RIP1 inhibitory compounds and methods for making and using the same

Patent metadata

Field	Value
Publication number	US-11564930-B2
Application number	US-202017013284-A
Country	US
Kind code	B2
Filing date	Sep 4, 2020
Priority date	Sep 6, 2019
Publication date	Jan 31, 2023
Grant date	Jan 31, 2023

Abstract

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.

First claim

We claim:

1. A compound, having a Formula I

wherein X is C or N;
Y is O;
the ring system denoted by

is a bicyclic heteroaryl optionally substituted on ring A, ring B, or both by one or more R 4 groups;
L is a divalent moiety selected from R a , a heteroatom; —CH 2 —, —CH 2 CH 2 —, or C 3-6 cycloalkyl;
Z is C 1-10 aliphatic, heteroaryl or aromatic;
each R 1 independently is 8- to 12-membered spiroheterocyclyl or a -linker-R 6 group, wherein the linker is C 2-10 alkyne, and R 6 is heterocyclyl, R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R 2 is R a ;
each R 4 independently is oxo, C 3-6 heterocyclyl or R e ;
R a is independently for each occurrence H or D, except for embodiments where L is R a , C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, C 3-6 heterocyclic, or C 3-10 spiroheterocyclic;
R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , —C(O)NR d R d , —OC(O)NR d R d , —OC(O)C 1-10 alkyl substituted with one or two NR d R d , carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH 2 ;
R c is independently for each occurrence C 1-10 alkyl, which can be substituted with 1, 2 or 3 R e , C 2-10 alkenyl, which can be substituted with 1, 2 or 3 R e , C 2-10 alkynyl, which can be substituted with 1, 2 or 3 R e , C 3-6 cycloalkyl, which can be substituted with 1, 2 or 3 R e , or C 5-10 aromatic, which can be substituted with 1, 2 or 3 R e ;
R d is independently for each occurrence H; C 1-6 alkyl, which can be substituted with 1, 2 or 3 R e or a C 3-9 heterocyclyl; C 3-6 cycloalkyl, which can be substituted with 1, 2 or 3 R e ; C 3-6 heterocyclic, which can be substituted with 1, 2 or 3 R e ; C 5-10 aryl, which can be substituted with 1, 2 or 3 R b ; C 5-10 heteroaryl, which can be substituted with 1, 2 or 3 R e ; or two R d groups together with the nitrogen bound thereto provide a C 3-9 heterocyclic, which can be substituted with one or more R e ), or a C 5-10 heteroaryl, which can be substituted with one or more R e ;
R e is independently for each occurrence halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-10 heteroaryl, or —OR a ; and
R f is independently for each occurrence -alkyl-phosphate, R a , R b , or R e , or two R f groups together with the carbon atom bound thereto provide a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, which can be substituted with one or more R e , or a C 3-10 heterocyclic, which can be substituted with one or more R e or acyl;

m is 1, 2, 3, or 4; and
n is 0, 1 or 2.

2. The compound of claim 1 according to the formula

3. The compound of claim 1 according to the formula

4. The compound of claim 1 according to the formula

5. The compound of claim 1 , wherein ring B is 5-membered or 6-membered heteroaryl wherein the heteroaryl has one or two ring nitrogen atoms and the remainder of the ring atoms are carbon.

6. The compound of claim 1 , wherein the ring system denoted by

has the formula

wherein p is 0 or 1; and ring A, ring B, or both optionally are substituted by one or more R 4 .

7. The compound of claim 1 , wherein the ring system denoted by

has the formula

wherein p is 0 or 1; and ring B is optionally substituted by one or more R 4 .

8. The compound of claim 1 , wherein the ring system denoted by

has the formula

wherein p is 0 or 1.

9. The compound of claim 1 , wherein the ring system denoted by

has the formula

10. The compound of claim 1 , wherein the ring system denoted by

has the formula

11. The compound of claim 1 , according to the formula

wherein ring B is 5-membered or 6-membered heteroaryl wherein the heteroaryl has one or two ring nitrogen atoms and the remainder of the ring atoms are carbon;
L is a heteroatom or R a , provided that R a is not H or D;
Z is C 1-10 aliphatic or aromatic;
each R 1 independently is 8- to 12-membered spiroheterocyclyl or a -linker-R 6 group, wherein the linker is C 2 -C 10 alkyne, and R 6 is heterocyclyl, R b , —C(R f ) 3 , or —C(R f )═C(R f ) 2 ;
R 2 is R a ;
R 3 is C 1-3 aliphatic optionally substituted with one or more R 4 , wherein together with the —N—C(O) moiety to which it is attached and two ring atoms from ring B forms a 5- or 6-membered heterocyclyl that is fused to ring B;
each R 4 independently is R e ;
R a is independently for each occurrence H or D, except for embodiments where L is R a , C 1-10 aliphatic, C 1-10 haloaliphatic, C 5-10 aromatic, C 3-6 heterocyclic, or C 3-10 spiroheterocyclic;
R b is independently for each occurrence —OH, —SH, —OR c , —SR c , —NR d R d , —Si(R a ) 3 , —C(O)OH, —C(O)OR c , —C(O)NR d R d , —OC(O)NR d R d , —OC(O)C 1-10 alkyl substituted with one or two NR d R d , carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH 2 ;
R c is independently for each occurrence C 1-10 alkyl, which can be substituted with 1, 2 or 3 R e , C 2-10 alkenyl, which can be substituted with 1, 2 or 3 R e , C 2-10 alkynyl, which can be substituted with 1, 2 or 3 R e , C 3-6 cycloalkyl, which can be substituted with 1, 2 or 3 R e , or C 5-10 aromatic, which can be substituted with 1, 2 or 3 R e ;
R d is independently for each occurrence H; C 1-6 alkyl, which can be substituted with 1, 2 or 3 R e or a C 3-9 heterocyclyl; C 3-6 cycloalkyl, which can be substituted with 1, 2 or 3 R e ; C 3-6 heterocyclic, which can be substituted with 1, 2 or 3 R e ; C 5-10 aryl, which can be substituted with 1, 2 or 3 R b ; C 5-10 heteroaryl, which can be substituted with 1, 2 or 3 R e ; or two R d groups together with the nitrogen bound thereto provide a C 3-9 heterocyclic, which can be substituted with one or more R e ), or a C 5-10 heteroaryl, which can be substituted with one or more R e ;
R e is independently for each occurrence halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalky

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Yu Jiaxin
• Darwish Ihab
• Taylor Vanessa
• Kolluri Rao
• Chen Yan
• Shaw Simon
• Bhamidipati Somasekhar
• Luo Zhushou

Classifications

• C07D267/14

  condensed with one six-membered ring · CPC title

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title