises the following Scheme 2 to prepare the reactant used in the second step of Scheme 1 :

9. The method of claim 8 , wherein 2-bromopropionic acid is reacted with the an amine dissolved in DMF and bubbled until substitution is complete to form the N-substituted alanine residue.

10. The method of claim 1 , further comprising preparing the A ring reactant used in the third step of Scheme 1 by condensation of an α-aminophenylacetonitrile hydrochloride and oxazole-2-carbaldehyde in the presence of sulfur and TEA according to Scheme 4:

Assignees

• Genentech Inc

Inventors

• Cohen Frederick
• Gazzard Lewis J
• Tsui Vickie Hsiao-Wei
• Flygare John A

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07K5/08

  Tripeptides · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title