Inhibitors of histone lysine specific demethylase (LSD1) and histone deacetylases (HDACS)

Patent metadata

Field	Value
Publication number	US-11565994-B2
Application number	US-202016892825-A
Country	US
Kind code	B2
Filing date	Jun 4, 2020
Priority date	Mar 7, 2014
Publication date	Jan 31, 2023
Grant date	Jan 31, 2023

Abstract

A series of phenelzine analogs comprising a phenelzine scaffold linked to an aromatic moiety and their use as inhibitors of lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs) is provided. The presently disclosed phenelzine analogs exhibit potency and selectivity for LSD1 versus MAO and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Accordingly, the presently disclosed phenelzine analogs can be used to treat diseases, conditions, or disorders related to LSD1 and/or HDACs, including, but not limited to, cancers and neurodegenerative diseases.

First claim

That which is claimed:

1. A compound of Formula (IIb):

wherein:
t is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
A is substituted or unsubstituted aryl;
B is aryl;
L is —[X 1 —C(═O)—NR 1 ] d —, wherein d is 1;
wherein X 1 is —(CH 2 ) n —, wherein n is 3, wherein the —(CH 2 ) n — group can optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and wherein one or more carbon atoms of —(CH 2 ) n — can optionally be replaced with one or more heteroatoms selected from the group consisting of O, S, and NR′ 1 , wherein each —(CH 2 ) n — group can contain a cycloalkyl or cycloheteroalkyl unit;
L 2 is selected from the group consisting of aryl, heteroaryl, —(CH 2 )n—, —(CH 2 )n—CH═CH—(CH 2 ) m —, —(CH 2 ) n —C≡C—(CH 2 ) m —,—(CH 2 ) m —O—, wherein n and m are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, wherein the —(CH 2 )n—, —(CH 2 ) m —, and —CH═CH— groups can optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and wherein one or more carbon atoms of —(CH 2 ) n — and —(CH 2 ) m — can optionally be replaced with one or more heteroatoms selected from the group consisting of 0, S, and NR′ 1 ;
R 1 and R′ 1 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and R 1 can form a ring system with ring B via a substituted or unsubstituted alkylene or heteroalkylene chain;
R 2 is selected from the group consisting of —(CH 2 ) p —NR 3 —NR 4 R 5 , —(CH 2 ) p —X 2 , and —NH 2 ; wherein p is an integer selected from the group consisting of 0, 1, 2, 3, and 4, and wherein the —(CH 2 ) p — group can be saturated or unsaturated or contain a cycloalkyl unit and optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and one or more carbon atoms of —(CH 2 ) p — can optionally be replaced with one or more heteroatoms selected from the group consisting of 0, S, and NR′ 1 ;
each R′ 2 is independently selected at each occurrence from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, allyl, hydroxyl, alkoxyl, amino, cyano, carboxyl, halogen, nitro, oxo, —CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and —C(═O)—O—R 21 , or R 4 and R 5 together can form a substituted or unsubstituted 4- to 6-membered cycloalkyl, and wherein R 24 is substituted or unsubstituted linear or branched alkyl;
X 2 is selected from the group consisting of hydroxyl, halogen, and —O—Si(R 21 R 22 ) 2 -R 23 , wherein R 21 , R 22 , and R 23 are each independently substituted or unsubstituted linear or branched alkyl;
Y is selected from the group consisting of null, —N(R 10 )C(═O)—,—C(═O)N(R 10 )—, —N(R 10 )C(═S)—, —C(═S)N(R 10 —, —SO 2 —, —N(R 10 ) SO 2 —, —N(R 10 SO 2 N(R 10 )—, —SO 2 N(R 10 )—, and —CH═CH—;
Z is selected from the group consisting of:
—C(═O)N(R 10 )OH, —C(═O)OR 16 , N(R 10 )OH, —N(R 10 )C(═O)C(R 11 ) n′ S(R 12 ),
—B(OR 13 ) m′ , —SR 14 ,

wherein R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
R 16 , R 17 , R 18 , and R 19 are each independently substituted or unsubstituted linear or branched alkyl;
and n′ and m′ are integers each independently selected from the group consisting of 0, 1, and 2; or pharmaceutically acceptable salts, hydrates, and solvates thereof.

2. The compound of claim 1 , wherein the compound of Formula (IIb) has the following structure:

3. The compound of claim 2 , wherein:

is selected from the group consisting of:

is selected from the group consisting of:

4. A pharmaceutical composition comprising the compound of claim 1 .

5. The pharmaceutical composition of claim 4 , further comprising one or more additional therapeutic agents.

6. The pharmaceutical composition of claim 5 , wherein the one or more additional therapeutic agents is selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a DNA methyltransferase (DNMT) inhibitor, and combinations thereof.

7. A method for inhibiting lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs), the method comprising administering to a subject a compound of Formula (IIb) of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit LSD1 or one or more HDACs.

Assignees

• Univ Johns Hopkins

Inventors

• Cole Philip
• Ming Shonoi
• Prusevich Polina
• Kalin Jay

Classifications

• C07D209/18

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

• C07C271/02

  Carbamic acids; Salts of carbamic acids (unsubstituted carbamic acid or salts thereof C01B21/12) · CPC title

• A61K31/325

  Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145) · CPC title

• C07C233/29

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings · CPC title

• A61K45/06

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