Search

EP-4100401-B1 - 3-((2-IMINO-6-OXOTETRAHYDROPYRIMIDIN-1(2H)-YL)METHYL)-BENZAMIDE DERIVATIVES AS INHIBITORS OF PLASMEPSIN IX AND X FOR THE TREATMENT OF MALARIA

EP4100401B1EP 4100401 B1EP4100401 B1EP 4100401B1EP-4100401-B1

Inventors

  • DE LERA RUIZ, MANUEL
  • TRIGLIA, TONY
  • ZHAN, Dongmei
  • ZHAO, LIANYUN
  • FAVUZZA, Paola
  • GUO, ZHUYAN
  • HU, BIN
  • KELLY III, MICHAEL J.
  • LEI, ZHIYU
  • MCCAULEY, JOHN A.
  • Olsen, David B.
  • SLEEBS, BRAD

Dates

Publication Date
20260513
Application Date
20210202

Claims (17)

  1. A compound having the structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein: U is N or CH, wherein when U is N, X, Y and Z are CH; X is N or CH, wherein when X is N, U, Y and Z are CH; Y is N or CH, wherein when Y is N, X, U and Z are CH; Z is N or CH, wherein when Z is N, X, Y and U are CH; R 1 is wherein R 1 is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOH, and phenyl; R 2 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH; R 3 is halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ); R 4 is hydrogen, halogen, CN, C 1 -C 6 alkylCN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, C 1 -C 6 alkylOC 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 1 -C 6 alkylSO 2 C 1 -C 6 alkyl, C 1 -C 6 alkylphenyl, phenyl, heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, heteroaryl, C 1 -C 6 alkylheteroaryl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R S ), N(R 7 )(R S ), C 1 -C 6 alkyl(OCH 2 CH 2 ) m N 3 , or C 1 -C 6 alkylN(R 7 )(R 8 ), wherein the C 1 -C 6 alkylphenyl, phenyl, heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, heteroaryl, C 1 -C 6 alkylheteroaryl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOH or C 3 -C 6 cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, SO 2 C 1 -C 6 alkyl, C 1 -C 6 alkySO 2 C 1 -C 6 alkyl, OSO 2 F, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ); R 5 is hydrogen, halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, phenyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ) or when taken with R 6 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl or when R 5 is C 1 -C 8 alkyl and R 1 is a heterocycloalkyl or C 3 -C 12 cycloalkyl, R 5 optionally bonds to R 1 to form a macrocycle; R 6 is hydrogen, halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, phenyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ) or when taken with R 5 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl; R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH; R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH; R 9 is hydrogen, halogen, or C 1 -C 6 alkyl; m is 1, 2 or 3; and n is 0, 1, 2 or 3.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is: wherein R 1 is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOH, and phenyl.
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is: wherein R 1 is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, OH, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOH, and phenyl.
  4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is:
  5. The compound of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  6. The compound of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  7. The compound of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 3 is halogen, trifluoromethyl or CN.
  8. The compound of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 5 is phenyl, C 1 -C 8 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl or C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  9. The compound of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein when R 5 is C 1 -C 8 alkyl and R 1 is a heterocycloalkyl or C 3 -C 12 cycloalkyl, R 5 optionally bonds to R 1 to form a macrocycle.
  10. The compound of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 6 is phenyl, C 1 -C 8 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOC 1 -C 6 alkyl or C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  11. The compound of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, phenyl, halogen, C 1 -C 6 alkyl, heteroaryl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylphenyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkylheterocycloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkylCN, C 1 -C 6 alkylheteroaryl, C 1 -C 6 alkylOC 1 -C 6 alkylOC 1 -C 6 alkyl, heterocycloalkyl, C 1 -C 6 alkylSO 2 C 1 -C 6 alkyl, or C 1 -C 6 alkyl(OCH 2 CH 2 ) m N 3 , wherein the phenyl, C 1 -C 6 alkylphenyl, heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 1 -C 6 alkylheteroaryl, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOH or C 3 -C 6 cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, CN, OH, alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, SO 2 C 1 -C 6 alkyl, C 1 -C 6 alkySO 2 C 1 -C 6 alkyl, and -OSO 2 F.
  12. The compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  13. A compound, or a pharmaceutically acceptable salt thereof of any previous claim for use in treating a Plasmodium infection, or for treating malaria.
  14. A compound, or a pharmaceutically acceptable salt thereof of any one of claims 1-12 for use in inhibiting plasmepsin X, inhibiting plasmepsin IX or for dual inhibition of plasmepsin IX and plasmepsin X.
  15. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof of any one of claims 1-12, and a pharmaceutically acceptable carrier.
  16. A combination comprising a compound, or a pharmaceutically acceptable salt thereof of any one of claims 1-12, and one or more additional anti-malarial agents for use in treating a Plasmodium infection or malaria.
  17. A compound, or a pharmaceutically acceptable salt thereof of any one of claims 1-12 for use in therapy.

Description

FIELD OF THE INVENTION The present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections. More specifically, the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections, more particularly for the treatment of malaria. BACKGROUND OF THE INVENTION Malaria is a major disease in humans with several hundred million infections and over 450,000 deaths each year. The most lethal form of malaria is caused by Plasmodium falciparum. This protozoan parasite is responsible for almost all malarial deaths with most occurring in Africa. P. falciparum has a complex life cycle starting in the Anopheles mosquito vector when sporozoite forms are injected into the human host during a blood feed. These sporozoites migrate to the liver and invade hepatocytes in which they develop to form thousands of liver merozoites that egress into the blood where they invade erythrocytes to commence the asexual cycle of the parasite responsible for the symptoms of malaria. The parasite develops within the protected niche of the red cell to form 16-32 merozoites that, once mature, egress from the host cell to invade new red blood cells. Some of these parasites differentiate to form gametocytes, the sexual form of the parasite. These can be taken up by the mosquito where male and female gametes form, fuse and differentiate into oocysts on the mosquito midgut extracellular matrix. Sporozoites form within the oocyst and upon egress migrate to the salivary gland for delivery to the next host during blood feeding for perpetuation and survival of the parasite. Other forms of malaria include a relapsing form of malaria caused by P. vivax which is responsible for significant morbidity, can cause virulent forms of this disease with some deaths and is mainly a problem outside Africa. P. knowlesi is found in South East Asia and is a zoonotic parasite that normally infects long-tailed macaques but has been shown to infect humans in Malaysian Borneo. Artemisinin combined with partner drugs have become a mainstay in the treatment and control of malaria. However, due to the increasing threat of artemisinin-based combination therapy (ACT) drug resistance, the development of new antimalarials with novel targets that inhibit multiple steps in the parasite life cycle is an urgent priority for the malaria control field. Such novel antimalarials, as monotherapies or ACT partner drugs, could make strides towards malaria elimination as there is a reduced likelihood of parasites with preexisting resistance mutations being present in the parasite population. Currently, aspartic acid proteases are prime targets for drug development: the HIV aspartic acid protease has been successfully targeted with a drug in clinical use; inhibitors that target human renin, BACE1 and gamma-secretase have been or are in clinical development. In the antimalarial drug space, P. falciparum aspartic acid proteases plasmepsin X and IX (PMX and PMIX) have been identified as potential targets since inhibitors block parasite egress and invasion of the host cell and prevent maturation of some rhoptry and micronemal proteins required for this process (Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017;358(6362):522-8.) WO 2017/142825 A2 relates to methods of treating malaria comprising administration of an N3-substituted iminopyrimidinone, as defined therein. SUMMARY OF THE INVENTION The present invention is directed to compounds of Formula (I): as defined by the appended claims. Any compounds described falling outside this definition do not fall within the literal scope of the claims. Any references to methods of treatment or diagnosis are to be interpreted as referring to compounds of the invention for use in such methods (in accordance with Article 53(c) EPC). Also described herein are methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also described herein are methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also described herein are methods of treatment of malaria comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further provides the use of compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), option