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EP-4734982-A2 - MITOCHONDRIAL COMPLEX I INHIBITORS WITH REDUCED PHOSPHODIESTERASE INHIBITION

EP4734982A2EP 4734982 A2EP4734982 A2EP 4734982A2EP-4734982-A2

Abstract

This disclosure provides compounds for treating medical disorders, and more particularly inhibitors of mitochondrial complex I which are useful in treating cancers, such as by sensitizing cancers to radiation therapy.

Inventors

  • DENKO, NICHOLAS
  • MITTON-FRY, Mark
  • HAINES, Ben
  • BENEJ, Martin

Assignees

  • Ohio State Innovation Foundation

Dates

Publication Date
20260506
Application Date
20240701

Claims (16)

  1. 1. A compound of Formula I or a pharmaceutically acceptable salt thereof; wherein: R 1 and R 2 are each independently selected from H or -O-(Ci-Ce alkyl), wherein at least one or R 1 and R 2 is H; X 1 and X 2 are each independently selected from N or C(R 4 ), wherein at least one or X 1 and X 2 is N; R 3 is 5- to 10-membered monocyclic or bicyclic aryl optionally substituted with one or more groups selected from R 5 ; R 4 is independent selected at each occurrence from H or halo; R 5 is selected from hydrogen, halo, nitro, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, R X O-(CO-C 3 alkyl)-, R x S-(Co-C 3 alkyl)-, (R x RyN)-(Co-C 3 alkyl)-, R x O-C(0)-(Co-C 3 alkyl)-, R X S-C(0)-(CO-C 3 alkyl)-, (R’TVN) C(0)-(Co-C 3 alkyl)-, R x O-S(0) 2 -(Co-C 3 alkyl)-, (R X R V N) S(0)2-(Co-C 3 alkyl)-, R z C(0)-0-(Co-C 3 alkyl)-, R z C(0)-(R x N)-(Co-C 3 alkyl)-, R Z S(0)2-0-(CO-C 3 alkyl)-, R z S(0) 2 -(R x N)-(Co-C 3 alkyl)-, R z C(0)-(Co-C 6 alkyl)-, R Z S(O)- (C0-C3 alkyl)-, and R z S(0)2-(Co-C3 alkyl)-, each of which may be optionally substituted by one or more groups selected from Y as allowed by valency; R x and R y are independently selected at each occurrence from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-Cealkynyl, (C3-C7cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; R z is independently selected at each occurrence from hydrogen, halo, Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-Cealkynyl, (C3-C7cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, -OR X , -SR X , and -NR , each of which may be optionally substituted with one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, phospho, thiol, or combinations thereof.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OCH3 and R 2 is H.
  3. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is H and R 2 is -OCH3.
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each H.
  5. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is C(R 4 ).
  6. 6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 4 ) and X 2 is N.
  7. 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
  8. 8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo.
  9. 9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.
  10. 10. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each N.
  11. 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl or 1 -naphthyl optionally substituted with one or more groups selected from R 5 .
  12. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:
  13. 13. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  14. 14. A pharmaceutical composition comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  15. 15. A method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14.
  16. 16. A method of sensitizing a cancer to radiation therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14 prior to or concurrently with the radiation therapy.

Description

MITOCHONDRIAL COMPLEX I INHIBITORS WITH REDUCED PHOSPHODIESTERASE INHIBITION CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to United States Provisional Application No. 63/524,052 filed June 29, 2023, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant/Contract Nos. CA255334 and CA262388 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD This disclosure relates to compounds for treating medical disorders, and more particularly to inhibitors of mitochondrial complex I which are useful in treating cancers, such as by sensitizing cancers to radiation therapy. BACKGROUND Mitochondrial complex I inhibitors such as papaverine and SMV-32 have been previously shown to sensitive tumors to radiation therapy (see Proc. Natl. Acad. Sci. 2018, 115(49), El 1561). However, papaverine also inhibits PDElOa, and this off-target activity is believed to lead to side effects that limit the dose that can be administered clinically. SMV- 32 partially overcomes this liability, but there is a clear need for additional compounds which further dissociate mitochondrial complex I inhibition from PDElOa inhibition. This disclosure addresses these as well as other needs. SUMMARY The present disclosure provides compounds which are useful as mitochondrial complex I inhibitors which also show limited inhibition of phosphodiesterases (particularly PDElOa). Also provided are methods of using the compounds described herein in the treatment of medical disorders. In one aspect, a compound is provided of Formula I or a pharmaceutically acceptable salt thereof; wherein all variables are as defined herein. In another aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In another aspect, a method of treating a cancer in a subject in need thereof is provided comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In a further aspect, a method of sensitizing a cancer to radiation therapy in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein prior to or concurrently with the radiation therapy. The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Other features, objects, and advantages of the disclosure will be apparent from the description and the claims. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiments. Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, benefiting from the teachings presented in the descriptions herein and the associated drawings. Therefore, it is understood that the disclosures are not limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. As apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or any other order that is logically possible. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not explicitly state in the claims or descriptions that the steps are to be limited to a particular order, it is in no way intended that an order be inferred in any respect. This holds for any possible nonexpress basis for interpretation, including logic concerning arrangement of steps or operational flow, meaning derived from grammatical organization or