US-12624025-B2 - Inhibitors of SARM1

Abstract

The present disclosure provides compounds and methods useful for inhibiting SARM1 and/or treating and/or preventing axonal degeneration. 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).

Inventors

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

Assignees

• DISARM THERAPEUTICS, INC.

Dates

Publication Date

20260512

Application Date

20200605

Claims (10)

1. 1 . A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from —CN, and —CON(R) 2 ; R 2 is selected from —H and —CH 3 ; R 3 is -Cy 1 ; R 4 is -Cy 2 ; Cy 1 is selected from each R x is independently selected from halogen, —OR, —C(O)R, and C 1-6 aliphatic optionally substituted with halogen; Cy 2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each phenyl, heterocyclic, and heteroaryl ring is substituted with 0-4 R v ; each R v is independently selected from halogen, —CN, —NO 2 , —SR, —N(R) 2 , —OR, —C(O)R, —SO 2 R, —CO 2 R, —SO 2 N(R) 2 , —CON(R) 2 , —N(R)SO 2 R, —N(R)C(O)R, C 1-6 aliphatic optionally substituted with halogen, and 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen; and each R is independently hydrogen or C 1-6 aliphatic optionally substituted with halogen, 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.
2. 2 . The compound according to claim 1 , wherein: R 1 is —CN; and R 2 is —H.
3. 3 . The compound according to claim 1 , wherein: R 1 is —CON(R) 2 ; and R 2 is —H.
4. 4 . The compound according to claim 1 , wherein Cy 2 is selected from
5. 5 . The compound according to claim 1 , wherein Cy 2 is selected from
6. 6 . The compound according to claim 1 , wherein Cy 2 is selected from
7. 7 . The compound according to claim 1 , wherein Cy 2 is selected from
8. 8 . A method comprising a step of: administering a compound of claim 1 to a subject who has a condition characterized by axonal degeneration.
9. 9 . A method of inhibiting SARM1 comprising contacting a biological sample with a compound of claim 1 .
10. 10 . A compound 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. 62/858,083, filed Jun. 6, 2019, 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. 3, 2020 is named 2012800-0036_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, whereinR1 is selected from —CN, —CON(R)2, —C(═NR)N(R)2, —NO2, —S(O)2R, —S(O)2N(R)2, —C(O)R, —CO2R, and a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R2 is —R;R3 is —(CH2)0-2Cy1;R4 is -Cy2;Cy1 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each phenyl and heteroaryl ring is substituted with 0-4 Rx;each Rx is independently selected from halogen, —CN, —NO2, —SR, —N(R)2, —OR, —C(O)R, —SO2R, —CO2R, —SO2N(R)2, —CON(R)2, —N(R)SO2R, —N(R)C(O)R, and optionally substituted C1-6 aliphatic;Cy2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each phenyl, heterocyclic, and heteroaryl ring is substituted with 0-4 Rv;each R is independently selected from halogen, —CN, —NO2, —SR, —N(R)2, —OR, —C(O)R, —SO2R, —CO2R, —SO2N(R)2, —CON(R)2, —N(R)SO2R, —N(R)C(O)R, optionally substituted C1-6 aliphatic, and an optionally substituted 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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-b, I-b-i, I-b-ii, I-b-iii, I-c, I-c-i, I-c-ii, and I-c-iii, as set forth below. In some embodiments, one or more compounds of Formula I is provided and/or utilized in a solid form (e.g., a crystal form or an amorphous form). In some embodiments, the present disclosure provides compositions that comprise and/or deliver a compound of Formula I (e.g., in a form as described herein), a prodrug or active metabolite thereof. In some embodiments, the present disclosure provides compositions that comprise and/or deliver a compound of Formula I. In some embodiments, such compositions are pharmaceutical compositions that include at least one pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, provided SARM1 inhibitors reduce or inhibit binding of NAD+ by SARM1. In some embodiments, provided SARM1 inhibitors bind to SARM1 within a pocket comprising one or more catalytic residues (e.g., a catalytic cleft of SARM1). In some embodiments, provided compounds and/or compositions inhibit activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodege