IP Library › Granted Patent US 12,331,036

Granted Patent B2

US 12,331,036 · App. 17/946,181 · Granted Jun 17, 2025

Heterocyclic RIP1 kinase inhibitors

Inventors: Simon Shaw (Oakland, CA); Somasekhar Bhamidipati (Foster City, CA); Vanessa Taylor (San Francisco, CA)

C07D401/14 A61K31/553 C07D267/02 C07D401/12 C07D403/12 C07D403/14 C07D405/14 C07D413/12 C07D413/14 C07D471/08 C07D487/04 C07D491/107 C07D493/04

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Quick Facts

Patent No.: US 12,331,036
App. No.: 17/946,181
Granted: Jun 17, 2025
Kind: B2

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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.

Claims (63)

1. A method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof; or (ii) a therapeutically effective amount of a pharmaceutical composition of a compound; wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or multiple sclerosis,

wherein the compound is:

wherein:

ring B is heteroaryl;

each R 1 independently is -linker-R 6 group, wherein the linker is 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 is R a ;

R 4 is C 1-6 alkyl;

if present, each R 4 independently is Re;

L is a heteroatom or R a , provided that R a is not H or D;

X is CH 2 or O;

Z is heteroaryl;

m is 1, 2, 3, or 4;

n is 0, 1 or 2;

R a is independently for each occurrence H or D, except for embodiments where L is R a , or is 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.

2. The method of claim 1 , wherein the disease is multiple sclerosis.

3. The method of claim 1 , wherein the disease is amyotrophic lateral sclerosis.

4. The method of claim 1 , wherein each R 1 independently is:

5. The method of claim 1 , wherein each R 1 independently is:

6. The method of claim 1 , wherein each R 1 independently is:

7. The method of claim 1 , wherein the compound is

I-1: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-2: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl) methyl)-1H-pyrazole-1-carboxamide;

I-3: (S)—N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl) oxy) picolinamide;

I-4: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl) oxy) picolinamide;

I-5: (S)-4-((6-fluoropyridin-3-yl) oxy)-N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide;

I-6: (S)-4-((6-fluoropyridin-3-yl) oxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide;

I-7: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide;

I-8: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-2-ylmethyl)-1H-pyrazole-1-carboxamide;

I-9: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-(trifluoromethyl) pyridin-2-yl) methyl)-1H-pyrazole-1-carboxamide;

I-10: (S)—N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-hydroxypyridin-2-yl) methyl) picolinamide;

I-11: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl) methyl) picolinamide;

I-12: (S)—N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-2-yl) methyl) picolinamide;

I-13: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide;

I-14: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-3-ylmethyl)-1H-pyrazole-1-carboxamide;

I-15: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-((6-methylpyridin-3-yl) methyl)-1H-pyrazole-1-carboxamide;

I-16: (S)-4-((6-fluoropyridin-3-yl) methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-17: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridazin-3-ylmethyl)-1H-pyrazole-1-carboxamide;

I-26: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide;

I-27: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) picolinamide;

I-29: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyridin-4-ylmethyl)-1H-pyrazole-1-carboxamide;

I-31: (S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(pyrimidin-2-ylmethyl)-1H-pyrazole-1-carboxamide;

I-32: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-33: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-34: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl) ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-36: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(8-((3-hydroxyoxetan-3-yl) ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;

I-37: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-38: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;

I-39: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;

I-40: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(8-((4-hydroxytetrahydro-2H-pyran-4-yl) ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;

I-41: (S)-4-((6-fluoropyridin-2-yl) methyl)-N-(8-((1-hydroxycyclobutyl) ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide;

I-43: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-44: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-45: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl) ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-46: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-47: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-((3-hydroxyoxetan-3-yl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide;

I-48: (S)-4-((2-fluoropyridin-3-yl) methyl)-N-(7-((1-hydroxycyclobutyl) ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide; or

I-50: (S)-4-((2,6-difluoropyridin-3-yl) methyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide.

Assignments (2)

SECURITY INTEREST Recorded May 8, 2026

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FUNDING IV TRUST

Reel/Frame 075576/0880 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 16, 2022

From: SHAW, SIMON; BHAMIDIPATI, SOMASEKHAR; TAYLOR, VANESSA

To: RIGEL PHARMACEUTICALS, INC.

Reel/Frame 061116/0758 →

Continuity (8)

Continuation 17013034 · Sep 4, 2020

Provisional Application 63004290 · Apr 2, 2020

Provisional Application 63004301 · Apr 2, 2020

Provisional Application 63004319 · Apr 2, 2020

Provisional Application 63001016 · Mar 27, 2020

Provisional Application 62932404 · Nov 7, 2019

Provisional Application 62897223 · Sep 6, 2019

Related Publication 20230057341A1 · Feb 23, 2023

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