Inhibitors of IAP

Patent metadata

Field	Value
Publication number	US-11963994-B2
Application number	US-202117392724-A
Country	US
Kind code	B2
Filing date	Aug 3, 2021
Priority date	Jan 3, 2012
Publication date	Apr 23, 2024
Grant date	Apr 23, 2024

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 of treating a patient suffering from a cancer that has failed to undergo apoptosis, the method comprising:
administering a compound of formula I, or a pharmaceutically acceptable salt thereof

wherein:
Ph is phenyl;
R 1 is C 3-7 cycloalkyl; and
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H or C 1-6 alkyl;
and
administering one or more agents that modulate:
a protein kinase selected from the group consisting of serine/threonine specific kinases, receptor tyrosine specific kinases, and non-receptor tyrosine specific kinases,
or a non-kinase target selected from the group consisting of histone deacetylases, DNA methyltransferases, heat shock proteins, hedgehog inhibitors, and proteosomes.

2. The method of claim 1 wherein the compound 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 cancer is selected from the group consisting of:
neuroblastoma, intestine carcinoma, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.

8. The method of claim 1 , wherein the protein kinase is a serine/threonine specific kinase selected from the group consisting of: mitogen activated protein kinases (MAPK), meiosis specific kinase (MEK), RAF, and aurora kinase.

9. The method of claim 1 , wherein the protein kinase is a member of a receptor kinase family selected from the group consisting of: epidermal growth factor receptors, fibroblast growth factor (FGF) receptors, hepatocyte growth/scatter factor receptors, insulin receptors; Eph, Axl, RET, and platelet-derived growth factor receptors.

10. The method of claim 1 , wherein the protein kinase is a member of a non-receptor tyrosine kinase family selected from the group consisting of: BCR-ABL, BTK, CSK, PAK, FPS, JAK, SRC, BMX, FER, CDK, and SYK.

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61K38/06 Primary

  Tripeptides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K5/08

  Tripeptides · CPC title

• C07K5/0804

  and aliphatic · CPC title

• C07K5/0806

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title