Stat6 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2025213586-A1
Application number	US-202519008194-A
Country	US
Kind code	A1
Filing date	Jan 2, 2025
Priority date	Jan 3, 2024
Publication date	Jul 3, 2025
Grant date	—

Abstract

The present invention provides compounds, compositions, and methods of using the same.

First claim

1 . An inhibitor compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
Ring W is phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 9-membered bicyclic saturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, naphthyl, a 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 13-membered tricyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R w is independently selected from halogen, —CN, —OR w1 , —N(R w1 ) 2 , —(CH 2 ) n C(O)NR 2 , —(CH 2 ) n N(R)C(O)NR 2 , —(O) m -phenyl, C 1-4 aliphatic, a 6-membered monocyclic saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclyl, or heteroaryl is optionally substituted with halogen, C 1-4 aliphatic, —OR, or —C(O)NR 2 ;
each R w1 is independently selected from hydrogen, C 1-4 aliphatic, phenyl, or 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with halogen, —OR, or —C(O)OR;
each R x is independently C 1-4 aliphatic, halogen, or —C(O)NR 2 ;
each R is independently hydrogen or C 1-4 aliphatic;
L XB is a bivalent straight or branched C 1-3 aliphatic wherein one methylene unit is optionally replaced with —NR—;
Ring Y is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R y is independently C 1-4 aliphatic, halogen, —OR, or —C(O)NR 2 ;
each m is independently 0 or 1;
each n is independently 0, 1, 2, or 3; and
each w, x, and y is independently 0, 1, 2, 3, or 4.

2 . An inhibitor compound of formula I-b:

Ring W′ is

W 1 is O, NH, or NR w ;
Ring X is a 5-membered monocyclic heteroarylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenylenyl, or a 5- or 7-membered saturated or partially unsaturated monocyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R w is independently selected from halogen, —CN, —OR w1 , —N(R w1 ) 2 , —(CH 2 ) n C(O)NR 2 , —(CH 2 ) n N(R)C(O)NR 2 , —(O) m -phenyl, C 1-4 aliphatic, a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclyl, or heteroaryl is optionally substituted with halogen, C 1-4 aliphatic, —OR, or —C(O)NR 2 ;
each R w1 is independently selected from hydrogen, C 1-4 aliphatic, phenyl, or 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with halogen, —OR, or —C(O)OR;
each R x is independently C 1-4 aliphatic, halogen, or —C(O)NR 2 ;
each R is independently hydrogen or C 1-4 aliphatic;
G is hydrogen or

L XA is a covalent bond or a bivalent straight or branched C 1-3 aliphatic;
L XB is a bivalent straight or branched C 1-3 aliphatic wherein one methylene unit is optionally replaced with —NR—;
Ring Y is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R y is independently C 1-4 aliphatic, halogen, —OR, or —C(O)NR 2 ;
each m is independently 0 or 1;
each n is independently 0, 1, 2, or 3; and
each w, x, and y is independently 0, 1, 2, 3, or 4.

3 . The inhibitor compound of claim 1 , wherein Ring W is:

4 . The inhibitor compound of claim 2 , wherein W 1 is O.

5 . The inhibitor compound of claim 2 , wherein W 1 is —NH— or —NR w —.

6 . The inhibitor compound of claim 2 , wherein Ring X is:

wherein # represents the point of attachment to G.

7 . The inhibitor compound of claim 2 , wherein G is hydrogen.

8 . The inhibitor compound of claim 2 , wherein G is

9 . The inhibitor compound of claim 1 , wherein Ring Y is:

10 . The inhibitor compound of claim 1 , wherein an occurrence of R w is —(O) m -phenyl, wherein the phenyl is optionally substituted with halogen, —OR, or —C(O)NR 2 .

11 - 15 . (canceled)

16 . The inhibitor compound of claim 1 , wherein the inhibitor compound is of formulae II-a, III-a, or IV-a:

or a pharmaceutically acceptable salt thereof.

17 . The inhibitor compound of claim 2 , wherein the inhibitor compound is of formula I-b-1 or 1-b-2:

or a pharmaceutically acceptable salt thereof.

18 . (canceled)

19 . The inhibitor compound of claim 2 , wherein the inhibitor compound is of formulae II-b, III-b, IV-b, V-b, VI-b, or VII-b:

or a pharmaceutically acceptable salt thereof.

20 . A compound selected from any one of the compounds depicted in Table 1A, Table 1B, Table 2A, or Table 2B, or a pharmaceutically acceptable salt thereof.

21 . A pharmaceutical composition comprising an inhibitor compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

22 . A method of inhibiting STAT6, the method comprising contacting STAT6 with an inhibitor compound of claim 1 , or a pharmaceutically acceptable salt thereof.

23 . The method of claim 22 , wherein the contacting occu

Assignees

• Kymera Therapeutics Inc

Inventors

• Dong Huijun
• Yang Bin
• Follows Bruce C
• Zhu Xiao
• Weiss Matthew M
• Zheng Xiaozhang
• Huang Xin
• Su Lijing
• Mainolfi Nello
• Beuming Thijs
• Fei Xue
• Collier Philip
• Zhang Yi

Classifications

• C07D498/20

  Spiro-condensed systems · CPC title

• C07D498/08

  Bridged systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title