WO2016083490A1 - Compounds for the treatment of amyloid-associated diseases - Google Patents

Compounds for the treatment of amyloid-associated diseases Download PDF

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Publication number
WO2016083490A1
WO2016083490A1 PCT/EP2015/077731 EP2015077731W WO2016083490A1 WO 2016083490 A1 WO2016083490 A1 WO 2016083490A1 EP 2015077731 W EP2015077731 W EP 2015077731W WO 2016083490 A1 WO2016083490 A1 WO 2016083490A1
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alkyl
group
cycloalkyl
heterocyclyl
haloci
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PCT/EP2015/077731
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French (fr)
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Maxime Robin
Gilles Casano
Sébastien ABEL
Gerard Griffioen
Katrien PRINCEN
Veronica Rojas De La Parra
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Remynd Nv
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Publication of WO2016083490A1 publication Critical patent/WO2016083490A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds and to the novel compounds for use as a medicine, more in particular for the prevention or treatment of amyloid-associated diseases, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease.
  • the present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such disorders.
  • the present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
  • amyloidoses entail the accumulation and/or aggregation of misfolded proteins as a pathological characteristic and are therefore also referred to as protein- misfolding diseases.
  • Most notably, Alzheimer's disease, Parkinson's disease and Huntington's disease are common diseases which involve aberrant aggregation of tau, alpha-synuclein and huntingtin respectively.
  • Alzheimer's disease, Parkinson's disease and Huntington's disease are common diseases which involve aberrant aggregation of tau, alpha-synuclein and huntingtin respectively.
  • the process or processes which lead to protein misfolding and aggregation is/are generally believed to be cytotoxic and as such may contribute to degeneration or failure of target cells such as neurons in the case of brain disorders such as Alzheimer's, Huntington's and Parkinson's diseases.
  • Such treatments will alter fundamentally the course of the disease as these preserve cellular integrity of the target cells such as neurons and beta-cells and thus are expected to be disease-modifying. As such these treatments are not merely reducing temporarily disease symptoms and therefore address an important current medical need.
  • treatments for neurodegenerative diseases are focused on delaying the onset, or reducing the existing symptoms. For example, cholinesterase inhibitors and/or Memantine are given to Alzheimer's patients to delay the onset of cognitive symptoms. Levodopa is given to Parkinson's patients to temporarily diminish motor symptoms. Tetrabenazine has been recently approved for the symptomatic treatment of the abnormal involuntary movement (chorea) characteristic of Huntington's disease.
  • a compound of formulae (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof is provided,
  • each dotted line individually represents an optional double bond
  • - r is an integer selected from 0; 1 ; 2 or 3;
  • a 1 is selected from the group consisting of S; N; NR. 8 ; and O;
  • a 2 is selected from the group consisting of N; NR. 9 , and S;
  • - X 1 is selected from the group consisting of NR 10 ; S; CO; SO; and SO2;
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • - A 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NR 13 ; O, and S,
  • - X 2 is selected from the group consisting of O; S; N; NH, SO; and SO2;
  • - Y 1 is selected from the group consisting of CR 14 ; NH; and N;
  • - R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ;
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl;
  • Ci- 6 alkoxycarbonyl Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 2 ;
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi -6 alkyloxy; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-8 cycloalkyl; C 6- i2aryl; hydroxyl; -OR 17 ; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; cyano; -NR 15 R 16 ; -NHC(0)NHR 19 ; and NHC(0)R 19 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ;
  • R 2 is selected from hydrogen; -NH 2 ; hydroxyl, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; C 1-6 alkyl; C 2-6 alkenyl; C 2 - 6 alkynyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 6 ;
  • R 3 is selected from hydrogen; -NH 2 ; hydroxyl, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; C 1-6 alkyl; C 2 - 6 alkenyl; C 2 - 6 alkynyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 7 ;
  • R 10 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ;
  • Ci_ 6 alkyl C 2-6 alkenyl; C2- 6 alkynyl, C6-i2aryl;
  • R 11 is hydrogen or is selected from the group consisting of ; Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ;
  • R 13 is hydrogen; or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 11 ;
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy; C 6 -i2arylaminocarbonyl; C 6 -i2arylaminocarbonylC 6 -i2aryl; NHC(0)R 19 ; carboxyl, Ci -6 alkyl; -OR 17 ; heteroaryl; C6-i2arylCi -6 alkyl; Ci -6 alkoxycarbonyl; C 6 -i2arylthioC 6 -i2aryl; C 3-8 cycloalkyl; hydroxyl; C 2-6 alkenyl; C 2-6 alkynyl; heterocyclyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; C6-i2aryloxyCi -6 alkyl; Ci -6 alkylcarbonyl; halo; halo
  • - R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i 2 arylCi- 6 alkyl; C6-i 2 arylC 2-6 alkenyl; C6-i 2 arylC 2-6 alkynyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; - N0 2 ; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 13 ; * and wherein a carbon atom or heteroatom of Ci- 6 alkyl; C 2 - 6 alkenyl; C 2 - 6 alkynyl; C6-i
  • - R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i 2 arylCi-6alkyl; C6-i 2 arylC 2-6 alkenyl; C6-i 2 arylC 2-6 alkynyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; - N0 2 ; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 14 ;
  • - R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i 2 aryl; Ci- 6 alkyl;
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 4 is independently selected from the group consisting of Ci- 6 alkyl; -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; haloCi- 6 alkyl; haloCi- 6 alkyloxy; hydrogen; C3-i 2 cycloalkyl; C6-i 2 aryl; C 6 -i 2 arylCi- 6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi-6alkyl; hydrogen, halo; Ci -6 alkyloxy; -NH 2 ; hydroxyl;C 6- i 2 aryl; -NR 15 R 16 ; Ci -6 alkyl; C 6- i 2 aryloxy; C6-i 2 arylCi -6 alkyloxy; - C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i 2 cycloalkyl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; cyano; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; - S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; -N0 2 ; -
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • - pyridinium 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
  • - pyridinium 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
  • - r is an integer selected from 0; 1 ; 2 or 3;
  • a 1 is selected from the group consisting of S; N; NR 8 ; and O;
  • a 2 is selected from the group consisting of N; NR 9 , and S;
  • - X 1 is selected from the group consisting of NR 10 ; S; SO; and SO2;
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • - A 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NR 13 ; O, and S,
  • - X 2 is selected from the group consisting of O; S; N; NH, SO; and SO2;
  • - Y 1 is selected from the group consisting of CR 14 ; NH; and N;
  • - R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ;
  • Ci -6 alkyl C 2 - 6 alkenyl; C 2 - 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi- 6 alkyl; haloCi- 6 alkyloxy; carboxyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ;
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl;
  • R 9 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl;
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi -6 alkyloxy; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-8 cycloalkyl; C 6- i2aryl; hydroxyl; -OR 17 ; heterocyclyl; heteroaryl; C6-i 2 arylCi -6 alkyl; C 6- i 2 arylC 2 - 6 alkenyl; C 6- i 2 arylC 2 - 6 alkynyl; cyano; -NR 15 R 16 ; -NHC(0)NHR 19 ; and NHC(0)R 19 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ;
  • R 2 is selected from hydrogen; -NH 2 ; hydroxyl, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; C 1-6 alkyl; C 2 - 6 alkenyl; C 2-6 alkynyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i 2 arylCi -6 alkyl; C 6- i 2 arylC 2 - 6 alkenyl; C 6- i 2 arylC 2 - 6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 6 ;
  • - R 3 is selected from hydrogen; -NH 2 ; hydroxyl, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; C 1-6 alkyl; C 2-6 alkenyl; C 2 - 6 alkynyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 7 ;
  • R 10 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl;
  • Ci- 6 alkylcarbonyl Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ;
  • R 11 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ;
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy; C 6 -i2arylaminocarbonyl; C 6 -i2arylaminocarbonylC 6 -i2aryl; NHC(0)R 19 ; carboxyl, Ci -6 alkyl; -OR 17 ; heteroaryl; C6-i2arylCi -6 alkyl; Ci -6 alkoxycarbonyl; C 6 -i2arylthioC 6 -i2aryl; C 3-8 cycloalkyl; hydroxyl; C 2-6 alkenyl; C 2-6 alkynyl; heterocyclyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; C6-i2aryloxyCi -6 alkyl; Ci -6 alkylcarbonyl; halo; halo
  • - R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i2arylCi- 6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; - NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 13 ;
  • - R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl;
  • - R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 1 together
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 2 together
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 9
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi-6alkyl; hydrogen, halo; Ci -6 alkyloxy; -NH 2 ; hydroxyl;C 6- i 2 aryl; -NR 15 R 16 ; Ci -6 alkyl; C 6- i 2 aryloxy; C6-i 2 arylCi -6 alkyloxy; - C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i 2 cycloalkyl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; cyano; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; - S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; -N0 2 ; -
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • - pyridinium 4-(dimethylamino)-1-(1 1 -hydroxy- 1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; - pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
  • the present invention also encompasses a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to the first aspect of the invention.
  • a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound of a compound according to the first aspect of the invention or a therapeutically effective amount of a compound selected from the group comprising 3-ethyl-[1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 2-hydrazino-1 ,6- dihydroimidazo[4,5-a]acridin-1 1-one; 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one.
  • the present invention also encompasses a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for use as a medicament.
  • the present invention also encompasses a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, or a compound selected from the group consisting of
  • the present invention also encompasses a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, or a compound selected from the group consisting of 2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6- cf][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-
  • the present invention also encompasses a compound or a pharmaceutical composition according to the fourth aspect of the invention, wherein the amyloid- related diseases is selected from Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden- Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay- Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloido
  • the present invention also encompasses method for the preparation of the compounds according to the first aspect of the invention.
  • a compound means one compound or more than one compound.
  • the term "and/or,” when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and/or C, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination.
  • substituted is meant to indicate that one or more hydrogen atoms on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation from a reaction mixture.
  • groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents.
  • Preferred substituents may be selected from but not limited to, for example, the group comprising halo; hydroxyl, Ci- 6 alkyl; Ci- 6 alkoxy; haloCi- 6 alkyl; haloCi- 6 alkyloxy; C 3- i2cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heteroaryl; Ci -6 alkylthio; cyano; amino; nitro; carboxyl, aminocarbonyl; hydroxycarbonylCi- 6 alkyl; Ci- 6 alkyloxycarbonyl; mono- or diCi- 6 alkylamino; mono- or diCi -6 alkylaminocarbonyl; Ci -6 alkylcarbonyl; -S(0)Ci -6 alkyl; -S(0) 2 Ci- 6 alky
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo, iodo.
  • amino refers to the group -NH 2 .
  • hydroxyl or "hydroxy” as used herein refers to the group -OH.
  • thiol or "sulfuhydryl” refers to the group -SH.
  • nitro refers to the group -NO2.
  • cyano refers to the group -CN.
  • carboxy or “carboxyl” or “hydroxycarbonyl” as used herein refers to the group -CO2H.
  • aminocarbonyl refers to the group -CO-NH 2 .
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl group of formula C n H 2n +i wherein n is a number greater than or equal to 1 .
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • Ci- 6 alkyl refers to a hydrocarbyl group of formula -C n H 2 n+i wherein n is a number ranging from 1 to 6.
  • “Ci_ 6 alkyl” includes all linear or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers.
  • Ci -5 alkyl includes all includes all linear or branched alkyl groups with between 1 and 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers.
  • Ci_ 3 alkyl includes all linear or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl.
  • alkylene when used in conjunction with an alkyl group, i.e. "alkylene”, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups.
  • Ci- 6 alkylene by itself or as part of another substituent, refers to Ci- 6 alkyl groups that are divalent, i.e., with two single bonds for attachment to two other groups.
  • Alkylene groups may be linear or branched and may be substituted as indicated herein.
  • Non-limiting examples of alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), methylmethylene (- CH(CH 3 )-), 1-methyl-ethylene (-CH(CH 3 )-CH 2 -), n-propylene (-CH 2 -CH 2 -CH 2 -), 2-methylpropylene (- CH 2 -CH(CH 3 )-CH 2 -), 3-methylpropylene (-CH 2 -CH 2 -CH(CH 3 )-), n-butylene (-CH 2 -CH 2 -CH 2 -CH 2 -), 2- methylbutylene (-CH 2 -CH(CH 3 )-CH 2 -CH 2 -), 4-methylbutylene (-CH 2 -CH 2 -CH 2 -CH(CH 3 )-), pentylene and its chain isomers, hexylene and its chain isomers.
  • hydroxyCi -6 alkyl refers to a Ci -6 alkyl group having the meaning as defined above wherein one or more hydrogen atoms are each replaced with one or more hydroxyl as defined herein.
  • Non-limiting examples of hydroxyCi- 6 alkyl group include hydroxymethyl, hydroxyethyl, and the like.
  • haloCi- 6 alkyl refers to a Ci- 6 alkyl group having the meaning as defined above wherein one or more hydrogen atoms are each replaced with one or more halogen as defined herein.
  • Non-limiting examples of such haloCi- 6 alkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 , 1 ,1-trifluoroethyl and the like.
  • Ci -6 alkoxy or "Ci -6 alkyloxy", as a group or part of a group, refers to a group having the formula -OR b wherein R b is Ci- 6 alkyl as defined herein above.
  • suitable Ci_ 6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • haloCi- 6 alkoxy refers to a group of formula -0-R c wherein R c is haloCi- 6 alkyl as defined herein.
  • suitable haloCi- 6 alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 , 1 ,2,2-tetrafluoroethoxy, 2- fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2- bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.
  • Ci -6 alkoxycarbonyl refers to a group formula -COO-R d wherein R d is selected from Ci- 6 alkyl as defined herein.
  • Ci- 6 alkylcarbonyl refers to a group formula -CO-R 1 wherein R 1 is selected from Ci- 6 alkyl as defined herein.
  • alkylamino refers to a group formula -N(R°)(R ) wherein R° and R are each independently selected from hydrogen, or Ci- 6 alkyl, wherein at least one of R° or R is Ci- 6 alkyl.
  • alkylamino include mono-alkyl amino group (e.g. mono-Ci- 6 alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-Ci- 6 alkylamino group such as dimethylamino and diethylamino).
  • Non-limiting examples of suitable mono- or di-Ci_ 6 alkylamino groups include n-propylamino, isopropylamino, n-butylamino, /-butylamino, sec- butylamino, f-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-/-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-/ ' -propylamino, n-butylmethylamino, /- butylmethylamino, f-butylmethylamino, ethyl-n-propylamino, ethyl-/ ' -propylamino, n-butylethylamino, i-butylethylamino, f-butylethylamino, di-n-butylamin
  • Ci- 6 alkylaminoCi- 6 alkyl as a group or part of a group, means a Ci -6 alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one Ci- 6 alkylamino as defined herein.
  • Ci- 6 alkylsulfinyl refers to a group of formula -SO-R 9 wherein R 9 is Ci- 6 alkyl as defined herein.
  • Ci- 6 alkylsulfonyl refers to a group of formula -S0 2 -R h wherein R h is Ci- 6 alkyl as defined herein.
  • cyanoCi- 6 alkyl refers to a group of formula -R -CN wherein R is Ci- 6 alkylene as defined herein.
  • Non-limiting examples of cyanoCi- 6 alkyl group include cyanomethyl, cyanoethyl, and the like.
  • alkenyl refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon double bonds.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • C2- 6 alkenyl refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon-carbon double bonds and comprising from 2 to 6 carbon atoms.
  • C2-4alkenyl includes all linear, or branched alkenyl groups having 2 to 4 carbon atoms.
  • C2- 6 alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl. and the like.
  • alkenyl groups as defined herein are divalent groups having single bonds for attachment to two other groups, they are termed "alkenylene".
  • alkenylene As used herein, the term "C2- 6 alkenylene”, by itself or as part of another substituent, refers to C2- 6 alkenyl groups that are divalent, i.e., with two single bonds for attachment to two other groups.
  • alkynyl by itself or as part of another substituent, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon triple bonds.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • C2- 6 alkynyl refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon- carbon triple bonds and comprising from 2 to 6 carbon atoms.
  • C2-4alkynyl includes all linear, or branched alkynyl groups having 2 to 4 carbon atoms.
  • Non limiting examples of C2- 6 alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its chain isomers, 2-hexynyl and its chain isomers, and the like.
  • alkynyl groups as defined herein are divalent groups having single bonds for attachment to two other groups, they are termed “alkynylene”.
  • alkynylene As used herein, the term "C2- 6 alkynylene”, by itself or as part of another substituent, refers to C2- 6 alkynyl groups that are divalent, i.e., with two single bonds for attachment to two other groups.
  • cycloalkyl refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 12 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms, still more preferably from 5 to 6 carbon atoms.
  • Cycloalkyl includes all saturated hydrocarbon groups containing one or more rings, including monocyclic or bicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • C 3- i2cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; cycloheptyl, cyclooctyl, bicycle[2.2.1 ]heptan-2yl; (1 S,4R)-norbornan-2-yl; (1 R,4R)- norbornan-2-yl; (1 S,4S)-norbornan-2-yl; (1 R,4S)-norbornan-2-yl.
  • Cs-scycloalkylene include 1 ,2-cyclopropylene, 1 ,1-cyclopropylene, 1 ,1-cyclobutylene, 1 ,2-cyclobutylene, 1 ,3-cyclopentylene, 1 ,1-cyclopentylene, and 1 ,4-cyclohexylene.
  • a Csalkylene group may be for example *- CH CH2CH2-*, * -CH(-CH 2 CH 3 )- * or * -CH 2 CH(-CH 3 )- * .
  • a C 3 cycloalkylene group may be
  • spiro atom refers to the atom that connects two cyclic structures in a spiro compound.
  • Non limiting examples of spiro atoms include quaternary carbon atoms.
  • spiro compound refers to a bicyclic compound wherein the two rings are connected through one atom.
  • C 6 -i2aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), or linked covalently, typically comprising 6 to 12 carbon atoms; wherein at least one ring is aromatic, preferably comprising 6 to 10 carbon atoms, wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (either cycloalkyi, heterocyclyl or heteroaryl) fused thereto.
  • suitable aryl include C6-ioaryl, more preferably C6-saryl.
  • Non-limiting examples of C6-i2aryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azulenyl, 4-, 5-, 6 or 7-indenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and 1 ,4-dihydronaphthyl; 1-, 2-, 3-, 4- or 5-pyrenyl.
  • arylene When the suffix "ene” is used in conjunction with an aryl group; i.e. arylene, this is intended to mean the aryl group as defined herein having two single bonds as points of attachment to other groups.
  • Suitable "C6-i2arylene” groups include 1 ,4-phenylene, 1 ,2-phenylene, 1 ,3-phenylene, biphenylylene, naphthylene, indenylene, 1-, 2-, 5- or 6-tetralinylene, and the like. Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • C6-i2arylCi -6 alkyl as a group or part of a group, means a Ci -6 alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryl as defined herein.
  • Non- limiting examples of C6-i2arylCi-6alkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.
  • C 6 -i2arylC2-6alkenyl as a group or part of a group, means a C 2- 6alkenyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryl as defined herein.
  • Non- limiting examples of C6-i2arylC2-6alkenyl group include styryl, cinnamyl, 2,2-diphenylvinyl, and the like.
  • C 6 -i2arylC2-6alkynyl as a group or part of a group, means a C 2 -6alkynyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryl as defined herein.
  • Non- limiting examples of C6-i2arylC2-6alkynyl group include 2-pneylethynyl, and the like.
  • C6-i2aryloxyCi- 6 alkyl as a group or part of a group, means a Ci -6 alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryloxy.
  • Non-limiting examples of C6-i2aryloxyCi-6alkyl group include phenoxymethyl, phenoxyethyl, naphthyloxymethyl, naphthyloxyethyl and the like.
  • C6-i2aryloxy refers to a group having the formula -OR 9 wherein R 9 is C6-i2aryl as defined herein above.
  • C6-i2aryloxyC 6 -i2aryl as a group or part of a group, means a C 6- i2aryl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryloxy.
  • Non-limiting examples of C6-i2aryloxyC6-i2aryl group include phenoxyphenyl, naphthyloxyphenyl, and the like.
  • C6-i2arylthio refers to a group having the formula -SR m wherein R m is C6-i2aryl as defined herein above.
  • C6-i2arylthioC 6 -i2aryl as a group or part of a group, means a C 6- i2aryl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2arylthio.
  • Non-limiting examples of C6-i2arylthioC6-i2aryl group include phenylsulfanylphenyl, naphthylsulfanylphenyl, and the like.
  • C 6 -i2arylaminocarbonyl refers to a group of formula -CO- N R°R wherein R°R are each independently selected from hydrogen, Ci-6alkyl or C6-i2aryl, wherein at least one of R° or R is C6-i2aryl as defined herein.
  • C6-i2arylaminocarbonylC 6 -i2aryl refers to a group of formula -R a -CO-NR°R wherein R°R are each independently selected from hydrogen, Ci-6alkyl or C6-i2aryl, wherein at least one of R° or R is C6-i2aryl, and R a is C6-i2arylene as defined herein.
  • heterocyclyl or “heterocycloakyl”, as a group or part of a group, refer to non-aromatic, fully saturated or partially unsaturated cyclic groups containing one or more cycles (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms) which can be fused together or linked covalently, wherein at least one the cycles contains at least one heteroatom, selected from N, O and/or S atoms, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized.
  • each heterocyclyl may contain from 3 to 12 atoms, preferably from 3 to 8 atoms, more preferably from 3 to 6 atoms.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, oxetanyl, pyrrolidinyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl); 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazin
  • aziridinyl as used herein includes aziridin-1-yl and aziridin-2-yl.
  • oxyranyl as used herein includes oxyranyl-2-yl.
  • thiiranyl as used herein includes thiiran-2-yl.
  • azetidinyl as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl.
  • oxetanyl as used herein includes oxetan-2-yl and oxetan-3-yl.
  • thietanyl as used herein includes thietan-2-yl and thietan-3- yl.
  • pyrrolidinyl as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl.
  • tetrahydrofuranyl as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl.
  • tetrahydrothiophenyl as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl.
  • succinimidyl as used herein includes succinimid-1-yl and succininmid-3-yl.
  • dihydropyrrolyl as used herein includes 2,3-dihydropyrrol-1-yl, 2,3- dihydro-1 H-pyrrol-2-yl, 2,3-dihydro-1 H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1 H-pyrrol-3-yl and 2,5-dihydropyrrol-5-yl.
  • 2H-pyrrolyl as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol- 3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl.
  • 3H-pyrrolyl as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol-5-yl.
  • dihydrofuranyl as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5- dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl.
  • dihydrothiphenyl as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3- dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl and 2,5-dihydrothiophen-5-yl.
  • imidazolidinyl as used herein includes imidazolidin-1-yl, imidazolidin-2-yl and imidazolidin-4-yl.
  • pyrazolidinyl as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl and pyrazolidin-4-yl.
  • imidazolinyl as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl.
  • pyrazolinyl as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin- 3- yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-
  • dioxolanyl also known as “1 ,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl.
  • dioxolyl also known as "1 ,3- dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl.
  • oxazolidinyl as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl.
  • isoxazolidinyl as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl.
  • oxazolinyl as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2- oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3- yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl.
  • isoxazolinyl as used herein includes 2- isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3-isoxazolinyl-4-yl, 3- isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl and 4-isoxazolinyl-5-yl.
  • thiazolidinyl as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl.
  • isothiazolid inyl as used herein includes isothiazolidin-2-yl, isothiazolidin- 3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl.
  • thiazolinyl as used herein includes 2- thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5- yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl and 4-thiazolinyl-5-yl.
  • isothiazolinyl as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3- yl, 4-isothiazolinyl-4-yl and 4-isothiazolinyl-5-yl.
  • piperidyl also known as “piperidinyl” as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl.
  • dihydropyridinyl as used herein includes 1 ,2-dihydropyridin-1-yl, 1 ,2-dihydropyridin-2-yl, 1 ,2- dihydropyridin-3-yl, 1 ,2-dihydropyridin-4-yl, 1 ,2-dihydropyridin-5-yl, 1 ,2-dihydropyridin-6-yl, 1 ,4- dihydropyridin-1-yl, 1 ,4-dihydropyridin-2-yl, 1 ,4-dihydropyridin-3-yl, 1 ,4-dihydropyridin-4-yl, 2,3- dihydropyridin-2-yl, 2,3-dihydropyridin-2-yl, 2,
  • tetrahyd ropy rid inyl includes 1 ,2,3,4-tetrahydropyridin-1-yl, 1 ,2,3,4-tetrahydropyridin-2-yl, 1 ,2,3,4- tetrahydropyridin-3-yl, 1 ,2,3,4-tetrahydropyridin-4-yl, 1 ,2,3,4-tetrahydropyridin-5-yl, 1 ,2,3,4- tetrahydropyridin-6-yl, 1 ,2,3,6-tetrahydropyridin-1-yl, 1 ,2,3,6-tetrahydropyridin-2-yl, 1 ,2,3,6- tetrahydropyridin-3-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, 1 ,2,3,6-tetrahydropyridin-5-yl, 1 ,2,3,6- te
  • tetrahydropyranyl also known as “oxanyl” or "tetrahydro-2H- pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4- yl.
  • 2H-pyranyl as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H- pyran-5-yl and 2H-pyran-6-yl.
  • 4H-pyranyl as used herein includes 4H-pyran-2-yl, 4H- pyran-3-yl and 4H-pyran-4-yl.
  • 3,4-dihydro-2H-pyranyl as used herein includes 3,4- dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran- 5-yl and 3,4-dihydro-2H-pyran-6-yl.
  • 3,6-dihydro-2H-pyranyl as used herein includes 3,6- dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran- 5-yl and 3,6-dihydro-2H-pyran-6-yl.
  • tetrahydrothiophenyl as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl.
  • 2H- thiopyranyl as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H- thiopyran-5-yl and 2H-thiopyran-6-yl.
  • 4H-thiopyranyl as used herein includes 4H- thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl.
  • 3,4-dihydro-2H-thiopyranyl as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H- thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl.
  • 3,6- dihydro-2H-thiopyranyl as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H- thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H- thiopyran-6-yl.
  • piperazinyl also known as "piperazidinyl” as used herein includes piperazin-1-yl and piperazin-2-yl.
  • morpholinyl as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl.
  • thiomorpholinyl as used herein includes thiomorpholin- 2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl.
  • dioxanyl as used herein includes 1 ,2- dioxan-3-yl, 1 ,2-dioxan-4-yl, 1 ,3-dioxan-2-yl, 1 ,3-dioxan-4-yl, 1 ,3-dioxan-5-yl and 1 ,4-dioxan-2-yl.
  • dithianyl as used herein includes 1 ,2-dithian-3-yl, 1 ,2-dithian-4-yl, 1 ,3-dithian-2-yl, 1 ,3- dithian-4-yl, 1 ,3-dithian-5-yl and 1 ,4-dithian-2-yl.
  • oxathianyl as used herein includes oxathian-2-yl and oxathian-3-yl.
  • trioxanyl as used herein includes 1 ,2,3-trioxan-4-yl, 1 ,2,3-trioxay-5-yl, 1 ,2,4-trioxay-3-yl, 1 ,2,4-trioxay-5-yl, 1 ,2,4-trioxay-6-yl and 1 ,3,4-trioxay-2-yl.
  • azepanyl as used herein includes azepan-1 -yl, azepan-2-yl, azepan-1-yl, azepan-3-yl and azepan-4-yl.
  • homoopiperazinyl as used herein includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl.
  • indolinyl as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl.
  • quinolizinyl as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl.
  • isoindolinyl as used herein includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl.
  • 3H- indolyl as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6- yl, and 3H-indol-7-yl.
  • quinolizinyl as used herein includes quinolizidin-1-yl, quinolizidin-2- yl, quinolizidin-3-yl and quinolizidin-4-yl.
  • quinolizinyl as used herein includes quinolizidin- 1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl.
  • tetrahydroquinolinyl as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl.
  • tetrahydroisoquinolinyl as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl.
  • chromanyl as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl.
  • 1 H-pyrrolizine as used herein includes 1 H-pyrrolizin-1-yl, 1 H-pyrrolizin-2-yl, 1 H-pyrrolizin-3-yl, 1 H-pyrrolizin-5-yl, 1 H-pyrrolizin-6-yl and 1 H-pyrrolizin-7-yl.
  • 3H- pyrrolizine as used herein includes 3H-pyrrolizin-1-yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3-yl, 3H- pyrrolizin-5-yl, 3H-pyrrolizin-6-yl and 3H-pyrrolizin-7-yl.
  • heterocyclylene when used in conjunction with a heterocyclyl group; i.e. "heterocyclylene”, this is intended to mean the heterocyclyl group as defined herein having two single bonds as points of attachment to other groups.
  • heterocyclylCi- 6 alkyl as a group or part of a group, means a Ci- 6 alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one heterocyclyl as defined herein.
  • each ring may contain from 5 to 10 atoms, preferably from 5 to 8 atoms, more preferably from 5 to 6 atoms.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • Non-limiting examples of such heteroaryl include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl,
  • pyrrolyl (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl.
  • furanyl (also called “furyl”) as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl).
  • thiophenyl (also called “thienyl”) as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl).
  • pyrazolyl (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
  • imidazolyl as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol- 4-yl and imidazol-5-yl.
  • oxazolyl (also called 1 ,3-oxazolyl) as used herein includes oxazol- 2- yl; oxazol-4-yl and oxazol-5-yl.
  • isoxazolyl also called 1 ,2-oxazolyl
  • isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl.
  • thiazolyl also called 1 ,3- thiazolyl
  • thiazol-2-yl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4- thiazolyl and 5-thiazolyl).
  • isothiazolyl (also called 1 , 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl.
  • trimazolyl as used herein includes 1 H- triazolyl and 4H-1 ,2,4-triazolyl
  • H-triazolyl includes 1 H-1 ,2,3-triazol-1-yl, 1 H-1 ,2,3-triazol-4-yl, 1 H- 1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1-yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl.
  • 41-1-1 ,2,4- triazolyl includes 4H-1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl.
  • oxadiazolyl as used herein includes 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl.
  • thiadiazolyl as used herein includes 1 ,2,3- thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl.
  • tetrazolyl as used herein includes 1 H- tetrazol-1-yl, 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl.
  • oxatriazolyl as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl.
  • thiatriazolyl as used herein includes 1 ,2,3,4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl.
  • pyridinyl also called “pyridyl” as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl, 3- pyridyl and 4-pyridyl).
  • pyrimidyl as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl.
  • pyrazinyl as used herein includes pyrazin-2-yl and pyrazin-
  • pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl.
  • oxazinyl (also called “1 ,4-oxazinyl”) as used herein includes 1 ,4-oxazin-4-yl and 1 ,4-oxazin-5-yl.
  • dioxinyl (also called “1 ,4-dioxinyl”) as used herein includes 1 ,4-dioxin-2-yl and 1 ,4-dioxin- 3-yl.
  • thiazinyl (also called “1 ,4-thiazinyl”) as used herein includes 1 ,4-thiazin-2-yl, 1 ,4- thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl.
  • triazinyl as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl.
  • imidazo[2,1-b][1 ,3]thiazolyl includes imidazo[2,1- b][1 ,3]thiazoi-2-yl, imidazo[2,1-b][1 ,3]thiazol-3-yl, imidazo[2,1-b][1 ,3]thiazol-5-yl and imidazo[2,1- b][1 ,3]thiazol-6-yl.
  • thieno[3,2-b]furanyl as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl.
  • thieno[3,2- b]thiophenyl as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2- b]thien-5-yl and thieno[3,2-b]thien-6-yl.
  • thieno[2,3-d][1 ,3]thiazolyl as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl.
  • thieno[2,3-d]imidazolyl as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4- yl and thieno[2,3-d]imidazol-5-yl.
  • tetrazolo[1 ,5-a]pyridinyl as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl.
  • indolyl as used herein includes indol-1-yl, indol-2-yl, indol-3- yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl.
  • indolizinyl as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl.
  • isoindolyl as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl.
  • benzofuranyl also called benzo[b]furanyl
  • benzofuran-2-yl benzofuran-3-yl
  • benzofuran-4-yl benzofuran-5-yl
  • benzofuran-6-yl benzofuran-7-yl
  • isobenzofuranyl also called benzo[c]furanyl
  • isobenzofuran-1-yl isobenzofuran-3-yl
  • isobenzofuran-4-yl isobenzofuran-5-yl
  • benzothiophenyl (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl).
  • isobenzothiophenyl also called benzo[c]thienyl
  • isobenzothien-1-yl isobenzothien-3-yl
  • isobenzothien-4-yl isobenzothien-5-yl
  • isobenzothien-6-yl isobenzothien-7- yl.
  • indazolyl (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H-indazol- 1 -yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol- 2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl.
  • benzimidazolyl as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl.
  • 1 ,2-benzisoxazolyl as used herein includes 1 ,2-benzisoxazol-3- yl, 1 ,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1 ,2-benzisoxazol-7-yl.
  • 2,1-benzisoxazolyl as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl.
  • the term "1 ,3- benzothiazolyl” as used herein includes 1 ,3-benzothiazol-2-yl, 1 ,3-benzothiazol-4-yl, 1 ,3- benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1 ,3-benzothiazol-7-yl.
  • the term "1 ,2-benzoisothiazolyl” as used herein includes 1 ,2-benzisothiazol-3-yl, 1 ,2-benzisothiazol-4-yl, 1 ,2-benzisothiazol-5-yl, 1 ,2- benzisothiazol-6-yl and 1 ,2-benzisothiazol-7-yl.
  • 2,1-benzoisothiazolyl as used herein includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol- 6-yl and 2,1-benzisothiazol-7-yl.
  • benzotriazolyl as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl.
  • 1 ,2,3- benzoxadiazolyl as used herein includes 1 ,2,3-benzoxadiazol-4-yl, 1 ,2,3-benzoxadiazol-5-yl, 1 ,2,3- benzoxadiazol-6-yl and 1 ,2,3-benzoxadiazol-7-yl.
  • 2,1 ,3-benzoxadiazolyl as used herein includes 2, 1 ,3-benzoxadiazol-4-yl, 2, 1 ,3-benzoxadiazol-5-yl, 2, 1 ,3-benzoxadiazol-6-yl and 2, 1 ,3- benzoxadiazol-7-yl.
  • 1 ,2,3-benzothiadiazolyl as used herein includes 1 ,2,3- benzothiadiazol-4-yl, 1 ,2,3-benzothiadiazol-5-yl, 1 ,2,3-benzothiadiazol-6-yl and 1 ,2,3- benzothiadiazol-7-yl.
  • 2,1 ,3-benzothiadiazolyl as used herein includes 2, 1 ,3- benzothiadiazol-4-yl, 2, 1 ,3-benzothiadiazol-5-yl, 2,1 ,3-benzothiadiazol-6-yl and 2, 1 ,3- benzothiadiazol-7-yl.
  • thienopyridinyl as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl.
  • purinyl as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl.
  • imidazo[1 ,2-a]pyridinyl includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2-a]pyridin-7-yl.
  • 1 ,3- benzodioxolyl includes 1 ,3-benzodioxol-4-yl, 1 ,3-benzodioxol-5-yl, 1 ,3-benzodioxol- 6-yl, and 1 ,3-benzodioxol-7-yl.
  • quinolinyl as used herein includes quinolin-2-yl, quinolin-3- yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl.
  • isoquinolinyl as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6- yl, isoquinolin-7-yl and isoquinolin-8-yl.
  • cinnolinyl as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl.
  • quinazolinyl as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl.
  • quinoxalinyl as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.
  • heteroarylene when used in conjunction with a heteroaryl group; i.e. "heteroarylene”, this is intended to mean the heteroaryl group as defined herein having two single bonds as points of attachment to other groups.
  • heteroarylCi- 6 alkyl as a group or part of a group, means a Ci- 6 alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one heteroaryl as defined herein.
  • a leaving group means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions.
  • a leaving group is selected from a halogen atom (e.g., CI, Br, I).
  • the term "compounds of the invention” or a similar term is meant to include the compounds of general formula (I) and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 and their derivatives, N-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, prodrugs, esters and metabolites, as well as their quaternized nitrogen analogues.
  • the N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • esters are meant to comprise compounds with hydroxyl and/or carboxyl which may accordingly form ester(s) with inorganic or organic acid(s) and/or alcohol(s) respectively.
  • amyloid refers to amyloidogenic proteins, peptides, or fragments thereof which can be soluble (e.g., monomeric or oligomeric) or insoluble (e.g., having fibrillary structure or in amyloid plaque). See, e.g., MP Lambert, et al, Proc. Nat 7 Acad. Sd. USA 95, 6448-53 (1998).
  • Amyloidosis or "amyloid disease” or “amyloid-related disease” refers to a pathological condition characterized by the presence of amyloid fibers.
  • Amyloid is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seen in a number of different diseases.
  • amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.
  • An amyloid related disease includes those diseases, disorders, conditions, pathologies, and other abnormalities, in which amyloid is observed either intracellularly or extracellularly in affected tissues.
  • each dotted line individually represents an optional double bond
  • - r is an integer selected from 0; 1 ; 2 or 3; preferably r is selected from 0, 1 or 2, more preferably from 0 or 1 ;
  • a 1 is selected from the group consisting of S; N; NR. 8 ; and O; preferably A 1 is S; N; or NR. 8 ; more preferably A 1 is S; N; NH or -N-Ci -6 alkyl;
  • a 2 is selected from the group consisting of N; NR 9 , and S; preferably A 2 is N; or NR 9 ; more preferably A 2 is N; NH or -N-Ci -6 alkyl;
  • - X 1 is selected from the group consisting of NR 10 ; S; CO; SO; and SO 2 ; preferably X 1 is selected from NR 10 ; S; CO; more preferably X 1 is NR 10 ; more preferably X 1 is NH; or -N-Ci -6 alkyl;
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • - A 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NR 13 ; O, and S; preferably A 5 is selected from the group consisting of N; NR 13 ; and O; more preferably A 5 is selected from the group consisting of N; NH; and O;
  • - X 2 is selected from the group consisting of O; S; N; NH, SO; and SO 2 ; preferably X 2 is selected from the group consisting of O; S; N; and NH;
  • - Y 1 is selected from the group consisting of CR 14 ; NH; and N; preferably Y 1 is CR 14 ; or NH; - R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ;
  • NHC(0)R 19 Ci -6 alkyl; C 2 - 6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi- 6 alkyl; haloCi- 6 alkyloxy; carboxyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; haloCi -6
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i 2 aryl;
  • R 1 and R 9 form together with the ring to which they are attached, a saturated or unsaturated 4-, 5- , or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 4 ; preferably R 1 and R 9 form together with the ring to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 4 ; preferably R 1 and R 9 form together with the ring to which they are attached, a saturated or unsaturated 5-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 4 ; preferably R 1 and R 9 form together with the ring to which they are attached, a saturated 5-membered ring, said saturated ring can be unsubstituted or substituted with one or more Z 4 ; preferably R 1 and R 9 form together with the ring to which
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi -6 alkyloxy; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-8 cycloalkyl; C 6- i2aryl; hydroxyl; -OR 17 ; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; cyano; -NR 15 R 16 ; -NHC(0)NHR 19 ; and NHC(0)R 19 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ; preferably R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi -6 alky
  • R 2 is selected from hydrogen; -NH 2 ; hydroxyl, -NO2; or cyano; or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; C 2 - 6 alkenyl; C 2 - 6 alkynyl; C 6 -i 2 aryl; C 3 - 8 cycloalkyl; heterocyclyl; heteroaryl; C6-i 2 arylCi -6 alkyl; C 6- i 2 arylC 2 - 6 alkenyl; C 6- i 2 arylC 2 - 6 alkynyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 6 ; preferably R 2 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R
  • R 3 is selected from hydrogen; -NH 2 ; hydroxyl, -NO2, or cyano, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; C 2 - 6 alkenyl; C 2 - 6 alkynyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i 2 arylCi -6 alkyl; C 6- i 2 arylC 2 - 6 alkenyl; C 6- i 2 arylC 2 - 6 alkynyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 7 ; preferably R 3 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ;
  • R 10 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci -6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can be un
  • R 11 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl;
  • R 13 is hydrogen; or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 11 ; preferably R 13 is hydrogen; or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci -6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy;
  • R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i2arylCi- 6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; - NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 13 ; preferably R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C
  • R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i 2 arylCi- 6 alkyl; C6-i 2 arylC 2-6 alkenyl; C6-i 2 arylC 2-6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -N0 2 ; cyano; wherein each group can be unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; C
  • - R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i 2 aryl; Ci- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring; - each R 17 is independently selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 2-6 alkenyl; C 2-6 alkynyl, C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heteroaryl; heterocyclylCi -6 alkyl; hetero
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl;
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 3 together
  • each Z 4 is independently selected from the group consisting of Ci-6alkyl; -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; haloCi-6alkyl; haloCi- 6 alkyloxy; hydrogen; C3-i 2 cycloalkyl; C6-i 2 aryl; C 6 -i 2 arylCi-6alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 4 together
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 8
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi-6alkyl; hydrogen, halo; Ci -6 alkyloxy; -NH 2 ; hydroxyl;C 6- i 2 aryl; -NR 15 R 16 ; Ci -6 alkyl; C 6- i 2 aryloxy; C6-i 2 arylCi -6 alkyloxy; - C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i 2 cycloalkyl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; cyano; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; - S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; -N0 2 ; -
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 13
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 14 together
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 15 R
  • each dotted line individually represents an optional double bond
  • - r is an integer selected from 0; 1 ; 2 or 3; preferably r is selected from 0, 1 or 2, more preferably from 0 or 1 ;
  • a 1 is selected from the group consisting of S; N; NR 8 ; and O; preferably A 1 is S; N; or NR 8 ; more preferably A 1 is S; N; NH or -N-Ci -6 alkyl;
  • a 2 is selected from the group consisting of N; NR 9 , and S; preferably A 2 is N; or NR 9 ; more preferably A 2 is N; NH or -N-Ci -6 alkyl;
  • - X 1 is selected from the group consisting of NR 10 ; S; SO; and SO2; preferably X 1 is NR 10 ; or S; more preferably X 1 is NR 10 ; more preferably X 1 is NH; or -N-Ci -6 alkyl;
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • - A 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NR 13 ; O, and S; preferably A 5 is selected from the group consisting of N; NR 13 ; and O; more preferably A 5 is selected from the group consisting of N; NH; and O;
  • - X 2 is selected from the group consisting of O; S; N; NH, SO; and SO2; preferably X 2 is selected from the group consisting of O; S; N; and NH;
  • - Y 1 is selected from the group consisting of CR 14 ; NH; and N; preferably Y 1 is CR 14 ; or NH;
  • - R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ;
  • NHC(0)R 19 Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi- 6 alkyl; haloCi- 6 alkyloxy; carboxyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ;preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; haloCi -6 alkyl
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl;
  • R 9 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl;
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi -6 alkyloxy; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-8 cycloalkyl; C 6- i2aryl; hydroxyl; -OR 17 ; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; cyano; -NR 15 R 16 ; -NHC(0)NHR 19 ; and NHC(0)R 19 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ; preferably R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi -6 alky
  • Ci_ 6 alkyl C 2-6 alkenyl; C2- 6 alkynyl; C 3-8 cycloalkyl;
  • R 2 is selected from hydrogen; -NH 2 ; hydroxyl, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; C 1-6 alkyl; C 2 - 6 alkenyl; C 2 - 6 alkynyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 6 ; preferably R 2 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ;
  • R 3 is selected from hydrogen; -NH 2 ; hydroxyl, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; C 1-6 alkyl; C 2-6 alkenyl; C 2 - 6 alkynyl; C 6- i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i 2 arylCi -6 alkyl; C6-i 2 arylC 2-6 alkenyl; C6-i 2 arylC 2-6 alkynyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -N0 2 ; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 7 ; preferably R 3 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -N0 2 , or is selected from the group consisting of -NR 15 R 16 ; -
  • R 10 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C 2 - 6 alkenyl; C 2 - 6 alkynyl; C 6- i 2 aryl; C 3-8 cycloalkyl; C6-i 2 arylCi -6 alkyl; C6-i 2 arylC 2-6 alkenyl; C6-i 2 arylC 2-6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; C6-i 2 arylCi -6 alkyl; Ci -6 alkylcarbonyl; and Ci- 6 alkoxy
  • R 11 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl;
  • Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 10 ; preferably R 12 is -NH 2 ; S, or halo, or is selected from the group consisting of Ci -6 alkyl; -NHC(0)NHR 19 ; C 6 -i 2 aryl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; NHC(0)R 19 ; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; haloCi- 6 alkyl; haloCi- 6 alkyloxy; carboxyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 10 ; preferably R 12 is -
  • R 13 is hydrogen; or is selected from the group consisting of Ci- 6 alkyl; C2- 6 alkenyl; C2- 6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; Ci- 6 alkylcarbonyl; Ci- 6 alkoxycarbonyl; Ci- 6 alkylsulfonyl; and Ci- 6 alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z 11 ; preferably R 13 is hydrogen; or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci -6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy; C 6 -i2arylaminocarbonyl; C 6 -i2arylaminocarbonylC 6 -i2aryl; NHC(0)R 19 ; carboxyl, Ci-ealkyl; -OR 17 ; heteroaryl; C6-i2arylCi -6 alkyl; Ci -6 alkoxycarbonyl; C 6 -i2arylthioC 6 -i2aryl; C 3-8 cycloalkyl; hydroxyl; C 2-6 alkenyl; C 2-6 alkynyl; heterocyclyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; C6-i2aryloxyCi -6 alkyl; Ci -6 alkylcarbonyl; halo; halo
  • R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i2arylCi- 6 alkyl; C 6- i2arylC2- 6 alkenyl; C 6- i2arylC2- 6 alkynyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; - NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z 13 ; preferably R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C
  • - R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; Ci -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl;
  • each group can be unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; C 1-6 alkyl; C 6 -i 2 aryl; C 3 - 8 cycloalkyl; heterocyclyl; heteroaryl; C 6 -i2arylCi- 6 alkyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; -N0 2 ; cyano; wherein each group can be unsubstituted
  • - R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl;
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 2 together
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; -
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci-6alkyl; hydrogen; C 3- i 2 cycloalkyl; C6-i 2 aryl; heterocyclyl; heteroaryl; preferably each Z 3 is independently selected from the group consisting of -
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 6
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; -
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 7 is independently selected from the group consisting of -
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z
  • each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 11
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; -NH 2 ; hydroxyl;C 6- i2aryl; -NR 15 R 16 ; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; - C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i2cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; cyano; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; - S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; -N0 2 ; -NHC(0)R
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl;
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; and C6-i2aryl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; and C6-i 2 aryl;
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -S(0)R 19 ; -S(0) 2 R 19 ; -S0 2 NR 15 R 16 ; - N0 2 ; -NHC(0)R 19 ; -NHS(0) 2 R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 15 together
  • the compound according to statement 1 or 2 having one of formula (I2), (I3), (II2), (II3), (II4), (II5), (II6), (II7), (IIS), (II9),
  • a 1 is selected from the group consisting of S; N; and NR 8 ;
  • - A 2 is N; or NR 9 ;
  • - X 1 is NR 10 .
  • a 1 is S; and A 2 is N; or
  • a 1 is N ; and A 2 is N R 9 , or
  • a 1 is NR 8 ; and A 2 is N.
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • - A 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; O; NH, and S,
  • - X 2 is selected from the group consisting of O; S; N; and NH,
  • - Y 1 is CR 14 ; or NH;
  • a 3 is S;
  • a 4 is CR 12 ; and
  • a 5 is N; or
  • a 3 is O;
  • a 4 is CR 12 ; and
  • a 5 is N, or
  • a 3 is NR 11 ;
  • a 4 is N; and
  • a 5 is N;
  • a 3 is N; A 4 is CH; and A 5 is O.
  • R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6- i2aryl; C 3- 8cycloalkyl; heterocyclyl; heteroaryl; haloCi -6 alkyl; haloCi -6 alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; hal
  • each R 15 is independently selected from the group consisting of hydrogen; Ci- 6 alkyl; C6-i2aryl; C3- 8 cycloalkyl; C6-i2arylCi- 6 alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci- 6 alkyl, C6-i2aryl, C 3-8 cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; 10 carboxyl; wherein two Z 1 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci -6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 2 ; preferably R 8 is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 2 ;
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; and C 3-8 cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 2 ; preferably R 8 is Ci- 6 alkyl; unsubstituted or substituted with one or more Z 2 ; preferably R 8 is Ci- 6 alkyl;
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 2 is independently selected from the group consisting of - NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • R 9 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci- 6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 3 ; preferably R 9 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi -6 alkyl; wherein each group can be
  • R 9 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i 2 aryl; and C 3-8 cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 3 ; preferably R 9 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 3 ; preferably R 9 is hydrogen or Ci- 6 alkyl;
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl;
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 3 is independently selected from the group consisting of - NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; and C6-i2aryl;each R 15 is independently
  • each R 15 is independently selected from the group consisting of hydrogen; Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; wherein at least one carbon atom of Ci -6 alkyl,
  • each R 15 is independently selected from hydrogen or Ci- 6 alkyl
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi- 6 alkyloxy;
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylC
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci- 6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi -6 alkyl; wherein each group can be
  • R 10 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or Ci- 6 alkyl;
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; 25 carboxyl; wherein two Z 8 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; C6-i2aryl; heterocyclyl; hetero
  • each R 15 is independently selected from the group consisting of hydrogen; Ci- 6 alkyl; C6-i2aryl;
  • each R 15 is independently selected from the group consisting of hydrogen; Ci- 6 alkyl; C6-i2aryl; C 3-8 cycloalkyl; wherein at least one carbon atom of
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci- 6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; and C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; heterocyclyl; heteroaryl; preferably each Z 9 is independently selected from the group consisting of -
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 10 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy; C 6 -i2arylaminocarbonyl; C 6 -i2arylaminocarbonylC 6 -i2aryl; NHC(0)R 19 ; carboxyl, Ci -6 alkyl; -OR 17 ; heteroaryl; C6-i2arylCi -6 alkyl; Ci -6 alkoxycarbonyl; C 6 -i2arylthioC 6 -i2aryl; C 3-8 cycloalkyl; hydroxyl; heterocyclyl; C6-i2aryloxyCi -6 alkyl; Ci -6 alkylcarbonyl; halo; haloCi -6 alkyl; haloCi -6 alkyloxy; -N0 2 ;
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; hydroxyl;C 6- i2aryl; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i2cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heteroaryl; preferably each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; hydroxyl;C 6- i2aryl; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; - C0 2 R 19 ; carboxyl;
  • R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; haloCi -6 alkyl; and haloCi -6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 15 ; preferably R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C 6- i2aryl; Ci -6 alkyl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 15 ; preferably R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2ary
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C6-i2
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 16 is independently selected from the group consisting of hydrogen; -NH 2 ; Ci- 6 alkyl; Ci- 6 alkylaminoCi- 6 alkyl; hydroxyCi -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heteroaryl; wherein at
  • each R 16 is independently selected from the group consisting of hydrogen; -NH 2 ; Ci- 6 alkyl;
  • Ci- 6 alkylaminoCi- 6 alkyl and hydroxyCi- 6 alkyl.
  • said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z ; 20 preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring.
  • each R 17 is independently selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci- 6 alkyl,
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci -6 alkyl; preferably each R 18 is independently C 6- i2aryl; or hydrogen; preferably each R 18 is independently C 6- i2aryl. .
  • - R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; d -6 alkyl;
  • R 8 is selected from the group consisting of Ci- 6 alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 2 ;
  • R 9 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 3 ;
  • R 4 is selected from or from a group consisting of hydrogen; -NO2; -NH 2 ; halo, haloCi- 6 alkyl; haloCi -6 alkyloxy; Ci -6 alkyl; C 3-8 cycloalkyl; C 6- i2aryl; and hydroxyl;
  • R 10 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 8 .
  • - R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C6-i2arylCi -6 alkyl; C 6- i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ;
  • R 13 is hydrogen; or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 11 ;
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy; C 6- i2arylaminocarbonyl; C 6 -i2arylaminocarbonylC 6 -i2aryl; NHC(0)R 19 ; carboxyl, Ci -6 alkyl; -OR 17 ; heteroaryl; C6-i2arylCi -6 alkyl; Ci -6 alkoxycarbonyl; C 6 -i2arylthioC 6 -i2aryl; Cs-scycloalkyl; hydroxyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z 12 ;
  • - R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl;
  • each R 15 is independently selected from the group consisting of hydrogen; Ci- 6 alkyl; C6-i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; and heteroaryl;
  • each R 16 is independently selected from the group consisting of hydrogen; -NH 2 ; Ci- 6 alkyl; Ci- 6 alkylaminoCi- 6 alkyl; hydroxyCi -6 alkyl, C 6- i2aryl; C 3 - 8 cycloalkyl; heterocyclyl; and heteroaryl; or R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or
  • each R 17 is independently selected from the group consisting of Ci -6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; C 6 -i 2 arylCi- 6 alkyl; heterocyclyl; and heteroaryl;
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; and heteroaryl;
  • each R 19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci- 6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; and heteroaryl;
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -N0 2 ; -NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 3 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; - each Z 5 is independently selected from the group consist
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; N0 2 ; -NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 6 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; C6-i 2 arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -N0 2 ; -NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 7 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each R 15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i 2 aryl; C 3-8 cycloalkyl; C6-i 2 arylCi -6 alkyl; heterocyclyl; and heteroaryl;
  • each R 16 is independently selected from the group consisting of hydrogen; -NH 2 ; Ci- 6 alkyl; Ci- 6 alkylaminoCi- 6 alkyl; hydroxyCi -6 alkyl, C 6- i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; and heteroaryl; or R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or
  • each R 17 is independently selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C 6 -i2arylCi- 6 alkyl; heterocyclyl; and heteroaryl;
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; and heteroaryl;
  • each R 19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci- 6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; and heteroaryl;
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl;
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -N0 2 ; -NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 10 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
  • each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -N0 2 ; -NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 11 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; -NH 2 ; hydroxyl;C 6- i2aryl; -NR 15 R 16 ; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i 2 cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; cyano; -C(0)NR 15 R 16 ; -C(0)R 19 ; -N0 2 ; - NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 12 together with the atom to which they
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; 5 C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; -SR 18 ; cyano; -C0 2 R 19 ; -C(0)NR 15 R 16 ; -C(0)R 19 ; -N0 2 ; -NHC(0)R 19 ; and -NHC(0)NR 15 R 16 ; wherein two Z 14 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; 10 hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl;
  • r is selected from 0, 1 or 2, more preferably from 0 or 1 ;
  • a 1 is S; N; or NR 8 ; more preferably A 1 is S; N; NH or -N-Ci -6 alkyl;
  • a 2 is N; or NR 9 ; more preferably A 2 is N; NH or -N-Ci -6 alkyl;
  • X 1 is NR 10 ; or S; more preferably X 1 is NR 10 ; more preferably X 1 is NH; or -N-Ci -6 alkyl;
  • R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -SR 18 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; Ci -6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; haloCi -6 alkyl; haloCi- 6 alkyloxy; carboxyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of
  • each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one
  • R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ;
  • R 8 is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; Ci- 6 alkylcarbonyl; and Ci- 6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 2 ; preferably R 8 is selected from the group consisting of Ci- 6 alkyl; C
  • R 9 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl;
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi -6 alkyloxy; Ci -6 alkyl; C 3-8 cycloalkyl; C 6- i2aryl; hydroxyl; -OR 17 ; heterocyclyl; heteroaryl; C 6 -i2arylCi -6 alkyl; cyano; -NR 15 R 16 ; -NHC(0)NHR 19 ; and NHC(0)R 19 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ; preferably R 4 is selected from hydrogen; -NO2; - NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi- 6 alkyloxy; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2aryl; hydroxyl; -OR
  • R 2 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; C 6 -i 2 aryl; C 3 - 8 cycloalkyl; heterocyclyl; heteroaryl; C 6- i2arylCi -6 alkyl; halo; haloCi- 6 alkyl; and
  • R 3 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; C 6 -i 2 aryl; C 3 - 8 cycloalkyl; heterocyclyl; heteroaryl; C 6- i2arylCi -6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 7 ; preferably R 3 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one
  • R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C 6 -i2arylCi- 6 alkyl; Ci -6 alkylcarbonyl; and Ci -6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or Ci- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5- , or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of
  • each R 18 is independently C 6- i2aryl; or hydrogen; preferably each R 18 is independently C 6- i2aryl;
  • each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 2 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 2 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 3 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 3 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl;
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; hydrogen; C 3- i 2 cycloalkyl; C 6- i 2 aryl; heterocyclyl; heteroaryl; preferably each Z 5 is independently selected from the group consisting of -
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 6 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 7 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 8 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each dotted line individually represents an optional double bond
  • r is selected from 0 or 1 ;
  • a 1 is S; N; NH or -N-Ci -6 alkyl;
  • a 2 is N; NH or -N-Ci -6 alkyl
  • X 1 is NR 10 ; preferably X 1 is NH; or -N-Ci -6 alkyl;
  • R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; haloCi -6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of halo; NH 2 ; -NR 15 R 16 ; -OR 17 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; C 1-6 alkyl; C 6 -i 2 aryl; C 3-8 cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of hal
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi- 6 alkyloxy; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2aryl; hydroxyl; -OR 17 ; cyano; -NR 15 R 16 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ; preferably R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi- 6 alkyloxy; Ci- 6 alkyl; cyano; -NR 15 R
  • R 2 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 6 ; preferably R 2 is selected from the group consisting of hydrogen; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; preferably R 2 is hydrogen or Ci- 6 alkyl; preferably R 2 is hydrogen;
  • R 3 is selected from hydrogen; -NH 2 ; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 7 ; preferably R 3 is selected from the group consisting of hydrogen; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; preferably R 3 is hydrogen or Ci- 6 alkyl; preferably R 3 is hydrogen;
  • R 10 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or Ci- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci- 6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; preferably each R 19 is independently hydrogen; or Ci -6 alkyl; preferably each R 19 is independently hydrogen;
  • each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci_ 6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6 -i2aryl;
  • each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci_ 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 6 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 7 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl.
  • each dotted line individually represents an optional double bond
  • r is selected from 0 or 1 ;
  • a 1 is S; N; NH or -N-Ci -6 alkyl;
  • a 2 is N; NH or -N-Ci -6 alkyl
  • X 1 is NH; or -N-Ci -6 alkyl
  • R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; -NHC(0)NHR 19 ; NHC(0)R 19 ; Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z 1 ; preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; C 6- i2aryl; C 3 - 8 cycloalkyl; and heterocyclyl; preferably R 1 is selected from the group consisting of halo; -NH 2 ; -NR 15 R 16 ; -OR 17 ; and heterocyclyl;
  • R 4 is selected from hydrogen; -NO2; -NH 2 , halo; or from a group consisting of haloCi- 6 alkyl; haloCi- 6 alkyloxy; Ci- 6 alkyl; cyano; -NR 15 R 16 ; wherein each group can be unsubstituted or substituted with one or more Z 5 ; preferably R 4 is selected from hydrogen; -NO2; -NH 2 , halo; cyano; or from a group consisting of haloCi- 6 alkyl; haloCi- 6 alkyloxy; Ci- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 5 ; preferably R 4 is selected from hydrogen; -NO2; - NH 2 ;
  • R 2 is selected from the group consisting of hydrogen; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; preferably R 2 is hydrogen or Ci- 6 alkyl; preferably R 2 is hydrogen;
  • R 3 is selected from the group consisting of hydrogen; Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; preferably R 3 is hydrogen or Ci- 6 alkyl; preferably R 3 is hydrogen;
  • R 10 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 8 ; preferably R 10 is hydrogen or Ci -6 alkyl;
  • each R 15 is independently selected from hydrogen or Ci- 6 alkyl
  • R 16 is independently selected from the group consisting of hydrogen; -NH 2 ; Ci- 6 alkyl; Ci- 6 alkylaminoCi- 6 alkyl; and hydroxyCi -6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 17 is independently selected from the group consisting of Ci -6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; preferably each R 17 is Ci -6 alkyl or C 6- i 2 aryl; each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; preferably each R 18 is independently C6-i2aryl; or hydrogen; preferably each R 18 is independently each R 19 is independently hydrogen; or Ci- 6 alkyl; preferably each R 19 is independently hydrogen; each Z 1 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i 2 cycloalkyl; and C 6- i 2 aryl;
  • each Z 5 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i 2 cycloalkyl; and C 6- i 2 aryl;
  • each Z 8 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i 2 cycloalkyl; and C 6- i 2 aryl.
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • a 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NR 13 ; and O; more preferably A 5 is selected from the group consisting of N; NH; and O;
  • X 2 is selected from the group consisting of O; S; N; and NH;
  • Y 1 is CR 14 ; or NH;
  • R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; C 6 -i2arylCi- 6 alkyl; Ci -6 alkylcarbonyl; and Ci -6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; and C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or
  • R 13 is hydrogen; or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; C 6 -i2arylCi- 6 alkyl; Ci -6 alkylcarbonyl; and Ci -6 alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z 11 ; preferably R 13 is hydrogen; or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; and C 3-8 cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 11 ; preferably R 13 is hydrogen; or Ci- 6 alkyl unsubstituted or substituted with one or more Z 11 ; preferably R 13 is hydrogen;
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy;
  • R 5 is hydrogen or is selected from the group consisting of -NH 2 ; hydroxyl; -NR 15 R 16 ; -OR 17 ; -SR 18 ; Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy
  • R 6 is hydrogen or is selected from the group consisting of -OR 17 ; -NH 2 ; hydroxyl, -NR 15 R 16 ; -SR 18 ; Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi -6 alkyl; halo; haloCi -6 alkyl; haloCi- 6 alkyloxy; -NO2; cyano; wherein each group can be unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; halo; haloCi- 6 alkyl; haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 14 ;
  • R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z 14 ; or preferably R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; C 3-8 cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of
  • each R 18 is independently C 6- i2aryl; or hydrogen; preferably each R 18 is independently C 6- i2aryl;
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 10 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 11 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 11 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo;
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci- 6 alkyloxy; hydroxyl;C6-i2aryl;
  • Ci -6 alkyl C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy;
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci- 6 alkyloxy; hydroxyl;C 6- i2aryl; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; and C6-i2arylCi -6 alkyl; each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; heterocyclyl; heterocyclylCi -6 alkyl; heteroaryl; heteroarylCi -6 alkyl; carboxyl; wherein two Z 14 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroary
  • each dotted line individually represents an optional double bond
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • a 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NH; and O;
  • X 2 is selected from the group consisting of O; S; N; and NH;
  • Y 1 is CR 14 ; or NH;
  • R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; C 3-8 cycloalkyl; and C6-i2arylCi- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C6-i2aryl; and C6-i2arylCi- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; C6-i2aryl; and C 6 -i2arylCi- 6 alkyl;
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy;
  • R 5 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; halo; haloCi- 6 alkyl; and haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 13 ; preferably R 5 is hydrogen or is Ci- 6 alkyl unsubstituted or substituted with one or more Z 13 ; preferably R 5 is hydrogen or is Ci- 6 alkyl; preferably R 5 is hydrogen;
  • R 6 is hydrogen or is selected from the group consisting of Ci- 6 alkyl; halo; haloCi- 6 alkyl; haloCi- 6 alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or Ci- 6 alkyl; preferably R 6 is hydrogen;
  • R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl; C 3-8 cycloalkyl; C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 15 ; preferably R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C 6- i2aryl; Ci -6 alkyl; C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 15 ;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci- 6 alkyl; C 6- i 2 aryl; C 3-8 cycloalkyl; preferably each R 19 is independently hydrogen; or Ci -6 alkyl; preferably each R 19 is independently hydrogen;
  • each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i 2 cycloalkyl; and C 6- i2aryl; each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2
  • each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; hydroxyl;C 6- i2aryl; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; C 3- i2cycloalkyl; C6-i2arylCi -6 alkyl; heterocyclyl; heteroaryl; preferably each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; hydroxyl;C 6- i2aryl; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl;
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci- 6 alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci -6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 15 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; -NR 15 R 16 ; -OR 17 ; Ci -6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3 -i 2 cycloalkyl; C6-i2aryl; C6-i2arylCi- 6 alkyl; wherein two Z 15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z 15 is independently selected from the group consisting of halo; hydroxyl; -OR 17 ; Ci- 6 alkyl; haloCi- 6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i2cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; wherein two Z 15 together with the atom to which they are attached can form
  • each dotted line individually represents an optional double bond
  • a 3 is selected from the group consisting of S; O; NR 11 ; and N;
  • a 4 is selected from the group consisting of CR 12 ; N; and CH;
  • a 5 is selected from the group consisting of N; NH; and O;
  • X 2 is selected from the group consisting of O; S; N; and NH;
  • Y 1 is CR 14 ; or NH;
  • R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; and C6-i2arylCi -6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 9 ; preferably R 11 is hydrogen or is selected from the group consisting of Ci -6 alkyl; C 6- i2aryl; and C6-i2arylCi -6 alkyl;
  • R 7 is selected from the group consisting of C 6 -i2aryloxyC 6 -i2aryl; C 6- i2aryl; hydrogen; Ci -6 alkyloxy; C 6 -i2arylaminocarbonyl; C 6 -i2arylaminocarbonylC 6 -i2aryl; NHC(0)R 19 ; carboxyl, Ci -6 alkyl; -OR 17 ; heteroaryl; C6-i2arylCi -6 alkyl; Ci -6 alkoxycarbonyl; C 6 -i2arylthioC 6 -i2aryl; and C 3-8 cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z 12 ;
  • R 5 is hydrogen or is Ci- 6 alkyl unsubstituted or substituted with one or more Z 13 ; preferably R 5 is hydrogen or is Ci- 6 alkyl; preferably R 5 is hydrogen;
  • R 6 is hydrogen or Ci- 6 alkyl unsubstituted or substituted with one or more Z 14 ; preferably R 6 is hydrogen or Ci- 6 alkyl; preferably R 6 is hydrogen;
  • R 14 is hydrogen or is selected from the group consisting of hydroxyl; -OR 17 ; C6-i2aryl; Ci- 6 alkyl; C6-i2arylCi- 6 alkyl; wherein each group can be unsubstituted or substituted with one or more Z 15 ; each R 15 is independently selected from hydrogen or Ci- 6 alkyl;
  • each R 16 is independently selected from the group consisting of hydrogen; -NH 2 ; Ci- 6 alkyl; Ci- 6 alkylaminoCi- 6 alkyl; and hydroxyCi- 6 alkyl;
  • R 15 and R 16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
  • each R 17 is Ci -6 alkyl or C 6- i2aryl
  • each R 18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci- 6 alkyl; preferably each R 18 is independently C6-i2aryl; or hydrogen; preferably each R 18 is independently each R 19 is independently hydrogen; or Ci- 6 alkyl; preferably each R 19 is independently hydrogen; each Z 9 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i 2 cycloalkyl; and C 6- i 2 aryl;
  • each Z 10 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i 2 cycloalkyl; and C 6- i 2 aryl; each Z 12 is independently selected from the group consisting of -OR 17 ; haloCi- 6 alkyl; hydrogen, halo; Ci -6 alkyloxy; hydroxyl;C 6- i2aryl; Ci -6 alkyl; C 6- i2aryloxy; C6-i2arylCi -6 alkyloxy; -C0 2 R 19 ; carboxyl; SR 18 ; haloCi -6 alkyloxy; and C6-i2arylCi -6 alkyl;
  • each Z 13 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 14 is independently selected from the group consisting of -NH 2 ; halo; hydroxyl; Ci- 6 alkyl; hydrogen; C 3- i2cycloalkyl; and C 6- i2aryl;
  • each Z 15 is independently selected from the group consisting of halo; hydroxyl; -OR 17 ; Ci- 6 alkyl; haloCi -6 alkyl; haloCi -6 alkyloxy; hydrogen; C 3- i2cycloalkyl; C 6- i2aryl; C6-i2arylCi -6 alkyl; wherein two Z 15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z 15 is independently selected from the group consisting of halo; hydroxyl; -OR 17 ; Ci- 6 alkyl; haloCi- 6 alkyl; haloCi- 6 alkyloxy; hydrogen; wherein two Z 15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.

Abstract

This invention provides novel compounds of formulae (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof, (I) (II) wherein the substituents are as defined in the specification. The present invention also relates to the novel compounds for use as a medicine, more in particular for the prevention or treatment of amyloid-related diseases, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such amyloid-related diseases. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.

Description

Compounds for the treatment of amyloid-associated diseases Field of the invention
The present invention relates to novel compounds and to the novel compounds for use as a medicine, more in particular for the prevention or treatment of amyloid-associated diseases, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
Background of the invention
Several human disorders referred to as amyloidoses entail the accumulation and/or aggregation of misfolded proteins as a pathological characteristic and are therefore also referred to as protein- misfolding diseases. Most notably, Alzheimer's disease, Parkinson's disease and Huntington's disease are common diseases which involve aberrant aggregation of tau, alpha-synuclein and huntingtin respectively. [Misfolded Proteins in Alzheimer's Disease and Type II Diabetes, DeToma et al, 2012, Chem. Soc. Rev., 608-621]
The process or processes which lead to protein misfolding and aggregation is/are generally believed to be cytotoxic and as such may contribute to degeneration or failure of target cells such as neurons in the case of brain disorders such as Alzheimer's, Huntington's and Parkinson's diseases.
In neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, the mechanism underlying the protein aggregation itself, despite the fact that it involves different proteins across different indications, has common denominators. [Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis; Rakez Kayedl, Elizabeth Head2,Jennifer L. Thompson 1, Theresa M. Mclntire3,Saskia C. Milton 1, Carl W. Cotman2, Charles G. Glabel; Science 18 April 2003: Vol. 300 no. 5618 pp. 486-489;]. These observed mechanistic commonalities between protein misfolding disorders indicate that therapeutic interventions aimed to preserve cellular integrity are expected to be efficacious over a variety of disorders which involve protein aggregation. However, the precise mechanism as to the pathways and processes involved in cellular degeneration and protein aggregation is/are still highly elusive. Therefore, in the absence of detailed mechanistic insights as to the molecular mechanism involved, the use of phenotypic assays to identify small molecules which preserve cellular integrity in cellular and animal models of amyloidosis is relevant to find effective treatments for patients suffering amyloidoses such as Alzheimer's, Huntington's and Parkinson's disease. Importantly, such treatments will alter fundamentally the course of the disease as these preserve cellular integrity of the target cells such as neurons and beta-cells and thus are expected to be disease-modifying. As such these treatments are not merely reducing temporarily disease symptoms and therefore address an important current medical need. To date, treatments for neurodegenerative diseases, are focused on delaying the onset, or reducing the existing symptoms. For example, cholinesterase inhibitors and/or Memantine are given to Alzheimer's patients to delay the onset of cognitive symptoms. Levodopa is given to Parkinson's patients to temporarily diminish motor symptoms. Tetrabenazine has been recently approved for the symptomatic treatment of the abnormal involuntary movement (chorea) characteristic of Huntington's disease.
There is therefore a great need for treatments which preserve and/or refunctionalize cells affected in amyloidoses to prevent the development of associated symptoms in patients.
Summary of the invention
According to a first aspect of the present invention, a compound of formulae (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof is provided,
Figure imgf000003_0001
wherein,
- each dotted line individually represents an optional double bond,
- r is an integer selected from 0; 1 ; 2 or 3;
- A1 is selected from the group consisting of S; N; NR.8; and O;
- A2 is selected from the group consisting of N; NR.9, and S;
- X1 is selected from the group consisting of NR10; S; CO; SO; and SO2;
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; NR13; O, and S,
- X2 is selected from the group consisting of O; S; N; NH, SO; and SO2;
- Y1 is selected from the group consisting of CR14; NH; and N;
- R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19;
NHC(0)R19; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z1; * and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R8 is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl;
Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z2;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl;
C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z3;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; or R1 and R9 form together with the ring to which they are attached, a saturated or unsaturated 4-, 5- , or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z4;
- R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or
S(0)2;
- R2 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z6;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R3 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z7;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z8;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl;
C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R11 is hydrogen or is selected from the group consisting of ; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z9;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z10;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety can be oxidized to form at least one C=0, C=S,
N=0, N=S, S=0 or S(0)2;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z11;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; C2-6alkenyl; C2-6alkynyl; heterocyclyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13; * and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z14;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; haloCi-6alkyl; haloCi-6alkyloxy; and -N02; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted
14
with one or more Z ;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z4 is independently selected from the group consisting of Ci-6alkyl; -NH2; halo; hydroxyl; -NR15R16; -OR17; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z4 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of said Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl or heteroarylCi-6alkyl; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - each Z is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -S(0)R19; - S(0)2R19; -S02NR15R16; -N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
with the proviso that said compound is not:
- 2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one;
- 2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid;
- 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid;
- pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-; - pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-;
- acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide;
- pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 4-(dimethylamino)-1-(1 1 -hydroxy- 1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-;
- benzamide, 4-methoxy-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4-dimethyl-7-phenyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-;
- 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-;
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof.
Preferably, a compound of formulae (I) or (II), stereoisomer, enantiomer, racemic or tautomer thereof is provided, wherein,
- each dotted line individually represents an optional double bond, - r is an integer selected from 0; 1 ; 2 or 3;
- A1 is selected from the group consisting of S; N; NR8; and O;
- A2 is selected from the group consisting of N; NR9, and S;
- X1 is selected from the group consisting of NR10; S; SO; and SO2;
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; NR13; O, and S,
- X2 is selected from the group consisting of O; S; N; NH, SO; and SO2;
- Y1 is selected from the group consisting of CR14; NH; and N;
- R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19;
NHC(0)R19; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z1;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0,
C=S, N=0, N=S, S=0 or S(0)2;
- R8 is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z2;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl;
C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z3;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or
S(0)2;
- R2 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z6;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R3 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z7;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl;
Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z8;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z9;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19;
C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z10;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z11 ; * and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; C2-6alkenyl; C2-6alkynyl; heterocyclyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S,
S=0 or S(0)2;
- R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl;
C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - NO2; cyano; wherein each group can be unsubstituted or substituted with one or more Z14;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; haloCi-6alkyl; haloCi-6alkyloxy; and -NO2; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted
14
with one or more Z ;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -S(0)R19; - S(0)2R19; -S02NR15R16; -N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
with the proviso that said compound is not:
- 2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one;
- 2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid;
- 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid;
- pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-;
- acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide;
- pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 4-(dimethylamino)-1-(1 1 -hydroxy- 1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; - pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-, chloride (1 :1 );
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-;
- benzamide, 4-methoxy-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-;
- 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-;
- 2-hydrazino-1 ,6-dihydroimidazo[4,5-a]acridin-1 1-one;
- 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one;
- 2-methyl-6H-thiazolo[5,4-f]quinolin-9-one;
- 3,6-dihydrotriazolo[4,5-f]quinolin-9-one;
- 2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one;
- 7,8-dimethyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 2-(2-furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 7-methyl-2-(p-tolyl)-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 2,7-diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; and
- 2-(2-chlorophenyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof. According to a second aspect, the present invention also encompasses a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to the first aspect of the invention.
Preferably, a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound of a compound according to the first aspect of the invention or a therapeutically effective amount of a compound selected from the group comprising 3-ethyl-[1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 2-hydrazino-1 ,6- dihydroimidazo[4,5-a]acridin-1 1-one; 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one.
According to a third aspect, the present invention also encompasses a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for use as a medicament.
According to a fourth aspect, the present invention also encompasses a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, or a compound selected from the group consisting of
- 2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one;
- 2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid;
- 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid;
- pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-; - thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-;
- acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide;
- pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 4-(dimethylamino)-1-(1 1 -hydroxy- 1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-; - 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-;
5 - benzamide, 4-methoxy-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-;
10 - thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4-dimethyl-7-phenyl-;
15 - 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-;
- 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-;
- 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-;
20 for the prevention or treatment of amyloid-related diseases.
Preferably, the present invention also encompasses a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, or a compound selected from the group consisting of 2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6- cf][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-
25 oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid; pyrano[3,2-e]benzimidazol-9(1 H)-one, 2- amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-; thiazolo[5,4-a]acridin-1 1 (6H)- one, 2-[[3-(diethylamino)propyl]amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2- hydroxyethyl)amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-; pyridinium, 1-(6,1 1- dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-; pyridinium, 1-(6,1 1-dihydro-1-methyl-
30 1 1-OXO-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2- (dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-; acetic acid, 2-(6,1 1-dihydro-1- methyl-1 1-OXO-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide; pyridinium, 4-(dimethylamino)-1-(1 1- hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H- imidazo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-
35 4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5- a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H- imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); thiazolo[4,5-a]acridin-1 1 (6H)-one, 2- chloro-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-; 1 1 H-imidazo[4,5- a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6- dihydro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-; benzamide, 4-methoxy-N-(9-oxo- 7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H- pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3- g]benzothiazol-2-yl)-; benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4- dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-; 9H- [1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5- f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-; 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2- methyl-9-oxo-; and thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-; 2-methyl-6H-thiazolo[5,4-f]quinolin- 9-one; 2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one; 7,8-dimethyl-2-phenyl-1 ,6- dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 2-(2- furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-(p-tolyl)-1 ,6-dihydroimidazo[4,5- f]quinolin-9-one; 2,7-diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 2-(2-chlorophenyl)-7-methyl- 1 ,6-dihydroimidazo[4,5-f]quinolin-9-one,
for the prevention or treatment of amyloid-related diseases.
According to a fifth aspect, the present invention also encompasses a compound or a pharmaceutical composition according to the fourth aspect of the invention, wherein the amyloid- related diseases is selected from Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden- Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay- Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy.
The present invention also encompasses method for the preparation of the compounds according to the first aspect of the invention.
The independent and dependent claims and statements set out particular and preferred features of the invention. Features from the dependent claims and statements may be combined with features of the independent or other dependent claims and statement as appropriate.
The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Detailed description
Before the present invention is described, it is to be understood that this invention is not limited to particular compounds, methods, and processes described, as such compounds, methods, and processes may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
When describing the compounds and processes of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.
As used in the specification and the appended claims, the singular forms "a", "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.
The terms "comprising", "comprises" and "comprised of as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of also include the term "consisting of.
The term "about" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/-10% or less, preferably +1-5% or less, more preferably +/-1 % or less, and still more preferably +/-0.1 % or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" refers is itself also specifically, and preferably, disclosed.
As used herein, the term "and/or," when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and/or C, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination.
The recitation of numerical ranges by endpoints includes all integer numbers and, where appropriate, fractions subsumed within that range (e.g. 1 to 5 can include 1 , 2, 3, 4 when referring to, for example, a number of elements, and can also include 1 .5, 2, 2.75 and 3.80, when referring to, for example, measurements). The recitation of end points also includes the end point values themselves (e.g. from 1 .0 to 5.0 includes both 1 .0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein.
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims and statements, any of the embodiments can be used in any combination.
Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, definitions for the terms used in the description are included to better appreciate the teaching of the present invention.
When describing the present invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.
Whenever the term "substituted" is used herein, it is meant to indicate that one or more hydrogen atoms on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation from a reaction mixture.
Where groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents. Preferred substituents may be selected from but not limited to, for example, the group comprising halo; hydroxyl, Ci-6alkyl; Ci-6alkoxy; haloCi-6alkyl; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; Ci-6alkylthio; cyano; amino; nitro; carboxyl, aminocarbonyl; hydroxycarbonylCi-6alkyl; Ci-6alkyloxycarbonyl; mono- or diCi-6alkylamino; mono- or diCi-6alkylaminocarbonyl; Ci-6alkylcarbonyl; -S(0)Ci-6alkyl; -S(0)2Ci-6alkyl; Ci-6alkylcarbonylamino; and mono or di-Ci-6alkylaminocarbonylCi-6alkyl.
The terminology regarding a chemical group "wherein a carbon atom or heteroatom of said group can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2" as used herein, refers to a group where two or more hydrogen atoms on a carbon atom or heteroatom of said group are taken together to form C=0, C=S, N=0, N=S, S=0 or S(0)2. As an example, the terminology "an alkyl wherein a carbon atom or heteroatom of said alkyl can oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2", includes among other examples CH3-C(0)-CH2-, CH3-C(0)-, CH3-C(S)-CH2- and (CH3)2-CH2-C(0)-CH2-CH2-. For example, the terminology "a 5-, 6-, or 7-membered heterocyclyl wherein a carbon atom or heteroatom of said heterocyclyl can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2", includes among other examples 6-oxo-1 H-pyridin-3-yl, 2-oxo-1 H-pyridin- 4yl, 6-thioxo-1 H-pyridin-3-yl and 2-thioxo-1 H-pyridin-4yl.
The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo, iodo. The term "amino" refers to the group -NH2.
The term "hydroxyl" or "hydroxy" as used herein refers to the group -OH.
The term "thiol" or "sulfuhydryl" refers to the group -SH.
The term "oxo" as used herein refers to the group =0.
The term "thioxo" as used herein refers to the group =S.
The term "nitro" as used herein refers to the group -NO2.
The term "cyano" as used herein refers to the group -CN.
The term "carboxy" or "carboxyl" or "hydroxycarbonyl" as used herein refers to the group -CO2H. The term "aminocarbonyl" as used herein refers to the group -CO-NH2.
The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl group of formula CnH2n+i wherein n is a number greater than or equal to 1 . Alkyl groups may be linear or branched and may be substituted as indicated herein. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "Ci-6alkyl", as a group or part of a group, refers to a hydrocarbyl group of formula -CnH2n+i wherein n is a number ranging from 1 to 6. Thus, for example, "Ci_6alkyl" includes all linear or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers. For example, "Ci-5alkyl" includes all includes all linear or branched alkyl groups with between 1 and 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers. For example,
Figure imgf000025_0001
includes all linear or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl). For example "Ci_3alkyl" includes all linear or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl.
When the suffix "ene" is used in conjunction with an alkyl group, i.e. "alkylene", this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term "Ci-6alkylene", by itself or as part of another substituent, refers to Ci-6alkyl groups that are divalent, i.e., with two single bonds for attachment to two other groups. Alkylene groups may be linear or branched and may be substituted as indicated herein. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2-CH2-), methylmethylene (- CH(CH3)-), 1-methyl-ethylene (-CH(CH3)-CH2-), n-propylene (-CH2-CH2-CH2-), 2-methylpropylene (- CH2-CH(CH3)-CH2-), 3-methylpropylene (-CH2-CH2-CH(CH3)-), n-butylene (-CH2-CH2-CH2-CH2-), 2- methylbutylene (-CH2-CH(CH3)-CH2-CH2-), 4-methylbutylene (-CH2-CH2-CH2-CH(CH3)-), pentylene and its chain isomers, hexylene and its chain isomers.
The term "hydroxyCi-6alkyl" as a group or part of a group, refers to a Ci-6alkyl group having the meaning as defined above wherein one or more hydrogen atoms are each replaced with one or more hydroxyl as defined herein. Non-limiting examples of hydroxyCi-6alkyl group include hydroxymethyl, hydroxyethyl, and the like.
The term "haloCi-6alkyl" as a group or part of a group, refers to a Ci-6alkyl group having the meaning as defined above wherein one or more hydrogen atoms are each replaced with one or more halogen as defined herein. Non-limiting examples of such haloCi-6alkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 , 1 ,1-trifluoroethyl and the like.
The term "Ci-6alkoxy" or "Ci-6alkyloxy", as a group or part of a group, refers to a group having the formula -ORb wherein Rb is Ci-6alkyl as defined herein above. Non-limiting examples of suitable Ci_ 6alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
The term "haloCi-6alkoxy", as a group or part of a group, refers to a group of formula -0-Rc wherein Rc is haloCi-6alkyl as defined herein. Non-limiting examples of suitable haloCi-6alkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 , 1 ,2,2-tetrafluoroethoxy, 2- fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2- bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.
The term "Ci-6alkoxycarbonyl", as a group or part of a group, refers to a group formula -COO-Rd wherein Rd is selected from Ci-6alkyl as defined herein.
The term "Ci-6alkylcarbonyl", as a group or part of a group, refers to a group formula -CO-R1 wherein R1 is selected from Ci-6alkyl as defined herein.
The term "Ci-6alkylamino", as a group or part of a group, refers to a group formula -N(R°)(R ) wherein R° and R are each independently selected from hydrogen, or Ci-6alkyl, wherein at least one of R° or R is Ci-6alkyl. Thus, alkylamino include mono-alkyl amino group (e.g. mono-Ci-6alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-Ci-6alkylamino group such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-Ci_ 6alkylamino groups include n-propylamino, isopropylamino, n-butylamino, /-butylamino, sec- butylamino, f-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-/-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-/'-propylamino, n-butylmethylamino, /- butylmethylamino, f-butylmethylamino, ethyl-n-propylamino, ethyl-/'-propylamino, n-butylethylamino, i-butylethylamino, f-butylethylamino, di-n-butylamino, di-/-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.
The term "Ci-6alkylaminoCi-6alkyl", as a group or part of a group, means a Ci-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one Ci-6alkylamino as defined herein.
The term "Ci-6alkylsulfinyl", as a group or part of a group, refers to a group of formula -SO-R9 wherein R9 is Ci-6alkyl as defined herein. The term "Ci-6alkylsulfonyl", as a group or part of a group, refers to a group of formula -S02-Rh wherein Rh is Ci-6alkyl as defined herein.
The term "cyanoCi-6alkyl", as a group or part of a group, refers to a group of formula -R -CN wherein R is Ci-6alkylene as defined herein. Non-limiting examples of cyanoCi-6alkyl group include cyanomethyl, cyanoethyl, and the like.
The term "alkenyl" as a group or part of a group, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon double bonds. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "C2-6alkenyl" refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon-carbon double bonds and comprising from 2 to 6 carbon atoms. For example, C2-4alkenyl includes all linear, or branched alkenyl groups having 2 to 4 carbon atoms. Examples of C2-6alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl. and the like.
Where alkenyl groups as defined herein are divalent groups having single bonds for attachment to two other groups, they are termed "alkenylene". As used herein, the term "C2-6alkenylene", by itself or as part of another substituent, refers to C2-6alkenyl groups that are divalent, i.e., with two single bonds for attachment to two other groups.
The term "alkynyl" by itself or as part of another substituent, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon triple bonds. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "C2-6alkynyl" refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon- carbon triple bonds and comprising from 2 to 6 carbon atoms. For example, C2-4alkynyl includes all linear, or branched alkynyl groups having 2 to 4 carbon atoms. Non limiting examples of C2-6alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its chain isomers, 2-hexynyl and its chain isomers, and the like.
Where alkynyl groups as defined herein are divalent groups having single bonds for attachment to two other groups, they are termed "alkynylene". As used herein, the term "C2-6alkynylene", by itself or as part of another substituent, refers to C2-6alkynyl groups that are divalent, i.e., with two single bonds for attachment to two other groups.
The term "cycloalkyl", as a group or part of a group, refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 12 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms, still more preferably from 5 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups containing one or more rings, including monocyclic or bicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "Cs-scycloalkyl", a cyclic alkyl group comprising from 3 to 8 carbon atoms. For example, the term "C3-6cycloalkyl", a cyclic alkyl group comprising from 3 to 6 carbon atoms. Examples of C3-i2cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; cycloheptyl, cyclooctyl, bicycle[2.2.1 ]heptan-2yl; (1 S,4R)-norbornan-2-yl; (1 R,4R)- norbornan-2-yl; (1 S,4S)-norbornan-2-yl; (1 R,4S)-norbornan-2-yl.
When the suffix "ene" is used in conjunction with a cycloalkyi group, i.e. cycloalkylene, this is intended to mean the cycloalkyi group as defined herein having two single bonds as points of attachment to other groups. Non-limiting examples of "Cs-scycloalkylene" include 1 ,2-cyclopropylene, 1 ,1-cyclopropylene, 1 ,1-cyclobutylene, 1 ,2-cyclobutylene, 1 ,3-cyclopentylene, 1 ,1-cyclopentylene, and 1 ,4-cyclohexylene.
Where an alkylene or cycloalkylene group is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a Csalkylene group may be for example *- CH CH2CH2-*, *-CH(-CH2CH3)-* or *-CH2CH(-CH3)-*. Likewise a C3cycloalkylene group may be
Figure imgf000028_0001
As used herein, the term "spiro atom" refers to the atom that connects two cyclic structures in a spiro compound. Non limiting examples of spiro atoms include quaternary carbon atoms. As used herein, the term "spiro compound" refers to a bicyclic compound wherein the two rings are connected through one atom.
The term "C6-i2aryl", as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), or linked covalently, typically comprising 6 to 12 carbon atoms; wherein at least one ring is aromatic, preferably comprising 6 to 10 carbon atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyi, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryl include C6-ioaryl, more preferably C6-saryl. Non-limiting examples of C6-i2aryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azulenyl, 4-, 5-, 6 or 7-indenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and 1 ,4-dihydronaphthyl; 1-, 2-, 3-, 4- or 5-pyrenyl.
When the suffix "ene" is used in conjunction with an aryl group; i.e. arylene, this is intended to mean the aryl group as defined herein having two single bonds as points of attachment to other groups. Suitable "C6-i2arylene" groups include 1 ,4-phenylene, 1 ,2-phenylene, 1 ,3-phenylene, biphenylylene, naphthylene, indenylene, 1-, 2-, 5- or 6-tetralinylene, and the like. Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring. The term "C6-i2arylCi-6alkyl", as a group or part of a group, means a Ci-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryl as defined herein. Non- limiting examples of C6-i2arylCi-6alkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.
The term "C6-i2arylC2-6alkenyl", as a group or part of a group, means a C2-6alkenyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryl as defined herein. Non- limiting examples of C6-i2arylC2-6alkenyl group include styryl, cinnamyl, 2,2-diphenylvinyl, and the like.
The term "C6-i2arylC2-6alkynyl", as a group or part of a group, means a C2-6alkynyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryl as defined herein. Non- limiting examples of C6-i2arylC2-6alkynyl group include 2-pneylethynyl, and the like.
The term "C6-i2aryloxyCi-6alkyl", as a group or part of a group, means a Ci-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryloxy. Non-limiting examples of C6-i2aryloxyCi-6alkyl group include phenoxymethyl, phenoxyethyl, naphthyloxymethyl, naphthyloxyethyl and the like.
The term "C6-i2aryloxy", as a group or part of a group, refers to a group having the formula -OR9 wherein R9 is C6-i2aryl as defined herein above.
The term "C6-i2aryloxyC6-i2aryl", as a group or part of a group, means a C6-i2aryl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2aryloxy. Non-limiting examples of C6-i2aryloxyC6-i2aryl group include phenoxyphenyl, naphthyloxyphenyl, and the like.
The term "C6-i2arylthio", as a group or part of a group, refers to a group having the formula -SRm wherein Rm is C6-i2aryl as defined herein above.
The term "C6-i2arylthioC6-i2aryl", as a group or part of a group, means a C6-i2aryl as defined herein, wherein at least one hydrogen atom is replaced by at least one C6-i2arylthio. Non-limiting examples of C6-i2arylthioC6-i2aryl group include phenylsulfanylphenyl, naphthylsulfanylphenyl, and the like.
The term "C6-i2arylaminocarbonyl", as a group or part of a group, refers to a group of formula -CO- N R°R wherein R°R are each independently selected from hydrogen, Ci-6alkyl or C6-i2aryl, wherein at least one of R° or R is C6-i2aryl as defined herein.
The term "C6-i2arylaminocarbonylC6-i2aryl", as a group or part of a group, refers to a group of formula -Ra-CO-NR°R wherein R°R are each independently selected from hydrogen, Ci-6alkyl or C6-i2aryl, wherein at least one of R° or R is C6-i2aryl, and Ra is C6-i2arylene as defined herein.
The terms "heterocyclyl" or "heterocycloakyl", as a group or part of a group, refer to non-aromatic, fully saturated or partially unsaturated cyclic groups containing one or more cycles (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms) which can be fused together or linked covalently, wherein at least one the cycles contains at least one heteroatom, selected from N, O and/or S atoms, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. Preferably, each heterocyclyl may contain from 3 to 12 atoms, preferably from 3 to 8 atoms, more preferably from 3 to 6 atoms. Preferably, each ring of the heterocyclyl contains 1 , 2, 3 or 4 heteroatoms selected from N , O and/or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=0. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, oxetanyl, pyrrolidinyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl); 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2- pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3- dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1- dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The term "aziridinyl" as used herein includes aziridin-1-yl and aziridin-2-yl. The term "oxyranyl" as used herein includes oxyranyl-2-yl. The term "thiiranyl" as used herein includes thiiran-2-yl. The term "azetidinyl" as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl. The term "oxetanyl" as used herein includes oxetan-2-yl and oxetan-3-yl. The term "thietanyl" as used herein includes thietan-2-yl and thietan-3- yl. The term "pyrrolidinyl" as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl. The term "tetrahydrofuranyl" as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term "tetrahydrothiophenyl" as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term "succinimidyl" as used herein includes succinimid-1-yl and succininmid-3-yl. The term "dihydropyrrolyl" as used herein includes 2,3-dihydropyrrol-1-yl, 2,3- dihydro-1 H-pyrrol-2-yl, 2,3-dihydro-1 H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1 H-pyrrol-3-yl and 2,5-dihydropyrrol-5-yl. The term "2H-pyrrolyl" as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol- 3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl. The term "3H-pyrrolyl" as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol-5-yl. The term "dihydrofuranyl" as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5- dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl. The term "dihydrothiphenyl" as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3- dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl and 2,5-dihydrothiophen-5-yl. The term "imidazolidinyl" as used herein includes imidazolidin-1-yl, imidazolidin-2-yl and imidazolidin-4-yl. The term "pyrazolidinyl" as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term "imidazolinyl" as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term "pyrazolinyl" as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin- 3- yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-
4- yl and 3-pyrazolin-5-yl. The term "dioxolanyl" also known as "1 ,3-dioxolanyl" as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term "dioxolyl" also known as "1 ,3- dioxolyl" as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl. The term "oxazolidinyl" as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term "isoxazolidinyl" as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term "oxazolinyl" as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2- oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3- yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term "isoxazolinyl" as used herein includes 2- isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3-isoxazolinyl-4-yl, 3- isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl and 4-isoxazolinyl-5-yl. The term "thiazolidinyl" as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term "isothiazolid inyl" as used herein includes isothiazolidin-2-yl, isothiazolidin- 3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term "thiazolinyl" as used herein includes 2- thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5- yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl and 4-thiazolinyl-5-yl. The term "isothiazolinyl" as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3- yl, 4-isothiazolinyl-4-yl and 4-isothiazolinyl-5-yl. The term "piperidyl" also known as "piperidinyl" as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl. The term "dihydropyridinyl" as used herein includes 1 ,2-dihydropyridin-1-yl, 1 ,2-dihydropyridin-2-yl, 1 ,2- dihydropyridin-3-yl, 1 ,2-dihydropyridin-4-yl, 1 ,2-dihydropyridin-5-yl, 1 ,2-dihydropyridin-6-yl, 1 ,4- dihydropyridin-1-yl, 1 ,4-dihydropyridin-2-yl, 1 ,4-dihydropyridin-3-yl, 1 ,4-dihydropyridin-4-yl, 2,3- dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3- dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5- dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4- dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl and 3,4-dihydropyridin-6-yl. The term "tetrahyd ropy rid inyl" as used herein includes 1 ,2,3,4-tetrahydropyridin-1-yl, 1 ,2,3,4-tetrahydropyridin-2-yl, 1 ,2,3,4- tetrahydropyridin-3-yl, 1 ,2,3,4-tetrahydropyridin-4-yl, 1 ,2,3,4-tetrahydropyridin-5-yl, 1 ,2,3,4- tetrahydropyridin-6-yl, 1 ,2,3,6-tetrahydropyridin-1-yl, 1 ,2,3,6-tetrahydropyridin-2-yl, 1 ,2,3,6- tetrahydropyridin-3-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, 1 ,2,3,6-tetrahydropyridin-5-yl, 1 ,2,3,6- tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5- tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl and 2,3,4,5- tetrahydropyridin-6-yl. The term "tetrahydropyranyl" also known as "oxanyl" or "tetrahydro-2H- pyranyl", as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4- yl. The term "2H-pyranyl" as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H- pyran-5-yl and 2H-pyran-6-yl. The term "4H-pyranyl" as used herein includes 4H-pyran-2-yl, 4H- pyran-3-yl and 4H-pyran-4-yl. The term "3,4-dihydro-2H-pyranyl" as used herein includes 3,4- dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran- 5-yl and 3,4-dihydro-2H-pyran-6-yl. The term "3,6-dihydro-2H-pyranyl" as used herein includes 3,6- dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran- 5-yl and 3,6-dihydro-2H-pyran-6-yl. The term "tetrahydrothiophenyl", as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl. The term "2H- thiopyranyl" as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H- thiopyran-5-yl and 2H-thiopyran-6-yl. The term "4H-thiopyranyl" as used herein includes 4H- thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl. The term "3,4-dihydro-2H-thiopyranyl" as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H- thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl. The term "3,6- dihydro-2H-thiopyranyl" as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H- thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H- thiopyran-6-yl. The term "piperazinyl" also known as "piperazidinyl" as used herein includes piperazin-1-yl and piperazin-2-yl. The term "morpholinyl" as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term "thiomorpholinyl" as used herein includes thiomorpholin- 2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term "dioxanyl" as used herein includes 1 ,2- dioxan-3-yl, 1 ,2-dioxan-4-yl, 1 ,3-dioxan-2-yl, 1 ,3-dioxan-4-yl, 1 ,3-dioxan-5-yl and 1 ,4-dioxan-2-yl. The term "dithianyl" as used herein includes 1 ,2-dithian-3-yl, 1 ,2-dithian-4-yl, 1 ,3-dithian-2-yl, 1 ,3- dithian-4-yl, 1 ,3-dithian-5-yl and 1 ,4-dithian-2-yl. The term "oxathianyl" as used herein includes oxathian-2-yl and oxathian-3-yl. The term "trioxanyl" as used herein includes 1 ,2,3-trioxan-4-yl, 1 ,2,3-trioxay-5-yl, 1 ,2,4-trioxay-3-yl, 1 ,2,4-trioxay-5-yl, 1 ,2,4-trioxay-6-yl and 1 ,3,4-trioxay-2-yl. The term "azepanyl" as used herein includes azepan-1 -yl, azepan-2-yl, azepan-1-yl, azepan-3-yl and azepan-4-yl. The term "homopiperazinyl" as used herein includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl. The term "indolinyl" as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term "isoindolinyl" as used herein includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term "3H- indolyl" as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6- yl, and 3H-indol-7-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2- yl, quinolizidin-3-yl and quinolizidin-4-yl. The term "quinolizinyl" as used herein includes quinolizidin- 1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term "tetrahydroquinolinyl" as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term "tetrahydroisoquinolinyl" as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term "chromanyl" as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl. The term "1 H-pyrrolizine" as used herein includes 1 H-pyrrolizin-1-yl, 1 H-pyrrolizin-2-yl, 1 H-pyrrolizin-3-yl, 1 H-pyrrolizin-5-yl, 1 H-pyrrolizin-6-yl and 1 H-pyrrolizin-7-yl. The term "3H- pyrrolizine" as used herein includes 3H-pyrrolizin-1-yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3-yl, 3H- pyrrolizin-5-yl, 3H-pyrrolizin-6-yl and 3H-pyrrolizin-7-yl.
When the suffix "ene" is used in conjunction with a heterocyclyl group; i.e. "heterocyclylene", this is intended to mean the heterocyclyl group as defined herein having two single bonds as points of attachment to other groups.
The term "heterocyclylCi-6alkyl", as a group or part of a group, means a Ci-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one heterocyclyl as defined herein.
The term "heteroaryl" as a group or part of a group, refers but is not limited to 5 to 12 atom aromatic rings or ring systems containing one or more rings (for example 1 , 2, or 3 rings) which can be fused together or linked covalently, typically containing 5 to 12 atoms; wherein at least one the rings is aromatic and contains at least one heteroatom, selected from N, O and/or S atoms, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=0. Preferably each ring may contain from 5 to 10 atoms, preferably from 5 to 8 atoms, more preferably from 5 to 6 atoms. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2- benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2, 1 ,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2, 1 ,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one; 2,3- dihydro-benzofuranyl; thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 6-oxo-pyridazin-1 (6H)-yl, 2- oxopyridin-1 (2H)-yl, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group consisting of pyridyl, 1 ,3-benzodioxolyl, benzo[d]oxazol-2(3H)-one; 2,3-dihydro- benzofuranyl; pyrazinyl, pyrazolyl, pyrrolyl, isoxazolyl; thiophenyl; imidazolyl, benzimidazolyl, pyrimidinyl, triazolyl and thiazolyl.
The term "pyrrolyl" (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl. The term "furanyl" (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term "thiophenyl" (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term "pyrazolyl" (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term "imidazolyl" as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol- 4-yl and imidazol-5-yl. The term "oxazolyl" (also called 1 ,3-oxazolyl) as used herein includes oxazol- 2- yl; oxazol-4-yl and oxazol-5-yl. The term "isoxazolyl" (also called 1 ,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term "thiazolyl" (also called 1 ,3- thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4- thiazolyl and 5-thiazolyl). The term "isothiazolyl" (also called 1 , 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term "triazolyl" as used herein includes 1 H- triazolyl and 4H-1 ,2,4-triazolyl, H-triazolyl" includes 1 H-1 ,2,3-triazol-1-yl, 1 H-1 ,2,3-triazol-4-yl, 1 H- 1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1-yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl. "41-1-1 ,2,4- triazolyl" includes 4H-1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term "oxadiazolyl" as used herein includes 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1 ,2,3- thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1 H- tetrazol-1-yl, 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1 ,2,3,4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term "pyridinyl" (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl, 3- pyridyl and 4-pyridyl). The term "pyrimidyl" as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl. The term "pyrazinyl" as used herein includes pyrazin-2-yl and pyrazin-
3- yl. The term "pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term "oxazinyl" (also called "1 ,4-oxazinyl") as used herein includes 1 ,4-oxazin-4-yl and 1 ,4-oxazin-5-yl.
The term "dioxinyl" (also called "1 ,4-dioxinyl") as used herein includes 1 ,4-dioxin-2-yl and 1 ,4-dioxin- 3-yl. The term "thiazinyl" (also called "1 ,4-thiazinyl") as used herein includes 1 ,4-thiazin-2-yl, 1 ,4- thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl. The term "triazinyl" as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl. The term "imidazo[2,1-b][1 ,3]thiazolyl" as used herein includes imidazo[2,1- b][1 ,3]thiazoi-2-yl, imidazo[2,1-b][1 ,3]thiazol-3-yl, imidazo[2,1-b][1 ,3]thiazol-5-yl and imidazo[2,1- b][1 ,3]thiazol-6-yl. The term "thieno[3,2-b]furanyl" as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term "thieno[3,2- b]thiophenyl" as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2- b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term "thieno[2,3-d][1 ,3]thiazolyl" as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl. The term "thieno[2,3-d]imidazolyl" as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4- yl and thieno[2,3-d]imidazol-5-yl. The term "tetrazolo[1 ,5-a]pyridinyl" as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl. The term "indolyl" as used herein includes indol-1-yl, indol-2-yl, indol-3- yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term "isoindolyl" as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term "benzofuranyl" (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term "isobenzofuranyl" (also called benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term "benzothiophenyl" (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term "isobenzothiophenyl" (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-7- yl. The term "indazolyl" (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H-indazol- 1 -yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol- 2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term "benzimidazolyl" as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term "1 ,3-benzoxazolyl" as used herein includes 1 ,3-benzoxazol-2-yl, 1 ,3-benzoxazol-4-yl, 1 ,3-benzoxazol-5-yl, 1 ,3-benzoxazol-6-yl and 1 ,3-benzoxazol-7-yl. The term "1 ,2-benzisoxazolyl" as used herein includes 1 ,2-benzisoxazol-3- yl, 1 ,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1 ,2-benzisoxazol-7-yl. The term "2,1-benzisoxazolyl" as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl. The term "1 ,3- benzothiazolyl" as used herein includes 1 ,3-benzothiazol-2-yl, 1 ,3-benzothiazol-4-yl, 1 ,3- benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1 ,3-benzothiazol-7-yl. The term "1 ,2-benzoisothiazolyl" as used herein includes 1 ,2-benzisothiazol-3-yl, 1 ,2-benzisothiazol-4-yl, 1 ,2-benzisothiazol-5-yl, 1 ,2- benzisothiazol-6-yl and 1 ,2-benzisothiazol-7-yl. The term "2,1-benzoisothiazolyl" as used herein includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol- 6-yl and 2,1-benzisothiazol-7-yl. The term "benzotriazolyl" as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term "1 ,2,3- benzoxadiazolyl" as used herein includes 1 ,2,3-benzoxadiazol-4-yl, 1 ,2,3-benzoxadiazol-5-yl, 1 ,2,3- benzoxadiazol-6-yl and 1 ,2,3-benzoxadiazol-7-yl. The term "2,1 ,3-benzoxadiazolyl" as used herein includes 2, 1 ,3-benzoxadiazol-4-yl, 2, 1 ,3-benzoxadiazol-5-yl, 2, 1 ,3-benzoxadiazol-6-yl and 2, 1 ,3- benzoxadiazol-7-yl. The term "1 ,2,3-benzothiadiazolyl" as used herein includes 1 ,2,3- benzothiadiazol-4-yl, 1 ,2,3-benzothiadiazol-5-yl, 1 ,2,3-benzothiadiazol-6-yl and 1 ,2,3- benzothiadiazol-7-yl. The term "2,1 ,3-benzothiadiazolyl" as used herein includes 2, 1 ,3- benzothiadiazol-4-yl, 2, 1 ,3-benzothiadiazol-5-yl, 2,1 ,3-benzothiadiazol-6-yl and 2, 1 ,3- benzothiadiazol-7-yl. The term "thienopyridinyl" as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term "imidazo[1 ,2-a]pyridinyl", as used herein includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2-a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2-a]pyridin-7-yl. The term "1 ,3- benzodioxolyl", as used herein includes 1 ,3-benzodioxol-4-yl, 1 ,3-benzodioxol-5-yl, 1 ,3-benzodioxol- 6-yl, and 1 ,3-benzodioxol-7-yl. The term "quinolinyl" as used herein includes quinolin-2-yl, quinolin-3- yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6- yl, isoquinolin-7-yl and isoquinolin-8-yl. The term "cinnolinyl" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term "quinoxalinyl" as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.
When the suffix "ene" is used in conjunction with a heteroaryl group; i.e. "heteroarylene", this is intended to mean the heteroaryl group as defined herein having two single bonds as points of attachment to other groups.
The term "heteroarylCi-6alkyl", as a group or part of a group, means a Ci-6alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one heteroaryl as defined herein.
The term "leaving group" as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., CI, Br, I).
Whenever used in the present invention the term "compounds of the invention" or a similar term is meant to include the compounds of general formula (I) and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 and their derivatives, N-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, prodrugs, esters and metabolites, as well as their quaternized nitrogen analogues. The N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. The term "metabolite," as used herein, refers to compounds formed by in vivo biotransformation of compounds of formula I by oxidation, reduction, hydrolysis, or conjugation. A thorough discussion of biotransformation is provided in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, hereby incorporated by reference. Esters are meant to comprise compounds with hydroxyl and/or carboxyl which may accordingly form ester(s) with inorganic or organic acid(s) and/or alcohol(s) respectively.
The term "amyloid" refers to amyloidogenic proteins, peptides, or fragments thereof which can be soluble (e.g., monomeric or oligomeric) or insoluble (e.g., having fibrillary structure or in amyloid plaque). See, e.g., MP Lambert, et al, Proc. Nat 7 Acad. Sd. USA 95, 6448-53 (1998). "Amyloidosis" or "amyloid disease" or "amyloid-related disease" refers to a pathological condition characterized by the presence of amyloid fibers. "Amyloid" is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra. An amyloid related disease includes those diseases, disorders, conditions, pathologies, and other abnormalities, in which amyloid is observed either intracellularly or extracellularly in affected tissues.
Preferred statements (features) and embodiments of the compounds, methods and uses of this invention are set herein below. Each statements and embodiments of the invention so defined may be combined with any other statement and/or embodiments unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered aspects and embodiments 1 to 60, with any other statement and/or embodiments. 1. A compound of formulae (I) or (II), stereoisomer, enantiomer, racemic or tautomer thereof,
Figure imgf000037_0001
wherein,
- each dotted line individually represents an optional double bond,
- r is an integer selected from 0; 1 ; 2 or 3; preferably r is selected from 0, 1 or 2, more preferably from 0 or 1 ;
- A1 is selected from the group consisting of S; N; NR.8; and O; preferably A1 is S; N; or NR.8; more preferably A1 is S; N; NH or -N-Ci-6alkyl;
- A2 is selected from the group consisting of N; NR9, and S; preferably A2 is N; or NR9; more preferably A2 is N; NH or -N-Ci-6alkyl;
- X1 is selected from the group consisting of NR10; S; CO; SO; and SO2; preferably X1 is selected from NR10; S; CO; more preferably X1 is NR10; more preferably X1 is NH; or -N-Ci-6alkyl;
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; NR13; O, and S; preferably A5 is selected from the group consisting of N; NR13; and O; more preferably A5 is selected from the group consisting of N; NH; and O;
- X2 is selected from the group consisting of O; S; N; NH, SO; and SO2; preferably X2 is selected from the group consisting of O; S; N; and NH;
- Y1 is selected from the group consisting of CR14; NH; and N; preferably Y1 is CR14; or NH; - R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19;
NHC(0)R19; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; and heterocyclyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R8 is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl; unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; - R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl;
C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
or R1 and R9 form together with the ring to which they are attached, a saturated or unsaturated 4-, 5- , or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z4; preferably R1 and R9 form together with the ring to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z4; preferably R1 and R9 form together with the ring to which they are attached, a saturated or unsaturated 5-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z4; preferably R1 and R9 form together with the ring to which they are attached, a saturated 5-membered ring, said saturated ring can be unsubstituted or substituted with one or more Z4; preferably R1 and R9 form together with the ring to which they are attached, a dioxolane ring;
- R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; cyano; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; - NH2;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R2 is selected from hydrogen; -NH2; hydroxyl, -NO2; or cyano; or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R2 is hydrogen or Ci-6alkyl; preferably R2 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R3 is selected from hydrogen; -NH2; hydroxyl, -NO2, or cyano, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R3 is hydrogen or Ci-6alkyl; preferably R3 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl;
Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19;
C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is - NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; haloCi-6alkyl; haloCi-6alkyloxy; and carboxyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is selected from the group consisting of -NH2; =S, or halo, Ci-6alkyl; -NHC(0)NHR19; and C6-i2aryl;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or Ci-6alkyl unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy;
C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl;
C2-6alkenyl; C2-6alkynyl; heterocyclyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; C6-i2aryloxyCi-6alkyl;
Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl,
Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl;
C3-8cycloalkyl; hydroxyl; heterocyclyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl;
C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl;
C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NH2; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl;
C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl;
C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S,
S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl; preferably R5 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S,
S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl; preferably R6 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; haloCi-6alkyl; haloCi-6alkyloxy; and -N02; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring; - each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z1 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z2 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z3 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z4 is independently selected from the group consisting of Ci-6alkyl; -NH2; halo; hydroxyl; -NR15R16; -OR17; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z4 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of said Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl or heteroarylCi-6alkyl; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z4 is independently selected from the group consisting of Ci-6alkyl; -NH2; halo; hydroxyl; -NR15R16; -OR17; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z4 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z4 is independently selected from the group consisting of Ci-6alkyl; -NH2; halo; hydroxyl; -NR15R16; -OR17; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z4 is independently selected from the group consisting of Ci-6alkyl; -NH2; halo; hydroxyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; preferably each Z4 is independently selected from the group consisting of Ci-6alkyl; -NH2; halo; hydroxyl; haloCi-6alkyl; haloCi-6alkyloxy; and hydrogen;
- each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z5 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z6 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z7 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z8 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z9 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl; - each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -S(0)R19; - S(0)2R19; -S02NR15R16; -N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; d-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; and cyano; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; and C6-i2arylCi-6alkyl;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; with the proviso that said compound is not:
2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one;
2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid;
2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid;
pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-;
pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-;
acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide;
pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt;
pyridinium, 4-(dimethylamino)-1-(1 1 -hydroxy- 1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt;
pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-;
1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-;
1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-;
1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-;
benzamide, 4-methoxy-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-;
9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4-dimethyl-7-phenyl-;
9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-;
9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-;
9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-;
9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-;
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof. 2. A compound of formulae (I) or (II), stereoisomer, enantiomer, racemic or tautomer thereof, according to statement 1 ,
wherein,
- each dotted line individually represents an optional double bond,
- r is an integer selected from 0; 1 ; 2 or 3; preferably r is selected from 0, 1 or 2, more preferably from 0 or 1 ;
- A1 is selected from the group consisting of S; N; NR8; and O; preferably A1 is S; N; or NR8; more preferably A1 is S; N; NH or -N-Ci-6alkyl;
- A2 is selected from the group consisting of N; NR9, and S; preferably A2 is N; or NR9; more preferably A2 is N; NH or -N-Ci-6alkyl;
- X1 is selected from the group consisting of NR10; S; SO; and SO2; preferably X1 is NR10; or S; more preferably X1 is NR10; more preferably X1 is NH; or -N-Ci-6alkyl;
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; NR13; O, and S; preferably A5 is selected from the group consisting of N; NR13; and O; more preferably A5 is selected from the group consisting of N; NH; and O;
- X2 is selected from the group consisting of O; S; N; NH, SO; and SO2; preferably X2 is selected from the group consisting of O; S; N; and NH;
- Y1 is selected from the group consisting of CR14; NH; and N; preferably Y1 is CR14; or NH;
- R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19;
NHC(0)R19; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z1;preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; and heterocyclyl; * and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R8 is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl; unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl;
C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci_6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; cyano; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; - NH2;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl;
C6-i2aryl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or
S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R2 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R2 is hydrogen or Ci-6alkyl; preferably R2 is hydrogen; * and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R3 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -N02, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -N02, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R3 is hydrogen or Ci-6alkyl; preferably R3 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl;
Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci_6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19;
C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl;
Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -
NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; haloCi-6alkyl; haloCi-6alkyloxy; and carboxyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of
Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is selected from the group consisting of -NH2; =S, or halo, Ci-6alkyl; -NHC(0)NHR19; and C6-i2aryl; * and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or Ci-6alkyl unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-ealkyl; C2-6alkenyl; C2-6alkynyl, Ce-^aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-ealkyl; Ce-^aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-ealkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-ealkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; C2-6alkenyl; C2-6alkynyl; heterocyclyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12;preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NH2; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl; preferably R5 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl;
C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - NO2; cyano; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl; preferably R6 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; haloCi-6alkyl; haloCi-6alkyloxy; and -NO2; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; - each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z1 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z2 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z3 is independently selected from the group consisting of -
NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z5 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z6 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z7 is independently selected from the group consisting of -
NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl; - each Z is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z8 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z9 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -S(0)R19; - S(0)2R19; -S02NR15R16; -N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; and cyano; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; and C6-i2arylCi-6alkyl;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
- each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; with the proviso that said compound is not:
2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one;
2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid;
2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid;
pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-;
pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-;
acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide;
pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt;
pyridinium, 4-(dimethylamino)-1-(1 1 -hydroxy- 1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt;
pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-;
1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-;
1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-;
1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-;
benzamide, 4-methoxy-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-;
9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-;
thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-;
2-hydrazino-1 ,6-dihydroimidazo[4,5-a]acridin-1 1-one;
2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one;
2-methyl-6H-thiazolo[5,4-f]quinolin-9-one;
3.6- dihydrotriazolo[4,5-f]quinolin-9-one;
2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one;
7,8-dimethyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
2-(2-furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
7-methyl-2-(p-tolyl)-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
2.7- diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; and
2-(2-chlorophenyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof.
The compound according to statement 1 or 2, having formula (11 ) or (111 ),
Figure imgf000072_0001
(11 ) (111 ).
The compound according to statement 1 or 2, having one of formula (I2), (I3), (II2), (II3), (II4), (II5), (II6), (II7), (IIS), (II9),
Figure imgf000072_0002
(118) (119).
The compound according to any one of statements 1 , 2 or 4, wherein,
- A1 is selected from the group consisting of S; N; and NR8;
- A2 is N; or NR9;
- X1 is NR10.
The compound according to any one of statements 1 , 2, 4, or 5 wherein,
A1 is S; and A2 is N; or
A1 is N ; and A2 is N R9, or
A1 is NR8; and A2 is N.
The compound according to any one of statements 1 , 2 or 4, wherein,
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; O; NH, and S,
- X2 is selected from the group consisting of O; S; N; and NH,
- Y1 is CR14; or NH;
The compound according to any one of statements 1 , 2, 4 or, 7; wherein
- A3 is S; A4 is CR12; and A5 is N; or
- A3 is O; A4 is CR12; and A5 is N, or
- A3 is NR11; A4 is N; and A5 is N;
- A3 is N; A4 is CH; and A5 is O.
The compound according to any one of statements 1 to 6; wherein R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; and heterocyclyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl,
C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or
N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of
Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of
C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl; each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; 5 Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen;
each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; 10 carboxyl; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z1 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl.
15 10. The compound according to any one of statements 1 to 6, and 9, wherein R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z2;
20 preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl; unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of 25 Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - 30 N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; preferably each Z2 is independently selected from the group consisting of -NH2; halo; 35 hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z2 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; 5 C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen.
10 11. The compound according to any one of statements 1 to 6, and 9 to 10, wherein R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be
15 unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be 20 oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl;
25 carboxyl; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z3 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;each R15 is independently
30 selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl;
C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl,
35 C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl; each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
12. The compound according to any one of statements 1 to 6, and 9 to 1 1 , wherein R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy;
Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -
NO2; -NH2, halo; cyano; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z5 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of 5 Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; 10 C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen.
15 13. The compound according to any one of statements 1 to 6, and 9 to 12, wherein R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be
20 unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl;
each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; 25 carboxyl; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z8 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
30 each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of
35 Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl; each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
14. The compound according to any one of statements 1 to 4, and 7 to 8, wherein R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl;
each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z9 is independently selected from the group consisting of -
NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl; each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
15. The compound according to any one of statements 1 to 4, 7 to 8, and 14, wherein R12 is -NH2;
=S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; haloCi-6alkyl; haloCi-6alkyloxy; and carboxyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is selected from the group consisting of -NH2; =S, or halo, Ci-6alkyl; -NHC(0)NHR19; and C6-i2aryl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; Cs-scycloalkyl; and C6-i2aryl;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring; each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
16. The compound according to any one of statements 1 to 4, 7 to 8, and 14 to 15, wherein R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl;
C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl;
C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NH2; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy;
C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Ca-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Ca-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; - C02R19; carboxyl; SR18; haloCi-6alkyloxy; and C6-i2arylCi-6alkyl;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen.
7. The compound according to any one of statements 1 to 4, 7 to 8, and 14 to 16, wherein R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or
18. The compound according to any one of statements 1 to 17, wherein each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, 5 C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl.
19. The compound according to any one of statements 1 to 18, wherein each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at
10 least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably
15 each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl;
Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl.
20. The compound according to any one of statements 1 to 17, wherein R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring,
14 said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z ; 20 preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring.
21. The compound according to any one of statements 1 to 20, wherein each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl,
25 C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl
30 22. The compound according to any one of statements 1 to 21 , wherein each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or N=0; preferably each R18 is
35 independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl. . The compound according to any one of statements 1 to 22, wherein each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen.
. The compound according to any one of statement 1 , 3 to 6, 9 to 13 and 18 to 23, wherein,
- R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; d-6alkyl;
C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein each group can be unsubstituted or substituted with one or more Z1;
- R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z2;
- R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z3;
- R4 is selected from or from a group consisting of hydrogen; -NO2; -NH2; halo, haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; and hydroxyl;
- R2 is hydrogen;
- R3 is hydrogen;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z8. . The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17 and 18 to 23, wherein,
- R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2arylCi-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z9; - R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19;
C6-i2aryl; -NR15R16; -OR17; Cs-scycloalkyl; heterocyclyl; and heteroaryl; wherein each group can be unsubstituted or substituted with one or more Z10;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z11;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; Cs-scycloalkyl; hydroxyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z12;
- R5 is hydrogen; - R6 is hydrogen;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z15.
. The compound according to any one of statements 1 to 7, 9 to 13, and 18 to 24, wherein,
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or
14
substituted with one or more Z ;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; and -NHC(0)R19; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; - each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 25, wherein,
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or
14
substituted with one or more Z ;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-, membered ring;
- each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -N02; - NHC(0)R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; 5 C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
- each Z15 is independently selected from the group consisting of -NH2; halo; 10 hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-, membered ring.
15 28. The compound according to any one of statements 1 , 3 to 6, 9 to 13, 18 to 24, and 26, wherein each dotted line individually represents an optional double bond,
r is selected from 0, 1 or 2, more preferably from 0 or 1 ;
A1 is S; N; or NR8; more preferably A1 is S; N; NH or -N-Ci-6alkyl;
A2 is N; or NR9; more preferably A2 is N; NH or -N-Ci-6alkyl;
20 X1 is NR10; or S; more preferably X1 is NR10; more preferably X1 is NH; or -N-Ci-6alkyl;
R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19; NHC(0)R19; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of
25 halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one
30 or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17;
Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; and heterocyclyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably 35 wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl; unsubstituted or substituted with one or more Z2; preferably R8 is Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl;
C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z3; preferably R9 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; - NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; cyano; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R2 is hydrogen or Ci-6alkyl; preferably R2 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R3 is hydrogen or Ci-6alkyl; preferably R3 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5- , or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl,
C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or
N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of
Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of
C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen; each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z1 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z2 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z3 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z5 is independently selected from the group consisting of -
NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z6 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z7 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z8 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl.
29. The compound according to any one of statements 1 , 3 to 6, 9 to 13, 18 to 24, 26, and 28, wherein
each dotted line individually represents an optional double bond,
r is selected from 0 or 1 ;
A1 is S; N; NH or -N-Ci-6alkyl;
A2 is N; NH or -N-Ci-6alkyl;
X1 is NR10; preferably X1 is NH; or -N-Ci-6alkyl;
R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; C1-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; and heterocyclyl;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; cyano; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R2 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z6; preferably R2 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R2 is hydrogen or Ci-6alkyl; preferably R2 is hydrogen;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R3 is selected from hydrogen; -NH2; hydroxyl, cyano, -NO2, or is selected from the group consisting of -NR15R16; -OR17; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z7; preferably R3 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R3 is hydrogen or Ci-6alkyl; preferably R3 is hydrogen;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, Ce-^aryl, Cs-scycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or C6-i2aryl;
each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; Cs-scycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, Cs-scycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen;
each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci_6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci_6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl. 30. The compound according to any one of statements 1 , 3 to 6, 9 to 13, 18 to 24, 26, 28 to 29, wherein
each dotted line individually represents an optional double bond,
r is selected from 0 or 1 ;
A1 is S; N; NH or -N-Ci-6alkyl;
A2 is N; NH or -N-Ci-6alkyl;
X1 is NH; or -N-Ci-6alkyl;
R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -NHC(0)NHR19; NHC(0)R19; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z1; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and heterocyclyl; preferably R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; and heterocyclyl;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; cyano; -NR15R16; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; -NH2, halo; cyano; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z5; preferably R4 is selected from hydrogen; -NO2; - NH2;
R2 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R2 is hydrogen or Ci-6alkyl; preferably R2 is hydrogen;
R3 is selected from the group consisting of hydrogen; Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; preferably R3 is hydrogen or Ci-6alkyl; preferably R3 is hydrogen;
R10 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z8; preferably R10 is hydrogen or Ci-6alkyl;
each R15 is independently selected from hydrogen or Ci-6alkyl;
R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R17 is Ci-6alkyl or C6-i2aryl; each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen; each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl.
31. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, and 27, wherein each dotted line individually represents an optional double bond,
A3 is selected from the group consisting of S; O; NR11; and N;
A4 is selected from the group consisting of CR12; N; and CH;
A5 is selected from the group consisting of N; NR13; and O; more preferably A5 is selected from the group consisting of N; NH; and O;
X2 is selected from the group consisting of O; S; N; and NH;
Y1 is CR14; or NH;
R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl;
* and a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of C1-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; haloCi-6alkyl; haloCi-6alkyloxy; and carboxyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is selected from the group consisting of -NH2; =S, or halo, Ci-6alkyl; -NHC(0)NHR19; and C6-i2aryl;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; Ci-6alkylcarbonyl; and Ci-6alkoxycarbonyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen; or Ci-6alkyl unsubstituted or substituted with one or more Z11; preferably R13 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy;
C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of
C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl;
C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl;
C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NH2; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl;
C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl;
C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl; preferably R5 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NO2; cyano; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl; preferably R6 is hydrogen;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; * and a carbon atom or heteroatom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, N=0, S=0 or S(0)2; preferably wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, N=0; preferably each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14; or preferably R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, N=0; preferably each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C6-i2aryl,
C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, or
N=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of
Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of
C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0; preferably each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen; each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z9 is independently selected from the group consisting of - NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo;
Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -
C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; and cyano; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl;
Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy;
C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; and C6-i2arylCi-6alkyl; each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5- or 6-membered ring; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; and wherein at least one carbon atom of Ci-6alkyl; C3-i2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0; preferably each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
32. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, 27, and 31 , wherein
each dotted line individually represents an optional double bond,
A3 is selected from the group consisting of S; O; NR11; and N;
A4 is selected from the group consisting of CR12; N; and CH;
A5 is selected from the group consisting of N; NH; and O; X2 is selected from the group consisting of O; S; N; and NH;
Y1 is CR14; or NH;
R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl moiety; can be oxidized to form at least one C=0;
R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C3-8cycloalkyl; haloCi-6alkyl; haloCi-6alkyloxy; and carboxyl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is selected from the group consisting of -NH2; =S, or halo, Ci-6alkyl; -NHC(0)NHR19; and C6-i2aryl;
R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy;
C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; heterocyclyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -NH2; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; preferably R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy;
C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R5 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl; preferably R5 is hydrogen;
R6 is hydrogen or is selected from the group consisting of Ci-6alkyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl; preferably R6 is hydrogen;
R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; preferably R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0;
each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety can be oxidized to form at least one C=0; preferably each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl; can be oxidized to form at least one C=0; preferably each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; wherein at least one carbon atom of said Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl moiety; can be oxidized to form at least one C=0; preferably each R17 is Ci-6alkyl or C6-i2aryl;
each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; wherein at least one carbon atom of Ci-6alkyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0; preferably each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently C6-i2aryl;
each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; preferably each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen;
each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl; each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; preferably each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; and C6-i2arylCi-6alkyl;
each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl; preferably each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
33. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, 27, and 31 to 32, wherein
each dotted line individually represents an optional double bond,
A3 is selected from the group consisting of S; O; NR11; and N;
A4 is selected from the group consisting of CR12; N; and CH;
A5 is selected from the group consisting of N; NH; and O;
X2 is selected from the group consisting of O; S; N; and NH;
Y1 is CR14; or NH; R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z9; preferably R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and C6-i2arylCi-6alkyl;
R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; wherein each group can be unsubstituted or substituted with one or more Z10; preferably R12 is selected from the group consisting of -NH2; =S, or halo, C1-6alkyl; -NHC(0)NHR19; and C6-i2aryl;
R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; and C3-8cycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z12;
* and wherein a carbon atom of Ci-6alkyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0;
R5 is hydrogen or is Ci-6alkyl unsubstituted or substituted with one or more Z13; preferably R5 is hydrogen or is Ci-6alkyl; preferably R5 is hydrogen;
R6 is hydrogen or Ci-6alkyl unsubstituted or substituted with one or more Z14; preferably R6 is hydrogen or Ci-6alkyl; preferably R6 is hydrogen;
R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl; C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z15; each R15 is independently selected from hydrogen or Ci-6alkyl;
each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; and hydroxyCi-6alkyl;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring;
each R17 is Ci-6alkyl or C6-i2aryl;
each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; preferably each R18 is independently C6-i2aryl; or hydrogen; preferably each R18 is independently each R19 is independently hydrogen; or Ci-6alkyl; preferably each R19 is independently hydrogen; each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl; each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; hydroxyl;C6-i2aryl; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; and C6-i2arylCi-6alkyl;
each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; Ci-6alkyl; hydrogen; C3-i2cycloalkyl; and C6-i2aryl;
each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring; preferably each Z15 is independently selected from the group consisting of halo; hydroxyl; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
34. The compound according to any one of statements 1 to 6, 9 to 13, 18 to 24, 26, 28 to 30, having one of formula (I4), (I5), (I6), (I7), (I8), (I9), (110), (11 1 ), (112), (113),
Figure imgf000111_0001
111
Figure imgf000112_0001
Figure imgf000113_0001
(1116) (1117).
36. The compound according to statement 35, wherein X2 is O and the bond between Y1 and CR7 is a double bond.
5 37. The compound according to statement 35, wherein X2 is S and the bond between Y1 and CR7 is a double bond.
38. The compound according to statement 35, wherein X2 is N, and the bond between X2 and CR7 is a double bond.
39. The compound according to statement 35, wherein X2 is NH and the bond between Y1 and CR7 10 is a double bond.
40. The compound according to any one of statements 35 to 39, wherein Y1 is CR14 and the bond between Y1 and CR7 is a double bond.
41. The compound according to any one of statements 35 to 39, wherein Y1 is NH and the bond between X2 and CR7 is a double bond.
15 42. The compound according to any one of statements 1 to 6, 9 to 13, 18 to 24, 26, 28 to 30, and 34, wherein R2 is hydrogen.
43. The compound according to any one of statements 1 to 6, 9 to 13, 18 to 24, 26, 28 to 30, 34 and 42, wherein R3 is hydrogen.
44. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, 27, 31 to 33, and 20 35 to 41 , wherein R5 is hydrogen.
45. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, 27, 31 to 33, 35 to 41 , and 44, wherein R6 is hydrogen.
46. The compound according to any one of statements 1 to 6, 9 to 13, 18 to 24, 26, 28 to 30, 34, 42 and 43, wherein the bond between A1 and CR1 is a double bond and the bond between A2 and
25 CR1 is a single bond, or the bond between A2 and CR1 is a double bond and the bond between A1 and CR1 is a single bond.
47. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, 27, 31 to 33, 35 to 41 , 44 and 45, wherein the bond between Y1 and CR7 is a double bond and the bond between X2 and CR7 is a single bond; or the bond between X2 and CR7 is a double bond and the bond
30 between Y1 and CR7 is a single bond.
48. The compound according to any one of statements 1 to 4, 7 to 8, 14 to 17, 25, 27, 31 to 33, 35 to 41 , 44, 45 and 47, wherein the bond between A3 and A4 is a double bond and the bond between A4 and A5 is a single bond; or the bond between A4 and A5 is a double bond and the bond between A3 and A4 is a single bond.
A compound selected from the group comprising 2-amino-7-(3-phenoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8- hydroxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-phenoxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7- phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-methoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-hydroxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7- (4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(benzo[d][1 ,3]dioxol-5- yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(4-methoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-phenyl-9H-thiochromeno[6,5-d]thiazol-9-one; ethyl 4-(2-amino-8- hydroxy-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate; 2-amino-8-methoxy-7-(4- methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3- (benzyloxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-8-hydroxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-hydroxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; ethyl 4-(2- amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate; 2-amino-8-hydroxy-7-(3-hydroxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol- 9-one; 2-amino-7-(4-fluorophenyl)-9H-thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4- phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-8-(4-fluorophenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-methoxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 7-([1 , 1 -biphenyl]-4-yl)- 2-amino-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(4-fluorophenoxy)phenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino- 8-methoxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3- fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-8-hydroxy-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-9-oxo-N-phenyl-9H-chromeno[6,5-d]thiazole-7- carboxamide; 2-amino-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino- 8-hydroxy-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one; 7-phenyl-2-thioxo-2H- chromeno[6,5-d]thiazol-9(3H)-one; 2-amino-7-(3-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)- one; 2-amino-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(4- isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-diisopropoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 4-(2-amino- 9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)-N-phenylbenzamide; 2-amino-7-(2-isopropoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2- bromo-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol- 9-one; 2-amino-8-hydroxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-9- oxo-9H-chromeno[6,5-d]thiazole-7-carboxylic acid; 2-amino-7-(2-methoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(2-methoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(benzyloxy)phenyl)-8- methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-8-methoxy-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin- 9(8H)-one; 2-amino-7-(3-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7- methyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(trifluoromethyl)phenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(furan-2-yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-chloro-7- phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-hydroxy-4-methoxy-7-phenyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-methyl-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(4- (trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-phenyl-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-hydroxy-7-(2-isopropoxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-8-methoxy-9H-chromeno[6,5- d] thiazol-9-one; 2-amino-7-phenylthiazolo[5,4-f]quinazolin-9(8H)-one; 1-(8-hydroxy-9-oxo-7-(3- phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; 2-amino-7-benzylthiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(3-(trifluoromethyl)phenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2- e] [1 ,3]oxazin-9(8H)-one; 2-amino-8-methoxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-7-(3,4,5-trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4- phenoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-7-(3- fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-phenoxyphenyl)-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-methoxy-7-phenyl-9H- chromeno[6,5-d]thiazol-9-one; ethyl 2-amino-9-oxo-9H-chromeno[6,5-d]thiazole-7-carboxylate;
1- (9-oxo-7-phenyl-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; 2,7-diphenyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2,5-diamino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7-phenyl-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
2- amino-7-(furan-2-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(3,4,5- trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4-dimethoxyphenyl)-8- methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2,4,5-trimethoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoic acid; 2- amino-7-(3,4-diisopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- diisopropoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- dihydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(phenylthio)phenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-bromo-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol- 9-one; 2-bromo-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7-(3- methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(2,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(3-methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(2- methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(4-methoxyphenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(3,5-dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2- amino-7-(3,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(3,4- dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-cyclohexylthiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-isopropylthiazolo[5,4-f]quinazolin-9(8H)-one; 2-bromo-8- methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(4- fluorophenoxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-methyl-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-8-ethoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-methyl-7- phenyl-9H-chromeno[6,5-d]oxazol-9-one; 2-methyl-7-(3-phenoxyphenyl)-9H-chromeno[6,5- d]oxazol-9-one; 2-methyl-7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one; 2-amino-8-benzyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-(3-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-(3-phenoxybenzyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-(4-fluorobenzyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-(benzo[d][1 ,3]dioxol-5-ylmethyl)-9H-chromeno[6,5- d]thiazol-9-one; 1-benzyl-7-(4-methoxyphenyl)chromeno[5,6-d][1 ,2,3]triazol-9(1 H)-one; 7-phenyl- 9H-chromeno[5,6-d]oxazol-9-one; 7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one; 7- phenyl-9H-chromeno[6,5-d]oxazol-9-one; 7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one; 2- aminothiazolo[5,4-a]acridin-1 1 (6H)-one; 2-bromothiazolo[5,4-a]acridin-1 1 (6H)-one; 2- chlorothiazolo[5,4-a]acridin-1 1 (6H)-one; 2-hydrazinylthiazolo[5,4-a]acridin-1 1 (6H)-one; 3-ethyl- [1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 6-butyl-2-chlorothiazolo[5,4-a]acridin- 1 1 (6H)-one; 2-(dimethylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one; 2-(propylamino)thiazolo[5,4- a]acridin-1 1 (6H)-one; 2-((3-(diethylamino)propyl)amino)thiazolo[5,4-a]acridin-1 1 (6H)-one; 2-((2- hydroxyethyl)amino)thiazolo[5,4-a]acridin-1 1 (6H)-one; 2-(piperidin-1-yl)thiazolo[5,4-a]acridin- 1 1 (6H)-one; 2-chloro-7-nitrothiazolo[5,4-a]acridin-1 1 (6H)-one; 7-amino-2-chlorothiazolo[5,4- a]acridin-1 1 (6H)-one; 2-chloro-3H-imidazo[4,5-a]acridin-1 1 (6H)-one; 2-chloro-3-methyl-3H- imidazo[4,5-a]acridin-1 1 (6H)-one; 2-chloro-1 -methyl- 1 H-imidazo[4,5-a]acridin-1 1 (6H)-one; 2- ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one; 2-methoxythiazolo[5,4-a]acridin-1 1 (6H)-one; 2- butoxythiazolo[5,4-a]acridin-1 1 (6H)-one; 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2- bromo-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-bromo-6-ethylthiazolo[5,4-a]acridin-1 1 (6H)- one; 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-amino-1 1 H-xantheno[2,1-d]thiazol- 1 1-one; 2-(diethylamino)-4-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one; and 2-amino-8-methyl-7- phenylthiazolo[5,4-f]quinolin-9(6H)-one.
A compound selected from the group comprising 2-amino-7-(3-phenoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8- hydroxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-phenoxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7- phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-methoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-hydroxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7- (4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(benzo[d][1 ,3]dioxol-5- yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(4-methoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-phenyl-9H-thiochromeno[6,5-d]thiazol-9-one; ethyl 4-(2-amino-8- hydroxy-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate; 2-amino-8-methoxy-7-(4- methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3- (benzyloxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-8-hydroxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-hydroxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; ethyl 4-(2- amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate; 2-amino-8-hydroxy-7-(3-hydroxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol- 9-one; 2-amino-7-(4-fluorophenyl)-9H-thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4- phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-8-(4-fluorophenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-methoxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 7-([1 , 1 -biphenyl]-4-yl)- 2-amino-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(4-fluorophenoxy)phenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino- 8-methoxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3- fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-8-hydroxy-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-9-oxo-N-phenyl-9H-chromeno[6,5-d]thiazole-7- carboxamide; 2-amino-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino- 8-hydroxy-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one; 7-phenyl-2-thioxo-2H- chromeno[6,5-d]thiazol-9(3H)-one; 2-amino-7-(3-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)- one; 2-amino-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(4- isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-diisopropoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 4-(2-amino- 9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)-N-phenylbenzamide; 2-amino-7-(2-isopropoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2- bromo-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol- 9-one; 2-amino-8-hydroxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-9- oxo-9H-chromeno[6,5-d]thiazole-7-carboxylic acid; 2-amino-7-(2-methoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(2-methoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(benzyloxy)phenyl)-8- methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-8-methoxy-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin- 9(8H)-one; 2-amino-7-(3-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7- methyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(trifluoromethyl)phenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(furan-2-yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-chloro-7- phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-hydroxy-4-methoxy-7-phenyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-methyl-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(4- (trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-phenyl-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-hydroxy-7-(2-isopropoxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-8-methoxy-9H-chromeno[6,5- d] thiazol-9-one; 2-amino-7-phenylthiazolo[5,4-f]quinazolin-9(8H)-one; 1-(8-hydroxy-9-oxo-7-(3- phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; 2-amino-7-benzylthiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(3-(trifluoromethyl)phenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2- e] [1 ,3]oxazin-9(8H)-one; 2-amino-8-methoxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-7-(3,4,5-trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4- phenoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-7-(3- fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-phenoxyphenyl)-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-methoxy-7-phenyl-9H- chromeno[6,5-d]thiazol-9-one; ethyl 2-amino-9-oxo-9H-chromeno[6,5-d]thiazole-7-carboxylate;
1- (9-oxo-7-phenyl-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; 2,7-diphenyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2,5-diamino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7-phenyl-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
2- amino-7-(furan-2-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(3,4,5- trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4-dimethoxyphenyl)-8- methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2,4,5-trimethoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoic acid; 2- amino-7-(3,4-diisopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- diisopropoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- dihydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(phenylthio)phenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-bromo-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol- 9-one; 2-bromo-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7-(3- methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(2,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(3-methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(2- methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(4-methoxyphenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(3,5-dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2- amino-7-(3,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(3,4- dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-cyclohexylthiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-isopropylthiazolo[5,4-f]quinazolin-9(8H)-one; 2-bromo-8- methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(4- fluorophenoxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-methyl-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-8-ethoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-methyl-7- phenyl-9H-chromeno[6,5-d]oxazol-9-one; 2-methyl-7-(3-phenoxyphenyl)-9H-chromeno[6,5- d]oxazol-9-one; 2-methyl-7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one; 2-amino-8-benzyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-(3-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-(3-phenoxybenzyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-(4-fluorobenzyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-(benzo[d][1 ,3]dioxol-5-ylmethyl)-9H-chromeno[6,5- d]thiazol-9-one; 1-benzyl-7-(4-methoxyphenyl)chromeno[5,6-d][1 ,2,3]triazol-9(1 H)-one; 7-phenyl- 9H-chromeno[5,6-d]oxazol-9-one; 7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one; 7- phenyl-9H-chromeno[6,5-d]oxazol-9-one; 7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one; 2- bromothiazolo[5,4-a]acridin-1 1 (6H)-one; 2-(propylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one; 2- chloro-7-nitrothiazolo[5,4-a]acridin-1 1 (6H)-one; 7-amino-2-chlorothiazolo[5,4-a]acridin-1 1 (6H)- one; 2-chloro-3H-imidazo[4,5-a]acridin-1 1 (6H)-one; 2-chloro-3-methyl-3H-imidazo[4,5-a]acridin- 1 1 (6H)-one; 2-chloro-1 -methyl- 1 H-imidazo[4,5-a]acridin-1 1 (6H)-one; 2-ethoxythiazolo[5,4- a]acridin-1 1 (6H)-one; 2-methoxythiazolo[5,4-a]acridin-1 1 (6H)-one; 2-butoxythiazolo[5,4- a]acridin-1 1 (6H)-one; 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-bromo-6- methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-bromo-6-ethylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2- chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-amino-1 1 H-xantheno[2,1-d]thiazol-1 1-one; 2-(diethylamino)-4-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one; and 2-amino-8-methyl-7- phenylthiazolo[5,4-f]quinolin-9(6H)-one.
A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to any one of statements 1 to 50. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to any one of any one of statements 1 to 50 or a therapeutically effective amount of a compound selected from the group comprising 3-ethyl-[1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 2-hydrazino-1 ,6- dihydroimidazo[4,5-a]acridin-1 1-one; 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one. The compound according to any of one of statements 1 to 50, or the pharmaceutical composition according to statement 51 or 52 for use as a medicine.
The compound according to any of one of statements 1 to 50, or the pharmaceutical composition according to statement 51 or 52, or a compound selected from the group comprising 3-ethyl- [1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 2-hydrazino-1 ,6-dihydroimidazo[4,5- a]acridin-1 1-one and 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one for use as a medicine.
The compound according to any of one of statements 1 to 50, or the pharmaceutical composition according to statement 51 or 52, or a compound selected from the group consisting of 2-(4- chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5- cf][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid; pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)- one, 2-(1 -piperidinyl)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-; pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-; thiazolo[5,4-a]acridin- 1 1 (6H)-one, 2-(butylthio)-; acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5- a]acridin-2-yl)hydrazide; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1 -(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5- a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1- one, 2-chloro-3,6-dihydro-3-methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2- hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-; benzamide, 4-methoxy-N-(9- oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H- pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3- g]benzothiazol-2-yl)-; benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4- dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5-f][1]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-; 9H- [1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5- f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-; 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-; for the prevention or treatment of amyloid-related diseases.
The compound according to any of one of statements 1 to 50, or the pharmaceutical composition according to statement 51 or 52, or a compound selected from the group consisting of 2-(4- chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5- cf][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid; pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)- one, 2-(1 -piperidinyl)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-; thiazolo[5,4-a]acridin- 1 1 (6H)-one, 2-(butylthio)-; acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5- a]acridin-2-yl)hydrazide; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1 -(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5- a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1- one, 2-chloro-3,6-dihydro-3-methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2- hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-; benzamide, 4-methoxy-N-(9- oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H- pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3- g]benzothiazol-2-yl)-; benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4- dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5-f][1]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-; 9H- [1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5- f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-; 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-; 2-methyl-6H- thiazolo[5,4-f]quinolin-9-one; 2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one; 7,8-dimethyl-2- phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5- f]quinolin-9-one; 2-(2-furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-(p- tolyl)-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 2,7-diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9- one; 2-(2-chlorophenyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
the prevention or treatment of amyloid-related diseases.
The compound or the pharmaceutical composition according to statement 55 or 56, wherein the amyloid-related diseases is selected from the group comprising Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay-Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy.
A method of treatment of amyloid-related diseases, comprising administering to a subject in need thereof an effective amount of a compound according to any one of statements 1 to 50, or a compound selected from the group or a compound selected from the group consisting of 2-(4- chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5- cf][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid; pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)- one, 2-(1 -piperidinyl)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-; pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-; thiazolo[5,4-a]acridin- 1 1 (6H)-one, 2-(butylthio)-; acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5- a]acridin-2-yl)hydrazide; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1 -(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5- a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1- one, 2-chloro-3,6-dihydro-3-methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2- hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-; benzamide, 4-methoxy-N-(9- oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H- pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3- g]benzothiazol-2-yl)-; benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4- dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5-f][1]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-; 9H- [1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5- f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-; 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-; or a pharmaceutical composition according to statement 51 or 52.
A method of treatment of amyloid-related diseases, comprising administering to a subject in need thereof an effective amount of a compound according to any one of statements 1 to 50, or a compound selected from the group or a compound selected from the group consisting of 2-(4- chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5- cf][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid; pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)- one, 2-(1 -piperidinyl)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-; thiazolo[5,4-a]acridin- 1 1 (6H)-one, 2-(butylthio)-; acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5- a]acridin-2-yl)hydrazide; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1 -(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-, chloride (1 :1 ); pyridinium, 1-(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5- a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1- one, 2-chloro-3,6-dihydro-3-methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2- hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-; benzamide, 4-methoxy-N-(9- oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H- pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3- g]benzothiazol-2-yl)-; benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4- dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5-f][1]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-; 9H- [1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5- f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-; 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; and thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-; 2-methyl-6H- thiazolo[5,4-f]quinolin-9-one; 2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one; 7,8-dimethyl-2- phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5- f]quinolin-9-one; 2-(2-furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-(p- tolyl)-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 2,7-diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9- one; 2-(2-chlorophenyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 3-ethyl-
[1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 2-hydrazino-1 ,6-dihydroimidazo[4,5- a]acridin-1 1-one; 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one; or a pharmaceutical composition according to statement 51 or 52.
60. The method according to statement 58 or 59, wherein the amyloid-related diseases is selected from the group comprising Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt- Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay-Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy.
The present invention also encompasses a pharmaceutical composition comprising one or more pharmaceutically excipients and a therapeutically effective amount of a compound formulae (I) or (II), and any subgroup thereof such as (I2), (I3), (I4), (I5), (I6), (I7), (I8), (I9), (110), (11 1 ), (112), (113), (II2), (II3), (II4), (II5), (II6), (II7), (IIS), (II9), (1110), (111 1 ), (1112), (1113), (1114), (1115), (1116), (1117).
The present invention includes all possible stereoisomers compounds of formulae (I) or (II) and any subgroup thereof and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.
The compounds of the invention may be in the form of pharmaceutically acceptable salts, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the prior art referred to below).
When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
Pharmaceutically acceptable salts of the compounds of formulae (I) or (II) and any subgroup thereof include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.
The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').
Pharmaceutically acceptable salts of compounds of formulae (I) or (II) may be prepared by one or more of these methods:
(i) by reacting the compound of formulae (I) or (II) with the desired acid;
(ii) by reacting the compound of formulae (I) or (II) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formulae (I) or (II) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or
(iv) by converting one salt of the compound of formulae (I) or (II) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.
All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Britain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non- stoichiometric amounts. Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.
The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO"Na+, -COO"K+, or -S03 _Na+) or non-ionic (such as -N"N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970), incorporated herein by reference. All references to compounds of formulae (I) or (II) or any subgroups thereof include references to salts, solvates, multi- component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.
The compounds of the invention include compounds of formulae (I) or (II) or any subgroups thereof as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of formulae (I) or (II).
In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of formula (I) or (II) above.
The invention also generally covers all pharmaceutically acceptable prodrugs or "pre-drugs" of the compounds of formulae (I) or (II) or any subgroups thereof for which general reference is made to the prior art cited hereinbelow.
The term "pro-drug" as used herein means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated. Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo. The term "pre-drug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre- drug reaches the area of the body where administration of the drug is indicated.
Where a compound of formulae (I) or (II) or any subgroup thereof contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the present invention are all stereoisomers, diastereomers, geometric isomers and tautomeric forms of the compounds of formula (I) or (II) or any subgroups thereof, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, of-lactate or /-lysine, or racemic, for example, dl- tartrate or d/-arginine.
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC).
The compounds of formulae (I) or (II) or any subgroups thereof may be prepared as described in the experimental section below using methods and chemistries with which those skilled in the art shall be familiar.
Generally, the compounds of the invention are prepared from the intermediates described hereinafter which may be reacted with complementary reactive molecules so as to form the desired compound.
The present invention also encompasses a compound selected from the group comprising:
- 2-amino-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-bromo-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,4-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-phenyl-9H-thiochromeno[6,5-d]thiazol-9-one;
- ethyl 4-(2-amino-8-hydroxy-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate;
- 2-amino-8-methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-methoxyphenyl)-9H-thiochromeno[6,5-d]thiazol-9-one; - 2-amino-7-(2-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-(benzyloxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- ethyl 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate;
- 2-amino-8-hydroxy-7-(3-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,5-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-fluorophenyl)-9H-thiochromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-8-(4-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-methoxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 7-([1 '-biphenyl]-4-yl)-2-amino-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-(4-fluorophenoxy)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-methoxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; - 2-amino-7-(3-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,5-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-9-oxo-N-phenyl-9H-chromeno[6,5-d]thiazole-7-carboxamide;
- 2-amino-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one;
- 7-phenyl-2-thioxo-2H-chromeno[6,5-d]thiazol-9(3H)-one;
- 2-amino-7-(3-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,5-diisopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)-N-phenylbenzamide;
- 2-amino-7-(2-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-bromo-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(2-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; - 2-amino-8-hydroxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-9-oxo-9H-chromeno[6,5-d]thiazole-7-carboxylic acid;
- 2-amino-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-methoxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,4-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-(benzyloxy)phenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,5-dimethoxyphenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(3-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-methyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(furan-2-yl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-chloro-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-methoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one;
- 2-amino-8-hydroxy-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-methoxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-methyl-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-methoxy-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-phenyl-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one;
- 2-amino-8-hydroxy-7-(2-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(2-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-phenylthiazolo[5,4-f]quinazolin-9(8H)-one;
- 1-(8-hydroxy-9-oxo-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; - 2-amino-7-benzylthiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(3-(trifluoromethyl)phenyl)-7H-thiazolo[4\5^5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one;
- 2-amino-8-methoxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,4,5-trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-phenoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one;
- 2-amino-7-(3-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-phenoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one;
- 2-amino-8-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one;
- ethyl 2-amino-9-oxo-9H-chromeno[6,5-d]thiazole-7-carboxylate;
- 1-(9-oxo-7-phenyl-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea;
- 2,7-diphenyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2,5-diamino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; - 2-bromo-7-phenyl-9H-thiochromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(furan-2-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-hydroxy-7-(3,4,5-trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; - 2-amino-7-(3,4-dimethoxyphenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(2,4,5-trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoic acid;
- 2-amino-7-(3,4-diisopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(3,4-diisopropoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; - 2-amino-7-(3,4-dihydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-(phenylthio)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-bromo-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-bromo-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-bromo-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-fluorophenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(2,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(3-methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(2-methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(4-methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(3,5-dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(3,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-(3,4-dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-cyclohexylthiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-amino-7-isopropylthiazolo[5,4-f]quinazolin-9(8H)-one;
- 2-bromo-8-methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-(4-fluorophenoxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-7-methyl-9H-thiochromeno[6,5-d]thiazol-9-one;
- 2-amino-7-(4-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-ethoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-methyl-7-phenyl-9H-chromeno[6,5-d]oxazol-9-one;
- 2-methyl-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one;
- 2-methyl-7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one;
- 2-amino-8-benzyl-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-(3-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-(3-phenoxybenzyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-(4-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one;
- 2-amino-8-(benzo[d][1 ,3]dioxol-5-ylmethyl)-9H-chromeno[6,5-d]thiazol-9-one; - 1-benzyl-7-(4-methoxyphenyl)chromeno[5,6-d][1 ,2,3]triazol-9(1 H)-one;
- 7-phenyl-9H-chromeno[5,6-d]oxazol-9-one;
- 7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one;
- 7-phenyl-9H-chromeno[6,5-d]oxazol-9-one;
- 7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one;
- 2-aminothiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-bromothiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-hydrazinylthiazolo[5,4-a]acridin-1 1 (6H)-one;
- 3-ethyl-[1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one;
- 6-butyl-2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-(dimethylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-(propylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-((3-(diethylamino)propyl)amino)thiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-((2-hydroxyethyl)amino)thiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-(piperidin-1-yl)thiazolo[5,4-a]acridin-1 1 (6H)-one;
- 7-amino-2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-chloro-3H-imidazo[4,5-a]acridin-1 1 (6H)-one;
- 2-chloro-3-methyl-3H-imidazo[4,5-a]acridin-1 1 (6H)-one;
- 2-chloro-1-methyl-1 H-imidazo[4,5-a]acridin-1 1 (6H)-one;
- 2-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-methoxythiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-butoxythiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-bromo-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-bromo-6-ethylthiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one;
- 2-amino-1 1 H-xantheno[2,1-d]thiazol-1 1-one;
- 2-(diethylamino)-4-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one; and
- 2-amino-8-methyl-7-phenylthiazolo[5,4-f]quinolin-9(6H)-one.
The present invention also encompasses processes for the preparation of compounds formulae (I) or (II) and any subgroup thereof. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1999. Protected forms of the inventive compounds are included within the scope of the present invention. The term "protected form" refers to compounds of the invention in which one or more functional groups have been protected with one or more suitable protecting groups. The term "protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect a fonctional group, for example, a hydroxyl, amino or carboxy group, against undesired reactions during synthetic procedures. After said synthetic procedure(s) the protecting group as described herein may be selectively removed. It will also be clear to the skilled person that compounds of the invention in which one or more functional groups have been protected with suitable protecting groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention.
The compounds formula (I) or (II), the subgroups thereof and their pharmaceutically acceptable salts can be prepared as described hereunder.
In the general schemes described below, all substituents are defined as in the general formula (I), (II), (I2), (I3), (I4), (I5), (I6), (I7), (I8), (I9), (110), (11 1 ), (112), (113), (II2), (II3), (II4), (IIS), (II6), (II7), (IIS), (II9), (1110), (111 1 ), (1112), (1113), (1114), (1115), (1116), (1117) or any subgroups thereof, unless otherwise mentioned or indicated.
The present compounds of formulae (I) or (I) and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, compounds of formula (I) can be prepared by cyclocondensation of a compound of formula l-AA with an acid of formula l-BB, wherein X1, A1, A2, r, R1, R2, R3, and R4 have the same meaning as that defined herein above.
Figure imgf000133_0001
l-AA l-BB
Yet another aspect of the invention provides a method for the preparation of a compound of formula II comprising the steps of:
a) cyclocondensation of a compound of formula ll-A with a compound of formula (ll-B) to afford a compound of formula ll-C,
Figure imgf000133_0002
ll-A ll-B ll-C b) cyclization of the compound of formula ll-C with a compound of formula A3=A4-LG (wherein LG means a leaving group), obtaining a compound of formula II wherein X2, Y1, A3, A4, R5, R6, R7, have the same meaning as that defined herein above.
Also the intermediates used in the preparation methods described herein are aspects of the present invention.
In an embodiment, the present invention provides a method for the preparation of the compounds of the invention which comprises the steps, according to Scheme 1 , described hereafter. Also the intermediates used in the preparation methods described herein are aspects of the present invention.
Figure imgf000134_0001
Scheme 1 : all R5, R6, R7, A3, A4, A5, X2, Y1 and LG are described for the compounds of the present invention and its embodiments and formulae.
Intermediates of formula ll-A are commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below. More detailed information can be found in the following references (e.g. Bioorganic and Medicinal Chemistry 15(10), 3356-3367, 2007; Bioorganic and Medicinal Chemistry 12(9), 2079-2098, 2004; Indian Journal of Chemistry, 44B(12), 2601-2603, 2005; Journal of Organic Chemistry 22, 304-306, 1957; Journal of Organic Chemistry 31-52, 1934; ChemMedChem, 3(10), 1572-1579, 2008; Bulletin of the Chemical Society of Japan, 61 , 3008-3010, 1988; Tetrahedron, 61 (12), 3031-3017, 2005; Tetrahedron Letters, 46(25), 4345-4347, 2005; Tetrahedron Letters, 46(21 ), 3707-3709, 2005; Journal of the Chemical Society of Japan, 55, 1256- 1261 , 1934; Journal of Medicinal Chemistry, 50(14), 3359-3368, 2007; Journal of Medicinal Chemistry, 39(10), 1975-1980, 1996; Journal of the American Chemical Society 60,1370-1371 , 1938; Synlett, 2687-2690, 2007; Synthesis, 901-903, 1979; Synthetic Communications, 40 632-641 , 2010). Cyclocondensation of intermediates of formula ll-A with intermediates of formula I l-B (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below), by procedures known to the skilled in the art or as set forth in the examples bellow provides compounds of formula ll-C which after cyclization with a compound of formula A3=A4-LG (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below), by procedures known to the skilled in the art or as set forth in the examples bellow, affords compounds of formula ll-D.
Synthesis of thiazoloflavonoids: This class of compounds can be prepared following the general procedure outlined hereunder, and schematically illustrated under scheme 2.
Figure imgf000135_0001
1. Oxidative
cyclization
2. Deprotection
Cyclization
Figure imgf000135_0002
1. Cyclization
(DMFDMA)
2. Deprotection
Figure imgf000135_0003
Scheme 2. All R5, R6, R7, R12 and R14 are as described for the compounds of the present invention and its embodiments and formulae.
Subjecting intermediates of formula ll-E (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) to aromatic electrophilic substitution with acetyl chloride and a suitable Lewis acid (AICI3, BCI3, ...) by procedures known to the skilled in the art or as set forth in the examples below (e.g. Friedel-Crafts arylation) provides intermediates of formula ll-F. Condensation of intermediates of formula ll-F with an aldehyde of formula ll-B (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) in the presence of a suitable base (NaOH, KOH,...), by procedures known to the skilled in the art or as set forth in the examples below (e.g. Aldol condensation), provides intermediates of formula ll-G. Said intermediates of formula ll-G can then be made to react with a suitable oxidant (H2O2, Se02, , - ). following standard procedures known to the skilled in the art or as set forth in the examples below (e.g. Algar-Flynn-Oyamada reaction), and subsequently treating the product of this reaction in acidic media to deprotect the amino group, providing intermediate ll-l as a result. Alternatively, when R7 is hydrogen, intermediates of formula II- H can be cyclized by methods know to the skilled in the art (e.g. treatment with dimethyl formamide dimethylacetal) and subsequently treating the product of this reaction in acidic media to deprotect the amino group, provides intermediate ll-l as a result. Finally, compounds of formula ll-J can be prepared by reacting intermediates of formula ll-l with a suitable thiocyanate (KSCN, NH4SCS,...) in acidic media, following standard procedures known to the skilled in the art or as set forth in the examples below (e.g. Hugeschoff reaction).
Synthesis of dihydroquinazolines: This class of compounds can be prepared following the general procedure outlined hereunder, and schematically illustrated under scheme 3.
Figure imgf000136_0001
ll-H
Scheme 3. All R5, R6, R7 and R12 are as described for the compounds of the present invention and its embodiments and formulae.
Cyclocondensation of intermediates of formula ll-K (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) with an aldehyde of formula ll-B (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) in the presence of ZnC in a suitable solvent (DMF, DMSO...), by procedures known to the skilled in the art or as set forth in the examples below (e.g. tandem intramolecular Pinner/Dimroth rearrangement), provides intermediates of formula ll-l Said intermediates of formula ll-L can then be made to react with molecular hydrogen or a compound capable of donating hydrogen under conditions known to the skilled in the art (NaBH4, LiAIH4...) in the presence of an appropriate catalyst (Pd on charcoal, Pt...), by procedures known to the skilled in the art or as set forth in the examples below (e.g. catalytic hydrogenation), and subsequently treating the product of this reaction with a suitable thiocyanate (KSCN, NH4SCS,...) in acidic media, following standard procedures known to the skilled in the art or as set forth in the examples below (e.g. Hugeschoff reaction), to provide compounds of formula ll-H.
Synthesis of thiochromenes: This class of compounds can be prepared following the general procedure outlined hereunder, and schematically illustrated under scheme 4. Condensation
Figure imgf000137_0001
ll-O LDeprotection
2.Cyclization
Figure imgf000137_0002
Scheme 4. All R5, R6, R7, R12 and R14 are as described for the compounds of the present invention and its embodiments and formulae.
Condensation of intermediates of formula ll-N (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) with an ethyl benzoylacetate of formula ll-O (commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) in the presence of heated (90-100°C) polyphosphoric acid by procedures known to the skilled in the art or as set forth in the examples below, provides intermediates of formula ll-P. Said intermediates of formula ll-P can then be made to react in acidic media to deprotect the amino group, and subsequently reacting the product of this reaction with a suitable thiocyanate (KSCN, NH4SCS,...) in acidic media, following standard procedures known to the skilled in the art or as set forth in the examples below (e.g. Hugeschoff reaction), to provide compounds of formula ll-Q.
Synthesis of acridines: This class of compounds can be prepared following the general procedure outlined hereunder, and schematically illustrated under scheme 5.
Figure imgf000138_0001
l-E l-D
Scheme 5. All R1, R2, R3, R4, r, A1 and A2 are as described for the compounds of the present invention and its embodiments and formulae.
The compound of formula l-A can be reduced to the amino derivative of formula l-B by procedures known to the skilled in the art or as set forth in the examples below (e.g. catalytic hydrogenation, use of iron powder in presence of hydrochloric acid...). The condensation of intermediate of formula l-B with o-bromobenzoic acid derivatives by methods known to the skilled in the art or as set forth in the examples below (e.g. Ulmann condensation) gave intermediates of formula l-C, which can be further reacted with sulfuric acid to provide cyclized derivative of formula l-D. Derivative of formula l-D can be further substituted on the nitrogen by methods known to the skilled in the art or as set forth in the examples below (e.g. nucleophilic substitution) to give derivatives of formula l-E. More detailed information can be found in the following references (e.g. Heterocycles, 2000, 53, 387-395; J. Heterocycl. Chem. 2002, 39, 1083-1085)
The present invention encompasses compounds according to the invention, as well as the compounds obtained by the methods of the invention. The present invention also encompasses pharmaceutical composition comprising at least one compound of the present invention. The present invention also encompasses pharmaceutical composition comprising at least one compound of the invention and at least one carrier, excipient or diluent acceptable for pharmaceutical purposes.
In some embodiments, the present invention relates to the use of at least one compound of formulae (I) or (II), or any subgroups thereof, in (the preparation of a composition for) the prevention and/or treatment of amyloid-related diseases.
In some embodiments, the present invention relates to a method of prevention and/or of treatment of amyloid-related diseases, comprising administering to a subject in need thereof an effective amount of at least one compound of formulae (I) or (II), or any subgroups thereof, or a pharmaceutical composition comprising said at least one compound of formulae (I) or (II) or any subgroups thereof. In some embodiments, the present invention relates to the use of at least one compound of formulae (I) or (II), or any subgroups thereof, in (the preparation of a composition for) the prevention and/or treatment of amyloid-related diseases, more preferably Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay-Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy.
The term "subject" as used herein refers to a mammal. The subject will preferably be a human, but may also be a domestic livestock, laboratory or pet animals.
In some embodiments, at least one compound of formulae (I) or (II) is used (for the preparation of a medicament) for preventing and/or treating a disease selected from the group comprising Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay-Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy.
As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
For use in therapy, therapeutically effective amounts of a compound of formula (I) or (II), as well as stereoisomers, tautomers, racemics, salts, hydrates or solvates thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions that include effective amounts of compounds of formulae (I) or (II), or stereoisomers, tautomers, racemics, salts, hydrates or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formulae (I) or (II) or stereoisomers, tautomers, racemics, salts, hydrates or solvates thereof, are as herein described.
The compounds according to the invention may be administered as the sole active ingredient or together, i.e. in a fixed or free combination, with other therapeutic agents used in clinical practice for the treatment of those diseases listed above.
The compounds according to the invention and the other pharmaceutical active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds according to the invention and the other pharmaceutically active agent (s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of formulae (I) or (II) or a stereoisomer, tautomer, racemic, salt, hydrate or solvate thereof, with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester. As used herein and unless otherwise stated, the term "solvate" includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like. Such salts, hydrates, solvates, etc. and the preparation thereof will be clear to the skilled person; reference is for instance made to the salts, hydrates, solvates, etc. described in US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733. The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. In addition, the basic nitrogen- containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6,372,778, US-A-6,369,086, US-A- 6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ α-, β- or γ- cyclodextrins or their derivatives. In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.
Appropriate cyclodextrins are α-, β- or γ-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl, particularly acetyl; alkoxycarbonylalkyl or carboxyalkoxyalkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl, particularly 2-acetyloxy propyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl- β-CD, 2-hydroxyethyl^-CD, 2- hydroxyethyl-y-CD, 2-hydroxypropyl-Y-CD and (2-carboxymethoxy)propyl- β-CD, and in particular 2- hydroxy propyl- β-CD (2-HP- β-CD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxyl groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors. In particular, the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin. The present invention also encompasses cyclodextrin complexes consisting of a compound according to the invention and a cyclodextrin.
Particular reference is made to the compositions, formulations (and carriers, excipients, diluents, etc. for use therein), routes of administration etc., which are known per se such as those described in US-A-4,997,834 and EP-A-0 370 498.
More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
In some embodiment, the water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20°C solution. Preferred water-soluble polymers are hydroxypropyl methylcelluloses (HPMC). HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy- propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
It may further be convenient to formulate the compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded, or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal- coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides, and derivatives thereof.
The preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
The compounds can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred. The at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of the formulae (I) or (II) above that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A-6,372,778,US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
For subcutaneous or intravenous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compositions are of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. - enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal. Thus, in a further aspect, the invention relates to a (pharmaceutical) composition for veterinary use that contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for veterinary use). The invention also relates to the use of a compound of the invention in the preparation of such a composition.
Examples
The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.
Part A represents the preparation of the compounds (intermediates and final compounds) whereas Part B represents the pharmacological examples. All chemicals used were of reagent grade and were used without further purification; progress of the reaction was monitored by TLC on silica gel plates (Merk Silica gel 60 F254). Microwave reactions were performed in a CEM discover labmate apparatus. Yields refer to purified products and are not optimized.
The Nuclear Magnetic Resonance spectra were recorded on Bruker Avance DRX-200, 300, 400 and DRX-500 spectrometers. The deuterated solvents employed are from the company Eurisotop. The 1H and 13C chemical shifts of the solvent were used as a secondary reference and referred to the tetramethylsilane signal from the usual relationships; the values of the chemical shifts (δ) are given in ppm and coupling constants (J) in Hz.
Elemental analyses were performed on a ThermoFinnigan FlashEA 1 1 12 elemental analyzer and the results are within ±0.4% of the theoretical values.
For conciseness, abbreviations with the meanings summarized in the following table were used throughout the examples.
Figure imgf000146_0001
Exemplary compounds of the present invention are shown in tables 1 and 2
Table 1
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Table 2
Compound
Compound Name
code
C001 2-amino-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C002 2-amino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C003 2-amino-8-hydroxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C004 2-amino-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C005 2-amino-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one
C006 2-amino-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C007 2-bromo-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C008 2-amino-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C009 2-amino-7-(4-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C010 2-amino-8-hydroxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C01 1 2-amino-8-hydroxy-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one
C012 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-9H-chromeno[6,5-d]thiazol-9-one
C013 2-amino-8-hydroxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C014 2-amino-7-(3,4-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C015 2-amino-7-phenyl-9H-thiochromeno[6,5-d]thiazol-9-one
C016 ethyl 4-(2-amino-8-hydroxy-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate
C017 2-amino-8-methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C018 2-amino-7-(4-methoxyphenyl)-9H-thiochromeno[6,5-d]thiazol-9-one
C019 2-amino-7-(2-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C020 2-amino-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one
C021 2-amino-7-(3-(benzyloxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C022 2-amino-9H-chromeno[6,5-d]thiazol-9-one
C023 2-amino-8-hydroxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C024 2-amino-8-hydroxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one
C025 ethyl 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate
C026 2-amino-8-hydroxy-7-(3-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C027 2-amino-7-(3,5-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C028 2-amino-7-(4-fluorophenyl)-9H-thiochromeno[6,5-d]thiazol-9-one
C029 2-amino-7-(4-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one
C030 2-amino-8-(4-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one
C031 2-amino-8-hydroxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C032 2-amino-8-methoxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C033 7-([1 '-biphenyl]-4-yl)-2-amino-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one
C034 2-amino-7-(4-(4-fluorophenoxy)phenyl)-9H-chromeno[6,5-d]thiazol-9-one
C035 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-9H-chromeno[6,5-d]thiazol-9-one
C036 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C037 2-amino-8-methoxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one C038 2-amino-7-(3-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one
C039 2-amino-7-(3,5-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C040 2-amino-9-oxo-N-phenyl-9H-chromeno[6,5-d]thiazole-7-carboxamide
C041 2-amino-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one
C042 2-amino-8-hydroxy-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one
C043 7-phenyl-2-thioxo-2H-chromeno[6,5-d]thiazol-9(3H)-one
C044 2-amino-7-(3-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one
C045 2-amino-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C046 2-amino-8-hydroxy-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C047 2-amino-7-(3,5-diisopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C048 2-amino-8-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C049 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)-N-phenylbenzamide
C050 2-amino-7-(2-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C051 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C052 2-amino-7-(4-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one
C053 2-bromo-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C054 2-amino-7-(2-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one
C055 2-amino-7-(3-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C056 2-amino-8-hydroxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C057 2-amino-9-oxo-9H-chromeno[6,5-d]thiazole-7-carboxylic acid
C058 2-amino-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C059 2-amino-8-methoxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C060 2-amino-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C061 2-amino-7-(3,4-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C062 2-amino-7-(3-(benzyloxy)phenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one
C063 2-amino-7-(3,5-dimethoxyphenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one
C064 2-amino-7-(3-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin-9(8H)-one
C065 2-amino-7-(3-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C066 2-amino-7-methyl-9H-chromeno[6,5-d]thiazol-9-one
C067 2-amino-7-(4-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin-9(8H)-one
C068 2-amino-7-(furan-2-yl)-9H-chromeno[6,5-d]thiazol-9-one
C069 2-chloro-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C070 2-amino-7-(4-methoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one
C071 2-amino-8-hydroxy-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C072 2-amino-8-methoxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C073 2-methyl-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one
C074 2-amino-8-methoxy-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one
C075 2-amino-7-phenyl-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one
C076 2-amino-8-hydroxy-7-(2-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C077 2-amino-7-(2-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one
Figure imgf000159_0001
C1 17 2-bromo-8-methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C1 18 2-amino-7-(4-(4-fluorophenoxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one
C1 19 2-amino-7-methyl-9H-thiochromeno[6,5-d]thiazol-9-one
C120 2-amino-7-(4-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C121 2-amino-8-ethoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one
C122 2-methyl-7-phenyl-9H-chromeno[6,5-d]oxazol-9-one
C123 2-methyl-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one
C124 2-methyl-7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one
C125 2-amino-8-benzyl-9H-chromeno[6,5-d]thiazol-9-one
C126 2-amino-8-(3-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one
C127 2-amino-8-(3-phenoxybenzyl)-9H-chromeno[6,5-d]thiazol-9-one
C128 2-amino-8-(4-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one
C129 2-amino-8-(benzo[d][1 ,3]dioxol-5-ylmethyl)-9H-chromeno[6,5-d]thiazol-9-one
C130 1-benzyl-7-(4-methoxyphenyl)chromeno[5,6-d][1 ,2,3]triazol-9(1 H)-one
C131 7-phenyl-9H-chromeno[5,6-d]oxazol-9-one
C132 7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one
C133 7-phenyl-9H-chromeno[6,5-d]oxazol-9-one
C134 7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one
C135 2-aminothiazolo[5,4-a]acridin-1 1 (6H)-one
C136 2-bromothiazolo[5,4-a]acridin-1 1 (6H)-one
C137 2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one
C138 2-hydrazinylthiazolo[5,4-a]acridin-1 1 (6H)-one
C139 3-ethyl-[1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one
C140 6-butyl-2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one
C141 2-(dimethylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one
C142 2-(propylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one
C143 2-((3-(diethylamino)propyl)amino)thiazolo[5,4-a]acridin-1 1 (6H)-one
C144 2-((2-hydroxyethyl)amino)thiazolo[5,4-a]acridin-1 1 (6H)-one
C145 2-(piperidin-1-yl)thiazolo[5,4-a]acridin-1 1 (6H)-one
C146 2-chloro-7-nitrothiazolo[5,4-a]acridin-1 1 (6H)-one
C147 7-amino-2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one
C148 2-chloro-3H-imidazo[4,5-a]acridin-1 1 (6H)-one
C149 2-chloro-3-methyl-3H-imidazo[4,5-a]acridin-1 1 (6H)-one
C150 2-chloro-1 -methyl- 1 H-imidazo[4,5-a]acridin-1 1 (6H)-one
C151 2-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one
C152 2-methoxythiazolo[5,4-a]acridin-1 1 (6H)-one
C153 2-butoxythiazolo[5,4-a]acridin-1 1 (6H)-one
C154 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one
C155 2-bromo-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one
C156 2-bromo-6-ethylthiazolo[5,4-a]acridin-1 1 (6H)-one C157 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one
C158 2-amino-1 1 H-xantheno[2,1-d]thiazol-1 1-one
C159 2-(diethylamino)-4-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one
C160 2-amino-8-methyl-7-phenylthiazolo[5,4-f]quinolin-9(6H)-one
PART A.
GENERAL METHODS FOR THE PREPARATION OF THE INTERMEDIATE COMPOUNDS.
Method AA. Preparation of Intermediate ll-F (Scheme 2).
To a stirring suspension of Intermediate ll-E (32 mmol) and acetyl chloride (93 mmol) in DCM, aluminium trichloride (109 mmol) was added in portions over 90 min. The reaction was then heated to reflux for 4.5 h and cooled overnight. The mixture was poured onto ice, then extracted with DCM (5x), dried (MgS04) and concentrated in vacuo to give Intermediate ll-F. Further purification of this product was achieved with crystallization from diethyl ether.
Method A. Preparation of Intermediate Il-G (Scheme 2).
A mixture of Intermediate ll-F (10 mmol), aldehyde ll-B (10 mmol) and LiOH.H20 (70 mmol) in MeOH (20 mL) was submitted to MWI in a CEM Apparatus (open vessel, 300 watts, at 80°C) for 2 min + 20 min. The resulting solution was allowed to cool to r.t., the solvent was removed under vacuum and the residue was poured into 50 mL HCI 1 N. The precipitate obtained was then filtered off, washed with excess water, dried and used without further purification.
Method B. Preparation of Intermediate Il-G' (Scheme 6).
Figure imgf000161_0001
Il-G Il-G'
Scheme 6
A mixture of intermediate Il-G (wherein R14 = H) (10 mmol) and l2 (10% wt) was solubilized in DMSO (10 mL). The solution was submitted to MWI at 140°C (DMSO, 2+20 min, open vessel). The solution was cooled to r.t. and poured onto cold 1 N HCI solution (100 mL). The solution was stirred for 1 h, and the resulting precipitate was then diluted with iced water (100 mL) and filtered off. The precipitate collected was washed with excess water to remove the solvent and was used without further purification.
Method C. Preparation of Intermediate Il-G" (Scheme 7).
Figure imgf000161_0002
Scheme 7 To a solution of 10 mmol of Intermediate ll-G (wherein R = H) in EtOH (50 mL), NaOH 5% (40 mL) and H2O2 25% (10 mL) were added. The solution was stirred overnight at r.t., then 100 mL water were added. The resulting mixture was acidified with HCI 2M until a precipitate was produced. The precipitate obtained was filtered, washed with water and dried, to give the corresponding 5 intermediate ll-G", which was used without further purification.
Method D. Methylation of Intermediate ll-G" (Scheme 8 .
Figure imgf000162_0001
Scheme 8 l-G
To a solution of Intermediate ll-G" (10 mmol) and K2CO3 (1 eq.) in acetone (20 mL), dimethyl sulfate (1 eq.) was added, and the resulting mixture was heated at 50°C for 6h. The reaction was monitored 10 by TLC and when no more starting material appeared, the solvent was removed under reduced pressure. The mixture obtained was poured onto water (100 mL) and the pH was adjusted to 7. The resulting precipitate was filtered off and washed with water and dried to afford a methylated Intermediary ll-G"-Me (Scheme 8).
Method E. Deprotection of Intermediates ll-G, ll-G', ll-G", ll-G"-Me or ll- .
15 10 mmol of Intermediate ll-G, ll-G', ll-G", ll-G"-Me or ll-P were added to a mixture of EtOH (20 mL) and cone. H2SO4 (5 mL). The solution was submitted to MWI in open vessel 80°C, 2+20 min; upon cooling, the solvent was removed under vacuum and the residue obtained was poured onto iced water (100 mL). The resulting solution was neutralized with NH4OH 16% until pH=7. The precipitate formed was collected by filtration and washed with excess cold water. The resulting amino derivative
20 (ll-l or ll-P') was used without further purification.
Method F. Preparation of Intermediate IX (Scheme 9).
Figure imgf000162_0002
Scheme 9 ll-l Il-R ll-l'
A mixture of Intermediate ll-l (1 eq.), sulfur (1 eq.) and Na2S.9H20 (0.15 eq.) in DMF was refluxed under N2 for 30 min. To the resulting mixture, 1 eq. of the aldehyde Il-R, were added, and reflux was continued for further 4h. At that time the solution was poured onto sat. NH4CI solution. The solid collected was washed with DCM to afford the desired compound, which was used without further purification.
Method G. lodination of intermediary ll-G (Scheme 10).
Figure imgf000163_0001
Scheme 10 ll-G-iodine
Intermediate ll-G (wherein R14 = H) (10 mmol) and (1 eq.) were solubilized in MeOH; the resulting solution was stirred at room temperature for 48h, to afford Intermediate ll-G-lodine (Scheme 10), which was used without further purification.
Method H. Pre aration of Intermediate ll-G-aryl (Scheme 1 1 ).
Figure imgf000163_0002
ll-G-iodine n
Scheme 1 1 ii-faa-aryl
Intermediate ll-G-lodine (2.5 mmol), phenylboronic acid ll-S (3.75 mmol), benzene (5 mL), and 2.0 M
Na2C03 (2.5 mL) were mixed in a 50 mL round bottom flask equipped with a magnetic stirring bar, a reflux condenser, gas inlet tube and septum. Prior to mixing with the reactants, the solvent was sparged with N2 for 30 minutes. Pd(PPh3)4 (86.7 mg, 0.075 mmol) was added and the reaction was sealed with a rubber septum and heated to reflux. After 24 hours the reaction was allowed to cool to ambient temperature. The mixture was extracted three times with ethyl acetate, washed once with brine, and dried over anhydrous Na2S04. Purified by flash column chromatography (S1O2, 10%
EtOAc/Hexanes) to afford Intermediate ll-G-aryl (Scheme 1 1 ).
Method I. Preparation of Intermediate ll-L (Scheme 3).
o-Aminobenzonitrile ll-K (2.5 mmol) and aldehyde ll-B (2.5 mmol) were added to a solution of DMF (10 mL) and ZnC (3.0 mmol). The mixture was heated at reflux for 1.5 h and allowed to cool. The cooled reaction mixture was quenched with water (10 mL), and Intermediate ll-L (Scheme 3) was separated by filtration and used without further purification.
Method J. Reduction of Intermediate ll-L.
2 mmol of Intermediate ll-L was dissolved in 15 mL EtOH 95% and Pd/C (0.2 mol%) was added. The mixture was placed under H2 with constant stirring, until no more beginning product appeared as indicated by TLC. The reaction mixture was filtered off to remove the Pd/C and the organic layer was removed under reduced pressure. The resulting solid was poured onto HCI 1 N to afford the pure amino-derivative of intermediate ll-L.
Method K. Acetylation of intermediate ll-T (Scheme 12).
Figure imgf000164_0001
Scheme 12 ll-T ll-N
Commercially available Intermediate ll-T (29,9 mmol) was mixed with 15 mL acetic anhydride. This mixture was submitted to MWI in a commercial oven at full power until all the solid disappeared into the solution. The solution was then stirred for 30 min at room temperature and poured into cold 5 water (200 mL) for 12h. The precipitate formed was filtered and washed with excess water to afford Intermediate Il-N, which was used without further purification.
Method L. Condensation of Intermediate Il-N with compound ll-O (Scheme 4).
10g PPA were heated at 100°C under stirring, then Intermediate Il-N (5 mmol) was added. The commercially available ll-O (5 mmoles) was introduced dropwise into the reaction mixture. The 10 mixture was stirred at 100°C for 30 min., then poured onto hot water (200 mL). The precipitate thus obtained was filtered off and washed with excess water to remove unreacted PPA. The precipitate was crystallized in EtOH (50 mL) affording Intermediate ll-P (Scheme 4).
INTERMEDIATE 1 - PREPARATION OF N-(4-Methoxy-phenyl)-acetamide.
To a stirring suspension of p-anisidine (6.036 g, 49 mmol) in DCM (20 mL), acetic anhydride (5 mL, 15 53 mmol) was added dropwise over a period of 1 h. The reaction was stirred for 1 h, then poured into hexane (60 mL) and stirred for further 1 h. The solid formed was collected by filtration and washed with hexane to afford the title compound (7.717 g, 95%, mp: 132°C) as a pale grey solid. HRMS: calcd for C9HnN02 165.0790 Found, 165.0789. LRMS (El): 165 (M+ , 71 %), 108 ([NH2C6H40]+, 100).
20 1H NMR (400 MHz, CDCI3) δ 2.13 (s, 3H) 3.78 (s, 3H) 6.83 (d, 2H, 9 Hz) 7.38 (d, 2H, 9 Hz). 13C NMR (100 MHz, CDCI3) δ 24.66, 55.85, 1 14.49, 122.37, 131 .41 , 156.82, 168.79.
INTERMEDIATE 2 - PREPARATION OF N-(3-acetyl-4-hydroxy-phenyl)-acetamide.
This compound was prepared according to Method AA, using Intermediate 1 as starting material.
The title compound was crystallized from diethyl ether as a pale green solid (5.336 g, 87%, mp: 25 163°C). HRMS: calcd for Ci0HnNO3 193.0739 Found, 193.0740. Anal. Calcd. for Ci0HnNO3: C,
62.17; H, 5.74; N, 7.25. Found: C, 62.1 1 ; H, 5.81 ; N, 7.12. LRMS (El): 193 (M+ , 100%).
1H NMR (300 MHz, CDCI3) δ 2.16 (s, 3H) 2.61 (s, 3H) 6.92 (d, 1 H, J= 9 Hz) 7.33 (dd, 1 H, J= 2.6 and
9 Hz) 8.16 (d, 1 H, J= 2.6 Hz) 12.09 (s, 1 H, OH). 13C NMR (75 MHz, CDCI3) δ 24.71 , 27.16, 1 19.08,
1 19.60, 122.94, 127.42, 129.58, 159.62, 168.86, 204.84.
30 INTERMEDIATE 3 - PREPARATION OF (E)-N-(3-cinnamoyl-4-hydroxyphenyl)acetamide
(E)-A/-(3-cinnamoyl-4-hydroxyphenyl)acetamide was prepared according to Method A, using Intermediate 2 (1 .93 g, 10 mmol) and benzaldehyde (10 mmol), to afford a yellow precipitate (2.3 g, 82% yield, mp: 190°C). Anal. Calcd. for Ci7H15N03: C, 72.58; H, 5.37; N, 4.98. Found : C, 72.01 ; H, 5.51 ; N, 4.89. 1H NMR (300 MHz, DMSO-d6) δ 2.03 (s, 3H), 6.96 (d, 1 H, J = 8.84 Hz), 7.47-7.50 (m, 3H), 7.68-7.73 (dd, 1 H, J = 2.5, 8.8 Hz), 7.78-7.84 (m, 4H), 8;15 (d, 1 H, J = 2.5 Hz), 9.89 (s, 1 H, OH), 1 1.70 (s, 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ 23.70, 1 17.71 , 120.99, 121 .28, 122.75, 128.07, 128.77, 129.08, 130.93, 131.07, 134.45, 144.13, 156.71 , 168.13, 192.87.
INTERMEDIATE 4 - PREPARATION OF N-(4-oxo-2-phenyl-4H-chromen-6-yl)acetamide.
A/-(4-oxo-2-phenyl-4/-/-chromen-6-yl)acetamide was prepared according to Method B, using Intermediate 3 (2.81 g, 10 mmol) and (0.28 g) as starting materials. The title compound was obtained as an orange powder (2.7 g, 96% yield, mp: 280°C). Anal. Calcd. for Ci7H13N03: C, 73.1 1 ; H, 4.69; N, 5.02. Found : C, 72.98; H, 4.84; N, 5.01.
1H NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 7.00 (s, 1 H), 7.56-7.61 (m, 3H), 7.73-7.76 (d, 1 H, J = 9.0 Hz), 7.94-7.98 (dd, 1 H, J = 2.7, 9.0 Hz), 8.07-8.1 1 (m, 2H), 8.33 (d, 1 H, J = 2.7 Hz), 10.27 (s, 1 H). 13C NMR (75 MHz, DMSO-d6) δ 23.98, 106.42, 1 13.01 , 1 19.01 , 123.50, 125.56, 126.29, 129.1 1 , 131.21 , 131.74, 136.79, 151.49, 162.34, 168.55, 176.98.
INTERMEDIATE 5 - PREPARATION OF N-(3-hydroxy-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide. N-(3-hydroxy-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide was prepared according to Method C, using 2.81 g (10 mmol) of Intermediate 3 to afford a yellow solid in 41 % yield. Anal. Calc. for Ci7H13N04: C, 69.15; H, 4.44; N, 4.74. Found: C, 69.12; H, 4.48; N, 4.68.
1H NMR (300MHz, DMSO-of6) δ 2.08 (s, 3H), 7.51 (m, 1 H), 7.55 (m, 2H), 7.71 (d, 1 H, J=9.2Hz), 7.90 (dd, 1 H, J=2.5Hz, 9.2Hz), 8.19 (m, 2H), 8.42 (d, 1 H, J=2.5Hz), 9.53 (s), 10.30 (s). 13C NMR (75 MHz, DMSO-ofe) δ 24.09, 1 12.77, 1 19.08, 121.48, 125.74, 127.75, 128.68, 130.02, 131 .43, 136.05, 138.87, 145.25, 150.76, 168.84, 172.96.
INTERMEDIATE 6 - PREPARATION OF N-(3-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide.
N-(3-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide was prepared according to Method D, using 2.93 g (l Ommol) of Intermediate 5, to afford a yellow solid in 86% yield; Anal. Calc. for Ci8H15N04: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.83; H, 4.92; N, 4.49.
1H NMR (300MHz, DMSO-of6) δ 2.08 (s, 3H), 3.81 (s, 3H), 7.56 (m, 2H), 7.58 (m, 1 H), 7.67 (d, 1 H, J=9.1 Hz), 7.94 (dd, 1 H, J=9.1 , 2.5Hz), 8.02 (m, 2H), 8.37 (d, 1 H, J=2.5Hz), 10.28 (s, 1 H). 13C NMR (75 MHz, DMSO-de) δ 23.96, 59.65, 1 12.84, 1 18.87, 123.68, 125.55, 128.19, 128.62, 130.5, 130.77, 136.38, 140.41 , 150.61 , 154.77, 168.54, 173.68.
INTERMEDIATE 7 - PREPARATION OF 6-amino-2-phenyl-4H-chromen-4-one.
2.3 g of the title compound were prepared starting from Intermediate 4, following the directions of Method E (96%, mp: 201 °C). Anal. Calcd. for Ci5HnN02: C, 75.94; H, 4.67; N, 5.90. Found : C, 75.77; H, 4.97; N, 5.58.
1H NMR (300 MHz, DMSO-d6) δ 6.87 (s, 1 H), 7.07-7.1 1 (dd, 1 H, J = 2.7, 8.8 Hz), 7.13 (d, 1 H, J = 2.7 Hz), 7.50-7.53 (d, 1 H, J = 8.8 Hz), 7.56-7.58 (m, 3H), 8.03-8.06 (m, 2H). 13C NMR (75 MHz, DMSO- d6) δ 105.24, 105.77, 1 19.03, 121.91 , 124.23, 126.1 1 , 129.08, 131.43, 131.60, 146.23, 148.08, 161.70, 177.14. INTERMEDIATE 8 - PREPARATION OF 6-amino-3-hydroxy-2-phenyl-4H-chromen-4-one.
6-amino-3-hydroxy-2-phenyl-4H-chromen-4-one was prepared, according to Method E, using Intermediate 5 as starting material to produce a white solid in 94% yield; Anal. Calc. for C15HHNO3: C, 71 .14; H, 4.38; N, 5.53. Found: C, 71.1 1 ; H, 4.42; N, 5.49.
5 1H NMR (300MHz, DMSO-of6) δ 7.10 (dd, 1 H, J=8.9, 2.6Hz), 7.18 (d, 1 H, J=2.6Hz), 7.48 (d, 1 H, J=8.9Hz), 7.50 (m, 1 H), 7.55 (m, 2H), 8.17 (m, 2H), 9.27 (s, 1 H).
INTERMEDIATE 9 - PREPARATION OF 6-amino-3-methoxy-2-phenyl-4H-chromen-4-one.
The title compound was synthesized from Intermediate 6, according to Method E, to afford a yellow solid in 80% yield; Anal. Calc. for Ci6H13N03: C, 71 .90; H, 4.90; N, 5.24. Found: C, 71 .88; H, 4.92; 10 N, 5.21.
1H NMR (300MHz, DMSO-of6) δ 3.78 (s, 3H), 7.13 (dd, 1 H, J=8.9, 2.6Hz), 7.21 (d, 1 H, J=2.6Hz), 7.48 (d, 1 H, J=8.9Hz), 7.57 (m, 1 H ), 7.58 (m, 2H), 8.00 (m, 2H).
INTERMEDIATE 10 - PREPARATION OF N-(4-oxo-2-phenyl-4H-chromen-6-yl)benzothioamide.
N-(4-oxo-2-phenyl-4H-chromen-6-yl)benzothioamide was prepared following the methodology 15 described in Method F, using 2.33 g of Intermediate 7 (10 mmol), 0.33 g of sulfur (10 mmol), 0.35 g of Na2S.9H20 (1.5 mmol) and 1 .1g benzaldehyde (10 mmol), affording the title compound in 51 % yield; Anal. Calc. for C22H15NO2S: C, 73.93; H, 4.23; N, 3.92. Found: C, 73.89; H, 4.26; N, 3.91.
1H NMR (300 MHz, DMSO-ofe) δ 7.05 (s,1 H), 7.52-7.60 (m), 7.73-7.78 (dd, 1 H, J= 2.91 , 8.6 Hz), 7.82 (d), 7.82-7.86 (d, J= 8.97 Hz), 7.95-8.00 (m, 2H), 8.08-8.13 (m, 2H), 8.75 (s, 1 H). 13C NMR (75MHz, 20 DMSO-de) δ 106.77, 1 15.16, 1 19.86, 124.1 , 126.55, 128.63, 129.02, 129.09, 129.31 , 131.29, 131.97, 132.02, 135.98, 148.7, 154.17, 162.3, 177.23, 193.26.
INTERMEDIATE 1 1 - PREPARATION OF 5-acetamido-2-hydroxy-3-nitroacetophenone.
In 28 ml of glacial acetic acid, 2.4 g of intermediate 2 (0.0124 mol) were dissolved. To this solution, a mixture of HNO3 69% (1 ,2 ml.) and glacial acetic acid (4 ml.) was added. The resulting mixture was 25 stirred at r.t. for 2h, poured onto iced water, the resulting precipitate was filtered and washed with water to afford the yellow title compound (1.91 g), with a yield of 65%; Anal. Calc. for CioH 0N205: C, 50.42; H, 4.23; N, 1 1 .76. Found: C, 50.39; H, 4.29; N, 1 1.74.
1H NMR (300MHz, DMSO-of6) δ 2.05 (1 H, s), 2.66 (1 H, s), 8.26 (1 H, d, J=2.66Hz), 8.52 (1 H, d, J=2.66Hz), 10.29 (1 H, s), 12.40 (1 H, s). 13C NMR (75 MHz, DMSO-ofe) δ 23.93, 28.55, 120.06, 30 123.79, 127.16, 130.70, 137.23, 149.94, 168.92, 203.47.
INTERMEDIATE 12 - PREPARATION OF (E)-N-(3-cinnamoyl-4-hydroxy-5-nitrophenyl)acetamide.
This compound was prepared following Method A, using Intermediate 1 1 and benzaldehyde as starting materials, with a yield of 94%; Anal. Calc. For Ci7H14N205: C, 62.57; H, 4.32; N, 8.59. Found: C, 62.51 ; H, 4.37; N, 8.51.
35 1H NMR (300MHz, DMSO-of6) δ 2.00 (3H, s), 7.43 (1 H, dd, J=Hz), 7.45 (3H, m, H-6c), 7.64 (1 H, d, J=15.92Hz), 7.71 (1 H, d, J=15.92Hz), 7.73 (2H, dd, J=3.79Hz, J=7.33Hz), 7.96 (1 H, d, J=3.29), 8.35 (1 H, d, J=2.91 Hz), 9.86 (1 H, s), 10.01 (1 H, s). 13C RMN (75 MHz, DMSO-ofe) δ 24.09, 120.42, 123.38, 126.56, 127.56, 129.04, 129.37, 129.48, 131 .72, 134.45, 137.16, 146.22, 149.81 , 159.30, 192.75.
INTERMEDIATE 13 - PREPARATION OF N-(8-nitro-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide.
5 N-(8-nitro-4-oxo-2-phenyl-4/-/-chromen-6-yl)acetamide was prepared according to Method B, using Intermediate 14 as starting material, affording a yield of 98%; Anal. Calc. For Ci7H 2N205: C, 62.96; H, 3.73; N, 8.64. Found: C, 62.89; H, 3.78; N, 8.62.
1 H NMR (300MHz, DMSO-of6) δ 2.1 1 (3H, s), 7.18 (1 H, s), 7.62 (3H, m), 8.12 (2H, dd, J=1 .89Hz, J=7.96Hz), 8.54 (1 H, d, J=2.83Hz), 8.80 (1 H, d, J=2.50Hz), 10.25 (1 H, s). 13C NMR (75 MHz, 10 DMSO-de) δ 24.1 1 5, 1 16.77, 121 .1 1 , 125.00, 126.45, 129.54, 128.00, 130.28, 130.30, 137.32, 139.00, 151 .37, 169.13, 171 .14, 225.43.
INTERMEDIATE 14 - PREPARATION OF 6-amino-8-nitro-2-phenyl-4H-chromen-4-one.
This compound was prepared following Method E, using Intermediate 13 as a starting material to afford a 76% yield; Anal. Calc. For Ci5H10N2O4: C, 63.83; H, 3.57; N, 9.92. Found: C, 63.80; H, 3.62; 15 N. 9.90.
1 H NMR (300MHz, DMSO-of6) δ 6.06 (1 H, s), 7.06 (1 H, s), 7.45 (1 H,d, J=2.66Hz), 7.61 (3H, m), 7.76 (1 H, d, J=2.66Hz), 8.08 (2H, dd, J=4.16Hz, J=7.07Hz). 13C RMN (75 MHz, DMSO-ofe) δ 104.5, 1 15.70, 121 .00, 125.60, 126.4, 128.00, 128.70, 130.30, 139.60, 143.00, 144.00, 163.60, 182.10.
INTERMEDIATE 15 - PREPARATION OF 6,8-diamino-2-phenyl-4H-chromen-4-one.
20 This compound was prepared in 95% yield from Intermediate 14, by reduction with SnC (5 eq.) in refluxing EtOH; Anal. Calc. For Ci5HnN04: C, 71 .42; H, 4.79; N, 1 1 .10. Found: C, 71 .39; H, 4.83; N, 1 1 .10.
1 H NMR (300MHz, DMSO-of6) δ 6.40 (1 H, d, J=2,78Hz), 6.40 (1 H, d, J=2,78Hz), 6.80 (1 H, s), 7.53 (3H, m), 8.16 (2H, m)' 13C NMR (75 MHz, DMSO-ofe) δ 87.21 , 94.58, 105.64, 124. 95, 126.59, 25 129.14, 131 .82, 138.31 , 139.26, 145.18, 161 .12, 177.72, 225.24.
INTERMEDIATE 16 - PREPARATION OF 1 -(2-hydroxy-4-methoxyphenyl)ethanone.
A solution of 2,4-dihydroxyacetophenone (30 mmol), dimethylsulfate (30 mmol), K2CO3 (90 mmol) in acetone (200 imL) was heated at 50°C for 12h. The solution thus obtained was filtered and the organic layer was removed under reduced pressure. The compound was purified by column 30 chromatography on silica gel, using DCM as eluent, to afford the desired product as a brown solid (85%); Anal. Calc. for C9H10O3: C, 65.05; H, 6.07; O, 28.88. Found: C, 65.01 ; H, 6.10; O, 28.81 .
1 H NMR (300MHz, DMSO-of6) δ 2.54 (s, 3H), 3.79 (s, 3H), 6.45 (d, 1 H, J=2.4Hz), 6.50 (dd, 1 H, J=2.4, 8.9Hz), 7.80 (d, 1 H, J=8.9Hz). 13C NMR (75 MHz, DMSO-ofe) δ 26.86, 55.73, 100.84, 107.17, 1 14.02, 133.27, 164.18, 165.71 , 202.96.
35 INTERMEDIATE 17 - PREPARATION OF 1 -(2-hydroxy-4-methoxy-5-nitrophenyl)ethanone. To 25 mL of HN03 (69%) at 0°C, Intermediate 16 (2g, 12mmol) was added and the mixture was kept under constant stirring at the same temperature for 4h. Then the solution was poured onto iced water (200 g) and allowed to precipitate overnight at 4°C. The brown solid formed was collected by filtration to afford 2.2 g (86%); Anal. Calc. for CgHgNOs: C, 51 .19; H, 4.30; N, 6.63. Found: C, 51 .19; H, 4.30; N, 6.63.
1H NMR (300MHz, DMSO-of6) δ 2.62 (s, 3H), 3.96 (s, 3H), 6.78 (s, 1 H), 8.48 (s, 1 H), 12.76 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 27.13, 57.30,101.61 , 1 13.36, 130.15, 131.56, 158.43, 165.98, 201 .76.
INTERMEDIATE 18 - PREPARATION OF 1-(5-amino-2-hydroxy-4-methoxyphenyl)ethanone.
To a solution of SnCI2.2H20 (3.2g, 14mmol) in ethanol (20ml_), Intermediate 17 (0.573mg, 2.87mmol) was added, and the mixture stirred and heated under reflux until no more Intermediate 17 could be detected by TLC. The solution was poured into water and neutralized with a solution of K2CO3 10%. The solution obtained was filtered off and the aqueous layer was extracted with EtOAc (3x 40 mL). The organic layer was dried over MgS04 and concentrated under reduced pressure to afford a black powder (65%); Anal. Calc. for C9HiiN03: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.61 ; H, 6.19; N, 7.69.
1H NMR (300MHz, DMSO-of6) δ 2.60 (s, 3H), 3.94 (s, 3H), 6.74 (s, 1 H), 8.45 (s, 1 H), 12.76 (s, 1 H). 13C NMR (75MHz, DMSO-of6) δ 27.78, 57.39, 101.67, 1 13.46, 130.26, 131.60, 158.57, 166.1 1 , 201 .87.
INTERMEDIATE 19 - PREPARATION OF N-(5-acetyl-4-hydroxy-2-methoxyphenyl) acetamide.
To a solution of Intermediate 18 (0.34g, 1.87mmol) in DCM (20 mL), acetic anhydride (3ml, 2.8mmol) was added; this solution was stirred at r.t. for 4h, checking by TLC the appearance of the desired compound. When no more Intermediate 18 was detected, the solvent was removed. The residue was mixed with hexane until the formation of a yellow precipitate, that was collected by filtration, yield: 90%; Anal. Calc. for CnH13N04: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.09; H, 5.89; N, 6.25.
1H NMR (300MHz, DMSO-of6) δ 2.13 (s, 3H), 2.46 (s, 3H), 3.85 (s, 3H), 6.56 (s, 1 H), 8.24 (s, 1 H), 9.14 (s, 1 H), 12.52 (s, 1 H). 13C NMR (75MHz, DMSO-of6) δ 23.59, 26.78, 56.39, 99.63, 1 12.27, 1 19.65, 125.50, 157.90, 160.94, 168.96, 203.10.
INTERMEDIATE 20 - PREPARATION OF (E)-N-(5-cinnamoyl-4-hydroxy-2- methoxyphenyl)acetamide.
E)-N-(5-cinnamoyl-4-hydroxy-2-methoxyphenyl)acetamide was prepared according to Method A, using Intermediate 19 and benzaldehyde as starting materials, with a yield of 66%; Anal. Calc. For Ci8H17N04: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.41 ; H, 5.57; N, 4.43.
1H NMR (300MHz, DMSO-of6) δ 2.08 (s, 3H), 3.88 (s, 3H), 6.63 (s, 1 H), 7.46 (m, 4H), 7.82 (s, 2H), 7.86 (m, 2H), 8.43 (s, 1 H), 9.23 (s, 1 H). 13C NMR (75MHz, DMSO-of6) δ 23.30, 56.28, 99.84, 1 12.48, 1 19.40, 121.29, 126.56, 129.00, 130.87, 134.50, 144.17, 159.10, 162.84, 168.76, 191.77. INTERMEDIATE 21 - PREPARATION OF N-(7-methoxy-4-oxo-2-phenyl-4H-chromen-6- yl)acetamide.
This compound was prepared according to method B, using Intermediate 20 as starting material, with 84% yield; Anal. Calc. For Ci8H15N04: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.78; H, 4.96; N, 5 4.51.
1H NMR (300MHz, DMSO-of6) δ 2.13 (s, 3H), 4.00 (s, 3H), 6.94 (s, 1 H), 7.42 (s, 1 H), 7.57 (m, 3H), 8.08 (m, 2H), 8.63 (s, 1 H), 9.36 (s, 1 H). 13C NMR (75MHz, DMSO-of6) δ 23.89, 56.69, 100.02, 106.54, 1 15.70, 1 16.46, 126.10, 126.19, 129.07, 131.26, 131 .56, 153.32, 154.55, 161.83, 168.82, 176.33.
10 INTERMEDIATE 22 - PREPARATION OF N-(3-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-chromen-6- yl)acetamide.
N-(3-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide was prepared from Intermediary 20, following Method C, with a 50% yield; Anal. Calc. For Ci8H15N05: C, 66.46; H, 4.65; N, 4.31. Found: C, 66.41 ; H, 4.69; N, 4.28.
15 1H NMR (300MHz, DMSO-of6) δ 2.13 (s, 3H), 3.99 (s, 3H), 7.37 (s, 1 H), 7.54 (m, 3H), 8.20 (m, 2H), 8.67 (s, 1 H), 9.38 (brs, 1 H), 10.21 (brs, 1 H). 13C NMR (75MHz, DMSO-d6) δ 23.97, 56.74, 99.65, 1 14.46, 1 15.34, 125.84, 127.38, 128.54, 129.64, 131.50, 138.72, 144.32, 152.54, 154.61 , 168.96, 172.26.
INTERMEDIATE 23 - PREPARATION OF 6-amino-7-methoxy-2-phenyl-4H-chromen-4-one.
20 6-amino-7-methoxy-2-phenyl-4H-chromen-4-one was prepared according to Method E, using Intermediate 21 as starting material (92%); Anal. Calc. For Ci6H13N03 : C, 71.90; H, 4.90; N, 5.24. Found: C, 71 .82; H, 4.93; N, 5.21.
1H NMR (300MHz, DMSO-of6) δ 3.94 (s, 3H), 5.17 (s, 2H), 6.83 (s, 1 H), 7.15 (s, 1 H), 7.21 (s, 1 H), 7.55 (m, 3H), 8.03 (dd, 2H, J=2.1 , 7.3Hz ). 13C NMR (75MHz, DMSO-of6) δ 56.20, 99.22, 104.26, 25 105.96, 1 17.52, 125.92, 129.05, 131.21 , 131.70, 136.81 , 149.42, 152.09, 161.16, 176.34.
INTERMEDIATE 24 - PREPARATION OF 6-amino-3-hydroxy-7-methoxy-2-phenyl-4H-chromen-4- one.
The title compound was prepared in 92% yield, from Intermediate 22, following Method E. Anal. Calc. For Ci6H13N04 : C, 67.84; H, 4.63; N, 4.94. Found: C, 67.80; H, 4.65; N, 4.91 .
30 1H NMR (300MHz, DMSO-of6) δ 3.94 (s, 3H), 7.17 (s, 1 H), 7.18 (s, 1 H), 7.50 (m, 3H), 8.18 (d, 2H, J=7.3Hz), 9.16 (s, 1 H).13C NMR (75MHz, DMSO-of6) δ 56.20, 98.83, 103.51 , 1 15.38, 127.19, 128.46, 129.29, 131.85, 136.41 , 138.24, 143.62, 148.95, 152.51 , 171.84.
INTERMEDIATE 25 - PREPARATION OF ethyl -acetamido-4-oxo-4H-chromene-2- carboxylate.
1.49 g of sodium (65 mmol) in 100 ml of EtOH were stirred at r.t. until no metal could be observed. 35 Then, a mixture of diethyloxalate (4.8ml, 35 mmol, 3.5 eq., d= 1.07) and Intermediate 2 (1.93g, l Ommol) in EtOH (10 mL) was added, and the resulting mixture was heated at reflux for 1 h. After cooling to r.t., the mixture was acidified with cone. HCI until the formation of a white precipitate, which was filtered off and washed with AcOEt (15 mL). Crystallization in MeOH/diisopropylether (4/1 ) afforded a white powder in 85% yield. Anal. Calc. for Ci4H13N05: C, 61.09; H, 4.76; N, 5.09. Found: C, 61 .05; H, 4.79; N, 5.01.
1H NMR (300MHz, DMSO-of6) δ 1.34 (3H, t, J= 7.18 Hz, J=14.36Hz), 2.08 (3H, s), 4.38 (2H, q, J=6.98Hz, J=7.18Hz), 6.90 (1 H, s), 7.73 (1 H, d, J=9.25Hz), 7.97 (1 H, dd, J=2.64Hz, J=9.06Hz), 8.34 (1 H, d, J=2.64Hz), 10.32 (1 H, s). 13C RMN (75 MHz, DMSO-ofe) δ 14.07, 24.19, 62.86, 1 12.95, 1 13.26, 1 19.69, 124.22, 126.72, 137.54, 151.32, 152.20, 160.23, 168.91 , 177.38.
INTERMEDIATE 26 - PREPARATION OF ethyl 6-amino-4-oxo-4H-chromene-2-carboxylate.
This compound was obtained in 97% yield, following Method E, using Intermediate 25 as starting material. Anal. Calc. for d2HnN04: C, 61 .80; H, 4.75; N, 6.01 . Found: C, 61 .76; H, 4.79; N, 6.00.
1H NMR (300MHz, DMSO-of6) δ 1.33 (3H, t, J=7.07Hz, J=14.14Hz), 4.36 (2H, q, J=7.07Hz, J=Hz), 5.65 (2H, s), 6.79 (1 H, s), 7.06 (1 H, dd, J=Hz), 7.45 (1 H, d, J=8.21 Hz). 13C RMN (75 MHz, DMSO- d6) 6 14.08, 62.69, 104.52, 1 12.40, 1 19.63, 123.01 , 125.07, 147.56, 151.45, 160.46, 177.37, 225.52.
INTERMEDIATE 27 - PREPARATION OF (E)-N-(3-(3-(dimethylamino)acryloyl)-4- hydroxyphenyl)acetamide.
A solution of Intermediate 2 (1.93 g, 10 mmol), in DMF (6g, 10 eq.), and DMF/DMA (1.4 g, 1 1 mmol) was heated, at 1 10°C for 2h, with constant stirring. The solution was allowed to cool down to r.t. and then the solvent was removed under reduced pressure. A yellow oil was obtained that was crystallized in EtOH (20 mL) to afford 2.1 g of yellow precipitate which was collected by filtration, yield: 84%; Anal. Calc. for Ci3H16N203: C, 62.89; H, 6.50; N, 1 1.28. Found: C, 62.81 ; H, 6.44; N, 1 1.21.
1H NMR (300 MHz, DMSO-ofe) δ 2.00 (3H, s), 2.97 (3H, s), 3.22 (3H, s), 5.71-5.75 (1 H, d, J= 12.08 Hz), 6.75-6.78 (1 H, d, J= 8.88 Hz), 7.52-7.55 (1 H, dd, J= 2.27, 8.69 Hz), 7.90-7.94 (1 H, d, J= 12.08 Hz), 7.97 (1 H, d, J= 2.27 Hz), 9.76 (1 H, s), 14.03 (1 H, s). 13C NMR (75 MHz, DMSO-ofe) δ 23.66, 37.29, 44.99, 88.77, 1 17.35, 1 19.23, 1 19.37, 126.24, 130.02, 155.54, 158.22, 167.85, 189.52.
INTERMEDIATE 28 - PREPARATION OF N-(4-oxo-4H-chromen-6-yl)acetamide.
A mixture of Intermediate 27 (10 mmol), and HCI 50 % (10 mL) was refluxed on water bath for 2 h. After cooling, the solution was diluted with water and allowed to stand. The solid obtained was filtered off to afford the title compound in 89% yield; Anal. Calc. for CnH9N03: C, 65.02; H, 4.46; N, 6.89. Found: C, 64.97; H, 4.51 ; N, 6.87.
1H NMR (300 MHz, DMSO-ofe) δ 2.08 (3H, s), 6.29-6.31 (1 H, d, J= 6.05 Hz), 7.59-7.62 (1 H, d, J= 8.88 Hz), 7.92-7.96 (1 H, dd, J= 2.64, 9.06 Hz), 8.25-8.27 (1 H, d, J= 5.86 Hz), 8.34 (1 H, d, J= 2.64 Hz), 10.41 (1 H, s). 13C NMR (75 MHz, DMSO-ofe) δ 23.94, 1 1 1 .65, 1 13.08, 1 18.91 , 124.37, 125.59, 136.78, 151 .79, 156.68, 168.61 , 176.27.
INTERMEDIATE 29 - PREPARATION OF N-(3-iodo-4-oxo-4H-chromen-6-yl)acetamide. This compound was prepared according to Method G, using Intermediate 27 (10 mmol) and (1 eq.), solubilized in MeOH (10 imL) as starting materials. Yield, 54%; Anal. Calc. for CnH8IN03: C, 40.15; H, 2.45; N, 4.26. Found: C, 40.1 1 ; H, 2.47; N, 4.22.
1H NMR (300 MHz, DMSO-ofe) δ 2.08 (3H, s), 7.60-7.65 (1 H, d, J= 8.88 Hz), 7.93-7.99 (1 H, dd, J= 5 2.64, 9.06 Hz), 8.32 (1 H, d, J= 2.6 Hz), 10.32 (1 H, s). 13C NMR (75 MHz, DMSO-ofe) δ 23.98, 86.13, 1 13.4, 1 18.89, 121 .29, 125.88, 137.21 , 151.47, 158.93, 168.65, 172.76.
INTERMEDIATE 30 - PREPARATION OF N-(3-(4-fluorophenyl)-4-oxo-4H-chromen-6-yl)acetamide.
N-(3-(4-fluorophenyl)-4-oxo-4H-chromen-6-yl)acetamide was prepared according to Method H, using Intermediate 29 as starting material (32%). Anal. Calc. for Ci7H12FN03: C, 68.68; H, 4.07; N, 4.71 . 10 Found: C, 68.62; H, 4.12; N, 4.70.
1H NMR (300 MHz, DMSO-ofe) δ 2.09 (3H, s), 7.28 (2H, t, J= 8.97 Hz), 7.64 (3H, m), 7.95-8.01 (1 H, dd, J= 2.67, 9.1 Hz), 8.40 (1 H, d, J= 2.65 Hz), 8.53 (1 H, s), 10.31 (1 H, s). 13C NMR (75 MHz, DMSO-de) δ 23.98, 1 13.6, 1 14.83-1 15.25 (J= 21 Hz), 1 18.9, 123.92, 125.25, 128.33, 130.92, 130.92-131 .09 (J= 8 Hz), 136.87, 151.49, 154.54, 162.08-166.94 (J= 245 Hz), 168.61 , 174.94.
15 INTERMEDIATE 31 - PREPARATION OF 6-amino-3-(4-fluorophenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, from Intermediate 30, in 89% yield; Anal. Calc. for Ci5H10FNO2: C, 70.58; H, 3.95; N, 5.49. Found: C, 70.58; H, 3.95; N, 5.49.
1H NMR (300 MHz, DMSO-ofe) δ 5.52 (2H, s), 7.05-7.09 (1 H, dd, J= 2.83, 8.87 Hz), 7.19 (1 H, d, J= 2.65 Hz), 7.26 (2H, t, J= 8.87 Hz), 7.39-7.42 (1 H, d, J= 8.87 Hz), 7;60-7.64 (2H, m ), 8.42 (1 H, s). 13C 20 NMR (75 MHz, DMSO-ofe) δ 105.25, 1 14.8-1 15.08 (J= 21 Hz), 1 18.81 , 121 .59, 121.81 , 124.67, 128.84-128.88 (J= 2,86 Hz), 130.89-131 (J= 8 Hz), 146.75, 147.92, 153.91 , 160.09-163.32 (J= 245 Hz), 174.97.
INTERMEDIATE 32 - PREPARATION OF N-(2-methyl-4-oxo-4H-chromen-6-yl)acetamide.
To a solution of Intermediate 2 (1 .93 g, 10 mmol) in pyridine (20 imL) acetyl chloride (0.78 imL, 1 1 25 mmol) were added, and the resulting mixture was stirred at r.t. for 1 h. Then, a solution of KOtBu (1 eq., 1.2 g) in 20 imL of THF was added, and the mixture was stirred under reflux for 1 h. To this solution, EtOH/H2S04 (20/5 imL) was introduced, and reflux was continued for further 2h. The solution was cooled to r.t. and extracted with DCM (3x30 imL). The organic layers were combined, dried with Na2S204 and concentrated under vacuo. The mixture obtained was crystallized with EtOH 30 to give the pure compound (1 .1 g, yield: 51 %). Anal. Calc. for Ci2HnN03: C, 66.35; H, 5.10; N, 6.45.
Found: C, 66.28; H, 5.12; N, 6.41. m/z: 217.07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 2.07 (s, 3H), 2.37 (s, 3H), 6.20 (s, 1 H), 7.54-7.57 (d, 1 H, J= 8.69 Hz), 7.87-7.91 (dd, 1 H, J= 2.64, 8.70 Hz), 8.27 (d, 1 H, J= 2.6 Hz), 10.22 (s, 1 H, NH). 13C NMR (75 MHz, DMSO-de) δ 19.98, 23.96, 109.4, 1 13.14, 1 18.52, 123.1 , 125.21 , 136.48, 151 .74, 166.56, 35 168.52, 176.65.
INTERMEDIATE 33 - PREPARATION OF 6-amino-2-methyl-4H-chromen-4-one. Acetamido deprotection of Intermediate 32 was performed as described in Method E, achieving a 78% yield. Anal. Calc. for Ci0H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.51 ; H, 5.23; N, 7.97. m/z: 175.06 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 2.32 (s, 3H), 6.18 (s, 1 H), 7.02 (d, 1 H, J= 2.6 Hz), 7.08-7.12 (dd, 5 1 H, J= 2.64, 8.8 Hz), 7.41-7.44 (d, 1 H, J= 8.69 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 22.54, 104.56, 108.87, 1 19.56, 122.95, 124.78, 147.44, 148.03, 166.41 , 177.54.
INTERMEDIATE 34 - PREPARATION OF 6-amino-5-bromo-2-phenyl-4H-chromen-4-one.
A solution of Intermediate 7 (0.5 g, 2.1 mmoles) in glacial acetic acid (5 imL) was stirred at r.t., then bromine (1 eq.) was added. The solution turned red and, after 30 min stirring, a brownish precipitate 10 appeared. This solution was poured onto water, the precipitate formed was filtered off and washed with DCM to afford the title compound (0.4 g, yield: 62%). Anal. Calc. for Ci5H10BrNO2: C, 56.99; H, 3.19; N, 4.43. Found: C, 56.96; H, 3.21 ; N, 4.40. m/z: 314.99 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 4.89 (2H, bs), 6.91 (s, 1 H), 7.30-7.33 (d, 1 H, J= 9.06 Hz), 7.54-7.57 (m, 3H), 7.58-7.61 (d, 1 H, J= 9.07 Hz), 8.03-8.06 (m, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 107, 15 1 13.63, 1 18.76, 121.34, 125.99, 126.52, 129.05, 130.91 , 131.51 , 144.41 , 149.25, 160.12, 176.13.
INTERMEDIATE 35 - PREPARATION OF 6-Nitro-2-Phenyl-1 ,2-dihydroquinazolin-4(3H)-one.
The synthesis of this compound was performed according to Method I, as follows: a solution of 5- nitroanthranilonitrile (2.5 mmol) in benzaldehyde (2.5 mmol) were added to a mixture of DMF (10 imL) and ZnCI2 (3 mmol). The resulting mixture was heated at reflux for 1.5 h and then allowed to 20 cool. The cooled reaction mixture was quenched with water and the resulting precipitate was collected by suction in 77% yield (Mp: 265°C). Anal. Calc. for C-uHnNsOs: C, 62.45; H, 4.12; N, 15.61 . Found: C, 62.30; H, 4.01 ; N, 15.27. m/z: 269.08 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.01 (1 H, s), 6.82 (1 H, d, J= 8.6 Hz), 7.42 (5H, m), 8.10 (1 H, dd, J= 8.6, 2.3 Hz), 8.42 (1 H, d, J= 2.3 Hz), 8.56 (1 H, bs), 8.74 (1 H, bs). 13C NMR (75 MHz, DMSO-ofe) δ 25 161.57, 66.60, 1 14.43, 129.12, 137.38, 124.40, 1 12.86, 152.37, 141.26, 126.80, 128.86, 129.15.
INTERMEDIATE 36 - PREPARATION OF 6-amino-2-phenylquinazolin-4(3H)-one.
Following Method J, this compound was prepared as follows: a mixture of 2 mmol of Intermediate 35 and Pd/C (0.2 mol%) in 15 mL EtOH 95% was placed under H2 with constant stirring, until no more Intermediate 35 appeared as indicated by TLC. The reaction mixture was filtered off to remove Pd/C 30 and the organic layer was removed under reduced pressure. The resulting solid was poured onto HCI 1 N to afford pure Intermediate 36 as a red precipitate in 92% yield. Anal. Calc. for C14HHN3O3: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.79; H, 4.69; N, 17.62. m/z: 237.09 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.12 (d, 1 H, J= 8.6 Hz), 7.24 (brs, 1 H), 7.48 (d, 1 H, J= 8.6 Hz), 7.50 (m, 3H), 8.12 (m, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 162.20, 147.3, 128.56, 122.59, 147.96, 35 106.32, 122.15, 139.68, 133.26, 127.17, 128.56, 130.48.
INTERMEDIATE 37 - PREPARATION OF p-acetylthioacetanilide. 5g of 4'-mercaptoacetanilide (29,9 mmol) were acetylated according to Method K, which afforded 6g (95% yield) of the title compound in the form of a white precipitate. Anal. Calc. for doHnNC^S: C, 57.39; H, 5.30; N, 6.69. Found: C, 57.35; H, 5.33; N, 6.67.
1H NMR (300 MHz, DMSO-ofe) δ 2.06 (s, 3H), 2.38 (s, 3H), 7.30-7.33 (d, 2H, J= 8.69 Hz), 7.64-7.67 5 (d, 2H, J= 8.69 Hz), 10.12 (s, bs). 13C NMR (75 MHz, DMSO-ofe) δ 24.24, 30.15, 1 19.65, 120.99, 135.31 , 140.73, 168.83, 194.4.
INTERMEDIATE 38 - PREPARATION OF N-(4-oxo-2-phenyl-4H-thiochromen-6-yl)acetamide.
The title compound was prepared according to Method L, using Intermediate 37 (1.045 g, 5 mmol) and ethyl benzoylacetate (0.87 ml_, 5 mmoles) as starting materials with a yield of 20% (0.3g). Anal. 10 Calc. for Ci7H13N02S: C, 69.13; H, 4.44; N, 4.74. Found: C, 69.06; H, 4.48; N, 4.71. m/z: 295.07 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 2.10 (s, 3H), 7.22 (s, 1 H), 7.57-7.59 (m, 3H), 7.79-7.83 (dd, 2H, J=9.63Hz), 7.88-7.91 (d, 1 H, J=8.87 Hz), 8.00-8.03 (dd, 1 H, J=2.46, 8.88 Hz), 8.61 (d, 1 H, J=2.46 Hz), 10.36 (bs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 24.06, 1 16.27, 121.98, 123.59, 126.77, 127.77, 15 129.48, 130.46, 130.73, 131.07, 135.85, 139.48, 151.93, 168.81 , 179.26.
INTERMEDIATE 39 - PREPARATION OF 6-amino-2-phenyl-4H-thiochromen-4-one.
This compound was prepared according to Method E, using Intermediate 38 (0.59 g, 2 mmol) as starting material, producing a red precipitate (0.47 g, yield 92%). Anal. Calc. for Ci5HnNOS: C, 71 .12; H, 4.38; N, 5.53. Found: C, 71.01 ; H, 4.42; N, 5.48. m/z: 253.06 (100.0%).
20 1H NMR (300 MHz, DMSO-ofe) δ 7.03-7.07 (1 H, dd, J= 2.46, 8.50 Hz), 7.10 (1 H, s), 7.51 (1 H, d, J= 2.46 Hz), 7.54-7.56 (3H, m), 7.57-7.60 (1 H, d, J= 8.69 Hz), 7.75-7.78 (2H, m). 13C NMR (75 MHz, DMSO-de) δ 109.28, 120.36, 121.50, 122.76, 126.86, 127.98, 129.62, 130.95, 131.60, 136.47, 149.53, 151 .56, 179.51.
INTERMEDIATE 43 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(3-
25 methoxyphenyl)acryloyl)phenyl)acetamide.
The title compound was prepared according to Method A, using Intermediate 2 and 3- methoxybenzaldehyde as starting materials, affording a yellow powder with an 85% yield (mp: 147°C)
1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 3.81 (s, 3H), 6.96 (d, 1 H, J=8.9Hz, ), 7.04 (m, 1 H), 7.37 30 (m, 3H), 7.71 (dd, 1 H, J=8.9, 2.5Hz), 7.72 (d, 1 H, J=15.7Hz), 7.79 (d, 1 H, J=15.7Hz), 8.14 (d, 1 H, J=2.5Hz), 9.92 (s, 1 H), 1 1 .71 (s,1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.88, 55.50, 1 13.97, 1 16.93, 1 17.86, 121.39, 121.44, 123.26, 128.29, 130.29, 131.27, 136.06, 144.28, 156.93, 159.87, 168.28, 193.13.
INTERMEDIATE 44 - PREPARATION OF (E)-N-(4-hydroxy-3-(3-(4-methoxyphenyl) acryloyl) 35 phenyl) acetamide.
This compound was prepared according to Method A, using Intermediate 2 and 4- methoxybenzaldehyde as starting materials, affording a yellow powder in 90% yield (mp: 136.6°C) 1H NMR (300MHz, DMSO-ofe) δ 2.04 (s, 3H), 3.82 (s, 3H), 6.96 (d, 1H, J=8.9Hz), 7.04 (d, 2H, J=8.7Hz), 7.64 (d, 1H, J=15.7Hz), 7.71 (dd, 1H, J=2.5, 8.9Hz), 7.78 (d, 2H, J=8.7Hz), 7.79 (d, 1H, J=15.7Hz), 8.19 (d, 1H, J=2.5Hz), 9.95 (s, 1H), 11.98 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 23.72, 55.45, 114.61, 117.69, 119.57, 120.89, 127.03, 128.08, 130.84,131.03, 144.55, 157.10, 161.71, 5 168.13, 192.89.
INTERMEDIATE 45 - PREPARATION OF (E)-N-(3-(3-(2-fluorophenyl)acryloyl)-4- hydroxyphenyl)acetamide.
The title compound was prepared following Method A, starting from Intermediate 2 and 2- fluorobenzaldehyde, to afford a yellow powder in 98% yield (mp: 179.7°C).
10 1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 6.96 (d, 1H, J=8.9Hz), 7.32 (m, 1H), 7.34 (m, 1H), 7.53 (m, 1H), 7.71 (dd, 1H, J=2.6, 8.9Hz), 7.79 (d, 1H, J=15.7Hz), 7.85 (d, 1H, J=15.7Hz), 7.92 (td, 1H, J=2.2, 7.6Hz), 8.14 (d, 1H, J=2.6Hz), 9.95 (s, 1H), 11.57 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 23.74, 116.28 ( J=21.9Hz), 117.75, 120.72, 121.47, 122.21 (J=11.3Hz), 125.16, 125.46 ( J=6.0Hz), 127.93, 129.87 ( J=2.1Hz), 131.26, 132.83 ( J=8.3Hz), 135.68 (J=3.0Hz), 156.52, 161.05 (
15 J=252Hz), 168.13, 192.45.
INTERMEDIATE 46 - PREPARATION OF (E)-N-(3-(3-(3-fluorophenyl)acryloyl)-4- hydroxyphenyl)acetamide.
This compound was prepared according to Method A, using Intermediate 2 and 3- fluorobenzaldehyde as starting materials, affording a yellow powder with a yield of 88% (mp: 20 169.3°C).
1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.96 (d, 1 H, J=8.9Hz), 7.29 (td, 1 H, J=2.6, 8.6Hz), 7.50 (m, 1H), 7.63 (d, 1H, J=7.8Hz), 7.72 (m, 2H), 7.74 (d, 1H, J=15.7Hz), 7.82 (d, 1H, J=15.7Hz), 8.11 (d, 1H, J=2.4Hz), 9.87 (s, 1H), 11.63 (s, 1H). 13C NMR (75MHz, DMSO-ofe) δ 23.84, 114.96 (J=21.9Hz), 117.66 (J=21.1Hz), 117.87, 121.46, 121.46, 121.46, 125.34 (J=3.0Hz), 128.52, 131.23, 25 131.28 (J=7.5Hz), 137.24 (J=7.5Hz), 142.66 (J=3.0Hz), 156.95, 162.67 (J=243Hz), 168.29, 193.00.
INTERMEDIATE 47 - PREPARATION OF (E)-A/-(3-(3-(4-fluorophenyl)acryloyl)-4- hydroxyphenyl)acetamide.
The title compound was prepared according to Method A, using Intermediate 2 and 4- fluorobenzaldehyde as starting materials, to afford a yellow powder in 84% yield (mp: 153.2°C).
30 1H NMR (300MHz DMSO-ofe) δ 2.03 (s, 3H), 6.97 (d, 1H, J=8.9Hz), 7.32 (t, 2H, J=8.9Hz), 7.71 (dd, 1H, J=2.5, 8.9Hz), 7.73 (d, 1H, J=15.7Hz), 7.78 (d, 1H, J=15.7Hz), 7.90 (t, 2H, J=8.9Hz), 8.18 (d, 1H, J=2.5Hz), 10.01 (s, 1H), 11.73 (s, 1H). 13C NMR (75MHz, DMSO-ofe) δ 23.70, 116.15 ( J=21.9Hz), 117.68, 121.11, 121.26, 122.69, 122.69, 128.10, 131.12, 131.18 (J=9.8Hz), 142.87, 156.74, 163.57 ( J=249.0Hz), 168.13, 192.81.
35 INTERMEDIATE 48 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-
((trifluoromethyl)phenyl)acryloyl)phenyl)acetamide. This compound was prepared following Method A, starting from Intermediate A and 3- (trifluoromethyl)benzaldehyde, to afford a yellow powder in 95% yield (169.3°C).
1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.97 (d, 1 H, J=8.9Hz), 7.69 (t, 1 H, J=7.9Hz), 7.71 (dd, 1 H, J=2.6, 8.9Hz), 7.82 (t, 1 H, J=7.9Hz), 7.83 (d, 1 H, J=15.7Hz), 7.93 (d, 1 H, J=15.7Hz), 8.10 (d, 5 1 H, J=2.6Hz), 8.1 1 (brd, 1 H, J=7.9Hz), 8.21 (brs, 1 H), 9.91 (s, 1 H), 1 1 .60 (s, 1 H). 13C NMR (75MHz, DMSO-de) δ 23.85, 1 17.87, 121.48, 121 .68, 125.28, 124.20 (q, J=270.00Hz), 125.36 (q, J=4.2Hz), 127.08 (q, J=4.2Hz), 128.54, 130.08 (q, J=31 .7Hz), 130.29, 131.24, 132.67, 135.89, 142.17, 156.85, 168.28, 192.93.
INTERMEDIATE 49 - PREPARATION OF (E)-N-(4-hydroxy-3-(3-
10 ((trifluoromethyl)phenyl)acryloyl)phenyl)acetamide.
The title compound was prepared according to Method A, using Intermediate 2 and 4- (trifluoromethyl)benzaldehyde as starting materials, affording a yellow powder in 91 % yield.
1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.97 (d, 1 H, J=8.9Hz), 7.70 (dd, 1 H, J=2.5, 8.9Hz), 7.79 (d, 1 H, J=15.7Hz), 7.82 (d, 2H, J=8.2Hz), 7.89 (d, 1 H, J=15.7Hz), 8.01 (d, 2H, J=8.2Hz), 8.1 1 15 (d, 1 H, J=2.5Hz), 9.92 (s, 1 H), 1 1 .50 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.85, 1 17.87, 121.28, 121 .78, 124.09 (J=269.0Hz), 126.04, 126.05 (J=3.8Hz), 128.27, 129.43, 130.27 (J=32.1 Hz), 131 .31 , 138.70, 141 .79, 156.60, 168.24, 192.66.
INTERMEDIATE 50 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(3,4,5- trimethoxyphenyl)acryloyl)phenyl)acetamide.
20 This compound was prepared according to Method A, starting from Intermediate 2 and 3,4,5- trimethoxybenzaldehyde, which afforded a yellow powder in 70% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.72 (s, 3H), 3.85 (s, 6H), 6.94 (d, 1 H, J=8.8Hz), 7.16 (s, 2H), 7.68 (d, 1 H, J=15.7Hz), 7.70 (dd, 1 H, J=2.4, 8.8Hz), 7.77 (d, 1 H, J=15.7Hz), 8.07 (d, 1 H, J=2.4Hz), 9.88 (s, 1 H), 1 1.81 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.82, 56.30, 60.34, 106.78, 1 17.80, 25 121.47, 122.12, 128.48, 130.19, 131.07, 140.27, 145.05, 153.33, 157.03, 168.27, 193.32.
INTERMEDIATE 51 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(4- phenoxyphenyl)acryloyl)phenyl)acetamide.
The title compound was prepared following Method A, using Intermediate 2 and 4- phenoxybenzaldehyde as starting materials, to afford a yellow powder in 94% yield.
30 1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.93 (d, 1 H, J=8.9Hz), 7.02 (d, 2H, J=8.7Hz), 7.06 (d, 2H, J=8.5Hz), 7.19 (t, 1 H, J=7.6Hz), 7.41 (t, 2H, J=7.4Hz), 7.64 (d, 1 H, J=15.7Hz), 7.66 (dd, 1 H, J=8.7, 2.6Hz), 7.74 (d, 1 H, J=15.7Hz), 7.80 (d, 2H, J=8.9Hz), 8.16 (d, 1 H, J=2.5Hz), 9.97 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.00, 1 18.07, 1 18.59, 1 19.87, 121.29, 121.40, 124.74, 128.55, 129.69, 130.61 , 131.31 , 144.15, 155.83, 157.41 , 159.70, 168.69, 193.22.
35 INTERMEDIATE 52 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(3- phenoxyphenyl)acryloyl)phenyl)acetamide. The title compound was prepared according to Method A, using Intermediate 2 and 3- phenoxybenzaldehyde as starting materials, affording a yellow powder in 94% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.94 (d, 1H, J=8.9Hz), 7.04 (m, 3H), 7.15 (t, 1H, J=7.2Hz), 7.40 (t, 2H, J=8.5Hz), 7.47 (t, 1H, J=7.7Hz), 7.54 (t, 1H, J=1.5Hz), 7.57 (d, 1H, J=7.9Hz), 5 7.71 (dd, 1H, J=8.9, 2.7Hz), 7.75 (d, 1H, J=15.7Hz), 7.79 (d, 1H, J=15.7Hz), 8.12 (d, 1H, J=2.7Hz), 9.89 (s, 1H), 11.69 (brs, 1H).13C NMR (75MHz, DMSO-ofe) δ 23.87, 117.87, 118.68, 119.06, 121.10, 121.35, 121.40, 123.79, 123.88, 124.31, 128.42, 130.33, 130.87, 131.26, 136.81, 143.39, 156.74, 156.98, 157.19, 168.23, 192.98.
INTERMEDIATE 53 - PREPARATION OF (E)-N-(3-(3-(3,5-dimethoxyphenyl)acryloyl)-4- 10 hydroxyphenyl)acetamide.
The title compound was prepared following Method A, using Intermediate A and 3,5- dimethoxybenzaldehyde as starting materials, affording a yellow powder in 97% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.83 (s, 6H), 6.61 (t, 1H, J=2.1Hz), 6.95 (d, 1H, J=8.9Hz), 6.98 (d, 2H, J=2.3Hz), 7.69 (d, 1H, J=15.7Hz), 7.73 (dd, 1H, J=2.6, 8.9Hz), 7.78 (d, 1H, 15 J=15.7Hz), 8.11 (d, 1H, J=2.5Hz), 9.90 (s, 1H), 11.55 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 23.88, 55.64, 103.10, 106.90, 117.86, 121.32, 121.44, 123.53, 128.41, 131.22, 136.61, 144.42, 156.97, 160.98, 168.29, 193.23.
INTERMEDIATE 54 - PREPARATION OF (E)-4-(3-(5-acetamido-2-hydroxyphenyl)-3-oxoprop-1- enyl)benzoic acid.
20 This compound was prepared according to Method A, starting from Intermediate A and 4- formyl benzoic acid, affording a yellow powder in 84% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.95 (d, 1H, J=8.9Hz), 7.70 (dd, 1H, J=8.9, 2.7Hz), 7.78 (d, 1H, J=15.7Hz), 7.85 (d, 1H, J=15.7Hz), 7.91 (d, 2H, J=8.1Hz), 8.00 (d, 2H, J=8.3Hz), 8.11 (d, 1H, J=2.5Hz), 9.89 (s, 1H). 13C NMR (75MHz, DMSO-ofe) δ 23.88, 117.90, 121.26, 121.68, 25 125.36, 128.34, 128.94, 130.05, 131.32, 132.62, 138.71, 142.58, 156.76, 164.04, 168.28, 192.79.
INTERMEDIATE 55 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(4- isopropoxyphenyl)acryloyl)phenyl)acetamide.
The title compound was prepared according to Method A, using Intermediate 2 and 4-(propan-2- yloxy)benzaldehyde as starting materials, affording a yellow powder in 89% yield.
30 1H NMR (300MHz, DMSO-ofe) δ 1.28 (d, 6H, J=6.0Hz), 2.04 (s, 3H), 4.70 (sept, 1H, J=6.0Hz), 6.94 (d, 1H, J=8.9Hz), 7.00 (d, 2H, J=8.8Hz), 7.60 (d, 1H, J=15.7Hz), 7.66 (dd, 1H, J=2.4, 8.9Hz), 7.74 (d, 2H, J=8.6Hz), 7.76 (d, 1H, J=15.7Hz), 8.17 (d, 1H, J=2.4Hz), 9.89 (s, 1H), 11.99 (brs, 1H).13C NMR (75MHz, DMSO-ofe) δ 21.94, 23.88, 69.79, 116.12, 117.92, 119.51, 121.05, 121.11, 126.85, 128.33, 131.10, 131.15, 144.86, 157.35, 160.28, 168.39, 193.11.
35 INTERMEDIATE 56 - PREPARATION OF (E)-N-(4-hydroxy-3-(3-(2- isopropoxyphenyl)acryloyl)phenyl)acetamide. This compound was prepared following Method A, using Intermediate 2 and 2-(propan-2- yloxy)benzaldehyde as starting materials, to afford a yellow powder in 90% yield.
1 H NMR (300MHz, DMSO-ofe) δ 1 .33 (d, 6H, J=6.0Hz), 2.04 (s, 3H), 4.73 (sept, 1 H, J=6.0Hz), 6.95 (d, 1 H, J=8.8Hz), 7.00 (brd, 1 H, J=7.5Hz), 7.10 (brd, 1 H, J=8.3Hz), 7.41 (td, 1 H, J=1 .5, 7.5Hz), 7.66 (dd, 1 H, J=2.5, 8.8Hz), 7.77 (dd, 1 H, J=1 .5, 7.5Hz), 7.85 (d, 1 H, J=15.7Hz), 8.03 (d, 1 H, J=15.7Hz), 8.28 (d, 1 H, J=2.5Hz), 10.06 (brs, 1 H), 1 1 .93 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 21 .83, 23.75, 70.47, 1 14.17, 1 17.76, 120.57, 120.64, 120.98, 122.24, 123.56, 127.91 , 129.70, 131 .19, 132.52, 139.90, 157.04, 168.13, 193.19.
INTERMEDIATE 57 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(3- (phenylthio)phenyl)acryloyl)phenyl)acetamide.
The title compound was prepared according to Method A, using Intermediate 2 and 3- (phenylsulfanyl)benzaldehyde as starting materials, to afford an orange powder in 55% yield.
1 H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.94 (d, 1 H, J=8.8Hz), 7.27 (d, 2H, J=8.4Hz), 7.44 (m),
7.73 (s, 2H), 7.68 (dd, 1 H, J=8.8, 2.5Hz), 7.76 (d, 2H, J=8.4Hz), 8.12 (d, 1 H, J=2.5Hz), 9.88 (brs, 1 H), 1 1 .72 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.86, 1 17.87, 121 .17, 121 .42, 122.76, 128.29,
128.67, 129.23, 129.84, 130.06, 131 .21 , 132.63, 132.78, 132.92, 139.90, 143.42, 156.94, 168.25, 192.88.
INTERMEDIATE 58 - PREPARATION OF (E)-A/-(5-cinnamoyl-4-hydroxy-2- methoxyphenyl)acetamide.
This compound was prepared following Method A, starting from A/-(5-acetyl-4-hydroxy-2- methoxyphenyl)acetamide and benzaldehyde, to afford a yellow powder in 66% yield.
1 H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.88 (s, 3H), 6.63 (s, 1 H), 7.46 (m, 4H), 7.82 (s, 2H), 7.86 (m, 2H), 8.43 (s, 1 H), 9.23 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ: 23.30, 56.28, 99.84, 1 12.48, 1 19.40, 121 .29, 126.56, 129.00, 130.87, 134.50, 144.17, 159.10, 162.84, 168.76, 191 .77.
INTERMEDIATE 59 - PREPARATION OF (E)-A/-(3-(3-(benzo[d][1 ,3]dioxol-5-yl)acryloyl)-4- hydroxyphenyl)acetamide.
This compound was prepared according to Method A, using Intermediate 2 and 1 ,3-benzodioxole-5- carbaldehyde as starting materials, to afford a yellow powder in 85% yield.
1 H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.10 (s, 2H), 6.93 (d, 1 H, J=8.8Hz), 7.01 (d, 1 H, J=9.1 Hz), 7.31 (dd, 1 H, J=1 .5, 8.1 Hz), 7.50 (d, 1 H, J=1 .3Hz), 7.64 (d, 1 H, J=15.7Hz), 7.68 (m, 1 H),
7.74 (d, 1 H, J=15.7Hz), 8.12 (d, 1 H, J=2.4Hz), 9.86 (s, 1 H), 1 1 .96 (s, 1 H). 13C NMR (75MHz DMSO- d6) δ 23.68, 101 .84, 107.02, 108.75, 1 17.71 , 120.24, 120.91 , 121 .33, 126.00, 128.46, 128.94, 130.88, 144.64, 148.23, 149.98, 157.22, 168.19, 193.02.
INTERMEDIATE 60 - PREPARATION OF (E)-N-(3-(3-(4-(4-fluorophenoxy)phenyl)acryloyl)-4- hydroxyphenyl ) acetamide.
The title compound was prepared following Method A, using Intermediate 2 and 4-(4- fluorophenoxy)benzaldehyde as starting materials, affording a yellow powder in 31 % yield. 1H NMR (300MHz, DMSO-ofe) δ 2.02 (s, 3H), 6.94 (d, 1H, J=8.9Hz), 7.04 (d, 2H, J=8.8Hz), 7.16 (dd, 2H, J=8.7, 4.9Hz), 7.27 (t, 2H, J=8.7Hz), 7.67 (d, 1H, J=15.5Hz), 7.67 (dd, 1H, J=8.9, 2.5Hz), 7.78 (d, 1H, J=15.5Hz), 7.82 (d, 2H, J=8.8Hz), 8.14 (d, 1H, J=2.5Hz), 11.79 (brs, 1H).13C NMR (75MHz, DMSO-de) δ 23.69, 116.81 (d, J=23.4Hz), 117.68, 117.87, 120.98, 121.14, 121.34, 121.58 (d, 5 J=9.1Hz), 128.08, 129.37, 130.95, 131.01, 143.64, 151.49 (d, J=3.0Hz), 156.84, 158.71 (d, J=240.00), 159.64, 168.07, 192.79.
INTERMEDIATE 61 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(3- isopropoxyphenyl)acryloyl)phenyl)acetamide.
This compound was prepared following Method A, starting from Intermediate 2 and 3-(propan-2- 10 yloxy)benzaldehyde, which afforded a yellow powder in 96% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.27 (d, 6H, J=6.0Hz), 2.03 (s, 3H), 4.70 (sept, 1H, J=6.0Hz), 6.94 (d, 1H, J=8.8Hz, 7.02 (dt, 1H, J=2.1, 7.0Hz), 7.37 (m, 3H), 7.67 (dd, 1H, J=2.6, 8.8 Hz), 7.70 (d, 1H, J=15.7Hz), 7.77 (d, 1H, J=15.7Hz), 8.21 (d, 1H, J=2.6Hz), 10.11 (brs, 1H), 11.53 (brs, 1H).
INTERMEDIATE 62 - PREPARATION OF N-(2-(2-methoxyphenyl)-4-oxo-4H-chromen-6- 15 yl)acetamide.
The title compound was prepared according to Method B, using Intermediate 83 as starting material, to afford a beige powder, in 98% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.06 (s, 3H), 3.79 (s, 3H), 6.84 (s, 1H), 7.10 (t, 1H, J=8.2Hz), 7.20 (d, 1H, J=8.2Hz), 7.52 (td, 1H, J=8.2, 1.5Hz), 7.64 (d, 1H, J=9.1Hz), 7.85 (dd, 1H, J=8.2, 1.5Hz), 20 7.89 (dd, 1H, J=9.1, 2.5Hz,), 8.30 (d, 1H, J=2.5Hz), 10.23 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 24.01, 55.98, 111.09, 112.59, 112.94, 118.96, 119.99, 120.76, 123.25, 125.54, 129.15, 132.86, 136.67, 151.76, 157.58, 160.47, 168.58, 177.02.
INTERMEDIATE 63 - PREPARATION OF N-(2-(3-methoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
25 This compound was prepared following Method B, starting from Intermediate 43, to afford a white powder in 89% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.87 (s, 3H), 7.02 (s, 1H), 7.15 (m, 1H), 7.47 (t, 1H, J=7.9Hz), 7.57 (t, 1H, J=2.4Hz), 7.64 (m, 1H), 7.73 (d, 1H, J=9.2Hz), 7.94 (dd, 1H, J=2.4, 9.0Hz), 8.33 (d, 1H, J=2.2Hz), 10.30 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 24.02, 106.72, 111.50, 113.01, 30 117.59, 118.60, 119.10, 123.51, 125.61, 130.31, 132.64, 136.82, 151.51, 159.79, 162.15, 168.64, 177.08.
INTERMEDIATE 64 - PREPARATION OF N-(2-(4-methoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method B, starting from Intermediate 44, to afford a 35 dark brown powder in 87% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H),3.85 (s, 3H), 6.90 (s, 1H), 7.12 (d, 2H, J=8.9Hz), 7.72 (d, 1H, J=9.1Hz), 7.94 (d, 1H, J=9.1, 2.5Hz), 8.04 (d, 2H, J=2.7Hz, 9.0Hz), 8.31 (d, 1H, J=2.5Hz), 10.27 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 24.01 , 55.56, 105.00, 113.13, 114.61, 118.91, 123.35, 125.40, 128.19, 136.69, 151.46, 162.14, 162.50, 168.61, 176.86.
INTERMEDIATE 65 - PREPARATION OF A/-(2-(2-fluorophenyl)-4-oxo-4H-chromen-6-yl)acetamide.
The title compound was prepared according to Method B, using Intermediate 45 as starting material, 5 affording a black powder in 87% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.07 (s, 3H), 6.70 (s, 1 H), 7.40 (t, 1 H, J=7.8Hz), 7.42 (m, 1 H), 7.62 (m, 1H, H4"), 7.65 (d, 1H, J=9.1Hz, H4), 7.93 (dd, 1H, J=2.6, 9.0Hz), 7.95 (dd, 1H, J=2.2, 7.6Hz), 8.31 (d, 1H, J=2.6Hz), 10.26 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 24.18, 111.10 (d, J=8.3Hz), 113.11, 117.10 (d, J=22.6Hz), 119.24, 119.24 (d, J=14.3Hz), 123.47, 125.37, 125.97, 129.75, 10 133.89 (d, J=6.8Hz), 137.12, 151.84, 159.50, 160.23 (d, J=248.0Hz), 168.80, 176.93.
INTERMEDIATE 66 - PREPARATION OF A/-(2-(3-fluorophenyl)-4-oxo-4H-chromen-6-yl)acetamide.
This compound was prepared following Method B, starting from Intermediate 46, affording a beige powder in 88% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 7.06 (s, 1 H), 7.43 (td, 1 H, J=8.5, 2.3Hz), 7.61 (td, 1 H, 15 J=8.0, 6.3Hz), 7.73 (d, 1H, J=9.0Hz), 7.92 (brd, 1H, J=8.0Hz), 7.93 (dd, 1H, J=9.0, 2.7Hz), 7.94 (dt, 1H, 11.1, 1.8Hz), 8.31 (d, 1H, J=2.7Hz), 10,27 (s, 1H). 13C NMR (75MHz, DMSO-ofe) δ 24.00, 107.11, 112.95, 113.18 (d, J=23.4Hz), 118.50 (d, J=21.1Hz), 119.08, 121.42 (d, J=2.1Hz), 123.47, 125.64, 131.21 (d, J=8.3Hz), 133.61 (d, J=7.5Hz), 136.89, 151.41, 160.81, 162.44 (d, J=246Hz), 168.59, 177.02.
20 INTERMEDIATE 67 - PREPARATION OF A/-(2-(4-fluorophenyl)-4-oxo-4H-chromen-6-yl)acetamide.
The title compound was prepared according to Method B, using Intermediate 47 as starting material, to afford a dark brown powder in 90% yield (274.6°C).
1H NMR (300MHz DMSO-ofe) δ 2.08 (s, 3H), 6.97 (s, 1H), 7.40 (t, 2H, J=8.9Hz), 7.71 (d, 1H, J=9.1Hz), 7.94 (dd, 1H, J=9.1 , 2.5Hz), 8.14 (dd, 2H, J=8.9, 5.3Hz), 8.31 (d, 1H, J=2.6Hz), 10.26 (s, 25 1H).13C NMR (75MHz, DMSO-ofe) δ 23.98, 106.32, 113.00, 116.21 (d, J=22.6Hz), 118.99, 123.40, 125.55, 127.80, 128.98 (d, J=9.8Hz), 136.80, 151.43, 161.40, 164.11 (d, J=250.00Hz), 168.56, 176.92.
INTERMEDIATE 68 - PREPARATION OF A/-(4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-6- yl)acetamide.
30 The title compound was prepared following Method B, starting from Intermediate 48, to afford a brown powder in 98% yield.
1H NMR (300MHz DMSO-ofe) δ 2.08 (s, 3H), 7.18 (s, 1H), 7.80 (d, 1H, J=8.9Hz), 7.81 (t, 1H, J=8.2Hz), 7.96 (dd, 1H, J=8.9, 2.6Hz), 7.96 (brd, 1H, J=8.2Hz), 8.32 (d, 1H, J=2.6Hz), 8.39 (brd, 1H, J=8.2Hz'), 8.40 (brs, 1H), 10.28 (s, 1H). 13C NMR (75MHz, DMSO-ofe) δ 24.01, 107.50, 112.96, 35 119.21, 122.90 (q, J=3.8Hz), 123.42 (q, J=270.00Hz), 123.51, 125.70, 128.08 (q, J=3.8Hz), 129.99 (q, J=31.7Hz), 130.33, 132.48, 136.94, 151.49, 160.60, 168.61, 177.04. INTERMEDIATE 69 - PREPARATION OF N-(4-oxo-2-(4-(trifluoromethyl)phenyl)-4H-chromen-6- yl)acetamide.
This compound was prepared according to Method B, using Intermediate 49 as starting material, which afforded a brown powder in 81 % yield (293.6°C).
5 1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 7.15 (s, 1 H), 7.78 (d, 1 H, J=9.1 Hz), 7.94 (d, 2H, J=8.8Hz), 7.97 (dd, 1 H, J=9.1 , 2.5Hz), 8.31 (d, 2H, J=8.8Hz), 8.35 (d, 1 H, J=2.5Hz), 10.30 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 22.99, 107.84, 1 12.94, 1 19.12, 123.50, 124.81 (q, J=272Hz), 125.78, 125.95 (q, J=3.8Hz), 127.17, 131.27 (q, J=32.4Hz), 135.19, 136.96, 151 .47, 160.62, 168.61 , 176.99.
10 INTERMEDIATE 70 - PREPARATION OF A/-(2-(benzo[cfl[1 ,3]dioxol-5-yl)-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method B, using Intermediate 59 as starting material, affording a black powder in 83% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 6.12 (s, 2H), 6.89 (s, 1 H), 7.09 (d, 1 H, J=8.3Hz), 7.64 15 (brs, 1 H), 7.66 (brd, 1 H, J=8.3Hz), 7.69 (d, 1 H, J=9.2Hz), 7.92 (dd, 1 H, J=9.2, 2.5Hz), 8.30 (d, 1 H, J=2.5Hz), 10.24 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.99, 101.19, 105.39, 106.26, 1 13.01 , 108.72, 1 18.91 , 121.50, 123.41 , 125.02, 125.37, 136.68, 148.18, 150.32, 151 .37, 162.02, 168.56, 176.88.
INTERMEDIATE 71 - PREPARATION OF N-(2-(furan-2-yl)-4-oxo-4H-chromen-6-yl)acetamide.
20 This compound was prepared according to Method B, starting from (E)-A/-(5-furanyl-4- hydroxyphenyl)acetamide, to afford a dark green powder in 80% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 6.61 (s, 1 H), 6.78 (dd, 1 H, J=3.6, 1 .7Hz), 7.38 (d, 1 H, J=3.4Hz), 7.61 (d, 1 H, J=9.1 Hz), 7.92 (dd, 1 H, J=9.1 , 2.8Hz), 8.02 (bd, J=1 .7Hz, 1 H), 8.28 (d, 1 H, J=2.6Hz). 13C NMR (75MHz, DMSO-ofe) δ 24.14, 104.24, 1 13.20, 1 13.34, 1 14.10, 1 18.87, 123.88, 25 125.68, 137.02, 145.55, 147.25, 151.16, 154.63, 168.72, 176.29.
INTERMEDIATE 72 - PREPARATION OF A/-(4-oxo-2-(4-phenoxyphenyl)-4H-chromen-6- yl)acetamide.
1.8 mmol of Intermediate 51 were mixed with 4.5 mmol of selenium dioxide and 50 imL of propan-2- ol. This mixture was heated with stirring for 12 h at 130°C. The reaction mixture was then filtered, the 30 solvent evaporated and the residue resuspended in the least amount of ethanol possible and allowed to precipitate, affording a yellow powder in 47% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 6.92 (s, 1 H), 7.13 (d, 2H, J=8.8Hz), 7.14 (m, 2H"), 7.24 (m, 1 H), 7.46 (m, 2H), 7.71 (d, 1 H, J=9.1 Hz), 7.95 (dd, 1 H, J=9.1 , 2.5Hz), 8.09 (d, 2H, J=8.8Hz"), 8.31 (d, 1 H, J=2.5Hz), 10.25 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.00, 105.69, 1 13.09, 35 1 18.03, 1 18.92, 1 19.78, 123.47, 124.62, 125.57, 125.74, 128.52, 130.33, 136.76, 151.46, 155.27, 160.07, 162.01 , 168.58, 176.88. INTERMEDIATE 73 - PREPARATION OF N-(4-oxo-2-(3-phenoxyphenyl)-4H-chromen-6- yl)acetamide.
1.8 mmol of Intermediate 52 were mixed with 4.5 mmol of selenium dioxide and 50 imL of propan-2- ol. This mixture was heated with stirring for 12 h at 130°C. The reaction mixture was then filtered, the solvent evaporated and the residue resuspended in the least amount of ethanol possible and allowed to precipitate, affording a beige powder in 50% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.00 (s, 1H), 7.08 (d, 2H, J=8.5Hz), 7.18 (m, 2H), 7.42 (t, 2H, J=8.5Hz), 7.57 (t, 1H, J=8.2Hz), 7.71 (d, 1H, J=9.1Hz), 7.75 (t, 1H, J=2.0Hz), 7.87 (m, 1H), 7.92 (dd, 1H, J=2.6, 9.1Hz), 8.32 (d, 1H, J=2.6Hz), 10.25 (brs, 1H).13C NMR (75MHz, DMSO-ofe) δ 24.19, 107.12, 113.17, 116.76, 118.94, 119.28, 121.67, 121.76, 123.69, 124.06, 125.82, 130.41, 131.09, 133.49, 137.04, 151.64, 156.52, 157.41, 161.68, 168.79, 177.19.
INTERMEDIATE 74 - PREPARATION OF 4-(6-acetamido-4-oxo-4H-chromen-2-yl)benzoic acid.
The title compound was prepared according to Method B, using Intermediate 54 as starting material, to afford a black powder in 93% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.07 (s, 1H), 7.74 (d, 1H, J=9.1Hz), 7.94 (dd, 1H, J=2.6Hz, 9.0Hz), 8.07 (d, 2H, J=8.7Hz), 8.20 (d, 2H, J=8.7Hz), 8.32 (d, 1H, J=2.6Hz), 10.27 (s, 1H). 13C NMR (75MHz, DMSO-ofe) δ 24.19, 107.77, 113.15, 119.29, 123.71, 125.93, 126.69, 130.02, 133.44, 135.25, 137.11, 151.68, 161.37, 166.79, 168.79, 177.17.
INTERMEDIATE 75 - PREPARATION OF A/-(2-(4-isopropoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
This compound was prepared following Method B, starting from Intermediate 55, affording a brown powder in 89% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.30 (d, 1H, J=6.0Hz), 2.08 (s, 3H), 4.73 (sept, 6H, J=6.0Hz), 6.85 (s, 1H), 7.07 (d, 2H, J=8.9Hz), 7.70 (d, 1H, J=9.1Hz), 7.92 (d, 1H, J=9.1, 2.5Hz), 7.99 (d, 2H, J=8.9Hz), 8.29 (d, 1H, J=2.5Hz), 10.27 (s, 1H).13C NMR (75MHz, DMSO-ofe) δ 21.84, 24.11, 69.61, 104.98, 113.27, 115.96, 118.95, 123.06, 123.61, 125.48, 128.30, 136.80, 151.55, 162.62, 160.57, 168.66, 176.91.
INTERMEDIATE 76 - PREPARATION OF A/-(2-(2-isopropoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method B, starting from Intermediate 56, with 97% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.32 (d, 1H, J=6.0Hz), 4.78 (sept, 6H, J=6.0Hz), 6.91 (s, 1H), 7.08 (t, 1H, J=7.8Hz), 7.22 (d, 1H, J=8.3Hz), 7.50 (td, 1H, J=8.3, 1.7Hz), 7.65 (d, 1H, J=9.1Hz), 7.85 (dd, 1H, J=7.8, 1.5Hz), 7.90 (dd, 1H, J=9.1, 2.4Hz), 8.31 (d, 1H, J=2.4Hz), 10.25 (brs, 1H).13C NMR (75MHz, DMSO-cfe) 621.75, 23.98, 70.69, 111.02, 112.95, 114.61, 118.86, 120.53, 120.76, 123.23, 125.54, 129.37, 132.67, 136.63, 151.72, 155.86, 160.80, 168.53, 177.00. INTERMEDIATE 77 - PREPARATION OF A/-(4-oxo-2-(4-(phenylthio)phenyl)-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method B, using (E)-A/-(4-hydroxy-3-(3-(4- (phenylthio)phenyl)acryloyl)phenyl)acetamide as starting material, to afford a black powder in 97% 5 yield.
1H NMR (300MHz, DMSO-ofe) δ 2.07 (s, 3H), 6.91 (s, 1 H), 7.27 (d, 2H, J=8.4Hz), 7.46 (m, 5H), 7.63 (d, 1 H, J=9.1 Hz), 7.91 (dd, 1 H, J=9.1 , 2.5Hz, 7.96 (d, 2H, J=8.4Hz), 8.29 (d, 1 H, J=2.5Hz), 10.25 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.17, 106.27, 1 13.17, 1 19.06, 123.63, 125.66, 127.24, 128.50, 129.02, 129.12, 130.15, 132.04, 133.23, 136.95, 141.53, 151.54, 161.82, 168.72, 177.03.
10 INTERMEDIATE 78 - PREPARATION OF A/-(2-(biphenyl-4-yl)-4-oxo-4H-chromen-6-yl)acetamide.
This compound was prepared according to Method B, using (E)-N-(3-(3-(biphenyl-4-yl)acryloyl)-4- hydroxyphenyl)acetamide as starting material, affording a yellow powder in 89% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.07 (s, 3H), 7.04 (s, 1 H), 7.40 (t, 1 H, J=7.1 Hz), 7.60 (t, 2H, J=7.6Hz), 7.75 (m, 3H), 7.86 (d, 2H, J=8.5Hz), 7.95 (dd, 1 H, J=2.7, 9.1 Hz), 8.15 (d, 2H, J=8.5Hz), 15 8.33 (d, 1 H, J=2.5Hz), 10.30 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.19, 106.52, 1 13.21 , 1 19.20, 123.74, 125.74, 127.05, 127.1 1 , 127.41 , 128.49, 129.29, 130.29, 136.99, 139.00, 143.33, 151.68, 162.21 , 168.77, 177.13.
INTERMEDIATE 79 - PREPARATION OF N-(2-(4-(4-fluorophenoxy)phenyl)-4-oxo-4H-chromen-6- yl)acetamide.
20 The title compound was prepared according to Method B, starting from Intermediary 60, which afforded a yellow powder in 88% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 6.92 (s, 1 H), 7.10 (d, 2H, J=8.7Hz), 7.19 (dd, 2H, J=8.8, 4.7Hz), 7.29 (t, 2H, J=8.8Hz), 7.71 (d, 1 H, J=9.1 Hz), 7.93 (dd, 1 H, J=9.1 , 2.4Hz), 8.09 (d, 2H, J=8.7Hz), 8.31 (d, 1 H, J=2.4Hz), 10.26 (brs, 1 H).13C NMR (75MHz, DMSO-ofe) δ 23.98, 105.68, 25 1 13.04, 1 16.89 (d, J=23.4Hz), 1 17.62, 1 18.91 , 121 .85 (d, J=8.3Hz), 123.45, 125.46, 125.69, 128.52, 136.71 , 151.21 (d, J=3.0Hz), 151 .42, 158.79 (d, J=240.00Hz), 160.34, 161 .95, 168.55, 176.84.
INTERMEDIATE 80 - PREPARATION OF N-(2-(3,4-diisopropoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method B, using (E)-A/-(4-hydroxy-3-(3-(3,4- 30 diisopropoxyphenyl)acryloyl)phenyl)acetamide as starting material, to afford a beige powder in 98% yield.
1H NMR (300MHz, DMSO-ofe) δ 1 .28 (d, 12H, J=6.0Hz), 4.70 (sept, 2H, J=6.0Hz), 6.93 (s, 1 H), 7.13 (d, 1 H, J=8.7Hz), 7.60 (m, 2H), 7.72 (d, 1 H, J=9.0Hz), 7.92 (dd, 1 H, J=2.3Hz, 9.0Hz), 8.29 (d, 1 H, J=2.3Hz), 10.23 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 21 .97, 23.96, 70.74, 71 .63, 105.23, 1 13.06, 35 1 15.37, 1 15.79, 1 18.91 , 120.55, 123.45, 123.61 , 125.29, 136.63, 148.04, 151 .41 , 151.79), 162.36, 168.53, 176.82. INTERMEDIATE 81 - PREPARATION OF A/-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
This compound was prepared following Method B, starting from (E)-A/-(4-hydroxy-3-(3-(3,4- dimethoxyphenyl)acryloyl)phenyl)acetamide, affording a brown powder in 96% yield.
5 1H NMR (300MHz, DMSO-ofe) δ 2.06 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H"), 6.97 (s, 1 H), 7.10 (d, 1 H, J=8.7Hz), 7.56 (d, 1 H, J=2.0 Hz), 7.69 (dd, 1 H, J=8.7, 2.0Hz), 7.74 (d, 1 H, J=9.1 Hz), 7.91 (dd, 1 H, J=9.1 , 2.6Hz), 8.29 (d, 1 H, J=2.6Hz), 10.28 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.18, 55.85), 55.98, 105.38, 109.45, 1 1 1.78, 1 13.25, 1 19.01 , 1 19.92, 123.62, 125.43, 136.81 , 149.15, 151.58, 152.03, 162.58, 177.05.
10 INTERMEDIATE 82 - PREPARATION OF N-(2-(3,5-diisopropoxyphenyl)-4-oxo-4H-chromen-6- yl)acetamide.
This compound was prepared according to Method B, starting from (E)-A/-(4-hydroxy-3-(3-(3,5- diisopropoxyphenyl)acryloyl)phenyl)acetamide, to afford a brown powder in 90% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.70 (d, 12H, J=6.0Hz), 5.17 (sept, 2H, J=6.0Hz), 7.06 (t, 1 H, 15 J=2.0Hz), 7.43 (s, 1 H), 7.55 (d, 2H, J=8.3Hz), 8.17 (d, 1 H, J=9.1 Hz), 8.34 (dd, 1 H, J=9.1 , 2.0Hz), 10.66 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 21.79, 23.99, 69.58, 105.76, 106.28, 106.79, 1 12.95, 1 19.14, 123.49, 125.51 , 133.29, 136.75, 151.47, 159.10, 162.08, 168.55, 177.07.
INTERMEDIATE 83 - PREPARATION OF (E)-A/-(4-hydroxy-3-(3-(2- methoxyphenyl)acryloyl)phenyl)acetamide.
20 This compound was prepared according to Method A, starting from Intermediate 2 and 2- methoxybenzaldehyde, to afford a yellow powder with a yield of 85% (mp: 168.3°C).
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.92 (s, 3H), 6.95 (d, 1 H, J=8.9Hz), 7.05 (t, 1 H, J=8.2Hz), 7.13 (d, 1 H, J=8.2Hz), 7.48 (td, 1 H, J=1.5, 8.2Hz), 7.68 (dd, 1 H, J=2.5, 8.9Hz), 7.78 (d, 1 H, J=8.2Hz), 7.85 (d, 1 H, J=15.7Hz), 8.04 (d, 1 H, J=15.7Hz), 8.26 (d, 1 H, J=2.5Hz), 9.95 (s, 1 H), 25 1 1 .91 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.85, 55.83, 1 12.03, 1 17.83, 120.56, 120.90, 120.93, 122.41 , 122.82, 127.97, 129.41 , 132.69, 131.27, 139.51 , 157.17, 158.69, 168.22, 193.22.
INTERMEDIATE 84 - PREPARATION OF 6-amino-2-(2-methoxyphenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 62 as starting material to afford a brown powder in 87% yield.
30 1H NMR (300MHz, DMSO-ofe) δ 3.90 (s, 3H), 5.75 (brs, 2H), 6.76 (s, 1 H), 7.08 (dd, 1 H, J=8.9, 2.5Hz), 7.12 (t, 1 H, J=8.2Hz), 7.14 (d, 1 H, J=2.5Hz), 7.22 (d, 1 H, J=8.2Hz), 7.45 (d, 1 H, J=8.9Hz), 7.54 (td, 1 H, J=8.2, 1.5Hz), 7.84 (dd, 1 H, J=8.2, 1.5Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.92, 105.30, 1 10.52, 1 12.48, 1 18.96, 120.49, 120.76, 121.96, 123.99, 129.06, 132.51 , 145.95, 148.45, 157.41 , 159.91 , 177.13.
35 INTERMEDIATE 85 - PREPARATION OF 6-amino-2-(3-methoxyphenyl)-4H-chromen-4-one.
This compound was prepared according to Method E, starting from Intermediate 63, to afford a brown powder in 91 % yield. 1H NMR (300MHz, DMSO-ofe) δ 3.86 (s, 3H), 6.91 (s, 1 H), 7.09 (dd, 1 H, J=2.8, 8.9Hz), 7.12 (d, 1 H, J=8.9Hz), 7.15 (m, 1 H), 7.47 (t, 1 H, J=7.9Hz), 7.53 (d, 1 H, J=9.1 Hz), 7.55 (t, 1 H, J=2.3Hz), 7.62 (m, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 55.75, 105.31 , 106.08, 1 1 1.31 , 1 17.24, 1 18.40, 1 19.1 1 , 122.07, 124.23, 130.22, 133.01 , 145.85, 148.21 , 159.69, 161.48, 177.16.
INTERMEDIATE 86 - PREPARATION OF 6-amino-2-(4-methoxyphenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 64 as starting material, affording a dark brown powder in 80% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.85 (s, 3H), 5.49 (s, 2H), 6.78 ( s, 1 H), 7.06 ( dd, 1 H, J=8.8, 2.7Hz), 7.08 (d, 1 H, J=2.7Hz), 7.10 (d, 2H, J=8.9Hz), 7.47 (d, 1 H, J=8.8Hz), 8.00 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.49, 104.38, 105.01 , 1 14.51 , 1 18.83, 121.45, 123.78, 124.18, 127.89,
146.55, 147.81 , 161.82, 177.03.
INTERMEDIATE 87 - PREPARATION OF 6-amino-2-(2-fluorophenyl)-4H-chromen-4-one.
This compound was prepared following Method E, starting from Intermediate 65.
1H NMR (300MHz, DMSO-ofe) δ 6.93 (s, 1 H), 5.55 (s, 2H), 7.09 (dd, 1 H, J=2.7, 8.8Hz), 7.1 1 (d, 1 H, J=2.7Hz), 7.41 (m, 1 H), 7.44 (m, 1 H), 7.46 (d, 1 H, J=8.8Hz), 7.65 (m, 1 H), 7.95 (td, 1 H, J=7.6, 2.1 Hz). 13C NMR (75MHz, DMSO-ofe) δ 104.72, 1 10.24 (d, J=9.0Hz), 1 16.88 (d, J=21.9Hz), 1 19.01 , 120.05 (d, J=9.8Hz), 121 .94, 124.05, 125.19, 129.47, 132.29 (d, J=9.1 Hz), 146.85, 148.09, 157.72 (d, J=3.0Hz), 159.58 (d, J=253.00Hz), 176.84.
INTERMEDIATE 88 - PREPARATION OF 6-amino-2-(3-fluorophenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 66 as starting material, affording a brown powder (mp: 122.0°C) in 95% yield.
1H NMR (300MHz, DMSO-ofe) δ 6.95 (s, 1 H), 7.07 (dd, 1 H, J=9.0, 2.7Hz), 7.10 (brs, 2H), 7.1 1 (d, 1 H, J=2.7Hz), 7.42 (td, 1 H, J=8.5, 2.3Hz"), 7.52 (d, 1 H, J=9.0Hz), 7.61 (td, 1 H, J=8.0, 6.3Hz), 7.91 (brd, 1 H, J=8.0Hz), 7.91 (dt, 1 H, J=1 1.1 , 1.8Hz). 13C NMR (75MHz, DMSO-ofe) δ 104.83, 106.43, 1 12.99 (d, J=23.3Hz), 1 18.16 (d, J=20.4Hz), 1 19.08, 121 .88,122.26, 124.23, 131 .20 (d, J=8.3Hz), 134.05 (d, J=8.9Hz), 146.72, 147.47, 160.13, 162.47 (d, J=246Hz), 177.18.
INTERMEDIATE 89 - PREPARATION OF 2-(4-fluorophenyl)-4-oxo-4H-chromen-6-aminium.
This compound was prepared following Method E, using Intermediate 67 as starting material, which afforded a brown powder in 94% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.08 (s, 1 H), 7.45 (t, 2H, J=8.8Hz), 7.63 (dd, 1 H, J=9.0, 2.6Hz), 7.82 (d, 1 H, J=2.6Hz), 7.87 (d, 1 H, J=9.0Hz), 8.20 (dd, 2H, J=8.8, 5.4Hz). 13C NMR (75MHz, DMSO-ofe) δ
106.56, 1 15.81 , 1 16.31 (d, J=22.6Hz), 120.32, 123.85, 127.47, 127.60, 129.14 (d, J=9.0Hz), 133.34, 153.09, 161.86, 164.25 (d, J=250.00Hz), 176.55.
INTERMEDIATE 90 - PREPARATION OF 6-amino-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one. The title compound was prepared according to Method E, using Intermediate 68 as starting material, affording a brown powder in 96% yield. 1H NMR (300MHz, DMSO-ofe) δ 7.06 (s, 1 H), 7.1 1 (dd, 1 H, J=8.9, 2.6Hz), 7.13 (d, 1 H, J=2.6Hz), 7.57 (d, 1 H, J=8.9Hz), 7.80 (t, 1 H, J=7.9Hz), 7.94 (t, 1 H, J=7.9Hz), 8.35 (brs, 1 H), 8.36 (brd, 1 H, J=7.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 105.31 , 106.98, 1 19.38, 122.82 (q, J=3.8Hz"), 122.26, 124.43, 124.05 (q, J=270.00Hz), 127.92 (q, J=3.8Hz), 130.1 1 (q, J=32.4Hz), 130.31 , 130.48, 133.02, 146.57, 160.07, 148.25, 177.34.
INTERMEDIATE 91 - PREPARATION OF 6-amino-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one.
This compound was prepared following Method E, starting from Intermediate 69, which afforded a brown powder in 95% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.08 (s, 1 H), 7.29 (dd, 1 H, J=2.5, 9.1 Hz), 7.36 (d, 1 H, J=2.5Hz), 7.65 (d, 2H, J=9.1 Hz), 7.93 (d, 2H, J=8.8Hz), 8.29 (d, 2H, J=8.8Hz). 13C NMR (75MHz, DMSO-ofe) δ 107.46, 108.75, 1 19.59, 124.06, 124.17, 124.81 (q, J=272Hz), 125.98 ( q, J=3.8Hz), 130.95, 129.25 (q, J=32.4Hz), 135.40, 142.06, 149.80, 160.07, 176.98.
INTERMEDIATE 92 - PREPARATION OF 6-amino-2-(3,4-dimethoxyphenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 81 as starting material, to afford a brown powder in 73% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.84 (s, 3H), 3.86 (s, 3H), 6.85 (s, 1 H), 7.06 (dd, 1 H, J=8.9, 2.5Hz), 7.09 (d, 1 H, J=8.5Hz), 7.10 (d, 1 H, J=2.5Hz), 7.49 (d, 1 H, J=8.9Hz), 7.54 (d, 1 H, J=2.0Hz), 7.63 (dd, 1 H, J=8.9, 2.0Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.66, 55.78, 104.67, 105.04, 109.22, 1 1 1.67, 1 18.87, 1 19.46, 121.43, 123.87, 124.17, 146.45, 147.84, 148.97, 151 .57, 161 .77, 177.05.
INTERMEDIATE 93 - PREPARATION OF 6-amino-2-(benzo[of][1 ,3]dioxol-5-yl)-4H-chromen-4-one.
This compound was prepared following Method E, starting from Intermediate 70, which afforded a black powder in 97% yield.
1H NMR (300MHz, DMSO-ofe) δ 6.12 (s, 2H), 6.76 (s, 1 H), 7.04 (dd, 1 H, J=8.9, 2.5Hz), 7.08 (d, 1 H, J=8.3Hz), 7.08 (d, 1 H, J=2.5Hz), 7.46 (d, 1 H, J=8.9Hz), 7.58 (brs, 1 H), 7.60 (brd, 1 H, J=8.3Hz) 13C NMR (75MHz, DMSO-ofe) δ 101 .19, 104.84, 105.01 , 106.17, 108.75, 1 18.95, 121.24, 121.63, 124.18, 125.52, 146.62, 147.87, 148.20, 150.08, 161 .46, 177.20.
INTERMEDIATE 94 - PREPARATION OF 6-amino-2-(furan-2-yl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 71 as starting material, which afforded a brown powder in 94% yield.
1H NMR (300MHz, DMSO-ofe) δ 6.52 (s, 1 H), 6.76 (dd, 1 H, J=3.4, 1.5Hz), 7.03 (dd, 1 H, J=2.8, 8.9Hz), 7.09 (d, 1 H, J=2.8Hz), 7.32 (d, 1 H, J=3.6Hz), 7.38 (d, 1 H, J=8.9Hz), 7.95 (m, 1 H). 13C NMR (75MHz, DMSO-de) δ 103.71 , 105.28, 1 13.20, 1 13.33, 1 18.85, 121.72, 124.61 , 145.91 , 146.81 , 146.90, 147.50, 154.10, 176.51.
INTERMEDIATE 95 - PREPARATION OF 4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-6- aminium. This compound was prepared following Method E, starting from A/-(2-(3,4,5-trimethoxyphenyl)-4-oxo- 4H-chromen-6-yl)acetamide, which afforded a brown powder in 92% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.72 (s, 3H), 3.88 (s, 6H), 6.94 (s, 1 H), 7.10 (dd, 1 H, J=2.7, 8.8Hz), 7.14 (d, 1 H, J=2.7Hz), 7.34 (s, 2H), 7.51 (d, 1 H, J=8.8Hz). 13C NMR (75MHz, DMSO-ofe) δ 56.40, 5 60.36, 103.96, 105.16, 105.88, 1 19.24, 121.78,124.36, 127.16, 138.49, 140.40, 146.67, 148.08, 152.40,161 .67, 172.55.
INTERMEDIATE 96 - PREPARATION OF 6-amino-2-(4-phenoxyphenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 72 as starting material, affording a brown powder in 98% yield.
10 1H NMR (300MHz, DMSO-ofe) δ 6.86 (s, 1 H), 7.09 (m, 1 H), 7.12 (d, 2H, J=8.8Hz), 7.14 (m, 2H), 7.24 (t, 1 H, J=7.7Hz), 7.46 (t, 2H, J=7.7Hz), 7.57 (d, 1 H, J=8.8Hz), 8.07 (d, 2H, J=8.8Hz). 13C NMR (75MHz, DMSO-ofe) δ 105.49, 108.42, 1 18.24, 1 19.47, 1 19.92, 123.52, 124.29, 124.77, 126.18, 128.57, 130.51 , 146.49, 149.60, 155.49, 160.07, 161.81 , 177.05.
INTERMEDIATE 97 - PREPARATION OF 6-amino-2-(3,5-dimethoxyphenyl)-4H-chromen-4-one.
15 This compound was prepared according to Method E, starting from A/-(2-(3,5-dimethoxyphenyl)-4- oxo-4H-chromen-6-yl)acetamide, which afforded a brown powder in 73% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.83 (s, 6H), 6.69 (t, 1 H, J=2.2Hz), 6.92 (s, 1 H), 7.04 (dd, 1 H, J=2.8, 8.7Hz), 7.08 (d, 1 H, J=2.3Hz), 7.15 (d, 2H, J=2.3Hz), 7.50 (d, 1 H, J=9.0Hz). 13C NMR (75MHz, DMSO-de) δ 55.76, 103.43, 104.30, 104.97, 106.39, 1 19.26, 121 .89, 124.42, 133.84, 146.86, 20 148.03, 161 .04, 161.47, 175.33.
INTERMEDIATE 98 - PREPARATION OF 6-amino-2-(4-isopropoxyphenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 75 as starting material, affording a black oil in 92% yield.
1H NMR (300MHz, DMSO-ofe) δ 1 .32 (d, 1 H, J=6.0Hz), 4.59 (sept, 6H, J=6.0Hz), 6.62 ( s, 1 H), 6.91 25 (d, 2H, J=9.1 Hz), 7.01 ( m, 1 H), 7.30 (brd, 1 H, J=8.9Hz), 7.36 (brs, 1 H), 7.76 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 21.86, 70.10, 105.09, 108.01 , 1 15.80, 1 18.75, 122.05, 123.80, 124.55, 127.82, 143.85, 149.81 , 160.62, 163.07, 178.33.
INTERMEDIATE 99 - PREPARATION OF 6-amino-2-(3-isopropoxyphenyl)-4H-chromen-4-one.
This compound was prepared according to Method E, starting from A/-(2-(3-isopropoxyphenyl)-4- 30 oxo-4H-chromen-6-yl)acetamide, which afforded an 85% yield. 13C NMR (75MHz, CDCI3-cfe) δ 21.59, 69.98, 106.12, 107.06, 1 13.37, 1 18.05, 1 18.22, 1 18.5, 122.13, 124.17, 129.65, 132.95, 144.50, 149.30, 157.89, 162.51 , 178.31.
INTERMEDIATE 100 - PREPARATION OF 6-amino-2-(2-isopropoxyphenyl)-4H-chromen-4-one.
The title compound was prepared following Method E, using Intermediate 76 as starting material, to 35 afford an 88% yield. 13C NMR (75MHz, CDCI3-ofe) δ 21.99, 71.21 , 108.09, 1 1 1.65, 1 14.17, 1 18.88, 120.37, 122.13, 122.25, 124.49, 129.50, 131.90, 143.50, 150.32, 156.23, 161.16, 178.75.
INTERMEDIATE 101 - PREPARATION OF 6-amino-2-(3,4-diisopropoxyphenyl)-4/-/-chromen-4-one.
This compound was prepared following Method E, using Intermediate 80 as starting material, to afford a 98% yield.
13C NMR (75MHz, CDCI3-ofe) δ 21.64, 71 .22, 72.42, 104.84, 107.27, 1 15.61 , 1 15.86, 1 18.35, 120.17, 121.61 , 123.99, 124.12, 143.69, 148.16, 149.25, 151.88, 162.58, 178.01.
INTERMEDIATE 102 - PREPARATION OF 6-amino-2-(4-(phenylthio)phenyl)-4H-chromen-4-one.
The title compound was prepared according to Method E, starting from Intermediate 77, which afforded a black oil in 95% yield.
1H NMR (300MHz, DMSO-ofe) δ 6.89 (s, 1 H), 7.30 (d, 2H, J=8.5Hz), 7.32 (d, 1 H, J=2.5Hz), 7.35 (dd, 1 H, J=9.1 , 2.5Hz), 7.46 (m, 5H), 7.57 (d, 1 H, J=8.9Hz), 7.98 (d, 2H, J=8.5Hz). 13C NMR (75MHz, DMSO-de) δ 106.25, 107.98, 1 18.88, 122.18, 124.59, 126.72, 128.66, 128.66, 129.56, 129.72, 132.76, 133.49, 142.41 , 144.07, 149.74, 162.63, 178.30.
INTERMEDIATE 103 - PREPARATION OF 6-amino-2-(4-(4-fluorophenoxy)phenyl)-4H-chromen-4- one.
This compound was prepared according to Method E, using Intermediate 79 as starting material, affording a brown powder in 96% yield.
1H NMR (300MHz, DMSO-ofe) δ 6.88 (s, 1 H), 7.09 (d, 2H, J=8.9Hz), 7.19 (dd, 2H, J=4.5, 9.0Hz), 7.29 (t, 2H, J=9.0Hz), 7.32 (dd, 1 H, J=8.9, 2.7Hz), 7.42 (d, 1 H, J=2.7Hz), 7.63 (d, 1 H, J=8.9Hz), 8.07 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 105.45, 1 10.16, 1 16.90 (d, J=23.4Hz), 1 17.62, 1 19.51 , 121.84 (d, J=9.0Hz), 124.05, 124.35, 125.83, 128.46, 140.25, 150.33, 151 .25 (d, J=2.3Hz), 158.85 (C-d, J=240.00Hz), 160.27, 161.79, 176.75.
INTERMEDIATE 104 - PREPARATION OF N-(3-hydroxy-2-(2-methoxyphenyl)-4-oxo-4H-chromen- 6-yl)acetamide.
This compound was prepared according to Method C, starting from Intermediate 83, which afforded a white powder in 66% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 2H), 3.79 (s, 3H), 7.08 (t, 1 H, J=8.2Hz), 7.19 (d, 1 H, J=8.2Hz), 7.48 (t, 1 H, J=8.2Hz), 7.49 (d, 1 H, J=8.2Hz), 7.58 (d, 1 H, J=9.1 Hz), 7.86 (dd, 1 H, J=9.1 , 2.6Hz), 8.46 (d, 1 H, J=2.6Hz), 8.87 (s, 1 H), 10.27 (s, 1 H).13C NMR (75MHz, DMSO-ofe) δ 24.02, 55.76, 1 1 1.96, 1 12.71 , 1 18.89, 1 19.94, 120.15, 122.06, 125.26, 131.06, 131.75, 135.89, 138.81 , 147.00, 151 .05, 157.13, 168.56, 172.56.
INTERMEDIATE 105 - PREPARATION OF N-(3-hydroxy-2-(3-methoxyphenyl)-4-oxo-4H-chromen- 6-yl)acetamide.
The title compound was prepared following Method C, using Intermediate 43 as starting material, affording a dark orange powder in 54% yield. 1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.82 (s, 3H), 7.09 (brd, 1 H, J=8.6Hz), 7.47 (t, 1 H, J=8.6Hz), 7.73 (d, 1 H, J=9.0Hz), 7.75 (t, 1 H, J=1 .8Hz), 7.77 (brd, 1 H, J=8.6Hz), 7.92 (dd, 1 H, J=9.0, 2.5Hz), 8.45 (d, 1 H, J=2.5Hz). 13C NMR (75MHz, DMSO-ofe) δ 24.05, 55.36, 1 12.71 , 1 13.46, 1 15.31 , 1 19.05, 120.10, 121.37, 125.76, 129.77, 132.65, 136.09, 138.97, 144.86, 150.68, 159.25, 168.82, 172.94.
INTERMEDIATE 106 - PREPARATION OF N-(3-hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-chromen- 6-yl)acetamide.
This compound was prepared according to Method C, starting from Intermediate 44, which afforded a pale yellow powder in 38% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.85 (s, 3H), 7.12 (m, 2H), 7.71 (d, 1 H, J= 9.1 Hz), 7.88 (dd, 1 H, J=2.5, 9.1 Hz), 8.19 (d, 2H, J= 9.1 Hz), 8.41 (d, 1 H), 9.40 (s, 1 H), 10.26 (s, 1 H). 13C NMR (75MHz, DMSO-de) 5 24.17, 55.53, 1 12.81 , 1 13.22, 1 18.98, 123.26, 124.43, 125.43, 129.53, 136.06, 138.05, 145.65, 150.62, 160.58, 168.70, 172.62.
INTERMEDIATE 107 - PREPARATION OF N-(2-(2-fluorophenyl)-3-hydroxy-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method C, using Intermediate 45 as starting material, affording a beige powder (mp: 210.7°C) in 52% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 3H), 7.37 (m, 1 H), 7.42 (m, 1 H), 7.59 (m, 1 H), 7.62 (d, 1 H, J=8.8Hz), 7.75 (td, 1 H, J=7.6, 2.2Hz), 7.88 (dd, 1 H, J=2.7, 8.8Hz), 8.48 (d, 1 H, J=8.8Hz), 9.36 (s, 1 H), 10.28 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.03, 1 12.72, 1 16.17 (d, J=21.1 Hz), 1 18.95, 1 18.97 (J=14.3Hz), 121.96, 124.40, 125.57, 131.22, 132.48 (d, J=9.0Hz), 136.08, 139.22, 143.36, 151.05, 159.18 (d, J=251.00Hz), 168.61 , 172.61 .
INTERMEDIATE 108 - PREPARATION OF N-(2-(3-fluorophenyl)-3-hydroxy-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method C, starting from Intermediate 46, which afforded a yellow powder in 45% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 3H), 7.10 (brs, 1 H), 7.33 (td, 1 H, J=8.5, 2.3Hz), 7.60 (td, 1 H, J=8.0, 6.3Hz), 7.73 (d, 1 H, J=9.1 Hz), 7.92 (dd, 1 H, J=9.1 , 2.5Hz), 8.02 (dt, 1 H, J=1 1.1 , 1.8Hz), 8.07 (brd, 1 H, J=8.0Hz), 8.45 (d, 1 H, J=2.5Hz). 13C NMR (75MHz, DMSO-ofe) δ 23.99,1 12.59, 1 14.24 (d, J=24.1 Hz), 1 16.65 (d, J=20.4Hz), 1 18.99, 121.31 , 123.59, 125.81 , 130.55 (d, J=8.3Hz), 134.05 (d, J=8.9Hz), 136.10, 139.32, 143.39,150.58, 162.03 (d, J=242Hz), 168.67, 177.97.
INTERMEDIATE 109 - PREPARATION OF N-(2-(4-fluorophenyl)-3-hydroxy-4-oxo-4H-chromen-6- yl)acetamide.
This compound was prepared following Method C, using Intermediate 47 as starting material, which afforded a yellow powder in 40% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.40 (t, 2H, J=9.0Hz), 7.71 (d, 1 H, J=9.0Hz), 7.91 (dd, 1 H, J=9.0, 2.5Hz), 8.27 (dd, 2H, J=9.0, 5.4Hz), 8.44 (d, 1 H, J=2.5Hz), 10.35 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.00, 1 12.63, 1 15.62 (d, J=21.0Hz), 1 18.90, 121 .37, 125.55, 128.00, 130.07 (d, J=8.0Hz), 136.01 , 138.86, 144.28, 150.55, 162.60 (d, J=247.00Hz), 168.62, 173.00.
INTERMEDIATE 1 10 - PREPARATION OF N-(3-hydroxy-4-oxo-2-(3-(trifluoromethyl)phenyl)-4H- chromen-6-yl)acetamide.
5 The title compound was prepared according to Method C, starting from Intermediate 48, which afforded a yellow powder in 26% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.76 (d, 1 H, J=8.9Hz), 7.80 (t, 1 H, J=8.2Hz), 7.85 (brd, 1 H, J=8.2Hz), 7.91 (dd, 1 H, J=8.9, 2.6Hz), 8.42 (d, 1 H, J=2.6Hz), 8.46 (brd, 1 H, J=8.2Hz), 8.54 (brs, 1 H),9.93 (brs, 1 H, OH), 10.25 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.98, 1 12.57, 1 19.04, 10 121 .36, 123.42 (q, J=270.00Hz), 123.96 (q, J=3.8Hz), 125.73, 126.03 (q, J=3.8Hz), 129.33 (q, J=31.7Hz), 129.78, 131 .10, 132.45, 136.07, 139.44, 143.1 1 , 150.59, 168.55, 172.95.
INTERMEDIATE 1 1 1 - PREPARATION OF N-(3-hydroxy-4-oxo-2-(3-(trifluoromethyl)phenyl)-4H- chromen-6-yl)acetamide.
This compound was prepared according Method C, using Intermediate 49 as starting material, which 15 afforded a beige powder in 30% yield.
1H NMR (300MHz DMSO-ofe) δ 2.09 (s, 3H), 7.73 (d, 1 H, J=8.9Hz), 7.90 (dd, 1 H, J=2.5, 8.9Hz), 7.92 (d, 2H, J=8.9Hz), 8.40 (d, 2H, J=8.9Hz), 8.44 (d, 1 H, J=2.5Hz), 9.98 (s, 1 H), 10.26 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.19, 1 12.76, 1 19.21 , 121.53, 124.68 (q, J=272.0Hz), 125.59 (q, J=3.8Hz), 126.02, 128.31 , 130.50 (q, J=32.4Hz), 135.58, 136.32, 150.82, 143.41 , 168.76, 172.65.
20 INTERMEDIATE 1 12 - PREPARATION OF N-(2-(furan-2-yl)-3-hydroxy-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared following Method C, starting from )-A/-(5-furanyl-4- hydroxyphenyl)acetamide, which afforded a pale yellow powder in 39% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 6.78 (dd, 1 H, J=3.4, 1.5Hz), 7.27 (d, 1 H, J=3.4Hz), 25 7.66 (d, 1 H, J=9.1 Hz), 7.88 (dd, 1 H, J=9.1 , 2.6Hz), 8.02 (brs, 1 H), 8.41 (d, 1 H, J=2.6Hz), 9.95 (brs, 1 H), 10.25 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.99, 1 12.75, 1 12.82, 1 15.22, 1 18.69, 121.94, 125.29, 136.04, 136.87, 139.20, 144.1 1 , 145.17, 150.02, 168.53, 171.64.
INTERMEDIATE 1 13 - PREPARATION OF A/-(2-(benzo[of][1 ,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H- chromen-6-yl)acetamide.
30 This compound was prepared according to Method C, using Intermediate 59 as starting material, affording a brown powder in 56% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 6.12 (s, 2H), 7.08 (d, 1 H, J=7.3Hz), 7.63 (brs, 1 H), 7.66 (brd, 1 H, J=7.3Hz), 7.69 (d, 1 H, J=9.2Hz), 7.92 (dd, 1 H, J=9.2, 2.5Hz), 8.35 (d, 1 H, J=2.5Hz), 9.40 (brs, 1 H), 10.25 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.01 , 101 .68, 107.49, 108.41 , 35 1 12.58,1 18.82, 121.30, 123.41 , 125.12, 125.33, 135.94, 138.06, 144.94, 147.50, 148.49, 150.41 , 168.58, 172.53. INTERMEDIATE 1 14 - PREPARATION OF N-3-hydroxy-4-oxo-2-(3-phenoxyphenyl)-4H-chromen-6- yl)acetamide.
The title compound was prepared following Method C, starting from Intermediate 52, which afforded a beige powder in 50% yield.
5 1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.05 (d, 2H, J=8.7Hz), 7.14 (m, 1 H), 7.17 (t, 1 H, J=7.4Hz), 7.40 (t, 2H, J=7.8Hz), 7.55 (t, 1 H, J=7.9Hz), 7.69 (d, 1 H, J=9.1 Hz), 7.90 (m, 2H), 7.97 (d, 1 H, J=7.7Hz), 8.42 (d, 1 H, J=2.3Hz), 10.33 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.19, 1 12.76, 1 18.21 , 1 18.67, 1 19.12, 120.15, 121 .50, 122.87, 123.79, 125.83, 130.34, 130.43, 133.52, 136.21 , 139.44, 144.20, 150.73, 156.68, 156.78, 168.78, 173.15.
10 INTERMEDIATE 1 15 - PREPARATION OF 4-(6-acetamido-3-hydroxy-4-oxo-4H-chromen-2- yl)benzoic acid.
The title compound was prepared according to Method C, starting from Intermediate 54, which afforded a beige powder in 42% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.70 (d, 1 H, J=9.1 Hz), 7.88 (dd, 1 H, J=2.5Hz, 9.1 Hz), 15 8.07 (d, 2H, J=8.7Hz), 8.28 (d, 2H, J=8.5Hz), 8.42 (d, 1 H, J=2.5Hz), 10.30 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.22, 1 12.79, 1 19.16, 121.52, 125.98, 127.62, 129.54, 132.73, 135.14, 136.24, 139.92, 144.09, 150.85, 167.47, 168.82, 173.25.
INTERMEDIATE 1 16 - PREPARATION OF N-(2-(3,5-dimethoxyphenyl)-3-hydroxy-4-oxo-4H- chromen-6-yl)acetamide.
20 This compound was prepared following Method C, using Intermediate 53 as starting material, affording a yellow powder in 59% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.81 (s, 6H), 6.64 (t, 1 H, J=2.3Hz), 7.35 (d, 2H, J=2.2Hz), 7.72 (d, 1 H, J=9.3Hz), 7.87 (dd, 1 H, J=2.5, 9.1 Hz), 8.40 (d, 1 H, J=2.5Hz), 9.56 (s, 1 H), 10.23 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.99, 55.38, 101 .46, 105.96, 1 12.55, 1 19.00, 121.24, 25 125.53, 132.99, 135.96, 139.01 , 144.54, 150.51 , 160.37, 168.53, 172.82.
INTERMEDIATE 1 17 - PREPARATION OF A/-(2-(biphenyl-4-yl)-3-hydroxy-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared following Method C, starting from (E)-N-(3-(3-(biphenyl-4- yl)acryloyl)-4-hydroxyphenyl)acetamide, to afford a yellow powder in 41 % yield.
30 1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 3H), 7.40 (t, 1 H, J=7.3Hz), 7.50 (t, 2H, J=7.6Hz), 7.75 (m, 3H), 7.86 (d, 2H, J=8.5Hz), 7.91 (dd, 1 H, J=2.5, 9.0Hz), 8.32 (d, 2H, J=8.5Hz), 8.43 (d, 1 H, J=2.5Hz), 10.26 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.01 , 1 12.61 , 1 18.90, 121 .39, 125.49, 126.65, 126.75, 128.01 , 128.09, 129.04, 130.42, 135.96, 139.16, 141 .09, 144.73, 150.58, 168.54, 172.89.
35 INTERMEDIATE 1 18 - PREPARATION OF A/-(3-hydroxy-4-oxo-2-(4-phenoxyphenyl)-4H-chromen- 6-yl)acetamide. The title compound was prepared according to Method C, using Intermediate 51 as starting material, which afforded a yellow powder in 66% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.05 (s, 3H), 7.02 (m, 4H"), 7.12 (tt, 1 H, J=1 .1 , 7.4Hz), 7.38 (t, 2H, J=7.6Hz), 7.54 (d, 1 H, J=9.1 Hz), 7.68 (dd, 1 H, J=2.7, 9.1 Hz), 8.31 (d, 1 H, J=2.4Hz), 8.70 (d, 2H, 5 J=9.1 Hz), 10.09 (s, 1 H.
INTERMEDIATE 1 19 - PREPARATION OF A/-(3-hydroxy-2-(naphthalen-1-yl)-4-oxo-4H-chromen-6- yl) acetamide.
This compound was prepared following Method C, starting from (E)-N-(3-(3-(naphthalen-1-yl)-4- hydroxyphenyl)acetamide, affording a yellow powder in 54% yield.
10 1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.54 (brd, 1 H, J=7.8Hz), 7.59 (t, 1 H, J=7.8Hz), 7.60 (d, 1 H, J=9.1 Hz), 7.66 (t, 1 H, J=7.8Hz), 7.80 (brd, 1 H, J=8.6Hz), 7.81 (brd, 1 H, J=7.8Hz), 7.94 (dd, 1 H, J=9.1 , 2.3Hz), 8.04 (brd, 1 H, J=8.0Hz"), 8.12 (brd, 1 H, J=8.2Hz), 8.57 (d, 1 H, J=2.3Hz), 9.10 (brs, 1 H), 10.48 (brs, 1 H). 13C NMR (75MHz DMSO-ofe) δ 24.10, 1 12.93, 1 18.98, 122.20, 125.29, 125.50, 125.54, 126.35, 126.98, 128.49, 128.73, 128.80, 130.32, 130.36, 133.21 , 136.13, 140.00, 147.43,
15 151.29, 168.73, 173.29.
INTERMEDIATE 120 - PREPARATION OF N-(3-hydroxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H- chromen-6-yl)acetamide.
The title compound was prepared according to Method C, using Intermediate 50 as starting material, which afforded a pale yellow powder in 63% yield.
20 1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.76 (s, 3H), 3.86 (s, 6H), 7.54 (s, 2H), 7.77 (d, 1 H, J=9.1 Hz). 7.91 (dd, 1 H, J=9.1 , 2.6Hz), 8.40 (d, 1 H, J=2.6Hz), 9.54 (brs, 1 H), 10.26 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.96, 56.08, 60.19, 105.64, 1 12.62, 1 18.97, 121.28, 125.40, 126.60, 135.95, 138.50, 139.16, 144.90, 150.46, 152.72, 168.54, 172.62.
INTERMEDIATE 121 - PREPARATION OF N-(2-(4-(4-fluorophenoxy)phenyl)-3-hydroxy-4-oxo-4H- 25 chromen-6-yl)acetamide.
This compound was prepared according to Method C, using Intermediate 60 as starting material, affording a pale yellow powder in 45% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 7.12 (d, 2H, J=8.7Hz), 7.19 (dd, 2H, J=8.8, 4.7Hz), 7.26 (t, 2H, J=8.8Hz), 7.68 (d, 1 H, J=9.1 Hz), 7.88 (dd, 1 H, J=9.1 , 2.4Hz), 8.21 (d, 2H, J=8.7Hz), 8.43 30 (d, 1 H, J=2.4Hz), 10.33 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.98, 1 12.64, 1 16.78 (d, J=23.4Hz), 1 17.50, 1 18.78, 121.38, 121 .40 (d, J=8.3Hz), 125.42, 126.23, 129.66, 135.96, 138.63, 144.84, 150.49, 151.69, 158.34, 158.63 (d, J=240.00Hz), 168.57, 172.82.
INTERMEDIATE 122 - PREPARATION OF A/-(3-hydroxy-2-(4-isopropoxyphenyl)-4-oxo-4H- chromen-6-yl)acetamide.
35 The title compound was prepared according to Method C, starting from Intermediate 55, which afforded a yellow powder in 53% yield. 1H NMR (300MHz, DMSO-ofe) δ 1.29 (d, 1 H, J=6.0Hz), 2.08 (s, 3H), 4.70 (sept, 6H, J=6.0Hz), 7.07 (d, 2H, J=8.9Hz), 7.68 (d, 1 H, J= 9.1 Hz), 7.88 (dd, 1 H, J=2.3, 9.1 Hz), 8.17 (d, 2H, J= 8.9Hz), 8.41 (d, 1 H, J=2.3Hz), 10.26 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 21.90, 24.1 1 , 69.57, 1 12.83, 1 15.52, 1 18.87, 121.55, 123.44, 125.40, 129.53, 136.03, 138.03, 145.69, 150.59, 158.85, 168.65, 172.61 . INTERMEDIATE 123 - PREPARATION OF A/-(3-hydroxy-2-(2-isopropoxyphenyl)-4-oxo-4H- chromen-6-yl)acetamide.
This compound was prepared following Method C, using Intermediate 56 as starting material, affording a yellow powder in 44% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.29 (d, 1 H, J=6.0Hz), 2.08 (s, 3H), 4.60 (sept, 6H, J=6.0Hz), 6.99 (t, 1 H, J=7.5Hz), 7.13 (brd, 1 H, J=8.5Hz), 7.40 (brt, 1 H, J=7.5Hz), 7.51 (d, 1 H, J=8.9Hz), 7.57 (brd, 1 H, J=7.5Hz), 7.82 (dd, 1 H, J=8.9, 2.5Hz), 8.43 (d, 1 H, J=2.5Hz), 10.29 (brs, 1 H). 13C NMR (75MHz, DMSO-de) δ 21.90, 23.96, 70.36, 1 12.74, 1 14.71 , 1 18.52, 1 19.87, 121 .70, 121 .89, 124.99, 130.93, 131.44, 135.43, 138.54, 146.78, 150.80, 155.48, 168.48, 172.34.
INTERMEDIATE 124 - PREPARATION OF N-(3-hydroxy-2-(3,4-dimethoxyphenyl)-4-oxo-4H- chromen-6-yl)acetamide.
The title compound was prepared according to Method C, starting from (E)-A/-(4-hydroxy-3-(3-(3,4- dimethoxyphenyl)acryloyl)phenyl)acetamide, which afforded a brown powder in 40% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.84 (s, 6H), 7.13 (d, 1 H, J=8.7Hz), 7.70 (d, 1 H, J=2.0 Hz), 7.79 (dd, 1 H, J=8.7, 2.0Hz), 7.74 (d, 1 H, J=9.1 Hz), 7.86 (m, 2H), 8.39 (d, 1 H, J=2.6Hz), 10.28 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.19, 55.62, 1 1 1.16, 1 1 1 .70, 1 12.05, 1 19.08, 121 .68, 123.12, 123.35, 125.41 , 136.08, 138.21 , 148.48, 148.59, 150.47, 167.30, 168.72, 172.62.
INTERMEDIATE 125 - PREPARATION OF 6-amino-3-hydroxy-2-(2-methoxyphenyl)-4H-chromen-4- one.
This compound was prepared according to Method E, starting from Intermediate 104, which afforded a beige powder in 98% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.78 (s, 3H), 5.45 (brs, 2H), 7.05 (dd, 1 H, J=8.9, 2.5Hz), 7.06 (t, 1 H, J=8.2Hz), 7.16 (d, 1 H, J=8.2Hz), 7.18 (d, 1 H, J=2.5Hz), 7.33 (d, 1 H, J=8.9Hz), 7.49 (t, 1 H, J=8.2Hz), 7.44 (d, 1 H, J=8.2Hz), 8.54 (brs, 1 H) 13C NMR (75MHz, DMSO-ofe) δ 55.71 , 104.22, 1 1 1.92, 1 18.82, 120.35, 120.10, 121.95, 122.81 , 131.02, 131.51 , 138.21 , 145.73, 146.36, 147.79, 157.10, 172.41 . INTERMEDIATE 126 - PREPARATION OF 3-hydroxy-2-(3-methoxyphenyl)-4-oxo-4H-chromen-6- aminium.
The title compound was prepared according to Method E, starting from Intermediate 105, which afforded a brown powder (mp: 152.7°C) in 98% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.86 (s, 3H), 7.09 (brd, 1 H, J=8.6Hz), 7.47 (t, 1 H, J=8.6Hz), 7.50 (d, 1 H, J=9.0Hz), 7.75 (t, 1 H, J=1 .8Hz), 7.77 (brd, 1 H, J=8.6Hz), 7.15 (dd, 1 H, J=9.0, 2.5Hz), 7.05 (d, 1 H, J=2.5Hz).13C NMR (75MHz, DMSO-ofe) δ 1 12.63, 1 13.29, 1 15.06, 1 19.34, 1 19.95, 121.96, 125.71 , 129.64, 131.58, 132.78, 138.60, 144.46, 148.72, 159.16, 172.58. INTERMEDIATE 127 - PREPARATION OF 6-amino-3-hydroxy-2-(4-methoxyphenyl)-4H-chromen-4- one.
This compound was prepared following Method E, using Intermediate 106 as starting material, which afforded a beige powder in 97% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.83 (s, 3H), 5.44 (s, 2H), 7.06 (dd, 1 H, J=8.9, 2.6Hz), 7.10 (d, 2H, J=8.9Hz) 7.12 (d, 1 H, J=2.6Hz), 7.45 (d, 1 H, J=8.9Hz), 8.15 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.36, 104.21 , 1 14.01 , 1 18.79, 122.06, 124.05, 129.22, 137.41 , 144.89, 145.82, 147.19, 160.24, 172.38.
INTERMEDIATE 128 - PREPARATION OF 6-amino-2-(2-fluorophenyl)-3-hydroxy-4H-chromen-4- one.
The title compound was prepared according to Method E, starting from Intermediate 107, which afforded a beige powder (mp: 198.9°C) in 98% yield.
1H NMR (300MHz, DMSO-ofe) δ 5.48 (s, 2H), 7.07 (dd, 1 H, J=2.7, 8.8Hz), 7.16 (d, 1 H, J=2.7Hz), 7.35 (m, 2H), 7.39 (d, 1 H, J=8.8Hz), 7.58 (m, 1 H), 7.73 (td, 1 H, J=2.2, 7.6Hz), 8.72 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) 5 104.14, 1 16.1 1 (d, J=21 .8Hz), 1 18.85, 1 19.30 ( d, J=14.3Hz), 122.27, 122.70, 124.36 (d, J=3.5Hz), 131.19, 132.22 (d, J=8.6Hz), 138.57, 142.76, 145.95, 147.75, 159.15 ( d, J=251.00Hz), 172.41.
INTERMEDIATE 129 - PREPARATION OF 6-amino-2-(3-fluorophenyl)-3-hydroxy-4H-chromen-4- one.
This compound was prepared following Method E, using Intermediate 108 as starting material, which afforded a brown powder in 96% yield.
1H NMR (300MHz DMSO-ofe) δ 7.10 (dd, 1 H, J=9.0, 2.7Hz), 7.15 (d, 1 H, J=2.7Hz), 7.32 (td, 1 H, J=8.5, 2.3Hz), 7.50 (d, 1 H, J=9.0Hz), 7.59 (td, 1 H, J=8.0, 6.3Hz'), 7.98 (dt, 1 H, J=1 1.1 , 1 .8Hz), 8.04 (brd, 1 H, J=8.0Hz). 13C NMR (75MHz, DMSO-ofe) δ 103.93, 1 13.99 (d, J=24.1 Hz), 1 16.28 (d, J=20.4Hz), 1 18.96, 122.06, 122.54, 123.40, 130.55 (d, J=8.3Hz), 133.93 (d, J=8.3Hz), 138.71 , 142.80, 145.96, 147.26, 162.02 (d, J=243Hz), 172.71 .
INTERMEDIATE 130 - PREPARATION OF 2-(4-fluorophenyl)-3-hydroxy-4-oxo-4H-chromen-6- aminium.
The title compound was prepared according to Method E, using Intermediate 109 as starting material, affording a brown powder in 96% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.42 (t, 2H, J=8.9Hz), 7.60 (dd, 1 H, J=9.0, 2.4Hz), 7.88 (d, 1 H, J=2.4Hz), 7.84 (d, 1 H, J=9.0Hz), 8.28 (dd, 2H, J=8.9, 5.4Hz). 13C NMR (75MHz, DMSO-ofe) δ 1 15.70, 1 15.71 (d, J=22.0Hz), 120.23, 121.86, 127.24, 127.74 (d, J=2.5Hz), 130.30 (d, J=8.0Hz), 132.48, 138.80, 144.85, 152.09, 162.73 (d, J=249.00Hz), 172.43.
INTERMEDIATE 131 - PREPARATION OF 6-amino-3-hydroxy-2-(3-(trifluoromethyl)phenyl)-4H- chromen-4-one. This compound was prepared according to Method E, starting from Intermediate 1 10, which afforded a beige powder in 94% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.27 (dd, 1 H, J=2.8, 9.1 Hz), 7.39 (d, 1 H, J=2.8Hz), 7.63 (d, 1 H, J=9.1 Hz), 7.80 (t, 1 H, J=8.2Hz), 7.85 (d, 1 H, J=8.2Hz), 8.45 (d, 1 H, J=8.2Hz), 8.52 (brs, 1 H), 9.75 5 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 108.1 1 , 1 19.67, 122.21 , 123.42 (q, J=270.00Hz), 124.07 (q, J=3.8Hz), 124.42, 126.13 (q, J=3.8Hz), 129.51 (q, J=31.7Hz), 130.00, 131.27, 132.81 , 139.35, 141.61 , 143.09, 149.14, 172.88.
INTERMEDIATE 132 - PREPARATION OF 3-hydroxy-4-oxo-2-(4-(trifluoromethyl)phenyl)-4H- chromen-6-aminium.
10 The title compound was prepared following Method E, using Intermediate 1 1 1 as starting material, affording a brown powder in 95% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.49 (dd, 1 H, J=2.6Hz, 9.1 Hz), 7.71 (d, 1 H, J=2.6Hz), 7.76 (d, 1 H, J=9.1 Hz), 7.93 (d, 2H, J=8.5Hz), 8.41 (d, 2H, J=8.5Hz). 13C NMR (75MHz, DMSO-ofe) δ 1 13.08, 120.17, 122.08, 124.81 (q, J=272Hz), 125.70 (q, J=3.8Hz), 126.58, 128.39, 129.50 (q, J=32.4Hz), 15 135.48, 140.04, 143.58, 151.22, 172.91.
INTERMEDIATE 133 - PREPARATION OF 2-(benzo[cfl[1 ,3]dioxol-5-yl)-3-hydroxy-4-oxo-4H- chromen-6-aminium.
This compound was prepared according to Method E, starting from Intermediate 1 13, which afforded a dark yellow powder in 96% yield.
20 1H NMR (300MHz, DMSO-ofe) δ 6.1 1 (s, 2H), 7.08 (d, 1 H, J=8.5Hz), 7.35 (dd, 1 H, J=2.7, 8.9Hz), 7.52 (d, 1 H, J=2.7Hz), 7.65 (d, 1 H, J=9.0Hz), 7.72 (d, 1 H, J=1.7Hz), 7.78 (dd, 1 H, J=1.7, 8.3Hz). 13C NMR (75MHz, DMSO-ofe) δ 101 .68, 107.68, 108.65, 1 10.77, 1 19.78, 122.09, 122.89, 125.08, 125.37, 138.18, 138.43, 145.21 , 147.72, 148.70, 150.03, 172.43.
INTERMEDIATE 134 - PREPARATION OF 6-amino-2-(furan-2-yl)-3-hydroxy-4H-chromen-4-one.
25 The title compound was prepared following Method E, using Intermediate 1 12 as starting material, to afford a beige powder in 93% yield.
1H NMR (300MHz, DMSO-ofe) δ 6.75 (dd, 1 H, J=3.4, 1.7Hz), 7.03 (dd, 1 H, J=2.8, 8.9Hz), 7.13 (d, 1 H, J=2.6Hz), 7.20 (d, 1 H, J=3.4Hz), 7.40 (d, 1 H, J=8.9Hz), 7.98 (d, 1 H, J=1.7Hz). 13C NMR (75MHz, DMSO-de) δ 105.52, 1 13.92, 1 15.83, 1 19.89, 123.20, 123.90, 137.64, 139.92, 145.67, 30 146.09, 147.20, 147.88, 172.80.
INTERMEDIATE 135 - PREPARATION OF 3-hydroxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H- chromen-6-aminium.
This compound was prepared following method E, starting from Intermediate 120, which afforded a yellow powder in 90% yield.
35 1H NMR (300MHz, DMSO-ofe) δ 3.74 (s, 3H), 3.85 (s, 6H), 7.35 (dd, 1 H, J=2.8, 9.0Hz), 7.53 (s, 2H), 7.54 (d, 1 H, J=2.8Hz), 7.70 (d, 1 H, J=9.0Hz). 13C NMR (75MHz, DMSO-ofe) δ 56.27, 60.41 , 105.75, 1 10.70, 1 19.93, 122.06,125.12, 126.88, 138.49, 138.69, 139.28, 145.09, 150.04, 152.92, 172.55. INTERMEDIATE 136 - PREPARATION OF 6-amino-3-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4- one.
The title compound was prepared according to Method E, using Intermediate 1 18 as starting material, which afforded a beige powder in 95% yield.
5 1H NMR (300MHz, DMSO-ofe) δ 7.10 (d, 2H, J=8.50Hz), 7.14 (d, 2H, J=9.1 Hz), 7.21 (t, 1 H, J=7.3Hz), 7.38 (dd, 1 H, J=9.1 , 2.8Hz), 7.45 (t, 2H, J=7.3Hz), 7.56 (d, 1 H, J=2.6Hz), 7.64 (d, 1 H, J=9.1 Hz), 8.20 (d, 2H, J=9.1 Hz). 13C NMR (75MHz, DMSO-ofe) δ 1 1 1.08, 1 18.18, 1 19.51 1 19.76, 122.17, 124.40, 125.27, 126.42, 129.90, 130.44, 138.12, 138.43, 145.16, 150.22, 155.92, 158.23, 172.53.
INTERMEDIATE 137 - PREPARATION OF 3-hydroxy-4-oxo-2-(3-phenoxyphenyl)-4H-chromen-6- 10 aminium.
This compound was prepared following Method E, starting from Intermediate 1 14, which afforded a beige powder in 92% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.03 (d, 2H, J=8.5Hz), 7.12 (m, 2H), 7.40 (t, 2H, J=8.5Hz), 7.55 (t, 1 H, J=8.1 Hz), 7.70 (dd, 1 H, J=2.6, 9.2Hz), 7.87 (d, 1 H, J=9.2Hz), 7.91 (t, 1 H, J=2.0Hz), 7.99 (d, 1 H, 15 J=8.7Hz), 8.02 (d, 1 H, J=2.6Hz). 13C NMR (75MHz, DMSO-ofe) δ 1 18.39, 1 18.45, 1 18.75, 120.52, 120.81 , 121.96, 123.10, 123.90, 128.67, 129.65, 130.41 , 130.57, 133.20, 139.76, 145.05, 153.39, 157.69, 157.79, 172.70.
INTERMEDIATE 138 - PREPARATION OF 2-(3,4-dimethoxyphenyl)-3-hydroxy-4-oxo-4H-chromen- 6-aminium.
20 The title compound was prepared according to Method E, using Intermediate 124 as starting material, affording a beige powder in 94% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.84 (s, 3H), 3.86 (s, 3H), 7.14 (d, 1 H, J=8.9Hz), 7.65 (dd, 1 H, J=9.0, 2.8Hz), 7.80 (d, 1 H, J=2.0Hz), 7.85 (dd, 1 H, J=8.7, 2.2Hz), 7.88 (d, 1 H, J=9.0Hz), 7.95 (d, 1 H, J=2.6Hz).13C NMR (75MHz, DMSO-ofe) δ 55,84, 55.84, 1 1 1.30, 1 1 1.79, 1 17.21 , 120.51 , 121.89, 25 121.98, 123.63, 127.71 , 130.76, 138.53, 146.34, 148.64, 150.72, 152.73, 172.17.
INTERMEDIATE 139 - PREPARATION OF 2-(3,5-dimethoxyphenyl)-3-hydroxy-4-oxo-4H-chromen- 6-aminium.
This compound was prepared according to Method E, starting from Intermediate 1 16, affording a beige powder in 98% yield.
30 1H NMR (300MHz, DMSO-ofe) δ 3.82 (s, 6H), 6.68 (t, 1 H, J=2.3Hz), 7.38 (d, 1 H, J=2.3Hz), 7.54 (dd, 1 H, J=9.1 , 2.6Hz), 7.79 (d, 1 H, J=2.6Hz), 7.83 (d, 1 H, J=9.1 Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.46, 101.60, 106.07, 1 14.21 , 120.21 , 121.76, 126.99, 132.90, 133.99, 139.20, 144.98, 151.49, 160.44, 172.51.
INTERMEDIATE 140 - PREPARATION OF 6-amino-2-(biphenyl-4-yl)-3-hydroxy-4H-chromen-4-one.
35 The title compound was prepared following Method E, using Intermediate 1 17 as starting material, which afforded a yellow powder in 88% yield. 1H NMR (300MHz, DMSO-ofe) δ 7.10 (dd, 1 H, J=2.9, 9.0Hz), 7.17 (d, 1 H, J=2.5Hz), 7.40 (t, 1 H, J=7.5Hz), 7.47 (d, 1 H, J=8.5Hz), 7.51 (brd, 2H, J=8.6Hz), 7.75 (d, 2H, J=8.4Hz), 7.85 (d, 2H, J=8.5Hz), 8.28 (d, 2H, J=8.5Hz).13C NMR (75MHz, DMSO-ofe) δ 104.18, 1 19.02, 122.25, 122.53, 126.76, 126.86, 128.14, 129.19, 130.82, 138.50, 139.30, 141 .06, 144.33, 145.99, 147.45, 172.70. INTERMEDIATE 141 - PREPARATION OF 6-amino-3-hydroxy-2-(naphthalen-1-yl)-4H-chromen-4- one.
The title compound was prepared according to Method E, using Intermediate 1 19 as starting material, which afforded a brown powder in 97% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.08 (dd, 1 H, J=9.1 , 2.7Hz), 7.23 (d, 1 H, J=2.7Hz), 7.35 (d, 1 H, J=9.1 Hz), 7.52 (ddd, 1 H, J=8.1 , 7.1 , 1.1 Hz), 7.57 (ddd, 1 H, J=8.3, 7.1 , 1.1 Hz), 7.63 (dd, 1 H, J=8.1 , 7.2Hz), 7.73 (dd, 1 H, J=8.1 , 1 .1 Hz), 7.75 (dd, 1 H, J=7.2, 1 .1 Hz), 8.02 (brd, 1 H, J=8.2Hz), 8.09 (brd, 1 H, J=8.2Hz). 13C NMR (75MHz, DMSO-ofe) δ 104.41 , 1 19.03, 122.28, 123.01 , 125.33, 125.54, 126.37, 126.98, 128.52, 128.62, 128.94, 130.32, 130.35, 133.21 , 138.66, 146.05, 147.01 , 148.07, 172.63.
INTERMEDIATE 142 - PREPARATION OF 6-amino-2-(3,4-diisopropoxyphenyl)-3-hydroxy-4H- chromen-4-one.
This compound was prepared following Method E, starting from A/-(3-hydroxy-2-(3,4- diisopropoxyphenyl)-4-oxo-4H-chromen-6-yl)acetamide, affording a brown powder in 82% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.27 (d, 6H, J=2.6Hz), 1.30 (d, 6H, J=2.6Hz), 4.52 (sept, 1 H, J=6.04Hz), 4.66 (sept, 1 H, J=6.04Hz), 7.05 (dd, 1 H, J=2.8, 9.0Hz), 7.12 (m, 2H), 7.45 (d, 1 H, J=9.0Hz), 7.75 (m, 2H), 9.05(brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 22.06, 22.22, 70.82, 72.06, 104.33, 1 15.98, 1 17.78, 1 18.97, 122.17, 122.80, 124.54, 137.66, 144.84, 145.96, 147.30, 147.61 , 150.16, 172.49.
INTERMEDIATE 143 - PREPARATION OF 6-amino-3-hydroxy-2-(2-isopropoxyphenyl)-4H- chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 123 as starting material, with an 89% yield.
1H NMR (300MHz, DMSO-ofe) δ 1.19 (d, 6H, J=2.6Hz), 4.62 (sept, 1 H, J=6.04Hz), 7.00 (t, 1 H, J=7.0Hz), 7.05 (dd, 1 H, J=8.8, 2.8Hz), 7.14 (d, 1 H, J=7.7Hz), 7.16 (d, 1 H, J=2.8Hz), 7.30 (d, 1 H, J=8.8Hz), 7.42 (t, 1 H, J=7.7Hz), 7.45 (t, 1 H, J=7.7Hz). 13C NMR (75MHz, DMSO-ofe) δ 22.05, 70.58, 104.39, 1 14.78, 1 18.81 , 120.1 1 , 121 .66, 122.17, 122.92, 131 .43, 138.22, 145.87, 146.80, 147.92, 155.74, 172.59.
INTERMEDIATE 144 - PREPARATION OF 6-amino-3-hydroxy-2-(4-isopropoxyphenyl)-4H- chromen-4-one.
This compound was prepared according to Method E, starting from Intermediate 122, which afforded a yellow powder in 90% yield. 1H NMR (300MHz, DMSO-ofe) δ 1 .29 (d, 6H, J=2.6Hz), 4.72 (sept, 1 H, J=6.04Hz), 5.42 (s, 2H), 7.05 (dd, 1 H, J=8.9, 2.6Hz), 7.07 (d, 2H, J=8.9Hz) 7.13 (d, 1 H, J=2.6Hz), 7.45 (d, 1 H, J=8.9Hz), 8.12 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 21.75, 69.35, 104.16, 1 15.32, 1 18.71 , 121.96, 122.1 1 , 123.63, 129.21 , 137.31 , 144.89, 145.76, 147.12, 158.47, 172.29.
INTERMEDIATE 145 - PREPARATION OF 6-amino-2-(4-(4-fluorophenoxy)phenyl)-3-hydroxy-4H- chromen-4-one
The title compound was prepared following Method E, using Intermediate 121 as starting material, which afforded a brown powder in 95% yield.
1H NMR (300MHz, DMSO-ofe) δ 7.13 (d, 2H, J=8.7Hz), 7.16 (dd, 2H, J=8.8, 4.5Hz), 7.27 (t, 2H, J=8.8Hz), 7.30 (dd, 1 H, J=9.1 , 2.5Hz), 7.46 (d, 1 H, J=2.5Hz), 7.61 (d, 1 H, J=9.1 Hz), 8.19 (d, 2H, J=8.7Hz). 13C NMR (75MHz, DMSO-ofe) δ 109.50, 1 16.83 (d, J=23.4Hz), 1 17.56, 1 19.43, 121 .45 (d, J=8.3Hz), 122.04, 124.44, 126.26, 129.71 , 138.15, 139.77, 144.84, 149.43, 151 .71 (d, J=2.3Hz), 158.39, 158.66 (d, J=240.00Hz), 172.38.
INTERMEDIATE 146 - PREPARATION OF N-(3-methoxy-2-(2-methoxyphenyl)-4-oxo-4H-chromen- 6-yl)acetamide
This compound was prepared according to Method D, starting from Intermediate 104, affording a white powder in 88% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 2H), 3.71 (s, 3H), 3.81 (s, 3H), 7.09 (t, 1 H, J=8.2Hz), 7.19 (d, 1 H, J=8.2Hz), 7.54 (t, 1 H, J=8.2Hz), 7.49 (d, 1 H, J=8.2Hz), 7.59 (d, 1 H, J=9.1 Hz), 7.92 (dd, 1 H, J=9.1 , 2.6Hz), 8.42 (d, 1 H, J=2.6Hz), 10.29 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.01 , 55.68, 59.66, 1 1 1.74, 1 12.92, 1 18.92, 1 19.70, 120.25, 124.08, 125.47, 130.44, 132.08, 136.37, 140.85, 151.04, 155.67, 156.89, 168.60, 173.39.
INTERMEDIATE 147 - PREPARATION OF N-(3-methoxy-2-(3-methoxyphenyl)-4-oxo-4H-chromen- 6-yl)acetamide
The title compound was prepared following Method D, using Intermediate 105 as starting material, affording a pale yellow powder in 84% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 7.16 (dd, 1 H, J=8.0, 2.0Hz), 7.50 (t, 1 H, J=8.0Hz), 7.57 (t, 1 H, J=2.0Hz), 7.62 (brd, 1 H, J=8.0Hz), 7.72 (d, 1 H, J=9.1 Hz), 7.94 (dd, 1 H, J=9.1 , 2.5Hz), 8.38 (d, 1 H, J=2.5Hz), 10.27 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.98, 55.29,55.29, 1 12.83, 1 13.78, 1 16.33, 1 19.00, 120.52, 123.67, 125.60, 129.83, 131 .72, 136.40, 154.57, 140.53, 150.61 , 159.17, 168.57, 173.71.
INTERMEDIATE 148 - PREPARATION OF N-(3-methoxy-2-(4-methoxyphenyl)-4-oxo-4H-chromen- 6-yl)acetamide.
This compound was prepared according to Method D, starting from Intermediate 106, which afforded a white powder in 91 % yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.79 (s, 3H), 3.86 (s, 3H), 7.14 (d, 2H, J=8.8Hz), 7.70 (d, 1 H, J=9.0Hz), 7.93 (dd, 1 H, J=9.0, 2.3Hz), 8.05 (d, 2H, J=8.8Hz), 8.36 (d, 1 H, J=2.3Hz), 10.29 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.98, 55.41 , 59.45, 1 12.89, 1 14.17, 1 18.81 , 122.64, 123.66, 125.40, 130.00, 136.30, 139.75, 150.49, 154.79, 161.17, 168.85, 173.47.
INTERMEDIATE 149 - PREPARATION OF N-(2-(2-fluorophenyl)-3-methoxy-4-oxo-4H-chromen-6- yl)acetamide.
5 The title compound was prepared following Method D, using Intermediate 107 as starting material, affording a yellow powder in 82% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 3H), 3.77 (s, 3H), 7.40 (m, 2H), 7.63 (m, 1 H), 7.64 (d, 1 H, J=8.8Hz), 7.73 (td, 1 H, J=2.2, 7.6Hz), 7.94 (dd, 1 H, J=2.7, 8.8Hz), 8.42 (d, 1 H, J=2.7Hz), 10.29 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.16, 60.06, 1 13.08, 1 16.28 (d, J=21 .1 Hz), 1 18.78 (d, 10 J=14.3Hz), 1 19.12, 124.16, 124.84, 125.88, 131.27, 133.18 (d, J=6.8Hz), 136.71 , 141.19, 151.14, 152.09, 159.35 (d, J=249.00Hz), 168.79, 173.51.
INTERMEDIATE 150 - PREPARATION OF N-(2-(3-fluorophenyl)-3-methoxy-4-oxo-4H-chromen-6- yl)acetamide.
This compound was prepared according to Method D, starting from Intermediate 108, which afforded 15 a yellow powder in 71 % yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.83 (s, 3H), 7.41 (td, 1 H, J=8.5, 2.3Hz), 7.62 (td, 1 H, J=8.0, 6.3Hz), 7.70 (d, 1 H, J=9.0Hz), 7.83 (dt, 1 H, J=1 1.1 , 1 .8Hz), 7.89 (brd, 1 H, J=8.0Hz), 7.93 (dd, 1 H, J=9.0, 2.5Hz) 8.36 (d, 1 H, J=2.5Hz). 10.26 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.16, 59.89, 1 12.98, 1 15.1 1 (d, J=23.4Hz), 1 17.86 (d, J=21 .1 Hz), 1 19.20, 123.83, 124.62 (d, J=3.0Hz), 20 125.89, 131.00 (d, J=7.5Hz), 132.83 (d, J=8.3Hz), 136.65, 140.94, 150.75, 153.25, 162.13 (d, J=243Hz), 168.78, 173.92.
INTERMEDIATE 151 - PREPARATION OF N-(2-(4-fluorophenyl)-3-methoxy-4-oxo-4H-chromen-6- yl)acetamide.
The title compound was prepared according to Method D, using Intermediate 109 as starting 25 material, affording a beige powder in 86% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.07 (s, 3H), 3.74 (s, 3H), 7.09 (t, 2H, J=9.0Hz), 7.37 (d, 1 H, J=9.2Hz), 8.00 (d, 1 H, J=2.7Hz), 8.01 (dd, 2H, J=9.0, 5.4Hz), 8.24 (dd, 1 H, J=9.2, 2.7Hz), 9.54 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.85, 59.61 , 1 13.96, 1 15.32 (d, J=21.9Hz), 1 18.02, 123.74, 126.05, 126.70, 130.38 (d, J=9.0Hz), 136.10, 140.43, 150.91 , 154.18, 163.50 (d, J=252Hz), 168.95, 30 174.32.
INTERMEDIATE 152 - PREPARATION OF N-(3-methoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)-4H- chromen-6-yl)acetamide.
This compound was prepared following Method D, starting from Intermediate 1 10, which afforded a yellow powder in 85% yield.
35 1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.84 (s, 3H), 7.72 (d, 1 H, J=9.2Hz), 7.82 (t, 1 H, J=8.4Hz), 7.94 (brd, 1 H, J=8.4Hz), 7.94 (dd, 1 H, J=9.2, 2.5Hz), 8.31 (brd, 1 H, J=8.4Hz), 8.32 (brs, 1 H), 8.37 (d, 1 H, J=2.5Hz), 10.28 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.10, 59.76 1 12.80, 1 19.09, 123.74, 123.42 (q, J=270.00Hz), 124.69 (q, J=3.8Hz), 125.73, 127.22 (q, J=3.8Hz), 129.47 (q, J=32.4Hz), 129.97, 131.60, 132.22, 136.55, 152.99, 140.85, 150.64, 168.63, 173.76.
INTERMEDIATE 153 - PREPARATION OF N-(3-methoxy-4-oxo-2-(4-(trifluoromethyl)phenyl)-4H- chromen-6-yl)acetamide.
5 The title compound was prepared according to Method D, using Intermediate 1 1 1 as starting material, affording a white powder in 93% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.83 (s, 3H), 7.70 (d, 1 H, J=9.1 Hz), 7.94 (d, 2H, J=8.9Hz), 7.95 (dd, 1 H, J=2.5, 9.1 Hz), 8.22 (d, 2H, J=8.9Hz), 8.37 (d, 1 H, J=2.5Hz), 10.28 (s, 1 H).13C NMR (75MHz, DMSO-ofe) δ 24.19, 60.06, 1 12.98, 1 19.22, 123.91 , 124.81 (q, J=272Hz), 10 125.72 (q, J=3.8Hz), 126.01 , 129.29, 130.49 (q, J=32.4Hz), 134.68, 136.73, 141.27, 150.83, 153.23, 173.98.
INTERMEDIATE 154 - PREPARATION OF A/-(3-methoxy-4-oxo-2-(4-phenoxyphenyl)-4H-chromen- 6-yl)acetamide.
This compound was prepared according to Method D, using Intermediate 1 18 as starting material, 15 affording a white powder in 88% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.81 (s, 3H), 7.13 (m, 2H), 7.15 (m, 2H), 7.24 (t, 1 H, J=7.3Hz), 7.47 (t, 2H, J=8.7Hz), 7.69 (d, 1 H, J=8.9Hz), 7.93 (dd, 1 H, J=8.9, 2.0Hz), 8.07 (d, 2H, J=8.7Hz), 8.36 (d, 1 H, J=2.0Hz), 10.27 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.99, 59.58, 1 12.85, 1 17.69, 1 18.90, 1 19.72, 123.67, 124.50, 125.20, 125.48, 130.38, 130.29, 136.36, 140.05, 20 150.52, 154.30, 155.33, 159.09, 168.55, 173.57.
INTERMEDIATE 155 - PREPARATION OF N-(3-methoxy-4-oxo-2-(3-phenoxyphenyl)-4H-chromen- 6-yl)acetamide.
The title compound was prepared following Method D, starting from Intermediate 1 13, which afforded a beige powder in 97% yield.
25 1H NMR (300MHz, DMSO-ofe) δ 2.07 (s, 3H), 3.73 (s, 3H), 7.08 (d, 2H, J=8.5Hz), 7.18 (m, 2H), 7.40 (t, 2H, J=7.8Hz), 7.58 (t, 1 H, J=8.2Hz), 7.64 (d, 1 H, J=9.1 Hz), 7.67 (t, 1 H, J=2.0Hz), 7.78 (d, 1 H, J=8.5Hz), 7.90 (dd, 1 H, J=2.6, 9.1 Hz), 8.35 (d, 1 H, J=2.6Hz), 10.25 (brs, 1 H). 13C NMR (75MHz, DMSO-d6) 6 24.12, 59.75, 1 12.99, 1 18.09, 1 19.10, 1 19.25, 120.84, 123.12, 123.82, 124.16, 125.82, 130.36, 130.58, 132.37, 136.59, 140.77, 150.72, 153.91 , 156.26, 157.10, 168.73, 173.87.
30 INTERMEDIATE 156 - PREPARATION OF N-(2-(3,5-dimethoxyphenyl)-3-methoxy-4-oxo-4H- chromen-6-yl)acetamide
This compound was prepared according to Method D, using Intermediate 1 16 as starting material, affording a white powder in 89% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.82 (s, 3H), 3.83 (s, 6H), 6.72 (t, 1 H, J=2.1 Hz), 7.17 35 (d, 2H, J=2.1 Hz), 7.72 (d, 1 H, J=9.1 Hz), 7.93 (dd, 1 H, J=9.3, 2.5Hz), 8.36 (d, 1 H, J=2.4Hz), 10.30 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 23.98, 55.44, 59.66, 102.47, 106.40, 1 12.80, 1 19.04, 123.62, 125.58, 132.13, 136.40, 140.60, 150.55, 154.45, 160.40, 168.56, 173.70. INTERMEDIATE 157 - PREPARATION OF N-(2-(3,4-dimethoxyphenyl)-3-methoxy-4-oxo-4H- chromen-6-yl)acetamide.
The title compound was prepared following Method D, starting from Intermediate 124, which afforded a brown powder in 85% yield.
5 1H NMR (300MHz, DMSO-ofe) δ 2.08 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (d, 1 H, J=8.6Hz), 7.65 (brd, 1 H, J=2.1 Hz), 7.68 (dd, 1 H, J=8.5, 2.3Hz), 7.70 (d, 1 H, J=9.1 Hz), 7.91 (dd, 1 H, J=9.1 , 2.7Hz), 8.35 (d, 1 H, J=2.4Hz), 10.26 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.19, 55.82, 55.82, 59.67, 1 1 1.53, 1 1 1 .73, 1 13.05, 1 19.1 1 , 122.09, 122.82, 123.83, 125.53, 136.50, 140.07, 148.60, 150.67, 151 .20, 154.94, 168.75, 173.67.
10 INTERMEDIATE 158 - PREPARATION OF N-(2-(biphenyl-4-yl)-3-methoxy-4-oxo-4H-chromen-6- yl)acetamide.
This compound was prepared according to Method D, using Intermediate 1 17 as starting material, affording a white powder in 80% yield.
1H NMR (300MHz, DMSO-ofe) δ 2.10 (s, 3H), 3.86 (s, 3H), 7.43 (t, 1 H, J=7.5Hz), 7.50 (t, 2H, 15 J=7.5Hz), 7.73 (d, 1 H, J=8.5Hz), 7.79 (d, 2H, J=8.4Hz), 7.89 (d, 2H, J=8.5Hz), 7.95 (dd, 1 H, J=2.6, 9.1 Hz), 8.15 (d, 2H, J=8.7Hz), 8.40 (d, 1 H, J=2.5Hz), 10.29 (s, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 24.10, 59.71 , 1 12.87, 1 18.96, 123.74, 125.60, 126.85, 128.22, 128.83, 129.1 1 , 129.47, 136.42, 138.99, 140.57, 142.26, 150.64, 154.41 , 168.59, 173.67.
INTERMEDIATE 159 - PREPARATION OF 6-amino-3-methoxy-2-(2-methoxyphenyl)-4H-chromen- 20 4-one.
The title compound was prepared following Method E, starting from Intermediate 146, which afforded a brown powder in 76% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.74 (s, 3H), 3.81 (s, 3H), 5.51 (s, 2H), 7.01 (dd, 1 H, J=2.8, 8.9Hz), 7.03 (t, 1 H, J=7.6Hz), 7.06 (d, 1 H, J=2.8Hz), 7.28 (d, 1 H, J=8.9Hz), 7.42 (dd, 1 H, J=1 .7, 7.6Hz), 7.44 25 (d, 1 H, J=2.8Hz), 7.46 (t, 1 H, J=7.6Hz). 13C NMR (75MHz, DMSO-ofe) δ 59.78, 60.13, 107.06, 1 1 1.22), 1 18.80, 120.17, 120.25, 122.30, 125.06, 130.39, 131 .60, 141.06, 143.93, 149.25, 155.64, 157.04, 174.48.
INTERMEDIATE 160 - PREPARATION OF 6-amino-3-methoxy-2-(3-methoxyphenyl)-4H-chromen- 4-one.
30 This compound was prepared from Intermediate 147, according to Method E, which afforded a yellow powder in 91 % yield.
1H NMR (300MHz, DMSO-ofe) δ 3.77 (s, 3H), 3.82 (s, 3H), 5.51 (s, 2H), 7.07 (dd, 1 H, J=2.8, 8.9Hz), 7.12 (dd, 1 H, J=2.0, 8.0Hz), 7.13 (d, 1 H, J=2.8Hz), 7.46 (d, 1 H, J=8.9Hz), 7.47 (t, 1 H, J=8.0Hz), 7.53 (t, 1 H, J=2.0Hz), 7.57 (d, 1 H, J=8.0Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.44, 59.78, 104.55, 35 1 13.84, 1 16.22, 1 19.13, 120.58, 122.24, 124.66, 129.95, 132.31 , 140.27, 146.50, 147.32, 154.14, 159.31 , 173.85. INTERMEDIATE 161 - PREPARATION OF 6-amino-3-methoxy-2-(4-methoxyphenyl)-4H-chromen- 4-one.
The title compound was prepared following Method E, using Intermediate 148 as starting material, affording a yellow powder in 93% yield.
5 1H NMR (300MHz, DMSO-ofe) δ 3.78 (s, 3H), 3.85 (s, 3H), 7.13 (d, 2H, J=8.8Hz), 7.27 (dd, 1 H, J=8.9, 2.6Hz), 7.40 (d, 1 H, J=2.6Hz),7.59 (d, 1 H, J=8.9Hz), 8.03 (d, 2H, J=8.8Hz).13C NMR (75MHz, DMSO-de) δ 55.43, 59.44, 108.96, 1 14.17, 1 19.31 , 122.83, 123.95, 124.32, 129.94, 139.59, 140.91 , 149.03, 154.58, 161.10, 173.33.
INTERMEDIATE 162 - PREPARATION OF 6-amino-2-(2-fluorophenyl)-3-methoxy-4H-chromen-4- 10 one.
This compound was prepared according to Method E, starting from Intermediate 149, which afforded a yellow powder in 82% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.78 (s, 3H), 7.19 (dd, 1 H, J=2.7, 8.8Hz), 7.33 (d, 1 H, J=2.7Hz), 7.42 (m, 1 H), 7.46 (d, 1 H, J=8.8Hz), 7.64 (m, 1 H), 7.73 (td, 1 H, J=2.2, 7.6Hz). 13C NMR (75MHz, 15 DMSO-ofe) δ 53.89, 107.19, 1 16.07 (d, J=21.1 Hz), 1 18.85 (d, J=14.3Hz), 1 19.19, 123.43, 124.58, 124.69, 131.03, 132.84 (d, J=7.5Hz), 140.68, 143.47, 148.74, 151.58, 160.60 (d, J=250.00Hz), 173.20.
INTERMEDIATE 163 - PREPARATION OF 6-amino-2-(3-fluorophenyl)-3-methoxy-4H-chromen-4- one.
20 The title compound was prepared following Method E, using Intermediate 150 as starting material, affording a yellow powder in 89% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.80, 7.08 (dd, 1 H, J=8.9, 2.7Hz), 7.12 (d, 1 H, J=2.7Hz), 7.40 (td, 1 H, J=8.5, 2.3Hz), 7.48 (d, 1 H, J=8.9Hz), 7.61 (td, 1 H, J=8.0, 6.3Hz), 7.81 (dt, 1 H, J=1 1.1 , 1.8Hz), 7.87 (brd, 1 H, J=8.0Hz). 13C NMR (75MHz, DMSO-ofe) δ 59.81 , 104.55, 1 14.98 (d, J=24.1 Hz), 25 1 17.56 (d, J=20.3Hz), 1 19.16, 122.41 ,124.47 (d, J=3.0Hz), 124.64, 130.93 (d, J=7.5Hz), 133.22 (d, J=8.3Hz), 140.48, 146.45, 147.32, 152.69 162.12 (d, J=243Hz), 172.83.
INTERMEDIATE 164 - PREPARATION OF 6-amino-2-(4-fluorophenyl)-3-methoxy-4H-chromen-4- one.
This compound was prepared according to Method E, starting from Intermediate 151 , which afforded 30 a yellow product in 91 % yield.
1H NMR (300MHz, DMSO-ofe) δ 3.77 (s, 3H), 5.51 (s, 2H), 7.06 (dd, 1 H, J=2.8, 8.8Hz), 7.12 (d, 1 H, J=2.8Hz), 7.40 (d, 2H, J=8.9, 5.3Hz), 7.44 (d, 1 H, J=8.8Hz), 8.28 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 59.76, 104.59, 1 15.92 ( d, J=21.9Hz), 1 19.07, 122.24, 124.68, 127.60 (d, J=3.0Hz), 130.90 (d, J=9.0Hz), 140.00, 146.54, 147.30, 153.48, 163.31 (d, J=250.00Hz), 173.81.
35 INTERMEDIATE 165 - PREPARATION OF 6-amino-3-methoxy-2-(3-(trifluoromethyl)phenyl)-4H- chromen-4-one. The title compound was prepared following Method E, using Intermediate 152 as starting material, affording a brown powder in 77% yield
1H NMR (300MHz, DMSO-ofe) δ 3.82 (s, 3H), 5.56 (brs, 2H), 7.09 (dd, 1 H, J=8.9, 2.6Hz), 7.14 (d, 1 H, J=2.6Hz), 7.51 (d, 1 H, J=8.9Hz), 7.82 (t, 1 H, J=8.4Hz), 7.93 (brd, 1 H, J=8.4Hz), 8.30 (brd, 1 H, 5 J=8.4Hz), 8.30 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 59.72, 104.28, 1 19.08, 124.56, 123.42 (q, J=270.00Hz), 124.55 (q, J=3.8Hz), 122.25, 126.97 (q, J=3.8Hz), 129.41 (q, J=32.4Hz), 129.65, 132.1 1 , 131.97, 146.48, 152.41 , 140.37, 147.19, 173.68.
INTERMEDIATE 166 - PREPARATION OF 6-amino-3-methoxy-2-(4-(trifluoromethyl)phenyl)-4H- chromen-4-one.
10 This compound was prepared according to Method E, starting from Intermediate 153, which afforded a yellow powder in 86% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.80 (s, 3H), 5.54 (s, 2H), 7.09 (dd, 1 H, J=2.5, 9.1 Hz), 7.12 (d, 1 H, J=2.5Hz), 7.47 (d, 1 H, J=9.1 Hz), 7.92 (d, 2H, J=8.9Hz), 8.21 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 60.01 , 104.49, 1 19.17, 122.53, 124.75, 124.81 (q, J=272Hz), 125.69 (q, J=3.8Hz), 15 129.16, 130.19 (q, J=32.4Hz), 135.07, 140.81 , 146.67, 147.69, 152.66, 173.91.
INTERMEDIATE 167 - PREPARATION OF 6-amino-3-methoxy-2-(4-phenoxyphenyl)-4H-chromen- 4-one.
The title compound was prepared following Method E, using Intermediate 154 as starting material, affording a brown powder in 70% yield.
20 1H NMR (300MHz, DMSO-ofe) δ 3.78 (s, 3H), 7.05 (dd, 1 H, J=8.9, 2.8Hz), 7.1 1 (m, 2H), 7.13 (m, 2H), 7.15 (m, 1 H), 7.22 (t, 1 H, J=7.3Hz), 7.45 (d, 1 H, J=8.9Hz), 7.47 (t, 2H, J=8.7Hz), 8.03 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 59.68, 104.74, 1 17.90, 1 18.90, 1 19.81 , 122.15, 124.58, 124.65, 125.67, 130.38, 130.44, 139.83, 146.28, 147.29, 153.89, 155.61 , 159.00, 173.70.
INTERMEDIATE 168 - PREPARATION OF 6-amino-3-methoxy-2-(3-phenoxyphenyl)-4H-chromen- 25 4-one.
This compound was prepared according to Method E, starting from Intermediate 155, which afforded a yellow powder in 97% yield.13C NMR (75MHz, DMSO-ofe) δ 59.69, 104.49, 1 17.87, 1 19.07, 1 19.25, 120.59, 123.01 , 122.30, 124.14, 124.63, 130.37, 130.55, 132.76, 140.33, 146.52, 147.25, 153.32, 156.29, 157.07, 173.81.
30 INTERMEDIATE 169 - PREPARATION OF 6-amino-2-(3,5-dimethoxyphenyl)-3-methoxy-4H- chromen-4-one.
The title compound was prepared according to Method E, using Intermediate 156 as starting material, affording a black oil in 81 % yield.
1H NMR (300MHz, DMSO-ofe) δ 3.82 (s, 3H), 3.83 (s, 6H), 6.58 (t, 1 H, J=2.1 Hz), 7.02 (brd, 1 H), 7.24 35 (d, 2H, J=2.1 Hz), 7.35 (d, 1 H, J=8.7Hz), 7.42 (brs, 1 H). 13C NMR (75MHz, DMSO-ofe) δ 55.91 , 60.53, 103.15, 106.99, 108.06, 1 19.39, 122.93, 125.31 , 133.21 , 141 .53, 143.96, 149.48, 155.48, 161.05, 175.33. INTERMEDIATE 170 - PREPARATION OF 6-amino-2-(3,4-dimethoxyphenyl)-3-methoxy-4H- chromen-4-one.
This compound was prepared according to Method E, starting from Intermediate 157, which afforded a yellow powder in 84% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.77 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (d, 1 H, J=8.7Hz), 7.62 (d, 1 H, J=2.1 Hz), 7.65 (dd, 1 H, J=8.5, 2.3Hz), 7.45 (d, 1 H, J=8.9Hz), 7.03 (dd, 1 H, J=8.9, 2.9Hz), 7.10 (d, 1 H, J=2.9Hz). 13C NMR (75MHz, DMSO-ofe) δ 55.80, 55.80, 59.60, 104.64, 1 1 1 .45, 1 1 1.71 , 1 19.04, 121.86, 121.97, 123.26, 124.61 , 139.67, 146.39, 148.57, 147.18, 151.20, 154.33, 173.66.
INTERMEDIATE 171 - PREPARATION OF 6-amino-2-(biphenyl-4-yl)-3-methoxy-4H-chromen-4- one.
The title compound was prepared following Method E, using Intermediate 158 as starting material, affording a beige powder in 98% yield.
1H NMR (300MHz, DMSO-ofe) δ 3.86 (s, 3H), 7.10 (dd, 1 H, J=2.9, 8.9Hz), 7.16 (d, 1 H, J=2.6Hz), 7.43 (t, 1 H, J=7.3Hz), 7.49 (d, 1 H, J=8.7Hz), 7.52 (t, 2H, J=7.2Hz), 7.76 (d, 2H, J=7.1 Hz), 7.88 (d, 2H, J=8.5Hz), 8.13 (d, 2H, J=8.5Hz). 13C NMR (75MHz, DMSO-ofe) δ 59.82, 104.59, 1 19.09, 122.24, 124.71 , 127.01 , 128.33, 128.87), 129.27, 130.06, 139.24, 140.31 , 142.16, 146.51 , 147.35, 153.97, 173.80.
GENERAL METHODS FOR THE PREPARATION OF THE COMPOUNDS OF THE INVENTION. Method M.
A mixture of 5 mm of either Intermediate ll-l (Scheme 2), amino-derivative of intermediate ll-L or ll-P' (amino derivative of ll-P) and KSCN (0.73 g, 7.5 mmol) were stirred in AcOH (40 mL) at r.t. for 30 min. A solution of bromine (5 mmol) in 10 mL of AcOH was added dropwise to this mixture under vigorous stirring at r.t. for 2h. During the course of the reaction a precipitate was formed. At that time, water was added (20 mL) and the pH was adjusted to 4-5 with NH4OH 16%. The resulting precipitate was filtered off and dried to afford the corresponding thiazoloderivatives ll-J (Scheme 2), ll-H (Scheme 3) or ll-Q (Scheme 4).
Method N.
A mixture of 1 eq. of intermediary 11— I * (Scheme 9) and Mn(OAc)3 (3 eq.) in AcOH was submitted to MWI in open vessel at 1 10°C for 10 min. The resulting dark solution was poured over water and extracted with DCM. The organic layer was removed under reduced pressure and crystallized in EtOH to afford the desired product ll-J (Scheme 2).
Method O. Halogenation of the thiazoloderivatives ll-J or ll-Q.
To a stirred mixture of CuX2 (wherein X is Br, CI or F; 2.5 eq.) and isoamyl nitrite (4 eq.) in MeCN (2 ml), protected with a CaC drying tube at ca. 80°C, a solution of 1 eq. of 2-aminothiazoloflavone (ll-J or ll-Q) in 1 mL MeCN was added dropwise. The mixture was kept at ca. 80°C until no starting material could be detected by TLC, allowed to cool to ca. 20°C. The crude material was purified by column chromatography on silica gel (eluted with hexane-DCM, 7:3) to afford the desired halogenated derivatives of compounds ll-J or ll-Q.
Example 1 . Synthesis of 2-amino-7-(3-phenoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C1 ).
This compound was obtained following Method M, starting from 6-amino-2-(3-phenoxyphenyl)-4H- 5 chromen-4-one, as a yellow powder (87%); Anal. Calc. for C22H14N2O3S: C, 68.38; H, 3.65; N, 7.25.
Found: C, 68.23; H, 3.75; N, 7.09. m/z: 386,07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.09 (brd, 2H, J=7.6Hz ), 7.15 (s, 1 H), 7.18 (m, 1 H ), 7.20 (m, 1 H), 7.43 (brt, 2H, J=7.6Hz), 7.59 (t, 1 H, J=7.9Hz ), 7.67 (d, 1 H, J=8.9Hz), 7.77 (d, 1 H, J=8.9Hz), 7.82 (d, 1 H, J=2.1 Hz ), 7.91 (brd, 1 H, J=7.7Hz ). 13C NMR (75 MHz, DMSO-ofe) δ 106.45, 1 15.75, 1 17.86, 10 1 18.68, 1 18.76, 121.55, 121.55, 123.15, 123.86, 124.47, 130.21 , 130.90, 133.29, 151.02, 151.02,
156.34, 157.24, 161 .80, 170.22, 176.24.
Example 2. Synthesis of 2-amino-7-phenyl-9H-chromenor6,5-Gflthiazol-9-one (C2).
The title compound was prepared according to Method M, using Intermediate 7, as starting material, to afford a brown powder in 72% yield; Anal. Calcd. for Ci6H10N2O2S: C, 65.29; H, 3.42; N, 9.52. 15 Found : C, 64.78; H, 3.56; N, 9.34. m/z: 294,05 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.14 (s, 1 H), 7.72 (m, 1 H), 7.60 (m, 2H ), 7.59 (brs, 2H), 7.69 (d, 1 H, J=8.8Hz), 7.81 (d, 1 H, J=8.8Hz), 8.13 (m, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 105.94, 1 15,51 , 1 17.86, 123.37, 124.93, 126.37, 129.15, 131 .26, 131 .79, 150.97, 150.78, 162.59, 170.15, 176.25.
Example 3. Synthesis of 2-amino-8-hvdroxy-7-(3-phenoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one 20 (C3).
The title compound was prepared according to Method M, using Intermediate 137 as starting material, to afford a yellow powder in 82% yield; Anal. Calc. for C22H14N2O4S: C, 65.66; H, 3.51 ; N, 6.96. Found: C, 65.57; H, 3.57; N, 6.87. m/z: 402.07 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.08 (m, 2H), 7.13 (brdd, 1 H, J=8.3, 2.2Hz), 7.17 (s, 1 H), 7.42 (m, 25 2H), 7.57 (d, 1 H, J=8.8Hz), 7.59 (brs, 2H), 7.61 (t, 1 H, J=8.3Hz ), 7.78 (d, 1 H, J=8.8Hz), 7.94 (t, 1 H, J=2.2Hz ), 8.03 (brd, 1 H, J=8.3Hz ), 9.85 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 1 15.47, 1 16.19, 1 18.06, 1 18.53, 120.03, 122.75, 123.58, 123.62, 124.39, 130.15, 130.28, 133.31 , 139.14, 144.48, 149.73, 150.14, 156.56, 156.56, 169.73, 171.77.
Example 4. Synthesis of 2-amino-7-(4-phenoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C4).
30 Intermediate 96 was obtained according to Method M, using 6-amino-2-(4-phenoxyphenyl)-4H- chromen-4-one as starting material in 81 % yield (yellow powder). Anal. Calc. for C22H14N2O3S: C, 68.38; H, 3.65; N, 7.25. Found: C, 68.1 1 ; H, 3.66; N, 7.12. m/z: 386,07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.08 (s, 1 H), 7.13 (m, 2H), 7.15 (m, 2H), 7.25 (tt, 1 H, J=1.1 , 7.4Hz), 7.47 (brd, 2H, J=7.4Hz), 7.72 (d, 1 H, J=8.9Hz), 7.82 (d, 1 H, J=8.9Hz), 8.13 (brd, 2H). 13C NMR (75
35 MHz, DMSO-ofe) δ 105.22, 1 16.20, 1 17.78, 1 18.04, 1 19.79, 122.26, 124.66, 124.66, 125.61 , 128.68,
130.35, 151.24, 151.24, 155.23, 160.19, 162.59, 170.35, 176.10. Example 5. Synthesis of 2-amino-7-(3-(trifluoromethyl)phenyl)-9H-chromenor6,5-(/lthiazol-9-one (C5L
The title compound was obtained following Method M, using Intermediate 90 as starting material, to afford a brown powder in 89% yield. Anal. Calc. for C17H9F3N2O2S: C, 56.35; H, 2.50; N, 7.73. 5 Found: C, 56.23; H, 2.57; N, 7.67. m/z: 362,03 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.32 (s, 1 H), 7.67 (brs, 2H), 7.75 (d, 1 H, J=9.2Hz), 7.81 (d, 1 H, J=9.2Hz), 7.82 (t, 1 H, J=8.7Hz ), 7.97 (brd, 1 H, J=8.7Hz ), 8.44 (brd, 1 H, J=8.7Hz ), 8.45 (brs, 1 H ). 13C NMR (75 MHz, DMSO-ofe) δ 107.02, 1 15,73, 1 17.89, 122.95 (q, J=3.8Hz), 123.47, 123.48, 124.85, 128.08 (q, J=3.8Hz), 130.02 (q, J=31.7Hz'), 130.36'), 130.36, 132.51 , 150.73, 151 .00,
10 160.84, 170.21 , 176.31.
Example 6. Synthesis of 2-amino-7-(4-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C6).
This compound was prepared according to Method M, using Intermediate 86 as starting material, affording an ochre yellow powder in 60% yield. Anal. Calc. for Ci7H12N203S: C, 62.95; H, 3.73; N, 8.64. Found: C, 62.88; H, 3.74; N, 8.52. m/z: 324.06 (100.0%).
15 1H NMR (300 MHz, DMSO-ofe) δ 3.87 (s, 3H), 7.04 (s, 1 H), 7.14 (d, 2H ), 7.59 (brs, 2H), 7.67 (d, 1 H, J=8.8Hz), 7.77 (d, 1 H, J=8.8Hz), 8.10 (d, 2H).13C NMR (75 MHz, DMSO-ofe) δ 55.54, 104.48, 1 14.58, 1 15,44, 1 17.79, 123.12, 123.37, 124.91 , 128.22, 150.84, 150.78, 162.1 1 , 162.69, 170.10, 176.07.
Example 7. Synthesis of 2-bromo-7-phenyl-9H-chromenor6,5-Gflthiazol-9-one (C7).
20 2-bromo-7-phenyl-9H-chromeno[6,5-of]thiazol-9-one was prepared according to Method O, starting from Compound C2 and CuBr2, with a yield of 65%; Anal. Calc. for Ci6H8BrN02S: C, 53.65; H, 2.25; N, 3.91. Found: C, 53.38; H, 2.61 ; N, 3.90. m/z: 358,94 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.26 (s, 1 H), 7.48-7.64 (m, 3 H), 7.95 (d, J=8.8 Hz, 1 H) 8.12 (m, 2 H), 8.38 (d, J=8.8 Hz, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 106.42, 1 17.54, 1 17.91 , 126.5, 127.7, 25 129.12, 130.69, 131.18, 132.08, 142.85, 149.32, 153.76, 163.35, 175.6.
Example 8. Synthesis of 2-amino-7-(3-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C8).
This compound was obtained following Method M, starting from Intermediate 85, as an ochre yellow powder (74%). Anal. Calc. for Ci7H12N203S: C, 62.95; H, 3.73; N, 8.64. Found: C, 62.87; H, 3.84; N, 8.57. m/z: 324.06 (100.0%).
30 1H NMR (300 MHz, DMSO-ofe) δ 3.87 (s, 3H), 7.16 (s, 1 H), 7.18 (d, 1 H), 7.50 (t, 1 H, J = 7.9 Hz), 7.60-7.63 (m, 2H), 7;68-7.71 (d, 1 H, J = 8.50 Hz), 7.77-7.80 (d, 1 H, J = 8.69 Hz). 13C NMR (75 MHz, DMSO-de) δ 55.68, 106.37, 1 1 1.68, 1 15.78, 1 17.80, 1 18.05, 1 18.82, 123.54, 125.06, 130.48, 132.82, 150.91 , 151.13, 159.92, 162.53, 170.35, 176.46.
Example 9. Synthesis of 2-amino-7-(4-fluorophenyl)-8-hydroxy-9H-chromenor6,5-dlthiazol-9-one 35 (C9).
Using Intermediate 130, and following the preparation methodology outlined in Method M, the title compound was prepared as an ochre yellow powder (yield: 63%); Anal. Calc. for Ci6H9FN203S: C, 58.53; H, 2.76; N, 8.53. Found: C, 58.47; H, 2.84; N, 8.42. m/z: 328.03 (100.0%). 1H NMR (300 MHz, DMSO-ofe) δ 7.42 (t, 2H, J=9.0Hz), 7.74 (d, 1 H, J=8.9Hz), 7.85 (d, 1 H, J=8.9Hz), 8.29 (dd, 2H, J=9.0, 5.4Hz). 13C NMR (75 MHz, DMSO-ofe) δ 1 16.77, 1 15.96 (d, J=21.9Hz), 1 16.23, 122.16, 122.56, 128.01 , 130.55 (d, J=8.3Hz), 139.00, 145.63, 150.80, 150.80, 163.00 (d,
J=247,00Hz), 170.29, 172.00.
Example 10. Synthesis of 2-amino-8-hvdroxy-7-(4-phenoxyphenyl)-9H-chromenor6,5-cflthiazol-9-one (C10).
Using Intermediate 136 as starting material, the title compound was obtained as an ochre yellow powder in 76% yield. Anal. Calc. for C22H14N2O4S: C, 65.66; H, 3.51 ; N, 6.96. Found: C, 65.54; H, 3.49; N, 6.87. m/z: 402.07 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.10-7.23 (m, 5H, 7.44 (dt, 1 H, J=8.12Hz), 7.61-7.64 (d, 1 H, J=8.87 Hz), 7.66 (bs, 2H), 7.75-7.78 (d, 1 H, J=8.87 Hz), 8.23-8.26 (d, 1 H, J=8.8 Hz), 9.72 (bs, 1 H). 13C NMR (75 MHz, DMSO-of6) δ 1 15.53, 1 16.28, 1 18.02, 1 19.36, 123.15, 124.18, 124.24, 126.24, 129.79, 130.26, 138.41 , 145.46, 149.10, 150.13, 155.77, 158.1 1 , 169.80, 171.58.
Example 1 1. Synthesis of 2-amino-8-hvdroxy-7-(4-(trifluoromethyl)phenyl)-9/-/-chromenor6,5- cflthiazol-9-one (C11 ).
Following Method M, and using Intermediate 132 as starting material, the title compound was obtained as an ochre yellow powder in 76% yield. Anal. Calc. for C17H9F3N2O3S: C, 53.97; H, 2.40; N, 7.40. Found: C, 53.85; H, 2.44; N, 7.21 . m/z: 378.03 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.61 (brs, 2H), 7.65 (d, 1 H, J=8.9Hz), 7.81 (d, 1 H, J=8.9Hz), 7.93 (d, 2H, J=8.3Hz ), 8.43 (d, 2H, J=8.3Hz ), 10.15 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 1 15.50,
1 16.25, 123.75, 124.06 (q, J=272.00Hz), 124.45, 125.40, 128.20, 129.38 (q, J=32.4Hz), 135.40, 139.85, 143.55, 149.78, 150.27, 169.79, 172.01.
Example 12. Synthesis of 2-amino-7-(benzorcfiri ,31dioxol-5-yl)-9H-chromenor6,5-Gflthiazol-9-one (C12).
Following Method M, and using Intermediate 93 as starting material, the title compound was obtained as an ochre yellow powder in 73% yield; Anal. Calc. for Ci7H10N2O4S: C, 60.35; H, 2.98; N, 8.28. Found: C, 60.18; H, 3.09; N, 8.12. m/z: 338,04 (100,0%). m/z: 338,04 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.15 (s, 2H), 7.02 (s, 1 H), 7.10 (d, 1 H, J=8.1 Hz), 7.66 (dd, 1 H, J=8.1 , 1 .8Hz), 7.66 (d, 1 H, J=8.7Hz), 7.68 (d, 1 H, J=1.8Hz), 7.75 (d, 1 H, J=8.7Hz).13C NMR (75 MHz, DMSO-ofe) δ 102.10, 104.94, 106.36, 108.80, 1 15,53, 1 17.80, 121.66, 123.24, 124.91 , 125.10,
148.26, 150.40, 150.70, 150.87, 162.35, 170.18, 176.20.
Example 13. Synthesis of 2-amino-8-hvdroxy-7-(4-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C13).
This compound was obtained following Method M, starting from Intermediate 127, as a yellow powder (58%). Anal. Calc. for Ci7H12N204S: C, 59.99; H, 3.55; N, 8.23. Found: C, 59.74; H, 3.38; N, 8.1 1. m/z: 340.05 (100.0%). 1H NMR (300 MHz, DMSO-ofe) δ 3.85 (s, 3H), 7.13 (d, 2H ), 7.57 (brs, 2H), 7.63 (d, 1 H, J=8.8Hz), 7.72 (d, 1 H, J=8.8Hz), 8.22 (d, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 55.93, 1 14.07, 1 15,38, 1 16.25, 123.71 , 124.39, 129.42, 131.26, 137.95, 145.94, 149.73, 149.99, 160.44, 169.70, 171.40.
Example 14. Synthesis of 2-amino-7-(3,4-dimethoxyphenyl)-8-hvdroxy-9H-chromenor6,5-cflthiazol-9- one (C14).
2-amino-7-(3,4-dimethoxyphenyl)-8-hydroxy-9/-/-chromeno[6,5-cf]thiazol-9-one was prepared according to Method M, using Intermediate 138 as starting material (yellow powder, 68%). Anal. Calc. for C18H14N2O5S: C, 58.37; H, 3.81 ; N, 7.56. Found: C, 58.37; H, 3.81 ; N, 7.56. m/z: 370.06 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.86 (s, 6H), 7.15-7.18 (d, 1 H, J=8.69Hz), 7.75-7.78 (d, 1 H, J=8.88 Hz), 7.81-7.84 (d, 1 H, J=8.88 Hz), 7.84 (d, 1 H, J=2.08 Hz), 7.89-7.92 (dd, 1 H, J=2.07, 8.47 Hz) Example 15. Synthesis of 2-amino-7-phenyl-9/-/-thiochromenor6,5-cflthiazol-9-one (C15).
This compound was prepared according to Method M, starting from Intermediate 39, with a 56% yield. Anal. Calc. for Ci6H10N2OS2: C, 61 .91 ; H, 3.25; N, 9.03. Found: C, 61.85; H, 3.34; N, 9.01 . m/z: 310,02 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.41 (s, 1 H), 7.56-7.59 (m, 3H), 7.80-7.83 (m, 2H), 7.87-7.90 (d, 1 H, J=8.5 Hz), 8.05-8.08 (d, 1 H, J=8.69 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 1 17.37, 1 18.88, 121.52, 124.3, 126.61 , 127.27, 129.9, 131.81 , 132.86, 135.65, 140.49, 154.62, 171.48, 178.94. Example 16. Synthesis of ethyl 4-(2-amino-8-hydroxy-9-oxo-9/-/-chromenor6,5-cflthiazol-7- vDbenzoate (C16).
The title compound was prepared according to Method M, using ethyl 4-(6-amino-3-hydroxy-4-oxo- 4/-/-chromen-2-yl)benzoate as starting material, to afford a yellow powder in 78% yield; Anal. Calc. for Ci9H14N205S: C, 59.68; H, 3.69; N, 7.33. Found: C, 59.56; H, 3.71 ; N, 7.28.m/z: 382,06 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1.34 (t, 3H, J=6.9Hz), 4.33 (q, 2H, J=6.7Hz), 7.58 (brs, 2H), 7.66 (d, 1 H, J=8.7Hz), 7.79 (d, 1 H, J=8.7Hz), 8.10 (d, 2H, J=7.7Hz ), 8.36 (d, 2H, J=7.8Hz), 10.07 (brs, 1 H).13C NMR (75 MHz, DMSO-d6) δ 14.36, 61.19, 1 15.66, 1 16.39, 123.93, 124.64, 127.86, 129.39, 130.46, 135.93, 140.04, 144.07, 150.02, 150.42, 165.43, 169.94, 172.07.
Example 17. Synthesis of 2-amino-8-methoxy-7-(4-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9- one (C17).
The title compound was prepared according to Method M with Intermediate 161 to afford an ochre yellow powder in 79% yield; Anal. Calc. for Ci8H14N204S: C, 61.01 ; H, 3.98; N, 7.90. Found: C, 61 .01 ; H, 3.98; N, 7.90. m/z: 354.07 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.82 (s, 3H), 3.85 (s, 3H), 7.12 (d, 2H, J=9.3Hz), 7.62 (d, 1 H, J=8.8Hz), 7.72 (brs, 2H), 7.75 (d, 1 H, J=8.8Hz), 8.06 (d, 2H, J=9.1 Hz ). 13C NMR (75 MHz, DMSO- d6) δ 55.62, 59.79, 1 14.40, 1 15.71 , 1 18.39, 122.84, 123.21 , 124.50, 130.24, 139.95, 149.56, 150.29, 155.20, 161 .41 , 170.25, 172.84.
Example 18. Synthesis of 2-amino-7-(4-methoxyphenyl)-9/-/-thiochromenor6,5-cflthiazol-9-one (C18). This compound was prepared according to Method M, using 6-amino-2-(4-methoxyphenyl)-4H- thiochromen-4-one as starting material, to afford 68% yield. Anal. Calc. for Ci7H 2N202S2: C, 59.98; H, 3.55; N, 8.23. Found: C, 59.81 ; H, 3.58; N, 8.12. m/z: 340,03 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.83 (s, 3H), 7.09-7.12 (d, 2H, J= 8.69 Hz), 7.36 (s, 1 H), 7.78-7.80 (d, 2H, J= 8.69 Hz), 7.85-7.88 (d, 1 H, J= 8.69 Hz), 8.02-8.05 (d, 1 H, J= 8.69 Hz). 13C NMR (75 MHz, DMSO-de) δ 55.61 , 1 14.99, 1 17.41 , 1 18.45, 121.02, 124.1 1 , 125.31 , 128.26, 128.58, 133.22, 141.01 , 151 .29, 151 .12, 172.09, 179.23.
Example 19. Synthesis of 2-amino-7-(2-fluorophenyl)-8-hydroxy-9/-/-chromenor6,5-cflthiazol-9-one (C19).
2-amino-7-(2-fluorophenyl)-8-hydroxy-9/-/-chromeno[6,5-cf]thiazol-9-one was prepared according to Method M, starting from Intermediate 128, as a yellow powder (70%). Anal. Calc. for C16H9FN2O2S: C, 61.53; H, 2.90; N, 8.97. Found: C, 61.53; H, 2.90; N, 8.97. m/z: 312.04 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.40 (m, 2H), 7.53 (d, 1 H, J=8.9Hz), 7.59 (m, 3H), 7.77 (d, 1 H, J=8.9Hz), 7.80 (dd, 1 H, J=8.5, 2.0Hz). 13C NMR (75 MHz, DMSO-ofe) δ 1 15.38, 1 16.17 (d, J=22.6Hz), 1 16.73, 1 19.06 (d, J=14.3Hz), 123.46, 124.42, 124.56, 131.25, 132.49 (d, J=9.0Hz), 139.18, 143.76, 149.84, 150.63, 159.30 (d, J=251.00Hz), 169.82, 171.54.
Example 20. Synthesis of 2-amino-7-(naphthalen-1-yl)-9/-/-chromenor6,5-cflthiazol-9-one (C20).
This compound was prepared following Method M starting from 6-amino-2-(naphtalen-1-yl)-4H- chromen-4-one. Anal. Calc. for C20H12N2O2S: C, 69.75; H, 3.51 ; N, 8.13. Found: C, 69.56; H, 3.66; N, 8.07. m/z: 344,06 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.75 (s, 1 H), 7.56-7.59 (d, 1 H, J = 8.69 Hz), 7.62-7.70 (m, 5H), 7.78-7.81 (d, 1 H, J = 8.8 Hz), 7.88-7.90 (d, 1 H, J = 6.8 Hz), 8.06-8.12 (m, 2H), 8.16-8.19 (d, 1 H, J = 8.31 Hz).
Example 21. Synthesis of 2-amino-7-(3-(benzyloxy)phenyl)-8-hydroxy-9/-/-chromenor6,5-cflthiazol-9- one (C21 ).
The title compound was produced according to Method M, using 6-amino-2-[3-(benzyloxy)phenyl]-3- hydroxy-4H-chromen-4-one; Anal. Calc. for C23H16N2O3S: C, 68.98; H, 4.03; N, 7.00. Found: C, 68.85; H, 4.13; N, 6.95. m/z: 400,09 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 5.23 (bs, 2H), 7.19 (s, 1 H), 7.23-7.26 (d, 1 H, J = 7.74 Hz), 7.34- 7.44 (m, 3H), 7.49-7.51 (m, 3H), 7.69-7.72 (d, 1 H, J = 8.5 Hz), 7.74 (bs, 2H), 7.75-7.79 (d, 1 H, J = 8.8 Hz), 7.82-7.84 (d, 1 H, J = 8.8 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 69.76, 106.41 , 1 12.75, 1 16.7, 1 18.01 , 1 18.67, 1 19.1 1 , 122.29, 123.17, 128.06, 128.15, 128.67, 130.52, 132.63, 136.95(1 "), 151.57(3a,5a), 159(3'), 162.89, 170.58, 176.44.
Example 22. Synthesis of 2-amino-9H-chromenor6,5-Gflthiazol-9-one (C22).
This compound was prepared according to Method M, using 6-amino-4/-/-chromen-4-one as starting material (78%). Anal. Calc. for Ci0H6N2O2S: C, 55,04; H, 2,77; N, 12,84. Found; C, 54,87; H, 2,85; N, 12,78. 1H NMR (300 MHz, DMSO-ofe) δ 6.44 (1 H, d, J= 6.0 Hz), 7.53 (1 H, d, J= 8.8 Hz), 7.60 (2H, bs), 7.74 (1 H, d, J= 8.8 Hz), 8.35 (1 H, d, J= 6.0 Hz). 13C NMR (75 MHz, DMSO-ofe) 5 1 1 1 .26, 1 15.52, 1 18.80, 123.46, 125.01 , 150.75, 151.43, 157.06, 170.22, 175.63.
Example 23. Synthesis of 2-amino-8-hvdroxy-7-(3-methoxyphenyl)-9H-chromenor6,5-cflthiazol-9-one (C23).
The title compound was prepared according to Method M, starting from Intermediate 126, as a brown powder (63%). Anal. Calc. for
Figure imgf000209_0001
C, 59.99; H, 3.55; N, 8.23. Found: C, 59.74; H, 3.66; N, 8.19. m/z: 340.05 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.82 (s, 3H), 7.05 (dd, 1 H, J=2.0, 7.9Hz), 7.50 (t, 1 H, J=7.9Hz), 7.52 (brs, 1 H), 7.54 (d, 1 H, J=7.9Hz), 7.73 (brs, 2H), 7.75 (d, 1 H, J=8.9Hz), 7.77 (d, 1 H, J=8.9Hz). 13C NMR (75 MHz, DMSO-ofe) δ 55.27, 1 13.35, 1 15.26, 1 15.50, 1 16.17, 120.06, 123.00, 123.46, 129.67, 132.62, 138.96, 145.16, 149.76, 150.13, 159.18, 169.70, 171.73.
Example 24. Synthesis of 2-amino-8-hvdroxy-7-(3-(trifluoromethyl)phenyl)-9/-/-chromenor6,5- cflthiazol-9-one (C24).
Intermediate 131 was prepared as a beige powder (88%), following Method M, and using 6-amino-3- hydroxy-2-[3-(trifluoromethyl)phenyl]-4/-/-chromen-4-one as starting material. Anal. Calc. for C17H9F3N2O3S: C, 53.97; H, 2.40; N, 7.40. Found: C, 53.87; H, 2.44; N, 7.32. m/z: 378,03 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.58 (bs, 2H), 7.67-7.70 (d, 1 H, J=8.89 Hz), 7.77-7.80 (d, 1 H, J=9.07 Hz), 7.81-7.87 (m, 2H), 8.50 (d, 1 H, J=7.17 Hz), 8.57 (bs, 1 H), 10.10 (bs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 1 15.54, 1 16.23, 123.67, 124.03, 124.43, 126.1 1 , 128.04 (q, J=3.8Hz), 129.57 (q, J=31.7Hz), 129.82, 131 .15, 132.48, 139.48, 143.52, 149.85, 150.20, 169.75, 171.85.
Example 25. Synthesis of ethyl 4-(2-amino-9-oxo-9/-/-chromenor6,5-cflthiazol-7-yl)benzoate (C25).
This compound was prepared following Method M, starting from ethyl 4-(6-amino-3-hydroxy-4-oxo- 4/-/-chromen-2-yl)benzoate, to afford a yellow powder in 80% yield. Anal. Calc. for Ci9H 4N204S: C, 62.28; H, 3.85; N, 7.65. Found: C, 62.12; H, 3.84; N, 7.56. m/z: 366,07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1 .33 (t, 3H, J=7.0Hz), 4.30 (q, 2H, J=7.0Hz), 7.17 (s, 1 H), 7.63 (d, 1 H, J=8.9Hz), 7.76 (d, 1 H, J=8.9Hz), 8.03 (d, 2H, J=8.7Hz ), 8.18 (d, 2H, J=8.7 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 14.27, 61.32, 107.33, 1 15.74, 1 18.02, 123.57, 124.96, 126.71 , 129.75, 132.32, 135.46, 150.63, 151.1 1 , 161.30, 165.12, 170.39, 176.32.
Example 26. Synthesis of 2-amino-8-hvdroxy-7-(3-hvdroxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C26).
This compound was prepared following Method M, starting from 6-amino-3-hydroxy-2-(3- hydroxyphenyl)-4/-/-chromen-4-one, to afford a yellow powder in 76% yield; Anal. Calc. for Ci6H10N2O4S: C, 58.89; H, 3.09; N, 8.58. Found: C, 58.65; H, 3.17; N, 8.53. m/z: 326,04 (100,0%). 1H NMR (300 MHz, DMSO-ofe) δ 6.87-6.90 (dd, 1 H, J=3.03,8.12 Hz), 7.35 (t, 1 H, J=8.12Hz), 7.57 (bs, 2H), 7.59-7.62 (d, 1 H, J=8.87 Hz), 7.64-7.67 (d, 1 H, J=8.12 Hz), 7.69 (d, 1 H, J=2.27 Hz), 7.75- 7.78 (d, 1 H, J=8.88 Hz), 9.70 (bs, 1 H), 1 1 .90 (bs, 1 H. Example 27. Synthesis of 2-amino-7-(3,5-dimethoxyphenyl)-9H-chromenor6,5-cflthiazol-9-one (C27).
Following Method M, and using Intermediate 97 as starting material, the title compound was prepared as a ocher yellow powder in 85% yield. Anal. Calc. for Ci8H14N204S: C, 61.01 ; H, 3.98; N, 7.90. Found: C, 60.88; H, 4.02; N, 7.67.m/z: 354,07 (100,0%).
5 1H NMR (300 MHz, DMSO-ofe) δ 3.84 (s, 3H), 6.70 (t, 1 H, J=2.3Hz), 7.16 (s, 1 H), 7.22 (d, 2H, J=2.3Hz), 7.62 (brs, 2H), 7.69 (d, 1 H, J=8.9Hz), 7.77 (d, 1 H, J=8.8Hz). 13C NMR (75 MHz, DMSO- cfe) δ 55.80, 103.77, 104.52, 106.57, 1 15.84, 1 18.05, 123.48, 124.96, 133.39, 150.79, 151 .1 1 , 161.08, 162.39, 170.33, 176.50.
Example 28. Synthesis of 2-amino-7-(4-fluorophenyl)-9/-/-thiochromenor6,5-cflthiazol-9-one (C28).
10 The title compound was prepared according to Method M, using 6-amino-2-(4-fluorophenyl)-4H- thiochromen-4-one as starting material, with a 73% yield. Anal. Calc. for C16H9FN2OS2: C, 58.52; H, 2.76; N, 8.53. Found: C, 58.43; H, 2.82; N, 8.49.
1H NMR (300 MHz, DMSO-ofe) δ 7.33 (1 H, s), 7.42 (2H, t, J= 8.87 Hz), 7.72 (2H, bs), 7.75-7.78 (1 H, d, J= 8.50 Hz), 7.82-7.84 (1 H, d, J= 8.50 Hz), 7.88-7.92 (2H, m). 13C NMR (75 MHz, DMSO-ofe) δ 15 1 16.57 (J=21 ,80 Hz), 1 16.86 (J=21 ,80 Hz), 121 .68, 122.24, 124.20, 124.26, 128.57, 129.21 , 129.48 (J=8,61 Hz), 129.59 (J=8,61 Hz), 132.42 (J=3,44 Hz), 132.46 (J=3,44 Hz), 151.55, 152.87, 162.27 (J=248,95 Hz), 165.58 (J=248,95 Hz), 171.32, 178.79.
Example 29. Synthesis of 2-amino-7-(4-phenoxyphenyl)thiazolor5,4-f7quinazolin-9(8/-/)-one (C29).
This compound was prepared according to Method M, using 6-amino-2-(4- 20 phenoxyphenyl)quinazolin-4(3H)-one as starting material, with a yield of 62%. Anal. Calc. for C2iH14N402S: C, 65.27; H, 3.65; N, 14.50. Found: C, 65.21 ; H, 3.69; N, 14.42.
1H NMR (75MHz, DMSO-of6) δ 7.07 (d, 2H), 7.08 (m, 2H), 7.19 (m, 2H), 7.42(m, 2H), 7.56 (d, 1 H), 7.58 (brs, 2H), 7.75 (d, 1 H), 8.17 (d, 2H), 12.55 (brs, 1 H). 13C NMR (75MHz, DMSO-of6) δ 1 15.07, 1 17.87, 1 19.81 , 124.46, 124.59, 124.93, 126.43, 127.74, 129.82, 130.48, 143.58, 149.35, 151.87, 25 155.73, 159.67, 161.66.
Example 30. Synthesis of 2-amino-8-(4-fluorophenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C30).
2-amino-8-(4-fluorophenyl)-9/-/-chromeno[6,5-cf]thiazol-9-one was prepared according to Method M, starting from Intermediate 31 , in 56% yield; Anal. Calc. for C16H9FN2O2S: C, 61 .53; H, 2.90; N, 8.97. Found: C, 61.53; H, 2.98; N, 8.88. m/z: 312,04 (100,0%).
30 1H NMR (300 MHz, DMSO-ofe) δ 7.27-7.33 (dt, 2H, J= 2.27, 9.07 Hz), 7.61-7.64 (d, 1 H, J= 8.69 Hz), 7.66-7.71 (dd, 2H, J= 5.66, 8.87 Hz), 7.79-7.82 (d, 1 H, J= 8.87 Hz), 8.64 (s, 1 H). 13C NMR (75 MHz, DMSO-d6) 6 1 14.97 (J= 21 Hz), 1 15.26 (J= 21 Hz), 1 15.66, 1 18.32, 122.09, 123.08, 124.79, 128.02 (J= 2,86 Hz), 128.06 (J= 2,86 Hz), 130.92 (J= 8 Hz), 131.03 (J= 8 Hz), 151.20, 151.27, 154.79, 160.31 (J= 245 Hz), 163.55 (J= 245 Hz), 170.20, 174.24.
35 Example 31. Synthesis of 2-amino-8-hvdroxy-7-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C31 ). The tile compound was prepared according to Method M, starting from Intermediate 8, to afford a brown powder in 78% yield. Anal. Calc. for Ci6H10N2O3S: C, 61.93; H, 3.25; N, 9.03. Found: C, 61 .82; H, 3.35; N, 9.01.
1H NMR (300 MHz, DMSO-ofe) δ 7.52 (m, 1 H), 7.57 (m, 2H), 7.63 (brs, 2H), 7.64 (d, 1 H, J=8.9Hz), 5 7.78 (d, 1 H, J=8.9Hz), 8.13 (m, 2H), 8.17 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 1 15.44, 1 16.24, 123.44, 124.41 , 127.67, 128.55, 129.86, 131.41 , 138.83, 145.50, 149.77, 150.17, 169.72, 171.75.
Example 32. Synthesis of 2-amino-8-methoxy-7-(4-phenoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9- one (C32).
The title compound was prepared following Method M, using Intermediate 167 as starting material, 10 affording a yellow powder in 79% yield. Anal. Calc. for C23H16N2O4S: C, 66.33; H, 3.87; N, 6.73.
Found: C, 66.14; H, 3.91 ; N, 6.54. m/z: 416,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.85 (s, 3H), 7.15 (m, 2H), 7.15 (d, 2H, J=8.8Hz), 7.24 (m, 1 H), 7.47 (m, 2H), 7.61 (brs, 2H), 7.61 (d, 1 H, J=8.9Hz), 7.78 (d, 1 H, J=8.9Hz), 8.1 1 (d, 2H, J=8.8Hz ). 13C NMR (75 MHz, DMSO-ofe) δ 59.78, 1 15.42, 1 17.80, 1 18.27, 1 19.75, 123.41 , 124.55, 124.65, 15 125.13, 130.35, 130.47, 140.12, 154.52, 150.13, 150.28, 155.40, 159.17, 170.09, 172.79.
Example 33. Synthesis of 7-(H ,1 '-biphenyll-4-yl)-2-amino-8-methoxy-9/-/-chromenor6,5-cflthiazol-9- one (C33).
This compound was obtained, as a yellow powder, following Method M, starting from Intermediate 171 (yield: 82%); Anal. Calc. for C23H16N2O3S: C, 68.98; H, 4.03; N, 7.00. Found: C, 68.87; H, 4.12; 20 N, 6.98. m/z: 400,09 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.88 (s, 3H), 7.41 (t, 1 H, J=7.3 Hz), 7.50 (dt, 2H, J=7.7 Hz), 7.63- 7.66 (d, 1 H, J=8.7Hz), 7.67 (bs, 2H), 7.75-7.77 (bd, 2H), 7.77-7.80 (d, 1 H, J=8.7Hz), 7.86-7.89 (d, 2H, J=8.5 Hz), 8.15-8.18 (d, 2H, J=8.5 Hz). 13C NMR (75MHz, DMSO-of6) δ 59.84, 1 15.48, 1 18.29, 123.39, 124.59, 126.84, 126.64, 128.21 , 128.85, 129.09, 129.48, 138.97, 140.57, 142.26, 150.04, 25 150.20, 154.54, 170.08, 172.82.
Example 34. Synthesis of 2-amino-7-r4-(4-fluorophenoxy)phenyl-9/-/-chromenor6,5-cfiri ,31thiazol-9- one (C34).
This compound was prepared according to Method M, starting from Intermediate 103, to afford an ochre yellow powder in 69% yield. Anal. Calc. for C22H13FN2O3S: C, 65.34; H, 3.24; N, 6.93. Found: 30 C, 65.29; H, 3.31 ; N, 6.91.
1H NMR (75MHz, DMSO-of6) δ 7.05 (s, 1 H), 7.1 1 (d, 2H, J=8.8Hz), 7.20 (dd, 2H, J=8.8, 4.5Hz), 7.29 (t, 2H, J=8.8Hz), 7.65 (d, 1 H, J=8.7Hz), 7.69 (brs, 2H), 7.77 (d, 1 H, J=8.7Hz), 8.13 (d, 2H, J=8.8Hz). 13C NMR (75MHz, DMSO-of6) δ 105.20, 1 15.59, 1 16.90 (d, J=23.4Hz), 1 17.65, 1 17.78, 121 .82 (d, J=10.6Hz), 123.02, 124.59, 125.70, 128.60, 149.86, 150.95, 151.23 (d, J=2.3Hz), 158.85 (d, 35 J=241 Hz), 160.38, 162.27, 170.18, 176.10.
Example 35. Synthesis of 7-(H , 1 '-biphenyll-4-yl)-2-amino-9/-/-chromenor6,5-cflthiazol-9-one (C35). 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-9H-chromeno[6,5-cf]thiazol-9-one was prepared according to Method M, using 6-amino-2-(biphenyl-4-yl)-4H-chromen-4-one as starting material; brown powder (75%). Anal. Calc. for C22H14N2O2S: C, 71.33; H, 3.81 ; N, 7.56. Found: C, 71.21 ; H, 3.87; N, 7.42. m/z: 370,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.16 (s, 1 H), 7.41 (t, 1 H, J=7.3 Hz), 7.50 (dt, 2H, J=7.7 Hz), 7.61 (brs, 2H), 7.67-7.70 (d, 1 H, J=8.9 Hz), 7.75-7.77 (bd, 2H), 7.77-7.80 (d, 1 H, J=8.9 Hz), 7.85-7.88 (d, 2H, J=8.5 Hz), 8.18-8.21 (d, 2H, J=8.5 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 106.03, 1 15.70, 1 18.09, 123.54, 125.15, 127.05, 127.16, 127.42, 128.50, 129.29, 130.33, 138.99, 143.34, 150.98, 151.14, 162.45, 170.36, 172.21.
Example 36. Synthesis of 2-amino-7-(benzorcfiri ,31dioxol-5-yl)-8-hydroxy-9H-chromenor6,5- cflthiazol-9-one (C36).
This compound was prepared according to Method M, starting from Intermediate 133, as an ocher yellow powder in 78% yield. Anal. Calc. for Ci7H10N2O5S: C, 57.62; H, 2.84; N, 7.91. Found: C, 57.43; H, 2.89; N, 7.65. m/z: 354,03 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.14 (s, 2H), 7.10-7.13 (d, 1 H, J=8.5 Hz), 7.67-7.70 (d, 1 H, J=8.8 Hz), 7.76-7.79 (d, 1 H, J=8.8 Hz), 7.77 (d, 1 H, J=1.9 Hz ), 7.82-7.86 (dd, 1 H, J=1.7, 8.3 Hz), 9.76 (bs, 1 H).
Example 37. Synthesis of 2-amino-8-methoxy-7-(3-(trifluoromethyl)phenyl)-9/-/-chromenor6,5- cflthiazol-9-one (C37).
Following Method M, and using Intermediate 165 as starting material, the title compound was synthesized as an orange powder in 75% yield. Anal. Calc. for C18HH F3N2O3S: C, 55.10; H, 2.83; N, 7.14. Found: C, 55.01 ; H, 2.87; N, 7.03. m/z: 392,04 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.89 (s, 3H), 7.68-7.71 (d, 1 H, J=8.87 Hz), 7.78-7.81 7.65 (d, 1 H, J=8.9 Hz), 7.84-7.86 7.65 (d, 1 H, J=8.31 Hz), 7.93-7.96 (d, 1 H, J=7.93 Hz), 8.33-8.35 (m, 2H). 13C NMR (75MHz, DMSO-cfe) 6 59.93, 1 15.91 , 1 18.28, 123.17, 124.00, 124.10 (q, J=272.00Hz), 124.71 (q, J=3.0Hz), 129.46 (q, J=31.7Hz), 130.02, 131.54, 132.28, 140.85, 150.36, 153.27, 170.17, 172.90.
Example 38. Synthesis of 2-amino-7-(3-fluorophenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C38).
This compound was prepared according to Method M, using Intermediate 88 as starting material, affording a brown powder in 80%yield. Anal. Calc. for C16H9FN2O2S: C, 61 .53; H, 2.90; N, 8.97. Found: C, 61.49; H, 2.97; N, 8.84. m/z: 312.04 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.22 (s, 1 H), 7.46 (td, 1 H, J=8.5, 2.3Hz), 7.64 (td, 1 H, J=8.0, 6.3Hz), 7.68 (d, 1 H, J=8.9Hz), 7.80 (d, 1 H, J=8.9Hz), 7.99 (brd, 1 H, J=8.0Hz), 8.00 (dd, 1 H, J=1 1.1 , 1.8Hz). 13C NMR (75 MHz, DMSO-ofe) δ 106.64, 1 13.26 (d, J=24.1 Hz), 1 15,84, 1 17.83, 1 18.57 (d, J=21.9Hz), 122.49, 123.10, 124.34, 131.23 (d, J=8.3Hz), 133.58 (d, J=8.3Hz), 151.03, 151.03, 161.17, 162.47 (d, J=247.00Hz), 170.23, 176.25. Example 39. Synthesis of 2-amino-7-(3,5-dimethoxyphenyl)-8-hydroxy-9H-chromenor6,5-cflthiazol-9- one (C39).
Intermediate 139 was used as starting material to prepare the title compound, following Method M, affording a beige powder, in 84% yield. Anal. Calc. for Ci8H14N205S: C, 58.37; H, 3.81 ; N, 7.56. Found: C, 58.25; H, 3.87; N, 7.47. m/z: 370.06 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.82 (s, 6H), 6.66 (t, 1 H, J=2.27 Hz), 7.40 (d, 2H, J=2.07 Hz), 7.57 (bs, 2H), 7.66-7.69 (d, 1 H, J=8.87 Hz), 7.76-7.79 (d, 1 H, J=9.07 Hz), 9.75 (bs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 55.42, 101 .56, 105.98, 1 15.57, 1 16.13, 123.48, 124.34, 133.05, 139.07, 144.97,
149.75, 150.09, 160.40, 169.72, 171.74.
Example 40. Synthesis of 2-amino-7-(4-(trifluoromethyl)phenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C41 ).
This compound was prepared according to Method M, using Intermediate 91 as starting material, to afford a brown powder in 75% yield. Anal. Calc. for C17H9F3N2O2S: C, 56.35; H, 2.50; N, 7.73. Found: C, 56.12; H, 2.56; N, 7.65. m/z: 362.03 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.25 (brs, 1 H), 7.64 (brs, 2H), 7.69 (d, 1 H, J=8.9Hz), 7.81 (d, 1 H, J=8.9Hz), 7.94 (d, 2H, J=8.3Hz), 8.33 (d, 2H, J=8.3Hz ). 13C NMR (75 MHz, DMSO-ofe) δ 107.35, 1 15.55, 1 17.87, 123.54, 124.83 (q, J=272.00Hz), 124.92, 125.92 (q, J=3.8Hz), 127.21 , 131.27 (q, J=31.7Hz), 135.22, 150.79, 150.97, 160.83, 170.20, 176.21.
Example 41. Synthesis of 2-amino-8-hydroxy-7-(naphthalen-1-yl)-9/-/-chromenor6,5-cflthiazol-9-one (C42).
The title compound was prepared according to Method M, starting from Intermediate 141 , affording a brown powder in 68% yield. Anal. Calc. for C20H12N2O3S: C, 66.65; H, 3.36; N, 7.77. Found: C, 66.59; H, 3.42; N, 7.76. m/z: 360,06 (100,0%).
1H NMR 300 MHz, DMSO-ofe) δ 7.50-7.53 (d, 1 H, J = 8.69 Hz), 7.53-7.59 (m, 5H), 7.66 (t, 1 H, J = 7.5 Hz), 7.75-7.78 (d, 1 H, J = 8.8 Hz), 7.80-7.82 (d, 1 H, J = 6.4 Hz), 8.03-8.06 (d, 1 H, J = 7.74 Hz), 8.1 1-8.13 (d, 1 H, J = 7.9 Hz), 9.28 (s, 1 H). 13C NMR (75MHz, DMSO-of6) δ 1 15.77, 1 17.18, 123.55,
124.76, 125.47, 125.54, 126.59, 127.25, 128.67, 128.93, 130.44, 130.68, 133.31 , 139.39, 148.19, 149.91 , 151 .07, 170.08, 171.87
Example 42. Synthesis of 7-phenyl-2-thioxo-2/-/-chromenor6,5-cflthiazol-9(3/-/)-one (C43).
A mixture of Intermediate 34 (0.3 g, 1 mmol), ethylxantic acid potassium salt (2.2 eq.), DMF (2 mL) was exposed to MWI full power 300 W, 100°C, 20 min. The resulting solution was poured into iced HCI 1 N, until a yellow precipitate appeared. This precipitate was filtered off and washed with water to afford the title compound (0.15 g, yield: 48%). Anal. Calc. for C16H9NO2S2: C, 61.72; H, 2.91 ; N, 4.50. Found: C, 61 .65; H, 3.01 ; N, 4.51. m/z: 31 1 ,01 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.21 (s, 1 H), 7.59-7.62 (m, 3H), 7.70 (d, 1 H, J= 8. 9 Hz), 7.87 (d, 1 H, J= 8.9 Hz), 8.13 (m, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 106.53, 1 17.23, 1 17.81 , 1 17.89, 125.09, 126.63, 129.26, 130.92, 132.21 , 139.06, 152.83, 163.49, 176.35, 192.01. Example 43. Synthesis of 2-amino-7-(3-phenoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C44).
The title compound was prepared according to Method M, using 6-amino-2-(3- phenoxyphenyl)quinazolin-4(3H)-one as starting material, with a 76% yield. Anal. Calc. for C2iH14N402S: C, 65.27; H, 3.65; N, 14.50. Found: C, 65.25; H, 3.67; N, 14.42.
1H NMR (75MHz, DMSO-of6) δ 7.08 (m, 2H), 7.18 (brd, 1 H, J= 7.9 Hz), 7.19 (m, 1 H), 7.42 (m, 2H), 7.57 (t, 1 H, J= 7.9 Hz), 7.62 (d, 1 H, J= 8.5 Hz), 7.80 (d, 1 H, J= 8.5 Hz), 7.85 (brs, 1 H), 7.96 (brd, 1 H, J= 7.9 Hz), 12.66 (brs, 1 H). 13C NMR (75MHz, DMSO-of6) δ 161.49, 149.38, 125.16, 123.81 , 150.16, 125.59, 1 15.24, 143.59, 170.29, 134.80, 1 17.80, 156.92, 121 .40, 130.41 , 122.76, 156.51 , 1 18.87, 130.22, 123.81.
Example 44. Synthesis of 2-amino-7-(4-isopropoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C45).
2-amino-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one was prepared following Method M, using Intermediate 98 as starting material, affording 6-amino-2-[4-(propan-2-yloxy)phenyl]-4H- chromen-4-one as a brown powder in 85% yield. Anal. Calc. for Ci9H 6N203S: C, 64.76; H, 4.58; N, 7.95. Found: C, 64.58; H, 4.62; N, 7.78. m/z: 352,09 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1 .89 (s, 6H), 4.74 (sept, 1 H, J=6.05Hz), 6.98 (s, 1 H), 7.06 (d, 2H, J=9.1 Hz), 7.57 (brs, 2H), 7.63 (d, 1 H, J=8.7Hz), 7.75 (d, 1 H, J=8.9Hz), 8.03 (d, 2H, J=8.9Hz). 13C NMR (75MHz, DMSO-of6) δ 22.07, 70.14, 104.68, 1 15.97, 1 16.26, 1 18.15, 123.44, 125.05, 128.69, 150.40, 151 .34, 160.90, 163.34, 170.63, 176.56.
Example 45. Synthesis of 2-amino-8-hvdroxy-7-r4-(propan-2-yloxy)phenyll-9/-/-chromenor6,5- GflM ,31thiazol-9-one (C46).
The title compound was prepared according to Method M, using Intermediate 144 as starting material, to afford a brown powder in 85% yield. Anal. Calc. for Ci9H16N204S: C, 61.89; H, 4.34; N, 7.6; O, 17.37; S, 8.69. Found: C, 61.94; H, 4.38; N, 7.60; O, 17.37; S, 8.70.
1H NMR (300 MHz, DMSO-ofe) δ 1.29 (d, 6H, J=6.0Hz), 4.72 (sept, 1 H, J=6.0Hz), 7.08 (d, 2H, J=8.9Hz), 7.62 (brd, 3H), 7.74 (d, 1 H, J=8.9Hz), 8.17 (d, 2H, J=8.9Hz), 9.55 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 21.76, 69.44, 1 15.41 , 1 16.26, 123.01 , 123.30, 124.21 , 129.48, 137.92, 146.08, 149.22, 150.02, 158.75, 169.75, 171.37.
Example 46. Synthesis of 2-amino-7-(3,5-diisopropoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C47).
2-amino-7-(3,5-diisopropoxyphenyl)-9H-chromeno[6,5-cf]thiazol-9-one was prepared following Method M, using 6-amino-2-[3,5-bis(propan-2-yloxy)phenyl]-4H-chromen-4-one as starting material (50%). Anal. Calc. for C22H22N204S: C, 64.37; H, 5.40; N, 6.82. Found: C, 64.21 ; H, 5.43; N, 6.76. m/z: 410,13 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1.30 (d, 12H, J=6.0Hz), 4.79 (sept, 2H, J=6.0Hz), 6.66 (t, 1 H, J=2.1 Hz), 7.16 (s, 1 H), 7.18 (d, 2H, J=2.1 Hz), 7.73 (d, 1 H, J=8.9Hz), 7.78 (d, 1 H, J=8.9Hz). 13C NMR (75 MHz, DMSO-d6) δ 21.96, 69.76, 106.03, 106.03, 106.50, 1 15.99, 1 18.02, 123.26, 124.63, 133.47, 151.19, 151.19, 159.30, 162.58, 170.34, 176.48. Example 47. Synthesis of 2-amino-8-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C48).
The title compound was prepared according to Method M, using 6-amino-3-phenyl-4/-/-chromen-4- one as starting material. Anal. Calc. for Ci6H10N2O2S: C, 65.29; H, 3.42; N, 9.52. Found: C, 65.24; H, 3.56; N, 9.78. m/z: 294,05 (100,0%).
5 1H NMR (300 MHz, DMSO-ofe) δ 7.40-7.48 (m, 3 H), 7.56-7.59 (d, 1 H, J= 8.88 Hz), 7.62-7.68 (4H, m), 7.77-7.80 (d, 1 H, J= 8.88 Hz), 8.59 (d, 1 H, J= 1 .13 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 1 15.34, 1 18.40, 123.02, 123.40, 125.39, 127.92, 128.22, 128.91 , 131 .80, 150.62, 151 .05, 154.61 , 170.14, 174.26.
Example 48. Synthesis of 4-(2-amino-9-oxo-9/-/-chromenor6,5-cflthiazol-7-yl)-/\/-phenylbenzamide 10 (C49).
The title compound was prepared according to Method M, using 4-(6-amino-4-oxo-4/-/-chromen-2- yl)-A/-phenylbenzamide as starting material.
1H NMR (300 MHz, DMSO-ofe) δ 7.1 1 (t, 1 H), 7.25 (s, 1 H), 7.36 (dt, 2H), 7.62 (bs, 2H), 7.68-7.71 (d, 1 H, J= 8.7 Hz), 7.78-7.80 (bd, 3H), 8.12-8.15 (d, 2H, J= 8.5 Hz), 8.26-8.29 (d, 2H, J= 8.5 Hz), 10.41 15 (bs, 1 H).13C NMR (75 MHz, DMSO-ofe) δ 107.05, 1 15.77, 1 18.1 1 , 120.68, 123.68, 125.14, 126.55, 128.54, 128.83, 130.03, 134.12, 137.54, 139.13, 151.05, 151.17, 161.72 164.75, 170.38, 176.44.
Example 49. Synthesis of 2-amino-7-(2-isopropoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C50).
This compound was prepared according to Method M, using Intermediate 100 as starting material, to afford a brown powder (76%). Anal. Calc. for Ci9H16N203S: C, 64.76; H, 4.58; N, 7.95. Found: C, 20 64.59; H, 4.72; N, 7.87. m/z: 352.09 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 1.30 (d, 6H, J=6.0Hz), 4.78 (sept, 1 H, J=6.0Hz), 7.02 (s, 1 H), 7.1 1 (t, 1 H, J=7.8Hz), 7.23 (d, 1 H, J=8.4Hz), 7.50 (t, 1 H, J=7.8Hz), 7.65 (brs, 2H), 7.60 (d, 1 H, J=8.8Hz), 7.76 (d, 1 H, J=8.7Hz), 7.90 (d, 1 H, J=8.3Hz). 13C NMR (75 MHz, DMSO-ofe) δ 22.03, 71 .07, 1 10.77, 1 14.96, 1 15,76, 1 17.83, 120.90, 121 .08, 123.54, 124.90, 129.75, 133.05, 150.31 , 151.54, 156.15, 25 161.47, 170.42, 176.53.
Example 50. Synthesis of 7-(H ,1 '-biphenyll-4-yl)-2-amino-8-hydroxy-9/-/-chromenor6,5-cflthiazol-9- one (C51 ).
The title compound was prepared according to Method M, starting from Intermediate 140, which afforded a yellow powder in 65% yield. Anal. Calc. for C22H14N2O3S: C, 68.38; H, 3.65; N, 7.25. 30 Found: C, 68.23; H, 3.75; N, 7.12. m/z: 386,07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.40 (t, 1 H, J=7.3 Hz), 7.49 (dt, 2H, J=7.7 Hz), 7.74-7.77 (m, 3H), 7.81-7.84 (d, 1 H, J=8.8 Hz), 7.84-7.87 (d, 2H, J=8.5 Hz), 8.30-8.33 (d, 2H, J=8.5 Hz), 9.98 (bs, 1 H). 13C NMR (75MHz, DMSO-d6) δ 1 16.23, 1 16.61 , 121.72, 122.10, 126.66, 126.76, 128.08, 128.25, 129.06, 130.17, 139.13, 141.32, 145.87, 150.37, 170.07, 171.61.
35 Example 51. Synthesis of 2-amino-7-(4-fluorophenyl)-8-methoxy-9/-/-chromenor6,5-cflthiazol-9-one (C52). The title compound was prepared according to Method M, using Intermediate 164 as starting material, which afforded a white powder in 70% yield. Anal. Calc. for C17HH FN2O3S: C, 59.64; H, 3.24; N, 8.18. Found: C, 59.56; H, 3.31 ; N, 8.04. m/z: 342.05 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.85(s, 3H), 7.46 (t, 2H, J=9.0Hz), 7.75 (d, 1 H, J=8.9Hz), 7.85 (d, 5 1 H, J=8.9Hz), 8.16 (dd, 2H, J=9.0, 5.4Hz). 13C NMR (75 MHz, DMSO-ofe) δ 59.84, 1 16.19, 1 16.38 (d, J=21.9Hz), 1 18.23, 122.50, 122.50, 126.95, 131 .00 (d, J=9.8Hz), 140.37, 150.46, 150.46, 154.37, 163.05 (d, J=247,00Hz), 170.25, 172.86.
Example 52. Synthesis of 2-bromo-7-(3-phenoxyphenyl)-9-H-chromenor6,5-GflH ,31thiazol-9-one (C53).
10 This compound was prepared according to Method O, using C1 and CuC as starting materials, to afford an orange powder in 81 % yield. Anal. Calc. for C22Hi2BrN03S: C, 58.68; H, 2.69; N, 3.1 1 . Found: C, 58.58; H, 2.78; N, 3.02. m/z: 450.97 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.93 (s, 1 H), 7.07 (brd, 2H, J=7.5Hz), 7.18 (m, 1 H), 7.20 (m, 1 H), 7.39 (brt, 2H, J=7.6Hz), 7.49 (t, 1 H, J=8.0Hz), 7.58 (d, 1 H, J=2.1 Hz), 7.67 (brd, 2H), 8.26 (d, 1 H, 15 J=9.0Hz). 13C NMR (75 MHz, DMSO-ofe) δ 107.47, 1 16.34, 1 17.01 , 1 18.28, 1 19.31 , 120.96, 121.85, 124.15, 127.70, 130.06, 130.58, 132.84, 133.07, 143.77, 149.86, 154.15, 156.29, 158.27, 163.45, 176.39.
Example 53. Synthesis of 2-amino-7-(2-fluorophenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C54).
This compound was prepared following Method M, using Intermediate 87 as starting material, to 20 afford a brown powder in 80% yield. Anal. Calc. for C16H9FN2O2S: C, 61 .53; H, 2.90; N, 8.97. Found:
C, 61 .47; H, 2.95; N, 8.87. m/z: 312.04 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.85 (s, 1 H), 7.42 (brd, 1 H, J=8.5 Hz), 7.47 (brd, 1 H, J=8.5 Hz), 7.62 (brd, 4H), 7.78 (d, 1 H, J=8.6 Hz), 8.04 (t, 1 H, J=7.5 Hz).13C NMR (75 MHz, DMSO-ofe) δ 1 10.60 (d, J=8.3Hz), 1 15.68, 1 17.05 (d, J=22.6Hz), 1 17.83, 1 19.92 (d, J=14.3Hz), 123.73, 125.08, 125.40, 25 129.82, 133.83 (d, J=6.8Hz), 150.96, 151 .33, 158.82, 159.95 (d, J=248.00Hz), 170.37, 176.15.
Example 54. Synthesis of 2-amino-7-(3-fluorophenyl)-8-hydroxy-9/-/-chromenor6,5-cflthiazol-9-one (C55).
The title compound was prepared according to Method M, using Intermediate 129 as starting material, to afford a yellow powder in 79% yield. Anal. Calc. for C16H9FN2O3S: C, 58.53; H, 2.76; N, 30 8.53Found: C, 58.47; H, 2.89; N, 8.42. m/z: 328.03 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.33-7.40 (dt, 1 H, J=2.26, 8.50 Hz), 7.61 (m, 3H), 7.67-7.70 (d, 1 H, J=8.87 Hz), 7.78-7.81 (d, 1 H, J=8.88 Hz), 8.03-8.07 (dd, 1 H, J=2.45, 10.39 Hz), 8.10-8.12 (d, 1 H, J=8.12 Hz). 13C NMR (300MHz, DMSO-of6) δ 1 14.30 (d, J=24.0Hz), 1 15.87, 1 16.36, 1 16.85 (d, J=21.9Hz), 123.55, 123.84, 124.22, 130.83 (d, J=8.3Hz), 133.76 (d, J=8.3Hz), 139.53, 144.08, 35 149.07, 150.39, 162.5 (d, J=247Hz), 169.96, 172.01.
Example 55. Synthesis of 2-amino-8-hvdroxy-7-(2-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C56). This compound was prepared according to Method M, starting from Intermediate 125, to afford an ocher yellow powder in 65% yield. Anal. Calc. for Ci7H12N204S: C, 59.99; H, 3.55; N, 8.23. Found: C, 59.78; H, 3.61 ; N, 8.12. m/z: 340,05 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.81 (s, 3H), 7.07 (t, 1 H, J=7.3Hz), 7.20 (d, 1 H, J=8.1 Hz), 7.50 (m, 5 3H), 7.60 (brs, 2H), 7.73 (d, 1 H, J=8.7Hz), 9.05 (brs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 55.78, 1 1 1 .99, 1 15.43, 1 16.83, 1 19.96, 120.16, 123.12, 124.40, 131 .79, 131 .08, 138.83, 147.45, 150.22, 150.62, 157.16, 169.78, 171.51.
Example 56. Synthesis of 2-amino-7-(2-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C58).
This compound was prepared according to Method M, using Intermediate 84 as starting material, 10 which afforded a brown powder in 72% yield. Anal. Calc. for Ci7H12N203S: C, 62.95; H, 3.73; N, 8.64. Found: C, 62.76; H, 3.78; N, 8.59. m/z: 324,06 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.93 (s, 3H), 7.00 (s, 1 H), 7.16 (t, 1 H, J=8.3Hz ), 7.26 (d, 1 H, J=8.3Hz), 7.57 (t, 1 H, J=8.3Hz), 7.61 (brs, 2H), 7.62 (d, 1 H, J=8.7Hz), 7.78 (d, 1 H, J=8.7Hz), 7.94 (d, 1 H, J=8.3Hz). 13C NMR (75 MHz, DMSO-ofe) δ 56.00, 1 10.58, 1 12.55, 1 15,46, 1 17.59, 120.03, 15 120.79, 123.32, 124.80, 129.23, 132.89, 150.53, 151.21 , 157.58, 160.70, 170.10, 176.21.
Example 57. Synthesis of 2-amino-8-methoxy-7-(2-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9- one (C59).
The title compound was prepared according to Method M, starting from Intermediate 159, to afford a yellow powder in 60% yield. Anal. Calc. for Ci8H14N204S: C, 61.01 ; H, 3.98; N, 7.90. Found: C, 20 60.89; H, 3.95; N, 7.87. m/z: 354,07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.74 (s, 3H), 3.81 (s, 3H), 7.1 1 (t, 1 H, J=8.3Hz), 7.22 (d, 1 H, J=8.3Hz), 7.52 (d, 1 H, J=8.3Hz), 7.55 (t, 1 H, J=8.3Hz), 7.62 (brs, 2H), 7.53 (d, 1 H, J=8.7Hz), 7.76 (d, 1 H, J=8.7Hz). 13C NMR (75 MHz, DMSO-ofe) δ 55.72, 59.82, 1 17.78, 1 15,40, 1 18.57, 1 19.71 , 120.28, 123.36, 124.74, 130.49, 132.13, 150.22, 150.62, 155.79, 156.93, 160.70, 170.09, 172.55.
25 Example 58. Synthesis of 2-amino-4-methoxy-7-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C60).
This compound was prepared according to Method M, starting from Intermediate 23, affording a brown powder in 60 yield. Anal. Calc. for Ci7H12N203S: C, 62.95; H, 3.73; N, 8.64. Found: C, 62.88; H, 3.78; N, 8.43. m/z: 324,06 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 4.00 (s, 3H), 7.03 (s, 1 H), 7.31 (s, 1 H), 7.56 (brs, 2H), 7.58 (m, 3H), 30 8.1 1 (m, 2H).
Example 59. Synthesis of 2-amino-7-(3,4-dimethoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C61 ).
This compound was prepared following Method M, using Intermediate 92 as starting material, to afford a brown powder in 73% yield. Anal. Calc. for Ci8H14N204S: C, 61.01 ; H, 3.98; N, 7.90. Found: C, 61 .08; H, 3.91 ; N, 7.87. m/z: 354.07 (100.0%).
35 1H NMR (300 MHz, DMSO-ofe) δ 3.90 (s, 3H), 3.85 (s, 3H), 7.08 (s, 1 H), 7.12 (d, 1 H, J=8.9Hz), 7.58 (brs, 2H), 7.61 (d, 1 H, J=2.0Hz), 7.65 (d, 1 H, J=8.9Hz), 7.70 (dd, 1 H, J=2.0, 8.9Hz), 7.76 (d, 1 H, J=8.7Hz). 13C NMR (75 MHz, DMSO-ofe) δ 55.77, 55.91 , 104.80, 109.85, 1 1 1 .75, 1 15.54, 1 17.82, 1 19.97, 123.15, 123.49, 124.92, 149.07, 150.70, 150.91 , 151.96, 162.77, 170.16, 176.19.
Example 60. Synthesis of 2-amino-7-(3-(benzyloxy)phenyl)-8-methoxy-9H-chromenor6,5-cflthiazol-9- one (C62).
The title compound was prepared according to Method M, using 6-amino-2-[3-(benzyloxy)phenyl]-3- methoxy-4/-/-chromen-4-one as starting material, to afford a yellow powder in 78% yield. Anal. Calc. for C24H18N2O4S: C, 66.86; H, 4.24; N, 6.45. Found: C, 66.96; H, 4.21 ; N, 6.51. m/z: 430.10 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.81 (s, 3H), 5.21 (bs, 2H), 7.21-7.25 (dd, 1 H, J=2.64, 7.55 Hz), 7.34-7.43 (m, 4H), 7.48-7.52 (m, 3H), 7.62-7;65 (d, 1 H, J=8.88 Hz), 7.67 (m, 3H), 7.77-7.80 (d, 1 H, J=8.88 Hz).
Example 61. Synthesis of 2-amino-7-(3,5-dimethoxyphenyl)-8-methoxy-9/-/-chromenor6,5-cflthiazol- 9-one (C63).
This compound was prepared using Method M, starting from Intermediate 169, to afford a brown powder in 52 yield. Anal. Calc. for Ci9H16N205S: C, 59.37; H, 4.20; N, 7.29. Found: C, 59.37; H, 4.20; N, 7.29. m/z: 384,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.83 (s, 6H), 3.86 (s, 3H), 6.72 (t, 1 H, J=2.09 Hz), 7.20 (d, 2H, J=2.26 Hz), 7.53-7.56 (d, 1 H, J=8.88 Hz), 7.61 (bs, 2H), 7.79-7.82 (d, 1 H, J=8.88 Hz).
Example 62. Synthesis of 2-amino-7-(3-(trifluoromethyl)phenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C64).
This compound as prepared according to Method M, starting from 6-amino-2-(3- (trifluoromethyl)phenyl)quinazolin-4(3H)-one, for a yield of 71 %. Anal. Calc. for C16H9F3N4OS: C, 53.04; H, 2.50; N, 15.46. Found: C, 52.98; H, 2.647; N, 15.40.
1H NMR (75MHz, DMSO-of6) δ 7.62 (d, 1 H), 7.70 (brs, 2H) 7.73 (t, 1 H), 7.77 (d, 1 H), 7.88 (brd, 1 H), 8.42 (brd, 1 H), 8.48 (brs, 1 H). 13C NMR (75MHz, DMSO-of6) δ 1 15.36, 124.18, 124.29 (brs), 124.30 (q, JC,F = 272.0 Hz), 125.17, 126.1 1 , 127.52 (brs), 129.52 (q, JC,F = 32.0 Hz), 129.88, 131 .61 , 133.92, 143.40, 148.52, 151 .58, 161.46, 170.37.
Example 63. Synthesis of 2-amino-7-(3-isopropoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C65).
The title compound was prepared according to Method M, using 6-amino-2-[3-(propan-2- yloxy)phenyl]-4/-/-chromen-4-one as starting material. Anal. Calc. for Ci9H 6N203S: C, 64.76; H, 4.58; N, 7.95. Found: C, 64.57, H, 4.81 ; N, 7.87. m/z: 352,09 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1 .32-1.34 (6H, d, J= 5.85 Hz), 4.81 (1 H, q), 7.03 (1 H, s), 7.09-7.14 (1 H, t, J= 7.18 Hz), 7.24-7.27 (1 H, d, J= 7.18 Hz), 7.50-7.55 (1 H, dt, J= 1.89, 8.50 Hz), 7.60-7.63 (1 H, d, J= 8.87 Hz), 7.72 (2H, bs), 7.76-7.79 (1 H, d, J= 8.89 Hz), 7.90-7.94 (1 H, dd, J= 1.50, 7.74 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 21.97, 70.95, 1 10.73, 1 14.87, 1 15.73, 1 17.77, 120.79, 120.99, 123.32, 124.68, 129.68, 132.96, 151.47, 156.08, 161.35, 170.34, 176.4.
Example 64. Synthesis of 2-amino-7-methyl-9H-chromenor6,5-Gflthiazol-9-one (C66). This compound was prepared following Method M starting from Intermediate 33, with 59% yield. Anal. Calc. for CiiH8N202S: C, 56.88; H, 3.47; N, 12.06. Found: C, 56.72; H, 3.49; N, 12.01. m/z: 232.03 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 2.43 (s, 3H), 6.34 (s, 1 H), 7.49-7.52 (d, 1 H, J= 8.88 Hz), 7.71-7.74 (d, 1 H, J= 8.88 Hz), 7.75 (bs, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 20.1 , 108.9, 1 15.01 , 1 17.42, 122.95, 124.94, 150.48, 151 .19, 166.8, 170.01 , 175.92.
Example 65. Synthesis of 2-amino-7-(4-(trifluoromethyl)phenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C67).
The title compound was prepared according to Method M, using 6-amino-2-(4- (trifluoromethyl)phenyl)quinazolin-4(3H)-one as starting material, affording 59% yield. Anal. Calc. for C16H9F3N4OS: C, 53.04; H, 2.50; N, 15.46. Found: C, 53.01 ; H, 2.57; N, 15.41 .
1H NMR (75MHz, DMSO-of6) δ 7.61 (d, 1 H), 7.66 (brs, 2H), 7.78 (d, 1 H), 7.86 (d, 2H), 8.32 (d, 2H). 13C NMR (75MHz, DMSO-of6) δ 1 15.40, 124.09 (q, JC,F = 272.0 Hz), 124.38, 125.17, 125.56 (brs), 126.39, 128.55, 130.83 (q, JC,F = 32.0 Hz), 136.83, 143.36, 148.52, 152.34, 161.40, 170.41.
Example 66. Synthesis of 2-amino-7-(furan-2-yl)-9/-/-chromenor6,5-cflthiazol-9-one (C68).
The title compound was prepared according to Method M, using Intermediate 94 as a starting material, as a brown powder (yield 80%); Anal. Calc. for C14H8N2O3S: C, 59.15; H, 2.84; N, 9.85. Found: C, 59.02; H, 2.85; N, 9.78. m/z: 284,03 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.75 (brs, 1 H), 6.82 (dd, 1 H, J=3.7, 1.5Hz), 7.45 (d, 1 H, J=3.7Hz), 7.59 (d, 1 H, J=8.8Hz), 7.64 (brs, 2H), 7.77 (d, 1 H, J=8.8Hz), 8.06 (brs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 106.61 , 1 13.09, 1 14.41 , 1 15,41 , 1 17.98, 122.98, 124.69, 145.40, 147.16, 149.69, 150.51 , 154.76, 170.23, 175.40.
Example 67. Synthesis of 2-chloro-7-phenyl-9H-chromenor6,5-Gflthiazol-9-one (C69).
This compound was prepared following Method O, using compound C2 and CuCI2 as starting materials, affording a brown powder in 54% yield. Anal. Calc. for Ci6H8CIN02S: C, 61 .25; H, 2.57; N, 4.46. Found: C, 61.09; H, 2.59; N, 4.32. m/z: 313.00 (100.0%).
1H NMR (300 MHz, Cd-CI3) δ 6.99 (s, 1 H), 7.54-7.57 (m, 3H), 7.71-7.74 (d, 1 H, J= 8.87 Hz), 7.94- 7.97 (m, 2H), 8.23-8.26 (d, 1 H, J= 9.07 Hz). 13C NMR (75 MHz, Cd-CI3) δ 107.09, 1 17.09, 126.42, 127.78, 129.2, 131 .3, 132.02, 148.49, 154.16, 157.67, 164.23, 176.47.
Example 68. Synthesis of 2-amino-8-hvdroxy-4-methoxy-7-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C71 ).
This compound was prepared starting from Intermediate 24, according to Method M, to afford a yellow powder in 81 % yield; Anal. Calc. for Ci7H12N204S: C, 59.99; H, 3.55; N, 8.23. Found: C, 59.89; H, 3.61 ; N, 8.19.
1H NMR (300MHz, DMSO-of6) δ 4.01 (s, 3H), 7.27 (s, 1 H), 7.53 (m, 5H), 8.22 (brd, 2H, J=7.2Hz), 9.61 (brs, 1 H). 13C NMR (75MHz, DMSO-of6) δ 56.45, 97.08, 1 10.26, 124.36, 127.36, 128.50, 129.57, 131.49, 138.66, 144.59, 152.18, 154.23, 168.89, 170.77. Example 69. Synthesis of 2-amino-8-methoxy-7-(3-phenoxyphenyl)-9H-chromenor6,5-cflthiazol-9- one (C72).
The title compound was prepared according to Method M, using Intermediate 168 as starting material, to afford an orange powder, in 78% yield. Anal. Calc. for C23H 6N204S: C, 66.33; H, 3.87; 5 N, 6.73 Found: C, 66.23; H, 3.88; N, 6.54. m/z: 416,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.78 (s, 3H), 7.10-7.13 (m, 2H), 7.20-7.25 (m, 2H), 7.45 (t, 2H), 7.58-7.61 (d, 1 H, J=8.8Hz), 7.65 (t, 1 H, J=8.3Hz), 7.68 (brs, 2H), 7.70 (t, 1 H, J=2.2Hz), 7.78-7.81 (d, 1 H, J=8.8Hz), 7.83-7.86 (brd, 1 H, J=8.3Hz). 13C NMR (75 MHz, DMSO-of6) δ 59.76, 1 16.20, 1 17.97, 1 18.19, 1 19.10, 120.82, 122.53, 123.05, 123.15, 124.02, 130.22, 130.50, 132.08, 140.66, 150.51 , 10 154.24, 156.06, 156.96, 170.23, 172.89.
Example 70. Synthesis of 2-methyl-7-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C73).
The title compound was prepared following Method N, using A/-(4-oxo-2-phenyl-4/-/-chromen-6- yl)ethanethiamide as starting material, affording a 43% yield; Anal. Calc. for C17HHNO2S: C, 69.61 ; H, 3.78; N, 4.77. Found: C, 69.37; H, 3.82; N, 4.65. m/z: 293,05 (100,0%).
15 1H NMR (300 MHz, DMSO-ofe) δ 2.84 (s, 3H), 7.22 (s, 1 H), 7.59-7.61 (m, 3H), 7.89-7.92 (d, 1 H, J= 9.06 Hz), 8.13-8.16 (m, 2H), 8.31-8.34 (d, 1 H, J= 9.06 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 19.58, 106.81 , 1 17.18, 1 18.06, 126.65, 127.69, 128.69, 129.34, 131 .19, 132.1 1 , 150.91 , 153.66, 163.06, 170.53, 176.07.
Example 71. Synthesis of 2-amino-8-methoxy-7-(4-(trifluoromethyl)phenyl)-9/-/-chromenor6,5- 20 cflthiazol-9-one (C74).
This compound was prepared according to Method M, starting from Intermediate 166, to afford a yellow powder in 82% yield. Anal. Calc. for C18H11 F3N2O3S: C, 55.10; H, 2.83; N, 7.14. Found: C, 55.01 ; H, 2.90; N, 7.01 . m/z: 392,04 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.89 (s, 3H), 7.63 (brs, 2H), 7.63 (d, 1 H, J=8.9Hz), 7.80 (d, 1 H, 25 J=8.9Hz), 7.95 (d, 2H, J=8.3Hz), 8.26 (d, 2H, J=8.3Hz ). 13C NMR (75 MHz, DMSO-ofe) δ 59.72, 1 15.15, 1 18.02, 123.38, 123.59 (q, J=272.00Hz), 124.42, 125.28, 128.83, 130.15 (q, J=32.0Hz), 134.22, 140.80, 152.86, 149.94, 150.09, 169.81 , 172.63.
Example 72. Synthesis of 2-amino-8-hvdroxy-7-(2-isopropoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9- one (C76).
30 The title compound was prepared according to Method M, using Intermediate 143 as starting material, to afford an orange powder in 69% yield. Anal. Calc. for Ci9H16N204S: C, 61 .94; H, 4.38; N, 7.60. Found: C, 61.87; H, 4.42; N, 7.56. m/z: 368.08 (100.0%).
1H NMR (75MHz, DMSO-of6) δ 1.20 (d, 6H, J=6.0Hz), 4.66 (sept, 1 H, J=6.0Hz), 7.04 (t, 1 H, J=8.1 Hz), 7.21 (t, 1 H, J=8.1 Hz), 7.46 (t, 1 H, J=8.1 Hz), 7.50 (brs, 2H), 7.51 (dd, 1 H, J=7.5, 1.7Hz), 35 7.55 (d, 1 H, J=9.0Hz), 7.77 (d, 1 H, J=9.0Hz).
Example 73. Synthesis of 2-amino-7-(2-fluorophenyl)-8-methoxy-9/-/-chromenor6,5-cflthiazol-9-one (C77). This compound was prepared following Method M, using Intermediate 162 as staring material, to afford a yellow powder (79%). Anal. Calc. for C17H11 FN2O3S: C, 59.64; H, 3.24; N, 8.18. Found: C, 59.59; H, 3.36; N, 8.14. m/z: 342,05 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.81 (s,3H), 7.38-7.42 (brd, 1 H, J=8.5 Hz), 7.43-7.47 (brd, 1 H, 5 J=8.5 Hz), 7.53-7.56 (d, 1 H, J=8.6 Hz), 7.63 (bs, 2H), 7.65 (brd, 1 H), 7.74 (t, 1 H, J=7.5 Hz), 7.76- 7.79 (d, 1 H, J=8.6 Hz).13C NMR (75 MHz, DMSO-ofe) δ 60.23, 1 15.61 , 1 16.33 ( d, J=20.1 Hz), 1 18.40, 1 18.80 (d, J=14.3Hz), 123.71 , 124.54, 124.90, 131 .35, 133.20 (d, J=8.6Hz), 141.19, 150.37,
150.78, 152.24, 159.20 (d, J=250.00Hz), 170.34, 172.71 .
Example 74. Synthesis of 2-amino-7-phenylthiazolor5,4-/lquinazolin-9(8/-/)-one (C78).
10 This compound was prepared according to Method M, starting from Intermediate 36, to afford the compound in 66% yield. Anal. Calc. for Ci5H10N4OS: C, 61 .21 ; H, 3.42; N, 19.04. Found: C, 61.12; H, 3.46; N, 19.00.
1H NMR (75MHz, DMSO-of6) δ 7.55 (m, 2H), 7.55 (m, 2H), 7.63 (d, 1 H, J = 8.6 Hz), 7.81 (d, 1 H, J = 8.6 Hz), 7.64 (brs, 2H), 8.17 (m, 1 H). 13C NMR (75MHz, DMSO-of6) δ 1 15.15, 124.35, 124.96, 15 126.32, 127.63, 128.66, 131.08, 132.97, 143.72, 149.80, 151.92, 161.50, 172.09.
Example 75. Synthesis of 1-(8-hvdroxy-9-oxo-7-(3-phenoxyphenyl)-9/-/-chromenor6,5-cflthiazol-2-yl)- 3-phenylurea (C79)
To a solution of compound C3 (1 eq.) in acetone 20 imL and K2C03 (2 eq.), phenylisocyanate (1 .1 eq.) was added, and the mixture was refluxed for 12h. After evaporation of the solvent, the mixture 20 was poured into water and acidified to pH=2 to give a white powder which was filtered off, washed with ether and dried. Yield: 67%; Anal. Calc. for C29H19N3O5S: C, 66.78; H, 3.67; N, 8.06. Found: C, 66.51 ; H, 3.68; N, 7.99. m/z: 521 ,10 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.09, (m, 3H), 7.1 1 (brdd, 1 H, J = 8.3; 2.2 Hz), 7.18 (m, 1 H) 7.36 (m, 2H), 7.43 (m, 2H), 7.54 (m, 2H), 7.60 (t, 1 H, J = 8.3 Ηζ·), 7.81 (d, 1 H, J = 8.8 Hz), 7.97 (t, 1 H, J = 2.2 25 Hz), 8.06 (brd, 1 H, J = 8.3 Hz), 8.1 1 (d, 1 H, J = 8.8 Hz), 9.17 (s, 1 H), 10.08 (brs, 1 H), 10.87 (brs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 1 16.39, 1 16.48, 1 18.07, 1 18.53, 1 18.87, 1 18.97, 120.02,
122.79, 123.08, 123.62, 124.51 , 125.50, 130.15, 130.27, 133.18, 138.31 , 139.48, 144.66, 151.34, 156.54, 156.54, 165.57, 170.33, 171.90.
Example 76. Synthesis of 2-amino-7-benzylthiazolor5,4-/lquinazolin-9(8/-/)-one (C80).
30 This compound was prepared following Method M, using 6-amino-2-benzylquinazolin-4(3H)-one as starting material, to afford 54% yield. Anal. Calc. for Ci6H12N4OS: C, 62.32; H, 3.92; N, 18.17. Found: C, 62.28; H, 3.99; N, 18.1 1.
1H NMR (75MHz, DMSO-of6) δ 3.91 (s, 2H), 7.27 (m, 1 H), 7.29 (m, 2H), 7.31 (m, 2H), 7.44 (d, 1 H), 7.52 (brs, 2H), 7.69 (d, 1 H). 13C NMR (75MHz, DMSO-of6) δ 40.89, 1 15.01 , 124.26, 124.26, 126.31 , 35 128.68, 129.02, 129.64, 137.00, 143.95, 151.66, 153.49, 161.34, 170.07.
Example 77. Synthesis of 2-amino-8-methoxy-7-(3-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9- one (C82). This compound was prepared according to method M using Intermediate 160 as starting material, affording a yellow powder in 86% yield. Anal. Calc. for
Figure imgf000222_0001
C, 61.01 ; H, 3.98; N, 7.90. Found: C, 59.87; H, 3.92; N, 7.76. m/z: 354,07 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.85 (s, 6H), 7.17 (dd, 1 H, J=8.4, 2.5Hz), 7.51 (t, 1 H, J=7.9Hz), 5 7.60 (t, 1 H, J=1.9Hz), 7.65 (m, 4H), 7.78 (d, 1 H, J=8.8Hz). 13C NMR (75 MHz, DMSO-ofe) δ 55.31 , 59.82, 1 13.79, 1 15.55, 1 16.37, 1 18.24, 120.57, 123.40, 124.52, 129.87, 131.74, 140.55, 150.00, 150.20, 154.71 , 159.19, 170.05, 172.88.
Example 78. Synthesis of 2-amino-7-(3,4,5-trimethoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C83).
10 The title compound was prepared according to Method M, starting from Intermediate 95, which afforded a yellow powder (82%). Anal. Calc. for Ci9H16N205S: C, 59.37; H, 4.20; N, 7.29. Found: C, 59.22; H, 4.28; N, 7.14. m/z: 384,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.75 (s, 3H), 3.90 (s, 6H), 7.22 (s, 1 H), 7.40 (s, 2H ), 7.66 (brs, 2H), 7.72 (d, 1 H, J=8.9Hz), 7.78 (d, 1 H, J=8.7Hz). 13C NMR (75 MHz, DMSO-ofe) δ 56.30, 60.21 , 104.08, 15 105.81 , 1 15,71 , 1 17.79, 123.10, 124.69, 126.51 , 140.57, 150.36, 150.92, 153.26, 162.40, 170.13, 176.24.
Example 79. Synthesis of 2-amino-7-(3-fluorophenyl)-8-methoxy-9/-/-chromenor6,5-cflthiazol-9-one (C85).
This compound was prepared according to Method M, using Intermediate 163 as starting material, to 20 afford a yellow powder (87%). Anal. Calc. for C17H11N2FO3S: C, 59.64; H, 3.24; N, 8.18. Found: C, 59.32; H, 3.31 ; N, 8.08. m/z: 342,05 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.87 (s, 3H), 7.43 (td, 1 H, J=8.5, 2.3Hz), 7.61 (td, 1 H, J=8.0, 6.3Hz), 7.62 (brs, 2H), 7.68 (d, 1 H, J=8.9Hz), 7.80 (d, 1 H, J=8.9Hz), 7.86 (dd, 1 H, 1 1 .1 , 1.8Hz), 7.92 (brd, 1 H, J=8.0Hz).13C NMR (75 MHz, DMSO-ofe) δ 60.03, 1 15.41 (d, J=24.1 Hz), 1 15,69, 1 18.41 , 25 1 17.88 (d, J=21.1 Hz), 124.64, 123.78, 124.80, 131.04 (d, J=8.3Hz), 132.85 (d, J=9.0Hz), 140.96, 150.33, 150.50, 153.36, 162.15 (d, J=243.00Hz), 170.24, 173.07.
Example 80. Synthesis of 2-amino-8-methoxy-7-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C87).
The title compound was prepared according to Method M, using Intermediate 9 as starting material, to afford a yellow powder in 85% yield. Anal. Calc. for
Figure imgf000222_0002
C, 62.95; H, 3.73; N, 8.64. 30 Found: C, 62.54; H, 3.71 ; N, 8.56. m/z: 324,06 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.86 (s, 3H), 7.61 (m, 1 H), 7.59 (m, 2H), 7.72 (brs, 2H), 7.65 (d, 1 H, J=9.0 Hz), 7.80 (d, 1 H, J=9.0Hz), 8.08 (m, 2H). 13C NMR (75 MHz, DMSO-ofe) δ 56.99, 1 15.70, 1 18.43, 123.46, 124.60, 128.44, 128.86), 131 .02, 130.70, 140.62, 149.84, 150.42, 155.19, 170.25, 173.04.
35 Example 81. Synthesis of ethyl 2-amino-9-oxo-9/-/-chromenor6,5-cflthiazole-7-carboxylate (C88) 2-amino-9-oxo-9H-chromeno[6,5-of]thiazole-7-carboxylate was prepared from Intermediate 26, following Method M (85%); Anal. Calc. for Ci3H10N2O4S: C, 53.79; H, 3.47; N, 9.65 . Found:. C, 53.52; H, 3.56; N, 9.44. m/z: 290,04 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1.35 (3H, t, J=7.07Hz), 4.41 (2H, q, J=7.07Hz), 7.03 (1 H, s), 7.63 (1 H, d, J=8.84Hz), 7.69 (2H, s), 7.82 (1 H, d, J=8.84Hz). 13C NMR (75 MHz, DMSO-ofe) δ 14.18, 63.09, 1 12.84, 1 16.07, 1 19.20, 124.66, 150.99, 152.35, 160.28, 170.71 , 176.65.
Example 82. Synthesis of 2-amino-9-oxo-9/-/-chromenor6,5-cflthiazole-7-carboxylic acid (C57).
The preparation of the title compound corresponds to the deprotection of C88, which was achieved by refluxing said compound in HCI 1 N for 3h. Anal. Calc. for CiiH6N204S: C, 50.38; H, 2.31 ; N, 10.68. Found: C, 50.02; H, 2.36; N, 10.44. m/z: 262,00 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.97 (1 H, s), 7.61 (1 H, d, J=8.87Hz), 7.68 (2H, s), 7.81 (1 H, d, J=8.87Hz). 13C NMR (75 MHz, DMSO-ofe) δ 1 17.3, 1 18.8, 1 19.2, 122.80, 128.30, 154,5, 157.70, 160.90, 164.50, 166.30, 182.10
Example 83. Synthesis of 2-amino-9-oxo-N-phenyl-9/-/-chromenor6,5-cflthiazole-7-carboxamide (C40).
This compound was prepared in 90% yield from Compound C57 and aniline; Anal. Calc. for C17H11 N3O3S: C, 60.52; H, 3.29; N, 12.46. Found: C, 60.25; H, 3.22; N, 12.1 1 . m/z: 337,05 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.05 (1 H, s), 7.21 (1 H, d, J=8.69Hz), 7.42 (2H, bs), 7.67 (5H, m), 7.81 , (1 H, d, J=8.69Hz), 10.75 (1 H, s). 13C NMR (75 MHz, DMSO-ofe) δ 1 10.16, 1 16.14, 1 18.55, 121.33, 124.31 , 125.15, 129.02, 137.73, 150.62, 151.34, 155.77, 157.90, 170.49, 176.55.
Example 84. Synthesis of 1-(9-oxo-7-phenyl-9/-/-chromenor6,5-cflthiazol-2-yl)-3-phenylurea (C89).
To a solution of compound C2 (1 eq.) in acetone 20 imL and K2C03 (2 eq.), phenylisocyanate (1 .1 eq.) was added, and the mixture was refluxed for 12h. After evaporation of the solvent, the mixture was poured into water and acidified to pH=2 to afford a powder which was filtered off, washed with ether and dried. Anal. Calc. for C23H15N3O3S: C, 66.82; H, 3.66; N, 10.16. Found: C, 66.66; H, 3.81 ; N, 10.02. m/z: 413,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.07 (m, 1 H), 7.23 (s, 1 H), 7.35 (m, 2H), 7.53 (m, 2H), 7.60 (m, 2H), 7.60 (m, 1 H), 7.83 (d, 1 H, J = 8.8 Hz), 8.12 (d, 1 H, J = 8.8 Hz), 8.13 (m, 2H), 9.16 (brs, 1 H), 10.83 (brs, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 106.32, 1 16.48, 1 18.10, 1 18.78, 123.07, 126.41 , 128.98, 129.15, 131.12, 131.86, 138.32, 152.27, 162.73, 166.84, 176.36.
Example 85. Synthesis of 2,7-diphenyl-9H-chromenor6,5-dlthiazol-9-one (C90).
This compound was obtained according to Method N, using A/-(4-oxo-2-phenyl-4H-chromen-6- yl)benzenecarbothioamide as starting material, to afford the compound in 33% yield; Anal. Calc. for C22H13NO2S: C, 74.35; H, 3.69; N, 3.94. Found: C, 74.01 ; H, 3.70; N, 3.77. m/z: 355,07 (100,0%).
1H NMR (300 MHz, CDCI3) δ 95 (1 H, s), 7;39-7.45 (6H, m), 7.64 (1 H, d, J= 8.88 Hz), 7.86-7.89 (2H, m), 8;00-8;03 (2H, m), 8.26-8.29 (1 H, d, J= 8.88 Hz). 13C NMR (75 MHz, CDCI3) δ 107.28, 1 16.84, 1 18.68, 126.36, 127.55, 128.2, 129.12, 130.57, 131.05, 131.53, 131.78, 133.53, 151.9, 154.24, 163.66, 171 .81 , 176.87.
Example 86. Synthesis of 2-amino-7-(3-hvdroxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C91 ).
The title compound was prepared according to Method M, using 6-amino-3-hydroxy-2-phenyl-4H- 5 chromen-4-one as starting material. Anal. Calc. for Ci6H10N2O3S: C, 61 .93; H, 3.25; N, 9.03. Found: C, 61.89; H, 3.33; N, 8.98. m/z: 310,04 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.99 (s, 1 H), 7.37 (t, 1 H, J = 6.4 Hz), 7.45 (s, 1 H), 7.52-7.60 (m, 4H), 7.64-7.66 (d, 1 H, J = 8.8 Hz), 7.76-7.79 (d, 1 H, J = 8.8 Hz), 9.84 (bs, 1 H). 13C NMR (75 MHz, DMSO-cfe) 5 106.1 1 , 1 13.03, 1 15.64, 1 17.39, 1 18.06, 1 19, 123.56, 125.14, 130.47, 132.75, 150.97, 10 151.1 1 , 158.1 1 , 162.92, 170.35, 176.4.
Example 87. Synthesis of 2,5-diamino-7-phenyl-9/-/-chromenor6,5-cflthiazol-9-one (C92).
The title compound was prepared using Method M, from Intermediary 15 in 72% yield; Anal. Calc. for C16H11 N3O2S: C, 62.12; H, 3.58; N, 13.58. Found: C, 62.02; H, 3.61 ; N, 13.44. m/z: 309,06 (100,0%).
15 1H NMR (300 MHz, DMSO-ofe) δ 5.58 (2H, s), 7.06 (1 H, s), 7.16 (1 H, s), 7.37 (2H, s), 7.59 (3H, m), 8.26 (2H, m). 13C NMR (75 MHz, DMSO-ofe) δ 105.86, 107.92, 1 18.18, 120.15, 126.87, 129.24, 131.52, 131.83. 137.04, 140.82, 151.02, 162.22, 170.36, 176.74.
Example 88. Synthesis of 2-amino-7-(4-(phenylthio)phenyl)-9/-/-chromenor6,5-cf/thiazol-9-one (C93).
The title compound was prepared following Method O, starting from C15 and CuBr2, with a yield of 20 43%. Anal. Calc. for Ci6H8BrNOS2: C, 51.34; H, 2.15; N, 3.74. Found: C, 51.1 1 ; H, 2.19; N, 3.55. m/z: 374.92 (100.0%).
1H NMR (300 MHz, DMSO-ofe) δ 7.52 (s, 1 H), 7.59-7.61 (m, 3H), 7.84-7.86 (m, 2H), 8.15-8.19 (d, 1 H, J=8.69 Hz), 8.38-8.41 (d, 1 H, J=8.5 Hz). 13C NMR (75 MHz, DMSO-ofe) δ 1 17.54, 1 19.67, 122.33, 131.18, 127.81 , 127.31 , 129.66, 131.86, 132.03, 137.25, 140.86, 142.22, 154.64, 176.66.
25 Example 89. Synthesis of 2-amino-7-(4-fluorophenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C94).
The title compound was prepared following Method M, using Intermediate 89 as starting material, to afford a beige powder in 62% yield. Anal. Calc. for C16H9FN2O2S: C, 61 .53; H, 2.90; N, 8.97. Found: C, 61.47; H, 2.94; N, 8.87. m/z: 312.04 (100.0%),
1H NMR (300 MHz, DMSO-ofe) δ 7.12 (s, 1 H), 7.44 (t, 2H, J=9.0Hz), 7.60 (brs, 2H), 7.68 (d, 1 H, 30 J=8.9Hz), 7.80 (d, 1 H, J=8.9Hz), 8.21 (dd, 2H, J=9.0, 5.4Hz). 13C NMR (75 MHz, DMSO-ofe) δ 105.85, 1 15,54, 1 16.23 (d, J=22.6Hz), 1 17.76, 123.35, 124.93, 127.82, 129.05 (d, J=9.1 Hz), 150.80, 150.92, 161.68, 163.41 (d, J=247,00Hz), 170.14, 176.19.
Example 90. Synthesis of 2-amino-7-(furan-2-yl)-8-hydroxy-9/-/-chromenor6,5-cflthiazol-9-one (C95).
This compound was prepared according to Method M, using Intermediate 134 as starting material, to 35 afford a brown powder in 65% yield. Anal. Calc. for C14H8N2O4S: C, 56.00; H, 2.69; N, 9.33. Found:
C, 55.89; H, 2.74; N, 9.1 1. m/z: 300.02 (100.0%). 1H NMR (300 MHz, DMSO-ofe) δ 6.80 (dd, 1 H, J=3.6, 1.9Hz), 7.29 (dd, 1 H, J=3.6, 0.8Hz), 7.58 (d, 1 H, J=8.8Hz), 7.60 (brs, 2H), 7.75 (d, 1 H, J=8.9Hz), 8.04 (dd, 1 H, J=1 .7, 0.8 Hz), 10.01 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 1 12.8, 1 15.21 , 1 15,26, 1 16.68, 123.1 1 , 124.50, 136.90, 139.58, 144.15, 145.23, 149.56, 149.65, 169.81 , 170.61.
5 Example 91. synthesis of 2-amino-8-hvdroxy-7-(3,4,5-trimethoxyphenyl)-9H-chromenor6,5-cflthiazol- 9-one (C96).
This compound was prepared according to Method M, starting from Intermediate 135, which afforded a brown powder in 69% yield. Anal. Calc. for Ci9H16N206S: C, 56.99; H, 4.03; N, 7.00. Found: C, 56.94; H, 4.21 ; N, 7.02. m/z: 400.07 (100.0%).
10 1H NMR (300 MHz, DMSO-ofe) δ 3.75 (s, 3H), 3.80 (s, 6H), 7.57 (s, 2H), 7.60 (brs, 2H), 7.68 (d, 1 H, J=9.0Hz), 7.78 (d, 1 H, J=8.8Hz), 9.65 (s, 1 H). 13C NMR (75 MHz, DMSO-ofe) δ 56.26, 60.40, 105.80, 1 15,77, 1 16.32, 123.45, 124.48, 126.83, 138.77, 139.33, 145.46, 149.84, 150.19, 152.92, 169.90, 171 .74.
Example 92. Synthesis of 2-amino-7-(3,4-dimethoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C97).
15 This compound was prepared according to Method M, using Intermediate 170 as starting material, to afford a yellow powder in 51 % yield. Anal. Calc. for Ci9H16N205S: C, 59.37; H, 4.20; N, 7.29. Found: C, 59.21 ; H, 4.25; N, 7.23. m/z: 384,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.85 (s, 9H), 7.15 (d, 1 H, J=8.9Hz), 7.65 (d, 1 H, J=8.9Hz), 7.68 (d, 1 H, J=2.1 Hz), 7.72 (dd, 1 H, J=8.5, 2.1 Hz ), 7.77 (d, 1 H, J=8.9Hz). 13C NMR (75 MHz, DMSO-ofe) δ 20 55.81 , 59.78, 1 1 1.55, 1 1 1 .75, 1 15.73, 1 18.34, 122.14, 122.82, 123.22, 124.55, 140.07, 148.63, 149.77, 150.22, 151 .23, 155.08, 170.22, 172.81.
Example 93. Synthesis of 2-amino-7-(2,4,5-trimethoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C98).
This compound was prepared according to Method M, using 6-amino-2-(2,4,5-trimethoxyphenyl)-4H- 25 chromen-4-one as starting material, to afford a red powder, in 75% yield. Anal. Calc. for Ci9H16N205S: C, 59.37; H, 4.20; N, 7.29. Found: C, 59.23; H, 4.23; N, 7.09. m/z: 384,08 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 3.82 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 6.85 (s, 1 H), 7.02 (s, 1 H), 7.51 (s, 1 H), 7.56 (brs, 2H), 7.65 (d, 1 H, J=8.9Hz), 7.75 (d, 1 H, J=8.9Hz). 13C NMR (75 MHz, DMSO-de) δ 56.13, 56.57, 56.78, 98.54, 109.49, 1 10.74, 1 12.25, 1 15.69, 123.20, 143.02, 150.69, 30 151.16, 152.89, 153.76, 160.65, 170.22, 176.32.
Example 94. Synthesis of 4-(2-amino-9-oxo-9/-/-chromenor6,5-cflthiazol-7-yl)benzoic acid (C99).
Compound C25 (0.36g, 1 mmol) and 0,09g (2.2 mmol) of NaOH were added to a flask containing a mixture of ethanol and water (50:50); the mixture was refluxed, under stirring for 12 h. The resulting solution was acidified by the addition of a solution of HCI 1 N and the precipitate formed was filtered 35 off. Recrystallization of the precipitate in a minimum amount of ethanol afforded the target compound in 60% yield, as a brown powder. Anal. Calc. for Ci7H10N2O4S: C, 60.35; H, 2.98; N, 8.28. Found: C, 60.35; H, 2.98; N, 8.28. m/z: 338.04 (100.0%). 1H NMR (300 MHz, DMSO-ofe) δ 7.21 (s, 1 H), 7.70 (d, 1 H, J=9.1 Hz), 7.80 (d, 1 H, J=9.1 Hz), 8.08 (d, 2H, J=8.1 Hz), 8.22 (d, 2H, J=8.3Hz). 13C NMR (75 MHz, DMSO-ofe) δ 107.31 , 1 16.28, 1 18.09, 121.13, 124.19, 126.82, 130.09, 133.56, 135.20, 148.51 , 151.44, 161 .86, 166.86, 170.59, 176.46.
Example 95. Synthesis of 2-amino-7-(3,4-diisopropoxyphenyl)-9H-chromenor6,5-cflthiazol-9-one (C100).
This compound was prepared according to Method M, using Intermediate 101 as starting material, to ford a brown powder in 68% yield. Anal. Calc. for C22H22N2O4S: C, 64.37; H, 5.40; N, 6.82. Found: C, 64.25; H, 5.47; N, 6.71. m/z: 410,13 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1.30 (d, 6H, J=2.6Hz), 1.32 (d, 6H, J=2.6Hz), 4.69 (sept, 1 H, J=6.04Hz), 4.70 (sept, 1 H, J=6.04Hz), 7.06 (s, 1 H), 7.15 (d, 1 H, J=8.9Hz), 7.62 (brd, 2H), 7.67 (d, 1 H, J=2.5Hz), 7.69 (d, 1 H, J=9.1 Hz), 7.73 (dd, 1 H, J=8.5, 2.3Hz), 7.77 (d, 1 H, J=8.9Hz). 13C NMR (75 MHz, DMSO-ofe) δ 22.01 , 22.17, 70.93, 71.85, 104.94, 1 15.62, 1 15.71 , 1 16.01 , 1 17.97, 120.84, 123.19, 123.85, 124.93, 148.26, 150.56, 151.06, 152.02, 162.83, 170.29, 176.28.
Example 96. Synthesis of 2-amino-7-(3,4-diisopropoxyphenyl)-8-hydroxy-9/-/-chromenor6,5-cflthiazol- 9-one (C101 ).
This compound was prepared according to Method M, starting from Intermediate 142, to afford a brown powder in 79% yield. Anal. Calc. for C22H22N2O5S: C, 61.96; H, 5.20; N, 6.57. Found: C, 61 .87; H, 5.36; N, 6.56. m/z: 426,12 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 1.27 (d, 6H, J=2.6Hz), 1.30 (d, 6H, J=2.6Hz), 4.52 (sept, 1 H, J=6.04Hz), 4.66 (sept, 1 H, J=6.04Hz), 7.15 (d, 1 H, J=9.4Hz), 7.57 (brs, 2H), 7.63 (d, 1 H, J=8.9Hz), 7.75 (d, 1 H, J=8.9Hz), 7.82 (dd, 1 H, J=9.2, 2.2Hz), 7.84 (d, 1 H, J=2.0Hz). 13C NMR (75 MHz, DMSO-de) δ 22.06, 22.22, 70.82, 72.06, 1 15.96, 1 15.62, 1 16.39, 1 17.89, 122.41 , 123.27, 124.17, 124.47, 138.22, 145.96, 147.64, 149.73, 150.16, 150.44, 169.87, 171.55.
Example 97. Synthesis of 2-amino-7-(3,4-dihvdroxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C102).
0.183 g (0.44 mmol) of C100 were dissolved in DCM and the solution was cooled to -30°C; a solution of BCI3 (10 ml) was then added dropwise and the mixture was stirred for 3 hours at said temperature. Then, the reaction mixture was allowed to warm up and acidified with HCI (1 N), until a precipitate was formed. This precipitate was filtered off, dissolved in ethanol, filtered again and the filtrate evaporated to afford the title compound as a beige powder in 53% yield. Anal. Calc. for Ci6H10N2O4S: C, 58.89; H, 3.09; N, 8.58. Found: C, 58.65; H, 3.21 ; N, 8.47. m/z: 326,04 (100,0%).
1H NMR (300 MHz, DMSO-ofe) δ 6.90 (s, 1 H), 6.94 (d, 1 H, J=8.3Hz), 7.48 (dd, 1 H, J=8.3, 2.2Hz), 7.50 (d, 1 H, J=2.3Hz), 7.76 (d, 1 H, J=8.9Hz), 7.89 (d, 1 H, J=8.9Hz).
Example 98. Synthesis of 2-amino-7-(4-(phenylthio)phenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C103).
The title compound was prepared according to Method M, using 6-amino-2-[4- (phenylsulfanyl)phenyl]-4/-/-chromen-4-one as starting material, affording an ocher yellow powder n 73% yield. Anal. Calc. for C22H14N2O2S2: C, 65.65; H, 3.51 ; N, 6.96. Found: C, 65.57; H, 3.65; N, 6.89. m/z: 402.05 (100.0%).
1H NMR (75MHz, DMSO-of6) δ 7.08 (s, 1 H), 7.32 (d, 2H, J=8.5Hz), 7.46 (m, 5H), 7.65 (d, 1 H, J=8.9Hz), 7.77 (d, 1 H, J=8.9Hz), 8.05 (d, 2H, J=8.5Hz).13C NMR (75 MHz, DMSO-ofe) δ 105.84, 5 1 15.86, 1 18.02, 123.19, 124.61 , 127.40, 128.57, 129.05, 129.15, 130.19, 132.03, 133.25, 141.67, 151.15, 162.23, 170.39, 176.30.
Example 99. Synthesis of 2-bromo-7-(3-(trifluoromethyl)phenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C104).
This compound was prepared according to Method O, using Compound C37 and CuBr2 as starting 10 materials, affording a white powder in 80% yield. Anal. Calc. for Ci7H7BrF3N02S: C, 47.91 ; H, 1 .66;
N, 3.29. Found: C, 47.87; H, 1.69; N, 3.32.
1H NMR (75MHz, CDCI3) δ 7.04 (s, 1 H), 7.74 (brt, 1 H, J=8.1 Hz), 7.79 (d, 1 H, J=8.9Hz), 7.84 (brt, 1 H, J=8.1 Hz), 8.17 (brd, 1 H, J=8.0Hz), 8.25 (brs, 1 H), 8.35 (d, 1 H, J=8.9Hz).13C NMR (75MHz, CDCI3) δ 108.06, 1 17.12, 1 18.41 , 123.37 (q, J=3.6Hz), 123.40 (q, J=272Hz), 128.08, 128.56 (q, 15 J=3.6Hz), 129.64, 130.00, 132.04 (q, J=31.7Hz), 132.39, 133.05, 144.05, 150.15, 154.30, 162.53, 176.36.
Example 100. Synthesis of 2-bromo-7-(4-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C105).
The title compound was prepared according to Method O, using Compound C6 and CuBr2 as starting materials (78%). Anal. Calc. for Ci7H10BrNO3S: C, 52.59; H, 2.60; N, 3.61. Found: C, 52.54; 20 H, 2.62; N, 3.62.
1H NMR (75MHz, CDCI3) δ 3.89 (s, 3H), 6.88 (s, 1 H), 7.02 (d, 2H, J=9.0Hz), 7.67 (d, 1 H, J=8.9Hz), 7.89 (d, 2H, J=9.0Hz), 8.25 (d, 1 H, J=9.0Hz).
Example 101. Synthesis of 2-bromo-7-(3-methoxyphenyl)-9/-/-chromenor6,5-cflthiazol-9-one (C106).
This compound was prepared according to Method O, using Compound C8 and CuBr2 as stating 25 materials, to afford a brown powder in 75% yield. Anal. Calc. for Ci7H10BrNO3S: C, 52.59; H, 2.60;
N, 3.61. Found: C, 52.52; H, 2.65; N, 3.60.
1H NMR (75MHz, CDCI3) δ 3.90 (s, 3H), 6.96 (s, 1 H), 7.10 (brd, 1 H, J=8.0Hz), 7.44 (m, 2H), 7.52 (brd, 1 H, J=8.0Hz), 7.70 (d, 1 H, J=9.0Hz), 8.27 (d, 1 H, J=9.0Hz). 13C NMR (75MHz, CDCI3) δ 56.09, 107.38, 1 12.31 , 1 18.24, 1 18.57, 1 18.66, 1 19.43, 128.36, 130.92, 131 .80, 132.74, 143.45, 149.99, 30 154.46, 160.32, 163.83, 176.37.
Example 102. Synthesis of 2-amino-7-(4-fluorophenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C107).
The title compound was prepared according to Method M, using 6-amino-2-(4- fluorophenyl)quinazolin-4(3H)-one as starting material, in 71 % yield. Anal. Calc. for C15H9FN4OS: C, 57.68; H, 2.90; N, 17.94. Found: C, 57.64; H, 2.98; N, 17.87.
35 1H NMR (75MHz, DMSO-of6) δ 7.33 (t, 2H, J= 8.6 Hz), 7.57 (d, 1 H, J= 8.5 Hz), 7.59 (brs, 2H), 7.76 (d, 1 H, J= 8.5 Hz), 8.19 (dd, 2H, J= 8.6, 5.5 Hz). 13C NMR (75MHz, DMSO-of6) δ 1 15.17, 1 15.79 (JC,F = 21 .6), 124.49, 125.03, 126.39, 129.64, 130.35, (JC,F = 8.6), 143.72, 148.98, 152.08, 161 .58, 170.28, 162.36-166.1 1 (JC,F = 252).
Example 103. Synthesis of 2-amino-7-(2,4,5-trimethoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C108).
This compound was prepared according to Method M, starting from 6-amino-2-(2,4,5- trimethoxyphenyl)quinazolin-4(3H)-one, with 62% yield. Anal. Calc. for Ci8H16N404S: C, 56.24; H, 4.20; N, 14.57. Found: C, 56.15; H, 4.21 ; N, 14. 48.
H NMR (75MHz, DMSO-of6) δ 3.78 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 6.78 (s, 1 H), 7.51 (s, 1 H), 7.58 (d, 1 H, J= 8.5 Hz), 7.60 (brs, 2H), 7.78 (d, 1 H, J= 8.5 Hz), 1 1 .80 (s, 1 H). 13C NMR (75MHz, DMSO- d6) 6 160.38, 149.14, 124.67, 124.24, 151 .48, 126.23, 1 14.72, 144, 170.04, 1 12.36, 1 13.39, 142.86, 152.31 , 97.93, 152.63, 56.24, 56.01 , 56.72.
Example 104. Synthesis of 2-amino-7-(3-methoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C109).
The title compound was prepared starting from 6-amino-2-(3-methoxyphenyl)quinazolin-4(3H)-one, according to Method M, with a yield of 76%. Anal. Calc. for Ci6H12N402S: C, 59.25; H, 3.73; N, 17.27. Found: C, 59.21 ; H, 3.76; N, 17.21 .
1 H NMR (75MHz, DMSO-of6) δ 3.87 (s, 3H), 7.13 (brd, 1 H, J=7.5 Hz), 7.45 (t, 1 H, J=7.5 Hz), 7.66 (d, 1 H, J=8.2 Hz), 7.74 (brs, 1 H), 7.78 (brd, 1 H, J=7.5 Hz), 7.82 (d, 1 H, J=8.2 Hz), 7.95 (brs, 2H). 13C NMR (75MHz, DMSO-of6) δ 55.47, 1 12.54, 1 15.20, 1 17.33, 120.06, 123.81 , 125.17, 125.54, 129.81 , 134.18, 143.75, 149.92, 149.92, 159.45, 161 .57, 170.29.
Example 105. Synthesis of 2-amino-7-(2-methoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C110).
The title compound was prepared according to Method M, using 6-amino-2-(2- methoxyphenyl)quinazolin-4(3H)-one as staring material, with a yield of 59%. Anal. Calc. for Ci6H12N402S: C, 59.25; H, 3.73; N, 17.27. Found: C, 59.22; H, 3.78; N, 17.19.
1 H NMR (75MHz, DMSO-of6) δ 3.81 (s, 3H), 7.04 (bt, 1 H, J=7.7 Hz), 7.13 (brd, 1 H, J=8.0 Hz), 7.46 (td, 1 H, J=7.7, 1 .7 Hz), 7.55 (d, 1 H, J=8.7 Hz), 7.65 (brs, 2H), 7.67 (dd, 1 H, J=7.8, 1 .7 Hz), 7.75 (d, 1 H, J=8.7 Hz). 13C NMR (75MHz, DMSO-of6) δ 55.73, 1 1 1 .99, 1 15.17, 120.58, 122.85, 124.09, 124.76, 126.83, 130.57, 132.14, 143.97, 149.91 , 151 .37, 157.26, 160.56, 170.22(1 1 ).
Example 106. Synthesis of 2-amino-7-(4-methoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C111 ).
This compound was prepared starting from 6-amino-2-(4-methoxyphenyl)quinazolin-4(3H)-one, using Method M, which afforded 84% yield. Anal. Calc. for Ci6H12N402S: C, 59.25; H, 3.73; N, 17.27. Found: C, 59.25; H, 3.82; N, 17.22.
1 H NMR (75MHz, DMSO-of6) δ 3.80 (s, 3H), 7.03 (d, 2H), 7.54 (d, 1 H), 7.61 (brs, 2H), 7.74(d, 1 H), 8.12 (d, 2H).13C NMR (75MHz, DMSO-of6) δ 55.64, 44.70, 1 14.18, 1 14.94, 124.35, 24.76, 125.20, 126.25, 129.42, 144.70, 149.74, 151 .29, 161 .79, 161 .79, 170.13.
Example 107. Synthesis of 2-amino-7-(3,5-dimethoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C112). This compound was prepared according to Method M, starting from 6-amino-2-(3,5- dimethoxyphenyl)quinazolin-4(3H)-one, affording a 78% yield. Anal. Calc. for Ci7H 4N403S: C, 57.62; H, 3.98; N, 15.81. Found: C, 57.59; H, 3.99; N, 15.75.
1H NMR (75MHz, DMSO-of6) δ 3.79 (s, 6H), 6.62 (t, 1H), 7.32 (d, 2H), 7.69 (d, 1H, 7.74 (brs, 2H), 5 7.75(d, 1H).13C NMR (75MHz, DMSO-of6) δ 55.76, 103.63, 105.56, 115.37, 124.31, 125.22, 126.17, 134.90, 143.66, 149.65, 151.41, 160.75, 161.69, 170.41.
Example 108. Synthesis of 2-amino-7-(3,4,5-trimethoxyphenyl)thiazolor5,4-/lquinazolin-9(8/-/)-one (C113).
The title compound was prepared according to Method M, using 6-amino-2-(3,4,5- 10 trimethoxyphenyl)quinazolin-4(3H)-one as starting material, with a 64% yield. Anal. Calc. for Ci8H16N404S: C, 56.24; H, 4.20; N, 14.57. Found: C, 56.18; H, 4.22; N, 14.51.
1H NMR (75MHz, DMSO-of6) δ 3.69 (s, 3H), 3.85 (s, 6H), 7.50 (s, 2H), 7.57 (d, 1H), 7.61 (brs, 2H), 7.75 (d, 1H), 12.59 (brs, 1H).13C NMR (75MHz, DMSO-of6) δ 56.31, 60.35, 105.13, 115.11, 124.48, 125.03, 126.41, 128.08, 140.11, 143.75, 149.37, 151.93, 153.08, 161.73, 170.26.
15 Example 109. Synthesis of 2-amino-7-(3,4-dimethoxyphenyl)thiazolor5,4-f7quinazolin-9(8/-/)-one (C114).
This compound was prepared starting from 6-amino-2-(3,4-dimethoxyphenyl)quinazolin-4(3H)-one, following Method M, with a 63% yield. Anal. Calc. for Ci7H14N403S: C, 57.62; H, 3.98; N, 15.81. Found: C, 57.59; H, 4.01; N, 15.78.
20 1H NMR (75MHz, DMSO-of6) δ 3.80 (s, 3H), 3.84 (s, 3H), 7.05 (d, 1 H, J=8.5 Hz), 7.55 (d, 1 H, J=8.6 Hz), 7.60 (brs, 2H), 7.74 (d, 1 H, J=8.6 Hz), 7.79 (m, 2H), 12.42 (brs, 1 H).13C NMR (75MHz, DMSO- d6) 555.75, 55.75, 110.61, 111.45, 114.85, 120.89, 124.36, 124.79, 125.08, 126.32, 143.91, 148.64, 149.43, 151.36, 151.61, 161.61, 170.02.
Example 110. Synthesis of 2-amino-7-cvclohexylthiazolor5,4-/lquinazolin-9(8/-/)-one (C115).
25 The title compound was prepared according to Method M, using 6-amino-2-cyclohexylquinazolin- 4(3H)-one as starting material, which yielded 51% of the desired product. Anal. Calc. for Ci5H16N4OS: C, 59.98; H, 5.37; N, 18.65. Found: C, 59.94; H, 5.41; N, 18.64.
1H NMR (75MHz, DMSO-of6) 51.22 (m, 2H), 1.55 (m, 2H), 1.75(m, 2H), 3.30 (brs, 1 H), 7.42 (d, 1 H), 7.51(brs, 2H), 7.68 (d, 1H), 12.14 (brs, 1H).13C NMR (75MHz, DMSO-of6) 5161.22, 158.22, 124.28, 30 124.03, 151.2, 126.13, 115.07, 143.91, 169.86, 42.83, 30.39, 25.64, 25.45.
Example 111. Synthesis of 2-amino-7-isopropylthiazolor5,4-/lquinazolin-9(8/-/)-one (C116).
This compound was prepared according to Method M, starting from 6-amino-2-isopropylquinazolin- 4(3H)-one Anal. Calc. for Ci2H12N4OS: C, 55.37; H, 4.65; N, 21.52. Found: C, 55.32; H, 4.66; N, 21.49.
35 1H NMR (75MHz, DMSO-of6) 51.27 (d, 6H, J= 6.9 Hz), 2.92 (hept, 1H, J= 6.9 Hz), 7.49 (d, 1H, J = 8.6 Hz), 7.59 (brs, 2H), 7.74 (d, 1H, J = 8.6 Hz), 12.22 (s, 1H). 13C NMR (75MHz, DMSO-of6) 5 161.27, 159.11, 124.25, 123.98, 151.07, 126.05, 115.05, 143.81, 169.89, 33.30, 20.55. Example 1 12. Synthesis of 2-bromo-8-methoxy-7-(4-methoxyphenyl)-9H-chromenor6,5- GflM .31thiazol-9-one (C117).
The title compound was prepared according to Method O, using C17 and CuBr2 as starting materials, to afford an orange powder in 71 % yield. Anal. Calc. for Ci8H12BrN03S: C, 51.69; H, 2.89; N, 3.35. Found: C, 51.64; H, 2.92; N, 3.32.
1H NMR (75MHz, DMSO-of6) δ 3.86 (s, 3H), 3.88 (s, 3H), 7.15 (d, 2H, J=9.1 Hz), 7.95 (d, 1 H, J=8.9Hz), 8.09 (d, 2H, J=9.1 Hz), 8.38 (d, 1 H, J=8.9Hz). 13C NMR (75MHz, DMSO-of6) δ 55.56, 59.76, 1 14.36, 1 17.95, 1 18.03, 122.28, 127.47, 131.25, 140.30, 142.62, 149.06, 152.86, 155.81 , 161.55, 172.30.
Example 1 13. Synthesis of 2-amino-7-r4-(4-fluorophenoxy)phenyll-8-hydroxy-9/-/-chromenor6,5- GflM ,31thiazol-9-one (C118).
This compound was prepared according to Method M, starting from Intermediate 145, to afford a brown powder in 72% yield. Anal. Calc. for C22H13FN2O4S: C, 62.85; H, 3.12; N, 6.66. Found: C, 62.78; H, 3.20; N, 6.68.
1H NMR (75MHz, DMSO-of6) δ 7.14 (d, 2H, J=8.6Hz), 7.17 (dd, 2H, J=8.8, 4.5Hz), 7.27 (t, 2H, J=8.8Hz), 7.62 (d, 1 H, J=8.9Hz), 7.66 (brs, 2H), 7.76 (d, 1 H, J=8.9Hz), 8.23 (d, 2H, J=8.6Hz), 9.70 (brs, 1 H). 13C NMR (75MHz, DMSO-of6) δ 1 15.47, 1 16.23, 1 16.77 (d, J=23.4Hz), 1 17.52, 121.41 (d, J=8.3Hz), 123.10, 124.15, 126.13, 129.75, 138.35, 145.37, 149.09, 150.08, 151 .67 (d, J=2.3Hz), 158.42, 158.63 (d, J=240Hz), 169.75, 171.53.
Example 1 14. Synthesis of 2-amino-7-r4-hvdroxyphenyll-9/-/-chromenor6,5-cflthiazol-9-one (C120).
0.44 mmol of C6 were dissolved in DCM and the solution was cooled to -30°C; a solution of BCI3 (10 ml) was then added dropwise and the mixture was stirred for 3 hours at said temperature. The reaction mixture was then allowed to warm up and acidified with HCI (1 N), until a precipitate was formed. This precipitate was filtered off, dissolved in ethanol, filtered again and the filtrate evaporated to afford an orange powder in 66% yield.
1H NMR (300MHz, DMSO-of6) δ 6.93 (s, 1 H), 6.95 (d, 2H, J=8.7Hz), 7.58 (brd, 2H), 7.63 (d, 1 H, J=8.9Hz), 7.74 (d, 1 H, J=8.0Hz), 7.97 (d, 2H, J=8.7Hz).
Example 1 15. Synthesis of 2-amino-8-ethoxy-7-(4-methoxyphenyl)-9H-chromenor6,5-dlthiazol-9-one (C121 ).
C13 (1 mmol) and potassium carbonate (3 mmol) were stirred at room temperature in acetone (10 ml_). Diethylsulfate (2 mmol) was then added and the solution was heated to 50°C for 12 hours. The resulting solution was filtered to remove the excess of potassium carbonate and the solvent was removed under reduced pressure, the crude residue poured on water and the resulting precipitate was filtered and dried to give 81 % of the title compound as a yellow powder.
1H NMR (300MHz, DMSO-o(6): δ ppm 8.1 1 (d, 2 H, J=8.7 Hz), 7.77 (d, 1 H, J=8.7 Hz), 7.70 (br s, 2 H, NH2), 7.63 (d, J = 8.7 Hz), 7.13 (d, 2 H J=8.7 Hz), 4.09 (q, J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 1.24 (t, 3H). 13C NMR (75 MHz, DMSO-o(6): δ 172.81 (C-9), 170.05 (C-2), 161 .18 (C-4'), 155.28 (C-8), 150.12 (C-5a*), 150.12 (C-3a*), 138.67 (C-7), 130.13 (C-2"), 124.29 (C-9b), 122.98 (C-1 "), 1 18.16 (C-9a), 1 15.53 (C-5), 1 14.12 (C-3"), 1 12.98 (C-4), 67.55 (OCH2), 55.43 (OCH3), 15.31 (CH3).
Example 1 16. Synthesis of 2-methyl-7-phenyl-9H-chromenor6,5-Gfloxazol-9-one (C122).
In a round-bottomed flask, N-(5-bromo-4-oxo-2-phenyl-4H-chromen-6-yl)acetamide (200 mg, 0.55 mmol, 1.0 eq.) and K2CO3 (203 mg, 1.46 mmol, 2.6 eq.) were suspended in 2.5 mL of anhydrous DMSO. The mixture was then heated to 140°C for 4 hours. The dark reaction mixture was cooled to room temperature, quenched with 50 mL of water. The precipitate was filtered, and washed with water to give 145 mg (94%) of title compound as a brownish solid. (Mp.: 205-207°C).
1H NMR (300MHz, CDCI3, 25°C): δ = 2.79 (s, 3 H, CH3), 6.93 (s, 1 H), 7.57 (d, J = 8.9 Hz, 1 H), 7.57 (m, 2 H), 7.57 (m, 1 H), 7.97 (d, J = 8.9 Hz), 7.97 (m, 2 H). 13C NMR (75MHz, CDCI3, 25°C): δ = 14.79 (CH3), 108.23 (C-8), 1 14.83 (C-5), 124.39 (C-4), 126.32 (C-2'), 129.12 (C-3'), 131 .48 (C-1 '), 131 .77 (C-4'), 138.90 (C-3a), 146.79 (C-9b), 154.10 (C-5a), 163.28 (C-7), 165.89 (C-2), 176.48 (C- 9).
Example 1 17. Synthesis of 2-methyl-7-(3-phenoxyphenyl)-9H-chromenor6,5-dloxazol-9-one (C123).
In a round-bottomed flask, N-(5-bromo-4-oxo-2-(3-phenoxyphenyl)-4H-chromen-6-yl)acetamide (1 .20 g, 2.6 mmol, 1.0 eq.) and K2C03 (4.40 g, 31.8 mmol, 1 1.9 eq.) were suspended in 10 mL of anhydrous DMSO. The mixture was then heated to 140°C for 8 hours. The dark reaction mixture was cooled to room temperature, quenched with 50 mL of an aqueous solution of 1 N hydrogen chloride. The precipitate was filtered, and washed with water. The insoluble undesired by-products were removed by filtration after dissolution of the crude material in dichloromethane and cyclohexane. The filtrate was evaporated to dryness to give 0.50 g (50%) of title compound. (Mp: 176-180°C).
1H NMR (300MHz, CDCI3, 25°C): δ = 2.77 (s, 3 H, CH3), 6.87 (s, 1 H), 7.09 (m, 2 H), 7.18 (m, 1 H), 7.18 (m, 1 H), 7.41 (m, 2 H), 7.50 (t, J = 7.7 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.58 (brs, 1 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.97 (d, J = 9.0 Hz, 1 H). 13C NMR (75MHz, CDCI3, 25°C): δ = 14.81 (CH3), 108.52 (C-8), 1 1 1.54 (C-9a), 1 14.66 (C-5), 1 16.22 (C-2'), 1 19.30 (C-2"), 120.88 (C-6'), 121 .73 (C-4'), 124.1 1 (C-4"), 124.50 (C-4), 130.05 (C-3"), 130.51 (C-5'), 133.18 (C-1 '), 138.91 (C-3a), 146.73 (C- 9b), 153.99 (C-5a), 156.36 (C-1 "), 158.22 (C-3'), 162.55 (C-7), 165.93 (C-2), 178.43 (C-9).
Example 1 18. Synthesis of 2-methyl-7-phenyl-9H-thiochromenor6,5-dloxazol-9-one (C124)
In a round-bottomed flask, N-(5-bromo-4-oxo-2-phenyl-4H-thiochromen-6-yl)acetamide (150 mg, 0.40 mmol, 1 .0 eq.) and K2CO3 (166 mg, 1 .20 mmol, 3.3 eq.) were suspended in 3 mL of anhydrous DMSO. The mixture was then heated to 140°C for 5 hours. The dark reaction mixture was cooled to room temperature, quenched with 50 mL of water. The precipitate was filtered, and washed with an excess of water to give 100 mg (85%) of title compound as a brownish solid. (Mp: 153-155°C).
1H NMR (300MHz, CDCI3, 25°C): δ = 2.73 (s, 3 H, CH3), 7.33 (s, 1 H), 7.54 (m, 2 H), 7.54 (m, 1 H), 7.63 (d, J = 8.3 Hz, 1 H), 7.72 (m, 2 H), 7.95 (d, J = 8.3 Hz, 1 H). 13C NMR (75MHz, CDCI3, 25°C): δ = 14.79 (CH3), 1 18.03 (C-9a), 122.70 (C-8), 123.53 (C-4), 124.26 (C-5), 127.04 (C-2'), 129.33 (C-3'), 130.96 (C-4'), 134.99 (C-5a), 136.09 (C-T), 141 .78 (C-3a), 149.60 (C-9b), 152.73 (C-7), 165.67 (C- 2), 179.47 (C-9).
Method P. Preparation of intermediates ll-H, ΙΙ-Η', ll-l and 11 -J
Figure imgf000232_0001
Scheme 13 ll-H-alkene ll-H
5 A mixture of Intermediate ll-H-alkene (2 g,) and 10% Pd/C catalyst in ethanol (20 mL), was hydrogenated (50 psi) at room temperature. The reaction mixture was filtered and the solvent evaporated to give the intermediate ll-H which was used without purification in the next step.
Figure imgf000232_0002
Scheme 14 "-H 11 -I -acetyl
Intermediate ll-H (6.6 mmoles), dimethylformamide dimethylacetal (0.95 g, 7 mmoles), and toluene 10 20 mL were heated to reflux during 5h. Evaporation of toluene and recrystallization from ethanol gives a pure precipitate of homoisoflavone intermediate ll-l-acetyl.
Figure imgf000232_0003
Scheme 15
Intermediate ll-l-acetyl was deprotected to intermediate ll-l following Method E.
Figure imgf000232_0004
Scheme 16 IN ""J
15 Intermediate ll-l (5 mmol) and KSCN (0.73 g, 7.5 mmol) were stirred in AcOH (40 mL) at room temperature for 30 min. A solution of bromine (5 mmol) in 10 mL of AcOH was added dropwise to the mixture under vigorous stirring for 2h. At that time, water was added (20 mL) and the pH was adjusted to 4-5 with ammonia 16%. The resulting colorless precipitate was filtered and dried to give the thiazolohomoisoflavone ll-J.
20 Example 1 19. Synthesis of 2-amino-8-benzyl-9H-chromenor6,5-dlthiazol-9-one (C125)
The title compound was prepared following Method P. In the last step, 6-amino-3-benzyl-4H- chromen-4-one (1.25g, 5 mmol) yielded 1.03 g (67%) of the title compound as a brown powder. 1H NMR (300MHz, DMSO-d6): δ 9.31 (brs, 2 H, NH2), 8.52 (s, 1 H), 7.90 (d, 1 H, J=8.9 Hz), 7.71 (d, 1 H, J=8.9 Hz), 7.31 (m, 2 H), 7.28 (m, 2 H), 7.18 (m, 1 H), 3.77 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6): δ 175.37(C-9), 170.34(C-2), 155.13(C-7), 152.26(C-5a), 140.60(C-3a), 139.90(C-1 '), 128.50 (C-2'), 128.27(C-3'), 126.15(C-4'), 122.73(C-4), 121.1 1 (C-9b), 120.78(C-8), 1 17.73(C-9a), 5 1 17.19(C-5), 30.63(CH2).
Example 120. Synthesis of 2-amino-8-(3-fluorobenzyl)-9H-chromenor6,5-dlthiazol-9-one (C126)
The title compound was prepared following Method P. In the last step, 6-amino-3-(3-fluorobenzyl)- 4H-chromen-4-one (1.35g, 5 mmol) yielded 1 .3 g (80%) of the title compound.
1H NMR (300MHz, DMSO-d6): δ 8.46 (s, 1 H, H-7), 7.76 (d, 1 H, J=8.9 Hz), 7.55 (d, 1 H, J=8.9 Hz), 10 7.75 (brs, 2 H, NH2), 7.32 (td, 1 H, J=7.8; 6.0 Hz), 7.16 (brd, 1 H, J=7.8 Hz), 7.15 (br d, 1 H, J=7.8 Hz), 7.01 (td, 1 H, J=7.8; 6.0 Hz), 3.79 (s, 2H, CH2).13C NMR (75 MHz, DMSO-d6): δ 175.30(C-9), 170.1 1 (C-2), 162.16 (d, 243.2 Hz, C-3'), 154.80(C-7), 151.65(C-5a), 148.25(C-3a), 142.41 (d, 7.7 Hz, C-1 '), 130.1 1 (d, 8.3 Hz, C-5'), 124.61 (d, 2.2 Hz, C-6'), 123.97(C-9b), 122.77(C-4), 121.89(C-8), 1 17.85(C-9a), 1 15.86(C-5), 1 15.23 (d, 21.5 Hz, C-2'), 1 12.94 (d, 20.9 Hz, C-4'), 30.49(CH2).
15 Example 121. Synthesis of 2-amino-8-(3-phenoxybenzyl)-9H-chromenor6,5-dlthiazol-9-one (C127)
The title compound was prepared following Method P. In the last step, 6-amino-3-(3- phenoxybenzyl)-4H-chromen-4-one (1.715g, 5 mmol) yielded 1 .52 g (76%) of title compound as a brown solid.
1H NMR (300MHz, DMSO-d6): δ 8.43 (s, 1 H), 7.76 (d, 1 H, J=8.9 Hz), 7.53 (d, 1 H, J=8.9 Hz), 7.70 20 (brs, 2 H, NH2), 7.36 (m, 2 H), 7.28 (t, 1 H, J=7.9 Hz), 7.1 1 (m, 1 H), 7.08 (brd, 1 H, J=7.9 Hz), 7.02 (brs, 1 H), 6.98 (m, 2 H), 6.79 (dd, 1 H, J=7.9, 1.9 Hz), 3.76 (s, 2H, CH2).13C NMR (75 MHz, DMSO- d6): δ 175.24 (C-9), 170.01 (C-2), 156.56 (C-1 "), 156.48 (C-3'), 154.45 (C-7), 151 .45 (C-5a), 149.73 (C-3a), 141.76 (C-1 '), 129.94 (C-3"), 129.77 (C-5'), 124.57 (C-9b), 123.63 (C-4"), 123.29 (C6'), 123.10 (C-4), 122.10 (C-8), 1 18.91 (C-2'), 1 18.47 (C-2"), 1 17.83 (C-9a), 1 16.16 (C-4'), 1 15.48 (C-5), 25 30.64 (CH2).
Example 122. Synthesis of 2-amino-8-(4-fluorobenzyl)-9H-chromenor6,5-dlthiazol-9-one (C128)
The title compound was prepared following Method P. In the last step, 6-amino-3-(4-fluorobenzyl)- 4H-chromen-4-one (1.35g, 5 mmol) yielded 1 .22 g (75%) of title compound as a pale brown powder.
1H NMR (300MHz, DMSO-d6): δ 8.44 (s, 1 H), 7.96 (brs, 2 H, NH2), 7.77 (d, 1 H, J=8.9 Hz), 7.34 30 (dd, 2 H, J=8.8, 5.8 Hz), 7.09 (t, 2 H, J=8.8 Hz), 3.75 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6): δ 175.28(C-9), 170.10(C-)), 160.77(d, 241 .5 Hz, C-4'), 154.53(C-7), 151.62(C-5a), 135.46 (d, 3.3 Hz, C-1 '), 130.28 (d, 7.7 Hz; C-2'), 122.67(C-4), 122.40(C-8), 1 17.82(C-9a), 1 15.81 (C-5), 1 14.90 (d, 20.9 Hz, C-3'), 29.97(C-10).
Example 123. Synthesis of 2-amino-8-(benzordiri ,31dioxol-5-ylmethyl)-9H-chromenor6,5-dlthiazol-9- 35 one (C129) The title compound was prepared following Method P. In the last step, 6-amino-3- (benzo[d][1 ,3]dioxol-5-ylmethyl)-4H-chromen-4-one (1 .475g, 5 mmol) yielded 1.27 g (72%) of title compound as a pale yellow powder.
1H NMR (300MHz, DMSO-d6): δ 8.47 (s, 1 H), 7.85 (d, 1 H, J=8.9 Hz), 7.70 (d, 1 H, J=8.9 Hz), 6.89 (brs, 1 H), 6.81 (d, 1 H, J=7.9 Hz), 6.77 (br d, 1 H, J=7.9 Hz), 5.94 (s, 2 H, OCH20), 3.67 (s, 2H, CH2).13C NMR (75 MHz, DMSO-d6): δ 175.36(C-9), 170.45(C-2), 155.10(C-7), 152.25(C-5a), 150.03(C-3a), 147.15(C-3'), 145.59(C-4'), 132.81 (C-1 '), 124.93(C-9b), 122.97(C-4), 121.48(C-6'), 120.83(C-8), 1 17.73(C-9a), 1 17.26(C-5), 109.05(C-5'), 108.04(C-2'), 100.71 (C-7'), 30.34(CH2).
Example 124. Synthesis of 1-benzyl-7-(4-methoxyphenyl)chromenor5,6-dlH ,2,3ltriazol-9(1 H)-one (C130)
To a stirred solution of 400 mg of 6-amino-5-(benzylamino)-2-(4-methoxyphenyl)-4H-chromen-4-one (1 .07 mmol, 1.0 eq.) in 6 mL of acetic acid, was added dropwise 5.4 mL of 1 M aqueous solution of NaN02 (5.40 mmol, 5.0 eq.). The stirring was continued for 1 h at 70°C. Upon cooling, the reaction mixture was quenched with a saturated solution of NaHCOs (40 mL) and extracted twice with dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM/AcOEt (9/1 ) to afford 132 mg (32%) of the title compound. Mp: 206°C.
1H NMR (300MHz, CDCI3, 25°C): δ = 3.89 (s, 3 H, OCH3), 6.81 (s, 1 H), 6.81 (s, 2 HH), 7.03 (d, J = 8.9 Hz, 2 H), 7.27 (m, 2 H), 7.27 (m, 1 H), 7.31 (m, 2 H), 7.55 (d, J = 9.1 Hz, 1 H), 7.87 (d, J = 8.9 Hz, 2 H), 8.32 (d, J = 9.1 Hz, 1 H). 13C NMR (75MHz, CDCI3, 25°C): δ = 55.55 (OCH3), 56.16 (C-1 "), 107.71 (C-3), 1 1 1 .55 (C-10), 1 14.60 (C-3'), 1 16.33 (C-8), 122.98 (C-1 '), 125.69 (C-7), 127.57 (C-5"), 127.65 (C-5), 127.65 (C-3"), 127.91 (C-4"), 128.43 (C-2'), 137.53 (C-2"), 144.36 (C-6), 157.65 (C-9), 162.29 (C-2), 162.62 (C-4'), 176.95 (C-4).
Example 125. Synthesis of 7-phenyl-9H-chromenor5,6-dloxazol-9-one (C131)
To a suspension of 5-amino-6-hydroxyflavone (CAS 742073-27-4; 0.67 g, 2.6 mmol, 1 .0 eq.) in 5 mL of triethylorthoformate (30.0 mmol, 1 1.5 eq.) was added 60 mg of 1 ,3-dibromo-5,5-dimethylhydantoin (0.2 mmol, 0.08 eq.). The mixture was refluxed for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate to afford the title compound (328 mg, 47%) as a yellow solid. Mp: 258-260°C.
1H NMR (400MHz, DMSO-d6, 25°C): δ = 7.10 (s, 1 H), 7.59 (m, 1 H), 7.60 (m, 2 H), 7.89 (d, J = 9.0 Hz, 1 H), 8.13 (m, 2 H), 8.26 (d, J = 9.0 Hz, 1 H), 8.96 (s, 1 H). 13C NMR (100MHz, DMSO-d6, 25°C): δ = 108.08 (C-8), 1 15.90 (C-9a), 1 16.59 (C-4), 1 17.07 (C-5), 126.30 (C-2'), 129.13 (C-3'), 130.96 (C- 1 '), 131.77 (C-4'), 136.00 (C-9b), 146.54 (C-3a), 154.12 (C-5a), 156.50 (C-2), 161.71 (C-7), 175.85 (C-9).
Example 126. Synthesis of 7-(3-phenoxyphenyl)-9H-chromenor6,5-dloxazol-9-one (C132)
To a suspension of 372 mg of 6-amino-5-hydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (1.07 mmol, 1.0 eq.) and 320 mL of trimethylorthoformate (2.92 mmol, 2.7 eq.) in 40 mL of toluene, was added a catalytic amount of para-toluene sulfonic acid monohydrate (46 mg, 0.24 mmol, 0.2 eq.). The mixture was refluxed for 4 h and the reaction mixture was concentrated in vacuo. The residue was neutralized with a saturated solution of NaHCOs (30 mL) and extracted twice with dichloromethane. The organic layer was dried over Na2S04, filtered and evaporated under reduced 5 pressure. The residue was recrystallized from dichloromethane and hexane to afford 204 mg (53%) of title compound as a beige solid. Mp: 209°C.
1H NMR (300MHz, CDCI3, 25°C): δ = 6.92 (s, 1 H), 7.10 (m, 2 H), 7.21 (m, 1 H), 7.43 (m, 2 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.60 (br s, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.69 (br d, J = 7.6 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 1 H), 8.36 (s, 1 H). 13C NMR (100MHz, CDCI3, 25°C): δ = 108.78 (C-8), 1 1 1 .93 (C-9a), 10 1 15.49 (C-5), 1 16.23 (C-2'), 1 19.36 (C-2"), 120.89 (C-4'), 121.81 (C-6'), 124.18 (C-4"), 125.59 (C-4), 130.08 (C-3"), 130.56 (C-5'), 133.10 (C-1 '), 137.58 (C-3a), 145.99 (C-9b), 154.14 (C-2), 154.89 (C- 5a), 156.37 (C-1 "), 158.33 (C-3'), 162.75 (C-7), 176.09 (C-9).
Example 127. Synthesis of 7-phenyl-9H-chromenor6,5-dloxazol-9-one (C133)
To a suspension of 6-amino-5-hydroxy-2-phenyl-4H-chromen-4-one (CAS 92497-96-6, 250 mg, 0.98 15 mmol, 1.0 eq.) and 0.80 mL of trimethylorthoformate (7.31 mmol, 7.4 eq.) in 10 mL of toluene, was added a catalytic amount of para-toluene sulfonic acid, monohydrate (50 mg, 0.26 mmol, 0.2 eq.). The mixture was refluxed for 8 h and the reaction mixture was concentrated in vacuo. The residue was neutralized with a solution of NaHCOs (40 mL). The precipitate was filtered, washed with water, and dried under vacuum. The residue was purified by silica gel column chromatography eluting with 20 chloroform to afford 81 mg (31 %) of the title compound as a beige solid. Mp: 270-272°C.
1H NMR (400MHz, CDCI3, 25°C): δ = 6.96 (s, 1 H), 7.56 (m, 1 H), 7.57 (m, 2 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.96 (m, 2 H), 8.12 (d, J = 9.0 Hz, 1 H), 8.34 (s, 1 H). 13C NMR (100MHz, CDCI3, 25°C): δ = 108.40 (C-8), 1 1 1 .91 (C-9a), 1 15.47 (C-5), 125.50 (C-4), 126.33 (C-2'), 129.16 (C-3'), 131.29 (C-1 '), 131 .89 (C-4'), 137.50 (C-3a), 146.02 (C-9b), 154.1 1 (C-2), 154.87 (C-5a), 163.47 (C-7), 176.20 (C- 25 9).
Example 128. Synthesis of 7-phenyl-9H-thiochromenor6,5-dloxazol-9-one (C134)
To a suspension of 55 mg of 6-amino-5-hydroxy-2-phenyl-4H-thiochromen-4-one (0.20 mmol, 1.0 eq.) and 145 μί of trimethylorthoformate (1 .32 mmol, 6.6 eq.) in 5 mL of toluene, was added a catalytic amount of para-toluene sulfonic acid monohydrate (10 mg, 0.05 mmol, 0.2 eq.). The mixture 30 was refluxed for 5 h and the reaction mixture was concentrated in vacuo. The residue was neutralized with a diluted solution of NaHCOs (40 mL). The precipitate was filtered, washed with water, and dried under vacuum. The residue was purified by silica gel column chromatography eluting from dichloromethane (1 to 5% methanol) to afford 15 mg (26%) of the title compound.
1H NMR (300MHz, CDCI3, 25°C): δ = 7.37 (s, 1 H), 7.53 (m, 1 H), 7.55 (m, 2 H), 7.71 (d, J = 8.6 Hz, 35 1 H), 7.74 (m, 2 H), 8.09 (d, J = 8.6 Hz, 1 H), 8.38 (s, 1 H) ppm. 13C NMR (100MHz, CDCI3, 25°C): δ = 1 18.59 (C-9a), 123.35 (C-8), 124.47 (C-5*), 124.57 (C-4*), 127.04 (C-2'), 129.40 (C-3'), 131.07 (C- 4'), 136.02 (C-1 '), 136.50 (C-5a), 140.35 (C-3a), 148.74 (C-9b), 152.79 (C-7), 153.84 (C-2), 179.25 (C-9). Example 129. Synthesis of 2-bromon ,3lthiazolor5,4-alacridin-1 1 (6H)-one (C136)
Copper bromide (1 .34g; 6 mmol), polyethylene glycol 200 (2.5 g), acetonitrile (75 mL) and isoamyl nitrite (1 mL; 7.5 mmol) were introduced in a 250 mL 3-necked flask under nitrogen. A solution of 2- bromo[1 ,3]thiazolo[5,4-a]acridin-1 1 (6H)-one (1 .34 g; 5 mmol) in acetonitrile (25 mL) and 5 polyethylene glycol (2.5 g) was added slowly with stirring at room temperature. The reaction mixture was then heated to 65°C for 3 h. It was then diluted in a 20% hydrochloric acid aqueous solution (500 mL) and the mixture was extracted with dichloromethane (3 x 100 mL). Combined organic layers were dried over sodium sulfate and concentrated to give 1 .07 g (3.2 mmol, 65%) of title compound as a yellow solid.
10 1 H NMR (300MHz, DMSO-of6) δ 7.34 (ddd, 1 H, J=7.9 Hz, 7.1 Hz, 0.8 Hz), 7.64 (dd, 1 H, J=8.4 Hz, 0.8 Hz), 7.68 (d, 1 H, J=8.9 Hz), 7.77 (ddd, 1 H, J=8.4 Hz, 7.1 Hz, 1 .3 Hz), 8.26 (dd, 1 H, J=7.9 Hz, 1 .3 Hz), 8.28 (d, 1 H, J=8.9 Hz), 12.39 (s, 1 H).
Example 130. Synthesis of 2-hydrazinylthiazolor5,4-alacridin-1 1 (6H)-one (C138)
In a 100 mL flask were introduced 2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one (1 .43 g, 5 mmol) and 15 hydrazine hydrate (15 mL). The mixture was stirred at 120-130°C for 2 h. 15 mL ethanol was added at the mixture was cooled down to room temperature. The precipitate was filtered, rinsed with ethanol and dried to give 1 .35 g (96%) of title compound as a yellow solid.
1 H NMR (300MHz, DMSO-of6) δ 4.96 (s, 2H), 7.25 (ddd, 1 H), 7.47 (d, 1 H), 7.57 (dd, 1 H), 7.72 (ddd, 1 H), 7.79 (d, 1 H), 8.25 (dd, 1 H), 8.83 (s, 1 H), 1 1 .92 (s, 1 H).
20 Example 131 . Synthesis of 3-ethyl-M ,2,4ltriazolor3',4':2,3lthiazolor5,4-alacridin-12(7H)-one (C139)
In a 50 mL flask were introduced 2-hydrazinylthiazolo[5,4-a]acridin-1 1 (6H)-one (0.28 g, 1 mmol), triethylorthopropionate (0.35 g, 2 mmol) and DMF (5 mL). The mixture was stirred 3 hours at 135°C and then cooled down to room temperature. The resulting precipitate was filtered, rinsed with ethanol and dried to give 0.28 g (88%) of title compound as a light yellow solid.
25 1 H NMR (300MHz, TFA-d) δ 1 .90 (t, 3H), 3.78 (q, 2H), 7.74 (ddd, 1 H), 7.93 (dd, 1 H), 8.13 (ddd, 1 H), 8.25 (d, 1 H), 8.53 (dd, 1 H), 8.63 (d, 1 H).
Example 132. Synthesis of 6-butyl-2-chlorothiazolor5,4-alacridin-1 1 (6H)-one (C140)
In a 50 mL flask were introduced 2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one (0.98 g, 3.4 mmol) and DMF (10 mL). Sodium hydride (0.24g, 3 eq.) was added under nitrogen and the mixture was stirred 30 40 min at 45-50°C and then cooled down to 0°C. Bromobutane (2.81 g, 6 eq.) was added and the mixture was heated to 95°C for 8 h. The mixture was poured onto ice and the resulting precipitate was filtered and dried. The crude material was purified by flash chromatography on silica gel eluting with 4% methanol in dichloromethane to give an orange solid, which was recrystallized from acetonitrile to yield 0.65 g (56%) of title compound as yellow flakes.
35 1 H NMR (300MHz, CDCI3): δ 1 .07 (m, 3H), 1 .59 (m, 2H), 1 .79 (m, 2H), 4.36 (m, 2H), 7.29 (ddd, 1 H), 7.50 (dd, 1 H), 7.54 (d, 1 H), 7.72 (ddd, 1 H), 8.14 (d, 1 H), 8.48 (dd, 1 H).
Example 133. Synthesis of 2-(dimethylamino)-thiazolor5,4-alacridine-1 1 (6H)-one (C141 ) In a 100 mL flask were introduced 2-chlorothiazolo[5,4-a]acridin-1 1 (6H)-one (0.45g, 1 .5 mmol) and HMPA (20 mL) and the mixture was heated to reflux for 24h. The mixture was then cooled down and poured onto water. The resulting precipitate was filtered and recrystallized from ethanol (50 mL) to give 0.24 g (54%) of title compound as a powder. Mp: 355°C.
1 H NMR (300MHz, DMSO-of6): δ 3.18 (s, 6H), 7.26 (m, 1 H), 7.66 (d, 1 H), 7.71 (m, 2H), 7.9 (d, 1 H), 8.25 (d, 1 H), J=8.1 Hz), 12.37 (s, 1 H).
Example 134. Synthesis of 2-(propylamino)-thiazolor5,4-alacridin-1 1 (6H)-one (C142)
In a 100 mL flask were introduced 2-(propylamino)-thiazolo[5,4-a]acridin-1 1 (6H)-one (Hout, S. et al; Parasitology, 129(5), 525-535; 2004; 1 g, 3 mmol) and concentrated sulfuric acid (10 mL) and the solution was stirred at 120°C for 2h. The resulting black mixture was poured onto ice and neutralized until formation of a yellow precipitate, which was filtered, washed with water and recrystallized to obtain 0.65 g (70%) of title compound (containing 10% of regioisomer 2-(propylamino)thiazolo[4,5- b]acridin-10(5H)-one).
1 H NMR (300MHz, DMSO-of6) δ 0.98 (t, 3H), 1 .69 (q, 2H), 3.48 (t, 2H), 7.32 (dt, 1 H), 7.75 (m, 3H), 7.96 (d, 1 H), 8.23 (d, 1 H), 12.47 (s, 1 H).
Example 135. Synthesis of 2-((3-(dimethylamino)propyl)amino)thiazolor5,4-alacridin-1 1 (6H)-one (C143)
In a 100 mL flask were introduced 2-((2-((3-(dimethylamino)propyl)amino)benzo[d]thiazol-6- yl)amino)benzoic acid (1 g, 2.5 mmol) and concentrated sulfuric acid (10 mL) and the solution was stirred at 120°C for 2h. The resulting black mixture was poured onto ice and neutralized until formation of a yellow precipitate, which was filtered, washed with water and recrystallized to obtain 0.66 g (70%) of title compound (containing 10% of regioisomer 2-[(3- (diethylamino)propyl)amino]thiazolo[4,5-b]acridin-10(5H)-one). Title compound can be further purified by recrystallization.
1 H NMR (300MHz, DMSO-of6): δ 0.99 (t, 6H), 1 .78 (q, 2H), 2.61 (m, 6H), 3.40 (t, 2H), 7.25 (dt, 1 H), 7.49 (d, 1 H), 7.60 (d, 1 H), 7.70 (dt, 1 H), 7.84 (d, 1 H), 8.23 (d, 1 H), 1 1 .74 (s, 1 H), 12.04 (s, 1 H).
Example 136. Synthesis of 2-((2-hvdroxyethyl)amino)thiazolor5,4-alacridin-1 1 (6H)-one (C144)
In a 100 mL flask were introduced 2-((2-((2-hydroxyethyl)amino)benzo[d]thiazol-6-yl)amino)benzoic acid (Hout, S. et al; Parasitology, 129(5), 525-535; 2004; 1 g, 3 mmol) and concentrated sulfuric acid (10 mL) and the solution was stirred at 120°C for 2h. The resulting black mixture was poured onto ice and neutralized until formation of a yellow precipitate, which was filtered, washed with water and recrystallized to obtain 0.82 g (88%) of title compound (containing 20% of regioisomer 2-((2- hydroxyethyl)amino)thiazolo[4,5-b]acridin-10(5H)-one). Title compound can be further purified by recrystallization.
1 H NMR (300MHz, DMSO-of6): δ 3.48 (s, 2H), 3.62 (t, 2H), 7.25 (ddd, 1 H), 7.51 (d, 1 H), 7.59 (dd, 1 H), 7.70 (ddd, 1 H), 7.82 (d, 1 H), 8.23 (d, 1 H), 1 1 .97 (s, 1 H).
Example 137. Synthesis of 2-(piperidin-1 -yl)thiazolor5,4-alacridin-1 1 (6H)-one (C145) In a 100 ml. flask were introduced 2-((2-(piperidin-1 -yl)benzo[d]thiazol-6-yl)amino)benzoic acid (Hout, S. et al; Parasitology, 129(5), 525-535; 2004; 1 g, 2.8 mmol) and concentrated sulfuric acid (10 imL) and the solution was stirred at 120°C for 2h. The resulting black mixture was poured onto ice and neutralized until formation of a yellow precipitate, which was filtered, washed with water and recrystallized to obtain 0.71 g (76%) of title compound (containing 30% of regioisomer 2-(piperidin-1 - yl)thiazolo[4,5-b]acridin-10(5H)-one). Title compound can be further purified by recrystallization.
1 H NMR (300MHz, DMSO-of6): δ 1 .62 (m, 6H), 3.59 (m, 4H), 7.26 (ddd, 1 H), 7.52 (d, 1 H), 7.58 (dd, 1 H), 7.71 (ddd, 1 H), 7.89 (d, 1 H), 8.25 (d, 1 H), 1 1 .99 (s, 1 H).
Example 138. Synthesis of 2-chloro-7-nitrothiazolor5,4-alacridin-1 1 (6H)-one (C146)
2-((2-Chlorobenzo[d]thiazol-6-yl)amino)-3-nitrobenzoic acid (1 g, 3 mmol) was introduced in a 250 ml. flask with polyphosphoric acid (40 g) and the solution was heated to 100°C for 3h. The mixture was poured onto ice (100 g) and neutralized with 10% ammonia. The orange precipitate was filtered, rinsed with water and dried to give 0.81 g (83%) of title compound.
1 H NMR (300MHz, CDCI3) δ 7.61 (t, 1 H, J=8.0 Hz), 7.81 (d, 1 H, J=8.9 Hz), 8.53 (d, 1 H, J=8.9 Hz), 8.92 (dt, 2H).
Example 139. Synthesis of 7-amino-2-chlorothiazolor5,4-alacridin-1 1 (6H)-one (C147)
2-Chloro-7-nitrothiazolo[5,4-a]acridin-1 1 (6H)-one (1 g, 3 mmol) was introduced in a 250 imL flask with palladium on carbon (0.1 g), ethanol (85 imL) and buffer solution (pH7, 15 imL). The system was stirred under hydrogen for 3h. The greenish solution was filtered and concentrated to give 0.8 g (88%) of title compound.
1 H NMR (300MHz, DMSO-of6) δ 5.72 (s, 2H), 7.09 (dt, 1 H), 7.14 (t, 1 H, J=7.6 Hz), 7.61 (dd, 1 H, J=5.5 Hz), 7.87 (d, 1 H, J=8.9 Hz), 8.26 (d, 1 H, J=8.9 Hz), 1 1 .40 (s, 1 H).
Example 140. Synthesis of 2-chloro-3H-imidazor4,5-alacridin-1 1 (6H)-one (C148)
In a 50 imL flask were introduced N-(2-chlorobenzimidazol-5-yl)anthranilic acid {Journal of Heterocyclic Chemistry, 1997, 34(6), 1781 -1787; 0.87 g, 3 mmol) and concentrated sulfuric acid (9 g). The mixture was stirred 3h at 100°C and then poured onto ice. The mixture was neutralized with 50% ammonia and the resulting precipitate was filtered, washed with hot ethanol and dried to yield 0.61 g (75%) of title compound as a green solid.
1 H NMR (300MHz, DMSO-of6) δ 7.33 (ddd, 1 H), 7.43 (d, 1 H), 7.63 (dd, 1 H), 7.77 (ddd, 1 H), 7.98 (d, 1 H), 8.32 (dd, 1 H), 12.07 (s, 1 H).
Example 141 . Synthesis of 2-chloro-3-methyl-3H-imidazor4,5-alacridin-1 1 (6H)-one (C149)
In a 50 imL flask were introduced N-(2-chloro-1 -methylbenzimidazol-5-yl)anthranilic acid [J. Heterocycl. Chem, 2002, 39, 1083] (1 .81 g, 6 mmol) and concentrated sulfuric acid. The mixture was heated to 100°C for 2h. The reaction mixture was poured onto ice and neutralized with 2N sodium hydroxide. The resulting precipitate was filtered, rinsed with water and dried. Recrystallization from 95% ethanol yielded 1 .37 g (81 %) of title compound as a green solid. Mp: 304°C. 1 H NMR (300MHz, DMSO-of6) δ 3.87 (s, 3H), 7.25 (ddd, 1 H), 7.48 (d, 1 H), 4.56 (dd, 1 H), 7.70 (ddd, 1 H), 8.00 (d, 1 H), 8.25 (dd, 1 H), 1 1 .84 (s, 1 H).
Example 142. Synthesis of 2-chloro-1 -methyl-1 H-imidazor4,5-alacridin-1 1 (6H)-one (C150)
In a 50 mL flask were introduced N-(2-chloro-1 -methylbenzimidazol-6-yl)anthranilic acid {Journal of Heterocyclic Chemistry, 1997, 34(6), 1781 -1787; 1 .81 g, 6 mmol) and concentrated sulfuric acid. The mixture was heated to 100°C for 2h. The reaction mixture was poured onto ice and neutralized with 2N sodium hydroxide. The resulting precipitate was filtered, rinsed with water and dried. Recrystallization from 95% ethanol yielded 1 .24 g (73%) of title compound as a light green solid.
1 H NMR (300MHz, DMSO-of6) δ 4.32 (s, 3H), 7.27 (ddd, 1 H), 7.40 (d, 1 H), 7.55 (dd, 1 H), 7.72 (ddd, 1 H), 7.92 (d, 1 H), 8.24 (dd, 1 H), 1 1 .95 (s, 1 H).
Example 143. Synthesis of 2-ethoxythiazolor5,4-alacridin-1 1 (6H)-one (C151 )
2-Chlorothiazolo[5,4-a]acridin-1 1 (6H)-one (1 g, 3 mmol) was placed in a 100 mL flask with 10 mL ethanol and a solution of sodium ethanolate (prepared by stirring at room temperature 0.57 g of sodium in 30 mL ethanol until total consumption of sodium) was added dropwise. The mixture was heated to 120°C for 2h. The ethanol was evaporated and the product was purified by flash chromatography on silica gel to yield title compound.
1 H NMR (300MHz, DMSO-of6) δ 2.41 (t, 3H), 4.56 (q, 2H), 7.28 (t, 1 H), 7.57 (d, 1 H), 7.60 (d, 1 H), 7.73 (t, 1 H), 8.01 (d, 1 H), 8.25 (d, 1 H), 12.1 , s, 1 H).
Example 144. Synthesis of 2-methoxythiazolor5,4-alacridin-1 1 (6H)-one (C152)
2-Chlorothiazolo[5,4-a]acridin-1 1 (6H)-one (1 g, 3 mmol) was placed in a 100 mL flask with 10 mL methanol and a solution of sodium methanolate (prepared by stirring at room temperature 0.57 g of sodium in 30 mL methanol until total consumption of sodium) was added dropwise. The mixture was heated to 120°C for 2h. The methanol was evaporated and the product was purified by flash chromatography on silica gel to yield title compound.
1 H NMR (300MHz, DMSO-of6): δ 4.10 (s, 3H), 6.94 (t, 1 H), 7.37 (td, 1 H), 7.51 (d, 1 H), 7.55 (d, 1 H), 7.71 (d, 1 H), 8.19 (d, 1 H), 8.19 (d, 1 H), 8.49 (s, 1 H).
Example 145. Synthesis of 2-butoxythiazolor5,4-alacridin-1 1 (6H)-one (C153)
2-Chlorothiazolo[5,4-a]acridin-1 1 (6H)-one (1 g, 3 mmol) was placed in a 100 mL flask with 10 mL butanol and a solution of sodium butanolate (prepared by stirring at room temperature 0.57 g of sodium in 30 mL butanol until total consumption of sodium) was added dropwise. The mixture was heated to 120°C for 2h. The butanol was evaporated and the product was purified by flash chromatography on silica gel to yield title compound.
1 H NMR (300MHz, DMSO-of6): δ 0.94 (t, 3H), 1 .46 (q, 2H), 1 .79 (m, 2H), 4.53 (t, 2H), 7.31 (t, 1 H), 7.62 (d, 1 H), 7.63 (d, 1 H), 7.76 (td, 1 H), 8.07 (d, 1 H), 8.27 (d, 1 H), 12.15 (s, 1 H).
PART B.
Example 146. Construction of a TAU gene over-expressing cell line. A TAU expression plasmid was constructed by sub-cloning the cDNA encoding for human TAU- P301 L protein, wherein proline at position 301 was substituted by a leucine residue, into mammalian expression vector pcDNA3.1 (Invitrogen #V790-20) resulting in the plasmid pcDNA3.1-TAUP301 L. Plasmid pcDNA3.1-TAU P301 L was transfected into human neuroblastoma cells (BE-M17; ATCC No. CRL-2267™) using lipofectamine reagent and subsequently, independent clonal cell lines with the plasmids stably integrated into the genome were selected by antibiotic resistance selection (Geneticin (G418)), resulting in cell line M17_3TAUP301 L. Expression of the TAUP301 L gene in the M17_3TAUP301 L cells was confirmed by Western blot analysis.
EXAMPLE 147. Use of TAU expressing cells as a model of neuronal degeneration
M17_3TAU(P301 L) cells were treated chronically with retinoic acid (RA) in low serum conditions to induce Alzheimer's disease-like intracellular signaling deregulation leading to increased TAU levels and cell death. Cytotoxicity of cells was measured by quantification of lactate dehydrogenase (LDH) levels. In dead cells LDH leaked out of the cells into the medium due to a loss of plasma-membrane integrity.
Experimental procedure: 3 days preceding the experiment, a pre-culture of M17_3TAU(P301 L) cells was prepared, starting from a stock culture, at a density of 50.000-100.000 cells/cm2 in culture medium (Opti-MEM® Reduced Serum with phenol red (Invitrogen, Cat. 31985-047)) supplemented with 10% fetal calf serum (FCS), 1 mM sodium pyruvate, 1 x non-essential amino acids (NEAA), 500 μg/ml G418 and 0,5 x (ABAM). At the day of the experiment these precultures were diluted to ~0,1x106 cells/ml in detection medium (Opti-MEM® Reduced Serum without phenol red (Gibco, Cat.1 1058-021 ) supplemented with 1 % fetal calf serum (FCS), 1 mM sodium pyruvate, 1 x nonessential amino acids (NEAA), 500 μg/ml G418 and 0,5 x ABAM) and 60 μί of this suspension was dispensed per well into a 96-well microtiter plate. After 3 hours of incubation at 37°C/5% CO2 an equal volume of detection medium (without FCS) containing 3.75 μΜ RA was added and subsequently incubated for 7 days at 37°C/5% CO2. Then LDH activity was determined using the Promega Cytotox 96 Non-Radioactive cytotoxicity assay (Cat. G1780) according to the manufacturer's instructions. Cytotoxicity was defined as the ratio of LDH relative the total LDH in the cells and supernatant.
EXAMPLE 148. Use of the neuroblastoma tauopathy model to screen compounds
The assay described above using the M17_3TAU(P301 L) cell line allowed to screen compounds for their ability to decrease cytotoxicity in RA-challenged cells. Compounds of the invention were tested for their ability to decrease toxicity at different concentrations, ranging from low non-effective concentrations to high potent concentrations. Afterwards, the dose-dependent inhibition curve was used to calculate their EC5o. A compound was considered to be active in this test when it inhibited toxicity by more than 20% relative to untreated M17_3TAU(P301 L) cells at a concentration of 10 μΜ or lower.
The EC50 values of toxicity inhibition of the compounds of the invention using the M17_3TAU(P301 L) cells are shown in Table 3 as "TAU EC50". Table 3
Figure imgf000241_0001
EXAMPLE 149. Full length Htt gene over-expressing cell line
PC12 cell lines overexpressing the full length Huntingtin (Htt) gene with a 23 CAG repeat (HttFIQ23) and a 145 CAG repeat (HttFIQI 45) were provided by the HD Community BioRepository through the Coriell Institute for Medical research (PC12, HTT-SW2-Q23, MIX, 1-3144, HUMAN, Clone 28 (Cat N° CH00284) and PC12, HTT-SW2-Q145, RDM, 1-3144, HUMAN, Clone 14 (Cat N° CH00288) respectively).
EXAMPLE 150. Use of PC12 full length Htt expressing cells as a model for neuronal degeneration HttFIQ23 and HttFIQ145 cells were grown for one week in low serum medium without refreshing medium (decreasing nutrients) to induce Huntington's disease-like intracellular signaling deregulation leading to elevated levels of apoptosis in the HttFIQI 45 compared to the HUFIQ23 cell line. Apoptosis was measured by quantification of activated caspase 3/7 in the cells. Additionally, over-expression of full length Huntington genes was confirmed by Western blot analysis in these conditions.
Experimental procedure: Three days preceding the experiment cells were cultured at a 1/3 split rate in culture medium (Kaighn's Modification of Ham's F-12 (ATCC #30-2004) medium supplemented with 2.5% FBS, 15% Horse serum, 1 % Pen/Strep, 0.2mg/ml_ Geneticin (G418), 0.2mg/ml_ Zeocin) in Collagen IV coated flasks. At the day of the experiment these cultures were diluted to 20 000 cells/mL in experiment medium (Kaighn's Modification of Ham's F-12 (ATCC #30-2004) medium supplemented with 2.5% FBS, 1 % Pen/Strep, 0.2mg/ml_l Geneticin (G418), 0.2mg/ml_ Zeocin; no Horse serum) and 100 μΙ_ of this suspension was dispensed per well into a 96-well microtiter plate. After 48 hours of incubation at 37°C/5% CO2 the medium was removed and 50μΙ_ experiment medium plus 50μΙ_ experiment medium with DMSO (later compound) was added and subsequently incubated for 7 days at 37°C/5% CO2. Then the amount of viable cells and additionally the Caspase 3/7 activity were measured sequentially using the Promega CellTiter-Fluor™ Cell Viability Assay (Promega #G6081 ) and Caspase-Glo® 3/7 Assay (Promega #G8091 ) respectively, according to the manufacturer's instructions. Caspase activity per cell was calculated by normalizing the Caspase activity to the number of viable cells per well. The ratio of the apoptosis level of HttFIQI 45 cells to HttFIQ23 should be at least 1 .5.
EXAMPLE 151. Use of the PC12 Huntington model to screen compounds
The assay described above using the HttFIQI 45 cell line allowed screening compounds for their ability to decrease apoptosis during the chronic incubation at lower serum. Compounds of the invention were tested for their ability to decrease apoptosis at different concentrations, ranging from low non-effective concentrations to high effective concentrations. Afterwards, a dose-dependent inhibition curve was used to calculate the EC5o. A compound was considered to be active in this test when it inhibited apoptosis by more than 20% relative to untreated HttFIQI 45 cells at a concentration of 10 μΜ or lower.
The EC50 values of toxicity inhibition of the compounds of the invention using the HttFIQI 45 cells are shown in Table 4 as "HD EC50". Table 4
Compound code HD EC50 (nM)
C136 18
C137 75
C141 109
C147 151
C148 102
C150 15
C152 126
C154 109
C155 261
C156 15
C157 170

Claims

Claims
1. A compound of formulae (I) or (II), stereoisomer, enantiomer, racemic or tautomer thereof,
Figure imgf000244_0001
wherein,
- each dotted line individually represents an optional double bond,
- r is an integer selected from 0; 1 ; 2 or 3;
- A1 is selected from the group consisting of S; N; NR.8; and O;
- A2 is selected from the group consisting of N; NR.9, and S;
- X1 is selected from the group consisting of NR10; S; SO; and S02;
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; NR13; O, and S,
- X2 is selected from the group consisting of O; S; N; NH, SO; and SO2;
- Y1 is selected from the group consisting of CR14; NH; and N;
- R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; -SR18; -NHC(0)NHR19;
NHC(0)R19; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; thioxo; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z1; * and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R8 is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z2;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl;
C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z3;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - R4 is selected from hydrogen; -NO2; -NH2, halo; or from a group consisting of haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2aryl; hydroxyl; -OR17; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; cyano; -NR15R16; -NHC(0)NHR19; and NHC(0)R19; wherein each group can be unsubstituted or substituted with one or more Z5;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl; Cs-scycloalkyl; C6-i2aryl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R2 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z6;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R3 is selected from hydrogen; -NH2; hydroxyl, or is selected from the group consisting of -NR15R16; -OR17; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z7;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; Cs-scycloalkyl; heterocyclyl; heteroaryl; moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl;
Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z8;
* and wherein a carbon atom or heteroatom of Ci_6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; Cs-scycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z9;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; -SR18; NHC(0)R19; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl; haloCi-6alkyl; haloCi-6alkyloxy; carboxyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z10;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; or heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; Ci-6alkylcarbonyl; Ci-6alkoxycarbonyl; Ci-6alkylsulfonyl; and Ci-6alkylsulfinyl; wherein each group can be unsubstituted or substituted with one or more Z11;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C6-i2aryl; C3-8cycloalkyl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; C3-8cycloalkyl; hydroxyl; C2-6alkenyl; C2-6alkynyl; heterocyclyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; C6-i2aryloxyCi-6alkyl; Ci-6alkylcarbonyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; -N02; cyano; -NH2; -SR18; -NR15R16; and -NHC(0)NHR19; wherein each group can be unsubstituted or substituted with one or more Z12; * and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R5 is hydrogen or is selected from the group consisting of -NH2; hydroxyl; -NR15R16; -OR17; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - N02; and cyano; wherein each group can be unsubstituted or substituted with one or more Z13;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R6 is hydrogen or is selected from the group consisting of -OR17; -NH2; hydroxyl, -NR15R16; -SR18; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; halo; haloCi-6alkyl; haloCi-6alkyloxy; - NO2; cyano; wherein each group can be unsubstituted or substituted with one or more Z14;
* and wherein a carbon atom or heteroatom of Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; heterocyclyl; heteroaryl moiety; can be oxidized to form a C=0, C=S, N=0, N=S, S=0 or S(0)2;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; C6-i2arylC2-6alkenyl; C6-i2arylC2-6alkynyl; haloCi-6alkyl; haloCi-6alkyloxy; and -NO2; wherein each group can be unsubstituted or substituted with one or more Z15;
* and wherein a carbon atom or heteroatom of C6-i2aryl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C3-8cycloalkyl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 4-, 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or substituted with one or more Z14;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl, C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; heteroarylCi-6alkyl; and cyanoCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; or heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C2-6alkenyl; C2-6alkynyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heteroaryl; heterocyclylCi-6alkyl; and heteroarylCi-6alkyl; wherein at least one carbon atom or heteroatom of Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-i2aryl, C3-8cycloalkyl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; d-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; -
N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2; - each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -
C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -S(0)R19; - S(0)2R19; -S02NR15R16; -N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety ; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
- each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -S(0)R19; -S(0)2R19; -S02NR15R16; - N02; -NHC(0)R19; -NHS(0)2R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, 6-, or 7-membered ring; and wherein at least one carbon atom or heteroatom of Ci_6alkyl; C3- 2cycloalkyl, C6-i2aryl, heterocyclyl; heteroaryl moiety; can be oxidized to form at least one C=0, C=S, N=0, N=S, S=0 or S(0)2;
with the proviso that said compound is not:
- 2-(4-chlorophenyl)-7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one;
- 2-methyl-9-oxo-9H-chromeno[6,5-of][1 ,3]thiazole-7-carboxylic acid;
- 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid;
- pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(1 -piperidinyl)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-;
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(butylthio)-;
- acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)hydrazide;
- pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt;
- pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 );
- pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-, chloride (1 :1 );
- pyridinium, 1 -(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-, chloride (1 :1 );
- thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-3,6-dihydro-3-methyl-;
- 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-hydrazinyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-;
- benzamide, 4-methoxy-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-;
- benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; - thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-;
- 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-;
- thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-;
- 2-hydrazino-1 ,6-dihydroimidazo[4,5-a]acridin-1 1 -one;
- 2-hydrazino-1 -methyl-6H-imidazo[4,5-a]acridin-1 1-one;
- 2-methyl-6H-thiazolo[5,4-f]quinolin-9-one;
- 3,6-dihydrotriazolo[4,5-f]quinolin-9-one;
- 2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one;
- 7,8-dimethyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 2-(2-furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 7-methyl-2-(p-tolyl)-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
- 2,7-diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; and
- 2-(2-chlorophenyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof.
2. The compound according to claim 1 , having one of formula (I2), (I3), (II2), (II3), (II4), (II5), (II6), (II7), (IIS), (II9),
Figure imgf000252_0001
Figure imgf000253_0001
(118) (119).
3. The compound according to claim 1 or 2, wherein,
- A1 is selected from the group consisting of S; N; and NR8;
- A2 is N; or NR9;
-X1 is NR10.
4. The compound according to any one of claims 1 to 3 wherein,
A1 is S; and A2 is N; or
A1 is N and A2 is NR9, or
A1 is NR8 and A2 is N.
5. The compound according to claims 1 or 2, wherein,
- A3 is selected from the group consisting of S; O; NR11; and N;
- A4 is selected from the group consisting of CR12; N; and CH;
- A5 is selected from the group consisting of N; O; NH, and S,
- X2 is selected from the group consisting of O; S; N; and NH,
-Y1 is CR14; or NH;
6. The compound according to any one of claims 1 or 2, 5; wherein
- A3 is S; A4 is CR12; and A5 is N; or
- A3 is O; A4 is CR12; and A5 is N, or
-A3 is NR11; A4 is N; and A5 is N;
- A3 is N; A4 is CH; andA5 is O.
7. The compound according to any one of claims 1 to 4, wherein,
- R1 is selected from the group consisting of halo; -NH2; -NR15R16; -OR17; Ci-6alkyl;
C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein each group can be unsubstituted or substituted with one or more Z1; - R8 is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z2;
- R9 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and
Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z3; - R4 is selected from or from a group consisting of hydrogen; -NO2; -NH2; halo, haloCi-6alkyl; haloCi-6alkyloxy; Ci-6alkyl; C3-8cycloalkyl; C6-i2aryl; and hydroxyl;
- R2 is hydrogen;
- R3 is hydrogen;
- R10 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z8.
8. The compound according to any one of claims 1 , 2, 5 and 6, wherein,
- R11 is hydrogen or is selected from the group consisting of Ci-6alkyl; C6-i2arylCi-6alkyl; C6-i2aryl; and Cs-scycloalkyl; wherein each group can be unsubstituted or substituted with one or more Z9;
- R12 is -NH2; =S, or halo, or is selected from the group consisting of Ci-6alkyl; -NHC(0)NHR19; C6-i2aryl; -NR15R16; -OR17; C3-8cycloalkyl; heterocyclyl; and heteroaryl; wherein each group can be unsubstituted or substituted with one or more Z10;
- R13 is hydrogen; or is selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; and C6-i2arylCi-6alkyl; wherein each group can be unsubstituted or substituted with one or more Z11;
- R7 is selected from the group consisting of C6-i2aryloxyC6-i2aryl; C6-i2aryl; hydrogen; Ci-6alkyloxy; C6-i2arylaminocarbonyl; C6-i2arylaminocarbonylC6-i2aryl; NHC(0)R19; carboxyl, Ci-6alkyl; -OR17; heteroaryl; C6-i2arylCi-6alkyl; Ci-6alkoxycarbonyl; C6-i2arylthioC6-i2aryl; Cs-scycloalkyl; hydroxyl; and heterocyclyl; wherein each group can be unsubstituted or substituted with one or more Z12;
- R5 is hydrogen;
- R6 is hydrogen;
- R14 is hydrogen or is selected from the group consisting of hydroxyl; -OR17; C6-i2aryl; Ci-6alkyl;
C3-8cycloalkyl; C6-i2arylCi-6alkyl; haloCi-6alkyl; and haloCi-6alkyloxy; wherein each group can be unsubstituted or substituted with one or more Z15.
9. The compound according to any one of claims 1 to 5, and 7, wherein,
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or
14
substituted with one or more Z ;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each Z1 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19;
N02; -NHC(0)R19;and -NHC(0)NR15R16; wherein two Z1 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z2 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; and -NHC(0)R19; wherein two Z2 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z3 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z3 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z5 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z5 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z6 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z6 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z7 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z7 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z8 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z8 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
10. The compound according to any one of claims 1 , 2, 5, 6 and 8, wherein,
- each R15 is independently selected from the group consisting of hydrogen; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R16 is independently selected from the group consisting of hydrogen; -NH2; Ci-6alkyl; Ci-6alkylaminoCi-6alkyl; hydroxyCi-6alkyl, C6-i2aryl; C3-8cycloalkyl; heterocyclyl; and heteroaryl; or R15 and R16 form together with the nitrogen to which they are attached, a saturated or unsaturated 5-, or 6-membered ring, said saturated or unsaturated ring can be unsubstituted or
14
substituted with one or more Z ;
- each R17 is independently selected from the group consisting of Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R18 is independently selected from the group consisting of C6-i2aryl; hydrogen; Ci-6alkyl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each R19 is independently selected from the group consisting of hydrogen; hydroxyl; Ci-6alkyl; C6-i2aryl; C3-8cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; and heteroaryl;
- each Z9 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z9 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-, membered ring;
- each Z10 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z10 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z11 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z11 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z12 is independently selected from the group consisting of -OR17; haloCi-6alkyl; hydrogen, halo; Ci-6alkyloxy; -NH2; hydroxyl;C6-i2aryl; -NR15R16; Ci-6alkyl; C6-i2aryloxy; C6-i2arylCi-6alkyloxy; -C02R19; carboxyl; SR18; haloCi-6alkyloxy; C3-i2cycloalkyl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; cyano; -C(0)NR15R16; -C(0)R19; -N02; - NHC(0)R19; and -NHC(0)NR15R16; wherein two Z12 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z13 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z13 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring;
- each Z14 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl; C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z14 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-membered ring.
- each Z15 is independently selected from the group consisting of -NH2; halo; hydroxyl; -NR15R16; -OR17; Ci-6alkyl; haloCi-6alkyl; haloCi-6alkyloxy; hydrogen; C3-i2cycloalkyl;
C6-i2aryl; C6-i2arylCi-6alkyl; heterocyclyl; heterocyclylCi-6alkyl; heteroaryl; heteroarylCi-6alkyl; carboxyl; -SR18; cyano; -C02R19; -C(0)NR15R16; -C(0)R19; -N02; -NHC(0)R19; and -NHC(0)NR15R16; wherein two Z15 together with the atom to which they are attached can form a saturated or unsaturated 5-, or 6-, membered ring.
1. A compound selected from the group comprising 2-amino-7-(3-phenoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8- hydroxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-phenoxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7- phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-methoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-hydroxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7- (4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(benzo[d][1 ,3]dioxol-5- yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(4-methoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4-dimethoxyphenyl)-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-phenyl-9H-thiochromeno[6,5-d]thiazol-9-one; ethyl 4-(2-amino-8- hydroxy-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate; 2-amino-8-methoxy-7-(4- methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3- (benzyloxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-8-hydroxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-hydroxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; ethyl 4-(2- amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoate; 2-amino-8-hydroxy-7-(3-hydroxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol- 9-one; 2-amino-7-(4-fluorophenyl)-9H-thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4- phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-8-(4-fluorophenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-methoxy-7-(4-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 7-([1 , 1 -biphenyl]-4-yl)- 2-amino-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(4-fluorophenoxy)phenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-7-(benzo[d][1 ,3]dioxol-5-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino- 8-methoxy-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3- fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-8-hydroxy-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-9-oxo-N-phenyl-9H-chromeno[6,5-d]thiazole-7- carboxamide; 2-amino-7-(4-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino- 8-hydroxy-7-(naphthalen-1-yl)-9H-chromeno[6,5-d]thiazol-9-one; 7-phenyl-2-thioxo-2H- chromeno[6,5-d]thiazol-9(3H)-one; 2-amino-7-(3-phenoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)- one; 2-amino-7-(4-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(4- isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-diisopropoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 4-(2-amino- 9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)-N-phenylbenzamide; 2-amino-7-(2-isopropoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 7-([1 ,1 '-biphenyl]-4-yl)-2-amino-8-hydroxy-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2- bromo-7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-fluorophenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol- 9-one; 2-amino-8-hydroxy-7-(2-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-9- oxo-9H-chromeno[6,5-d]thiazole-7-carboxylic acid; 2-amino-7-(2-methoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(2-methoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-amino-4-methoxy-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- dimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(benzyloxy)phenyl)-8- methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,5-dimethoxyphenyl)-8-methoxy-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-(trifluoromethyl)phenyl)thiazolo[5,4-f]quinazolin- 9(8H)-one; 2-amino-7-(3-isopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7- methyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(trifluoromethyl)phenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(furan-2-yl)-9H-chromeno[6,5-d]thiazol-9-one; 2-chloro-7- phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-methoxyphenyl)-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-hydroxy-4-methoxy-7-phenyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(3-phenoxyphenyl)-9H-chromeno[6,5- d]thiazol-9-one; 2-methyl-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-methoxy-7-(4- (trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-phenyl-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-hydroxy-7-(2-isopropoxyphenyl)- 9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2-fluorophenyl)-8-methoxy-9H-chromeno[6,5- d] thiazol-9-one; 2-amino-7-phenylthiazolo[5,4-f]quinazolin-9(8H)-one; 1-(8-hydroxy-9-oxo-7-(3- phenoxyphenyl)-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; 2-amino-7-benzylthiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(3-(trifluoromethyl)phenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2- e] [1 ,3]oxazin-9(8H)-one; 2-amino-8-methoxy-7-(3-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-7-(3,4,5-trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4- phenoxyphenyl)-7H-thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-7-(3- fluorophenyl)-8-methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-phenoxyphenyl)-7H- thiazolo[4',5':5,6]benzo[1 ,2-e][1 ,3]oxazin-9(8H)-one; 2-amino-8-methoxy-7-phenyl-9H- chromeno[6,5-d]thiazol-9-one; ethyl 2-amino-9-oxo-9H-chromeno[6,5-d]thiazole-7-carboxylate;
1- (9-oxo-7-phenyl-9H-chromeno[6,5-d]thiazol-2-yl)-3-phenylurea; 2,7-diphenyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2,5-diamino-7-phenyl-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7-phenyl-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)-9H-chromeno[6,5-d]thiazol-9-one;
2- amino-7-(furan-2-yl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-hydroxy-7-(3,4,5- trimethoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4-dimethoxyphenyl)-8- methoxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(2,4,5-trimethoxyphenyl)-9H- chromeno[6,5-d]thiazol-9-one; 4-(2-amino-9-oxo-9H-chromeno[6,5-d]thiazol-7-yl)benzoic acid; 2- amino-7-(3,4-diisopropoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- diisopropoxyphenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(3,4- dihydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(phenylthio)phenyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-bromo-7-(3-(trifluoromethyl)phenyl)-9H-chromeno[6,5-d]thiazol- 9-one; 2-bromo-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-bromo-7-(3- methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-fluorophenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(2,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(3-methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(2- methoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(4-methoxyphenyl)thiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-(3,5-dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2- amino-7-(3,4,5-trimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-(3,4- dimethoxyphenyl)thiazolo[5,4-f]quinazolin-9(8H)-one; 2-amino-7-cyclohexylthiazolo[5,4- f]quinazolin-9(8H)-one; 2-amino-7-isopropylthiazolo[5,4-f]quinazolin-9(8H)-one; 2-bromo-8- methoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-(4- fluorophenoxy)phenyl)-8-hydroxy-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-7-methyl-9H- thiochromeno[6,5-d]thiazol-9-one; 2-amino-7-(4-hydroxyphenyl)-9H-chromeno[6,5-d]thiazol-9- one; 2-amino-8-ethoxy-7-(4-methoxyphenyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-methyl-7- phenyl-9H-chromeno[6,5-d]oxazol-9-one; 2-methyl-7-(3-phenoxyphenyl)-9H-chromeno[6,5- d]oxazol-9-one; 2-methyl-7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one; 2-amino-8-benzyl-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-(3-fluorobenzyl)-9H-chromeno[6,5-d]thiazol-9-one; 2- amino-8-(3-phenoxybenzyl)-9H-chromeno[6,5-d]thiazol-9-one; 2-amino-8-(4-fluorobenzyl)-9H- chromeno[6,5-d]thiazol-9-one; 2-amino-8-(benzo[d][1 ,3]dioxol-5-ylmethyl)-9H-chromeno[6,5- d]thiazol-9-one; 1-benzyl-7-(4-methoxyphenyl)chromeno[5,6-d][1 ,2,3]triazol-9(1 H)-one; 7-phenyl- 9H-chromeno[5,6-d]oxazol-9-one; 7-(3-phenoxyphenyl)-9H-chromeno[6,5-d]oxazol-9-one; 7- phenyl-9H-chromeno[6,5-d]oxazol-9-one; 7-phenyl-9H-thiochromeno[6,5-d]oxazol-9-one; 2- bromothiazolo[5,4-a]acridin-1 1 (6H)-one; 2-(propylamino)thiazolo[5,4-a]acridin-1 1 (6H)-one; 2- chloro-7-nitrothiazolo[5,4-a]acridin-1 1 (6H)-one; 7-amino-2-chlorothiazolo[5,4-a]acridin-1 1 (6H)- one; 2-chloro-3H-imidazo[4,5-a]acridin-1 1 (6H)-one; 2-chloro-3-methyl-3H-imidazo[4,5-a]acridin- 1 1 (6H)-one; 2-chloro-1 -methyl- 1 H-imidazo[4,5-a]acridin-1 1 (6H)-one; 2-ethoxythiazolo[5,4- a]acridin-1 1 (6H)-one; 2-methoxythiazolo[5,4-a]acridin-1 1 (6H)-one; 2-butoxythiazolo[5,4- a]acridin-1 1 (6H)-one; 2-chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-bromo-6- methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-bromo-6-ethylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2- chloro-6-methylthiazolo[5,4-a]acridin-1 1 (6H)-one; 2-amino-1 1 H-xantheno[2,1-d]thiazol-1 1-one; 2-(diethylamino)-4-ethoxythiazolo[5,4-a]acridin-1 1 (6H)-one; and 2-amino-8-methyl-7- phenylthiazolo[5,4-f]quinolin-9(6H)-one.
12. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to any one of claims 1 to 1 1 or a therapeutically effective amount of a compound selected from the group comprising 3-ethyl- [1 ,2,4]triazolo[3',4':2,3]thiazolo[5,4-a]acridin-12(7H)-one; 2-hydrazino-1 ,6-dihydroimidazo[4,5- a]acridin-1 1-one; 2-hydrazino-1-methyl-6H-imidazo[4,5-a]acridin-1 1-one.
13. The compound according to any of one of claims 1 to 1 1 , or the pharmaceutical composition according to claim 12 for use as a medicine.
14. The compound according to any of one of claims 1 to 1 1 , or the pharmaceutical composition according to claim 12, or a compound selected from the group consisting of 2-(4-chlorophenyl)- 7-phenyl-9H-chromeno[5,6-of][1 ,3]oxazol-9-one; 2-methyl-9-oxo-9H-chromeno[6,5- cf][1 ,3]thiazole-7-carboxylic acid; 2-methyl-9-oxo-9H-chromeno[5,6-of][1 ,3]thiazole-7-carboxylic acid; pyrano[3,2-e]benzimidazol-9(1 H)-one, 2-amino-7-phenyl-; thiazolo[5,4-a]acridin-1 1 (6H)- one, 2-(1 -piperidinyl)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[[3-(diethylamino)propyl]amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-[(2-hydroxyethyl)amino]-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(diethylamino)-; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-
(dimethylamino)-; pyridinium, 1-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-(dimethylamino)-; thiazolo[5,4-a]acridin- 1 1 (6H)-one, 2-(butylthio)-; acetic acid, 2-(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5- a]acridin-2-yl)hydrazide; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxythiazolo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 4-(dimethylamino)-1-(1 1-hydroxy-1 H-imidazo[4,5-a]acridin-2-yl)-, inner salt; pyridinium, 1-(6,1 1-dihydro-1 1-oxothiazolo[4,5-a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); pyridinium, 1 -(6,1 1-dihydro-1-methyl-1 1-oxo-1 H-imidazo[4,5-a]acridin-2-yl)-4- (dimethylamino)-, chloride (1 :1 ); pyridinium, 1 -(6,1 1-dihydro-3-methyl-1 1-oxo-3H-imidazo[4,5- a]acridin-2-yl)-4-(dimethylamino)-, chloride (1 :1 ); thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-chloro-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-1 -methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1- one, 2-chloro-3,6-dihydro-3-methyl-; 1 1 H-imidazo[4,5-a]acridin-1 1-one, 2-chloro-1 ,6-dihydro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2- hydrazinyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 6-butyl-2-chloro-; benzamide, 4-methoxy-N-(9- oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-methyl-N-(9-oxo-7-phenyl-9H- pyrano[2,3-g]benzothiazol-2-yl)-; benzamide, 4-chloro-N-(9-oxo-7-phenyl-9H-pyrano[2,3- g]benzothiazol-2-yl)-; benzamide, N-(9-oxo-7-phenyl-9H-pyrano[2,3-g]benzothiazol-2-yl)-; thiazolo[4,5-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-amino-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-chloro-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-methyl-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-ethyl-; 9H-[1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2,4- dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5-f][1]benzopyran-9-one, 4,8-dimethyl-2,7-diphenyl-; 9H- [1 ,3]oxathiolo[4,5-f][1 ]benzopyran-9-one, 2-ethyl-4,8-dimethyl-7-phenyl-; 9H-[1 ,3]oxathiolo[4,5- f][1 ]benzopyran-9-one, 2,4,8-trimethyl-7-phenyl-; 9H-pyrano[2,3-g]benzoxazole-7-carboxylic acid, 2-methyl-9-oxo-; thiazolo[5,4-a]acridin-1 1 (6H)-one, 2-phenyl-; 2-methyl-6H-thiazolo[5,4- f]quinolin-9-one; 2-methyl-1 ,6-dihydrothiazolo[4,5-f]quinolin-9-one; 7,8-dimethyl-2-phenyl-1 ,6- dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-phenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 2-(2-furyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; 7-methyl-2-(p-tolyl)-1 ,6- dihydroimidazo[4,5-f]quinolin-9-one; 2,7-diphenyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one; and 2- (2-chlorophenyl)-7-methyl-1 ,6-dihydroimidazo[4,5-f]quinolin-9-one;
for the prevention or treatment of amyloid-related diseases.
15. The compound or the pharmaceutical composition according to claim 14, wherein the amyloid- related diseases is selected from Huntington's disease, Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP- 17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann- Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob's disease, cystic fibrosis, phenylketonuria, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay-Sachs disease, oantitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy.
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