Rip1 inhibitory compounds and methods for making and using the same

Patent metadata

Field	Value
Publication number	US-2021069208-A1
Application number	US-202017013284-A
Country	US
Kind code	A1
Filing date	Sep 4, 2020
Priority date	Sep 6, 2019
Publication date	Mar 11, 2021
Grant date	—

Abstract

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP 1) 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 selected from O, S and CH 2 ;
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 Z is C 1-10 aliphatic, heteroaromatic or aromatic;
each R 1 independently is a halogen, —C≡CH or a -linker-R 6 group, wherein the linker is a bond or R a provided that R a is not H or D, 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 a halogen, —C≡CH or a -linker-R 6 group, wherein the linker is a bond or R a provided that R a is not H or D, 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 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 independe

Assignees

• Rigel Pharmaceuticals Inc

Inventors

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

Classifications

• A61K31/553 Primary

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title