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.

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 cancer ⁴² 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:

Formula I wherein 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; 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(R ₆ ); 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:

Formula IA wherein 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; 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: 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; 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:

Formula IA wherein 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; 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:

Formula Γ 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; 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: 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; 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:

Formula I' wherein:

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-|- 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:

Formula IA wherein 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; 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: 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; 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-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.

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-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. 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 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. 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. 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. For example, C ₃ _ 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 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) 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 C _1-6 0 (such as a C _1-3 0).

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., 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-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., 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. Examples of 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. 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:

Formula I wherein 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; 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(R ₆ ); 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:

Formula IA wherein 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; 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-R ₅ .

In some aspects, L is an optionally substituted cyclic linking group and R ₅ is H, halo, hydroxy, nitrile, nitro, amino, or hydrocarbyl.

In some aspects, 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.

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. R ₅ is H, halo, hydroxy, nitriie, nitro, amino, or hydrocarbyl. When R ₅ is H, L is unsubstituted.

In one embodiment, R ₅ is halo, hydroxy, nitriie, nitro, amino, or hydrocarbyl.

In one embodiment, 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-| ₀ alkyi, heteroaryl-C ₁ -C ₁₀ alkyi, ferrocenyl, or aryl-(C _1-3 alkoxy)carbonylamino-C C ₃ alkyi.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, R ₅ is halo, hydroxy, nitriie, nitro, amino, C-|-C ₁₀ alkyi, C C 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.

In one embodiment, R ₅ is H.

In one embodiment, the halo is F, CI or Br.

In one embodiment, 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.

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 C ₁₀ alkyl, such as C C ₆ alkyl, and C C ₃ alkyl. In one embodiment, the hydrocarbyl group is selected from C ₂ -C ₁₀ alkenyl, such as C ₂ -C ₆ alkenyl, and C ₂ -C ₃ alkenyl. In one embodiment, the hydrocarbyl group is selected from C ₂ -C ₁₀ alkynyl, such as C ₂ -C ₆ alkynyl, and C ₂ -C ₃ alkynyl.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, R ₅ is halo, Ci-C ₀ alkyl, C-|-C ₀ alkoxy, Ci-C ₀ haloalkyi, hydroxy, nitrile, nitro, or amino. In one embodiment, R ₅ is halo, CVC ₁₀ alkyl, C-rC ₁₀ alkoxy, C _r C ₁₀ haloalkyi, or hydroxy. In one embodiment, R ₅ is halo, C C ₁₀ alkyl, Ci-C-| ₀ alkoxy, or C-|-C ₀ haloalkyi. In one embodiment, R ₅ is CI, F, Br, C C ₀ alkyl, C-|-C ₁₀ alkoxy, or C-r C-io haloalkyi. In one embodiment, 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 .

In one embodiment, R ₅ is an alkoxy group, preferably a methoxy or an ethoxy group.

In one embodiment, R ₅ is an alkyl group, preferably a methyl or an ethyl group.

In one embodiment, R ₅ is a haloalkyi group, preferably a CI or F containing haloalkyi group.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, R ₅ is nitro or nitrile.

R ₅ 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 R ₅ is present on the ring at the para position. In one embodiment, 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. In one embodiment, the optional substituent is present and is selected from halo, hydroxy, or C C ₆ alkyl.

In one embodiment, 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^ alkoxy)carbonylamino-Ci-C ₃ alkyl.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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 ₆ alkyl, C-|-C ₆ alkoxy, or Ci-C ₆ haloalkyl. In one embodiment, 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-|-C ₆ alkyl, and C C ₆ alkene, CI, F, nitro or nitrile.

In one embodiment, 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 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.

In any of the above embodiments, L may not be further substituted. R ₂

R ₂ is absent or is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl.

In one embodiment, R ₂ is absent. In the compounds of formula I, when Y is C, R ₂ may not be absent. In the compounds of formula IV, when Y is N and ring B is pyridine, R ₂ may be absent. In the compounds of formula V, when Y is N and ring B is piperidine, R ₂ may or may not be absent.

In one embodiment, R ₂ is halo, hydroxy, nitro, nitrile, amino, oxo, or hydrocarbyl.

In one embodiment, 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-|-C ₃ alkyl, C C ₃ alkoxy, C C ₃ haloalkyl, nitro, nitrile, and oxo. In one embodiment, R ₂ is selected from halo, C C ₆ haloalkyl, C†-C ₆ alkyl, and C-|-C ₆ alkoxy. In one embodiment, R ₂ is selected from CI, F, Br, methyl, ethyl, CF ₃ , CCI ₃ , amino, methoxy and ethoxy. In one embodiment, R ₂ is selected from CI, F, Br, methyl, ethyl, CF ₃ , CCI ₃ , methoxy and ethoxy. In one embodiment, R ₂ is selected from CI, F, Br, methyl, ethyl, CF ₃ , CCI ₃ , methoxy and ethoxy. In one embodiment, R ₂ is halo, preferably CI or F.

In one embodiment, R ₂ is C C ₁₀ haloalkyl, preferably C C ₆ haloalkyl, preferably C C ₃ haloalkyl, preferably CF ₃ or CCI ₃ .

In one embodiment, R ₂ is C C^ ₀ alkyl, preferably C^Ce alkyl, preferably C C _z alkyl, preferably methyl or ethyl.

In one embodiment, R ₂ is C C ₁₀ alkoxy, preferably C C ₆ alkoxy, preferably C C ₁₃ alkoxy, preferably -OMe or -OEt.

In one embodiment, R ₂ 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(R ₆ ) (wherein R ₆ 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(R ₆ ).

R ₆

R ₆ is H or C _1-6 alkyl.

In one embodiment, 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

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

wherein 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.

In one embodiment, the hydrocarbyl groups for R ₃ , R ₄ and R ₈ are as defined above as for R ₅ . 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. 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:

wherein 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.

In one embodiment, the hydrocarbyl groups for R ₃ , R ₄ and R ₈ are as defined above as for R ₅ . 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.

In one embodiment, ring B is an optionally substituted piperidine group. In this embodiment, the compound is of formula V

wherein: 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.

In one embodiment, 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.

In one embodiment, 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. In one aspect, the group Y is a quaternary nitrogen atom, the group R ₂ providing the quaternary substituent. In this aspect, preferably 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

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(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.

In one embodiment, 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.

In one embodiment, 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-C -C ₃ alkyl, and X is C(R ₆ ) wherein R ₆ is H or methyl.

In one embodiment, 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 alkyl, and X is CH.

In one embodiment, 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, and X is C(R ₆ ) wherein R ₆ is H or methyl.

In one embodiment, 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, and X is CH.

In one embodiment, 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, and X is CH. In one embodiment, 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, and R ₃ , R ₄ and R ₈ are independently hydrogen or a substituent selected from halo, hydroxy, and C C ₆ alkyi.

In one embodiment, 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, and R ₃ , R and R ₈ are independently hydrogen or a substituent selected from halo, hydroxy, and C-|-C ₆ alkyi.

In one embodiment, the compound is of formula III

wherein R-i , R ₂ , R ₃ , R ₄ and R ₈ are as defined above.

In one embodiment, the compound is of formula III

wherein 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 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, Ο-ι-Οβ alkyl, -i-C ₆ alkoxy, nitro, nitrile, amino, and oxo; and

R ₃ , R ₄ and R ₈ are each H.

In one embodiment, the compound is of formula III

wherein 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,

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, C C 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, C ₁ -C ₆ alkyl, C C ₆ alkoxy, nitro, nitrile and oxo; and

R ₃ , R ₄ and R ₈ are as defined above.

wherein 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.

In one embodiment, the compound is of formula IV:

Formula IV wherein 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 _-3 alkoxyJcarbonylamino-C Ca alkyl, and X is C(R ₆ ) wherein R ₆ is H or methyl.

In one embodiment, the compound is of formula V:

wherein: 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, ferrocenyl, or aryl-(C _1-3 alkoxy)carbonylamino-C -C ₃ alkyl, and X is C(R ₆ ) wherein R ₆ is H or methyl.

In some aspects, when X is nitrogen, R ₂ 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)quina zolin-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)quina zolin-4-one;

or a pharmaceutically acceptable salt or solvate thereof.

Examples of compounds of the present invention include the following:

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 fibrosis ⁴⁷ 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 MgCI ₂ , 20μΜ 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 ^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.

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 H ₂ 0. 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 H ₂ 0. 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 IC ₅₀ 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 MgCI ₂ , 20 μΜ 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 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. H ₂ S0 ₄ (1 .0 M, 25 μί) 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 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_ 10 ^χ PARP cocktail (catalogue # 4671 -096-03), 2.5 μΙ_ 10 ^χ 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 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 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 (r ² ) 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 IC ₅₀ (μΜ)

Tank-2 = Tankyrase-2 IC ₅₀ (μΜ)

PARP-1 = PARP-1 IC ₅₀ (μΜ)

IMPDH2 = IMPDH2 IC ₅₀ (μ )

Cyt Col = Cytotoxicity vs. HT29 human colon adenocarcinoma cells IC ₅₀ (μΜ)

Cyt Fib = Cytotoxicity vs. FEK4 human fibroblasts IC ₅₀ (μΜ)

Table 2

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. ¹ H and ¹³ C and ¹⁹ F NMR spectra were recorded at 400.04 or 500.13 MHz ( ¹ H) and 100.59 or 125.76 MHz ( ¹³ C), using containing tetramethylsilane as an internal standard. ¹⁹ F 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 2 ⁸⁵ (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 v _max (KBr) 1747, 1645, 1524, 1347 cm ^'1 ; ¹ H NMR (CDCI ₃ ) δ 1.17 (3 H, t, J = 7.6 Hz, Me), 2.55 (2 H, q, J = 7.6 Hz, CH ₂ ), 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); ¹³ C NMR (CDCI ₃ ) δ 1 1.73 (Me), 27.99 (CH ₂ ), 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) ⁺ (C ₁₁ H ₉ N0 ₄ 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 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. 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 v _max (film) 1736, 1646, 1530, 1344 cm ^"1 ; ¹ H NMR (CDCI ₃ ) δ 0.92 (3 H, m, pentyl 5-H ₃ ), 1.35-1.40 (4 H, m, pentyl 3,4-H ₄ ), 1.70-1.78 (2 H, m, pentyl 2-H ₂ ), 2.59 (2 H, t, J = 7.8 Hz, pentyl 1 -H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) δ 13.96 (pentyl 5-C), 22.37 (CH ₂ ), 26.61 (CH ₂ ), 31.18 (CH ₂ ), 34.20 (CH ₂ ), 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) ⁺ (C ₁₄ H ₁₅ N0 ₄ 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 2 ⁸⁵ (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 v _max (KBr) 1739, 1626, 1525, 1341 cm ^"1 ; ¹ H NMR (CDCI ₃ ) δ 7.50-7.53 (3 H, m, Ph 3,4,5-H ₃ ), 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) 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) ⁺ (C ₁₅ H ₉ N0 ₄ 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 2 ⁸⁵ (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 v _max (KBr) 1737, 1618, 1511 , 1321 cm ^"1 ; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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) ⁺ (C ₁₆ HnN0 ₄ requires 282.0766).

3-(4-Methoxyphenyl)-5-nitroisocoumarin (3e). 1 ,3-Di(4-methoxyphenyl)-1 ,3- propanedione ⁸⁷ (10.0 g, 35 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 2 ⁸⁵ (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 v _max (KBr) 1738, 1620, 1511 , 1346 cm ^-1 : ¹ H NMR (CDCI ₃ ) δ 3.88 (3 H, s, Me), 6.99 (2 H, d, J = 9.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) 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-dione ⁸⁸ (7.1 g, 36 mmol) was boiled under reflux with 2-bromo-3-nitrobenzoic acid 2 ⁸⁵ (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 v _max (KBr) 1745, 1522, 1340 cm ^"1 ; H NMR (CDCI ₃ ) δ 7.47 (2 H, d, J = 9.0 Hz, Ph 3,5-H ₂ ), 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- H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) 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) ⁺ (C ₁₅ H ₈ ³⁷ CIN0 ₄ requires 303.0 12), 301.0137 (M) ⁺

(C ₁₅ H ₈ ³⁵ CIN0 ₄ 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 v _max (KBr) 3432, 1666, 1524, 1372 cm ^"1 ; ¹ H NMR ((CD ₃ ) ₂ SO) δ

I .22 (3 H, t, J = 7.5 Hz, Me), 2.59 (2 H, q, J = 7.5 Hz, CH ₂ ), 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 v _max (KBr) 3467, 1666, 1524, 1375 cm ^"1 ; ¹ H NMR ((CD ₃ ) ₂ SO) δ 0.88 (3 H, m, pentyl 5-H ₃ ), 1.28-1.34 (4 H, m, pentyl 3,4-H ₄ ), 1.64 (2 H, m, pentyl 2-H ₂ ), 2.55 (2 H, t, J = 7.6 Hz, pentyl 1 -H ₂ ), 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) ⁺ (C ₁₄ H ₁₆ N ₂ 0 ₃ 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 v _ma x (KBr) 3482, 1655, 1536, 1348 crrf ¹ ; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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) ⁺ (C ₁₅ H ₁₀ 2O ₃ 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 v _max (KBr) 3457, 1673, 1620, 1516, 1324 cm ^'1 ; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.62 (1 H, t, J = 8.2 Hz, 7-H), 7.66 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 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) ⁺ (C ₁₆ H ₁₂ N ₂ 0 ₃ requires 280.0848); Anal. Calcd. for C ₁₆ H ₁₂ N ₂ 0 ₃ : 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 v _max (KBr) 3468, 1677, 1615, 1515, 1323 cm ^"1 : ¹ H NMR ((CD ₃ ) ₂ SO) δ 3.82 (3 H, s, Me), 7.07 (2 H, d, J = 9.0 Hz, Ph 3,5-H ₂ ), 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- H ₂ ), 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) ⁺ (C ₁₆ H ₁₂ N ₂ 0 ₄ requires 296.0797), 250 (M - N0 ₂ ) ⁺ ; Anal. Calcd. for C ₁₆ H ₁₂ N ₂ O ₄ -0.5H ₂ O: 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 v _max (KBr) 3465, 1674, 1625, 1525, 1325 cm ^"1 ; ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.22 (1 H, d, J = 0.8 Hz, 4-H), 7.59 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 7.65 (1 H, t, J = 8.2 Hz, 7-H), 7.79 (2 H, d, J = 8.6 Hz, Ph 2,6-H ₂ ), 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) ⁺ (C ₁₅ H ₁₀ ³⁷ CIN ₂ O3 requires 303.0350), 301.0377 (M + H) ⁺

(C ₁₅ H ₁₀ ³⁵ CIN ₂ O ₃ requires 301.0380); Anal. Calcd. for C ₁₅ H ₉ CIN ₂ O ₃ -0.25H ₂ O: 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 v _max (KBr) 3447, 3395, 3164, 1646 cnV ¹ ; H NMR ((CD ₃ ) ₂ SO) δ 1.21 (3 H, t, J = 7.5 Hz, Me), 2.47 (2 H, q, J = 7.4 Hz, CH ₂ ), 5.51 (2 H, br, NH ₂ ), 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) ⁺

(CiiH ₁₃ N ₂ 0 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 v _max (KBr) 3448, 3395, 3166, 1651 cm ^'1 ; ¹ H NMR (CDCI ₃ ) δ 0.82 (3 H, m, pentyl 5-H ₃ ), 1.21-1.34 (4 H, m, pentyl 3,4-H ₄ ), 1.72 (2 H, m, pentyl 2-H ₂ ), 2.57 (2 H, t, J = 7.6 Hz, pentyl 1-H ₂ ), 3.94 (2 H, br, NH ₂ ), 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) ⁺ (C ₁₄ H ₁₈ N ₂ 0 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 v _max (KBr) 3569, 3329, 3230, 1655 cm ^"1 ; H NMR (CDCI ₃ ) δ 4.00 (2 H, br, NH ₂ ), 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-H ₃ ), 7.65 (2 H, m, Ph 2,6-H ₂ ), 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) ⁺ (C ₁₅ H ₁₃ N ₂ 0 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 v _max (KBr) 3476, 3253, 1669 cm ^"1 ; ¹ H NMR (CDCI ₃ ) δ 2.41 (3 H, s, Me), 4.06 (2 H, br, NH ₂ ), 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-H ₂ ), 7.59 (2 H, d, J = 7.8 Hz, Ph 2,6-H ₂ ), 7.86 (1 H, d, J = 7.8 Hz, 8-H), 9.92 (1 H, br, NH); MS m/z 251.1181 (M + H) ⁺ (C ₁₆ H ₁₅ N ₂ 0 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 v _max (KBr) 3438, 3233, 1660 cm ^"1 ; H NMR (CDCI ₃ ) δ 3.86 (3 H, s, Me), 4.1 1 (2 H, br, NH ₂ ), 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-H ₂ ), 7.25 (1 H, t, J = 7.8 Hz, 7-H), 7.66 (2 H, d, J = 8.8 Hz, Ph 2,6-H ₂ ), 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) ⁺ (C ₁₆ H ₁₅ N ₂ 0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 1 1.50 (1 H, br, NH); MS m/z 273.0618 (M + H) ⁺ (C ₁₅ H ₁₂ ³⁷ CIN ₂ 0 requires 273.0609); 271.0629 (M + H) ⁺ (C ₁₅ H ₁₂ ³⁵ CIN ₂ 0 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; ¹ H NMR (CD ₃ OD) 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); ³ C NMR

(CD ₃ OD) (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) ⁺ (C ₁₆ H ₁₅ N ₂ 0 ₂ 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; ¹ H NMR (CD ₃ OD) 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-H ₂ ), 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); ¹³ C NMR (CD ₃ OD) (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) ⁺ (C ₁₆ H ₁₃ N ₂ 0 ₂ 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; ¹ H NMR (CD ₃ OD) δ 6.71 (1 H, s, 4-H), 7.51 (2 H, m, Ph 4,5-H ₂ ), 7.60 (2 H, m, Ph 3,6-H ₂ ), 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); ³ C NMR (CD ₃ OD) (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) (C ₁₅ H ₁₂ ³⁷ CIN ₂ 0 requires 273.0609), 271.0623 (M + H) ⁺ (C ₁₅ H ₁₂ ³⁵ CIN ₂ 0 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 (CD ₃ OD) δ 6.93 (1 H, s, 4-H), 7.55 (2 H, m, Ph 4,6-H ₂ ), 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); ¹³ C NMR (CD ₃ OD) (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) ⁺

(C ₁₅ H ₁₂ ³⁷ CIN ₂ 0 requires 273.0609), 271.0616 (M + H) ⁺ (C ₁₅ H ₁₂ ³⁵ C[N ₂ 0 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; ¹ H NMR (CD ₃ OD) 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-H ₂ ), 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); ¹³ C NMR (CD ₃ OD) (HSQC / HMBC) δ 101.69 (4-C), 128.44 (7-C), 128.98 (6-C), 129.47 (8-C), 129.57 (Ph 3,5-C ₂ ), 133.13 (Ph 4-C), 133.42 (5-C), 133.88 (Ph 1-C), 136.46 (Ph 2,6-C ₂ ), 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; ¹ H NMR (CD ₃ OD) δ 6.99 (1 H, s, 4-H), 7.34 (3 H, m, 8 & Ph 3,5-H ₃ ), 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-H ₂ ), 1 1.71 (1 H, bs, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 98.62 (4-C), 1 15.48 (8-C), 1 15.68 (d, J =6.1 Hz, Ph 3,5-C ₂ ), 124.75 (Ph 1-C), 125.72 (3-C), 126.66 (7-C), 128.99 (d, J = 17.2 Hz, Ph 2,6-C ₂ ), 130.1 1 (6-C), 137.96 (Ph 4-C), 141.34 (5-C), 162.63 (1-C); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -112.47 (m, F); MS m/z 253.0756 (M - H) ^" (C ₁₅ H ₁₀ FN ₂ O 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.17 (2 H, m, 4,6-H ₂ ), 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- H ₂ ), 8.04 (2 H, d, J = 8.0 Hz, Ph 2,6-H ₂ ), 1 1.63 (1 H, br, NH); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ - 61.02 (s, CF ₃ ); ¹³ C NMR ((CD ₃ ) ₂ SO) (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, CF ₃ ), 125.64 (q, J = 3.5 Hz, Ph 3,5-C ₂ ), 126.28 (4a-C), 127.41 (7-C + Ph 2,6-C ₂ ), 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) ^' (C ₁₆ H ₁₀ F ₃ N ₂ O 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; ¹ H NMR (CD ₃ OD) 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); ¹³ C NMR (CD ₃ OD) (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) (C ₁₆ HnN ₃ 0 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 ((CD ₃ ) ₂ SO) δ 7.15 (2 H, m, 4,6-H ₂ ), 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-H ₂ ), 7.99 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ), 1 1.53 (1 H, bs, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 127.09 (7-C), 127.89 (Ph 3,5-C ₂ ), 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; ¹ H NMR (CD ₃ OD) δ 6.65 (1 H, s, 4-H), 7.69 (4 H, m, 7-H + Ph 4,5,6-H ₃ ), 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); ¹³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 100.84 (4-C), 125.24 (q, J = 271.3 Hz, CF ₃ ), 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); ¹⁹ F NMR (CD ₃ OD) δ -59.36 (s, CF ₃ ); MS m/z 305.0872 (M + H) ⁺

(C ₁₆ H ₁₂ F ₃ N ₂ 0 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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); ⁹ F NMR

((CD ₃ ) ₂ SO) δ -61.03 (s, CF ₃ ) ¹³ C NMR ((CD ₃ ) ₂ SO) (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) ^" (C ₁₆ H ₁₀ F ₃ N ₂ O 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 6.88 (3 H, m, 4-H + Ph 3,5-H ₂ ), 7.36 (2 H, m, 6,7-H ₂ ), 7.67 (2 H, d, J = 9.0 Hz, Ph 2,6-H ₂ ), 7.88 (1 H, d, J = 9.0 Hz, 8-H), 1 .46 (1 H, br s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 96.01 (4-C), 115.55 (Ph 3,5-C ₂ ), 124.59 (7-C), 125.36 (6-C), 125.94 (8-C), 128.09 (Ph 2,6-C ₂ ), 139.99 (3-C), 158.69 (Ph

4- C), 162.45 (1-C); MS m/z 253.0958 (M + H) ⁺ (C ₁₅ H ₁₃ N ₂ 0 ₂ 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; ¹ H NMR (CD ₃ OD) δ 2.95 (2 H, t, J = 7.0 Hz, ethyl 1-H ₂ ), 3.06 (2 H, t, J = 6.0 Hz, ethyl 2-H ₂ ), 6.48 (1 H, s, 4-H), 7.24 (5 H, m, Ph-H ₅ ), 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); ¹³ C NMR (CD ₃ OD) (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-C ₂ ), 129.62 (Ph 3,5-C ₂ ), 134.04 (5-C), 141.57 (Ph 1-C), 145.88 (3-C), 164.03 (1 -C); MS m/z 265.1320 (M + H) ⁺ (C ₁₇ H ₁₇ N ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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); ³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₇ H ₁₄ N ₂ Na0 ₄ requires 333.0852), 311.1030 (M + H) ⁺

(C ₁₇ H ₁₅ N ₂ 0 ₄ 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₇ H ₁₅ N ₂ 0 ₄ 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 (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₆ H ₁₂ ³⁵ CIN ₂ 0 ₃ 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; ¹ H NMR (CDCI ₃ ) δ 4.18 (3 H, s, Me), 7.41 (2 H, m, Ph 5,6-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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) ⁺

(C ₁₆ H ₁₂ ³⁵ CIN ₂ 0 ₃ 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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); ³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 54.61 (Me), 11 1.16 (4-C), 120.08 (4a-C), 125.36 (7-C), 128.24 (Ph 3,5-C ₂ ), 128.56 (6-C), 129.82 (Ph 4-C), 130.75 (8a-C), 131.32 (8-C), 134.86 (Ph 2,6-C ₂ ), 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; ¹ H NMR (CDCI ₃ ) δ 4.27 (3 H, s, Me), 7.19 (2 H, t, J = 8.5 Hz, Ph 3,5-H ₂ ), 7.57 (1 H, t, J = 8.0 Hz, 7-H), 8.19 (2 H, m, Ph 2,6-H ₂ ), 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; ³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 54.11 (Me), 104.79 (4-C), 1 15.68 (d, J = 21.5 Hz, Ph 3,5-C ₂ ), 1 19.91 (4a-C), 124.53 (7-C), 128.72 (6-C), 128.97 (d, J = 8.3 Hz, Ph 2,6-C ₂ ), 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) ⁺ (C ₁₆ H ₁₂ FN ₂ 0 ₃ 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 8.25 (2 H, d, J = 8.1 Hz, Ph 2,6-H ₂ ), 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); ¹⁹ F NMR (CDCI ₃ ) δ -62.56 (s, CF ₃ ); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 126.42 (q, J = 275.0 Hz, CF ₃ ), 127.20 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₇ H ₁₂ F ₃ N ₂ 0 ₃ 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; ¹ H NMR (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 8.32 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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-H ₂ ), 128.85 (6-C), 129.67 (4a-C), 131.26 (8-C), 132.53 (Ph 3,5-H ₂ ), 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 (CDCI ₃ ) 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-H ₂ 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); ¹³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 54.44 (Me), 109.28 (4-C), 119.80 (8a-C), 124.15 (q, J = 270.4 Hz, CF ₃ ), 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); ¹⁹ F NMR (CDCI ₃ ) δ -56.75 (s, CF ₃ ); MS m/z 349.0798 (M + H) ⁺ (C ₁₇ H ₁₂ F ₃ N ₂ 0 ₃ 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 (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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, CF ₃ ), 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); ¹⁹ F NMR (CDCI ₃ ) δ -62.66 (s, CF ₃ ); MS m/z 349.0826 (M + H) ⁺ (C ₁₇ H ₁₂ F ₃ N ₂ 0 ₃ 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 4.23 (3 H, s, Me), 6.95 (2 H, dd, J = 8.8, 2.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 8.24 (1 H, s, 4-H), 8.59 (2 H, m, 6,8-H ₂ ). 9.87 (1 H, br, OH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 54.05 (O-Me), 102.51 (4-C), 115.73 (Ph 3,5-C ₂ ), 1 18.51 (8a-C), 125.13 (7-C), 128.30 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₆ H ₁₃ N ₂ 0 ₄ 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; ¹ H NMR (CDCI ₃ ) δ 4.22 (3 H, s, Me), 7.38 (3 H, m, Ph 3,4,5-H ₃ ), 7.60 (1 H, t, J = 8.0 Hz, 7-H), 7.64 (2 H, m, Ph 2,6-H ₂ ), 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); ³ C NMR (CDCI ₃ ) (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-C ₃ ), 128.82 (6- C), 130.52 (8a-C), 131.30 (8-C), 132.13 (Ph 2,6-C ₂ ), 137.55 (3-C), 144.15 (5-C), 160.76 (1 -C); MS m/z 305.0901 (M + H) ⁺ (C ₁₈ H ₁₃ N ₂ 0 ₃ 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; ¹ H NMR ((CD ₃ ) ₂ SO)) δ 7.19 (1 H, s, 4-H), 7.36 (2 H, t, J = 8.6 Hz, Ph 3,5-H ₂ ), 7.65 (1 H, J = 7.9 Hz, 7-H), 7.84 (2 H, dd, J = 8.2, 5.3 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 96.94 (4-C), 1 15.56 (d, J = 21.8 Hz, Ph 3,5-C ₂ ), 125.41 (7-C), 126.38 (8a-C), 129.36 (8-C), 129.43 (Ph 2,6-C ₂ ), 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); ⁹ F NMR ((CD ₃ ) ₂ SO) δ - 110.96 (m, F); MS m/z 283.0524 (M - H) ^" (C ₁₅ H ₈ FN ₂ 0 ₃ 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.99 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 98.63 (4-C), 124.01 (q, J = 270.8 Hz, CF ₃ ), 125.81 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 126.36 (7-C), 126.89 (8a-C), 128.27 (Ph 2,6-C ₂ ), 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); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -61.22 (s, CF ₃ ); MS m/z 333.0493 (M - H) ^" (C ₁₆ H ₈ F ₃ N ₂ 0 ₃ 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; ¹ H NMR (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₇ H ₁₆ N ₂ Na0 ₂ 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ + 8-H); ¹³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₇ H ₁₆ N ₂ Na0 ₂ requires 303.1 1 10), 281.1278 (M + H) ⁺ (C ₁₇ H ₁₇ N ₂ 0 ₂ 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₆ H ₁₄ ³⁵ CIN ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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) ⁺ (C ₁₆ H ₁₄ ³⁵ CIN ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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- H ₂ ), 7.74 (1 H, dt, J = 8.2, 1.0 Hz, 8-H); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 129.30 (Ph 4-C), 1 19.69 (4a-C), 127.62 (8a-C), 135.25 (Ph 2,6-C ₂ ), 138.92 (Ph 1-C), 141.65 (5-C), 144.58 (3-C), 160.94 (1-C); MS m/z 321.0356 (M + H) ⁺ (C ₁₆ H ₁₃ ³⁵ CI ³⁷ CIN ₂ 0 requires 321.0375), 319.0387 (M + H) ⁺ (C ₁₆ H ₁₃ ³⁵ CI ₂ N ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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-H ₂ ); ¹⁹ F NMR (CDCI ₃ ) δ -1 14.31 (m, F); ¹³ C NMR (CDCI ₃ ) (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- C ₂ ), 1 19.40 (4a-C), 126.72 (7-C), 128.62 (d, J = 10.4 Hz, Ph 2,6-C ₂ ), 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) ⁺ (C ₁₆ H ₁₄ FN ₂ 0 requires 269.1092); MS m/z 267.0925 (M - H) ^" (C ₁₆ H ₁₂ FN ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 8.25 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ); ¹⁹ F NMR (CDCI ₃ ) δ -62.40 (s, CF ₃ ); ¹³ C NMR (CDCI ₃ ) (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, CF ₃ ), 125.48 (q, J = 3.9 Hz, Ph 3.5-C2), 126.68 (Ph 2,6-C ₂ ), 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) ^' (C ₁₇ H ₁₂ F ₃ N ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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); ¹³ C MR (CDCI ₃ ) (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) ⁺ (C ₁₇ H ₁₄ N ₃ 0 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; ¹ H NMR (CDCi ₃ ) 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-H ₂ ), 8.25 (2 H, d, J = 8.7 Hz, Ph 2,6-H ₂ ); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 127.77 (7-C), 127.98 (8a-C), 132.39 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₇ H ₁₄ N ₃ 0 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 7.73 (1 H, d, J = 8.5 Hz, 8-H), 7.81 (1 H, d, J = 8.0 Hz, Ph 3-H); ¹³ C NMR (CDCI ₃ ) (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, CF ₃ ), 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) ⁺ (C ₁₇ H ₁₃ F ₃ N ₂ NaO 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; ¹ H NMR (CDCI ₃ ) 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); ¹⁹ F NMR (CDCI ₃ ) δ -62.50 (s, CF ₃ ); ¹³ C NMR (CDCI ₃ ) (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, CF ₃ ), 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) ⁺ (C ₁₇ H ₁₄ F ₃ N ₂ 0 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; ¹ H NMR (CD ₃ OD) δ 4.17 (3 H, s, Me), 6.87 (2 H, d, J = 7.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ); ¹³ C NMR (CD ₃ OD) (HSQC / HMBC) δ 53.84 (Me), 104.35 (4-C), 114.14 (8-C), 1 14.63 (6-C), 116.24 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₆ H ₁₅ N ₂ 0 ₂ 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 H ₂ for 6 h. Filtration (Celite ^® ) and evaporation gave 5-amino-1 -methoxy-3-phenethylisoquinoline 14 (51 mg, 87%) as buff oil; ¹ H NMR (CDCI ₃ ) δ 3.15 (4 H, m, CH ₂ CH ₂ ), 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-H ₅ ), 7.69 (1 H, d, J = 8.5 Hz, 8-H); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 128.30 (8a-C), 128.51 (Ph 3,5-C ₂ ), 140.79 (5-C), 142.17 (Ph 1-C), 150.72 (3-C), 160.69 (1-C); MS m/z 279.1560 (M + H) ⁺ (C ₁₇ H ₁₆ N ₂ 0 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: ¹ H NMR (CDCI ₃ ) (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); ¹³ C NMR (CDCI ₃ ) (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) (CnH ₁₆ NO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₃ ), 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-H ₂ ), 8.07 (1 H, d, J = 8.0 Hz, 8-H), 1 1.60 (1 H, s, N-H); ³ C NMR ((CD ₃ ) ₂ SO)) (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-C ₂ ), 128.72 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₆ H ₁₃ NNaO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 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-H ₂ ), 8.06 (1 H, d, J = 8.0 Hz, 8-H), 1 1.54 (1 H, br, N-H); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.36 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₇ H ₁₆ NO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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- H ₃ ), 7.90 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 8.12 (1 H, d, J = 7.8 Hz, 8-H), 11.70 (1 H, s, N-H); ¹³ C NMR ((CD ₃ ) ₂ SO)) (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-C ₂ ), 128.78 (Ph 3,5-C ₂ ), 133.01 (4a-C), 133.34 (6-C), 133.96 (Ph 1 ,4-C ₂ ), 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 8.03 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 8.08 (1 H, d, J = 8.0 Hz, 8-H), 1 1.75 (1 H, bs, N-H); ³ C NMR ((CD ₃ ) ₂ SO)) (HSQC / HMBC) δ 18.77 (Me), 101.54 (4-C), 124.62 (8-C), 125.23 (q, J = 295.9 Hz, CF ₃ ), 125.51 (8a-C), 125.56 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 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); ⁹ F NMR ((CD ₃ ) ₂ SO)) -61.0808 (s, CF ₃ ); MS m/z 302.0808 (M - H) ^" (C ₁₇ HnF ₃ NO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 8.08 (1 H, d, J = 8.0 Hz, 8-H), 1 1.59 (1 H, br, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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) ⁺ (C ₁₆ H ₁₂ ³⁵ CINNaO 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 ((CD ₃ ) ₂ SO) (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- H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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) ⁺ (C ₁₆ H ₁₂ ³⁵ CINNaO requires 292.0506), 270.0661 (M + H) ⁺

(C ₁₆ H ₁₃ ³⁵ CINO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 8.09 (1 H, d, J = 7.9 Hz, 8-H), 11.62 (1 H, br, NH); 3C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 131.67 (Ph 4-C), 133.19 (Ph 1-C), 133.29 (6- C), 133.75 (4a-C), 134.69 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₆ H ₁₂ ³⁵ CI ₂ NO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 7.78 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ), 8.07 (1 H, d, J = 8.0 Hz, 8-H), 1.59 (1 H, br, NH); ¹³ C NMR

((CD ₃ ) ₂ SO) (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-C ₂ ), 131.66 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₆ H ₁₂ ⁷⁹ BrNNaO 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 ((CD ₃ ) ₂ SO) (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-H ₂ ), 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-H ₂ ), 8.05 (1 H, d, J = 8.0 Hz, 8-H), 1 1.45 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.81 (5-Me), 55.34 (OMe), 98.87 (4-C), 1 14.15 (Ph 3,5-C ₂ ), 124.57 (8-C), 124.63 (8a-C), 125.51 (7-C), 126.51 (Ph 1 -C), 128.23 (Ph 2,6-C ₂ ), 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) ⁺ (C ₃ 4H ₃ o ₂ Na0 ₄ requires 553.2104); 288.0994 (M + Na) ⁺ (C ₁₇ H ₁₅ NNa0 ₂ requires 288.1000), 266.1 179 (M + H) ⁺ (C ₁₇ H ₁₆ N0 ₂ 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 ((CD ₃ ) ₂ SO) (COSY) δ 2.54 (3 H, s, Me), 6.10 (2 H, s, CH ₂ ), 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); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.83 (Me), 99.37 (4-C), 101.52 (CH ₂ ), 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) ^" (C ₁₇ H ₁₂ N0 ₃ 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₃ ), J = 7.6 Hz, 7-H), 7.45 (3 H, m, Ph 3,4,5-H ₃ ), 7.56 (1 H, d, J = 7.4 Hz, 6-H), 7.59 (2 H, m, Ph 2,6-H ₂ ), 7.67 (2 H, d, J = 8.0 Hz, Ar 3,5-H ₂ ), 7.90 (2 H, d, J = 8.0 Hz, Ar 2,6-H ₂ ), 8.08 (1 H, d, J = 7.9 Hz, 8-H), 1 1.62 (1 H, br, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.84 (Ph 3,5-C ₂ ), 129.03 (Ph 10-C), 131.47 (Ph 2,6-C ₂ ), 131.66 (Ar 3,5-C ₂ ), 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) ⁺ (C ₂₄ H ₁₇ NNaO requires 358.1208), 336.1402 (M + H) ⁺ (C ₂₄ H ₁₈ NO 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); ¹ H NMR (CDCI ₃ ) δ 7.38 (3 H, m, Ph 3,4,5-H ₃ ), 7.55 (2 H, m, Ph 2,6-H ₂ ), 7.60 (4 H, m, NCPh 2,3,5,6-H ₄ ); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 129.04 (Ph 4-C), 131.69 (Ph 2,6-C ₂ ), 131 .93 (NCPh 2,6-C ₂ ), 131.95 (NCPh 3,5-C ₂ ).

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: ¹ H NMR (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₃ ), 7.77 (3 H, m, 8-H + Ph 2,6-H ₂ ), 1 1.59 (1 H, br, N-H); ³ C MR ((CD ₃ ) ₂ SO) (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-C ₂ ), 126.85 (7-C), 128.40 (8a-C), 128.83 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₆ H ₁₃ NaN0 ₂ 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 ((CD ₃ ) ₂ SO) (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-H ₂ ), 7.41 (1 H, t, J = 8.0 Hz, 7-H), 7.66 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 7.77 (1 H, dt, J = 8.0, 0.8 Hz, 8-H), 11.54 (1 H, br, N-H); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 126.64 (7-C), 128.52 (8a-C), 129.40 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₇ H ₁₅ NaN0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 7.84 (3 H, m, 8-H + Ph 2,6-H ₂ ), 1 1.71 (1 H, br, N- H); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.79 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₆ H ₁₂ ³⁵ CINNa0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 7.98 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 11.75 (1 H, bs, N-H); ¹³ C NMR

((CD ₃ ) ₂ SO) (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, CF ₃ ), 125.51 (q, J = 3.8 Hz, Ph 3,5-C ₂ ), 126.15 (4a-C), 127.40 (7-C), 127.49 (Ph 2,6-C ₂ ), 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); ¹⁹ F NMR ((CD ₃ ) ₂ SO) 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: ¹ H NMR (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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); ¹⁹ F NMR (CDCI ₃ ) δ -1 5.66 (d, J = 6.1 Hz, 3-F); MS m/z (M + H) ⁺ 182.0973 (C ₁₀ H ₁₃ FNO 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 ((CD ₃ ) ₂ SO) (COSY) δ 6.91 (1 H, s, 4-H), 7.55 (4 H, m, 7-H + Ph 3,4,5-H ₃ ), 7.66 (1 H, m, 6-H), 7.87 (2 H, m, Ph 2,6-H ₂ ), 8.10 (1 H, d, J = 7.9 Hz, 8-H), 11.84 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.83 (Ph 3,5-C ₂ ), 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); ⁹ F NMR ((CD ₃ ) ₂ SO) δ - 21.96 (dd, J = 9.9, 5.2 Hz, F); MS m/z 238.0670 (M - H) ^~ (C ₁₅ H ₉ FNO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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- H ₂ ), 7.84 (2 H, d, J = 8.6 Hz, Ph 2,6-H ₂ ), 8.05 (1 H, d, J = 7.9 Hz, 8-H), 11.63 (1 H, br, N-H); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.57 (Ph 2,6-C ₂ ), 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); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -122.79 (m, F); MS m/z 272.0762 (M - HV (C ₁₅ H ₈ ³⁵ CIFNO 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 8.05 (3 H, m, Ph 2,6-H ₂ + 8-H), 1 1.92 (1 H, br, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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, CF ₃ ), 125.63 (q, J = 3.5 Hz, Ph 3,5-H ₂ ), 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-C ₂ ), 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); ¹⁹ F NMR (DMSO) δ -61.19 (3 F, s, CF ₃ ), -121.55 (1 F, m, F); MS m/z 306.0559 (M - H) ^" (C ₁₆ H ₈ F ₄ NO 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 8.02 (1 H, d, J = 8.0 Hz, 8-H), 1 1.66 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.37 (Me), 93.59 (d, J = 5.3 Hz, 4-C), 1 14.23 (Ph 3,5- C ₂ ), 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-C ₂ ), 141.19 (3-C), 157.19 (d, J = 247.5 Hz, 5-C), 160.41 (Ph 4-C), 161.82 (1- C); ¹⁹ F NMR (DMSO) δ -122.20 (dd, J = 9.9, 5.2 Hz, F); MS m/z 561.1593 (2 M + Na) ⁺ (C ₃₂ H ₂₄ F ₂ N ₂ Na0 ₄ requires 561.1602), 292.0747 (M + Na) ⁺ (C ₁₆ H ₁₂ FNNa0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 7.78 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 8.03 (1 H, d, J = 7.9 Hz, 8-H), 1 1.87 (1 H, bs, N-H); ¹³ C NMR ((CD ₃ ) ₂ SO) 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-C ₂ ), 131.45 (Ph 2,6-C ₂ ), 133.27 (Ph 1-C), 140.87 (3-C), 157.20 (d, J = 248.3 Hz, 5-C), 162.10 (1 -C); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -121.89 (m, F); MS m/z

317.9760 (M - HV (C ₁₅ H ₈ ⁸¹ BrFNO requires 317.9753), 315.9773 (M - H) ^~

(C ₁₅ H ₈ ⁷⁹ BrFNO requires 315.9773).

3-Cyano-2-(phenylethynyl)pyridine (28a). 2-Bromo-3-cyanopyridine 27 ⁹⁰ (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); ¹ H NMR (CDCI ₃ ) δ 7.33 (1 H, dd, J = 8.0, 4.8 Hz, 5-H), 7.40 (m, Ph 3,4,5- H ₃ ), 7.68 (d, J = 5.6 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.99 (Ph 4-C), 132.47 (Ph 2,6-C ₂ ), 139.76 (4-C), 146.04 (2-C), 152.77 (6-C); MS m/z 227.0575 (M + Na) ⁺ (C ₁₄ H ₈ N ₂ Na requires 227.0586), 205.0755 (M + H) ⁺ (C ₁₄ H ₉ N ₂ 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 27 ⁹⁰ (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; ¹ H NMR (CDCI ₃ ) δ 3.83 (3 H, s, Me), 6.90 (2 H, d, J = 9.5 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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- C ₂ ), 1 16.09 (C≡N), 121.45 (3-C), 134.23 (Ph 2,6-C ₂ ), 139.74 (4-C), 146.36 (6-C), 152.74 (2-C), 161.05 (Ph 4-C); MS m/z 257.0670 (M + Naf (C ₁₅ H ₁₀ N ₂ NaO 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 27 ⁹⁰ (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; ¹ H 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-H ₂ ), 7.58 (2 H, d, J = 8.1 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR (HSQC) (CDCI ₃ ) δ 21.70 (Me), 112.66 (2- C), 121.73 (5-C), 129.32 (Ph 3,5-C ₂ ), 132.50 (Ph 2,6-C ₂ ), 139.84 (4-C), 140.61 (Ph 4- C), 152.8 (6-C); MS m/z 219.0905 (M + H) ⁺ (C ₁₅ HnN ₂ 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 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

(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; ¹ H NMR (CDCI ₃ )□ NMR (CDCI%) as J = 4.8, 2.4 Hz, 5-H), 7.37 (2 H, d, J = 8.7 Hz, Ph 3,5-H ₂ ), 7.61 (2 H, d, J = 6.7 Hz, Ph 2,6-H ₂ ), 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); ³ C NMR (CDCI ₃ ) (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-C ₂ ), 133.63 (Ph 2,6-C ₂ ), 136.30 (Ph 4-C), 139.77 (4-C), 145.75 (2-C), 152.85 (6-C); MS m/z 239.0353 (M + H) ⁺ (C ₁₄ H ₈ ³⁵ CIN ₂ H 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 7.79 (2 H, d, J = 8.0 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 131.8 (q, J = ca. 30 Hz, Ph 4- C), 132.75 (Ph 2,6-C ₂ ), 139.87 (4-C), 145.48 (2-C), 152.95 (6-C); ¹⁹ F NMR (CDCI ₃ ) δ -63.03 (s, CF ₃ ); MS m/z 295.0428 (M + Na) ⁺ (C ₁₅ H ₇ F ₃ N ₂ Na requires 295.0459), 273.0622 (M + H) ⁺ (C ₁₅ H _S N ₂ F ₃ 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 27 ⁹⁰ (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 (CDCI ₃ ) δ 3.96 (2 H, br, NH ₂ ), 6.64 (2 H, d, J = 9.1 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 82.87 (ethyne 2-C), 98.10 (ethyne 1-C), 106.48 (Ph 1-C), 1 13.68 (Ph 3,5-C ₂ ), 1 16.51 (5-C), 121.94 (C≡N), 133.58 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₄ H ₉ N ₃ Na requires 242.0694), 220.0876 (M + H) ⁺ (C ₁₄ H ₁₀ N ₃ requires 220.0875).

3- Cyano-2-((4-phenylmethoxyphenyl)ethynyl)pyridine (28h). 4-Ethynyl-1 -phenyl- methoxybenzene ⁹² (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 v _max 3073 (C-H), 2233 (C≡N) 2189 (C≡C), 1599 (C=C _Ar ), 1506, 1464 (C=N) cm ^'1 ; ¹ H NMR (CDCI ₃ ) δ 5.08 (2 H, s, CH ₂ ), 6.98 (2 H, d, J = 9.5 Hz,

phenylethynyl 3,5-H ₂ ) 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-H ₅ ), 7.62 (2 H, d, J = 9.5 Hz, phenylethynyl 2,6-H ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 70.06 (CH ₂ ), 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-C ₂ ), 1 16.08 (phenylethynyl 1-C), 121.47 (5-C), 127.40 (Ph 3,5-C ₂ ), 128. 1 (Ph 4-C), 128.60 (Ph 2,6-C ₂ ), 134.24 (phenylethynyl 3,5-C ₂ ), 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) ⁺ (C ₂₁ H ₁₅ N ₂ 0 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 (lit ⁶⁹ mp 228-229°C); H NMR ((CD ₃ ) ₂ SO) 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-H ₃ ), 7.89 (2 H, d, J = 7.9 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 104.56 (8-C), 120.40 (3-C), 121.62 (4a-C), 126.99 (2C, Ph 3,5-C ₂ ), 128.82 (2C, Ph 2,6-C ₂ ), 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); ¹⁵ N NMR ((CD ₃ ) ₂ SO) δ 124.89 (6-N), 278.87 (1-N); MS m/z 245.0676 (M + Na) ⁺ (C ₁₄ H ₁₀ N ₂ NaO 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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- H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.36 (OMe), 1 14.24 (Ph 3,5-C ₂ ), 120.01 (8-C), 122.42 (4a-C), 123.65 (Ph 1 -C), 125.60 (3-C), 128.39 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₅ H ₁₂ N ₂ Na0 ₂ requires 275.0796), 253.0978 (M + H) ⁺ (C ₁₅ H ₁₃ N ₂ 0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) δ (HSQC / HMBC) 20.81 (Me), 103.99 (8-C), 120.27 (4a- C), 121.43 (3-C), 126.82 (Ph 2,6-C ₂ ), 129.38 (2C, Ph 3,5-C ₂ ), 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) ⁺ (C ₁₅ H ₁₂ N ₂ NaO 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 v _max 3163 (NH), 1669 (C=0), 1627 (C=C _Ar ), 1588, 720 (C-CI) cm ^"1 ; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.91 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 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); ¹³ C ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 104.95 (8-C), 120.58 (4a-C), 121.83 (3-C), 128.82 (Ph 3,5-C ₂ ), 128.93 (Ph 2,6-C ₂ ), 134.60 (4-C), 135.03 (Ph 1-C), 155.05 (C=0), 162.90 (8a-C); ¹⁵ N NMR ((CD ₃ ) ₂ SO) (HMBC) δ 124.20 (s, 6-N); MS m/z 279.0303 (M + H) ⁺ (C ₁₄ H ₉ N ₂ 0 ³⁵ CINa 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.10 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 105.92 (8-C), 120.90 (4a- C), 122.13 (3-C), 124.1 (q, J = 264 Hz, CF ₃ ), 125.62 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 128.03 (Ph 2,6-C ₂ ), 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); ⁵ N NMR ((CD ₃ ) ₂ SO) δ 123.4 (6-N), 279.7 (1 -N); ¹⁹ F NMR ((CD ₃ ) ₂ SO) DO) R ((CDN), 2 ₃ ); MS m/z 291.0727 (M + H) ⁺ (C ₁₅ H ₁₀ N ₂ O 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); ((CD ₃ ) ₂ SO) δ 5.65 (2 H, br, NH ₂ ), 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-H ₂ ), 7.71 (2 H, d, J = 8.7 Hz, Ph 2,6-H ₂ ), 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); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 99.08 (8-C), 1 13.59 (Ph 2,6-C ₂ ), 117.55 (3-C), 122.16 (4a-C), 124.87 (Ph 1 -C), 127.78 (4-C), 130.51 (Ph 3,5- C ₂ ), 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 v _max 3423, 1660, 1617, 1589 cm ^"1 ; ¹ H NMR ((CD ₃ ) ₂ SO) δ 6.87 (1 H, s, 8-H), 6.93 (2H, d, J = 8.6 Hz, Ph 2,6-H ₂ ), 7.37 (1 H, d, J = 7.4 Hz, 3-H), 7.73 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.42 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₄ HnN ₂ 0 ₂ 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 CHCI ₃ . 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₃ ), 7.83 (2 H, d, J = 7.5 Hz, Ph 2,6-H ₂ ), 7.99 (1 H, d, J = 8.0 Hz, 4-H), 8.62 (1 H, dd, J = 6.5, 1.0 Hz, 2-H); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 130.29 (4-C), 137.31 (Ph 1-C), 140.80 (7-C), 162.11 (8a-C); ¹⁵ N NMR ((CD ₃ ) ₂ SO) δ 252.76 (s, 1 -N), 129.56 (s, 6-N); MS m/z 261.0627 (M + Na) ⁺ (C ₁₄ H N ₂ Na0 ₂ 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.47 (1 H, dd, J = 8.0, 4.5, 3-H), 7.73 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC) δ 20.84 (Me), 103.99 (8-C), 121.49 (3-C), 126.86 (Ph 2,6-C ₂ ), 129.42 (Ph 3,5-C ₂ ), 135.03 (4-C), 154.96 (2-C); MS m/z 253.0996 (M + H) ⁺

(C ₁₅ H ₁₃ N ₂ 0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 4.40 (3 H, s, Me), 7.18 (1 H, s, 8-H), 7.63 (3 H, m, Ph 3,4,5-H ₃ ), 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-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 44.97 (Me), 93.61 (8-C), 121.24 (3-C), 123.03 (4a-C), 128.05 (Ph 2,6-C ₂ ), 128.98 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₅ H ₁₃ N ₂ 0 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 44.0 (NMe), 57.0 (OMe), 127.0 (Ph 2,6-C ₂ ), 132.0 (Ph

3.5- C ₂ ), 148.0 (4-C); MS m/z 267.1 136 (M + H) ⁺ (C ₁₆ H ₁₅ N ₂ 0 ₂ 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.31 (2 H, d, J = 8.2 Hz, Ph 3,5-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 48.56 (Me), 90.0 (8-C), 1 18.0 (3-C), 127.0 (Ph 2,6-C ₂ ), 130.0 (Ph 3,5-C ₂ ), 151.0 (2-C); MS m/z 273.0626 (M + H) ⁺ (C ₁₅ H ₁₂ ³⁷ CIN ₂ 0 requires 273.0608); 271.0634 (M + H) ⁺ (C ₁₅ H ₁₂ ³⁵ CIN ₂ 0 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 4.40 (3 H, s, NMe), 6.89 (2 H, d, J = 9.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 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); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 44.73 (Me), 90.53 (8-C), 111.59 (Ph 3,5- C ₂ ), 1 17.33 (Ph 1-C), 1 19.33 (3-C), 122.18 (4a-C), 129.25 (Ph 2,6-C ₂ ), 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 v _max 1655 (C=0), 1620 (C=C _Ph ) cm ^"1 ; ¹ H NMR (CDCI ₃ ) δ 1.89 (2 H, m, 3-H ₂ ), 2.51 (2 H, m, 4-H ₂ ), 3.1 1 (3 H, s, N-CH ₃ ), 3.36 (2 H, m, 2-H ₂ ), 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-H ₂ ); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.25 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₅ H ₁₆ N ₂ NaO 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 v _max 2222 (C≡N), 2150 (C≡C), 1582 (C=C _Ar ), 1495 (C=N) cm ^"1 ; ¹ H NMR (CDCI ₃ ) δ 7.39-7.43 (3 H, m, Ph 3,4,5-H ₃ ), 7.45 (1 H, d, J = 5.2 Hz, 5-H), 7.63 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 8.75 (1 H, d, J = 5.2 Hz, 6-H), 8.87 (1 H, s, 2-H); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 130.28 (Ph 4- C), 132.38 (Ph 2,6-C ₂ ), 134.87 (3-C), 152.40 (2-C), 152.68 (6-C); MS m/z 227.0569 (M + Na) ⁺ (C ₁₄ H ₈ N ₂ Na 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 v _max 3447 (NH ₂ ), 1669 (C=0), 1631 (C=C _Ar ), 1595, 1461 (C=N) cm ^'1 ; ¹ H NMR ((CD ₃ ) ₂ SO) δ 6.97 (1 H, s, 4-H), 7.58 (3 H, m, Ph 3,4,5-H ₃ ), 7.66 (1 H, d, J = 5.4 Hz, 5-H), 7.86 (2 H, dd, J = 7.6 Hz, Ph 2,6-H ₂ ), 8.76 (1 H, d, J = 5.4 Hz, 6-H), 9.38 (1 H, s, 8-H), 11.91 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 101.41 (4-C), 1 19.66 (5-C), 127.12 (Ph 2,6-C ₂ ), 128.87 (Ph 3,5-C ₂ ), 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 (CDCI ₃ ) δ 7.45 (1 H, dd, 7-H), 7.60 (5 H, m, Ph- H ₅ ), 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); ¹³ C NMR (CDCI ₃ ) δ 1 16.1 1 (8a-C), 121.48 (7C), 128.49 (Ph 3,5-C ₂ ), 128.98 (3C), 129.10 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₃ H ₁₀ N ₃ O 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, ¹ H NMR ((CD ₃ )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-H ₂ ), 7.94 (2 H, d, J = 8.1 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) δ 20.99 (Me), 1 19.07 (4a-C), 1 19.84 (6-C), 127.31 (Ph 3,5-C ₂ ), 129.53 (Ph 1-C), 129.61 (Ph 2,6-C ₂ ), 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 (C ₁₄ H ₁₀ N ₃ O 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.29 (1 H, dd, J = 6.8, 4.0 Hz, 6-H), 8.04 (2 H, m, Ph 2,6-H ₂ ), 8.22 (2 H, m, Ph 3,5-H ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 119.0 (6-C), 126.10 (Ph 2,6-C ₂ ), 128.22 (q J = 2.7 Hz, Ph 3,5-C ₂ ), 140.10 (5-C), 149.5 (7-C); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ - 61.35 (CF ₃ ); MS 292.0699 (M + H) ⁺ (C ₁₄ H ₉ F _{3 3} 0 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.25 (1 H, m, 6-H), 7.73 (2 H, d, J = 8.9 Hz, Ph 2,6-H ₂ ), 8.06 (2 H, d, J = 8.9 Hz, Ph 3,5-H ₂ ), 8.42 (1 H, m, 5-H), 8.45 (1 H, m, 7-H), 1 1.10 (1 H, br, NH); ³ C NMR ((CD ₃ ) ₂ SO) δ 1 19.30 (4a-C), 119.75 (6-C), 129.27 (Ph 3,5-C ₂ ), 129.50 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₃ H ₈ ³⁷ CIN ₃ NaO requires 282.0224), 280.0257 (M + Na) ⁺ (C ₁₃ H ₈ ³⁵ CIN ₃ NaO requires 280.0254).

2-Phenylpyrido[3,4-c(|pyrimidin-4-one (41a). 3-Bromopyridine-3-carboxylic acid 40 ⁹³ (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 ((CD ₃ ) ₂ SO) δ 7.62 (3 H, m, Ph 3,4,5-H ₃ ), 8.02 (1 H, d, J = 5.0 Hz, 5-H), 8.26 (2 H, d, J = 6.9 Hz, Ph 2,6-H ₂ ), 8.68 (1 H, d, J = 5.0 Hz, 6-H), 9.16 (1 H, s, 8-H), 10.40 (1 H, br, NH); ¹³ C NMR

((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 18.09 (5-C), 127.42 (Ph 1-C), 127.93 (Ph 2,6-C ₂ ), 128.97 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₃ H ₉ N ₃ NaO requires 246.0641).

2-(4-Methylphenyl)pyrido[3,4-djpyrimidin-4-one (41b). 3-Bromopyridine-3-carboxylic acid 40 ⁹³ (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, ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.44 (3 H, s, Me), 7.36 (2 H, d, J = 8.1 Hz, Ph 3,5-H ₂ ), 7.91 (1 H, d, J = 5.2 Hz, 5-H), 8.24 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 8.52 (1 H, d, J = 5.2 Hz, 6-H), 9.03 (1 H, s, 7-H), 10.20 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.85 (Ph 3,5-C ₂ ), 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 (C ₁₄ H ₁₀ N ₃ O 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.71 (1 H, br, 6- H), 9.23 (1 H, br, 8-H), 13.10 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 125.24 (q, J = 289.3 Hz, CF ₃ ), 125.56 (q, J = 2.3 Hz, Ph 3,5-C ₂ ), 128.91 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₄ H ₉ F ₃ N ₃ 0 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), ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.61 (1 H, m, 8-H), 7.63 (3 H, m, Ph 3,4,5-H ₃ ), 8.28 (2 H, d, J = 7.2 Hz, Ph 2,6-H ₂ ), 8.83 (1 H, br, 7-H), 9.33 (1 H, br, 5-H), 12.80 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 17.5 (4a-C), 120.0 (8-C), 124.0 (Ph 1-C), 128.26 (Ph 3,5-C ₂ ), 128.64 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₃ H ₁₀ N ₃ O 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.45 (3 H, s, Me), 7.29 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 7.64 (1 H, d, J = 5.4 Hz, 5-H), 8.18 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 8.85 (1 H, br, 6-H), 9.33 (1 H, br, 8-H); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 21.0 (Me), 120.12 (8a-C), 120.39 (5-C), 128.17 (Ph 2,6-C ₂ ), 129.21 (Ph 3,5- C ₂ ), 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) ⁺ (C ₁₄ H ₁₂ N ₃ 0 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.71 (1 H, d, J = 4.4 Hz, 8-H), 8.00 (2 H, d, J = 8.3 Hz, Ph 2,6-H ₂ ), 8.44 (2

H, d, J = 8.2 Hz, Ph 3,5-H ₂ ), 9.08 (1 H, br, 7-H), 9.38 (1 H, br, 5-H), 13.10 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 122.04 (8a-C), 125.21 (8-C), 125.24 (Ph 2,6- C ₂ ), 125.51 (q, J = 3.5 Hz, Ph 3,5-C ₂ ), 129.17 (6-C), 131.76 (q, J = 340.6 Hz, CF ₃ ), 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); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -61.34 (s, CF ₃ ); MS m/z 292.0702 (M + H) (C ₁₄ H ₉ F ₃ N ₃ 0 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 ((CD ₃ ) ₂ SO) δ 7.66 (1 H, d, J = 5.6 Hz, 5-H), 7.69 (2 H, d, J = 8.6 Hz, Ph 2,6-H ₂ ), 8.29 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 8.86 (1 H, d, J = 5.5 Hz, 6-H), 9.34 (1 H, br, 8-H), 13.05 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 120.0 (5-C), 126.50 (8a-C), 128.78 (Ph 3,5-C ₂ ), 130.09 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₃ H ₈ ³⁵ CIN ₃ NaO 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); ¹ H NMR (CDCI ₃ ) δ 7.50-7.56 (3 H, m, Ar 3,4,5-H ₃ ), 7.86 (1 H, d, J = 3.5 Hz, 7- H), 8.10-8.1 1 (2 H, m, Ph 2,6-H ₂ ), 8.51 (1 H, d, J = 3.5 Hz, 5-H), 11.93 (1 H, s, NH); ¹³ C NMR (CDCI ₃ ) δ 118.32 (7-C), 125.01 (4a-C), 127.61 (Ph 2,6-C ₂ ), 127.89 (5-C), 128.50 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.37 (3H, s, Me), 5.77 (2H, br, NH ₂ ), 7.22 (2H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 7.61 (2H, d, J = 8.0 Hz, Ph 2,6-H ₂ ), 9.55 (1 H, s, OH); ¹³ C NMR ((CD ₃ ) ₂ SO) δ 20.78 (Me), 125.24 (2,6-C ₂ ), 128.60 (3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 6.01 (2 H, br, NH ₂ ), 7.79 (2 H, d, J = 8.4 Hz, Ph 2,6-H ₂ ), 7.94 (2 H, d, J = 8.4 Hz, Ph 3,5-H ₂ ), 9.96 (1 H, s, OH); ¹³ C NMR ((CD ₃ ) ₂ SO) δ 124.98 (q, J = 3.1 Hz, 3,5-C ₂ ), 125.54 (q, J = 331 Hz, CF ₃ ), 126.05 (2,6-C ₂ ), 129.17 (1 -C), 137.28 (q, J = 28 Hz, 4-C), 149.76 (C=N); ¹⁹ F NMR (CDCI ₃ ) δ -62.84 (CF ₃ ); MS m/z 205.0610 (M + H) ⁺ (C ₈ H ₈ N ₂ OF ₃ 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 5.90 (2 H, br, NH ₂ ), 7.48 (2 H, d, J = 9.2 Hz, Ph 2,6-H ₂ ), 7.74 (2 H, d, J = 9.2 Hz, Ph 3,5-H ₂ ), 9.76 (1 H, s, OH); ³ C NMR ((CD ₃ ) ₂ SO) δ 127.10 (3,5-C ₂ ), 128.10 (2,6-C ₂ ), 132.19 (1- C), 133.41 (4-C), 149.89 (C=N); MS m/z 171.0320 (M + H) ⁺ (C ₇ H ₈ N ₂ 0 ³⁵ CI 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) ₃ SO) δ 2.42 (3H, s, CH ₃ ), 6.72 (3H, br, NH and NH ₂ ), 7.25 (2H, d, J = 8.4 Hz, Ph 3,5-Hz), 7.72 (2H, d, J = 8.3 Hz, Ph 2,6-H ₂ ); ¹³ C NMR ((CD) ₃ SO) δ 20.08 (CH ₃ ), 126.46 (2,6-Cz), 128.56 (3,5-C ₂ ), 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; ¹ H NMR ((CD) ₃ SO) δ 6.72 (2 H, br, NH ₂ ), 7.30 (1 H, br, NH), 7.81 (2 H, d, J = 8.1 Hz, Ph 2,6-H ₂ ), 8.03 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ); ¹³ C NMR ((CD) ₃ SO) δ 24.07 (q, J = 278 Hz, CF ₃ ), 126.43 (2,6-C ₂ ), 128.70 (q, J = 4.5 Hz, 3,5-C ₂ ), 133.16 (1-C), 140.95 (q, J - 35.4 Hz, 4-C), 166.50 (C=N); ¹⁹ F NMR (CDCI ₃ ) δ -61.16 (CF ₃ ); MS m/z 189.0661 (M + H) ⁺ (C ₈ H ₈ N ₂ F ₃ 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; ¹ H NMR ((CD) ₃ SO) δ 7.39 (2 H, br, NH ₂ ), 7.50 (2 H, d, J = 7.5 Hz, Ph 2,6-H ₂ ), 7.93 (2 H, d, J = 8.1 Hz, Ph 3,5-H ₂ ), 8.01 (1 H, br, NH); ¹³ C NMR ((CD) ₃ SO) δ 26.81 (1-C), 127.42 (3,5-C ₂ ), 128.16 (2,6-C ₂ ), 167.88 (4-C), 171.43 (C=N); MS m/z 155.0430 (M + H) (C ₇ H ₈ N ₂ CI 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 8.49 (1 H, s, NHH), 8.73 (1 H, d, J = 7.5 Hz, 3- H), 13.07 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 132.61 (4-C), 134.03 (Ph 1-C), 137.81 (Ph 3,5-C ₂ ), 139.92 (2-C), 163.72 (NHCO), 171.1 1 (CONH ₂ ); MS m/z 388.9780 (M + Na) ⁺ (C ₁₄ HnlN ₂ NaO 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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- H ₂ ), 8.13 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 19.34 (1-C), 120.17 (3-C), 123.84 (q, J = 270.8 Hz, CF ₃ ), 123.08 (5-C), 125.99 (q, J = 3.7 Hz, Ph 3,5-C ₂ ), 126.02 (Ph 1 -C), 127.89 (Ph 2,6-C ₂ ), 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 (CONH ₂ ); MS m/z 331.0670 (M + Na) ⁺ (C ₁₅ H ₁₁ F ₃ N ₂ Na0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 4.24 (5 H, s, Cp ₂ -H ₅ ), 4.49 (2 H, m, Cp^ 3,4- H ₂ ), 4.78 (2 H, m, C ^ 2,5-H ₂ ), 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); ¹³ C NMR ((CD) ₃ SO) (HSQC / HMBC) δ 68.07 (C ^ 2,5-C ₂ ), 69.56 (Cp ₂ -C ₅ ), 70.77 (Cp _! 3,4-C ₂ ), 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 (CONH ₂ ); MS m/z 371.0468 (M + Na) ⁺ (C ₁₈ H ₁₆ ⁵⁶ FeN ₂ Na0 ₂ 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.48-7.59 (4 H, m, Ph 2,4,6-H ₃ + 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-H ₂ + 5-H), 12.49 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 120.97 (C-4a), 125.83 (5-C), 126.54 (6-C), 127.44 (Ph 3,5-C ₂ ), 128.56 (Ph 2,6-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.36 (3 H, s, Me), 7.31 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 8.12 (1 H, dd, J = 8.0, 1.2 Hz, 5-H), 12.39 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.14 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 3.83 (3 H, s, Me) 7.06 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ). ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.44 (Me), 133.97 (Ph 2,6-C ₂ ), 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-C ₂ ), 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 ((CD ₃ ) ₂ SO) δ 7.58 (1 H, m, 6-H), 7.63 (2 H, d, J = 8.7 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 12.59 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 120.96 (4a-C), 125.84 (5-C), 126.73 (6-C), 127.43 (8-C), 128.65 (Ph 3,5-C ₂ ), 129.59 (Ph 2,6-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.54 (1 H, m, 6-H), 7.73-7.77 (3 H, m, 8-H + Ph 3,5-H ₂ ), 7.83-7.86 (1 H, m, 7-H), 8.13 (2 H, d, J = 7.0 Hz, Ph 2,6-H ₂ ), 8.16 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 12.61 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 132.28 (Ph 3,5-C ₂ ), 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ + 3,5-H ₂ ), 8.16 (1 H, dd, J=8.0, 1.0, 5-H), 12.59 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 132.21 (Ph 1-C), 134.62 (7-C), 137.44 (Ph 3,5-C ₂ ), 148.52 (8a-C), 151.75 (2-C), 163.90 (4-C); MS (electron impact) m/z 348.9829 (M) ⁺ (C ₁₄ H ₁₀ IN ₂ O 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.39 (2 H, m, Ph 3,5-H ₂ ), 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-H ₂ ), 12.56 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HMBC / HSQC) δ 115.59 (d, J = 21.7 Hz, Ph 3,5-C ₂ ), 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-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.18 (1 H, dd, J = 8.0, 1.0 Hz, 5-H), 8.37 (2 H, d, = 8.0 Hz, Ph 2,6-H ₂ ), 12.75 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 121.21 (4a-C), 123.96 (q, J = 270.3 Hz, CF ₃ ), 125.50 (q, J = 3.5 Hz, Ph 3,5-H ₂ ), 125.12 (5-C), 127.12 (6-C), 127.69 (8-C), 128.73 (Ph 2,6-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.18 (1 H, dd, J = 8.0, 1.5 Hz, H-5), 8.34 (2 H, m, Ph 2,6-H ₂ ), 12.63 (1 H, m, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 132.27 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.41 (2 H, d, J = 7.2 Hz, Ph 2,6-H ₂ ), 12.82 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 121.22 (4a-C), 123.60 (Ph 3,5-C ₂ ), 125.88 (5-C), 127.33 (6-C), 127.75 (8-C), 129.27 (Ph 2,6-C ₂ ), 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 4.25 (5 H, s, Cp ₂ -H ₅ ), 4.60 (2 H, m Cp<, 3,4-H ₂ ), 5.33 (2 H, m, Cp, 2,5-H ₂ ), 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); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 68.17 (C ^ 2,5-C ₂ ), 69.67 (Cp ₂ -C ₅ ), 71.00 (Cp ₁ 3,4-C ₂ ), 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) ⁺

(C ₁₈ H ₁₄ ⁵⁶ FeN ₂ NaO requires 353.0353).

2- Benzamido-3-methylbenzamide (53a). Dry pyridine (134 mg, 1.7 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ +NHH), 7.53 (2 H, m, Ph 3,5- H ₂ ), 7.58-7.60 (1 H, m, Ph 4-H), 7.71 (1 H, s, NHH), 7.96 (2 H, m, Ph 2,6-H ₂ ), 10.20 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.34 (Me), 125.80 (6-C), 125.99 (5- C), 127.48 (Ph 2,6-C ₂ ), 128.49 (Ph 3,5-C ₂ ), 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 (CONH ₂ ).

3- Methyl-2-(4-methylbenzamido)benzamide (53b). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.44-7.50 (3 H, m, 4,6-H ₂ + NHH), 7.75 (1 H, s, NHH), 7.91 (2 H, d, J = 7.9 Hz, Ph 2,6-H ₂ ), 10.22 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.01 (Ph 3,5-C ₂ ), 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 (CONH ₂ ); MS (electron impact) m/z 269.1261 (M) ⁺ (C ₁₆ H ₁₇ N ₂ 0 ₂ requires 269.1290).

2-(4-Methoxybenzamido)-3-methylbenzamide (53c). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR

((CD ₃ ) ₂ SO) δ 2.26 (3 H, s, 3-Me), 3.89 (3 H, s, OMe), 7.1 1 (2 H, m, Ph 3,5-H ₂ ), 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-H ₂ ) 10.18 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.41 (3-Me), 55.43 (OMe), 1 13.74 (Ph 3,5-C ₂ ), 125.78 (6-C), 126.42 (5-C), 129.39 (Ph 2,6-C ₂ ), 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 (CONH ₂ ); MS m/z 285.1235 (electron impact) (M) ⁺ C ₁₆ H ₁₇ N ₂ 0 ₃ requires 285.1239).

2- (4-Chlorobenzamido)-3-methylbenzamide (53d). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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

((CD ₃ ) ₂ SO) 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-H ₂ + NHH), 7.66 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 7.74 (1 H, s, NHH), 8.03 (2 H, d, J = 8.6 Hz, Ph 2,6-H ₂ ), 10.27 (1 H, s, NH); C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.23 (Me), 125.81 (6-C), 126.15 (5-C), 128.56 (Ph 3,5-H ₂ ), 129.45 (Ph 2,6-H ₂ ), 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 (CONH ₂ ); MS m/z 313.0505 (M + Na) ⁺ (C ₁₅ H ₁₃ ³⁷ CIN ₂ Na0 ₂ requires 313.0527), 31 1.0533 (M + Na) ⁺ (C ₁₅ H ₁₃ ³⁵ CIN ₂ Na0 ₂ requires 311.0563).

2-(4-Bromobenzamido)-3-methylbenzamide (53e). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR

((CD ₃ ) ₂ S0) 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-H ₂ + NHH), 7.73 (1 H, s, NHH), 7.80 (2 H, d, J = 8.6 Hz, Ph 3,5-H ₂ ), 7.95 (2 H, d, J = 8.6 Hz, Ph 2,6-H ₂ ), 10.27 (1 H, s NH); ¹³ C NMR ((CD ₃ ) ₂ S0) (HSQC / HMBC) δ 18.23 (Me), 125.34 (Ph 4-C), 125.82 (6-C), 126.15 (5-C), 129.63 (Ph 2,6-C ₂ ), 131.50 (Ph 3,5-C ₂ ), 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 (CONH ₂ ); MS m/z 357.0033 (M + Na) ⁺ (C ₁₅ H ₁₃ ⁸¹ BrN ₂ Na0 ₂ requires 359.0078), 355.0052 (M + Na) ⁺ (C ₁₅ H ₁₃ ⁷⁹ BrN ₂ Na0 ₂ requires 355.0058).

2- (4-Fluorobenzamido)-3-methylbenzamide (53f). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR

((CD ₃ ) ₂ SO) 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-H ₂ + N/-/H + Ph 3,5-H ₂ ), 7.70 (1 H, s, NHH), 8.03-8.04 (2 H, m, Ar 2,6-H ₂ ), 10.19 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.27 (Me), 1 15.43 (d, J = 21.6 Hz, Ph 3,5-H ₂ ), 125.81 (6-C), 125.10 (5-C), 130.23 (d, J = 9.1 Hz, Ph 2,6-H ₂ ), 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 (CONH ₂ ); MS m/z 295.8043 (M + Na) ⁺ (C ₁₅ H ₁₃ FN ₂ Na0 ₂ requires 295.0859).

3- Methyl-2-(4-trifluoromethylbenzamido)benzamide (53g). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ + NHH), 7.71 (1 H, s, NHH), 7.92 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 8.15 (2 H, d, J = 8.0 Hz, Ph 2,6-H ₂ ), 10.33 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.17 (Me), 123.92 (q, J = 270.8 Hz, CF ₃ ), 125.50 (q, J = 3.6 Hz, Ph 3,5-H ₂ ), 125.86 (6-C), 126.33 (5-C), 128.45 (Ph 2,6-H ₂ ), 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 (CONH ₂ ); MS m/z 345.0828 (M + Na) ⁺ (C ₁₆ H ₁₃ F ₃ N ₂ Na0 ₂ requires 345.0827). 3-Methyl-2-(4-nitrobenzamido)benzamide (53h). Dry pyridine (205 mg, 2.6 mmol) was added to 2-amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.73 (1 H, s, NHH), 8.18 (2 H, m, Ph 2,6-H ₂ ), 8.38 (2 H, d, J = 7.5 Hz, Ph 3,5-H ₂ ), 10.39 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.13 (Me), 123.67 (Ph 3,5-H ₂ ), 125.87 (6-C), 126.43 (5-C), 129.04 (Ph 2,6-H ₂ ), 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 (CONH ₂ ); MS m/z 322.0796 (M + Na) ⁺ (C ₁₅ H ₁₃ N ₃ 0 ₄ Na 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₃ ), 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-H ₂ ), 12.51 (1 H, s, NH); ¹³ C NMR

((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.14 (Me), 120.87 (4a-C), 123.47 (5-C), 126.02 (6-C), 127.71 (Ph 2,6-C ₂ ), 128.59 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.39 (3 H, s, PhMe), 2.61 (3 H, s, 8-Me), 7.35-7.39 (3 H, m, Ph 3,5-H ₂ + 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-H ₂ ), 12.44 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.19 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₆ H ₁₅ N ₂ 0 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 12.39 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.16 (8-Me), 55.45 (OMe) , 14.00 (Ph 3,5-C ₂ ), 120.55 (4a-C), 123.45 (5-C), 125.07 (Ph 1-C), 125.56 (6-C), 129.39 (Ph 2,6-C ₂ ), 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 12.59 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.14 (Me), 120.91 (4a-C), 123.51 (7-C), 126.25 (6-C), 128.70 (Ph 3,5-C ₂ ), 129.56 (Ph 2,6-H ₂ ), 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) ⁺ (C ₁₅ H ₁₂ ³⁷ CIN ₂ NaO requires 295.0426), 293.0438 (M + Na) ⁺ (C ₁₅ H ₁₂ ³⁵ CIN ₂ NaO 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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- H ₂ ), 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-H ₂ ), 12.58 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 131.62 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₅ H ₁ ⁸ BrN ₂ NaO requires 338.9967), 336.9953 (M + Na) ⁺ (C ₁₅ H ₁ ⁷⁹ BrN ₂ NaO 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.61 (3 H, s, Me), 7.38- 7.42 (3 H, m, Ph 3,5-H ₂ + 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-H ₂ ), 12.55 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.14 (Me), 1 15.64 (d, J = 21.8 Hz, Ph 3,5-C ₂ ), 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-C ₂ ), 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) ⁺ (C ₁₅ H ₁₂ FN ₂ 0 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.00 (1 H, d, J = 8.0 Hz, 5- H), 8.41 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 12.74 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.13 (Me), 123.97 (d, J = 271.3 Hz, CF ₃ ), 123.54 (5-C), 125.53 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 126.67 (6-C), 128.67 (Ph 2,6-C ₂ ), 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.63 (2 H, d, J = 9.0 Hz, Ph 2,6-Hz); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.34 (Me), 121.56 (4a-C), 123.11 (Ph

3.5- C ₂ ), 123.54 (5-C), 123.59 (6-C), 128.83 (Ph 2,6-C ₂ ), 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)quinazol in-4-one (54i). 2-Amino-3-methylbenzamide 52 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.60 (3 H, s, Me), 4.29 (2 H, d, J = 6.5 Hz, Ar 4-CCH ₂ ), 5.07 (2 H, s, Cbz-CH ₂ ), 7.23-7.39 (8 H, m, 6-H + Ar 3,5-H ₂ + Ph-H ₅ ), 7.59 (1 H, d, J = 7.0 Hz, 7-H), 7.93 (1 H, br, Ar 4-CH ₂ N/-/), 8.22 (2 H, d, J = 8.0 Hz, Ar 2,6-H ₂ ), 12.50 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.96 (Me), 44.36 (Ar 4-CCH ₂ ), 66.17 (Cbz-CH ₂ ), 121.78 (4a-C), 124.22 (5-C), 125.43 (6-C), 127.58 (Ar 3,5-C ₂ ), 128.48 (Ar 2,6-C ₂ + Ph

2.6- C ₂ ), 128.53 (Cbz 4-C), 129.09 (Ph 3,5-C ₂ ), 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) ⁺ (C ₂ 4H ₂₁ N ₃ Na0 ₃ requires 422.1481).

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. 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.44-7.50 (3 H, m, 4,6-H ₂ + NHH), 7.75 (1 H, s, NHH), 7.91 (2 H, d, = 7.9 Hz, Ph 2,6- H ₂ ), 10.22 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.01 (Ph 3,5-C ₂ ), 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 (CONH ₂ ); MS (electron impact) m/z 269.1261 (M) ⁺

(C ₁₆ H ₁₇ N ₂ 0 ₂ requires 269.1290).

3- Methoxy-2-(4-methylbenzamido)benzamide (56b). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ + 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-H ₂ ), 9.65 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.92 (Ph 3,5-C ₂ ), 131.46 (Ph 4-C), 134.89 (1 -C), 141.52 (Ph 1-C), 154.97 (3-C), 165.27 (NHCO), 168.92 (CONH ₂ ); MS (electron impact) m/z 285.1221 (M) ⁺ (C ₁₆ H ₁₇ N ₂ 0 ₃ requires 285.1239).

3- Rflethoxy-2-(4-methoxybenzamido)benzamide (56c). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 9.60 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.42 (Ph 4-OMe), 55.93 (3- OCH ₃ ), 1 13.47 (4-C), 113.62 (Ph 3,5-C ₂ ) 1 19.86 (6-C), 124.50 (2-C), 126.43 (Ph 1-C), 127.01 (5-C), 129.52 (Ph 2,6-C ₂ ), 134.90 (1-C), 154.97 (3-C), 161.88 (Ph 4-C), 164.94 (NHCO), 168.96 (CONH ₂ ).

2-(4-Chlorobenzamido)-3-methoxybenzamide (56d). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.96 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 9.79 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.57 (Ph 3,5-C ₂ ), 133.08 (Ph 1-C), , 135.08 (1-C), 136.35 (Ph 4-C), 154.96 (3-C), 164.39 (NHCO), 168.83 (CONH ₂ ); MS (electron impact) m/z 305.0677 (M) ⁺

(C ₁₅ H ₁₄ ³⁵ CIN ₂ 0 ₃ requires 305.0692).

2-(4-Bromobenzamido)-3-methoxybenzamide (56e). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.88 (2 H, d, J = 9.0 Hz, Ph 2,6-H ₂ ), 9.79 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 131.41 (Ph 2,6-C ₂ ), 133.45 (Ph 1- C), 135.07 (1-C), 154.93 (3-C), 164.52 (NHCO), 168.82 (CONH ₂ ). MS m/z 372.9988 (M + Na) ⁺ (C ₁₅ H ₁₄ ⁸ BrN ₂ Na0 ₃ requires 372.9992), 371.0012 (M + Na) ⁺ (C ₁₅ H ₁₄ ⁷⁹ Br 2Na03 requires 371.0007).

2- (4-Fluorobenzamido)-3-methoxybenzamide (56f). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ + NHH + 5-H), 7.51 (1 H, s, NHH), 8.02 (2 H, m, Ph 2,6-H ₂ ), 9.74 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.93 (Me), 1 13.45 (4-C), 1 15.31 (d, J = 21.3 Hz, Ph 3,5-C ₂ ), 1 19.82 (6-C), 124.12 (2-C), 127.24 (5-C), 130.31 (Ph 2,6- C ₂ ), 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 (CONH ₂ ); MS (electron impact) m/z 289.0962 (M) ⁺

(C ₁₅ H ₁₄ FN ₂ 0 ₃ requires 289.0988).

3- IWethoxy-2-(4-trifluoromethylbenzamido)benzamide (56g). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.13 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 9.94 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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, CF ₃ ), 125.41 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 127.44 (5-C), 128.54 (Ph 2,6-C ₂ ), 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 (CONH ₂ ); MS (electron impact) m/z

339.0956 (M) ⁺ (C ₁₆ H ₁₄ F ₃ N ₂ 0 ₃ requires 339.0957).

3-Methoxy-2-(4-nitrobenzamido)benzamide (56h). Dry pyridine (213 mg, 2.7 mmol) was added to 2-amino-3-methoxybenzamide 55 ⁹⁷ (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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.35 (2 H, m, Ar 3,5-H ₂ ), 10.04 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.97 (Me), 1 13.51 (4-C), 1 19.84 (6-C), 123.59 (Ph 2,6-C ₂ ), 123.70 (2-C), 127.53 (5-C), 129.13 (Ph 3,5-C ₂ ), 135.14 (1-C), 140.08 (Ph 1-C), 149.14 (Ph 4-C), 154.94 (3-C), 163.88 (NHCO), 168.75 (CONH ₂ ).

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 ((CD ₃ ) ₂ SO) 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-H ₃ ), 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-H ₂ ), 12.55 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.56 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.93 (3 H, s, Ph-Me), 3.94 (3 H, s, OMe), 7.34-7.37 (3 H, m, Ph 3,5-H ₂ + 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-H ₂ ), 12.47 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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- C ₂ ), 129.14 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 3.84 (3 H, s, Ph-OMe), 3.94 (8-OMe), 7.09 (2 H, m, Ph 3,5-H ₂ ), 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-H ₂ ), 12.41 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.45 (Ph-OMe), 1 13.96 (Ph 3,5-C ₂ ), 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-C ₂ ), 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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-H ₂ ), 12.59 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.55 (Ph 2,6-C ₂ ), 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) ⁺ (C ₁₅ H ₁₁ ³⁵ CIN ₂ Na0 ₂ requires 309.0407], 287.0569 (M) ⁺ (C ₁₅ H ₁₂ ³⁵ CIN ₂ 0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ S0) 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-H ₂ ), 8.12 (2 H, d, J = 8.0 Hz, Ph 2,6-H ₂ ), 12.61 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 131.58 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₅ H ₁₂ ⁸¹ BrN ₂ 0 ₂ requires 333.0040), 331.0053 (M) ⁺ (C ₁₅ H ₁₂ ⁷⁹ BrN ₂ 0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 3.94 (3 H, s, Me), 7.37-7.41 (3 H, m, Ph 3,5-H ₂ +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-H ₂ ), 12.56 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 56.03 (Me), 115.19 (7-C), 1 15.58 (d, J = 21.8 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 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) ⁺ C ₁₅ H ₁₂ FN ₂ 0 ₂ 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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- H ₂ ), 8.37 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ), 12.76 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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, CF ₃ ), 125.49 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 127.47 (6-C), 128.65 (Ph 2,6-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.43 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 12.72 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 127.49 (6-C), 129.02 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 9.61 (1 H, s, OH), 12.49 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 128.42 (Ph 3,5-C ₂ ), 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 ((CD ₃ ) ₂ SO) 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-H ₂ + 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-H ₂ ), 9.54 (1 H, s, OH), 12.38 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 129.04 (Ph 3,5-C ₂ ), 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) ⁺ (C ₁₅ H ₁₃ N ₂ 0 ₂ 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 6.87 (2 H, d, J = 9.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 9.41 (1 H, s, 8-OH), 10.1 1 (1 H, s, PhOH), 12.23 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 15.16 (Ph 3,5-C ₂ ), 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-C ₂ ), 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.45 (2 H, d, J= 7.0 Hz, Ph 2,6-H ₂ ), 9.66 (1 H, s, OH), 12.52 (1 H, s, NH); ¹³ C NMR

((CD ₃ ) ₂ SO) (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-C ₂ ), 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) ⁺

(C ₁₄ H ₉ ³⁷ CIN ₂ Na0 ₂ requires 297.0250), 295.0218 (M + Na) ⁺ (C ₁₄ H ₉ ³⁵ CIN ₂ Na0 ₂ 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 ((CD ₃ ) ₂ SO) 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-H ₂ ); 8.37 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 9.66 (1 H, s, OH), 12.51 (1 H, s, NH); ³ C NMR

((CD ₃ ) ₂ SO) (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-C ₂ ), 131.44 (Ph 3,5-C ₂ ), 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) ⁺

(C ₁₄ H ₉ ⁸¹ BrN ₂ Na0 ₂ requires 340.8908), 338.9745 (M + Na) ⁺ (C ₁₄ H ₉ ⁷⁹ BrN ₂ Na0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.57 (1 H, dd, J = 8.0, 1.5 Hz, 5-H), 8.50 (2 H, m, Ph 2,6-H ₂ ), 9.62 (1 H, s, OH), 12.49 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 15.45 (d, J = 21.8 Hz, Ph 3,5-C ₂ ), 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-C ₂ ), 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) ⁺ (C ₁₄ H ₁₀ FN ₂ O ₂ 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.61 (2 H, d, J = 8.0 Hz, Ph 2,6-H ₂ ), 9.76 (1 H, s, OH), 12.66 (1 H, s, NH); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 15.69 (5-C), 118.64 (7-C), 121.99 (4a-C), 124.02 (q, J = 270.8, CF ₃ ), 125.32 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 127.72 (6-C), 128.85 (Ph 2,6-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 8.66 (2 H, m, Ph 2,6-H ₂ ), 9.83 (1 H, s, OH), 12.72 ( 1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 15.71 (5-C), 1 18.74 (7-C), 122.04 (4a-C), 123.44 (Ph 3,5-C ₂ ), 128.01 (6-C), 129.38 (Ph 2,6-C ₂ ), 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); ¹ H NMR((CD ₃ ) ₂ SO) δ 5.84 (2 H, s, NH ₂ ), 6.63 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 8.08 (1 H, dd, J = 7.5, 1.0 Hz, 5-H), 12.06 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 3.02 (Ph 3,5-C ₂ ), 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-C ₂ ), 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 ((CD ₃ ) ₂ SO) δ 2.57 (3 H, s, Me), 5.82 (2 H, s, NH ₂ ), 6.64 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 12.05 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.20 (Me), 113.03 (Ph 3,5-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 3.92 (3 H, s, Me), 5.80 (2 H, s, NH ₂ ), 6.63 (2 H, dt, J = 8.5, 2.5 Hz, Ar 3,5-H ₂ ), 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-H ₂ ), 12.09 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 55.97 (OMe), 1 3.01 (Ar 3,5-C ₂ ), 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-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 5.80 (2 H, s, NH ₂ ), 6.62 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 9.25 (1 H, s, OH), 1 1.99 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 112.90 (Ph 3,5-C ₂ ), 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-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 6.88 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 1 15.34 (Ph 3,5-C ₂ ), 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-C ₂ ), 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); ¹ H NMR ((CD ₃ ) ₂ SO) δ 2.60 (3 H, s, Me), 6.90 (2 H, d, J = 9.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 12.28 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.89 (Me), 116.06 (Ph 3,5-C ₂ ), 121.16 (4a-C), 124.16 (5-C), 124.20 (Ph 1-C), 126.07 (6-C), 130.24 (Ph 2,6-C ₂ ), 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-o ne 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 ((CD ₃ ) ₂ SO / CD ₃ OD 1 :1) 5 2.69 (3 H, s, Me), 4.14 (2 H, m, CH ₂ ), 7.41 (1 H, t, J = 7.5 Hz, 6-H), 7.64 (2 H, d, J = 8.0 Hz, Ph 3,5-H ₂ ), 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-H ₂ ), 8.28 (br, NH ₃ ), 12.59 (1 H, s, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 17.16 (Me), 41.89 (CH ₂ ), 120.92 (4a-C), 123.52 (5-C), 126.25 (6-C), 127.93 (Ph 2,6-Cz), 129.00 (Ph 3,5-C ₂ ), 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) ⁺ (Ci ₆ H ₁₅ N ₃ NaO 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; ¹ H NMR (CDCI ₃ ) δ 1 .93 (2 H, qn, J = 6.2 Hz, 3-H ₂ ), 2.61 (2 H, t, J = 6.4 Hz, 4-H ₂ ), 3.02 (3 H, s, NMe), 3.28 (2 H, t, J = 5.4 Hz, 2-H ₂ ), 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-H ₂ ), 7.47 (2 H, d, J = 8.9 Hz, Ph 2,6-H ₂ ); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 126.95 (Ph 1-C), 127.18 (Ph 2,6-C ₂ ), 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) (C ₁₆ H ₁₈ N ₂ Na0 ₂ requires 293.1266), 271.1452 (M + H) (C ₁₆ H ₁₉ N ₂ 0 ₂ 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; ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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, CF ₃ ), 125.81 (q, J = 3.6 Hz, Ph 3,5-C ₂ ), 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); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -61.35 (CF ₃ ); MS (ESI) m/z 305.0895 (C ₁₆ H ₁₂ N ₂ OF ₃ 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 (CDCI ₃ ) δ 1.94 (2 H, qn, J = 5.5 Hz, 3-H ₂ ), 2.63 (2 H, t, J = 6.0 Hz, 4-H ₂ ), 3.31 (2 H, t, J = 5.5 Hz, 2-H ₂ ), 6.09 (1 H, s, 8-H), 7.67 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 7.72 (2 H, d, J = 8.5 Hz, Ph 3,5-H ₂ ); ¹³ C NMR (CDCI ₃ ) (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, CF ₃ ), 126.38 (m, Ph 2,3,5,6-C ₄ ), 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); ¹⁹ F NMR (CDCI ₃ ) δ - 62.79 (CF ₃ ); MS (ESI) m/z 331.1061 (M + Na) (C ₁₆ H ₁₅ F ₃ N ₂ NaO requires 331.1034), 309.1239 (M + H) (C ₁₆ H ₁₆ F ₃ N ₂ 0 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; ¹ H NMR (CDCI ₃ ) δ 1.95 (2 H, qn, J = 6.4 Hz, 3-H ₂ ), 2.60 (2 H, t, J = 6.4 Hz, 4-H ₂ ), 3.04 (3 H, s, N e), 3.30 (2 H, t, = 5.6 Hz, 2-H ₂ ), 6.06 (1 H, s, 8-H), 7.43 (2 H, d, J = 8.6 Hz, Ph

3.5- H ₂ ), 7.54 (2 H, d, J = 8.7 Hz, Ph 2,6-H ₂ ); ¹³ C NMR (CDCI ₃ ) (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- C ₂ ), 129.33 (Ph 3,5-C ₂ ), 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) (C ₃ oH ₃ i ³⁵ CIN ₂ 0 requires 549.1824), 275.0941 (M + H) (C ₁₅ H ₁₆ ³⁵ CIN ₂ 0 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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 7.81 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 8.57 (1 H, d, J = 8.0 Hz, 4-H), 8.97 (1 H, d, J = 4.5 Hz, 2-H); ¹³ C NMR (CDCI ₃ ) (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- C ₂ ), 130.28 (Ph 1-C), 132.30 (Ph 3,5-C ₂ ), 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) (C ₁₅ H _l3 ⁸¹ BrN0 ₃ requires 336.0054), 334.0063 (M + H) (C ₁₅ H ₁₃ ⁷⁹ BrN0 ₃ 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 ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.84 (2 H, d, J = 8 Hz, Ph 2,6-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 130.75 (Ph 3,5-C ₂ ), 131.91 (7-C), 134.61 (4-C), 156.71 (8a-C), 168.09 (5-C); MS (ESI) m/z

324.9771 (M + Na) (C ₁₄ H ₉ ⁸¹ BrN ₂ NaO requires 324.9774), 322.9790 (M + Na)

(C ₁₄ H ₉ ⁷⁹ BrN ₂ NaO 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, ¹ H NMR ((CD ₃ ) ₂ SO) 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-H ₂ ), 7.97 (1 H, m, 3-H), 7.98 (2 H, d, J = 8.7 Hz, Ph 3,5-H ₂ ), 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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 130.50 (Ph 1-C), 131.98 (Ph 3,5-C ₂ ), 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)

(C ₁₅ H ₁₂ ⁸¹ BrN ₂ NaO requires 317.0221), 315.0128 (M + H) (C ₁₅ H ₁₂ ⁷⁹ BrN ₂ NaO 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; ¹ H NMR (CDCI ₃ ) δ 1.95 (2 H, qn, J = 6.4 Hz, 3-H ₂ ), 2.61 (2 H, t, J = 6.3 Hz, 4-H ₂ ), 3.29 (3 H, s, Me), 3.29 (2 H, t, J = 5.5 Hz, 2-H ₂ ), 6.02 (1 H, s, 8-H), 7.42 (2 H, d, J = 8.7 Hz, Ph 2,6-H ₂ ), 7.59 (2 H, d, J = 8.7 Hz, Ph 3,5-H ₂ ); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 132.27 (Ph 3,5-C ₂ ), 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) (C ₁₅ H ₁₅ ^8l BrN ₂ NaO requires 343.0245), 341.0264 (M + Na) (C ₁₅ H ₁₅ ⁷⁹ BrN ₂ NaO requires 341.0265), 321.0426 (M + H) (C ₁₅ H ₁₆ ⁸¹ BrN ₂ 0 requires 321.0426), 319.0448 (M + H)

(C ₁₅ H ₁₆ ⁷⁹ BrN ₂ 0 requires 319.0446).

3- Bromo-4-cyanopyridine (34). 3-Bromopyridine-4-carboxamide ⁹⁸ (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); ¹ H NMR (CDCI ₃ ) 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); ¹³ C NMR (CDCI ₃ ) (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) (C ₆ H ₄ N ₂ ⁷⁹ Br 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; ¹ H NMR (CDCI ₃ ) δ 2.39 (3 H, s, Me), 7.20 (2 H, d, J = 8.4 Hz, Ph 3,5-H ₂ ), 7.51 (3 H, m, 5-H, Ph 2,6-H ₂ ), 8.65 (1 H, d, J = 5.0 Hz, 6- H), 8.90 (1 H, s, 2-H); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 132.03 (Ph 2,6-C ₂ ), , 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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 7.07 (1 H, s, 4-H), 7.38 (2 H, d, J = 7.9 Hz, Ph 3,5-H ₂ ), 7.76 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 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); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 20.70 (Me), 100.10 (4-C), 119.80 (8-C), 127.10 (Ph 2,6-C ₂ ), 129.53 (Ph 3,5-C ₂ ), 146.20 (7-C), 148.90 (5-C); MS (ESI) m/z 259.0834 (M + Na)

(C ₁₅ H ₁₂ N ₂ NaO requires 259.0847), 237.1022 (M + H) (C ₁₅ H ₁₃ N ₂ 0 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 v _max 3450, 1654 cm ^-1 ; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 8.10 (1 H, d, J = 8.0 Hz, 8-H), 8.69 (2 H, d, J = 6.2 Hz„ Ph 2,6- H ₂ ), 11.70 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.76 (Me), 101.87 (4-C), 120.96 (pyridine 3,5-C ₂ ), 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 (C ₁₅ HnN ₂ 0 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 v _max 3481 , 1668, 1235 cm ¹ ; ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₂ ), 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-H ₂ ), 8.03 (1 H, d, J = 8.0 Hz, 8-H), 1 1.70 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (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-C ₂ ), 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); ¹⁹ F NMR ((CD ₃ ) ₂ SO) δ -122.08 (dd, J = 10.4, 5.2 Hz, F); MS m/z 252.0807 (M - H) ^" (C _1e HnFNO 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 CH ₂ CI ₂ 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 v _max 3448, 1647 crrf ¹ ; ¹ H NMR ((CD ₃ ) ₂ SO) (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); ¹³ C NMR ((CD ₃ ) ₂ SO) (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) (C ₁₄ HnNNaOS 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: ¹ H NMR (CDCI ₃ ) (COSY/ NOESY) δ 1.14 (3 H, t, J = 7.6 Hz, CH ₂ Me), 2.34 (3 H, s, 3-Me), 2.60 (2 H, m, CH ₂ ), 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); ¹³ C NMR (CDCI ₃ ) (HSQC / HMBC / DEPT) δ 14.25 (CH ₂ /We), 19.26 (3-Me), 23.55 (CH ₂ ), 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) ⁺ (C ₁₂ H ₁₇ NO 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 v _max 3453 (NH), 1644 (C=0); ¹ H NMR ((CD ₃ ) ₂ SO) (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-H ₅ ), 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); ¹³ C NMR

((CD ₃ ) ₂ SO) (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-C ₂ ), 128.65 (Ph 4-C), 129.74 (Ph 2,6-C ₂ ), 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) (C ₁₇ H ₁₆ NO 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)benzonitrile ¹⁰⁰ (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; ¹ H NMR ((CD ₃ ) ₂ SO) δ 1.70 (4 H, m, pyrrolidine 3,4-H ₄ ), 2.44 (4 H, m, pyrrolidine 2,5-H ₄ ), 2.54 (3 H, s, Me), 3.61 (2 H, s, PhCH ₂ ), 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-H ₂ ), 7.54 (1 H, d, J = 7.2 Hz, 6- H), 7.76 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 8.05 (1 H, d, J = 7.9 Hz, 8-H), 11.52 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.77 (Me), 23.12 (pyrrolidine 3,4-C ₂ ), 53.50 (pyrrolidine 2,5-C ₂ ), 59.15 (PhCH ₂ ), 99.72 (4-C), 124.55 (8-C), 124.92 (8a-C), 125.80 (7-C), 126.64 (Ph 2,6-C ₂ ), 128.71 (Ph 3,5-C ₂ ), 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) ⁺ (C ₂₁ H ₂₃ N ₂ 0 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)benzonitrile ¹⁰¹ (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 v _max 3440, 1644 cm ^"1 ; ¹ H NMR

((CD ₃ ) ₂ SO) δ 1.40 (2 H, m, piperidine 4-H ₂ ), 1.50 (4 H, m, piperidine 3,5-H ₄ ), 2.34 (4 H, m, piperidine 2,6-H ₄ ), 2.55 (3 H, s, Me), 3.47 (2 H, s, PhCH ₂ ), 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-H ₂ ), 7.54 (1 H, d, J = 7.1 Hz, 6-H), 7.76 (2 H, d, J = 8.2 Hz, Ph 2,6-H ₂ ), 8.06 (1 H, d, J = 7.9 Hz, 8-H), 11.48 (1 H, bs, N-H); ³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.76 (Me), 23.96 (piperidine 4), 25.55 (piperidine 3,5-C ₂ ), 53.91 (piperidine 2,6-C ₂ ), 62.37 (PhCH ₂ ), 99.73 (4-C), 124.56 (8-C), 124.90 (8a-C), 125.79 (7-C), 126.61 (Ph 2,6-C ₂ ), 129.01 (Ph 3,5-C ₂ ), 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) ⁺ (C ₄₄ H ₄₉ N ₄ 0 ₂ requires 665.3855), 355.1805 (M + Na) ⁺ (C ₂₂ H ₂₄ N ₂ NaO 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 v _max 3295, 1642 cm ^"1 ; ¹ H NMR ((CD ₃ ) ₂ SO) (COSY) δ 1.33 (9 H, s, CMe ₃ ), 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-H ₂ ), 7.54 (1 H, d, J = 7.2 Hz, 6-H), 7.75 (2 H, d, J = 7.6 Hz, Ph 2,6-H ₂ ), 8.06 (1 H, d, J = 8.0 Hz, 8-H), 1 1.48 (1 H, br, NH); ¹³ C NMR ((CD ₃ ) ₂ SO) (HSQC / HMBC) δ 18.75 (Me), 30.97 (CMe ₃ ), 34.44 (CMe ₃ ), 99.60 (4-C), 124.56 (8-C), 124.86 (8a-C), 125.51 (Ph 3,5-C ₂ ), 125.72 (7-C), 126.56 (Ph 2,6-C ₂ ), 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) ⁺ (C ₂₀ H ₂₂ NO 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-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 ^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); ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 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-H ₂ ), 8.41 (1 H, d, J = 8.0 Hz, 4-H), 8.81 (1 H, m, 2- H); ¹³ C NMR (CDCI ₃ ) (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-C ₂ ), 122.43 (3-C), 129.49 (Ph 2,6-C ₂ ), 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) (C ₁₆ H ₁₆ N0 ₄ 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-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 ^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; ¹ H NMR (CDCI ₃ ) 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-H ₂ ), 7.78 (2 H, d, J = 8.5 Hz, Ph 2,6-H ₂ ), 8.47 (1 H, d, J = 8.0 Hz, 4-H), 8.87 (1 H, d, J = 4.5 Hz, 2-H); ¹³ C NMR (CDCI ₃ ) (HSQC / HMBC) δ 1 17.02 (8a-C), 123.02 (3-C), 126.91 (Ph 3,5-C ₂ ), 129.34 (Ph 2,6-C ₂ ), 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) (C ₁₅ H ₁₃ ³⁷ CIN0 ₃ requires 292.0554), 290.0590 (M + H) (C ₁₅ H ₁₃ ³⁵ CIN0 ₃ 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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