N-myristoyltransferase inhibitors and methods of use

Abstract

Provided herein are compounds of Formula (I), which are useful as Nmyristoyltransferase (NMT) inhibitors. Also provided herein are methods of treating, ameliorating, and / or preventing malaria with compounds of Formula (I), including treating dormant forms of malaria known as hypnozoites.

Description

Original text: N-MYRISTOYLTRANSFERASE INHIBITORS AND METHODS OF USE Provided herein are compounds of Formula (I), which are useful as Nmyristoyltransferase (NMT) inhibitors. Also provided herein are methods of treating, ameliorating, and / or preventing malaria with compounds of Formula (I), including treating dormant forms of malaria known as hypnozoites. Translation: N-Myristoyltransferase Inhibitors and Methods of Use This article provides compounds of Formula (I), which can be used as N-myristoyltransferase (NMT) inhibitors. This article also provides methods of treating, ameliorating, and / or preventing malaria with compounds of Formula (I), including treating dormant forms of malaria, i.e., hypnozoites. Abstract

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein A is an optionally fused 6-membered aryl or heteroaryl ring, which is optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, and C(O)N(R)2; X is C, CH, or N, provided that if A is present then X is C; Z is CH or N; Y is CH or N; R1is selected from the group consisting of hydrogen, F, Cl, and Br; L is O, NR, or =N-*, wherein the bond with * is attached to the aryl ring; T is -C1-6 alkyl-C5-6 heteroaryl, wherein the C5-6 heteroaryl is optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, and C(O)N(R)2; V is -C0-6 alkyl-C5-6 heterocyclyl, -O-C0-6 alkyl-C5-6 heterocyclyl, -C0-6 alkyl-NR2, or - O-C2-6alkyl-NR2, wherein the C5-6heterocyclyl is optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, and C(O)N(R)2; R is independently at each occurrence selected from the group consisting of hydrogen or optionally substituted C1-12alkyl; R2is independently at each occurrence selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R,SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, and C(O)N(R)2; R3is independently at each occurrence selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, and C(O)N(R)2; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.

2. The compound of claim 1, which has the structure B).

3. The compound of claim 1, wherein L is O.

4. The compound of claim 1, wherein R1is H or F.

5. The compound of claim 1, wherein T is C2alkyl-C5-6heteroaryl.

6. The compound of claim 5, wherein T is selected from the group consisting of: N ,7. The compound of claim 1, wherein m is 0.

8. The compound of claim 1, wherein n is 0.

9. The compound of claim 1, wherein V is C5-6heterocyclyl.

10. The compound of claim 9, wherein V is -C1-6alkyl-C5-6heterocyclyl or -O-C2-6alkyl- NR2.

11. The compound of claim 10, wherein V is or .

12. The compound of claim 1, wherein A is whereineach A1, A2, A3, and A4 is independently CH or N, provided no more than two of A1, A2, A3, and A4 are N; and each CH group in A1 to A4 is optionally substituted.

13. The compound of claim 1, which is at least one compound selected from the group consisting of:26a 26b 26c14. A method of treating, ameliorating, or preventing malaria in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of claim 1 and at least one pharmaceutically acceptable excipient or carrier.

15. The method of claim 14, wherein the administering is by a route selected from the group consisting of oral, buccal, transdermal, transmucosal, (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

16. The method of claim 14, wherein the subject is a human.

17. The method of claim 14, wherein the subject is infected by Plasmodium falciparum or Plasmodium vivax.

18. The method of claim 17, wherein the Plasmodium vivax is in a dormant form (hypnozoites) in the subject.

19. A method of killing or inhibiting a Plasmodium falciparum or Plasmodium vivax parasite, the method comprising: contacting the parasite with an effective amount of the compound of claim 1 sufficient to kill the parasite or render the parasite incapable of causing malaria in a subject.

20. The method of claim 19, wherein the Plasmodium vivax is in a dormant form.

21. A pharmaceutical composition comprising at least one compound of any one of claims 1-13 and at least one pharmaceutically acceptable excipient or carrier.

22. The pharmaceutical composition of claim 21, wherein the at least one compound is present in an amount of about 0.01 to about 5,000 mg.

23. The pharmaceutical composition of claim 21, which is formulated as a tablet or capsule.

24. The pharmaceutical composition of claim 21, which is a liquid formulation.

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