# US 12,110,285 B2 · Substituted pyridine derivatives as SARM1 inhibitors

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- Number: US 12,110,285 B2
- Document ID: US12110285B2
- Status: Granted
- Kind: B2
- Application number: 18/178,325
- Filed: 2023-03-03
- Published: 2023-09-14
- Granted: 2024-10-08
- Earliest claimed: 2021-07-28
- Assignees: Nura Bio, Inc.
- Applicants: Nura Bio, Inc.
- Inventors: Rao Kolluri; Christopher Michael Tegley; Liusheng Zhu; Sean Pomeroy Brown; Charles Howard Reynolds; Andrew Stewart Tasker; Cheryl A. Grice
- Web page: https://patentgrep.com/patent/US12110285B2

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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.

## Claims

### Claim 1

A method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of 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, C3-7 cycloalkyl, 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 Roy 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, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy;
each Re is independently selected from H, C1-4 alkyl, and CN;
n is 0, 1, or 2; and
m is 1 or 2; wherein the neurological disorder is selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, traumatic brain injury (TBI), ocular neuropathy, Parkinson's disease, Alzheimer's disease, and peripheral neuropathy.

### Claim 2 (depends on 1)

The method of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is H.

### Claim 3 (depends on 2)

The method of claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is H.

### Claim 4 (depends on 3)

The method of claim 3, or a pharmaceutically acceptable salt thereof, wherein R4a is H.

### Claim 5 (depends on 4)

The method of claim 4, or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are each independently selected from H and OH.

### Claim 6 (depends on 5)

The method of claim 5, or a pharmaceutically acceptable salt thereof, wherein at least one of R6 and R7 is H.

### Claim 7 (depends on 6)

The method of claim 6, or a pharmaceutically acceptable salt thereof, wherein both R6 and R7 are H.

### Claim 8 (depends on 6)

The method of claim 6, or a pharmaceutically acceptable salt thereof, wherein R6 is OH and R7 is H.

### Claim 9 (depends on 6)

The method of claim 6, or a pharmaceutically acceptable salt thereof, wherein Q is —CF3.

### Claim 10 (depends on 6)

The method of claim 6, or a pharmaceutically acceptable salt thereof, wherein Q is —Cy.

### Claim 11 (depends on 10)

The method of claim 10, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from C6-10 aryl and 5-6 membered heteroaryl, 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(═NRc)NRcRd, NRcC(═NRc)NRcRd, NRCS(O)Rb, NRCS(O)2Rb, NRCS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.

### Claim 12 (depends on 11)

The method of claim 11, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from 5-6 membered heteroaryl optionally substituted by 1, 2, 3, or 4 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.

### Claim 13 (depends on 12)

The method of claim 12, or a pharmaceutically acceptable salt thereof, wherein Cy is thiazoyl optionally substituted by 1 or 2 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.

### Claim 14 (depends on 13)

The method of claim 13, or a pharmaceutically acceptable salt thereof, wherein Cy is

### Claim 15 (depends on 13)

The method of claim 13, or a pharmaceutically acceptable salt thereof, wherein each Roy substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa, C(O)Rb, C(O)NRcRd, C(O)ORa, NRcRd, NRcC(O)Rb, NRCS(O)2Rb, S(O)2Rb, and S(O)2NRcRd.

### Claim 16 (depends on 9)

The method of claim 9, or a pharmaceutically acceptable salt thereof, wherein n is 0.

### Claim 17 (depends on 16)

The method of claim 16, or a pharmaceutically acceptable salt thereof, wherein m is 1.

### Claim 18

A method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of 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)-1/-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-4-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)-1/-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; wherein the neurological disorder is selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, traumatic brain injury (TBI), ocular neuropathy, Parkinson's disease, Alzheimer's disease, and peripheral neuropathy.

### Claim 19 (depends on 1)

The method of claim 1, comprising administering to the patient a further pharmaceutically active agent.