Histone demethylase inhibitors

Patent metadata

Field	Value
Publication number	US-11001568-B2
Application number	US-202016751432-A
Country	US
Kind code	B2
Filing date	Jan 24, 2020
Priority date	Dec 28, 2015
Publication date	May 11, 2021
Grant date	May 11, 2021

Abstract

The present disclosure relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyridine derivative compounds, and compositions (including pharmaceutical compositions) that include these compounds. The subject compounds and compositions are useful for inhibition of at least one histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer or neoplastic disease, such as prostate cancer, breast cancer, bladder cancer, lung cancer, melanoma, retinoblastoma, or multiple endocrine neoplasia type 1.

First claim

We claim:

1. A method of treating acute T cell leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a compound of Formula 1:

wherein a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and wherein:
n is 0, 1, or 2;
R 4 is hydrogen or optionally substituted C 1 -C 6 alkyl;
R 6 is hydrogen or X—Y, wherein
X is a bond, O, S, N(R), C(O), N(R)C(O), C(O)N(R), or optionally substituted C 1 -C 3 alkyl, wherein
R is hydrogen or optionally substituted C 1 -C 6 alkyl, and

Y is optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and

R 5 , R 7 , and R 8 are each independently selected from hydrogen, halogen, hydroxyl, cyanyl, N(R 1 )(R 2 ), or optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkynyl, C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 carbocyclyl, C 3 -C 7 carbocyclyloxy, C 4 -C 12 carbocyclylalkyl, C 4 -C 12 carbocyclylalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-S, C 6 -C 10 aryl-SO 2 , C 7 -C 14 aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S, wherein
R 1 is hydrogen or optionally substituted C 1 -C 6 alkyl, and
R 2 is optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,

cycloalkylalkyl, aryl-CO, heteroaryl-CO, cycloalkyl-CO, or alkyl-CO.

2. The method of claim 1 , wherein n is 0 or 1, and R 4 is methyl.

3. A method of treating acute T cell leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a compound of Formula 2:

wherein a compound of Formula 2 or a pharmaceutically acceptable salt thereof, and wherein:
n is 0, 1, or 2;
R 4 is hydrogen or optionally substituted C 1 -C 6 alkyl; and
R 3 is N(R)(R 9 ), N(R)C(O), C(O)N(R), or optionally substituted C 3 -C 7 carbocyclyl, C 3 -C 7 carbocyclyloxy, C 4 -C 12 carbocyclylalkyl, C 4 -C 12 carbocyclylalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-S, C 6 -C 10 aryl-SO 2 , C 7 -C 14 aralkoxy, C 1 -C 6 alkoxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S, wherein
R is hydrogen or optionally substituted C 1 -C 6 alkyl, and
R 9 is optionally substituted C 3 -C 7 carbocyclyl, C 3 -C 7 carbocyclyloxy, C 1 -C 6 alkoxy, C 4 -C 12 carbocyclylalkyl, C 4 -C 12 carbocyclylalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-S, C 6 -C 10 aryl-SO 2 , C 7 -C 14 aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S.

4. The method of claim 3 , wherein n is 0 or 1.

5. The method of claim 3 , wherein R 4 is hydrogen or methyl.

6. The method of claim 3 , wherein R 3 is N(R)(R 9 ), and wherein R is methyl.

7. The method of claim 6 , wherein R 9 is optionally substituted C 6 -C 10 aryl selected from optionally substituted halophenyl, alkylphenyl, haloalkylphenyl, halo(alkyloxy)phenyl, or haloalkyloxyphenyl.

8. The method of claim 6 , wherein R 9 is optionally substituted chlorophenyl, difluorophenyl, chlorofluorophenyl, (trifluoroethyl)phenyl, (trifluoropropyl)-phenyl, methylphenyl (tolyl), dimethylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl, hexylphenyl, (cyclopropylethyl)phenyl, cyclopropylphenyl, cyclobutylphenyl, cyclopentylphenyl, cyclohexylphenyl, (cyclobutylmethyl)phenyl, propoxyphenyl, (propylmethoxy)phenyl, (trifluoroethoxy)phenyl, (trifluoroethoxy)fluorophenyl, (trifluoroethoxy)dimethylphenyl, (propoxy)methylphenyl, (difluoromethoxy)methylphenyl, (quinolinyl)methylphenyl, (dihydroquinolinyl)methylphenyl, indolinylphenyl, dimethylaminophenyl, pyranylphenyl, methyldihydrobenzofuranyl, (indolinyl)methylphenyl, (pyrrolidinyl)methylphenyl, or thiole.

9. The method of claim 3 , wherein R 3 is optionally substituted C 6 -C 10 aryl, selected from optionally substituted flurophenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, cycloalkoxyphenyl, cycloalkoxymethylphenyl, or (cyclopropylmethoxy)methylphenyl.

10. The method of claim 3 , wherein R 3 is optionally substituted C 6 -C 10 aryl-S, heterocyclyl, heteroaryl, or C 4 -C 12 carbocyclylalkoxy.

11. The method of claim 3 , wherein R 3 is optionally substituted chlorophenyl, fluorophenyl, difluorophenyl, chlorofluorophenyl, (trifluoroethyl)phenyl, (trifluoropropyl)phenyl, methylphenyl (“tolyl”), dimethylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl, hexylphenyl, cyclopropylphenyl, cyclobutylphenyl, cyclopentylphenyl, cyclohexylphenyl, (cyclopropylethyl)phenyl, (cyclobutylmethyl)phenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, (cyclopropylmethoxy)phenyl, (trifluoroethoxy)phenyl, (methoxy)fluorophenyl, (trifluoroethoxy)fluorophenyl, (trifluoroethoxy)methylphenyl, (trifluoroethoxy)dimethylphenyl, (difluoromethoxy)methylphenyl, (propoxy)methylphenyl, (quinolinyl)methylphenyl, (dihydroquinolinyl)methylphenyl, (dihydroisoquinolinyl)methylphenyl, indolinylphenyl, dimethylaminophenyl, pyranylphenyl, methyldihydrobenzofuranyl, (indolinyl)methylphenyl, (pyrrolidinyl)methylphenyl, or thiole.

12. A method of treating acute T cell leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a compound of Formula 3:

wherein the compound of Formula 3 or a pharmaceutically acceptable salt thereof, and wherein:
n is 0, 1, or 2;
R 6 is X—Y, wherein
X is a bond, O, S, N(R), C(O), N(R)C(O), C(O)N(R), or optionally substituted C 1 -C 3 alkyl, wherein
R is hydrogen or optionally substituted C 1 -C 6 alkyl, and

Y is optionally substituted C 1 -C 6 alkyl, cycloalkyl, C 3 -C 7 carbocyclyl, C 1 -C 6 alkoxy, C 3 -C 7 carbocyclyloxy, C 4 -C 12 carbocyclylalkyl, C 4 -C 12 carbocyclylalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-S, C 6 -C 10 aryl-SO 2 , C 7 -C 14 aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S; and

R 5 , R 7 , and R 8 are each independently selected from hydrogen, halogen, hydroxyl, cyanyl, or N(R 1 )(R 2 ), or optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkynyl, C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 carbocyclyl, C 3 -C 7 carbocyclyloxy, C 4 -C 12 carbocyclylalkyl, C 4 -C 12 carbocyclylalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-S, C 6 -C 10 aryl-SO 2 , C 7 -C 14 aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy, or heteroaryl-S, in which
R 1 is hydrogen or optionally substituted C 1 -C 6 alkyl, and
R 2 is optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl-CO, heteroaryl-CO, cycloalkyl-CO, or alkyl-CO.

13. A method of treating acute T cell leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a compound of Formula 4:

wherein a compound of Formula 4 or a pharmaceutically acceptable salt thereof, and wherein:
n is 0, 1, or 2; and
R 3 is N(R)(R 9 ), N(R)C(O), C(O)N(R), or optionally substituted C 3 -C 7 carbocyclyl, C 3 -C 7 carbocyclyloxy, C 4 -C 12 carbocyclylalkyl,

Assignees

• Celgene Quanticel Res Inc

Inventors

• Chen Young K
• Wallace Michael Brennan

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C12Y114/11027

  [Histone H3]-lysine-36 demethylase (1.14.11.27) · CPC title