Tricyclic IRAK inhibitors

Patent metadata

Field	Value
Publication number	US-12459941-B2
Application number	US-202318192813-A
Country	US
Kind code	B2
Filing date	Mar 30, 2023
Priority date	Mar 31, 2022
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Disclosed embodiments concern compounds according to Formula I

In some embodiments, the compounds are useful as kinase inhibitors, such as interleukin receptor associated kinases (IRAK) inhibitors. Also disclosed are compositions comprising such inhibitors, and methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent a kinase-associated disease or condition, particularly an IRAK-associated disease or condition.

First claim

We claim:

1. A compound according to Formula I

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
Y is O(CH 2 ) n ;
n is 1, or 2;
Z 1 is N;
Z 2 and Z 3 are CR 5 ;
R 1 is H, halo, cyano, —SO 2 alkyl, N 3 , Si(C 1-6 alkyl) 3 , heterocycloalkyl, heteroaryl, or R a ;
R 2 is pyrrolidi-2-one, optionally substituted with a halogen and/or C 1 -C 4 alkyl;
R 3 is H or R a ;
each R 5 is H;
each R a is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aralkyl, or C 3-8 cycloalkyl, and may be optionally substituted with 1, 2, or 3 R b ;
each R b is independently selected from OH, —OR a , halo, oxo, —NR c R c , —C(O)OR d , —C(O)NR c R c , —N(R d )C(O)OR a , or —N(R d )C(O)NR c R c ;
each R c is independently selected from R d or two R c , together, with the nitrogen atom to which they are attached, form a C 2-8 heterocyclyl optionally having one or two additional heteroatoms selected from O and NR d and optionally substituted with one or more of the same or different R a or R b , and
each R d is independently selected from hydrogen and C 1-6 alkyl.

2. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the compound has a structure according to Formula II

3. The compound of claim 1 , wherein:
R 1 is R a ;
R 3 is H;
each R 5 is H;
or a combination thereof.

4. The compound of claim 1 , wherein R 1 is C 1-6 alkyl optionally substituted with 1, 2 or 3 R b .

5. The compound of claim 1 , wherein Y is —OCH 2 —.

6. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the compound has a structure according to Formula III

7. The compound of claim 1 , wherein:
R 2 is

m is 0, 1, 2 or 3; and
each R 6 independently is R a or R b .

8. The compound of claim 1 , wherein:
R 2 is

 and
each of R 7 and R 8 independently is halo or C 1-6 alkyl.

9. The compound of claim 8 , wherein the compound has a structure selected from Formulas IV-B, IV-C, or IV-D

10. The compound or a pharmaceutically acceptable salt or solvate thereof of claim 1 , selected from:
I-1: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(thiazol-5-yl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-2: (S)-4-methyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one formic acid salt;
I-3: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(pyridin-3-yl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-4:4-cyclopropyl-6-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-5: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-6: (S)-4-iodo-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-7: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-vinylpyrido [3,4-g]isoquinolin-1(2H)-one;
I-8: (S)-4-ethyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-9: (S)-4-allyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-10: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-propylpyrido [3,4-g]isoquinolin-1(2H)-one;
I-11: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(prop-1-en-2-yl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-12: (S)-4-cyclobutyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-13: (S)-4-cyclopentyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-14: (S)-4-cyclopropyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-15: (S)-4-isopropyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-16: (S)-1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido [3,4-g]isoquinoline-4-carbonitrile;
I-17: (S)-4-(2,2-difluoroethyl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-18: (S)-4-ethynyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-19: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(2,2,2-trifluoroethyl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-20: (S)-4-(2-hydroxypropan-2-yl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-21: (S)-4-(3-hydroxyprop-1-yn-1-yl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-22: (S)-4-(2-hydroxyethyl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-23: (S)-4-(azetidin-3-yl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-24: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(prop-1-yn-1-yl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-25: (S)-4-methyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-26: (S)-4-(2-aminopropan-2-yl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-27: (S)-1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido [3,4-g]isoquinoline-4-carboxamide;
I-28: (S)-4-acetyl-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-29: (S)-4-(3-aminoprop-1-yn-1-yl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-30: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(trifluoromethyl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-31: (S,Z)-4-(2-ethoxyvinyl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-32: (S)-4-(1-ethoxyvinyl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-33: (S)-6-((5-oxopyrrolidin-2-yl)methoxy)-4-(1H-pyrazol-4-yl)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-34: (S)-2-(1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido[3,4-g]isoquinolin-4-yl)acetaldehyde;
I-36:4-(1-hydroxyethyl)-6-(((S)-5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-37:4-(2-hydroxybut-3-yn-2-yl)-6-(((S)-5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-38: tert-butyl(S)-3-(1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido[3,4-g]isoquinolin-4-yl) azetidine-1-carboxylate;
I-39: tert-butyl(S)-2-(1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido[3,4-g]isoquinolin-4-yl)acetate;
I-40: (S)-2-(1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido[3,4-g]isoquinolin-4-yl)acetic acid;
I-41: (S)-2-(1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido[3,4-g]isoquinolin-4-yl)acetamide;
I-42: tert-butyl(S)-(3-(1-oxo-6-((5-oxopyrrolidin-2-yl)methoxy)-1,2-dihydropyrido[3,4-g]isoquinolin-4-yl) prop-2-yn-1-yl)carbamate;
I-44: 6-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-4-iodopyrido[3,4-g]isoquinolin-1(2H)-one;
I-45: 6-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-4-methylpyrido[3,4-g]isoquinolin-1(2H)-one;
I-46: 6-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-47: 6-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-1-oxo-1,2-dihydropyrido[3,4-g]isoquinoline-4-carbonitrile; or
I-48: (S)-4-(methylsulfonyl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-49: (S)-4-(3-hydroxy-3-methylbut-1-yn-1-yl)-6-((5-oxopyrrolidin-2-yl)methoxy)pyrido[3,4-g]isoquinolin-1(2H)-one;
I-50: (S)-4-isobutyl-6-((5-oxopyrroli

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Luo Zhushou
• Shaw Simon
• Darwish Ihab
• Masuda Esteban
• Lamagna Chrystelle

Classifications

• C07F7/0812

  comprising a heterocyclic ring · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title