US 11,629,136 B1Granted

Substituted pyridine derivatives as SARM1 inhibitors

AssigneeNura Bio, Inc.

InventorsRao Kolluri, Christopher Michael Tegley, Liusheng Zhu, Sean Pomeroy Brown, Charles Howard Reynolds, Andrew Stewart Tasker, Cheryl A. Grice

Life of this patent

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Abstract

This disclosure is drawn to pyridine derivatives, compositions thereof, and associated methods, useful for inhibition of SARM1 activity and/or for treating or preventing neurological disorders.

Claims29

Dependent claims

A compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:
Q is -Cy, —C1-4 alkyl-Cy, —CF3, or C1-4 alkyl-CF3;
R1 is H;
R2 is H or C1-4 alkyl;
R4 and R4a are each independently selected from H, halo, and C1-4 alkyl;
each R5 is independently selected from halo and C1-4 alkyl, wherein R5 is attached to a carbon atom;
R6 and R7 are each independently selected from H, —ORa, —NRcRd, C1-4 alkyl, and C1-4 haloalkyl;
Cy is selected from C6-10 aryl, C3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 RCy substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(═NRe)Rb, C(═NRe)NRcRd, NRcC(═NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
or two adjacent RCy substituents together with the atoms to which they are attached form a fused phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, C(═NRe)Rb, C(═NRe)NRcRd, NRcC(═NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd;
each Ra, Rb, Rc, and Rd is independently selected from H, C1-4 alkyl, and C1-4 haloalkyl, wherein said C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4alkyl, C1-4alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy;
each Re is independently selected from H, C1-4alkyl, and CN;
n is 0, 1, or 2;
and
m is 1 or 2.

11 more elements

A compound selected from:

4-((2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;
4-((2-(3,3,3-trifluoropropyl)-1H-imidazol-4-yl)methyl)pyridine;
2-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)acetonitrile;
3-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)propanenitrile;
rac-4-(1-(2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)ethyl)pyridine;
(R)-4-(1-(2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)ethyl)pyridine;
(S)-4-(1-(2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)ethyl)pyridine;
5-((4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)methyl)thiazole;
4-((5-(2,2,2-Trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)pyridine;
2-(Pyridin-4-ylmethyl)-4-(2,2,2-trifluoroethyl)thiazole;
4-(Pyridin-4-ylmethyl)-2-(2,2,2-trifluoroethyl)thiazole;
rac-4-(1-(5-(2,2,2-trifluoroethyl)-1H-pyrrol-2-yl)ethyl)pyridine;
(S)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-ol;
(R)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-ol;
2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-one;
(E/Z)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-one oxime;
4-((5-Methyl-2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;
(S)-2,2,2-trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;
(R)-2,2,2-trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;
(S)-2,2,2-Trifluoro-N-methyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;
(R)-2,2,2-Trifluoro-N-methyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;
(S)-2,2,2-Trifluoro-N,N-dimethyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;
(R)-2,2,2-Trifluoro-N,N-dimethyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;
(E/Z)-2, 2, 2-Trifluoro-1-(4-(pyridin-4-ylmethyl)thiazol-2-yl) ethan-1-one oxime;
(R)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)thiazol-2-yl)ethan-1-amine;
(S)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)thiazol-2-yl)ethan-1-amine;
(S)-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;
(R)-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;
(5-((3-Methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;
3,5-Dichloro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)pyridine;
1-(4-((3-Chloropyridin-4-yl)methyl)-1H-imidazol-2-yl)-2,2,2-trifluoroethan-1-ol;
(S)-2,2,2-trifluoro-1-(4-((S)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;
(R)-2,2,2-trifluoro-1-(4-((S)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;
(S)-2,2,2-trifluoro-1-(4-((R)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;
(R)-2,2,2-trifluoro-1-(4-((R)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;
3-Methyl-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;
(R)-2,2,2-Trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-1-(thiazol-5-yl)ethan-1-ol;
(S)-2,2,2-Trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-1-(thiazol-5-yl)ethan-1-ol;
3-Chloro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;
2-Chloro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)pyridine;
2-Fluoro-4-((2-(2, 2, 2-trifluoroethyl)-3H-imidazol-4-yl)methyl)pyridine;
(S)-(5-((3-Methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;
(R)-(5-((3-Methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;
(R)-(5-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-2-yl)methanol;
(S)-(5-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-2-yl)methanol;
(R)-1,1,1-Trifluoro-2-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol;
(S)-1,1,1-Trifluoro-2-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol;
(S)-4-((2-(2,2,2-trifluoro-1-methoxyethyl)-1H-imidazol-5-yl)methyl)pyridine;
(R)-4-((2-(2,2,2-trifluoro-1-methoxyethyl)-1H-imidazol-5-yl)methyl)pyridine;
(R)-2,2,2-Trifluoro-1-(5-((2-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;
(S)-2,2,2-Trifluoro-1-(5-((2-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;
Pyridin-2-yl(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)methanol;
3-Fluoro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;
(S)-2,2,2-Trifluoro-1-(4-((3-methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;
(R)-2,2,2-Trifluoro-1-(4-((3-methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;
(S)-2,2,2-Trifluoro-1-(4-((3-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;
(R)-2,2,2-Trifluoro-1-(4-((3-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;
1,1,1,3,3,3-Hexafluoro-2-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol;
and
1,1,1-Trifluoro-2-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol
or a pharmaceutically acceptable salt of any of the aforementioned.

58 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/875,301Filed 27 Jul 2022 · us provisional application
Priority: 28 Jul 2021
Published: US 2023/0105696 A16 Apr 2023
Granted: 18 Apr 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
C07D 417/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…

Family

Application63/226,557Us provisional application · filed 28 Jul 2021
Application63/305,103Us provisional application · filed 31 Jan 2022
Application63/368,034Us provisional application · filed 8 Jul 2022
US 2023/0105696 A1Published application
US 11,629,136 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

This disclosure is drawn to pyridine derivatives, compositions thereof, and associated methods, useful for inhibition of SARM1 activity and/or for treating or preventing neurological disorders.

Facts

Application

17/875,301Filed 27 Jul 2022 · us provisional application

Priority

28 Jul 2021

Published

US 2023/0105696 A16 Apr 2023

Granted

18 Apr 2023

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
C07D 417/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…

Family

Application63/226,557Us provisional application · filed 28 Jul 2021

Application63/305,103Us provisional application · filed 31 Jan 2022

Application63/368,034Us provisional application · filed 8 Jul 2022

US 2023/0105696 A1Published application

US 11,629,136 B1This patent

From the US filing history. Foreign family members aren’t listed.