PRC1 inhibitors and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11319302-B2
Application number	US-201916434508-A
Country	US
Kind code	B2
Filing date	Jun 7, 2019
Priority date	Jun 7, 2018
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

Provided herein are small molecule inhibitors of Polycomb Repressive Complex 1 (PRC1) activity, and methods of use thereof for the treatment of disease, including leukemia and other cancers, as well as other diseases dependent on the activity of PRC1.

First claim

The invention claimed is:

1. A polycomb repressive complex 1 (PRC1) inhibitor of Formula (II):

wherein A is a 5 or 6-member aryl or heteroaryl ring, A′ is a 5-member heteroaryl ring, E is a 5 or 6-member aryl or heteroaryl ring, and E′ is absent or is a 5-member or heteroaryl ring;
wherein R 2 is a straight, branched, or cyclic alkyl group of 1-6 carbons and comprising 0-3 halogen atoms or OH;
wherein R 4 is a (CH 2 ) 0-5 COOH, (CH 2 ) 0-6 OH, tetrazole, —(CH 2 ) 0-5 C(O)NH 2 , —(CH 2 ) 0-5 C(O)NH(CH 2 ) 0-3 , C(O)O(CH 2 ) 1-5 , —(CH 2 ) 0-5 SO 2 NH 2 , —(CH 2 ) 0-5 SO 2 CH 3 , or —NHSO 2 NH 2 —, wherein X is, NH, NR 5 , O, or S;
wherein R 5 , when present, is CH 3 , (CH 2 ) 1-5 CH 3 , (CH 2 ) 1-6 —COOH, (CH 2 ) 1-6 —CONH 2 , (CH 2 ) 1-6 —SO 2 NH 2 , (CH 2 ) 1-6 —OH, or NH 2 ; and
wherein R A1-5 , R A′1-5 , R E1-5 , and R E′1-5 may be absent or present, may be located at any position on A, A′, E, E′, respectively, and when present is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OCF 3 , —OH, —O(CH 2 ) 1-5 , CH 2 OH, (CH 2 ) 0-3 OH, (CH 2 ) 1-5 O(CH 2 ) 1-5 CH 3 , —OR 6 , OCH 3 , O(CH 2 ) 1-3 CH3, (CH 2 ) 0-2 CONH 2 , O(CH 2 ) 1-4 COOH, —(CH 2 ) 0-5 NHCOR 6 , —(CH 2 ) 0-5 CONHR 6 , —NH 2 , (CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-6 SR 6 , —(CH 2 ) 0-4 COOH, —(CH 2 ) 0-3 SO 2 NH 2 , —(CH 2 ) 0-3 SO 2 CH3, —NHSO 2 NH 2 , —NHSO 2 CH 3 , —SH, —CN, —NO 2 , halogen, a 5- or 6-member heteroaryl ring, a 5-6 member cycloalkyl heteroalkyl ring, —CH 2 -cyclobuthyl, and —(CH 2 ) 0-3 —S(CH 2 ) 0-3 ;
wherein R 6 , when present, is C 1 -C 6 alkyl, C 1 -C 5 haloalkyl, —(CH 2 ) 1-6 OH, —(CH 2 ) 1-6 COOH, —(CH 2 ) 1-5 O(CH 2 ) 1-5 CH 3 , —(CH 2 ) 1-6 CONH 2 , a 5- or 6-member heteroaryl ring, or a 5-6 member cycloalkyl or heteroalkyl ring.

2. A PRC1 inhibitor comprising a compound selected from:

3. A pharmaceutical composition comprising the PRC1 inhibitor of claim 1 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is formulated for oral administration.

5. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is formulated for injection.

6. A method of inhibiting PRC1 with an effective amount of a pharmaceutical composition of claim 3 .

7. The method of claim 6 , wherein PRC1 activity is inhibited by binding of the compound or pharmaceutical composition to PRC1.

8. A method of treating a subject comprising administering to the subject a pharmaceutical composition of claim 3 .

9. The method of claim 8 , wherein the subject suffers from cancer.

10. The method of claim 9 , wherein the cancer comprises leukemia, hematologic malignancy, solid tumor cancer, breast cancer, prostate cancer, colon cancer, pancreatic cancer, ovarian cancer, liver cancer or thyroid cancer.

11. The method of claim 10 , wherein the pharmaceutical composition is co-administered with an additional therapeutic.

12. The method of claim 11 , wherein the subject is a human.

13. The PRC1 inhibitor of claim 1 , wherein the compound is selected from:

Assignees

• Univ Michigan Regents

Inventors

• Cierpicki Tomasz
• Grembecka Jolanta
• Ying Weijiang
• Yao Yiwu
• Gray Felicia
• Zhao Qingjie

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D498/06

  Peri-condensed systems · CPC title

• C07D498/16

  Peri-condensed systems · CPC title

• C07D207/34

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• A61K45/06

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