SMYD2 inhibitors

Patent metadata

Field	Value
Publication number	US-9598381-B2
Application number	US-201514812726-A
Country	US
Kind code	B2
Filing date	Jul 29, 2015
Priority date	Jul 31, 2014
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The present disclosure generally relates to compounds having cellular anti-proliferative activities, and more particularly relates to compounds which inhibit the activity of human SMYD2, a SET and MYND domain-containing protein lysine methyltransferase.

First claim

What is claimed is:

1. A compound having a structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen or C 1-6 alkyl;
x has a value from 0 to 1;
y has a value from 0 to 3;
R 7 is a C 4 -C 6 cycloalkyl;
R 8 is —OR 9 or —NHR 10 ;
R 9 is a C 1-10 alkyl;
R 10 is a C 1-2 alkyl substituted with a phenyl, wherein the phenyl is optionally further substituted with halogen; and,
(i) R 11 and R 12 are taken together with the nitrogen atom to which they are bound to form an optionally substituted heterocyclic ring having a structure:

wherein R x is selected from hydrogen and methoxypyridinyl, and R y is selected from hydrogen and indolinyl; or alternatively,
(ii) one of R 11 and R 12 is hydrogen, and the other is selected from:
(a) a pyrazolopyrimidinyl ring having a structure:

and being optionally substituted with one or more C 1-5 alkyl substituents; and,

(b) a C 1-3 substituted alkyl or a C 1-3 substituted hydoxyalkyl, wherein said substituent is selected from the group consisting of piperidinyl, pyrrolidinyl, cyanophenyl, methylindolizinyl, and a moiety having a structure:

wherein R 13 , R 14 , and R 15 are each independently selected from hydrogen, halogen, hydroxyl, trifluoromethyl, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylcarbonyl; provided that if one of R 11 and R 12 is C 1-3 substituted alkyl and R 15 is hydroxyl, then R 7 comprises a C 4 or C 5 unsubstituted cycloalkyl, or R 8 is —OR 9 , or R 8 is —NHR 10 , wherein R 10 is methyl substituted with a phenyl, optionally further substituted with a halogen.

2. The compound of claim 1 , wherein R 11 and R 12 are taken together with the nitrogen atom to which they are bound to form a heterocyclic ring having the structure:

wherein R x comprises the following structure:

3. The compound of claim 1 , wherein R 11 and R 12 are taken together with the nitrogen atom to which they are bound to form a heterocyclic ring having a structure:

wherein R y comprises the following structure:

4. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a pyrazolopyrimidinyl ring having a structure:

5. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 piperidinyl-substituted alkyl.

6. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 pyrrolidinyl-substituted alkyl.

7. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 cyanophenyl-substituted alkyl.

8. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 methylindolizinyl-substituted alkyl.

9. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 substituted alkyl comprising a substituent having the structure:

and R 7 comprises a C 4 or C 5 unsubstituted cycloalkyl.

10. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 substituted alkyl comprising a substituent having the structure:

and R 8 is —OR 9 .

11. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 substituted alkyl comprising a substituent having the structure:

and R 10 is methyl substituted with an optionally substituted phenyl.

12. The compound of claim 1 , wherein one of R 11 and R 12 is hydrogen and the other comprises a C 1-3 substituted hydroxyalkyl comprising a substituent having the structure:

13. The compound selected from the group consisting of:
N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)propanamide;
N-cyclohexyl-3-((3,4-dichlorobenzyl)amino)-N-(2-((2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)propanamide;
N-cyclopentyl-N-(2-((2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)-3-(phenethylamino)propanamide;
N-cyclopentyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)propanamide;
N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((3-(piperidin-1-yl)propyl)-amino)ethyl)propanamide;
N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-(pyrrolidin-1-yl)ethyl)-amino)ethyl)propanamide;
N-(2-((4-cyanobenzyl)amino)ethyl)-N-cyclohexyl-3-((3,4-dichlorophenethyl)-amino)propanamide;
N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((6-methyl-3-neopentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)amino)ethyl)propanamide;
(S)-N-cyclohexyl-3-(phenethylamino)-N-(2-(2-((pyridin-3-yloxy)methyl)azetidin-1-yl)ethyl)propanamide;
(R)-N-cyclohexyl-3-(phenethylamino)-N-(2-(2-((pyridin-3-yloxy)methyl)-azetidin-1-yl)ethyl)propanamide;
N-cyclohexyl-N-(2-((2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)-3-methoxypropanamide;
N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-(4-(indolin-4-yl)piperazin-1-yl)ethyl)propanamide;
N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((3-(pyrrolidin-1-yl)-propyl)amino)ethyl)propanamide;
N-cyclobutyl-N-(2-((2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)-3-(phenethylamino)propanamide;
N-cyclobutyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)propanamide;
N-cyclohexyl-3-((2,3-dichlorophenethyl)amino)-N-(2-((2-(2-methylindolizin-1-yl)ethyl)amino)ethyl)propanamide;
and pharmaceutically acceptable salts thereof.

14. The compound (R)-N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)-propanamide, or a pharmaceutically acceptable salt thereof.

15. The compound (S)-N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)ami

Assignees

• Abbvie Inc

Inventors

• Chiang Gary G
• Pappano William N
• Sweis Ramzi F
• Wang Zhi

Classifications

• C07C2101/14

  Chemistry & Metallurgy · mapped topic

• C07D295/13

  to an acyclic saturated chain · CPC title

• C07C255/58

  containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton · CPC title

• C07D209/40

  Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title