US-12624026-B2 - Inhibitors of SARM1

Abstract

Compounds having a structure set forth in Formula I below are provided herein. Such compounds and methods disclosed herein, may be useful, for example, for inhibiting SARM1 and/or treating and/or preventing axonal degeneration.

Inventors

• Robert Owen Hughes
• Rajesh Devraj
• Todd Bosanac
• Richard Andrew Jarjes-Pike
• Andrew Simon Brearley
• Jonathan Bentley

Assignees

• DISARM THERAPEUTICS, INC.

Dates

Publication Date

20260512

Application Date

20190606

Claims (1)

1. 1 . A compound, which is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62/682,054, filed Jun. 7, 2018, which is herein incorporated by reference in its entirety. SEQUENCE LISTING The instant application contains a Sequence Listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created Jun. 6, 2019, is named 2012800-0024_SL.txt, and is 13,851 bytes in size. BACKGROUND Axonal degeneration is a hallmark of several neurological disorders including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 348 2016, pp. 453-457, hereby incorporated by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. Costs associated with these diseases currently exceed several hundred billion dollars annually in the Unites States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing as demographics change. SUMMARY The present disclosure provides technologies useful, among other things, for treating and/or preventing neurodegeneration (e.g., for reducing axonal degeneration). In some embodiments, provided technologies inhibit SARM1. In some embodiments, the present disclosure provides certain compounds and/or compositions that are useful in medicine, and particularly for treating neurodegeneration (e.g., for reducing axonal degeneration). In some embodiments, the present disclosure provides compounds having a structure as set forth in Formula I. or a pharmaceutically acceptable salt thereof, wherein R1 is selected from —CN, —NO2, —C(O)R, —S(O)2R, —CON(R)2, —S(O)2N(R)2, and —CO2R;R2 is —R;R3 is —(CH2)0-2Cy, or: R2 and R3, together with the nitrogen atom to which they are attached, form a 4- to 7-membered saturated or partially unsaturated ring fused to Cy or a 4- to 7-membered saturated or partially unsaturated ring substituted with -Cy; Cy is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic aryl ring, wherein each phenyl, heteroaryl and aryl ring is substituted with 0-4 Rx;each Rx is independently selected from halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —CO2R, —CON(R)2, —N(R)SO2R, —N(R)C(O)R, and optionally substituted C1-6 aliphatic;R4 is —R; andeach R is independently hydrogen or optionally substituted C1-6 aliphatic, or: two instances of R, together with the atom to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring. In some embodiments, provided compounds have structures of Formulae I-a, I-a-i, I-a-ii, I-a-iii, I-a-iv, I-a-v, I-a-vi, I-b, I-b-i, I-b-ii, I-b-iii, I-b-iv, I-b-v, I-b-vi, I-c, I-c-i, I-c-ii, I-c-iii, I-c-iv, I-c-v, and I-c-vi, as set forth below. In some embodiments, the present disclosure provides compounds having a structure as set forth in Formula II: or a pharmaceutically acceptable salt thereof, wherein R1 is selected from —CN, —NO2, —C(O)R, —S(O)2R, —CON(R)2, —S(O)2N(R)2, —CO2R, —C(═NR)N(R)2, and a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R2 is —R;R3 is —(CH2)0-2Cy, or: R2 and R3, together with the nitrogen atom to which they are attached, form a 4- to 7-membered saturated or partially unsaturated ring fused to Cy or a 4- to 7-membered saturated or partially unsaturated ring substituted with -Cy; Cy is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic aryl ring, wherein each phenyl, carbocyclic, heteroaryl and aryl ring is substituted with 0-4 Rx;each Rx is independently selected from halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —CO2R, —CON(R)2, —N(R)SO2R, —N(R)C(O)R, an optionally substituted C1-6 aliphatic group, an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an optionally substituted 8- to 10-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R4 is —R; andeach R is independently hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted phenyl, and an optionally substituted 3- to 7-membere