Indazolones as modulators of tnf signaling

Patent metadata

Field	Value
Publication number	US-10160748-B2
Application number	US-201715670708-A
Country	US
Kind code	B2
Filing date	Aug 7, 2017
Priority date	Apr 17, 2015
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

The disclosure provides indazolone compounds, pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variables are defined herein. The compounds of the disclosure may be useful for treating immunological and oncological conditions.

First claim

What is claimed:

1. A method for measuring TNF-alpha competitive binding of a test compound,
the method comprising:
(i) treating TNF-alpha trimer with a mixture of the test compound and a fluorescent probe, and measuring the fluorescence polarization;
(ii) treating TNF-alpha trimer with the fluorescent probe, and measuring the fluorescence polarization; and
(ii) subtracting the fluorescence polarization of (ii) from (i), wherein the subtracted result is used to determine the competitive binding of the test compound to TNF-alpha;
wherein the fluorescent probe is a compound of Formula:

2. The method of claim 1 , wherein the test compound is a compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
X, Y and Z are independently CR 4 or N;
provided that Y and Z are not both N;

L is a bond, optionally substituted (C 1 -C 3 )alkylene, or —C(O)—;
R 1 is H, CD 3 , optionally substituted (C 1 -C 3 )alkyl, or optionally substituted (C 3 -C 6 )cycloalkyl;
R 2 is optionally substituted aryl or optionally substituted heteroaryl;
R 3 is —R 3a -R 3b , wherein:
R 3a is an optionally substituted saturated, unsaturated, or partially saturated heterocyclyl or optionally substituted heteroaryl;
R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) p -optionally substituted heterocyclyl, or —(CH 2 ) p -optionally substituted oxetanyl; wherein
R a and R b are independently selected from the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, —(CH 2 ) n -optionally substituted heterocyclyl, and —(CH 2 ) n -optionally substituted oxetanyl;

R 4 is independently H, Cl, CN, F, CF 3 , methoxy, or optionally substituted (C 1 -C 3 )alkyl;
n is 0 or 1; and
p is 0, 1 or 2;

wherein heterocyclyl is:
(i) a non-aromatic monocylic, bicyclic, tricyclic, or spirocyclic ring having 5 to 12 ring atoms including at least one nitrogen, oxygen, or sulfur ring atom; or
(ii) an azetidinyl ring.

3. A method for measuring TNF-alpha competitive binding of a test compound,
the method comprising:
(i) treating TNF-alpha trimer with a mixture of the test compound and a fluorescent probe, and measuring the fluorescence polarization;
(ii) treating TNF-alpha trimer with the fluorescent probe, and measuring the fluorescence polarization; and
(ii) subtracting the fluorescence polarization of (ii) from (i), wherein the subtracted result is used to determine the competitive binding of the test compound to TNF-alpha;
wherein the test compound is a compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
X, Y and Z are independently CR 4 or N;
provided that Y and Z are not both N;

L is a bond, optionally substituted (C 1 -C 3 )alkylene, or —C(O)—;
R 1 is H, CD 3 , optionally substituted (C 1 -C 3 )alkyl, or optionally substituted (C 3 -C 6 )cycloalkyl;
R 2 is optionally substituted aryl or optionally substituted heteroaryl;
R 3 is —R 3a -R 3b , wherein:
R 3a is an optionally substituted saturated, unsaturated, or partially saturated heterocyclyl or optionally substituted heteroaryl;
R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) p -optionally substituted heterocyclyl, or —(CH 2 ) p -optionally substituted oxetanyl; wherein
R a and R b are independently selected from the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, —(CH 2 ) n -optionally substituted heterocyclyl, and —(CH 2 ) n -optionally substituted oxetanyl;

R 4 is independently H, Cl, CN, F, CF 3 , methoxy, or optionally substituted (C 1 -C 3 )alkyl;
n is 0 or 1; and
p is 0, 1 or 2;

wherein heterocyclyl is:
(i) a non-aromatic monocylic, bicyclic, tricyclic, or spirocyclic ring having 5 to 12 ring atoms including at least one nitrogen, oxygen, or sulfur ring atom; or
(ii) an azetidinyl ring.

4. A compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
X, Y and Z are independently CR 4 or N;
provided that Y and Z are not both N;

L is a bond, optionally substituted (C 1 -C 3 )alkylene, or —C(O)—;
R 1 is H, CD 3 , optionally substituted (C 1 -C 3 )alkyl, or optionally substituted (C 3 -C 6 )cycloalkyl;
R 2 is optionally substituted aryl or optionally substituted heteroaryl;
R 3 is —R 3a —R 3b , wherein:
R 3a is an optionally substituted saturated, unsaturated, or partially saturated heterocyclyl or optionally substituted heteroaryl;
R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) p -optionally substituted heterocyclyl, or —(CH 2 ) p -optionally substituted oxetanyl; wherein
R a and R b are independently selected from the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, —(CH 2 ) n -optionally substituted heterocyclyl, and —(CH 2 ) n -optionally substituted oxetanyl;

R 4 is independently H, Cl, CN, F, CF 3 , methoxy, or optionally substituted (C 1 -C 3 )alkyl;
n is 0 or 1; and
p is 0, 1 or 2;

wherein heterocyclyl is:
(i) a non-aromatic monocylic, bicyclic, tricyclic, or spirocyclic ring having 5 to 12 ring atoms including at least one nitrogen, oxygen, or sulfur ring atom; or
(ii) an azetidinyl ring.

5. A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

6. The compound of claim 4 of Formula (Ia):

or a pharmaceutically acceptable salt or stereoisomer thereof.

7. The compound of claim 4 of Formula (Ie):

or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted (C 1 -C 3 )alkyl or optionally substituted cyclopropyl.

9. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is optionally substituted heteroaryl or optionally substituted phenyl.

10. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3a is optionally substituted 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted 1,2,4-thiadiazolyl.

11. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 3 )alkyl, —(CH 2 ) p -optionally substituted 2-oxa-6-azaspiro[3.3]heptanyl, —(CH 2 ) p -optionally substituted 2-azaspiro[3.3]heptanyl, —(CH 2 ) p -optionally substituted 5-azaspiro[2.3]hexanyl, —(CH 2 ) p -optionally substituted azetidinyl, —(CH 2 ) p -optionally substituted morpholinyl, —(CH 2 ) p -optionally substituted oxetanyl, —(CH 2 ) p -optionall

Assignees

• Abbvie Inc

Inventors

• Argiriadi Maria
• Breinlinger Eric
• Dietrich Justin D
• Friedman Michael
• Ihle David
• Morytko Michael
• Mullen Kelly
• OSUMA Augustine
• Loschiavo Gloria Y
• Wilson Noel S

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title