Anti-proliferative compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9969679-B2
Application number	US-201314413745-A
Country	US
Kind code	B2
Filing date	Jul 10, 2013
Priority date	Jul 10, 2012
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates, polymorphs, and compositions thereof. Also provided are methods and kits involving the inventive compounds for treating proliferative diseases (e.g., cancers (e.g., breast cancer, prostate cancer, lung cancer, and ovarian cancer), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound of the invention may enhance the anti-tumor immune response by inhibiting or eliminating the immune suppression mediated by immune suppressor myeloid cells (MDSCs), inducing apoptosis, and/or inhibit or down-regulate proteins (e.g., epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), X-linked inhibitor of apoptosis protein (XIAP), and heat shock protein 90 (Hsp90)) in the subject.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein:
each one of Rings A, B, and C is a phenyl ring;
R is a group of formula:

each occurrence of R A is independently halogen, unsubstituted C 1-8 alkyl, C 1-8 alkyl substituted with one or more instances of halogen, —OR A1 , —SR A1 , —CN, or —NO 2 , wherein each occurrence of R A1 is independently hydrogen, unsubstituted C 1-8 alkyl, or C 1-8 alkyl substituted with one or more instances of halogen;
each occurrence of R B is independently halogen, unsubstituted C 1-8 alkyl, C 1-8 alkyl substituted with one or more instances of halogen, —OR B1 , —SR B1 , —CN, or —NO 2 , wherein each occurrence of R B1 is independently hydrogen, unsubstituted C 1-8 alkyl, or C 1-8 alkyl substituted with one or more instances of halogen;
each occurrence of R C is independently halogen, unsubstituted C 1-8 alkyl, C 1-8 alkyl substituted with one or more instances of halogen, —OR C1 , —SR C1 , —CN, or —NO 2 , wherein each occurrence of R C1 is independently hydrogen, unsubstituted C 1-8 alkyl, or C 1-8 alkyl substituted with one or more instances of halogen;
R D is —C(═O)R D1 , wherein R D1 is optionally substituted, fully saturated, 5- or 6-membered, monocyclic heterocyclyl that is not fused with an optionally substituted aryl ring or optionally substituted heteroaryl ring;
j is 0, 1, 2, 3, or 4;
k is 0, 1, 2, 3, 4, or 5; and
m is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein j, k, and m are each 0.

3. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

4. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, and optionally a pharmaceutically acceptable excipient.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein R D1 is optionally substituted, fully saturated, 5-membered, monocyclic heterocyclyl that is not fused with an optionally substituted aryl ring or optionally substituted heteroaryl ring.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein R is

8. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

9. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein R D1 is optionally substituted, fully saturated, 6-membered, monocyclic heterocyclyl that is not fused with an optionally substituted aryl ring or optionally substituted heteroaryl ring.

12. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

14. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein R D1 is optionally substituted piperidinyl that is not fused with an optionally substituted aryl ring or optionally substituted heteroaryl ring.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof, wherein R D1 is fully saturated, 5- or 6-membered, monocyclic heterocyclyl that is not fused with an optionally substituted aryl ring or optionally substituted heteroaryl ring and is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, and acyloxy.

17. The pharmaceutical composition of claim 5 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.

18. The pharmaceutical composition of claim 5 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 5 further comprising an additional therapeutic agent.

20. The pharmaceutical composition of claim 5 further comprising a proteasome inhibitor or a heat shock protein 90 (Hsp90) inhibitor.

Assignees

• Dana Farber Cancer Inst Inc
• Massachusetts Gen Hospital

Inventors

• Anderson Kenneth C
• Hideshima Teru
• Mazitschek Ralph
• Gorgun Gullu

Classifications

• C07C223/06 Primary

  having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D233/80

  with hetero atoms or acyl radicals directly attached to ring nitrogen atoms · CPC title

• A61K31/216

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61K31/655

  Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds · CPC title