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WO2014087165A1 - Tankyrase inhibitors - Google Patents

Tankyrase inhibitors Download PDF

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Publication number
WO2014087165A1
WO2014087165A1 PCT/GB2013/053215 GB2013053215W WO2014087165A1 WO 2014087165 A1 WO2014087165 A1 WO 2014087165A1 GB 2013053215 W GB2013053215 W GB 2013053215W WO 2014087165 A1 WO2014087165 A1 WO 2014087165A1
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Prior art keywords
mmol
nmr
isoquinolin
methyl
amino
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Ceased
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PCT/GB2013/053215
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French (fr)
Inventor
Michael David THREADGILL
Matthew David LLOYD
Andrew Spencer THOMPSON
Amit NATHUBHAI
Pauline Joy Wood
Helen Angharad PAINE
Ekaterina KUMPAN
Peter Thomas SUNDERLAND
Esther CHUE YEN WOON
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University of Bath
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University of Bath
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    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds that are capable of inhibiting tankyrases.
  • the present invention also relates to compounds for use in medicine.
  • PARPs poly(ADP-ribose)polymerases
  • PARPs poly(ADP-ribose)polymerases
  • Small-molecule inhibitors of PARP-1 and PARP-2 are in clinical trial in combination as potentiators of the anti-tumour activities of DNA-damaging drugs and ionising radiation and as single-agent drugs in BRCA-deficient tumours. 1 These inhibitors have also shown a variety of other potential applications in animal models, as anti-angiogenic and anti-metastatic agents in cancer, in protection against ischaemia-reperfusion injury and in inflammatory diseases. 2"7 Other members of the PARP family of enzymes have other functions within the cell and are not activated by damage to DNA.
  • Tankyrase-1 (also known as PARP-5a) was first reported in 1998 as a protein carrying ankyrin repeats and a PARP-like catalytic domain. 8 The isoform tankyrase-2 (PARP- 5b) was discovered some three years later. 9 Tankyrase-1 and tankyrase-2 have several cellular functions in common (giving redundancy) but some functions are performed selectively by one or the other.
  • Tankyrase-1 and tankyrase-2 are both multi-domain proteins, with the only significant differences being in the N-terminal HPS domain of tankyrase-1 , which tankyrase-2 lacks.
  • the catalytic domains are located at the C-terminus and are very similar. These catalytic domains contain the binding site for the substrate NAD + and are the target sites for drug design.
  • Tankyrases & telomeres
  • telomeres are lengths of untranscribed DNA, attached to the ends of chromosomes, which are complexed with proteins. With each cell cycle, the telomeres shorten but are built up again by the action of telomerase. Somatic (non- growing) cells have little or no telomerase activity, as they are not in cycle, but >90% of tumour cells have active telomerase, giving them unlimited growth potential.
  • telomeres Maintenance of telomeres during proliferation is important to the immortality of malignant cell lines; inhibition of the enzyme directly responsible for telomere elongation (telomerase) has been a major goal in anti-cancer drug design.
  • TRF-1 Telomere repeat binding factor
  • Tankyrase-1 poly(ADP-ribosyl)ates TRF-1 , forming oligomers of ca. 20 ADP-ribose units.
  • the ADP-ribosylated TRF-1 leaves the telomere, allowing telomerase access to the telomere to carry out its telomere-lengthening activity.
  • the loss of TRF-1 from the telomere is an intrinsically reversible process, rendered irreversible by ubiquitination and degradation of the ADP-ribosylated TRF-1.
  • tankyrase-1 acts to promote elongation of telomeres.
  • centrosomes part of the cellular apparatus that is responsible for separating the two sets of DNA molecules during mitosis (cell division). 8 It has also been reported that poly(ADP-ribosyl)ation is required for assembly and structure of the mitotic spindle and tankyrase-1 has been identified as the PARP enzyme responsible. 17,18
  • tankyrase-1 has been proposed as a target in BRCA-associated tumours. 23 Inhibition of the tankyrases should therefore interfere with cell division and proliferation, an important step in the progression of cancer.
  • the intracellular Wnt signalling pathway is critical in the growth and development of the embryo. This development depends upon regulated cell division and proliferation. Thus, it is not surprising that Wnt signalling is important in the growth and development of several cancers. 24"26
  • XAV939 is a known tankyrase inhibitor.
  • tankyrase-1 could be a target for design of drugs for the treatment of cancer has been recognised, 16 building on the requirement for its activity for re-elongation of the telomeres after replication of tumour cells. This was followed by observations that one or both tankyrases are over-expressed in high grade non-Hodgkin's lymphomas, 34 breast cancer, 35"37 colon cancer, 38,39 gastric cancer, 40 brain tumours 41 bladder cancer 42 and chronic myeloid leukaemia. 43
  • the present invention provides inhibitors of tankyrases and thus provides compounds which are suitable for use in medicine, in particular in the treatment of cancer.
  • R-i is a substituent L-R 5 wherein L is an optionally substituted aromatic or heteroaromatic linking group and R 5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • Y is C or N
  • R 2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R 2 may not be absent;
  • X is C(Re) or N
  • R 6 is hydrogen or C 6 alkyl
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
  • the present invention provides a compound of formula IA:
  • Ri is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • a pharmaceutical composition comprising a compound of formula I, as defined above, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
  • composition comprising a compound of formula IA: Formula IA wherein is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms;
  • the present invention provides a compound for use in medicine, wherein the compound is of formula IA:
  • R-i is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms. According to a further aspect of the present invention, there is provided use of a compound of formula ⁇ :
  • Formula ⁇ wherein is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • Y is C or N
  • R 2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R 2 may not be absent;
  • X is C(R B ) or N
  • R 6 is hydrogen or C 6 alkyl
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
  • the tankyrase may be tankyrase-1 , tankyrase-2, or a mixture thereof.
  • a compound for the in vitro inhibition of a tankyrase enzyme wherein the compound is of formula IA: Formula IA wherein is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyi;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyi;
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • R T is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyi;
  • Y is C or N
  • R 2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyi; provided that when Y is C, R 2 may not be absent;
  • X is C(R 6 ) or N
  • R 6 is hydrogen or C-
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
  • the tankyrase may be tankyrase-1 , tankyrase-2, or a mixture thereof.
  • a compound for use in the treatment of a disease or condition associated with tankyrase wherein the compound is of formula IA:
  • R 1 is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • a compound for use in the treatment of cancer wherein the compound is of formula IA: Formula IA wherein F is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo, alkoxy, nitro, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen. A non-limiting example of a hydrocarbyl group is an acyl group.
  • a typical hydrocarbyl group is a hydrocarbon group.
  • hydrocarbon means any one of an alkyl group, an alkenyl group, an alkynyl group, which groups may be linear, branched or cyclic, or an aryl group.
  • the term hydrocarbon also includes those groups but wherein they have been optionally substituted. If the hydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
  • one or more hydrocarbyl groups is independently selected from optionally substituted alkyl group, optionally substituted haloalkyl group, aryl group, alkylaryl group, alkylarylalkyl group, and an alkene group.
  • alkyl (either when used alone or as part of a larger group, such as arylalkyl) means a saturated hydrocarbyl radical containing a straight or branched chain of carbon atoms.
  • one or more hydrocarbyl groups is independently selected from C1-C1 0 alkyl group, such as C C 6 alkyl group, and C Cs alkyl group.
  • Typical alkyl groups include C-i alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, and C 8 alkyl.
  • one or more hydrocarbyl groups is independently selected from alkene groups (also referred to as alkenyl groups when the alkene group has only one point of attachment to the rest of the molecule).
  • Typical alkene groups include C-i-C 10 alkene group, C- ⁇ -C 6 alkene group, C C 3 alkene group, in particular C 2 -C 10 alkene group, C 2 - C 6 alkene group, C 2 -C 3 alkene group, such as C 2 , C 3 , C 4 , C 5 , C 6 , or C 7 alkene group.
  • one or more hydrocarbyl groups is independently selected from alkyne groups (also referred to as alkynyl groups when the alkyne group has only one point of attachment to the rest of the molecule).
  • alkynyl means a hydrocarbyl radical containing a straight or branched chain of carbon atoms and at least one C ⁇ C bond.
  • Typical alkyne groups include C 2 -C 10 alkyne group, C 2 -C 6 alkyne group, C 2 -C 3 alkyne group, such as C 2 , C 3 , C 4 , C 5 , C 6 , or C 7 alkene group.
  • the alkyne group contains 1 , 2 or 3 C ⁇ C bonds. In a preferred aspect the alkyne group contains 1 C ⁇ C bond. In some preferred aspects at least one C ⁇ C bond or the only C ⁇ C bond is to the terminal C of the alkyne chain, that is the bond is at the distal end of the chain to the ring system.
  • one or more hydrocarbyl groups is independently selected from cycloalkyl groups.
  • cycloalkyl means a saturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly.
  • C x cycloalkyl and C X _Y cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • Typical cycloalkyl groups include C 3 -C 0 cycloalkyl groups, C 4 -C 8 cycloalkyl groups, C 5 -C 7 cyclohexyl groups.
  • C 3 _ 10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantan-1 -yl, and decahydronaphthyl.
  • one or more hydrocarbyl groups is independently selected from oxy hydrocarbyl groups.
  • hydrocarbyl group is an oxy hydrocarbyl group.
  • oxyhydrocarbyl means a group comprising at least C, H and O and may optionally comprise one or more other suitable substituents.
  • oxyhydrocarbyl groups include alkoxy groups (where an alkyl group, as defined above, is attached to the rest of the molecule via an oxygen atom, and include C C 10 alkoxy group, such as C C 6 alkoxy group, and C r C 3 alkoxy group, typical alkoxy groups include alkoxy, C 2 alkoxy, C 3 alkoxy, C 4 alkoxy, C 5 alkoxy, C 6 alkoxy, C 7 alkoxy, and C 8 alkoxy) and alkoxyalkyl groups (where an alkyl group, as defined above, is substituted with an alkoxy group, as defined above)
  • substituents may include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc.
  • substituents being a cyclic group
  • a combination of substituents may form a cyclic group.
  • the oxyhydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group.
  • the oxyhydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulfur and nitrogen.
  • the oxyhydrocarbyl group is a oxyhydrocarbon group.
  • oxyhydrocarbon means any one of an alkoxy group (as defined above), an oxyalkenyl group, an oxyalkynyl group, which groups may be linear, branched or cyclic, or an oxyaryl group (aryl being as defined below).
  • oxyhydrocarbon also includes those groups but wherein they have been optionally substituted. If the oxyhydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
  • the oxyhydrocarbyl group is of the formula C 1-6 0 (such as a C 1-3 0).
  • heterocyclic when the group is monovalent, i.e. has one point of attachment to the rest of the molecule; "heterocyclene” when the group is divalent, i.e. has two points of attachment to the rest of the molecule
  • heterocyclic refers to a saturated or partially unsaturated (preferably saturated) monocyclic or bicyclic (preferably monocylic) group having 3 to 14 (preferably 3 to 10, such as 4 to 8, such as 5, 6 or 7) ring atoms composed of carbon atoms and 1 to 4 heteroatoms (such as 1 to 3, such as 1 or 2, such as 1 heteroatom) independently selected from nitrogen, oxygen, and sulfur.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C 3 . 6 heterocyclyl refers to a heterocyclyl group having 3 to 6 carbon atoms and 1 to 4 heteroatoms as ring members).
  • the heterocyclyl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • Examples of monocyclic heterocyclyl groups include oxiranyl, thiaranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1 ,4-dioxanyl, 1 ,4-oxathianyl, morpholinyl, 1 ,4- dithianyl, piperazinyl, 1 ,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1 ,4-dioxepanyl, 1 ,4-oxathiepanyl, 1 ,4-oxazepanyl, 1 ,
  • aromatic when the group is monovalent, i.e. has one point of attachment to the rest of the molecule and "arylene” when the group is divalent, i.e. has two points of attachment to the rest of the molecule refers to a fully unsaturated monocyclic aromatic hydrocarbons (i.e.
  • n ia an integer, preferably 1 to 3, such as 1 or 2, preferably 1
  • polycyclic hydrocarbons having at least one aromatic ring both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ring members (e.g., C 6- 14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members).
  • the aryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • aryl groups include C 6 - C-I4 aryl groups, such as C 6 -C 0 aryl group, include phenyl, biphenyl, indenyl, naphthyl, and fluorenyl groups.
  • the aryl group is a phenyl or naphthyl group, especially a phenyl group.
  • Typical arylene groups include phenylene and napthylene, especially phenylene, and particularly 1 ,4-phenylene.
  • heteroaryl when the group is monovalent, i.e. has one point of attachment to the rest of the molecule and “heteroarylene” when the group is divalent, i.e. has two points of attachment to the rest of the molecule
  • both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g. ,
  • Ci-10 heteroaryl refers to a heteroaryl group having 1 to 10 carbon atoms and 1 to 4 heteroatoms as ring members) and include any bicyclic group in which any of the above-listed monocyclic heterocycles are fused to a benzene ring.
  • the heteroaryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3- triazolyl, 1 ,3,4-triazolyl, 1 -oxa-2,3-diazolyl, 1 -oxa-2,4-diazolyl, 1 -oxa-2,5-diazolyl, 1 -oxa- 3,4-diazolyl, 1-thia-2,3-diazolyl, 1 -thia-2,4-diazolyl, 1 -thia-2,5-diazolyl, 1 -thia-3,4- diazolyl, tetrazolyl, pyridinyl
  • heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzo[d][1 ,3]dioxole, benzothienyl, benzo[c]thienyl, indolyl, 3H-indolyl, isoindolyl, 1 H- isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H- pyrrolo[2,3-b]pyridinyl, 1/- -pyrrolo[2,3-c]pyridinyl, 1/- -pyrrolo[3,2-c]pyridinyl, 1H- pyrrolo[3,2-6]pyridinyl, 3H-imidazo[4,5-6]pyridiriyl, 3 -/-imidazo[4,5-c]pyridinyl, 1/-/- pyrazolo[
  • R is a substituent L-R 5 wherein L is an optionally substituted aromatic or heteroaromatic linking group and R 5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • Y is C or N
  • R 2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R 2 may not be absent;
  • X is C(Re) or N
  • R 6 is hydrogen or C 6 alkyl
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
  • the present invention provides a compound of formula IA:
  • R-i is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl
  • X is CH or N
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • the compounds of the present invention also include pharmaceutically acceptable forms thereof such as salts, solvates and other derivatives thereof, as defined in more detail below.
  • the group Y is C or N.
  • Y is C. In one embodiment, Y is N.
  • the group R- is a substituent L-R 5 .
  • L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl.
  • L is an optionally substituted aromatic or heteroaromatic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl.
  • L may be linked directly to ring A or it may be linked via a suitable bridging group, such as a C C 3 alkyl group. Preferably, L is linked directly to ring A.
  • L is an optionally substituted cyclic linking group comprising from 5 to 7 members and at least one carbon atom and optionally at least one hetero atom. In one embodiment, L is an optionally substituted carbocyclic linking group comprising from 5 to 7 members. In one embodiment, L is an optionally substituted heterocyclic linking group comprising from 5 to 7 members. In one embodiment, L is an optionally substituted heterocyclic linking group comprising from 5 to 7 members and at least one nitrogen atom.
  • the above mentioned cyclic, carbocyclic or heterocyclic group comprises from 5 to 7 members. In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group comprises from 5, 6 or 7 members. In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group comprises 6 members.
  • the above mentioned cyclic, carbocyclic or heterocyclic group may be saturated or unsaturated, aromatic or aliphatic. In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group is aromatic.
  • L is an arylene group, preferably a phenylene group, especially a 1 ,4-phenylene group.
  • L is a heteroaromatic group, especially a monocyclic heteroarylene group, such as pyrrolyl, pyridyl, furyl or thienyl group, especially pyridyl or thienyl.
  • R 5 is H, halo, hydroxy, nitriie, nitro, amino, or hydrocarbyl. When R 5 is H, L is unsubstituted.
  • R 5 is halo, hydroxy, nitriie, nitro, amino, or hydrocarbyl.
  • R 5 is H, halo, hydroxy, nitriie, nitro, amino, C C 10 alkyi, d-C-io haloalkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, C C 10 alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl, heterocyclyl-C C ⁇ alkyi, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, acylamide, aryl-C -Ci o alkyi, aryl-C 2 -C 0 alkenyl, aryl-C 2 -C 10 alkynyl, heterocyclyl-C C-
  • R 5 is H, halo, hydroxy, nitriie, nitro, amino, C C 10 alkyi, C C 10 haloalkyl, C 2 -C 0 alkenyl, C 2 -C 0 alkynyl, C C 10 alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, acylamide, phenyl-C C 6 alkyi, phenyl-C 2 -C 6 alkenyl, phenyl-C 2 -C 6 alkynyl, heterocyclyl-C C 6 alkyi, ferrocenyl, or (phenylmethoxycarbonyl)aminomethyl.
  • R 5 is H, halo, hydroxy, nitriie, nitro, amino, C ⁇ C ⁇ alkyi, CrC 10 haloalkyl, C 2 -C 10 alkenyl, C C 10 alkoxy, C 5 -C 7 cycloalkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, or acylamide.
  • R 5 is halo, hydroxy, nitriie, nitro, amino, C-
  • R 5 is H.
  • the halo is F, CI or Br.
  • the C C 10 haloalkyl group is a C C 6 halo alkyi group, such as CF 3 , CCI 3 , CHF 2 , CH 2 CF 3 etc.
  • the hydrocarbyl group is a hydrocarbon group or an
  • the hydrocarbyl group is an alkyl group, an alkoxy group, an alkenyl group, an aryl group, a heteroaryl group, a heterocyclic group or an alkynyl group.
  • the hydrocarbyl group is selected from C C 10 alkyl, such as C C 6 alkyl, and C C 3 alkyl.
  • the hydrocarbyl group is selected from C 2 -C 10 alkenyl, such as C 2 -C 6 alkenyl, and C 2 -C 3 alkenyl.
  • the hydrocarbyl group is selected from C 2 -C 10 alkynyl, such as C 2 -C 6 alkynyl, and C 2 -C 3 alkynyl.
  • the hydrocarbyl group is selected from C -5 alkyl groups, C 3-6 cycloalkyi groups, ether groups containing from 1 to 5 carbons, thioether groups containing from 1 to 5 carbons, d -5 alkoxy groups, C -5 haloalkyi group, alkylamines, amides, alkyl amides, dialkyl amides, or acylamides.
  • R 5 is halo, Ci-C 0 alkyl, C C 10 alkoxy, C C 10 haloalkyi, hydroxy, nitrile, nitro, amino, alkylamino, heterocyclyl-CrC alkyl, ferrocenyl, or (phenylmethoxycarbonyl)aminomethyl.
  • R 5 is halo, Ci-C 0 alkyl, C-
  • R 5 is CI, F, Br, C C 10 alkyl, C C 10 alkoxy, or C C 10 haloalkyi. In one embodiment, R 5 is CI, F, Br, C ⁇ -C 6 alkyl, C -C e alkoxy, or C ⁇ Ce haloalkyi. In one embodiment, R 5 is CI, F, Br, Ci-C 3 alkyl, C C 3 alkoxy, or C C 3 haloalkyi. In one embodiment, R 5 is CI, F, methyl, ethyl, methoxy, ethoxy, CF 3 or CCI 3 .
  • R 5 is an alkoxy group, preferably a methoxy or an ethoxy group.
  • R 5 is an alkyl group, preferably a methyl or an ethyl group.
  • R 5 is a haloalkyi group, preferably a CI or F containing haloalkyi group.
  • R 5 is a group (CH 2 ) n NR 6 R 7 where n is from 0 to 5, and R 6 and R 7 are independently selected from H and hydrocarbyl.
  • R 5 is a group (CH 2 ) n NR 6 R 7 where n is from 0 to 5, and R 6 and R 7 are independently selected from H, C C 6 alkyl, -(CO)O-alkyl, -(CO)O-alkylaryl and C C 6 alkene.
  • R 5 is nitro or nitrile.
  • R 5 may be located at any position on the cyclic group L.
  • L is an optionally substituted 6 membered ring as defined above, and R 5 is present on the ring at the para position.
  • L is an optionally substituted 6 membered ring as defined above, and R 5 is present on the ring at the meta or ortho position.
  • L is optionally substituted.
  • the optional substituent is present and is selected from halo, hydroxy, or C C 6 alkyl.
  • R is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C ⁇ 0 alkyl, C C 0 haloalkyl, C 2 -C 0 alkenyl, C 2 -C 0 alkynyl, C C 10 alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl, heterocyclyl-C-i-C 10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-C C 0 alkyl, aryl-C 2 -C 10 alkenyl, aryl-C 2 -C 0 alkynyl, heterocyclyl-Ci-C 10 alkyl, heteroaryl-C C 0 alkyl, ferrocenyl, or ary C
  • Ri is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is H, halo, C- 1 -C 10 alkyl, C-i-Ci 0 alkoxy, C C 10 haloalkyl, hydroxy, nitrile, nitro, or amino.
  • R- is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is halo, C C 10 alkyl, C C 10 alkoxy, C r C 10 haloalkyl, hydroxy, nitrile, nitro, or amino.
  • R-i is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is halo, C C 6 alkyl, d-Ce alkoxy, C ⁇ -Ce haloalkyl, hydroxy, nitrile, nitro, or amino.
  • R ! is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is halo, C-
  • Ri is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is selected from H, methoxy, ethoxy, methyl, ethyl, C C 6 halo alkyl group, (CH 2 ) n NR 6 R 7 where n is from 0 to 5, and R 6 and R 7 are independently selected from H, C-
  • L is an optionally substituted phenyl group and R 5 is located at the para position and is selected from methoxy, ethoxy, methyl, ethyl, C ⁇ -Ce halo alkyl group, (CH 2 ) n NR 6 R 7 where n is from 0 to 5, and R 6 and R 7 are independently selected from H, C C 6 alkyl, and C C 6 alkene, CI, F, nitro or nitrile.
  • L may not be further substituted.
  • R 2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl.
  • R 2 is absent.
  • R 2 when Y is C, R 2 may not be absent.
  • R 2 when Y is N and ring B is pyridine, R 2 may be absent.
  • R 2 when Y is N and ring B is piperidine, R 2 may or may not be absent.
  • R 2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl.
  • R 2 is selected from halo, hydroxy, C C 0 alkyl, Ci-C 0 alkoxy, C-,- C 10 haloalkyl, nitro, nitrile, and oxo. In one embodiment, R 2 is selected from halo, hydroxy, C C e alkyl, C ⁇ Ce alkoxy, C C 6 haloalkyl, nitro, nitrile, and oxo. In one embodiment, R 2 is selected from halo, hydroxy, C-
  • R 2 is selected from halo, C C 6 haloalkyl, C ⁇ -C 6 alkyl, and C-
  • R 2 is C C 10 haloalkyl, preferably C C 6 haloalkyl, preferably C C 3 haloalkyl, preferably CF 3 or CCI 3 .
  • R 2 is C C ⁇ 0 alkyl, preferably C ⁇ Ce alkyl, preferably C C z alkyl, preferably methyl or ethyl.
  • R 2 is C C 10 alkoxy, preferably C C 6 alkoxy, preferably C C 13 alkoxy, preferably -OMe or -OEt.
  • R 2 is oxo.
  • the oxo group can either be linked to a carbon atom in which case a carbonyl group is formed, or the oxo group can be linked to a nitrogen atom, in which case an oxime group or salt can be formed.
  • X is C(R 6 ) (wherein R 6 is as defined below) or N.
  • X is CH or N.
  • X is CH. In one embodiment, X is N.
  • R 6 is H or C 1-6 alkyl.
  • R 6 is H. In one embodiment, R 6 is H or C ⁇ e alkyl, such as C 1-3 alkyl, preferably methyl or ethyl, and especially methyl.
  • Ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • the one more hetero atoms is a nitrogen or sulphur atom.
  • ring B is a saturated or unsaturated optionally substituted carbocyclic group containing from 5 to 7 members. In one embodiment, ring B is a saturated carbocyclic group containing from 5 to 7 members. In one embodiment, ring B is an unsaturated carbocyclic group containing from 5 to 7 members. In one embodiment, ring B is an aryl group. In one embodiment, ring B is a saturated or unsaturated heterocyclic group containing from 5 to 7 members. In one embodiment, ring B is a saturated or unsaturated heterocyclic group containing 6 members. In one embodiment, ring B is a heteroaryl group.
  • ring B contains from 5 to 7 members. In one embodiment, ring B contains 5, 6 or 7 members. In one embodiment, ring B contains 6 members.
  • ring B is an optionally substituted phenyl group.
  • the compound is of formula II
  • R 3 , R 4 and R 8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups, and R-i and R 2 are as defined above.
  • the hydrocarbyl groups for R 3 , R 4 and R 8 are as defined above as for R 5 .
  • R 3 , R 4 and R 8 are each H.
  • R 3 is a hydrocarbyl and R 4 and R 8 are each H.
  • R 4 is a hydrocarbyl and R 3 and R 8 are each H.
  • R 8 is a hydrocarbyl and R 3 and R 4 are each H.
  • ring B is an optionally substituted saturated monocyclic
  • ring B is an optionally substituted saturated monocyclic 5- to 7-membered (preferably 6-membered) heterocyclic group, such as a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl group, especially piperidyl.
  • ring B contains at least one nitrogen atom.
  • ring B is a 6-membered ring and the nitrogen atom is at the 5-position.
  • ring B is a 6-membered ring and the nitrogen atom is at the 6-position.
  • ring B is a 6-membered ring and the nitrogen atom is at the 6- position.
  • ring B is a 6-membered ring and the nitrogen atom is at the 7-position.
  • ring B is a 6-membered ring and the nitrogen atom is at the 8-position.
  • ring B is an optionally substituted pyridyl group.
  • the compound is of formula IV:
  • R 3 , R 4 and R 8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups, and is as defined above.
  • the hydrocarbyl groups for R 3 , R 4 and R 8 are as defined above as for R 5 .
  • R 3 , R 4 and R 8 are each H.
  • R 3 is a hydrocarbyl and R 4 and R 8 are each H.
  • R 4 is a hydrocarbyl and R 3 and R 8 are each H.
  • R 8 is a hydrocarbyl and R 3 and R 4 are each H.
  • ring B is an optionally substituted piperidine group.
  • the compound is of formula V
  • R 3 , R 4 and R 8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups; R 9 is hydrocarbyl; and is as defined above.
  • R 3 is H. In one embodiment, R 4 is H. In one embodiment, R 8 is H. In one embodiment, R 3 , R 4 and R 8 are each H. In one embodiment, R 3 is a hydrocarbyl and R 4 and R 8 are each H. In one embodiment, R 4 is a hydrocarbyl and R 3 and R 8 are each H. In one embodiment, R 8 is a hydrocarbyl and R 3 and R 4 are each H.
  • R 9 is C i0 alkyl. In one embodiment, R 9 is C 6 alkyl. In one embodiment, R 9 is C 4 alkyl. In one embodiment, R 9 is methyl or ethyl. In one embodiment, R 9 is methyl.
  • the compounds of the invention also include derivatives thereof when one or more (preferably only one) nitrogen atom is quaternised.
  • the group Y is a quaternary nitrogen atom, the group R 2 providing the quaternary substituent.
  • R 2 is hydrocarbyl, more preferably C 1-6 alkyl, and most preferably methyl or ethyl.
  • the compounds of the invention also include tautomers.
  • Tautomers are constitutional isomers of organic compounds that readily interconvert by a chemical reaction called tautomerisation. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid reaction, tautomers are constitutional isomers of organic compounds that readily interconvert by a chemical reaction called tautomerisation. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid
  • tautomers are generally considered to be the same chemical compound.
  • X is C(R 6 ) wherein R 6 is H or methyl and R 2 is a substituent selected from halo, C C 6 haloalkyi, hydroxy, C C 6 alkyl, C r C 6 alkoxy, nitro, nitrile, and oxo.
  • X is CH and R 2 is a substituent selected from halo, CrC 6 haloalkyi, hydroxy, CrC 6 alkyl, CrC 6 alkoxy, nitro, nitrile, and oxo.
  • L is a phenyl ring
  • R 5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C 10 alkyl, C 1 -C 10 haloalkyi, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, C Ci 0 alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl, heterocyclyl-C C 10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-C C 10 alkyl, aryl-C 2 -C 10 alkenyl, aryl-C 2 -C 0 alkynyl, heterocyclyl-C-i-C 10 alkyl, heteroaryl-C C-io alkyl, ferrocenyl, or aryl-(Ci -3 alkoxy)carbonylamino
  • L is a phenyl ring
  • R 5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, CrC 10 alkyl, CrC 10 haloalkyi, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, CrC 10 alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl, heterocyclyl-CrC 10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-C C 10 alkyl, aryl-C 2 -Cio alkenyl, aryl-C 2 -C 10 alkynyl, heterocyclyl-CrC 0 alkyl, heteroaryl-CrC 10 alkyl, ferrocenyl, or aryl-(C -3 alkoxy)carbonylamino-C -C 3 al
  • L is a phenyl ring
  • R 5 is located at the para position and is H, halo, C C 6 alkyl, Ci-C 6 alkoxy, or C C 6 haloalkyi
  • R 2 is halo, C C 6 haloalkyi, C Ce alkyl, or Ci-C 6 alkoxy
  • X is C(R 6 ) wherein R 6 is H or methyl.
  • L is a phenyl ring
  • R 5 is located at the para position and is H, halo, C-i-Ce alkyl, CVC 6 alkoxy, or C C 6 haloalkyi
  • R 2 is halo, C C 6 haloalkyi, C C 6 alkyl, or C Ce alkoxy
  • X is CH.
  • L is a phenyl ring
  • R 5 is located at the para position and is halo, Ci-Ce alkyl, C Ce alkoxy, or C Ce haloalkyi
  • R 2 is halo, CrC 6 haloalkyi, CrC 6 alkyl, or CrCe alkoxy
  • X is CH.
  • L is a phenyl ring
  • R 5 is located at the para position and is H, halo, C C 6 alkyi, C C 6 alkoxy, or C C 6 haloalkyi
  • R 2 is halo, C C 6 haloalkyi, C ⁇ Ce alkyi, or C C 6 alkoxy
  • ring B is a phenyl ring
  • R 3 , R 4 and R 8 are independently hydrogen or a substituent selected from halo, hydroxy, and C C 6 alkyi.
  • L is a phenyl ring
  • R 5 is located at the para position and is halo, C C 6 alkyi, C C B alkoxy, or C-i-Ce haloalkyi
  • R 2 is halo, C C 6 haloalkyi, CrC 6 alkyi, or C C 6 alkoxy
  • ring B is a phenyl ring
  • R 3 , R and R 8 are independently hydrogen or a substituent selected from halo, hydroxy, and C-
  • the compound is of formula III
  • R-i , R 2 , R 3 , R 4 and R 8 are as defined above.
  • the compound is of formula III
  • L is an optionally substituted phenyl group and R 5 is located at the para position and is selected from H, methoxy, ethoxy, methyl, ethyl, C C 6 haloalkyi, (CH 2 ) n NR 6 R7 where n is from 0 to 5, and R 6 and R 7 are independently selected from H, CrC 6 alkyl, and C C 6 alkene, CI, F, nitro or nitrile;
  • R 2 is a substituent selected from halo, C C 6 haloalkyi, hydroxy, ⁇ - ⁇ - ⁇ alkyl, -i-C 6 alkoxy, nitro, nitrile, amino, and oxo;
  • R 3 , R 4 and R 8 are each H.
  • the compound is of formula III
  • R-i is a group L-R 5 wherein L is an optionally substituted phenyl group and R 5 is located at the para position and is selected from H, methoxy, ethoxy, methyl, ethyl,
  • R 2 is a substituent selected from halo, C-
  • R 3 , R 4 and R 8 are as defined above.
  • R-i is a substituent L-R 5 wherein L is an optionally substituted cyclic linking group and R 5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
  • R 2 is halo, hydroxy, nitro, nitrile, oxo, or hydrocarbyl; X is CH; and
  • ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
  • the compound is of formula IV:
  • R 3 , R 4 and R s are each H, R-i is L-R 5 wherein L is a phenyl ring, R 5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C 10 alkyl, C C-io haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C CKJ alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl, heterocyclyl-C C 10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, an/l-CrC ⁇ alkyl, aryl-C 2 -C 10 alkenyl, aryl-C 2 -C 10 alkynyl, heterocyclyl-CrC 0 alkyl, alkyl, ferrocenyl, or aryl-(C
  • the compound is of formula V:
  • R 3 , R 4 and R 8 are each H;
  • R 9 is C 1-10 alkyl; is L-R 5 wherein L is a phenyl ring, R 5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C 10 alkyl, C C-io haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C C 0 alkoxy, C 5 -C 7 cycloalkyl, heterocyclyl, heterocyclyl-C Cio alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-CrC 10 alkyl, aryl-C 2 -C 0 alkenyl, aryl-C 2 -C 0 alkynyl, heterocyclyl-CrC ⁇ alkyl, heteroaryl-CrC alkyl,
  • R 2 when X is nitrogen, R 2 may be other than methyl, methoxy or hydroxy.
  • the compound may be selected from any one of the following compounds:
  • the compound may be selected from any one of the following compounds:
  • Examples of compounds of the present invention include the following:
  • the compounds of the present invention may form pharmaceutically acceptable complexes, salts, solvates and hydrates.
  • These salts include acid addition salts (including di-acids) and base salts.
  • Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts include 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, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate,
  • Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum.
  • suitable amines include arginine, ⁇ , ⁇ '- dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, /V-methylglucamine, olamine, 2- amino-2-hydroxymethyl-propane-1 ,3-diol, and procaine.
  • the compounds of the present invention may also exist in unsolvated and solvated forms.
  • solvate describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).
  • hydrate is a solvate in which the solvent is water.
  • the present invention provides a compound for use in medicine wherein the compound is as defined above.
  • the present invention provides a compound for use in the treatment of a disease or condition associated with tankyrase-1 or tankyrase-2, wherein the compound is as defined above.
  • the present invention provides a compound for use in the treatment of cancer, wherein the compound is as defined above.
  • the cancer is selected from breast, colon, stomach, liver, kidney, lung, ovary, thyroid, pancreas and prostate cancer.
  • the present invention provides the use of a compound as defined above for the in vitro inhibition of tankyrase.
  • the tankyrase is tankyrase- 1.
  • the tankyrase is tankyrase-2.
  • tankyrase is preferably tankyrase-1.
  • tankyrase is preferably tankyrase-2.
  • the compound of the present invention is capable of acting as a tankyrase inhibitor.
  • the selective inhibition of tankyrase is achieved, i.e. tankyrase is preferentially inhibited compared to another enzyme.
  • the term "inhibitor” as used herein with respect to the compound of the present invention means a compound that can inhibit tankyrase activity - such as reduce and/or eliminate and/or mask and/or prevent the detrimental action of tankyrase.
  • the tankyrase inhibitor may act as an antagonist.
  • tankyrase-2 The ability of compounds to inhibit tankyrase activity can be assessed using the suitable biological assay presented in the Examples section.
  • an assay for tankyrase-2 is provided.
  • an assay utilizing tankyrase-2 also provides an corresponding indication for tankyrase-1 inhibition.
  • the compounds of the present invention may be used as therapeutic agents - i.e. in therapy applications.
  • the term "therapy” includes curative effects, alleviation effects, and prophylactic effects.
  • the therapy may be on humans or animals, preferably female animals or humans, such as female humans.
  • the present invention provides a pharmaceutical composition, which comprises a compound according to the present invention and optionally a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).
  • compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985).
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
  • the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the formulation may be designed to be delivered by both routes.
  • the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
  • compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • the compound of the present invention may be used in combination with one or more other active agents, such as one or more other pharmaceutically active agents.
  • the compounds of the present invention may be used in combination with other tankyrase inhibitors and/or other inhibitors.
  • the compound of the present invention may be used in combination with a biological response modifier.
  • biological response modifier includes cytokines, immune modulators, growth factors, haematopoiesis regulating factors, colony stimulating factors, chemotactic, haemolytic and thrombolytic factors, cell surface receptors, ligands, leukocyte adhesion molecules, monoclonal antibodies, preventative and therapeutic vaccines, hormones, extracellular matrix components, fibronectin, etc.
  • the biological response modifier is a cytokine.
  • cytokines examples include: interleukins (IL) - such as IL-1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11 , IL-12, IL-19; Tumour Necrosis Factor (TNF) - such as TNF-a; Interferon alpha, beta and gamma; TGF- ⁇ .
  • TNF Tumour Necrosis Factor
  • the cytokine is tumour necrosis factor (TNF).
  • the TNF may be any type of TNF - such as TNF-a, TNF- ⁇ , including derivatives or mixtures thereof. More preferably the cytokine is TNF-a. Teachings on TNF may be found in the art - such as WO-A-98/08870 and WO-A-98/13348.
  • a physician will determine the actual dosage which will be most suitable for an individual subject and it will vary with the age, weight and response of the particular patient.
  • the dosages below are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.
  • compositions of the present invention may be administered by direct injection.
  • the composition may be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular or transdermal administration.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • the agents of the present invention may be administered in accordance with a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • administered also includes delivery by techniques such as lipid mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof.
  • routes for such delivery mechanisms include but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.
  • administered includes but is not limited to delivery by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution; a parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.
  • the compounds of the present invention can be formulated in any suitable manner utilising conventional pharmaceutical formulating techniques and pharmaceutical carriers, adjuvants, excipients, diluents etc. and usually for parenteral administration.
  • Approximate effective dose rates may be in the range from 1 to 1000 mg/day, such as from 10 to 900 mg/day or even from 100 to 800 mg/day depending on the individual activities of the compounds in question and for a patient of average (70Kg) bodyweight. More usual dosage rates for the preferred and more active compounds will be in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day, most preferably from 200 to 250 mg/day.
  • the compounds may be given in single dose regimes, split dose regimes and/or in multiple dose regimes lasting over several days.
  • oral administration they may be formulated in tablets, capsules, solution or suspension containing from 100 to 500 mg of compound per unit dose.
  • the compounds will be formulated for parenteral administration in a suitable parenterally administrable carrier and providing single daily dosage rates in the range 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250 mg.
  • Such effective daily doses will, however, vary depending on inherent activity of the active ingredient and on the bodyweight of the patient, such variations being within the skill and judgement of the physician.
  • Other Therapies will, however, vary depending on inherent activity of the active ingredient and on the bodyweight of the patient, such variations being within the skill and judgement of the physician.
  • the tankyrase enzyme is known to be implicated in a number of other diseases and conditions, such as pulmonary fibrosis 47 and the Herpes simplex virus.
  • the compounds of the present invention may also be useful for the treatment of these conditions.
  • the compounds were evaluated for inhibition of the auto-poly(ADP-ribosyl)ation activity of tankyrase-2. Briefly, a protein construct comprising the catalytic (NAD + -binding) domain of tankyrase-2 and the adjacent SAM domain was immobilised in the wells of 96-well plates, followed by blocking the remaining surfaces with milk protein. The immobilised enzyme was incubated with the natural substrate NAD + and with NAD + carrying biotin attached to the adenine, in the presence or absence of the candidate inhibitor. This allows the enzyme to build a short poly(ADP-ribose) on its SAM domain, with some units carrying biotin.
  • the solution was removed and replaced with a solution containing a commercial streptavidin-horseradish peroxidase construct, which bound to the biotin.
  • the horseradish peroxidase was then assayed by its enzymatic activity, which generated a colorimetric readout giving a measure of the activity of the tankyrase-2.
  • a suspension of tankyrase-2 protein (7.5 ng, BPS Bioscience and AMS Bio Europe Ltd. Catalogue # 80515) in buffer solution (25 ⁇ _ consisting of 50 mM TRIS-HCI pH 8.0, 5 Mm MgCI 2 , 20 ⁇ ZnCI 2 , pH 7.4) was loaded into ELlSA-quality, half-volume, high binding 96-well plates (Greiner Bio-One) and stored at 4°C for 16h.
  • the wells were then washed with phosphate buffer saline (pH 7.4) and Tween 20 (Aldrich) (4 ⁇ 250 ⁇ ) and treated with skimmed milk power (Marvel, Cadbury's) suspended in buffer solution (5% w/v, 100 ⁇ _) and left at room temperature for 1 h.
  • the wells were then washed with PBS-T (4 x 250 ⁇ [_) and treated with buffer, inhibitor and a 1 : 1 mixture of biotinylated NAD + (BioLog Life Science Institute) and unlabelled NAD + (Enzo Life Sciences) (5 ⁇ ). The mixture was incubated for 2 h at 30°C.
  • the wells were then washed with PBS-T (4 x 250 ⁇ ) and treated with HRP/Strep solution (100 ⁇ , R & D Systems) for 2 h at room temperature.
  • the wells were then washed with PBS-T (4 x 250 ⁇ _) and treated with substrate solution (100 ⁇ _, R & D Systems) for 30 min at room temperature and then quenched with aqueous sulfuric acid (2.0 M); the plate was read immediately at 450 nm.
  • Tankyrase-1 assays were performed using a commercial kit (Amsbio Europe Ltd. Catalogue # 4700-096-K), using pre-coated histone well plates.
  • the 20* l-PAR assay buffer (catalogue # 4684-096-07) was diluted 1 in 20 with distilled H 2 0. This buffer (50 ⁇ _) was added to rehydrate the histone-coated wells (30 min at room temperature), then removed by aspiration.
  • the reaction volume (50 ⁇ _) consisted of l-PAR assay buffer with tankyrase-1 protein (5 mU in 25 ⁇ _ l-PAR assay buffer), solutions of test inhibitors (5 ⁇ _) in l-PAR buffer prepared from stock solutions in DMSO to give a final concentration of 1% DMSO, assay substrate (15 ⁇ _) (catalogue # 4700-096-02). Background wells were treated with l-PAR assay buffer alone. Maximum enzyme activity was established using wells containing enzyme only + 1% DMSO. The plates were held for 30 min at room temperature. The wells were washed with 2x PBS-T (as described above) and 2x PBS.
  • the antibody diluent was prepared from 5x stock solution (catalogue # 4684-096-03) using distilled H 2 0.
  • the anti-PAR monoclonal antibody (catalogue # 4684-096-04) was diluted 1000-fold with 1 ⁇ antibody diluent and 50 ⁇ _ were added per well. The reaction was held for 30 min at room temperature. The wells were washed with 2 ⁇ PBS-T and 2 ⁇ PBS.
  • Goat anti-mouse IgG-HRP conjugate (catalogue # 4684-096-05) was diluted 1000-fold with 1 x antibody diluent and 50 ⁇ [_ was added per well. The reaction was held for 30 min at room temperature.
  • a suspension of tankyrase-2 protein (catalytic + SAM domains) (7.5 ng, BPS Bioscience and AMS Bio Europe Ltd. Catalogue # 80515) in reaction buffer (25 ⁇ , 50 mM TRIS-HCI pH 8.0, 5.0 mM MgCI 2 , 20 ⁇ ZnCI 2 ) was loaded into ELISA-quality, half-volume, high binding 96-well plates (Greiner bio-one) and these were held at 4°C for 16 h. The wells were then washed four times with phosphate-buffered saline solution pH 7.4 (+ 0.05% v/v tween 20 (PBS-T) (250 ⁇ )).
  • reaction buffer 25 ⁇ , 50 mM TRIS-HCI pH 8.0, 5.0 mM MgCI 2 , 20 ⁇ ZnCI 2
  • reaction buffer 25 ⁇ , 50 mM TRIS-HCI pH 8.0, 5.0 mM MgCI 2 , 20 ⁇ ZnCI 2
  • the wells were then washed with PBS-T (4 ⁇ 250 ⁇ ), then streptavidin / HRP solution (100 ⁇ , R & D systems) was added per well and the plates were held at room temperature for 2 h.
  • the wells were then washed with PBS-T (4 ⁇ 250 ⁇ ), a 1 : 1 mixture of substrate solutions A and B (100 ⁇ , R & D systems) was added per well and the plates were held for 30 min.
  • the reaction was stopped by the addition of aq. H 2 S0 4 (1 .0 M, 25 ⁇ ) and the absorbance at 450 nm was read within 20 min.
  • the IC 50 values for inhibitors were determined using a four-parameter logistic curve and SigmaPlot 12.0 software.
  • PARP-1 assays were performed using a commercial kit (Amsbio Europe Ltd. Catalogue # 4676-096-K) using pre-coated histone well plates. A solution of 20* PARP assay buffer (catalogue # 4671 -096-02) was diluted to 1 x with distilled water. PARP assay buffer was used to rehydrate the histone-coated wells (50 ⁇ per well) for 30 min, then this solution was removed by aspiration. A reaction volume of 50 ⁇ .
  • PARP assay buffer with PARP-1 protein 25 ⁇ , 0.5 mU in 1 x PARP assay buffer
  • 5 ⁇ _ of inhibitor solutions in PARP assay buffer prepared from stock solutions in DMSO to give a final concentration of 1 % DMSO and 20 ⁇ L ⁇ of substrate 2.5 ⁇ _ 10 ⁇ PARP cocktail (catalogue # 4671 -096-03), 2.5 ⁇ _ 10 ⁇ activated DNA (catalogue # 4671 -096-06), 15 ⁇ _ PARP assay buffer).
  • the plates were held for 1 h at room temperature. The wells were washed twice with PBS-T and twice with PBS (250 ⁇ _ each).
  • Streptavidin-HRP solution (catalogue # 4800-30-06) was diluted 500- fold with 1 streptavidin-HRP diluent (catalogue # 4671 -096-04), 50 ⁇ _ was added to each well and the plates were held for 1 h at room temperature. The wells were washed with PBS-T (2 x) and PBS (2 x). Pre-warmed TACS-SapphireTM (50 ⁇ _) was added per well and the mixtures were left at room temperature in the dark for 30 min. The reaction was quenched by the addition of HCI (0.2 M, 50 ⁇ _) and the absorbance at 450 nm was measured within 20 min. The IC 50 values were calculated using a four- parameter logistic curve and SigmaPlot 12.0 software. IMPDH2 assay
  • Lyophilized human IMPDH-2 recombinant protein (Novocib SAS, catalogue # E-Nov1) was suspended in storage buffer (40 mM Tris-HCI, pH 8.0, 1 10 mM NaCI, 2.2 mM KCI, 3.0 mM dithiothreitol, 4.0 mM glutathione and 20% glycerol) to make a 100 ⁇ stock solution.
  • Kinetic assays were performed at 37°C in assay buffer (100 ⁇ Tris-HCI, pH 9.0, 100 mM KCI and 5.0 mM dithiothreitol) using final concentrations of 1 ⁇ IMPDH- 2, 0.5 mM NAD + (Enzo Life Sciences, catalogue # BML-KI282-0500) 1.0 mM inosine monophosphate (Sigma Aldrich, catalogue # I4625) and varying concentrations of inhibitor (prepared from stock solutions in DMSO, to give a final DMSO concentration of 1 %) in a total reaction volume of 100 ⁇ .
  • assay buffer 100 ⁇ Tris-HCI, pH 9.0, 100 mM KCI and 5.0 mM dithiothreitol
  • 6-thioinosine monophosphate (Carbosynth, catalogue # NT10843) was used at varying concentrations as a positive control. Reactions were monitored at 340 nM using a BMG LABTECH FLUOstar OmegaTM plate reader. Linear regression fit (r 2 ) and rates were calculated using Omega MARSTM LABTECH software.
  • Tank-1 Tankyrase-1 IC 50 ( ⁇ )
  • Tank-2 Tankyrase-2 IC 50 ( ⁇ )
  • PARP-1 PARP-1 IC 50 ( ⁇ )
  • IMPDH2 IMPDH2 IC 50 ( ⁇ )
  • Cyt Col Cytotoxicity vs. HT29 human colon adenocarcinoma cells IC 50 ( ⁇ )
  • Cyt Fib Cytotoxicity vs. FEK4 human fibroblasts IC 50 ( ⁇ )
  • Tridecane-6,8-dione (31.8 g, 150 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 2 85 (7.4 g, 30 mmol), potassium f-butoxide (6.8 g, 61 mmol) and copper powder (190 mg, 3.0 mmol) in 2-methyl-2- propanol (100 mL) for 16 h.
  • the mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether.
  • 3-Ethyl-5-nitroisoquinolin-1-one (4a) A solution of 3-ethyl-5-nitroisocoumarin 3a (520 mg, 2.4 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 3-ethyl-5-nitro- isoquinolin-1 -one 4a (200 mg, 38%) as bright yellow crystals: mp 196-197°C
  • 5-Nitro-3-pentylisoquinolin-1 -one (4b) A solution of 5-nitro-3-pentylisocoumarin 3b (70 mg, 0.3 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 5-nitro-3-pentyl- isoquinolin-1-one 4b (20 mg, 29%) as bright yellow crystals: mp 158-159°C
  • 5-Amino-3-pentylisoquinolin-1 -one 5b.
  • 5-Nitro-3-pentylisoquinolin-1-one 4b (240 mg, 0.9 mmol) was heated with tin(ll) chloride (550 mg, 2.9 mmol) in ethanol (20 mL) at 70°C for 4 h. The mixture was poured carefully into ice-water (200 mL). The
  • 5-Amino-3-phenylisoquinolin-1-one (5c).
  • 5-Nitro-3-phenylisoquinolin-1-one 4c (100 mg, 0.4 mmol) was heated with tin(ll) chloride (220 mg, 1.2 mmol) in ethanol (20 mL) at 70°C for 4 h. The mixture was poured carefully into ice-water (200 mL). The
  • 5-Amino-3-(2-methoxyphenyl)isoquinolin-1 -one hydrobromide 5g.
  • 5-Amino-1 - methoxy-3-(2-methoxyphenyl)isoquinoline 4g 33.5 mg, 0.12 mmol
  • hydrogen bromide in acetic acid 33%, 1.1 mL
  • 5- Amino-3-(3-methoxyphenyl)isoquinolin-1 -one hydrobromide 5h.
  • 5-Amino-1- methoxy-3-(3-methoxyphenyl)isoquinoline 4h 31 mg, 0.11 mmol was stirred with hydrogen bromide in acetic acid (33%, 1.1 ml_) at 65°C for 5 h.
  • 5-Amino-3-(2-chlorophenyl)isoquinolin-1-one hydrobromide (5i).
  • 5-Amino-3-(2- chlorophenyl)-1-methoxyisoquinoline 4i (40.4 mg, 0.14 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.6 ml_) at 65°C for 5 h.
  • 5-Amino-3-(3-chlorophenyl)isoquinolin-1 -one hydrobromide (5j).
  • 5-Amino-3-(3- chlorophenyl)-1-methoxyisoquinoline 4j (38.5 mg, 0.14 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.5 mL) at 65°C for 5 h.
  • 5-Amino-3-(2,6-dichlorophenyl)isoquinolin-1 -one hydrobromide (5k).
  • 5-Amino-3- (2,6-dichlorophenyl)-1-methoxyisoquinoline 13e (12.7 mg, 0.04 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.0 mL) at 65°C for 5 h.
  • 5-Amino-3-(4-fluorophenyl)isoquinolin-1 -one hydrobromide 5I.
  • 5-Amino-3-(4- fluorophenyl)-1-methoxyisoquinoline 13f 65 mg, 0.24 mmol was stirred with hydrogen bromide in acetic acid (33%, 3.5 mL) at 65°C for 5 h.
  • 5-Amino-3-(4-trifluorophenyl)isoquinolin-1 -one hydrobromide 5m.
  • 5-Amino-1- methoxy-3-(4-trifluoromethylphenyl)isoquinoline 13g 85.2 mg, 0.27 mmol
  • hydrogen bromide in acetic acid (33%, 4.0 mL) at 65°C for 7 h.
  • 5-Amino-3-(3-cyanophenyl)isoquinolin-1 -one hydrobromide 5n.
  • 5-Amino-3-(3- cyanophenyl)-1 -methoxyisoquinoline 13h 1 1.2 mg, 0.04 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.5 ml_) at 65°C for 16 h.
  • 5-Amino-3-(4-cyanophenyl)isoquinolin-1-one hydrobromide 5o.
  • 5-Amino-3-(4- cyanophenyl)-1-methoxyisoquinoline 13i 14 mg, 0.05 mmol was stirred with hydrogen bromide in acetic acid (33%, 1.0 ml_) at 65°C for 16 h.
  • Amino-1-methoxy-3-(2-trifluoromethylphenyl)isoquinoline 13j (22.4 mg, 0.07 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.25 ml.) at 65°C for 5 h.
  • Amino-1-methoxy-3-(3-trifluoromethylphenyl)isoquinoline 13k (70.5 mg, 0.22 mmol) was stirred with hydrogen bromide in acetic acid (33%, 3.75 mL) at 65°C for 7 h.
  • 5-Amino-3-(4-hydroxyphenyl)isoquinolin-1 -one hydrobromide 5r.
  • 5-Amino-3-(4- hydroxyphenyl)-1-methoxyisoquinoline 4r was stirred with hydrogen bromide in acetic acid (33%, 2.5 mL) at 65°C for 16 h.
  • Amino-1 -methoxy-3-(2-phenylethyl)isoquinoline 14 (40 mg, 0.14 mmol) was stirred with hydrogen bromide in acetic acid (33%, 2.0 mL) at 65°C for 16 h.
  • 5- nitroisoquinoline 9 (103 mg, 0.43 mmol) were added tris(dibenzylideneacetone)- dipalladium (1 1.6 mg, 0.013 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (22 mg, 0.054 mmol), 3-methoxybenzeneboronic acid (153 mg, 1.0 mmol) and potassium phosphate (203 mg, 0.96 mmol).
  • Degassed toluene (3.0 mL) was added and the mixture was stirred at 100°C for 16 h. The evaporation residue, in chloroform, was filtered.
  • 3-(2-Chlorophenyl)-1 -methoxy-5-nitroisoquinoline 11c.
  • 3-bromo-1 -methoxy-5- nitroisoquinoline 9 200 mg, 0.71 mmol
  • 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl 66 mg, 0.14 mmol
  • 2-chlorobenzeneboronic acid 165.7 mg, 1.06 mmol
  • potassium phosphate 450 mg, 2.1 mmol
  • 3-(3-ChlorophenyI)-1-methoxy-5-nitroisoquinoline 11d.
  • 3-bromo-1 -methoxy-5- nitroisoquinoline 9 200 mg, 0.71 mmol
  • tris(dibenzylideneacetone)- dipalladium 65 mg, 0.07 mmol
  • 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl 66 mg, 0.14 mmol
  • 3-chlorobenzeneboronic acid 166 mg, 1.1 mmol
  • potassium phosphate 450 mg, 2.1 mmol
  • 3-(2,6-Dichlorophenyl)-1-methoxy-5-nitroisoquinoline 11e.
  • 3-(4-Fluorophenyl)-1-methoxy-5-nitroisoquinoIine 11f.
  • 3-(4-Cyanophenyl)-1 -methoxy-5-nitroisoquinoline (11 i).
  • 3-bromo-1 -methoxy-5- nitroisoquinoline 9 (151.0 mg, 0.63 mmol) were added tris(dibenzylideneacetone)- dipalladium (58 mg, 0.063 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (58 mg, 0.014 mmol), 4-cyanobenzeneboronic acid (150 mg, 1.3 mmol) and potassium phosphate (279 mg, 1.3 mmol).
  • 3-(4-Hydroxyphenyl)-1 -methoxy-5-nitroisoquinoline 111.
  • 3-bromo-1 -methoxy-5- nitroisoquinoline 9 102 mg, 0.36 mmol
  • 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl 33.5 mg, 0.07 mmol
  • 4-hydroxybenzeneboronic acid 74 mg, 0.54 mmol
  • potassium phosphate 229 mg, 1.1 mmol.
  • Degassed toluene (3.0 mL) was added and the mixture was stirred at 100°C for 16 h.
  • 3-(4-Fluorophenyl)-1-methoxy-5- nitroisoquinoline 11f (16 mg, 0.05 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.0 mL) at 65°C for 7 h.
  • Benzonitrile (133 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate).
  • 2- (4-Chlorophenylethynyl)-3-cyanopyridine (28d). N,N-Diisopropylamine (10 mL) and tetrahydrofuran (10 mL) were added to 2-bromo-3-cyanopyridine 27 90 (400 mg, 2.2 mmol), bis(triphenylphosphine)palladium(ll) dichloride (76 mg, 0. 1 mmol), copper(l) iodide (40 mg, 0.22 mmol) and sodium ascorbate (25 mg, 0.12 mmol) under argon. The mixture was stirred at 40°C for 30 min. 4-Chlorophenylethyne (2.2 mmol) was added and the mixture was stirred at 40°C for 12 h. Evaporation and chromatography
  • 3-Phenyl-2,7-naphthyridin-1-one (37).
  • 3-Cyano-4-(phenylethynyl)pyridine 35 (50 mg, 0.25 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (5 ⁇ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2-methoxyethanol (10 mL).
  • 2-Phenylpyrido[2,3-cflpyrimidin-4-one (39a).
  • 2-Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol), benzamidine (60 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) were stirred in dimethyiformamide at room temperature under argon for 10 h, then at 80 °C for 3 h. The mixture was cooled and filtered. The solvent was evaporated from the filtrate. The residue was dissolved in methanol, filtered and evaporated.
  • 2-Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 4-methylbenzimidamide 48b (67 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethyiformamide (5 mL) at 80 °C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the filtrate was evaporated.
  • 2-(4-Trifluoromethylphenyl)pyridot2,3-d]pyrimidin-4-one (39c).
  • 2-Bromopyridine-3- carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 4-trifluoromethyl- benzimidamide 48b (94 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80 °C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the filtrate was evaporated.
  • 2-Bromopyridine-3- carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 4-chlorobenzimidamide 48b (77 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80 °C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the filtrate was evaporated.
  • N-Hydroxy-4-methylbenzimidamide (47b).
  • 4-Methylbenzonitrile 46b (940 mg, 8.0 mmol) in ethanol (30 mL) was added to hydroxylamine hydrochloride (3.34 g, 48 mmol) and sodium hydrogen carbonate (2.54 g, 24 mmol) in water (30 mL) and the mixture was stirred at 100°C for 3 h.
  • the ethanol was evaporated from the cooled mixture and the residue was poured into ice-cold water. The precipitate was collected by filtration, washed (water) and dried to give N-hydroxy-4-methylbenzimidamide 47b (940 mg, 78%) as a white powder: mp 138-139°C (lit.
  • N-Hydroxy-4-trifluoromethylbenzimidamide (47c).
  • 4-Trifluoromethylbenzonitrile 46c (1.37 g, 8.0 mmol) in ethanol (30 mL) was added to hydroxylamine hydrochloride (3.34 g, 48 mmol) and sodium hydrogen carbonate (2.54 g, 24 mmol) in water (30 mL) and the mixture was stirred at 100°C for 3 h. The ethanol was evaporated from the cooled mixture and the residue was poured into ice-cold water.
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol was heated with benzaldehyde (310 mg, 2.9 mmol) and sodium hydrogen sulphite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (dichloromethane ⁇ dichloromethane / methanol 97:3), followed by recrystallisation (ethyl acetate) gave 2-phenylquinazolin-4-one 51a (350 mg, 54%) as white crystals: mp 235-236°C (lit.
  • 2-(4-Methylphenyl)quinazolin-4-one (51 b).
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-methylbenzaldehyde 350 mg, 2.9 mmol
  • sodium hydrogen sulfite 454 mg, 4.3 mmol
  • the cooled mixture was poured into water and the precipitate was collected by filtration.
  • 2-(4-Methoxyphenyl)quinazolin-4-one (51c).
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-methoxybenzaldehyde 395 mg, 2.9 mmol
  • sodium hydrogen sulfite 454 mg, 4.3 mmol
  • the cooled mixture was poured into water and the precipitate was collected by filtration.
  • 2-(4-ChlorophenyI)quinazolin-4-one (51 d).
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-chlorobenzaldehyde (408 mg, 2.9 mmol)
  • sodium hydrogen sulfite (454 mg, 4.3 mmol)
  • the cooled mixture was poured into water and the precipitate was collected by filtration.
  • 2-(4-Bromophenyl)quinazolin-4-one (51 e).
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-bromobenzaldehyde 542 mg, 2.9 mmol
  • sodium hydrogen sulfite 454 mg, 4.3 mmol
  • the cooled mixture was poured into water and the precipitate was collected by filtration.
  • 2-(4-lodophenyI)quinazolin-4-one (51 f).
  • 2-(4-lodobenzamido)benzamide 50f (1.51 g, 4.1 mmol) was heated with aqueous sodium hydroxide (0.5 M, 400 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-Fluorophenyl)quinazolin-4-one 51 g.
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-fluorobenzaldehyde 360 mg, 2.9 mmol
  • sodium hydrogen sulfite 454 mg, 4.3 mmol
  • the cooled mixture was poured into water and the precipitate was collected by filtration.
  • 2-(4-Trifluoromethylphenyl)quinazolin-4-one (51 h).
  • 2-(4-Trifluoromethylbenzamido)- benzamide 50h (700 mg, 2.3 mmol) was stirred with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • the precipitate was collected by filtration and dried under vacuum to give 2-(4-trifluoromethylphenyl)quinazolin-4-one 51 h (620 mg, 94%) as a white solid: mp 305-308°C (lit.
  • 2-(4-Cyanophenyl)quinazolin-4-one (51 i).
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-cyanobenzaldehyde 380 mg, 2.9 mmol
  • sodium hydrogen sulfite 454 mg, 4.3 mmol
  • the cooled mixture was poured into water and the precipitate was collected by filtration.
  • 2-(4-Nitrophenyl)quinazolin-4-one (51 j).
  • 2-Aminobenzamide 49 400 mg, 2.9 mmol
  • 4-nitrobenzaldehyde (438 mg, 2.9 mmol)
  • sodium hydrogen sulfite (454 mg, 4.3 mmol)
  • the cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (dichloromethane / methanol 19:1 ), followed by
  • 2-(4-Ferrocenylphenyl)quinazolin-4-one 51 k.
  • a suspension of 2-(4-ferrocenylbenz- amido)benzamide 50k (400 mg, 1.1 mmol) in aqueous sodium hydroxide (0.5 M, 100 mL) was heated to 100°C for 16 h.
  • the mixture was cooled to room temperature and acidified to pH ⁇ 1 by addition of aqueous hydrochloric acid (9 M).
  • the aqueous phase was extracted thrice with ethyl acetate.
  • 8-Methyl-2-phenylquinazolin-4-one (54a).
  • 2-Benzamido-3-methylbenzamide 53a (93 mg, 0.37 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • the precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2- phenylquinazolin-4-one 54a (39 mg, 43%) as a white solid: mp 215-217°C (lit.
  • 8-Methyl-2-(4-methylphenyl)quinazolin-4-one (54b).
  • 2-(4-Methylbenzamido)-3- methylbenzamide 53b (100 mg, 0.37 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • the precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2-(4-methylphenyl)quinazolin-4-one 54b (75 mg, 81 %) as a white solid: mp 269-271 X (lit.
  • 2-(4-Methoxyphenyl)-8-methylquinazolin-4-one (54c).
  • 2-(4-Methoxybenzamido)-3- methylbenzamide 53c (100 mg, 0.35 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • the precipitate was collected by filtration, washed (water) and dried to give 2-(4-methoxyphenyl)-8-methylquinazolin-4-one 54c (68 mg, 73%) as a white solid: mp 225-228°C (lit.
  • 2-(4-Chlorophenyl)-8-methylquinazolin-4-one 54d.
  • 2-(4-Chlorobenzamido)-3- methylbenzamide 53d 100 mg, 0.35 mmol was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-Bromophenyl)-8-methylquinazolin-4-one 54e.
  • 2-(4-Bromophenyl)-8-methylquinazolin-4-one 54e.
  • 2-(4-Bromobenzamido)-3- methylbenzamide 53e 100 mg, 0.30 mmol was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 8-Methyl-2- ⁇ 4-trifluoromethylphenyl)quinazolin-4-one (54g).
  • 2-(4-Trifluoromethyl- benzamido)-3-methylbenzamide 53g (100 mg, 0.30 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • the precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2-(4-trifluoromethyl- phenyl)quinazolin-4-one 54g (71 mg, 78%) as a white solid: mp 258-259°C (lit.
  • 2- Benzamido-3-methoxybenzamide (56a). Dry pyridine (553 mg, 7.0 mmol) was added to 2-amino-3-methoxybenzamide 55 97 (1.0 g, 7.0 mmol) in dry tetrahydrofuran (7.0 mL), followed by benzoyl chloride (930 mg, 6.6 mmol) in dry tetrahydrofuran (7.0 mL). The mixture was stirred for 16 h.
  • 2-(4-Chlorophenyl)-8-methoxyquinazolin-4-one (57d).
  • 2-(4-Chlorobenzamido)-3- methoxybenzamide 56d (409 mg, 1.3 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-Bromophenyl)-8-methoxyquinazolin-4-one (57e).
  • 2-(4-Bromobenzamido)-3- methoxybenzamide 56e (463 mg, 1.3 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-Fluorophenyl)-8-methoxyquinazolin-4-one (57f).
  • 2-(4-Fluorobenzamido)-3- methoxybenzamide 56f 400 mg, 1.4 mmol was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h.
  • the mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 8-Hydroxy-2-phenylquinazolin-4-one (58a). 8-Methoxy-2-phenylquinazolin-4-one 57a (500 mg, 2.0 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 6.0 mL) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 100 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 8-Hydroxy-2-(4-methylphenyl)quinazolin-4-one (58b). 8-Methoxy-2-(4-methyl- phenyl)quinazolin-4-one 57b (100 mg, 0.4 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.5 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 8-Hydroxy-2- ⁇ 4-hydroxyphenyl)quinazolin-4-one (58c).
  • 8-Methoxy-2-(4-methoxy- phenyl)quinazolin-4-one 57c (100 mg, 0.35 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.4 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-ChlorophenyI)-8-hydroxyquinazolin-4-one (58d).
  • 2-(4-Chlorophenyl)-8- methoxyquinazolin-4-one 57d (100 mg, 0.35 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.4 ml_) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-Fluorophenyl)-8-methoxy- quinazolin-4-one 57f (100 mg, 0.37 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.5 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 8-Hydroxy-2-(4-trifluoromethylphenyl)quinazolin-4-one (58g).
  • 8-Methoxy-2-(4- trifluoromethylphenyl)quinazolin-4-one 57g (76 mg, 0.24 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.9 mL) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 20 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 8-Hydroxy-2-(4-nitrophenyl)quinazolin-4-one (58h). 8-Methoxy-2-(4-nitrophenyl)- quinazolin-4-one 57 h (100 mg, 0.34 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.3 ml_) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 ml_) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2.
  • 2-(4-Aminophenyl)quinazolin-4-one (59a). 2-(4-Nitrophenyl)quinazolin-4-one 51j (75 mg, 0.28 mmol), in methanol (6 ml_) and dimethylformamide (6 ml_), was stirred with palladium on charcoal (10%, 10 mg) and ammonium formate (170 mg, 2.7 mmol) under argon for 3 h. The mixture was filtered through a pad of Celite.
  • 2-(4-HydroxyphenyI)quinazolin-4-one 60a.
  • 2-(4-Methoxyphenyl)quinazolin-4-one 51c 467 mg, 1.9 mmol was boiled under reflux with boron tribromide in dichloro- methane (1.0 M, 1 1 ml_) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 100 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The mixture was extracted with ethyl acetate (3 x 20 mL).
  • 2-(4-Hydroxyphenyl)-8-methylquinazolin-4-one 60b.
  • 2-(4-Methoxyphenyl)-8- methylquinazolin-4-one 54c (25 mg, 0.094 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 0.56 mL) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 10 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The mixture was extracted with ethyl acetate (3 x 20 mL).
  • borane. pyridine complex (0.10 mL). The mixture was stirred for 10 d. Each day, additional borane. pyridine complex (0.01 mL) was added. The solvent was evaporated. The residue was dissolved in water (5 mL) and the mixture was sonicated.
  • lodomethane (179 mg, 1.26 mmol) was stirred with 7-(4-bromophenyl)-1 ,6- naphthyridin-5-one 30i (64 mg, 0.21 mmol) in dry dimethylformamide (5.0 mL) for 3 d. The mixture was poured into ethyl acetate (3.0 mL).
  • lodomethane (343 mg, 2.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C, then at 20°C for 16 h.
  • Water (1.0 mL) was added.
  • the mixture was diluted with dichloromethane. This mixture was washed thrice with brine and dried.
  • reaction mixture was then cooled to 0°C and quenched with deuterium oxide (0.1 1 mL, 6.0 mmol) and stirred for 10 min.
  • deuterium oxide 0.1 1 mL, 6.0 mmol
  • the mixture was diluted with dichloromethane and washed thrice with saturated brine.
  • Butyllithium (2.5 M in hexanes, 0.46 mL, 1.14 mmol) was added to dry
  • Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 1 ,3-di-(4- methoxyphenyl)propane-1 ,3-dione 102 (142 mg, 0.5 mmol) and caesium carbonate (163 mg, 0.5 mmol) in acetonitrile (15 mL) under reflux for 2 d. The mixture was cooled and poured into water (10 mL). The mixture was extracted with dichloromethane (3 ⁇ 25 mL). The combined organic layers were washed with saturated brine and dried. The solvent was evaporated.
  • Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 1 ,3-di-(4- chlorophenyl)propane-1 ,3-dione 104 (146.5 mg, 0.5 mmol) and caesium carbonate (163 mg, 0.5 mmol) in acetonitrile (15 mL) under reflux for 12 h. The mixture was cooled and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 ⁇ 25 mL). The combined organic layers were washed with saturated brine and dried. The solvent was evaporated.
  • Seimiya, H.; Muramatsu, Y.; Ohishi, T.; Tsuruo, T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell 2005, 7, 25-37. Seimiya, H.; The telomeric PARP, tankyrases, as targets for cancer therapy. Br. J. Cancer 2006, 94, 341-345.
  • Herpes simplex virus requires poly(ADP-ribose) polymerase activity for efficient replication and induces extracellular signal-related kinase-dependent phosphorylation and ICPO-dependent nuclear localization of tankyrase 1. J. Virol. 2012, 86, 492-503.

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Abstract

The present invention relates to a compound of formula I wherein X is C(R6) or N, Y is C or N, and ring A, ring B, R1 and R2 have the meanings defined herein, provided that when ring B is carbocyclic, X is C(R6); or a pharmaceutically acceptable salt or solvate thereof. The compounds are tankyrase-1 and tankyrase-2 inhibitors and are useful in the treatment of a number of conditions, including cancer.

Description

TANKYRASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to compounds that are capable of inhibiting tankyrases. The present invention also relates to compounds for use in medicine.
BACKGROUND TO THE INVENTION
The poly(ADP-ribose)polymerases (PARPs) form a family of enzymes that catalyse the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to substrate proteins to build polymers (PAR) which are highly negatively charged. The archetypal PARP, PARP-1 , is activated in response to damage to DNA. The isoform PARP-2 responds similarly.
Small-molecule inhibitors of PARP-1 and PARP-2 are in clinical trial in combination as potentiators of the anti-tumour activities of DNA-damaging drugs and ionising radiation and as single-agent drugs in BRCA-deficient tumours.1 These inhibitors have also shown a variety of other potential applications in animal models, as anti-angiogenic and anti-metastatic agents in cancer, in protection against ischaemia-reperfusion injury and in inflammatory diseases.2"7 Other members of the PARP family of enzymes have other functions within the cell and are not activated by damage to DNA.
Tankyrase
Tankyrase-1 (also known as PARP-5a) was first reported in 1998 as a protein carrying ankyrin repeats and a PARP-like catalytic domain.8 The isoform tankyrase-2 (PARP- 5b) was discovered some three years later.9 Tankyrase-1 and tankyrase-2 have several cellular functions in common (giving redundancy) but some functions are performed selectively by one or the other.
Tankyrase-1 and tankyrase-2 are both multi-domain proteins, with the only significant differences being in the N-terminal HPS domain of tankyrase-1 , which tankyrase-2 lacks. The catalytic domains are located at the C-terminus and are very similar. These catalytic domains contain the binding site for the substrate NAD+ and are the target sites for drug design. Tankyrases & telomeres
As proliferating cells, especially cancer cells, go through the cell cycle, a new copy of the chromosomal DNA must be synthesised, using the existing DNA as template. Replication of DNA cannot proceed to the ends of the strands; there would be loss of genetic information with each cycle without protection of the DNA ends. Telomeres provide this protection. Telomeres are lengths of untranscribed DNA, attached to the ends of chromosomes, which are complexed with proteins. With each cell cycle, the telomeres shorten but are built up again by the action of telomerase. Somatic (non- growing) cells have little or no telomerase activity, as they are not in cycle, but >90% of tumour cells have active telomerase, giving them unlimited growth potential.
Maintenance of telomeres during proliferation is important to the immortality of malignant cell lines; inhibition of the enzyme directly responsible for telomere elongation (telomerase) has been a major goal in anti-cancer drug design.10,12
Compounds which inhibit different parts of the telomerase machinery have been developed but many, e.g. the planar macrocycles which stabilise the G quadruplex, lack potency, lack selectivity (binding also to double-stranded DNA) or are not druglike.10
Telomere repeat binding factor (TRF-1) binds to the telomeres and blocks access to telomerase, regulating the activity of the latter complex. Tankyrase-1 is located at the telomeres, binding along their length and to TRF-1.8,13
Tankyrase-1 poly(ADP-ribosyl)ates TRF-1 , forming oligomers of ca. 20 ADP-ribose units. The ADP-ribosylated TRF-1 leaves the telomere, allowing telomerase access to the telomere to carry out its telomere-lengthening activity. The loss of TRF-1 from the telomere is an intrinsically reversible process, rendered irreversible by ubiquitination and degradation of the ADP-ribosylated TRF-1. Thus, tankyrase-1 acts to promote elongation of telomeres.
On this basis, inhibition of tankyrase-1 has been proposed as a target for drug design for cancer therapy.14, 1S. This approach to preventing elongation of telomeres may not suffer from the long induction time seen with some telomerase inhibitors.16 Tankyrases & mitosis
Soon after the discovery of tankyrase-1 , it was found to be localised also at
centrosomes, part of the cellular apparatus that is responsible for separating the two sets of DNA molecules during mitosis (cell division).8 It has also been reported that poly(ADP-ribosyl)ation is required for assembly and structure of the mitotic spindle and tankyrase-1 has been identified as the PARP enzyme responsible.17,18
Simultaneously, it has been observed that siRNA knockdown of tankyrase-1 arrested in the early anaphase of the cell cycle, probably owing to failure to resolve sister telomeres;19 NuMA (nuclear mitotic apparatus protein) was also later identified as the major target of tankyrase-1 -mediated poly(ADP-ribosyl)ation in the mitotic
apparatus.20,21 Silencing of NuMA results in apoptotic disintegration of the cell nucleus.22
In the light of these observations, inhibition of tankyrase-1 has been proposed as a target in BRCA-associated tumours.23 Inhibition of the tankyrases should therefore interfere with cell division and proliferation, an important step in the progression of cancer.
Tankyrases and Wnt signalling
The intracellular Wnt signalling pathway is critical in the growth and development of the embryo. This development depends upon regulated cell division and proliferation. Thus, it is not surprising that Wnt signalling is important in the growth and development of several cancers.24"26
Mutations that lead to activation of the Wnt pathway are present in cancer of the colon, stomach, liver, kidney, lung, ovary, thyroid, pancreas and prostate.24 Notably, ca. 90% of colon cancers and all pancreatic adenocarcinomas show unusual Wnt signalling.25,27"
29
In 2009, library screening was used to identify XAV939 as an inhibitor of the Wnt system.30 It was also shown that this inhibition was due to inhibition of tankyrase-1 and -2 and that it led to antiproliferative activity in DLD-1 human colon carcinoma cells. Thus, XAV939 is a known tankyrase inhibitor.
Figure imgf000006_0001
Subsequently, it has been shown that three further inhibitors of the tankyrases (highly selective but of limited potency and identified through library screening) decrease canonical Wnt signalling in colon cancer cells, decrease spontaneous carcinogenesis in the colons of experimental mice and inhibit the growth of experimental SW480 human colon tumours in SCID immunocompromised mice.31 ,32 The involvement of tankyrases in this pathway was confirmed by a crystal structure showing binding of axin, a component of the Wnt pathway, to tankyrase.33
Tankyrases as therapeutic targets
Cancer
That tankyrase-1 could be a target for design of drugs for the treatment of cancer has been recognised,16 building on the requirement for its activity for re-elongation of the telomeres after replication of tumour cells. This was followed by observations that one or both tankyrases are over-expressed in high grade non-Hodgkin's lymphomas,34 breast cancer,35"37 colon cancer,38,39 gastric cancer,40 brain tumours 41 bladder cancer42 and chronic myeloid leukaemia.43
A role for inhibition of tankyrases in the treatment of BRCA-associated cancers has also been demonstrated.44
Further validation of the effects of inhibition of tankyrases in cancer cells is provided by inhibition of invasion by human cervical tumour cells when the tankyrase activity is knocked down with an miRNA45 and the synergistic enhancement of telomere shortening when both tankyrase and telomerase activities are inhibited.46 The anti-proliferative activity of tankyrase inhibitors, mediated by inhibition of the Wnt signalling pathway, has also been demonstrated.30"32
Therefore, small-molecule inhibitors of the tankyrases therefore have potential in the treatment of cancer by three mechanisms in the cell:
(i) shortening of telomeres as the cells replicate;
(ii) interference with the function of the mitotic spindle and centrosome as the cells divide, leading to aborted division and apoptosis; and
(iii) inhibition of the Wnt signalling pathway which regulates proliferation in many tumour types.
The present invention provides inhibitors of tankyrases and thus provides compounds which are suitable for use in medicine, in particular in the treatment of cancer.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a compound of formula I:
Figure imgf000007_0001
Formula I wherein R-i is a substituent L-R5 wherein L is an optionally substituted aromatic or heteroaromatic linking group and R5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R2 may not be absent;
X is C(Re) or N;
R6 is hydrogen or C 6 alkyl; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
provided that when ring B is carbocyclic, X is C(R6); and with the exception of the following compounds:
7-Phenyl-1 ,6-naphthyridin-5-one;
2-Phenylpyrido[2,3-c/]pyrimidin-4-one
2-(4-Chlorophenyl)pyrido[2,3-c ]pyrimidin-4-one.
In one aspect the present invention provides a compound of formula IA:
Figure imgf000008_0001
Formula IA wherein Ri is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I, as defined above, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
According to another aspect of the present invention, there is provided a
pharmaceutical composition comprising a compound of formula IA:
Figure imgf000009_0001
Formula IA wherein is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms;
and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
According to another aspect of the present invention, there is provided a compound of formula I, as defined above, for use in medicine.
In one aspect, the present invention provides a compound for use in medicine, wherein the compound is of formula IA:
Figure imgf000009_0002
Formula IA wherein R-i is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms. According to a further aspect of the present invention, there is provided use of a compound of formula Γ:
Figure imgf000010_0001
Formula Γ wherein is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R2 may not be absent;
X is C(RB) or N;
R6 is hydrogen or C 6 alkyl; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
for the in vitro inhibition of a tankyrase enzyme. The tankyrase may be tankyrase-1 , tankyrase-2, or a mixture thereof.
According to one aspect of the present invention, there is provided the use of a compound for the in vitro inhibition of a tankyrase enzyme, wherein the compound is of formula IA:
Figure imgf000011_0001
Formula IA wherein is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyi;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyi;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
According to a further aspect of the present invention, there is provided a compound of formula Γ:
Figure imgf000011_0002
Formula I' wherein:
RT is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyi;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyi; provided that when Y is C, R2 may not be absent;
X is C(R6) or N;
R6 is hydrogen or C-|-6 alkyl; and ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
for use in the treatment of a disease or condition associated with tankyrase. The tankyrase may be tankyrase-1 , tankyrase-2, or a mixture thereof.
According to another aspect of the present invention, there is provided a compound for use in the treatment of a disease or condition associated with tankyrase, wherein the compound is of formula IA:
Figure imgf000012_0001
Formula IA wherein R1 is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
According to another aspect of the present invention, there is provided a compound of formula I, as defined above, for use in the treatment of cancer.
According to another aspect of the present invention, there is provided a compound for use in the treatment of cancer, wherein the compound is of formula IA:
Figure imgf000013_0001
Formula IA wherein F is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
For ease of reference, these and further aspects of the present invention are now discussed under appropriate section headings. However, the teachings under each section are not necessarily limited to each particular section and may be combined.
DETAILED DESCRIPTION
Definitions
The term "hydrocarbyl group" as used herein means a group comprising at least C and H and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo, alkoxy, nitro, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen. A non-limiting example of a hydrocarbyl group is an acyl group.
A typical hydrocarbyl group is a hydrocarbon group. Here the term "hydrocarbon" means any one of an alkyl group, an alkenyl group, an alkynyl group, which groups may be linear, branched or cyclic, or an aryl group. The term hydrocarbon also includes those groups but wherein they have been optionally substituted. If the hydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
In some aspects of the present invention, one or more hydrocarbyl groups is independently selected from optionally substituted alkyl group, optionally substituted haloalkyl group, aryl group, alkylaryl group, alkylarylalkyl group, and an alkene group. The term "alkyl" (either when used alone or as part of a larger group, such as arylalkyl) means a saturated hydrocarbyl radical containing a straight or branched chain of carbon atoms. In some aspects of the present invention, one or more hydrocarbyl groups is independently selected from C1-C10 alkyl group, such as C C6 alkyl group, and C Cs alkyl group. Typical alkyl groups include C-i alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, and C8 alkyl.
In some aspects of the present invention, one or more hydrocarbyl groups is independently selected from alkene groups (also referred to as alkenyl groups when the alkene group has only one point of attachment to the rest of the molecule). The term "alkenyl" means a hydrocarbyl radical containing a straight or branched chain of carbon atoms and at least one C=C bond. Typical alkene groups include C-i-C10 alkene group, C-\-C6 alkene group, C C3 alkene group, in particular C2-C10 alkene group, C2- C6 alkene group, C2-C3 alkene group, such as C2, C3, C4, C5, C6, or C7 alkene group. In a preferred aspect the alkene group contains 1 , 2 or 3 C=C bonds. In a preferred aspect the alkene group contains 1 C=C bond. In some preferred aspects at least one C=C bond or the only C=C bond is to the terminal C of the alkene chain, that is the bond is at the distal end of the chain to the ring system.
In some aspects of the present invention, one or more hydrocarbyl groups is independently selected from alkyne groups (also referred to as alkynyl groups when the alkyne group has only one point of attachment to the rest of the molecule). The term "alkynyl" means a hydrocarbyl radical containing a straight or branched chain of carbon atoms and at least one C≡C bond. Typical alkyne groups include C2-C10 alkyne group, C2-C6 alkyne group, C2-C3 alkyne group, such as C2, C3, C4, C5, C6, or C7 alkene group. In a preferred aspect the alkyne group contains 1 , 2 or 3 C≡C bonds. In a preferred aspect the alkyne group contains 1 C≡C bond. In some preferred aspects at least one C≡C bond or the only C≡C bond is to the terminal C of the alkyne chain, that is the bond is at the distal end of the chain to the ring system.
In some aspects of the present invention, one or more hydrocarbyl groups is independently selected from cycloalkyl groups. The term "cycloalkyl" means a saturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly. Cx cycloalkyl and CX_Y cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. Typical cycloalkyl groups include C3-C 0 cycloalkyl groups, C4-C8 cycloalkyl groups, C5-C7 cyclohexyl groups. For example, C3_10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, adamantan-1 -yl, and decahydronaphthyl.
In some aspects of the present invention, one or more hydrocarbyl groups is independently selected from oxy hydrocarbyl groups.
One particular hydrocarbyl group is an oxy hydrocarbyl group. The term "oxyhydrocarbyl" group as used herein means a group comprising at least C, H and O and may optionally comprise one or more other suitable substituents. Examples of oxyhydrocarbyl groups include alkoxy groups (where an alkyl group, as defined above, is attached to the rest of the molecule via an oxygen atom, and include C C10 alkoxy group, such as C C6 alkoxy group, and CrC3 alkoxy group, typical alkoxy groups include alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, C7 alkoxy, and C8 alkoxy) and alkoxyalkyl groups (where an alkyl group, as defined above, is substituted with an alkoxy group, as defined above) Examples of such substituents may include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the oxyhydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the oxyhydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulfur and nitrogen.
In one embodiment of the present invention, the oxyhydrocarbyl group is a oxyhydrocarbon group. Here the term "oxyhydrocarbon" means any one of an alkoxy group (as defined above), an oxyalkenyl group, an oxyalkynyl group, which groups may be linear, branched or cyclic, or an oxyaryl group (aryl being as defined below). The term oxyhydrocarbon also includes those groups but wherein they have been optionally substituted. If the oxyhydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
Typically, the oxyhydrocarbyl group is of the formula C1-60 (such as a C1-30).
The term "heterocyclic" ("heterocyclyl" when the group is monovalent, i.e. has one point of attachment to the rest of the molecule; "heterocyclene" when the group is divalent, i.e. has two points of attachment to the rest of the molecule) refers to a saturated or partially unsaturated (preferably saturated) monocyclic or bicyclic (preferably monocylic) group having 3 to 14 (preferably 3 to 10, such as 4 to 8, such as 5, 6 or 7) ring atoms composed of carbon atoms and 1 to 4 heteroatoms (such as 1 to 3, such as 1 or 2, such as 1 heteroatom) independently selected from nitrogen, oxygen, and sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized. Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C3.6 heterocyclyl refers to a heterocyclyl group having 3 to 6 carbon atoms and 1 to 4 heteroatoms as ring members). The heterocyclyl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of monocyclic heterocyclyl groups include oxiranyl, thiaranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1 ,4-dioxanyl, 1 ,4-oxathianyl, morpholinyl, 1 ,4- dithianyl, piperazinyl, 1 ,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1 ,4-dioxepanyl, 1 ,4-oxathiepanyl, 1 ,4-oxaazepanyl, 1 ,4-dithiepanyl, 1 ,4-thiazepanyl, 1 ,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1 ,2,3,4- tetrahydropyridinyl, and 1 ,2,5,6-tetrahydropyridinyl. Preferred heterocyclic groups include piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,
tetrahydropyranyl and tetrahydrothiopyranyl, especially piperidyl.
The term "aromatic" ("aryl" when the group is monovalent, i.e. has one point of attachment to the rest of the molecule and "arylene" when the group is divalent, i.e. has two points of attachment to the rest of the molecule) refers to a fully unsaturated monocyclic aromatic hydrocarbons (i.e. rings having 4n+2 pi electrons, where n ia an integer, preferably 1 to 3, such as 1 or 2, preferably 1 ) and to polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ring members (e.g., C6-14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members). The aryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of aryl groups include C6- C-I4 aryl groups, such as C6-C 0 aryl group, include phenyl, biphenyl, indenyl, naphthyl, and fluorenyl groups. Preferably the aryl group is a phenyl or naphthyl group, especially a phenyl group. Typical arylene groups include phenylene and napthylene, especially phenylene, and particularly 1 ,4-phenylene.
The term "heteroaromatic" ("heteroaryl" when the group is monovalent, i.e. has one point of attachment to the rest of the molecule and "heteroarylene" when the group is divalent, i.e. has two points of attachment to the rest of the molecule) refer,
respectively, to an unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each of the groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms (such as 1 to 3, 1 to 2, or 1 heteroatom) independently selected from nitrogen, oxygen, and sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized. Both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g. ,
Ci-10 heteroaryl refers to a heteroaryl group having 1 to 10 carbon atoms and 1 to 4 heteroatoms as ring members) and include any bicyclic group in which any of the above-listed monocyclic heterocycles are fused to a benzene ring. The heteroaryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3- triazolyl, 1 ,3,4-triazolyl, 1 -oxa-2,3-diazolyl, 1 -oxa-2,4-diazolyl, 1 -oxa-2,5-diazolyl, 1 -oxa- 3,4-diazolyl, 1-thia-2,3-diazolyl, 1 -thia-2,4-diazolyl, 1 -thia-2,5-diazolyl, 1 -thia-3,4- diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzo[d][1 ,3]dioxole, benzothienyl, benzo[c]thienyl, indolyl, 3H-indolyl, isoindolyl, 1 H- isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H- pyrrolo[2,3-b]pyridinyl, 1/- -pyrrolo[2,3-c]pyridinyl, 1/- -pyrrolo[3,2-c]pyridinyl, 1H- pyrrolo[3,2-6]pyridinyl, 3H-imidazo[4,5-6]pyridiriyl, 3 -/-imidazo[4,5-c]pyridinyl, 1/-/- pyrazolo[4,3-ib]pyridinyl, 1/-/-pyrazolo[4,3-c]pyridinyl, 1/-/-pyrazolo[3,4-c]pyridinyl, 1H- pyrazolo[3,4-6]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5- a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, pyrrolo[1 ,2-ib]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,6- naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, 1 ,5-naphthyridinyl, 2,6- naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-6]pyrazinyl, pyrido[3,4- /)]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3- )]pyrazinyl, and pyrimido[4,5- cfjpyrimidinyl. Preferably the heteroaromatic group is monocyclic. Preferred heteroaryl groups include pyrrolyl, pyridinyl, furyl and thienyl, especially pyridyl and thienyl.
Compounds of the Invention
According to one aspect of the invention, there is provided a compound of formula I:
Figure imgf000018_0001
Formula I wherein R is a substituent L-R5 wherein L is an optionally substituted aromatic or heteroaromatic linking group and R5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R2 may not be absent;
X is C(Re) or N;
R6 is hydrogen or C 6 alkyl; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
provided that when ring B is carbocyclic, X is C(R6); and with the exception of the following compounds:
7-Phenyl-1 ,6-naphthyridin-5-one;
2-Phenylpyrido[2,3- /]pyrimidin-4-one
2-(4-Chlorophenyl)pyrido[2,3-d]pyrimidin-4-one.
As previously mentioned, in one aspect the present invention provides a compound of formula IA:
Figure imgf000019_0001
Formula IA wherein R-i is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl;
X is CH or N; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
For the avoidance of doubt, the compounds of the present invention also include pharmaceutically acceptable forms thereof such as salts, solvates and other derivatives thereof, as defined in more detail below.
Y
The group Y is C or N.
In one embodiment, Y is C. In one embodiment, Y is N. Ri
The group R-, is a substituent L-R5.
In some aspects, L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl.
In some aspects, L is an optionally substituted aromatic or heteroaromatic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl.
L may be linked directly to ring A or it may be linked via a suitable bridging group, such as a C C3 alkyl group. Preferably, L is linked directly to ring A.
In one embodiment, L is an optionally substituted cyclic linking group comprising from 5 to 7 members and at least one carbon atom and optionally at least one hetero atom. In one embodiment, L is an optionally substituted carbocyclic linking group comprising from 5 to 7 members. In one embodiment, L is an optionally substituted heterocyclic linking group comprising from 5 to 7 members. In one embodiment, L is an optionally substituted heterocyclic linking group comprising from 5 to 7 members and at least one nitrogen atom.
In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group comprises from 5 to 7 members. In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group comprises from 5, 6 or 7 members. In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group comprises 6 members.
In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group may be saturated or unsaturated, aromatic or aliphatic. In one embodiment, the above mentioned cyclic, carbocyclic or heterocyclic group is aromatic. In one embodiment, L is an arylene group, preferably a phenylene group, especially a 1 ,4-phenylene group. In another embodiment, L is a heteroaromatic group, especially a monocyclic heteroarylene group, such as pyrrolyl, pyridyl, furyl or thienyl group, especially pyridyl or thienyl. R5 is H, halo, hydroxy, nitriie, nitro, amino, or hydrocarbyl. When R5 is H, L is unsubstituted.
In one embodiment, R5 is halo, hydroxy, nitriie, nitro, amino, or hydrocarbyl.
In one embodiment, R5 is H, halo, hydroxy, nitriie, nitro, amino, C C10 alkyi, d-C-io haloalkyl, C2-C 0 alkenyl, C2-C10 alkynyl, C C10 alkoxy, C5-C7 cycloalkyl, heterocyclyl, heterocyclyl-C C^ alkyi, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, acylamide, aryl-C -Ci o alkyi, aryl-C2-C 0 alkenyl, aryl-C2-C10 alkynyl, heterocyclyl-C C-|0 alkyi, heteroaryl-C1-C10 alkyi, ferrocenyl, or aryl-(C1-3 alkoxy)carbonylamino-C C3 alkyi.
In one embodiment, R5 is H, halo, hydroxy, nitriie, nitro, amino, C C10 alkyi, C C10 haloalkyl, C2-C 0 alkenyl, C2-C 0 alkynyl, C C10 alkoxy, C5-C7 cycloalkyl, heterocyclyl aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, acylamide, phenyl-C C6 alkyi, phenyl-C2-C6 alkenyl, phenyl-C2-C6 alkynyl, heterocyclyl-C C6 alkyi, ferrocenyl, or (phenylmethoxycarbonyl)aminomethyl.
In one embodiment, R5 is H, halo, hydroxy, nitriie, nitro, amino, C^C^ alkyi, CrC10 haloalkyl, C2-C10 alkenyl, C C10 alkoxy, C5-C7 cycloalkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, or acylamide.
In one embodiment, R5 is halo, hydroxy, nitriie, nitro, amino, C-|-C10 alkyi, C C10 haloalkyl, C2-C10 alkenyl, C C10 alkoxy, C5-C7 cycloalkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyi amide, or acylamide.
In one embodiment, R5 is H.
In one embodiment, the halo is F, CI or Br.
In one embodiment, the C C10 haloalkyl group is a C C6 halo alkyi group, such as CF3, CCI3, CHF2, CH2CF3 etc.
In one embodiment, the hydrocarbyl group is a hydrocarbon group or an
oxyhydrocarbon group. In one embodiment, the hydrocarbyl group is an alkyl group, an alkoxy group, an alkenyl group, an aryl group, a heteroaryl group, a heterocyclic group or an alkynyl group. In one embodiment, the hydrocarbyl group is selected from C C10 alkyl, such as C C6 alkyl, and C C3 alkyl. In one embodiment, the hydrocarbyl group is selected from C2-C10 alkenyl, such as C2-C6 alkenyl, and C2-C3 alkenyl. In one embodiment, the hydrocarbyl group is selected from C2-C10 alkynyl, such as C2-C6 alkynyl, and C2-C3 alkynyl.
In one embodiment, the hydrocarbyl group is selected from C -5 alkyl groups, C3-6 cycloalkyi groups, ether groups containing from 1 to 5 carbons, thioether groups containing from 1 to 5 carbons, d-5 alkoxy groups, C -5 haloalkyi group, alkylamines, amides, alkyl amides, dialkyl amides, or acylamides.
In one embodiment, R5 is halo, Ci-C 0 alkyl, C C10 alkoxy, C C10 haloalkyi, hydroxy, nitrile, nitro, amino, alkylamino, heterocyclyl-CrC alkyl, ferrocenyl, or (phenylmethoxycarbonyl)aminomethyl.
In one embodiment, R5 is halo, Ci-C 0 alkyl, C-|-C 0 alkoxy, Ci-C 0 haloalkyi, hydroxy, nitrile, nitro, or amino. In one embodiment, R5 is halo, CVC10 alkyl, C-rC10 alkoxy, Cr C10 haloalkyi, or hydroxy. In one embodiment, R5 is halo, C C10 alkyl, Ci-C-|0 alkoxy, or C-|-C 0 haloalkyi. In one embodiment, R5 is CI, F, Br, C C 0 alkyl, C-|-C10 alkoxy, or C-r C-io haloalkyi. In one embodiment, R5 is CI, F, Br, C C10 alkyl, C C10 alkoxy, or C C10 haloalkyi. In one embodiment, R5 is CI, F, Br, C^-C6 alkyl, C -Ce alkoxy, or C^Ce haloalkyi. In one embodiment, R5 is CI, F, Br, Ci-C3 alkyl, C C3 alkoxy, or C C3 haloalkyi. In one embodiment, R5 is CI, F, methyl, ethyl, methoxy, ethoxy, CF3 or CCI3.
In one embodiment, R5 is an alkoxy group, preferably a methoxy or an ethoxy group.
In one embodiment, R5 is an alkyl group, preferably a methyl or an ethyl group.
In one embodiment, R5 is a haloalkyi group, preferably a CI or F containing haloalkyi group.
In one embodiment, R5 is a group (CH2)nNR6R7 where n is from 0 to 5, and R6 and R7 are independently selected from H and hydrocarbyl.
In one embodiment, R5 is a group (CH2)nNR6R7 where n is from 0 to 5, and R6 and R7 are independently selected from H, C C6 alkyl, -(CO)O-alkyl, -(CO)O-alkylaryl and C C6 alkene.
In one embodiment, R5 is nitro or nitrile.
R5 may be located at any position on the cyclic group L. However, in one embodiment, L is an optionally substituted 6 membered ring as defined above, and R5 is present on the ring at the para position. In one embodiment, L is an optionally substituted 6 membered ring as defined above, and R5 is present on the ring at the meta or ortho position.
L is optionally substituted. In one embodiment, the optional substituent is present and is selected from halo, hydroxy, or C C6 alkyl.
In one embodiment, R is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C†0 alkyl, C C 0 haloalkyl, C2-C 0 alkenyl, C2-C 0 alkynyl, C C10 alkoxy, C5-C7 cycloalkyl, heterocyclyl, heterocyclyl-C-i-C10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-C C 0 alkyl, aryl-C2-C10 alkenyl, aryl-C2-C 0 alkynyl, heterocyclyl-Ci-C10 alkyl, heteroaryl-C C 0 alkyl, ferrocenyl, or ary C^ alkoxy)carbonylamino-Ci-C3 alkyl.
In one embodiment, Ri is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is H, halo, C-1-C10 alkyl, C-i-Ci0 alkoxy, C C10 haloalkyl, hydroxy, nitrile, nitro, or amino.
In one embodiment, R-, is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is halo, C C10 alkyl, C C10 alkoxy, Cr C10 haloalkyl, hydroxy, nitrile, nitro, or amino.
In one embodiment, R-i is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is halo, C C6 alkyl, d-Ce alkoxy, C^-Ce haloalkyl, hydroxy, nitrile, nitro, or amino.
In one embodiment, R! is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is halo, C-|-C6 alkyl, C-|-C6 alkoxy, or Ci-C6 haloalkyl. In one embodiment, Ri is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is selected from H, methoxy, ethoxy, methyl, ethyl, C C6 halo alkyl group, (CH2)nNR6R7 where n is from 0 to 5, and R6 and R7 are independently selected from H, C-|-C6 alkyl, and C C6 alkene, CI, F, nitro or nitrile.
In one embodiment, is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is selected from methoxy, ethoxy, methyl, ethyl, C^-Ce halo alkyl group, (CH2)nNR6R7 where n is from 0 to 5, and R6 and R7 are independently selected from H, C C6 alkyl, and C C6 alkene, CI, F, nitro or nitrile.
In any of the above embodiments, L may not be further substituted. R2
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl.
In one embodiment, R2 is absent. In the compounds of formula I, when Y is C, R2 may not be absent. In the compounds of formula IV, when Y is N and ring B is pyridine, R2 may be absent. In the compounds of formula V, when Y is N and ring B is piperidine, R2 may or may not be absent.
In one embodiment, R2 is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl.
In one embodiment, R2 is selected from halo, hydroxy, C C 0 alkyl, Ci-C 0 alkoxy, C-,- C10 haloalkyl, nitro, nitrile, and oxo. In one embodiment, R2 is selected from halo, hydroxy, C Ce alkyl, C^Ce alkoxy, C C6 haloalkyl, nitro, nitrile, and oxo. In one embodiment, R2 is selected from halo, hydroxy, C-|-C3 alkyl, C C3 alkoxy, C C3 haloalkyl, nitro, nitrile, and oxo. In one embodiment, R2 is selected from halo, C C6 haloalkyl, C†-C6 alkyl, and C-|-C6 alkoxy. In one embodiment, R2 is selected from CI, F, Br, methyl, ethyl, CF3, CCI3, amino, methoxy and ethoxy. In one embodiment, R2 is selected from CI, F, Br, methyl, ethyl, CF3, CCI3, methoxy and ethoxy. In one embodiment, R2 is selected from CI, F, Br, methyl, ethyl, CF3, CCI3, methoxy and ethoxy. In one embodiment, R2 is halo, preferably CI or F.
In one embodiment, R2 is C C10 haloalkyl, preferably C C6 haloalkyl, preferably C C3 haloalkyl, preferably CF3 or CCI3.
In one embodiment, R2 is C C^0 alkyl, preferably C^Ce alkyl, preferably C Cz alkyl, preferably methyl or ethyl.
In one embodiment, R2 is C C10 alkoxy, preferably C C6 alkoxy, preferably C C13 alkoxy, preferably -OMe or -OEt.
In one embodiment, R2 is oxo. In this embodiment, the oxo group can either be linked to a carbon atom in which case a carbonyl group is formed, or the oxo group can be linked to a nitrogen atom, in which case an oxime group or salt can be formed.
X
X is C(R6) (wherein R6 is as defined below) or N.
In one embodiment, X is CH or N.
In one embodiment, X is CH. In one embodiment, X is N.
In the compounds of formula I, when Ring B is carbocyclic, X is C(R6).
R6
R6 is H or C1-6 alkyl.
In one embodiment, R6 is H. In one embodiment, R6 is H or C^e alkyl, such as C1-3 alkyl, preferably methyl or ethyl, and especially methyl.
Ring B
Ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms. In one embodiment, the one more hetero atoms is a nitrogen or sulphur atom.
In one embodiment, ring B is a saturated or unsaturated optionally substituted carbocyclic group containing from 5 to 7 members. In one embodiment, ring B is a saturated carbocyclic group containing from 5 to 7 members. In one embodiment, ring B is an unsaturated carbocyclic group containing from 5 to 7 members. In one embodiment, ring B is an aryl group. In one embodiment, ring B is a saturated or unsaturated heterocyclic group containing from 5 to 7 members. In one embodiment, ring B is a saturated or unsaturated heterocyclic group containing 6 members. In one embodiment, ring B is a heteroaryl group.
In the above mentioned cyclic groups, ring B contains from 5 to 7 members. In one embodiment, ring B contains 5, 6 or 7 members. In one embodiment, ring B contains 6 members.
In one embodiment, ring B is an optionally substituted phenyl group. In this
embodiment, the compound is of formula II
Figure imgf000026_0001
wherein R3, R4 and R8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups, and R-i and R2 are as defined above.
In one embodiment, the hydrocarbyl groups for R3, R4 and R8 are as defined above as for R5. In one embodiment, R3, R4 and R8 are each H. In one embodiment, R3 is a hydrocarbyl and R4 and R8 are each H. In one embodiment, R4 is a hydrocarbyl and R3 and R8 are each H. In one embodiment, R8 is a hydrocarbyl and R3 and R4 are each H. In one embodiment, ring B is an optionally substituted saturated monocyclic
heterocyclic group, as defined above. In one embodiment, ring B is an optionally substituted saturated monocyclic 5- to 7-membered (preferably 6-membered) heterocyclic group, such as a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl group, especially piperidyl.
In one embodiment, ring B contains at least one nitrogen atom. In one embodiment, ring B is a 6-membered ring and the nitrogen atom is at the 5-position. In one embodiment, ring B is a 6-membered ring and the nitrogen atom is at the 6-position. In one embodiment, ring B is a 6-membered ring and the nitrogen atom is at the 6- position. In one embodiment, ring B is a 6-membered ring and the nitrogen atom is at the 7-position. In one embodiment, ring B is a 6-membered ring and the nitrogen atom is at the 8-position.
In one embodiment, ring B is an optionally substituted pyridyl group. In this
embodiment, the compound is of formula IV:
Figure imgf000027_0001
wherein R3, R4 and R8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups, and is as defined above.
In one embodiment, the hydrocarbyl groups for R3, R4 and R8 are as defined above as for R5. In one embodiment, R3, R4 and R8 are each H. In one embodiment, R3 is a hydrocarbyl and R4 and R8 are each H. In one embodiment, R4 is a hydrocarbyl and R3 and R8 are each H. In one embodiment, R8 is a hydrocarbyl and R3 and R4 are each H.
In one embodiment, ring B is an optionally substituted piperidine group. In this embodiment, the compound is of formula V
Figure imgf000028_0001
wherein: R3, R4 and R8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups; R9 is hydrocarbyl; and is as defined above.
In one embodiment, R3 is H. In one embodiment, R4 is H. In one embodiment, R8 is H. In one embodiment, R3, R4 and R8 are each H. In one embodiment, R3 is a hydrocarbyl and R4 and R8 are each H. In one embodiment, R4 is a hydrocarbyl and R3 and R8 are each H. In one embodiment, R8 is a hydrocarbyl and R3 and R4 are each H.
In one embodiment, R9 is C i0 alkyl. In one embodiment, R9 is C 6 alkyl. In one embodiment, R9 is C 4 alkyl. In one embodiment, R9 is methyl or ethyl. In one embodiment, R9 is methyl.
The compounds of the invention also include derivatives thereof when one or more (preferably only one) nitrogen atom is quaternised. In one aspect, the group Y is a quaternary nitrogen atom, the group R2 providing the quaternary substituent. In this aspect, preferably R2 is hydrocarbyl, more preferably C1-6 alkyl, and most preferably methyl or ethyl.
The compounds of the invention also include tautomers. Tautomers are constitutional isomers of organic compounds that readily interconvert by a chemical reaction called tautomerisation. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid
interconversion, tautomers are generally considered to be the same chemical compound. In the compounds of the invention, typical tautomers include those where the -C(0)-NH- group in ring A is replaced by a -C(OH)=N- group to make ring A fully aromatic. Preferred aspects
In one embodiment, X is C(R6) wherein R6 is H or methyl and R2 is a substituent selected from halo, C C6 haloalkyi, hydroxy, C C6 alkyl, CrC6 alkoxy, nitro, nitrile, and oxo.
In one embodiment, X is CH and R2 is a substituent selected from halo, CrC6 haloalkyi, hydroxy, CrC6 alkyl, CrC6 alkoxy, nitro, nitrile, and oxo.
In one embodiment, L is a phenyl ring, R5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C10 alkyl, C1-C10 haloalkyi, C2-C 0 alkenyl, C2-C10 alkynyl, C Ci0 alkoxy, C5-C7 cycloalkyl, heterocyclyl, heterocyclyl-C C10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-C C10 alkyl, aryl-C2-C10 alkenyl, aryl-C2-C 0 alkynyl, heterocyclyl-C-i-C10 alkyl, heteroaryl-C C-io alkyl, ferrocenyl, or aryl-(Ci-3 alkoxy)carbonylamino-C -C3 alkyl, and X is C(R6) wherein R6 is H or methyl.
In one embodiment, L is a phenyl ring, R5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, CrC10 alkyl, CrC10 haloalkyi, C2-C10 alkenyl, C2-C10 alkynyl, CrC10 alkoxy, C5-C7 cycloalkyl, heterocyclyl, heterocyclyl-CrC10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-C C10 alkyl, aryl-C2-Cio alkenyl, aryl-C2-C10 alkynyl, heterocyclyl-CrC 0 alkyl, heteroaryl-CrC10 alkyl, ferrocenyl, or aryl-(C -3 alkoxy)carbonylamino-C -C3 alkyl, and X is CH.
In one embodiment, L is a phenyl ring, R5 is located at the para position and is H, halo, C C6 alkyl, Ci-C6 alkoxy, or C C6 haloalkyi, R2 is halo, C C6 haloalkyi, C Ce alkyl, or Ci-C6 alkoxy, and X is C(R6) wherein R6 is H or methyl.
In one embodiment, L is a phenyl ring, R5 is located at the para position and is H, halo, C-i-Ce alkyl, CVC6 alkoxy, or C C6 haloalkyi, R2 is halo, C C6 haloalkyi, C C6 alkyl, or C Ce alkoxy, and X is CH.
In one embodiment, L is a phenyl ring, R5 is located at the para position and is halo, Ci-Ce alkyl, C Ce alkoxy, or C Ce haloalkyi, R2 is halo, CrC6 haloalkyi, CrC6 alkyl, or CrCe alkoxy, and X is CH. In one embodiment, L is a phenyl ring, R5 is located at the para position and is H, halo, C C6 alkyi, C C6 alkoxy, or C C6 haloalkyi, R2 is halo, C C6 haloalkyi, C^Ce alkyi, or C C6 alkoxy, ring B is a phenyl ring, and R3, R4 and R8 are independently hydrogen or a substituent selected from halo, hydroxy, and C C6 alkyi.
In one embodiment, L is a phenyl ring, R5 is located at the para position and is halo, C C6 alkyi, C CB alkoxy, or C-i-Ce haloalkyi, R2 is halo, C C6 haloalkyi, CrC6 alkyi, or C C6 alkoxy, ring B is a phenyl ring, and R3, R and R8 are independently hydrogen or a substituent selected from halo, hydroxy, and C-|-C6 alkyi.
In one embodiment, the compound is of formula III
Figure imgf000030_0001
wherein R-i , R2, R3, R4 and R8 are as defined above.
In one embodiment, the compound is of formula III
Figure imgf000030_0002
wherein is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is selected from H, methoxy, ethoxy, methyl, ethyl, C C6 haloalkyi, (CH2)nNR6R7 where n is from 0 to 5, and R6 and R7 are independently selected from H, CrC6 alkyl, and C C6 alkene, CI, F, nitro or nitrile;
R2 is a substituent selected from halo, C C6 haloalkyi, hydroxy, Ο-ι-Οβ alkyl, -i-C6 alkoxy, nitro, nitrile, amino, and oxo; and
R3, R4 and R8 are each H.
In one embodiment, the compound is of formula III
Figure imgf000031_0001
wherein R-i is a group L-R5 wherein L is an optionally substituted phenyl group and R5 is located at the para position and is selected from H, methoxy, ethoxy, methyl, ethyl,
C†-C6 haloalkyi, (CH2)nNR6R7 where n is from 0 to 5, and R6 and R7 are independently selected from H, C C6 alkyl, and C C6 alkene, CI, F, nitro or nitrile;
R2 is a substituent selected from halo, C-|-C6 haloalkyi, hydroxy, C1-C6 alkyl, C C6 alkoxy, nitro, nitrile and oxo; and
R3, R4 and R8 are as defined above.
Figure imgf000031_0002
wherein R-i is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
R2 is halo, hydroxy, nitro, nitrile, oxo, or hydrocarbyl; X is CH; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms.
In one embodiment, the compound is of formula IV:
Figure imgf000032_0001
Formula IV wherein R3, R4 and Rs are each H, R-i is L-R5 wherein L is a phenyl ring, R5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C10 alkyl, C C-io haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C CKJ alkoxy, C5-C7 cycloalkyl, heterocyclyl, heterocyclyl-C C10 alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, an/l-CrC^ alkyl, aryl-C2-C10 alkenyl, aryl-C2-C10 alkynyl, heterocyclyl-CrC 0 alkyl,
Figure imgf000032_0002
alkyl, ferrocenyl, or aryl-(C -3 alkoxyJcarbonylamino-C Ca alkyl, and X is C(R6) wherein R6 is H or methyl.
In one embodiment, the compound is of formula V:
Figure imgf000032_0003
wherein: R3, R4 and R8 are each H; R9 is C1-10 alkyl; is L-R5 wherein L is a phenyl ring, R5 is located at the para position and is H, halo, hydroxy, nitrile, nitro, amino, C C10 alkyl, C C-io haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C C 0 alkoxy, C5-C7 cycloalkyl, heterocyclyl, heterocyclyl-C Cio alkyl, aryl, heteroaryl, alkylamine, amide, alkylamide, dialkyl amide, acylamide, aryl-CrC10 alkyl, aryl-C2-C 0 alkenyl, aryl-C2-C 0 alkynyl, heterocyclyl-CrC^ alkyl, heteroaryl-CrC alkyl, ferrocenyl, or aryl-(C1-3 alkoxy)carbonylamino-C -C3 alkyl, and X is C(R6) wherein R6 is H or methyl.
In some aspects, when X is nitrogen, R2 may be other than methyl, methoxy or hydroxy.
In one embodiment, the compound may be selected from any one of the following compounds:
5-Amino-3-(4-cyanophenyl)isoquinolin-1-one;
5-Methyl-3-phenylisoquinolin-1-one,
5-Methyl-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methylisoquinolin-1-one,
5-Methyl-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
3-(4-Bromophenyl)-5-methylisoquinolin-1-one;
3-(4-Methoxyphenyl)-5-methylisoquinolin-1-one;
5-Methyl-3-(4-phenylethynylphenyl)isoquinolin-1-one;
5-Methoxy-3-phenylisoquinolin-1-one;
5-Methoxy-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methoxyisoquinolin-1-one;
5-Methoxy-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
5-Fluoro-3-phenylisoquinolin-1-one;
3-(4-Chlorophenyl)-5-fluoroisoquinolin-1-one;
5-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-one,
2-(4-Chlorophenyl)-8-methylquinazolin-4-one;
2-(4-Bromophenyl)-8-methylquinazolin-4-one;
2- (4-Fluorophenyl)-8-methylquinazolin-4-one;
8-Methyl-2-(4-(phenylmethoxycarbonylaminomethyl)phenyl)quinazolin-4-one;
7-(4-Methoxyphenyl)-1 -methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one;
1-Methyl-5-oxo-7-(4-trifluoromethylphenyl)-5,6-dihydro-1 ,6-naphthyridin-1-ium iodide; 1 -Methyl-7-(4-trifluoromethylphenyl)-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one;
7-(4-Chlorophenyl)-1 -methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one
7-(4-Bromophenyl)-1 ,6-naphthyridin-5-one;
7-(4-Bromophenyl)-1 -methyl-5-oxo-1 ,6-naphthyridin-1 -ium iodide;
7-(4-Bromophenyl)-1 -methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one;
3- (4-Methylphenyl)-2,6-naphthyridin-1-one;
5-Methyl-3-(pyridin-4-yl)isoquinolin-1-one; 5-Fluoro-3-(4-methylphenyl)isoquinolin-1-one;
5-Methyl-3-(thiophen-3-yl)isoquinolin-1-one;
4,5-Dimethyl-3-phenylisoquinoliri-1-one;
5-Methyl-3-(4-(pyrrolidin-1-ylmethyl)phenyl)isoquinolin-1-one;
5-Methyl-3-(4-(piperidin-1 -yltnethyl)phenyl)isoquinolin-1 -one; and
3-(4-(1 , 1 -Dimethylethyl)phenyl)-5-methylisoquinolin-1 -one;
or a pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the compound may be selected from any one of the following compounds:
5-Amino-3-(4-cyanophenyl)isoquinolin-1 -one hydrobromide;
5-Methyl-3-phenylisoquinolin-1-one,
5-Methyl-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methylisoquinolin-1-one,
5-Methyl-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
3-(4-Bromophenyl)-5-methylisoquinolin-1-one;
3-(4-Methoxyphenyl)-5-methylisoquinolin-1-one;
5-Methyl-3-(4-phenylethynylphenyl)isoquinolin-1-one;
5-Methoxy-3-phenylisoquinolin-1-one;
5-Methoxy-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methoxyisoquinolin-1-one;
5-Methoxy-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
5-Fluoro-3-phenylisoquinolin-1-one;
3-(4-Chlorophenyl)-5-fluoroisoquinolin-1-one;
5-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-one,
2-(4-Chlorophenyl)-8-methylquinazolin-4-one;
2-(4-Bromophenyl)-8-methylquinazolin-4-one; and
8-Methyl-2-(4-(phenylmethoxycarbonylaminomethyl)phenyl)quinazolin-4-one;
or a pharmaceutically acceptable salt or solvate thereof.
Examples of compounds of the present invention include the following:
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
99f 99g 99h
As will be appreciated the above compounds may be applied in any of the aspects of the present invention.
Salts and Solvates
The compounds of the present invention may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including di-acids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include 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, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, Ν,Ν'- dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, /V-methylglucamine, olamine, 2- amino-2-hydroxymethyl-propane-1 ,3-diol, and procaine. The compounds of the present invention may also exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is a solvate in which the solvent is water.
In one aspect, the present invention provides a compound for use in medicine wherein the compound is as defined above.
In one aspect, the present invention provides a compound for use in the treatment of a disease or condition associated with tankyrase-1 or tankyrase-2, wherein the compound is as defined above.
In one aspect, the present invention provides a compound for use in the treatment of cancer, wherein the compound is as defined above. In one embodiment, the cancer is selected from breast, colon, stomach, liver, kidney, lung, ovary, thyroid, pancreas and prostate cancer.
In one aspect, the present invention provides the use of a compound as defined above for the in vitro inhibition of tankyrase. In one embodiment, the tankyrase is tankyrase- 1. In one embodiment, the tankyrase is tankyrase-2.
Tankyrase
In some aspects of the invention tankyrase is preferably tankyrase-1.
In some aspects of the invention tankyrase is preferably tankyrase-2.
Tankyrase Inhibitor
In accordance with the present invention, the compound of the present invention is capable of acting as a tankyrase inhibitor. In some embodiments, the selective inhibition of tankyrase is achieved, i.e. tankyrase is preferentially inhibited compared to another enzyme.
Here, the term "inhibitor" as used herein with respect to the compound of the present invention means a compound that can inhibit tankyrase activity - such as reduce and/or eliminate and/or mask and/or prevent the detrimental action of tankyrase. The tankyrase inhibitor may act as an antagonist.
The ability of compounds to inhibit tankyrase activity can be assessed using the suitable biological assay presented in the Examples section. In this regard, an assay for tankyrase-2 is provided. However, it is known and understood that an assay utilizing tankyrase-2 also provides an corresponding indication for tankyrase-1 inhibition.
Therapy
The compounds of the present invention may be used as therapeutic agents - i.e. in therapy applications.
The term "therapy" includes curative effects, alleviation effects, and prophylactic effects. The therapy may be on humans or animals, preferably female animals or humans, such as female humans.
Pharmaceutical Compositions
In one aspect, the present invention provides a pharmaceutical composition, which comprises a compound according to the present invention and optionally a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).
The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985).
The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
There may be different composition/formulation requirements dependent on the different delivery systems. By way of example, the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by both routes.
Where the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
Where appropriate, the pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
Combination Pharmaceutical
The compound of the present invention may be used in combination with one or more other active agents, such as one or more other pharmaceutically active agents. By way of example, the compounds of the present invention may be used in combination with other tankyrase inhibitors and/or other inhibitors.
In addition, or in the alternative, the compound of the present invention may be used in combination with a biological response modifier.
The term biological response modifier ("BRM") includes cytokines, immune modulators, growth factors, haematopoiesis regulating factors, colony stimulating factors, chemotactic, haemolytic and thrombolytic factors, cell surface receptors, ligands, leukocyte adhesion molecules, monoclonal antibodies, preventative and therapeutic vaccines, hormones, extracellular matrix components, fibronectin, etc. For some applications, preferably, the biological response modifier is a cytokine. Examples of cytokines include: interleukins (IL) - such as IL-1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11 , IL-12, IL-19; Tumour Necrosis Factor (TNF) - such as TNF-a; Interferon alpha, beta and gamma; TGF-β. For some applications, preferably the cytokine is tumour necrosis factor (TNF). For some applications, the TNF may be any type of TNF - such as TNF-a, TNF-β, including derivatives or mixtures thereof. More preferably the cytokine is TNF-a. Teachings on TNF may be found in the art - such as WO-A-98/08870 and WO-A-98/13348.
Administration
Typically, a physician will determine the actual dosage which will be most suitable for an individual subject and it will vary with the age, weight and response of the particular patient. The dosages below are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.
The compositions of the present invention may be administered by direct injection. The composition may be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular or transdermal administration. Depending upon the need, the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
By way of further example, the agents of the present invention may be administered in accordance with a regimen of 1 to 4 times per day, preferably once or twice per day. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Aside from the typical modes of delivery - indicated above - the term "administered" also includes delivery by techniques such as lipid mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof. The routes for such delivery mechanisms include but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.
The term "administered" includes but is not limited to delivery by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution; a parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.
Thus, for pharmaceutical administration, the compounds of the present invention can be formulated in any suitable manner utilising conventional pharmaceutical formulating techniques and pharmaceutical carriers, adjuvants, excipients, diluents etc. and usually for parenteral administration. Approximate effective dose rates may be in the range from 1 to 1000 mg/day, such as from 10 to 900 mg/day or even from 100 to 800 mg/day depending on the individual activities of the compounds in question and for a patient of average (70Kg) bodyweight. More usual dosage rates for the preferred and more active compounds will be in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day, most preferably from 200 to 250 mg/day. They may be given in single dose regimes, split dose regimes and/or in multiple dose regimes lasting over several days. For oral administration they may be formulated in tablets, capsules, solution or suspension containing from 100 to 500 mg of compound per unit dose. Alternatively and preferably the compounds will be formulated for parenteral administration in a suitable parenterally administrable carrier and providing single daily dosage rates in the range 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250 mg. Such effective daily doses will, however, vary depending on inherent activity of the active ingredient and on the bodyweight of the patient, such variations being within the skill and judgement of the physician. Other Therapies
The tankyrase enzyme is known to be implicated in a number of other diseases and conditions, such as pulmonary fibrosis47 and the Herpes simplex virus. Thus, the compounds of the present invention may also be useful for the treatment of these conditions.
The present invention will now be described in further detail in the following examples. EXAMPLES
The compounds were evaluated for inhibition of the auto-poly(ADP-ribosyl)ation activity of tankyrase-2. Briefly, a protein construct comprising the catalytic (NAD+-binding) domain of tankyrase-2 and the adjacent SAM domain was immobilised in the wells of 96-well plates, followed by blocking the remaining surfaces with milk protein. The immobilised enzyme was incubated with the natural substrate NAD+ and with NAD+ carrying biotin attached to the adenine, in the presence or absence of the candidate inhibitor. This allows the enzyme to build a short poly(ADP-ribose) on its SAM domain, with some units carrying biotin. The solution was removed and replaced with a solution containing a commercial streptavidin-horseradish peroxidase construct, which bound to the biotin. The horseradish peroxidase was then assayed by its enzymatic activity, which generated a colorimetric readout giving a measure of the activity of the tankyrase-2.
Tankyrase-2 inhibition assay
A suspension of tankyrase-2 protein (7.5 ng, BPS Bioscience and AMS Bio Europe Ltd. Catalogue # 80515) in buffer solution (25 μί_ consisting of 50 mM TRIS-HCI pH 8.0, 5 Mm MgCI2, 20μΜ ZnCI2, pH 7.4) was loaded into ELlSA-quality, half-volume, high binding 96-well plates (Greiner Bio-One) and stored at 4°C for 16h. The wells were then washed with phosphate buffer saline (pH 7.4) and Tween 20 (Aldrich) (4 χ 250 μί) and treated with skimmed milk power (Marvel, Cadbury's) suspended in buffer solution (5% w/v, 100 μΙ_) and left at room temperature for 1 h. The wells were then washed with PBS-T (4 x 250 μ[_) and treated with buffer, inhibitor and a 1 : 1 mixture of biotinylated NAD+ (BioLog Life Science Institute) and unlabelled NAD+ (Enzo Life Sciences) (5 μΜ). The mixture was incubated for 2 h at 30°C. The wells were then washed with PBS-T (4 x 250 μί) and treated with HRP/Strep solution (100 μί, R & D Systems) for 2 h at room temperature. The wells were then washed with PBS-T (4 x 250 μΙ_) and treated with substrate solution (100 μΙ_, R & D Systems) for 30 min at room temperature and then quenched with aqueous sulfuric acid (2.0 M); the plate was read immediately at 450 nm.
Compounds were tested at a range of concentrations; the data are shown in Table 1.
Figure imgf000044_0001
Enzyme assay methods
Tankyrase-1 assay
Tankyrase-1 assays were performed using a commercial kit (Amsbio Europe Ltd. Catalogue # 4700-096-K), using pre-coated histone well plates. The 20* l-PAR assay buffer (catalogue # 4684-096-07) was diluted 1 in 20 with distilled H20. This buffer (50 μΐ_) was added to rehydrate the histone-coated wells (30 min at room temperature), then removed by aspiration. The reaction volume (50 μΙ_) consisted of l-PAR assay buffer with tankyrase-1 protein (5 mU in 25 μΙ_ l-PAR assay buffer), solutions of test inhibitors (5 μΙ_) in l-PAR buffer prepared from stock solutions in DMSO to give a final concentration of 1% DMSO, assay substrate (15 μΙ_) (catalogue # 4700-096-02). Background wells were treated with l-PAR assay buffer alone. Maximum enzyme activity was established using wells containing enzyme only + 1% DMSO. The plates were held for 30 min at room temperature. The wells were washed with 2x PBS-T (as described above) and 2x PBS. The antibody diluent was prepared from 5x stock solution (catalogue # 4684-096-03) using distilled H20. The anti-PAR monoclonal antibody (catalogue # 4684-096-04) was diluted 1000-fold with 1 χ antibody diluent and 50 μΙ_ were added per well. The reaction was held for 30 min at room temperature. The wells were washed with 2 χ PBS-T and 2 χ PBS. Goat anti-mouse IgG-HRP conjugate (catalogue # 4684-096-05) was diluted 1000-fold with 1 x antibody diluent and 50 μ[_ was added per well. The reaction was held for 30 min at room temperature. The wells were washed with 2 χ PBS-T and 2 PBS. Pre-warmed TACS-Sapphire™ (50 μΙ_) was added per well and held at room temperature in the dark for 30 min. The reaction was stopped by the addition of HCI (0.20 M, 50 μΙ_) and the absorbance at 450nm was read within 20 min. The IC50 values were calculated using a four-parameter logistic curve and SigmaPlot 12.0 software.
Tankyrase-2 assay
A suspension of tankyrase-2 protein (catalytic + SAM domains) (7.5 ng, BPS Bioscience and AMS Bio Europe Ltd. Catalogue # 80515) in reaction buffer (25 μί, 50 mM TRIS-HCI pH 8.0, 5.0 mM MgCI2, 20 μΜ ZnCI2) was loaded into ELISA-quality, half-volume, high binding 96-well plates (Greiner bio-one) and these were held at 4°C for 16 h. The wells were then washed four times with phosphate-buffered saline solution pH 7.4 (+ 0.05% v/v tween 20 (PBS-T) (250 μΐ)). Skimmed milk (Marvel) in reaction buffer (5%, 00 μί) was added per well and the mixture was allowed to stand for 1 h. The wells were then washed with PBS-T (4 χ 250 μΙ_). A reaction volume of 25 μΙ_ was used and consisted of reaction buffer with 5 μΙ_ of varying concentrations of inhibitor from stock solutions in DMSO, to give a final DMSO concentration of 1 %, and 5 μΙ_ of a solution of biotinylated NAD+ (12.5 μΜ, BioLog Life Science Institute) and NAD+ (12.5 μΜ, Enzo Life Sciences) to give a final reaction concentration (total NAD+ and derivatives) of 5 μΜ. The plates were incubated at 30°C for 2 h. The wells were then washed with PBS-T (4 χ 250 μί), then streptavidin / HRP solution (100 μΐ, R & D systems) was added per well and the plates were held at room temperature for 2 h. The wells were then washed with PBS-T (4 χ 250 μί), a 1 : 1 mixture of substrate solutions A and B (100 μί, R & D systems) was added per well and the plates were held for 30 min. The reaction was stopped by the addition of aq. H2S04 (1 .0 M, 25 μί) and the absorbance at 450 nm was read within 20 min. The IC50 values for inhibitors were determined using a four-parameter logistic curve and SigmaPlot 12.0 software.
PARP-1 assay
PARP-1 assays were performed using a commercial kit (Amsbio Europe Ltd. Catalogue # 4676-096-K) using pre-coated histone well plates. A solution of 20* PARP assay buffer (catalogue # 4671 -096-02) was diluted to 1 x with distilled water. PARP assay buffer was used to rehydrate the histone-coated wells (50 μΐ per well) for 30 min, then this solution was removed by aspiration. A reaction volume of 50 μΐ. was used and consisted of PARP assay buffer with PARP-1 protein (25 μί, 0.5 mU in 1 x PARP assay buffer), 5 μΐ_ of inhibitor solutions in PARP assay buffer prepared from stock solutions in DMSO to give a final concentration of 1 % DMSO and 20 μL· of substrate (2.5 μΙ_ 10χ PARP cocktail (catalogue # 4671 -096-03), 2.5 μΙ_ 10χ activated DNA (catalogue # 4671 -096-06), 15 μΙ_ PARP assay buffer). The plates were held for 1 h at room temperature. The wells were washed twice with PBS-T and twice with PBS (250 μΙ_ each). Streptavidin-HRP solution (catalogue # 4800-30-06) was diluted 500- fold with 1 streptavidin-HRP diluent (catalogue # 4671 -096-04), 50 μΙ_ was added to each well and the plates were held for 1 h at room temperature. The wells were washed with PBS-T (2 x) and PBS (2 x). Pre-warmed TACS-Sapphire™ (50 μΙ_) was added per well and the mixtures were left at room temperature in the dark for 30 min. The reaction was quenched by the addition of HCI (0.2 M, 50 μΙ_) and the absorbance at 450 nm was measured within 20 min. The IC50 values were calculated using a four- parameter logistic curve and SigmaPlot 12.0 software. IMPDH2 assay
Lyophilized human IMPDH-2 recombinant protein (Novocib SAS, catalogue # E-Nov1) was suspended in storage buffer (40 mM Tris-HCI, pH 8.0, 1 10 mM NaCI, 2.2 mM KCI, 3.0 mM dithiothreitol, 4.0 mM glutathione and 20% glycerol) to make a 100 μΜ stock solution. Kinetic assays were performed at 37°C in assay buffer (100 μΜ Tris-HCI, pH 9.0, 100 mM KCI and 5.0 mM dithiothreitol) using final concentrations of 1 μΜ IMPDH- 2, 0.5 mM NAD+ (Enzo Life Sciences, catalogue # BML-KI282-0500) 1.0 mM inosine monophosphate (Sigma Aldrich, catalogue # I4625) and varying concentrations of inhibitor (prepared from stock solutions in DMSO, to give a final DMSO concentration of 1 %) in a total reaction volume of 100 μΐ. A known inhibitor, 6-thioinosine monophosphate (Carbosynth, catalogue # NT10843) was used at varying concentrations as a positive control. Reactions were monitored at 340 nM using a BMG LABTECH FLUOstar Omega™ plate reader. Linear regression fit (r2) and rates were calculated using Omega MARS™ LABTECH software.
The results are shown in Table 2, wherein the following abbrevations are used:
Tank-1 = Tankyrase-1 IC50 (μΜ)
Tank-2 = Tankyrase-2 IC50 (μΜ)
PARP-1 = PARP-1 IC50 (μΜ)
IMPDH2 = IMPDH2 IC50 (μ )
Cyt Col = Cytotoxicity vs. HT29 human colon adenocarcinoma cells IC50 (μΜ)
Cyt Fib = Cytotoxicity vs. FEK4 human fibroblasts IC50 (μΜ)
Table 2
Figure imgf000048_0001
3-(3-Chlorophenyr)-5-methylisoquinolin- 0.181 0.091 >10 >50 >50 1-one (17f)
3-(2,6-Dichlorophenyl)-5- 1.34 0.84 37 107 methylisoquinolin-1-one (17g)
5-Methyl-3-(4-phenylethynyl- >0.1 0.0096 >10 >500 >50 phenyl)isoquinolin-1-one (17k).
5-Methyl-3-(pyridin-4-yl)isoquinolin-1-one 0.029 0.102 111 12 >500 (99b)
5-Fluoro-3-(4-methylphenyl)isoquinolin- 0.064 0.0038 >10 >500 >500 1-one (99c)
5-Methyl-3-(thiophen-3-yl)isoquinolin-1- 0.080 0.019 0.72 43 >500 one (99d)
4,5-Dimethyl-3-phenylisoquinolin-1-one 0.244 0.017 0.86 15 >200 (99e)
5-Methyl-3-(4-(pyrrolidin~1-yl- 11.7 1.2 >10 220 >500 methyl)phenyl)isoquinolin-1 -one
hydrochloride (99f)
5-Methyl-3-(4-(piperidin-1 -yl- 0.152 0.0098 >10 8.2 27 methyl)phenyl)isoquinolin-1 -one (99g)
3-(4-(1 , 1 -Dimethylethyl)phenyl)-5- 0.390 0.0056 4.5 >500 methylisoquinolin-1-one (99h)
Experimental section
General. 1H and 13C and 19F NMR spectra were recorded at 400.04 or 500.13 MHz (1H) and 100.59 or 125.76 MHz (13C), using containing tetramethylsilane as an internal standard. 19F NMR spectra were recorded at 376 MHz. Mass spectra were recorded using the electrospray ionisation technique and were calibrated with sodium formate, except where noted otherwise. Melting points were obtained using a heated stage microscope. Reactions were carried out at ambient temperature, except where noted otherwise.
3-Ethyl-5-nitroisocoumarin (3a). Heptane-3,5-dione (6.4 g, 50 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 285 (2.5 g, 10 mmol), potassium f-butoxide (2.3 g, 20 mmol) and copper powder (65 mg, 1.0 mmol) in 2-methyl-2- propanol (50 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 9: 1 ) gave 3-ethyl-5-nitroisocoumarin 3a (520 mg, 24%) as yellow crystals: mp 77-78°C; IR vmax (KBr) 1747, 1645, 1524, 1347 cm'1; 1H NMR (CDCI3) δ 1.17 (3 H, t, J = 7.6 Hz, Me), 2.55 (2 H, q, J = 7.6 Hz, CH2), 7.01 (1 H, d, J = 0.9 Hz, 4-H), 7.48 (1 H, t, J = 8.1 Hz, 7-H), 8.32 (1 H, dd, J = 8.1 , 2.6 Hz, 6-H), 8.44 (1 H, ddd, J = 8.1 , 2.6, 0.9 Hz, 8-H); 13C NMR (CDCI3) δ 1 1.73 (Me), 27.99 (CH2), 97.41 (C-4), 122.65, 127.41 , 131.84, 132.38, 136.22, 144.43, 161.43, 163.92;
MS (electron impact) m/z 219.0533 (M)+(C11H9N04 requires 219.0532).
5-Nitro-3-pentylisocoumarin (3b). Tridecane-6,8-dione (31.8 g, 150 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 285 (7.4 g, 30 mmol), potassium f-butoxide (6.8 g, 61 mmol) and copper powder (190 mg, 3.0 mmol) in 2-methyl-2- propanol (100 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 4:1) gave 5-nitro-3-pentylisocoumarin 3b (2.8 g, 36%) as a yellow oil: IR vmax (film) 1736, 1646, 1530, 1344 cm"1; 1H NMR (CDCI3) δ 0.92 (3 H, m, pentyl 5-H3), 1.35-1.40 (4 H, m, pentyl 3,4-H4), 1.70-1.78 (2 H, m, pentyl 2-H2), 2.59 (2 H, t, J = 7.8 Hz, pentyl 1 -H2), 7.12 (1 H, d, J = 0.8 Hz, 4-H), 7.55 (1 H, t, J = 7.8 Hz, 7-H), 8.41 (1 H, dd, J = 7.8, 1.6 Hz, 6-H), 8.56 (1 H, ddd, J = 7.8, 1.6, 0.8 Hz, 8-H); 13C NMR (CDCI3) δ 13.96 (pentyl 5-C), 22.37 (CH2), 26.61 (CH2), 31.18 (CH2), 34.20 (CH2), 97.69 (4-C), 122.08, 126.83, 131.34, 131.85, 135.71 , 143.82, 160.99, 162.36 (C=0); MS m/z 261.1002 (electron impact) (M)+ (C14H15N04 requires 261.1001).
5-Nitro-3-phenylisocoumarin (3c). 1 ,3-Diphenylpropane-1 ,3-dione (22.9 g, 102 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 285 (4.5 g, 20 mmol), potassium f-butoxide (4.6 g, 41 mmol) and copper powder (150 mg, 2.4 mmol) in 2- methylpropan-2-ol (100 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 10:1) gave 5-nitro-3-phenylisocoumarin 3c (4.2 g, 78%) as yellow crystals: mp 142-143°C; IR vmax (KBr) 1739, 1626, 1525, 1341 cm"1; 1H NMR (CDCI3) δ 7.50-7.53 (3 H, m, Ph 3,4,5-H3), 7.62 (1 H, t, J = 7.8 Hz, 7-H), 7.89 (1 H, d, J = 0.8 Hz, 4-H), 7.93-7.97 (2 H, m, Ph 2,6-H2), 8.51 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.65 (1 H, ddd, J = 8.2, 1.2, 0.8 Hz, 8-H); 13C NMR (CDCI3) δ 117.18 4-C, 121.01 , 125.61 , 127.59, 127.90, 128.28, 128.77, 129.83, 131.18, 135.44, 148.42, 157.06, 165.07 (C=0); MS (electron impact) m/z 267.0532 (M)+ (C15H9N04 requires 267.0532). 3-(4-Methylphenyl)-5-nitroisocoumarin (3d). 1-(4-Methylphenyl)butane-1 ,3-dione (22.7 g, 0.1 mol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 285 (6.3 g, 26 mmol), potassium i-butoxide (5.8 g, 52 mmol) and copper powder (170 mg, 2.7 mmol) in 2-methylpropan-2-ol (100 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 10:1) gave 3-(4-methylphenyl)-5- nitroisocoumarin 3d (1.5 g, 21 %) as yellow crystals: mp 161-162°C; IR vmax (KBr) 1737, 1618, 1511 , 1321 cm"1; 1H NMR (CDCI3) δ 2.42 (3 H, s, Me), 7.29 (2 H, d, J = 8.2 Hz, Ph 3,5-Hz), 7.56 (1 H, t, J = 8.2 Hz, 7-H), 7.80 (1 H, s, 4-H), 7.81 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.46 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.60 (1 H, td, J = 8.2, 1.2 Hz, 8-H); MS m/z 282.0762 (M + H)+ (C16HnN04 requires 282.0766).
3-(4-Methoxyphenyl)-5-nitroisocoumarin (3e). 1 ,3-Di(4-methoxyphenyl)-1 ,3- propanedione87 (10.0 g, 35 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 285 (2.5 g, 10 mmol), potassium i-butoxide (2.3 g, 20 mmol) and copper powder (63 mg, 1.0 mmol) in 2-methylpropan-2-ol (50 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 4:1) gave 3-(4- methoxyphenyl)-5-nitroisocoumarin 3e (180 mg, 60%) as yellow crystals: mp 241- 242°C; IR vmax (KBr) 1738, 1620, 1511 , 1346 cm-1: 1H NMR (CDCI3) δ 3.88 (3 H, s, Me), 6.99 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.54 (1 H, t, J = 8.2 Hz, 7-H), 7.76 (1 H, s, 4-H), 7.88 (2 H, d, J = 9.0 Hz, Ph 2,6-H2), 8.46 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.59 (1 H, dd, J = 8.2, 1.2 Hz, 8-H); 13C NMR (CDCI3) δ 55.56 (Me), 94.74 (4-C), 1 14.52), 126.56, 127.73, 131.71 , 135.92; MS m/z (electron impact) 297.0639 (M)+ (C^HnNOs requires 297.0637).
3-(4-Chlorophenyl)-5-nitroisocoumarin (3f). 1 -(4-Chlorophenyl)butane-1 ,3-dione88 (7.1 g, 36 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 285 (1.8 g, 7.3 mmol), potassium i-butoxide (5.8 g, 52 mmol) and copper powder (47 mg, 0.7 mmol) in 2-methylpropan-2-ol (50 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 9:1) gave 3-(4-chlorophenyl)-5- nitroisocoumarin 3f (720 mg, 33%) as yellow crystals: mp 204-205°C; IR vmax (KBr) 1745, 1522, 1340 cm"1; H NMR (CDCI3) δ 7.47 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.61 (1
H, t, J = 8.2 Hz, 7-H), 7.85 (1 H, d, J = 0.8 Hz, 4-H), 7.87 (2 H, d, J = 9.0 Hz, Ph 2,6- H2), 8.49 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.62 (1 H, ddd, J = 8.2, 1.2, 0.8 Hz, 8-H); 13C NMR (CDCI3) δ 96.62 (4-C), 127.23, 127.50, 129.44, 131.74, 135.92; MS (electron impact) m/z 303.01 1 1 (M)+ (C15H8 37CIN04 requires 303.0 12), 301.0137 (M)+
(C15H8 35CIN04 requires 301.0142).
3-Ethyl-5-nitroisoquinolin-1-one (4a). A solution of 3-ethyl-5-nitroisocoumarin 3a (520 mg, 2.4 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 3-ethyl-5-nitro- isoquinolin-1 -one 4a (200 mg, 38%) as bright yellow crystals: mp 196-197°C
(decomposition); IR vmax (KBr) 3432, 1666, 1524, 1372 cm"1; 1H NMR ((CD3)2SO) δ
I .22 (3 H, t, J = 7.5 Hz, Me), 2.59 (2 H, q, J = 7.5 Hz, CH2), 6.80 (1 H, s, 4-H), 7.56 (1 H, t, J = 8.1 Hz, 7-H), 8.40 (1 H, dd, J = 8.1 , 1.5 Hz, 6-H), 8.51 (1 H, dd, J = 8.1 , 1.5 Hz, 8-H), 1 1.79 (1 H, br s, NH); MS m/z 219.0779 (M + H)+ (Ο^Η^Ν^ requires
219.0770).
5-Nitro-3-pentylisoquinolin-1 -one (4b). A solution of 5-nitro-3-pentylisocoumarin 3b (70 mg, 0.3 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 5-nitro-3-pentyl- isoquinolin-1-one 4b (20 mg, 29%) as bright yellow crystals: mp 158-159°C
(decomposition); IR vmax (KBr) 3467, 1666, 1524, 1375 cm"1; 1H NMR ((CD3)2SO) δ 0.88 (3 H, m, pentyl 5-H3), 1.28-1.34 (4 H, m, pentyl 3,4-H4), 1.64 (2 H, m, pentyl 2-H2), 2.55 (2 H, t, J = 7.6 Hz, pentyl 1 -H2), 6.79 (1 H, s, 4-H), 7.56 (1 H, t, J = 7.8 Hz, 7-H), 8.39 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 8.50 (1 H, dd, J = 7.8, 1.2 Hz, 8-H), 1 1.77 (1 H, br, NH); MS (electron impact) m/z 260.1162 (M)+ (C14H16N203 requires 260.1 161 ).
5-Nitro-3-phenylisoquinolin-1 -one (4c). A solution of 5-nitro-3-phenylisocoumarin 3c (1.0 g, 3.7 mmol) in 2-methoxyethanol (100 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 5-nitro-3-phenyl- isoquinolin-1 -one 4c (730 mg, 73%) as bright yellow crystals: mp 127-128°C; IR vmax (KBr) 3482, 1655, 1536, 1348 crrf1; 1H NMR ((CD3)2SO) δ 7.25 (1 H, s, 4-H), 7.53-7.55 (3 H, m, Ph 3,4,5-Hs), 7.66 (1 H, t, J = 7.8 Hz, 7-H), 7.79 (2 H, m, Ph 2,6-H2), 8.49 (1 H, d, J = 7.8 Hz, 6-H), 8.60 (1 H, d, J = 7.8 Hz, 8-H), 12.11 (1 H, br, NH); MS m/z
266.0694 (electron impact) (M)+ (C15H10 2O3 requires 266.0691).
3-{4-Methylphenyl)-5-nitroisoquinolin-1 -one (4d). A solution of 3-(4-methylphenyl)-5- nitroisocoumarin 3d (1.0 g, 3.6 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 3-(4- methylphenyl)-5-nitroisoquinolin-1 -one 4d (860 mg, 86%) as bright yellow crystals: mp 175°C; IR vmax (KBr) 3457, 1673, 1620, 1516, 1324 cm'1; 1H NMR ((CD3)2SO) δ 2.37 (3 H, s, Me), 7.20 (1 H, d, J = 0.8 Hz, 4-H), 7.32 (2 H, d, J = 8.2 Hz, Ph 3,5-H2), 7.62 (1 H, t, J = 8.2 Hz, 7-H), 7.66 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.45 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.56 (1 H, ddd, J = 8.2, 1.2, 0.8 Hz, 8-H), 12.03 (1 H, br, NH); MS m/z (electron impact) 280.0856 (M)+ (C16H12N203 requires 280.0848); Anal. Calcd. for C16H12N203: C, 68.56; H, 4.32; N, 9.99. Found: C, 68.2; H, 4.28; N, 10.0.
3-(4-Methoxyphenyl)-5-nitroisoquinolin-1 -one (4e). A solution of 3-(4-methoxy- phenyl)-5-nitroisocoumarin 3e (230 mg, 0.8 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 3-(4-methoxyphenyl)-5-nitroisoquinolin-1-one 4e (150 mg, 65%) as bright yellow crystals: mp 236-237°C (decomposition); IR vmax (KBr) 3468, 1677, 1615, 1515, 1323 cm"1: 1H NMR ((CD3)2SO) δ 3.82 (3 H, s, Me), 7.07 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.18 (1 H, d, J = 0.8 Hz, 4-H), 7.60 (1 H, t, J = 8.2 Hz, 7-H), 7.73 (2 H, d, J = 9.0 Hz, Ph 2,6- H2), 8.45 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.55 (1 H, ddd, J = 8.2, 1.2, 0.8 Hz, 8-H), 12.00 (1 H, br, NH); MS m/z 296.0802 (electron impact) (M)+ (C16H12N204 requires 296.0797), 250 (M - N02)+; Anal. Calcd. for C16H12N2O4-0.5H2O: C, 62.95; H, 4.26; N, 9.18. Found: C, 63.2; H, 4.12; N, 9.49. 3-(4-Chlorophenyl)-5-nitroisoquinolin-1 -one (4f). A solution of 3-(4-chlorophenyl)-5- nitroisocoumarin 3f (720 mg, 2.4 mmol) in 2-methoxyethanol (50 mL) was saturated with ammonia and boiled under reflux for 4 h. The solvent was evaporated until 10 mL remained. The concentrate was stored at 4°C for 16 h. The crystals were collected by filtration, washed (water, then ethanol) and recrystallised (methanol) to give 3-(4- chlorophenyl)-5-nitroisoquinolin-1 -one 4f (460 mg, 64%) as bright yellow crystals: mp 271 -273°C (decomposition); IR vmax (KBr) 3465, 1674, 1625, 1525, 1325 cm"1; 1H NMR ((CD3)2SO) δ 7.22 (1 H, d, J = 0.8 Hz, 4-H), 7.59 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 7.65 (1 H, t, J = 8.2 Hz, 7-H), 7.79 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 8.47 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.58 (1 H, ddd, J = 8.2, 1.2, 0.8 Hz, 8-H), 12.13 (1 H, br, NH); MS m/z 303.0360 (M + H)+ (C15H10 37CIN2O3 requires 303.0350), 301.0377 (M + H)+
(C15H10 35CIN2O3 requires 301.0380); Anal. Calcd. for C15H9CIN2O3-0.25H2O: C, 59.02; H, 3.1 1 ; N, 9.18. Found: C, 58.8; H, 3.1 1 ; N, 9.1 1.
5-Amino-3-ethylisoquinolin-1 -one (5a). 3-Ethyl-5-nitroisoquinolin-1-one 4a (200 mg, 0.9 mmol) was heated with tin(ll) chloride (520 mg, 2.7 mmol) in ethanol (20 mL) at 70°C for 4 h. The mixture was poured carefully into ice-water (200 mL). The
suspension was made alkaline by addition of aqueous sodium hydroxide (2 M). The suspension was filtered. The filtrate was extracted (ethyl acetate). The ethyl acetate was evaporated and the residue was recrystallised (ethyl acetate / hexanes) to give 5- amino-3-ethylisoquinolin-1-one 5a (40 mg, 24%) as pale yellow crystals: mp 162- 163°C; IR vmax (KBr) 3447, 3395, 3164, 1646 cnV1; H NMR ((CD3)2SO) δ 1.21 (3 H, t, J = 7.5 Hz, Me), 2.47 (2 H, q, J = 7.4 Hz, CH2), 5.51 (2 H, br, NH2), 6.44 (1 H, d, J = 0.8 Hz, 4-H), 6.80 (1 H, dd, J - 7.8, 1.2 Hz, 6-H), 7.05 (1 H, t, J = 7.8 Hz, 7-H), 7.33 (1 H, ddd, J = 7.8, 1.2, 0.8 Hz, 8-H), 1 1.04 (1 H, br, NH); MS m/z 89.1026 (M + H)+
(CiiH13N20 requires 189.1028).
5-Amino-3-pentylisoquinolin-1 -one (5b). 5-Nitro-3-pentylisoquinolin-1-one 4b (240 mg, 0.9 mmol) was heated with tin(ll) chloride (550 mg, 2.9 mmol) in ethanol (20 mL) at 70°C for 4 h. The mixture was poured carefully into ice-water (200 mL). The
suspension was made alkaline by addition of aqueous sodium hydroxide (2 M). The suspension was filtered. The filtrate was extracted (ethyl acetate). The ethyl acetate was evaporated and the residue was recrystallised (ethyl acetate / hexanes) to give 5- amino-3-pentylisoquinolin-1-one 5b (140 mg, 67%) as yellow crystals: mp 75-76°C; IR vmax (KBr) 3448, 3395, 3166, 1651 cm'1; 1H NMR (CDCI3) δ 0.82 (3 H, m, pentyl 5-H3), 1.21-1.34 (4 H, m, pentyl 3,4-H4), 1.72 (2 H, m, pentyl 2-H2), 2.57 (2 H, t, J = 7.6 Hz, pentyl 1-H2), 3.94 (2 H, br, NH2), 6.21 (1 H, s, 4-H), 6.92 (1 H, dd, J = 7.7, 1.2 Hz, 6-H), 7.20 (1 H, t, J = 7.7 Hz, 7-H), 7.84 (1 H, dd, J = 7.7, 1.2 Hz, 8-H), 1 1.75 (1 H, br s, NH); MS (electron impact) m/z 230.1418 (M)+ (C14H18N20 requires 230.1419).
5-Amino-3-phenylisoquinolin-1-one (5c). 5-Nitro-3-phenylisoquinolin-1-one 4c (100 mg, 0.4 mmol) was heated with tin(ll) chloride (220 mg, 1.2 mmol) in ethanol (20 mL) at 70°C for 4 h. The mixture was poured carefully into ice-water (200 mL). The
suspension was made alkaline by addition of aqueous sodium hydroxide (2 M). The suspension was filtered. The filtrate was extracted (ethyl acetate). The ethyl acetate was evaporated and the residue was recrystailised (ethyl acetate / hexanes) to give 5- amino-3-phenylisoquinolin-1-one 5c (51 mg, 57%) as yellow crystals: mp 215-217°C; IR vmax (KBr) 3569, 3329, 3230, 1655 cm"1; H NMR (CDCI3) δ 4.00 (2 H, br, NH2), 6.64 (1 H, s, 4-H), 6.93 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 7.22 (1 H, t, J = 7.8 Hz, 7-H), 7.36- 7.45 (3 H, m, Ph 3,4,5-H3), 7.65 (2 H, m, Ph 2,6-H2), 7.80 (1 H, dd, J = 7.8, 1.2 Hz, 8- H), 10.08 (1 H, br, NH); MS m/z 237.1019 (M + H)+ (C15H13N20 requires 237.1028).
5-Amino-3-(4-methylphenyl)isoquinolin-1 -one (5d). 3-(4-Methylphenyl)-5-nitro- isoquinolin-1-one 4d (280 mg, 1.0 mmol) was heated with tin(ll) chloride (550 mg, 2.9 mmol) in EtOH (30 mL) at 70°C for 4 h, then carefully poured into ice-water (200 ml). The suspension was made alkaline by addition of aqueous sodium hydroxide (2 M). The suspension was filtered. The filtrate was extracted (ethyl acetate). The ethyl acetate was evaporated and the residue was recrystailised (ethyl acetate / hexanes) to give 5-amino-3-(4-methylphenyl)isoquinolin-1-one 5d (230 mg, 92%) as pale yellow crystals: mp 213-214°C; IR vmax (KBr) 3476, 3253, 1669 cm"1; 1H NMR (CDCI3) δ 2.41 (3 H, s, Me), 4.06 (2 H, br, NH2), 6.68 (1 H, s, 4-H), 6.99 (1 H, d, J = 7.8 Hz, 6-H), 7.28 (1 H, t, J = 7.8 Hz, 7-H), 7.29 (2 H, d, J = 7.8 Hz, Ph 3,5-H2), 7.59 (2 H, d, J = 7.8 Hz, Ph 2,6-H2), 7.86 (1 H, d, J = 7.8 Hz, 8-H), 9.92 (1 H, br, NH); MS m/z 251.1181 (M + H)+ (C16H15N20 requires 251.1184).
5-Amino-3-(4-methoxyphenyl)isoquinolin-1 -one (5e). 3-(4-Methoxyphenyl)-5-nitro- isoquinolin-1-one 4e (80 mg, 0.3 mmol) was heated with tin(ll) chloride (160 mg, 0.8 mmol) in ethanol (30 mL) at 70°C for 4 h. The mixture was poured carefully into ice- water (200 mL). The suspension was made alkaline by addition of aqueous sodium hydroxide (2 M). The suspension was filtered. The filtrate was extracted (ethyl acetate). The ethyl acetate was evaporated and the residue was recrystallised (ethyl acetate / hexanes) to give 5-amino-3-(4-methoxyphenyl)isoquinolin-1-one 5e (60 mg, 83%) as pale yellow crystals: mp 189-190°C; IR vmax (KBr) 3438, 3233, 1660 cm"1; H NMR (CDCI3) δ 3.86 (3 H, s, Me), 4.1 1 (2 H, br, NH2), 6.64 (1 H, s, 4-H), 6.97 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 6.99 (2 H, d, J = 8.8 Hz, Ph 3,5-H2), 7.25 (1 H, t, J = 7.8 Hz, 7-H), 7.66 (2 H, d, J = 8.8 Hz, Ph 2,6-H2), 7.85 (1 H, dd, J = 7.8, 1.2 Hz, 8-H), 10.45 (1 H, br, NH); MS /77/Z 267.1 132 (M + H)+ (C16H15N202 requires 267.1 134).
5-Amino-3-(4-chlorophenyl)isoquinolin-1-one hydrochloride (5f). A slurry of palladium on charcoal (10%, 80 mg) in ethanol (5 ml_) was added to 3-(4-chloro- phenyl)-5-nitroisoquinolin-1-one 4f ( 70 mg, 0.57 mmol) in ethanol (10 ml.) and aqueous hydrochloric acid (9 M, 0.4 ml_). The mixture was stirred vigorously under hydrogen for 2 h. The suspension was filtered through Celite®. The Celite® pad and residue were suspended in water (100 mL) and heated. The hot suspension was filtered through a second Celite® pad. Evaporation of the solvent from the combined filtrates and drying gave 5-amino-3-(4-chlorophenyl)isoquinolin-1-one hydrochloride 5f (90 mg, 52%) as a pale buff solid: mp >350°C; 1H NMR ((CD3)2SO) δ 7.08 (1 H, s, 4-H), 7.14 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 7.28 (1 H, t, J = 7.8 Hz, 7-H), 7.56 (2 H, d, J = 9.0 Hz, Ar 3,5-Hz), 7.64 (1 H, dd, J = 7.8, 1.2 Hz, 8-H), 7.83 (2 H, d, J = 9.0 Hz, Ar 2,6-H2), 1 1.50 (1 H, br, NH); MS m/z 273.0618 (M + H)+ (C15H12 37CIN20 requires 273.0609); 271.0629 (M + H)+ (C15H12 35CIN20 requires 271.0638).
5-Amino-3-(2-methoxyphenyl)isoquinolin-1 -one hydrobromide (5g). 5-Amino-1 - methoxy-3-(2-methoxyphenyl)isoquinoline 4g (33.5 mg, 0.12 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.1 mL) at 65°C for 5 h. Evaporation yielded 5- amino-3-(2-methoxyphenyl)isoquinolin-1 -one 5g (31 mg, 72%) as a pale buff solid: mp 172-175°C; 1H NMR (CD3OD) δ 3.91 (3 H, s, Me), 6.79 (1 H, d, J = 0.5 Hz, 4-H), 7.1 1 (1 H, td, J = 7.5, 0.9 Hz, Ph 5-H), 7.18 (1 H, d, J = 8.3 Hz, Ph 3-H), 7.52 (1 H, td, J = 7.6, 1.7 Hz, Ph 4-H), 7.56 (1 H, dd, J = 7.6, 1.7 Hz, Ph 6-H), 7.62 (1 H, t, J = 7.9 Hz, 7- H), 7.82 (1 H, dd, J = 7.7, 1.2 Hz, 6-H), 8.44 (1 H, d, J = 7.3 Hz, 8-H); 3C NMR
(CD3OD) (HSQC / HMBC) δ 56.20 (Me), 99.86 (4-C), 112.74 (Ph 3-C), 122.06 (Ph 5- C), 124.1 1 (Ph 1-C), 127.25 (8a-C), 127.33 (4a-C), 127.54 (7-C), 128.60 (6-C), 129.33 (8-C), 131.26 (Ph 6-C), 132.91 (Ph 4-C), 134.01 (5-C), 142.77 (3-C), 158.49 (Ph 2-C), 163.82 (1 -C); MS m/z 267.1 126 (M + H)+ (C16H15N202 requires 267.1 135). 5- Amino-3-(3-methoxyphenyl)isoquinolin-1 -one hydrobromide (5h). 5-Amino-1- methoxy-3-(3-methoxyphenyl)isoquinoline 4h (31 mg, 0.11 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.1 ml_) at 65°C for 5 h. Evaporation yielded 5- amino-3-(3-methoxyphenyl)isoquinolin-1-one hydrobromide 5h (29 mg, 73%) as a pale buff solid: mp 202-205°C; 1H NMR (CD3OD) δ 3.89 (3 H, s, Me), 6.13 (1 H, s, N-H), 6.95 (1 H, s, 4-H), 7.10 (1 H, dt, J = 8.2, 0.6 Hz, Ph 4-H), 7.35 (2 H, m, Ph 2,6-H2), 7.46 (1 H, t, J = 7.9 Hz, Ph 5-H), 7.61 (1 H, t, J = 7.9 Hz, 7-H), 7.83 (1 H, dd, J = 7.7, 1.0 Hz,
6- H), 8.42 (1 H, d, J = 8.1 Hz, 8-H); 13C NMR (CD3OD) (HSQC / HMBC) δ 56.14 (Me), 98.49 (4-C), 1 13.73 (Ph 2-C), 116.98 (Ph 4-C), 120.39 (Ph 6-C), 127.56 (8a-C), 127.66 (4a-C), 127.82 (7-C), 128.96 (6-C), 129.47 (8-C), 131.60 (Ph 5-C), 134.01 (5-C), 136.68 (Ph 1-C), 144.29 (3-C), 161.82 (Ph 3-C), 164.54 (1-C); MS m/z 267.1 115 (M + H)+ (C16H13N202 requires 267.1 135).
5-Amino-3-(2-chlorophenyl)isoquinolin-1-one hydrobromide (5i). 5-Amino-3-(2- chlorophenyl)-1-methoxyisoquinoline 4i (40.4 mg, 0.14 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.6 ml_) at 65°C for 5 h. Evaporation yielded 5- amino-3-(2-chlorophenyl)isoquinolin-1-one hydrobromide 5i (47.5 mg, 95%) as a buff solid: mp >230°C; 1H NMR (CD3OD) δ 6.71 (1 H, s, 4-H), 7.51 (2 H, m, Ph 4,5-H2), 7.60 (2 H, m, Ph 3,6-H2), 7.66 (1 H, t, J = 8.0 Hz, 7-H), 7.85 (1 H, d, J = 7.5 Hz, 6-H), 8.45 (1 H, d, J = 8.5 Hz, 8-H); 3C NMR (CD3OD) (HSQC / HMBC) δ 100.92 (4-C), 127.61 (4a- C), 128.14 (7-C), 128.55 (Ph 5-C), 128.83 (6-C), 129.34 (8-C), 131.22 (Ph 3-C or Ph 6- C), 132.35 (Ph 6-C or Ph 3-C), 132.51 (Ph 4-C), 133.54 (5-C), 134.17 (Ph 2-C), 134.98 (Ph 1 -C), 142.26 (3-C), 163.87 (1 -C); MS m/z 273.0597 (M + H) (C15H12 37CIN20 requires 273.0609), 271.0623 (M + H)+ (C15H12 35CIN20 requires 271.0638).
5-Amino-3-(3-chlorophenyl)isoquinolin-1 -one hydrobromide (5j). 5-Amino-3-(3- chlorophenyl)-1-methoxyisoquinoline 4j (38.5 mg, 0.14 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.5 mL) at 65°C for 5 h. Evaporation yielded 5- amino-3-(2-chlorophenyl)isoquinolin-1-one hydrobromide 5j (46.1 mg, 97%) as a buff solid: mp >230°C; H NMR (CD3OD) δ 6.93 (1 H, s, 4-H), 7.55 (2 H, m, Ph 4,6-H2), 7.63 (1 H, t, J = 7.5 Hz, 7-H), 7.71 (1 H, m, Ph 5-H), 7.79 (1 H, d, J = 7.5 Hz, 6-H), 7.83 (1 H, s, Ph 2-H), 8.41 (1 H, d, J = 8.0 Hz, 8-H); 13C NMR (CD3OD) (HSQC / HMBC) δ 98.93 (4-C), 126.52 (Ph 5-C), 128.09 (7-C), 128.17 (Ph 2-C), 128.47 (6-C), 128.93 (8- C), 131.16 (Ph 4-C or Ph 6-C), 131.84 (Ph 6-C or Ph 4-C), 133.56 (5-C), 136.19 (Ph 1 - C), 137.24 (Ph 3-C), 142.63 (3-C), 166.31 (1 -C); MS m/z 273.0584 (M + H)+
(C15H12 37CIN20 requires 273.0609), 271.0616 (M + H)+ (C15H12 35C[N20 requires 271.0638).
5-Amino-3-(2,6-dichlorophenyl)isoquinolin-1 -one hydrobromide (5k). 5-Amino-3- (2,6-dichlorophenyl)-1-methoxyisoquinoline 13e (12.7 mg, 0.04 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.0 mL) at 65°C for 5 h. Evaporation yielded 5- amino-3-(2,6-dichlorophenyl)isoquinolin-1-one hydrobromide 5k (9.0 mg, 58%) as an amber-coloured solid: mp 226-228°C; 1H NMR (CD3OD) δ 6.73 (1 H, s, 4-H), 7.56 (1 H, t, J = 6.6 Hz, Ph 4-H), 7.63 (2 H, d, J = 7.0 Hz, Ph 3,5-H2), 7.74 (1 H, t, J = 7.9 Hz, 7- H), 7.91 (1 H, d, J = 7.5Hz, 6-H), 8.53 (1 H, d, J = 8.0 Hz, 8-H); 13C NMR (CD3OD) (HSQC / HMBC) δ 101.69 (4-C), 128.44 (7-C), 128.98 (6-C), 129.47 (8-C), 129.57 (Ph 3,5-C2), 133.13 (Ph 4-C), 133.42 (5-C), 133.88 (Ph 1-C), 136.46 (Ph 2,6-C2), 139.26 (3- C), 164.19 (1 -C).
5-Amino-3-(4-fluorophenyl)isoquinolin-1 -one hydrobromide (5I). 5-Amino-3-(4- fluorophenyl)-1-methoxyisoquinoline 13f (65 mg, 0.24 mmol) was stirred with hydrogen bromide in acetic acid (33%, 3.5 mL) at 65°C for 5 h. Evaporation yielded 5-amino-3-(4- fluorophenyl)isoquinolin-1-one hydrobromide 5I (80 mg, 98%) as a buff solid: mp >230°C; 1H NMR (CD3OD) δ 6.99 (1 H, s, 4-H), 7.34 (3 H, m, 8 & Ph 3,5-H3), 7.39 (1 H, t, J = 8.5 Hz, 7-H), 7.45 (1 H, d, J = 8.5 Hz, 6-H), 7.89 (2 H, m, Ph 2&6-H2), 1 1.71 (1 H, bs, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 98.62 (4-C), 1 15.48 (8-C), 1 15.68 (d, J =6.1 Hz, Ph 3,5-C2), 124.75 (Ph 1-C), 125.72 (3-C), 126.66 (7-C), 128.99 (d, J = 17.2 Hz, Ph 2,6-C2), 130.1 1 (6-C), 137.96 (Ph 4-C), 141.34 (5-C), 162.63 (1-C); 19F NMR ((CD3)2SO) δ -112.47 (m, F); MS m/z 253.0756 (M - H)" (C15H10FN2O requires
253.0777).
5-Amino-3-(4-trifluorophenyl)isoquinolin-1 -one hydrobromide (5m). 5-Amino-1- methoxy-3-(4-trifluoromethylphenyl)isoquinoline 13g (85.2 mg, 0.27 mmol) was stirred with hydrogen bromide in acetic acid (33%, 4.0 mL) at 65°C for 7 h. Evaporation yielded 5-amino-3-(4-trifluorophenyl)isoquinolin-1 -one hydrobromide 5m (101 mg, 98%) as a buff solid: mp >230°C; 1H NMR ((CD3)2SO) δ 7.17 (2 H, m, 4,6-H2), 7.32 (1 H, t, J = 7.5 Hz, 7-H), 7.67 (1 H, d, J = 7.5 Hz, 8-H), 7.88 (2 H, d, J = 8.0 Hz, Ph 3,5- H2), 8.04 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 1 1.63 (1 H, br, NH); 19F NMR ((CD3)2SO) δ - 61.02 (s, CF3); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 99.53 (4-C), 1 17.08 (8-C), 1 18.87 (6-C), 124.1 1 (q, J = 270.6 Hz, CF3), 125.64 (q, J = 3.5 Hz, Ph 3,5-C2), 126.28 (4a-C), 127.41 (7-C + Ph 2,6-C2), 129.20 (q, J = 31.8 Hz, Ph 4-C), 136.82 (Ph 1-C), 137.83 (3-C), 139.92 (5-C), 162.46 (1 -C); MS m/z 303.0756 (M - H)' (C16H10F3N2O requires 303.0743).
5-Amino-3-(3-cyanophenyl)isoquinolin-1 -one hydrobromide (5n). 5-Amino-3-(3- cyanophenyl)-1 -methoxyisoquinoline 13h 1 1.2 mg, 0.04 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.5 ml_) at 65°C for 16 h. Evaporation yielded 5- amino-3-(3-cyanophenyl)isoquinolin-1-one hydrobromide 5n (13.5 mg, 99%) as an amber-coloured solid: mp >360°C; 1H NMR (CD3OD) δ 7.01 (1 H, s, 4-H), 7.65 (2 H, m, 7-H + Ph 5-H), 7.84 (1 H, d, J = 7.6 Hz, 6-H), 7.97 (1 H, d, J = 7.7 Hz, Ph 6-H), 8.02 (1 H, d, J = 7.7 Hz, Ph 4-H), 8.33 (1 H, s, Ph 2-H), 8.44 (1 H, d, J = 7.9 Hz, 8-H); 13C NMR (CD3OD) (HSQC / HMBC) δ 98.90 (4-C), 127.94 (7-C), 128.96 (6-C), 129.44 (8-C), 130.06 (Ph 4-C), 130.53 (Ph 5-C), 131.34 (Ph 6-C), 133.83 (5-C), 135.66 (Ph 1-C), 142.45 (3-C), 143.28 (Ph 3-C), 156.84 (1-C); MS m/z 261.1298 (M + H) (C16HnN30 requires 261.0902).
5-Amino-3-(4-cyanophenyl)isoquinolin-1-one hydrobromide (5o). 5-Amino-3-(4- cyanophenyl)-1-methoxyisoquinoline 13i (14 mg, 0.05 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.0 ml_) at 65°C for 16 h. Evaporation yielded 5-amino-3- (4-cyanophenyl)isoquinolin-1-one hydrobromide 5o (17.0 mg, 99%) as an amber- coloured solid: mp >230°C; H NMR ((CD3)2SO) δ 7.15 (2 H, m, 4,6-H2), 7.30 (1 H, t, J = 7.8 Hz, 7-H), 7.66 (1 H, d, J = 7.7 Hz, 8-H), 7.92 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 7.99 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 1 1.53 (1 H, bs, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 98.81 (4-C), 119.83 (8-C), 120.91 (6-C), 126.12 (Ph 4-C), 126.30 (Ph 2,6-C2), 127.09 (7-C), 127.89 (Ph 3,5-C2), 134.48 (3-C), 136.30 (Ph 1-C), 138.15 (5-C), 162.50 (1-C), 167.13 (CN).
5-Amino-3-(2-trifIuoromethylphenyl)isoquinolin-1 -one hydrobromide (5p). 5-
Amino-1-methoxy-3-(2-trifluoromethylphenyl)isoquinoline 13j (22.4 mg, 0.07 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.25 ml.) at 65°C for 5 h.
Evaporation yielded 5-amino-3-(2-trifluoromethylphenyl)isoquinolin-1-one hydrobromide 5p (25.2 mg, 94%) as a buff solid: mp >230 °C; 1H NMR (CD3OD) δ 6.65 (1 H, s, 4-H), 7.69 (4 H, m, 7-H + Ph 4,5,6-H3), 7.85 (1 H, d, J = 8.5 Hz, 6-H), 7.88 (1 H, d, J = 8.0 Hz, Ph 3-H), 8.45 (1 H, d, J = 8.0 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 100.84 (4-C), 125.24 (q, J = 271.3 Hz, CF3), 127.40 (q, J = 5.3 Hz, Ph 1-C), 127.56 (q, J = 4.8 Hz, Ph 3-C), 128.21 (7-C), 128.94 (6-C), 129.36 (8-C), 131.44 (Ph 6-C), 130.10 (q, J = 30.6 Hz, Ph 2-C), 132.95 (5-C), 133.23 (Ph 4-C), 133.50 (Ph 5-C), 141.90 (3-C), 163.54 (1 -C); 19F NMR (CD3OD) δ -59.36 (s, CF3); MS m/z 305.0872 (M + H)+
(C16H12F3N20 requires 305.0904).
5-Amino-3-(3-trifluoromethylphenyl)isoquinolin-1-one hydrobromide (5q). 5-
Amino-1-methoxy-3-(3-trifluoromethylphenyl)isoquinoline 13k (70.5 mg, 0.22 mmol) was stirred with hydrogen bromide in acetic acid (33%, 3.75 mL) at 65°C for 7 h.
Evaporation yielded 5-amino-3-(3-trifluoromethylphenyl)isoquinolin-1 -one hydrobromide 5q (82.4 mg, 97%) as a buff solid: mp >230°C; 1H NMR ((CD3)2SO) δ 7.05 (1 H, d, J = 7.7 Hz, 6-H), 7.16 (1 H, s, 4-H), 7.25 (1 H, t, J = 7.8 Hz, 7-H), 7.57 (1 H, d, J = 7.7 Hz, 8-H), 7.71 (1 H, t, J = 7.8 Hz, Ph 5-H), 7.77 (1 H, d, J = 7.9 Hz, Ph 4-H), 8.1 1 (1 H, d, J = 8.0 Hz, Ph 6-H), 8.17 (1 H, s, Ph 2-H), 1.56 (1 H, br, NH); 9F NMR
((CD3)2SO) δ -61.03 (s, CF3) 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 99.07 (4-C), 1 16.52 (8-C), 1 19.27 (6-C), 123.26 (q, J = 3.9 Hz, Ph 2-C), 125.67 (q, J = 3.9 Hz, Ph 4- C), 126.19 (4a-C), 127.27 (7-C), 129.74 (q, J = 31.8 Hz, Ph 3-C), 129.89 (Ph 5-C), 130.52 (Ph 6-C), 134.85 (5-C), 136.28 (Ph 1-C), 137.31 (3-C), 162.53 (1-C); MS m/z 303.0740 (M - H)" (C16H10F3N2O requires 303.0743).
5-Amino-3-(4-hydroxyphenyl)isoquinolin-1 -one hydrobromide (5r). 5-Amino-3-(4- hydroxyphenyl)-1-methoxyisoquinoline 4r (55 mg, 0.21 mmol) was stirred with hydrogen bromide in acetic acid (33%, 2.5 mL) at 65°C for 16 h. Evaporation yielded 5- amino-3-(4-hydroxyphenyl)isoquinolin-1-one hydrobromide 5r (68.5 mg, 98%) as a buff solid: mp >230°C; 1H NMR ((CD3)2SO) δ 6.88 (3 H, m, 4-H + Ph 3,5-H2), 7.36 (2 H, m, 6,7-H2), 7.67 (2 H, d, J = 9.0 Hz, Ph 2,6-H2), 7.88 (1 H, d, J = 9.0 Hz, 8-H), 1 .46 (1 H, br s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 96.01 (4-C), 115.55 (Ph 3,5-C2), 124.59 (7-C), 125.36 (6-C), 125.94 (8-C), 128.09 (Ph 2,6-C2), 139.99 (3-C), 158.69 (Ph
4- C), 162.45 (1-C); MS m/z 253.0958 (M + H)+ (C15H13N202 requires 253.0977).
5- Amino-3-(4-(2-phenylethyl)phenyl)isoquinolin-1 -one hydrobromide (5s). 5-
Amino-1 -methoxy-3-(2-phenylethyl)isoquinoline 14 (40 mg, 0.14 mmol) was stirred with hydrogen bromide in acetic acid (33%, 2.0 mL) at 65°C for 16 h. Evaporation yielded 5- amino-3-(4-(2-phenylethyl)phenyl)isoquinolin-1 -one hydrobromide 5s (35 mg, 70%) as a dark red-brown solid: mp >230°C; 1H NMR (CD3OD) δ 2.95 (2 H, t, J = 7.0 Hz, ethyl 1-H2), 3.06 (2 H, t, J = 6.0 Hz, ethyl 2-H2), 6.48 (1 H, s, 4-H), 7.24 (5 H, m, Ph-H5), 7.56 (1 H, t, J = 8.0 Hz, 7-H), 7.75 (1 H, dd, J = 8.0, 1.0 Hz, 6-H), 8.38 (1 H, d, J = 8.0 Hz, 8- H); 13C NMR (CD3OD) (HSQC / HMBC) δ 35.83 (ethyl 2-C), 36.51 (ethyl 1-C), 97.82 (4- C), 126.76 (7-C), 127.07 (Ph 3-C), 127.48 (6-C), 129.36 (8-C), 129.43 (Ph 2,6-C2), 129.62 (Ph 3,5-C2), 134.04 (5-C), 141.57 (Ph 1-C), 145.88 (3-C), 164.03 (1 -C); MS m/z 265.1320 (M + H)+ (C17H17N20 requires 265.1341).
1-Methoxy-3-(2-methoxyphenyl)-5-nitroisoquinoline (11a). To 3-bromo-1 -methoxy- 5-nitroisoquinoline 9 (102 mg, 0.43 mmol) were added tris(dibenzylideneacetone)- dipalladium (1 1.5 mg, 0.013 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (23 mg, 0.056 mmol), 2-methoxybenzeneboronic acid ( 50.5 mg, 1.0 mmol) and potassium phosphate (204 mg, 1.0 mmol). Degassed toluene (3.0 mL) was added and the mixture was stirred at 100°C for 16 h. The evaporation residue, in chloroform, was filtered. Chromatography (ethyl acetate / petroleum ether 1 :99) gave 1-methoxy-3-(2- methoxyphenyl)-5-nitroisoquinoline 11a (74 mg, 58%) as a yellow solid: mp 1 15-117°C; 1H NMR (CDCI3) δ 3.97 (3 H, s, PhOMe), 4.23 (3 H, s, 1-OMe), 7.06 (1 H, d, J = 8.3 Hz, Ph 3-H), 7.1 1 (1 H, td, J = 7.6, 1.1 Hz, Ph 4-H), 7.39 (1 H, td, J = 7.8, 1.8 Hz, Ph 5-H), 7.55 (1 H, t, J = 7.9 Hz, 7-H), 8.15 (1 H, dd, J = 7.8, 1.8 Hz, Ph 6-H), 8.43 (1 H, dd, J = 7.8, 1.3 Hz, 6-H), 8.59 (1 H, dt, J = 8.2, 1.1 Hz, 8-H), 8.78 (1 H, s, 4-H); 3C NMR (CDCI3) (HSQC / HMBC) δ 54.06 (1-OMe), 55.71 (PhOMe), 110.12 (4-C), 1 1 1.79 (Ph 3-C), 1 19.70 (8a-C), 120.87 (Ph 4-C), 124.36 (7-C), 128.18 (6-C), 130.17 (Ph 5-C), 130.91 (8-C), 131.22 (Ph 6-C), 146.81 (5-C), 157.82 (Ph 2-C), 160.04 (1-C); MS m/z 333.0858 (M + Na)+ (C17H14N2Na04 requires 333.0852), 311.1030 (M + H)+
(C17H15N204 requires 31 1.1034).
1 - ethoxy-3-(3-methoxyphenyl)-5-nitroisoquinoline (11 b). To 3-bromo-1 -methoxy-
5- nitroisoquinoline 9 (103 mg, 0.43 mmol) were added tris(dibenzylideneacetone)- dipalladium (1 1.6 mg, 0.013 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (22 mg, 0.054 mmol), 3-methoxybenzeneboronic acid (153 mg, 1.0 mmol) and potassium phosphate (203 mg, 0.96 mmol). Degassed toluene (3.0 mL) was added and the mixture was stirred at 100°C for 16 h. The evaporation residue, in chloroform, was filtered. Chromatography (ethyl acetate / petroleum ether 1 :99) gave 1-methoxy-3- (3-methoxyphenyl)-5-nitroisoquinoline 11b (81 mg, 81 %) as a yellow solid: mp 87- 90°C; 1H NMR (CDCI3) δ 3.93 (3 H, s, Ph OMe), 4.28 (3 H, s, 1-OMe), 7.00 (1 H, m, Ph
6- H), 7.42 (1 H, t, J = 8.0 Hz, Ph 5-H), 7.57 (1 H, t, J = 8.0 Hz, 7-H), 7.78 (2 H, m, Ph 2& 4-H2), 8.48 (1 H, dd, J = 7.8, 1.3 Hz, 6-H), 8.51 (1 H, s, 4-H), 8.61 (1 H, dt, J = 8.2, 1.0 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.16 (Ph-OMe), 56.00 (1 -OMe), 105.38 (4-C), 112.98 (Ph 4-C), 1 14.79 (Ph 6-C), 1 19.62 (Ph 2-C), 124.53 (7-C), 128.54 (6-C), 129.76 (Ph 5-C), 131.20 (8-C), 139.72 (Ph 3-C), 144.35 (5-C), 160.26 (1-C); MS m/z 31 1.1030 (M + H)+ (C17H15N204 requires 31 1.1034).
3-(2-Chlorophenyl)-1 -methoxy-5-nitroisoquinoline (11c). To 3-bromo-1 -methoxy-5- nitroisoquinoline 9 (200 mg, 0.71 mmol) were added tris(dibenzylideneacetone)- dipalladium (65 mg, 0.07 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (66 mg, 0.14 mmol), 2-chlorobenzeneboronic acid (165.7 mg, 1.06 mmol) and potassium phosphate (450 mg, 2.1 mmol). Dry dimethylformamide (7.5 ml_) was added and the mixture was stirred at 135°C for 16 h. The solvent was evaporated. The residue, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 3: 197→ 1 : 19) gave 3-(2-chlorophenyl)-1 -methoxy-5-nitroisoquinoline 11 c (132 mg, 60%) as a yellow solid: mp 122-127°C; H NMR (CDCI3) δ 4.21 (3 H, s, Me), 7.39 (1 H, t, J = 7.2 Hz, Ph 5-H), 7.40 (1 H, t, J = 7.0 Hz, Ph 4-H), 7.53 (1 H, dd, J = 7.5, 1.5 Hz, Ph 6-H), 7.63 (1 H, t, J = 7.9 Hz, 7-H), 7.73 (1 H, dd, J = 7.8, 1.7 Hz, Ph 3-H), 8.37 (1 H, s, 4-H), 8.49 (1 H, dd, J = 7.8, 1.3 Hz, 6-H), 8.65 (1 H, dt, J = 8.2, 1.1 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.39 (Me), 1 10.19 (4-C), 1 19.79 (8a-C), 125.05 (7-C), 126.84 (Ph 4-C), 128.46 (6-C), 129.62 (Ph 5-C), 130.48 (Ph 6-C), 130.74 (4a-C), 131.13 (8-C), 131.67 (Ph 3-C), 144.95 (5-C), 160.29 (1-C); MS m/z 315.0533 (M + H)+ (C16H12 35CIN203 requires 315.0538).
3-(3-ChlorophenyI)-1-methoxy-5-nitroisoquinoline (11d). To 3-bromo-1 -methoxy-5- nitroisoquinoline 9 (200 mg, 0.71 mmol) were added tris(dibenzylideneacetone)- dipalladium (65 mg, 0.07 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (66 mg, 0.14 mmol), 3-chlorobenzeneboronic acid (166 mg, 1.1 mmol) and potassium phosphate (450 mg, 2.1 mmol). Dry dimethylformamide (7.5 ml_) was added and the mixture was stirred at 135°C for 16 h. The solvent was evaporated. The residue, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 3:197→ 1 :19) gave 3-(3-chlorophenyl)-1 -methoxy-5-nitroisoquinoline 11 d (1 16 mg, 52%) as a yellow solid: mp 134-141 °C; 1H NMR (CDCI3) δ 4.18 (3 H, s, Me), 7.41 (2 H, m, Ph 5,6-H2), 7.58 (1 H, t, J = 8.0 Hz, 7-H), 8.03 (1 H, dt, J = 6.9, 1.9 Hz, Ph 4- H), 8.18 (1 H, s, Ph 2-H), 8.47 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 8.48 (1 H, s, 4-H), 8.60 (1 H, dt, J = 8.2, 1.1 , 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.29 (Me), 105.53 (4-C), 120.18 (8a-C), 124.90 (7-C), 125.05 (Ph 4-C), 127.21 (Ph 2-C), 128.73 (6-C), 129.24 (Ph 6-C), 129.93 (Ph 5-C), 131.26 (8-C), 131.33 (4a-C), 134.81 (Ph 3-C), 140.43 (3a- C), 144.95 (5-C), 150.30 (3-C), 160.58 (1-C); MS m/z 315.0529 (M + H)+
(C16H12 35CIN203 requires 315.0538).
3-(2,6-Dichlorophenyl)-1-methoxy-5-nitroisoquinoline (11e). To 3-bromo-1- methoxy-5-nitroisoquinoline 9 (240 mg, 0.85 mmol) in a dry flask was added tris(di- benzylideneacetone)dipalladium (78 mg, 0.085 mmol), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (79 mg, 0.17 mmol), 2,6-dichlorobenzeneboronic acid (243 mg, 1.3 mmol) and potassium phosphate (541 mg, 2.5 mmol). Dry dimethylformamide (8.0 mL) was added and the mixture was stirred at 135°C for 16 h. The mixture was filtered through Celite® and the solvent was evaporated. Chromatography (ethyl acetate / petroleum ether 1 : 99) gave 3-(2,6-dichlorophenyl)-1-methoxy-5-nitroisoquinoline 11e (35 mg, 12%) as a yellow solid: mp 122-124°C; 1H NMR (CDCI3) δ 4.17 (3 H, s, Me), 7.30 (1 H, t, J = 8.7 Hz, Ph 4-H), 7.44 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.66 (1 H, t, J = 8.1 Hz, 7-H), 8.08 (1 H, s, 4-H), 8.52 (1 H, dd, J = 7.8, 1.3 Hz, 6-H), 8.67 (1 H, dt, J = 8.2, 1.1 Hz, 8-H); 3C NMR (CDCI3) (HSQC / HMBC) δ 54.61 (Me), 11 1.16 (4-C), 120.08 (4a-C), 125.36 (7-C), 128.24 (Ph 3,5-C2), 128.56 (6-C), 129.82 (Ph 4-C), 130.75 (8a-C), 131.32 (8-C), 134.86 (Ph 2,6-C2), 138.19 (Ph 1-C), 144.94 (5-C), 149.95 (3-C), 160.73 (1-C); MS m/z 348.9740 (M - H) (C^Hn^C CINzOs requires 348.9961).
3-(4-Fluorophenyl)-1-methoxy-5-nitroisoquinoIine (11f). To 3-bromo-1-methoxy-5- nitroisoquinoline 9 (200 mg, 0.71 mmol) in a dry flask was added tris(dibenzylidene- acetone)dipalladium (65 mg, 0.07 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy- biphenyl (66 mg, 0.14 mmol), 4-fluorobenzeneboronic acid (148 mg, 1.1 mmol) and potassium phosphate (448 mg, 2.1 mmol). Dry dimethylformamide (6.0 mL) was added and the mixture was stirred at 135°C for 16 h. The solvent was evaporated. The residue was filtered, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 1 :99→ 1 :49) gave 3-(4-fluorophenyl)-1-methoxy-5- nitroisoquinoline 11f (60 mg, 28%) as a yellow solid: mp 199-200°C; 1H NMR (CDCI3) δ 4.27 (3 H, s, Me), 7.19 (2 H, t, J = 8.5 Hz, Ph 3,5-H2), 7.57 (1 H, t, J = 8.0 Hz, 7-H), 8.19 (2 H, m, Ph 2,6-H2), 8.47 (1 H, s, 4-H), 8.49 (1 H, dd, J = 8.0, 1.0 Hz, 6-H), 8.61 (1 H, d, J = 8.0 Hz; 3C NMR (CDCI3) (HSQC / HMBC) δ 54.11 (Me), 104.79 (4-C), 1 15.68 (d, J = 21.5 Hz, Ph 3,5-C2), 1 19.91 (4a-C), 124.53 (7-C), 128.72 (6-C), 128.97 (d, J = 8.3 Hz, Ph 2,6-C2), 131.26 (8-C), 131.56 (8a-C), 134.81 (Ph 1-C), 144.91 (5-C), 150.93 (3-C), 160.58 (1 -C), 163.75 (d, J = 248.3 Hz, Ph 4-C); MS m/z 299.0808 (M + H)+ (C16H12FN203 requires 299.0834).
1-Methoxy-5-nitro-3-(4-trifluoromethylphenyl)isoquinoline (11g). To 3-bromo-1- methoxy-5-nitroisoquinoline 9 (300 mg, 1.06 mmol) in a dry flask was added tris(di- benzylideneacetone)dipalladium (97 mg, 0.1 1 mmol), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (99 mg, 0.21 mmol), 4-trifluorophenylbenzeneboronic acid (403 mg, 2.1 mmol) and potassium phosphate (675 mg, 3.2 mmol). Dry dimethylformamide (8.0 mL) was added and the mixture was stirred at 135°C for 16 h. The mixture was filtered through Celite® and the solvent was evaporated. Chromatography (ethyl acetate / petroleum ether 3: 197) gave 1-methoxy-5-nitro-3-(4-trifluoromethylphenyl)isoquinoline 11 g (209 mg, 57%) as a yellow solid: mp 125-127°C; 1H NMR (CDCI3) δ 4.25 (3 H, s, Me), 7.58 (1 H, t, J = 7.9 Hz, 7-H), 7.72 (2 H, d, J = 8.2 Hz, Ph 3,5-H2), 8.25 (2 H, d, J = 8.1 Hz, Ph 2,6-H2), 8.46 (1 H, dd, J = 7.8, 1.3 Hz, 6-H), 8.50 (1 H, s, 4-H), 8.58 (1 H, dt, J = 8.2, 1.1 Hz, 8-H); 19F NMR (CDCI3) δ -62.56 (s, CF3); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.23 (Me), 105.94 (4-C), 120.18 (4a-C), 125.11 (7-C), 125.57 (q, J = 3.6 Hz, Ph 3,5-C2), 126.42 (q, J = 275.0 Hz, CF3), 127.20 (Ph 2,6-C2), 128.75 (6-C), 131.17 (8a-C), 131.20 (8-C), 141.79 (Ph 1 -C), 144.82 (5-C), 150.01 (3-C), 160.56 (1 -C); MS m/z 371.0601 (M + Na)+ (C^HuFsNzOsNa requires 371.0622), 349.0775 (M + H)+ (C17H12F3N203 requires 349.0780).
3-(3-Cyanophenyl)-1-methoxy-5-nitroisoquinoline (11 h). To 3-bromo-1 -methoxy-5- nitroisoquinoline 9 (200 mg, 0.71 mmol) were added tris(dibenzylideneacetone)- dipalladium (65 mg, 0.07 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (66 mg, 0.14 mmol), 3-cyanobenzeneboronic acid (148 mg, 1.1 mmol) and potassium phosphate (448 mg, 2.1 mmol). Dry dimethylformamide (6.0 mL) was added and the mixture was stirred at 135°C for 16 h. The solvent was evaporated. The residue, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 1 :99→ 1 : 10) gave 3-(3-cyanophenyl)-1-methoxy-5-nitroisoquinoline 11 h (20 mg, 9%) mp 195-196°C; 1H NMR (CDCI3) δ 4.29 (3 H, s, Me), 7.62 (1 H, t, J = 8.0 Hz, Ph 5- H), 7.64 (1 H, t, J = 8.0 Hz, 7-H), 7.72 (1 H, dt, J = 7.8, 1.3 Hz, Ph 6-H), 8.38 (1 H, dt, J = 8.2, 1.2 Hz, Ph 4-H), 8.52 (1 H, dd, J = 7.8, 1.3 Hz, 6-H), 8.55 (1 H, s, 4-H), 8.56 (1 H, s, Ph 2-H), 8.65 (1 H, dt, J = 8.2, 1.1 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.44 (Me), 105.90 (4-C), 1 13.31 (Ph 1-C), 121.03 (4a-C), 125.39 (7-C), 128.88 (6-C), 129.55 (Ph 2,5-C2), 130.98 (Ph 6-C), 131.30 (8-C), 132.45 (Ph 4-C), 140.32 (CN), 145.67 (5-C), 160.92 ( -C).
3-(4-Cyanophenyl)-1 -methoxy-5-nitroisoquinoline (11 i). To 3-bromo-1 -methoxy-5- nitroisoquinoline 9 (151.0 mg, 0.63 mmol) were added tris(dibenzylideneacetone)- dipalladium (58 mg, 0.063 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (58 mg, 0.014 mmol), 4-cyanobenzeneboronic acid (150 mg, 1.3 mmol) and potassium phosphate (279 mg, 1.3 mmol). Degassed toluene (4.5 mL) was added and the mixture was stirred at 100°C for 16 h. The evaporation residue, in chloroform, was filtered. Chromatography (ethyl acetate / petroleum ether 1 :99) gave 3-(4-cyanophenyl)-1- methoxy-5-nitroisoquinoline 11 i (53 mg, 28%) as a yellow solid: mp 206-210°C; 1H NMR (CDCI3) δ 4.30 (3 H, s, Me), 7.66 (1 H, t, J = 8.0 Hz, 7-H), 7.81 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 8.32 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 8.53 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 8.59 (1 H, s, 4-H), 8.66 (1 H, d, J = 8.2 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.36 (Me), 106.64 (4-C), 1 12.68 (CN), 18.79 (Ph 4-C), 120.80 (8a-C), 125.56 (7-C), 127.58 (Ph 2,6-H2), 128.85 (6-C), 129.67 (4a-C), 131.26 (8-C), 132.53 (Ph 3,5-H2), 142.86 (3-C), 145.16 (5-C), 149.59 (Ph 1-C), 160.84 (1-C).
1 -Methoxy-5-nitro-3-(2-trifluoromethylphenyl)isoquinoline (11j). To 3-bromo-1 - methoxy-5-nitroisoquinoline 9 (175 mg, 0.62 mmol) were added tris(dibenzylidene- acetone)dipalladium (57 mg, 0.06 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy- biphenyl (58 mg, 0.12 mmol), 2-trifluoromethylbenzeneboronic acid (176 mg, 0.93 mmol) and potassium phosphate (394 mg, 1.9 mmol). Dry dimethylformamide (5.0 mL) was added and the mixture was stirred at 135°C for 16 h. The solvent was evaporated, The residue, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 1 :99→ 1 :19) gave 1 -methoxy-5-nitro-3-(2-trifluoromethylphenyl)- isoquinoline 11j (90 mg, 42%) as a yellow solid: mp 95-99°C; H NMR (CDCI3) δ 4.18 (3 H, s, Me), 7.57 (1 H, tt, J = 7.0, 1.4 Hz, Ph 5-H), 7.64 (3 H, m, Ph 4,6-H2 and 7-H), 7.83 (1 H, d, J = 7.9 Hz, Ph 3-H), 8.18 (1 H, s, 4-H), 8.51 (1 H, dd, J = 7.8, 1.2 Hz, 6- H), 8.66 (1 H, dt, J = 8.3, 1.0 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.44 (Me), 109.28 (4-C), 119.80 (8a-C), 124.15 (q, J = 270.4 Hz, CF3), 125.1 1 (7-C), 126.89 (q, J = 5.0 Hz, Ph 3-C), 128.56 (Ph 5-C), 128.58 (6-C), 128.76 (q, J = 30.6 Hz, Ph 2-C), 130.86 (4a-C), 131.29 (8-C), 131.62 (Ph 6-C), 131.75 (Ph 4-C), 139.69 (Ph 1-C), 144.96 (5-C), 153.10 (3-C), 160.05 (1-C); 19F NMR (CDCI3) δ -56.75 (s, CF3); MS m/z 349.0798 (M + H)+ (C17H12F3N203 requires 349.0802). 1 -Methoxy-5-nitro-3-(3-trifluoromethylphenyl)isoquinoline (11 k). To 3-bromo-1 - methoxy-5-nitroisoquinoline 9 (101 mg, 0.42 mmol) were added tris(dibenzylidene- acetone)dipalladium (41 mg, 0.045 mmol), 2-dicyclohexylphosphino-2',6'-dirnethoxy- biphenyl (40 mg, 0.10 mmol), 3-trifluoromethylbenzeneboronic acid (161 mg, 0.85 mmol) and potassium phosphate (179 mg, 0.84 mmol). Degassed toluene (3.0 mL) was added and the mixture was stirred at 100°C for 6 h. The evaporation residue, in chloroform, was filtered. Chromatography (diethyl ether / petroleum ether 1 :199) gave 1-methoxy-5-nitro-3-(3-trifluoromethylphenyl)isoquinoline 11 k (80.4 mg, 55%) as a yellow solid: mp 135-137°C; H NMR (CDCI3) δ 4.29 (3 H, s, Me), 7.62 (2 H, m, 7-H + Ph 5-H), 7.70 (1 H, d, J = 8.0 Hz, Ph 4-H), 8.34 (1 H, d, J = 7.9 Hz, Ph 6-H), 8.47 (1 H, s, Ph 2-H), 8.49 (1 H, dd, J = 7.7, 1.2 Hz, 6-H), 8.53 (1 H, s, 4-H), 8.62 (1 H, dt, J = 7.2, 1.0 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.31 (Me), 105.70 (4-C), 120.30 (8a-C), 123.98 (q, J = 3.9. Hz, Ph 2-C), 124.19 (q, J = 270.4 Hz, CF3), 125.08 (7-C), 125.84 (q, J = 3.9 Hz, Ph 4-C), 126.89, 128.77 (6-C), 128.78, 29.20 (Ph 5-C), 130.12 (Ph 6-C), 131.27 (8-C), 131.27 (4a-C), 131.30 (q, J = 32.3 Hz, Ph 3-C), 139.47 (Ph 1- C), 145.04 (5-C), 150.25 (3-C), 160.75 (1-C); 19F NMR (CDCI3) δ -62.66 (s, CF3); MS m/z 349.0826 (M + H)+ (C17H12F3N203 requires 349.0802).
3-(4-Hydroxyphenyl)-1 -methoxy-5-nitroisoquinoline (111). To 3-bromo-1 -methoxy-5- nitroisoquinoline 9 (102 mg, 0.36 mmol) was added tris(dibenzylideneacetone)- dipalladium (32 mg, 0.036 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (33.5 mg, 0.07 mmol), 4-hydroxybenzeneboronic acid (74 mg, 0.54 mmol) and potassium phosphate (229 mg, 1.1 mmol). Degassed toluene (3.0 mL) was added and the mixture was stirred at 100°C for 16 h. The solvent was evaporated. The residue, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 1 :49→ 1 :3) gave 3-(4-hydroxyphenyl)-1-methoxy-5-nitroisoquinoline 111 (10 mg, 9%) as a bright red solid: mp >230°C; 1H NMR ((CD3)2SO) δ 4.23 (3 H, s, Me), 6.95 (2 H, dd, J = 8.8, 2.0 Hz, Ph 3,5-H2), 7.72 (1 H, t, J = 8.0 Hz, 7-H), 8.08 (2 H, dd, J = 8.8, 2.0 Hz, Ph 2,6-H2), 8.24 (1 H, s, 4-H), 8.59 (2 H, m, 6,8-H2). 9.87 (1 H, br, OH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 54.05 (O-Me), 102.51 (4-C), 115.73 (Ph 3,5-C2), 1 18.51 (8a-C), 125.13 (7-C), 128.30 (Ph 2,6-C2), 128.79 (4a-C), 129.11 (6-C), 130.81 (8-C), 144.43 (5-C), 150.95 (3/Ph 1-C), 159.06 (Ph 4-C), 159.93 (1 -C); MS m/z
297.0861 (M + H)+ (C16H13N204 requires 297.0877). 1-Methoxy-5-nitro-3-(2-phenylethynyl)isoquinoline (11m). To 3-bromo-1 -methoxy- 5-nitroisoquinoline 9 (100 mg, 0.35 mmol) in a dry flask was added bis(triphenyl- phosphine)palladium(ll) dichloride (12.6 mg, 0.018 mmol), copper(l) iodide (6.7 mg, 0.035 mmol) and sodium ascorbate (4.0 mg, 0.02 mmol). Degassed tetrahydrofuran (3.0 mL) and N,N-diisopropylamine (2.0 mL) were added and the mixture was stirred at 50°C for 30 min, after which phenylethyne (72 mg, 0.35 mmol) was added. The mixture was stirred for 16 h at 50°C. The solvents were evaporated. The residue, in chloroform, was filtered through Celite®. Chromatography (ethyl acetate / petroleum ether 1 :99→ 1 :19) gave 1 -methoxy-5-nitro-3-(2-phenylethynyl)isoquinoline 11 m (100 mg, 93%) as a bright yellow solid: mp 153-154X; 1H NMR (CDCI3) δ 4.22 (3 H, s, Me), 7.38 (3 H, m, Ph 3,4,5-H3), 7.60 (1 H, t, J = 8.0 Hz, 7-H), 7.64 (2 H, m, Ph 2,6-H2), 8.32 (1 H, s, 4-H), 8.48 (1 H, dd, J = 7.8, 1.2 Hz, 6-H), 8.59 (1 H, dt, J = 7.1 , 1.0 Hz, 8-H); 3C NMR (CDCI3) (HSQC / HMBC) δ 54.63 (Me), 89.26 (ethyne 2-C), 90.14 (ethyne 1-C), 1 3.94 (4-C), 120.27 (4a-C), 122.19 (Ph 1-C), 125.51 (7-C), 128.39 (Ph 3,4,5-C3), 128.82 (6- C), 130.52 (8a-C), 131.30 (8-C), 132.13 (Ph 2,6-C2), 137.55 (3-C), 144.15 (5-C), 160.76 (1 -C); MS m/z 305.0901 (M + H)+ (C18H13N203 requires 305.0928)
3-(4-FluorophenyI)-5-nitroisoquinoIin-1 -one (12a). 3-(4-Fluorophenyl)-1-methoxy-5- nitroisoquinoline 11f (16 mg, 0.05 mmol) was stirred with hydrogen bromide in acetic acid (33%, 1.0 mL) at 65°C for 7 h. Evaporation yielded 3-(4-fluorophenyl)-5-nitro- isoquinolin-1-one 12a (7.8 mg, 55%) as a dark yellow solid: mp >360°C; 1H NMR ((CD3)2SO)) δ 7.19 (1 H, s, 4-H), 7.36 (2 H, t, J = 8.6 Hz, Ph 3,5-H2), 7.65 (1 H, J = 7.9 Hz, 7-H), 7.84 (2 H, dd, J = 8.2, 5.3 Hz, Ph 2,6-H2), 8.46 (1 H, d, J = 7.8 Hz, 8-H), 8.59 (1 H, d, J = 7.7 Hz, 6-H), 1 1.95 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 96.94 (4-C), 1 15.56 (d, J = 21.8 Hz, Ph 3,5-C2), 125.41 (7-C), 126.38 (8a-C), 129.36 (8-C), 129.43 (Ph 2,6-C2), 129.86 (4a-C), 130.63 (Ph 1-C), 132.83 (6-C), 143.07 (3-C), 144.55 (5-C), 160.99 (1-C), 162.94 (d, J = 246.6 Hz, Ph 4-C); 9F NMR ((CD3)2SO) δ - 110.96 (m, F); MS m/z 283.0524 (M - H)" (C15H8FN203 requires 283.0524).
5-Nitro-3-(4-trifluoromethylphenyl)isoquinolin-1 -one (12b). 1-Methoxy-5-nitro-3-(4- trifluoromethyl)isoquinoline 11g (78 mg, 0.22 mmol) was stirred with hydrogen bromide in acetic acid (33%, 3.5 mL) at 65°C for 7 h. Evaporation yielded 5-nitro-3-(4- trifluoromethylphenyl)isoquinolin-1 -one 12b (34.5 mg, 47%) as a dark yellow solid: mp: 292-294°C; H NMR ((CD3)2SO) δ 7.30 (1 H, s, 4-H), 7.70 (1 H, t, J = 8.0 Hz, 7-H), 7.89 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.99 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.49 (1 H, d, J = 7.5 Hz, 8-H), 8.60 (1 H, d, J = 7.5 Hz, 6-H), 12.26 (1 H, br, N-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 98.63 (4-C), 124.01 (q, J = 270.8 Hz, CF3), 125.81 (q, J = 3.6 Hz, Ph 3,5-C2), 126.36 (7-C), 126.89 (8a-C), 128.27 (Ph 2,6-C2), 129.99 (8-C), 130.04 (q, J = 31.8 Hz, Ph 4-C), 130.59 (4a-C), 133.19 (6-C), 137.44 (Ph 1-C), 142.64 (3-C), 144.94 (5-C), 161.33 (1 -C); 19F NMR ((CD3)2SO) δ -61.22 (s, CF3); MS m/z 333.0493 (M - H)" (C16H8F3N203 requires 333.0493).
5-Amino-1-methoxy-3-(2-methoxyphenyl)isoquinoline (13a). 1-Methoxy-3-(2- methoxyphenyl)-5-nitroisoquinoline 11a (40.3 mg, 0.14 mmol) was stirred vigorously with palladium on charcoal (10%, 44 mg) in ethanol (9 ml_) under hydrogen for 5 h. Filtration (Celite®) and evaporation yielded 5-amino-1 -methoxy-3-(2-methoxyphenyl)- isoquinoline 13a (33.5 mg, 88%) as a pale yellow solid: mp 1 19-121°C; 1H NMR (CDCI3) 5 3.93 (3 H, s, PhOMe), 4.18 (3 H, s, 1-OMe), 6.92 (1 H, dd, J = 7.5, 0.8 Hz, 6- H), 7.04 (1 H, d, J = 8.2 Hz, Ph 3-H), 7.12 (1 H, td, J = 7.4, 1.0 Hz, Ph 5-H), 7.30 (1 H, t, J = 7.8 Hz, 7-H), 7.35 (1 H, td, J = 8.3, 1.8 Hz, Ph 4-H), 7.69 (1 H, d, J = 8.2 Hz, 8-H), 7.93 (1 H, s, 4-H), 8.14 (1 H, dd, J = 7.7, 1.7 Hz, Ph 6-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.55 (1-OMe), 55.79 (PhOMe), 109.00 (4-C), 1 1 1.67 (Ph 3-C), 113.74 (6-C),
1 14.28 (8-C), 1 19.15 (8a-C), 120.95 (Ph 5-C), 126.60 (7-C), 128.15 (4a-C), 128.91 (3- C), 129.04 (Ph 4-C), 131.05 (Ph 6-C), 141.42 (5-C), 144.22 (Ph 1-C), 157.20 (Ph 2-C),
160.29 (1-C); MS m/z 303.1 1 19 (M + Na)+ (C17H16N2Na02 requires 303.1 1 10).
5-Amino-1 -methoxy-3-(3-methoxyphenyl)isoquinoline (13b). 1-Methoxy-3-(3- methoxyphenyl)-5-nitroisoquinoline 11 b (40.1 mg g, 0.14 mmol) was stirred vigorously with palladium on charcoal (10%, 44 mg) in ethanol (9 ml_) under hydrogen for 5 h. Filtration (Celite®) and evaporation yielded 5-amino-1 -methoxy-3-(3-methoxyphenyl)- isoquinoline 13b (31 mg, 81 %) as a pale yellow solid: mp 146-149°C; 1H NMR (CDCI3) δ 3.91 (3 H, s, Ph OMe), 4.21 (3 H, s, 1-OMe), 6.93 (2 H, m, Ph 6-H + 6-H), 7.31 (1 H, t, J = 7.8 Hz, 7-H), 7.39 (1 H, t, J = 8.0 Hz, Ph 5-H), 7.60 (1 H, s, 4-H), 7.71 (3 H, m, Ph 2,4-H2 + 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.60 (1 -OMe), 55.31 (Ph-OMe), 104.17 (4-C), 1 12.39 (Ph 2-C), 1 13.47 (Ph 6-C), 114.05 (6-C), 1 14.47 (8-C), 118.94 (Ph 4-C), 1 19.57 (8a-C), 126.75 (7-C), 128.36 (4a-C), 129.54 (Ph 5-C), 141 .22 (Ph 1 - C), 141.58 (5-C), 146.53 (3-C), 159.92 (Ph 3-C), 160.68 (1 -C); MS m/z 303.1110 (M + Na)+ (C17H16N2Na02 requires 303.1 1 10), 281.1278 (M + H)+ (C17H17N202 requires 281.1290). 5-Amino-3-(2-chlorophenyl)-1 -methoxyisoquinoline (13c). 3-(2-Chlorophenyl)-1 - methoxy-5-nitroisoquinoline 11c (75 mg, 0.24 mmol) was stirred vigorously with platinum on charcoal (1 %, 84 mg) in ethanol (6.0 mL) under hydrogen for 5 h. Filtration (Celite®) and evaporation gave 5-amino-3-(2-chlorophenyl)-1 -methoxyisoquinoline 13c (70 mg, 100%) as a yellow solid: mp 102-103 °C; 1H NMR (CDCI3) 5 4.18 (Me), 6.93 (1 H, dd, J = 7.5 Hz, 6-H), 7.35 (3 H, m, 7-H + Ph 4,5-H2), 7.51 (1 H, dd, J = 8.0, 1.0 Hz, Ph 3-H), 7.56 (1 H, s, 4-H), 7.73 (1 H, d, J = 8.0 Hz, 8-H), 7.76 (1 H, dd, J = 7.5, 1.5 Hz, Ph 6-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.78 (Me), 109.13 (4-C), 1 13.89 (6- C), 1 14.14 (8-C), 1 19.29 (4a-C), 126.75 (Ph 4-C), 127.17 (7-C), 127.59 (8a-C), 128.83 (Ph 5-C), 130.27 (Ph 3-C), 131.75 (Ph 6-C), 132.32 (Ph 1-C), 139.34 (Ph 2-C), 141.65 (5-C), 145.86 (3-C), 160.57 (1-C); MS m/z 285.0803 (M + H)+ (C16H14 35CIN20 requires 285.0796).
5-Amino-3-(3-chlorophenyl)-1 -methoxyisoquinoline (13d). 3-(3-Chlorophenyl)-1 - methoxy-5-nitroisoquinoline 11d (75 mg, 0.24 mmol) was stirred vigorously with platinum on charcoal (1 %, 84 mg) in ethanol (6.0 mL) under hydrogen for 5 h. Filtration (Celite®) and evaporation gave 5-amino-3-(3-chlorophenyl)-1 -methoxyisoquinoline 13d (62 mg, 91 %) as a yellow solid: mp 94-95°C; 1H NMR (CDCI3) δ 4.20 (Me), 6.93 (1 H, dd, J = 7.5, 0.5 Hz, 6-H), 7.33 (3 H, m, 7-H + Ph 5,6-H2), 7.57 (1 H, s, 4-H), 7.69 (1 H, d, J = 8.5 Hz, 8-H), 8.01 (1 H, d, J = 7.5 Hz, Ph 3-H), 8.14 (1 H, s, Ph 2-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.69 (Me), 104.39 (4-C), 1 14.31 (6-C), 1 14.53 (8-C), 19.72 (4a-C), 124.47 (Ph 4-C), 126.57 (Ph 2-C), 127.07 (7-C), 128.19 (8a-C), 128.01 (Ph 5-C), 129.74 (Ph 6-C), 134.56 (Ph 3-C), 141.47 (5-C), 141.57 (Ph 1 -C), 145.18 (3- C), 160.78 (1-C); MS m/z 285.0793 (M + H)+ (C16H14 35CIN20 requires 285.0796).
5-Amino-3-(2,6-dichlorophenyl)-1 -methoxyisoquinoline (13e). 3-(2,6-Dichloro- phenyl)-1-methoxy-5-nitroisoquinoline 11e (30.1 mg, 0.09 mmol) was stirred vigorously with palladium on charcoal (10%, 33 mg) in ethanol (5.0 mL) under hydrogen for 5.0 h. Filtration (Celite®) and evaporation gave 5-amino-3-(2,6-dichlorophenyl)-1 - methoxyisoquinoline 13e (27.1 mg, 94%) as an orange solid: mp 103-104°C; 1H NMR (CDCI3) 5 4.12 (3 H, s, Me), 6.95 (1 H, dd, J = 7.5, 1.0 Hz, 6-H), 7.19 (1 H, d, J = 0.9 Hz, 4-H), 7.25 (1 H, t, J = 8.6 Hz, Ph 4-H), 7.36 (1 H, t, J = 7.6 Hz, 7-H), 7.42 (2 H, d, J = 8.3 Hz, Ph 3,5- H2), 7.74 (1 H, dt, J = 8.2, 1.0 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 54.02 (Me), 109.70 (4-C), 1 14.00 (6-C), 114.37 (8-C), 127.36 (7-C), 128.15 (Ph 3,5-C2), 129.30 (Ph 4-C), 1 19.69 (4a-C), 127.62 (8a-C), 135.25 (Ph 2,6-C2), 138.92 (Ph 1-C), 141.65 (5-C), 144.58 (3-C), 160.94 (1-C); MS m/z 321.0356 (M + H)+ (C16H13 35CI37CIN20 requires 321.0375), 319.0387 (M + H)+ (C16H13 35CI2N20 requires 319.0405).
5-Amino-3-(4-fluorophenyl)-1-methoxyisoquinoline (13f). 3-(4-Fluorophenyl)-1 - methoxy-5-nitroisoquinoline 11f (108 mg, 0.36 mmol) was stirred vigorously with palladium on charcoal (10%, 1 18 mg) in ethanol (8.0 ml_) under hydrogen for 6 h. Filtration (Celite®) and evaporation gave 5-Amino-3-(4-fluorophenyl)-1-methoxy- isoquinoline 13f (90 mg, 69%) as an off-white solid: mp 154-155°C; 1H NMR (CDCI3) δ 4.21 (3 H, s, Me), 6.94 (1 H, dd, J = 7.5, 1.0 Hz, 6-H), 7.15 (2 H, m, Ph 3,5-H2), 7.31 (1 H, t, J = 7.5 Hz, 7-H), 7.54 (1 H, s, 4-H), 7.69 (1 H, dt, J = 8.2, 1.0 Hz, 8-H), 8.13 (2 H, m, Ph 2,6-H2); 19F NMR (CDCI3) δ -1 14.31 (m, F); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.62 (Me), 103.64 (4-C), 1 14.31 (6-C), 114.67 (8-C), 1 15.42 (d, = 21.5 Hz, Ph 3,5- C2), 1 19.40 (4a-C), 126.72 (7-C), 128.62 (d, J = 10.4 Hz, Ph 2,6-C2), 128.53 (8a-C), 135.85 (d, J = 3.3 Hz, Ph 1-C), 141.37 (5-C), 145.98 (3-C), 160.82 (1-C), 163.04 (d, J = 246.0 Hz, Ph 4-C); MS m/z 269.1074 (M + H)+ (C16H14FN20 requires 269.1092); MS m/z 267.0925 (M - H)" (C16H12FN20 requires 267.0932).
5-Amino-1 -methoxy-3-(4-trifluoromethylphenyl)isoquinoline (13g). 1 -Methoxy-5- nitro-3-(4-trifluoromethylphenyl)isoquinoline 11 g (151 mg, 0.43 mmol) was stirred vigorously with palladium on charcoal (10%, 165 mg) in ethanol (8.0 ml_) under hydrogen for 5.5 h. Filtration (Celite®) and evaporation gave 5-amino-1 -methoxy-3-(4- trifluoromethylphenyl)isoquinoline 13g (120 mg, 87%) as a buff solid: mp 141-142X; 1H NMR (CDCI3) δ 4.21 (3 H, s, Me), 6.95 (1 H, dd, J = 7.5, 0.8 Hz, 6-H), 7.34 (1 H, t, J = 7.7 Hz, 7-H), 7.65 (1 H, s, 4-H), 7.71 (3 H, m, 8-H + Ph 3,5-H2), 8.25 (2 H, d, J = 8.2 Hz, Ph 2,6-H2); 19F NMR (CDCI3) δ -62.40 (s, CF3); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.70 (Me), 104.97 (4-C), 1 14.40 (6-C), 1 14.58 (8-C), 1 19.96 (4a-C), 123.26 (q, J = 269.9 Hz, CF3), 125.48 (q, J = 3.9 Hz, Ph 3.5-C2), 126.68 (Ph 2,6-C2), 127.37 (7-C), 128.16 (8a-C), 129.86 (q, J = 31.9 Hz, Ph 4-C), 141.78 (5-C), 143.06 (Ph 1-C), 145.21 (3-C), 160.97 (1-C); MS m/z 317.0907 (M - H)' (C17H12F3N20 requires 317.0900).
5-Amino-3-(3-cyanophenyl)-1-methoxyisoquinoline (13h). 3-(3-Cyanophenyl)-1 - methoxy-5-nitroisoquinoline 11 h (34 mg, 0.1 1 mmol) was stirred vigorously with palladium on charcoal (10%, 38 mg) in ethanol (5.0 ml_) under hydrogen for 6.5 h. Filtration (Celite®), evaporation and chromatography (ethyl acetate / petroleum ether 1 :39→ 1 :4) gave 5-amino-3-(3-cyanophenyl)-1-methoxyisoquinoline 13h (1 1.2 mg, 37%) as a golden buff solid: mp 183-184°C; 1H NMR (CDCI3) 5 4.22 (3 H, s, Me), 6.96 (1 H, dd, J = 7.5, 1.0 Hz, 6-H), 7.35 (1 H, t, J = 7.6 Hz, 7-H), 7.56 (1 H, t, J = 7.4 Hz, Ph 5-H), 7.62 (1 H, s, 4-H), 7.63 (1 H, dt, J = 7.9, 1.5 Hz, Ph 6-H), 7.70 (1 H, dt, J = 8.2, 0.9 Hz, 8-H), 8.36 (1 H, dt, J = 7.9, 1.3 Hz, Ph 4-H), 8.46 (1 H, t, J = 1.3 Hz, Ph 2-H); 13C MR (CDCI3) (HSQC / HMBC) δ 53.80 (Me), 104.72 (4-C), 1 12.74 (Ph 3-C), 114.52 (6-C), 1 14.58 (8-C), 119.14 (CN), 120.03 (8a-C), 127.53 (7-C), 128.08 (4a-C), 129.31 (Ph 5-C), 130.26 (Ph 2-C), 130.49 (Ph 4-C), 131.27 (Ph 6-C), 140.84 (Ph 1-C), 141.81 (5-C), 144.22 (3-C), 161.09 (1-C); MS m/z 276.1 128 (M + H)+ (C17H14N30 requires 276.1137).
5-Amino-3-(4-cyanophenyl)-1 -methoxyisoquinoline (13i). 3-(4-Cyanophenyl)-1 - methoxy-5-nitroisoquirioline 11 i (37 mg, 0.12 mmol) was stirred vigorously with palladium on charcoal (10%, 41 mg) in ethanol (5.5 ml_) under hydrogen for 6.5 h. Filtration (Celite®), evaporation and chromatography (ethyl acetate / petroleum ether 1 :39→ 1 :4) gave 5-amino-3-(4-cyanophenyl)-1 -methoxyisoquinoline 13i (17.3 mg, 52%) as an amber-coloured solid: mp 203-204X; 1H NMR (CDCi3) δ 4.21 (3 H, s, Me), 6.96 (1 H, dd, J = 7.6, 1.0 Hz, 6-H), 7.36 (1 H, t , J = 7.6 Hz, 7-H), 7.67 (1 H, s, 4-H), 7.70 (1 H, dt, J = 7.3, 0.9 Hz, 8-H), 7.74 (2 H, d, J = 8.7 Hz, Ph 3,5-H2), 8.25 (2 H, d, J = 8.7 Hz, Ph 2,6-H2); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.76 (Me), 105.55 (4-C), 1 1 1.27 (Ph 4-C), 1 14.58 (6-C), 1 14.61 (8-C), 1 19.17 (CN), 120.18 (4a-C), 126.89 (Ph 2,6-C2), 127.77 (7-C), 127.98 (8a-C), 132.39 (Ph 3,5-C2), 141.93 (5-C). 143.93 (Ph 1- C), 144.45 (3-C), 161.04 (1-C); MS m/z 276.1 124 (M + H)+ (C17H14N30 requires 276.1137).
5-Amino-1 -methoxy-3-(2-trif luoromethyIphenyl)isoquinoline (13j). 1 -Methoxy-5- nitro-3-(2-trifluoromethylphenyl)isoquinoline 11j (48 mg, 0.14 mmol) was stirred vigorously with platinum on charcoal (1 %, 53 mg) in ethanol (6.0 mL) under hydrogen for 4 h. Filtration (Celite®) and evaporation gave 5-amino-1-methoxy-3-(2-trifluoro- methylphenyl)isoquinoline 13j (29 mg, 66%) as a dark yellow solid: mp 172-174°C; 1H NMR (CDCI3) δ 4.13 (OMe), 6.96 (1 H, dd, J = 7.5, 0.5 Hz, 6-H), 7.28 (1 H, s, 4-H), 7.37 (1 H, t, J = 7.5 Hz, 7-H), 7.51 (1 H, t, J = 7.5 Hz, Ph 5-H), 7.63 (2 H, m, Ph 4,6-H2), 7.73 (1 H, d, J = 8.5 Hz, 8-H), 7.81 (1 H, d, J = 8.0 Hz, Ph 3-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.85 (Me), 108.10 (4-C), 1 14.03 (6-C), 1 14.32 (8-C), 119.34 (8a- C), 124.28 (q, J = 272 Hz, CF3), 126.69 (q, J = 5.1 Hz, Ph 3-C), 127.17 (7-C), 127.57 (4a-C), 127.81 (Ph 5-C), 128.54 (q, J = 30.1 Hz, Ph 2-C), 131.41 (Ph 6-C), 131.90 (Ph
4- C), 140.55 (Ph 1-C), 141.56 (5-C), 147.56 (3-C), 160.35 (1-C); MS m/z 341.0872 (M + Na)+ (C17H13F3N2NaO requires 341.0880).
5- Amino-1 -methoxy-3-(3-trifluoromethylphenyl)isoquinoline (13k). 1 -Methoxy-5- nitro-3-(3-trifluoromethylphenyl)isoquinoline 11 k (152 mg, 0.44 mmol) was stirred vigorously with palladium on charcoal (10%, 165 mg) in ethanol (8.0 ml_) under hydrogen for 5.5 h. Filtration (Celite®) and evaporation gave 5-amino-1-methoxy-3-(3- trifluoromethylphenyl)isoquinoline 13k (120 mg, 87%) as a pale buff solid: mp 89-91 °C; 1H NMR (CDCI3) δ 4.22 (3 H, s, Me), 6.94 (1 H, d, J = 7.4 Hz, 6-H), 7.33 (1 H, t, J = 7.8 Hz, 7-H), 7.55 (1 H, t, J = 7.7 Hz, Ph 5-H), 7.62 (2 H, m, 4-H + Ph 4-H), 7.70 (1 H, d, J = 8.2 Hz, 8-H), 8.32 (1 H, d, J = 7.6 Hz, Ph 6-H), 8.40 (1 H, s, Ph 2-H); 19F NMR (CDCI3) δ -62.50 (s, CF3); 13C NMR (CDCI3) (HSQC / HMBC) δ 53.70 (Me), 104.50 (4- C), 1 14.37 (6-C), 1 14.57 (8-C), 1 19.87 (4a-C), 123.23 (q, J = 3.9 Hz, Ph 2-C), 124.39 (q, J = 270.8 Hz, CF3), 124.63 (q, J = 3.9 Hz, Ph 4-C), 127.24 (7-C), 128.22 (8a-C), 129.00 (Ph 5-C), 129.66 (Ph 6-C), 130.95 (q, J = 31.8 Hz, Ph 3-C), 140.44 (Ph 1-C), 141.75 (5-C), 145.16 (3-C), 160.97 (1-C); MS m/z 319.1048 (M + H)+ (C17H14F3N20 requires 319.1060).
5-Amino-3-(4-hydroxyphenyl)-1 -methoxyisoquinoline (13I). 3-(4-Hydroxyphenyl)-1 - methoxy-5-nitroisoquinoline 111 (65 mg, 0.22 mmol) was stirred vigorously with palladium on charcoal (10%, 71.5 mg) in ethanol (5.0 mL) under hydrogen for 6 h. Filtration (Celite®) and evaporation gave 5-amino-1-methoxy-3-(4-hydroxyphenyl)- isoquinoline 131 (63 mg, 98%) as a yellow solid: mp >230°C; 1H NMR (CD3OD) δ 4.17 (3 H, s, Me), 6.87 (2 H, d, J = 7.0 Hz, Ph 3,5-H2), 6.94 (1 H, d, J = 7.0 Hz, 6-H), 7.22 (1 H, t, J = 8.0 Hz, 7-H), 7.53 (1 H, d, J = 8.5 Hz, 8-H), 7.81 (1 H, s, 4-H), 8.07 (2 H, d, J = 7.0 Hz, Ph 2,6-H2); 13C NMR (CD3OD) (HSQC / HMBC) δ 53.84 (Me), 104.35 (4-C), 114.14 (8-C), 1 14.63 (6-C), 116.24 (Ph 3,5-C2), 120.52 (4a-C), 127.40 (7-C), 128.85 (Ph 2,6-Cz), 130.19 (8a-C), 132.74 (Ph 1-C), 144.38 (5-C), 147.73 (3-C), 158.86 (Ph 4- C), 161.74 (1 -C); MS m/z 267.1 123 (M + H)+ (C16H15N202 requires 267.1 135).
5-Amino-1 -methoxy-3-(2-phenylethyl)isoquinoline (14). 1 -Methoxy-5-nitro-3-(2- phenylethynyl)isoquinoline 11m (65 mg, 0.21 mmol) was stirred vigorously with Pd/C (10%, 71 mg) in EtOH (5.0 mL) under H2 for 6 h. Filtration (Celite®) and evaporation gave 5-amino-1 -methoxy-3-phenethylisoquinoline 14 (51 mg, 87%) as buff oil; 1H NMR (CDCI3) δ 3.15 (4 H, m, CH2CH2), 4.15 (Me), 6.88 (1 H, dd, J = 7.5, 1.0 Hz, 6-H), 6.90 (1 H, s, 4-H), 7.26 (6 H, m, 7-H + Ph-H5), 7.69 (1 H, d, J = 8.5 Hz, 8-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 35.65 (ethyl 1-C), 39.92 (ethyl 2-C), 53.47 (Me), 105.65 (4- C), 113.64 (6-C), 114.38 (8-C), 1 18.79 (4a-C), 125.72 (Ph 4-C), 125.85 (7-C), 128.24 (Ph 2,6-C2), 128.30 (8a-C), 128.51 (Ph 3,5-C2), 140.79 (5-C), 142.17 (Ph 1-C), 150.72 (3-C), 160.69 (1-C); MS m/z 279.1560 (M + H)+ (C17H16N20 requires 279.1499).
2,3,N,N-Tetramethylbenzamide (16). Thionyl chloride (3.0 g, 25 mmol) was added to 2,3-dimethylbenzoic acid 15 (1.00 g, 6.7 mmol) at 0°C. The mixture was then heated at reflux for 16 h, then the excess thionyl chloride was evaporated. The residue, in dichloromethane (1.0 mL), was added dropwise to a stirred solution of dimethylamine in water (40 %, 3.7 mL) at 0-20 °C. The mixture was then stirred at room temperature for 1 h. The mixture was diluted with dichloromethane, then washed thrice with water and dried (magnesium sulfate). The solvent was evaporated to give 2,3,N,N- tetramethylbenzamide 16 (990 mg, 84%) as a pale yellow oil: 1H NMR (CDCI3) (COSY / NOESY) δ 2.16 (3 H, s, 2-Me), 2.27 (3 H, s, 3-Me), 2.81 (3 H, s, N-Me), 3.12 (3 H, s, N- Me'), 6.99 (1 H, dd, J = 7.2, 1.8 Hz, 4-H), 7.10 (1 H, t, J = 7.5 Hz, 5-H), 7.13 (1 H, dd, J = 7.6, 1.8 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 16.00 (2-Me), 20.03 (3-Me), 34.48 (N-Me'), 38.37 (M-Me), 123.40 (4-C), 125.82 (5-C), 130.01 (6-C), 132.25 (2-C), 137.02 (1-C), 137.42 (3-C), 171.99 (C=0); MS m/z 178.1226 (M + H) (CnH16NO requires 178.1232).
5- ethyl-3-phenylisoquinolin-1 -one (17a). Butyllithium (1.6 M in hexanes, 0.90 mL, 1.4 mmol) was added to dry diisopropylamine (172 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (250 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. Benzonitrile (144 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 2 h. Water (1.0 mL) was added. The mixture was extracted with dichloromethane. The extract was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated to give 5-methyl-3-phenylisoquinolin-1 -one 17a (68 mg, 20%) as white crystals: mp 214-215°C; 1H NMR ((CD3)2SO) (COSY / NOESY) δ 2.56 (3 H, s, Me), 6.86 (1 H, s, 4- H), 7.37 (1 H, t, J = 7.7 Hz, 7-H), 7.49 (3 H, m, Ph 3,4,5-H3), 7.56 (1 H, d, J = 7.1 Hz, 6- H), 7.82 (2 H, dd, J = 6.6, 1.6 Hz, Ph 2,6-H2), 8.07 (1 H, d, J = 8.0 Hz, 8-H), 1 1.60 (1 H, s, N-H); 3C NMR ((CD3)2SO)) (HSQC / HMBC) δ 18.76 (Me), 100.00 (4-C), 124.57 (8- C), 125.00 (8a-C), 125.90 (7-C), 126.86 (Ph 2,6-C2), 128.72 (Ph 3,5-C2), 129.21 (Ph 4- C), 133.20 (6-C), 133.75 (4a-C), 134.20 (Ph 1-C), 136.61 (5-C), 139.87 (3-C), 162.94 (1 -C); MS m/z 258.0834 (M + Na)+ (C16H13NNaO requires 258.0889).
5-Methyl-3-(4-methylphenyl)isoquinolin-1-one (17b). Butyllithium (1.6 M in hexanes, 0.9 mL, 1.4 mmol) was added to dry diisopropylamine (172 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (250 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Methylbenzonitrile (164 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallised (ethanol) give 5-methyl-3-(4- methylphenyl)isoquinolin-1-one 17b (90 mg, 26%) as off-white crystals: mp 205-207°C; 1H NMR ((CD3)2SO) (COSY) δ 2.36 (3 H, s, Ph-Me), 2.55 (3 H, s, 5-Me), 6.82 (1 H, s, 4-H), 7.30 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.35 (1 H, t, J = 7.6 Hz, 7-H), 7.54 (1 H, d, J = 7.2 Hz, 6-H), 7.72 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.06 (1 H, d, J = 8.0 Hz, 8-H), 1 1.54 (1 H, br, N-H); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.86 (Ph-Me), 20.85 (5- Me), 99.48 (4-C), 124.62 (8-C), 124.89 (8a-C), 125.79 (7-C), 126.76 (Ph 2,6-C2), 129.36 (Ph 3,5-C2), 131.38 (Ph 1-C), 133.23 (6-C), 133.69 (4a-C), 136.77 (5-C), 138.94 (Ph 4-C), 139.92 (3-C), 163.05 (1-C); MS m/z 250.1226 (M + H)+ (C17H16NO requires 250.1232).
3-(4-ChIorophenyI)-5-methylisoquinoiin-1-one (17c). Butyllithium (1.6 M in hexanes, 1.1 mL, 1.7 mmol) was added to dry diisopropylamine (202 mg, 2.0 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (300 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Chlorobenzonitrile (233 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 2 h. Water (1.0 mL) was added, followed by dichloromethane (20 mL). The precipitate was collected by filtration and dried to give 3-(4-chlorophenyl)-5-methylisoquinolin-1-one 17c (456 mg, 99%) as a white solid, mp >360°C; 1H NMR ((CD3)2SO) (COSY) δ 2.61 (3 H, s, Me), 6.93 (1 H, s, 4-H), 7.44 (1 H, t, J = 7.6 Hz, 7-H), 7.61 (3 H, d, J = 8.5 Hz, 6-H + Ph 2,6- H3), 7.90 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 8.12 (1 H, d, J = 7.8 Hz, 8-H), 11.70 (1 H, s, N-H); 13C NMR ((CD3)2SO)) (HSQC / HMBC) δ 18.80 (Me), 100.49 (4-C), 124.60 (8-C), 125.11 (8a-C), 126.19 (7-C), 128.73 (Ph 2,6-C2), 128.78 (Ph 3,5-C2), 133.01 (4a-C), 133.34 (6-C), 133.96 (Ph 1 ,4-C2), 136.49 (5-C), 138.67 (3-C), 162.95 (1-C); MS m/z 270 (M - H)", 268.0533 (M - H)" (C^Hn^CINO requires 268.0535).
5- ethyl-3-(4-trifluoromethylphenyl)isoquinolin-1-one (17d). Butyllithium (1 .6 M in hexanes, 1.1 mL, 1.7 mmol) was added to dry diisopropylamine (202 mg, 2.0 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (300 mg, 1.7 mmol) in dry
tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Tri- fluoromethylbenzonitrile (289 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was extracted with dichloromethane. The extract was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated. The residue was recrystallised (ethanol) (25 mL) to give 5-methyl-3-(4-trifluoromethylphenyl)isoquinolin-1-one 17d (242 mg, 47%) as white crystals: mp 251-252°C; 1H NMR ((CD3)2SO) (COSY) δ 2.56 (3 H, s, Me), 6.96 (1 H, s, 4-H), 7.40 (1 H, t, J = 7.6 Hz, -H), 7.57 (1 H, d, J = 7.2 Hz, 6-H), 7.84 (2 H, d, J = 8.3 Hz, Ph 3,5-H2), 8.03 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.08 (1 H, d, J = 8.0 Hz, 8-H), 1 1.75 (1 H, bs, N-H); 3C NMR ((CD3)2SO)) (HSQC / HMBC) δ 18.77 (Me), 101.54 (4-C), 124.62 (8-C), 125.23 (q, J = 295.9 Hz, CF3), 125.51 (8a-C), 125.56 (q, J = 3.6 Hz, Ph 3,5-C2), 126.54 (7-C), 129.25 (q, J = 31.6 Hz, Ph 4-C), 133.40 (6-C), 134.21 (4a-C), 136.29 (5-C), 138.10 (Ph 1-C), 138.36 (3-C), 162.91 (1-C); 9F NMR ((CD3)2SO)) -61.0808 (s, CF3); MS m/z 302.0808 (M - H)" (C17HnF3NO requires 308.0798).
3-(2-Chlorophenyl)-5-methylisoquinolin-1-one (17e). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (141 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 0 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 2-Chlorobenzonitrile (155 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was washed (ethanol) and dried to give 3-(2-chlorophenyl)- 5-methylisoquinolin-1-one 17e (4.9 mg, 2%) as a white solid: mp 178-180°C; 1H NMR ((CD3)2SO) (COSY) δ 2.53 (3 H, s, Me), 6.58 (1 H, s, 4-H), 7.41 (1 H, t, J = 7.7 Hz, 7- H), 7.47 (1 H, td, J = 7.5, 1.3 Hz, Ph 4-H), 7.51 (1 H, td, J = 7.5, 2.0 Hz, Ph 5-H), 7.59 (3 H, m, 6-H + Ph 3,6-H2), 8.08 (1 H, d, J = 8.0 Hz, 8-H), 1 1.59 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.69 (Me), 102.43 (4-C), 124.61 (8-C), 125.33 (8a-C), 126.25 (7-C), 127.34 (Ph 4-C), 129.70 (Ph 6-C), 130.84 (Ph 5-C), 131.56 (Ph 3-C), 132.29 (Ph 2-C), 133.22 (6-C), 133.69 (4a-C), 134.24 (Ph 1 -C), 136.31 (5-C), 138.15 (3-C), 162.24 (1-C); MS m/z 292.0514 (M + Na)+ (C16H12 35CINNaO requires 292.0505).
3-(3-Chlorophenyl)-5-methylisoquinolin-1-one (17f). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (141 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 3-Chlorobenzonitrile (155 mg, 1.1 mmol) in dry THF (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallised (ethanol) to give 3-(3-chlorophenyl)-5-methylisoquinolin-1- one 17f (33 mg, 1 1 %) as a white solid: mp 275-276°C; H NMR ((CD3)2SO) (COSY) δ 2.57 (3 H, s, Me), 6.93 (1 H, s, 4-H), 7.39 (1 H, t, J = 7.6 Hz, 7-H), 7.52 (2 H, m, Ph 4,5- H2), 7.57 (1 H, d, J = 7.2 Hz, 6-H), 7.80 (1 H, m, Ph 6-H), 7.93 (1 H, s, Ph 2-H), 8.07 (1 H, d, J = 8.0 Hz, 8-H), 1 1.61 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.82 (Me), 100.92 (4-C), 124.57 (8-C), 125.28 (8a-C), 125.64 (Ph 6-C), 126.32 (7-C), 126.74 (Ph 2-C), 129.01 (Ph 4-C), 130.54 (Ph 5-C), 133.33 (6-C), 133.55 (Ph 1 -C), 134.14 (4a-C), 136.20 (Ph 3-C), 136.41 (5-C), 138.31 (3-C), 162.87 (1-C); MS m/z 292.0453 (M + Na)+ (C16H12 35CINNaO requires 292.0506), 270.0661 (M + H)+
(C16H13 35CINO requires 270.0686).
3-(2,6-Dichlorophenyl)-5-methylisoquinolin-1 -one (17g). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (141 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 2,6- Dichlorobenzonitrile (194 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at - 78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallised (ethanol) to give 3-(2,6- dichlorophenyl)-5-methylisoquinolin-1-one 17g (35 mg, 10%) as a pale buff solid: mp 202-204°C; 1H NMR ((CD3)2SO) (COSY) δ 2.47 (3 H, s, Me), 6.58 (1 H, s, 4-H), 7.43 (1 H, t, J = 7.6 Hz, 7-H), 7.55 (1 H, t, J = 7.2 Hz, Ph 4-H), 7.58 (1 H, d, J = 7.3 Hz, 6-H), 7.59 (2 H, d, J = 7.6 Hz, Ph 3,5-H2), 8.09 (1 H, d, J = 7.9 Hz, 8-H), 11.62 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.66 (Me), 102.81 (4-C), 124.61 (8-C), 125.58 (8a-C), 126.45 (7-C), 128.28 (Ph 3,5-C2), 131.67 (Ph 4-C), 133.19 (Ph 1-C), 133.29 (6- C), 133.75 (4a-C), 134.69 (Ph 2,6-C2), 135.20 (3-C), 136.24 (5-C), 162.37 (1-C); MS m/z 326.0991 (M + Na)+ (C^Hn^C^ aO requires 326.01 15), 304.0286 ((M + H)+ (C16H12 35CI2NO requires 304.0296).
3-(4-BromophenyI)-5-methylisoquinolin-1-one (17h). Butyllithium (1.6 M in hexanes, 0.9 mL, 1.4 mmol) was added to dry diisopropylamine (162 mg, 1.6 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (241 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Bromobenzonitrile (248 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane (20 mL). The solid was collected by filtration, washed (ethanol) and dried to give 3-(4-bromophenyl)-5- methyIisoquinolin-1-one 17h (181 mg, 42%) as a white solid: mp 278-279°C; 1H NMR ((CD3)2SO) (COSY) δ 2.55 (3 H, s, Me), 6.88 (1 H, s, 4-H), 7.38 (1 H, t, J = 7.7 Hz, 7- H), 7.56 (1 H, d, J = 7.2 Hz, 6-H), 7.69 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 7.78 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 8.07 (1 H, d, J = 8.0 Hz, 8-H), 1.59 (1 H, br, NH); 13C NMR
((CD3)2SO) (HSQC / HMBC) δ 18.81 (Me), 100.47 (4-C), 122.66 (Ph 4-C), 124.62 (8-C), 125.13 (8a-C), 126.20 (7-C), 129.03 (Ph 3,5-C2), 131.66 (Ph 2,6-C2), 133.34 (6-C), 133.43 (Ph 1-C), 133.97 (4a-C), 136.51 (5-C), 138.81 (3-C), 162.99 (1 -C); MS m/z 335.9966 (M + Na)+ (C16H12 79BrNNaO requires 336.0000). 3-{4-Methoxyphenyl)-5-methylisoquinolin-1-one (17i). Butyllithium (1.6 M in hexanes, 0.7 ml_, 1.1 mmol) was added to dry diisopropylamine (141 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 ml.) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry
tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4- Methoxybenzonitrile (151 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at - 78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was washed (ethanol) to give 3-(4- methoxyphenyl)-5-methylisoquinolin-1 -one 17i (48 mg, 17%) as a white solid: mp 207- 208°C; H NMR ((CD3)2SO) (COSY) δ 2.54 (1 H, s, 5-Me), 3.82 (3 H, s, OMe), 6.77 (1 H, s, 4-H), 7.04 (2 H, d, J = 8.8 Hz, Ph 3,5-H2), 7.33 (1 H, t, J = 7.6 Hz, 7-H), 7.53 (1 H, d, J = 7.1 Hz, 6-H), 7.78 (2 H, d, J = 8.8 Hz, Ph 2,6-H2), 8.05 (1 H, d, J = 8.0 Hz, 8-H), 1 1.45 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.81 (5-Me), 55.34 (OMe), 98.87 (4-C), 1 14.15 (Ph 3,5-C2), 124.57 (8-C), 124.63 (8a-C), 125.51 (7-C), 126.51 (Ph 1 -C), 128.23 (Ph 2,6-C2), 133.15 (6-C), 133.49 (4a-C), 136.86 (5-C), 139.70 (3-C), 160.14 (Ph 4-C), 163.02 (1 -C); MS m/z 553.2099 (2 M + Na)+ (C34H3o 2Na04 requires 553.2104); 288.0994 (M + Na)+ (C17H15NNa02 requires 288.1000), 266.1 179 (M + H)+ (C17H16N02 requires 266.1181).
3-(Benzo-1,3-dioxoI-5-yl)-5-methylisoquinolin-1-one (17j). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (141 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry
tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 5- Cyanobenzo-1 ,3-dioxole (166 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture Was diluted with dichloromethane. The solid was collected by filtration, washed (ethanol) and dried to give 3-(benzo-1 ,3-dioxol-5-yl)-5-methylisoquinolin-1 -one 17j (199 mg, 63%) as a white solid, mp >360°C; H NMR ((CD3)2SO) (COSY) δ 2.54 (3 H, s, Me), 6.10 (2 H, s, CH2), 6.78 (1 H, s, 4-H), 7.02 (1 H, d, J = 8.2 Hz, benzodioxole 6-H), 7.33 (1 H, t, J = 7.7 Hz, 7-H), 7.34 (1 H, dd, J = 8.1 , 1.8 Hz, benzodioxole 7-H), 7.43 (1 H, d, J = 1.8 Hz, benzodioxole 4-H), 7.52 (1 H, d, J = 7.2 Hz, 6-H), 8.04 (1 H, d, J = 8.0 Hz, 8-H), 1 1.44 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.83 (Me), 99.37 (4-C), 101.52 (CH2), 107.27 (benzodioxole 4-C), 108.46 (benzodioxole 7-C), 121.07 (benzodioxole 6- C), 124.56 (8-C), 124.72 (8a-C), 125.60 (7-C), 128.40 (benzodioxole 5-C), 133.12 (6- C), 133.62 (4a-C), 136.80 (5-C), 139.77 (3-C), 147.71 (benzodioxole 7a-C), 148.17 (benzodioxole 3a-C), 163.14 (1-C); MS m/z 278.0797 (M - H)" (C17H12N03 requires 278.0817).
5-Methyl-3-(4-phenylethynylphenyl)isoquinolin-1-one (17k). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (141 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (230 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Phenyl- ethynylbenzonitrile 19 (194 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room
temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. The solid was collected by filtration, washed (ethanol) and dried to give 5-methyl-3-(4-phenylethynylphenyl)isoquinolin-1 -one 17k (1 17 mg, 31 %) as a white solid: mp 285-287°C; 1H NMR ((CD3)2SO) (COSY) δ (2.57, s, Me), 6.94 (1 H, s, 4-H), 7.39 (1 H, t, J = 7.6 Hz, 7-H), 7.45 (3 H, m, Ph 3,4,5-H3), J = 7.6 Hz, 7-H), 7.45 (3 H, m, Ph 3,4,5-H3), 7.56 (1 H, d, J = 7.4 Hz, 6-H), 7.59 (2 H, m, Ph 2,6-H2), 7.67 (2 H, d, J = 8.0 Hz, Ar 3,5-H2), 7.90 (2 H, d, J = 8.0 Hz, Ar 2,6-H2), 8.08 (1 H, d, J = 7.9 Hz, 8-H), 1 1.62 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.82 (Me), 88.99 (ethyne 1-C), 90.86 (ethyne 2-C), 100.64 (4-C), 122.09 (Ph 1 -C), 122.92 (Ar 4-C), 124.61 (8-C), 125.18 (8a-C), 126.21 (7-C), 126.15 (Ar 2,6-C2), 128.84 (Ph 3,5-C2), 129.03 (Ph 10-C), 131.47 (Ph 2,6-C2), 131.66 (Ar 3,5-C2), 133.29 (6-C), 134.03 (4a-C), 134.17 (Ar 1-C), 136.50 (5-C), 139.00 (3-C), 163.00 (1-C); MS m/z 358.1218 (M + Na)+ (C24H17NNaO requires 358.1208), 336.1402 (M + H)+ (C24H18NO requires 336.1388).
4-(Phenylethynyl)benzonitrile (19). Bis(triphenylphosphine)palladium(ll) dichloride (96.5 mg, 0.14 mmol), Cul (52 mg, 0.3 mmol), sodium ascorbate (33 mg, 0.16 mmol) and 4-bromobenzonitrile 18 (500 mg, 2.75 mmol) were mixed in a dry flask. Degassed terahydrofuran (10 mL) and dry diisopropylamine (5.0 mL) were added and the mixture was stirred at 50 °C for 30 min. Phenylethyne (281 mg, 2.75 mmol) was added and the mixture was stirred for 16 h at 50 °C. The mixture was filtered through Celite®.
Evaporation and chromatography (ethyl acetate / petroleum ether 1 : 199→ 1 :99) gave 19 (394 mg, 70%) as an off-white solid: mp 78-79°C (lit.89 mp 109-1 10°C); 1H NMR (CDCI3) δ 7.38 (3 H, m, Ph 3,4,5-H3), 7.55 (2 H, m, Ph 2,6-H2), 7.60 (4 H, m, NCPh 2,3,5,6-H4); 13C NMR (CDCI3) (HSQC / HMBC) δ 87.66 (ethyne 1-C), 93.69 ((ethyne 2- C), 1 1 1.34 (CN), 1 18.42 (NCPh 1-C), 122.1 1 (Ph 1-C), 128.11 (NCPh 4-C), 128.42 (Ph 3,5-C2), 129.04 (Ph 4-C), 131.69 (Ph 2,6-C2), 131 .93 (NCPh 2,6-C2), 131.95 (NCPh 3,5-C2).
3-Methoxy-2,N,N-trimethylbenzamide (21 ). Thionyl chloride (2.74 g, 23 mmol) was added to 3-methoxy-2-methylbenzoic acid 20 (1.00 g, 6.0 mmol) at 0°C. The mixture was heated at reflux for 16 h, then the excess thionyl chloride was evaporated. The residue, in dichloromethane (3.0 mL), was added dropwise to a stirred solution of dimethylamine in water (40 %, 3.7 mL) at 10°C. The mixture was then stirred at room temperature for 3.5 h. The mixture was diluted with dichloromethane, then washed thrice with water and dried (magnesium sulfate). The solvent was evaporated to give 3- methoxy-2,N,N-trimethylbenzamide 21 (980 mg, 85%) as a pale yellow oil: 1H NMR (CDCI3) δ 2.12 (3 H, s, 2-Me), 2.81 (3 H, s, N-Me), 3.12 (3 H, s, N-Me), 3.82 (3 H, s, OMe), 6.76 (1 H, dd, J = 7.6, 0.8 Hz, 4-H), 6.81 (1 H, d, J = 8.2 Hz, 6-H), 7.18 (1 H, t, J = 7.6 Hz, 5-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 12.42 (Me), 34.44 (N-Me), 38.24 (N-Me), 55.44 (OMe), 110.10 (6-C), 1 17.73 (4-C), 122.69 (2-C), 126.97 (5-C), 137.99 (1 -C), 157.76 (3-C), 171.23 (C=0); MS m/z 216.0988 (M + Na)+ (C^H^NNaOa requires 216.0995).
5-Methoxy-3-phenylisoquinolin-1 -one (22a). Butyllithium (1 .6 M in hexanes, 0.8 mL, 1.3 mmol) was added to dry diisopropylamine (156 mg, 1.55 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3- Methoxy-2,N,N-trimethylbenzamide 21 (250 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. Benzonitrile (133 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallised (ethanol) give 5-methoxy-3-phenylisoquinolin-1 -one 22a (97 mg, 30%) as pale peach-coloured crystals: mp 219-220°C; 1H NMR ((CD3)2SO) (COSY) δ 3.94 (3 H, s, Me), 6.94 (1 H, s, 4-H), 7.27 (1 H, dd, J = 8.0, 0.8 Hz, 6-H), 7.43 (1 H, t, J = 8.0 Hz, 7-H), 7.47 (3 H, m, Ph 3,4,5-H3), 7.77 (3 H, m, 8-H + Ph 2,6-H2), 1 1.59 (1 H, br, N-H); 3C MR ((CD3)2SO) (HSQC / HMBC) δ 55.94 (Me), 96.95 (4-C), 1 12.28 (6-C), 1 18.23 (8-C), 125.81 (4a-C), 126.68 (Ph 2,6-C2), 126.85 (7-C), 128.40 (8a-C), 128.83 (Ph 3,5-C2), 129.23 (Ph 4-C), 134.07 (Ph 1-C), 139.62 (3-C), 154.39 (5- C), 162.50 (1-C); MS m/z 274.0846 (M + Na)+ (C16H13NaN02 requires 274.0844).
5-Methoxy-3-(4-methylphenyl)isoquinolin-1-one (22b). Butyllithium (1 .6 M in hexanes, 0.8 mL, 1.3 mmol) was added to dry diisopropylamine (156 mg, 1.55 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Methoxy-2,N,N-trimethylbenzamide 21 (250 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4- Methylbenzonitrile (151 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added at - 78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallised (ethanol) give 5- methoxy-3-(4-methylphenyl)isoquinolin-1-one 22b (16 mg, 5%) as pale yellow crystals: mp 249-251 °C; H NMR ((CD3)2SO) (COSY) δ 2.36 (3 H, s, Ph-Me), 3.94 (3 H, s, OMe), 6.92 (1 H, s, 4-H), 7.25 (1 H, dd, J = 8.0, 0.9 Hz, 6-H), 7.29 (2 H, d, J = 7.9 Hz, Ph 3,5-H2), 7.41 (1 H, t, J = 8.0 Hz, 7-H), 7.66 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 7.77 (1 H, dt, J = 8.0, 0.8 Hz, 8-H), 11.54 (1 H, br, N-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.81 (Me), 55.92 (OMe), 96.35 (4-C), 1 12.22 (6-C), 1 18.23 (8-C), 125.66 (4a-C), 126.51 (Ph 2,6-C2), 126.64 (7-C), 128.52 (8a-C), 129.40 (Ph 3,5-C2), 131.22 (Ph 1-C), 138.88 (3-C), 139.62 (Ph 4-C), 154.33 (5-C), 162.54 (1-C); MS m/z 288.0995 (M + Na)+ (C17H15NaN02 requires 288.1001).
3-(4-Chlorophenyl)-5-methoxyisoquinolin-1 -one (22c). Butyllithium (1.6 M in hexanes, 0.8 mL, 1.3 mmol) was added to dry diisopropylamine (156 mg, 1.55 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Methoxy-2,N,N-trimethylbenzamide 21 (250 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4- Chloromethylbenzonitrile (178 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was washed with ethanol and dried to give 3-(4-chlorophenyl)-5-methoxyisoquinolin-1 -one 22c (86 mg, 23%) as an off-white solid: mp 243-245°C; 1H NMR ((CD3)2SO) (COSY) δ 4.00 (3 H, s, Me), 7.01 (1 H, s, 4-H), 7.33 (1 H, d, J = 7.4 Hz, 6-H), 7.50 (1 H, t, J = 8.0 Hz, 7-H), 7.60 (2 H, d, J = 6.8 Hz, Ph 3,5-H2), 7.84 (3 H, m, 8-H + Ph 2,6-H2), 1 1.71 (1 H, br, N- H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.95 (Me), 97.34 (4-C), 1 12.39 (6-C), 1 18.23 (8-C), 125.89 (4a-C), 127.11 (7-C), 128.20 (8a-C), 128.56 (Ph 2,6-C2), 128.79 (Ph 3,5-C2), 132.88 (Ph 1 -C), 133.91 (Ph 4-C), 138.42 (3-C), 154.44 (5-C), 162.44 (1- C); MS m/z 308.0413 (M + Na)+ (C16H12 35CINNa02 requires 308.0449).
5-Methoxy-3-(4-trifluoromethylphenyl)isoquinolin-1 -one (22d). Butyllithium (1.6 M in hexanes, 0.8 mL, 1.3 mmol) was added to dry diisopropylamine (157 mg, 1.55 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Methoxy-2,N,N-trimethylbenzamide 21 (250 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4- Trifluoromethylbenzonitrile (221 mg, 1.3 mmol) in dry THF (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. Water (1.0 mL) was added. The mixture was extracted with dichloromethane. The extract was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated. The residue was recrystallised (ethanol) (25 mL) to give 5-methoxy-3-(4-trifluoromethylphenyl)- isoquinolin-1-one 22d (113 mg, 27%) as white crystals: mp 259-260°C; 1H NMR ((CD3)2SO) (COSY) δ 3.95 (3 H, s, Me), 7.04 (1 H, s, 4-H), 7.30 (1 H, d, J = 8.0 Hz, 6- H), 7.48 (1 H, t, J = 8.0 Hz, 7-H), 7.80 (1 H, d, J = 8.0 Hz, 8-H), 7.83 (2 H, d, J = 8.3 Hz, Ph3,5-H2), 7.98 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 11.75 (1 H, bs, N-H); 13C NMR
((CD3)2SO) (HSQC / HMBC) δ 55.93 (Me), 98.28 (4-C), 1 12.46 (6-C), 1 18.18 (8-C), 124.03 (q, J = 270.5 Hz, CF3), 125.51 (q, J = 3.8 Hz, Ph 3,5-C2), 126.15 (4a-C), 127.40 (7-C), 127.49 (Ph 2,6-C2), 127.93 (8a-C), 129.14 (q, J = 31.9 Hz, Ph 4-C), 137.85 (Ph 1-C), 137.96 (3-C), 154.54 (5-C), 162.30 (1-C); 19F NMR ((CD3)2SO) DO) R ((CD, Ph 3); MS m/z 318.0740 (M - H)~ (C^HnFa Oz requires 318.0747).
3-Fluoro-2,N,N-trimethylbenzamide (24). Thionyl chloride (3.0 g, 25 mmol) was added to 3-fluoro-2-methylbenzoic acid 23 (1.00 g, 6.5 mmol) at 0°C. The mixture was heated at reflux for 16 h, then the excess thionyl chloride was evaporated. The residue, in dichloromethane (1.0 mL), was added dropwise to a stirred solution of dimethyl- amine in water (40 %, 3.7 mL) at 10°C. The mixture was then stirred at room temperature for 2.5 h. The mixture was diluted with dichloromethane, then washed thrice with water and dried (magnesium sulfate). The solvent was evaporated to give 3- fluoro-2,N,N-trimethylbenzamide 24 (1.00 g, 85%) as a pale orange oil: 1H NMR (CDCI3) δ 2.19 (3 H, d, J = 2.0 Hz, 2-Me), 2.82 (3 H, s, N-Me), 3.13 (3 H, s, N-Me), 6.96 (1 H, d, J = 7.6 Hz, 6-H), 7.01 (1 H, ddd, J = 7.4, 6.1 , 0.8 Hz, 4-H), 7.18 (1 H, m, 5-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 1 1.20 (d, J = 4.5 Hz, 2-Me), 34.54 (N-Me), 38.28 (N-Me), 1 15.31 (d, = 22.5 Hz, 4-C), 121.39 (d, J = 3.6 Hz, 6-C), 121.59 (d, J = 18.3 Hz, 2-C), 127.45 (d, J = 8.6 Hz, 5-C), 138.90 (d, J = 3.9 Hz, 1-C), 161.25 (d, J = 244.5 Hz, 3-C), 169.98 (d, J = 3.3 Hz, C=0); 19F NMR (CDCI3) δ -1 5.66 (d, J = 6.1 Hz, 3-F); MS m/z (M + H)+ 182.0973 (C10H13FNO requires 182.0976).
5-Fluoro-3-phenylisoquinolin-1-one (25a). Butyllithium (1.6 M in hexanes, 0.9 mL, 1.4 mmol) was added to dry diisopropylamine (172 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3- Fluoro-2,N,N-trimethylbenzamide 24 (250 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. Benzonitrile (142 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallised (ethanol) give 5-fluoro-3-phenylisoquinolin-1-one 25a (113 mg, 34%) as an off-white solid: mp 216-217°C; H NMR ((CD3)2SO) (COSY) δ 6.91 (1 H, s, 4-H), 7.55 (4 H, m, 7-H + Ph 3,4,5-H3), 7.66 (1 H, m, 6-H), 7.87 (2 H, m, Ph 2,6-H2), 8.10 (1 H, d, J = 7.9 Hz, 8-H), 11.84 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 94.80 (d, J = 5.3 Hz. 4-C), 1 17.64 (d, J = 19.3 Hz, 6-C), 122.78 (d, J = 3.4 Hz, 8-H), 126.61 (d, J = 3.3 Hz, 8a-C), 126.82 (d, J = 7.9 Hz, 7-C), 126.95 (d, J = 16.4 Hz, 4a-C), 126.96 (Ph 2,6-C2), 128.83 (Ph 3,5-C2), 129.64 (Ph 4-C), 133.59 (Ph 1- C), 141.40 (3-C), 157.31 (d, J = 247.8 Hz, 5-C), 161.78 (d, J = 2.8 Hz, 1-C); 9F NMR ((CD3)2SO) δ - 21.96 (dd, J = 9.9, 5.2 Hz, F); MS m/z 238.0670 (M - H)~ (C15H9FNO requires 238.0668).
3-(4-Chlorophenyl)-5-fluoroisoquinolin-1-one (25b). Butyllithium (1.6 M in hexanes, 0.9 mL, 1.4 mmol) was added to dry diisopropylamine (170 mg, 1.7 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Fluoro-2,N,N-trimethylbenzamide 24 (250 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Chlorobenzonitrile (190 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h.
Water (1.0 mL) was added. The mixture was diluted with dichioromethane (20 mL). The solid was collected by filtration, washed (ethanol) and dried to give 3-(4-chlorophenyl)- 5-fluoroisoquinolin-1 -one 25b (269 mg, 71 %) as a white solid: mp 296-297°C; 1H NMR ((CD3)2SO) (COSY) δ 6.86 (1 H, s, 4-H), 7.49 (1 H, m, 7-H), 7.57 (3 H, m, 6-H + Ph 3,5- H2), 7.84 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 8.05 (1 H, d, J = 7.9 Hz, 8-H), 11.63 (1 H, br, N-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 94.91 (d, J = 5.4 Hz, 4-C), 1 17.36 (d, J = 19.6 Hz, 6-C), 122.53 (d, J = 3.5 Hz, 8-C), 126.73 (d, J = 8.0 Hz, 7-C), 126.52 (8a-C), 126.65 (d, J = 16.2 Hz, 4a-C), 128.51 (Ph 3,5-C2), 128.57 (Ph 2,6-C2), 132.26 (Ph 1-C), 134.15 (Ph 4-C), 140.00 (3-C), 157.15 (d, J = 248.4 Hz, 5-C), 161.42 (1 -C); 19F NMR ((CD3)2SO) δ -122.79 (m, F); MS m/z 272.0762 (M - HV (C15H8 35CIFNO requires 272.0784).
5-Fluoro-3-(4-trifluoromethylphenyI)isoquinoIin-1-one (25c). Butyllithium (1.6 M in hexanes, 0.9 mL, 1.4 mmol) was added to dry diisopropylamine (170 mg, 1 .7 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Fluoro-2,N,N-trimethylbenzamide 24 (250 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4- Trifluoromethylbenzonitrile (236 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichioromethane (20 mL). The solid was collected by filtration, washed (ethanol) and dried to give 5-fluoro-3-(4-trifluoromethylphenyl)isoquinolin-1-one 25c (424 mg, 99%) as a white solid: mp >360°C; 1H NMR ((CD3)2SO) (COSY) δ 6.97 (1 H, s, 4-H), 7.55 (1 H, td, J = 7.6, 5.7 Hz, 7-H), 7.63 (1 H, t, J = 8.7 Hz, 6-H), 7.86 (2 H, d, J = 8.1 Hz, Ph 3,5-H2), 8.05 (3 H, m, Ph 2,6-H2 + 8-H), 1 1.92 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 96.30 (d, J = 4.9 Hz, 4-C), 1 7.86 (d, J = 19.5 Hz, 6-C), 122.83 (d, J = 3.4 Hz, 8-C), 124.07 (q, J = 270.1 Hz, CF3), 125.63 (q, J = 3.5 Hz, Ph 3,5-H2), 126.59 (d, J = 16.3 Hz, 4a-C), 126.91 (8a-C), 127.52 (d, J = 7.6 Hz, 7-C), 127.99 (Ph 2,6-C2), 129.58 (q, J = 31.9 Hz, Ph 4-C), 137.47 (1-C), 139.86 (3-C), 157.44 (d, J = 248.5 Hz, 5- C), 161.70 (1-C); 19F NMR (DMSO) δ -61.19 (3 F, s, CF3), -121.55 (1 F, m, F); MS m/z 306.0559 (M - H)" (C16H8F4NO requires 306.0548). 5-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-one (25d). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (131 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Fluoro-2,N,N-trimethylbenzamide 24 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4- Methoxybenzonitrile (147 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at - 78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried (magnesium sulfate). The solvent was evaporated and the residue was washed (ethanol) and dried to give 5- fluoro-3-(4-methoxyphenyl)isoquinolin-1-one 25d (8.1 mg, 3%) as an off-white solid, mp 238-240 ; H NMR ((CD3)2SO) δ 3.82 (3 H, s, Me), 6.78 (1 H, s, 4-H), 7.05 (2 H, d, J = 8.9 Hz, Ph 3,5-H2), 7.45 (1 H, m, 7-H), 7.57 (1 H, t, J = 8.9 Hz, 6-H), 7.77 (2 H, d, J = 8.9 Hz, Ph 2,6-H2), 8.02 (1 H, d, J = 8.0 Hz, 8-H), 1 1.66 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.37 (Me), 93.59 (d, J = 5.3 Hz, 4-C), 1 14.23 (Ph 3,5- C2), 1 17.52 (d, J = 19.6 Hz, 6-C), 122.74 (d, J = 3.2 Hz, 8-C), 125.84 (Ph 1-C), 126.24 (d, J = 3.6 Hz, 8a-C), 126.32 (d, J = 7.6 Hz, 7-C), 129.20 (d, J = 16.5 Hz, 4a-C), 128.35 (Ph 2,6-C2), 141.19 (3-C), 157.19 (d, J = 247.5 Hz, 5-C), 160.41 (Ph 4-C), 161.82 (1- C); 19F NMR (DMSO) δ -122.20 (dd, J = 9.9, 5.2 Hz, F); MS m/z 561.1593 (2 M + Na)+ (C32H24F2N2Na04 requires 561.1602), 292.0747 (M + Na)+ (C16H12FNNa02 requires 292.0750).
3-(4-Bromophenyl)-5-fluoroisoquinolin-1 -one (25e). Butyllithium (1.6 M in hexanes, 0.64 mL, 1.2 mmol) was added to dry diisopropylamine (121 mg, 1.2 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Fluoro-2,N,N-trimethylbenzamide 24 (180 mg, 1.0 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Bromobenzonitrile (186 mg, 1.0 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78 °C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h.
Water (1.0 mL) was added. The mixture was diluted with dichloromethane (20 mL). The solid was collected by filtration, washed (ethanol) and dried to give 3-(4-bromophenyl)- 5-fluoroisoquinolin-1-one 25e (238 mg, 61 %) as a white solid: mp >360°C; 1H NMR ((CD3)2SO) (COSY) δ 6.86 (1 H, s, 4-H), 7.47 (1 H, m, 7-H), 7.52 (1 H, t, J = 8.1 Hz, 6- H), 7.67 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 7.78 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 8.03 (1 H, d, J = 7.9 Hz, 8-H), 1 1.87 (1 H, bs, N-H); 13C NMR ((CD3)2SO) δ (HSQC / HMBC) 94.61 (d, J = 5.1 Hz, 4-C), 1 17.08 (d, J = 19.3 Hz, 6-C), 122.60 (d, J = 3.5 Hz, 8-C), 122.66 (Ph 4-C), 126.45 (d, J = 7.9 Hz, 7-C), 126.53 (8a-C), 126.80 (d, J = 16.3 Hz, 4a- C), 128.85 (Ph 3,5-C2), 131.45 (Ph 2,6-C2), 133.27 (Ph 1-C), 140.87 (3-C), 157.20 (d, J = 248.3 Hz, 5-C), 162.10 (1 -C); 19F NMR ((CD3)2SO) δ -121.89 (m, F); MS m/z
317.9760 (M - HV (C15H8 81BrFNO requires 317.9753), 315.9773 (M - H)~
(C15H8 79BrFNO requires 315.9773).
3-Cyano-2-(phenylethynyl)pyridine (28a). 2-Bromo-3-cyanopyridine 2790 (150 mg, 0.80 mmol) in tetrahydrofuran (5.0 mL) was added to copper(l) iodide (15.2 mg, 80 □ (150 mg, 0.80 mmol) in tetrahydrpalladium(ll) dichloride (28 mg, 0.04 mmol) in N,N- diisopropylamine (5.0 mL) under argon. The mixture was stirred at 45°C for 30 min. Phenylethyne (163 mg, 1.6 mmol) was added and the mixture was stirred at 40°C for 5 d. Evaporation and chromatography (petroleum ether / ethyl acetate 3:1) gave 3-cyano-
2- (phenylethynyl)pyridine 28a (80 mg, 50%) as a pale buff powder: mp 83-85°C (lit.91 mp 85-87°C); 1H NMR (CDCI3) δ 7.33 (1 H, dd, J = 8.0, 4.8 Hz, 5-H), 7.40 (m, Ph 3,4,5- H3), 7.68 (d, J = 5.6 Hz, Ph 2,6-H2), 7.95 (1 H, dd, J = 8.0, 2.0 Hz, 4-H), 8.77 (1 H, dd, J = 4.8, 1.6 Hz, 6-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 85.62 (ethyne 2-C), 96.20 (ethyne 1 -C), 1 12.82 (3-C), 1 15.91 (C≡N), 120.98 (5-C), 121.87 (Ph 1-C), 128.47 (Ph 3,5-C2), 129.99 (Ph 4-C), 132.47 (Ph 2,6-C2), 139.76 (4-C), 146.04 (2-C), 152.77 (6-C); MS m/z 227.0575 (M + Na)+ (C14H8N2Na requires 227.0586), 205.0755 (M + H)+ (C14H9N2 requires 205.0766).
3- Cyano-2-(4-methoxyphenylethynyl)pyridine (28b). N,N-Diisopropylamine (10 mL) and tetrahydrofuran (10 mL) were added to 2-bromo-3-cyanopyridine 2790 (400 mg, 2.2 mmol), bis(triphenylphosphine)palladium(ll) dichloride (76 mg, 0.1 1 mmol), copper(l) iodide (40 mg, 0.22 mmol) and sodium ascorbate (25 mg, 0.12 mmol) under argon. The mixture was stirred at 40°C for 30 min. 4-Methoxyphenylethyne (290 mg, 2.2 mmol) was added and the mixture was stirred at 40°C for 12 h. Evaporation and
chromatography (petroleum ether / ethyl acetate 5:1→ 1 :3) gave 3-cyano-2-(4- methoxyphenylethynyl)pyridine 28b (400 mg, 81%) as a pale buff powder: mp 1 18- 120°C; 1H NMR (CDCI3) δ 3.83 (3 H, s, Me), 6.90 (2 H, d, J = 9.5 Hz, Ph 3,5-H2), 7.30 (1 H, dd, J = 8.0, 4.9 Hz, 5-H), 7.62 (2 H, d, J = 9.5 Hz, Ph 2,6-H2), 7.93 (1 H, dd, J = 6.2, 3.1 Hz, 4-H), 8.75 (1 H, dd, J = 4.9, 1.7 Hz, 6-H); 13C NMR (CDCI3) (HMBC) δ 55.32 (OMe), 85.01 (ethyne 2-C), 96.94 (ethyne 1-C), 1 12.94 (5-C), 1 14.22 (Ph 3,5- C2), 1 16.09 (C≡N), 121.45 (3-C), 134.23 (Ph 2,6-C2), 139.74 (4-C), 146.36 (6-C), 152.74 (2-C), 161.05 (Ph 4-C); MS m/z 257.0670 (M + Naf (C15H10N2NaO requires 257.0691 ).
3-Cyano-2-(4-methylphenylethynyl)pyridine (28c). N,N-Diisopropylamine (5.0 mL) and tetrahydrofuran (5.0 mL) were added to 2-bromo-3-cyanopyridine 2790 (184 mg, 1.0 mmol), copper(l) iodide (19.2 g, 0.1 mmol), sodium ascorbate (20 mg, 0.10 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (35 mg, 0.05 mmol) under argon. The mixture was stirred at 40°C for 30 min. 1-Ethynyl-4-methylbenzene (1 16 mg, 1.0 mmol) was added and the mixture was stirred at 40°C for 36 h. Evaporation and chromatography (petroleum ether / ethyl acetate 5:1→ 3:1 ) gave 3-cyano-2-(4-methyl- phenylethynyl)pyridine 28c (170 mg, 80%) as a pale buff powder: mp 175-178°C; 1H NMR (CDCIs) δ 2.38 (3 H, s, Me), 7.32 (1 H, dd, J = 8.0, 4.9 Hz, 5-H), 7.40 (2 H, J = 8.2 Hz, Ph 3,5-H2), 7.58 (2 H, d, J = 8.1 Hz, Ph 2,6-H2), 7.95 (1 H, dd, J = 8.0, 1.8 Hz, 4-H), 8.77 (1 H, dd, J = 4.9, 1.7 Hz, 6-H); 13C NMR (HSQC) (CDCI3) δ 21.70 (Me), 112.66 (2- C), 121.73 (5-C), 129.32 (Ph 3,5-C2), 132.50 (Ph 2,6-C2), 139.84 (4-C), 140.61 (Ph 4- C), 152.8 (6-C); MS m/z 219.0905 (M + H)+ (C15HnN2 requires 219.0922).
2- (4-Chlorophenylethynyl)-3-cyanopyridine (28d). N,N-Diisopropylamine (10 mL) and tetrahydrofuran (10 mL) were added to 2-bromo-3-cyanopyridine 2790 (400 mg, 2.2 mmol), bis(triphenylphosphine)palladium(ll) dichloride (76 mg, 0. 1 mmol), copper(l) iodide (40 mg, 0.22 mmol) and sodium ascorbate (25 mg, 0.12 mmol) under argon. The mixture was stirred at 40°C for 30 min. 4-Chlorophenylethyne (2.2 mmol) was added and the mixture was stirred at 40°C for 12 h. Evaporation and chromatography
(petroleum ether / ethyl acetate 5:1→ 1 :3) gave 2-(4-chlorophenylethynyl)-3- cyanopyridine 28d (1 3 mg, 25%) as a pale amber powder: mp 84-86°C; 1H NMR (CDCI3)□ NMR (CDCI%) as J = 4.8, 2.4 Hz, 5-H), 7.37 (2 H, d, J = 8.7 Hz, Ph 3,5-H2), 7.61 (2 H, d, J = 6.7 Hz, Ph 2,6-H2), 7.98 (1 H, dd, J = 7.9, 1.7 Hz, 4-H), 8.79 (1 H, dd, J = 5.0, 1.7 Hz, 6-H); 3C NMR (CDCI3) (HSQC / HMBC) δ 86.38 (ethyne 2-C), 94.80 (ethyne 1 -C), 112.87 (3-C), 1 15.82 (C≡N), 119.43 (Ph 1-C), 122.31 (5-C), 128.92 (Ph 3,5-C2), 133.63 (Ph 2,6-C2), 136.30 (Ph 4-C), 139.77 (4-C), 145.75 (2-C), 152.85 (6-C); MS m/z 239.0353 (M + H)+ (C14H8 35CIN2H requires 239.0376).
3- Cyano-2-(4-trifluoromethylphenylethynyl)pyridine (28e). N,N-Diisopropylamine (10 mL) was added to copper(l) iodide (36 mg, 0.02 mmol) and bis(triphenyl- phosphine)palladium(ll) dichloride (66.5 mg, 0.01 mmol) under argon and the mixture was stirred until a green suspension formed. 2-Bromo-3-cyanopyridine 27 (350 mg, 1.9 mmol) in tetrahydrofuran (10 mL) was added and the mixture was stirred for 30 min. 4-Methylphenylethyne (441 mg, 3.8 mmol) was added and the mixture was stirred at 40°C for 12 h. Evaporation and chromatography (petroleum ether / ethyl acetate 5:1 → 1 :3) gave 3-cyano-2-(4-trifluoromethylphenylethynyl)pyridine 28e (215 mg, 52%) as a pale buff powder: mp 129-132°C; 1H NMR (CDCI3) δ 7.40 (1 H, dd, J = 7.9, 4.9 Hz, 6- H), 7.66 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.79 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 8.00 (1 H, dd, J = 8.0, 1.8 Hz, 4-H), 8.81 (1 H, dd, J = 4.9, 1.8 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 87.25 (ethyne 2-C), 94.03 (ethyne 1-C), 1 13.22 (3-C), 1 15.78 (C≡N), 122.50 (5-C), 124.73 (Ph 1-C), 125.49 (q, J = 3.6 Hz, Ph 3,5-C2), 131.8 (q, J = ca. 30 Hz, Ph 4- C), 132.75 (Ph 2,6-C2), 139.87 (4-C), 145.48 (2-C), 152.95 (6-C); 19F NMR (CDCI3) δ -63.03 (s, CF3); MS m/z 295.0428 (M + Na)+ (C15H7F3N2Na requires 295.0459), 273.0622 (M + H)+ (C15HSN2F3 requires 273.0640).
2- {4-Aminophenylethynyl)-3-cyanopyridine (28f). N,N-Diisopropylamine (10 mL) was added to copper(l) iodide (36 mg, 0.02 mmol) and bis(triphenylphosphine)- palladium(ll) dichloride (66.5 mg, 0.01 mmol) under argon and the mixture was stirred until a green suspension formed. 2-Bromo-3-cyanopyridine 2790 (350 mg, 1.9 mmol) in tetrahydrofuran (10 mL) was added and the mixture was stirred for 30 min. 4-Amino- phenylethyne (445 mg, 3.8 mmol) was added and the mixture was stirred at 40°C for 12 h. Evaporation and chromatography (petroleum ether / ethyl acetate 5:1→ 1 :3) gave 2-(4-aminophenylethynyl)-3-cyanopyridine 28f (362 mg, 87%) as a dark green powder: mp 128-130°C; H NMR (CDCI3) δ 3.96 (2 H, br, NH2), 6.64 (2 H, d, J = 9.1 Hz, Ph 3,5-H2), 7.30 (1 H, dd, J = 8.5, 1.8 Hz, 5-H), 7.49 (2 H, d, J = 6.6 Hz, Ph 2,6-H2), 7.92 (1 H, dd, J = 7.9, 1.7 Hz, 4-H), 8.73 (1 H, dd, J = 4.9, 1.7 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 82.87 (ethyne 2-C), 98.10 (ethyne 1-C), 106.48 (Ph 1-C), 1 13.68 (Ph 3,5-C2), 1 16.51 (5-C), 121.94 (C≡N), 133.58 (Ph 2,6-C2), 140.65 (3-C), 145.43 (4-C), 150.12 (6-C), 151.16 (Ph 4-C), 153.27 (2-C); MS m/z 242.0693 (M + Na)+ (C14H9N3Na requires 242.0694), 220.0876 (M + H)+ (C14H10N3 requires 220.0875).
3- Cyano-2-((4-phenylmethoxyphenyl)ethynyl)pyridine (28h). 4-Ethynyl-1 -phenyl- methoxybenzene92 (206 mg, 1.0 mmol), copper(l) iodide (19.2 mg, 0.1 mmol), bis(tri- phenylphosphine)palladium(ll) dichloride (35 mg, 0.05 mmol), 2-bromo-3-cyanopyridine 27 (184 mg, 1.0 mmol) and sodium ascorbate (19.8 mg, 0.1 mmol) were placed in a flask, which was degassed and filled with argon. Diisopropylamine (5.0 mL) was added, followed by tetrahydrofuran (5.0 ml_). The mixture was stirred at 40°C for 16 h.
Evaporation and chromatography (petroleum ether / ethyl acetate 3:1) gave 3-cyano-2- ((4-phenylmethoxyphenyl)ethynyl)pyridine 28h (89 mg, 29%) as an off-white powder: mp 129-132°C; IR vmax 3073 (C-H), 2233 (C≡N) 2189 (C≡C), 1599 (C=CAr), 1506, 1464 (C=N) cm'1; 1H NMR (CDCI3) δ 5.08 (2 H, s, CH2), 6.98 (2 H, d, J = 9.5 Hz,
phenylethynyl 3,5-H2) 7.29 (1 H, dd, J = 7.9, 4.9 Hz, 5-H), 7.31-7.44 (5 H, m, Ph 2,3,4,5,6-H5), 7.62 (2 H, d, J = 9.5 Hz, phenylethynyl 2,6-H2), 7.93 (1 H, dd, J = 7.9 1.7 Hz, 4-H), 8.74 (1 H, dd, J = 4.9, 1.7 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 70.06 (CH2), 85.08 (C≡N), 96.85 (ethyne 2-C), 112.41 (ethyne 1-C), 1 13.22 (3-C), 1 15.11 (phenylethynyl 2,6-C2), 1 16.08 (phenylethynyl 1-C), 121.47 (5-C), 127.40 (Ph 3,5-C2), 128. 1 (Ph 4-C), 128.60 (Ph 2,6-C2), 134.24 (phenylethynyl 3,5-C2), 136.26 (Ph 1-C), 139.73 (4-C), 146.33 (2-C), 152.73 (6-C), 160.21 (phenylethynyl 4-C); MS m/z 31 1.1179 (M + H)+ (C21H15N20 requires 311.1 181).
7-Phenyl-1 ,6-naphthyridin-5-one (30a). 3-Cyano-2-(phenylethynyl)pyridine 28a (300 mg, 1.47 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (5 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2-methoxyethanol (10 mL). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin-layer chromatography. Evaporation and recrystallisation (2-methoxyethanol) gave 7-phenyl-1 ,6-naphthyridin-5- one 30a (245 mg, 75%) as a white solid; mp 226-230°C (lit69 mp 228-229°C); H NMR ((CD3)2SO) δ 6.98 (1 H, s, 8-H), 7.54 (1 H, dd, J = 8.4, 2.9 Hz, 3-H), 7.57-7.60 (3 H, m, Ph 3,4,5-H3), 7.89 (2 H, d, J = 7.9 Hz, Ph 2,6-H2), 8.57 (1 H, dd, J = 8.0, 1.3 Hz, 4-H), 8.98 (1 H, dd, J = 4.5, 1.8 Hz, 2-H), 1 1.74 (br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 104.56 (8-C), 120.40 (3-C), 121.62 (4a-C), 126.99 (2C, Ph 3,5-C2), 128.82 (2C, Ph 2,6-C2), 129.82 (Ph 4-C), 133.36 (Ph 1-C), 135.00 (4-C), 143.97 (7-C), 154.16 (2-C), 54.97 (8a-C), 162.93 (5-C); 15N NMR ((CD3)2SO) δ 124.89 (6-N), 278.87 (1-N); MS m/z 245.0676 (M + Na)+ (C14H10N2NaO requires 245.0691). 7-(4-Methoxyphenyl)-1 ,6-naphthyridin-5-one (30b). 3-Cyano-2-(4-methoxyphenyl- ethynyl)pyridine 28b (300 mg, 1.26 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (5 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2- methoxyethanol (10 mL). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin-layer chromatography. Evaporation and recrystallisation (2-methoxyethanol) gave 7-(4- methoxyphenyl)-1 ,6-naphthyridin-5-one 30b (226 mg, 70%) as an off-white solid: mp 276-280°C; 1H NMR ((CD3)2SO) δ 3.89 (3 H, s, Me), 6.92 (1 H, s, 8-H), 7.12 (2 H, d, J = 8.9 Hz, Ph 3,5-H2), 7.50 (1 H, dd, J = 8.0, 4.6 Hz, 3-H), 7.86 (2 H, d, J = 8.9 Hz, Ph 2,6- H2), 8.54 (1 H, dd, J = 8.0, 1.8 Hz, 4-H), 8.95 (1 H, dd, J = 4.5, 1.8 Hz, 2-H), 1 1.65 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.36 (OMe), 1 14.24 (Ph 3,5-C2), 120.01 (8-C), 122.42 (4a-C), 123.65 (Ph 1 -C), 125.60 (3-C), 128.39 (Ph 2,6-C2), 134.94 (7-C), 136.92 (4-C), 143.77 (2-C), 154.90 (8a-C), 156.99 (5-C), 158.82 (Ph 4-C); MS m/z 275.0767 (M + Na)+ (C15H12N2Na02 requires 275.0796), 253.0978 (M + H)+ (C15H13N202 requires 253.0977).
7-(4-Methylphenyl)-1 ,6-naphthyridin-5-one (30c). 3-Cyano-2-(4-methylphenyl- ethynyl)pyridine 28c (300 mg, 1.38 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (5 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2- methoxyethanol (10 mL). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin-layer chromatography. Evaporation and recrystallisation (2-methoxyethanol) gave 7-(4- methyIphenyl)-1 ,6-naphthyridin-5-one 30c (159 mg, 48%) as an off-white solid: mp 255-258°C; 1H NMR ((CD3)2SO) δ 2.43 (3 H, s, Me), 6.95 (1 H, s, 8-H), 7.38 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.54 (1 H, dd, J = 8.0, 4.5 Hz, 3-H), 7.79 (2 H, d, J = 8.2 Hz, Ph 2,6- Ha), 8.55 (1 H, dd, J = 8.0, 1.6 Hz, 4-H), 8.97 (1 H, dd, J = 4.5, 1.8 Hz, 2-H), 1 1.74 (1 H, br, NH); 13C NMR ((CD3)2SO) δ (HSQC / HMBC) 20.81 (Me), 103.99 (8-C), 120.27 (4a- C), 121.43 (3-C), 126.82 (Ph 2,6-C2), 129.38 (2C, Ph 3,5-C2), 130.54 (Ph 1-C), 134.97 (4-C), 139.60 (Ph 4-C), 144.01 (7-C), 154.27 (8a-C), 154.93 (2-C), 162.94 (5-C); MS m/z 259.0826 (M + Na)+ (C15H12N2NaO requires 259.0847).
7-(4-Chlorophenyl)-1 ,6-naphthyridin-5-one (30d). 2-(4-Chlorophenylethynyl)3-cyano- pyridine 28d (100 mg, 0.42 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (3 χ 30 mL). The combined organic layers were dried and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2-methoxyethanol (10 mL). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin-layer chromatography. Evaporation and recrystallisation (2-methoxyethanol) gave 7-(4-chlorophenyl)-1 ,6- naphthyridin-5-one 30d (33 mg, 33%): mp 296-298°C; IR vmax 3163 (NH), 1669 (C=0), 1627 (C=CAr), 1588, 720 (C-CI) cm"1; 1H NMR ((CD3)2SO) δ 6.95 (1 H, s, 8-H), 7.50 (1 H, dd, J = 8.0, 4.5 Hz, 3-H), 7.58 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.91 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.51 (1 H, d, J = 8.0 Hz, 4-H), 8.98 (1 H, d, J = 4.5 Hz, 2-H), 1.74 (1 H, br, NH); 13C ((CD3)2SO) (HSQC / HMBC) δ 104.95 (8-C), 120.58 (4a-C), 121.83 (3-C), 128.82 (Ph 3,5-C2), 128.93 (Ph 2,6-C2), 134.60 (4-C), 135.03 (Ph 1-C), 155.05 (C=0), 162.90 (8a-C); 15N NMR ((CD3)2SO) (HMBC) δ 124.20 (s, 6-N); MS m/z 279.0303 (M + H)+ (C14H9N2035CINa requires 279.0296).
7-(4-Trif luoromethylphenyl)-1 ,6-naphthyridin-5-one (30e). 3-Cyano-2-(4-trifluoro- methylphenylethynyl)pyridine 28e (300 mg, 1.10 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (5 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2-methoxyethanol (10 mL). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin-layer chromatography. Evaporation and recrystallisation (2- methoxyethanol) gave 7-(4-trifluoromethylphenyl)-1 ,6-naphthyridin-5-one 30e (176 mg, 55%) as a white solid: mp >325°C; H NMR ((CD3)2SO) δ 7.03 (1 H, s, 8-H), 7.53 (1 H, dd, J = 8.0, 4.6 Hz, 3-H), 7.92 (2 H, d, J = 8.4 Hz, Ph 3,5-H2), 8.10 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.53 (1 H, dd, J = 8.0, 1.7 Hz, 4-H), 9.00 (1 H, dd, J = 4.5, 1.8 Hz, 2-H), 1 1.25 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 105.92 (8-C), 120.90 (4a- C), 122.13 (3-C), 124.1 (q, J = 264 Hz, CF3), 125.62 (q, J = 3.6 Hz, Ph 3,5-C2), 128.03 (Ph 2,6-C2), 129.78 (q, J = 32 Hz, Ph 4-C), 135.05 (4-C), 137.31 (Ph 1 -C), 142.51 (7- C), 153.90 (2-C), 155.09 (8a-C), 162.86 (5-C); 5N NMR ((CD3)2SO) δ 123.4 (6-N), 279.7 (1 -N); 19F NMR ((CD3)2SO) DO) R ((CDN), 23); MS m/z 291.0727 (M + H)+ (C15H10N2O requires 291.0745).
7-(4-Aminophenyl)-1 ,6-naphthyridin-5-one (30f). 2-(4-Aminophenylethynyl)3- cyanopyridine 28f (58 mg, 0.26 mmol) was stirred at 130°C in poiyphosphoric acid (5.6 ml_) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to the solution until the pH was 9. The mixture was extracted with EtOAc (5 x 25 ml_). The combined organic extracts were dried (magnesium sulfate) and the solvent was evaporated to give crude 7-(4-aminophenyl)pyrano[4,3-jb]pyridin-5-one 29f (42 mg, 72%) as a yellow powder. This material was dissolved in 2-methoxyethanol (10 mL) and ammonia was bubbled through the solution for 15 min. The solution was placed in a pressure tube and was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated twice. Evaporation and recrystallisation (2-methoxyethanol) gave 7-(4- aminophenyl)-1 ,6-naphthyridin-5-one 30f (38 mg, 66%) as a yellow powder: mp >300°C (decomposition); ((CD3)2SO) δ 5.65 (2 H, br, NH2), 6.80 (1 H, s, 8-H), 7.43 (1 H, dd, J = 8.0, 4.5 Hz, 3-H), 7.60 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 7.71 (2 H, d, J = 8.7 Hz, Ph 2,6-H2), 8.49 (1 H, dd, J = 8.0, 1.8 Hz, 4-H), 8.90 (1 H, dd, J = 4.8, 1.8 Hz, 2-H), 1 1.50 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 99.08 (8-C), 1 13.59 (Ph 2,6-C2), 117.55 (3-C), 122.16 (4a-C), 124.87 (Ph 1 -C), 127.78 (4-C), 130.51 (Ph 3,5- C2), 136.95 (7-C), 150.62 (2-C), 53.57 (Ph 4-C), 156.59 (8a-C), 161.65 (5-C).
7-(4-Hydroxyphenyl)-1 ,6-naphthyridin-5-one (30g). 3-Cyano-2-(4-phenylmethoxy- phenylethynyl)pyridine 28h (270 mg) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (3 χ 30 ml_). The combined organic layers were dried and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2-methoxyethanol (10 ml_). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin-layer chromatography. Evaporation and recrystallisation (2-methoxyethanol) gave 7-(4-hydroxyphenyl)-1 ,6- naphthyridin-5-one 30g (20 mg, 10%): mp 258-260°C; IR vmax 3423, 1660, 1617, 1589 cm"1; 1H NMR ((CD3)2SO) δ 6.87 (1 H, s, 8-H), 6.93 (2H, d, J = 8.6 Hz, Ph 2,6-H2), 7.37 (1 H, d, J = 7.4 Hz, 3-H), 7.73 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 8.52 (1 H, d, J = 2.5 Hz, 4-H), 8.94 (1 H, d, J = 2.5 Hz, 2-H), 9.99 (1 H, br, OH), 1 1.67 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.57 (8-C), 119.0 (3-C), 121.0 (Ph 1-C), 126.0 (4a-C), 128.11 (Ph 2,6-C2), 128.42 (Ph 3,5-C2), 135.0 (4-C), 147.0 (2-C), 153.0 (Ph 4-C), 154.89 (8a-C), 163.0 (5-C); MS m/z 239.0815 (M + H)+ (C14HnN202 requires
239.0816).
7-Phenyl-1 ,6-naphthyridin-5-one 1-oxide (31a). Urea. hydrogen peroxide complex (78 mg, 0.8 mmol) was added to 7-phenyl-1 ,6-naphthyridin-5-one 30a (100 mg, 0.45 mmol) in dimethylformamide (15 ml_). The mixture was cooled to 0°C. Trifluoroacetic anhydride (189 mg, 0.9 mmol) was added dropwise. The mixture was stirred at 0°C for 12 h. The precipitate was collected and washed with water and CHCI3. The solvent was evaporated from the filtrate. The solid fractions were combined and purified by flash chromatography (petroleum ether / ethyl acetate 1 :7→ acetic acid / petroleum ether / ethyl acetate 1 :3:21) to give 7-phenyl-1 ,6-naphthyridin-5-one 1-oxide 31a (51 mg, 50%) as a white solid: mp 293-295°C; 1H NMR ((CD3)2SO) δ 7.31 (s, 8-H), 7.41 (1 H, dd, J = 8.0, 6.5 Hz, 3-H), 7.53 (3 H, m, Ph 3,4,5-H3), 7.83 (2 H, d, J = 7.5 Hz, Ph 2,6-H2), 7.99 (1 H, d, J = 8.0 Hz, 4-H), 8.62 (1 H, dd, J = 6.5, 1.0 Hz, 2-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 93.77 (8-C), 121.90 (4a-C), 123.19 (3-C), 123.31 (Ph 4-C), 127.15 (Ph 2,6-Cz), 128.95 (Ph 3,5-C2), 130.29 (4-C), 137.31 (Ph 1-C), 140.80 (7-C), 162.11 (8a-C); 15N NMR ((CD3)2SO) δ 252.76 (s, 1 -N), 129.56 (s, 6-N); MS m/z 261.0627 (M + Na)+ (C14H N2Na02 requires 261.0977).
7-(4-Methylphenyl)-1 ,6-naphthyridin-5-one 1-oxide (31 b). Urea. hydrogen peroxide complex (60 mg, 0.6 mmol) was added to 7-(4-methoxyphenyl)-1 ,6-naphthyridin-5-one 30b (75 mg, 0.30 mmol) in dimethylformamide (10 mL). The mixture was cooled to 0°C. Trifluoroacetic anhydride (123 mg, 0.6 mmol) was added dropwise. The mixture was stirred at 0°C for 12 h. The precipitate was collected and washed with water and acetone. The solvent was evaporated from the filtrate. The combined solids were recrystallised (petroleum ether / ethyl acetate) to give 7-(4-methylphenyl)-1 ,6- naphthyridin-5-one 1-oxide 31 b (20 mg, 29%) as a white solid; mp 258-260°C; H NMR ((CD3)2SO) δ 2.38 (3 H, s, Me), 6.90 (1 H, s, 8-H), 7.32 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.47 (1 H, dd, J = 8.0, 4.5, 3-H), 7.73 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.50 (1 H, dd, J = 7.5, 1.0 Hz, 4-H), 8.62 (1 H, dd, J = 4.5, 1 .5 Hz, 2-H), 1 .78 (1 H, s, 6-H); 13C NMR ((CD3)2SO) (HSQC) δ 20.84 (Me), 103.99 (8-C), 121.49 (3-C), 126.86 (Ph 2,6-C2), 129.42 (Ph 3,5-C2), 135.03 (4-C), 154.96 (2-C); MS m/z 253.0996 (M + H)+
(C15H13N202 requires 253.0977).
1 -Methyl-5-oxo-7-phenyl-1 ,6-naphthyridinium iodide (32a). lodomethane (410 mg, 2.9 mmol) was stirred with 30a (120 mg, 0.54 mmol) in dry dimethylformamide (5 mL) for 36 h. The mixture was poured into acetone (3 mL). The solid was collected, washed with acetone and dried to give 1 -methyl-5-oxo-7-phenyl-1 ,6-naphthyridinium iodide 32a (142 mg, 72%) as a yellow solid: mp 280-284°C; 1H NMR ((CD3)2SO) δ 4.40 (3 H, s, Me), 7.18 (1 H, s, 8-H), 7.63 (3 H, m, Ph 3,4,5-H3), 7.88 (1 H, dd, J = 8.0, 6.0 Hz, 3-H), 7.98 (2 H, d, J = 7.5 Hz, Ph 2,6-H2), 9.09 (1 H, d, J = 7.5 Hz, 4-H), 9.20 (1 H, d, J = 5.5 Hz, 2-H), 12.87 (1 H, s, 6-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 44.97 (Me), 93.61 (8-C), 121.24 (3-C), 123.03 (4a-C), 128.05 (Ph 2,6-C2), 128.98 (Ph 3,5-C2), 131.55 (Ph 4-C), 132 (Ph 1-C), 144.13 (4-C), 147.98 (8a-C), 150.91 (2-C), 153 (7-C), 161 (5-C); MS m/z 237.1022 (M + H)+ (C15H13N20 requires 237.1028).
7-{4-Methoxyphenyl)-1 -methyl-5-oxo-1,6-naphthyridin-1 -ium iodide (32b). lodomethane (144 mg, 1.02 mmol) was stirred with 30b (76 mg, 0.3 mmol) in dry dimethylformamide (5 mL) for 72 h. The mixture was poured into the mixture of ethyl acetate and petroleum ether (1 : 1). The solid was collected, washed with petroleum ether and dried to give 7-(4-methoxyphenyl)-1-methyl-5-oxo-1 ,6-naphthyridin-1-ium iodide 32b (5 mg, 4%) as a yellow solid: mp >300°C (extensive decomposition); 1H NMR ((CD3)2SO) δ 3.94 (3 H, s, OMe), 4.46 (3 H, s, NMe), 7.19 (1 H, s, 8-H), 7.22 (2 H, d, J = 8.9 Hz, Ph 3,5-H2), 7.93 (1 H, dd, J = 8.0, 1.8 Hz, 3-H), 8.04 (2 H, d, J = 8.9 Hz, Ph 2,6-H2), 9.13 (1 H, d, J = 7.5 Hz, 4-H), 9.25 (1 H, d, J = 6.3 Hz, 2-H), 12.77 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 44.0 (NMe), 57.0 (OMe), 127.0 (Ph 2,6-C2), 132.0 (Ph
3.5- C2), 148.0 (4-C); MS m/z 267.1 136 (M + H)+ (C16H15N202 requires 267.1 134).
7-(4-Chlorophenyl)-1 -methyl-5-oxo-1 ,6-naphthyridin-1 -ium iodide (32c). lodo- methane (226 mg, 1.6 mmol) was stirred with 30d (78 mg, 0.3 mmol) in dry dimethyl- formamide (5 mL) for 96 h. The solvent was evaporated. The residue was washed with ethyl acetate and petroleum ether and dried to give 7-(4-chlorophenyl)-1-methyl-5-oxo-
1.6- naphthyridin-1 -ium iodide 32c (20 mg, 16%) as a yellow solid: mp >300°C
(extensive decomposition); 1H NMR ((CD3)2SO) δ 4.42 (3 H, s, Me), 7.26 (1 H, s, 8-H), 7.84 (1 H, dd, J = 6.5, 5.8 Hz, 3-H); 7.99 (2 H, d, J = 8.3 Hz, Ph 2,6-H2), 8.31 (2 H, d, J = 8.2 Hz, Ph 3,5-H2), 9.07 (1 H, d, J = 6.5 Hz, 4-H), 9.18 (1 H, d, J = 5.8 Hz, 2-H), 12.53 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 48.56 (Me), 90.0 (8-C), 1 18.0 (3-C), 127.0 (Ph 2,6-C2), 130.0 (Ph 3,5-C2), 151.0 (2-C); MS m/z 273.0626 (M + H)+ (C15H12 37CIN20 requires 273.0608); 271.0634 (M + H)+ (C15H12 35CIN20 requires 271.0638).
7-(4-Aminophenyl)-1-methyl-5-oxo-1,6-naphthyridin-1 -ium iodide (32d). lodo- methane (144 mg, 1.02 mmol) was stirred with 30f (42 mg, 0.19 mmol) in dry dimethyl- formamide (5 mL) for 96 h at room temperature, then at 80°C for 2 h. The mixture was poured into the mixture of ethyl acetate and petroleum ether (1 :1). The solid was collected, washed with petroleum ether and dried to give 7-(4-aminophenyl)-1-methyl- 5-OXO-1 ,6-naphthyridin-1 -ium iodide 32d (28 mg, 41 %) as a yellow solid: mp >300°C (decomposition); 1H NMR ((CD3)2SO) δ 4.40 (3 H, s, NMe), 6.89 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.08 (1 H, s, 8-H), 7.78 (1 H, dd, J = 7.8, 6.2 Hz, 3-H), 7.98 (2 H, d, J = 9.1 Hz, Ph 2,6-H2), 9.03 (1 H, d, J = 7.8 Hz, 4-H), 9.14 (1 H, d, J = 5.2 Hz, 2-H), 12.53 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 44.73 (Me), 90.53 (8-C), 111.59 (Ph 3,5- C2), 1 17.33 (Ph 1-C), 1 19.33 (3-C), 122.18 (4a-C), 129.25 (Ph 2,6-C2), 143.61 (7-C), 148.21 (2-C), 150.70 (Ph 4-C), 151.69 (4-C), 152.58 (8a-C), 160.61 (5-C).
1 -Methyl-7-phenyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one (33). To 1-methyl-5- oxo-7-phenyl-5,6-dihydro-1 ,6-naphthyridin-1-ium iodide 32a (80 mg, 0.22 mmol) in formic acid (5 mL) at 0°C was added dropwise borane. pyridine complex (0.06 mL). The mixture was stirred for 5 d. Each day, additional amount borane. pyridine complex (0.01 mL) was added. The mixture was then concentrated in vacuo. The residue was triturated with methanol (10 mL) and was recrystallised (propan-2-ol) to give 1-methyl- 7-phenyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one 33 (21 mg, 20%) as a pale grey solid: mp 315-317°C; IR vmax 1655 (C=0), 1620 (C=CPh) cm"1; 1H NMR (CDCI3) δ 1.89 (2 H, m, 3-H2), 2.51 (2 H, m, 4-H2), 3.1 1 (3 H, s, N-CH3), 3.36 (2 H, m, 2-H2), 6.30 (1 H, s, 8-H), 7.43 (3 H, m, Ph 3,4,5-Hs), 7.68 (2 H, m, Ph 2,6-H2); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 19.59 (4-C), 20.12 (N-Me), 50.78 (2-C), 96.80 (8-C), 100.22 (4a-C), 126.58 (Ph 2,6-C2), 129.25 (Ph 3,5-C2), 130.47 (4-C), 132.79 (Ph 1-C), 144.28 (7-C), 155.00 (8a-C), 158.96 (5-C); MS m/z 263.1177 (M + Na)+ (C15H16N2NaO requires 263.1 160).
3-Cyano-4-(phenylethynyl)pyridine (35). Copper(l) iodide (9.6 mg, 0.05 mmol), bis- (triphenylphosphine)palladium(ll) dichloride (29 mg, 0.025 mmol) and sodium ascorbate (9.9 mg, 0.05 mmol) were placed in a flask, which was degassed and filled with argon. Triethylamine (5.0 mL) was added, followed by 4-bromo-3-cyanopyridine 34 (92 mg, 0.5 mmol) in tetrahydrofuran (5.0 mL). The mixture was stirred at 40°C for 30 min. Phenylethyne (76.5 mg, 0.75 mmol) was added and the mixture was stirred at 40°C for 10 h. Evaporation and chromatography (petroleum ether / ethyl acetate 3: 1) gave 3-cyano-4-(phenylethynyl)pyridine 35 (80 mg, 78%) as an off-white powder: mp 74-75°C (lit.91 85-87°C); IR vmax 2222 (C≡N), 2150 (C≡C), 1582 (C=CAr), 1495 (C=N) cm"1; 1H NMR (CDCI3) δ 7.39-7.43 (3 H, m, Ph 3,4,5-H3), 7.45 (1 H, d, J = 5.2 Hz, 5-H), 7.63 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.75 (1 H, d, J = 5.2 Hz, 6-H), 8.87 (1 H, s, 2-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 83.50 (ethyne 2-C), 101.29 (ethyne 1-C), 1 1.74 (4-C), 1 15.54 (C≡N), 120.76 (Ph 1-C), 125.06 (5-C), 128.59 (Ph 3,5-C2), 130.28 (Ph 4- C), 132.38 (Ph 2,6-C2), 134.87 (3-C), 152.40 (2-C), 152.68 (6-C); MS m/z 227.0569 (M + Na)+ (C14H8N2Na requires 227.0585).
3-Phenyl-2,7-naphthyridin-1-one (37). 3-Cyano-4-(phenylethynyl)pyridine 35 (50 mg, 0.25 mmol) was stirred under reflux in aqueous sulfuric acid (9 M, 20 mL) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 9. The mixture was extracted with ethyl acetate (5 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2-methoxyethanol (10 mL). Ammonia was bubbled through the solution, the vessel was closed and the mixture was heated at 100°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete (as shown by thin-layer chromatography). Evaporation and recrystallisation (2-methoxyethanol) gave 3-phenyl-2,7-naphthyridin-1- one 37 (22 mg, 40%) as an off-white solid: mp 236-237°C; IR vmax 3447 (NH2), 1669 (C=0), 1631 (C=CAr), 1595, 1461 (C=N) cm'1; 1H NMR ((CD3)2SO) δ 6.97 (1 H, s, 4-H), 7.58 (3 H, m, Ph 3,4,5-H3), 7.66 (1 H, d, J = 5.4 Hz, 5-H), 7.86 (2 H, dd, J = 7.6 Hz, Ph 2,6-H2), 8.76 (1 H, d, J = 5.4 Hz, 6-H), 9.38 (1 H, s, 8-H), 11.91 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 101.41 (4-C), 1 19.66 (5-C), 127.12 (Ph 2,6-C2), 128.87 (Ph 3,5-C2), 130.14 (Ph 4-C), 133.26 (Ph 1-C), 143.1 1 (4a-C), 145.27 (8a-C), 149.84 (8-C), 150.98 (6-C), 162.37 (1-C); MS m/z 223.0866 (M + H)+ (C^H^O requires 223.0935).
2-Phenylpyrido[2,3-cflpyrimidin-4-one (39a). 2-Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol), benzamidine (60 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) were stirred in dimethyiformamide at room temperature under argon for 10 h, then at 80 °C for 3 h. The mixture was cooled and filtered. The solvent was evaporated from the filtrate. The residue was dissolved in methanol, filtered and evaporated. The residue was dissolved in ethyl acetate / dichloromethane (1 : 1) and filtered. The filtrate was washed with aqueous solution of ethylenediaminetetraacetic acid and the organic layer was separated and evaporated. The aqueous layer was extracted with dichloromethane (6 χ 20 mL) and ethyl acetate (6 χ 20 mL). The combined organic layers were evaporated to give 2- phenylpyrido[2,3-d]pyrimidin-4-one 39a (58 mg, 53%) as an off-white solid: mp 225- 227°C (lit.70 mp 284-285°C); H NMR (CDCI3) δ 7.45 (1 H, dd, 7-H), 7.60 (5 H, m, Ph- H5), 8.41 (1 H, dd, J = 7.5, 2.0 Hz, 8-H), 8.91 (1 H, dd, J = 4.5, 2.0 Hz, 6-H), 1 1.10 (1 H, br, NH); 13C NMR (CDCI3) δ 1 16.1 1 (8a-C), 121.48 (7C), 128.49 (Ph 3,5-C2), 128.98 (3C), 129.10 (Ph 2,6-C2), 132.53 (Ph 4-C), 134.06 (Ph 1-C), 140.16 (8-C), 155.49 (6- C), 159.26 (4a-C), 166.46 (1-C); MS m/z 224.0818 (M + H)+ (C13H10N3O requires 224.0835).
2-(4-Methylphenyl)pyrido[2,3-d]pyrimidin-4-one (39b). 2-Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 4-methylbenzimidamide 48b (67 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethyiformamide (5 mL) at 80 °C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the filtrate was evaporated. The evaporation residue was dissolved in saturated aqueous ethylene- diaminetetraacetic acid (20 mL). The solution was kept at 2-8 °C for 30 min and the solid was collected by filtration. The solid was washed with petroleum ether and with water and was dried to give 2-(4-methylphenyl)pyrido[2,3-c/]pyrimidin-4-one 39b (41 mg, 35%) as a white powder: mp 249-251 °C, 1H NMR ((CD3)SO) δ 2.47 (3 H, s, Me), 7.28 (1 H, dd, J = 7.4, 5.1 Hz, 6-H), 7.48 (2 H, d, J = 8.1 Hz, Ph 3,5-H2), 7.94 (2 H, d, J = 8.1 Hz, Ph 2,6-H2), 8.44 (1 H, d, J = 7.5 Hz, 5-H), 8.48 (1 H, d, J = 4.7 Hz, 7-H), 1 1.09 (1 H, br, NH); 13C NMR ((CD3)2SO) δ 20.99 (Me), 1 19.07 (4a-C), 1 19.84 (6-C), 127.31 (Ph 3,5-C2), 129.53 (Ph 1-C), 129.61 (Ph 2,6-C2), 140.15 (5-C), 142.84 (Ph 4- C), 148.29 (7-C), 155.60 (8a-C), 159.67 (2-C), 166.78 (4-C); MS m/z 236.0836 (M - HV (C14H10N3O requires 236.0824).
2-(4-Trifluoromethylphenyl)pyridot2,3-d]pyrimidin-4-one (39c). 2-Bromopyridine-3- carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 4-trifluoromethyl- benzimidamide 48b (94 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80 °C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the filtrate was evaporated. The evaporation residue was dissolved in saturated aqueous ethylenediaminetetraacetic acid (20 mL). The solution was kept at 2-8 °C for 30 min and the solid was collected by filtration. The solid was washed with petroleum ether and with water and was dried to give 2-(4-trifluoromethylphenyl)pyrido- [2,3-d]pyrimidin-4-one 39c (64 mg, 45%) as a white powder: mp 254-256°C; 1H NMR ((CD3)2SO) δ 7.29 (1 H, dd, J = 6.8, 4.0 Hz, 6-H), 8.04 (2 H, m, Ph 2,6-H2), 8.22 (2 H, m, Ph 3,5-H2), 8.46 (1 H, d, J = 7.0 Hz, 5-H), 8.54 (1 H, d, J = 4.0 Hz, 7-H), 1 1.01 (1 H, br, NH); 1H NMR ((CD3)2SO) (HSQC / HMBC) δ 119.0 (6-C), 126.10 (Ph 2,6-C2), 128.22 (q J = 2.7 Hz, Ph 3,5-C2), 140.10 (5-C), 149.5 (7-C); 19F NMR ((CD3)2SO) δ - 61.35 (CF3); MS 292.0699 (M + H)+ (C14H9F3 30 requires 292.0692).
2-(4-ChIorophenyl)pyrido[2,3-d]pyrimidin-4-one (39d). 2-Bromopyridine-3- carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 4-chlorobenzimidamide 48b (77 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80 °C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the filtrate was evaporated. The evaporation residue was dissolved in saturated aqueous ethylene- diaminetetraacetic acid (20 ml_). The solution was kept at 2-8 °C for 30 min. The solid was collected by filtration and recrystallised (ethyl acetate / dichloromethane) to give 2- (4-chlorophenyl)pyrido[2,3-d]pyrimidin-4-one 39d (10 mg, 8%) as a pale grey powder: mp 266-268°C (lit.71 mp 300.5°C); 1H NMR ((CD3)2SO) δ 7.25 (1 H, m, 6-H), 7.73 (2 H, d, J = 8.9 Hz, Ph 2,6-H2), 8.06 (2 H, d, J = 8.9 Hz, Ph 3,5-H2), 8.42 (1 H, m, 5-H), 8.45 (1 H, m, 7-H), 1 1.10 (1 H, br, NH); 3C NMR ((CD3)2SO) δ 1 19.30 (4a-C), 119.75 (6-C), 129.27 (Ph 3,5-C2), 129.50 (Ph 2,6-C2), 132.0 (Ph 1-C), 137.0 (Ph 4-C), 140.25 (5-C), 149.34 (7-C), 151.0 (8a-C), 156.99 (2-C), 160.15 (1-C); MS 282.0225 (M + Na)+ (C13H8 37CIN3NaO requires 282.0224), 280.0257 (M + Na)+ (C13H8 35CIN3NaO requires 280.0254).
2-Phenylpyrido[3,4-c(|pyrimidin-4-one (41a). 3-Bromopyridine-3-carboxylic acid 4093 (101.5 mg, 0.50 mmol) was stirred with benzimidamide 48a (60 mg, 0.50 mmol), copper(l) iodide (19 mg, 0.10 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 ml_) at 80°C for 3 h, then at room temperature for 12 h under argon. The mixture was cooled and filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the solvent was evaporated from the filtrate. The residue was dissolved in saturated aqueous ethylene- diaminetetraacetic acid (20 ml_) and sonicated for 5 min. The solution was kept at 2- 8°C for 1 h. The solid was collected by filtration. The filtrate was extracted with ethyl acetate (4 χ 25 ml_). The combined extracts were dried (magnesium sulfate) and the solvent was evaporated. The combined solids were washed (water, then petroleum ether) and were dried to give 2-phenylpyrido[3,4-c/]pyrimidin-4-one 41 b (14 mg, 13%) as a white powder: mp 228-230°C (lit.69 mp 266-267°C); H NMR ((CD3)2SO) δ 7.62 (3 H, m, Ph 3,4,5-H3), 8.02 (1 H, d, J = 5.0 Hz, 5-H), 8.26 (2 H, d, J = 6.9 Hz, Ph 2,6-H2), 8.68 (1 H, d, J = 5.0 Hz, 6-H), 9.16 (1 H, s, 8-H), 10.40 (1 H, br, NH); 13C NMR
((CD3)2SO) (HSQC / HMBC) δ 1 18.09 (5-C), 127.42 (Ph 1-C), 127.93 (Ph 2,6-C2), 128.97 (Ph 3,5-C2), 129. 04 (4a-C), 131.56 (8a-C), 132.99 (Ph 4-C), 145.44 (6-C), 150.70 (8-C), 155.07 (2-C), 162.13 (4-C); MS m/z 246.0448 (M + Na)+ (C13H9N3NaO requires 246.0641).
2-(4-Methylphenyl)pyrido[3,4-djpyrimidin-4-one (41b). 3-Bromopyridine-3-carboxylic acid 4093 (101.5 mg, 0.50 mmol) was stirred with 4-methylbenzimidamide 48b (67 mg, 0.50 mmol), copper(l) iodide (19 mg, 0.10 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80°C for 3 h, then at room temperature for 10 h under argon. The mixture was cooled and filtered and the solvent was evaporated. The residue was dissolved in methanol, the precipitate was filtered and the solvent was evaporated from the filtrate. The residue was dissolved in saturated aqueous ethylenediaminetetraacetic acid (20 mL) and this solution was extracted with dichloromethane (3 χ 25 mL). The combined extracts were dried (magnesium sulfate) and the solvent was evaporated to give 2-(4-methylphenyl)pyrido[3,4-cf]pyrimidin-4-one 41 b (10 mg, 9%) as a white powder: mp 214-216°C, 1H NMR ((CD3)2SO) δ 2.44 (3 H, s, Me), 7.36 (2 H, d, J = 8.1 Hz, Ph 3,5-H2), 7.91 (1 H, d, J = 5.2 Hz, 5-H), 8.24 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.52 (1 H, d, J = 5.2 Hz, 6-H), 9.03 (1 H, s, 7-H), 10.20 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.97 (Me), 1 18.16 (5-C), 126.00 (4a-C), 127.47 (Ph 1-C), 127.47 (Ph 2,6-C2), 128.85 (Ph 3,5-C2), 129.45 (Ph 4-C), 144.00 (6- C), 149.00 (8a-C), 150.40 (8-C), 168.90 (2-C); MS m/z 236.0836 (M - HV (C14H10N3O requires 236.0824).
2-(4-Trifluoromethylphenyl)pyrido[3,4-tflpyrimidin-4-one (41 c). 3-Bromopyridine-4- carboxylic acid (101.5 mg, 0.5 mmol) was stirred with 4-trifluoromethylbenzimidamide (94 mg, 0.5 mmol), copper(l) iodide (19.2 mmol, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80°C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was suspended in methanol, the suspension was filtered and the solvent was evaporated from the filtrate. The residue was dissolved in aqueous ethylenediaminetetraacetic acid (saturated, 20 mL). The solution was kept at 2-8 °C for 1 h and the solid was collected by filtration. The filtrate was extracted with ethyl acetate (6 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated. The combined solids were washed with petroleum ether and water and were dried to give 2-(4-trifluoromethylphenyl)pyrido[3,4-c]pyrimidin-4-one 41 c (34 mg, 24%) as a pale green powder: H NMR ((CD3)2SO) δ 7.87 (2 H, d, J = 8.3 Hz, Ph 2,6-Hz), 8.12 (1 H, m, 5-H), 8.43 (2 H, d, J = 8.2 Hz, Ph 3,5-H2), 8.71 (1 H, br, 6- H), 9.23 (1 H, br, 8-H), 13.10 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 125.24 (q, J = 289.3 Hz, CF3), 125.56 (q, J = 2.3 Hz, Ph 3,5-C2), 128.91 (Ph 2,6-C2), 131.5 (4a-C), 136.27 (q, J = 31.7 Hz, Ph 4-C), 138.0 (Ph 1 -C), 147.0 (5-C), 149.0 (8-C), 154.0 (2-C), 155.5 (6-C), 158.0 (8a-C), 161.32 (4-C); MS m/z 292.0705 (M + H)+ (C14H9F3N30 requires 292.0692). 2-Phenylpyrido[4,3-d]pyrimidin-4-one (43a). 4-Bromopyridine-3-carboxylic acid (101.5 mg, 0.5 mmol) was stirred with benzimidamide (60 mg, 0.5 mmol), copper(l) iodide (19.2 mg, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in
dimethylformamide (5 mL) at 80°C for 3 h, then at 50 °C for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was suspended in methanol, the precipitate was filtered and the filtrate was evaporated. The evaporation residue was dissolved in aqueous ethylenediaminetetraacetic acid (saturated, 20 mL) and the suspension was sonicated for 5 min. This mixture was extracted with ethyl acetate (6 χ 25 mL). The combined organic layers were dried (magnesium sulfate). The solvent was evaporated to give 2-phenylpyrido[4,3-c/]pyrimidin-4-one 43a (50 mg, 44%) as an ivory-coloured powder: mp 273-275°C (lit.72 284-286°C), 1H NMR ((CD3)2SO) δ 7.61 (1 H, m, 8-H), 7.63 (3 H, m, Ph 3,4,5-H3), 8.28 (2 H, d, J = 7.2 Hz, Ph 2,6-H2), 8.83 (1 H, br, 7-H), 9.33 (1 H, br, 5-H), 12.80 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 17.5 (4a-C), 120.0 (8-C), 124.0 (Ph 1-C), 128.26 (Ph 3,5-C2), 128.64 (Ph 2,6-C2), 132.0 (Ph 4-C), 135.0 (3-C), 149.0 (5-C), 152.0 (7-C), 156.0 (8a-C), 162.0 (4- C); MS m/z 224.0818 (M + H)+ (C13H10N3O requires 224.0813).
2-(4-Methylphenyl)pyrido[4,3-d]pyrimidin-4-one (43b). 4-Bromopyridine-3-carboxylic acid (101.5 mg, 0.5 mmol) was stirred with 4-methylbenzimidamide (67 mg, 0.5 mmol), copper(l) iodide (19.2 mmol, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80°C for 12 h under argon. The mixture was filtered and the solvent was evaporated. The residue was suspended in methanol. The mixture was filtered and the solvent was evaporated from the filtrate. The evaporation residue was dissolved in aqueous ethylenediaminetetraacetic acid (saturated, 20 mL). The solution was extracted with ethyl acetate (6 χ 25 mL). The combined organic extracts were dried (magnesium sulfate) and the solvent was evaporated to give 2-(4- methylphenyl)pyrido[4,3-d]pyrimidin-4-one 43b (46 mg, 42%) as an ivory-coloured powder: mp 276-278°C (lit.72 296-299°C); 1H NMR ((CD3)2SO) δ 2.45 (3 H, s, Me), 7.29 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.64 (1 H, d, J = 5.4 Hz, 5-H), 8.18 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.85 (1 H, br, 6-H), 9.33 (1 H, br, 8-H); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 21.0 (Me), 120.12 (8a-C), 120.39 (5-C), 128.17 (Ph 2,6-C2), 129.21 (Ph 3,5- C2), 129.82 (Ph 1-C), 131.48 (Ph 4-C), 142.27 (3-C), 149.45 (8-C), 157.37 (4a-C), 162.37 (1-C); MS m/z 238.0975 (M + H)+ (C14H12N30 requires 238.0984). 2-{4-TrifIuoromethylphenyl)pyrido[4,3-cdpyrimidin-4-one (43c). 4-Bromopyridine-3- carboxylic acid (101.5 mg, 0.5 mmol) was stirred with 4-trifluoromethylbenzimidamide (94 mg, 0.5 mmol), copper(l) iodide (19.2 mmol, 0.1 mmol) and caesium carbonate (325 mg, 1.0 mmol) in dimethylformamide (5 mL) at 80°C for 3 h, then at room temperature for 10 h under argon. The mixture was filtered and the solvent was evaporated. The residue was suspended in methanol. The suspension was filtered. The solvbent was evaporated from the filtrate. The residue was dissolved in aqueous ethylenediaminetetraacetic acid (saturated, 20 mL). The solution was kept at 2-8 °C for 1 h and the precipitated solid was collected by filtration. The filtrate was extracted with ethyl acetate (6 χ 25 mL). The combined organic extracts were dried (magnesium sulfate) and the solvent was evaporated. The combined solids were washed with petroleum ether and water and were dried to give 2-(4-trifluoromethylphenyl)pyrido[4,3- c(]pyrimidin-4-one 43c (70 mg, 50%) as a pale green powder: mp 267-268°C; 1H NMR ((CD3)2SO) δ 7.71 (1 H, d, J = 4.4 Hz, 8-H), 8.00 (2 H, d, J = 8.3 Hz, Ph 2,6-H2), 8.44 (2
H, d, J = 8.2 Hz, Ph 3,5-H2), 9.08 (1 H, br, 7-H), 9.38 (1 H, br, 5-H), 13.10 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 122.04 (8a-C), 125.21 (8-C), 125.24 (Ph 2,6- C2), 125.51 (q, J = 3.5 Hz, Ph 3,5-C2), 129.17 (6-C), 131.76 (q, J = 340.6 Hz, CF3), 134.0 (q, J = 27.5 Hz, Ph 4-C), 138.0 (Ph 1-C), 149.53 (5-C), 153.49 (4a-C), 156.32 (3- C), 162.0 (1 -C); 19F NMR ((CD3)2SO) δ -61.34 (s, CF3); MS m/z 292.0702 (M + H) (C14H9F3N30 requires 292.0692).
2-(4-Chlorophenyl)pyrido[4,3-£flpyrimidin-4-one (43d). 4-Bromopyridine-3- carboxylic acid (101.5 mg, 0.5 mmol) was stirred with 4-chlorobenzimidamide (77.3 mg, 0.5 mmol), copper(l) iodide (19.2 mmol, 0.1 mmol) and caesium carbonate (325 mg,
I .0 mmol) in dimethylformamide (5 mL) at 80°C for 12 h under argon. The mixture was filtered. The solvent was evaporated from the filtrate. The residue was dissolved in methanol and filtered. The solvent was evaporated from the filtrate. The residue was dissolved in aqueous ethylenediaminetetraacetic acid (saturated, 20 mL). The solution was extracted with ethyl acetate (6 χ 25 mL). The combined organic extracts were dried (magnesium sulfate). The solvent was evaporated and the residue was washed with petroleum ether and water and dried to give 2-(4-chlorophenyl)pyrido[4,3- d]pyrimidin-4-one 43d (17 mg, 13%) as a white powder: H NMR ((CD3)2SO) δ 7.66 (1 H, d, J = 5.6 Hz, 5-H), 7.69 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 8.29 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 8.86 (1 H, d, J = 5.5 Hz, 6-H), 9.34 (1 H, br, 8-H), 13.05 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 120.0 (5-C), 126.50 (8a-C), 128.78 (Ph 3,5-C2), 130.09 (Ph 2,6-C2), 131.02 (Ph 4-C), 137.15 (Ph 1-C), 146.0 (4-C), 153.52 (8-C), 155.99 (3-C), 162.0 (1 -C); MS m/z m/z 282.0269 (M + Na)+ (requires 282.0222), 280.0248 (M + Na)+ (C13H8 35CIN3NaO requires 280.0260).
2-Phenylthieno[3,4-d]pyrimidin-4-one (45). 4-Bromothiophene-3-carboxamide 45 (580 mg, 2.8 mmol) was stirred with potassium carbonate (1.17 g, 8.5 mmol), copper(l) bromide (40 mg, 0.28 mmol) and benzylamine (610 mg, 5.7 mmol) at 125°C in an open flask for 16 h in dimethylsulfoxide (28 mL). The mixture was diluted with ethyl acetate (30 mL) and was washed with water (2 x 15 mL) and saturated brine (2 x 15 mL). The organic solution was dried (sodium sulfate) and the solvent was evaporated.
Chromatography (dichloromethane→ ethyl acetate / dichloromethane 1 :5) gave a crude solid which was recrystallised (dichloromethane) to give 2-phenylthieno[3,4- c]pyhmidin-4-one 45 (102 mg, 16%) as a yellow solid: mp 245-247°C (lit.73 mp 242- 243X); 1H NMR (CDCI3) δ 7.50-7.56 (3 H, m, Ar 3,4,5-H3), 7.86 (1 H, d, J = 3.5 Hz, 7- H), 8.10-8.1 1 (2 H, m, Ph 2,6-H2), 8.51 (1 H, d, J = 3.5 Hz, 5-H), 11.93 (1 H, s, NH); 13C NMR (CDCI3) δ 118.32 (7-C), 125.01 (4a-C), 127.61 (Ph 2,6-C2), 127.89 (5-C), 128.50 (Ph 3,5-C2), 131.04 (Ph 4-C), 132.91 (Ph 1 -C), 148.72 (7a-C), 150.86 (2-C), 158.91 (4- C).
N-Hydroxy-4-methylbenzimidamide (47b). 4-Methylbenzonitrile 46b (940 mg, 8.0 mmol) in ethanol (30 mL) was added to hydroxylamine hydrochloride (3.34 g, 48 mmol) and sodium hydrogen carbonate (2.54 g, 24 mmol) in water (30 mL) and the mixture was stirred at 100°C for 3 h. The ethanol was evaporated from the cooled mixture and the residue was poured into ice-cold water. The precipitate was collected by filtration, washed (water) and dried to give N-hydroxy-4-methylbenzimidamide 47b (940 mg, 78%) as a white powder: mp 138-139°C (lit.94 136- 37°C); 1H NMR ((CD3)2SO) δ 2.37 (3H, s, Me), 5.77 (2H, br, NH2), 7.22 (2H, d, J = 8.0 Hz, Ph 3,5-H2), 7.61 (2H, d, J = 8.0 Hz, Ph 2,6-H2), 9.55 (1 H, s, OH); 13C NMR ((CD3)2SO) δ 20.78 (Me), 125.24 (2,6-C2), 128.60 (3,5-C2), 130.55 (1-C), 138.21 (4-C), 150.74 (C=N); MS m/z 151.0888 (M + H)+ (CgHnNaO-i requires 151.0871).
N-Hydroxy-4-trifluoromethylbenzimidamide (47c). 4-Trifluoromethylbenzonitrile 46c (1.37 g, 8.0 mmol) in ethanol (30 mL) was added to hydroxylamine hydrochloride (3.34 g, 48 mmol) and sodium hydrogen carbonate (2.54 g, 24 mmol) in water (30 mL) and the mixture was stirred at 100°C for 3 h. The ethanol was evaporated from the cooled mixture and the residue was poured into ice-cold water. The precipitate was collected by filtration, washed (water) and dried to give N-hydroxy-4-trifluoromethyl- benzimidamide 47c (1.60 g, 98%) as a white powder: 1 18-120°C (lit.95 128-129°C); 1H NMR ((CD3)2SO) δ 6.01 (2 H, br, NH2), 7.79 (2 H, d, J = 8.4 Hz, Ph 2,6-H2), 7.94 (2 H, d, J = 8.4 Hz, Ph 3,5-H2), 9.96 (1 H, s, OH); 13C NMR ((CD3)2SO) δ 124.98 (q, J = 3.1 Hz, 3,5-C2), 125.54 (q, J = 331 Hz, CF3), 126.05 (2,6-C2), 129.17 (1 -C), 137.28 (q, J = 28 Hz, 4-C), 149.76 (C=N); 19F NMR (CDCI3) δ -62.84 (CF3); MS m/z 205.0610 (M + H)+ (C8H8N2OF3 requires 205.0589).
4-Chloro-N-hydroxybenzimidamide (47d). 4-Chlorobenzonitrile 46d (550 mg, 4.0 mmol) in ethanol (15 mL) was added to hydroxy!amine hydrochloride (1.67 g, 24 mmol) and sodium hydrogen carbonate (1.27 g, 12 mmol) in water (15 mL) and the mixture was stirred at 100°C for 2 h. The ethanol was evaporated from the cooled mixture and the residue was poured into ice-cold water. The precipitate was collected by filtration, washed (water) and dried to give N-hydroxy-4-chlorobenzimidamide 47d (650 mg, 95%) as a white powder: mp 126-128°C (lit.94 128-129°C); 1H NMR ((CD3)2SO) δ 5.90 (2 H, br, NH2), 7.48 (2 H, d, J = 9.2 Hz, Ph 2,6-H2), 7.74 (2 H, d, J = 9.2 Hz, Ph 3,5-H2), 9.76 (1 H, s, OH); 3C NMR ((CD3)2SO) δ 127.10 (3,5-C2), 128.10 (2,6-C2), 132.19 (1- C), 133.41 (4-C), 149.89 (C=N); MS m/z 171.0320 (M + H)+ (C7H8N2035CI requires 171.0325).
4-Methylbenzimidamide (48b). Ammonium formate (403 mg, 6.3 mmol) was boiled with N-hydroxy-4-methylbenzimidamide 47b (150 mg, 1.0 mmol) and palladium on charcoal (1 %, 150 mg) in acetic acid (5.0 mL) under reflux for 4 d under argon. The cooled mixture was filtered through Celite®. The solvent was evaporated from the filtrate. Aqueous sodium hydroxide (1.0 M, 20 mL) was added and the mixture was extracted with ethyl acetate (3 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated evaporated in vacuo to give 4- methylbenzimidamide 48b (82 mg, 61%) as a white powder: mp 53-55X (lit.96 68°C); H NMR ((CD)3SO) δ 2.42 (3H, s, CH3), 6.72 (3H, br, NH and NH2), 7.25 (2H, d, J = 8.4 Hz, Ph 3,5-Hz), 7.72 (2H, d, J = 8.3 Hz, Ph 2,6-H2); 13C NMR ((CD)3SO) δ 20.08 (CH3), 126.46 (2,6-Cz), 128.56 (3,5-C2), 133.16 (1-C), 139.44 (4-C), 162.57 (C=N); MS m/z 135.1018 (M + H)+ (CsH^Nz requires 135.0922). 4-(Trifluoromethyl)benzimidamide (48c). Ammonium formate (806 mg, 12.6 mmol) was boiled with N-hydroxy-4-(trifluoromethyl)benzimidamide 47c (267 mg, 1.3 mmol) and palladium on charcoal (10%, 267 mg) in acetic acid (5.0 mL) under reflux for 10 h under argon. The cooled mixture was filtered through Celite®. The solvent was evaporated from the filtrate. Aqueous sodium hydroxide (1.0 M, 20 mL) was added and the mixture was extracted with ethyl acetate (3 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated evaporated in vacuo to give 4-(trifluoromethyl)benzimidamide 48c (220 mg, 92%) as a white powder: mp 43- 45°C; 1H NMR ((CD)3SO) δ 6.72 (2 H, br, NH2), 7.30 (1 H, br, NH), 7.81 (2 H, d, J = 8.1 Hz, Ph 2,6-H2), 8.03 (2 H, d, J = 8.0 Hz, Ph 3,5-H2); 13C NMR ((CD)3SO) δ 24.07 (q, J = 278 Hz, CF3), 126.43 (2,6-C2), 128.70 (q, J = 4.5 Hz, 3,5-C2), 133.16 (1-C), 140.95 (q, J - 35.4 Hz, 4-C), 166.50 (C=N); 19F NMR (CDCI3) δ -61.16 (CF3); MS m/z 189.0661 (M + H)+ (C8H8N2F3 requires 189.0640).
4-Chlorobenzimidamide (48d). Ammonium formate (1.03 g, 16.1 mmol) was boiled with N-hydroxy-4-chlorobenzimidamide 47d (279 mg, 1.6 mmol) and platinum on charcoal (5%, 300 mg) in acetic acid (5.0 mL) under reflux for 36 h under argon. The cooled mixture was filtered through Celite®. The solvent was evaporated from the filtrate. Aqueous sodium hydroxide (1.0 M, 20 mL) was added and the mixture was extracted with ethyl acetate (3 χ 25 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was evaporated to give 4-chlorobenzimidamide 48d (173 mg, 70%) as a white powder: mp 89-92°C; 1H NMR ((CD)3SO) δ 7.39 (2 H, br, NH2), 7.50 (2 H, d, J = 7.5 Hz, Ph 2,6-H2), 7.93 (2 H, d, J = 8.1 Hz, Ph 3,5-H2), 8.01 (1 H, br, NH); 13C NMR ((CD)3SO) δ 26.81 (1-C), 127.42 (3,5-C2), 128.16 (2,6-C2), 167.88 (4-C), 171.43 (C=N); MS m/z 155.0430 (M + H) (C7H8N2CI requires 155.0430).
2-(4-lodobenzamido)benzamide (50f). Dry pyridine 755 mg, 9.5 mmol) was added to 2-aminobenzamide 49 1.00 g, 7.3 mmol) in dry tetrahydrofuran (40 mL), followed by 4- iodobenzoyl chloride 380 mg, 2.2 mmol) in dry tetrahydrofuran 40 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 7:3) gave 2-(4-iodobenzamido)benzamide 50f (1.61 g, 60%) as a white solid: mp 222- 223°C; 1H NMR ((CD3)2SO) δ 7.24 (1 H, t, J = 7.5 Hz, 5-H), 7.63 (1 H, t, J = 7.5 Hz, 4- H), 7.76 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 7.93 (1 H, s, NHH), 7.96 (1 H, d, J = 7.5 Hz, 6- H), 8.03 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 8.49 (1 H, s, NHH), 8.73 (1 H, d, J = 7.5 Hz, 3- H), 13.07 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 99.92 (Ph 4-C), 119.13 (1 -C), 120.04 (3-C), 122.78 (5-C), 128.73 (6-C), 128.77 (Ph 2,6-C2), 132.61 (4-C), 134.03 (Ph 1-C), 137.81 (Ph 3,5-C2), 139.92 (2-C), 163.72 (NHCO), 171.1 1 (CONH2); MS m/z 388.9780 (M + Na)+ (C14HnlN2NaO requires 388.9763).
2-(4-Trifluoromethylbenzamido)benzamide (50h). 2-Aminobenzamide 49 (350 mg, 2.6 mmol) was stirred with dry pyridine (261 mg, 3.3 mmol) and 4-trifluoromethyl- benzoyl chloride (590 mg, 2.8 mmol) under argon for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 4:1) gave 2-(4-trifluoromethylbenz- amido)benzamide 50h (590 mg, 83%) as a white solid: mp 204-206 °C; 1H NMR ((CD3)2SO) δ 7.21 (1 H, td, J = 8.0, 1.0 Hz, 5-H), 7.59 (1 H, td, J = 8.0, 1.0 Hz, 4-H), 7.88 (1 H, s, NHH), 7.92 (1 H, dd, J = 8.0, 1.5 Hz, 6-H), 7.97 (2 H, d, J = 8.5 hz, Ph 3,5- H2), 8.13 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.45 (1 H, s, NHH), 8.68 (2 H, dd, J = 8.0, 1.5 Hz, 3-H), 13.14 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 19.34 (1-C), 120.17 (3-C), 123.84 (q, J = 270.8 Hz, CF3), 123.08 (5-C), 125.99 (q, J = 3.7 Hz, Ph 3,5-C2), 126.02 (Ph 1 -C), 127.89 (Ph 2,6-C2), 128.78 (6-C), 131.70 (q, J = 31.7 Hz, Ar 4-C), 132.67 (4-C), 139.78 (2-C), 163.16 (NHCO), 171.10 (CONH2); MS m/z 331.0670 (M + Na)+ (C15H11F3N2Na02 requires 331.0670).
2-(4-Ferrocenylbenzamido)benzamide (50k). Ferrocenecarboxylic acid (1.00 g, 4.4 mmol) was treated with oxalyl chloride (3.87 g, 30.5 mmol) in dry dichloromethane (20 ml_) under argon for 4 h. The solvent and excess reagent were evaporated. The residue was extracted with hexane (30 ml_). The suspension was filtered and the solvent was evaporated from the filtrate to give crude ferrocenecarbonyl chloride (820 mg) as a red oil. This material, in dry tetrahydrofuran (20 ml_), was added to 2-amino- benzamide 49 (410 mg, 3.0 mmol), dry pyridine (316 mg, 4.0 mmol) and 4-dimethyl- aminopyridine (82 mg, 0.7 mmol in dry tetrahydrofuran (20 ml_). The mixture was stirred for 16 h under argon. The solvent was evaporated. Chromatography (ethyl acetate / petroleum ether 3:2) gave 2-(4-ferrocenylbenzamido)benzamide 50k (980 mg, 98%) as a red oil; 1H NMR ((CD3)2SO) δ 4.24 (5 H, s, Cp2-H5), 4.49 (2 H, m, Cp^ 3,4- H2), 4.78 (2 H, m, C ^ 2,5-H2), 7.1 1 (1 H, t, J = 7.5 Hz, 5-H), 7.51 (1 H, t, J = 7.5 Hz, 4- H), 7.82 (1 H, s, CONHH), 7.85 (1 H, d, J = 7.5 Hz, 6-H), 8.35 (1 H, s, CONHH), 8.57 (1 H, d, J = 7.5 Hz, 3-H); 13C NMR ((CD)3SO) (HSQC / HMBC) δ 68.07 (C ^ 2,5-C2), 69.56 (Cp2-C5), 70.77 (Cp! 3,4-C2), 76.58 (Cp 1-C), 1 18.49 (1-C), 1 19.63 (3-C), 121.73 (5-C), 128.58 (6-C), 132.35 (4-C), 140.23 (2-C), 168.13 (NHCO), 171.13 (CONH2); MS m/z 371.0468 (M + Na)+ (C18H16 56FeN2Na02 requires 371.0459). 2-Phenylquinazolin-4-one (51a). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with benzaldehyde (310 mg, 2.9 mmol) and sodium hydrogen sulphite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (dichloromethane→ dichloromethane / methanol 97:3), followed by recrystallisation (ethyl acetate) gave 2-phenylquinazolin-4-one 51a (350 mg, 54%) as white crystals: mp 235-236°C (lit.74 236-237°C); 1H NMR ((CD3)2SO) δ 7.48-7.59 (4 H, m, Ph 2,4,6-H3 + 6-H), 7.72 (1 H, d, J = 8.0 Hz, 8-H), 7.81 (1 H, t, J = 8.0 Hz, 7-H), 8.13-8.18 (3 H, m, Ph 3,5-H2 + 5-H), 12.49 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 120.97 (C-4a), 125.83 (5-C), 126.54 (6-C), 127.44 (Ph 3,5-C2), 128.56 (Ph 2,6-C2), 131.35 (Ph 4-C), 132.70 (Ph 1-C), 134.54 (7-C), 148.69(8a-C), 152.27 (2-C), 162.17 (4-C).
2-(4-Methylphenyl)quinazolin-4-one (51 b). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-methylbenzaldehyde (350 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (dichloromethane / methanol 19:1), followed by recrystallisation (ethyl acetate) gave 2-(4-methylphenyl)quinazolin-4-one 51 b (300 mg, 56%) as white crystals: mp 258-260°C (lit.75 259-260°C); 1H NMR ((CD3)2SO) δ 2.36 (3 H, s, Me), 7.31 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.47 (1 H, m, 6-H), 7.69 (1 H, d, J = 8.1 Hz, 8-H), 7.79 (1 H, m, 7-H), 8.07 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 8.12 (1 H, dd, J = 8.0, 1.2 Hz, 5-H), 12.39 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.95 (Me), 120.89 (4a-C), 125.81 (6-C), 126.32 (5-C), 127.38 (8-C), 127.65 (Ph 2,6-C2), 129.14 (Ph 3,5-C2), 129.89 (Ph 1-C), 134.48 (7-C), 141.39 (Ph 4-C), 148.89 (8a-C), 152.20 (2-C), 162.21 (4-C).
2-(4-Methoxyphenyl)quinazolin-4-one (51c). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-methoxybenzaldehyde (395 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (ethyl acetate / petroleum ether 3:7→ dichloromethane / methanol 99:1), followed by recrystallisation (ethyl acetate) gave 2- (4-methoxyphenyl)quinazolin-4-one 51c (330 mg, 51%) as white crystals: mp 248- 249°C (lit.76 248-249X); 1H NMR ((CD3)2SO) δ 3.83 (3 H, s, Me) 7.06 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.45 (1 H, m, 6-H), 7.67 (1 H, d, J = 8.0 Hz, 8-H), 7.78 (1 H, m, 7-H), 8.1 1 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 8.17 (2 H, d, J = 8.0 Hz, Ph 2,6-H2). 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.44 (Me), 133.97 (Ph 2,6-C2), 120.68 (4a-C), 124.82 (Ph 1-C), 125.80 (5-C), 126.06 (C-6), 127.26 (C-8), 129.44 (Ph 3,5-C2), 134.47 (7-C), 148.93 (8a-C), 151.84 (Ph 4-C), 162.25 (4-C).
2-(4-ChlorophenyI)quinazolin-4-one (51 d). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-chlorobenzaldehyde (408 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N.N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (dichloromethane / methanol 19: 1 ) gave 2- (4-chlorophenyl)quinazolin-4-one 51 d (490 mg, 65%) as a white solid: mp 297-299°C (lit.75 299-300°C); H NMR ((CD3)2SO) δ 7.58 (1 H, m, 6-H), 7.63 (2 H, d, J = 8.7 Hz, Ph 3,5-H2), 7.73 (1 H, d, J = 8.0 Hz, 8-H), 7.84 (1 H, m, 7-H), 8.15 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.20 (2 H, d, J = 8.7 Hz, Ph 2,6-H2), 12.59 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 120.96 (4a-C), 125.84 (5-C), 126.73 (6-C), 127.43 (8-C), 128.65 (Ph 3,5-C2), 129.59 (Ph 2,6-C2), 131.55 (Ph 1 -C), 134.62 (7-C), 136.25 (Ph 4-C), 148.49 (8a-C), 151.36 (2-C), 162.18 (4-C).
2-(4-Bromophenyl)quinazolin-4-one (51 e). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-bromobenzaldehyde (542 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. The solid was recrystallised (dimethylformamide / petroleum ether) to give 2-(4-bromophenyl)quinazolin-4-one 51 e (500 mg, 57%) as a white solid: mp 287-290X (lit.77 296-297°C); 1H NMR ((CD3)2SO) δ 7.54 (1 H, m, 6-H), 7.73-7.77 (3 H, m, 8-H + Ph 3,5-H2), 7.83-7.86 (1 H, m, 7-H), 8.13 (2 H, d, J = 7.0 Hz, Ph 2,6-H2), 8.16 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 12.61 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 121.66 (4a-C), 125.89 (5-C), 126.54 (6-C), 127.44 (7-C), 128.15 (Ph 4-C), 130.46 (Ph 2,6-C2), 132.28 (Ph 3,5-C2), 132.59 (Ph 1 -C), 135.33 (8-C), 148.21 (8a-C), 152.16 (2-C), 162.85 (4-C).
2-(4-lodophenyI)quinazolin-4-one (51 f). 2-(4-lodobenzamido)benzamide 50f (1.51 g, 4.1 mmol) was heated with aqueous sodium hydroxide (0.5 M, 400 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4- iodophenyl)quinazolin-4-one 51f (1.23 g, 86%) as a white solid: mp >300°C; 1H NMR ((CD3)2SO) δ 7.52-7.55 (1 H, m, 6-H), 7.75 (1 H, d, J = 8.0 Hz, 8-H), 7.83-7.86 (1 H, m, 7-H), 7.93-7.98 (4 H, m, Ph 2,6-H2 + 3,5-H2), 8.16 (1 H, dd, J=8.0, 1.0, 5-H), 12.59 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 99.14 (Ph 4-C), 120.99 (4a-C), 125.85 (5-C), 126.72 (6-C), 127.43 (8-C), 129.60 (Ph 2,6-C2), 132.21 (Ph 1-C), 134.62 (7-C), 137.44 (Ph 3,5-C2), 148.52 (8a-C), 151.75 (2-C), 163.90 (4-C); MS (electron impact) m/z 348.9829 (M)+ (C14H10IN2O requires 348.9837).
2-(4-Fluorophenyl)quinazolin-4-one (51 g). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-fluorobenzaldehyde (360 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 mL) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Recrystallisation (dichloromethane / petroleum ether) gave 2-(4-fluorophenyl)quinazolin-4-one 51 g (400 mg, 57%) as a white solid: mp 286-289°C (lit.78 288-289°C); 1H NMR ((CD3)2SO) δ 7.39 (2 H, m, Ph 3,5-H2), 7.52 (1 H, t d, J = 7.0, 1.0 Hz, 6-H), 7.74 (1 H, dd, J = 8.0, 0.5 Hz, 8-H), 7.83 (1 H, m, 7-H), 8.15 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.25 (2 H, m, Ph 2,5-H2), 12.56 (1 H, s, NH); 13C NMR ((CD3)2SO) (HMBC / HSQC) δ 115.59 (d, J = 21.7 Hz, Ph 3,5-C2), 120.85 (4a-C), 125.83 (5-C), 126.57 (6-C), 127.36 (8-C), 129.24 (Ph 1-C), 130.24 (d, J = 9.0 Hz, Ph 2,6-C2), 134.60 (7-C), 148.57 (8a-C), 151.54 (2-C), 162.18 (4-C), 164.02 (d, J = 248.0 Hz, Ph 4-C).
2-(4-Trifluoromethylphenyl)quinazolin-4-one (51 h). 2-(4-Trifluoromethylbenzamido)- benzamide 50h (700 mg, 2.3 mmol) was stirred with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration and dried under vacuum to give 2-(4-trifluoromethylphenyl)quinazolin-4-one 51 h (620 mg, 94%) as a white solid: mp 305-308°C (lit.79 306-308°C); 1H NMR ((CD3)2SO) δ 7.56 (1 H, t, J = 7.5 Hz, 6-H), 7.78 (1 H, d, J = 7.5 Hz, 8-H), 7.87 (1 H, m, 7-H), 7.30 (2 H, d, J = 8.0, Ph 3,5-H2), 8.18 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 8.37 (2 H, d, = 8.0 Hz, Ph 2,6-H2), 12.75 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 121.21 (4a-C), 123.96 (q, J = 270.3 Hz, CF3), 125.50 (q, J = 3.5 Hz, Ph 3,5-H2), 125.12 (5-C), 127.12 (6-C), 127.69 (8-C), 128.73 (Ph 2,6-C2), 130.98 (q, J = 32.1 Hz, Ph 4-C), 134.74 (7-C), 136.61 (Ph 1-C), 148.44 (8a-C), 151.17 (2-C), 162.10 (4-C). 2-(4-Cyanophenyl)quinazolin-4-one (51 i). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-cyanobenzaldehyde (380 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in N,N-dimethylacetamide (3.5 ml_) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Recrystallisation (dimethylformamide / diethyl ether) gave 2-(4- cyanophenyl)quinazolin-4-one 51 i (280 mg, 39%) as a white solid: mp 255-257°C (lit.80 260°C); 1H NMR ((CD3)2SO) δ 7.57 (1 H, m, 6-H), 7.7 (1 H, dd, J = 8.0, 0.5 Hz, 8-H), 7.86 (1 H, m, 7-H), 8.01 (1 H, d, J = 8.5 Hz, Ph 3,5-H2), 8.18 (1 H, dd, J = 8.0, 1.5 Hz, H-5), 8.34 (2 H, m, Ph 2,6-H2), 12.63 (1 H, m, NH); 13C NMR ((CD3)2SO) (HMBC / HSQC) δ 1 13.44 (ON), 1 18.08 (Ph 4-C), 121.07 (4a-C), 125.70 (5-C), 126.98 (6-C), 127.47 (8-C), 128.43 (Ph 2,6-C2), 132.27 (Ph 3,5-C2), 134.48 (Ph 1 -C) 136.75 (7-C), 148.16 (8a-C), 150.80 (2-C), 161.84 (4-C).
2-(4-Nitrophenyl)quinazolin-4-one (51 j). 2-Aminobenzamide 49 (400 mg, 2.9 mmol) was heated with 4-nitrobenzaldehyde (438 mg, 2.9 mmol) and sodium hydrogen sulfite (454 mg, 4.3 mmol) at 150°C for 3.5 h in Ν,Ν-dimethylacetamide (3.5 ml_) in an open flask. The cooled mixture was poured into water and the precipitate was collected by filtration. Chromatography (dichloromethane / methanol 19:1 ), followed by
recrystallisation (dimethylformamide / diethyl ether) gave 2-(4-nitrophenyl)quinazolin-4- one 51j (300 mg, 56%) as pale yellow crystals: mp 302-304°C (lit.75 300°C); 1H NMR ((CD3)2SO) δ 7.58 (1 H, t, J = 6.0 Hz, 6-H), 7.79 (1 H, d, J = 6.4 Hz, 8-H), 7.88 (1 H, t, J = 6.0 Hz, 7-H), 8.18 (1 H, d, J = 6.0 Hz, 5-H), 8.38 (2 H, d, J = 7.2 Hz, Ph 3,5-H2), 8.41 (2 H, d, J = 7.2 Hz, Ph 2,6-H2), 12.82 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 121.22 (4a-C), 123.60 (Ph 3,5-C2), 125.88 (5-C), 127.33 (6-C), 127.75 (8-C), 129.27 (Ph 2,6-C2), 134.76 (7-C), 138.51 (Ph 1 -C), 148.31 (8a-C), 148.95 (Ph 4-C), 150.68 (2-C), 161.99 (4-C).
2-(4-Ferrocenylphenyl)quinazolin-4-one (51 k). A suspension of 2-(4-ferrocenylbenz- amido)benzamide 50k (400 mg, 1.1 mmol) in aqueous sodium hydroxide (0.5 M, 100 mL) was heated to 100°C for 16 h. The mixture was cooled to room temperature and acidified to pH~1 by addition of aqueous hydrochloric acid (9 M). The aqueous phase was extracted thrice with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and the solvent was evaporated to give 2-(4-ferrocenylphenyl)- quinazolin-4-one 51 k (290 mg, 90%) as a brown solid: mp >300°C; 1H NMR ((CD3)2SO) δ 4.25 (5 H, s, Cp2-H5), 4.60 (2 H, m Cp<, 3,4-H2), 5.33 (2 H, m, Cp, 2,5-H2), 7.50 (1 H, m, 5-H), 7.66 (1 H, m, 3-H), 7.82 (1 H, m, 4-H), 8.15 (1 H, m, 6-H), 12.01 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 68.17 (C ^ 2,5-C2), 69.67 (Cp2-C5), 71.00 (Cp1 3,4-C2), 120.61 (4a-C), 125.48 (6-C), 125.88 (5-C), 126.75 (8-C), 134.41 (7- C), 149.22 (8a-C), 155.48 (2-C), 161.97 (4-C). MS m/z 353.0335 (M + Na)+
(C18H14 56FeN2NaO requires 353.0353).
2- Benzamido-3-methylbenzamide (53a). Dry pyridine (134 mg, 1.7 mmol) was added to 2-amino-3-methylbenzamide 5297 (200 mg, 1.3 mmol) in dry tetrahydrofuran (5.0 mL), followed by benzoyl chloride (210 mg, 1.5 mmol) in dry tetrahydrofuran (5.0 ml_). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 4:1) gave 2-benzamido-3-methylbenzamide 53a (280 mg, 83%) as a white solid: mp 193-197°C (lit.81 190-193°C); 1H NMR ((CD3)2SO) δ 2.22 (3 H, s, Me), 7.26 (1 H, t, J = 7.5 Hz, 5-H), 7.39-7.44 (3 H, m, 4,6-H2 +NHH), 7.53 (2 H, m, Ph 3,5- H2), 7.58-7.60 (1 H, m, Ph 4-H), 7.71 (1 H, s, NHH), 7.96 (2 H, m, Ph 2,6-H2), 10.20 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.34 (Me), 125.80 (6-C), 125.99 (5- C), 127.48 (Ph 2,6-C2), 128.49 (Ph 3,5-C2), 131.63 (Ph 4-CH), 132.14 (4-C), 132.88 (1- C), 134.26 (2-C), 134.49 (Ph 1-C), 135.98 (3-C), 165.02 (NHCO), 169.70 (CONH2).
3- Methyl-2-(4-methylbenzamido)benzamide (53b). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-nitrobenzoyl chloride (340 mg, 2.2 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 1 :1→ 4:1) gave 3-methyl-2-(4- methylbenzamido)benzamide 53b (380 mg, 71%) as a white solid: mp 237-239°C; 1H NMR ((CD3)2SO) δ 2.27 (3 H, s, 3-Me), 2.44 (3 H, s, Ph 4-Me), 7.31 (1 H, t, J = 7.6 Hz, 5-H), 7.39 (2 H, d, J = 7.9 Hz, Ph 3,5-H2), 7.44-7.50 (3 H, m, 4,6-H2 + NHH), 7.75 (1 H, s, NHH), 7.91 (2 H, d, J = 7.9 Hz, Ph 2,6-H2), 10.22 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.38 (3-Me), 20.98 (Ph 4-Me), 125.80 (5-C), 125.87 (6-C), 127.51 (Ph 2,6-C2), 129.01 (Ph 3,5-C2), 131.48 (Ph 1-C), 32.17 (4-C), 132.68 (1 -C), 134.65 (2-C), 135.94 (3-C), 141.63 (Ph 4-C), 164.92 (NHCO), 169.77 (CONH2); MS (electron impact) m/z 269.1261 (M)+ (C16H17N202 requires 269.1290).
2-(4-Methoxybenzamido)-3-methylbenzamide (53c). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetra- hydrofuran (5.0 mL), followed by 4-methoxybenzoyl chloride (380 mg, 2.2 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 7:3) gave 2-(4-methoxybenzamido)-3- methylbenzamide 53c (160 mg, 28%) as a white solid: mp 182-185°C; 1H NMR
((CD3)2SO) δ 2.26 (3 H, s, 3-Me), 3.89 (3 H, s, OMe), 7.1 1 (2 H, m, Ph 3,5-H2), 7.30 (1 H, t, J = 7.6 Hz, 5-H), 7.43-7.45 (2 H, m, 4-H + N/- H), 7.48 (1 H, m, 6-H), 7.74 (1 H, s, NHH), 7.99 (2 H, m, Ph 2,6-H2) 10.18 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.41 (3-Me), 55.43 (OMe), 1 13.74 (Ph 3,5-C2), 125.78 (6-C), 126.42 (5-C), 129.39 (Ph 2,6-C2), 132.17 (4-C), 132.62 (1-C), 134.79 (2-C), 135.93 (3-C), 140.90 (Ph
1 - C), 161.96 (Ph 4-C), 164.54 (NHCO), 169.81 (CONH2); MS m/z 285.1235 (electron impact) (M)+ C16H17N203 requires 285.1239).
2- (4-Chlorobenzamido)-3-methylbenzamide (53d). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-chlorobenzoyl chloride (380 mg, 2.2 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 7:3) gave 2-(4-chlorobenzamido)-3- methylbenzamide 53d (400 mg, 69%) as a white solid: mp 220-223°C; H NMR
((CD3)2SO) δ 2.27 (3 H, s, Me), 7.32 (1 H, t, J = 7.6 Hz, 5-H), 7.42-7.50 (3 H, m, 4,6-H2 + NHH), 7.66 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 7.74 (1 H, s, NHH), 8.03 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 10.27 (1 H, s, NH); C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.23 (Me), 125.81 (6-C), 126.15 (5-C), 128.56 (Ph 3,5-H2), 129.45 (Ph 2,6-H2), 132.09 (4-C), 133. 1 (1-C), 133.14 (Ph 1 -C), 134.25 (2-C), 136.04 (3-C), 136.43 (Ph 4-C), 164.09 (NHCO), 169.59 (CONH2); MS m/z 313.0505 (M + Na)+ (C15H13 37CIN2Na02 requires 313.0527), 31 1.0533 (M + Na)+ (C15H13 35CIN2Na02 requires 311.0563).
2-(4-Bromobenzamido)-3-methylbenzamide (53e). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-bromobenzoyI chloride (483 mg, 2.2 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 7:3) gave 2-(4-bromobenzamido)-3- methylbenzamide 53e (410 mg, 62%) as a white solid: mp 221-224°C; 1H NMR
((CD3)2S0) δ 2.27 (3 H, s, Me), 7.32 (1 H, t, J = 7.6 Hz, 5-H), 7.42-7.49 (3 H, m, 4,6-H2 + NHH), 7.73 (1 H, s, NHH), 7.80 (2 H, d, J = 8.6 Hz, Ph 3,5-H2), 7.95 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 10.27 (1 H, s NH); 13C NMR ((CD3)2S0) (HSQC / HMBC) δ 18.23 (Me), 125.34 (Ph 4-C), 125.82 (6-C), 126.15 (5-C), 129.63 (Ph 2,6-C2), 131.50 (Ph 3,5-C2), 132.09 (4-C), 133.13 (1-C), 133.49 (Ph 1-C), 134.24 (2-C), 136.03 (3-C), 164.22 (NHCO), 169.58 (CONH2); MS m/z 357.0033 (M + Na)+ (C15H13 81BrN2Na02 requires 359.0078), 355.0052 (M + Na)+ (C15H13 79BrN2Na02 requires 355.0058).
2- (4-Fluorobenzamido)-3-methylbenzamide (53f). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-fluorobenzoyl chloride (349 mg, 2.2 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 7:3) gave 2-(4-fluorobenzamido)-3- methylbenzamide 53f (520 mg, 95%) as a white solid: mp 286-288°C; 1H NMR
((CD3)2SO) δ 2.21 (3 H, s, Me), 7.26 (1 H, t, J = 8.0 Hz, 5-H), 7.34-7.43 (5 H, m, 4,6-H2 + N/-/H + Ph 3,5-H2), 7.70 (1 H, s, NHH), 8.03-8.04 (2 H, m, Ar 2,6-H2), 10.19 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.27 (Me), 1 15.43 (d, J = 21.6 Hz, Ph 3,5-H2), 125.81 (6-C), 125.10 (5-C), 130.23 (d, J = 9.1 Hz, Ph 2,6-H2), 130.80 (d, J = 2.6 Hz, Ph 1-C), 132.09 (4-C), 133.13 (2-C), 134.35 (1-C), 136.04 (3-C), 164,04 (NHCO), 164.10 (d, J = 247.5 Hz, Ph 4-C), 169.65 (CONH2); MS m/z 295.8043 (M + Na)+ (C15H13FN2Na02 requires 295.0859).
3- Methyl-2-(4-trifluoromethylbenzamido)benzamide (53g). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-trifluoromethylbenzoyl chloride (460 mg, 2.2 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 7:3) gave 3-methyl-2-(4- trifluoromethylbenzamido)benzamide 53g (460 mg, 71 %) as a white solid: mp 259- 261 °C; 1H NMR ((CD3)2SO) δ 2.23 (3 H, s, Me), 7.28 (1 H, t, J = 7.5 Hz, 5-H), 7.38-7.44 (3 H, m, 4,6-H2 + NHH), 7.71 (1 H, s, NHH), 7.92 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 8.15 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 10.33 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.17 (Me), 123.92 (q, J = 270.8 Hz, CF3), 125.50 (q, J = 3.6 Hz, Ph 3,5-H2), 125.86 (6-C), 126.33 (5-C), 128.45 (Ph 2,6-H2), 131.41 (q, J = 27.7 Hz, Ph 4-C), 132.08 (4-C), 133.38 (1-C), 134.01 (2-C), 136.07 (3-C), 138.20 (Ph 1-C), 164.01 (NHCO), 169.50 (CONH2); MS m/z 345.0828 (M + Na)+ (C16H13F3N2Na02 requires 345.0827). 3-Methyl-2-(4-nitrobenzamido)benzamide (53h). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 5297 (300 mg, 2.0 mmol) in dry tetrahydro- furan (5.0 mL), followed by 4-nitrobenzoyl chloride (390 mg, 2.2 mmol) in dry tetra- hydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate / petroleum ether 1 :1→ 4:1) gave 3-methyl-2-(4- nitrobenzamido)benzamide 53h (380 mg, 83%) as a pale yellow solid: mp 191-193°C; 1H NMR ((CD3)2SO) δ 2.23 (3 H, s, Me), 7.29 (1 H, t, J = 7.5 Hz, 5-H), 7.37 (1 H, s, N/-/H), 7.42-7.44 (2 H, m, 4,6-H2), 7.73 (1 H, s, NHH), 8.18 (2 H, m, Ph 2,6-H2), 8.38 (2 H, d, J = 7.5 Hz, Ph 3,5-H2), 10.39 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.13 (Me), 123.67 (Ph 3,5-H2), 125.87 (6-C), 126.43 (5-C), 129.04 (Ph 2,6-H2), 132.07 (4-C), 133.48 (1-C), 133.86 (2-C), 136.08 (3-C), 140.12 (Ph 1-C), 149.19 (Ph 4- C), 163.61 (NHCO), 169.45 (CONH2); MS m/z 322.0796 (M + Na)+ (C15H13N304Na requires 322.0803).
8-Methyl-2-phenylquinazolin-4-one (54a). 2-Benzamido-3-methylbenzamide 53a (93 mg, 0.37 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2- phenylquinazolin-4-one 54a (39 mg, 43%) as a white solid: mp 215-217°C (lit.81 206- 209°C); 1H NMR ((CD3)2SO) δ 2.62 (3 H, s, Me), 7.39 (1 H, t, J = 7.6 Hz, 6-H), 7.54- 7.60 (3 H, m, Ph 3,4,5-H3), 7.69 (1 H, d, J = 7.1 Hz, 7-H), 8.00 (1 H, dd, J = 7.8, 1.2 Hz, 5-H), 8.23 (2 H, dd, J = 7.8, 1.2 Hz, Ph 2,6-H2), 12.51 (1 H, s, NH); 13C NMR
((CD3)2SO) (HSQC / HMBC) δ 17.14 (Me), 120.87 (4a-C), 123.47 (5-C), 126.02 (6-C), 127.71 (Ph 2,6-C2), 128.59 (Ph 3,5-C2), 131.29 (Ph 4-C), 132.96 (Ph 1-C), 134.88 (7- C), 135.58 (8-C), 147.10 (8a-C), 151.03 (2-C), 162.54 (4-C).
8-Methyl-2-(4-methylphenyl)quinazolin-4-one (54b). 2-(4-Methylbenzamido)-3- methylbenzamide 53b (100 mg, 0.37 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2-(4-methylphenyl)quinazolin-4-one 54b (75 mg, 81 %) as a white solid: mp 269-271 X (lit.81 255-257X); 1H NMR ((CD3)2SO) δ 2.39 (3 H, s, PhMe), 2.61 (3 H, s, 8-Me), 7.35-7.39 (3 H, m, Ph 3,5-H2 + 6-H), 7.69 (1 H, dt, J =7 .0, 1.0 Hz, 7-H), 7.97 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 8.14 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 12.44 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.16 (8-Me), 20.99 (PhMe), 120.78 (4a-C), 123.47 (5-C), 125.85 (6-C), 127.65 (Ph 2,6-C2), 129.19 (Ph 3,5-C2), 130.14 (8-C), 134.86 (7-C), 135.48 (Ph 1-C), 141.37 (Ph 4-C), 147.18 (8a- C), 150.97 (2-C), 162.56 (4-C); MS (electron impact) m/z 251.11 15 (M)+ (C16H15N20 requires 251.1 106).
2-(4-Methoxyphenyl)-8-methylquinazolin-4-one (54c). 2-(4-Methoxybenzamido)-3- methylbenzamide 53c (100 mg, 0.35 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-methoxyphenyl)-8-methylquinazolin-4-one 54c (68 mg, 73%) as a white solid: mp 225-228°C (lit.81 227-229°C); 1H NMR ((CD3)2SO) δ 2.60 (3 H, s, 8-Me), 3.48 (3 H, s, OMe), 7.09 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.35 (1 H, t, J = 7.5 Hz, 6-H), 7.66 (1 H, d, J = 7.0 Hz, 7-H), 7.97 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 8.23 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.39 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.16 (8-Me), 55.45 (OMe) , 14.00 (Ph 3,5-C2), 120.55 (4a-C), 123.45 (5-C), 125.07 (Ph 1-C), 125.56 (6-C), 129.39 (Ph 2,6-C2), 134.81 (7-C), 135.30 (8-C), 147.30 (8a-C), 150.61 (2-C), 161.82 (Ph 4-C), 162.60 (4-C).
2-(4-Chlorophenyl)-8-methylquinazolin-4-one (54d). 2-(4-Chlorobenzamido)-3- methylbenzamide 53d (100 mg, 0.35 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-chlorophenyl)-8-methylquinazolin-4-one 54d (80 mg, 85%) as a white solid: mp >300°C; 1H NMR ((CD3)2SO) δ 2.61 (3 H, s, Me), 7.41 (1 H, t, J = 7.5 Hz, 6-H), 7.64 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.70 (1 H, d, J = 7.0 Hz, 7- H), 7.98 (1 H, d, J = 8.0 Hz, 5-H), 8.25 (2 H, d, J = 9.0 Hz, Ph 2,6-H2), 12.59 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.14 (Me), 120.91 (4a-C), 123.51 (7-C), 126.25 (6-C), 128.70 (Ph 3,5-C2), 129.56 (Ph 2,6-H2), 131.78 (Ph 1-C), 134.98 (5-C), 135.64 (8-C), 136.24 (Ph 4-C), 146.94 (8a-C), 150.06 (2-C), 162.46 (4-C); MS m/z 295.0418 (M + Na)+ (C15H12 37CIN2NaO requires 295.0426), 293.0438 (M + Na)+ (C15H12 35CIN2NaO requires 293.0458).
2-(4-Bromophenyl)-8-methylquinazolin-4-one (54e). 2-(4-Bromobenzamido)-3- methylbenzamide 53e (100 mg, 0.30 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-bromophenyl)-8-methylquinazolin-4-one 54e (77 mg, 81%) as a white solid: mp >300°C; 1H NMR ((CD3)2SO) δ 2.61 (3 H, s, Me), 7.41 (1 H, t, J = 7.5 Hz, 6-H), 7.70 (1 H, d, J = 7.0 Hz, 7-H), 7.77 (2 H, d , J = 8.5 Hz, Ph 3,5- H2), 7.99 (1 H, dd, J = 8.5, 1.5 Hz, 5-H), 8.17 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.58 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.16 (Me), 120.91 (4a-C), 123.50 (5-C), 125.16 (Ph 1-C), 126.25 (6-C), 129.74 (Ph 3,5-C2), 131.62 (Ph 2,6-C2), 132.13 (Ph 4-C), 134.97 (7-C), 135.63 (8-C), 146.92 (8a-C), 150.17 (2-C), 162.44 (4-C); MS m/z 338.9934 (M + Na)+ (C15H 1 8 BrN2NaO requires 338.9967), 336.9953 (M + Na)+ (C15H1 79BrN2NaO requires 336.9952).
2-(4-Fluoropheny!)-8-methylquinazolin-4-one (54f). 2-(4-Fluorobenzamido)-3- methylbenzamide 53f (100 mg, 0.37 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 ml_) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-fluorophenyl)-8-methylquinazolin-4-one 54f (80 mg, 86%) as a white solid: mp >300°C; 1H NMR ((CD3)2SO) δ 2.61 (3 H, s, Me), 7.38- 7.42 (3 H, m, Ph 3,5-H2 + 6-H), 7.69 (1 H, d, J = 7.0 Hz, 7-H), 7.99 (1 H, m, 5-H), 8.30 (2 H, m, Ph 2,6-H2), 12.55 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.14 (Me), 1 15.64 (d, J = 21.8 Hz, Ph 3,5-C2), 120.77 (4a-C), 123.48 (5-C), 126.07 (6-C), 129.44 (Ph 1-C), 130.30 (d, J = 9.0 Hz, Ph 2,6-C2), 134.94 (7-C), 135.55 (8-C), 147.01 (8a-C), 150.09 (2-C), 162.77 (d, J = 248.0 Hz, Ph 4-C), 165.01 (4-C); MS (electron impact) m/z 255.0919 (M)+ (C15H12FN20 requires 255.0933).
8-Methyl-2-{4-trifluoromethylphenyl)quinazolin-4-one (54g). 2-(4-Trifluoromethyl- benzamido)-3-methylbenzamide 53g (100 mg, 0.30 mmol) was heated with aqueous sodium hydroxide (0.5 M, 15 mL) at 60°C for 3.5 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2-(4-trifluoromethyl- phenyl)quinazolin-4-one 54g (71 mg, 78%) as a white solid: mp 258-259°C (lit.81 255- 257°C); 1H NMR ((CD3)2SO) δ 2.69 (3 H, s, Me), 7.44 (1 H, t, J = 7.5 Hz, 6-H), 7.72 (1 H, d, J = 7.5 Hz, 7-H), 7.93 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 8.00 (1 H, d, J = 8.0 Hz, 5- H), 8.41 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.74 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.13 (Me), 123.97 (d, J = 271.3 Hz, CF3), 123.54 (5-C), 125.53 (q, J = 3.6 Hz, Ph 3,5-C2), 126.67 (6-C), 128.67 (Ph 2,6-C2), 131.05 (q, J = 31.8 (Ph 4-C), 135.06 (7-C), 135.85 (8-C), 136.85 (Ph 1-C), 146.82 (8a-C), 149.90 (2-C), 162.41 (4- C).
8- ethyl-2-(4-nitrophenyl)quinazolin-4-one (54h). 2-(4-Nitrobenzamido)-3-methyl- benzamide 53h (100 mg, 0.33 mmol) was heated with aqueous sodium hydroxide (2.5 M, 15 ml_) at 100°C for 16 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methyl-2-(4-nitrophenyl)quinazolin-4-one 54h (90 mg, 97%) as a yellow solid: mp >300°C (lit.81 317-319°C); H N R ((CD3)2SO) δ 2.59 (3 H, s, Me), 7.18 (1 H, t, J = 7.5 Hz, 6-H), 7.47 (1 H, dd, J = 6.5, 0.5 Hz, 7-H), 7.90 (1 H, dd, J = 6.5, 0.5 Hz, 5-H), 8.30 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 8.63 (2 H, d, J = 9.0 Hz, Ph 2,6-Hz); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.34 (Me), 121.56 (4a-C), 123.11 (Ph
3.5- C2), 123.54 (5-C), 123.59 (6-C), 128.83 (Ph 2,6-C2), 132.02 (7-C), 134.31 (8-C), 145.22 (Ph 1-C), 149.35 (8a-C), 152.03 (Ph 4-C), 156.05 (2-C), 169.33 (4-C).
8- ethyI-2-(4-(phenylmethoxycarbonyIaminomethyl)phenyl)quinazolin-4-one (54i). 2-Amino-3-methylbenzamide 5297 (290 g, 1.9 mmol) was stirred with dry pyridine (316 mg, 4.0 mmol) and 4-(phenylmethoxycarbonylaminomethyl)benzoyl chloride (700 mg, 2.3 mmol) in dry tetrahydrofuran (20 mL) under argon for 16 h. The solvent was evaporated. The residue, in ethyl acetate (30 mL) was washed twice with water and twice with with saturated brine. The solution was dried (magnesium sulfate) and the solvent was evaporated to give crude 3-methyl-2-(4-(phenylmethoxycarbonyl- aminomethyl)benzamido)benzamide 53i (480 mg) as a white solid. This material (100 mg, 0.24 mmol) was suspended in aqueous potassium carbonate (1.0 M, 58 mL) and the mixture was stirred vigorously for 16 h at 100°C. The mixture was cooled to room temperature and acidified to pH~1 by addition of aqueous hydrochloric acid (9 M). The precipitate was collected by filtration and dried under vacuum. Chromatography (ethyl acetate / petroleum ether 3:2) gave 8-methyl-2-(4-(phenylmethoxycarbonylamino- methyl)phenyl)quinazolin-4-one 54i (86 mg, 89%) as a white solid: mp 280-283°C; 1H NMR ((CD3)2SO) δ 2.60 (3 H, s, Me), 4.29 (2 H, d, J = 6.5 Hz, Ar 4-CCH2), 5.07 (2 H, s, Cbz-CH2), 7.23-7.39 (8 H, m, 6-H + Ar 3,5-H2 + Ph-H5), 7.59 (1 H, d, J = 7.0 Hz, 7-H), 7.93 (1 H, br, Ar 4-CH2N/-/), 8.22 (2 H, d, J = 8.0 Hz, Ar 2,6-H2), 12.50 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.96 (Me), 44.36 (Ar 4-CCH2), 66.17 (Cbz-CH2), 121.78 (4a-C), 124.22 (5-C), 125.43 (6-C), 127.58 (Ar 3,5-C2), 128.48 (Ar 2,6-C2 + Ph
2.6- C2), 128.53 (Cbz 4-C), 129.09 (Ph 3,5-C2), 134.43 (7-C), 135.64 (8-C), 137.87 (Ar 1 - C + Ph 1-C), 143.10 (Ar 4-C), 148.79 (8a-C), 157.15 (Cbz-CO), 165.60 (4-C); MS m/z 422.1497 (M + Na)+ (C24H21N3Na03 requires 422.1481).
2- Benzamido-3-methoxybenzamide (56a). Dry pyridine (553 mg, 7.0 mmol) was added to 2-amino-3-methoxybenzamide 5597 (1.0 g, 7.0 mmol) in dry tetrahydrofuran (7.0 mL), followed by benzoyl chloride (930 mg, 6.6 mmol) in dry tetrahydrofuran (7.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 1 :1→ 4:1 ) gave 2-benzamido-3-methoxybenzamide 56a (380 mg, 71 %) as a white solid: mp 237-239°C; 1H NMR ((CD3)2SO) δ 2.27 (3 H, s, 3-Me), 2.44 (3 H, s, Ph 4-Me), 7.31 (1 H, t, J = 7.6 Hz, 5-H), 7.39 (2 H, d, J = 7.9 Hz, Ph 3,5-H2), 7.44-7.50 (3 H, m, 4,6-H2 + NHH), 7.75 (1 H, s, NHH), 7.91 (2 H, d, = 7.9 Hz, Ph 2,6- H2), 10.22 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.38 (3-Me), 20.98 (Ph 4-Me), 125.80 (5-C), 125.87 (6-C), 127.51 (Ph 2,6-C2), 129.01 (Ph 3,5-C2), 131.48 (Ph 1-C), 132.17 (4-C), 132.68 (1 -C), 134.65 (2-C), 135.94 (3-C), 141.63 (Ph 4-C), 164.92 (NHCO), 169.77 (CONH2); MS (electron impact) m/z 269.1261 (M)+
(C16H17N202 requires 269.1290).
3- Methoxy-2-(4-methylbenzamido)benzamide (56b). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-methylbenzoyl chloride (360 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate) gave 3-methoxy-2-(4-methylbenzamido)benzamide 56b (479 mg, 80%) as a white solid: mp 219-222°C; 1H NMR ((CD3)2SO) δ 2.08 (3 H, s, Ph 4-Me), 3.77 (3 H, s, OMe), 7.15(1 H, dd, J = 7.5, 1.0 Hz, 6-H), 7.19 (1 H, dd, J = 7.5, 1.0 Hz, 4-H), 7.30-7.33 (3 H, m, Ph 2,6-H2 + 5-H), 7.36 (1 H, s, HH ), 7.50 (1 H, s, NHH), 7.84 (2 H, d, J = 8.5 Hz, Ar 3,5-H2), 9.65 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) 5 21.01 (Ph 4-Me), 55.94 (OMe), 1 13.51 (4-C), 1 19.86 (6-C), 124.39 (2-C), 127.09 (5-C), 127.64 (Ph 2,6-C2), 128.92 (Ph 3,5-C2), 131.46 (Ph 4-C), 134.89 (1 -C), 141.52 (Ph 1-C), 154.97 (3-C), 165.27 (NHCO), 168.92 (CONH2); MS (electron impact) m/z 285.1221 (M)+ (C16H17N203 requires 285.1239).
3- Rflethoxy-2-(4-methoxybenzamido)benzamide (56c). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) and 4- dimethylaminopyridine (52 mg, 0.4 mmol) in dry tetrahydrofuran (5.0 mL), followed by
4- methoxybenzoyl chloride (390 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 3:2) gave 3-methoxy-2-(4-methoxybenzamido)benzamide 56c (540 mg, 81 %) as a white solid: mp 175-179X (lit.81 179-181 °C); 1H NMR ((CD3)2SO) δ 3.77 (3 H, s, 3-OMe), 3.83 (3 H, s, Ph 4-OMe), 7.04 (2 H, dd, J = 7.0 Hz, Ph 3,5-H2), 7.15 (1 H, dd, J = 7.5, 1.0 Hz, 6-H), 7.18 (1 H, dd, J = 7.5, 1.0 Hz, 4-H), 7.31 (1 H, t, J = 7.5 Hz, 5-H), 7.36 (1 H, s, NHH), 7.49 (1 H, s, NHH), 7.92 (2 H, d, J = 7.0 Hz, Ar 2,6-H2), 9.60 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.42 (Ph 4-OMe), 55.93 (3- OCH3), 1 13.47 (4-C), 113.62 (Ph 3,5-C2) 1 19.86 (6-C), 124.50 (2-C), 126.43 (Ph 1-C), 127.01 (5-C), 129.52 (Ph 2,6-C2), 134.90 (1-C), 154.97 (3-C), 161.88 (Ph 4-C), 164.94 (NHCO), 168.96 (CONH2).
2-(4-Chlorobenzamido)-3-methoxybenzamide (56d). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-chlorobenzoyl chloride (410 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate) gave 2-(4-chlorobenzamido)-3-methoxybenzamide 56d (536 mg, 83%) as a white solid: mp 220-223°C; 1H NMR ((CD3)2SO) δ 3.78 (3 H, s, Me), 7.15 (1 H, dd, J = 8.0, 1.5 Hz, 6-H), 7.20 (1 H, dd, J = 8.0, 1.5 Hz, 4-H), 7.31-7.34 (2 H, m, NHH + 5-H), 7.52 (1 H, s, NHH), 7.59 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.96 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 9.79 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.95 (Me), 113.48 (4-C), 1 19.84 (6-C), 124.03 (2-C), 127.29 (5-C), 128.48 (Ph 3,5-C2), 129.57 (Ph 3,5-C2), 133.08 (Ph 1-C), , 135.08 (1-C), 136.35 (Ph 4-C), 154.96 (3-C), 164.39 (NHCO), 168.83 (CONH2); MS (electron impact) m/z 305.0677 (M)+
(C15H14 35CIN203 requires 305.0692).
2-(4-Bromobenzamido)-3-methoxybenzamide (56e). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-bromobenzoyl chloride (510 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 3:2) gave 2-(4-bromobenzamido)-3- methoxybenzamide 56e (600 mg, 82%) as a white solid: mp 221-224°C; 1H NMR ((CD3)2SO) δ 3.77 (3 H, s, Me), 7.14 (1 H, dd, J = 8.0, 1.0 Hz, 6-H), 7.20 (1 H, dd, J = 8.5, 1.0 Hz, 4-H), 7.31-7.34 (2 H, m, 5-H + NHH), 7.52 (1 H, s, NHH), 7.73 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.88 (2 H, d, J = 9.0 Hz, Ph 2,6-H2), 9.79 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.95 (Me), 1 13.48 (4-C), 1 19.83 (6-C), 124.02 (2-C), 125.28 (Ph 4-C), 127.29 (5-C), 129.76 (Ph 3,5-C2), 131.41 (Ph 2,6-C2), 133.45 (Ph 1- C), 135.07 (1-C), 154.93 (3-C), 164.52 (NHCO), 168.82 (CONH2). MS m/z 372.9988 (M + Na)+ (C15H14 8 BrN2Na03 requires 372.9992), 371.0012 (M + Na)+ (C15H14 79Br 2Na03 requires 371.0007).
2- (4-Fluorobenzamido)-3-methoxybenzamide (56f). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-fluorobenzoyl chloride (368 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and
chromatography (ethyl acetate) gave 2-(4-fluorobenzamido)-3-methoxybenzamide 56f (540 mg, 88%) as a white solid: mp 210-213°C; 1H NMR ((CD3)2SO) δ 3.77 (3 H, s, Me), 7.15 (1 H, dd, J = 8.0, 1.5 Hz, 6-H), 7.20 (1 H, dd, J = 8.0, 1.5 Hz, 4-H), 7.31 -7.36 (4 H, m, Ph 3,5-H2 + NHH + 5-H), 7.51 (1 H, s, NHH), 8.02 (2 H, m, Ph 2,6-H2), 9.74 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.93 (Me), 1 13.45 (4-C), 1 15.31 (d, J = 21.3 Hz, Ph 3,5-C2), 1 19.82 (6-C), 124.12 (2-C), 127.24 (5-C), 130.31 (Ph 2,6- C2), 130.76 (Ph 1-C), 135.09 (1-C), 154.97 (3-C), 164.05 (d, J = 247.3 Hz, Ph 4-C), 164.37 (NHCO), 168.85 (CONH2); MS (electron impact) m/z 289.0962 (M)+
(C15H14FN203 requires 289.0988).
3- IWethoxy-2-(4-trifluoromethylbenzamido)benzamide (56g). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-trifluoromethylbenzoyl chloride (480 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 4:1) gave 3-methoxy-2-(4- trifluoromethylbenzamido)benzamide 56g (590 mg, 83%) as a white solid: mp 191- 193°C; 1H NMR ((CD3)2SO) δ 3.78 (3 H, s, Me), 7.16 (1 H, dd, J = 7.5, 1.0 Hz, 6-H), 7.20 (1 H, dd, J = 7.5, 1.0 Hz, 4-H), 7.33-7.36 (2 H, m, NHH + 5-H), 7.54 (1 H, s, NHH), 7.90 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 8.13 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 9.94 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.97 (Me), 1 13.50 (4-C), 119.85 (6-C), 123.83 (2-C), 123.95 (q, J = 270.7 Hz, CF3), 125.41 (q, J = 3.6 Hz, Ph 3,5-C2), 127.44 (5-C), 128.54 (Ph 2,6-C2), 131.35 (q, J = 31.8 Hz, Ph 4-C), 135.14 (1-C), 138.16 (Ar 1- C), 154.96 (3-C), 164.31 (NHCO), 168.77 (CONH2); MS (electron impact) m/z
339.0956 (M)+ (C16H14F3N203 requires 339.0957).
3-Methoxy-2-(4-nitrobenzamido)benzamide (56h). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 5597 (350 mg, 2.1 mmol) in dry tetrahydrofuran (5.0 mL), followed by 4-nitrobenzoyl chloride (430 mg, 2.3 mmol) in dry tetrahydrofuran (5.0 mL). The mixture was stirred for 16 h. Evaporation and chromatography (ethyl acetate / petroleum ether 3:2) gave 3-methoxy-2-(4-nitro- benzamido)benzamide 56h (530 mg, 80%) as a yellow solid: mp 280-283°C (lit.81 289- 290°C); 1H NMR ((CD3)2SO) δ 3.78 (3 H, s, Me), 7.16 (1 H, dd, J = 8.0, 1.5 Hz, 6-H), 7.21 (1 H, dd, J = 8.5, 1.5 Hz, 4-H), 7.33-7.36 (2 H, m, 5-H + NHH), 7.57 (1 H, s, NHH), 8.16 (2 H, d, J = 7.0 Hz, Ph 2,6-H2), 8.35 (2 H, m, Ar 3,5-H2), 10.04 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.97 (Me), 1 13.51 (4-C), 1 19.84 (6-C), 123.59 (Ph 2,6-C2), 123.70 (2-C), 127.53 (5-C), 129.13 (Ph 3,5-C2), 135.14 (1-C), 140.08 (Ph 1-C), 149.14 (Ph 4-C), 154.94 (3-C), 163.88 (NHCO), 168.75 (CONH2).
8- ethoxy-2-phenylquinazolin-4-one (57a). 3-Methoxy-2-benzamido-3-methoxy- benzamide 56a (1.27 g, 4.7 mmol) was heated with aqueous sodium hydroxide (0.5 M, 75 ml_) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methoxy-2-phenylquinazolin-4-one 57a (1.00 g, 84%) as a white solid: mp 258-261 °C (lit.81 252-256°C); H NMR ((CD3)2SO) δ 3.94 (1 H, s, Me), 7.46 (1 H, t, J = 8.0 Hz, 7-H), 7.53-7.58 (3 H, m, Ph 3,4,5-H3), 7.70 (1 H, dd, J = 7.5, 1.0 Hz, 5-H), 8.18 (2 H, dt, J = 8.0, 1.5 Hz, Ph 2,6-H2), 12.55 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 56.04 (Me), 115.19 (7-C), 116.87 (5-C), 122.02 (4a-C), 126.86 (6-C), 127.73 (Ph 2,6-C2), 128.56 (Ph 3,5-C2), 131.20 (Ph 4-C), 132.94 (Ph 1-C), 150.90 (2-C), 154.71 (8-C), 162.17 (4-C).
8-Methoxy-2-(4-methylphenyl)quinazolin-4-one (57b). 3-Methoxy-2-(4-methyl- benzamido)benzamide 56b (334 mg, 1.2 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methoxy-2-(4-methylphenyl)quinazolin-4-one 57b (280 mg, 90%) as a white solid: mp 242-245°C (lit.82 248-249°C); 1H NMR ((CD3)2SO) δ 2.93 (3 H, s, Ph-Me), 3.94 (3 H, s, OMe), 7.34-7.37 (3 H, m, Ph 3,5-H2 + 6-H), 7.42 (1 H, t, J = 8.0 Hz, 7-H), 7.70 (1 H, dd, J = 8.0, 1 ,0 Hz, 5-H), 8.10 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.47 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.98 (Ph-Me), 56.02 (OMe), 1 15.13 (7-C), 116.86 (5-C), 121.92 (4a-C), 126.64 (6-C), 127.64 (Ph 2,6- C2), 129.14 (Ph 3,5-C2), 130.1 1 (Ph 1-C), 139.37 (8a-C), 141.23 (Ph 4-C), 150.80 (2- C), 154.65 (8-C), 162.17 (4-C). 8-Methoxy-2-(4-methoxyphenyl)quinazolin-4-one (57c). 3-Methoxy-2-(4-methoxy- benzamido)benzamide 56c (378 mg, 1.3 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methoxy-2-(4-methoxyphenyl)quinazolin-4-one 57c (272 mg, 77%) as a white solid: mp 230-232°C (lit.81 226-228°C); 1H NMR ((CD3)2SO) δ 3.84 (3 H, s, Ph-OMe), 3.94 (8-OMe), 7.09 (2 H, m, Ph 3,5-H2), 7.35 (1 H, dd, J = 8.0, 1.0 Hz, 7-H), 7.40 (1 H, t, J = 8.0 Hz, 6-H), 7.68 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 8.18 (2 H, m, Ph 2,6-H2), 12.41 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.45 (Ph-OMe), 1 13.96 (Ph 3,5-C2), 1 15.1 1 (7-C), 1 16.88 (5-C), 121.69 (4a-C), 125.09 (Ph
1 - C), 126.34 (6-C), 129.40 (Ph 2,6-C2), 139.10 (8a-C), 150.50 (2-C), 154.54 (8-C), 161.74 (Ph 4-C), 162.25 (4-C).
2- (4-Chlorophenyl)-8-methoxyquinazolin-4-one (57d). 2-(4-Chlorobenzamido)-3- methoxybenzamide 56d (409 mg, 1.3 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-chlorophenyl)-8-methoxyquinazolin-4-one 57d (330 mg, 87%) as a white solid: mp 297-299°C; 1H NMR ((CD3)2SO) δ 3.94 (3H, s, Me), 7.39 (1 H, dd, J = 8.0, 1.0 Hz, 7-H), 7.45 (1 H, t, J = 8.0 Hz, 6-H), 7.63 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.70 (1 H, dd, J = 7.5, 1.0 Hz, 5-H), 8.20 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.59 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 56.03 (Me), 115.21 (7-C), 1 16.86 (5-C), 122.04 (4a-C), 127.06 (6-C), 128.64 (Ph 3,5-C2), 129.55 (Ph 2,6-C2), 131.77 (Ph 1-C), 136.08 (Ph 4-C), 149.90 (2-C), 154.70 (8-C), 162.1 1 (4-C); MS m/z 31 1.0371 (M + Na)+ (C^H^CINzNaOa requires 3 1.0407), 309.0391 (M + Na)+ (C15H11 35CIN2Na02 requires 309.0407], 287.0569 (M)+ (C15H12 35CIN202 requires
287.0587).
2-(4-Bromophenyl)-8-methoxyquinazolin-4-one (57e). 2-(4-Bromobenzamido)-3- methoxybenzamide 56e (463 mg, 1.3 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-bromophenyl)-8-methoxyquinazolin-4-one 57e (400 mg, 92%) as a white solid: mp >300°C; 1H NMR ((CD3)2S0) δ 3.94 (3 H, s, Me), 7.39 (1 H, d, J = 8.0 Hz, 7-H), 7.45 (1 H, t, J = 8.0 Hz, 6-H), 7.70 (1 H, d, J = 8.0 Hz, 5- H), 7.77 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 8.12 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 12.61 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 56.03 (Me), 1 15.23 (7-C), 1 16.86 (5-C), 122.06 (4a-C), 125.03 (Ph 1-C), 127.09 (6-C), 129.74 (Ph 2,6-C2), 131.58 (Ph 3,5-C2), 132.12 (Ph 4-C), 139.09 (8a-C), 150.00 (2-C), 154.71 (8-C), 162.09 (4-C); MS (electron impact) m/z 333.0040 (M)+ (C15H12 81BrN202 requires 333.0040), 331.0053 (M)+ (C15H12 79BrN202 requires 331.0082).
2-(4-Fluorophenyl)-8-methoxyquinazolin-4-one (57f). 2-(4-Fluorobenzamido)-3- methoxybenzamide 56f (400 mg, 1.4 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4-fluorophenyl)-8-methoxyquinazolin-4-one 57f (296 mg, 79%) as a white solid: mp >300°C; 1H NMR ((CD3)2SO) δ 3.94 (3 H, s, Me), 7.37-7.41 (3 H, m, Ph 3,5-H2 +7-H), 7.44 (1 H, t, J = 8.0 Hz, 6-H), 7.70 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.24 (2 H, m, Ph 2,6-H2), 12.56 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 56.03 (Me), 115.19 (7-C), 1 15.58 (d, J = 21.8 Hz, Ph 3,5-H2), 116.85 (5-C), 121.91 (4a-C), 126.87 (6-C), 129.46 (d, J = 2.6 Hz, Ph 1-C), 130.30 (d, J = 9.0 Hz, Ph 2,6-H2), 139.17 (8a-C), 149.98 (2-C), 154.66 (8-C), 162.55 (d, J = 247.5 Hz, Ph 4-F), 164.92 (4-C); MS (electron impact) m/z 271.0895 (M)+ C15H12FN202 requires 271.0883).
8-Methoxy-2-(4-trifluoromethylphenyl)quinazolin-4-one (57g). 3-Methoxy-2-(4- trifluoromethylbenzamido)benzamide 56g (490 mg, 1.5 mmol) was heated with aqueous sodium hydroxide (0.5 M, 80 mL) at 60°C for 6 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methoxy-2-(4-trifluoromethylphenyl)- quinazolin-4-one 57g (200 mg, 42%) as a white solid: mp 283-286°C (lit.81 287-289°C); 1H NMR ((CD3)2SO) δ 3.95 (3 H, s, Me), 7.41 (1 H, dd, J = 8.0, 1.0 Hz, 7-H), 7.49 (1 H, t, J = 8.0 Hz, 6-H), 7.72 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 7.93 (2 H, d, J = 8.5 Hz, Ph 2,6- H2), 8.37 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 12.76 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 56.06 (Me), 1 15.31 (7-C), 1 16.87 (5-C), 122.27 (4a-C), 123.99 (q, J = 270.9 Hz, CF3), 125.49 (q, J = 3.6 Hz, Ph 3,5-C2), 127.47 (6-C), 128.65 (Ph 2,6-C2), 130.93 (q, J = 31.7 Hz, Ph 4-C), 136.80 (2-C), 138.92 (8a-C), 149.69 (Ph 1 -C), 154.84 (8-C), 162.04 (4-C). 8-Methoxy-2-(4-nitrophenyl)quinazolin-4-one (57h). 3-Methoxy-2-(4-nitro- benzamido)benzamide 56h (394 mg, 1.3 mmol) was heated with aqueous sodium hydroxide (2.5 M, 80 mL) at 100°C for 16 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 ) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-methoxy-2-(4-nitrophenyl)quinazolin-4-one 57h (256 mg, 69%) as a yellow solid: mp >300°C (lit.81 306-308°C); 1H NMR ((CD3)2SO) δ 3.97 (3 H, s, Me), 7.42 (1 H, d, J = 8.0 Hz, 7-H), 7.50 (1 H, t, J = 8.0 Hz, 6-H), 7.73 (1 H, d, J = 8.0 Hz, 5-H), 8.37 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 8.43 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.72 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 56.06 (Me), 1 15.40 (7-C), 1 16.80 (5-C), 122.21 (4a-C), 123.39 (Ph 2,6-C2), 127.49 (6-C), 129.02 (Ph 3,5-C2), 138.66 (Ph 4-C), 138.77 (8a-C), 148.77 (Ph 1 -C), 149.09 (2-C), 154.83 (8- C), 161.77 (4-C).
8-Hydroxy-2-phenylquinazolin-4-one (58a). 8-Methoxy-2-phenylquinazolin-4-one 57a (500 mg, 2.0 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 6.0 mL) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 100 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-hydroxy-2-phenylquinazolin-4-one 58a (350 mg, 75%) as a white solid: mp 275-278°C (lit.81 280-284X); 1H NMR ((CD3)2SO) δ 7.28 (1 H, dd, J =7.8, 1.4 Hz, 7-H), 7.39 (1 H, t, J = 7.8 Hz, 6-H), 7.57-7.65 (4 H, m, Ph 3,4,5-Hs +5-H), 8.46 (2 H, d, J = 8.6 Hz, Ph 2,6-H2), 9.61 (1 H, s, OH), 12.49 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.65 (5-C), 1 18.32 (7-C), 121.70 (4a- C), 127.09 (6-C), 127.96 (Ph 2,6-C2), 128.42 (Ph 3,5-C2), 131.26 (Ph 4-C), 132.51 (Ph 1-C), 137.63 (8a-C), 150.37 (2-C), 152.96 (8-C), 162.23 (4-C).
8-Hydroxy-2-(4-methylphenyl)quinazolin-4-one (58b). 8-Methoxy-2-(4-methyl- phenyl)quinazolin-4-one 57b (100 mg, 0.4 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.5 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-hydroxy-2-(4- methylphenyl)quinazolin-4-one 58b (89 mg, 94%) as a white solid: mp 270-290°C (decomposition); H NMR ((CD3)2SO) δ 2.39 (3 H, s, Me), 7.20 (1 H, dd, J = 7.5, 1.5 Hz, 7-H), 7.30-7.35 (3 H, m, Ph 3,5-H2 + 6-H), 7.56 (1 H, dd, J = 7.5, 1.5 Hz, 5-H), 8.33 (2H, d, J = 8.0, Ph 2,6-H2), 9.54 (1 H, s, OH), 12.38 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.99 (Me), 115.64 (5-C), 1 18.24 (7-C), 121.58 (4a-C), 126.87 (6- C), 127.91 (Ph 2,6-C2), 129.04 (Ph 3,5-C2), 129.63 (Ph 1-C), 137.70 (8a-C), 141.33 (Ph 4-C), 150.33 (8-C), 152.86 (2-C), 162.25 (4-C); MS (electron impact) m/z 253.0953 (M)+ (C15H13N202 requires 253.0977).
8-Hydroxy-2-{4-hydroxyphenyl)quinazolin-4-one (58c). 8-Methoxy-2-(4-methoxy- phenyl)quinazolin-4-one 57c (100 mg, 0.35 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.4 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-hydroxy-2-(4- hydroxyphenyl)quinazolin-4-one 58c (76 mg, 86%) as a white solid: mp 280-284°C (lit.81 288-290°C); 1H NMR ((CD3)2SO) δ 6.87 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.19 (1 H, dd, J = 8.0, 1.5 Hz, 7-H), 7.27 (1 H, t, J = 8.0 Hz, 6-H), 7.54 (1 H, dd, J = 8.0, 1.5 Hz, 5- H), 8.30 (2 H, s, J = 9.0 Hz, Ph 2,6-H2), 9.41 (1 H, s, 8-OH), 10.1 1 (1 H, s, PhOH), 12.23 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.16 (Ph 3,5-C2), 1 15.61 (5-C), 1 18.00 (7-C), 121.18 (4a-C), 123.08 (Ph 1-C), 121.34 (6-C), 129.87 (Ph 2,6-C2), 137.94 (8a-C), 150.38 (2-C), 152.63 (8-C), 160.47 (Ph 4-C), 162.31 (4-C).
2-(4-ChlorophenyI)-8-hydroxyquinazolin-4-one (58d). 2-(4-Chlorophenyl)-8- methoxyquinazolin-4-one 57d (100 mg, 0.35 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.4 ml_) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4- chlorophenyl)-8-hydroxyquinazolin-4-one 58d (85 mg, 89%) as a white solid: mp 260- 263°C; 1H NMR ((CD3)2SO) δ 7.23 (1 H, dd, J = 7.5, 1.0 Hz, 7-H), 7.34 (1 H, t, J = 8.0 Hz, 6-H), 7.57 (1 H, dd, J = 7.5, 1.0 Hz, 5-H), 7.62 (2 H, d, J = 7.0 Hz, Ph 3,5-H2), 8.45 (2 H, d, J= 7.0 Hz, Ph 2,6-H2), 9.66 (1 H, s, OH), 12.52 (1 H, s, NH); 13C NMR
((CD3)2SO) (HSQC / HMBC) δ 1 15.67 (5-C), 118.47 (7-C), 121.74 (4a-C), 127.33 (6-C), 128.51 (Ph 3,5-C2), 129.84 (Ph 2,6-C), 131.36 (Ph 1-C), 136.24 (Ph 4-C), 137.45 (8a- C), 149.31 (2-C), 153.05 (8-C), 162.20 (4-C); MS m/z 297.0227 (M + Na)+
(C14H9 37CIN2Na02 requires 297.0250), 295.0218 (M + Na)+ (C14H9 35CIN2Na02 requires 295.0250). 2-(4-BromophenyI)-8-hydroxyquinazolin-4-one (58e). 2-(4-Bromophenyl)-8- methoxyquinazolin-4-one 57e (100 mg, 0.30 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.2 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4- bromophenyl)-8-hydroxyquinazolin-4-one 58e (87 mg, 90%) as a white solid: mp >300°C; H NMR ((CD3)2SO) δ 7.23 (1 H, dd, J = 8.0, 1.5 Hz, 7-H), 7.35 (1 H, t, J = 8.0 Hz, 6-H); 7.57 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 7.75 (2 H, d, J = 8.5 Hz, Ph 3,5-H2); 8.37 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 9.66 (1 H, s, OH), 12.51 (1 H, s, NH); 3C NMR
((CD3)2SO) (HSQC / HMBC) δ 1 15.67 (5-C), 1 18.48 (7-C), 121.75 (4a-C), 125.21 (Ph 4-C), 127.34 (6-C), 130.03 (Ph 2,6-C2), 131.44 (Ph 3,5-C2), 131.73 (Ph 1-C), 137.44 (8a-C), 149.43 (2-C), 153.06 (8-C), 162.19 (4-C); MS m/z 340.9756 (M + Na)+
(C14H9 81BrN2Na02 requires 340.8908), 338.9745 (M + Na)+ (C14H9 79BrN2Na02 requires 338.9745).
2-(4-Fluorophenyl)-8-hydroxyquinazolin-4-one (58f). 2-(4-Fluorophenyl)-8-methoxy- quinazolin-4-one 57f (100 mg, 0.37 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.5 mL) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 2-(4- fluorophenyl)-8-hydroxyquinazolin-4-one 58f (93 mg, 99%) as a white solid: mp 296- 298°C; 1H NMR ((CD3)2SO) δ 7.22 (1 H, dd, J = 8.0, 1.5 Hz, 7-H), 7.33 (1 H, t, J = 8.0 Hz, 6-H), 7.38 (2 H, m, Ph 3,5-H2), 7.57 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.50 (2 H, m, Ph 2,6-H2), 9.62 (1 H, s, OH), 12.49 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.45 (d, J = 21.8 Hz, Ph 3,5-C2), 1 15.64 (5-C), 1 18.39 (7-C), 121.58 (4a- C), 127.13 (6-C), 129.02 (Ph 1-C), 130.63 (d, J = 9.0 Hz, Ph 2,6-C2), 137.53 (8a-C), 149.40 (2-C), 152.97 (8-C), 162.24 (4-C), 164.08 (d, J - 247.6 Hz, Ph 4-C); MS (electron impact) m/z 257.0703 (M)+ (C14H10FN2O2 requires 257.0726).
8-Hydroxy-2-(4-trifluoromethylphenyl)quinazolin-4-one (58g). 8-Methoxy-2-(4- trifluoromethylphenyl)quinazolin-4-one 57g (76 mg, 0.24 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.9 mL) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 20 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-hydroxy- 2-(4-trifluoromethylphenyl)quinazolin-4-one 58g (64 mg, 88%) as a white solid: mp 296-298°C (lit.81 303-306°C); 1H NMR ((CD3)2SO) δ 7.26 (1 H, dd, J = 8.0, 1.5 Hz, 7-H), 7.38 (1 H, t, J = 8.0, 1.5 Hz, 6-H), 7.60 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 7.91 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 8.61 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 9.76 (1 H, s, OH), 12.66 (1 H, s, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.69 (5-C), 118.64 (7-C), 121.99 (4a-C), 124.02 (q, J = 270.8, CF3), 125.32 (q, J = 3.6 Hz, Ph 3,5-C2), 127.72 (6-C), 128.85 (Ph 2,6-C2), 130.99 (q, J = 31.8 Hz, Ph 4-C), 136.42 (Ph 1-C), 137.32 (8a-C), 149.04 (2-C), 153.25 (8-C), 162.15 (4-C).
8-Hydroxy-2-(4-nitrophenyl)quinazolin-4-one (58h). 8-Methoxy-2-(4-nitrophenyl)- quinazolin-4-one 57 h (100 mg, 0.34 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 1.3 ml_) for 16 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 15 ml_) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The precipitate was collected by filtration, washed (water) and dried to give 8-hydroxy-2-(4- nitrophenyl)quinazolin-4-one 58h (65 mg, 68%) as a white solid: mp >300°C (lit.81 321- 323°C); 1H NMR ((CD3)2SO) δ 7.26 (1 H, dd, J = 8.0, 1.5 Hz, 7-H), 7.39 (1 H, t, J = 8.0 Hz, 6-H), 7.60 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.36 (2 H, m, Ph 3,5-H2), 8.66 (2 H, m, Ph 2,6-H2), 9.83 (1 H, s, OH), 12.72 ( 1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.71 (5-C), 1 18.74 (7-C), 122.04 (4a-C), 123.44 (Ph 3,5-C2), 128.01 (6-C), 129.38 (Ph 2,6-C2), 137.22 (8a-C), 138.38 (Ph 4-C), 148.51 (Ph 1-C), 148.91 (2-C), 153.38 (8-C), 162.09 (4-C).
2-(4-Aminophenyl)quinazolin-4-one (59a). 2-(4-Nitrophenyl)quinazolin-4-one 51j (75 mg, 0.28 mmol), in methanol (6 ml_) and dimethylformamide (6 ml_), was stirred with palladium on charcoal (10%, 10 mg) and ammonium formate (170 mg, 2.7 mmol) under argon for 3 h. The mixture was filtered through a pad of Celite. Evaporation and chromatography (ethyl acetate / petroleum ether 4:1 ) gave 2-(4-aminophenyl)- quinazolin-4-one 59a (42 mg, 63%) as a white solid: mp 288-290°C (lit.83 mp 277- 279°C); 1H NMR((CD3)2SO) δ 5.84 (2 H, s, NH2), 6.63 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.40 (1 H, m, 6-H), 7.61 (1 H, d, J = 8.0 Hz, 8-H), 7.76 (1 H, m, 7-H), 7.96 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.08 (1 H, dd, J = 7.5, 1.0 Hz, 5-H), 12.06 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 3.02 (Ph 3,5-C2), 1 18.74 (Ph 1-C), 120.30 (4a-C), 125.25 (6-C), 125.76 (5-C), 126.91 (8-C), 129.10 (Ph 2,6-C2), 134.37 (7-C), 149.39 (8a- C), 152.14 (Ph 4-C), 152.40 (2-C), 162.36 (4-C).
2-(4-Aminophenyl)-8-methylquinazolin-4-one (59b). Compound 53 h (74 mg, 0.26 mmol) was stirred with palladium on charcoal (10%, 10 mg) and ammonium formate (170 mg, 2.6 mmol) in methanol (6 mL) and dimethylformamide (6 mL) under argon for 3 h. The mixture was filtered through Celite. Evaporation and chromatography (ethyl acetate) gave 2-(4-aminophenyl)-8-methylquinazolin-4-one 59b (41 mg, 62%) as a white solid: mp 256-258°C (lit.81 254-256°C); H NMR ((CD3)2SO) δ 2.57 (3 H, s, Me), 5.82 (2 H, s, NH2), 6.64 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.28 (1 H, t, J = 7.5 Hz, 6-H), 7.62 (1 H, d, J = 7.0 Hz, 7-H), 7.92 (1 H, dd, J = 7.0, 0.5 Hz, 5-H), 8.00 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 12.05 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.20 (Me), 113.03 (Ph 3,5-C2), 1 19.09 (Ph 1-C), 120.13 (4a-C), 123.41 (5-C), 124.69 (6-C), 129.08 (Ph 2,6-C), 134.61 (7-C), 134.86 (8-C), 147.74 (8a-C), 151.22 (2-C), 152.03 (Ph 4-C), 162.68 (4-C).
2-(4-Aminophenyl)-8-methoxyquinazolin-4-one (59c). 8-Methoxy-2-(4-nitrophenyl)- quinazolin-4-one 57h (100 mg, 0.34 mmol) was stirred with palladium on charcoal (10%, 100 mg) and ammonium formate (212 mg, 3.4 mmol) in methanol (6 mL) and dimethylformamide (6 mL) under argon for 3 h. The mixture was filtered through Celite®. Evaporation and chromatography (ethyl acetate / petroleum ether 4:1 ) gave 2- (4-aminophenyl)-8-methoxyquinazolin-4-one 59c (65 mg, 83%) as a white solid: mp 271 -274°C (lit.81 263-265°C); 1H NMR ((CD3)2SO) δ 3.92 (3 H, s, Me), 5.80 (2 H, s, NH2), 6.63 (2 H, dt, J = 8.5, 2.5 Hz, Ar 3,5-H2), 7.29-7.34 (2 H, m, 6-H + 7-H), 7.64 (1 H, dd, J = 7.5, 2.0 Hz, 5-H), 7.95 (2 H, dt, J = 9.5, 2.5 Hz, Ar 2,6-H2 ), 12.09 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 55.97 (OMe), 1 3.01 (Ar 3,5-C2), 1 14.91 (7-C), 1 16.91 (5-C), 1 19.11 (Ar 1-C), 121.28 (4a-C), 125.38 (6-C), 129.07 (Ar 2,6-C2), 140.05 (8a-C), 151.1 1 (Ar 4-C), 151.98 (2-C), 154.32 (8-C), 162.30 (4-C).
2-(4-Aminophenyl)-8-hydroxyquinazolin-4-one (59d). 8-Hydroxy-2-(4-nitrophenyl)- quinazolin-4-one 58h (35 mg, 0.12 mmol) was stirred with palladium on charcoal (10%, 5 mg) and ammonium formate (78 mg, 1 .24 mmol) in methanol (3.0 mL) and dimethylformamide (3.0 mL) under argon for 3 h. The mixture was filtered (Celite). Evaporation and chromatography (ethyl acetate) gave 2-(4-aminophenyl)-8-hydroxy- quinazolin-4-one 59d (18 mg, 58%) as a white solid: mp 277-279°C (lit.81 274-276°C); 1H NMR ((CD3)2SO) δ 5.80 (2 H, s, NH2), 6.62 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.15 (1 H, dd, J = 8.0, 1.5 Hz, 7-H), 7.22 (1 H, t, J = 8.0 Hz, 6-H), 7.50 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.16 (2 H, d, J = 8.0, Ph 2,6-H2), 9.25 (1 H, s, OH), 1 1.99 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 112.90 (Ph 3,5-C2), 1 15.60 (5-C), 117.66 (7-C), 1 18.71 (Ph 1-C), 120.98 (4a-C), 125.63 (6-C), 129.45 (Ph 2,6-C2), 138.05 (8a-C), 150.89 (2- C), 152.06 (Ph 4-C), 152.33 (8-C), 162.04 (4-C).
2-(4-HydroxyphenyI)quinazolin-4-one (60a). 2-(4-Methoxyphenyl)quinazolin-4-one 51c (467 mg, 1.9 mmol) was boiled under reflux with boron tribromide in dichloro- methane (1.0 M, 1 1 ml_) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 100 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to give 2-(4-hydroxyphenyl)quinazolin-4-one 60a (420 g, 95%) as a white solid: mp 258-261 °C (lit.84 262-264°C); 1H NMR ((CD3)2SO) δ 6.88 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.46 (1 H, m, 6-H), 7.67 (1 H, d, J = 8.0 Hz, 8-H), 7.80 (1 H, m, 7-H), 8.08 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.12 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 10.15 (1 H, s, OH), 12.30 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 1 15.34 (Ph 3,5-C2), 120.57 (4a-C), 123.19 (Ph 1-C), 125.79 (5-C), 125.91 (6-C), 127.18 (8-C), 129.56 (Ph 2,6-C2), 134.50 (7-C), 149.04 (8a-C), 152.11 (2-C), 160.53 (Ph 4-C), 162.30 (4-C).
2-(4-Hydroxyphenyl)-8-methylquinazolin-4-one (60b). 2-(4-Methoxyphenyl)-8- methylquinazolin-4-one 54c (25 mg, 0.094 mmol) was boiled under reflux with boron tribromide in dichloromethane (1.0 M, 0.56 mL) for 3 h. The solvent was evaporated. The residue was stirred with aqueous sodium hydroxide (2.5 M, 10 mL) for 3 h. The mixture was acidified by addition of aqueous hydrochloric acid (9 M) to pH 2. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to give 2-(4-hydroxyphenyl)-8- methylquinazolin-4-one 60b (20 g, 83%) as a white solid: mp 262-265°C (lit.81 258- 261°C); 1H NMR ((CD3)2SO) δ 2.60 (3 H, s, Me), 6.90 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.34 (1 H, t, J = 7.5 Hz, 6-H), 7.66 (1 H, d, J = 7.0 Hz, 7-H), 7.95 (1 H, d, J = 7.5 Hz, 5- H), 8.13 (2 H, d, J = 9.0 Hz, Ph 2,6-H2), 12.28 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.89 (Me), 116.06 (Ph 3,5-C2), 121.16 (4a-C), 124.16 (5-C), 124.20 (Ph 1-C), 126.07 (6-C), 130.24 (Ph 2,6-C2), 135.48 (7-C), 135.92 (8-C), 148.13 (8a-C), 151.59 (2-C), 161.21 (Ph 4-C), 163.34 (4-C). 2-(4-Aminomethylphenyl)-8-methylquinazolin-4-one hydrobromide (61). 8-Methyl- 2-(4-(phenylmethoxycarbonylaminomethyl)phenyl)quinazolin-4-one 54i (200 mg, 0.62 mmol) was treated with hydrogen bromide in acetic acid (33%, 1.5 mL) for 16 h.
Evaporation gave 2-(4-aminomethylphenyl)-8-methylquinazolin-4-one hydrobromide 61 (190 mg, 93%) as a white solid: mp>300°C; H NMR ((CD3)2SO / CD3OD 1 :1) 5 2.69 (3 H, s, Me), 4.14 (2 H, m, CH2), 7.41 (1 H, t, J = 7.5 Hz, 6-H), 7.64 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.71 (1 H, d, J = 7.5 Hz, 7-H), 8.06 (1 H, d, J = 7.5 Hz, 5-H), 8.26 (2 H, d, J = 8.0 Hz, Ar 2.6-H2), 8.28 (br, NH3), 12.59 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 17.16 (Me), 41.89 (CH2), 120.92 (4a-C), 123.52 (5-C), 126.25 (6-C), 127.93 (Ph 2,6-Cz), 129.00 (Ph 3,5-C2), 130.35 (Ph 1-C), 135.01 (7-C), 135.64 (8-C), 137.00 (Ph 4-C), 147.00 (8a-C), 150.08 (2-C), 162.04 (4-C); MS m/z 288.1 101 (M + Na)+ (Ci6H15N3NaO requires 288.1 113).
7-(4-Methoxyphenyl)-1-methyl-1 ,2,3)4-tetrahydro-1,6-naphthyridin-5-one (33b). To
1-methyl-7-(4-methoxyphenyl)-5-oxo-5,6-1 ,6-naphthyridin-1-ium iodide 32b (50 mg, 0.127 mmol) in formic acid (5.0 mL) at 0°C was added dropwise borane. pyridine complex (0.10 mL). The mixture was stirred for 5 d. Each day, additional
borane. pyridine complex (0.01 mL) was added. The the solvent was evaporated. The residue was dissolved in acetic acid (2.0 mL) and the solution was diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 x 15 mL). The solvent was evaporated from the combined organic layers. The residue was recrystallised from water (5 mL) to give 7-(4-methoxyphenyl)-1 -methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin- 5-one 33b (1.0 mg, 3%) as a white powder: mp 221 -223°C; 1H NMR (CDCI3) δ 1 .93 (2 H, qn, J = 6.2 Hz, 3-H2), 2.61 (2 H, t, J = 6.4 Hz, 4-H2), 3.02 (3 H, s, NMe), 3.28 (2 H, t, J = 5.4 Hz, 2-H2), 3.85 (3 H, s, OMe), 5.98 (1 H, s, 8-H), 6.96 (2 H, d, J = 8.9 Hz, Ph 3,5-H2), 7.47 (2 H, d, J = 8.9 Hz, Ph 2,6-H2); 13C NMR (CDCI3) (HSQC / HMBC) δ 20.60 (4-C), 20.83 (3-C), 38.81 (NMe), 50.79 (2-C), 55.44 (OMe), 94.01 (8-C), 100.49 (4a-C), 1 4.62 (Ph 3,5-C2), 126.95 (Ph 1-C), 127.18 (Ph 2,6-C2), 142.51 (Ph 4-C), 153.33 (8a- C), 160.67 (7-C), 162.28 (5-C); MS (ESI) m/z 293.1259 (M + Na) (C16H18N2Na02 requires 293.1266), 271.1452 (M + H) (C16H19N202 requires 271.1447).
1 -Methyl-5-oxo-7-(4-trifluoromethylphenyl)-5,6-dihydro-1 ,6-naphthyridin-1 -ium iodide (32e). lodomethane (90 mg, 0.63 mmol) was stirred with 7-(4- trifluoromethylphenyl)-1 ,6-naphthyridin-5-one 30e (30 mg, 0.21 mmol) in dry dimethylformamide (5.0 mL) for 72 h. The mixture was poured into ethyl acetate (3 mL). The solid was collected, washed with ethyl acetate and dried to give 32e (40 mg, 90%) as a yellow solid, mp 298-299°C; 1H NMR ((CD3)2SO) δ 4.45 (3H, s, NMe), 7.31 (1 H, s, 8-H), 7.59 (1 H, m, 3-H), 7.99 (2H, d, J = 8.8 Hz, Ph 2,6-H2), 8.17 (2H, d, J = 6.4 Hz, Ph 3,5-Hz), 9.15 (1 H, d, J = 6.4 Hz, 4-H), 9.30 (1 H, d, J = 4.4 Hz, 2-H), 13.00 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) 845.34 (N-Me), 95.52 (8-C), 122.44 (3- C), 123.64 (4a-C), 124.94 (q, J = 271.0 Hz, CF3), 125.81 (q, J = 3.6 Hz, Ph 3,5-C2), 129.21 (Ph 2,6-Cz), 131.16 (q, J = 34.0 Hz, Ph 4-C), 136.15 (7-C), 144.30 (3-C), 147.81 (8a-C), 149.89 (Ph 1-C), 151.41 (2-C), 160.46 (1-C); 19F NMR ((CD3)2SO) δ -61.35 (CF3); MS (ESI) m/z 305.0895 (C16H12N2OF3 requires 305.0896).
1 -Methyl-7-(4-trifluoromethylphenyl)-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one (33e). To 1 -methyl-7-(4-trifluoromethylphenyl)-5-oxo-1 ,6-naphthyridin-1-ium iodide 32e (30 mg, 0.069 mmol) in formic acid (5.0 mL) at 0°C was added dropwise
borane. pyridine complex (0.10 mL). The mixture was stirred for 10 d. Each day, additional borane. pyridine complex (0.01 mL) was added. The solvent was evaporated. The residue was dissolved in water (5 mL) and the mixture was sonicated. The precipitate was collected by filtration and recrystallised from water to give 1-methyl-7- (4-trifluoromethylphenyl)-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one 33e (5.0 mg, 24%) as a white powder: mp 287-288°C; H NMR (CDCI3) δ 1.94 (2 H, qn, J = 5.5 Hz, 3-H2), 2.63 (2 H, t, J = 6.0 Hz, 4-H2), 3.31 (2 H, t, J = 5.5 Hz, 2-H2), 6.09 (1 H, s, 8-H), 7.67 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 7.72 (2 H, d, J = 8.5 Hz, Ph 3,5-H2); 13C NMR (CDCI3) (HSQC / HMBC) δ 20.61 (4-C), 20.94 (3-C), 50.01 (2-C), 96.10 (8-C), 101.76 (4a-C), 125.10 (q, J = 275 Hz, CF3), 126.38 (m, Ph 2,3,5,6-C4), 131.95 (q, J = 37.5 Hz, Ph 4- C), 140.02 (Ph 1-C), 141.80 (7-C), 149.10 (5-C), 157.22 (8a-C); 19F NMR (CDCI3) δ - 62.79 (CF3); MS (ESI) m/z 331.1061 (M + Na) (C16H15F3N2NaO requires 331.1034), 309.1239 (M + H) (C16H16F3N20 requires 309.1215).
7-{4-Chlorophenyl)-1 -methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one (33c). To 1- methyl-7-(4-chlorophenyl)-5-oxo-1 ,6-naphthyridin-1 -ium iodide 32c (91 mg, 0.23 mmol) in formic acid (5.0 mL) at 0°C was added dropwise borane. pyridine complex (0.10 mL). The mixture was stirred for 10 d. Each day, additional borane. pyridine complex (0.01 mL) was added. The solvent was evaporated. The residue was dissolved in water (5 mL) and the mixture was sonicated. The precipitate was collected by filtration and recrystallised from water to give 7-(4-chlorophenyl)-1-methyl-1 ,2,3,4-tetrahydro-1 ,6- naphthyridin-5-one 33c (27 mg, 44%) as a white powder: mp 195-197°C; 1H NMR (CDCI3) δ 1.95 (2 H, qn, J = 6.4 Hz, 3-H2), 2.60 (2 H, t, J = 6.4 Hz, 4-H2), 3.04 (3 H, s, N e), 3.30 (2 H, t, = 5.6 Hz, 2-H2), 6.06 (1 H, s, 8-H), 7.43 (2 H, d, J = 8.6 Hz, Ph
3.5- H2), 7.54 (2 H, d, J = 8.7 Hz, Ph 2,6-H2); 13C NMR (CDCI3) (HSQC / HMBC) δ 20.62 (4-C), 20.83 (3-C), 38.76 (NMe), 50.43 (2-C), 95.28 (8-C), 101.97 (4a-C), 127.54 (Ph
2.6- C2), 129.33 (Ph 3,5-C2), 134.29 (Ph 1 -C), 137.70 (Ph 4-C), 142.30 (7-C), 153.97 (8a-C), 157.50 (5-C); MS (ESI) m/z 549.1819 (2M + H) (C3oH3i35CIN20 requires 549.1824), 275.0941 (M + H) (C15H16 35CIN20 requires 275.0946).
7-{4-Bromophenyl)pyrano[4,3-b]pyridin-5-one (29i). 2-Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 1 ,3-di-(4-bromophenyl)propane-1 ,3- dione (available from Sigma-Aldrich - catalogue number R431966) (382 mg, 1.0 mmol) and caesium carbonate ( 63 mg, 0.5 mmol) in acetonitrile (15 ml_) under reflux for 16 h. The mixture was cooled and poured into water (10 ml_). The mixture was extracted with ethyl acetate (3 χ 25 ml_). The combined organic layers were washed with brine and the solvent was evaporated. The residue was washed with petroleum ether to give 7-(4-bromophenyl)pyrano[4,3-£>]pyridin-5-one 29i (140 mg, 93%) as an off-white powder: mp 170-171°C; 1H NMR (CDCI3) δ 7.25 (1 H, s, 8-H), 7.47 (1 H, dd, J = 8.0, 5.0 Hz, 3-H), 7.66 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.81 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.57 (1 H, d, J = 8.0 Hz, 4-H), 8.97 (1 H, d, J = 4.5 Hz, 2-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 104.01 (8-C), 1 17.01 (4a-C), 123.12 (3-C), 125.36 (Ph 4-C), 127.09 (Ph 2,6- C2), 130.28 (Ph 1-C), 132.30 (Ph 3,5-C2), 137.65 (4-C), 154.85 (8a-C), 156.27 (3-C), 156.49 (2-C), 161.78 (5-C); MS (ESI of solution in methanol, which converts 29i to methyl 2-(2-(4-bromophenyl)-2-oxoethyl)pyridine-3-carboxylate) m/z 336.0074 (M + H) (C15Hl3 81BrN03 requires 336.0054), 334.0063 (M + H) (C15H13 79BrN03 requires
334.0073).
7-(4-Bromophenyl)-1 ,6-naphthyridin-5-one (30i). Ammonia was passed through a suspension of 7-(4-bromophenyl)pyrano[4,3-0]pyridin-5-one 29i (140 mg, 0.47 mmol) in 2-methoxyethanol (10 ml_) for 10 min in a pressure vessel. The vessel was closed and the mixture was heated at 120°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin layer chromatography. Evaporation and recrystallisation (ethanol) gave 7-(4-bromophenyl)-1 ,6-naphthyridin-5- one 30i (100 mg, 75%) as a buff powder: mp 304-305°C; H NMR ((CD3)2SO) δ 7.05 (1 H, s, 8-H), 7.50 (1 H, dd, J = 7,7, 4.0 Hz, 3-H), 7.39 (2 H, d, J = 8 Hz, Ph 3,5-H2), 7.84 (2 H, d, J = 8 Hz, Ph 2,6-H2), 8.30 (1 H, d, J = 7.7 Hz, 4-H), 8.69 (1 H, d, J = 4.8 Hz, 2- H), 9.15 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 105.80 (8-C), 122.51 (4a-C), 122.97 (Ph 4-C), 123.61 (3-C), 127.41 (Ph 1-C), 130.22 (Ph 2,6-C2), 130.75 (Ph 3,5-C2), 131.91 (7-C), 134.61 (4-C), 156.71 (8a-C), 168.09 (5-C); MS (ESI) m/z
324.9771 (M + Na) (C14H9 81BrN2NaO requires 324.9774), 322.9790 (M + Na)
(C14H9 79BrN2NaO requires 322.9805).
7-(4-Bromophenyl)-1 -methyl-5-oxo-1 ,6-naphthyridin-1 -ium iodide (32i).
lodomethane (179 mg, 1.26 mmol) was stirred with 7-(4-bromophenyl)-1 ,6- naphthyridin-5-one 30i (64 mg, 0.21 mmol) in dry dimethylformamide (5.0 mL) for 3 d. The mixture was poured into ethyl acetate (3.0 mL). The solid was collected by filtration, washed with acetone and dried to give 7-(4-bromophenyl)-1-methyl-5-oxo-1 ,6- naphthyridin-1-ium iodide 32i (50 mg, 52%) as a yellow solid: mp 292-294°C, 1H NMR ((CD3)2SO) δ 4.48 (3 H, s, Me), 7.29 (1 H, s, 8-H), 7.89 (2 H, d, J = 8.7 Hz, Ph 2,6-H2), 7.97 (1 H, m, 3-H), 7.98 (2 H, d, J = 8.7 Hz, Ph 3,5-H2), 9.18 (1 H, d, J = 7.9 Hz, 4-H), 9.30 (1 H, d, J = 5.8 Hz, 2-H), 12.94 (1 H, s, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 45.98 (Me), 95.00 (8-C), 122.40 (3-C), 123.00 (4a-C), 126.00 (Ph 4-C), 130.12 (Ph 2,6-C2), 130.50 (Ph 1-C), 131.98 (Ph 3,5-C2), 132.55 (3-C), 144.50 (4-C), 148.50 (8a-C), 152.50 (2-C), 155.5 (1-C); MS (ESI) m/z 317.0108 (M + H)
(C15H12 81BrN2NaO requires 317.0221), 315.0128 (M + H) (C15H12 79BrN2NaO requires 315.0110).
7-(4-Bromophenyl)-1 -methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one (33i). To 1- methyl-7-(4-bromophenyl)-5-oxo-1 ,6-naphthyridin-1-ium iodide 32i (12 mg, 0.027 mmol) in formic acid (2.0 mL) at 0°C was added dropwise borane. pyridine complex (0.02 mL). The mixture was stirred for 10 d. Each day, additional borane. pyridine complex (0.01 mL) was added. The solvent was evaporated. The residue was dissolved in water (5 mL) and the mixture was sonicated. The precipitate was collected by filtration and recrystallised from water (1 mL) to give 7-(4-bromophenyl)-1 -methyl- 1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one 331 (4.0 mg, 47%) as a white powder: mp 205-207 °C; 1H NMR (CDCI3) δ 1.95 (2 H, qn, J = 6.4 Hz, 3-H2), 2.61 (2 H, t, J = 6.3 Hz, 4-H2), 3.29 (3 H, s, Me), 3.29 (2 H, t, J = 5.5 Hz, 2-H2), 6.02 (1 H, s, 8-H), 7.42 (2 H, d, J = 8.7 Hz, Ph 2,6-H2), 7.59 (2 H, d, J = 8.7 Hz, Ph 3,5-H2); 13C NMR (CDCI3) (HSQC / HMBC) δ 20.75 (4-C), 21.63 (3-C), 38.70 (NMe), 50.76 (2-C), 94.44 (8-C), 101.46 (4a- C),123.93 (Ph 4-C), 127.41 (Ph 2,6-C2), 132.27 (Ph 3,5-C2), 133.39 (Ph 1-C), 141.80 (7-C), 153.16 (8a-C), 162.35 (5-C); MS (ESI) m/z 343.0249 (M + Na) (C15H15 8lBrN2NaO requires 343.0245), 341.0264 (M + Na) (C15H15 79BrN2NaO requires 341.0265), 321.0426 (M + H) (C15H16 81BrN20 requires 321.0426), 319.0448 (M + H)
(C15H16 79BrN20 requires 319.0446).
3- Bromo-4-cyanopyridine (34). 3-Bromopyridine-4-carboxamide98 (687 mg, 3.4 mmol) was added to phosphorus oxychloride (5.0 ml_) at 0°C. The mixture was then stirred at reflux for 2 h. The mixture was cooled, poured onto ice (100 g) with stirring and was neutralised with aqueous sodium hydroxide (5 M, 60 ml_). The mixture was extracted with diethyl ether (2 χ 50 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, treated with charcoal and filtered. The solvent was evaporated. The solid was recrystallised from petroleum ether to give 34 (292 mg, 42%) as an off-white powder: mp 79-81 °C (lit.99 mp 96.6-98.2°C); 1H NMR (CDCI3) δ 7.53 (1 H, d, J = 4.9 Hz, 5-H), 8.69 (1 H, d, J = 4.9 Hz, 6-H), 8.92 (1 H, s, 2- H); 13C NMR (CDCI3) (HSQC / HMBC) δ 1 14.79 (C≡N), 122.14 (4-C), 124.17 (3-C), 126.75 (5-C), 148.76 (6-C), 152.69 (2-C); MS (ESI) m/z 182.9552 (M + H) (C6H4N2 79Br requires 182.9541).
4- Cyano-3-(4-methylphenylethynyl)pyridine (98b). A mixture of 3-bromo-4- cyanopyridine 34 (91.5 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.025 mmol), copper(l) iodide (9.6 mg, 0.05 mmol) and sodium ascorbate (9.9 mg, 0.05 mmol) in tetrahydrofuran (5.0 mL) and diisopropylamine (5.0 mL) was stirred at 40°C under argon for 30 min. 1-Ethynyl-4-methylbenzene 98a (available from Acros Organics - catalogue number 39256) (120 mg, 1.0 mmol) was added and the mixture was stirred at 40°C under argon for 16 h. The mixture was cooled and the solvent was evaporated. The residue was purified by chromatography (petroleum ether / ethyl acetate 4: 1→ 3: 1→ 3:2) to give 4-cyano-3-(4-methylphenylethynyl)pyridine 98b (66 mg, 62%) as a buff powder: mp 94-96°C; 1H NMR (CDCI3) δ 2.39 (3 H, s, Me), 7.20 (2 H, d, J = 8.4 Hz, Ph 3,5-H2), 7.51 (3 H, m, 5-H, Ph 2,6-H2), 8.65 (1 H, d, J = 5.0 Hz, 6- H), 8.90 (1 H, s, 2-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 21.62 (Me), 100.01 (ethynyl 1-C), 1 13.20 (C=N), 114.90 (ethynyl 2-C), 119.50 (Ph 1 -C), 123.50 (4-C), 124.90 (5-C), 129.15 (Ph 4-C), 129.31 (Ph 3,5-C2), 132.03 (Ph 2,6-C2), , 140.50 (3-C), 148.15 (6-C), 152.02 (2-C); MS (ESI) m/z 219.0910 (M + H) (C^H^Nz requires 219.0922). 3-(4- ethylphenyI)-2,6-naphthyridin-1-one (99a). 4-Cyano-3-(4- methylphenylethynyl)-pyridine 98b (100 mg, 0.46 mmol) was stirred at 150°C in polyphosphoric acid ( 0 ml.) for 1 h. After cooling, aqueous sodium hydroxide (5 M) was added to pH 8. The mixture was extracted with ethyl acetate (3 x 30 ml_). The combined organic layers were dried and the solvent was evaporated. The residue was transferred into a pressure tube equipped with magnetic stirrer and dissolved in 2- methoxyethanol (5.0 ml_). Ammonia was passed through the solution, the vessel was closed and the mixture was heated at 130°C for 30 min. The reaction mixture was cooled in ice and ammonia was bubbled again, followed by closure and heating (30 min). The cycle was repeated until the reaction was complete, as shown by thin layer chromatography. Evaporation of the solvent and recrystallisation (ethanol) gave 3-(4- methylphenyl)-2,6-naphthyridin-1-one 99a (6.5 mg, 6%) as an off-white solid: mp 188- 189°C; 1H NMR ((CD3)2SO) δ 7.07 (1 H, s, 4-H), 7.38 (2 H, d, J = 7.9 Hz, Ph 3,5-H2), 7.76 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.04 (1 H, d, J = 5.3 Hz, 8-H), 8.66 (1 H, d, J = 5.3 Hz, 7-H), 9.15 (1 H, d, J = 0.8 Hz, 5-H), 1 1.90 (1 H, br, NH); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.70 (Me), 100.10 (4-C), 119.80 (8-C), 127.10 (Ph 2,6-C2), 129.53 (Ph 3,5-C2), 146.20 (7-C), 148.90 (5-C); MS (ESI) m/z 259.0834 (M + Na)
(C15H12N2NaO requires 259.0847), 237.1022 (M + H) (C15H13N20 requires 237.1028).
5-Methyl-3-(pyridin-4-yl)isoquinolin-1-one (99b). Butyllithium (1.6 M in hexanes, 0.7 ml_, 1.1 mmol) was added to dry diisopropylamine (142 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at -78°C for 0 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Cyanopyridine (1 18 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78°C and the mixture was stirred for 1 h at -78°C, then at 20°C for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried. The solvent was evaporated and the residue was recrystallised (ethanol) to give 5-methyl-3-(pyridin-4-yl)isoquinolin-1-one 99b (16.5 mg, 6%) as white crystals: mp 268- 269°C; IR vmax3450, 1654 cm-1; 1H NMR ((CD3)2SO) (COSY) δ 2.59 (3 H, s, Me), 7.1 1 (1 H, s, 4-H), 7.44 (1 H, t, J = 7.7 Hz, 7-H), 7.60 (1 H, d, J = 7.2 Hz, 6-H), 7.87 (2 H, d, J = 6.2 Hz, Ph 3,5-H2), 8.10 (1 H, d, J = 8.0 Hz, 8-H), 8.69 (2 H, d, J = 6.2 Hz„ Ph 2,6- H2), 11.70 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.76 (Me), 101.87 (4-C), 120.96 (pyridine 3,5-C2), 124.65 (8-C), 125.83 (8a-C), 126.91 (7-C), 133.49 (6- C), 134.50 (4a-C), 136.06 (5-C), 137.06 (pyridine 4-C), 141.03 (3-C), 150.13 (pyridine 2,6-Cz), 162.85 (1-C); MS m/z 235.0864 (M - HV (C15HnN20 requires 235.0871).
5- Fluoro-3-(4-methylphenyI)isoquinolin-1 -one (99c). Butyiiithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (142 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 3-Fluoro-2,N,N-trimethylbenzamide 24 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-Methylbenzonitrile (129 mg, 1 .1 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78°C and the mixture was stirred for 1 h at -78°C, then at 20°C for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried. The solvent was evaporated and the residue was
recrystallised (ethanol) to give 99c (50 mg, 18%) as white crystals: mp 232-233°C; IR vmax 3481 , 1668, 1235 cm 1; 1H NMR ((CD3)2SO) (COSY) δ 2.37 (3 H, s, Me), 6.81 (1 H, s, 4-H), 7.30 (2 H, d, J = 8.0 Hz, Ph 3,5-H2), 7.48 (1 H, m, 7-H), 7.58 (1 H, t, J = 8.1 Hz,
6- H), 7.71 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 8.03 (1 H, d, J = 8.0 Hz, 8-H), 1 1.70 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 20.83 (Me), 94.19 (d, J = 5.1 Hz, 4-C), 1 17.57 (d, J = 19.5 Hz, 6-C), 122.77 (d, J = 3.3 Hz, 8-C), 126.46 (d, J = 3.4 Hz, 8a-C); 126.59 (d, J = 7.6 Hz, 7-C), 126.79 (Ph 2,6-C2), 127.06 (d, J = 16.5 Hz, 4a-C), 129.40 (Ph 3,5-Ha), 130.74 (Ph 1-C), 139.38 (Ph 4-C), 141.40 (3-C), 157.26 (d, J = 248.1 Hz, 5-C), 161.81 (d, J = 2.8 Hz, 1 -C); 19F NMR ((CD3)2SO) δ -122.08 (dd, J = 10.4, 5.2 Hz, F); MS m/z 252.0807 (M - H)" (C1eHnFNO requires 252.0824).
5-Methyl-3-{thiophen-3-yl)isoquinoiin-1 -one (99d). Butyiiithium (2.5 M in hexanes, 0.46 mL, 1.14 mmol) was added to dry diisopropylamine (127.5 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at this temperature for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.13 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 3-Cyanothiophene (123 mg, 1.13 mmol) in dry tetrahydrofuran (2.0 mL) was added at -78°C and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with CH2CI2 and washed thrice with saturated brine. The solvent was evaporated from the organic layer was then evaporated and the residue was washed (ethanol) to give 5-methyl-3-(thiophen-3- yl)isoquinolin-1-one 99d (17 mg, 6%) as a pale buff solid: mp >360°C; IR vmax 3448, 1647 crrf1; 1H NMR ((CD3)2SO) (COSY) δ 2.56 (3 H, s, Me), 6.99 (1 H, s, 4-H), 7.34 (1 H, t, J = 7.6 Hz, 7-H), 7.54 (1 H, d, J = 7.1 Hz, 6-H), 7.70 (1 H, m, thiophene 4-H), 7.78 (1 H, d, J = 4.6 Hz, thiophene 5-H), 8.04 (1 H, d, J = 8.0 Hz, 8-H), 8.28 (1 H, d, J = 1.5 Hz, thiophene 2-H), 11.47 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ (18.80 (Me), 99.09 (4-C), 123.46 (thiophene 2-C), 124.58 (8-C), 124.95 (8a-C), 125.74 (7-C), 126.16 (thiophene 5-C), 127.27 (thiophene 4-C), 133.25 (6-C), 133.73 (4a-C), 134.95 (thiophene 1-C), 135.37 (3-C), 136.72 (5-C), 162.80 (1-C); MS m/z 264.0454 (M + Na) (C14HnNNaOS requires 264.0459).
2-Ethyl-N,N,3-trimethylbenzamide (98c). Butyllithium (1.6 M in hexanes, 1.65 mL, 2.6 mmol) was added to dry diisopropylamine (463 mg, 3.3 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at -78°C for 10 min. 2,3,N,N- Tetramethylbenzamide 16 (390 mg, 2.2 mmol) in dry tetrahydrofuran (3.0 mL) was added and the mixture was stirred for 1 h at -78°C. lodomethane (343 mg, 2.4 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C, then at 20°C for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with brine and dried. Evaporation and chromatography (ethyl acetate / petroleum ether 1 :9→ 1 : 1) gave 2-ethyl-N,N,3- trimethylbenzamide 98c (100 mg, 24%) as a colourless oil: 1H NMR (CDCI3) (COSY/ NOESY) δ 1.14 (3 H, t, J = 7.6 Hz, CH2Me), 2.34 (3 H, s, 3-Me), 2.60 (2 H, m, CH2), 2.81 (3 H, s, NMe), 3.13 (3 H, s, NMe), 6.96 (1 H, d, J = 7.3 Hz, 4-H), 7.10 (1 H, t, J = 7.5 Hz, 5-H), 7.14 (1 H, d, J = 7.3 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC / DEPT) δ 14.25 (CH2/We), 19.26 (3-Me), 23.55 (CH2), 34.56 (NMe), 38.91 (NMe), 123.62 (4-C), 125.84 (5-C), 130.74 (6-C), 136.64 (3-C), 136.92 (1-C), 138.52 (2-C), 171.98 (C=0); MS m/z 192.1491 (M + H)+ (C12H17NO requires 192.1310).
4,5-Dimethyl-3-phenylisoquinolin-1-one (99e). Sec-Butyllithium (1.4 M in
cyclohexane, 0.47 mL, 0.66 mmol) was added to 2-ethyl-N,N,3-trimethylbenzamide 98c (1 15 mg, 0.6 mmol) in dry tetrahydrofuran (1.0 mL) at -78°C and the mixture was stirred at -78°C for 30 min. Benzonitrile (62 mg, 0.6 mmol) in dry tetrahydrofuran (1.0 mL) was added at -78°C and the mixture was stirred for 1 h at this temperature, then at 20°C for 16 h. The reaction mixture was then cooled to 0°C and quenched with deuterium oxide (0.1 1 mL, 6.0 mmol) and stirred for 10 min. The mixture was diluted with dichloromethane and washed thrice with saturated brine. The solvent was evaporated from the dried organic layer and the residue was washed (ethanol) to give 4,5-dimethyl-3-phenylisoquinolin-1-one 99e (19.5 mg, 13%) as a white solid: mp >360°C; IR vmax 3453 (NH), 1644 (C=0); 1H NMR ((CD3)2SO) (COSY) δ 2.25 (3 H, s, 4- Me), 2.76 (3 H, s, 5-Me), 7.37 (1 H, t, J = 6.8 Hz, 7-H), 7.47 (5 H, m, Ph-H5), 7.53 (1 H, d, J = 7.1 Hz, 6-H), 8.18 (1 H, d, J = 6.9 Hz, 8-H), 1 1.21 (1 H, br, NH); 13C NMR
((CD3)2SO) (HSQC / HMBC) δ 18.98 (4-Me), 24.54 (5-Me), 108.26 (4-C), 125.52 (8-C), 125.86 (7-C), 127.04 (8a-C), 128.33 (Ph 3,5-C2), 128.65 (Ph 4-C), 129.74 (Ph 2,6-C2), 134.92 (4a-C), 135.65 (Ph 1-C), 136.41 (6-C), 138.17 (5-C), 138.34 (3-C), 161.39 (1- C); MS m/z 250.1219 (M + H) (C17H16NO requires 250.1232).
5-Methyl-3-(4-(pyrrolidin-1-ylmethyl)phenyl)isoquinolin-1-one hydrochloride (99f).
Butyllithium (2.5 M in hexanes, 0.46 mL, 1.14 mmol) was added to dry
diisopropylamine (127.5 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at -78°C for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.13 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-(Pyrrolidin-1 -ylmethyl)benzonitrile100 (210.5 mg, 1.13 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at this temperature, then at 20°C for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with brine and dried.
Evaporation and washing (ethanol) gave 5-methyl-3-(4-(pyrrolidin-1-ylmethyl)phenyl)- isoquinolin-1 -one hydrochloride 99f (32 mg, 9%) as a pale yellow solid: mp >360°C; IR Vmax 341 3, 1640 cm"1; The solid was then treated for 16 h with aqueous hydrochloric acid (6.0 M, 2.0 mL). Evaporation and drying gave the hydrochloride salt salt as a white solid: mp >360°C; 1H NMR ((CD3)2SO) δ 1.70 (4 H, m, pyrrolidine 3,4-H4), 2.44 (4 H, m, pyrrolidine 2,5-H4), 2.54 (3 H, s, Me), 3.61 (2 H, s, PhCH2), 6.83 (1 H, s, 4-H), 7.35 (1 H, t, J = 7.7 Hz, 7-H), 7.41 (2 H, d, J = 8.2 Hz, Ph 3,5-H2), 7.54 (1 H, d, J = 7.2 Hz, 6- H), 7.76 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.05 (1 H, d, J = 7.9 Hz, 8-H), 11.52 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.77 (Me), 23.12 (pyrrolidine 3,4-C2), 53.50 (pyrrolidine 2,5-C2), 59.15 (PhCH2), 99.72 (4-C), 124.55 (8-C), 124.92 (8a-C), 125.80 (7-C), 126.64 (Ph 2,6-C2), 128.71 (Ph 3,5-C2), 132.64 (Ph 1-C), 133.30 (6-C), 133.68 (4a-C), 136.81 (5-C), 139.86 (3-C), 140.96 (Ph 4-C), 163.24 (1-C); MS m/z 319.1788 (M + H)+ (C21H23N20 requires 319.1810).
5- ethyl-3-(4-(piperidin-1 -ylmethyl)phenyl)isoquinolin-1 -one (99g). Butyllithium (1.6 M in hexanes, 0.7 mL, 1.1 mmol) was added to dry diisopropylamine (142 mg, 1.4 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at -78°C for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 ml_) was added and the mixture was stirred for 1 h at -78°C. 4-(Piperidin-1- ylmethyl)benzonitrile101 (226 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 ml_) was added and the mixture was stirred for 1 h at this temperature, then at room temperature for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with saturated brine and dried. Evaporation and washing (ethanol) gave 5-methyl-3-(4-(piperidin-1-ylmethyl)phenyl)isoquinolin-1-one 99g (78 mg, 21 %) as a white solid: mp 196-197°C; IR vmax3440, 1644 cm"1; 1H NMR
((CD3)2SO) δ 1.40 (2 H, m, piperidine 4-H2), 1.50 (4 H, m, piperidine 3,5-H4), 2.34 (4 H, m, piperidine 2,6-H4), 2.55 (3 H, s, Me), 3.47 (2 H, s, PhCH2), 6.84 (1 H, s, 4-H), 7.36 (1 H, t, J = 7.7 Hz, 7-H), 7.40 (2 H, d, J = 8.2 Hz, Ph 3,5-H2), 7.54 (1 H, d, J = 7.1 Hz, 6-H), 7.76 (2 H, d, J = 8.2 Hz, Ph 2,6-H2), 8.06 (1 H, d, J = 7.9 Hz, 8-H), 11.48 (1 H, bs, N-H); 3C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.76 (Me), 23.96 (piperidine 4), 25.55 (piperidine 3,5-C2), 53.91 (piperidine 2,6-C2), 62.37 (PhCH2), 99.73 (4-C), 124.56 (8-C), 124.90 (8a-C), 125.79 (7-C), 126.61 (Ph 2,6-C2), 129.01 (Ph 3,5-C2), 132.67 (Ph 1-C), 33. 8 (6-C), 133.68 (4a-C), 136.66 (5-C), 139.78 (Ph 4-C), 140.06 (3-C), 162.95 (1- C); MS m/z 665.3884 (2 M + H)+ (C44H49N402 requires 665.3855), 355.1805 (M + Na)+ (C22H24N2NaO requires 355.1786).
3-(4-(1,1-Dimethylethyl)phenyl)-5-methylisoquinolin-1-one (99h). Butyllithium (2.5 M in hexanes, 0.46 mL, 1.14 mmol) was added to dry diisopropylamine (127.5 mg, 1.3 mmol) in dry tetrahydrofuran (2.0 mL) at -78°C and the mixture was stirred at -78°C for 10 min. 2,3,N,N-Tetramethylbenzamide 16 (200 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C. 4-(1 ,1-Dimethylethyl)- benzonitrile (available from Sigma-Aldrich - catalogue number 527785) (180 mg, 1.1 mmol) in dry tetrahydrofuran (2.0 mL) was added and the mixture was stirred for 1 h at -78°C, then at 20°C for 16 h. Water (1.0 mL) was added. The mixture was diluted with dichloromethane. This mixture was washed thrice with brine and dried. The solvent was evaporated and the residue was washed (EtOH) to give 3-(4-(1 ,1-dimethylethyl)- phenyl)-5-methylisoquinolin-1-one 99h (96.5 mg, 29%) as a white solid: mp 204-206°C; IR vmax3295, 1642 cm"1; 1H NMR ((CD3)2SO) (COSY) δ 1.33 (9 H, s, CMe3), 2.55 (3 H, s, 5-Me), 6.82 (1 H, s, 4-H), 7.35 (1 H, t, J = 7.6 Hz, 7-H), 7.51 (2 H, d, J = 7.6 Hz, Ph 3,5-H2), 7.54 (1 H, d, J = 7.2 Hz, 6-H), 7.75 (2 H, d, J = 7.6 Hz, Ph 2,6-H2), 8.06 (1 H, d, J = 8.0 Hz, 8-H), 1 1.48 (1 H, br, NH); 13C NMR ((CD3)2SO) (HSQC / HMBC) δ 18.75 (Me), 30.97 (CMe3), 34.44 (CMe3), 99.60 (4-C), 124.56 (8-C), 124.86 (8a-C), 125.51 (Ph 3,5-C2), 125.72 (7-C), 126.56 (Ph 2,6-C2), 131.44 (Ph 1-C), 133.15 (6-C), 133.60 (4a-C), 136.69 (5-C), 139.84 (3-C), 151.87 (Ph 4-C), 162.97 (1-C); MS m/z 292.1686 (M + H)+ (C20H22NO requires 292.1703).
Alternative synthesis of 7-(4- ethoxyphenyl)pyrano[4,3-fc]pyridin-5-one (29b). 2-
Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 1 ,3-di-(4- methoxyphenyl)propane-1 ,3-dione102 (142 mg, 0.5 mmol) and caesium carbonate (163 mg, 0.5 mmol) in acetonitrile (15 mL) under reflux for 2 d. The mixture was cooled and poured into water (10 mL). The mixture was extracted with dichloromethane (3 χ 25 mL). The combined organic layers were washed with saturated brine and dried. The solvent was evaporated. The residue was washed with petroleum ether and dried to give 7-(4-methoxyphenyl)pyrano[4,3-j ]pyridin-5-one 29b (28.3 mg, 22%) as an off- white powder: mp 169-171°C (lit.103 177-178°C); 1H NMR (CDCI3) δ 3.78 (3 H, s, Me), 6.63 (1 H, s, 8-H), 6.88 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.28 (1 H, dd, J = 7.5, 4.0 Hz, 3- H), 7.76 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.41 (1 H, d, J = 8.0 Hz, 4-H), 8.81 (1 H, m, 2- H); 13C NMR (CDCI3) (HSQC / HMBC) δ 50.43 (Me), 91.46 (Ph 1-C), 101.86 (8-C), 1 13.77 (4a-C), 1 16.51 (Ph 3,5-C2), 122.43 (3-C), 129.49 (Ph 2,6-C2), 137.67 (4-C), 156.13 (2-C), 157.46 (7-C), 161.77 (8a-C), 163.66 (5-C); MS (ESI of solution in methanol, which converts 29b to methyl 2-(2-(4-methoxyphenyl)-2-oxoethyl)pyridine-3- carboxylate) m/z 286.1075 (M + H) (C16H16N04 requires 286.1082).
Alternative synthesis of 7-(4-Chlorophenyl)pyrano[4,3- j]pyridin-5-one (29d). 2-
Bromopyridine-3-carboxylic acid 38 (101.5 mg, 0.5 mmol) was stirred with 1 ,3-di-(4- chlorophenyl)propane-1 ,3-dione104 (146.5 mg, 0.5 mmol) and caesium carbonate (163 mg, 0.5 mmol) in acetonitrile (15 mL) under reflux for 12 h. The mixture was cooled and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 χ 25 mL). The combined organic layers were washed with saturated brine and dried. The solvent was evaporated. The residue was washed with petroleum ether to give 7-(4- chlorophenyl)pyrano[4,3-6]pyridin-5-one 29d (80 mg, 63%) as an off-white powder: mp 188-190°C; 1H NMR (CDCI3) δ 7.13 (1 H, s, 8-H), 7.36 (1 H, dd, J = 8.0, 5.0 Hz, 3-H), 7.40 (2 H, d, J = 8.5 Hz, Ph 3,5-H2), 7.78 (2 H, d, J = 8.5 Hz, Ph 2,6-H2), 8.47 (1 H, d, J = 8.0 Hz, 4-H), 8.87 (1 H, d, J = 4.5 Hz, 2-H); 13C NMR (CDCI3) (HSQC / HMBC) δ 1 17.02 (8a-C), 123.02 (3-C), 126.91 (Ph 3,5-C2), 129.34 (Ph 2,6-C2), 129.83 (8-C), 136.98 (Ph 4-C), 137.62 (4-C), 154.87 (7-C), 156.19 (4a-C), 156.49 (2-C), 161.78 (5- C); MS (ESI of solution in methanol, which converts 29d to methyl 2-(2-(4- chlorophenyl)-2-oxoethyl)pyridine-3-carboxylate) m/z 292.0582 (M + H) (C15H13 37CIN03 requires 292.0554), 290.0590 (M + H) (C15H13 35CIN03 requires 290.0578). All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.
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Claims

A compound of formula I
Figure imgf000152_0001
Formula I wherein is a substituent L-R5 wherein L is an optionally substituted aromatic or heteroaromatic linking group and R5 is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R2 may not be absent;
X is C(R6) or N;
R6 is hydrogen or C-i-6 alkyl; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms;
or a pharmaceutically acceptable salt or solvate thereof;
or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
provided that when ring B is carbocyclic, X is C(R6); and with the exception of the following compounds:
7-Phenyl-1 ,6-naphthyridin-5-one;
2-Phenylpyrido[2,3-Gf]pyrimidin-4-one; and
2-(4-Chlorophenyl)pyrido[2,3-d]pyrimidin-4-one.
2. A compound according to claim 1 , wherein L is an optionally substituted phenyl, pyridyl or thienyl group.
3. A compound according to claim 2, wherein L is an optionally substituted phenyl group.
4. A compound according to any one of the preceding claims, wherein R5 is halo, hydroxy, nitrile, nitro, amino, Ci-C10 alkyl, C2-C10 alkenyl, C2-C 0 alkynyl, C-|-C 0 alkoxy, C5-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, C C10 haloalkyi group, alkylamine, amide, alkylamide, dialkyl amide, or acylamide, aryl-C-|-C 0 alkyl, aryl-C2-C10 alkenyl, aryl C2-C10 alkynyl, heterocyclyl-CrC1 0 alkyl, heteroaryl-C C 0 alkyl, or aryl-(C1-3 alkoxy)carbonylamino-C1-C3 alkyl.
5. A compound according to any one of the preceding claims, wherein R5 is halo, C-rC6 alkyl, C C6 alkoxy, C^Ce haloalkyi, or a saturated 5- or 6-membered nitrogen- containing heterocycle.
6. A compound according to claim 5, wherein R5 is CI, F, Br, methyl, ethyl, methoxy, ethoxy, CF3 or CCI3.
7. A compound according to claim 6, wherein R5 is F or CI.
8. A compound according to claim 6, wherein R5 is methoxy or ethoxy.
9. A compound according to claim 6, wherein R5 is methyl or ethyl.
10. A compound according to any one of the preceding claims, wherein L is a phenyl ring and R5 is present on the ring L at the para position.
1 1. A compound according to any one of the preceding claims, wherein R2 is C-|-C6 alkoxy.
12. A compound according to claim 11 , wherein R2 is methoxy.
13. A compound according to any one of claims 1 to 10, wherein R2 is C^CB alkyl.
14. A compound according to claim 13, wherein R2 is methyl.
15. A compound according to any one of the preceding claims, wherein the compound is of formula II
Figure imgf000154_0001
Formula II wherein R3, R4 and R8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups, and and R2 are as defined above.
16. A compound according to claim 15, wherein R3 is H.
17. A compound according to claim 15 or claim 16, wherein R4 is H.
18. A compound according to any one of claims 15 to 17, wherein R8 is H.
19. A compound according to claim 1 , wherein the compound is of formula IV
Figure imgf000154_0002
Formula IV wherein R3, R4 and R8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups, and R-i is as defined above.
20. A compound according to claim 1 , wherein the compound is of formula V
Figure imgf000155_0001
wherein: R3, R4 and R8 are independently selected from H, halo, hydroxy, nitrile, nitro, amino and hydrocarbyl groups,
R9 is hydrocarbyl; and
is as defined above.
21. A compound according to claim 20, wherein R3 is H. compound according to claim 20 or claim 21 , wherein R4 is H.
23. A compound according to any one of claims 20 to 22, wherein R8 is H.
24. A compound according to any one of claims 20 to 23, wherein R9 is C 6 alkyl.
25. A compound according to claim 1, wherein X is CH and R2 is selected from halo, C-|-C6 haloalkyi, hydroxy, C C6 alkyl, C C6 alkoxy, nitro, nitrile, and oxo.
26. A compound selected from:
5-Amino-3-(4-cyanophenyl)isoquinolin-1-one;
5-Methyl-3-phenylisoquinolin-1-one,
5-MethyI-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methylisoquinolin-1-one,
5-Methyl-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
3-(4-Bromophenyl)-5-methylisoquinolin-1-one;
3-(4-Methoxyphenyl)-5-methylisoquinolin-1-one;
5-Methyl-3-(4-phenylethynylphenyl)isoquinolin-1-one;
5-Methoxy-3-phenylisoquinolin-1-one;
5-Methoxy-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methoxyisoquinolin-1-one; 5-Methoxy-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
5-Fluoro-3-phenylisoquinolin-1-one;
3-(4-Chlorophenyl)-5-fluoroisoquinolin-1-one;
5-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-one,
2-(4-Chlorophenyl)-8-methylquinazolin-4-one;
2-(4-Bromophenyl)-8-methylquinazolin-4-one;
2- (4-Fluorophenyl)-8-methylquinazolin-4-one;
8-Methyl-2-(4-(phenylmethoxycarbonylaminomethyl)phenyl)quinazolin-4-one; 7-(4-Methoxyphenyl)-1-methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one;
1 -Methyl-5-oxo-7-(4-trifluoromethylphenyl)-5,6-dihydro-1 ,6-naphthyridin-1 -ium ' 1 -Methyl-7-(4-trifluoromethylphenyl)-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one; 7-(4-Chlorophenyl)-1 -met yl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one
7-(4-Bromophenyl)-1 ,6-naphthyridin-5-one;
7-(4-Bromophenyl)-1-methyl-5-oxo-1 ,6-naphthyridin-1-iuin iodide;
7-(4-Bromophenyl)-1-methyl-1 ,2,3,4-tetrahydro-1 ,6-naphthyridin-5-one;
3- (4-Methylphenyl)-2,6-naphthyridin-1-one;
5-Methyl-3-(pyridin-4-yl)isoquinolin-1-one;
5-Fluoro-3-(4-methylphenyl)isoquinolin-1-one;
5-Methyl-3-(thiophen-3-yl)isoquinolin-1-one;
4,5-Dimethyl-3-phenylisoquinolin-1-one;
5-IVIethyl-3-(4-(pyrrolidin-1-ylmethyl)phenyl)isoquinolin-1-one;
5-Methyl-3-(4-(piperidin-1 -ylmethyl)phenyl)isoquinolin-1 -one; and
3-(4-(1 , 1 -Dimethylethyl)phenyl)-5-methylisoquinolin-1 -one;
or a pharmaceutically acceptable salt or solvate thereof.
27. A compound selected from:
5-Amino-3-(4-cyanophenyl)isoquinolin-1 -one hydrobromide;
5-Methyl-3-phenylisoquinolin-1-one,
5-Methyl-3-(4-methylphenyl)isoquinolin-1-one;
3-(4-Chlorophenyl)-5-methylisoquinolin-1-one,
5-Methyl-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
3-(4-Bromophenyl)-5-methylisoquinolin-1-one;
3-(4-Methoxyphenyl)-5-methylisoquinolin-1-one;
5-Methyl-3-(4-phenylethynylphenyl)isoquinolin-1-one;
5-Methoxy-3-phenylisoquinolin-1-one;
5-Methoxy-3-(4-methylphenyl)isoquinolin-1-one; 3-(4-Chlorophenyl)-5-methoxyisoquinolin-1-one;
5-Methoxy-3-(4-trifluoromethylphenyl)isoquinolin-1-one;
5-Fluoro-3-phenylisoquinolin-1-one;
3-(4-Chlorophenyl)-5-fluoroisoquinolin-1-one;
5-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-one,
2-(4-Chlorophenyl)-8-methylquinazolin-4-one;
2-(4-Bromophenyl)-8-methy[quinazolin-4-one; and
8-Methyl-2-(4-(phenylmethoxycarbonylaminomethyl)phenyl)quinazolin-4-one;
or a pharmaceutically acceptable salt or solvate thereof.
28. A compound as defined in any one of the preceding claims for use in medicine.
Figure imgf000157_0001
wherein:
R-i is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyi;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyi; provided that when Y is C, R2 may not be absent;
X is C(Re) or N;
R6 is hydrogen or C 6 aikyl; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms; or a pharmaceutically acceptable salt or solvate thereof;
or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
for use in the treatment of a disease or condition associated with tankyrase.
30. A compound for use according to claim 29, wherein the disease or condition is associated with tankyrase-1.
31. A compound for use according to claim 29, wherein the disease or condition is associated with tankyrase-2.
32. A compound as defined in any one of claims 1 to 27 for use in the treatment of cancer.
33. A compound for use as in claim 32, wherein the cancer is selected from breast, colon, stomach, liver, kidney, lung, ovary, thyroid, pancreas and prostate cancer.
34. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 27 and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
Use of a compound of formula
Figure imgf000158_0001
Formula I wherein is a substituent L-R5 wherein L is an optionally substituted cyclic linking group and R5 is halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl;
Y is C or N;
R2 is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl; provided that when Y is C, R2 may not be absent;
X is C(RB) or N;
R6 is hydrogen or C 6 alkyl; and
ring B is a saturated or unsaturated optionally substituted carbon containing cyclic group containing from 5 to 7 members, and optionally one or more hetero atoms;
or a pharmaceutically acceptable salt or solvate thereof; or a tautomer thereof;
or a derivative thereof wherein the nitrogen atom is quaternized;
for the in vitro inhibition of tankyrase.
36. Use according to claim 35, wherein the tankyrase is tankyrase-1.
37. Use according to claim 35, wherein the tankyrase is tankyrase-2.
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