WO2015063544A1 - Novel substituted 2-aminoquinazolin-4(3h)-one derivatives as malarial aspartic protease inhibitors - Google Patents

Novel substituted 2-aminoquinazolin-4(3h)-one derivatives as malarial aspartic protease inhibitors Download PDF

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WO2015063544A1
WO2015063544A1 PCT/IB2013/059782 IB2013059782W WO2015063544A1 WO 2015063544 A1 WO2015063544 A1 WO 2015063544A1 IB 2013059782 W IB2013059782 W IB 2013059782W WO 2015063544 A1 WO2015063544 A1 WO 2015063544A1
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alkyl
nhr
mhz
nhc
cdci
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Aigars Jirgensons
Ilona Domraceva
Iveta KANEPE-LAPSA
Dace RASINA
Kristaps JAUDZEMS
Martins OTIKOVS
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Latvian Institute Of Organic Synthesis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

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  • the present invention relates to medicine, and in particular to the treatment of malaria, more particularly to inhibitors of malaria aspartic proteases known as plasmepsins. Even more particularly, the invention relates to novel substituted 2- aminoquinazolin-4(3H)-one derivatives and pharmaceutical compositions thereof and their use as inhibitors of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
  • Malaria is a life threatening infectious disease caused by the Plasmodium parasite carried by mosquitoes.
  • World Health Organization has estimated 219 million cases of malaria infection, resulting in 660,000 deaths (WHO. World Malaria Report 2012; World Health Organization: Geneva, 2012; p 59).
  • Widespread resistance to practically all currently used drugs has activated the search for antimalarials with novel mechanisms of action (Hyde, J. E. Drug- resistant malaria - an insight. FEBS J. 2007, 274, 4688-4698; Choi, S. R.; Mukherjee, P.; Avery, M. A. The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr. Med. Chem.
  • the invention features a method of treating malaria in humans, comprising administering to a human in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
  • the invention features a pharmaceutical composition for treatment of malaria comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
  • the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases, in the manufacture of a medicament for treatment or prevention of malaria.
  • the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug for use in treating malaria, wherein the compound is an inhibitor of a malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
  • the inhibitor of a malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases is a compound of Formula I, generally referred herein as 2-aminoquinazolin-4(3H)-one:
  • R 1 , R 2 , R 3 , R 4 , R 4 , R 5 , R 6 R 7 R 8 , R 9 , R 10 , R 11 , R 12 , R 13 R 14 are independently -H, -F, -CI, -Br, -I, -CF 3 , -CH 2 CF 3 , -CF 2 CF 2 H, -OH, -L-OH,-O-L-OH, -OR 15 , -O-L-NH2, -O-L-NHR 15 , -O-L-NR 15 2, -O-L-NR 15 R 16 , -L-OR 15 ,-O-L-OR 15 ,-OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 2 H,
  • L represents -W-X-Y-Z-
  • W represents a single bond, oxygen, sulfur, -NR 15 or -CR 15 R 16 ,
  • X represents oxygen, sulfur, -NR 15 or -CR 15 R 16 ,
  • Y represents oxygen, sulfur, -NR 15 or -CR 15 R 16 ,
  • Z represents oxygen, sulfur, -NR 15 or -CR 15 R 16 ;
  • R 15 and R 16 are independently H, d -6 alkyl, cycloC 3- i 2 alkyl, cycloC 3- i 2 alkyl- Ci -6 alkyl, C 2- 6alkenyl, C 2- 6alkynyl, aryl, biaryl, arylCi -6 alkyl, arylC 2-6 alkenyl, arylC 2- 6alkynyl, heteroaryl, heteroarylCi -6 alkyl, heteroarylC 2-6 alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, Ci- 6 alkoxyCi- 6 alkyl, aryloxyarylCi- 6 alkoxy, Ci -6 alkylthio, C 4-6 alkenylthio, cycloC 3 -i 2 alkylthio, cycloC3-i 2 alkyl-Ci -6 alkylthio, cycloC3-i2alkyl-C 3- 6al
  • the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of plasmepsins (malarial aspartic protease) or human aspartic proteases.
  • the treatment is treatment of a disease or disorder that is treated by a plasmepsins (malarial aspartic protease) or human aspartic proteases inhibitor.
  • plasmepsins malarial aspartic protease
  • human aspartic proteases inhibitor a plasmepsins (malarial aspartic protease) or human aspartic proteases inhibitor.
  • the invention features a kit comprising a 2-aminoquinazolin- 4(3H)-one compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
  • the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • the invention features the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • Plasmepsins (I, II, IV) are malarial aspartic proteases have been identified as a group of promising biological targets for the development of new anti-malaria agents as these are used by the parasite in the first stage of hemoglobin digestion, which is the main nutrition source during its erythrocytic cycle (K. Ersmark, B. Samuelsson, A. Hallberg, Plasmepsins as Potential Targets for New Antimalarial Therapy. Med. Res. Rev., 2006, 26, 626-666; G. H. Coombs, D. E. Goldberg, M. Klemba, C. Berry, J. Kay and J. C. Mottram, Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends in Parasitology, 2001 , 17, 532-537).
  • Intermediates 5 could also be prepared by replacing substituents R 7 -R 9 at the benzene ring in compound 5 as exemplified by transformation of N-benzoyl- aminoquinazolin-4ones 5q,r to derivatives 5s-z and 7.41 -7.43 by SnAr or metal catalyzed coupling reactions (scheme 2).
  • Starting material 1 a is commercially available.
  • Other amines 1 b-p could be prepared according to scheme 3. Allylmagnesium bromides 10b-p were prepared from the corresponding allylbromides 9b-p and added to aldehydes (or ketones) providing alcohols 1 1 b-p. N-bromosuccinimide (NBS) promoted cyclization provided bromomethyltetrahydrofurane derivatives 12b-p. These were converted to amines 1 b-p by amination either with potassium phtalimide (KPhth) followed by deprotection with hydrazine or sodium azide followed by reduction (T. Voelker, H. Xia, K. Fandrick, R. Johnson, A.
  • 3C (CDCI 3 , 400 MHz): 29.91 , 35.37, 46.67, 80.35, 81.50, 1 15.94, 122.34, 122.36, 125.37, 127.33, 127.66, 127.68, 128.17, 128.51 , 128.29, 140.1 1 , 142.14, 147.37, 149.15, 153.33, 162.98.
  • Fluorescence resonance energy transfer (FRET) assay was performed to evaluate ability of compounds to inhibit plasmepsin I, II, IV and Cathepsin D.
  • Substrate (DABCYL-Glu-Arg-Nle-Phe-Leu-Ser-Phe-Pro-EDANS, AnaSpec Inc) was added to reach final concentration 5 uM. Hydrolysis of substrate was detected as an increase in fluorescence (Em 490 nm, Ex 336 nm) at 37°C. Compounds were tested in three repeated triplicate experiments.

Abstract

The present invention discloses novel substituted 2-aminoquinazolin-4(3H)-one derivatives and their use as inhibitors of malarial aspartic protease plasmepsin I,II,IV or related malarial aspartic proteases, as well as pharmaceutical compositions thereof for treatment of malaria.

Description

NOVEL SUBSTITUTED 2-AMINOQUINAZOLIN-4(3H)-ONE DERIVATIVES AS MALARIAL ASPARTIC PROTEASE INHIBITORS
Field of invention The present invention relates to medicine, and in particular to the treatment of malaria, more particularly to inhibitors of malaria aspartic proteases known as plasmepsins. Even more particularly, the invention relates to novel substituted 2- aminoquinazolin-4(3H)-one derivatives and pharmaceutical compositions thereof and their use as inhibitors of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
Background of invention
Malaria is a life threatening infectious disease caused by the Plasmodium parasite carried by mosquitoes. In 2010, World Health Organization has estimated 219 million cases of malaria infection, resulting in 660,000 deaths (WHO. World Malaria Report 2012; World Health Organization: Geneva, 2012; p 59). Widespread resistance to practically all currently used drugs has activated the search for antimalarials with novel mechanisms of action (Hyde, J. E. Drug- resistant malaria - an insight. FEBS J. 2007, 274, 4688-4698; Choi, S. R.; Mukherjee, P.; Avery, M. A. The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr. Med. Chem. 2008, 15, 161 -171 ; Wells, T. N.; Alonso, P. L.; Gutteridge, W. E. New medicines to improve control and contribute to the eradication of malaria. Nat. Rev. Drug Discov. 2009, 8, 879-891 ). Resistance to current anti-malaria agents in regions threatened by malaria continues to spread, and it means that current therapeutic agents will be practically ineffective in the near future. A precondition for the development of a new resistance free malaria agent is inhibition of malaria parasite life cycle by a mechanism that differs from the mode of action of currently used therapeutic agents (N. K. Sahu, S. Sahu and D. V. Kohli, Novel Molecular Targets for Antimalarial Drug. Chem. Biol. Drug. Des., 2008, 71 , 287-297). Such product would be resistance free for a particular period of time, and it would be effective in all malaria endemic regions. One group of promising biological targets for the development of new anti-malaria agents are plasmepsins (I, II, IV and HAP) - aspartic proteases of the parasite Plasmodium, which are used by the parasite in the first stage of hemoglobin digestion, which is the main nutrition source during its erythrocytic cycle (K. Ersmark, B. Samuelsson, A. Hallberg, Plasmepsins as Potential Targets for New Antimalarial Therapy. Med. Res. Rev., 2006, 26, 626-666; G. H. Coombs, D. E. Goldberg, M. Klemba, C. Berry, J. Kay and J. C. Mottram, Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends in Parasitology, 2001 , 17, 532- 537). Therapeutic potential of plasmepsins (I, II, IV and HAP) in the treatment of malaria is still unused as there is no marketed anti-malarial drug acting on this target. Most of known plasmepsin inhibitors are based on N-acylated amino alcohols as transition state analogues that are peptidic or peptide-like compounds which suffer from problems in bioavailability and pharmacokinetic profile (K. Ersmark, B. Samuelsson, A. Hallberg, Plasmepsins as Potential Targets for New Antimalarial Therapy. Med. Res. Rev., 2006, 26, 626-666). In order to find more drug-like compound there is an increased interest for non- peptidic plasmepsin inhibitors and several such inhibitors have been reported (O. Corminboeuf, G. Dunet, M. Hafsi, J. Grimont, C. Grisostomi, S. Meyer, C. Binkert, D. Bur, A. Jones, L. Prade, R. Brun, C. Boss, Inhibitors of Plasmepsin II— potential antimalarial agents. Bioorganic & Medicinal Chemistry Letters 2006, 16, 6194-6199; F. Hof, A. Schutz, C. Fah, S. Meyer, D.Bur, J. Liu, D. E. Goldberg, and F. Diederich, Starving the Malaria Parasite: Inhibitors Active against the Aspartic Proteases Plasmepsins I, II, IV Angew. Chem. Int. Ed. 2006, 45, 2138 -2141 ; T. Luksch, A. Blum, N. Klee, W. E. Diederich, C. A. Sotriffer, G. Klebe, Pyrrolidine Derivatives as Plasmepsin Inhibitors: Binding Mode Analysis Assisted by Molecular Dynamics Simulations of a Highly Flexible Protein. ChemMedChem., 2010, 5, 443-454).
Summary of the invention
In a first aspect, the invention features a method of treating malaria in humans, comprising administering to a human in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
In another aspect, the invention features a pharmaceutical composition for treatment of malaria comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
In another aspect, the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases, in the manufacture of a medicament for treatment or prevention of malaria.
In another aspect, the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug for use in treating malaria, wherein the compound is an inhibitor of a malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases.
In one embodiment the inhibitor of a malarial aspartic protease plasmepsin l,ll,IV or related malarial aspartic proteases is a compound of Formula I, generally referred herein as 2-aminoquinazolin-4(3H)-one:
Figure imgf000004_0001
Formula I wherein:
R1 , R2, R3, R4, R4, R5, R6 R7 R8, R9, R10, R11, R12, R13 R 14 are independently -H, -F, -CI, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR15, -O-L-NH2, -O-L-NHR15, -O-L-NR152, -O-L-NR15R16, -L-OR15,-O-L-OR15,-OCF3, -OCH2CF3, -OCF2CF2H,
-L-OR15,-O-L-OR15,-OCF3, -OCH2CF3, -OCF2CF2H, SR15, SCF3,
CN, -NO2, -NO2, -NH2, -NHR15, -NR15 2, -NR15R16,
-L-NH2, -L-NHR15, -L-NR15 2, -L-NR15R16,
-NH-L-NH2, -NH-L-NHR15, -NH-L-NR15 2, -NH-L-NR15R16,
-NR15-L-NH2, -NR15-L-NHR15, -NR15-L-NR15 2, -NR15-L-NR15R16,
L-NR15R16,
-C(=O)OH, -C(=O)OR15, -C(=O)NH2, -C(=O)NHR15, -C(=O)NR15 2, -C(=O)NR15R16,
-NHC(=O)R15, -NR15C(=O)R16, -NHC(=O)OR15, -NR15C(=O)OR16, -OC(=O)NH2, -OC(=O)NHR15, -OC(=O)NR152, -OC(=O)NR15R16,-OC(=O)R15,
-C(=O)R15,-NHC(=O)NH2, -NHC(=O)NHR15, -NHC(=O)NR15 2, -NHC(=O)NR15R16, -NR15C(=O)NH2, -NR15C(=O)NHR16, -NR15C(=O)NR16 2, -NR15C(=O)N
-NHS(=O)2R15, -NR15S(=O)2R16,
-S(=O)2NH2, -S(=O)2NHR15, -S(=O)2NR15 2, -S(=O)2NR15R16,-S(=O)R15, -S(=O)2R15,-OS(=O)2R15,-S(=O)2OR15,
Ci-6alkyl, cycloC3-i2alkyl, cycloC3-i2alkyl-Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylCi-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylCi-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2, 3-dihydro-1 H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci-6alkylpiperazino, 4-arylpiperazino, hexamethyleneinnino, benzazepinyl, 1 ,3-dihydro-2H-isoindol- 2-yl; or R1, R2, R3, R4, R4, R5, R6 are independently =O,=NR15,=NOH, or =NOR15;
L represents -W-X-Y-Z-;
R1 and R2
or R1 and R3
or R3 and R4
or R3 and R6
or R5 and R6
or R7 and R8
or R8 and R14
or R9 and R10
or R10 and R11
or R11 and R12
or R12 and R13
or R13 and R14
taken together represent -W-X-Y-Z-, wherein
W represents a single bond, oxygen, sulfur, -NR15 or -CR15R16,
X represents oxygen, sulfur, -NR15 or -CR15R16,
Y represents oxygen, sulfur, -NR15 or -CR15R16,
Z represents oxygen, sulfur, -NR15 or -CR15R16;
R15 and R16 are independently H, d-6alkyl, cycloC3-i2alkyl, cycloC3-i2alkyl- Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylCi-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylCi-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, Ci-6alkoxyCi-6alkyl, aryloxyarylCi-6alkoxy, Ci-6alkylthio, C4-6alkenylthio, cycloC3-i2alkylthio, cycloC3-i2alkyl-Ci-6alkylthio, cycloC3-i2alkyl-C3-6alkenylthio, Ci-6alkoxyCi-6alkylthio, Ci-6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylCi-6alkylthio, Ci-6alkylsulfonyl, cycloC3-i2alkyl- Ci-6alkylsulfonyl, arylCi-6alkylsulfonyl, Ci-6alkylannino, di-Ci-6alkylannino, cycloC3-i2alkylamino, Ci-C6alkoxy-cycloC3-Ci2alkylannino, cycloC3-i2alkyl- Ci-6alkylamino, di-Ci-6alkylaminoCi-6alkyl, Ci-6alkoxy-C2-6alkylannino, arylamino, arylCi-6al kylannino, N-cycloC3-i2alkyl-N-Ci-6alkylannino, N-aryl-N-Ci-6alkylannino, N-arylCi-6alkyl-N-Ci-6alkylannino, 2-indanylamino, tetrahydrofuryl, pyrrolidine piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1 ,3-dihydro-2H-isoindol-2-yl, heteroarylCi-6alkoxy, heteroarylamino, or heteroarylCi-6alkylamino, and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. In one embodiment, the treatment is treatment of a disease or disorder that is mediated by plasmepsins (malarial aspartic protease) or human aspartic proteases.
In one embodiment, the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of plasmepsins (malarial aspartic protease) or human aspartic proteases.
In one embodiment, the treatment is treatment of a disease or disorder that is treated by a plasmepsins (malarial aspartic protease) or human aspartic proteases inhibitor.
In another aspect, the invention features a kit comprising a 2-aminoquinazolin- 4(3H)-one compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
In another aspect, the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
In another aspect, the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
In another aspect, the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein. In another aspect, the invention features the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
Description of invention
Plasmepsins (I, II, IV) are malarial aspartic proteases have been identified as a group of promising biological targets for the development of new anti-malaria agents as these are used by the parasite in the first stage of hemoglobin digestion, which is the main nutrition source during its erythrocytic cycle (K. Ersmark, B. Samuelsson, A. Hallberg, Plasmepsins as Potential Targets for New Antimalarial Therapy. Med. Res. Rev., 2006, 26, 626-666; G. H. Coombs, D. E. Goldberg, M. Klemba, C. Berry, J. Kay and J. C. Mottram, Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends in Parasitology, 2001 , 17, 532-537).
When testing the novel substituted 2-aminoquinazolin-4(3H)-one derivatives for their ability to inhibit plasmepsins I, II, IV, we have unexpectedly discovered, that said derivatives exhibit pronounced inhibitor properties toward said plasmepsins and thus are useful in treatment of malaria. According to this invention, the results from plasmepsin inhibition studies demonstrate that substituted 2-aminoquinazolin-4(3H)-one derivatives are novel class of non-peptidic inhibitors of malarial aspartic proteases - plasmepsins. Several example compounds from the present invention display high nanomolar to low micromolecular inhibitory potency that is comparable to known non- peptidic inhibitors (e.g. F. Hof et. al., Starving the malaria parasite: Inhibitors active against the aspartic proteases plasmepsins I, II, and IV. Angew. Chem. Int. Ed. 2006, 45, 2138-2141 ; T. Luksch et.al., Computer-Aided Design and Synthesis of Nonpeptidic Plasmepsin II and IV Inhibitors. ChemMedChem., 2008, 3, 1323-1336.; C. Boss et.al., Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential antimalarial agents. Curr Med Chem. 2003, 10, 883-907; C. Fah et. al., Enantiomerically Pure and Highly Substituted Alicyclic α,α-Difluoro Ketones: Potential Inhibitors for Malarial Aspartic Proteases, the Plasmepsins. Eur.J.Chem., 2010, 4617-4629.; T. Luksch et.al., Pyrrolidine Derivatives as Plasmepsin Inhibitors: Binding Mode Analysis Assisted by Molecular Dynamics Simulations of a Highly Flexible Protein. ChemMedChem., 2010, 5, 443-454)
Stereochemistry
Many of the chemical structures shown herein indicate one or more specific stereoisomeric configurations. Similarly, many of the chemical structures shown herein are silent in this respect, and do not indicate any stereoisomeric configuration. Similarly, many of the chemical structures shown herein indicate the specific stereoisomeric configurations at one or more positions, but are silent with respect to one or more other positions. Where a chemical structure herein is silent with respect to the stereoisomeric configuration at a position, that structure is intended to depict all possible stereoisomeric configurations at that position, both individually, as if each possible stereoisomeric configuration was individually recited, and also as a mixture (e.g., a racemic mixture) of stereoisomers.
Combinations
Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.
Examples
The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.
General Synthesis 2-Aminoquinazolin-4(3H)-one derivatives 8.1 -8.48 were prepared to exemplify the current invention starting from 2-aminomethyltetrahedrofuran derivatives 1 a-p and commercially available anthranilic acid (Scheme 1 ). The coupling reaction provided amides 3a-r which, in the reaction with benzoylisothiocyanate were transformed to thiourea derivatives 4a-r. Scheme 1 . General preparation of 2-aminoquinazolin-4(3H)-one derivatives 8.
Figure imgf000010_0001
These were cyclized to N-benzoylaminoquinazoline derivatives 5a-v and subjected to Suzuki-Miyaura reaction with boronic acid which led to intermediates 7.1 -7.48. Debenzoylation provided final compounds: 2-aminoquinazoline-4-one derivatives 8.1 -8.48 (Scheme 1 ).
Intermediates 5 could also be prepared by replacing substituents R7-R9 at the benzene ring in compound 5 as exemplified by transformation of N-benzoyl- aminoquinazolin-4ones 5q,r to derivatives 5s-z and 7.41 -7.43 by SnAr or metal catalyzed coupling reactions (scheme 2).
Scheme 2. Preparation of intermediates 5 and 7.
Figure imgf000011_0001
Starting material 1 a is commercially available. Other amines 1 b-p could be prepared according to scheme 3. Allylmagnesium bromides 10b-p were prepared from the corresponding allylbromides 9b-p and added to aldehydes (or ketones) providing alcohols 1 1 b-p. N-bromosuccinimide (NBS) promoted cyclization provided bromomethyltetrahydrofurane derivatives 12b-p. These were converted to amines 1 b-p by amination either with potassium phtalimide (KPhth) followed by deprotection with hydrazine or sodium azide followed by reduction (T. Voelker, H. Xia, K. Fandrick, R. Johnson, A. Janowsky, J. R. Cashman. 2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors. Bioorganic & Medicinal Chemistry 2009,17, 2047-2068) Scheme 3. Synthesis of starting materials 1 .
Figure imgf000012_0001
Synthesis of starting materials 1 , general method I
Exemplified by the synthesis of Compound 1 p: Mg turnings (1 .19g, 0.049 mol, 1 eq.) in dry Et2O (5 mL) are activated with l2 crystals under a nitrogen atmosphere. A mixture of 4-bromobutene (9p) (5ml_, 0.049 mol, 1 equiv.) in Et2O (15 mL) is added dropwise in such a rate, that the solution is kept reflux. After complete addition the mixture is stirred for an additional 2 h. The concentration of the resultant Grignard reagent (3-butenylmagnesium bromide) 10p was around 2
M.
To the solution of benzaldehyde ( (2.0 mL, 19.66 mmol, 1 equiv.) in dry THF (30 mL) was added 2 M homoallylmagnesiumbromide 10p solution in Et2O (9.8 mL, 19.66 mmol, 1 equiv.) at -78 °C. Mixture was allowed to reach r. t. over 1 h and sat. NH CI solution was added, followed by extraction with EtOAc. Organic phase was separated, washed with brine and dried over Na2SO4. Product was purified by column chromatography (1 :8 = EtOAc: PE) to yield Compound 1 1 p (2.94 g, 92 % yield) as a colorless oil.
To a solution of Compound 1 1 p (1 .50 g, 9.24 mmol, 1 equiv.) in dry DCM (25 mL) at 0 °C was added N-bromosuccinimide (91 .81 g, 10.2 mmol, 1 .1 equiv.) portionwise and the reaction was warmed to room temperature for 2 h. The solvent was then removed in vacuo and the remaining residue was purified by flash column chromatography (1 :4 = EtOAc: PE) to yield 12p (1 .84 g, 83 %) as yellow oil as diastereomeric mixture that could be separated by flash chromatography to give Compound 12p-cis and Compound 12p-trans.
To a solution of Compound 12p (0.352 g, 1 .45 mmol, 1 equiv.) in DMF (2 mL), potassium phthalimide (0.324, 1 .75 mmol, 1 .2 equiv.) was added and mixture was heated at 80 °C for 6 h. After the reaction was completed, the solution was cooled to room temperature, then partitioned between H2O and EtOAc, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1 :2 = EtOAc: PE) to afford the protected intermediate (0.425 g, 95 % yield). This was dissovled in EtOH (10 mL), hydrazine hydrate (0.5 mL) was added and mixture was refluxed for 2 h. Solvent was evaporated, waters was added and extracted with EtOAc. Organic phase was separated, washed with brine and dried over Na2SO4. Evaporation of solvent provided Compound 1 p (0.250 g, 99% yield). Isomers 12p-cis and 12p-trans provided 1 p-cis and 1 p-trans, respectively.
Following a method analogous to method I the following compounds were obtained:
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Synthesis of intermediates 3, general method A
Exemplified by the synthesis of Compound 3a: DIPEA (1 .15 mL, 6.94 mmol, 3 equiv.) and HATU (1 .32 g, 3.47 mmol, 1 .5 equiv.) was added to the suspension of 2-amino-4-bromobenzoic acid (2a) (0.5 g, 2.31 mmol, 1 equiv.) in dry DCM (20 mL) and mixture was stirred at r.t. for 15 min. Then tetrahydrofurfurylamine (1 a) (0.36 mL, 3.47 mmol, 1 .5 equiv.) was added and the mixture was stirred at r.t. for 2 h. The solvent was then removed in vacuo and the remaining residue was purified by column chromatography (1 :1 = EtOAc: PE) to yield Compound 3a (0.664 g, 96% yield) as colorless solid.
By a method analogous to Method A, the following compounds were obtained:
Figure imgf000015_0002
Figure imgf000016_0001

Figure imgf000017_0001
Figure imgf000018_0001
Synthesis of intermediates 4, general method B
Exemplified by the synthesis of Compound 4a: Benzoyl isothiocyanate (0.298 ml_, 2.22 mmol, 1 equiv.) was added dropwise to the solution of 2-amino-N- alkylbenzamide derivative 3a (0.664 g, 2.22 mmol, 1 equiv.) in 10 ml of ether and mixture was stirred a r. t. for 1 .5 h. The solid was collected, giving the desired Compound 4a (0.988 g, 96%).
Following a method analogous to Method B, the following compounds were obtained:
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000020_0001
Synthesis of intermediates 5, general method C
Exemplified by the synthesis of Compound 5a: To the solution of 4a (0.445 g, 0.984 mmol, 1 equiv.) in 20 mL dry THF was added TEA (0.273 mL, 1 .96 mmol, 2 equiv.) followed by addition of methyl iodide (0.067 mL, 1 .08 mmol, 1 .1 equiv.). The solution was stirred at r.t. for 2 h and then NaH (60% suspension in mineral oil, 1 18 g, 2.95 mmol, 3 equiv.) was added portion-wise. Mixture was stirred at r. t. overnight and then diluted with water. pH of the mixture was adjusted to 7 with 5% NaHSO4 and extracted with EtOAc. Organic phase was separated, washed with brine and dried over Na2SO4. Product was purified by column chromatography (1 :1 = EtOAc: PE) and crystallized in EtOH to yield Compound 5a (0.406 g, 96% yield) as colorless solid.
Synthesis of intermediates 5, general method D
Exemplified by the synthesis of Compound 5s: NaH (60 % suspension in mineral oil, 8 mg, 0.2 mmol, 2 equiv.) was added to DMF (1 mL) and mixture was stirred at r .t. 30 min, then intermediate 5r (58 mg, 0.1 mmol, 1 equiv.) was added and mixture was heated at 120 °C over night and then diluted with water, pH was adjusted to 7 with 5% NaHSO4 and extracted with EtOAc. Organic phase was separated, washed with brine and dried over Na2SO4. Product was purified by column chromatography (1 :4 = EtOAc: PE) and crystallized in MeOH to yield Compound 5s (15 mg, 27 % yield) as a dark oil.
Synthesis of intermediates 5, general method E
Exemplified by the synthesis of Compound 5v: K-amylate (25w/w solution in toluene, 0.252 mL, 0.5 mmol, 5 equiv.) was added to the solution of phenol (47 mg, 0.5 mmol, 5 equiv.) in DMSO (1 mL) and the mixture was stirred at r .t. 30 min, then bromide 5r (58 mg, 0.1 mmol, 1 equiv.) was added and the mixture was heated at 120 °C overnight. Then it was diluted with water, pH was adjusted to 7 with 5% NaHSO4 and extracted with EtOAc. Organic phase was separated, washed with brine and dried over Na2SO4. Product was purified by column chromatography (1 :4 = EtOAc: PE) and crystallized in MeOH to yield 534 mg (57% yield) of colorless solid. Following a methods analogous to Methods C, D, E the following compounds were obtained:
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000025_0001
Synthesis of intermediates 7, general method F
Exemplified by the synthesis of Compound 7.1 . To a solution of bromide 5a (100 mg 0.233 mmol, 1 equiv.) in THF (4 ml_) and H2O (0.2 ml_) was added phenyl boronic acid (6a) (37 mg, 0.303 mmol, 1 .3 equiv.), tetrakis-(triphenylphosphine)- palladium (13 mg, 0.01 1 mmol, 5 mol%) and Na2CO3 (97 mg, 0.699 mmol, 3 equiv.). The result mixture was stirred and refluxed for 6 h. After the reaction was completed, the solution was cooled to room temperature, and then partitioned between H2O and EtOAc, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1 :4 = EtOAc: PE) to afford the Compound 7.1 (86 mg, 86% yield).
Synthesis of intermediates 7, general method G
Exemplified by the synthesis of Compound 7.43. To a solution of dibromide 5r-cis (25 mg 0.043 mmol, 1 equiv.) in THF (2 ml_) and H2O (0.1 ml_) was added phenyl boronic acid (6a) (16 mg, 0.128 mmol, 3 equiv.), tetrakis-(triphenylphosphine)- palladium (2.4 mg, 0.002 mmol, 5 mol%) and Na2CO3 (30 mg, 0.214 mmol, 5 equiv.). The resultin mixture was stirred and refluxed for 6 h. After the reaction was completed, the solution was cooled to room temperature, then partitioned between H2O and EtOAc, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1 :4 = EtOAc: PE) to afford the Compound 7.43 (19 mg, 79 % yield). Following methods analogous to Methods F, G the following compounds were obtained:
Figure imgf000026_0001
Figure imgf000027_0001

Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Synthesis of 2-aminoquinazolin-4(3H)-one derivatives 8, general method H
Exemplified by the synthesis of Compound 8.1 . To a suspension of Compound 7.1 (0.084 mg, 0.197 mmol) in EtOH (5 mL), hydrazine hydrate (0.2 mL) was added and the mixture was refluxed for 2 h. Solvent was evaporated, waters was added and extracted with EtOAc. Organic phase was separated, washed with brine and dried over Na2SO4. Product was crystallized in MeOH to yield Compound 8.1 . (60 mg, 95%) as colorless solid. Following a method analogous to Method H the following compounds were obtained:
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
All compounds were characterized by 1H-NMR and occasionally by 13C-NMR spectroscopy performed on Varian Mercury spectrometer (400 MHz) with chemical shifts values (δ) in ppm relative to TMS using the residual chloroform signal as internal standard and by tandem LC/MS spectrometer on Water Acquity UPLC with SQ mass selective detector.
Physicochemical characterization of compounds 8.1 -8.48:
Figure imgf000037_0002
UPLC/MS: [M+1] = 352 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.90-1.99 (2H, m), 2.15- 2.22 (1H, m), 3.78-3.83 (1H, m), 3.90-3.95 (1H, m), 4.14-4.27 (2H, m), 4.51 (1H, d, J=14.48 Hz), 5.81 (2H, s), 7.36-7.41 (3H, m), 7.51
8.3. DR689
(1H, d, J=1.57 Hz), 7.54 (1H, dt, J=7.04, 1.57 Hz), 7.65 (1H, m), 8.17 (1H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 356 H (CDCI3, 400 MHz): 1.28 (3H, t, J=7.83 Hz), 1.61-1.71 (1H, m), 1.89-1.96 (2H, m), 2.13-2.21 (1H, m), 2.70 (2H, m), 3.77-3.82 (1H, m), 3.88-3.94 (1H, m), 4.13-4.26 (2H, m), 4.49 (1H, d, J=14.09 Hz),
8.4. DR690
5.91 (2H, brs), 7.41-7.44 (3H, m), 7.50 (1H, m), 7.57 (2H, d, J=8.22 Hz), 8.15 (1H, d, J=8.61 Hz).
UPLC/MS: [M+1] = 350 H (CDCI3, 400 MHz): 1.64-1.72 (1H, m), 1.89-1.97 (2H, m), 2.14- 2.21 (1H, m), 3.77-3.83 (1H, m), 3.89-3.94 (1H, m), 4.14-4.27 (2H, m), 4.49 (1H, d, J=14.48 Hz), 5.76 (2H, s), 6.01 (2H, s), 6.90 (1H, d,
8.5 DR691 J=7.83 Hz), 7.15 (1H, s), 7.16 (1H, dd, J=7.83, 1.96 Hz), 7.36 (1H, dd, J=1.57, 8.22 Hz), 7.46 (1H, d, J=1.57 Hz), 8.13 (1H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 366 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.89-1.97 (2H, m), 2.14- 2.21 (1H, m), 3.23-3.25 (4H, m), 3.77-3.83 (1H, m), 3.87-3.94 (5H, m), 4.15-4.27 (2H, m), 4.49 (1H, d, J=14.08 Hz), 5.72 (2H, s), 6.99
8.6 DR692
(2H, d, J=9.00 Hz), 7.43 (1H, dd, J=1.96, 8.22 Hz), 7.51 (1H, d, J=1.57 Hz), 7.63 (2H, d, J=9.00 Hz), 8.13 (1H, d, J=8.61 Hz).
UPLC/MS: [M+1] = 407 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.90-1.99 (2H, m), 2.15- 2.22 (1H, m), 3.78-3.84 (1H, m), 3.90-3.95 (1H, m), 4.14-4.27 (2H, m), 4.52 (1H, d, J=14.87 Hz), 5.76 (2H, s), 7.31 (2H, d, J=8.61 Hz),
8.7 DR693
7.40 (1H, dd, J=1.96, 8.22 Hz), 7.51 (1H, d, J=1.97 Hz), 7.68 (2H, d, J=8.61 Hz), 8.17 (1H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 406 H (CDCI3, 400 MHz): 1.63-1.73 (1H, m), 1.90-1.98 (2H, m), 2.15-
8.8 DR694
2.23 (1H, m), 3.78-3.84 (1H, m), 3.90-3.95 (1H, m), 4.16-4.28 (2H, m), 4.51 (1H, d, J=14.48 Hz), 5.75 (2H, s), 7.36-7.39 (1H, m), 7.44- 7.49 (2H, m), 7.51 (1H, dd, J=1.96, 8.22 Hz), 7.55 (1H, d, J=7.43 Hz), 7.62-7.67 (5H, m), 7.90 (1H, t, J=1.57 Hz), 8.19 (1H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 398 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.90-1.97 (2H, m), 2.14- 2.21 (1H, m), 3.76-3.83 (3H, m), 3.89-3.95 (1H, m), 4.15-4.27 (2H, m), 4.50 (1H, d, J=14.28 Hz), 5.77 (2H, s), 6.72 (1H, ddd, J=0.97,
8.9 DR697 2.15, 7.83 Hz), 6.98 (1H, dd J=1.76, 2.15 Hz), 7.06 (1H, ddd, J=0.97,
1.76, 7.83 Hz), 7.24 (1H, t, J=7.83 Hz), 7.42 (1H, dd, J=1.76, 8.41 Hz), 7.51 (1H, d, J=1.76 Hz), 8.14 (1H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 337 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.90-1.98 (2H, m), 2.13- 2.22 (1H, m), 3.77-3.83 (1H, m), 3.89-3.95 (4H, m), 4.12-4.27 (2H,
8.10 DR698 m), 4.50 (1H, d, J=14.28 Hz), 5.76 (2H, s), 7.05 (1H, d, J=8.41 Hz),
7.37-7.44 (3H, m), 7.47 (1H, d, J=1.76 Hz), 8.15 (1H, d, J=8.80 Hz).
UPLC/MS: [M+1] = 370 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.90-1.98 (2H, m), 2.15- 2.23 (1H, m), 3.78-3.84 (1H, m), 3.90-3.96 (1H, m), 4.14-4.28 (2H, m), 4.52 (1H, d, J=14.67 Hz), 5.81 (2H, s), 7.43 (1H, dd, J=1.76, 8.41
8.11 DR699
Hz), 7.55 (1H, d, J=1.76 Hz), 7.72 (2H, d, J=8.21 Hz), 7.77 (2H, d, J=8.21 Hz), 8.15 (1H, d, J=8.41 Hz).
UPLC/MS: [M+1] = 390 H (CDCI3, 400 MHz): 1.62-1.72 (1H, m), 1.91-1.98 (2H, m), 2.15- 2.23 (1H, m), 3.79-3.84 (1H, m), 3.90-3.96 (1H, m), 4.14-4.28 (2H, m), 4.52 (1H, d, J=14.48 Hz), 5.62 (1H, brs), 5.87 (2H, brs), 6.06
8.12 DR700 (1H, brs), 7.45 (1H, dd, J=1.76, 8.41 Hz), 7.56 (1H, d, J=1.76 Hz),
7.75 (2H, d, J=8.60 Hz), 7.91 (2H, d, J=8.60 Hz), 8.19 (1H, d, J=8.41 Hz).
UPLC/MS: [M+1] = 365 H (CDCI3, 400 MHz): 1.89-2.06 (2H, m), 2.35-2.49 (2H, m), 4.33- 4.42 (1H, m), 4.58 (1H, d, J=14.87 Hz), 4.69-4.75 (1H, m), 5.22 (1H,
8.13 DR750
dd, J=6.26, 8.61 Hz), 5.83 (2H, brs), 7.37-7.51 (7H, m), 7.57 (1H, d, J=1.56 Hz), 7.68-7.70 (2H, m), 7.73-7.75 (1H, m), 7.80-7.84 (3H, m), 8.21 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 448 H (CDCI3, 400 MHz): 1.87-2.07 (2H, m), 2.35-2.49 (2H, m), 4.34- 4.39 (1 H, m), 4.58 (1 H, d, J=14.99 Hz), 4.69-4.74 (1 H, m), 5.22 (1 H, dd, J=6.17, 8.82 Hz), 5.91 (2H, brs), 7.31 (2H, d, J=7.94 Hz), 7.37-
8.14 DR762
7.55 (5H, m), 7.65-7.70 (2H, m), 7.74 (1 H, s), 7.79-7.84 (3H, m), 8.21 (1 H, d, J=8.38 Hz).
UPLC/MS: [M+1] = 532 H (CDCI3, 400 MHz): 1.98-2.06 (2H, m), 2.29-2.48 (2H, m), 4.27 (1 H, dd, J=7.04, 14.87 Hz), 4.43-4.48 (1 H, m), 4.68 (1 H, d, J=14.48
8.15 DR751 Hz), 5.07 (1 H, dd, J=6.65, 7.04 Hz), 5.78 (2H, brs), 7.37-7.55 (8H, m), 7.64-7.84 (6H, m), 8.20 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 448 H (CDCI3, 400 MHz): 1.94-2.08 (2H, m), 2.31-2.56 (2H, m), 4.25- 4.30 (1 H, m), 4.43-4.50 (1 H, m), 4.70 (1 H, d, J=14.87 Hz), 5.07-5.1 1 (1 H, m), 5.58 (2H, brs), 7.31 (2H, d, J=7.86 Hz), 7.40-7.43 (2H, m),
8.16 DR763
7.48-7.52 (3H, m), 7.68-7.73 (3H, m), 7.80-7.86 (3H, m), 8.21 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 532 H (CDCI3, 400 MHz): 1.62-1.77 (2H, m), 2.00-2.10 (1 H, m), 2.22- 2.29 (1 H, m), 2.76-2.86 (2H, m), 4.01-4.10 (1 H, m), 4.15-4.28 (0.4aH, 0.8bH, m), 4.35-4.46 (1.6bH, m), 4.58 (0.2aH, d, J=14.48 Hz), 5.48
8.17 DR764
(2H, brs), 7.18-7.32 (7H, m), 7.37-7.40 (1 H, m), 7.46-7.50 (1 H, m), 7.66-7.68 (2H, m), 8.16 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 496 H (CDCI3, 400 MHz): 1.60-1.78 (2H, m), 2.00-2.10 (1 H, m), 2.21- 2.29 (1 H, m), 2.76-2.85 (2H, m), 4.00-4.27 (2H, 0.2aH, m), 4.35-4.41 (0.8bH, m), 4.44 (0.8bH, d, J=14.87 HzJ, 4.57 (0.2aH, d, J=14.48 Hz),
8.18 DR765
5.59 (2H, brs), 7.17-7.23 (3H, m), 7.27-7.31 (2H, m), 7.37-7.48 (4H, m), 7.23-7.54 (1 H, m), 7.66-7.68 (2H, m), 8.16 (1 H, d, J=8.61 Hz).
UPLC/MS: [M+1] = 412 H (CDCI3, 400 MHz): 0.84-0.88 (3H, m), 0.93-0.96 (3H, m), 1.56-
8.19 DR775
1.73 (3H, m), 1.94-2.02 (1 H, m), 2.18-2.24 (1 H, m), 3.58 (0.2aH, q, J=7.43, 14.48 Hz), 3.63-3.69 (0.8DH, m), 4.04-4.10 (0.2aH, m), 4.13- 4.24 (1 H, m), 4.28-4.34 (0.8bH, m), 4.48 (0.8bH, d, J=14.87 Hz), 4.58 (0.2aH, d, J=14.87 Hz), 5.74 (0.4aH, brs), 5.89 (1.6bH, brs), 7.38-7.49 (4H, m), 7.55 (1 H, s), 7.66-7.68 (2H, m), 8.17 (1 H, d, J=8.61 Hz).
UPLC/MS: [M+1] = 364 H (CDCI3, 400 MHz): 0.84-0.89 (3H, m), 0.93-0.96 (3H, m), 1.59- 1.74 (3H, m), 1.93-2.03 (1 H, m), 2.16-2.25 (1 H, m), 3.56-3.69 (1 H, m), 4.02-4.08 (0.2aH, m), 4.13-4.24 (1 H, m), 4.28-4.34 (0.8bH, m), 4.49 (0.8bH, d, J=14.47 Hz), 4.58 (0.2aH, d, J=14.87 Hz), 5.75
8.20 DR776
(0.4aH, brs), 5.90 (1.6bH, brs), 7.31 (2H, d, J=8.61 Hz), 7.40 (1 H, d, J=8.22 Hz), 7.51 (1 H, d, J=1.17 Hz), 7.68 (2H, d, J=9.00 Hz), 8.17 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 448 H (CDCI3, 400 MHz): 1.85-2.02 (2H, m), 2.31-2.47 (2H, m), 4.16- 4.46 (1 H, m), 4.55 (1 H, d, J=14.87 Hz), 4.62-4.71 (1 H, m), 4.96
8.21 DR853 (0.2aH, m), 5.1 1 (0.8bH, m), 5.63 (0.4aH, brs), 5.85 (1.6bH, brs), 7.35- 7.69 (16H, m), 8.20 (1 H, d, J=7.83 Hz).
UPLC/MS: [M+1] = 474 H (CDCI3, 400 MHz): 1.82-1.97 (2H, m), 2.26-2.42 (5H, m), 4.22 (0.3aH, dd, J=7.04, 14.48 Hz), 4.29-4.42 (1 H, m), 4.53 (0.7bH, d, J=14.08 Hz), 4.61-4.68 (1 H, m), 4.88 (0.3aH, t, J=7.04 Hz), 4.53
8.22 DR854 (0.7bH, m), 5.64 (0.6aH, brs), 5.88 (1.4bH, brs), 7.07-7.12 (3H, m),
7.22 (1 H, t, J=7.43 Hz), 7.37-7.42 (1 H, m), 7.45-7.49 (3H, m), 7.55- 7.56 (1 H, m), 7.67-7.69 (2H, m), 8.19 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 412 H (CDCI3, 400 MHz): 1.81-1.96 (2H, m), 2.24-2.41 (2H, m), 3.78 (0.6aH, s), 3.79 (2.4bH, s), 4.20 (0.2aH, dd, J=7.04, 14.87 Hz), 4.30- 4.42 (1 H, m), 4.52 (0.8bH, d, J=14.87 Hz), 4.60-4.69 (1 H, m), 4.89 (0.2aH, t, J=7.04 Hz), 5.01-5.05 (0.8bH, m), 5.70 (0.4aH, brs), 5.92
8.23 DR855
(1.6bH, brs), 6.79-6.88 (3H, m), 7.25 (1 H, t, J=7.83 Hz), 7.37-7.49 (4H, m), 7.54-7.56 (1 H, m), 7.66-7.68 (2H, m), 8.19 (1 H, d, J=8.61 Hz).
UPLC/MS: [M+1] = 428 H (CDCI3, 400 MHz): 1.83-1.97 (2H, m), 2.30-2.49 (2H, m), 4.29- 4.43 (1 H, m), 4.54-4.71 (2H, m), 4.96 (0.1aH, m), 5.12 (0.9bH, m),
8.24 DR856 5.53 (0.2aH, s), 5.75 (1.8bH, s), 7.39-7.49 (6H, m), 7.57-7.69 (5H, m),
8.19 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 466 H (CDCI3, 400 MHz): 1.89-1.98 (2H, m), 2.31-2.41 (2H, m), 3.78 (3H, s), 4.09-4.68 (3H, m), 4.83-4.91 (0.4aH, m), 4.94-5.08 (0.6bH,
8.25 DR864 m), 6.01 (2H, brs), 6.85-6.87 (2H, m), 7.19-7.21 (2H, m), 7.40-7.76
(7H, m), 8.19 (1 H, d, J=7.83 Hz).
UPLC/MS: [M+1] = 428 H (CDCI3, 400 MHz): 1.63-1.76 (2H, m), 2.01-2.28 (2H, m), 3.98- 4.08 (1 H, m), 4.16-4.26 (0.4aH, 0.8bH, m), 4.35-4.40 (0.8bH, m), 4.45 (0.8bH, d, J=14.48 Hz), 4.58 (0.2aH, d, J=14.87 Hz), 5.68 (2H, brs),
8.26 DR865
7.18-7.32 (4H, m), 7.38-7.57 (5H, m), 7.66-7.70 (2H, m), 8.16 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 416 H (CDCI3, 400 MHz): 1.82-1.92 (2H, m), 2.25-2.43 (2H, m), 4.19 (0.4aH, dd, J=7.04, 14.87 Hz), 4.32 (0.6bH, dd, J=6.26, 14.48 Hz), 4.34-4.41 (0.4aH, m), 4.52 (0.6bH, d, J=14.48 Hz), 4.59-4.64 (0.6bH,
8.27 DR867 m), 4.68 (0.4aH, d, J=14.87 Hz), 4.86 (0.4aH, t, J=7.04 Hz), 5.01
(0.6bH, t, J=6.26 Hz), 5.93 (2H, s), 6.85-6.87 (1 H, m), 7.12-7.27 (2H, m), 7.38-7.56 (6H, m), 7.63-7.76 (2H, m), 8.18 (1 H, m).
UPLC/MS: [M+1] = 412 H (CDCI3, 400 MHz): 1.82-1.92 (2H, m), 2.25-2.43 (2H, m), 4.19 (0.4aH, dd, J=7.04, 14.87 Hz), 4.30-4.41 (1 H, m), 4.52 (0.6bH, d, J=14.48 Hz), 4.59-4.70 (1 H, m), 4.85-4.88 (0.4aH, m), 5.00-5.04
8.28 DR866
(0.6bH, m), 5.92 (2H, brs), 7.12-7.27 (2H, m), 7.38-7.57 (7H, m), 7.64-7.69 (2H, m), 8.19 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 432 H (CDCI3, 400 MHz): 1.82-1.97 (2H, m), 2.25-2.40 (2H, m), 3.85 (1.2aH, s), 3.88 (1.8bH, s), 4.23-4.43 (1 H, 0.4aH, m), 4.52 (0.6bH, d,
8.29 DR868 J=14.87 Hz), 4.59-4.67 (1 H, m), 4.85 (0.4aH, t, J=7.04 Hz), 4.98-5.01
(0.6bH, m), 5.76 (2H, brs), 6.77-6.91 (2H, m), 7.20-7.24 (1 H, m), 7.37-7.55 (5H, m), 7.64-7.69 (2H, m), 8.19 (1 H, d, J=8.61 Hz). UPLC/MS: [M+1] = 446 H (CDCI3, 400 MHz): 1.83-1.96 (2H, m), 2.25-2.43 (2H, m), 4.1 1- 4.17 (0.3aH, m), 4.29-4.40 (1 H, m), 4.45 (0.7bH, d, J=14.87 Hz), 4.57-4.62 (0.7bH, m), 4.68 (0.3bH, d, J=14.87 Hz), 4.89 (0.3aH, t,
8.30 DR871 J=7.04 Hz), 5.03-5.06 (0.7bH, m), 5.98 (2H, brs), 6.84-6.98 (3H, m),
7.06-7.24 (2H, m), 7.30-7.55 (7H, m), 7.52-7.55 (1 H, m), 7.62-7.77 (2H, m), 8.18 (1 H, m).
UPLC/MS: [M+1] = 558 H (CDCI3, 400 MHz): 1.80-1.93 (2H, m), 2.25-2.42 (2H, m), 4.17- 4.39 (1 H, m), 4.47-4.67 (2H, m), 4.86 (0.2aH, t, J=7.04 Hz), 5.01 (0.8bH, dd, J=6.26, 8.22 Hz), 5.99 (2H, brs), 7.20 (2H, m), 7.29 (2H,
8.31 DR878
m), 7.37-7.52 (5H, m), 7.64 (1 H, m), 7.74 (1 H, m), 8.18 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 432 H (CDCI3, 400 MHz): 1.80-1.93 (2H, m), 2.25-2.42 (2H, m), 4.17- 4.39 (1 H, m), 4.47-4.67 (2H, m), 4.87 (0.2aH, t, J=7.04 Hz), 4.99-5.04 (0.8bH, m), 5.98 (2H, brs), 7.19-7.21 (2H, m), 7.28-7.30 (2H, m),
8.32 DR879
7.39-7.52 (3H, m), 7.64 (2H, d, J=8.61 Hz), 7.74-7.76 (2H, m), 8.18 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 516 H (CDCI3, 400 MHz): 1.83-1.98 (2H, m), 2.31-2.43 (2H, m), 4.32 (1 H, dd, J=5.87, 14.87 Hz), 4.55 (1 H, d, J=14.87 Hz), 4.60-4.68 (1 H, m), 5.07 (1 H, dd, J=5.87, 8.99 Hz), 5.95 (2H, s), 7.26-7.36 (5H, m),
8.33 DR719
7.40-7.47 (2H, m), 7.52 (1 H, m), 7.68 (2H, d, J=8.61 Hz), 7.74 (1 H, dd, J=1.57, 8.22 Hz), 8.19 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 482 H (CDCI3, 400 MHz): 1.80-1.94 (2H, m), 2.26-2.40 (2H, m), 4.30 (1 H, dd, J=5.64, 14.77 Hz), 4.51 (1 H, d, J=14.77 Hz), 4.57-4.62 (1 H, m), 5.01-5.05 (1 H, m), 5.89 (2H, s), 7.22-7.25 (3H, m), 7.29-7.32
8.34 DR717A (2H, m), 7.34-7.38 (1 H, m), 7.42-7.46 (3H, m), 7.53 (1 H, d, J=1.34
Hz), 7.64 (2H, d, J=7.25 Hz), 8.16 (1 H, d, J=8.06 Hz).
3C (CDCI3, 400 MHz): 29.91 , 35.37, 46.67, 80.35, 81.50, 1 15.94, 122.34, 122.36, 125.37, 127.33, 127.66, 127.68, 128.17, 128.51 , 128.29, 140.1 1 , 142.14, 147.37, 149.15, 153.33, 162.98.
2D-NOESY
UPLC/MS: [M+1] = 398 H (CDCI3, 400 MHz): 1.83-1.94 (2H, m), 2.23-2.38 (2H, m), 4.18 (1 H, dd, J=7.04, 14.87 Hz), 4.34-4.40 (1 H, m), 4.64 (1 H, d, J=14.87 Hz), 4.88 (1 H, t, J=7.04 Hz), 5.76 (2H, s), 7.22-7.32 (7H, m), 7.37
8.35 DR720
(1 H, dd, J=1.57, 8.22 Hz), 7.46 (1 H, d, J=1.57 Hz), 7.63 (2H, d, J=8.61 Hz), 8.16 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 482 H (CDCI3, 400 MHz): 1.83-1.94 (2H, m), 2.20-2.39 (2H, m), 4.18 (1 H, dd, J=7.04, 14.87 Hz), 4.34-4.39 (1 H, m), 4.63 (1 H, m), 4.87 (1 H, t, J=7.04 Hz), 5.66 (2H, s), 7.22-7.26 (3H, m), 7.28-7.32 (2H, m), 7.34-7.37 (1 H, m), 7.41-7.45 (3H, m), 7.51 (1 H, d, J=1.57 Hz), 7.63 (2H, d, J=7.24 Hz), 8.16 (1 H, d, J=8.22 Hz).
8.36 DR718A
3C (CDCI3, 400 MHz): 28.81 , 33.24, 46.56, 79.81 , 82.03, 1 16.04, 122.30, 122.44, 125.95, 127.32, 127.61 , 127.93, 128.12, 128.64, 128.86, 140.12, 141.38, 147.25, 149.22, 153.27, 162.93.
2D-N0ESY
UPLC/MS: [M+1] = 398 H (CDCI3, 400 MHz): 1.28 (3H, t, J=7.83 Hz), 1.82-1.97 (2H, m), 2.26-2.42 (2H, m), 2.71 (2H, q, J=7.83, 15.26 Hz), 4.21 (0.4aH, dd, J=7.43, 14.87 Hz), 4.29-4.42 (1 H, m), 4.53 (0.6bH, d, J=14.87 Hz), 4.60-4.69 (1 H, m), 4.90 (0.4aH, dd, J=6.65, 7.04 Hz), 5.04-5.07
8.37 DR892
(0.6bH, m), 5.78 (0.8aH, brs), 6.02 (1.2bH, brs), 7.27-7.35 (7H, m), 7.46 (1 H, d, J=8.22 Hz), 7.55 (1 H, s), 7.61 (2H, d, J=7.83 Hz), 8.18 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 426 H (CDCI3, 400 MHz): 1.85-1.98 (2H, m), 2.27-2.42 (2H, m), 4.19- 4.24 (0.4aH, m), 4.30-4.43 (1 H, m), 4.54 (0.6bH, d, J=14.87 Hz), 4.61-4.70 (1 H, m), 4.90 (0.4aH, t, J=7.04 Hz), 5.04-5.08 (0.6bH, m),
8.38 DR893 5.78 (0.8aH, brs), 6.02 (1.2bH, brs), 7.27-7.40 (6H, m), 7.47 (2H, t,
J=7.3 Hz), 7.51-7.56 (2H, m), 7.62-7.67 (5H, m), 7.90-7.91 (1 H, m), 8.21 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 474 H (CDCI3, 400 MHz): 1.84-1.98 (2H, m), 2.27-2.42 (2H, m), 4.20 (0.4aH, dd, J=7.43, 14.87 Hz), 4.28-4.33 (0.6bH, m), 4.37-4.43 (0.4aH, m), 4.55 (0.6bH, d, J=14.87 Hz), 4.60-4.70 (1 H, m), 4.91
8.39 DR894 (0.4aH, t, J=7.04 Hz), 5.04-5.08 (0.6bH, m), 5.84 (0.8aH, brs), 6.08
(1.2bH, brs), 7.27-7.35 (5H, m), 7.42-7.44 (1 H, m), 7.53-7.54 (1 H, m), 7.69-7.76 (4H, m), 8.21 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 466 H (CDCI3, 400 MHz): 1.82-1.98 (2H, m), 2.26-2.43 (2H, m), 4.19 (0.4aH, dd, J=7.43, 14.87 Hz), 4.28-4.33 (0.6bH, m), 4.37-4.43 (0.4aH, m), 4.54 (0.6bH, d, J=14.87 Hz), 4.60-4.70 (1 H, m), 4.91
8.40 DR895 (0.4aH, t, J=7.04 Hz), 5.04-5.08 (0.6bH, m), 5.83 (0.8aH, brs), 6.08
(1.2bH, brs), 7.27-7.43 (8H, m), 7.52-7.54 (2H, m), 7.64 (1 H, s), 8.19 (1 H, d, J=8.22 Hz).
UPLC/MS: [M+1] = 432 H (CDCI3, 400 MHz): 1.50-1.60 (1 H, m), 1.86-1.93 (2H, m), 2.04- 2.12 (1 H, m), 3.75-3.80 (1 H, m), 3.90-3.95 (2H, m), 4.10-4.16 (1 H,
8.41 PS-436 m), 4.46 (1 H, d, J=14.87 Hz), 5.72 (2H, s), 7.25 (1 H, d, J=1.96 Hz),
7.35-7.47 (8H, m), 7.58 (1 H, d, J=1.96 Hz), 7.69 (2H, d, J=7.04 Hz).
UPLC/MS: [M+1] = 398 H (CDCI3, 400 MHz): 1.72-1.95 (2H, m), 2.18-2.48 (2H, m), 3.96- 4.09 (1 H, m), 4.31 (0.4aH, dd, J=6.65, 14.87 Hz), 4.48-4.54 (1.2bH, m), 4.60 (0.4aH, d, J=14.87 Hz), 4.89 (0.4aH, dd, J=7.04, 7.43 Hz),
8.42 DR922 5.08 (0.6bH, dd, J=6.26, 8.61 Hz), 5.74 (0.8aH, brs), 5.97 (1.2bH, brs), 7.16-7.17 (1 H, m), 7.24-7.40 (9H, m), 7.55-7.46 (1 H, m), 7.67- 7.71 (2H, m).
UPLC/MS: [M+1] = 642 H (CDCI3, 400 MHz): 1.75-1.93 (2H, m), 2.14-2.22 (1 H, m), 2.29- 2.39 (1 H, m), 3.98 (1 H, dd, J=7.83, 14.87 Hz), 4.29 (1 H, m), 4.61 (1 H, d, J=14.87 Hz), 4.88 (1 H, dd, J=7.04, 7.43 Hz), 5.77 (2H, brs),
8.43 DR914
7.26-7.47 (14H, m), 7.59 (1 H, d, J=1.95 Hz), 7.69 (2H, dd, J=8.22, 1.17 Hz).
UPLC/MS: [M+1] = 474 H (CDCI3, 400 MHz): 1.83-1.96 (2H, m), 2.27-2.42 (2H, m), 2.96
8.44 DR916
(6H, s), 4.1 1-4.28 (1 H, m), 4.36-4.42 (0.3aH, m), 4.50 (0.7bH, d, J=14.48 Hz), 4.59-4.68 (1 H, m), 4.90 (0.3aH, t, J=7.04 Hz), 5.06 (0.7bH, dd, J=6.26, 8.22 Hz), 5.58 (0.6aH, brs), 5.84 (1.4bH, brs), 6.90 (1 H, m), 7.08-7.09 (1 H, m), 7.27-7.48 (8H, m), 7.65-7.68 (2H, m).
UPLC/MS: [M+1] = 441 H (CDCI3, 400 MHz): 1.59 (3H, t, J=7.04 Hz), 1.84-1.95 (2H, m), 2.26-2.43 (2H, m), 4.01-4.17 (1 H, m), 4.26 (2H, q, J=7.04, 13.89 Hz), 4.36-4.42 (0.4aH, m), 4.55-7.63 (1.2aH, m), 4.72 (0.4aH, d, J=14.67 Hz), 4.90 (0.4aH, dd, J=6.85, 7.24 Hz), 5.05-5.09 (0.6bH, m), 5.63
8.45 DR910 (0.8aH, brs), 5.88 (1.2bH, brs), 6.84 (1 H, m), 7.12-7.13 (1 H, m), 7.25- 7.41 (6H, m), 7.43-7.48 (2H, m), 7.64-7.66 (2H, m).
2D, NOESY
UPLC/MS: [M+1] = 442 H (CDCI3, 400 MHz): 1.1 1-1.15 (3H, m), 1.84-2.04 (4H, m), 2.26- 2.42 (2H, m), 4.02-4.18 (3H, m), 4.37-4.42 (0.4aH, m), 4.55-4.63 (1.2bH, m), 4.71 (0.4aH, d, J=14.87 Hz), 4.48-4.91 (0.4bH, m), 5.07
8.46 DR915 (0.6bH, dd, J=6.26, 8.22 Hz), 5.63 (0.8aH, brs), 5.87 (1.2bH, brs),
6.84 (1 H, m), 7.12-7.13 (1 H, m), 7.26-7.48 (8H, m), 7.64-7.67 (2H, m).
UPLC/MS: [M+1] = 456 H (CDCI3, 400 MHz): 1.79-1.94 (2H, m), 2.19-2.41 (2H, m), 4.51 (0.4aH, dd, J=7.43, 14.48 Hz), 4.13-4.18 (0.6bH, m), 4.35 (0.4aH, dd, J=7.04, 14.48 Hz), 4.51-4.59 (1.2bH, m), 4.68 (0.4aH, d, J=14.87 Hz),
8.47 DR925 4.90 (0.4aH, dd, J=6.65, 7.43 Hz), 5.06 (0.6bH, dd, J=6.26, 8.61 Hz),
5.77 (2H, brs), 6.91 (1 H, d, J=1.96 Hz), 7.05-7.1 1 (2H, m), 7.27-7.43 (12H, m), 7.56-7.58 (2H, m).
UPLC/MS: [M+1] = 490 H (CDCI3, 400 MHz): 1.71-1.90 (2H, m), 2.20-2.39 (2H, m), 2.52 (0.9aH, s), 2.53 (2.1 bH, s), 3.91-4.05 (1 H, m), 4.22-4.30 (0.3aH, m), 4.43-4.51 (1.4bH, m), 4.57 (0.3aH, d, J=14.87 Hz), 4.87 (0.3aH, t,
8.48 DR930
J=7.43 Hz), 5.05 (0.7bH, dd, J=5.86, 9.00 Hz), 5.59 (0.6aH, brs), 5.82 (1.4bH, brs), 6.83-6.84 (1 H, m), 7.07-7.08 (1 H, m), 7.26-7.41 (10H, m). In vitro Assay
Fluorescence resonance energy transfer (FRET) assay was performed to evaluate ability of compounds to inhibit plasmepsin I, II, IV and Cathepsin D. Solution of compounds for testing (concentration 0.01 -100uM) on 96 well plate were added to the enzyme (Plasmepsin I, II, IV or Cathepsin D) in buffer (0.1 M NaOAc, pH = 4.5, 10% glycerin). The mixture was incubated for 30 min at 37°C. Substrate (DABCYL-Glu-Arg-Nle-Phe-Leu-Ser-Phe-Pro-EDANS, AnaSpec Inc) was added to reach final concentration 5 uM. Hydrolysis of substrate was detected as an increase in fluorescence (Em 490 nm, Ex 336 nm) at 37°C. Compounds were tested in three repeated triplicate experiments.
IC50 values for selected inhibitors on plasmepsins I, II, IV and cathepsin D:
Figure imgf000047_0001
DR776 8.20 n.d. n.d. i.a. n.d.
DR853 8.21 n.d. n.d. 50 n.d.
DR854 8.22 n.d. n.d. 8,8 n.d.
DR855 8.23 n.d. n.d. 17 n.d.
DR856 8.24 14,7 3,0 2,4 1,3
DR864 8.25 n.d. n.d. 11 n.d.
DR865 8.26 16,1 4,1 3,5 1,5
DR867 8.27 n.d. n.d. 7 n.d.
DR866 8.28 n.d. n.d. 7,5 n.d.
DR868 8.29 15,4 3,4 2 0,85
DR871 8.30 44,7 4,3 2,6 4,8
DR878 8.31 7,0 3,1 1,9 1,4
DR879 8.32 n.d. n.d. 12,7 n.d.
DR719 8.33 17,2 1,6 6,6 1,5
DR717A 8.34 9,0 2,4 2,9 1,1
DR720 8.35 9,5 0,6 0,64 0,7
DR718A 8.36 13,8 1,3 0,21 0.6
DR892 8.37 n.d. n.d. 2 n.d.
DR893 8.38 n.d. n.d. 5,3 n.d.
DR894 8.39 n.d. n.d. 3,1 n.d.
DR895 8.40 16,0 3,5 2,3 1
PS-436 8.41 i.a. 1,6 0,96 2,4
DR922 8.42 i.a. i.a. i.a. i.a.
DR914 8.43 13,3 1,5 0,72 0,95
DR916 8.43 20,1 3,8 2,2 2,5
DR910 8.45 n.d. n.d. 1,4 n.d.
DR915 8.46 9 3,2 1,8 2,2
DR925 8.47 21,0 3,2 2,2 2,7
DR930 8.48 3,2 2,4 0,87 1,4
nactive at the concentration below 200 not deternnined

Claims

Claims
1 . 2-Aminoquinazolin-4(3H)-one of the formula I
Figure imgf000049_0001
wherein: R1 , R2, R3, R4, R4, R5, R6 R7 R8, R9, R10, R11, R12, R13 R 14 are independently
-H, -F, -CI, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH,
-OR15, -O-L-NH2, -O-L-NHR15, -O-L-NR152, -O-L-NR15R16,
-L-OR15,-O-L-OR15,-OCF3, -OCH2CF3, -OCF2CF2H,
-L-OR15,-O-L-OR15,-OCF3, -OCH2CF3, -OCF2CF2H, SR15, SCF3,
CN, -NO2, -NO2, -NH2, -NHR15, -NR15 2, -NR15R16,
-L-NH2, -L-NHR15, -L-NR15 2, -L-NR15R16,
-NH-L-NH2, -NH-L-NHR15, -NH-L-NR15 2, -NH-L-NR15R16,
-NR15-L-NH2, -NR15-L-NHR15, -NR15-L-NR15 2, -NR15-L-NR15R16, L-NR15R16,
-C(=O)OH, -C(=O)OR15, -C(=O)NH2, -C(=O)NHR15, -C(=O)NR15 2, -C(=O)NR15R16,
-NHC(=O)R15, -NR15C(=O)R16, -NHC(=O)OR15, -NR15C(=O)OR16, -OC(=O)NH2, -OC(=O)NHR15, -OC(=O)NR152, -OC(=O)NR15R16,-OC(=O)R15, -C(=O)R15,-NHC(=O)NH2, -NHC(=O)NHR15, -NHC(=O)NR15 2, -NHC(=O)NR15R16, -NR15C(=O)NH2, -NR15C(=O)NHR16, -NR15C(=O)NR16 2, -NR15C(=O)N
-NHS(=O)2R15, -NR15S(=O)2R16, -S(=O)2NH2, -S(=O)2NHR15, -S(=O)2NR15 2, -S(=O)2NR15R16,-S(=O)R15, -S(=O)2R15,-OS(=O)2R15,-S(=O)2OR15,
Ci-6alkyl, cycloC3-i2alkyl, cycloC3-i2alkyl-Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylCi-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1 ,3-dihydro-2H-isoindol- 2-yl;
or R1, R2, R3, R4, R4, R5, R6 are independently =O,=NR15,=NOH, or =NOR15;
L represents -W-X-Y-Z-;
R1 and R2 or R1 and R3 or R3 and R4 or R3 and R6 or R5 and R6 or R7 and R8 or R8 and R14 or R9 and R10 or R10 and R11 or R11 and R12 or R12 and R13 or R13 and R14 taken together represent -W-X-Y-Z-, wherein W represents a single bond, oxygen, sulfur, -NR15 or -CR 5R16, X represents oxygen, sulfur, -NR15 or -CR15R16, Y represents oxygen, sulfur, -NR15 or -CR15R16, Z represents oxygen, sulfur, -NR15 or -CR15R16; R15 and R16 are independently H, Ci-6alkyl, cycloC3-i2alkyl, cycloCs-^alkyl- Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylCi-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroaryl Chalky I, heteroarylC2-6alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, Ci-6alkoxyCi-6alkyl, aryloxyarylCi-6alkoxy, Ci-6alkylthio, C4-6alkenylthio, cycloCs-^alkylthio, cycloC3-i2alkyl-Ci-6alkylthio, cycloC3-i2alkyl-C3-6alkenylthio, Ci-6alkoxyCi-6alkylthio, Ci-6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylCi-6alkylthio, Ci-6alkylsulfonyl, cycloCs-^alkyl- Ci-6alkylsulfonyl, arylCi-6alkylsulfonyl, Ci-6alkylamino, di-Ci-6alkylamino, cycloC3-i2alkylamino, Ci-C6alkoxy-cycloC3-Ci2alkylamino, cycloCs-^alkyl- Ci-6alkylamino, di-Ci-6alkylaminoCi-6alkyl, Ci-6alkoxy-C2-6alkylannino, arylamino, arylCi-6alkylamino, N-cycloC3-i2alkyl-N-Ci-6alkylannino, N-aryl-N-Ci-6alkylamino, N-arylCi-6alkyl-N-Ci-6alkylannino, 2-indanylamino, tetrahydrofuryl, pyrrolidine piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-Ci-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1 ,3-dihydro-2H-isoindol-2-yl, heteroarylCi-6alkoxy, heteroarylamino, or heteroarylCi-6alkylamino.
2. Use of 2-aminoquinazolin-4(3H)-one of claim 1 , or a pharmaceutically acceptable salt, solvate, morphological form and prodrug thereof, in the manufacture of a medicament for the treatment of a disease that is mediated by plasmepsins or human aspartic proteases.
3. The use according to the claim 2, wherein said disease is malaria.
4. The use according to any of the claims 2-3, wherein said medicament comprises (i) 2-aminoquinazolin-4(3H)-one or a pharmaceutically acceptable salt, solvate, morphological form and prodrug thereof, and (ii) a pharmacautically acceptable carrier.
5. The use according to any of the claims 2-5, wherein said medicament is administered to human.
PCT/IB2013/059782 2013-10-30 2013-10-30 Novel substituted 2-aminoquinazolin-4(3h)-one derivatives as malarial aspartic protease inhibitors WO2015063544A1 (en)

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