GB2626567A - Quinazoline derivatives for use as a medicament - Google Patents

Quinazoline derivatives for use as a medicament Download PDF

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Publication number
GB2626567A
GB2626567A GB2301138.0A GB202301138A GB2626567A GB 2626567 A GB2626567 A GB 2626567A GB 202301138 A GB202301138 A GB 202301138A GB 2626567 A GB2626567 A GB 2626567A
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formula
trifluoro
compound according
indicates
attachment
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GB202301138D0 (en
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Bhambra Avninder
Weaver George
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De Montfort University
Loughborough University
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De Montfort University
Loughborough University
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Priority to GB2301138.0A priority Critical patent/GB2626567A/en
Publication of GB202301138D0 publication Critical patent/GB202301138D0/en
Priority to PCT/GB2024/050205 priority patent/WO2024157021A1/en
Publication of GB2626567A publication Critical patent/GB2626567A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A compound comprising a 5,6,8-trifluoroquinazoline moiety wherein the compound is for use as a medicament. The compound may be of Formula I; Wherein R1 is selected from NR4R5, NR6R7, OR4 or SR4; R2 is H, NH2 or NHCH3; R3 is H, CH3, NH2, SCH3 or phenyl; R4 is acyclic alkyl, aryl, cycloalkyl, heterocyclyl or methylene substituted with cycloalkyl, heterocyclyl, acetal or aryl; R5 is H or CH3; and R6 and R7 together with the N form a heterocycle. R4 may be isopropyl. The compounds may be used in the treatment of a parasitic infection, such as Chagas disease, Human African Trypanosomiasis, leishmaniases, malaria or cryptosporidiosis; or a bacterial infection such as tuberculosis. Pharmaceutical compositions comprising the disclosed compounds are also disclosed, including pharmaceutically acceptable salts, solvates and prodrugs thereof in association with a diluent or carrier.

Description

TITLE
QUINAZOLINE DERIVATIVES FOR USE AS A MEDICAMENT
TECHNOLOGICAL FIELD
Embodiments of the present disclosure relate to quinazoline derivatives for use as a medicament, and in particular to quinazoline derivatives comprising a 5,6,8-trifluoroquinazoline moiety.
BACKGROUND
Current treatments for infectious diseases caused by parasites and bacteria including: Human African Trypanosomiasis (HAT, also known as sleeping sickness); Chagas disease (CD); leishmaniases; cryptosporidiosis; malaria; and tuberculosis along with other neglected tropical diseases (NTDs) can be ineffective and have safety concerns.
There is, therefore, a need to provide new effective and safe treatments for such diseases.
BRIEF SUMMARY
According to various, but not necessarily all, embodiments there is provided a compound comprising a 5,6,8-trifluoroquinazoline moiety, wherein the compound is for use as a medicament.
Possibly, the compound has the general structure of formula I R2 (Formula I) wherein R1 is selected from: NR4R5, NR6R7, OR4, or SR4; R2 is selected from: H, CH3, NH2, or NHCH3; R3 is selected from: H, CH3, NH2, SCH3, or phenyl; R4 is selected from: acyclic alkyl, aryl, carbonyl, cycloalkyl, heterocyclyl, Ci alkyl substituted with cycloalkyl, Ci alkyl substituted with heterocyclyl, Ci alkyl substituted with acetal, or Ci alkyl substituted with aryl; R5 is selected from: H or CH3; and R5 and R7 together with N form a heterocycle.
R5 may be H. R5 may be CH3.
R2 may be H. R2 may be CH3. R2 may be NH2. R2 may be NHCH3.
R3 may be H. R3 may be CH3. R3 may be NH2. R3 may be SCH3. R3 may be phenyl.
Possibly, R2 is NH2 and R3 is H. Possibly, R2 is NH2 and R3 is CH3. Possibly, R2 is NH2 and R3 is NH2. Possibly, R2 is NH2 and R3 is SCH3. Possibly, R2 is NH2 and R3 is phenyl. Possibly, R2 is NHCH3 and R3 is CH3. Possibly, R2 is H and R3 is H. Possibly, R2 is H and R3 is CH3. Possibly, R2 is H and R3 is NH2. Possibly, R2 is CH3 and R3 is H. Possibly, R2 is CH3 and R3 is CH3.
The acyclic alkyl of R4 may be isopropyl.
The aryl of R4 may be selected from: CH3 CH3 NO2 wherein R indicates the attachment of R4 to the N, 0 or S of IRl* The carbonyl of R4 may be:
CI
wherein R indicates the attachment of R4 to the N, 0 or S of R1.
The cycloalkyl of R4 may be a 3-, 4-, 5-, 6-or 7-membered cycloalkyl. The 3-, 4-, 5-, 6-or 7-membered cycloalkyl may be selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4,4-difluorocyclohexyl, 2-fluorocyclopentyl, 2-methoxycyclopentyl, and 3-methoxycyclopentyl.
The heterocyclyl of R4 may be a 4-, 5-, 6-or 7-membered heterocycle with 1 or 2 heteroatoms independently selected from N, 0 or S. The 4-, 5-, 6-or 7-membered heterocycle with 1 or 2 heteroatoms independently selected from N, 0 or S may be selected from: CH3 CH3 I C H3 wherein R indicates the attachment of R4 to the N, 0 or S of R1.
The Ci alkyl substituted with cycloalkyl of R4 may be: wherein R indicates the attachment of R4 to the N, 0 or S of R1 The Ci alkyl substituted with heterocycle of R4 may be selected from: o "3C wherein R indicates the attachment of R4 to the N, 0 or S of R1.
The Ci alkyl substituted with acetal of IR4 may be: OCH3 wherein R indicates the attachment of R4 to the N, 0 or S of R1.
The Ci alkyl substituted with aryl of R4 may be: wherein R indicates the attachment of R4 to the N, 0 or S of R1.
R4 may be acyclic alkyl. R4 may be aryl. R4 may be carbonyl. R4 may be cycloalkyl.
R4 may be heterocyclyl. R4 may be C1 alkyl substituted with cycloalkyl. R4 may be C1 alkyl substituted with heterocyclyl. R4 may be Ci alkyl substituted with acetal. R4 may be Ci alkyl substituted with aryl.
R6 and R7 together with N may form a 4-, 5-, 6-or 7-membered heterocycle.
Possibly, R6 and R7 together with N has the general structure of formula II
N-R
(Formula II) wherein R indicates the attachment of N to the structure of formula (0; and wherein R8 is selected from: H, acyclic alkyl, halide, trifluoromethyl, heterocyclyl, carbonyl, amine or ester.
The acyclic alkyl of R8 may be methyl. The halide of R8 may be F or Br.
The amine of R8 may be:
H CH3
wherein R indicates the attachment of R8 to the structure of formula II.
The heterocycle of R8 may be selected from: R8 ( wherein R indicates the attachment of R8 to the structure of formula II.
The carbonyl of R8 may be: wherein R indicates the attachment of R8 to the structure of formula II.
Possibly, R6 and R7 together with N has the general structure of formula Ill R14 N-R Ris (Formula Ill) wherein R indicates the attachment of N to the structure of formula (0; and wherein R14 is H or F and R15 is H or F. R6 and R7 together with N may be: CH3 wherein R indicates the attachment of N to the structure of formula (I).
Possibly, IR6 and IR7 together with N has the general structure of formula IV R9 N-R (Formula IV) wherein R indicates the attachment of N to the structure of formula (0; and wherein R9 is alkoxy or heterocyclyl.
The alkoxy of R9 may be methoxy.
Possibly, the heterocyclyl of R9 is: wherein R indicates the attachment of R9 to the structure of formula IV.
Possibly, R6 and R7 together with N form a 4-, 5-, 6-or 7-membered heterocycle, wherein the 4-, 5-, 6-or 7-membered heterocycle comprises another heteroatom independently selected from N, 0 or S. Possibly, R9 and R7 together with N has the general structure of formula V 0 /
_N N-R
(Formula V) wherein R indicates the attachment of N to the structure of formula (0; and wherein R1° is acyclic alkyl, amine, carbonyl, ether, cycloalkyl, heterocyclyl, aromatic heterocyclyl, Ci alkyl substituted with carbonyl, or Ci alkyl substituted with aryl.
The acyclic alkyl of R10 may be selected from: methyl, ethyl, or isopropyl.
The amine of R19 may be selected from: CH3 sp/ wherein R indicates the attachment of R19 to the structure of formula V. Possibly, the carbonyl of R1° is selected from: CH3 0 0 wherein R indicates the attachment of R1° to the structure of formula V. The ether of IR1° may be 2-methoxyethyl. The cycloalkyl of IR' may be cyclopentyl.
Possibly, the aromatic heterocycle of R1° is: wherein R indicates the attachment of R10 to the structure of formula V. Possibly, the Ci alkyl substituted with carbonyl of R1° is selected from: CH3 wherein R indicates the attachment of R1° to the structure formula V. Possibly, the Ci alkyl substituted with aryl of Rl° is: wherein R indicates the attachment of R1° to the structure of formula V. Possibly, R6 and R7 together with N has the general structure of formula VI (Formula VI) wherein R indicates the attachment of N to the structure of formula (0; and wherein R12 and R13 are H or CH3.
Possibly, R6 and R7 together with N is selected from: N"NN"----R wherein R indicates the attachment of N to the structure of formula (I).
Possibly, R6 and R7 together with N is selected from:
N-R
wherein R indicates the attachment of N to the structure of formula (I) Possibly, R6 and R7 together with N is:
NR
wherein R indicates the attachment of N to the structure of formula (I).
1;(1 may be NR4R6. 1;(1 may be NR6R7. R1 may be OR4. 1;(1 may be SR4.
Possibly, the compound is selected from: N7-cyclohepty1-5,6,8-trifluoroquinazoline-4,7-diamine; 7-(cyclohexylthio)-5,6,8-trifluoroquinazolin-4-amine; 5,6,8-trifluoro-7-(4-methylpiperidin-1-yl)quinazolin-4-amine; 5,6,8-trifluoro-2-methy1-7-(4-(trifluoromethyl)piperidin-1-yl) quinazolin-4-amine; N7-cyclohexy1-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine; N7-(4,4-difluorocyclohexyl)-5,6,8-trifluoro-2-methylquinazoline-4, 7-diamine; 5,6,8-trifluoro-7-(4-fluoropiperidin-1-yI)-2-methylquinazolin-4-amine; 5,6,8-trifluoro-2-methy1-7-(4-(trifluoromethyDpiperidin-1-y1) quinazolin-4-amine; 5,6,8-trifluoro-7-(4-fluoropiperidin-1-yI)-2-methylquinazolin-4-amine; N7-(cyclohexylmethyl)-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine; 5,6,8-trifluoro-N7-morpholinoquinazoline 4,7 diamine; N7-cyclohepty1-5,6,8-trifluoro-2-methylquinazoline 4,7 diamine; 7-(cyclohexylthio)-5,6,8-trifluoro-2-methylquinazolin-4-amine; N7-cyclopenty1-5,6,8-trifluoroquinazoline-4,7-diamine; and N7-cyclopenty1-5,6,8-trifluoro-2-methylquinazoline 4,7 diamine; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be N7-cyclohepty1-5,6,8-trifluoroquinazoline-4,7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be 7-(cyclohexylthio)-5,6,8-trifluoroquinazolin 4 amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be NH2 5,6,8-trifluoro-7-(4-methylpiperidin-1-yl)quinazolin-4-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof The compound may be 5,6,8-trifluoro-2-methyl-7-(4-(trifluoromethyl)piperidin-1-yl) quinazolin-4-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be NH2 CH3 F3C N7-cyclohexy1-5,6,8-trifluoro-2-methylguinazoline-4,7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be
F F
N7-(4,4-difluorocyclohexyl)-5,6,8-trifluoro-2-methylquinazoline-4, 7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be 5,6,8-trifluoro-7-(4-fluoropiperidin-1-yI)-2-methylguinazolin-4-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be NH2 CH3 F3C 5,6,8-trifluoro-2-methyl-7-(4-(trifluoromethyl)piperidin-1-yl) guinazolin-4-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be 5,6,8-trifluoro-7-(4-fluoropiperidin-1-yI)-2-methylguinazolin-4-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be N17-(cyclohexylmethyl)-5,6,8-trifluoro-2-methylguinazoline-4,7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be 5,6,8-trifluoro-N7-morpholinoguinazoline-4,7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof The compound may be N7-cyclohepty1-5,6,8-trifluoro-2-methylguinazoline-4,7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be 7-(cyclohexylthio)-5,6,8-trifluoro-2-methylguinazolin-4-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be N7-cyclopenty1-5,6,8-trifluoroguinazoline-4,7-diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
The compound may be N7-cyclopenty1-5,6,8-trifluoro-2-methylguinazoline 4,7 diamine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Possibly, the compound is for use in the treatment of a microbial infection. The microbial infection may be a parasitic infection Possibly, the compound is for use in the treatment of a parasitic infection.
Possibly, the compound is for use as an inhibitor of parasitic lysyl-tRNA synthetase.
Possibly, the compound is for use in the treatment of a parasitic disease. Possibly, the parasitic disease is selected from Human African Trypanosomiasis (HAT), Chagas disease (CD), or leishmaniases. Possibly the parasitic disease is a Neglected Tropical Disease (NTD).
Possibly, the compound is for use in the treatment of a condition, disease or disorder caused by a parasite. The parasite may be from the Plasmodium genus, the Trypanosoma genus or the Leishmania genus.
According to various, but not necessarily all, embodiments there is provided a pharmaceutical composition which comprises a compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
According to various, but not necessarily all, embodiments there is provided examples as claimed in the appended claims.
BRIEF DESCRIPTION
For a better understanding of various examples that are useful for understanding the detailed description, reference will now be made by way of example only.
DETAILED DESCRIPTION
The disclosure provides compounds comprising a 5,6,8-trifluoroquinazoline moiety and pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The disclosure also provides a pharmaceutical composition which comprises the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
The compounds are for use as a medicament. The compounds are for use in the treatment of microbial infection, such as a parasitic or bacterial infection.
Target parasites (i.e., organisms) include (but are not limited to) Trypanosoma brucei rhodesiense (T.b.r, sleeping sickness), Trypanosoma cruzi (T.c, Chagas disease), Leishmania donovani (L.d, leishmaniasis), Plasmodium falciparum (Pt, malaria), Cfyptosporidium parvum and Mycobacterium tuberculosis.
The therapeutic mode of action has been experimentally validated and compounds exhibit their antimicrobial action through the inhibition of lysyl-tRNA synthetase (KRS), for instance, in each organism listed above.
Compounds according to the disclosure may be orally bioavailable.
In some examples, the compounds have the general structure of formula I. R2 (Formula I) In the structure of formula I, R1 is selected from: NIR4R5, NIR6R7, OR'', or SR'.
In the structure of formula I, R2 is selected from: H, CH3, NH2, or NHCH3.
In the structure of formula I, R3 is selected from. H, CH3, NH2, SCH3, or phenyl.
In the structure of formula I, R4 is selected from: acyclic alkyl, aryl, carbonyl, cycloalkyl, heterocyclyl, Ci alkyl substituted with cycloalkyl, Ci alkyl substituted with heterocyclyl, Cl alkyl substituted with acetal, or Ci alkyl substituted with aryl.
In the structure of formula I, R5 is selected from: H or CH3.
In the structure of formula I, R6 and R2 together with N form a heterocycle.
Examples of compounds according to the disclosure are provided in Table 1.
Table 1
ID Structure 1 F NH2 F 0 HN N-7.. H
F
N7-cyclopropy1-5,6,8-trifluoroquinazoline-4,7-diamine 2 F NH2 F..,...-7\".
HN N NH2
F
N7-cyclohepty1-5,6,8-trifluoroquinazoline-2,4,7-triamine 3 HN F F NH2 H 0 %....."N "^-...., N
F
N7-cyclohepty1-5,6,8-trifluoroquinazoline-4,7-diamine 4 F F ea.....,_,N NH2 c......"..."......." S N NH2
F
7-(cyclohexylthio)-5,6,8-trifluoroquinazoline-2,4-diamine F NH2 F is."..."-\"
S NH
F
7-(cyclohexylthio)-5,6,8-trifluoroquinazolin-4-amine 6 F F NH2 1.1."-^....,,.. NH2
F
5,6,8-trifluoro-7-(4-methylpiperidin-1-yl)quinazoline-2,4-diamine 7 F NH2
F
NH
F
5,6,8-trifluoro-7-(4-methylpiperidin-1-yl)quinazolin-4-amine 8 F NH2 F 0 %......%-N HN NCH3 /N".."" F 5,6,8-trifluoro-2-methyl-N7-morpholinoquinazoline-4,7-diamine 9 F3C N F 5,6,8-trifluoro-2-methy1-7-(4-(trifluoromethyl)pipendin-1-yl) quinazolin-4-amine NH2 H3 F N-Cj-C
F
HN F F W-cyclohexy1-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine NH2 CH3 F el..----- N 11 HN F ip...--%---F NH2 CH3 "..- N F N 1 CH3 /----.....s, N 5,6,8-trifluoro-2-methyl-N7-(1-methylpiperidin-4-yl)quinazoline-4, 7-diamine 12 F NH2 HN F 40 N CH3 /.-.-----*-*\,-"--'-' F 0.,........",..,..."..- 5,6,8-trifluoro-2-methyl-N7-((tetrahydro-2H-pyran-4-yOmethyl) quinazoline-4,7-diamine 13 F NH2 F el....%.."- N 1......--4^% HN N CH3
F
5,6,8-trifluoro-2-methyl-N7-(tetrahydro-2H-pyran-4-yl)quinazoline- 4,7-diamine 14 F ail NH2 NH2 F.."., N KIIIiii F 5,6,8-trifluoro-7-(pyrrolidin-1-yl)quinazoline-2,4-diamine F NH2 F el.------ N 7--------....,"
N N H
F
5,6 8-trifluoro-7-(pyrrolidin-1-yl)quinazolin-4-amine 16 F NH2 F ill-..----- N 7---...," HN N CH3 H3C0....s"...........",.- F OCH3 W-(2,2-dimethoxyethyl)-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine 17 F NH2 HN F 40 N CH3
F
F F
W-(4,4-difluorocyclohexyl)-5,6,8-trifluoro-2-methylquinazoline-4, 7-diamine 18 F NH2 F 0...-%%"* N
N NC H3
F F
6 8-trifluoro-7-(4-fluoropiperidin-1-y1 -2-methylquinazolin-4-amine 19 F NH2 F el.---.%- N N N CH3 H3C-
F
5,6,8-trifluoro-2-methyl-7-(4-methyl-1, 4-diazepan-1-yDquinazolin-4-amine F NH2 HN N --., .... CH3
--..,....,,...,,,,.N-...." CH3 5,6,8-trifluoro-2-methyl-N7-(1-methylpiperidin-3-yDquinazoline-4,7-diamine 21 F F NH2 HN N CH3
F
3C,4 "..,..N.,,,"..",....".
5,6,8-trifluoro-2-methyl-N7-((1-methylpiperidin-4-yl)methyl) quinazoline-4,7-diamine F NH2 F ----*%-1\1 I. ../".-N CH3
F
N (:'
5,6,8-trifluoro-2-methy1-7-(4-morpholinopiperidin-1-yl) quinazolin-4-amine 23 F F NH2 --%%"-N ON ---------...---...'N N.N....."...,...,^ N"..-------%%-tH3
F
5,6,8-trifluoro-2-methyl-7-(4-morpholinopiperidin-1-yl) quinazolin-4-amine 24 F NH2
F
CH3 N N CH3
N N F H3C
4-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-y1)-N, N-dimethylpiperazine-1-carboxamide 0-..,,N,___......"....",..- N (4-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-yl)piperazin-1-yl) (morpholino)methanone F N NH2 CH3 0 F 0 ----s-11 F,.../.5"...,..
26 F NH2
F
"-----,.." N N CH3 Oy- F CH3 7-((2S,6R)-2,6-dimethylmorpholino)-5,6, 8-trifluoro-2-methylquinazolin-4-amine 27 F NH2 F 0 %.--%-* N N "."-^^,,,.. N CH3 H3C,....", N......"...--.......................y. F
I CH3
7-(4-(dimethylamino)piperidin-1-yI)-5,6, 8-trifluoro-2-methylquinazolin-4-amine 28 F NH2
F
N 10 N --........" CH3 F3C F 5,6,8-trifluoro-2-methy1-7-(4-(trifluoromethyDpiperidin-1-yl)quinazolin 4 amine 29 F NH2 F...-.- N HN N CH3
I
F
N
I CH3
5,6,8-trifluoro-2-methyl-N7-(4-methylpiperazin-1-yl)quinazoline-4, 7-diamine F NH2 F 0...-%%"*N HN N CH3
F
5,6,8-trifluoro-2-methyl-N7-(piperidin-1-yl)quinazoline 4,7 diamine 31 F NH2 F es1.--x----........
HN N CH3 -.."..".. F
N CH3
5,6,8-trifluoro-2-methyl-N7-(1-methylpiperidin-4-yl)quinazoline-4, 7-diamine 32 F NI-12 F 0.-....%*-
N
N N ->\" CH3
F
F
5,6,8-trifluoro-7-(4-fluoropiperidin-1-y1)-2-methylquinazolin-4-amine 33 F NH2
F
N kl.."---.%...."CH 0 F H3C/ methyl 1-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-yl)piperidine0 4-carboxylate 34 F NH2 Illi
N H
5,6,8-trifluoro-7-(1,4-dioxa-8-azaspiro[4.5] clecan-8-yOquinazolin-4-amine F N1-12
F
N N----.1.4%.CH3 H3C..N,,,.........,"."-- F CH3 5,6,8-trifluoro-7-(4-isopropylpiperazin-1-y1)-2-methylquinazolin-4-amine 36 F NH2
F
7.------.,", N CH3
F
H3C,,s, ......."--...., 0
N CH3
2-(4-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-yl)piperazin-1-y1) -N,N-dimethylacetamide 37 F NH2
F
N le Ne.---7---- CH3
F
-^.......... N..........--"--.s,....." 0.,,,,______.".^ 2-(4-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-yl)piperazin-1-yI)- 1-morpholinoethan-1-one 38 F NH2
F
I-IN N CH3
F
N7-(cyclohexylmethyl)-5,6,8-trifluoro-2-methylquinazoline diamine 39 F F NH2 N/ / "..-.....5^-N -...", CH3
N
I
NN F
W-(cyclohexylmethyl)-5,6,8-thfluoro-2-methylquinazoline-4,7-diamine F NH2
F
-.....-"- N 3/4
HN N H
F
5,6,8-thfluoro-N7-morpholinoquinazoline-4,7-diamine 41 F NH2 F 0 -.--."-N
HN N H
F
5,6,8-thfluoro-N7-morpholinoquinazoline-4,7-diamine 42 F- F 5,6,8-trifluoro-7-(4-fluoropiperidin-14)quinazoline-2,4-diamine F NH2 NH2 N F NZ".
43 F NH2 F el "....1"........
HN N CH3 ell F 43
F
0'...., CH3 5,6,8-trifluoro-N7-(3-fluoro-4-methoxyphenyI)-2-methylquinazoline- 4,7-diamine 44 F NH2 F 0 ".... -*.,,t--^,........
HN N CH3 0 F 0-...." CH3 5,6,8-trifluoro-N7-(4-methoxyphenyI)-2-methylquinazoline diamine F NH2
F
------. N CH3
N1....",, N.,,............- F
N
5,6,8-trifluoro-2-methy1-7-(4- (pyrazin-2-yhpiperazin-1-yOquinazolin-4-amine 46 F NH2
F
N 141-#------%-.NH2
F F3C
5,6,8-trifluoro-7-(4-(trifluoromethyl)piperidin-1-yl)quinazoline-2, 4-diamine F NH2 F 1.1 CH3 N / H
N
u r"----N..3., N.,_.......,,.."-- F 4-(4-amino-5,6,8-trifluoroquinazolin-7-A-N, N-dimethylpiperazine-1-carboxamide 48 F NH2 F ---%--- N N N,- ,,--......" CH3
F CH3
7-(4-ethylpiperazin-1-y1)-5,6,8-trifluoro-2-methylquinazolin-4-amine 49 N 7-(4-cyclopentylpiperazin-1-yI)-5,6,8-trifluoro-2-methylquinazolin-4- F 1.1 N NH2 \....
F amine F CH3 -....","..52<.N 5,6,8-trifluoro-2-methyl F amine F -7-(4-(pyridin-2-yl)piperazin-1-yl)quinazolin-4- NH2 CH3
N F N
51 F 5,6,8-trifluoro-2-methy1-7-(pyrrolidin-1-yl)quinazolin N NH2 CH3 KIIIiii F..,".1"..," 4 amine el
F
52 F NH2 F * ----%
N "-\..
HN N CH3
F
N7-cyclohepty1-5,6,8-trifluoro-2-methylquinazoline 4,7 diamine 53 F NH2
F
101,---.."7"--N N CH3
F H3C
N7-cyclohepty1-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine 54 F el.......N F NH2
N
F 1101 6 8-thfluoro-2-pheny1-7-(pyrrolidin-1-yOquinazolin-4-amine F NH2 F 0
HN
F IP
N17-cyclohepty1-5,6,8-trifluoro-2-phenylquinazoline 4,7 diamine 56 F NH2 F -----*-N N"- CH3 S.,...".,.."......"-- F 6 8-trifluoro-2-methy1-7-thiomorpholinoquinazolin-4-amine 57 F NH2
F
N
F * 6 8-trifluoro-2-methy1-7-thiomorpholinoquinazolin-4-amine 58 F NH2 F 0.----%-N r N NC.1:-----H
N F *
7-(1H-benzo[d]imidazol-1-y1)-5,6,8-trifluoroquinazolin-4-amine 59 F NH2
F
F 0 H3C 5,6,8-trifluoro-7-(4-methylpiperidin-1-yI)-2-phenylquinazolin-4-amine F NH2
F
N. N,---/P---.. __... CH3
F
5,6,8-trifluoro-2-methy1-7-(piperidin-1-yl)quinazolin-4-amine 61 F NH2 F 0 S N CH3
F
7-(cyclohexylthio)-5,6,8-trifluoro-2-methylquinazolin-4-amine 62 F NH2 F ip
HN N H
F
N7-cyclopenty1-5,6,8-trifluoroquinazoline-4,7-diamine 63 F NH2 F 410
S
F 110 7-(cyclohexylthio)-5,6,8-trifluoro-2-phenylquinazolin-4-amine 64 F F CH3 1\r-...#7.4...---'CH3
F
4-(5,6,8-trifluoro-2,4-dimethylquinazolin-7-yl)morpholine F NH2 F so-.%-"-- N HN 01
F
N17-cyclopentyl-5,6,8-trifluoro-2-phenylquinazoline-4,7-diamine 66 F NH2
F
eill...."-..,..s., H3
___C
N N S
0."...%,.........- F 5,6,8-trifluoro-2-(methylthio)-7-morpholinoquinazolin-4-amine 67 F HN
F
N 11101 %%2: N CH3
F
W-cyclopenty1-5,6,8-trifluoro-N4, N7,2-trimethylquinazoline-4,7-diamine 68 F NH2
F
N 0 "e"----_,% CH3
N
0..",..."..."e",., F 5,6,8-trifluoro-2-methyl-7-morpholinoquinazolin-4-amine 69 F NH2 F..---N N CH3 e.e.." N,....",.,....e.,,- F 5,6,8-trifluoro-2-methy1-7-(4-methylpiperazin-1-yhquinazolin-4-amine F NH2
F rNCH3
N F
7-(1H-benzo[d]imidazol-1-y1)-5,6,8-trifluoro-2-methylquinazolin-4-amine 71 F NH2 F 40 %....--%N :...--#"..",.
HN N CH3
F
W-cyclopropy1-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine 72 F NH2 02 N F 0 N "." NZ' 0 NH2
F
5,6,8-trifluoro-7-(4-nitrophenoxy)quinazoline-2,4-diamine 73 F F N NH2, HN 0 CH3
F
N7-cyclopenty1-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine 74 F NH2 F 40 -%-%--
N
%^....".. N CH3
F...,4.7*---"," W-benzy1-5,6,8-trifluoro-N7,2-dimethylquinazoline-4,7-diamine F NH2 F IP...--.--N r N N.----7-....%.---t H3
N
F
5,6,8-trifluoro-7-(1H-imidazol-1-y1)-2-methylquinazolin-4-amine 76 02N 0 F F N NH2.......,..0 H3 0 0 -.----"-- S c.:-.."......
N
F
5,6,8-trifluoro-2-(methylthio)-7-(4-nitrophenoxy)quinazolin-4-amine 77 F NH2 Br F ---2---..,".
0 N CH3
F
7-(4-bromophenoxy)-5,6,8-trifluoro-2-methylquinazolin-4-amine 78 F NH2
F
N 1.1 N NH2 0.,...,,...,....".., F 6,8-trifluoro-7-morpholinoquinazoline-2,4-diamine 79 F NH2 Br F "-\...
0 N NH2
F
7-(4-bromophenoxy)-5,6,8-trifluoroquinazoline-2,4-diamine F NH2 F 0.....%%-N HN N. NH2
F
N7-cyclopenty1-5,6,8-trifluoroquinazoline-2,4,7-triamine 81 F NH2 F IIP ----%-
N
r'N N*-----;.---%.---NH2
N F
7-(1H-benzo[d]imidazol-1-y1)-5,6,8-trifluoroquinazoline-2,4-diamine 82 F NH2
F
N le N' NH2 N,....,..____,,.- F 5,6,8-trifluoro-7-(4-methylpiperazin-1-yl)quinazoline-2,4-diamine 83 F NH2 F 110......%%-N r N F N.,:#7,---..,_,, N _CH 3
S
7-(1H-benzo[d]imidazol-1-y1)-5,6,8-trifluoro-2-(methylthio) quinazolin-4-amine 84 F NH2
F
Nr ---. 1110
F
7-(1H-benzo[d]imidazol-1-14)-5,6,8-trifluoro-2-phenylquinazolin-4-amine F NH2
F
c#1,--4---^,,_
N N H
0,...,"..... F 5,6,8-trifluoro-7-morpholinoquinazolin-4-amine 86 Br F 10 F NH2 H 0 N
F
7-(4-bromophenoxy)-5,6,8-trifluoroquinazolin-4-amine 87 F NH2
F
N."."_,......,,,..- F al. 5,6,8-trifluoro-7-(4-methylpiperazin-1-yI)-2-phenylquinazolin-4-amine 88 F NH2
F
0,...,,,,- F 110 5,6,8-trifluoro-7-morpholino-2-phenylquinazolin-4-amine 89 F F NH2 0 F 0 NO2 5,6,8-trifluoro-7-(4-nitrophenoxy)-2-phenylquinazolin-4-amine
F H
F 0.....%'-- N 4-j---......" N N NH2
F
5,6,8-trifluoro-7-(pyrrolidin-1-yl)quinazolin-2-amine 91 F H
F
N NNH2
F
5,6,8-trifluoro-7-morpholinoquinazolin-2-amine 92 F H
F
N N---.1.........%.%...-NFI2 "-------- F 5,6,8-trifluoro-7-(piperidin-1-yl)quinazolin-2-amine 93 F H F..-%-*-N N 0 NH2
F
H _3 _c
5,6,8-trifluoro-7-(4-methylpiperidin-1-yl)quinazolin-2-amine 94 F NH2 F 0 N CH3
F
5,6,8-trifluoro-2-methyl-7-(1,4-dioxa-8-azaspiro[4.5] decan-8-yOquinazolin-4-amine F F NH2 N 1101 N..--7.-..%- CH3 ".,....",N,."......".".."...- F CH3 5,6,8-trifluoro-7-(4-(2-methoxyethyl)piperazin-1-yI) -2-methylquinazolin-4-amine 96 F NH2 F 40,....-/P\,..
HN N CH3
F
W-cyclobuty1-5,6,8-trifluoro-2-methylquinazoline-4,7-diamine 97 F F NI-I2.
HN N NH2
F
",".N",..."...",,.."-H3C 5,6,8-trifluoro-N7((1-methylpiperidin-4-Amethyl)quinazoline-2,4,7-triamine 98 F NH2 F 11111 ----.."--N N,--27-*^.".. N CH3 H3C/o N"......".",.."."..- F 0 methyl 4-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-yl)piperazine- 1-carboxylate 99 F NH2 F io N N CH3 0 F 5,6,8-trifluoro-7-(3-methoxyazetidin-1-yI)-2-methylquinazolin-4-amine
F H
F
ip..%-.-N 1.-/..7%.
N N H
F
5,6,8-trifluoro-7-(pyrrolidin-1-yl)quinazoline 101 F NH2 F 0 %%%---N "-----....." HN N NH2
F
N7-cyclohexy1-5,6,8-trifluoroquinazoline-2,4,7-triamine 102 F F NH2 --.%%-N "."---- --.."...
HN N
F
N7-cyclohexy1-5,6,8-trifluoroquinazoline-2,4,7-triamine 103 F CH3 F * %....%--N HN., H
N 0 F
F
0-.,..,. CH3
5,6,8-trifluoro-N-(3-fluoro-4-methoxypheny1)-4-methylquinazolin-7-amine 104 F NH2 F 0....--.."-N "..---N N NH2
F
5,6,8-trifluoro-7-(1,4-dioxa-8-azaspiro[4.5]decan-8-yOquinazoline- 2,4-diamine
F F NE
* -I2 %-....."--N HN.."......%\,, NH2
N
F
N7-(cyclohexylmethyl)-5,6,8-trifluoroquinazoline-2,4,7-triamine 106 F CH3 F ii,----^..
HN N CH3
F
0...................",..- 5,6,8-trifluoro-2,4-dimethyl-N-((tetrahydro-2H-pyran-4-yl)methyl) quinazolin-7-amine 107 F CH3
F
N ell NI---..c.---------%-% CH3
F F3C
5,6,8-trifluoro-2,4-dimethy1-7-(4-(trifluoromethyl)piperidin-1-yl) quinazoline 108 F NH2 F 0.-..."-.N ".."------,..
HN N NH2 0 F
F
0-...." CH3 5,6,8-trifluoro-N7-(3-fluoro-4-methoxyphenyOquinazoline-2,4,7-triamine 109 F NH2 F el HN N NH2 ",./ N^.,... F 5,6,8-trifluoro-N7-morpholinoquinazoline-2,4,7-triamine F F CH3 * ----%N 1".",.
HN N CH3
F
N-cyclohepty1-5,6,8-trifluoro-2,4-dimethylquinazolin-7-amine 111 F CF-13
F
N NCH,
F
F
5,6,8-trifluoro-7-(4-fluoropiperidin-1-y1)-2,4-dimethylquinazoline 112 F H F el-.--%"- N "...-........ N, CH3
HN
F
0.,...."......,....,-- 5,6,8-trifluoro-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl) quinazolin-7-amine 113 F H N F 0 N-C/CH3
F F.
5,6,8-trifluoro-7-(4-fluoropiperidin-1-y1)-2-methylquinazoline 114 F H F 40 -..%.----N ".../.."7-....".
HN N CH3
F
N-cyclohepty1-5,6,8-trifluoro-2-methylquinazolin-7-amine F CH3 F is.....70"....s, S N CH3
F
7-(cyclohexylthio)-5,6,8-trifluoro-2,4-dimethylquinazoline 116 F NH2 F * -.-%%-- N HN,......"--,, -..., H
F
F F
N7-(4,4-difluorocyclohexyl)-5,6,8-trifluoroquinazoline-4,7-diamine 117 F CH3 F 0 ----%-N HN F N CH3 ciiiii N-cyclohexy1-5,6,8-trifluoro-2,4-dimethylquinazolin-7-amine 118 F NH2 F * %....."%
N
"^%.,....
HN N NH2 M.........". F 5,6,8-trifluoro-W-(piperidin-1-yhquinazoline-2,4,7-thamine 119 S F F 7-(cyclohexylthio)-5,6,8-trifluoro-2-methylquinazoline H CH3 F. .%....%-N
N
HN F F N-(4,4-difluorocyclohexyl)-5,6,8-thfluoro-2,4-dimethylquinazolin-7- CH3 F F F el.....%"-N.."---,-amine N CH3 121 F F H 0....---/.. .?\., HN NCH3
F
N-cyclohexy1-5,6,8-trifluoro-2-methylquinazolin-7-amine 122 F F H asi*-..N,7./...-^^.,%., HN N CH3
F
F F
N-(4,4-difluorocyclohexyl)-5,6,8-trifluoro-2-methylquinazolin-7-amine 123 F H
F
"..-7--........." N N CH3
F F3C
5,6,8-trifluoro-2-methy1-7-(4-(trifluoromethyl)piperidin-1-yl) quinazoline 124 F NH2 F....."...-5^-,,,,, HN N NH2 ----#.------- F 0....," 5,6,8-trifluoro-N7-((tetrahydro-2H-pyran-4-yOmethyl)quinazoline- 2,4,7-triamine F NH2 F el.----"-N
HN N H
/....%%.--------- F 0...,,,,.....",..."-- 5,6,8-trifluoro-N7-((tetrahydro-2H-pyran-4-yOmethyl)quinazoline-4, 7-diamine 126 F CH3
F
is....-.-N..,--,---HN N CH3
F
N-cyclopenty1-5,6,8-trifluoro-2,4-dimethylquinazolin-7-amine 127 HN F F N-cyclopenty1-5,6,8-trifluoro-2-methylquinazolin-7-amine H CH3 0 N
F
128 F F 5,6,8-trifluoro-7-(4-fluoropiperidin-1-yl)quinazoline-2,4-diamine F NH2 NH2 N F if------,s, N 129 HN 5,6,8-trifluoro-N7-(4-methylpiperazin-1-yl)quinazoline-4,7-diamine is......--%-F NH2 N
F F N H
N CH3
HN F F NH2 -", NH2 1 0...---N*N 1----,, N ",,./N'^,,.... F
N CH3
5,6,8-trifluoro-N7-(4-methylpiperazin-1-yhquinazoline-2,4,7-triamine 131 F H F 0....-%."-N N CH3
F
5,6,8-trifluoro-2-methy1-7-(pyrrolidin-1-yl)quinazoline 132 F NH2 F 0.,:r%.*-^.,,",
HN N H
I
F
5,6,8-trifluoro-N7-(piperidin-1-yOquinazoline-4,7-diamine F F NH2 N **-*-%%-N N CH3
F
>,....0 N ter -butyl 6-(4 amino-5,6.8-trifluoro-2-methylquinazolin-7-yI)-2,6-diazaspiro[3.3] heptane-2-carboxylate 134 F NH2
F
/7 --......" CH3 HN NCH3 0 F
F
5,6,8-trifluoro-N7-(5-fluoro-2-methoxypheny1)-2-methylquinazoline- 4,7-diamine
F
F
F
5,6,8-trifluoro-7-(4-(4-fluorobenzyl)piperazin-1-yI) -2-methylquinazolin-4-amine _.,,..."N",....,.......",...- F H3C,,...." ......"..--
N 1 CH3
7-(4-(2-(dimethylamino)ethyl)piperazin-1-yI)-5,6, 8-trifluoro-2-methylquinazolin-4-amine 137 F NH2 F 0........"-- N ",------,,..
HN NCH3
F
0 CH3
----
5,6,8-trifluoro-N7-(3-methoxypheny1)-2-methylquinazoline 4,7 diamine 138 F NH2 F.%..--. N ell 14-1"..----%%C H3 / N F fat 0---CH3 5,6,8-trifluoro-7-(6-methoxy-1H-indo1-1-y1)-2-methylquinazolin-4-amine 139 F NH2 F --%%- N cH3 H3CS N CH3
F
5,6,8-trifluoro-7-(isopropylthio)-2-methylquinazolin-4-amine F F NH2 0.."--HN N CH3 0 F to N7-(benzo[d][1,3]dioxo1-5-y1)-5,6,8-trifluoro-2-methylquinazoline-4, 7-diamine 141 F NI-I2 F 0./..,7-. ^.."., HN N CH3
F
CI II. 0 N-(4-amino-5,6,8-trifluoro-2-methylquinazolin-7-yI)-4-chlorobenzamide 142 ""......eN.,,,.., "...".....N...,",,,,,..."-- 5,6,8-trifluoro-2-methy1-7-(4-(3-morpholinopropyl)piperazin-1-yl) quinazolin-4-amine F F NI-12 %-..,., 0 N F."---N CH3 143 F F 7-(cyclopentylthio)-5,6,8-trifluoro-2-methylquinazolin-4-amine CH3 S is%.---"-N F NH2
N
144 F NH2 F 0.....%%.-N 7.--^,..., HN N CH3
F
5,6,8-trifluoro-2-methyl-N7-(tetrahydrofuran-3-yOquinazoline-4, 7-diamine F NH2
F
N."-%%C H3
N F
/...'. %-\\./.'...""-.../-
N
5,6,8-trifluoro-2-methy1-7-(4-(pyrazin-2-yl)piperazin-1-yl) quinazolin-4-amine F NH2 F is-......-- N
---
CN N CH3
S
F
6 8-trifluoro-2-methy1-7-(thiazolidin-3-yl)quinazolin-4-amine 147 Br ---------%----"--------- F 7-(4-bromopiperidin-1-yI)-5,6,8-trifluoro-2-methylquinazolin-4-amine F NH2.cr...,s, N F N CH3 148 F 5,6,8-trifluoro-7-(5-methoxy-1H-benzo[d]imidazol-1-y1) -2-methylquinazolin-4-amine le F dal%--%--N NH2 NCH3 rN F
N 0\ CH3
149 F F F N NH2..,,, 0 F F "5.-1--^- CH3
HN moi
N7-(2-(difluoromethoxy)phenyI)-5,6,8-trifluoro-2-methylquinazoline- 4,7-diamine CH3 1 F F 5,6,8-trifluoro-N7-(2-methoxyphenyI)-2-methylquinazoline-4,7- NH2 CH3 HN F issi N 00 diamine 151 HN F F 5,6,8-trifluoro-2-methyl-N7-(tetrahydrofuran-2-Aquinazoline-4,7- N NH2,.."-......" n F is CH3 diamine 152 F NH2 F 0....%%"-N HN N CH3
F
F
5,6,8-thfluoro-N7-(2-fluorocyclopenty1)-2-methylquinazoline-4,7-diamine 153 F NH2 F ill.%-..%'*N ".....,-......, HN N CH3
F \ CH3
5,6,8-thfluoro-N7-(3-methoxycyclopenty1)-2-methylquinazoline-4, 7-diamine 154 F NH2 F 0,--/"...."......, N N CH3
F
F
5,6,8-trifluoro-7-(3-fluoropyrrolidin-1-0-2-methylquinazolin-4-amine F NH2 F 0 -.'-'* N "---..."., HN N CH3 H3C \ F 5,6,8-trifluoro-N7-(2-methoxycyclopenty1)-2-methylquinazoline-4,7-diamine 156 F NH2 F "...-X--isoF N CH3
N
F
F
7-(3,3-difluoropyrrolidin-1-y1)-5,6, 8-thfluoro-2-methylquinazolin-4-amine An example preparation of a compound according to the disclosure is now described.
Preparation of N17-cyclopenty1-5,6,8-trifluoroquinazoline-4,7-diamine (compound 62)
THE TEA
RI 1 2
DmF, DBU reflux NH H2 N Cyclopentylamine (2) (1.0 eq) and Triethylamine (TEA) (2.5 eq) were stirred in THE (5 mL) followed by the addition of a solution of 2,3,4,5,6-pentafluorobenzonitrile (1) (1.0 eq), which was added dropwise in THF (3 mL). The reaction mixture was stirred at room temperature for 12 h and subsequently poured into deionised water and extracted with ethyl acetate (15 ml). The organic solution was then dried over MgSO4 and the crude residue was purified by either recrystallisation with Et0H or Me0H or by column chromatography (elution with hexane/ethyl acetate) to yield 4-(cyclopentylamino)-2,3,5,6-tetrafluorobenzonitrile.
4-(cyclopentylamino)-2,3,5,6-tetrafluorobenzonitrile (1.0 eq), DBU (2.5 eq) and formamidine (3) (1.5 eq) were stirred in DMF (3 mL) at reflux for 15 h and subsequently poured into deionised water and extracted with DCM (3 x 15 ml). The organic solution was dried over MgSO4 and the crude residue was purified by either recrystallisation with Et0H or Me0H or by column chromatography (elution with hexane/ethyl acetate) to yield N17-cyclopenty1-5,6,8-trifluoroguinazoline-4,7-diamine (compound 62).
In the example preparation above, (1) is 2,3,4,5,6-pentafluorobenzonitrile. In other examples, (1) may be instead, for example, 2,3,4,5,6-pentafluorobenzaldehyde or 1-(perfluorophenyl)ethan-1-one (2,3,4,5,6-pentafluoroacetophenone).
In the example preparation above, (2) is cyclopentanamine (cyclopentylamine). In other examples, (2) may be instead any reagent which acts as a nucleophile to provide R1 of the structure of formula I. In the example preparation above, (3) is formimidamide (formamidine). In other examples, (3) may be instead any reagent to provide R3 of the structure of formula I, 15 e.g., acetimidamide (acetamidine), guanidine, methyl carbamimidothioate, or benimidamide.
The in vitro antitrypanosomal activities of a selection of compounds of the disclosure against Trypanosoma brucei rhodesiense (sleeping sickness), Trypanosoma cruzi (Chagas disease), and Leishmania donovani (leishmaniasis) are indicated in Table 2, along with Cytotoxicity L6.
Table 2
ID MW Trypanosoma brucei rhodesiense (IC5OpM) Trypanosoma cruzi Leishmania donovani (1C5OpM) Cytotoxicity L6 (IC500) (1C5OpM) 1 254 25.268 33.789 88.162 123.781 2 325 16.746 4.106 11.026 26.372 3 310 0.011 0.008 0.085 0.545 4 311 3.315 5.962 6.573 44.193 296 0.132 0.068 0.059 3.119 6 328 5.593 5.059 5.776 24.048 7 313 2.068 0.586 3.913 8.959 8 313 134.296 64.832 211.424 247.034 9 364 2.323 0.629 19.211 62.618 310 0.785 0.119 5.191 4.965 11 325 153.006 176.533 >100 228.509 12 326 17.002 3.572 119.429 116.209 13 312 57.350 16.596 172.049 166.282 14 283 48.922 53.037 19.586 63.581 268 72.549 18.706 74.974 115.445 16 316 180.850 92.322 199.820 186.383 17 346 5.836 1.034 29.108 54.172 18 314 5.648 1.158 16.927 13.300 19 325 35.538 215.077 166.462 198.154 325 119.077 133.846 270.154 181.538 21 339 91.445 184.513 271.091 198.525 22 381 90.157 148.425 208.268 141.207 23 394 130.964 115.228 135.914 129.569 24 368 108.288 89.810 88.451 131.386 410 129.878 127.195 111.220 129.512 26 326 149.847 42.945 92.945 222.699 27 339 70.354 195.280 133.628 289.676 28 350 1.831 0.886 7.829 43.143 29 326 176.380 172.086 272.699 >100 311 5.370 37.219 38.055 20.064 31 311 41.961 38.103 190.997 232.637 32 300 3.673 1.097 11.583 171.500 33 354 145.480 260.311 17.825 11.893 34 353 102.975 120.397 77.054 135.552 339 60.472 181.416 149.263 157.817 36 382 128.665 >100 114.005 178.534 37 424 136.085 >100 >100 >100 38 324 0.171 0.020 0.983 127.778 39 357 145.798 200.560 66.527 116.947 299 23.294 27.609 102.341 126.087 41 310 0.026 <0.002 0.066 3.066 42 315 17.778 16.746 12.714 16.079 43 352 7.557 23.324 37.088 0.689 44 334 7.874 98.952 38.249 93.114 375 17.320 118.400 32.933 174.133 46 365 31.932 4.425 14.452 96.575 47 354 126.554 171.328 133.475 154.661 48 325 76.000 164.923 256.308 182.923 49 365 177.260 >100 199.452 >100 374 1.155 3.783 6.537 44.786 51 282 9.592 30.674 50.355 84.929 52 324 0.556 0.042 0.725 3.369 53 310 5.352 1.395 18.516 146.774 54 344 - 145.640 16.744 188.953 386 - 170.466 32.642 84.974 56 314 7.086 7.341 6.465 22.006 57 376 33.125 96.410 8.205 102.394 58 315 132.381 144.286 54.286 204.603 59 372 72.312 128.226 26.129 70.968 296 9.966 3.398 7.095 12.568 61 327 0.291 0.020 0.157 10.749 62 282 0.991 0.559 1.619 4.025 63 389 115.938 138.560 25.167 91.645 64 297 236.700 159.933 205.387 294.781 358 166.480 41.397 119.832 66 330 84.545 102.727 83.485 67 324 - - - - 68 298 43.121 39.597 60.906 126.510 69 311 141.318 78.457 189.389 246.302 329 18.191 58.055 8.526 16.778 71 268 29.067 50.746 76.866 169.590 72 351 - 87.749 55.342 - 73 296 0.856 0.216 3.579 34.125 74 332 - 20.181 237.952 130.422 279 178.674 191.039 21.380 238.710 76 382 80.105 111.518 25.668 102.094 77 384 27.969 25.911 9.766 72.526 78 299 89.799 38.127 61.706 47.492 79 385 5.545 35.584 7.935 90.909 297 17.239 6.195 28.771 40.421 81 330 130.152 201.212 51.364 183.788 82 312 117.468 172.436 260.897 151.763 83 261 15.958 68.582 7.375 65.709 84 391 5.102 33.248 7.609 12.864 284 66.901 36.620 37.324 126.056 86 370 185.946 114.865 87 373 44.370 63.271 142.627 51.475 88 360 - 158.889 102.333 75.139 89 412 22.597 74.515 9.891 31.711 Table 2 presents data from compounds screened against Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani parasites. Assays are conducted using whole cell parasites and such methods have the advantage of identifying compounds which are effective against the whole organism, showing downstream development issues such as cell uptake or cell efflux are not a concern. Also included is data from screening compounds against rat skeletal myoblast cells (L6) as a measure of potential toxicity.
Recombinant KRS assays were carried out on compounds 61 and 73 (see Table 1), the results of which are indicated in Table 3.
Table 3
Enzyme 73 61 IC50 (uM) n SI* IC50 (LIM) n SI* T. cruzi KRS 0.299 5 50 0.015 4 6546 P. falciparum KRS 0.671 4 22 0.081 4 1242 C. parvum KRS 11.169 2 1 0.968 4 103 M. tuberculosis KRS 1.560 3 10 8.054 3 12 H. sapiens KRS 14.894 4 >100.000 4 *SI -selectivity index with respect to Hs KRS Table 3 presents data derived from screening compounds against recombinant lysyltRNA synthetase (KRS) enzymes from a range of organisms, as we have experimentally validated the mode of action of active compounds through target deconvolution studies primarily using T.cruzi parasites. As protein structures can be conserved from organism to organism, we have broadened our enzyme panel to include those listed within table 3. Importantly, H.sapiens KRS corresponds to the human homologue from which potential toxicity is evaluated and the selective indexes of compounds are determined Broad spectrum activity was determined for compounds 61 and 73 (see Table 1), the results of which are indiated in Table 4.
Table 4
Cell Line 73 61 EC50 (nM) Sel* N EC50 (nM) Sel* N P.falciparum (NF54- 412 ± 20 14 3 121 ± 2 140 3 AttB) C.Parvum 5,121 ± 1,005 1 2 679 ± 169 25 3 H. sapiens (Hep G2) 5,819 ± 500 1 3 16,935 ± 5,379 1 2 H. sapiens (HCT-8) 17,730 ± 0.3 1 6,893 2.5 2 3,590 ±901 * Selectivity with respect to human Hep G2 cell line Table 4 presents data derived from screening compounds against whole cell parasites to include P.falciparum and C.parvum. Also included is data from screening compounds against human derived cell lines (H. sapiens) as a measure of potential toxicity, where selective indexes for analogues tested are determined against H. sapiens Hep G2.
There is thus described compounds according to examples of the disclosure with a number of advantages as detailed above.
Although embodiments of the present invention have been described in the preceding paragraphs with reference to various examples, it should be appreciated that modifications to the examples given can be made without departing from the scope of the invention as claimed The term 'comprise' is used in this document with an inclusive not an exclusive meaning. That is any reference to X comprising Y indicates that X may comprise only one Y or may comprise more than one Y. If it is intended to use 'comprise' with an exclusive meaning then it will be made clear in the context by referring to "comprising only one" or by using "consisting".
In this description, reference has been made to various examples. The description of features or functions in relation to an example indicates that those features or functions are present in that example. The use of the term 'example' or 'for example' or 'can' or 'may' in the text denotes, whether explicitly stated or not, that such features or functions are present in at least the described example, whether described as an example or not, and that they can be, but are not necessarily, present in some of or all other examples. Thus 'example', 'for example', 'can' or 'may' refers to a particular instance in a class of examples. A property of the instance can be a property of only that instance or a property of the class or a property of a sub-class of the class that includes some but not all of the instances in the class. It is therefore implicitly disclosed that a feature described with reference to one example but not with reference to another example, can where possible be used in that other example as part of a working combination but does not necessarily have to be used in that other example.
Features described in the preceding description may be used in combinations other than the combinations explicitly described above.
Although functions have been described with reference to certain features, those functions may be performable by other features whether described or not.
Although features have been described with reference to certain examples, those features may also be present in other examples whether described or not.
The term 'a' or 'the' is used in this document with an inclusive not an exclusive meaning. That is any reference to X comprising a/the Y indicates that X may comprise only one Y or may comprise more than one Y unless the context clearly indicates the contrary. If it is intended to use 'a' or 'the' with an exclusive meaning then it will be made clear in the context. In some circumstances the use of 'at least one' or 'one or more' may be used to emphasis an inclusive meaning but the absence of these terms should not be taken to infer any exclusive meaning.
The presence of a feature (or combination of features) in a claim is a reference to that feature or (combination of features) itself and also to features that achieve substantially the same technical effect (equivalent features). The equivalent features include, for example, features that are variants and achieve substantially the same result in substantially the same way. The equivalent features include, for example, features that perform substantially the same function, in substantially the same way to achieve substantially the same result.
In this description, reference has been made to various examples using adjectives or adjectival phrases to describe characteristics of the examples. Such a description of a characteristic in relation to an example indicates that the characteristic is present in some examples exactly as described and is present in other examples substantially as described.
Whilst endeavoring in the foregoing specification to draw attention to those features believed to be of importance it should be understood that the applicant may seek protection via the claims in respect of any patentable feature or combination of features hereinbefore referred to whether or not emphasis has been placed thereon.

Claims (25)

  1. CLAIMS1. A compound comprising a 5,6,8-trifluoroquinazoline moiety, wherein the compound is for use as a medicament.
  2. 2. A compound according to claim 1, wherein the compound has the general structure of formula I (Formula I) wherein R1 is selected from: NR4R5, NR6R7, OR4, or SR4; R2 is selected from: H, CH3, NH2, or NHCH3; R3 is selected from: H, CH3, NH2, SCH3, or phenyl; R4 is selected from: acyclic alkyl, aryl, carbonyl, cycloalkyl, heterocyclyl, Ci alkyl substituted with cycloalkyl, C1 alkyl substituted with heterocyclyl, Ci alkyl substituted with acetal, or Ci alkyl substituted with aryl; R5 is selected from: H or CH3; and R6 and R7 together with N form a heterocycle.
  3. 3. A compound according to any of the preceding claims, wherein the acyclic alkyl of R4 is isopropyl.
  4. 4. A compound according to any of the preceding claims, wherein the aryl of R4 is selected from: wherein R indicates the attachment of R4 to the N, 0 or S of R1.
  5. 5. A compound according to any of the preceding claims, wherein the carbonyl of R4 is: Cl Br NO2 wherein R indicates the attachment of R4 to the N, 0 or S of Rl*
  6. 6. A compound according to any of the preceding claims, wherein the cycloalkyl of R4 is a 3-, 4-, 5-, 6-or 7-membered cycloalkyl.
  7. 7. A compound according to claim 6, wherein the 3-, 4-, 5-, 6-or 7-membered cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4,4- difluorocyclohexyl, 2-fluorocyclopentyl, 2-methoxycyclopentyl, and 3-methoxycyclopentyl.
  8. 8. A compound according to any of the preceding claims, wherein the heterocyclyl of R4 is a 4-, 5-, 6-or 7-membered heterocycle with 1 or 2 heteroatoms independently selected from N, 0 or S.
  9. 9. A compound according to any of the preceding claims, wherein the Ci alkyl substituted with cycloalkyl of R4 is: wherein R indicates the attachment of R4 to the N, 0 or S of R1
  10. 10. A compound according to any of the preceding claims, wherein the Ci alkyl substituted with heterocycle of R4 is selected from: /\/ H3C wherein R indicates the attachment of R4 to the N, 0 or S of R1.
  11. 11. A compound according to any of the preceding claims, wherein the Ci alkyl substituted with acetal of R4 is: ocH3 wherein R indicates the attachment of R4 to the N, 0 or S of R1.
  12. 12. A compound according to any of the preceding claims, wherein the Ci alkyl substituted with aryl of R4 is: wherein R indicates the attachment of R4 to the N, 0 or S of R1.
  13. 13. A compound according to any of the preceding claims, wherein R6 and R' together with N form a 4-, 5-, 6-or 7-membered heterocycle.
  14. 14. A compound according to claim 13, wherein R6 and R' together with N has the general structure of formula II R8 N-R (Formula II) wherein R indicates the attachment of N to the structure of formula (0; and wherein R6 is selected from: H, acyclic alkyl, halide, trifluoromethyl, heterocyclyl, carbonyl, amine or ester.
  15. 15. A compound according to claim 13, wherein R6 and R7 together with N has the general structure of formula III R14 N-R Rth (Formula III) wherein R indicates the attachment of N to the structure of formula (I); and wherein R14 is H or F and R15 is H or F.
  16. 16. A compound according to claim 13, wherein R6 and R7 together with N is: wherein R indicates the attachment of N to the structure of formula (I).
  17. 17. A compound according to any of claims 1 to 13, wherein R6 and R7 together with N has the general structure of formula IV R9 ON-R (Formula IV) wherein R indicates the attachment of N to the structure of formula (0; and wherein R5 is alkoxy or heterocyclyl.
  18. 18. A compound according to any of claims 1 to 13, wherein R6 and R7 together with N form a 4-, 5-, 6-or 7-membered heterocycle, wherein the 4-, 5-, 6-or 7-membered heterocycle comprises another heteroatom independently selected from N, 0 or S.
  19. 19. A compound according to claim 18, wherein R6 and R7 together with N has the general structure of formula V Rio_N N-R \ / (Formula V) wherein R indicates the attachment of N to the structure of formula (0; and wherein R1° is selected from: acyclic alkyl, amine, carbonyl, ether, cycloalkyl, heterocyclyl, aromatic heterocyclyl, Ci alkyl substituted with carbonyl, or Ci alkyl substituted with aryl.
  20. 20. A compound according to claim 18, wherein R6 and R7 together with N has the general structure of formula VI R12 0 R R13 (Formula VI) wherein R indicates the attachment of N to the structure of formula (0; and wherein R12 and R13 are H or CH3.
  21. 21. A compound according to claim 18, wherein R6 and R7 together with N is selected from: Nd)NNN----R wherein R indicates the attachment of N to the structure of formula (I).
  22. 22. A compound according to claim 18, wherein R6 and R7 together with N is selected from:N-Rwherein R indicates the attachment of N to the structure of formula (I).
  23. 23. A compound according to claim 18, wherein R6 and R7 together with N is: H3CNRwherein R indicates the attachment of N to the structure of formula (I).
  24. 24. A compound according to any of the preceding claims for use in the treatment of a parasitic infection.
  25. 25. A pharmaceutical composition which comprises a compound according to any of the preceding claims, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
GB2301138.0A 2023-01-26 2023-01-26 Quinazoline derivatives for use as a medicament Pending GB2626567A (en)

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EP2557927A4 (en) * 2010-04-15 2013-12-18 Basf Se Fungicidal mixtures i comprising quinazolines
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