WO2024254795A1 - Agents antipaludiques - Google Patents

Agents antipaludiques Download PDF

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Publication number
WO2024254795A1
WO2024254795A1 PCT/CN2023/100293 CN2023100293W WO2024254795A1 WO 2024254795 A1 WO2024254795 A1 WO 2024254795A1 CN 2023100293 W CN2023100293 W CN 2023100293W WO 2024254795 A1 WO2024254795 A1 WO 2024254795A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
alkyl
compound
compound according
Prior art date
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PCT/CN2023/100293
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English (en)
Inventor
Bin Hu
Michael J. Kelly Iii
Manuel De Lera Ruiz
Philippe Nantermet
John A. Mccauley
Alvaro GUTIERREZ-BONET
Zhuyan Guo
Dongmei ZHAN
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Priority to PCT/CN2023/100293 priority Critical patent/WO2024254795A1/fr
Priority to CN202480048184.0A priority patent/CN121548583A/zh
Priority to MX2025015072A priority patent/MX2025015072A/es
Priority to KR1020267000533A priority patent/KR20260022399A/ko
Priority to AU2024303384A priority patent/AU2024303384A1/en
Priority to PCT/US2024/033203 priority patent/WO2024258769A1/fr
Publication of WO2024254795A1 publication Critical patent/WO2024254795A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections. More specifically, the present disclosure relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, useful for the treatment of malaria.
  • 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.
  • 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.
  • 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.
  • P. falciparum aspartic acid proteases plasmepsin X and IX 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. )
  • 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.
  • compositions including pharmaceutical compositions, comprising one or more compounds of the disclosure (e.g., one compound of the disclosure) , or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound (s) and/or said tautomer (s) , optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent, for the treatment of malaria.
  • pharmaceutical compositions comprising one or more compounds of the disclosure (e.g., one compound of the disclosure) , or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound (s) and/or said tautomer (s) , optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent, for the treatment of malaria.
  • the present disclosure provides methods for the use of pharmaceutical compositions comprising one or more of said compounds in the free form or in pharmaceutically acceptable salt form, together with one or more customary pharmaceutical excipient (s) , for the treatment of Plasmodium infections, the treatment of malaria, the inhibition of plasmepsin X, or the dual inhibition of plasmepsin X and plasmepsin IX.
  • methods for the use of combinations of the compounds or salts of the disclosure together with one or more additional pharmaceutically active agents are also provided.
  • the present disclosure further provides methods for the inhibition of plasmepsin X, or the dual inhibition of plasmepsin X and plasmepsin IX activity and of treatment, prevention, amelioration and/or delaying onset of diseases or disorders in which the inhibition of plasmepsin X and/or plasmepsin IX has or may have a therapeutic effect, e.g., malaria.
  • the present dislosure further provides methods for the inhibition of P. falciparum aspartic acid proteases.
  • the present disclosure further provides methods for blocking P. falciparum growth by inhibiting plasmepsin X.
  • the present disclosure further provides methods for blocking P. falciparum growth by inhibiting both PMX and Plasmepsin IX.
  • the present disclosure further provides methods for the treatment of malaria by inhibiting plasmepsin X.
  • the present disclsoure further provides methods for the treatment of malaria by inhibiting both PMX and Plasmepsin IX.
  • A is a straight or branched, saturated or unsaturated (C 3 -C 10 ) alkylene, comprising at least one –CH 2 -group, wherein one or more additional –CH 2 -groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO 2 , and SO 2 NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C 1-3 haloalkyl;
  • X is selected from:
  • J is a six membered aryl or heteroaryl selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, said phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl unsubstituted or substituted with 1 to 3 groups independently selected from R;
  • G is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, bicyclobutanyl, bicyclopentanyl, bicyclohexyl, bicycloheptyl, bicyclononanyl, pyridyl, pyrimidinyl, benzylpyrimidinyl, pyrazolyl, imidazolyl, said groups optionally substituted with 1 to 3 groups of R;
  • R is hydrogen, halogen, 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, C 1 -C 6 alkoxy, COC 1 -C 6 alkyl, C 1 -C 6 alkylO-C 1 -C 6 alkyl, or COOC 1 -C 6 alkyl;
  • Z is a bond, - (CH 2 ) p C (O) (CH 2 ) p -, -phenyl-, -C 1-10 heteroaryl-, said phenyl and heteroaryl optionally substituted with 1 to 3 groups of R;
  • Q is selected from:
  • R 1 is hydrogen, halogen, CN, OH, C 1 -C 6 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 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON (R 2 ) (R 3 ) , N (R 2 ) (R 3 ) or C 1 -C 6 alkylN (R 2 ) (R 3 ) ;
  • 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, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl;
  • R 3 is hydrogen, 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, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl;
  • k is an integer from 0 to 4.
  • p is an integer independently selected from 0 to 4.
  • An embodiment of Formula I is realized when A is a straight or branched, saturated or unsaturated (C3-C6) alkylene.
  • a subembodiment of aspect of the disclosure is realized when A is is a straight or branched, saturated or unsaturated C3-alkylene.
  • a subembodiment of aspect of the disclosure is realized when A is is a straight or branched, saturated or unsaturated C4-alkylene.
  • a subembodiment of aspect of the disclosure is realized when A is is a straight or branched, saturated or unsaturated C5-alkylene.
  • a subembodiment of aspect of the disclosure is realized when A is is a straight or branched, saturated or unsaturated C6-alkylene.
  • A is a straight or branched, saturated or unsaturated (C3-C10) alkylene, wherein one or more additional –CH2-groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl.
  • each R 1 is independently selected from halogen, CN, OH, C 1 -C 6 alkoxy-, -COOH, oxo, -COOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -haloC 1 -C 6 alkyl, and C 1 -C 6 alkylOH.
  • a subembodiment of this aspect of the disclosure is realized when each R 1 is independently selected from halogen, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, -C 1 -haloC 1 -C 6 alkyl, and C 1 -C 6 alkylOH.
  • each R 1 is independently selected from OH, methyl and trifluoromethyl. In one class, R 1 is OH. In another class, each R 1 is independently selected from OH and methyl. In another class R 1 is methyl. In still another class, R 1 is trifluoromethyl.
  • R is selected from hydrogen, halogen, C 1 -C 6 alkylCOOH, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, and C 1 -C 6 alkoxy.
  • R is selected from hydrogen, CH 2 COOH, (CH 2 ) 2 COOH, CH (CH 3 ) COOH, CH 3 , CH 2 CH 3 , (CH 2 ) 2 OCH 3 , (CH 2 ) 3 OCH 3 , (CH 2 ) 2 OCH 2 CH 3 , (CH 2 ) 3 OCH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , (CH2) 2OH, C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, and (CH 2 ) 3 OH.
  • R is hydrogen.
  • R is selected from hydrogen, methyl, CH 2 COOH, (CH 2 ) 2 COOH, and CH (CH 3 ) COOH.
  • R is selected from hydrogen, CH 3 , CH 2 CH 3 , (CH 2 ) 2 OCH 3 , (CH 2 ) 3 OCH 3 , (CH 2 ) 2 OCH 2 CH 3 , (CH 2 ) 3 OCH 2 CH 3 .
  • R is selected from hydrogen, methyl, (CH 2 ) 2 OCH 3 , (CH 2 ) 3 OCH 3 , (CH 2 ) 2 OCH 2 CH 3 , (CH 2 ) 3 OCH 2 CH 3 .
  • R is hydrogen, methyl, or (CH 2 ) 2 OCH 3 .
  • Still another aspect is realized when R is hydrogen or (CH 2 ) 2 OCH 3 .
  • Yet another aspect of this disclosure is realized when R is hydrogenor (CH 2 ) 2 OCH 3 .
  • R is (CH 2 ) 2 OCH 3 .
  • Another subembodiment of this aspect of the disclosure is realized when R is CH 2 F, CHF 2 , CF 3 .
  • R 1 , k and the single and double squiggly lines are as described herein.
  • R 1 , k, and the single and double squiggly lines are as described herein.
  • R 1 , k, and the single and double squiggly lines are as described herein.
  • Another embodiment of Formula I is realized when Z is a bond. Another embodiment of Formula I is realized when Z is -C (O) (CH 2 ) p -. Another embodiment of Formula I is realized when Z is -C (O) -wherein p is 0. Yet another embodiment of Formula I is realized when Z is -C (O) (CH 2 ) 2 -. Still another emobidment of Formula (I) is realized when Z is -C (O) (CH 2 ) 3 -. And still another embodiment of Formula (I) is realized when Z is -C (O) (CH 2 ) -. Another embodiment of Formula I is realized when Z is -phenyl-, optionally substituted with 1 to 3 groups of R. Another embodiment of Formula I is realized when Z is -C 3-10 heteroaryl-, optionally substituted with 1 to 3 groups of R.
  • Formula I Another embodiment of Formula I is realized when X is a straight or branched, saturated or unsaturated (C 3 -C 10 ) alkylene.
  • a subembodiment of this aspect is realized when X is a straight or branched, saturated or unsaturated (C 3 -C 6 ) alkylene.
  • Another subembodiment of this aspect is realized when X is a straight or branched, saturated or unsaturated (C 3 -C 4 ) alkylene.
  • J is as described herein.
  • a subembodiment of this aspect of the disclosure is realized when J is a fused phenyl ring unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another subembodiment of this aspect of the disclosure is realized when J is selected from fused pyridyl, fused pyrimidinyl, fused pyridazinyl, and fused pyrazinyl, said pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another subembodiment of this aspect of the disclosure is realized when J is fused pyridyl, wherein said pyridyl is unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another subembodiment of this aspect of the disclosure is realized when J is fused pyrimidinyl, said pyrimidinyl, unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another subembodiment of this aspect of the disclosure is realized when J is fused pyridazinyl, said pyridazinyl unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another subembodiment of this aspect of the disclosure is realized when J is fused pyrazinyl, said pyrazinyl unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another embodiment of Formula I is realized when X is A subembodiment of this aspect of this disclosure is realized when G is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, bicyclohexyl, bicycloheptyl, bicyclononanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, bicyclohexyl, bicycloheptyl, and bicyclononanyl, unsubstituted or substituted with 1 to 3 groups of R.
  • G is pyrimidinyl, said pyrimidinyl unsubstituted or substituted with 1 to 3 groups of R.
  • G is benzylpyrimidinyl, said benzylpyrimidinyl unsubstituted or substituted with 1 to 3 groups of R.
  • G is pyrazolyl, said pyrazolyl unsubstituted or substituted with 1 to 3 groups of R.
  • G is imidazolyl, said imidazolyl unsubstituted or substituted with 1 to 3 groups of R.
  • G is cyclopropyl, cyclobutyl, bicyclopentanyl, pyridyl, phenyl, or trifluromethyl-phenyl.
  • each R 1 is independently selected fromhalogen, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, -C 1 -haloC 1 -C 6 alkyl, and C 1 -C 6 alkylOH.
  • each R 1 is independently selected from OH, C 1 -C 6 alkyl, and halo- C 1 -C 6 alkyl.
  • each R 1 is independently selected from OH, methyl and trifluoromethyl.
  • k is an integer between zero and 4, and R 1 is selected from hydrogen, halogen, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, -C 1 -haloC 1 -C 6 alkyl, and C 1 -C 6 alkylOH. In one aspect of this embodiment, k is zero.
  • k is an integer between zero and four, and R 1 is selected from hydrogen, halogen, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, -C 1 -haloC 1 -C 6 alkyl, and C 1 -C 6 alkylOH.
  • k is zero.
  • k is one and R 1 is hydroxy.
  • Formula II Another embodiment of Formula II is realized when X is a straight or branched, saturated or unsaturated (C 3 -C 6 ) alkylene.
  • Another embodiment of Formula II is realized when X is and J is selected from phenyl, pyridyl, pyrimidinyl, said phenyl, pyridyl, and pyrimidinyl, unsubstituted or substituted with 1 to 3 groups independently selected from R.
  • Another embodiment of Formula II is realized when J is unsubstituted or substituted phenyl.
  • J is phenyl.
  • Another embodiment of Formula II is realized when J is unsubstituted or substituted pyridyl.
  • Another embodiment of Formula II is realized when J is unsubstituted or substituted pyrimidinyl.
  • Another embodiment of Formula II is realized when X is A subembodiment of this aspect of this disclosure is realized when G is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, phenyl, pyridyl, pyrimidinyl, benzylpyrimidinyl, pyrazolyl, and imidazolyl said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, phenyl, pyridyl, pyrimidinyl, benzylpyrimidinyl, pyrazolyl, and imidazolyl unsubstituted or substituted with 1 to 3 groups of R.
  • G is selected from cyclopropyl, cyclobutyl, bicyclobutanyl, bicyclopentanyl, phenyl, pyridyl, pyrimidinyl, benzylpyrimidinyl, said cyclopropyl, cyclobutyl, bicyclobutanyl, bicyclopentanyl, phenyl, pyridyl, pyrimidinyl, and benzylpyrimidinyl, unsubstituted or substituted with 1 to 3 groups of R.
  • G is selected from unsubstituted or substituted cyclopropyl.
  • Another subembodiment of this aspect of this disclosure is realized when G is selected from unsubstituted or substituted cyclobutyl. Another subembodiment of this aspect of this disclosure is realized when G is selected from unsubstituted or substituted bicyclobutanyl. Another subembodiment of this aspect of this disclosure is realized when G is selected from unsubstituted or substituted bicyclopentanyl. Another subembodiment of this aspect of this disclosure is realized when G is selected from unsubstituted or substituted phenyl. Another subembodiment of this aspect of this disclosure is realized when G is selected from unsubstituted or substituted pyridyl.
  • R is selected from hydrogen, halogen, C 1 -C 6 alkylCOOH, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, and C 1 -C 6 alkoxy.
  • R is selected from hydrogen, CH 2 COOH, (CH 2 ) 2 COOH, CH (CH 3 ) COOH, CH 3 , CH 2 CH 3 , (CH 2 ) 2 OCH 3 , (CH 2 ) 3 OCH 3 , (CH 2 ) 2 OCH 2 CH 3 , (CH 2 ) 3 OCH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , (CH2) 2OH, and (CH 2 ) 3 OH.
  • R is selected from hydrogen, methyl, and (CH 2 ) 2 OCH 3 .
  • Another embodiment of Formula II is realized when n is 0. Another embodiment of Formula II is realized when n is 1. Another embodiment of Formula II is realized when n is 2. Another embodiment of Formula II is realized when n is 3.
  • each variable (including those in each of Formulae I-II, and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated.
  • the compounds described herein may exit in different forms of the compounds such as, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof.
  • alkyl refers to “alkyl” as well as the “alkyl” portion of “hydroxyalkyl” , “haloalkyl” , arylalkyl , alkylaryl , “alkoxy” etc.
  • each variable is selected independently of the others unless otherwise indicated.
  • “Drug resistant” means, in connection with a Plasmodium parasite strain, a Plasmodium species which is no longer susceptible to at least one previously effective drug; which has developed the ability to withstand attack by at least one previously effective drug.
  • a drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
  • Non-human animals include those research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, dogs, and house cats.
  • “Pharmaceutical composition” means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the disclosure or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers or diluents.
  • pharmaceutically acceptable carriers or diluents include but not limited to, butyl alcohol, benzyl ether, benzyl-N-(2-aminol) a pharmaceutically acceptable carriers or diluents.
  • pharmaceutically active agents such as, for example, a compound of the present disclosure and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents" .
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present disclosure is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • Halogen and halo mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Alkylene by itself or as part of another substituent means a divalent hydrocarbon chain radical having the stated number of carbon atoms.
  • - (C1-C5) alkylene would include, e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH (CH3) CH2-or -CH2CH2CH2CH2CH2-.
  • a straight alkylene means a divalent straight hydrocarbon chain radical having the stated number of carbon atoms.
  • a branched alkylene means a divalent branched hydrocarbon chain radical having the stated number of carbon atoms.
  • a saturated alkylene means a divalent saturated hydrocarbon chain radical having the stated number of carbon atoms.
  • An unsaturated alkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and one or more double or triple covalent bonds within the chain.
  • a cycloalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a cycloalkyl moiety within the chain.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Haloalkyl means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • “Monocyclic aryl” means phenyl.
  • Cycloalkyl means a non-aromatic mono-or multicyclic ring system comprising about 3 to about 12 carbon atoms, preferably about 3 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 10 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein.
  • Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Multicyclic cycloalkyls refers to multicyclic, including bicyclic, rings that include a non-aromatic ring.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • a non-aromatic ring is fused to an aromatic ring.
  • Heterocycloalkyl (or “heterocyclyl” ) means a non-aromatic, saturated or partially saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any —NH in a heterocyclyl ring may exist protected such as, for example, as an -N (Boc) , -N (CBz) , -N (Tos) group and the like; such protections are also considered part of this disclosure.
  • the heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
  • oxygen when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S, S-dioxide.
  • pyrrolidinone or pyrrolidone
  • the term “monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moieties described herein and include a 4-to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S (O) , and S (O) 2.
  • the point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
  • a non-limiting example of a monocyclic heterocycloalkyl group include the moiety:
  • Non-limiting examples of multicyclic heterocycloalkyl groups include, bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to,
  • Alkoxy means an alkyl-O-group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • variables can be the same or different at each occurence.
  • a solid line - - , as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R) -and (S) -stereochemistry.
  • R -and (S) -stereochemistry.
  • the wavy line as used herein shown crossing a line representing a chemical bond, indicates a point of attachment to the rest of the compound. Lines drawn into the ring systems, such as, for example indicates that the indicated line (bond) may be attached to any of the substitutable ring atoms.
  • Oxo is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or another ring described herein, e.g.,
  • the compounds useful in the methods of the disclosure, and/or compositions comprising them useful in said methods are present in isolated and/or purified form.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture) , or natural source or combination thereof.
  • purified refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed “protected” , this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991) , Wiley, New York.
  • prodrugs and/or solvates of the compounds of the disclosure.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes) , such as, for example, through hydrolysis in blood.
  • prodrugs are used as Novel Delivery Systems, ” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1–C8) alkyl, (C2-C12) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6) alkanoyloxymethyl, 1- ( (C1-C6) alkanoyloxy) ethyl, 1-methyl-1- ( (C1-C6) alkanoyloxy) ethyl, (C1-C6) alkoxycarbonyloxymethyl, N- (C1-C6) alkoxycarbonylaminomethyl, succinoyl, (C1-C6) alkanoyl, ⁇ -amino (C1-C4) alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P (O) (OH) 2, -P (O) (O (C1-
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR’-carbonyl where R and R’ are each independently (C1-C10) alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, -C (OH) C (O) OY1 wherein Y1 is H, (C1-C6) alkyl or benzyl, -C (OY2) Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6) alkyl, carboxy (C1-C6) alkyl, amino (C1-C4) alkyl or mono-N-or di-N, N- (C1-C6) alkylamin
  • One or more compounds used in the methods of the disclosure may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of the disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • One or more compounds used in the methods of the disclosure may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al., J. Pharmaceutical Sci., 1993, 3, 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5 (1) , article 12 (2004) ; and A. L. Bingham et al., Chem. Commun., 603-604 (2001) .
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate) .
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition used in the methods of the present disclosure effective in inhibiting the above-noted diseases or enzyme activity and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • salts denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • salts of the compounds used in the methods of the disclosure may be formed, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates, ) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides) , dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl) , alkoxyalkyl (for example, methoxymethyl) , aralkyl (for example, benzyl) , aryloxyalkyl (for example, phenoxymethyl) , aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino) ; (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl) ; (3) amino acid esters
  • another embodiment provides tautomers of the compounds of the disclosure to be used in the methods herein, and salts, solvates, esters and prodrugs of said tautomers. It shall be understood that all tautomeric forms of such compounds are within the scope of the compounds used in the methods of the disclosure. For example, all keto-enol and imine-enamine forms of the compounds, when present, are included in the disclosure.
  • the compounds used in the methods of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds used in the methods of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.
  • the present disclosure embraces use of all geometric and positional isomers. For example, if a compound used in the methods of the disclosure incorporates a double bond or a fused ring, both the cis-and trans-forms, (E) and (Z) forms, as well as mixtures, are embraced within the scope of the disclosure.
  • Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • some of the compounds used in the methods of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure.
  • Enantiomers can also be separated by use of chiral
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • the compounds used in the methods of the disclosure including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons) , rotameric forms, atropisomers, and diastereomeric forms, are contemplated as embodiments within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl) .
  • Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt” , “solvate” , “ester” , “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • isotopically-labelled compounds to be used in the methods the disclosure. Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.
  • Certain isotopically-labelled compounds of the disclosure are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present disclosure is meant to include all suitable isotopic variations of the compounds of the disclosure.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H) .
  • deuterium The presence of deuterium in the compounds of the disclosure is indicated by "D” .
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the present disclosure is directed to methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof. More specifically, the methods of the disclosure comprise administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of Formula I, or a pharmaceutically acceptable salt thereof, are administered in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method for treating a Plasmodium infection, or for treating malaria, or for inhibiting plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula I described in the Summary of the Disclosure.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition.
  • a pharmaceutically acceptable carrier as a pharmaceutical composition.
  • the disclosure also relates to the use of a compound of Formulae I -II or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria.
  • the disclosure further relates to the use of a compound of Formulae I -II or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria.
  • the compounds of Formulae I -II or pharmaceutically acceptable salts thereof described in any of the embodiments of the disclosure herein are useful for any of the uses above.
  • the present disclosure provides a method for treating a Plasmodium infection, or for treating malaria, or for inhibiting plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula I described in the Summary of the Disclosure.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition.
  • a pharmaceutically acceptable carrier as a pharmaceutical composition.
  • the disclosure also relates to the use of a compound of Formulae I -II or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the disclosure further relates to the use of a compound of Formulae I -II or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the compounds of Formulae I -II or pharmaceutically acceptable salts thereof described in any of the embodiments of the disclosure herein are useful for any of the uses above.
  • the present disclosure provides a method for treating a Plasmodium infection, or for treating malaria, or for inhibiting plasmepsin X and plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula I described in the Summary of the Disclosure.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition.
  • a pharmaceutically acceptable carrier as a pharmaceutical composition.
  • the disclosure also relates to the use of a compound of Formulae I -II or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the disclosure further relates to the use of a compound of Formulae I -II or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the compounds of Formulae I -II or pharmaceutically acceptable salts thereof described in any of the embodiments of the disclosure herein are useful for any of the uses above.
  • the methods of the present disclosure are useful for treating malaria in that they inhibit the onset, growth, or progression of the condition, ameliorate the symptoms of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition.
  • the terms “treat” , “treating” , and grammatical variations thereof, as well as the phrase “method of treating” are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject of infection, such as in a subject that has been exposed to a parasite as disclosed herein.
  • Embodiments of the disclosure also include one or more of the compounds of Formulae I -II or a pharmaceutically acceptable salt thereof I for use in, (ii) for use as a medicament or composition for, or (iii) for use in the preparation of a medicament for: (a) therapy (e.g., of the human body) ; (b) medicine; (c) inhibition of parasite/Plasmodium growth, (d) treatment or prophylaxis of infection by Plasmodium species; (e) reduction of the progression, onset or severity of pathological symptoms associated with Plasmodium infection and/or reduction of the likelihood of severe Plasmodium infection or, (f) treatment, prophylaxis of, or delay in the onset, severity, or progression of Plasmodium -associated disease (s) , including, but not limited to: malaria.
  • therapy e.g., of the human body
  • medicine e.g., of the human body
  • inhibition of parasite/Plasmodium growth e.g., of
  • another embodiment provides methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration of combinations comprising an amount of at least one compound of Formulae I -II, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described below.
  • described herein are methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration of combinations comprising an amount of at least one compound of Formulae I -II, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-malarial agents.
  • described herein are methods for the treatment of malaria by inhibition of plasmepsin X, IX and at least one other mechanism, comprising administration of combinations comprising an amount of at least one compound of Formulae I -II, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-malarial agents, wherein the additional anti-malarial agents act through a different mechanism than inhibiting plasmepsin IX or plasmepsin X.
  • the pharmacological properties of the compounds of Formulae I -II, or a pharmaceutically acceptable salt thereof may be confirmed by several pharmacological assays.
  • Suitable dosages and dosage forms of the compounds used in the methods of the disclosure may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the disclosure. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate of said compound.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, in specific embodiments from about 1 mg to about 50 mg, in specific embodiments from about 1 mg to about 25 mg, according to the particular application.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, in specific embodiments 1 mg/day to 200 mg/day, in two to four divided doses.
  • the amount and frequency of administration of the compounds of the disclosure and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example, may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • compositions comprising a compound of Formulae I -II, or a pharmaceutically acceptable salt thereof formulated for transdermal delivery.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • compositions comprising a compound of Formulae I -II, or a pharmaceutically acceptable salt thereof formulated for subcutaneous delivery.
  • compositions suitable for oral delivery it may be advantageous for the pharmaceutical preparation comprising one or more compounds of Formulae I -II, or a pharmaceutically acceptable salt thereof to be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the compounds used in the methods of this disclosure i.e., the compounds of Formulae I -II
  • compounds of the disclosure may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference.
  • such combination products employ the compounds of Formulae I -II, or a pharmaceutically acceptable salt thereof within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • compositions comprising a compound of the disclosure, either as the neat chemical or optionally further comprising additional ingredients.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose.
  • Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed. ) , Remington’s Pharmaceutical Sciences, 18 th Edition, (1990) , Mack Publishing Co., Easton, Pennsylvania.
  • Non-limiting examples of additional drugs and active agents useful in combination therapies for the treatment of malaria include the following: (Novartis International AG, Basel, Switzerland; artemether + lumefantrine) , (Sigma-Tau Pharmaceuticals, Inc., Rome, Italy; dihydroartemisinin-piperaquine) , (Shin Poong Pharmaceutical Co., Ltd., Seoul, Korea; pyronaridine-artesunate) , ASAQ (Sanofi SA (Gentilly, France) /DNDi (Geneva, Switzerland) ; artesunate + amodiaquine) , ASMQ (Cipla Limited (Mumbai, India) /DNDi, artesunate + mefloquine) , SPAQ-CO TM (Guilin Pharmaceutical Co., Ltd.
  • the disclosure also provides methods of using the compounds of Formulae I-II, or a pharmaceutically acceptable salt thereof to inhibit plasmepsin X, plasmepsin IX or plasmepsin X and IX, to treat Plasmodium infection or treat malaria wherein the method further comprises administering to a subject in need thereof, one or more additional anti-malarial agents.
  • the one or more additional anti-malarial agents are selected from the group consisting of: artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil.
  • Boc tert-butyloxycarbonyl
  • DIAD Diisopropyl azodicarboxylate
  • HG-II (1, 3-Bis- (2, 4, 6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-isopropoxyphenylmethylene) ruthenium
  • H 3 PO 4 phosphoric acid
  • LCMS or LC/MS Liquid chromatography–mass spectrometry
  • MgSO 4 Magnesium sulfate
  • MnO 2 manganese dioxide
  • NaBH 4 sodium borohydrate
  • Na 2 SO 4 sodium sulfate
  • SiO 2 silica
  • TMSOK potassium trimethylsilanolate
  • Step 5 Preparation of tert-butyl (4- (but-3-en-1-yl) -1- (3- ( (3- (but-3-en-1-yl) chroman-4- yl) carbamoyl) benzyl) -4-ethyl-6-oxotetrahydropyrimidin-2 (1H) -ylidene) carbamate
  • Step 6 Preparation of tert-butyl ( (12E, 9E) -14-ethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5- aza-1 (1, 4) -pyrimidina-6 (4, 3) -chromana-3 (1, 3) -benzenacyclododecaphan-9-en-12- ylidene) carbamate
  • Step 7 Preparation of tert-butyl (E) - (14-ethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5-aza- 1 (1, 4) -pyrimidina-6 (4, 3) -chromana-3 (1, 3) -benzenacyclododecaphane-12-ylidene) carbamate
  • Step 8 Preparation of tert-butyl (E) - (14-ethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5-aza- 1 (1, 4) -pyrimidina-6 (4, 3) -chromana-3 (1, 3) -benzenacyclododecaphane-12-ylidene) carbamate (PEAK 3)
  • Step 9 Preparation of 14-ethyl-12-imino-11, 12, 13, 14, 15, 16-hexahydro-5-aza-1 (1, 4) -pyrimidina- 6 (4, 3) -chromana-3 (1, 3) -benzenacyclododecaphane-16, 4-dione
  • Step 3 Preparation of methyl (R) -3- (11, 11-dimethyl-9-oxo-7-thioxo-2, 10-dioxa-6, 8- diazadodecan-5-yl) benzoate
  • N-bisboc-thiourea (1.324 g, 4.79 mmol) in THF (10 mL) was added sodium hydride (0.383g, 9.58 mmol) at 0°C under an atmosphere of N2 in portions. After 20 min at this temperature 2, 2, 2-trifluoroacetic anhydride (0.844 mL, 5.99 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at 0°C for another 20 min. Then a solution of methyl (R) -3- (1-amino-3-methoxypropyl) benzoate (1.07 g, 4.79 mmol) in THF (10 mL) was added dropwise at 0°C.
  • Step 4 Preparation of methyl 3- ( (5R, Z) -9- (but-3-en-1-yl) -7- ( (tert-butoxycarbonyl) imino) -9- ethyl-11-oxo-2, 12-dioxa-6, 8-diazatridecan-5-yl) benzoate
  • Step 5 Preparation of methyl 3- ( (1R) -1- ( (E) -4- (but-3-en-1-yl) -2- ( (tert-butoxycarbonyl) imino) - 4-ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) -3-methoxypropyl) benzoate
  • Step 6 Preparation of compound 3- ( (1R) -1- ( (E) -4- (but-3-en-1-yl) -2- ( (tert- butoxycarbonyl) imino) -4-ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) -3-methoxypropyl) benzoic acid
  • Step 7 Preparation of tert-butyl ( (E) -4- (but-3-en-1-yl) -4-ethyl-1- ( (R) -1- (3- ( ( (3S, 4R) -3-hydroxy- 2, 2-dimethyl-6-vinylchroman-4-yl) carbamoyl) phenyl) -3-methoxypropyl) -6- oxotetrahydropyrimidin-2 (1H) -ylidene) carbamate
  • reaction mixture was stirred at 25°C, and followed by LC/MS. After 16 hours the reaction mixture was quenched with water (10 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by prep-TLC (Pet.
  • Step 8 Preparation of compound tert-butyl ( (12E, 63S, 64R, 2R, 7E) -14-ethyl-63-hydroxy-2- (2- methoxyethyl) -62, 62-dimethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5-aza-1 (1, 4) - pyrimidina-6 (4, 6) -chromana-3 (1, 3) -benzenacyclodecaphan-7-en-12-ylidene) carbamate
  • reaction mixture was stirred at 50°C under N2 atmosphere and followed by LC/MS. After 16 hours the reaction mixture was concentrated. The resulting resdue was purified by flash silica gel chromatography ( 4 g Silica Flash Column, Eluent of 15%EtOAc/Pet. ether gradient @30mL/min) .
  • tert-butyl (12E, 63S, 64R, 2R, 7E) -14-ethyl-63-hydroxy-2- (2-methoxyethyl) -62, 62-dimethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5-aza-1 (1, 4) -pyrimidina-6 (4, 6) -chromana-3 (1, 3) -benzenacyclodecaphan-7-en-12-ylidene) carbamate (PEAK 1) and tert-butyl ( (12E, 63S, 64R, 2R, 7E) -14-ethyl-63-hydroxy-2- (2-methoxyethyl) -62, 62-dimethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5-aza-1 (1, 4) -pyrimidina-6 (4, 6) -chromana-3 (1, 3) -benzena
  • Step 9 Preparation of compound tert-butyl ( (63S, 64R, 2R, E) -14-ethyl-63-hydroxy-2- (2- methoxyethyl) -62, 62-dimethyl-16, 4-dioxo-11, 12, 13, 14, 15, 16-hexahydro-5-aza-1 (1, 4) - pyrimidina-6 (4, 6) -chromana-3 (1, 3) -benzenacyclodecaphane-12-ylidene) carbamate
  • Step 10 Preparation of (63S, 64R, 2R) -14-ethyl-63-hydroxy-12-imino-2- (2-methoxyethyl) -62, 62- dimethyl-11, 12, 13, 14, 15, 16-hexahydro-5-aza-1 (1, 4) -pyrimidina-6 (4, 6) -chromana-3 (1, 3) - benzenacyclodecaphane-16, 4-dione
  • Step 1 Preparation of ethyl (1S, 2S) -2- ( (R) -1-azido-3-methoxypropyl) cyclopropane-1- carboxylate
  • Step 2 Preparation of ethyl (1S, 2S) -2- ( (R) -1-amino-3-methoxypropyl) cyclopropane-1- carboxylate
  • Step 3 Preparation of ethyl (1S, 2S) -2- ( (R) -11, 11-dimethyl-9-oxo-7-thioxo-2, 10-dioxa-6, 8- diazadodecan-5-yl) cyclopropane-1-carboxylate
  • N-bisboc-thiourea (3.57 g, 12.92 mmol) in THF (40 mL) was added sodium hydride (1.033 g, 25.8 mmol) at 0 °C in portions under N2 atmosphere.
  • sodium hydride 1.033 g, 25.8 mmol
  • 2, 2, 2-trifluoroacetic anhydride 2.323 mL, 16.15 mmol
  • THF 10 mL
  • Step 4 Preparation of ethyl (1S, 2S) -2- ( (5R, 9R, Z) -9- (but-3-en-1-yl) -7- ( (tert- butoxycarbonyl) imino) -9-ethyl-11-oxo-2, 12-dioxa-6, 8-diazatridecan-5-yl) cyclopropane-1- carboxylate
  • Step 5 Preparation of ethyl (1S, 2S) -2- ( (R) -1- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert- butoxycarbonyl) imino) -4-ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) -3- methoxypropyl) cyclopropane-1-carboxylate
  • Step 6 Preparation of (1S, 2S) -2- (can-1- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert- butoxycarbonyl) imino) -4-ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) -3- methoxypropyl) cyclopropane-1-carboxylic acid
  • Step 7 Preparation of tert-butyl ( (R, E) -4- (but-3-en-1-yl) -1- ( (R) -1- ( (1S, 2S) -2- ( ( (S) -2, 2- dimethyl-6-vinylchroman-4-yl) carbamoyl) cyclopropyl) -3-methoxypropyl) -4-ethyl-6- oxotetrahydropyrimidin-2 (1H) -ylidene) carbamate
  • reaction mixture was stirred at 15°C and followed by LC/MS. After 16 hours the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with brine (10 mL) , dried over Na2SO4, filtered and concentrated. The resulting residue was purified by prep-TLC (Pet.
  • Step 8 Preparation of tert-butyl ( (1aS, 2R, 6R, 16aS, 18aS, 22E) -6-ethyl-2- (2-methoxyethyl) - 15, 15-dimethyl-4, 18-dioxo-1a, 2, 5, 6, 7, 8, 15, 16, 16a, 17, 18, 18a-dodecahydro-1H, 4H-6, 3- (epiminomethano) -11, 13-ethenocyclopropa [c] pyrano [4, 3-g] [1, 6] diazacycloheptadecin-22- ylidene) carbamate
  • Step 9 Preparation of tert-butyl ( (1aS, 2R, 6R, 16aS, 18aS, E) -6-ethyl-2- (2-methoxyethyl) -15, 15- dimethyl-4, 18-dioxo-1a, 2, 5, 6, 7, 8, 9, 10, 15, 16, 16a, 17, 18, 18a-tetradecahydro-1H, 4H-6, 3- (epiminomethano) -11, 13-ethenocyclopropa [c] pyrano [4, 3-g] [1, 6] diazacycloheptadecin-22- ylidene) carbamate
  • Step 10 Preparation of (1aS, 2R, 6R, 16aS, 18aS) -6-ethyl-22-imino-2- (2-methoxyethyl) -15, 15- dimethyl-1, 1a, 2, 5, 6, 7, 8, 9, 10, 15, 16, 16a, 17, 18a-tetradecahydro-4H, 18H-6, 3- (epiminomethano) - 11, 13-ethenocyclopropa [c] pyrano [4, 3-g] [1, 6] diazacycloheptadecine-4, 18-dione
  • Tetrahydro-4H-pyran-4-one (6 g, 59.9 mmol) and pyrrolidine (5.11 g, 71.9 mmol) in toluene (80 mL) were refuxed at 130 °C using a Dean &Stark apparatus. After 6 h the solvent and excess pyrrolidine were removed under reduced pressure and the crude enamine was dissolved in THF (60 mL) . Then isopropyl acrylate (8.21 g, 71.9 mmol) was added followed by heating to 90 °C for 4 hours. The solvent was then removed under reduced pressure and the crude product was diluted with EtOAc. The organic phase was washed with dilute HCl and brine.
  • Step 3 Preparation of isopropyl 3- (4- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert-butoxycarbonyl) imino) -4- ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) tetrahydro-2H-pyran-3-yl) propanoate.
  • Step 4 SFC Chiral Separation of isopropyl 3- (4- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert- butoxycarbonyl) imino) -4-ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) tetrahydro-2H-pyran-3- yl) propanoate.
  • Step 5 Preparation of 3- (4- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert-butoxycarbonyl) imino) -4-ethyl-6- oxotetrahydropyrimidin-1 (2H) -yl) tetrahydro-2H-pyran-3-yl) propanoic acid
  • Step 6 Preparation of tert-butyl ( (4R, E) -4- (but-3-en-1-yl) -1- (3- (3- ( ( (S) -2, 2-dimethyl-6- vinylchroman-4-yl) amino) -3-oxopropyl) tetrahydro-2H-pyran-4-yl) -4-ethyl-6- oxotetrahydropyrimidin-2 (1H) -ylidene) carbamate
  • Step 7 Preparation of tert-butyl ( (8R, 11E, 18aS, 26E) -8-ethyl-17, 17-dimethyl-6, 20-dioxo- 4, 4a, 7, 8, 9, 10, 17, 18, 18a, 19, 20, 21, 22, 22a-tetradecahydro-1H, 3H, 6H-8, 5- (epiminomethano) - 13, 15-ethenodipyrano [4, 3-b: 4', 3'-h] [1, 7] diazacyclooctadecin-26-ylidene) carbamate
  • Step 8 Preparation of tert-butyl ( (8R, 18aS, E) -8-ethyl-17, 17-dimethyl-6, 20-dioxo- 4, 4a, 7, 8, 9, 10, 11, 12, 17, 18, 18a, 19, 20, 21, 22, 22a-hexadecahydro-1H, 3H, 6H-8, 5- (epiminomethano) -13, 15-ethenodipyrano [4, 3-b: 4', 3'-h] [1, 7] diazacyclooctadecin-26- ylidene) carbamate
  • reaction mixture was degassed and backfilled with H2 (3x) .
  • the resulting mixture was stirred under an atmosphere of H2 (15 psi) at 25 °C.
  • H2 15 psi
  • LC/MS LC/MS
  • Step 9 Preparation of (18aS) -8-ethyl-26-imino-17, 17-dimethyl- 3, 4, 4a, 7, 8, 9, 10, 11, 12, 17, 18, 18a, 19, 21, 22, 22a-hexadecahydro-1H, 6H, 20H-8, 5- (epiminomethano) -13, 15-ethenodipyrano [4, 3-b: 4', 3'-h] [1, 7] diazacyclooctadecine-6, 20-dione.
  • Step 2 Preparation of isopropyl (E) -3- (4-oxo-4H-chromen-3-yl) acrylate
  • Step 4 Preparation of isopropyl 3- (4- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert-butoxycarbonyl) imino) -4- ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) chroman-3-yl) propanoate
  • Step 5 Preparation of isopropyl 3- ( (3S, 4S) -4- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert- butoxycarbonyl) imino) -4-ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) chroman-3-yl) propanoate (PEAK 2)
  • Step 6 Preparation of 3- ( (3S, 4S) -4- ( (R, E) -4- (but-3-en-1-yl) -2- ( (tert-butoxycarbonyl) imino) -4- ethyl-6-oxotetrahydropyrimidin-1 (2H) -yl) chroman-3-yl) propanoic acid
  • Step 7 Preparation of tert-butyl ( (R, E) -4- (but-3-en-1-yl) -1- ( (3S, 4S) -3- (3- ( ( (S) -2, 2-dimethyl-6- vinylchroman-4-yl) amino) -3-oxopropyl) chroman-4-yl) -4-ethyl-6-oxotetrahydropyrimidin- 2 (1H) -ylidene) carbamate.
  • Step 8 Preparation of tert-butyl ( (4aS, 8aS, 14bS, 15R, 18R, 21E, 28E) -18-ethyl-3, 3-dimethyl-6, 16- dioxo-4, 4a, 5, 6, 7, 8, 8a, 14b, 17, 18, 19, 20-dodecahydro-3H, 9H, 16H-18, 15- (epiminomethano) -1, 23- ethenochromeno [4, 3-b] pyrano [4, 3-h] [1, 7] diazacyclooctadecin-28-ylidene) carbamate
  • the reaction was stirred at 50 °C for 8 hours while bubbled with N2 continuously.
  • the reaction was followed by LC/MS. After 8 hours the reaction mixture was concentrated.
  • the resulting residue was purified by flash silica gel chromatography ( 4 g Silica Flash Column, Eluent of 30% EtOAc/Pet. ether gradient @60 mL/min) .
  • Step 9 Preparation of tert-butyl ( (4aS, 8aS, 14bS, 15R, 18R, E) -18-ethyl-3, 3-dimethyl-6, 16-dioxo- 4, 4a, 5, 6, 7, 8, 8a, 14b, 17, 18, 19, 20, 21, 22-tetradecahydro-3H, 9H, 16H-18, 15- (epiminomethano) - 1, 23-ethenochromeno [4, 3-b] pyrano [4, 3-h] [1, 7] diazacyclooctadecin-28-ylidene) carbamate
  • Step 10 Preparation of (4aS, 8aS, 14bS, 15R, 18R) -18-ethyl-28-imino-3, 3-dimethyl- 3, 4, 4a, 5, 7, 8, 8a, 14b, 17, 18, 19, 20, 21, 22-tetradecahydro-6H, 9H, 16H-18, 15- (epiminomethano) - 1, 23-ethenochromeno [4, 3-b] pyrano [4, 3-h] [1, 7] diazacyclooctadecine-6, 16-dione.
  • Example 1 The compounds in Table 1 were prepared in an analogous fashion to that described for Example 1 through Example 5. The isomers were separated by preparative HPLC or/and preparative chiral SFC.
  • the asterisk (*) in a chemical structure drawing indicates the location of a chiral center.
  • the parasite stock was maintained at 4%haematocrit in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 5%heat inactivated human serum and 0.5%albumax. Approximately 42 hours prior to the potency assay being set up, parasites were synchronized with 5%sorbitol to select for ring stage parasites. On the day of assay set up, a blood smear of the parasite culture was Giemsa stained and counted. The parasitemia was adjusted to 0.7%rings and the haematocrit was diluted to 2%in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 5%heat inactivated human serum and 0.5%albumax.

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Abstract

La présente invention concerne des composés de formule (I) : et des méthodes de traitement d'infections par Plasmodium comprenant l'administration à un sujet en ayant besoin d'un composé de formule (I), ou d'un sel pharmaceutiquement acceptable de celui-ci.
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WO2017142825A2 (fr) * 2016-02-18 2017-08-24 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
WO2021026884A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2021155612A1 (fr) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Agents antipaludiques

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US20100113359A1 (en) * 2008-11-06 2010-05-06 Auspex Pharmaceuticals, Inc. Dimethylphenoxy modulators of viral protease activity and/or parasitic enzyme activity
WO2017089453A1 (fr) * 2015-11-25 2017-06-01 Ucb Biopharma Sprl Dérivés d'iminotétrahydropyrimidinone utilisés comme inhibiteurs de plasmepsine v

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Publication number Priority date Publication date Assignee Title
WO2017142825A2 (fr) * 2016-02-18 2017-08-24 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
WO2021026884A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques
WO2021155612A1 (fr) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Agents antipaludiques

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