US 10,590,118 B2Granted

Bicyclic heterocyclic derivatives as bromodomain inhibitors

AssigneeOrion Corporation

InventorsSusanta Samajdar, Chandrasekhar Abbineni, Sanjita Sasmal, Subramanya Hosahalli

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Abstract

The present disclosure provides bicyclic heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as bromodomain inhibitors; (I), in which R1, R2, R3, R4, L1, L2, Cy1, Cy2, X, n, and dotted line have the same meaning given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in diseases or disorders associated as bromodomain inhibitors. The present disclosure also provides preparation of compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent, or excipient.

Claims9

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof;
wherein,
dotted line [- - -] represents a single bond;
X is O;
L1 is a direct bond or a linker selected from —NH—, —NHC(O)—, or —NHS(O)2—;
L2 is a linker selected from —(CHR6)n—, —C(O)—, or —S(O)2—;
Cy1 is an optionally substituted 5-6 membered monocyclic ring containing 1-4 hetero atoms/-hetero groups independently selected from N, NH, O, or —C(O)—;
wherein the optional substituent at each occurrence is independently selected from one or more R7;
Cy2 is an optionally substituted 4-12 membered monocyclic or bicyclic ring containing 0-3 hetero atoms/hetero groups independently selected from N, NH, O, or S;
wherein the optional substituent at each occurrence is independently selected from one or more R8;
R1 is selected from hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclyl, or heterocyclylalkyl;
R2 and R3 independently are hydrogen, alkyl, or together form an oxo group;
R4 at each occurrence is independently selected from hydrogen, alkyl, cycloalkyl, cyanoalkyl, hydroxyalkyl, or optionally substituted haloalkyl;
wherein the optional substituent is one or more hydroxyl;
R6 is hydrogen or alkyl;
R7 is selected from alkyl, hydroxyl, or cycloalkyl;
R8 is selected from alkyl, alkoxy, amino, cyano, halogen, haloalkyl, hydroxy, —C(O)alkyl, or optionally substituted heterocyclyl;
wherein the optional substituent is selected from one or more alkyl or hydroxy;
and
n is an integer selected from 1 or 2.

17 more elements

A compound selected from the group consisting of:

4-(4-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine;
4-(1-(4-chlorophenyl)ethyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(1-(pyridin-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine;
4-((3-chlorophenyl)sulfonyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(pyridin-3-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine;
N-(4-(4-chlorobenzyl)-6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3,5-dimethylisoxazole-4-sulfonamide;
2-((7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)aniline;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(pyridin-4-ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
4-(4-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(1-(pyridin-4-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Isomer-1);
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(1-(pyridin-4-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Isomer-2);
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(pyridin-3-ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(pyridin-2-ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((tetrahydro-2H-pyran-4-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(1-(pyridin-3-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Isomer-1);
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(1-(pyridin-3-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Isomer-2);
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((6-methoxypyridin-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
6-((7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)nicotinonitrile;
4-((5-chloropyridin-2-yl)methyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)methyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((5-methoxypyridin-2-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(1-(pyridin-2-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((6-methylpyridin-3-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
4-(1-(4-chlorophenyl)ethyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (Isomer-1);
4-(1-(4-chlorophenyl)ethyl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (Isomer-2);
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(2-(pyridin-2-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2,2-dimethyl-4-(pyridin-3-ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-(piperidin-4-ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
4-(4-chlorobenzyl)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-4-((6-hydroxypyridin-3-yl)methyl)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-(2-methoxyethoxy)-4-(pyridin-4-ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-propionylpiperidin-4-yl )methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;
N-(4-(4-chlorobenzyl)-6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3,5-dimethylisoxazole-4-carboxamide;
4-(4-chlorobenzyl)-7-((3,5-dimethylisoxazol-4-yl)amino)-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/051,913Filed 1 Aug 2018 · division
Priority: IN 125/CHE/20149 Jan 2014
Published: US 2018/0339982 A129 Nov 2018
Granted: 17 Mar 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 413/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 35/00
Antineoplastic agents
A61P 37/00
Drugs for immunological or allergic disorders

Family

PCT/IB2015/050090Parent of this division · filed 6 Jan 2015
US 10,077,259 B2Parent of this division · filed 7 Jul 2016
US 2018/0339982 A1Pre-grant publication · published 29 Nov 2018
Application15/110,361Parent of this division
US 2016/0368906 A1Published application
US 10,590,118 B2This patent

From the US filing history. Foreign family members aren’t listed.