3TNE DERIVATIVES AS TERT MODULATORS
The invention relates to 3-deazap~riue derivatWes. The invention further relates to processes for the preparation of. intermediates usod in the orepar~tion of, pharmaceutical compositions containing, and uses of such 3-deazapurine derivatives.

Toll-Like Receptors (TLR) are primary transmembrane proteins characterized by an extracellular leucinerich domain and a cytoplasmic tail that contains a conserved region named th~ Toll/IL-i receptor (TIR) domain. They are expressed predominantly on immune cells (for Example dendritic cells, T lymphocytes, macrophages, monocytes and natural killer celis), which serve as a key part of the innate immune system. They are a group of pattern recognition receptors which bind to pathogen-associated molecular patterns [for reviews, see for Example, Ulevitch, R. J., Nature Reviews: Immunology, 4, 512-520, 2004 and Akira, S., Takeda, K, and Kaisho, T., Annual Rev. lmmunol., 21, 335-376, 20031. Their name derives from sequence homology to the Drosophila melanogaster gene Toll, which was found in fruit flies to play a key role in protecting the fly from fungal infections [Hoffmann, J. A., Nature, 426, 33-38, 2003]. There are 11 TLRs which have been identified in mammalian systems, and other non-mammalian TLRs have been found in other vertebrates. All TLRs appear to function as either a hornodimer or heterodimer in the recognition of a specific, or set of specific, molecular determinants present on pathogenic organisms including bacterial cell-surface lipopolysacoharides, lipoproteins, bacterial flagellin, DNA from both bacteria and viruses and viral RNA. The cell urar response to TLR activation involves activation of one or more transcription factors, reading to the production and secretion of cytokines and co-stimulatory molecules such as interferons, TNF-, interleukins, MIP-1 and MCP-1 which contribute to the killing and clearance of the pathogenic invasion.

Accordingly, there is an ongoing need to provide TLR7 modulators, in particular agonists. Preferably, such compounds should have one or more of the following properties: they should bind selectively to the TLR7 receptor, be well absorbed from the gastrointestinal tract, be metabolically stable and ~ossess favourable pharmacokinetic properties, demonstrate few side effects and be easily formulated.

We have now found a series of 3-deazapurine derivatives which are modulators, in particular agonists, of the TLR7 rebeptor and have utility in a variety of therapeutic areas in which modulation, in particular agonism, of the TLR7 receptor is implicated, including the treatment of viral infections (such as 'HCV or HBV), cancers and tumours, and T2 Helper cell (TH2) mediated diseases.

According to a first aspect of the invention, there is provided a compound of formula (I)

(Formula Removed)

or a pharmaceutically acceptable salt or so~vate of said compound, wherein

(a) Y is a direct bond, and R~ is selected from aryl, (C1-C6)alkyl and -(C1-C4alkylene-O-(C1-C4)alkyl; or Y
(b) Y (C1-4)alkyleneand are R3 is selected from aryl, (C3-C7)arylalkyl and a 3 to10- memberane

Z is an oxygen or is absent;

R is selected from H, halo, OH, CN, (C1-C6)alkyl~ (C3-C7)cycloalkyl, (C1-C6)alkoxy,
-NHSO2R8, -NR6R7, -C(O)R8, -C02H6, -C{C)NR6R7, -C(O)NR6SO2R8, aryl and 3 to lO-membered heterocyclyl;

R2 is selected from H, halo, OH, (01-C6)alkyl, (C1-C7)cycloalkyl, (C1-C6)alkoxy, -NR6R7,
-CO2R -C(O)NR6R7, -C(Q)NR6SO2R8, and 3 to lO-membered heterocyclyl; or

R' and R2 may be joined to form a (C2-C5)alkylene link, said link optionally incorporating 1 or 2 heteroatoms each independently selected from N, 0 and S;

R5 is absent and R4 is selected from H, (Cs-07)cycloalkyl, aryl, -(CH2)aryl, -C(0)R9, -C02R9,
-(C1-C6)alkylene-O-C(0)R9, -(C1 -06)alkylene-O-002R9), -C(O)NR9R'0,
-(C1 -C6)alkylene-O-C(0)NR9R10 and -(C1 -C6)alkylene-o-P(0)(0l-I)2; or

R4 is absent and R6 is selected from R9, -C(O)R9, -C02R9, -(C1-C6)alkylene-0-C(O)R9,
-(C1-C6)alkylene-O-002R9, -C(O)NR9R'0, ~ and
-(C1-C6)alkylene-O-P(O)(QH)a;

R6 and R7 are each independently selected from ~-l, (C1-C6)alkyl, (C3-07)cycloalkyl, and
-(C1-C6)alkylene(C3-C7)cycloalkyl; or R5 and P~' taken together with the nitrogen to which they are attached form a 3 to 6 membered saturated lieterocycle optionally containing a further one or two heteroatoms selected from N, 0 and S;

R8 is selected from (C1-C8)alkyl, (C3-C7)cycloalkyl and phenyl;

R9 and F'0 are each ndependently selected from H, (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl,
-(0H2}aryl and 3 to ~lO-mernbered h~eracycIyi or

R9 and R'0, taken together wth the otrogen to which they are attached, form a 3 to 10-membered heterocyclyl group

R" and R12 are independently selected from H and (C1-C5)alkyl; or R11 and F'2 together With the N to which they are attached form a 3 to 10 merrbered safura~ed haterocyclyl opt~ona~y containing a further one or two heteroatoms selected from N,O and S.

said alkyl, cycloalkyl, alkoxy, aryl and heterocy~lyl groups being optionally substituted by one or more atoms or groups independently selected from halo, OH, oxo, OR3, ON, (G,-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, -(C,-C6)alkylene-O-(C,-Ce)alkyl, -(C,-C6)alkylene-OH, —NR" F12, -(C, -C6)alkylene-NR" F'2, aryl and 3 to lO-membered heterocyciyl;

with the proviso that when F' and Ft2 are H, and ~ and F5 are absent, then (a)R4 is not methyl when V-R3 ethyl; and
(b)R4 is not H or methyl when Y-R3 is methyl.

Unless otherwise indicated, alkyl and alkoxy groups may be straight or branched and contain 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxy include methoxy, ethoxy, isopropoxy and n-butoxy.

Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicycloheptanes.

Halo means fluoro, chioro, bromo or iodo and is preferably fluoro or chioro.

Aryl includes phenyl, naphthyl, anthracenyl and phenanthrenyl and is preferably phenyl.

Unless otherwise stated, a heterocycle may be saturated, partially saturated or aromatic and conlain one or more heteroatoms independently selected fron N, 0 and S. For Example, the heterocyle may be a 5 to 6 membered saturated, partially saturated or aromatic heterocycle. Examples of saturated heterocyclic groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, azepiriyl, oxazepinyl and thiazepinyl. Examples of aromatic monoheterocyclic groups are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazoles (such as 1,2,3 triazolyl arid 1,2,4-triazolyl), oxadiazoles (such as 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl and 1-oxa-3,4-diazolyl), thiadiazoles (such as 1-thia-
2,3-diazolyl, I -thia-2,4-diazolyl, 1 -thia-2,5-diazolyl and I .thia-3~4-cliazolyl), tetrazolyl, pyridinyl, pyridazinyl,

pyrimidinyl, pyrazinyl and triazinyl. Examples of bicyclic aromatic heterocyclic groups are benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl. indazolyi, benzotria~oiyl, quinolinyl and isoquinoilnyl.

In the case where a plurality of substituents be selected from a number of alternative groups. the selected groups may be the same or different.

In one embodiment, 2 is oxygen such that N-oxides are formed.

In a futher embodiment of the invention, Z is absent.

In a yet further embodiment of the invention Ft' is selected from (a) H;
(b) ON;
(c) halo
(d ) (C,-C6)alkyl optionally substituted by one to three halo atoms; (e) tetrahydrofuranoxy;
(f) (C1-C6)alkyl substituted by a 3 to 6 membered saturated heterocycyl containing 1 to 3 hetero atoms independently selected from N, 0 and S wherein said heterocyclyl is optionally substituted by one to three groups independently selected from CFa, (C, -C8)alkyl, (C, -C6)alkoxy and -(C, -C8)alkylene-O-(C, -C6)alkyl; (g) -(C,-O4afkylene-Q-(C1-C6)alkyl;
(h) -(C,-C4alkylene-N(H)-(C,-C4alkylene-Q-(Ci-C4)aiky!;
(i) (C1-C6)alkoxy optionally substituted by OH or cyclopropyl; {j) (C3-C7)cycloalkyl;
(k) -(C1 -C4)alkylene(C3-07)cycloalkyl;
(I) -C(O)NF8R7; (in) -C02R6;
(n) -C(O) R6;
(a) a S membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) I oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms, said 5 and 6 mernbered aromatic heterocyclyl being optionally substituted by one to three atoms or groups indeper~dentJy selected from halo, OH, OR3, (C1-C6)alkyl, (Ci08)alkoxy, -(C,-C6)alkylene-O-(C,-C8)alkyl, -(Oi-C8)alkylene-OH , —NF"R'2 and -(C,-C6)alkylene-

(p) phenyf optionally substituted by 1 to S halo atoms;
(q) -NF6R7;
(r) -NH-(C,-C4alkylene-O-(C,-C8)alkyl;
(s) or R' and F2 may be joined to form a (02-C5)alkylene link;
wherein
Fl6, F7, F" and F12 are as defined in the first aspect of the invention.

In a further embodiment, R' is selected from

{a)H:
(b) ON;
(c)halo
(d) (C1-C6)alkyl optionally sobstituted by one to three l~alo atoms; (e) tetrahydrofuranoxy;
(t) (C1-C6)alkyl substituted by morrholine, pinerazine or pyrrolodine which are optionally substituted by one or two methyl groups;
(h) -(C1-C4)alkylene-N(H)-(C1-C4)alkylene-C-(C,-C4)alkyl;
(i} {C1-C6)alkoxy optionally substituted by OH or cyclopropyl;
U) (C3-C7)cycloalkyl;
(k) -(0, -O4alkylene(C3-07)cycloalkyi;
(I) -O(O)NR6R7; (in) -002R6;
(n) -0(0) F6;
(a) a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms, said 5 and 6 membered aromatic heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, OR3, (C,-C6)alkyl, (0,-11 1206)alkoxy, -(C1-C6)alkylene-O-(C1-C6)alkyl, -(C,-C6)alkylene-OH , —NF F and -(C1-C6)alkylene-
NR"R 12;
{p) phenyl optionally substituted by I to 3 halo atoms;
(q) -NR6R7;
(r) -NH-(C1-C4)alkylene-O-(C1-C6)alkyl; wherein
R6, F7, Fl'1 and F'2 are as defined in the first aspect of the invention.

In a yet further embodiment, R' is selected from (C1-C4)alkyl optionally substituted by one to three halo atoms; (03-07)cycloalkyl; or a 5 to 6 membered aromatic heterocyclyl optionally substituted by one to three atoms or groups independently selected from halo, OH, OR3, (C1-C6)alkyl, (C1-C6)alkoxy, -(C1-C6)alkylene-O-(01-06)alkyl and -NH(C1-C6)alkyl.

In a yet further embodiment, R' is selected from methyl or ethyl substituted by one to three fluor~ atoms; cyclopropyl; -(C1-C2)alkylene-O-(O, -02)alkyl; (01-04)alkoxy optionally substituted by OH or cyclopropyl;
-COOH3; -0H200H3; and -0020H3.

In a yet further embodiment, R' is cyclopropyl or OR3.

In a yet further embodiment, R' is a 5 menibered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) I oxygen or sulphur atom, said 5 membered aromatic heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, OR3, (C1-C6)alkyl, (C, -06)alkoxy,
-(C1-C3)alkylene-O.(C1-C6)alkyl, -(q-O4)alkylena-OH ~1~I2 and -(C,-C3)alkylene-NR'R'2, wherein Fl" and are as detned in claim in the tirrt aspect ot the inventiorf.

In a yet further embodiment, R' is setected f~um :ma~azoIyl, oxazolyl, oxad~azolyl, triazole, pyrazole and thiazole, all of which are optionally substituted by by one Ia three atoms or groups independently selected from halo, OH, OR3, (01-C6)alkyl. (C1-C6)alkoxv.
-(C,-C3)alkylene-O-(C1-C4alKyl, -(C1-C6)alkylene-OH and -(C1-C3)aYn;lene-NR"R'2, wherein R" and R1' are as defined in the first aspect of the invention.

In a yet further embodiment, F' is selected f rom unsubsttuted oxazolyl, triazole, pyrazole and thiazole.

In a yet further embodiment, F' is oxazolyl.

In ayet further embodiment, F2 is selected from (a)H;
(by halo

(c) (01-06)alkyl optionally substituted by one to three halo atoms; (d) tetrahydrofuranoxy;
(e) (C1-C6)alkyl substituted by a 3 to 6 membered saturated heterocycyl containing 1 to 3 hetero atoms independently selected from N, 0 and S wherein said heterocyclyl is optionally substituted by one to three groups independently selected from OR3, (C1-C6)atkyl, (C1-C6)alkoxy and -(C1-C6)alkylene-O-(C,-C6)alkyl; (f) -(C1-C4)alkylene-O-(C, -06)alkyl;
(g)-(C1-C4)alkylene-N(H)-(C1-C4)alkylene-O-(C1-C4)alkyl;
(Ii) (C1-C6)alkoxy optionally substituted by OH or cyclopropyl; (i) (C3-07)cycloalkyl;
(j) -(C1-C4alkylene(03-Q)cycloalkyl;
(k) -C(O)NR5R7;
(I) -C02R6;
(in) -0(0) F6;
(n) a 5 membered aromatic heterocyclyl comprising {i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms, said S and 6 membered aromatic heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, OR3, (C1-C6)alkyl, (C,11 12

C6)alkoxy, -(C1-C6)alkylene-O-(C1-C6)alkyl, -(C1-C6)alkylene-OH , —NR F and -(C1-C6)alkylene-NR"R'2;

(o) phenyl optionally substituted by 1 to 3 halo atoms;
(p) -NF6R7;
(q) -NH-(C1-C4)alkylene-O-(C, -05)alkyl;
wherein

F8, F7, F" and F'2 are as defined in the first aspect of the invention.

In a yet further ernbodinment, R~ is H or methyl. In a yet further embodiment, R2 is H.
In a yet further embodiment, Y is methylene; and R3 is aryl, or a 5 to C menibered hsterocyclyi containing one to three heteroatoms independently selected from N. C anrl S, said ary~ and heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, oxo, OR3, ON, (C1 -C6)alkyl, (C3-C7)cycloalkyl, (C, -06)alkoxy, -(0, -O6)alkylene~O-(C, -06)alkyl,
-NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, aryl and 3 to 10-in embered heterocyclyl.

In a yet further embodiments Y is methylene; and R3 is selected from aryl; a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; and a e-niembered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms; said aryt and aromatic heterocycle being optionally substituted by one to three atoms or groups independently selected from halo, OH, oxo, OR3, ON, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, -(C, -C6)alkylene-O-(C1-C6)alkyl,
-(C, -06)alkylene-OH, —NR" F'2, -(C,-C6)alkylene-NR "R'2, aryl and 3 to 1 0-membered heterocyclyl, wherein R" and F'2 are as defined in the first aspect of the invention.

In a yet further embodiment, Y is methylene; and R3 is selected from phenyl, pyridyl, pyrimidyl, pyridizinyl and pyrazinyl each of which are optionally substituted by one to three atoms or groups independently selected from halo, (01 4alkyl, (C1-C4)alkoxy and C13.

In a yet further embodiment, Y is methylene; and R3 is selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl.

In a yet further embodiment, Y is in ethylene;
F' is selected from (01-C4alkyl substituted by one to three halo atoms; (C3-C7)cycloalkyl; and a 5 to 6 membered aromatic heterocyclyl optionally substituted by one to three groups independently selected from halo, OH, OR3, (C1-C6)alkyl, (C1-C6)alkoxy, -(0, -O8yalkylene-O-(C1-C6)alkyl and -NH(C1-C6)alkyl;
(Formula Removed)
R isH;
R3 is phenyl or 3-pyridyl each of which are optionally substituted by one to three atoms or groups
independently selected from halo, (0, .4alkyl and OF:3;
R4 isH;and
R5 is absent.

in a yet further embodiment,
Y is methylene;
R1 is selected from OR3; cyclopropyl; and oxazole;
F2 is H;

(Formula Removed)

R3 is selected from phenyl, pyridin-3-yl ano 6-meThyl-pyridin-3-yl.

Fl is 1-1; and
R5 is absent.

In a yet further embodiment. R5 is absent; and
Fl4 is selected from ~ ~{O1-.Coa1~kyiene-O-CO2R3,
-(C1-O6)alkylene-O-O(O)NR9R'~ and -(C1-C6)alkyiene-O-P(O)(Ch,2, wherein Y, Z, R', R2, Plo, R9 and R'0 are as defined in the first aspect of the invention, to give a compound of formula

(Formula Removed)

In a yet further embodiment, R4 is H and F5 is absent.

In a yet further embodiment, F4is absent; and
R5 is selected from -(C1-C6)alkylene-O-O(O) R9, -(C, -C6)alkylene-O-002R9),
-(C1-C6)alkylene-O-O(O)NR9F'0 and -(C,-Oa)alkytene-O-P(O)(OH)2, wherein Y, R', R2, R3, R9 and F'0 are as defined hereinbefore, to give a compound of formula (Ib):

(Formula Removed)

The Examples of the invention form a yet further embodiment of the invention.

Preterred compounds of the invention are those of Examples 1-4, 12, 15-18, 26, 27, 36-38, 4054, 60, 70,
76, 78, 82, 83, 86, 92-94, 96-98 and 100-102
and tautomers thereof and pharmaceutically acceptable salts or solvates of said compound or tautomer.

Yet further preferred compounds are selected from:
4-Amino-i -benzyl-6-cyclopropyl-1 ,3-dThydro-imidazo[4,5-c]pyridin-2-one (Example 1);
4-Amino-i -benzyl-6-oxazol-2-yl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (Example 12);
4-Amino-i -benzyl-6-trifluoromethyl-1 ,3-dihydro-im idazo(4,5-clpyridine-2-one (Example 15);
and tautorners thereof and pharmaceutically acceptable salts or solvates of said compound or tautomer.

In a further embodiment of the invention, there is provided a compound o2 formula (10)
(Formula Removed)

wherein
Y is methylene;
F' and F2 are each independently selected from H, halo, OH, (C1-C6)alkyl, (C3-C7)cycloalkyl,
(C1-C6)alkoxy, -NR6R7, -002R6, -O(O)NRt7, -O(O)NR6S09R8, aryl and 3 to lO-membered heterocyclyl;
or
R' andR12 may be joined to form a (OrCs)alkytene link, said link optionally incorporating 1 or 2
heteroatoms each independently selected from N, 0 and S;
R3 is selected from (C,-C6)alkyl, (OrCy)cycloalkyl, aryil and 3 to lO-membered heterocyclyl;
R4 is selected from R9, -O(O)R3~, -002R9 and -C(O)NR9R'0, and F5 is absent; or
R15is selected from R2, -O(O)R9, -OO?~ and -C(O)NR9&0, and R4 is absent;

R6 and R7 are each independently selected from H and (C, -06)alkyl;
R8 is selected from (C1-C6)alkyl, (C3-07)cycloalkyi and phenyl;
R9 and R10 are each independently selected from H, (C1-C6)alkyl. (C3-C7)cycloalkyl, aryl, -(0H2)aryl and 3 to lO-membered heterocyclyl; or
R9 and F'0, taken together with the nitrogen to which they are attached, form a 3 to lO-membered heterocyclyl group;
said alkyl, cycloalkyt, alkoxy, aryl and heterocyclyl groups being optionally substitued by one or more groups independently selected from halo, 01-I, oxo, OR3, ON, (C,-Cs)alkyl, (C3-C7)cycloalkyl, (01-06)alkoxy, (C,-C6)alkoxy(C,-C6)alkyl, NI-l(Oi-06)alky], N((C1-C6)alkyl)3, aryl and 3 to lO-membered heterocyclyl;
or a pharmaceutically acceptable salt or solvate of said compound; with the proviso that when F' and F2 are H,and Z and R5 are absent, then
(a)R4 is not methyl when Y-R3is ethyl; or
(b)R4 not H or methyl when Y-R3 is methyl.

A yet further embodiment of the invention, comprises compounds of formula (Ic) wherein A4 is selected from F2, -C(O)R9, -C02R9 and -C(O)NR9R'0; F5 is absent; and Y, Ft F2, R3, A9 and A'0 are as defined in the second aspect of the invention, to give the compound of formula (Ia) as shown hereinbefore.

A yet further embodiment of the invention, comprises compounds of formula (Ic) wherein

Y is methylene;
R1 and R2 are each independently selected from H (C1-C6)akyI, {C;-C7)cyo!oaikyl, -CO£H. -
CO2(C1-C6)a!kyl and -C(0)NH(C,-Cr:jiaikyiene(C3-C-7)cycloaIKyl; or n and Ra may be joined So form a
(C2-C5)alkylene link;
R3 is phenyl, which is optionally substitued by one or rmra groups independently selected from halo, OH,
CF3l CN, {C1-C6)alkyl, (C3-C7:icyc!oalky1, (C1-C6]aikoxy. Nti(C*rCr)aiky\ and N((Ci-Cs'iaikyl)2;
R5 is absent; and
R4 is H.
A yet further embodiment of the second aspect of the invention comprises compounds of formula (Ic) wherein
Y is methylene;
R1 and R2 are each independently selected from H, (C1-C6]alkyl, (C3-C7)cycloaIkyl, -COzH, -
C02(C1-C6)alkyl and -C(0)NH(C1-C6]aIkylene(C3-C7)cycloalkyl,- or R1 and R2 may be joined to form a
(C2-C5)alkylene Jink;
R3 is phenyl, which is optionally substitued by one or more groups independently selected from halo and
CF3;
R5 is absent; and
R4 is H.
A yet further embodiment of the second aspect of the invention, comprises compounds of formula (lc) wherein Rs is selected from R9, -C(0)R9, -C02R9 and -C(0)NR9R10; R4ls absent; and Y, R1, R2 and R3 are as hereinbefore defined, to give the compound of formufa (lb) as shown hereinbefore.
A yet further embodiment of the second aspect of the invention, comprises compounds of formula (Ic) wherein R1 and R2 are each independently selected from H, (C1-C6)alkyl, (Qj-C^cycioalkyl, -C02R6, -C(0)NR6R7 and -C(0)NR6SO2RB; or R1 and R2 may be joined to form a (C2-C5)alkylen'e link, said link optionally incorporating 1 or 2 heteroatorns each independently sefected from N, O and S.
A yet further embodiment of the second aspect of the invention, comprises compounds of formula (Ic) wherein R1 and R2 are each independently selected from H, (C1-C6allkyl, (C3-C7)cycloalkyl, -C02H, -C02(C1-C6)alkyl and -C(0)NH(C1-C6)alkylene(C3-C7)cycloalky[; or R1 and R2 may be joined to form a (C2-C5)alkylene link.
A yet further embodiment of the second aspect of the invention, comprises compounds of formula (Ic) wherein R1 and R2 are each independentiy selected from H, (CrC3)alkyl, cyclopropyl, -COaH, -C02CH3 and -C(0)NH(CH2)cycIopropyI; or R1 and Ra may be joined to form a C5-alkylene link.
A yet further embodiment of the second aspect of the invention, comprises compounds of formula (Ic) wherein, RJ is selected from H, methyl, n-propyl, isopropyE, cyclopropyl, -C02H, -C02CH3 and –

C(O)NH(CH2)cyclopropyl; and R2 is selected from H and methyl; or R~ and P7 may be joined to form ula
(Formula Removed)

C5-alkylene link.

A yet further embodiment of the second aspect of the invention, comprises compounds of formula (Ic) wherein P7 is an/i, which is opPonailv substitued by one or snore groups indepenoently selected from halo. OH, oxo, OR3, OW (0 -%aikyi, (03-07)cyclca ~kyl, (Ci -C~)alkoxy, f01-06)alkoxy(01 -G~alkyl, NH(C1-C6)alkyf, N((C1-C6)alkyl)2, aryl endS to i&'membered heterocyclyi.

A yet further embodiment of the second aspect of tbe in'sention, comprises compounds of formula (Ic) wherein Ft3 is phenyl, which is optionally substitued by one or more gouips independently selected from halo, OH, CR3, ON, (C1-C6)alkyl, (C3-C7)cycloafkyl. (C1-C8)alkoxy, NH(01—Cs)alkyi and N((C1 -C6)alkyl.
Yet more preferably, P7 is phenyl, which is optionally substitued by one or more groups independently selected from halo and CR3.

A yet further embodiment of the second aspect of the invention, comprises compounds of formula (Ic) wherein P7 is selected from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and 3-trifluoromethyiphenyl.

Unless otherwise indicated, reference to compounds of The invention includes compounds of formula (I), (Ia)dlb) and (Ic).

It is to be understood that the invention covers all combinations of particular embodiments of the invention as described hereinabove, consistent with the definition of the compounds of formula (9.

In athird aspect of the invention, there is provided aprocess for preparing a compound of formula (Ic)

wherein in each of formulae La, XVIII, XVUIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII, Y-R3 is as defined in claim 14, R1 is as defined in claIm 2, Ft2 is as defined in claim 10, PG1 and PG2 are nitrogen protecting agents and Ft13 is (C16)alkyl,

said process comprising

(a) Reaction of a compound of formula (XVlII) or (XVII [a) with a carbonyf donating agent
(Formula Removed)

to form a corresponding compound of formula (Xb() or (XIXa)
(Formula Removed)

then subsequent deprotection of the compound of formula (XIX) or (XlXa); or

(b) reduction of a compound of formula (XXa)
(Formula Removed)

to form a compound of formula (XXb)
(Formula Removed)

and then cyclisation of the compound of forrriula XXb by treatment with a p:ctic asic; or

(C) reduction of a compound of form la

(Formula Removed)

to form a compound of formula (XV)
(Formula Removed)

and then cyclisation of a compound of formula (XV) in the presence of a carbonyl moiety; or

(e) cyclisation of a compound of formula (UV) in The presence of dipl-ienyfphosptionyl azide to a corresponding compound of formula (XIXA) hereabove and then subsequent deprotection of the amino protection group
(Formula Removed)

(U hydrolysis of a compound of formula (LXIII)
(Formula Removed)

In a fourth aspect of the invention there is provicfed intermediates of formulae XVIII, XVIIIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII, wherein Y-R3 is as defined in claim 14, F' is as defined in claim 2, El2 is as defined in claim 10, PG' and PG2 are nitrogen protecting agents and R3 is (O,~)alkyJ.

Pharmaceutically acceptable salts of the compounds of formula (I) comprise the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/suiphate, borate, cainsylate, citrate, cyclamate, edisylate, esylate, lormate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/oh bride, hydrobromidetromide, hydrolodide/bodide, isethionate, lactate, malate, maleate, malonate, n-iesylate, methylsuiphate, naphihylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, sacoharate, stearate, succirtate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolainine, glycine, lysine, magnesium, meglumine, olainine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for Example, hem isulphate and hemicalcium salts.

For a review on suitable salts, see "l-{andbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:
(i)
by reacting the compound of formula (I) with the desired acid or base;

(ii) by removing an acid- crjaase-fabile protecting group from a suitable precursor of the compound of formula (!) using the desired ac''d or base; o<-
fiii) by converting one salt of the compound of formula (f) to ancfiier by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried o'.it in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the sofveM. The degree of ionisalion in tha resulting salt nay vary from completely ionised to almost non-ionissd.
The compounds of the invention may exist ;n both unsolvafed and soivateo forms The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutical^ acceptable solvent molecules, for exanrple, ethanol. The term 'hydrate' is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where ihey are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. When the solvent or water is tightly bound, the complex will 'have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order {'glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting poirof).
Also included within the scope of the invention are multi-component complexes {other than salts and solvates) wherein the drug and at feast one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type Include clathrates {drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral

molecuie with a salt. Co-crystals may be prepared by melt cysta!hsatiori. by recrystallisalion from solvents, or by physically grinding the components together - see Cherrs Commons. 27, 1883-1396. by O. - Aimarsson and M. J. Zaworotko {2004}, incorporated herein by reference. For a genera! review of multi-component complexes, see J Pharm Sci, 64 (B). 126SM283, by Ha'sblian (August 1375), incorporated herein by reference.
The compounds of the invention may also exist in a meswephic state (mssophasp or liquid crystal) when subjected to suitable conditions. The mesomorphic state -s intermediate pefween the true crystalline state and the true liquid stats (either melt or solution). Mssamarpltisrn arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as Jamphiphflsc' and consist of molecules which possess an ionic (such as -COO'Na+. -COO'K+, or -S03"Nal or non-ionic (such as -N'N*(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshome and A. Stuart, 4th Edition (Edward Arnold, 1S70), incorporated herein by reference.
Hereinafter all references to compounds of formula (I) include references to salts, solvates, multi-component complexes and liquid crystals thereof and! to solvates, multi-component complexes and liquid crystals of salts thereof.
The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopicaily-Sabeled compounds oil formuEa (I).
As indicated, so-called 'pro-drugs' of the compounds of formula (I) aire also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for Example, by hydrofytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Tro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Htguchi and W. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1937 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for Example, be produced by replacing appropriate functtonalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for Example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).
Some Examples of prodrugs in accordance with the invention include
(i) where the compound of formula I contains a carboxylic acid functionality, an ester thereof, for
Example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (C1-C6)alkyl; and
(ii) where the compound of formula 15) contaIns a primary or secondary amino funotlonalty an amide thereof, for Example, a compoind wherein, as The case may be. one or both hdrosens of the amino funchonality of the compound of formula 15) ~sa;e replaced by (C1-C~~3a1kanoyl.

Further Examples of replacement groups in aenordance with The iorag~nng exampies ano exampiss of other prodrug types may be found in the afoi-ementioned references Morecver, certain compounds of formula (I) may themselves act as prodrugs of other compounds of form ufa 15).

Specifically, compounds of the present invention of formula (I) wherein 'A4 is as herein defined, other than H, and R5 is absent (i.e compounds of formula (la)~, may be converted into compounds of formula (I) wherein R4 is H and R5 is absent via metaioolic actions or solvolysis, Addhtionaly, compounds of the present invention of formula (I) wherein A4 is absent and A5 is as herein defined, other than H (i.e compounds of formula (Ib)), may be converted into compounds of formula (I) wherein R4 is absent and A5 is H via metabolic actions or solvolys~s.

Also fncluded within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed invivo upon administration of the drug. Some Examples ot me~abolites in accordance with the invention include
(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof
(-CH3 -~ -CH2OH):
(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof
(-OR -> -OH);
(iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -> -NHR' or -NHR2);
(iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2);
(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -PhOH);
(vi) where the compound of formuta (I) contains an amide group, a carboxytic acid derivative thereof (-CONH2 -> COOH).

Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound at formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for Example, a keto group, or so-called valence tautomerism in compounds which contain an aromatic moiety. [t follows that a single compound may exhibit more than one type of isomerism.

For Example and for explanation of the dotted line in formula (I), the compound of formula (la) wherein R4 is H is the tautomer of the compound of formula (Ib) wherein A5 is 1-I:

'9
(Formula Removed)

Included within the scope of the present invention are all stercoisomers, geomeFiric isomers and tautomeric forms of the compounds of formula (I), including compourics exhibiting more than one bjpe of isomerism, and mixtures of one or more Thereof. Also included are acid addit,on salts wherein the counterion is optically active, for Example, d-laotate or -lysine. or racemic, for Example, dl-tartrate or dI-arginine.

Cisltrans isomers may be separated by conventional techniques well known to those skiled in the art, for Example, chromatography and fractional crysiallisation.

Conventional techniques for the preparation/isolation of individual enatiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for Example, chiral high pressure liquid chromatography (1-IPLO).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for Example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enanliomericallyenriched form using chromatography, typically 1-IPLO, on an asymmetnic resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume ol an alkylarnine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

The present invention includes all crystal forms of the compounds of formula (II including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for Example, "Stereochemistry of Organic Compounds" by E. L. Etiel and S. H. Wilen (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptable isotopically-Iabe~ed compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an
atomic mass or mass number different from the atomic mass or mass nurter which predominates in nature.

Examples of isotopes suitable Icr rictuson hi the compounds of the invention ~ncfude isotopes of hydrogen, such as 2H and 3i-i, carbon, such as 110,130 and 140, chlorine, such as CI, fluorThe, such as '0F, iodine, such as 1231 and 1251, nitrogen, such as IdN and 'Mi. oxygen. such as 150, 170 and 180 phosphorus, such as 32P, and sulphur, such as

Certain isotopically-labelled compounds of formula (I), for Example, Those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studes. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. "'C, are particularly useful for this purpose in view of theincr ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H may afford certain Therapeutic advantages resulting from greater metabolic stability, for Example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as "C, '8F, 150 and 'RN, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. t3~0, d6-acetone, d6-DMSO.

Also within the scope of the invention are intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I). The invention includes all polyrnorphs of the aforementioned species and crystal habits thereof.

When preparing compounds of formula (I) in accordance with The invention, it is open 10 a person skilled in the art to routinely select the form of intermediate which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may be obtained, for Example, as solid plugs, powders, or films by methods such as

precipitation, crystaluzation, treezo aryng spray drug or eveincrative dmng Microwave or racic frequency drying may be used for this purnoso.

They may be administered alone or in comb~nat on wit one or more other compounds of The invention or in combination with one or more other drugs (c: as any combinarc~ th~recf) Ccrrratly, nicy wil uc administered as a formulation in assoc,ation wEth one or more pharrraceutca~iy acceptable cxc&onts The term 'excipient' is used herein to desonbe any ingredient other tan the compound(s) of the invention. The choice of excipient will to a large extent depeno on factors such as the paiticular mode of administration, the effect of the excipient on solubility and stability, aod the nature of The dosage form.

Pharmaceaboal compositions suitable for the defrvery of compounds at the present iriverton arid methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may he found, for Example, in "Remington's Pharmaceutical Sciences 19th Edition (Mack Publishing Company, 1 995).

Suitable modes of administration include oral, parenteral, topical, inhaledfinfiranasal. rectal/intravaginal. and ocular/aural administration.

The compounds of the invention may be administered orally. Oral administration may involve swallowino, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters The blood stream directfy from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches..

Liquid formulations include suspensions. solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for Example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsnying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution olKa solid, for Example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 1± (6), 981-986, by Uang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxyrnethyl cellulose, calcium carboxym ethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl

cellulose, starcin, pregelatinised starch ano socium alginate. Generally, the disintegrant will comprise from I weight % to 25 weight %, Prere~abiy from 5 wefoht % to 23 weight % of the dosage form.

Binders are generally used to rnpart cohesive qualities to a tablet fc~mu1atlcn. Suitable binders induce microcrystalline cellulose, golalin, s~gars, polyethylene glyco~, natural aind synthetic gums, polyvinylpyrrolidone, pregelatinised starch. hydroxypropyl cell Wose and .hydroxypropyl m ethylcellulose. Tablets may also contain diluents, such as lactose (morohydra~e. ~pray-oried roonohydrate, anhydrou~ and the like), mannitol, xylitol, dextrose, sucrose, sorbitoi, rnicrocnlstalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surtace active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present. surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet. and gltdants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 05 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions oIl blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated~ it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets~', Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliable water-soluble or water-s,wellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modilying agent and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (I) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of The composition, typically up to 88 weight % of the solutes. Aiternatively, the compound of formula (I) maybe in the form of multiparticulate beads.

The film-forming polymer may be seiccied from naturW polysacchazides, protects. or synthetic hydrocoiloids and is typically presenr in We range 0.01 to 99' weight %, more typosby in the range 39 to 80 weight %.

Other possibte ingredients include anti-oxidants, colorants, tlavouriRgs and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including &ls. emollients, hulking agents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared' by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coaler dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations for the purposes of the invention are described in US Patent No.
6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic
and coated particles are to be found ii, "Pharmaceutical Technology On-line", 25(2), 1-14, by Verma et al
(2001). The use of chewing gum to achieve controlled release is described in VVO 00/35298.

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, Intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates arid buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitabLy formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation 01 parenteral formulations under sterile conditions, for Example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubilityenhancing agents. Formulations for parenleral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semisolid, or thixotropic liquid for administration as an implanted depot providing modified release of the active

compound. Examples of such form u1ations incude educated stents and poly~di-iactio-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may a~so be administered top:cally to tke sido or mucosa, that i'~, dermally or transdermai~y. Typ:cai form ulatfcns for this rmrpose include gels, hvdrcgels, iOtiOfls, sciutions, creams, ointments, dusting powders, dressings, foams. fims sian patches. ~af*>rs. implants, sponges, fibres, bandages and mioroemulsions. Liposomes mey aso be used. Fy~cai carr~rs include elcohol, water, mineral ol!, liqu~d petrolatum, white petrolatuim glycerin, polyethylene 9~COi ann propylene glyco~. Penetration enhancers may be incorporated - see, for Example, J Phar.m Sci, 8~ (1 0), 955-958, by Finnin and Morgan (October 1999). Other means of topical administraton include delivery by electroporation, lontophoresis, phonophoresis, sonophoresis and micron aedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustaln ad-, pulsed-, controlled-, targeted and programmed release.

The compounds of The invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for Example, in a dry blend wth lactose, or as a mixed component particle, for Example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebutiser, with or without the use of a suitable propellant, such as 1,1,1 ,2-tetrafluoroethane or 1,1,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bloadhesive agent, for Example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for Example, ethanoF, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for Example, from gelatin or hydroxypropylniethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modilier such as 1-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

-2-4-

A suitable solution formulaton for use in an atcmlser using electrohvdrodynamics to produce a fine mist may contain from 1µg to 20mg of the compound of the inverton per 6ctuaflon and the actuation volume may vary from 1µl to l00µl A typical formulation may comprise a camound 'c-f formula (I). propylene glycol, sterile water, ethanol and sodium citlonde. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and lovor~benthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaied/intranasa1 administration.

Formulation for inhaled/intransed administration may be formulated to be immidiate and/or modified release using, for Example, POLA. Modified release formulations include delayen-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1µg to 100mg of the compound of formula (I). The overall daily dose will typically be in the range 1µg to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, for Example, in the form of a suppository, pessary, microbicide, vaginal ring or enema Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for Example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for
Example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives Thereof or polyethylene glycol-containing polymers, in order to knwove their solubly dissolution rater taste-making, bioavailability and/or stability for use in any of the

aforementioned modes of administraUon. Drug-cycto'dextrin cornolexes, 1c Example, are found to be generally useful for most desage forms arid administration routes. Both nciunfor~ and non-inclusion complexes may be used. As an alternative to direct complexatior wit The drug, The cyolodextrin may be used as an au4liary additive i.e. as a carrier, diluerit, or solubiliser Most commonly u-sod f0r these purposes are alpha-, beta- and gamma cyclodexatrims, Examples et which may be found ii International Patent Applications Nos. WO 91/! 1172, WO 94/0251.3 and WO 3/55t43.

Inasmuch as it may desirable to administer a combination of active compounds, for Example, for the purpose of treating a particular disease or condition, flow within the scope of the present invention that Iwo or more pharmaceutical compositions, at [east one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a com pound ot formula (0 in accordance with the invention. and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An Example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for Example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 1mg to lOg, such as 10mg to 1g. for Example 25mg to 500mg depending, of course, on the mode of administration and efficacy. For Example, oral administration may require a total daily dose of from 50mg to 100mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

In order to improve dissolution properties, a solid amorphous spray-dried dispersion (SDD) of 4-Amino-i-benzyl-6-trifluoromethyl-1 ,3-dihydro-imidazo[4,5-cjpyridine-2-one (exam pie 15 hereinafter) and
hydroxypropyl methyl cellulose (HPMC E3 Prem LV, Methocel®, available from Dow Chemical Company, Midland, Ml) was prepared as follows. First, a spray solution was formed containing 2.97 g water, 16.83 g methanol, and 250 jL iM KOH (containing 9.8 mg potassium cations), to which was added 51.27mg of the crystalline neutral form of 4-Amino-i -benzyl-6-trifluoromethyl-1 p3-dihydro-imidazo[4,5-c]pyridine-2-
one. Next, 140.4mg HPMC was added to the solution and the solution was stirred for 5 minutes and sonicated for 2 minutes. The solution was pumped via a Cole Parmer 74900 series rate-controlling
syringe pump at a rate of 1.1 mI/mm into a small-scale spray-drying apparatus consisting of an 11-cm diameter stainless steel chamber. The solution was atomized through a two-fluid nozzle (Spraying
Systems Co., Wheaton, Illinois, Model No. SUl A) using a heated stream of nitrogen at a flow rate of 1 standard ft3/min. The heated gas entered the chamber at an Inlet temperature of 850C and exited at an

outlet temperature of 220C. The resulting solid amorphous dispersion was seLected on Whatman #1
microceliulose filter media (11 wn pore size, 11 cm outer diameter), dried under vacuum. and stored in a
desiccator. The dispersion contained 25.4 wl% 4-Amino-i -berizyl-6-triflu"orometiyi-tJ-dihydro-
imidazo[4,5-c]pyridine-2-one, 4.9 wt% potassium cations. and 59.7 wt% HRLNC. The yield was about
60%.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

The following schemes illustrate general methods for the preparation of compounds of formula (I), and intermediates thereto.
It will be appreciated by those skilled in the art that certain of the procedures described in the schemes for the preparation of compounds of formula (I) or intermed~ates thereto may not be applicable to some of the possible substituents.

It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in the schemes in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I').

It will be still further appreciated by those skilled in the art that, as illustrated in the schemes that follow, it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for Example, those described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter 0 M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 7, pages 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.

The amino protecting groups boc, benzyloxycarbonylk, benzyl and acetyl are of particular use in the preparation of compounds of formula (I) and intermediates thereto.

Unless otherwise indicated, R1 to R7 and Y in the schemes are as defined herein. PG' and PG2 are nitrogen protecting groups.

The compounds of formula (I) may be prepared as depicted in Scheme 1, and preparations 1 to 27 hereinafter further Illustrate scheme 1.

It will be appreciated that the amino protected group N(PG1)(P02) in form u[ae (XVII) to (XIX) is some instances may be N(H)PG1.

(XI}

Scheme 1

(Scheme Removed)
Scheme 1 depicts a variety of means of accessing compounds of formula (I).


a) A commercially available nitrile (II) -or nitrile (14) praoared by any of the standard methods described in the chemical iterature, is reacted with a laso acetate (iii) such as ethyibromoacetate for Example, in the presence of a sourcc of Zn, Tat. Letis. t~97, 3S, 443-416 describes this conversion to afford an enamine of generai structure (JV) provided basic conditions are applied to isolate the product.
b) If acidic conditions are applied to Step a) above, the ketoeaster (f) is produced, which may Then be reconverted to enamine (iv) in a separate step us~-ig a source of arnmcn;a, for Example ammonium acetate. ln this way. a variety of ketoenters of general structure (V) can intercept the above synthetic route at intermediate (iV}.
C) The enamine (IV) may then be reacted with a dialkyl rnalonate (Vii) under basic conditions such as sodium ethoxide, sodium hydride or potassium tert-butoxide to give (VIII). J. Org. Chem., 1981 46 (15), 3040-3048 describes examoles of this transformation.
d) Alternatively, the enamine (IV) may be reacted with malonyl dLch~loride (VI) to give the amidated form (IX) in the presence of a suitable base such as potassium carbonate or triethylamine.
e) (IX) may then be reacted with a suitable base in a separate step to ring close to the pyridine (VIII). Suitable bases include sodium ethoxide, sodium hydride or potassium tert-butoxide.
f) (VIII) is then saponilied under either acidic or basic conditions to provide the corresponding acid, for Example HOI, HBr, sulluric acid, sodium hydroxide or lithium hydroxide which under the influence of heat, spontaneously decarboxylates to give the pyridine (XJ'. An Example of this transformation is described in WOOl 101949.
g) (X) may be nitrated using any literature conditi-ons known to those skilled in the art, for Example using mixtures of nitric and sulfuric acid or mixtures of acetic and nitric acid to provide the nitro pyridine (Xl). For Example, Bioorg. Med. Cliem. Lett., 1996, 6 (2),173-178, descri6es such a transformation.
h) (Xl) may be chlorinated using a variety of conditions which convert hydroxyl groups to chlorines, such as thionyl chloride or phosphorus oxychioride to give (XII). it will be appreciated by those skilled in the art that the two hydroxyl groups may be chlorinated separately, or converted to an alternative leaving group such as another halogen atom, or an activated ester such as a methane sulfonate ester or a trifluoromethyl sulfonate ester. Examples of all of these processes are included in the sections below.
i) (XII) is reacted with an amine of general formula R3YNH2 which preferentially reacts at the 4-chioro group to give (XIII). Dependent on the nature of the R3Y grouping, some displace'ment of both chlorine groups or a minor amount of displacement at the 2-chioro group can occur, but does not detract from the abilLty to secure predominantly (XIII).
j) (XIII) Is then reacted with ammonia or an ammonia equivalent such as ammonium acetate to give
(XIV).

k) (XIV) may then be reduced under any of the conditions known in the literature to reduce a nitro aromatic compound to an amine using for Example iron or tin in HCI, hydrogenation in the presence of a transition metal catalyst such as palladium, platinum or nickel or a chemical reductant such as lithium aluminium hydride to give (XV').
29-

I) (XV) may then be reacted with a source of C=O such as t,1-carbonyidiim~azele or phosgerie to give miKtlires of the imidazolones (XVI) and (I). ~:om which li) may be ocrained by careful chromatograpl-c purihcation.
m) Alternatively, (Xlii) may be reacted with a protected form of ainmonia in wh~ch two of the hydrogen atoms are replaced with two group which can removed under mild cond~t~ons, such as dibenzylamine or diallylamine. -'see, fc e~ampe, those groups described in 'F'roteciive Groups in Organic Synthesis' by Theofoia W Green and Peter 0 iVl WL'ts, Thenedition, tJohn Wiley and Sons, 1929), in particular chater7. pages 94-t353 ('Protecvon for the Amino Group'), for alternatives to these Examples.
n)-o) See steps k)-l).
p) (XIX) is then deprotecled under a variety of conditions suitable for remo'u'al of the protecting
groups PG1 and PG2 to give (I). See, for Example, those groups described ird 'Protective Groups in Organic Synthesis' by TheodoraW Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 7, pages 494-653 (Protection tar the Amino Group'), and the conditions for their removaL
q) Alternatively, (XUI) can be protected as an alkyl carbam ate, R~3CG2X 'A'here R'~ is a 01.6 alkyl X is halo, preferably using a strong base such as sodium hydride, potassium tert-butoxide or
lithium diisopropylamide in combination with an appropriate acylating agent such as
ethylchloroformate or any other alkyl or aryl chloroforrnate, cyanoformate or anhydride, to form
(XX).

r) Steps j) arid k) may be applied to (XX) as above, and the products from this sequence can then be regioselectively cyclised to (I) by simple treatment with a protic acid such as acetic or formic
acid.

An alternative version of the intermediate (XVII) in which a halogen atom is present at the C2 position, and forms a suitable intermediate (XXVII in scheme 2~ for further manipulation can also be used according to scheme 2 below to prepare compounds of general formula (i).

(Scheme Removed)

a)-e) Commercially available dibromopyridine (XXI) can be manipulated accordIng to a modified literature procedure (described in W020050261 64) to give the intermediate (XXVI). Many of the steps between (XXI) and (XXVI) rely on either thermally hazardous reagents or generate potentially thermally hazardous products and should therefore be handled with caution.

f) (XXVI) is reacted using a variety of conditions which are I~riown to generate a diazonium species from an amino group, for Example nitrous acid, generated in situ from HO! and sodium nitrite, conditions which replace the diazonium species with a Cl atom. The transformation of (XXVI) to the pivotal intermediate (XXVII) may then be completed by addition of an excess of an amine to the crude chloride, for Example

berizylamine. This step replaces both the 02 and the 04 haiogen atoms with the amine group. Any primary or secondary amine groups are suitab~efor this transformation.

g)-i) The 02 halogen atom in (Xxvii) can then be reacted under a var~ety of conditions to replace the 02 halogen group with a variety of functional groups, to allow access to a range o~ substituted products (i). For Example, a heterocyolic coupling to {XXViI) using a range of c-ganometallic reagents such as boronic acids, zincates, magnesium reagents, cuprates, stanna~nes etc. gives ~XXVlll~, a vinyl organometallic reagent such as vinyl tributyl stannane and a palladium catalyst such as ~d(PPh~ gives the vinyl species (XXX) and a carbonylation reaction, in which ~XXVit) is treated with CO gas under pressure in the presence of a base such as trietliylamine and a palladium catalyst to. give acyl products of general structure (XXIX). Compounds of structure (XXVIII) and (XXIX) can then be coverted to compounds of formula (I) in accordance with steps ri, o, and p of scheme 1.

1)-I) (XXX) can then be manipulated by oxidation to give the aldehyde (XXXII) and then either (XXXII) or (XXXI) can be ti~eated with an amine in the presence of a base such as triethyllamine or a reducing agent such as sodium triacetoxyborohydride respectively to give the products (I) (following steps n, o and p of schmeme 1).

An alternative version of intermediate (XIII) can be prepared according to Scheme 3 and then taken through to compounds of formula (I) as follows.

Scheme 3

(Scheme Removed)

a)-e) Steps a)-e) are simifar~ in nature to those descrfbed for Scheme 1, except that the monohalide (XXXIV) is prepared to ensure regiochemicai integrity of the 06 and tue 04 substituen~s in ~XXXV1).

f) (XXX\IIll) may be brominated under a variety of conditions known to tnose skilled in the art, such as bromine waler in a non-polar solvent such as 0CM or l'Ae0r'~ to give Tha C3~romide ~0(XlX).

g) (XXXIX) may then be carbonylated using CO gas under pressure in the presence of a base such so triethylamine, an alcohol such as methanol and a pailadium catalyst s~rch as Pd(~Ph~ to give the ester
(XXXX).

h)-i) (XXXX) may then be reacted with an amine NRTh~ to give the arnides (XXXXI), which may be deprotected as above to give the products (I).

An alternative synthesis of the intermediate (Xl) is shown in Scheme 4 below.

Sctieme4

(Scheme Removed)

a) Any nitrile (XXXXII) which possesses a methylene group adjacent to the nitrile function may be reacted with malonyl dich?oride (XXXXIII) to provide the pyridines (XXXXlV). This transformation is described in Synthesis, 1984, 765-766.

b) The pyridines (XXXXIV) may then be nitrated using any literature conditions known to those skilled in the art, for Example using mixtures of nitric and sulfuric acids or mixtures of acetic and nitric acid to provide the nitro pyridine (XXXXV).

c) The chlorine atom in (XXXXV) can then be coupled under a variety of conditions in which a reactive organometallic reagent can be treated with (XXXXVJ in the presence of a transition metal catalyst, for Example a stannane, zincate or boronic acid in the presence of a palladium catalyst,
to give the substituted pyridine (Xl). ln the cases ~.'here PA~H, a shriple hydrogenation in the presence of a suitable catalyst such as pailadised charcoat or pa ladium hydroxide is effective.
A further alternative synthesis of the intermediate (X) is shovm in Scheme S baiow.

Scheme
5(Scheme Removed)

In this method, a malonyl ester, preferably a diphenyl ester (XXXXVI) is reacted with a Schiff's base (XXXXVII) and heated to produce the pyridine of genera! formufa (X).

A further alternative means of accessing compounds of general formula (X) is shown in Scheme 6. Scheme 6

(Scheme Removed)

a) Ketoacids of general formula (XXXXViII), wf-iicl— are either availaule co~nmerea'Ay or can ~e made directly by saponification of ketoesfers of I cmvula (V) are reacted ~'it~i a source of C=O. such as 1,1-carbonyldiirnidazo!e in a suita~ie salvent at elevated temperature to produce the cyclised pyranones (XXXXIX).

b) (XXXXIX) is treated with a strong mineral acid such as sulfuric acid or hydrochloric acid to eliminate the 03-acyl substituent and give the pyrardones (L).

c) (L) may be reacted with a source of ammoma such as concentrated aqueous aromonium hydroxide under heating to convert the pyranone ring into the pyridines (X), to intercept the same intermediate described in Scheme 1. Alternatively, several pyranones of general formula (L) are avaifabte from commercial sources, whicii can be appfied direotfy to Step c. Conversion of compounds of general formula (L) to those of general formula (X~ is described in several sources, for Example W09504730.

An alternative means of accessing compounds of general formula (XIX) is shown in Scheme 7.

Scheme 7
(Scheme Removed)

a) Commercially available dichloropyridines at general formula (LI) can be reacted with an amine of formula R3YNH2 to selectively displace the 4-chloro group to give the pyridiries (LII).
b) (LII) can then be reacted with a protected form of ammonia PG1NI-12 or PGIPG2NH to displace the 2-chloro group, in which two of the hydrogen atoms aie replaced with two groups which can later removed under mild conditions, such as benzylaxn[ne, allylamine, diberizylamine or diallylamine. See, for Example, those groups described in 'Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G Wi Wuts, third edition, (John Whey and Sons, 1999), in particular chapter 7, pages 494-653 ("Protection for the Amino Group"), for alternatives

to these Examples. If an excess of ~ie emma group from Step a. R3YNI-f2 is used, this group can displace both the 2 and the 4-chioro groups.
c) The ester of (LIII) may be hydrolysed wider a variety of conditions which are known to depro~ect esters, for Example sodium hydroxide or lithium hydroxide to give the acid (LlV). See, for Example, those conditions described in 'Protective Groc~ps Th Orgar~io Synthesis' by macdora W Greene and Peter G M Wuts, third ediion, (~obn Wiley and Sons, 1999), in particular chapter 5, pages 373-441 ("Protection for the Carboxy~ Group"), for alternatives to these reagents.
d) (LIV) may then be reacted with a reagent which is known to convert an acid into a~i acyl azide, for Example diphenylphosphoryl azide. Under the ~nXluence of heat, the intermediate acyl azide undergoes a rearrangement in which an isocyanate is produced and is trapped internally by 4-amino substituent to give the imidazolones (XIX), thereby intercepting the same intermediate described in Scheme 1.

alternative means of accessing compounds of 9eneral formula (I) is shown in Scheme 8.

Scheme 8

(Scheme Removed)

a) (LVI), prepared according to Org. BioMol. Chem., 2003, 1~ 1354-1365, may be halogenated by reaction of the amino group In (LVI) with an activating reagent, for Example isoamyl nitrite and a halogenating agent such as diiodo or dibromomethane to give the halogenated material (LVII).
b) (LVII) may then undergo a variety of transition metal-mediated coupling reactions in which the iodo group is selectively reacted wiih, for Example, a terminal alkyne. For Examples of this transformation on an imidazole template, see J. Med. Chem., ~(2), 1991, 778-786

V -~
c) (LVIII) may then be reacted with ~mrnonia, to cycise the alkynyl.rntrile to a pyridine ring. For Examples of this transformation on an mida2ole template, see for examp~s Tetr~bedron, ~i9(3),
1993, 557-570.

d) The bromine atom in (LIX) may men be hydrolysed under either strongly acidic coniit,ons, for Example hydrochloric acid or sulfuric acic. or reacted with a nuclecl3hilic source ol OH, such as sodium hydroxide or sodium methoode, ~ollowso ny a milder actuic hyorelysis to give (I).

The intermediate (LVIII) can also be used according to Scheme 9 below to prepaie compounds of general formula jl).

Scheme 9

(Scheme Removed)

e) (LVIII) may be reacted with an alcohol, for Example methanol, ethanol, propanol, or any other alcohol, to form the acetal (LX) under mild heating.
f) The acetal (LX) may then undergo hydrolysis under any conditions which are known to hy~Irolyse acetals or ketals to ketones, for Example aqueous hydrochloric acid. See, for Example, those conditions described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 4, pages 297-~47 ("Protection for the Carbonyl Group"), for alternatives to these conditions.
g) The ketone (LXI) may then be alk~rlated in the presence of a suitable base such as sodium hydride, potassium tert-butoxide or Potassium carbonate and an alkylating agent such as an ~,Kyl halide, alkyl sulfonate or alkyl trifluor~methane sulfonate to give (LXII).
h) (LXII) may then be reacted with ammonia, to cyclise the keto-nitrile to a pyridine ring.
i) The bromine atom in (LXIII) may then be hydrolysed under e~her strongly acidic conditions, for Example hydrochloric acid or sulfuric acid, or reacted with a nucleophilic source o~ OH, such as sodium hydroxice or sodium methoxide, followed by a mUder acidic hydrolysis to give (I). During the alcoholysis Step e, elevated temperature can lead to the brcmine atom being displaced with an alcohol, which will then introduce an alternative means of introducing the cxo group in (I).

Schemes 8 and 9 are illustrated using bromo (w~nich is preferred), but it will be appreciated that other halo atoms can also be used.

An alternative synthesis of the intermediate (XVII) is shown in Scheme 10 below.
Scheme 10

(Scheme Removed)

a) (LXIV) may be treated under any nitration conditions known to those skilled in the art. It is known that transformations of this type proceed through an intermediate N-nitro analogue. For Example, see the analogous chemistry described in W020050261 64.
b) (LXV) is treated with HBr to convert the chlorine atoms to brom ines (LXVI).
c) (LXVI) is then treated with any conditions known to those skilled in the art which convert an amino group to an N-nitroso or diazonium group, which is then treated with HOI to produce the chloride (LXVII).
d) (LXVI!) is treated with an amine PG1NH, for Example berizylamine to displace both the 4-chioro and the 2-bromo groups to give (LX VI II).
e) The remaining 6-bromo group can then be used to introduce a variety of substituents using transition metal-mediated methods, for Example Pd-catalysed carbonylation, organometallic cross-coupling reactions via Sn, Zn, or B reagents or with Li or Mg reagents using Fe or Ni as

catalysts. In the Example shown, a carbony!ation produces the particular analogue (LXIX) shown. This can then be converted to a compound of formula (I) in accordance with steps n, o and p of scheme 1.

An alternative means of accessing compounds or general formula (XIX) is shown in Scheme 11.

Scheme 11

(Scheme Removed)

a) (LXX) is sequentially halogenated to give the dihalopyridine (LXXI) under a variety of conditions which can introduce a halogen atom, for Example NOS, NBS, NIS, bromine water etc.
b) (LXXI) is then treated with an amine of general structure R3YNH2 to give a mixture of the two compounds (LXXII) and (LXXIII).
c)—e) The desired compound, (LXXII) may then be cyclised, the remaining halogen displaced and
then final deprotection may give (1).

A further method of preparing compounds of general formulae (X), (XI) and (I) is shown in Scheme 12.

0

RI

(LXXV)

Scheme 12

(Scheme Removed)

a) Thus, a commercially available amide of formula (LXXV) may be reacted with a malonyl diester, for Example a dialkyl-1 .3-acetonedicarboxylate in the presence of a strong base, under conditions which lead to the in situ formation of a nitrite, via dehydration of the starting amide, for Example using a common dehydrating agent such as POOl3, SOd2, PPA or triflic anhydride. These conditions lead directly to the formation of the dihydroxypyridine (X).

b) (X) may be nitrated according to the methods described in Scheme 1 to give (XI).

c) (X) may be saponified and decarboxylated according to the methods described in Scheme 1.

d and e) (X) or (XI) can then be converted to compounds of formula (I) using any of the methods described in Scheme 1.

Methods to prepare prodrug derivatives of (I) are shown in Scheme 13 below.

(Scheme Removed)

Scheme 13

Reaction of active parent compounds with a reagent which features the group R4 or R5 attached to a suitable leaving group in the presence of a suitable base provides prodrug derivatives of (I). Suitable reagents include but are not limited to alkyl halides, acid chlorides, chloroformates and carbamoyl chlorides shown below.
(Scheme Removed)

Suitable bases include triethylamine, dilsopropyJethylamine, potassium carbonate, cesium carbonate, sodium hydride and n-butyllithium. A range of solvents can also be used to effect this transformation, Including but not limited to THF, acetonitrile, dim ethylformamide, dichloromethane and diethyl ether. The specific choice of both solvent and base can influence the regioselectivity of the alkylation/acylation reaction i.e. whether the reacting group is appended to the 0 atom (R6) or the N atom (R4). For Example, the reaction of a parent molecule with ethyl chlorotormate in the presence of triethylamine in 0CM will give predominantly 0 acylation.

All of the above reactions and the preparations of novel starting materials disclosed in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the Examples arid preparations hereto.

The compounds of the invention are useful because they have pharmacological activity in mammals, including humans. More 'particulaily, they are usefui in the treatment of a disorder in which the modulation, especially agonism, of TLR7 is implicated.

In a further aspect, the invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the treatment of a disorder or condition where modulation of TLR7 receptor is implicated.

Thus the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate Thereof for the treatment of a disorder or condition where modulation of flR7 receptor is known, or can be shown, to produce a beneficial effect.

In a yet further aspect, the compounds of the invention are useful in the treatment of viral infections , scuh as infections caused by an adenovirus, a herpesvirus (e.g., HSV-l, HSV-II, CMV, or VZV), a ~ioxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, or respiratory syncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses, such as those that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B virus), a flavivirus (e.g., hepatitis C virus or Dengue virus), a retrovirus (e.g., a lentivirus such as HIV) or a filovirus (e.g., ebola virus or marbug virus).

In a further aspect, the compounds of the invention are useful in the treatment of Hepatitis C viral infection.

In a yet further aspect, the compounds of the invention are useful to treat tumors or cancers including but not limited to carcinomas, sarcomas, and leukemias, e.g. squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, renal cell carcinoma, myeLogeous leukemia, chronic lymphocytic leukemia, multiple myeloma, non- Hodgkin's lyrnphoma.

In a yet further aspect, the compounds of the invention are useful to treat bacteria!, fungal, and protozoal infections including but not limited to infections caused by bactena of the genus Eschenchia, Enterobacter, Salmonella, Staphylococcus, Klebsiella~ Proteus, Pseudomonas, Streptococcus, Chiamydia; or fungal infections such as candidiasis, aspergiliosis, histoptasmosis, cryptococcal meningitis.

In a yet further aspect, the compounds of the invention are useful to treat T- helper cells (Th2) mediated diseases (see e.g. Dabbagh et al., Curr Opin Infect Dis 2003, 16: 199-204, incorporated herein by reference), including but not limited to atopic diseases, such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis.

in a yet further aspect, the compounds of the invention are useful for the treatment of damaged or ageing skin such as scarring and wrinkles.

In a yet further aspect, the compounds of the invention are useful in the treatment of autoimmune diseases, such as Crohns disease and inflammatory bowel disease.

The compounds of formula (I) and the ph'armaceutically acceptable salts or solvates hereof, may be administered alone or as part of a combination therapy. Thus included within the scope of the present invention are embodiments comprising co-administration of, and compositions which contain, in addition to a compound of the invention, one or more additional therapeutic agents.

In one embodiment, combinations of the present invention include treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more additional agents' having anti-HCV activity, i.e. agents which can inhibit a target such as, but not limited to, HCV N53 protein, HCV NS5A protein, HCV NS4B protein, HCV polymerase, HCV metalloprotease, HCV serine protease, HCV helicase, p7 protein. Examples of such agents include, but are not limited to, interferons, pegylated interferons (e.g. peginterferon alfa-2a and peginterferon alfa-2b), long-acting interferons (e.g. albumin-interferon alfa), lamivudine, ribavarin, emtricitabine, viramidine, celgosivir, vatopicitabine, HCV-086, HCV796, EMZ7O2, BILN2O6I, 1DN6566, NM283, SCH 6 and VX-950.

In a further embodiment, ccmbinat~cns of the presen: inventon include trc-a~ment with a compound of formula (I) or a pharmaceuticafy acceptable salt or sol\ata thereof, and one or more TLR &goflsts e.g. agonists of TLR3, TLR7, TLPB or TLFS receorors.

In a further embodmerd, combinations of We present nvr-ntion ;nc'ude ceatment of HCV-HIV co-iniection with a compound of formula (I) or a pharmaceutically acceptabte salt or solvate thereof, and one or moro additional antivira! agents selected from HIV protease inhibitors (PIs), non—nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), CORS antagonists, agents which inhibit the interaction of gpl2O with CD4. agents wnich inhibit the entry of HIV into a target cell (such as fusion inhibitors), integrase inhibitors, prenylation inhibitors, RNaseH inhibitors and maturation inhibitors.

Examples of NNRTIs include, but are not l7rnited to, efavirenz, l-IBY-097, nevirapine, TMC-120 (dapivirine), TMC-125, etravirine, delavirdine, DPC-083, DPC-961, capravirine, rilpivirine, 5-{113,5-Diethyl-1 -(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}isophthalonitrile or pharmaceutically acceptable salts, solvates or derivatives thereof; GW-678248, GW-695634, fvllV-i 50, calanolide, and tricyclic pyrimidinone derivatives as disclosed in WO 031062238.

Examples of CCR5 antagonists include, but are not limited to, TAK-779, 50-35 1125, ancriviroc (formerly known as SCH-C), vicriviroc (formerly known as SCH-D), maraviroc, PRO-140, aplaviroc (also known as GW-8731 40, Ono-41 28, AK-602), AMD-887 CMPD-1 67, methyl 1 -endo-{8-[(SS)-3-(acetylam ino)-3-(3-fluorophenyl)propylj-8-azabicyclo[3.2.1 ]oct-3-yl)-2-rnethyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-cjpyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, methyl 3-endo-{8-[(3S)-3-(acetam ido)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2. 1 ]oct-3-yI}-2-methyl-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, ethyl 1 -endo-{8-I7(35)-3-(acetylamino)-3-(3-lluorophenyl}propylj-8-azabioyclo[3.2. I ]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-cjpyridine-5-carboxylate or pharmaceuticafly acceptable salts, solvates or derivatives thereof, and N-fl S)-3-[3-endo-(5-lsobutyryl-2-methyl-4,5,6,7-tetrahydro-1 H-im idazo[4,5-c]pyridin-1 -yl)-8-azabicyclo[a2. 1 ]oct-8-yIJ-1 -(3-fluorophenyl)propyl}acetamide) or pharmaceutically acceptable salts, solvates or derivatives thereof.

Examples of entry and fusion inhibitors include, but are not limited to, BMS-806, BMS-488043, 5-fl S)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1 -yl]-1 -m eThyI-2-oxo-ethoxy}-4-methoxy-pyridine-2-carboxylic acid methylamide and 4-fl S)-2-II(2R)-4-Benzoyi-2-methyl-piperazin- 1 -yi]-1 -methyl-2-oxo-ethoxy}-3-methoxy-N-methyl-benzamide, enfuvirtide (T-20), sifuvirtide SP-O1A, T1249, PRO 542, AMO-alGO, soluble CD4, compounds disclosed in JP 2003171381, and compounds disclosed in JP 2003119137.

Examples Of inhibitors of l-IIV integrase include, but are not limited to, L00087081 0, OW-Si 0781, 1,5-naphthyridine-3-carboxamide derivatives disclosed in WO 03/062204, compounds disclosed in WO 03/047564, compounds disclosed in WO 03/049690, and 5-hydroxypyrimidine-4-carboxamide derivatives

disclosed Th WO 03/035076, MK-051 8 (5-(1 A -d~xo- 1 2-thiazinan-2-yl)-N- (4-fluorobenzyl)—a.hyoroxy-1 6-naphthyridine-7-carboxamide- disclosed in WO 03016315), GS-91 37 (JTK-303).

Examples of prenylation inhibitors include, but are not fmtted to, HMG GcA reductase inhibitors, such as statins (e.g. atc~vastatin).

Examples of maturation inhibitors incIud~ 3-C-(3'3'-dim.ethy succ~nyl) b&uTh acid (otherwise krtnwn as PA-457) and alphaHGA.

In yet a further embodiment, combinations of the present invention include treatment with a compound of formula (I), or a pharmaceutically acceptable san, so~vate or p~iymorph thereof, and one or more additional agents such as, but not limited to, antifungals, e.g. fluconazo!e, foafluconazole, itraconazole or voriconazole; antibacterials e.g. azithromycin or clarithromycin; interferons. daunorubicin, doxorubicin, and paclitaxel for the treatment of AIDS related Kaposi's sarcoma; and cidofovir, fomivirsen, foscarnet, ganciclovir and valcyte for the treatment of cytom egalovkus (CMV) retinitis.

In yet a further embodiment, combinations of the present invention include treatment with a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and one or more additional therapeutic agents that enhance the body's immune system, including low-dose cyclophosphamide, thymostimulin, vitamins and nutritional supplements (e. g., antioxidants, including vitamins A, C, E, beta-carotene, zinc, selenium, glutathione, coenzyme Q-IO and echinacea), and vaccines, e.g., the immunostimulating complex (ISCOM), which comprises a vaccine formulation that combines a multimeric 5 presentation of antigen and an adluvant.

Further combinations for use according to the invention include combination of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof with a CORi antagonist, such as BX-471; a beta adrenoceptor agonist, such as salmeterol; a corticosteroid agonist, such as fluticasone propionate; a LTD4 antagonist, such as montelukast; a muscarinic antagonist, such as tiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast; a COX-2 Inhibitor, such as celecoxib, valdecoxib or rofecoxib; an alpha-2-delta ligand, such as gabapentin or pregabalin; a TNF receptor modulator, such as a TNFalpha inhibitor (e.g. adalimumab); or an immunosuppressant, such as cyclosporin or a macrolide such as tacrolim us.

There is also included within the scope the present invention, combinations of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together wiTh one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients. Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose. The metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP45O) enzymes, particularly GYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes. Thus, among the agents that

may be used to increase the exposure of ~ patient to a com~o~ind of the present invention are those that can act as inhibitors of at least one isoform of thecytocbrome ~45O (0YP450) enzymes. The isoforms of CYP45O that may be beneficially inhib:ted include, but are not ternited to, CYPIA2, 0YP208, CYP2C~, CYP2C19 and CYPSA4. Suitable ogents that may be used ro irhibt CYP 3A4 include, but are not limted to, ritonavir, saquinavir or Iaetoccnazoe.

In the above-described combinations, the compound of form ul~1 ~l) or a pharmaceutically acceptable salt or solvate thereof and other therapeutic agent(s) e~s4y be administered, fri terms of dosage forms, either separately or in conjunction with each other; and in terms of their time ci administration, either simultaneously or sequentially. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

It will be appreciated that the invention includes the following aspects.

(i) A compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt or solvate of said compound or tautom em;
(ii) A pharmaceutical composition comprising a compound of formula (I) as defined in any one of the preceding claims,or a tautomer thereof or a pharmaceutical]y acceptable salt or solvate of said compound or tautomer, together with one or more pharmaceutically acceptable excipients;
(iii) A compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt or solvate of said compound or tautomer for use as a medicament;
(iv) A compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt or solvate of said compound or tautomer for the treatment of a disorder or condition in which modulation of the TLR7 receptor is implicated;
(v) Use of a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt or solvate of said compound or tautomer in the preparation of a medicament for the treatment of a disorder or condition in which modulation of the TLR7 receptor is implicated;
(vi) A pharmaceutical composition including one or more additional therapeutic agents;
(vii) A pharmaceutical product (such as in the form of a kit) comprising a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt or solvate of said compound or tautomer, together with an additional therapeutically active agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a disorder in which modulation of the TLR7 receptor is implicated.
(viii) use of a compound of formula (I) or a lautomer thereof or a pharmaceutically acceptable salt or solvate of said compound or tautomer in the preparation of a medicament for use in combination with an additional therapeutically active agent for simultaneous, separate or sequential use in the treatment of a disorder in which modulation of the TLR7 receptor is implicated.
(ix) A method of treatment of a disorder or condition where modulation of TLR7 receptor is implicated in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of

formula (I) a tautomer thereof or a pharmaceuticellv acceptable salt or solvate of said compound or tautomer.
(x) a process for the preparation of a compound of formula (1) or a tautomer Thereof or a pharmaceutically acceptable salt or solvate of said compound or (automer.
(xi) certain novel intermediates disclosed heretn.

The invention is illustrated by the following non4irniting Examples in which the following abbreviations and definitions are used:

Arbocel®
APCI4
Bn
br
d
dd
DM50
ELSD
ES~
ESI
eq
HRMS
1H NMR
LC-MS
LRMS
m
m/z
Reacti-ViaI~

q
$

t
0
*

Filtration agent, from 1. Rettenmaler & Sohne, Germany
Atmospheric Pressure Chemical lonisation (positive scan)
Benzyl
Broad
Doublet
Doublet of doublets
Dimethylsulf oxide
Evaporalive Light Scattering Detection
Electrospray ionisation positive scan.
Electrospray lonisation (positive or negative scan)
Equivalent
High Resolution Mass Spectroscopy
Proton Nuclear Magnetic Resonance Spectroscopy
Liquid Chromatography — Mass Spectrometry
Low Resolution Mass Spectroscopy
Multiplet
Mass spectrum peak
Reaction Vial available from Fisher Scientific, US
Quartet
Singlet
Triplet
Chemical shift
denotes the point of attachment

Exam pIe 1
4-Amino-i -benzvl-6-cvcloproi,vl-1 .3-dihvdro-imidazof4.5-cloyridin-2-one

(Formula Removed)

4-Allylamino-1 -Benzyl-6-cyclopropyl-1 ,3-dihydro-imidazof.A-,5-c~pyridin-2-one (70mg, C.2rnmol) was dissolved in ethanol (2mL) and 10% Pd-C (70mg, wlw) was added followed by dropwise addition of BFS.OEt2 (270), O.2mmol). The mixture was heated at ref~ux under N2 overnight. The mixture was allowed to cool to room temperature and filtered lhrough arbocel, rinsing with fresh EtOH and the filtrate was concentrated in vacuo to give the crude (150mg). Column chromatography through silica eluting with 98:2—~ 95:5 DCM:MeOH gave the title compound (17mg) as an off white solid.

'H NMR (CD3OD) 0 7.35-7.27 (in, 5H), 6.26 (s, 1H), 5.00 (5, 2H), 1.89-1.82 (in, 1H), 0.85-0.80 (m, 2H), 0.77-0.73 (m, 2H); HRMS for C,~H,6N4O calculated 281.1397, found 281A 395.

Example 2

4-Amino-I -benzvl-6-methvl-1 .3-dihvdro-iinidazof4,5-clnyridin-2-one

(Formula Removed)

1 -Benzyl-4-dibenzylamino-6-methyl-1 ,3-dihydro-im idazo[4,5-clpyridin-2-one (34mg, 0.O8mmol) was suspended in ethanol (5mL) and hydrogenated over 10% Pd(OH)2 (7mg) at room temperature, 60psi for 6 hours. The reaction mixture was filtered Through a short plug of Arbocel and the filtrate was then evaporated in vacuo to an opaque gum. The gum was dissolved in methanol and preabsorbed onto silica gel and was then purified by column chromatography, eluting with 5% methanol in EtOAc. Appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid, 7mg.

'H NMR (CD8OD) 0 2.31 (s, 3H), 5.01 (s, 2H), 6.40 (s, 1 H), 7.31 (in, 5H). LRMS (ES~) mlz 255 (MH4).

Example 3

(Formula Removed)

0

1 -Benzyl-4-amino-6.7-dimethyi-1 . 3-dihvdro-imidazof4i3-clpvridin-2-one

1 -Benzyl-4-diallylain ino-6,7-dimethyl-1,3-dihydro-im idazof4,5-c)pyridin-2-one (358mg, 1 inmol) was taken up in water (lOmL) and acetonitrile (25mL) and RhCl(PPh3~3 (286mg, Q.3ininol) was added in one portion and the mixture then heated at reflux for 1 6h. The mixture was allowed to cool to room temperature, and then concentrated in vacuo, and the residue purified by column chromatography on silica gel using a gradient of 95:5—*85:15 DCM:MeOl-l to afford the title compound as a pale brown solid (77mg, 29%).

1H NMR (DMSO) lii 1.98 (5, 3H), 2.14 (s, 3H), 5.13 (s, 2H), 5.34 (s, 2H), 7.03-7.31 (in, 5H), 10.38 (s, 1H). LRMS (ES~) m/z 269 MH+

Example 4
4-Amino-1-benzvl-2-oxo-2.3-dihvdro-I H-iinidazof4.5-clpvridine-6-carboxvlic acid methyl ester

(Formula Removed)

1 -Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1 H-iinklazo[4,5-clpyridine-6-carboxylic acid methyl ester (0.02g) was taken up in sulfuric acid (2mL), and stirred rapidly for iSmins. The reaction mixture was cooled to OC, and water was added, which resulted in a precipitate which was filtered and dried in vacuo to give the title compound (10mg) as a white solid.

'I-I NMR (d6-DMSO, 400MHz) LI 3.75 (s, 3H), 4.95 (5, 2H), 7.20-750 (in, 6H), 10.20 (s, 1H). LRMS (ES±) m/z 299 1MH}~-

Examola 5

(Formula Removed)

4-Amino-1 -benzyl -6-pyrirazin-2-A-1,3-dihychlo—imidazo[4,.5-c]pyridine-2-one

N-2,N-4-Dibenzyl-6-pyrazin-2-yl-pyridine-2,3,4-triamine (1 OQin gs / 0.261 minols) was dissolved in DMF (5mls) and CDI (95.3mgs / 0.523mmols) added, heated at 600C for 5 hours then concentrated in vacuo. The reaction mixure was then dissolved in cono. sulfuric acid (3mis) and stirred at room temperature for 30inins. ice was then added ice to reaction and quenched by pouring onto K2C03 (8g) in water (5m Is). It was then extracted with EtOAc, dried over sodium sulphale and concentrated in vacuo. The residue was purified by column chromatography. More particularly, EtOAc then 95:5 EtOAc:MeOH was used to separate the two regloisomers to give the title compound (l5ings) as a pale orange solid.

1l~1 NMR (CD3OD, 400MHz) LI 5.10(s, 2H), 7.20-7.40 (in, 5H), 7.55 (s, 1$), 8.45 (d, 11-1), 8.55 (d, 1H), 9.4 (s, 1H)

Exam pIe 6

4-amino-i -benzvl-6-momholin-4-vlmethvl-1 ,3-dihydro-imidazolor4.5.c]pvridine-2-one

(Formula Removed)

N-2,N-4-dibenzyl-6-morpholin-4-yl-methyl-pyridine-2,3,4-triamine (240mg, 0.5Ommol) was dissolved in 2OmL of dichlororoinethane then 1,1 '-carbonyldiiinidazole was added (91mg, 1 .77mmoI) and the reaction was stirred at room temperature for 48 hours. 2OmL of water was added and the organic layer was isolated, dried over magnesium sulfate and the solvent was removed in vacuo. The crude residue was
purified by column chromatography on silica gel using 4% methanol in dichiorometharie to give 140mg of a mixture of 2 isomers. 60mg of this mixture of the 2 isomers was dissolved in 2mL of concentratod sulfuric acid and stirred at room temperature for 30 minutes. Water (5inL) was carefully added followed by potassium carbonate (5.2g untilpH—7).The mixture was extracted with ethyl acetate, the organic layer was isolated, dried over magnesium sulfate and the solvent was removed in vacuc. The crude residue was purified by column chromatography on silica gel using ~% ammonia and 10% methanol in dichloromethane to give 10mg of the title compound and ~ rn~ 01 V~o other isomer.

'H NMR (CD300) : 7.38—7.2 (in, 5H), 6.58 (s, 1H). 5.0~ ~d, 21-t), t3.65 (m, 4H). 3.4 (s, 2k4), 2.4 (in, 41-i). LRMS (ESD m/z 340 (MH]~

Example7

4-amino-i -benzvl-2-oxo-2.3-dihydro- 1 H-imidazof45.ci~vridine-7-carboxvfic acid cvclooroovlmethvl

amide

(Formula Removed)

1 -benzyl-4-dibenzylamino-2-oxo-2,3-dihydro-1 H-im idazo~4~5,c~pyridine-7-carboxylic acid cyclopropylmethyl-amide (10mg, 0.O2mmol} was dissolved in linL of concentrated sulphuric acid and the mixture was stirred at room temperature. for 30 minutes. Once completed, the mixture was diluted in 5mL of water and potassium carbonate was added portion wise until pH—12. The mixture was then extracted with ethyl acetate (2x5OinL). The organic layers were combined, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel using 20% of methanol in ethyl acetate to give 1mg of the title compound.

LRMS (ES~) m/z 338 [MHI~

Exam rle 8

4-amino-i -benzyl-7-bromo-6-methvl-1 .3-dihvdro-imidazor4.5.clnvridine-2-one

(Formula Removed)

4-Amino-i -benzyl-6-methyl-1 ,3-dihydro-imidazo[4, 5-c]pyridin-2-one t2omg. 0.08m mol) was suspended in SmL of acetic acid then sodium acetate (5mg, 0.O8mmol) was added followed by bromine (40L, 0.OSmmotJ dropwise. The mixture was stirred at room temperature for $0 rn~'utes. The mixture was diluted in water (5OmL) and extracted with ethyl acetate (5OmL), the organic layer was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 10% of methanol in ethyl acetate to give 15mg of the title compound as a brown solid.

'H NMR (d6 DM50) LI: 7.40-7.10(m, 5H), 6.85 (s, 2ll-l~, 5.30 (s, 21-I), 2.35 (s, 3H).

LRMS (ES~) mlz 333, 335 [MH]4

Example 9

4-amino-I -benzyl-6-methyl-5-oxv-1 .3-dihydro-im idazol4.5clpvridine-2-one

(Formula Removed)

4-Amino-i -benzyl-6-methyl-1 ,3-dihydro-imidazo[4,5-cjpyridin-2-one (20mg. 0.OBmmol) was dissplved in lOmL of dichioromethane then 3-chloroperoxybenzoic acid (15mg, 0.Ogmmol) was added and the mixture stirred at room temperature for 2 hours. The mixture was washed with water, dried over magnesium sulfate and the solvent was removed in vacuoto give 5mg of the title compound.

'H NMR (CD3OD) LI: 7.40-720 (in, 5H), 6.59 (s, 11-i), 5.05 (s, 21-1), 2.45 (s, 3H). LRMS (ES4J m/z 271 [MH]+

Example 10
4-Amino-i -benzvl-6-(2-methoxv-ethvFj-1 .3-d ihvdro-imidazor4,5-OlDvridine-2-one
(Formula Removed)

I -Benzyl-4-benzylamino-6-(2-methoxy-ethyl)-1 .3-dihydro-im idazof4,5-ojpyridine-2-one (32mg, 0.O82mmol) was stirred in concentrated sulphuric acid (2m1) for SOminutes. Water (Smi) was added and the mixture added drop-wise to a stirred solution of saturated Nat-ICC3 to achieve a basic pH. The aqueous was extracted with 2 x EtOAc and the combined organics dried and concentrated to afford a yellow solid. The mixture of isomers was separated by colu-mn chromatography on silica, eluting with DCM:MeOH, 97:3 with increasing gradient to DCM:MeCH:NH3 95:5:0.5 to afford the title compound as a pale yellow solid, (3.1mg, 13%)

'H NMR (MeOD) LI 2.82-2.85(t, 2H), 3.66-3.69(t, 2H), 5.08(s, 2H), 6.36(s, 1H), 7.19-7.34(m, 5H); LRMS (ES) mlz 299 [MHJ+

Exam ple 11

4-Amino-i -benzyl-6-f2-~2-metho~,-ethvlamino1-ethvll-1 .3-dihvdro-imidazof4.5-clpyridine-2-one

(Formula Removed)

[2-(1 -Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1 H-imidazo[4,5-c]pyridine-6-~jl)-ethyl]-(2-m ethoxy-ethyl)carbamic acid tert-butyl ester (64mg, 0.l2mmol) was stirred in concentrated sulphuric acid (2m1) for SOminutes. Water (5m1) was added and the mixture added drop-wise to a stirred solution of saturated NaHCO3 to achieve a basic pH. The aqueous was extracted with 2 x EtOAc and the combined organics dried and concentrated to afford a yellow solid, The mixture of isomers was separated by column chromatography on silica, eluting with DCM:MeOH, 98:2 with increasing gradient to DCM:MeOH:NH3 gO:lo:1 to afford the title compound as a yellow solid, (4.2mg, 11%).

1H NMR (MeOD) LI 2.34-2.86 (t, 2H), 3.02-3.05(t, 2Hi~ 3.27 is, 3H~ 3.4~5-34t3(t. 2H~, 5.09(s. 2H), 634(5,

1H), 7.20-7.34(m, 6H); LRMS (ES) m/x 342 [MH]+

EXAMPLE-12

4-Amino-i -benzyl -6-oxazol-2-yl]1,3-didroimidazol[4,5-c]pridine-2-one

(Formula Rmeoved)
CDI (821 mg, 5.06 mm 01) was added to a solution of ~ triamine (940 mg, 2.53 mmol) in THF (15 ml). The solution was heated at 60 0C for 18 hrs under nitrogen. The reaction mixture was allowed to cool then concentrated in vacuo. The crude mixture was then dissolved in concentrated l-12S04 (15 ml) and left tor 30 minutes at room temperature. The dark brown solution was added drop-wise onto crushed ice. The p1-f was adjusted to —9 by addition of a saturated aqueous solution of K2C03 then the mixture was filtered. The solid was washed with EtOAc (200 ml) then the organic and aqueous filtrates were transferred to a separating funnel. The layers were separated and the aqueous was re-extracted with EtOAc (200n-il). The organics were combined, dried (MgSO4) and evaporated to an orange gummy solid. The crude material was triturated with EtOAc and toluene. The solid obtained was filtered and washed with EtOAc to give an off-white solid. This material was purified by HPLC on a Phenomenex Gemini 5 pm column (150 x 212 mmid), eluted with 0.05% formic acid (aq) and 0.05% formic acid in MeCN at a flow rate of 15 ml/rnin. The gradient was isocratic at 5 % organic for 0.6 minutes, then increased linearly from 5 % to 80 % organic over 12 minutes.

The filtrate from the trituration was evaporated than columned on Isco Companion on a silica column (12 g, Redisep). The resultant material was then eluted wilh EtOAc:MeOi-f, increasing the gr~adient linearly from 95:5 to 98:2 over 8 column volumes. The desired fractions were combined and evaporated to an orange gummy solid. rhis material was purified by HPLC as above. The desired fractions from both HPLC columns were combined and evaporated to yield the title compound as a white solid (26 mg, 3 %).
'H NMR (CD3OD) LI 5.07 (s, 2H) 7.17-7.36 (in, 7H) 7.92 (s, 1 H)

LCMS R~ 2.15 m/z 308 tMH]~
An alternative means of accessing Example 12 is described below.

4-Amino-1-benzvl-6-ozazol-2-vl-i .3-dihvdro-imidazof4.5-clpvridin-2-one

(Formula Rmeoved)

Butyl lithium solution in hexane (1.6M, iB3ul, O-?9mmo~ was added drop wise to a noution of oxazole (16u1, 0.24mmol) in THF (imi) at -780C urlOer N2. The so~uticn was stirred at —780C for 10 m~nutes then a solutton of zinc chloride (1 00mg1 0.73mmot) in THi~ (-irni) was added drop wise. The solution was stirred at -780C for 15 minutes then allowed to warm to room ternpe~ature. The solution was then added via a syringe to a pre-sealed, nitrogen purged micror~ave vial (Biotage, Q~5-20ml) containing 4-Amino-i-benzyl-6-bromo-1 ,3-dihydro-imidazo~45-c~pyrkfin-2-one (13mg, O.O4inrnol) and palladium bis(triphenylphosphine) dichloride (12mg, 0.O2mmol). The vial was heated under microwave irradiation (Biotage, Initiator 8) for 15 minutes at I 100C. The reaction mixture vias partitioned between ethyl acetate (20m1) and saturated NH4CI ~ (lOmi). The mixture was filtered through celite, washing through with ethyl acetate (20m1). The layers were separated and the organics were washed with water (lOmI) and brine (lOmI), dried over MgSO4 and concentrated in vacua to give the crude. The sample was dissolved in a mixture of acetonitrile:water:DMSO (2:11) and purified by preparative I—IPLC (FractionLynx) to give the title compound (2mg) as a white solid.

1H NMR (d6-DMSO) LI 10.60 (bins, 1H), 8A0 (s, 1H), 7.36-7.27(m, 6H), 7.19 (s, 1H), 6.01 (brs, 2H), 5.04 (s, 2H); LRMS (APCI and ES) m/z 308 [MH]+.

Example 13

4-Amino-i -benzvl-6-(1 -methyl-I H-imidazol-2-yl)-1 3-dibvdro-imtdazor4,5-cThvridine-2-one

(Formula Rmeoved)

CDI (184 mg, 1.13 mmol) was added to a solution of the ~ yl)-pyridine-2,3,4-triamine (218 mg, 0.567 mmol) in DMF (3 ml) in a ReactiVial. The vial was flushed with nitrogen then sealed and heated in an aluminium block at 60 ~C (block temperature). The dark brown

solution was left to stir at this temperature for 16 hrs. The solution aas concentrated under high-vacuum then dissolved in concentrated siWphuric acid (5 ml) The brown solufon was left to stir at room temperature for 30 minutes then poured onto crushod ito (-20 mU A saturated aqueous solution of potassium carbonate was added drop-wise until pH — 8. The aqueous solution was decanted from the solid that had precipitated out during neutralisaton, then extractee wit ~OAc 2 x 50 ml). The combined organics were dried (MgSO4) and evaporated to a yellow solid (106 mgj.

A sample (58 mg) by HPLC on a Phenomenex Gern'n~ 5 pm column (150 x 2 2 mrnid). Eluted with
0.05% DEA (aq) and 005% DEA in MeOW at a flow rate of 18 mikmin. The oradient was isocratic at 5 %
organic for 0.6 minutes, then increased linearly from 5 % to 100 % organic over IS iii iniutes.
The desired fractions were combined and evaporated to yield the title compound as a white solid (10 mg,

1H NMR (CD3OD) U3.94 (s, 3H) 5.08 (s, 2H) 6.91 - 6.95 (in, 1H) 7.00 (s, 1K) 7.07-7.10 (in, 1H) 7.16--
7.38 (in, 5H).

LRMS (ES~) m/z 321 [MH]+

Example 14
4-Amino-i -benzvl-6-(3-methvl-F1 ,2.4loxadiazol-5-vl)-1 .3-dihvdro-imidazof4,5-clpvridin-2-one

(Formula Rmeoved)

1 -Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1 H-imidazo[4,5-o]pyridine-6-carboxylic acid (1 -hydroxyiminoethyl)-amide was suspended in toluene and sealed in a microwave vial (Biotage, '0.5-2.0 ml). The vial was sealed and heated under microwave irradiation (Biotage initiator 8) for 15 minutes at 150 0C. Sample heated in microwave for a further 30 minutes at 150 OQ and again for a further 30 minutes at 150 0C. The mixture was evaporated then partitioned between EtOAc (lOmI) and water (5 ml). The aqueous was extracted twice more with EtOAc (2 x 10 ml) Then the combined organics were dried (MgSO4) and evaporated. The residue was suspended in acetonitrile (2 ml) and this mixture was sealed in a microwave vial then heated under microwave irradiation for 30 minutes at 170 ~C, then at iso 0C for a further 30 minutes. The reaction mixture was concentrated in vacuo then dissolved in concentrated H2S04 (2 ml). The solution was left to stir for 30 minutes then poured onto crushed ice. A saturated aqueous K2C03 solution was added drop-wise until pH was —8. The aqueous was decanted from the solid into a

separating funnel then extracted with EtOAc (3 x 15 nil). The combined organics were dried (MgSQ4) and evaporated. The mixture of isomers was purified by HPLC on a Ltina 10 micron 013(2) coumn (150 x 21.2 mmid). Eluted wiTh 0.1% formic acid (aq) and 0.1% formic acid in MaCN at a flow rate of 25 mhnin. The gradient was isocratic at S % organic for 0.6 minutes, then increased linearly from S % to gg % organic over 8-50 minutes. The desired fractions were evaporated to give the title com pound as a white solid (0.5 nig, 1 %).

LOMS P.~ = 2.46 m/z 323 [MH]+

Exarnrnle 15

4-Amino-i -benzvl-6-trifluorcrnethvl-1 .3-dihydro-im idazoi'4. 5-ciovridtne-2-one

(Formula Rmeoved)

1 -Benzyl-4-benzylam ino-6-trifluoromethyU-1 3-dihydro-im idazo~4,5-cJpyrid(ne-2-one (2.63g, 6.6Qmmol)
was dissolved in c.H2S04 (SOmI) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0~C and ice was added. 1(2003 {150g) was dissolved in water (700m1) and the reaction mixture was added dropwise. The aqueous was extracted with EtOAc (6x500m9. The combined organics were washed with brine (200m I), dried over MgSO4 and concentrated in vacuo to give the title compound (1 .20g) as a white solid.

'H NMR (CDCI3) 0 10.77 (br s, 1H). 7.36-7.25 (in, 5H), 7.01 (s, 1H), 6.20(brs, 2K), 5.04 (s, 2H); LRMS (APOI and ES) m/z 309 LMH]t 307 [MH]+. Found 0.54.55 H.3.60 N.18.17%. C,4H11R3N40 requires %C.54.36 H.3.61 N.17.86

An alternative synthesis of Example 15 is described below;

Ethyl-[2,3-diamino-6-(trit(uoromeUiyl)-pyridin.4-yij-benzylcarbamate (35gm, S9mmal) was dissolved in glacial acetic acid (300mL) at room temperature. Ffltered to remove any insoluble material and then the clear yellow filtrate was heated with stirring to 8000. Within 10 minutes a white precipitate began to form. Heating was continued for a total of 40 minutes. The reaction mixture was allowed to cool to ambient temperature and the precipitate was collected by filtration, washed with acetic acid and dried in vacuo at 50CC for 3 hours to give the title compound (26.4gm, 86% yield) as a white solid.

Example16
4-Amino-i -(6-methvl-pvridin-3-vlmelhvl)-6.oxazol-2-y-1 .3-dihvdro-imidazof4.5-clovridine-2-one
(Formula Rmeoved)

CDI (272 ing) was added to a soluiion of N2,N2-dibenzyl~I\~4-(6-m othyl-pyiidi n-3-ylm eti~,d)-'6-oxazol-2-yl-pyridine-2,3,4-triamine (400 mg) in THF (10 ml). The solution was left to stir under 1% at 60 0C for 5h. A further 3 equivalents of CDI (408 ing) were added and the reaction hea~ed at ref lux for 16h. The reaction mixture was allowed to cool then ooncentra~ed [n vacuo. The crude mixture was then dissolved in concentrated H2S04 (5 ml) and left for 30 minutes at AT. The dark brovvn solution was added drop-wise onto crushed ice. The pH was adjusted to —8 by addition of a saturated soFuton of K2CO~ then the mixture was filtered. The solid obtained was washed with EtOAc (50 m~) then The organic and aqueous filtrates were transferred to a separating funnel. The layers were separated and the aqueous was reextracted with EtOAc (50 ml). The organics were combined, dried (MgSO.~) and evaporated to provide a gummy solid. This was triturated with Et2O and the solid collected by filtration and washed with Et2O, giving the title compound as an off-white solid (30 mg).

'H NMR (COd3, 400MHZ) El 2.45 (S 3H), 5.09 (s, 2H), 7.21 -7.28 (m, 2H), 7.30 (s, 1H), 7.70 (dd, 1 H), 7.95{s, lI-I), 8.42 (d, 1H). LCMS R, 2.29 mlz 323 [MH]+

Example 17
4-Amino-i -benzvl-6-f2-methow-ethox[4-1 .3-dihydro-im idazor4,5-clpvridin-2-one

(Formula Rmeoved)

[2-Amino-6-(2-methoxy-ethoxy)-3-nitro-pyridin-4-ylI-benzyl- carbamic acid ethyl ester (118 ing) was dissolved in ethanol (5 ml) and 10% Pd on carbon (15 mg) added. The reaction was stirred under a hydrogen atmosphere (50 psi) for 1 h at RT. The reaction mixture was then filtered through a Celite pad and evaporated. The crude was dissolved in glacial acetic acid (2 ml) and transferred to a microwave vial (Biotage, 0.5-2.0 ml). The vial was sealed and heated under microwave irradiation at 100 0C for 5

F

minutes. The resultant brown mixture was evaporated then solid loaded on silica and columned on soc Companion on a silica column (4 g, Red isep), c-lrutino tm rtoAc:heptane, increasing the gradient linearly from 60:40 to 100 % EtOAc over 8 column volumes (OW) then socratic at 100 % EtOAc for 3 OVs. The desired fractions were combined and evaporated to provide tho title compound as a white solid (50 mg).

'H NMR (0D013, 400MHZ) LI 3.35 (s, SH), 3.62 (t, 2H), 4.20 (t. 2H\ 4.95 (s, 2Ht 5.80 (s, li-i), 7.20-7.38 (in, 5H). LOMS R~ = 2.13 m/z 318 [Mt

Example 18

4-Amino-i -(6-methvl-pvridin-3-vlmethvD-6-trifluoromethvi-1 ,3-dihvdro-imidazor4-,5-clovrid ine-2-one

(Formula Rmeoved)

(2-Am ino-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbam ic acid ethyl ester (27mg, 0.O7mmol) was stirred in glacial acetic acid (5m1) and the solution stirred at ambient temperature, 4opsi H2, in the presence of 10% Pd/C (5.4mg, 20%wt) for 4h. The suspension was filtered through an Arbocel pad, washed with 2 x 3m1 AcOH and the filtrate concentrated in vacua Acetonitrile (5m1) was added to the residue and the material triturated. the resulting solid removed by filtration and dried in vacuo to afford 10.6mg of the title compound as a white solid.

1H NMR (d6-DMSO): 68.45(s, 1H), 7.57-7.55(d, IH), 7.20-7.18(d, 1H), 7.1O(s, 1H), 6.20(bs, 2H), 5.01(s,
2H), 2.40(s, 3H); LRMS (APCI) m/z 324 [MH]+

An alternative means of accessing Example 18 is described below.

4-amino-i -(6-methvl-nvridvin-3-vlm ethvVl-6-trifluoromethvl-1 ,3-dihvdro-imidazo(4, 5-clpvridine-2-one
(Formula Rmeoved)

4-benzylamino-1 -(6-methyl-pyridyin-3-y[n'eThyI)-E~~trifluorom slhvl-1 2-dih ydro-ini~dazo(4,5-c)pyridine-2-
one (30mg, O.O7mmol) was dissolved in lmL of concentrated sulfuric acid andi the reaction mixture was sti~reo' at room ~einperak~ure i'or fri. The mi~ture was poure& (nto water (fGGrnLJ and por~assYwii carbonate was added portionwise until pH—basic. It was then extracted with ethyl acetate (lOOmL). The organic layer~was separated, dried over magnesium sulfate and the solvent was removed in vacuo to give 16mg of the title compound as a white solid.

11-I NMR (d6-DMSO): 6 8.45(s, iN), 7.57-7.55(d, 1H), 7.20.7.18(d, 11-f), 7.10(s, il-I), 6.20(bs, 2H), 5.0l(s, 21-I), 2.40(s, 31-I); LRMS (APOI) m/z 324 IMHIJ÷

ExamDle 19
4-Am ino-6-l'4-m ethyl-oxazol-2-yl)-1 -(6-in ethvl-pv~idin-3-ylmethyl)-1 3-dihvdro-imidazor4,5-clpvridin-2-one

(Formula Rmeoved)

A mixture of Raney nickel (5 mg) and i2-amino-6-(4-methyl-oxazol-2-yl)-3-nitro-pyridin.4-yl~-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (69 mg) In acetic acid (3 ml) was stirred under a hydrogen atmosphere (80 psi) for 1 hour. Arobcel was added onto the top of a sulphonic acid cation-exchange cartridge (Bakerbond, ig), and the reaction mixture loaded onto the top and allowed to fiLter through. The catalyst and Arbocel were removed with a spatula then the cartridge was washed with methanol (5 ml) to remove impurities. The product was released frorr~ the cartridge by eluting with methanolic ammonia (2M, 2 x S ml). The crude solution was evaporated, ~nd then IPA (3 ml) was added, causing precipition of solids that were collected by filtration and washe~j with IPA. The off-white solid obtained was dried under high-vacuum to provide the title compound (16 me).

1 H NMR (400 MHz, DMSO-d6) ~ ppm 2.13 (s, 3 H) 2.42 (s, 3 H) 5.05 (s, 2 H) 5.98 (s, 2 H} 7.21 (d, J=7.90
Hz, 1 H) 7.25 (5, 1 H) 7.56 (dd, J7.90, 2.44 HZ, 1 H) 7.80 (s, I H) 8.47 (d, J=2.44 Hz, I H) 10.68 (br. s.,
1 H), LAMS (ES I) rn/z 337 jMHI~, 335 [MHf

Example 20
4-Amino-6.-( 4-eth ~A-oxazol-2-v~)-1 ~

(Formula Rmeoved)

[2-am ino-6-(4-ethyl-oxazol-2-yl)-3-nitro-pyridin-4-y l1-(&-m ethyl-pyridin-3-ylmethyl)-carbam ic acid ethyl ester (74 mg~ was dissolved in acetic acid (2 r~.l) and zinc powder (113 mg, Aldrich, 99%) was added to the reaction. The mixture was left to stir at room temperature under nitrogen tor 116 hours, The reaction mixture was filtered directly onto a cation exchange cartridge tRakerbond SOX, sui.ohonic acid bonded-phase, 1 g). The SCX cartridge was washed with methanol (2 x 4 ml) to remove impurities, then the product released with ammonia in methanoll (2 M, 4 ml). The desired fractions were combined and evaporated to an oft-white solid lhat was triturated with isopropanol, filtered, and then washed with isopropanol, providing the title compound (32 mg) as a white solid.

IH NMR (400 MHz, DMSO-d6) 6 ppm 1.16 (t, J=7.42 Hz, 3 H) 2.40 (5, 3 H) 2.44 - 2.56 (in, 2 H) 5.04 (s, 2
H) 5.98 (s, 2 H) 7.19 (d, J=8.02 Hz, 1 H) 7.23 (s, 1 H) 7.54 (dd, J=8.02, 2.34 Hz, 1 H) 7.79 (s, I H) 8.45
(d, J~234 Hz, I H) 10.65 (s, 1 H), LOMS R~= 1.73 mfz 351 [MI-IT

Example21
4-Amino-i -benzvl-6-(1 H-im idazol-2-yl-1,3-dihvdro-imidazoi4.5-clovridin-2-one

(Formula Rmeoved)

The title compound was prepared following the method of Example 20 using (2-amino-3-nitro-6-[1-(2-trim ethylsilanyl-ethoxymethyl)-1 H-imidazal-2-ylJ-pyridin-4-yl}-benzyl-carbarriic acid ethyl ester (174 mg) and Raney nickel (5 mg) in acetic acid (3 ml). This gave initially the SEM protected imidazole compound. Hydrogen chloride in dioxane (4 M, 1 ml) was then added drop-wise and the solution left to stir at room temperature for 24 hours. The reaction mixture was then transferred to a microwave vial (Biotage, 2-5 ml) and heated under microwave irradiation for 10 minutes at 110 0C (Biotage, Initiator 8). The reaction mixture was evaporated then re-dissolved in methanol and the solution loaded onto a cation-exchange

cartridge (Baherbond, suiphonic acid bonded-phase, ig). The cartddge was washed ~ith meThanol (2 x S ml) to remove impurities and then The product released by elutinq wit~ ammo~n~a n methanol (2 M. 5 ml). The desired fractions were combned ~nd e~apOcated to a brown so~d. This was tniturated with sopropanol and the solid collected by filtration Then washed with more scm~opanol, providing the title compound (28 ing) as a pale brown solid.

IH NMR (400 MHz, DMSO-d6) ~ ppm 5.02 (s. 2 i-I) 5,58 (s, 2 H) 6.91 (s. I H) 7.05 (s, 1 1-1) 7.11 (s, 1 H) 7.25-7.36 (in, 5 H) 10.53 (s, 1 H) 11.99 (s, 1 H), LCMS R 1.52 m/z 307 [MHV

Example 22
4-Amino-i -benzvl-6-(2-fluoro-ohen~-l .a-dihvdro-imidazoy4.5-clovrid in-2-one

(Formula Rmeoved)

[2-Amino-6-(2-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-carbamic acid ethyl ester (31 ing) was dissolved in acetic acid (1 ml). Zinc powder (Aldrich, gg %, 20 ing) was added and the mixture left to stir at room temperature under nitrogen for 2 hours. Additional zinc powder (30 mg) was added and mixture left to stir for a further 1 hour. The reaction mixture was diluted with methanol (2 ml) then filtered directly onto a cation exchange cartridge (Bakerbond SCX, sulpilonic acid bonded-phase, I g). The SOX cartridge was washed with methanol (2 x 5 ml) to remove impurities and then the product was released with ammonia in methanol (2 M, 5 ml). The desired fraction was evaporated to a pale brown solid. This was triturated with ethyl acetate then filtered and washed with more ethyl acetate to yield the title compound (8 mg) as a pale purple solid.

1H NMR (400 MHz, DMSO-d6) ~ ppm 4.99 (s, 2 H) 5.82 (S, 2 H) 6.87 (d, .J=1.95 Hz, 1 H~ 7.15- 7.29 (in, 3
H) 7.29- 7.39 (in, 5 H) 7.81 (td, J=~8.01, 1.95 Hz, 1 H) 10.51 (s, 1 H), LCMS R~ 2.21 mlz 335 [MH]+

The following Examples 23 to 119 can be or were prepared in an analogous manner to Examples 1 —22 from analogous intermediates described within the Preparation section using analogous chemistry.

Examples 23-28 were prepared following the method of Example 1, Examples 54-60, 65-72 and 107-110 were all prepared following the method described tor Examples 15 and 18, Examples 31 and 61 were
prepared following the method described for Example 3, ExampleS 42-49, 83-95 and 101-102 were all
prepared following the method described for Example 17, Examples 73-78, 96-99, 103-106 and 111-112 were all prepared following the method described for Example 19, Examples 79-81 were prepared
following the method described for Example 22, Examples ~4-35 and 40 were prepared following the method described for Example 5, Examples 29-30. 38-39, 41 and 50-53 were prepared following The method described for Example 4, Examples 32-33 were prepared following the method described for Example 5 was prepared following the method described for example 14.

Examples 62-64 can be prepared following the methed decoribed for Exarnp4es I ~ and 13, Example 82
can be prepared following the method descilbed for Example 14 and Example 100 can be prepared
following the method described for Example 17,

in the following table of Examples, the asterisk indicates the point of attachment.
(Formula Rmeoved)
(Table Rmeoved)

Precaration 1
3-Am ino-3-cvclonronvl-ac~Lc acid etj~yi ester

CyclopronanecarbonliTile {2.7g, 40.5mmol) was dissoived in dry THU (lOOn-iL) and firstly zinc (132g, 202.3mmol) and then zinc oxide (i.Sg, 2O.2mmo~) were added followed by dropwise addition of ethyibromoacetate (6.7g, 40.Smmol). The mixture was sonicated in a 35 kHz ultrason'c bath under N2 for 2 tiours. After 30 minutes a green colour vvas observed. The mixture was filtered through celite to remove the zinc and zinc oxide. The filtrate was added to 2&t: of 50% 1<2003 (aq) solution. A thick precipPxte formed which was filtered to remove the solid and the aaueous was extracted with lOOm I EtOAc. The extract was washed with 20m1 brine, dried over MgSC4 and concentrated in vacuo to give the crude product (3.8g). The crude material was purified by column chromatography on silica gel eluting with 90:10 pentane:EtOAc to give the title compound (tS2g) as a yellow cir.
'H NMR (CDCI3) 04.47 (s, 1K), 4.11 (quad, 2K), 1.45-1.39 (in, 1K), 1.26 (t, 3K), 0.88-0.83 (in, 2K), 0.76-0.72 (m, 2H); LRMS (APCI+) mlz 156 [MK]+.

Prenaration 2
6-Cvclonronvl-2.4-dihvdroxv-n icotin ic acid ethyl ester

Sodium metal (8.1g. 1 l9minol) was cut into small pieces and added portionwise to stirred ethanol (l2OmL) at room temperature under a nitrogen atmosphere. The mixture was then stirred at 60CC under N2 overnight to ensure complete dissolution of the metal. Diethyl malonate (18.lml, I l9mmol) was added to The sodium ethoxide solution at 6000 and the mixture was stirred at 60CC under N2 for lh. A solution of 3-Amino-3-cyclopropyl-acryiic acid ethyl ester (10.3g, 4Oinmol) in ethanol (lOmL) was added dropwise at
60CC and the mixture was heated at ref lux under N2 for 5 days to give an orange suspension. The mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The filtrate was concentrated in vacuo to give more solid. The combined solids were dissolved in water (l5OmL) and the solution washed with EtOAc (150mL). The aqueous was acidified to pH2 using concentrated HOl causing a white solid to precipitate. The solid was collected by filtration, washed with cold water and then Et2O, and then dried in vacuo at 400C overnight to give the title product (5.32g) as a fine white solid. The filtrate was concentrated in vacuo to half its volume causing more product to precipitate- This second crop of solid was collected by filtration, washed with water and Et2O and dried in vacuo at 40CC to give g further 0.35g of the title compound as a pale beige solid.

'N NMR (d6-DMSO) 0 12.71 (br s, 1H), 11.43 (br s, 1K), 5.51 (s, 1K), 4.26 (quart, 2H), 1.86-1.79 (in, 11-I), 1.26 (t, 3H), 1.06-1.01 (m, 2H), O.gO-o.se (m, 2H); LRMS (APCI) m/z 224 [MK]+.

Prenaration 3
6-Cvcionronvl-2.4-dihvdroxv-nyridine

6-Cyclopropyl-2,4-dihydroxy-nicotinic acid ethyl ester (5.3g, 20.Smmol) was dissolved in concentrated KOl (25mL} and the mixture was ref luxed overnight. The mixture was cooled to room temperature and

then neutralised with concentrated ammonia. The resulUng precipitate was collected by filtration, washed with cold water and acetonitri!e and dried in vacuo at 40CC over 2 days to give the tille compound (3.39g) as a bei9e powder.

1H NMR (d6-DMSO) 0 10.96 (br s, 1H~, 10.25 ~br s, 1H) 5.38, (d, 1H), 5.32 (d, 1H), 1.79-1.72 (in, 1H),
0.93-0.89 (m, 2H), 0.75-0.71 (m, 2H); LRMS (ES)m/z[jMH]±.

Pr~paretion4
6-Cyclopropyl-24-dihydroxy-pyridine (ig, OSinmol) was suspended in AcOH:EtOAc (4:1, IOmL) at room temperature. The mixture was warmed to 300C and a small portion of fuming nitric acid (0.05m1, 1 .2mmol) was added dropwise, keeping the temperature between 30 and 3500. Upon addition the mixture became a clear solution. The remainder of the fuming nitric acid (0.25ml, 6.3mmol) was added dropwise. The clear solution was allowed to cool to room temperature upon which a precipitate started to form. The rruxtire was stirred at room temperature overnight. The solid was collected by filtration, washed with cold water and Et2O and dried in vacuo at room temperature over the weekend to give the title compound (1.21 g) as a yellow powder.

'H NMR (d6-DMSO) u 12.17 (br s, 1H), 14.88 (brs, IH), 5.57 (s, IH), 1.88-1.81 (in, 1H), 1.08-1.03 (m, 2H), 0.87-0.83 (m, 2H); LRMS (APCI) mfz 197 LMHI+

Pret~aration S

6-Cvclopropvi-2,4-dichloro-3-nitro-r,vridine

6-Cyclopropyl-2,4-dihydroxy-3-nitro-pyriciine (1 .2g, 6.1 mmoi) was suspended in POOl3 (Sm L). The mixture was heated at 85 C under a caustic scrubber overnight. Excess POOl3 was removed in vacuo, the reaction residue was dissolved in EtOAc (5OmL) and added dropwise to stirred warm water (5OmL) using ice to control the temperature. The layers were separated and the aqueous was extracted with 90:10 EtOAc:MeOH (lOOmL). The organics were washed with brine (5OmL), dried over MgSO4 and concentrated to give the crude product (2g). Column chromatography through silica gel eluting with 90:10 pentane:EtOAc gave the title compound (893mg) as a pale yellow crystalline solid.
1fl NMR (da-DMSO) 0 7.94 (s, 1H), 2.31-2.24 (in, 1H), 1.18-1.14 (m, 2H), 1.06-1.02 (in, 2H~; LRMS (APOI) m/z 233 EMHJ+.

Preparation 6

Benzvl-(2-chloro-6-cvclopropvl-3-nitro-pyridin-4-vF)-amine

8-Cyclopropyl-2,4-dichloro-3-nitro-pyrldine (160mg, 0.Bmmol) was dissolved in THF (2mL) and triethylamine (10401, 0.Bmmol) and benzylamine (81 Dl, 0.8mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours by which time a yellow precipitate had formed. The volatiles were removed in vacuo and the residue was stored in a stoppered flask at room

temperature for 10 days. The residue was pu'nheo cv coiumn chromatography on silica gel eluting with 99:1 DOM MaSK then 93:2 DCM:MeOH to give the title ccnipound iji 35mg) as a yellow crystalline solid.

'H NMR {0D013) -i 7 '~-7 31 (in., 5K), 7.05 (br s, il-i). 6 47 (s. lI-i), 4.49 (d, 2K, 1.88-i .81 (in, 1K), 1.09-1.04 (in, 2K), 1 01-0.96 (m. 2H); LRMS (APSI) m/z 304 [MH]

Preperation-17
Benzvl-R3-amino-2-chloi o-6-cvclocrcovljvridin-4-vl)-amine

Benzyl-(2-chloro-6-cyclopropyl-3-nitro-pyridin-4-yl)-amine (245mg, 0.8mrmol) was dissolved in AcOH:H20 ~9.0:0.9mL). Iron powder (270mg, 4.Smmol) was added and the mixture was vigorously stirred at room temperature under a nitrogen atmosphere over the weekend, during which an off-while precipitate had precipitated out. The reaction mixture was diluted with EtOAc (20inL.) and water (2OmL), the mixture filtered through celite, and the filter cake washed with EtOAc ~20mL). The phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (lOmL) and brine (1 OmL), dried over MgSO4 and concentrated in vacuo. The residue was dried in vacuo at 4000 overnight to give the title compound (215mg) as an off-white crystalline solid.

'H NMR (0001) El 7.40-7.31 (in, 5K), 6.29 (a, 1K), 4,59 (bi s 11-9, 4.37 (ci, 2K), 3.30 (br s 2K), 1.89-1.82 (in, 1K), 0.87-0.86 (m, 4H); LRMS (APOI) m/z 274 EMHB-.

Preparation 8

1 -Benzvl-4-chloro-6-cvclopropvl-1 .3-dihvdro-in,idazo[4.5-clpvridin-2-one

Benzyl-(3-amino-2-chloro-6-cyclopropyl-pyridin-4-yl)-amine (210mg, 0.8mmol) was dissolved in acetonitrile (IOmL). 1,1-Carbonyldiimidazo!e (370mg, 2.3mmol) was added and the mixture was heated at 800C under a nitrogen atmosphere for 2 hours. A further 250mg (1 .Sminoi) of I ,1-carbonylciuimidazole was added and the mixture was heated at 8000 overnight. The mixture was allowed to cool to room temperature and the solvent was removed in vacue. The residue was dissolved in 0CM (2OmL) and washed with iN HOl (lOmL), then water (lOmL) and brine (lOmL), dried over MgSO4 and concentrated in vacuo. The residue was dried in vacuo at 4000 overnight to give the title compound (21 7mg) as a white fluffy solid.

'I-I NMR (00C13) 08.20 (br s, 1K), 7.38-7.31 (in, 5K), 6.59(s, 1K), 5.03 (s, 2K), 1.96-1.91 (in, 1K), 0.94-0.92 (m, 4H); LRMS (APOI) m/z 300 (MH]-i-.
Preparation 9
4-Allvlamino-1 -Benzvl-6-cvclopropvl-1 .3-dihvdro-Em idazoF4.5-clnvridin-2-one

1 -Benzyl-4-chloro-6-cyclopropyl-1 ,3-dihydro-iinidazo[4,5-clpyridin-2-one (100mg, Q.Smmol) was dissolved in allylamine (2mL) in a Reactivial"'. Copper (]I) sulphate (83mg, O.Gmmol) was added and the vial was sealed. The mixture was heated at 8500 overnight. Further portions of copper (II) sulphate (83mg,

0.3 mmol) and a1lylarnine (ImL~ were added and the Vial was se~led once again. The mixture was heated at 85CC over The weekend, The mixture was allowed to co3l to room temperature. The excess allylamine was removed in vacua and the residue was dissolved in EtOAc (5OmL) and treated with saturated aqueous NaHC03 (2OmL). The layers were separated and the organics washed with more saturated aqueous NaHCO~ (lOrnL), then brine (lOmL), dried over MgSO.~ and concentratc-d in vacua to g:ve the crude product (l20mg). Column chromatography through silica gel eluting with 98:2 DCIVtMeOH gave the title compound (73mg) as an off white solid.

'H NMR (CDCI3) 0 10.40 (br s, 1K), 7.34-7.25 (in, 5H), 617-6.15 (in, 11-1), 5.96-5.87 (in, IH), 5.17 (d, 1H), 5.02-5.00 (in, 1K), 4.89 (s, 2H), 4.05-4.00 (in, 2K), 1.85-1.80 (in, 1K), 0.97-0.93 (in, 2K), 0.84-0.76 (m, 2H); LRMS (APCI) m!z 321 IMH]+.

Preparation 10
Benzvl-(2-chloro-6-inethyl-3-nitro-pvridin-4-vl)-amine
2,4-Dichloro-6-methyl-3-nitro-pyridine (2g, 9.7mniol) and triethylamine (1 .35inL, 9.7inmol) were dissolved in 4OmL THF and cooled (ice/water) to -5 ~C. A solution of benzylamine (1.04g, 9.7mmol) in lOmL THF was added dropwise and the mixture was then allowed to warm gradually to room temperature overnight. The mixture was evaporated in vacuo, partitioned between EtOAc (5OmL) and water (2OmL). The organic layer was washed with saturated aqueous NaHCO3 (lOmL), dried (MgSO4) and evaporated in vacua to an orange gum. This gum was preabsorbed onto silica gel and then purified by column chromatography, eluting with DCM:pentane 3:1. Appropriate fractions combined and evaporated in vacuo to yield the title compound as a yellow solid (71 6mg).

1H NMR (CDCI3) n 2.32 (s, 3H), 4.38 (d, 2H), 6.39 (s, 1H), 6.90 (broad s, 1H), 7.21 (m, 2H), 7.29 (in, 3K). LC-MS (ELSD, ES~) m/z 278 (MH~).

Preparation 11

N-2'. N-2~, N-4'-Tribenzvl-6-methvl-3-nitro-2.4-diam me

BenzyI-(2-chloro-6-methyi-3-nitro-pyridin-4-yl)-amine (99mg, 0.4minol) and triethylamine (5501, d.4mmol) were dissolved in THF (2mL) and dibenzylamine (77mg, 0.4mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature overnight, and then evaporated in vacuo. The residue was partitioned between EtOAc (5mL) and saturated aqueous NaHCO3 (3mL). The organic layer was dried (MgSO4) and evaporated in vacuo to a yellow gum which was preabsorbed onto silica gel and then purified by column chromatography, eluting with 1:1 DCM:pentane. Appropriate fractions were combined arid evaporated in vacuo to a bright yellow gum which solidified on standing to give the title compound (75mg).

'H NMR (COOl,) n 2.32 (s, 3K), 4.45 (d, 2i-Th 4.54 (s, 4K), 5.96 (s, iH), 7.13-7.40 (in, 15K), 8.12 (broad 5,1K). LRMS (ES+) m/z 439 (MK}

B~p.arationi2

l~4~~J±43fl:ibenzvl-6-m ethvl-2,3,4-triamine

N-2', N-2', N-4'-Tribenzyl-6-methyl-3-nitro-2,4-diam inc (59mg, 0.1 4mmol) was dissolved in ethanol (5mL) and hydrogenated at 30psi over Raney nickel (6mg) at room temperature for 1 hour. A further 12mg Raney nickel was added and the mixture was hydrogenated at 30psi and room temperature for a further 1 .5 hours. The reaction mixture was filtered Through a short plug of Arbocel and the filtrate was then evaporated in vacuo to an opaque gum of the title compound, 39mg.

1H NMR (DM50) 0 2.08 (s, 3K), 4.07 (s, 4K), 4.21 (s, 2K), 4.30 (ci, 2K), 5.83 (t, 1K exchangeable), 6.05 (s, iN), 7.14-7.34 (in, 15K). LRMS (APCl~) mlz 409 (MH~).

Preoaration 13

1 -Benzvl-4-dibenzvlamino-6-methyl-1 ,3-dihvdro-im idazor4,5-clpvridin-2-one

N-2', N-2', N-4'-Tribenzyl-6-methyl-2,3,4-triamine (35mg, 0.O9mmol) and 1,1 -carbonylduimidazole (139mg, 0.86rnmol) was dissolved in acetonitrile (3mL) and the mixture heated under ref lux for 3 hours. The reaction mixture was evaporated in vacuo and the residue purified by column chromatography using DOM as the eluarit. Appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid, 30mg.

'H NMR (CDCI3) El 2.32 (broad s, 3K), 4.68 (s, 4K), 4.85 (s, 2K), 6.18 (s, 1K), 7.18-7.26 (in, 15H). LRMS (ES~) m/z 435 (MH~).

Preparation 14
N4-Benzvl-2-chloro-6-trifluoromethvl-pvridine-3.4-diamine

Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pj,ridine-4-yl)-amine (345mg, 1.Ommol) was dissolved in a mixture of AcOK (18m1) and water (2m1). Fe powder (349mg, 6.2inmol) was added and the mixture was vigorously stirred at room temperature for 24h. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (lOmI) and water (lOmi). The mixture was filtered through celite, washing through with EtOAc (20m1). The layers were separated and the organic layer was washed with sat. NaKCO3 (aq) (2xIOml) and brine (lOmi), dried over MgSO4 and concentrated in vacuo to give the title compound (304g) as a pale yellow solid.

'K I\IMR (CDCI3) 0 7.43-7.34 (in, 5K), 6.87 (s, iN), 4.46 (br s, 1K), 4.42 (d, 2H), 3.72 (br 5, 2H); LRMS (APOI and ES) m/z 302 [MH].

Preoaration 15

1 -Benzyl-4~chlcro~-trifljoromethvl-ovridine-2-one

N4-BenzVl-2-chloro-6-trifluoromethyl-pyridine-3;4-dir~m me (300mg, 1.0mm oi) was dissolved in MeON (20m1). CDI (806mg, 4.9mmol) was added and tho mi~tura was heated at 8000 for 48h. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in EtOAc (50m~) ano washed with IN HC~ ~ (20m II, the water (20m1) and brine (2Omf), dried over MgSO4 and concentrated in vacuo to give the title compound (325g) as a pale yellow solid.
'K NMR (CDCI3) El 7.41-7.33 (in, 5K), 7.14 (s, 1 H), 5.11 (s, 2H); LRMS (APCI and ES) m/z 328 [MHI~.

Pre~aration 16
1 -Benzvl-4-benzvtamino-6-trifluoroin ethyl-i .3-dihvdro-iinjciazof4.5-clpx'ridine-2-one

1-Benzyl-4-chloro-6-trifluoromethyl-pyridine-2-one (100mg, 0.3mmol) was dissolved in BnNH2 (2m1) in a reactivial. CuSO4 (152mg, 0.Gmmol) was added and the vial was sealed. The reaction mixture was heated at 800C for 120h. The reaction mixture was allowed to cool to room temperature and dissolved in EtOAc (20in1). The mixture was washed with sat. NaNCO3 (aq) (2x5m1) and brine (5m1), dried over MgSO4 and concentrated in vacuo to give the crude (700mg). Column chromatography through silica eluting with 99:1 DCM:MeOK gave the title compound (50mg) as a yellow solid.

'H NMR (CDCI3) El 10.66 (br s, 1K), 7.34-7.10 (in, 10K), 6.58 (5, 1K), 5.86-5.84 (in, 1K), 4.70 (ci, 2K), 4.66 (s, 2H); LRMS (APOI and ES) miz 399 tMH]~.

An alternative preparation of the above title compound is described below;

N2,N4-Dibenzyl-6-trifluoromethyl-pyridine-2,3,4-triamine (9.02g, 24.2mmol) was dissolved in TBME (i8omt) and CDI (19.6g, 121 minol) was added. The reaction mixture was stirred at room temperature for 72h. Water (1 OOm I) was added to the reaction mixture and the layers were separated. The aqueous was extracted with EtOAc (200m1). The combined organ ics were washed with brine (SOm I), dried over MgSO4 and concentrated in vacuo to give the crude (25g). Column chromatography through silica eluting with 30:70—* 60:40 Heptane:EtOAc gave the title compound (2.64g) as a white fluffy solid.

1H NMR (CDCI3) 0 10.52 (br s,IH), 7.44-7.12 (in, iON), 6.60 (s, 1K), 5.76-5.72 (in, 1K), 4.71 -4.70 (in,
4H); LRMS (APCI and ES) in/z 399 [MH]+.

Preparation 17
N2.N4-Dibenzvl-3-nilro-6-trifluoroinethvl-pyridine-2,4-diamine

3-Nitro-6-tri~luoromstny~-pyridine-2,4-diol (5.Og, 22.Smmol) was dissolved in DOM (5OrnL) and EtSN (6.22m1, 44.6rnmol) was added. The mixture was cooled to 0~O and Tf2O (7.32m1, 44.6mmol) was added dropwise. The mixture was atlowed to warm to room tempera'~ure and stirred for 1 hour. Tne reaction mixture was concentrated in vacuc and the residue was dissolved in THU (SOmI). BnNH2 (7.3rnl, 66.9mmol) was added and the mixture was stirred at 500C for 2-IL The reaction mixture was cooled to room temperature and concentrated in vacuc. The residue was treated with water (SOmI) and extracted with EtOAc ~1 5Dml). The extract was washed with brine (50ml), dried over MgSO.~ and concentrated in vacua to give ~h ecrude(27g}.
A second batch of 3-T~itro-6-trifluoromethyl-pyridine-2,4-dioi (11.069, 49.4mm 01) was dissolved in 0CM (lOOmLi and Et3N (13.Sn~l, 98.7mmol) was added. The mixture was cooled to 00C and Tf2O (16.2m1, 98.7mm ol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated ~n vacuc end the residue was dissolved in TKF (lOOmI). BnNK2 (16.2in1, l4Smrnol) was added and the mixture was stirred at 500C for 24h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Th'~ residue was treated with water (lOOmI) and extracted with EtOAc (200m1). The extract was washed with brine (50m1), dried over MgSO4 and concentrated in vacuo to give the crude (53g). The two crudes were combined. Column chromatography through silica eluting with 95:5—* 90:10 Pentane:EtOAc gave the title compound (15.93g) as a yellow solid.
1I~l NMR (CDCIS) 0 9.68-9.64 (in, 1K), 9.36-9.32 (in, 1K), 7.43-7.29 (in, 10K), 6.38 (s, 1K), 4.81 (d, 2K),
4.55 (ci, 21-i); LRMS (APCI and ES) mfz 403 [MH]+.

Preparation 18
N2,N4-Dibenzvl-6-trifluoromethvl-pyridine-2.3,4-triamine

N2, N4-Dibenzyl-3-nitro-6-trifluoromethyl-pyriciine-2,4-diamine (1 5.9g, 35.6mmol) was dissolved in a mixture of THF (lOOmI) and MeOK (200m1). Raney Nickel (3.18g, 2Owt%) was added and the mixture was stirred at room temperature under 8opsi H2 for 1 hour. The mixture was filtered through celite to remove the catalyst and the filtrate was concentrated in vacuo to give an oil. Trituration in MeOK with a small amount of water gave a precipitate which was collected by filtration, washed with cold MeOK and dried in vacuo to give the title compound (9.02g} as a white solid.

'I-I NMR (CDCI3) 0 7.43-728 (in, 10K), 6.57 (s, 11-1), 4.66 (ci, 2K), 4.62-4.59 (in, 1K), 4.57-4.54 (in, 1K),
4.39 (ci, 2H), 2.49 (m, 2H); LRMS (APCI and ES) m/z 373 [MH]+.

Preparation 19

2.4-Dihvdroxv-6-trifluoromethyl-nicotinic acid ethyl ester

Pyridine (S3rnls (66Ommols) was added to dissolve 3-Amino-4,4,4-trifluorocrotonlc acid ethyl ester (100g / 546mmols) in DCM(6000m Is). The mixture was then placed under nitrogen and cooled to 5C by suspending in an ice-bath. Ethyl malonyl chloride was added dropwise over approx 1 hr such that temperature did not exceed 20 C. The resulting pale brown solution was stirred at 5 C for 3hrs then

allowed to warm t6 room temperature overnight to give a dark green solution. The mixture was then washed with 1 M KCl(aq~ (200mls) then sat.NaHCOsca,i (250m1s). Aqueous washings were sequentially reextracted with further 0CM (2x25Ornls). The Organic layers were combined, dried over Na2SO4, filtered and concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetyiamino'i-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175g). A portion of the crude material (120g) was dissolved in EtOK (300m!s) and placed under nitrogen. Potassium tert-butoxide (54g I 48Ommols) was then added in several oortions such that temperature did not exceed 600C resulting in a purple solution, the mixture was then heated at 700C for 3hrs. EtOK (lOOmfs) was then added to reduce viscosity and heated at 80CC for a further hour. The mixture was then allowed to cool and then concentrated in vacuo to a red solid. The mixture was dissolved in water (SOOmIs) and citric acid {lBOg) then added, causing precipitation. EtOAc (GOOmIs) was then added and the mixture poured into a separating funnel and the aqueous layer run off. The organic layer containing much undissolved solid was filtered to give the title compound (46.5g) as a white solid. Concentration of the organic filtrate and trituration with MeOK afforded further title compound (1 5.3g) as a white solid.

'H NMR (d6-DMSO, 400MHz) 2 1.20-1.25 (t, 3K), 4.20-4.25 (q, 2K), 6.8 (s, 1K)

Preparation 20

6-Trifluoromethyl-pyriciine-2,4-diol

2,4-Dihydroxy-6-trifluoromethyl-nicotinic acid ethyl ester (629 / 247mmols) was added in several portions over 30mins to 6M HCI(aq) (620m1s) at ref lux. The resulting mixture was then heated at 10000 overnight with vigorous stirring to obtain complete solution. The solution was then allowed to cool and concentrated in vacuo to a white solid. This was siurried in water (250mIs) and adjusted to pH 7 with conc. ammonia to get heavy white suspension. The resulting solid was collected by filtration, rinsed through with fresh water, and dried to provide the title compound (44.Og) as a white solid.

'H NMR (d6-OMSO, 400MHz) 5 6.05 (5, iN), 6.6 (s, 1K)

Preoaration 21

Ethvl-f2.3-diamino-6-(trifluoromethvl)-pvridin-4-vll
-benzvlcarbamate

Crude e~hyl-[2-Amino-3-nitro-6-(trifluoromethy])-pyridin-4-yl]-benzylcarbamate (65gm, 1 7Ommol) was dissolved in ethanol (1000mL) and 10% Pd-C (6gm) was added. Hydrogenation at 40CC and 4opsi for 1 hour gave complete reduction of the nitro group: The catalyst was removed by filtration and the filtrate evaporated to dryness under reduced pressure to give a light brown semi-solid. Trituration with t-butyl methyl ether (l5OmL) followed by filtration and washing with the same solvent (3OmL) gave the title compound (36gm, 60% yield) as a white solid.

-1K NMR {DMSOo6} p7.30-721 (in, 51-i), 6.32 (broad s, 1K), 6.15 (broad s, 2K), 5.39 (broad s, 21-1), 5.00 (broad d, 1K), 425 ~broad d), 4.09 (broad d, 2K), 1.12 (broad s, 3H); LRMS (ES~) mlz 355 (MH~)

Prepeeration22
Ethvl-r2.ain ino-3.nitro~6-(trifluorornethyl
-pvridn-4-vfl-benzylcarbamato
Ethyl-[2-chloro-3-nitro-6-(trifluoromethyi)-pyridin-4-yl]-benzylcarbamate (63gm 160 mmci) was dissolved in tetrahydrofuran (300rnL~ and to this was added 0.880 ammonia solution (lOOmL) to give two phases. This was transterred to a pressure vessel, sealed and heated to 800C with stirring for 2 hours. The tetrahydrofuran was evaporated and the residue was partitioned between saturated brine and diethyl ether. The organic extracts were dried over sodium sulphate, filtered and evaporated to give a thick yellow slurry (65gm) of crude product.

LRMS (ES4) m/z 385 (MI-I4), (ESD m/z 383 (MH).

Preparation 23
Ethyl-f2-chloro-3-nitro-6-(trifluorom ethyl)

-pyridin-4-vil-beiizylcarbamate

Senzyl-(2-chloro-3-nitrc-6-trifluoromethyl-pyridin-4-yl)-amine (57gm 1 7Ommol) was dissolved in tetrahydroluran (750mL) and stirred under N2. The resulting mixture was then cooled in an ice/salt bath to
.500. A solution of potassium t-butoxide (21.2gm, l89mmol) in tetrahydrofuran (200mL) was added drop wise over a period of —30 minutes, maintaining the temperature between ~5O and 0 to give a deep red reaction mixture. The resulting mixture was then stirred at this temperature for 15 minutes before the drop wise addition of a solution of ethyl chloroformate (21.4gm, l98mmol) in tetrahydrofuran (lOOmL), keeping the temperature below 5 C.
The cooling bath was removed and the reactJon mixture was allowed to reach ambient temperature over 1 hour to give a light brown hazy solution. Evaporation of the solvent was followed by partition of the residue between saturated brine (5OmL) arid t-butyl methyl ether (300mL). The organic phase was washed with water (5OmL) followed by saturated brine (5OmL), dried over sodium sulphate, filte~ed and evaporated to give a brown oil. The oil was dissolved in n-pentane (250mL) and stored at ambient temperature overnight.
The n-pentane solution was decanted from a dark brown tar which had precipitated out. Evaporation of the solvent gave the title compound as a pale brown viscous oil (63gm, 91% yield).

'H NMR (CDCl~) 0 7.28-7.10 (in, 5K), 4.80 (s, 2K) 4.15 (q, 2K) 1.18 (t, 3H); LRMS (ES4) m/z 404/406 [MH]+

Preosrabon 24

BenzyN2-chloro-3-nitro-6-tr fluorom ethvl-ovridin-4-vl)-arn me

4-Benzylamino-3-nitro-6-trifluoromethyl-pyridin-2-ol (31 7gm l97rnmol) was added to phenvlphosphonic dichioride (lSOinL) aid heated to 1000C in an oil bath. un~ier N2 overnight. The starting material dissolved on heating to give a light yellow solution. The mixture v~es tien quenched on to ice water (600gm of icP~-~lOOmL water) to give a pale yellow solid. ~iitered off arid washed the solid well with water. The solid was dissolved in ethyl acetate (600mL~ and washed with aqueous sodium hydrogen carbonate solution (10% w/v) until there was no further effervescence and the pH o~ the aqueous washings were basic. The organic layer was dried over sodium sulpnate, filtered and evaporated to give a dirty yellow solid. The solid was then dissoived ~n diethyl ether. T~ this was then added n-hexane until the solution was cloudu'. Within a few minutes a thick flocculent solid had formed, which was then filtered off, washed with nhexane and dried to give the title compound (60.59gm 92% yield).

'K NMR (CDCI3) ui 7.44-7.30 (in, 5K), 7.04 (s, 1K), 6.95 (broad s, lI-I) 4.53 (d, 2H); LRMS (ES~) m/z 332 (MV).

Freparation 25
2-Chioro-3-nitro-6-trifluoromelhvl-r,vridin-4-vlam me

Benzyf-(2-chloro-3-nifro-6-trifluoromethyl-pyridin-4-yl)-amine (3.Ig, 9.3mmol) was stirred in 5m1 concentrated sulphuric acid for 0.5h before cautiously pouring the solution into a beaker of crushed ice. Solid K2C03 was added portion-wise until a basfo pH was achieved and the aqueous extracted with 2 x SOmI EtOAc. The combined organics were dried over MgSO4 and concentrated in vacua to afford 2.2g of the title compound as a pale yellow solid.
1H NMR (COOl3) 6 7~06(s, 1K), 5.87(bs, 2K; LRMS (ESCI) m/z 240 I~M-HI+

Preparation 26
(2-Chroro-3-nitro-6-tr~luoromethvf-pwkIin-4-vJ'l-carbamic acid ethyl ester

2-Chloro-3-nitro-6-trifluoromethyl-pynidin-4-ylan~ine (2.2g, 9.lmmol) was stirred in 2-MeTKF (2 triethylarnine added (1 .52m1, 1O.9mmol). The solution was cooled in an ice bath to —50C bi
dropwise addition of ethyl chioroformate (1.04m1, 10.9mmol), the solution warmed to ambient temperature and left to stir under a nitrogen atmosphere for 16h. 20in1 EtOAc and lOmI H20 were added and the phases separated, washed with a additional 2 x lOinl sat'd brine solution. The organic extract was dried over MgSO4, concentrated in vacua and preabsorbed onto a silica column. Elution with Kept;EtOAc, 9:1 gave 21g of the title compound as a white solid.

'H NMR (CDCI3) ~ 8.79(S, 1H), 8.02(b5, 1K), 4.35-4.30(t, 2K), 1.38-1.35(qt, 3H); LRMS (ESCI) m/z 312 [MH]+

Preparation 27
(2-benzylamino-3-nitro-6-tniflu~nom~i-yddr1-4-yl)-carbam ic acid ethyl estC4

(2-Chiono-S-nirro-6-tri~luoromethyl-pynidin-4-vi).carbamic acid ethyl ester (300mg, 0.~mm ol) was dissolved in lOmL of tetrahydi-ofuran and beri~'iornino jO lO3mL. 0.96rnmol) was added followed by triethylamine (0.194mL, 1.9lmmol) and the re~cton rni~ture was stirred at 6000 overnight. The soveni was removed and the solid was partitioned in ethyl acetate / water (5OmL/3OmL), the organic layer was dried over MgSO4, concentrated and pwThed by column chromatography on silica eluting with a gradient of 0% to 10% of methanol in ethyl acetate ii to g've 323mg of the title compound as a yellow Solid.

Il-I NMB (CDCI3): 6 10.75(s, 1K), 8.89(s, 1K), ~,22(s, 1K), 7.35(m, 5K), 4.82(d, 2K), 4.31 (q, 2K), 1.36(t, 3H)~ LRMS (APOI) mlz 385 IMK]+

Preparation 28

£3-ainino-2-benzvlem ino-6-trifJuorrnethvl-o~jidin-4-vl)-carbam ic acid ethyl ester

(2-benzylamino-3-nitro-6-trifluormethyl-pyridiri-4-yl)-cartamic acid ethyl ester (95mg, 0.25mmol) was dissolved in lOmL of ethanol and Raney Nickel (20mg, 2~J%MW) was added then the reaction mixture was stirred at room temperature in a bomb under 50 PSI of hydrogen for 2 h. The mixture was filtered through arbocel and the filtrate was concentrated in vacuo to give 88mg of the title compound as a pale green gum.

LRMS (APOI) m/z 355 ~MH]+

Preoaration 29
4-benzvlamino-6-trifluoromethyl-1 ,3-dihvdro-imidazo(4.5-c)ovridine-2-one

(3-ainino.2-benzylainino-6-trifluormethyl-pyridin-4-yl)-carbamic acid ethyl ester (88mg, 0.25mmol) was dissolved in 5mL of acetic acid and the reaction mixture was stirred at 800C overnight. The solvent was removed and the gum was partitioned in waterfethyl acetate. The organic layer was isolated, dried over MgSO4, the solvent was removed in vacuo and purified by column chromatography on silica eluting with a gradient of 1% to 5% of methanol in ethyl acetate to give 37mg of the title compound as a colourless gum.

1K NMR (CDCI3): 6 10.56(s, 1K), 7.51-7.47Cm, 5K), 6.61-6.58(m, 2K), 5.87 (5, 1K), 4.61(ci, 2H); LRMS (APOI) m/z 309 [MH]+
Preparation 30
4-benzvlamino-1 -(6-methvl-pvridvin-3-vlm ethvl)-6-tnifluoromethvl-1 ,3-dihvdro-imidazo(4.5-c'ipvridine-2-one

4-benzylamino.6-tnifiuorometh'fl-1 ,~-dihyd~-o-imidazcf4.5-c)pyr;dine-2.one (100mg, 0.32mrnol) was dissolved in 5mL ol dim ethylformam~de and potassWm carhonete (39mg, O65mmoi) was added followed by 5-chlorometl-iyl-2-methyl-pyridine (46mg, 0.32mmol) and the reaction mixture v.as stirred at 800C overnight. Mass spec showed product expected' 'vth some bibenzy!ated product. The solvent was removed in vacuo and the residue was partitioned in athyl acetate / water. The organic layer was isoated, dried over t~gSO4 the solvent was removed in vacue and the residue was purifieo by column chromatography on silica eluting w~:h a grad~nt ci' 1% to 10% of methanol in ethyl acetate to give 30mg of the title compound as a white solid.
1K NMR (d6 DMSO): ~ 8.46(s, 1 H). 7.57-7.55(dd. Il-I). 7.33-7.16(m, 7K), 6.63(t, 1K), 5.02 (s, 2K), 4.59(d,
2K), 2.40(s, 3H); LRMS (APOI) m/z 414 IjMHI+

Preoaration 31
(2-Chiono-3-nitro-6-trifluoromethvl-pvridin-4-vfl-(6-m ethvl-pvridin-3-vlmethvl'l-carbamic acid ethyl ester

Potassium carbonate (88mg, 0.64mrnol) was added to a stirred solution of (2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-carbamic acid ethyl (100mg, 0.32mmoi) in acetone (bOmI). 5-(chloromethyl)-2-methylpyridine (54.2mg, 0.38minol) was added folfowed by sodium iodide (57.4mg, 0.38mmol) and the suspension stirred under a nitrogen atmosphere ion 161,. 20m1 EtOAc was added and the organic phases washed with 2 x H20, dried over MgSO4 and concentrated in vacua to afford a red oil. The crude material was purified by column chromatography on silica, eluting with l-lept:EtOAc, 3:2 to give 54mg of the title compound as an orange solid.

'K NMR (CDCI3) ~ 8.35(d, 1K), 7.54-7.5~(dd, 11-I), 7.31(s, 18), 7.16-7.15(d, 1K), 4.84(s, 2H), 4.23-4.18(qt, 21-1), 2.55(s, 3H), 1.26-1.22(t, 3H); LRMS (ESCI) m/z 419 [MH]+

Preparation 32

(2-Amino-3-nitro-6-trifluoromethvl-Dvridin-4-vl)-(6-methvl-pvridin-3-vlinethvl)-carbam ic acid ethyl ester

(2-Chloro-3-nitro-6-triftuoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (54mg, 0.l3mrno!) was dissolved in THF (imI) and transferred to a lOmI reactivial. 880 Ammonia (ml) was added, the vessel sealed and the mixture stirred vigorously at ambient temperature for 1 6h. The solution was concentrated in vacuo to give a crude oil which was purified directly by column chromatography on silica, eluting with 100% EtOAc to give 27mg of the title compound as a yellow residue.
'H NMR (CDCl~,) ~ 8.39(s, 1K), 7.61 -7.59(d, 1K), 7.1 5-7.13(d, 1K), 6.76(s, 1K), 6.25(bs, 2K), 4.92(s,2K), 4.23-4.14{qt, 2H), 2.54(s, 3K), 1 .22-1.19(t, 3K): LRMS (APCI) mlz 400 (MH]-iPreparation 33

4-Benrvlamino-3-niiro-6-trifluoromethyfrpyridin-2-ol
4-~bioro-3-nitro-6-trifluoromethyl-pyridin-2-ol (55. f gin 2S3rnmol) was dissolved in tetrahydrofuran (350mL3 and stirred at room temperature under N2. Berizylam ins (86.3gm 505mmol) in tetrahydrofuran (5OmL} was added drop wise over 30 minutes to give a bright yellow solution. The reaction was heated in an oil bath at 5YC for 18 hours, (a solid formed during the reaction). The resulting mixture was then cooled to ambient temperature, diluted with diethyi ether (200mL) and the resulting solid (benzy~amine hydrochloride) was then filtered off. The filtrate was evaporated to low buW under reduced pressure to give a thick yellow slurry. Added diethyl etheT (300mL) and filtered off the yellow solid, dried on the filter pad to give the benzylamine salt (96.5gm). The desfred product was liberated by partition of the solid between aqueous 2N HOI and dichioroinethane and crystallization from ethyl acetate/n-pentane gave the title compound as a pale yellow solid (61.7gm' 73.4% yield).

'H NMR ('DM80 ~Q 9.04 (broad s, iN), 7.38-7.25 (in, 5K), 6.54 (s,1H), 4.67 (ci, 2H); LRMS (ESt m/z 314 (MH4}.

Prenaration 34
4-Chtoro-3-nitro-6-trifluoromethvl-vvridin-2-ol

3-Nitro-6-tr(fluoroinethyl-pyridine-2,4-diol (5.8gm, 2Smmol) was heated in phenylphosphonic dichioride (SGmL) at l00~C for 19 hours. The resulting naixure was then cooled and poured on to ice (60gm), and then extracted with ethyl acetate (3 x SGmL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (10%wAr) until the washings remained basic (pH —8). The deep yellow organic layer was then washed with saturated brine, dried over sodium sulphate, filtered and evaporated to give a yellow gum. Trituration ol the gum with dichioromethane gave a yellow solid which was filtered off and dried (4.65gm). The solid was dissolved in water (25m L) and acidified with 2N hydrochloric acid (7.SmL) to give a thick white precipitate which was filtered off and washed with water. The precipitate was dissolved in ethyl acetate, dried over sodium sulphate, filtered and evaporated to give the title compound as a white solid (3.75gm).

'K NMR (DMSOd6) 0 7.78 (a, 1K), '~o NMR (DMSOd6) n 157.2 (s) 145.2 (q) 138.1 (s) 136.98 (s~ 120.6 (q) 113.86 (s). LRMS (ES) m/z 241/243 (MH~

Preoaralion 35
3-Nitro-6-trifluoromethvl-pvridine-2.4-diol

6-Trifluorornetlayl-pyridine-2A-diol (56gm, 31 Ommol) was added in 3-5gm portions to cono. sulphuric acid (l4OmL) with stirring to give a pale brown solution. The temperature increased to —500C during the addition. Nitric acid (21.1 mL 328mmo1, 70% KNOS &4 .4gm/in I) was added drop wise at such a rate as to maintain a reaction temperature of between 450 and 500C which took approximately 90 minutes. Once all


the nitric acid had been added the reaction was allowed to cool tc ambient temperature over 3 hours. The reaction mixture was then poured into ice/water (—i.31g) with stfrrinq, and after a few minutes a pale yellow precipitate formed which was i~ltered ofi, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop at material was obtained ~ extraction of the aqueous ffltrate with ethyl acetate. Combined batc~ies and purified by crystallization from ethyl acetate/ n-heptane gave tue title compound as a white fluffl solid {49~gm 71% yield).

~H NMR (DMSOd6) p6.82 (s, 1H). ~C NM~ (DMSQd~) ~ 159.82 (s) 157.58 (s) 14310 (broad s) 127.26 (s) 120.85 (q) 102.83 (s).

Preparation 36
2.6-dibrom,o pyridine 1-oxide

2,6-dibromo pyridine (79g, 334mmol) was dissolved in B00m~ of dry dichioromethane and cooled under nitrogen to 5~C then urea hydrogen peroxide (104g. 1.lmol) was added in one portion. When the mixture had cooled again to 300, a solution of trifluoro acetic acid anhydride (l4OmL, imol) in 100 ml DCM was added via dropping funnel over 45 mm, whilst keeping the temperature between 5-70C. The mixture was allowed to wami to room temperature and stirred for 20 hours. The mixture was cooled in an ice bath to 1000 and 10% aq. Na2SO3 (—SOg/SOOmI) was added dropwise over 60 minutes until test with starch iodhde paper was negative. The resulting mixture was filtered to remove a quantity of fluffy solid and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 200in1) and the combined extracts were dried over MgSO4 and concentrateci under reduced pressure to give a light brown solid. Recrystallisation of crude product using 600m1 of boiling acetone gave 48.47g of the title corn pound.

1H NMR (00013) 5 7.65 (d, 2K), 6.95 (in, 1K).

Preparation 37

2.6-dibromo-4-nitro pyridine 1-oxide

2,6-dibromo pyridine 1-oxide (lOg, 39.Smmo~) was added to 65mL of concentrated sulfuric acid at room temperature without cooling. Concentrated sutiuric acid (15ml) and nitric acid (13.3m1) were mixed and placed in a pressure equalising dropping funnel. The reaction mixture was heated to 7900 then the nitrating mixture was added in portions over 25 minutes. When the addition was complete the n~ixture was stirred at 83-850C for 3.5 hours. The mixture was cooled to room temperature and slowly poured onto —250g crushed ice. A very pale yellow solid formed which was filtered off and washed with water (10Cm]), dried in vacuum oven at 5000 overnight to give 1 0.9g of the title compound.

'H NMR (00013) 0 8.45 (s, 2H).

Preparation 38
2-6-dibromo ovridin-4-ylamire

2,6-dibromo-4-rntro pyndine 1-oxide (44.5g. 43.6mmoi~ vas taken up in l3OmL of acetic aC1d and iron powder (11g. 19&9inmol) was added in portionwise and the mixture was stirred at room temperature for A5 minutes. 5OJmL of water was added and The product was extracted with EtOAc (500mL). The organic layer was washed with SOOinL of water Then with 303mL of a sat K2003 sol and then with 300mL of brine. The organic fayer was dried over magnesium sultate ano the solvent was removed in vacuo to give it .1 g of the tide compound as a white soNiC

'H NMR (CDCI3) 5 6.65 (s, 2K), 4.4-4.1 (s broad, 21-N)

LRMS (ES') in/z 251,253 [MH]+

Prenararion 39'

2.6-dibroin o pvridin-4-vl-N-n itroarnine

2,6-dibromo pyridin-4-ylainine (hg, 43.Sinmol) was dissolved in lOOinL of sulfuric acid at room temperature and then cooled at -5CC. 6mL of nitric acid was added dropwise keeping the temperature between -lOt to -50C and the mixture was stirred at -50C for 30 minutes. The mixture was then poured onto 400rnL of crushed ice. The solid formed was filtered off then dissolved in EtOAc. The residual water was removed and the organic layer was washed with SOOmS of brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 1 2.Sg of the title product as a yellow solid.

'I-i NMR (CDCI3) 0 6.85 (s 1K), 5.7-5A(s broad, 2K).

Prenaratfon 40

2,6-dibron,o-3-nitro-pvridin-4-vlam me

Concentrated sulphuric acid (2SOrnl) was heated in an oil bath until the temperature of the acid reached 470C. 2,6—dibromo pyridin-4-yl-N-nilroamine (34.Og, 114.5 rnmol) was added in portions over OSmins. The temperature of the mixture gradually rose throughout the addition period until it was 560C at the end. The mixture was stirred at 53-550C for 1 hour. Once the reaction was completed, the reaction mixture was cooled to in an ice-bath and poured on —2L of crushed ice with stirring. The product precipitated and was filtered off. Combined with other batch 00110916-140-001 from an identical scale reaction. Thd crude, wet amino nitro pyridine was dissolved In 70Gm I EtOAc and the water layer was separated. The organic layer was washed with water (2 x iSOmI), 1 x 150 ml aq. NaKCO3, brine (2 x iSOmI), dried (MgSO4) and concentrated under reduced pressure to give 28g of the title compound.

'K NMR (CDCI3) 0 7.3-7.2 (s bmad, IH), 7.55 {s, 2K).

Prenaration 41

N-2,N-4-dibenzvl-6-bron,o-s-nilro-ovridine-2.4-diam me

• 2,6-dibromo-3-nitro-pyridin-4-ylamine (6.5g. 21 .9mrnoFt was su5pended in concontrated 1101 (1 OOmL) and cooled to 0CC, then sodium nitrite (7.5g. 1O9mrnoi~ was added. There mixture was stirred for 30 minutes then warmed to room temperature.lOOmL of coded watec were added and the mixture was extracted with I OOrnL of ethyl acetate. The oreanic layer was wesh~d with iOOmL of water, dried over magnesium sulphate and tbe solvent was removed in vacuc to give &8 g of 2,6-dibromo-3-nitro-4-chloro pyridine as an orange oil. The cii was disso~ved in BOmL of and cco'ed to 000. 6enzylarnina (94.9mL, 44.9mrrol) was dissolved in 2OmL of THP and added clropwise to the reaction followed by potassium carbonate (6.6g, 48.2mmo9. The mixture was warmed to rooms ~ernpera[ure then heated at 50CC overnglit. Once the reaction was complete, the mixture was partilioned in v~atar (l5OmL) and ethyl acetate (lOOmL). The organic layer was washed with 200mL of water and 2C'OmL of brine, dried over magnesium sulphate and the solvent was removed in vacuo. lOOmL of etuariol was added and the mixture was sonicated for five minutes and let in the fume hood overnight. Tne precipitate was filtered off and washed with 3OmL of ethanol to give 4.56g of the title compound as a yellow solid.

'F-f NMR (CDCl~) ~ 9.6-9.4 (m broad, 2H), 7.4-7.2 (in, 1011), 6.2 (s, 1H), 4.8 (d, 2H), 4.45 (d, 21-I).

IRMS (ES4) m/z 413,415 ~MHI4

Preparation 42

N-2,N-4-dibenzvl-3-nitro-6-v~nxd-pvridine-2,4-diam me

N-2,N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2,4-diamine (2g, Smmol) was dissolved in THF (6OmL) and vinyl tributyltin (3.4g, 10.8mmol), paBadium acetate (350mg, 10% weight) and triphenylphosphine (380mg) were added. The mixture was degazed with argon then heated at 80 degrees overnight. The solvent was removed in vacuo and the crude residue was purilied by column chromatography on silica gel using 10% ethyl acetate in pentane as the eluant to give 1 .9§ of the title compound as an orange solid.

'H NMR {CDCI3) lj ~ (a broad, 1H), 9.4 (s broad, 1H), 7.45-7.2 (in, iGH), 6.5-6.4 (in, 1K), 6.35 (in, Il-I), 5.95 (s, 111), 5.5 ~m, 1K), 4.85 (d, 21-C), 4.55 (ii, 2H).

LFIMS (ES4) mlz 361 [MH]4

Preparation 43

46-bis-benzvlamino-5-njtro-Dvridine-2-carbaldehyde

N-2,N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2,4-diamine (800mg. 2mmol) was dissolved in lOmL of letrahydroturan and 3OmL of water then osmium tetroxide (60mg, O.2minol) was added followed by sodium metaperiodate (1.2g, 5.6mmol).The mixture was stirred at room temperature overnight. The mixture was partitioned in water (3QmL) and ethyl acetate (3QmL), the organic layer was washed with 5OmL of brine, dried over magnesium sulfate and the crude residue was purified by column chromatography on silica gel using 10% ethyl acetate in peritane as the eluant to give 450mg of the title compound as wi orange solid.

'H NMF~ (CiDCI~) ~ 9.76 4s, 11-4). 9.65 (s L'.oad~ ii-t~, 9..3 is broad~, IF-I), 7.4~7.2 (in, 1DM), 7.62 (s, 1H), 5.5 (in, 1K), 4.9 (d, 2K). 4.6 (ci, 2H).

LRMS (ES~) m!z 363 {MHJ~

Preparation 44

N-2.N-4-dibenzvl-6-inorpholin-4-vl-inethvl-Qyridine-2.3.4-triainine

6-bis-benzylamino-5-nitro-pyridine-2-carbaidehyde (150mg, 0.41 inmol) was dissolved in l5inL of j~chloroinetj,ane at room temperature and 2-inethoxy-ethylamine (43mg, 0.4gininol) was added followed ~y acetic acid (25mg, 0.41 mmcl). The mixtur& was stirred for 5 minutes then sodium-triacetoxyboron iydride '(130mg, 0.62mmol) was added and the mixture w~ stirred at room temperature for lhour. 2OinL ~f water was added into the mixture, and then the organic layer ~vas isolated, washed with 2OinL of water hen dried over MgSO4. The solvent was removed in vacuo to give 180mg of the title compound as an ~range gum

K NMR (CDCI3) 5 9.55 (s broad, il-f), 9.4(s broad, 1 H), 7.4-7.2 (in, 10K), 6.19 (s, 11-I), 4.8 (d, 2K), 4.55 ci, 21-I), 3.6 (in, 41-1), 3.45 (in, 2K), 3.3 (s, 2K), 2.35 (m, 4H).

RMS (ES'~) m/z 434 [MHII4

Preparation 45

N-2.N-4-dibenzvl-6-inorpholin-4-vl-inethvl-Qyridine-2.3.4-triainine

'J-2,N-4-dibenzyl-6-morpholin-4-yl-inethyl-3-nitro-pyridine-2,4-diamine (190mg, 0.43mmol) was dissolved i SGmL of methanol and Raney nickel (40mg, 20% weight) was added, then the mixture was stirred at oem temperature under 80 psi of hydrogen for 1 hour. After conipletion, the mixture was filtered through Lrbocel and the solvent was removed in vacuo to give 180mg of Ihe title compound as a green oil.

H NMR (C0300) :5 7.4-7.2 (in, 10K), 6.1 (s, 1 H}, 4.6 (di, 22-1), 4.4 {d, 2K), 3.3 (in, 6K), 2.4-2.2 (s broad, ~H), 2.15 (in, 4K).

RMS (ES4) inlz 417 fMHJ~

Preparation 46

N-2,N-4-dibenzvl-6-ethvl-pyridine.2.3.4-triamine

l-2,N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2,4-diamlne (300mg, 0.75mmol) was dissolved in 2OinL of etrahydrofuran end Raney nickel (40mg, 13% weight) was added, then the mixture was stirred at room emperature under 60 psi of hydrogen for 1.5 hour. After completion, the mixture was filtered through irbocel and the solvent was removed in vacua to give 230mg of the title compound.

'K NMfl (CDCI33. :5 7.40-7.20 (in, SH), 6.0. (s. IN), 4.90-4.30 (s broad, 2H), 4 65 (d, 2K), 4.35 (d, 2HX
2.55 ~q, 21-i), 1 .20 (t, 3M).

Prenaration 4-7

1 -(4. 6-bis-ben~lamino-5-nitro-.ovridin-2-v!)-etharione

N-2,N-4-dibenzyi-6-bromo-3-nitro-pyridine-2,4-diarnine (800mg, 1 .94mmol) was dissolved in 4OmL of tetrahydrofu'ran then (1 -etho,cyvinyl)-tri-n-butyltin (909mg, 2.52mmol) was added followed by palladium acetate (90mg. WIW') and triphenylphosphine (100mg, w/w) and the mixture was stirred at 800C for 1 hour. Once the reaction was complete, SGmL of ethyl acetate and 4OmL of a solution of HOl 3N were added. The mixture is vigorously stirred for 30 minutes at 600C. The organic layer was separated, washed with SGmL of brine and the solvent was removed in vacuo. The crude residue was purified by column chromatography on silica gel using 10% of ethyl acetate in pentane to give 680mg of the title compound as a yellow solid.

'H NMR (CDCl~) :5 9.55 (s broad, 1K), 9.35 (s broad, 1K), 7.40-7.0 (in, 10K), 6.75 (s, 1K), 5.25 Cs, 1K), £k85 (d, 21-i), 4.55 (d, 2H), 2.50 (s, 3K).

LRMS (ES') m/z 377 [MJ-l~

Preparation 48

N-2.N-4-dibenzvl-6-difluoroinethvl-3-nitro-nvridine-2,4-diam me

~,6-bis-benzylainino-5-nitro-pyridine-2-carbaldehyde (250mg, 0.6gininol) was dissolved in l5inL of ilohioromethane and cooled down to 00C then bis-(2-methoxyethyl) aminosulphur trifluoride (611mg, ~.76minol) was added and the reaction mixture was stirred at room temperature for 3 hours. Once the ~eaction was complete. 30m L of water was added into the mixture, and then the organic layer was solated, washed with 3OmL of a saturated solution of potassium carbonate, and brine then dried over ~AgSO4. The solvent was removed in vactio and the crude residue was purified by column ~hromatography on silica gel using 10% of ethyl acetate in pentane to give 220mg of the title compound is a yellow solid.

H NMR (CDCI3) 0 9.60 (s broad, 1H), 9.3 (s broad, 1K), 7.4-7.2 (in, 101-I), 6.30 (s, 1K), 6.35-6.05 ~t, 1K), j.75 (ci, 2K), 6.50 (d, 2H).

..RMS (ES') m/z 385 ~MH]

Preparation 49

4.6-bis-benzylamino-5-nitro-pvridine-2-carbonitrile

~J-2,N-4-dibenzy1-6-brorno-3-nitro-pyridine-2,4-diamine (500mg, 1.21 mmol) was suspended in 1Gm L of oluene then tributyltin cyanide (765mg, 2.42inmol) was added followed by palladium acetate (60mg, ~WW) and triphenylphosphine (70mg, wfw) and the mixture was microwaved at 1300C for 25 minutes.

cOnce the reaction was complete, the solve—it was rem oved in ~acLo and the crdde residue was purified by column chromatography on silica gel usir~ 10% of eThyl acetate in pentane to give 408mg of the title compound as a yellow solid.

'H NMR (CDCl~) :0 965 (s broad, IH), 930 (5 broed~ ~ 7 4~-7 20 (in, 1DM), 6.40 (s, 1K), 4.75 (d, 2H), 4.50 (d, 2H).

LRMS (ES4) rzik. 360 [MM]4
Precaration 50

Pi,6-bis-benzvlaruno-5-nitro-pwidin-2-~,l I-methanol

N-2,N-4-ddbenzyl-8-broino-3-nifro-pyridine-2,4-diarnirle (315mg. 0 87minol) was suspended in 2OinL of tetrahydrofuran and cooled down to O~C then sodium borohydnde (40mg, 1.lminol) and the mixture was stirred at 00C for 15 minutes. The mixture was partitioned in water (lOmL) and ethyl acetate (lOmL). The organic layer was isolated, washed with 1 5inL of bdne, dried over magnesium sulfate and the solvent was removed in vacuo to give 31 5mg of the title compound as a yellow solid

'H NMFI (ODd3) :0 9.50 (s broad, Il-f), 7.40-7.20 (in, 10K), 5.85 (s, 1K), 4.59 (d, 2K), 4.45 (d, 2K), 4.35 (s,2K)..
LRMS (ES4) m/z [MH]+

Preparation 51

N-2.N-4-dibenzvl-6-bromein ethvl-3-nitro-pvridine-2.4-diamine

(4,6-bis-benzylamino-5-nitro-pyridin-2-yl)-methanol (300mg, 0.82minol) was dissolved in 2OinL of dichioromethane and cooled down to 0a0 then triphenylphosphine (237mg, 0.91 inmol) was added followed by N-bromosuccinimide (161mg, 0.82inmol) arid the mixture was stirred at 00C for 30 minutes then warmed to room tempereature and stirred for 2 hours. The soLvent was removed in vacuo and the crude residue was purified by column chromatography on silica gel using 20% of ethyl acetate in pentane to give 220mg of ~he title compound as a yellow solid.

'i-I NMR (CDC13) :1111 ~.59 (s broad, 1K), 9.40 (s broad, IH), 7.40-7.20 (in, 10K), 6.15 (s, 1K), 4.80 (d, 2H), 4.55 (d, 2K), 4-. 15 (s, 21-f)..
LRMS (ES') in/z 427,429 [MH]4
Precaration 52

N-2.N-4-dibenzvl-Gmethoxvmethvl-3-nitro-ovridine-2.4-diamine

N-2,N4-dibenzyl-6-broinomethyl-3-nitro-pyridine-2,4-d[amine (1 00mg, 0.23mmol) was dissolved in lOmL of methanol then sodium methoxide (25mg, 0.46mm 01) was added followed was stirred at 60CC overnight. The solvent was removed in vacuo and the crude was partitioned in lOmL of dichioromethane and lOmL of water. The organic layer was isolated, dried over magnesium sulfate arid the solvent removed in vacuo to give 80mg of the title compound as a yellow solid.
'IMA (CDCl~) :Th 959 (s broad IH), 94D (s brcad, 1K), 7~~2-720 jm 1DH), 8.20 (s, 1K), 4.80 (d. 2K), 4.55 (d, 2K), 4-25 (s. 2K), 3.35 (s, 3K).

LRMS (ES'] m/z 379 [MHF
Preparation 53

f'f-2. N-4-Dibenvl-3—nilro—6-nvrazn-2-y~-ovridine-2.4-diamine
N-2, N-4-DJbenyl-6-bromo-3-nitro-p~n1dine-2.4-diarnine (lOOmgs / O.242mmols), 2-Tn-n-

bulylstannylpyrazine (11 Sings / 0.31 Smnols), palladuin acetate (1 Sings) and triphenyiphosphine (2oings) were dissolved in toluene (2rnls) and subjected to microwave irradiation at 13000 for 25mins in a Biotage Initiator. The reaction was repeated on the same scale on two more occasions. The three reactions were combined, diluted with EtOAc (lOinis), washed with wafer (Smils) and concentrated in vacuo. Purification by column chromatography eluting with 10:1 Pentane:EtOAc gave the title compound (lOsings) as a yellow solid.
11-I NMR (00013, 400MHZ) 0 4.60-4.65 (ci, 2K), 4.90-4.95 (d, 2K), 7.20-7.40 (mult, 10K), 8.55-8.60 (mult,

2K), 9.40-9.50 (mull, 2K), 9.60 (mull, 1H); LRMS (ESCI) m/x 413 [MK]t

Precaration 54

N-2, N-4-Dibenzvl-6-pvrazin-2-vl-pvridine-2,3,4-triam me

N-2, N-4-Dibenyl-3-nitro-6-pyrazin-2-yl-pyridine-2,4-diain me (1 O5mgs I G.255min015) was dissolved in MeOH (2Oinls) / TI-IF (2Omls). Raney Nickel (3Oings) was added and The reaction placed under BOpsi hydrogen at room temperature for 5 hours. Filtered through celite and concentrated in vacuo to give the title compound (95mgs) as a pale green oil

LRMS (ESCI) m/x 383 IMKI+, 381 [Ml-l~.

Preparation 55
6-Allvl-N2.N4-dibenzvl-3-nitro-nvnidine-2.4-diamine

(Ig, 2.4mmol) was stirred in anhydrous tetrahydrofuran (2OmJ) and the solution degassed with nitrogen prior to the addition of palladium acetate (109mg, 0.4Sminol) and allyltributyltin (1.lml, 3.6minol). The reaction mixture was degassed for 10 minutes before heating the suspension at 80CC for 16W The suspension was cooled to ambient temperature, concentrated in vacuo and purified directly by column chromatography on silica, eluting with pentane:EtQAc, 9:1 to afford the title compound as a yellow solid, (696mg, 77%)

1l~1 NMR (CDOl~) 0 323-3.25 (d, 2K), 4.47-4.49(d, 2K), 4.81-4.62(d, 2K), 5.07-5.14(m, 2K), 5.89-5.99(m, fl-i), 7.29-7.40 (in, IlH); LRMS (ES) mix 375 [MKJ-i.

Preparation 56
2-(4.6-Bis-benzvlainino-5-nitro-pvridin-2-vl)-ethanol

6-Allyl-N2,N4-dibenzyh3-nitro-pyridine-24-d~amine (i.Qq, 2.7mmol~ was suspended in a mixture ci lEmi tetrahydmofuman and 3Omnl water. Upon the addtion & potassivrn osmate (143mg, OAmmoI) and sodium pariodate (1.17g. 5.4mmo!), the solution was stirred ~Agorous[y at room temperature for 3Ominutes. Ethyl acetate ~20ml) was added to the reaction mixture and ho phases partitioned, the organic extract dmied over magnesium ettiphate, concontrated in vacua and purified t3y column chromatography on siUca, eluting with 100% EtOAc to afford 3-(4,0-Bis-benzvlamirw1-5-nitro.pymidin-2-yl)-propane-1 2-dial (992mg, 91%). The intermediate dial was stmrod in 20m1 acetone in the presence of sodium periodate (1.17g.
5.5mrnol). After 2h the solution was partitioned between EtOAc and water, the organic extract dried (MgSO4 and concentrated to give the title compound as an orange oil, (962mg, 96%).

li-f NMR (CDCl~) C 3.49(d, 2K), 4.49-4.50(d, 2H)I 4-65-4.66(d, 2K), 7.52-7.90(m, 11K), 10.03(s, 1H); LOMS (APCI-i-) RT@3.74min, mlz 409 [MH]-i.

Preparation 57

2-(4.6-Bis-benzvlainino-5-nitro-pvridin-2-vl)-ethanol

(4,6-Bis-benzylamino-5-nitro-pymidin-2-yl)-acetaldehyde (250mg,, 0.66mmol) was stirred in iSmi dichloromethane. Sodium borohydride (38mg, O.9Smmol} was added and the solution stirred at ambient temperature overnight. The reaction mixture was partitioned between 13CM and water, the organics dried over magnesium sulphate and concentrated to give a crude solid which was purified by column chromatography on silica, eluting with pentane:EtOAc, 4:1 to 1:1 to afford the title compound as a yellow solid, (134mg, 53%).

'H WAR (CDCIs) ii 2.68-2.70 (I, 21-i), ass-ass (1, 2K), 4.49-4.51 4 21-1), 4.72-4.74 (d, 2H), 5.86 (s, 1K),
7.29-7.38 (in, 10K), 9.50-9.54 (bd, 2H); LRMS (ES) mfl 379 JMH]-r
Prenaration 58
N2.N4-Dibenzvl-6-(2-methoxv-ethvl~-3-nitro-ovridine-2.4-diamine

2-(4,6-Bis-benzylamino-5-nitro-pyridin-2-y~-ethanol (134mg, 3Smmol), was suspended in a mixture of dichioromethane (iSmI) and triethylamine (59p1, 0.43ramot) and the solution cooled to 50C in an ice bath. Methanesuiphony! chloride (33p1, 0.43mmol) was added and the reaction mixture stirred at ambient temperature br lh. A further lOmi 0CM was added, the organics washed with 2 x K2003 (10% aq solution), dried and concentrated to afford a crude oil. The intermediate mesylate was suspended in acetone (20m1) and sodium methoxide added (96mg, 1 .YmmoO, heating the mixture at ref lux for 1 h. Residual solvent was removed in vacuo, 13CM added and the solution washed with 2 x K20. The combined organics were dried over MgSO4, concentrated and purified by column chromatography on silica, eluting with Pent:EtOAc, 8:1 to 4:1 to afford the title compound as a yellow oil, (68mg, 47%).
1H- NMR (CDC~ UJ 2.70-2.73(t, 211), 3Z9(s, 3H). 3 64-&67(t, 2H). 4.49-4.50 (d, 2K), 4.81-~.S2(d, 2H).
5.91{s, 1H~, 7.29-7.39(m, 10K), 9.40-9.48(bd, 2H): LAMS (ES) m/z 393 fMH]+

Preperation 59

N2.N4-Dibenzvl-6-(2-methoxv-ethvl~-3-nitro-ovridine-2.4-diamine
(~5mg, O.l7mmoi) was stirred in
TH~ (lOmE) in the presencs of Raney Nickel (20%wl. ~3mg). The mixture was stirred at RT, GOpsi H2 for
2h then fiJtemed Through an Arbocel pad, washing w~r~ 2 x THF. The filtrate was concentrated in vacuo to
g[ve the title compound as a brown oil, (47mg, 78%), which was used immedhAely in the following step
with no further purification.

LRMS (ES) m/z 363 [MKJ+

Preparation 60
I -Benzvt-4-benzvlam ino-6-(2-metlioxv-ethyVl-1 .3-dihvdro-imidazor4.5-clpvridine-2-one

N*2* ~ (47mg, 0.1 3mmol) was stirred in acetonitrile (5m1). N,N-Carbodiimidazole was added, (105mg, 0.6Smmol) and the mixture heated at reflux for i6h. The solution was concentrated in vacuo and purified directly by column chromatography on silica, eluting with 100% 13CM to 96:4 to afford the title compound as a pale brown solid, (32mg, 64%) present as a 3:2 mixture with the isomeric 1 -deazapurine.

LRMS (ES) mlz 389 [MH]+

Preparation 61
N2. N4-Dibenzvl-6-[2-(2-methoxv-ethylam ino)-ethvll-3-nitro-pvridine-2,4-diamine

N*2*N*4*Dibenzyl3..nitro6..vinylpyridine24diam me (50mg, 0.1 4mmol) was suspended in 2-methoxy-ethylamine (1 ml) and the mixture refluxed for I h. Excess reagents was removed in vacuo, the 'residue dissolved in DCM (lOmi), washed with 2 x H20, dried and concentrated. The crude material was purified by column chromatography on silica, eluting with DCM:MeOI-I, 92:8 to give the title compound as a yellow oil, (58mg, 96%).

1H NMR (013C13) Q 2.75-2.80 (in, 41-1), 2.96-3.00 (t, 2H). 3.29 (s, 3H), 3.48-3.51 (t, 2K), 4.48-4.49 (d, 2K),
4.76-4. 78 (d, 2K), 5.87 (s, 1K), 7.27-7.40 (in, 1OH), 9.41-9.51 (dt, 2H); LRMS (ES) mlz 436 [MK]+

Preparation 62

r2-(4,6-Bis-benzvlamino-5-nitro-pvridin-2-vfl-ethvl1~(2-methoxv-ethvfl-carbamic acid tert-butvl ester

N~2*,N*4~.Dibenzyl.6~[2~(2.methcxy.ethviarr ino)-ethvl)-3-n tro-pyndine-2,4-diamine (150mg, 0.34mmol) was suspenood in DCM (IGmI) and the solution cooled to 00C before the drop-wise addition of hoc anhydode (95p1, O4imrnol) as a solution in 5m! SCM The mixture was allowed to warn to room temperature and after lh, quenched with lOin1 K20 The organic ectract was dried and concentrated in vacua to give the title compound as a yellow cii, (170mg, 92%).

1K NMR (CDCI3J 0 1.41 (s, 9K), 2.68(t, 2H), SSO(s, 3H), 3.42(bs, 2K), 3.50(m, 4K), 4.47-4.48(d, 2K),
4.80-4.814 2K), 5.82(s, 1k-I), 7.24-7.39(rn, 10H); LRMS (ES) m/z 536 [Mi-It

Preparation 63
N2.N4-Dibenzy,i-$-nttrc-6-oxazol-2-vq-ovridine-z4-diain?ne

Butyt lithium (12.8 ml, 20.Smmol) was added drop-wise to a stirred solution of oxaxole (1.13 ml, 17.1 mmol) in dry Ti-IF (20 ml) at -78 0C (dry ice/acetone bath), keeping the addition rate slow so that the reaction temperature did not go above - 60 0C. The solution was stirred at this temperature for 10 minutes then a solution of zinc chloride (5.00 g, 36.7 mmcl) in TKF (30 ml) was added drop-wise. The solution was stirred for 15 minutes at - 78 0C then the cooling bat', was removed and the reaction mixture allowed to warm to RT.

An aliquot (19 ml) of the reaction mixture was added via a syringe to a pre-sealed and nitrogen purged microwave vial (Biotage, 10-20 ml) containing N*2*, ~ (1.11 g, 2.68 mmol) and palladium bis(triphenylphosphine) dichloride (373 mg, 0.53 mmol). The vial was heated under microwave irradiation (Biotage, Initiator 8) for 15 minutes at 130 0C. The reaction mixture was concentrated in vacuo then partitioned between 2-methyl TI-IF (80 in)) and saturated ammonium chloride solution (80 ml). The mixture was filtered Then transferred to a separating funnel. The layers were separated then the aqueous was extracted with more 2-methyl THE (50 ml). The combined organics were dried (MgSO4) arid evaporated. The brown solid obtained was triturated with EtOAc anq the solid collected by Mtration then washed with EtOAc to yield the product as a brown solid (1.03 g, 96 %).

'K NMR (CDCI3) 0 4.59 (d, J=5.47 Hz, 2K) 4.91 (d, J~5A7 Hz, 2K) 6.93 (s, 1K) 7.21 - 7.47 (in, 11K)
7.78 (s, 1 H) 9.31 - a~ (in, 1K) 9.54 - 9.53 (in, 1 H).

LRMS (ES4) m/z 402 [MH]+

Preparation 64
H2,N4-Dibenzvl-6-oxazol-2-vl-pvridine-a,3,4-triamine

~ (1.02 g, 2.54 inmol) was dissolved in TKF
(60 ml) then MeOK (60 ml) was added. The solution was hydrogenated over Raney nickel (210 mg, 0.25
mmol) under a hydrogen atmosphere (80 psi) for 1 hour. The reaction mixture was filtered through a
Gelite pad then evaporated to yield the title compound as a brown gum (944 ing, 100 %). Taken on
without further purification due to stability concems.

Prenaration 65
N2. N4-Dibenzvl-6-[2-(2-methoxv-ethylam ino)-ethvll-3-nitro-pvridine-2,4-diamine

N-Methylimidazole (0.728 ml, 9,18 mmcl) was dissclved ii dry THF (25 ml) then the solution was cooled to -15 0C (ice/salt bath). n-Eutyl lithium in hexane (631 ml, 10.1 mmo!) was added drop-wise to the solution (colour changed from colourless to yellow). The solution was left to stir for 1 hour a! — 15 0C tnen a solution of anhydrous zinc chloride (5.00 g, 36.7 inmol) in dry TKF (35 ml) was adder drop-wise. The solution was stirred at -15 ~C for 1 hour then allowed to warm slowly to RT then stirred for 1 more hour.

An aliquot (16 ml) of the soh.ition was added to a pre-sealed and nitrogen purged microwave vial (Biotage, 2.0-5.0 ml), which contained ~ me (400 mg, 0.968 mmol) and palladium bis(triphenylphosphine) dichloride (136 mg, 0.193 inmol). The vial was heated under microwave irradiation (Biotage lnitiator 8) for 15 minutes at 130 0C. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (15 ml) and 2 M ammonia solution (15 ml). The majority of the aqueous phase was removed using a separating funnel (small amount of emulsion between layers). The organic layers were washed with more 2 M ammonia solution (15 ml) then brine (15 ml) then dried (MgSO4) and evaporated. The crude was columned on Isco Companion on a silica column (12 g, Redisep). Eluted with EtOAc:heptane, increasing the gradient linearly from 20:80 to 60:40 over 8 column volumes, then socratic at 60:40 for 4 column volumes. The desired fractions were combined and evaporated to yield the title compound as a yellow solid (240 mg, 60 %).

1K NMR (CD3OD) 113.88 (s, 3K) 4.67 {d, J=5,48 Hz, 2K) 4.83 (d, J=5.48 Hz, 2K) 6.92 (d, J=1.17 Hz, 1K)
7.14 (d, J=1 .17 Hz, 1K) 7.17 (s, Il-I) 7.26- 7.42 (in, 1OH) 9AS -9.66 (in, 2K).

LRMS (ESI m/z 415 [MH]+

Preparation 66
N2,N4-Dibenzyl-6-(1-m ethyl-I H-imidazol-2-vl-pvridine-2.3,4-triamine

N*2*,N*4*~OibenzyI~6.(1 -methyl-i H-imidazol-2-yl)-3-nitro-pyridine-2,4-diainine (0.235 g, 0.567 minol) was dissolved in THF (10 inD then MeOK (10 ml) was added. The solution was hydrogenated over. Raney nickel (0.050 g, 0.58 inmot) under a hydrogen atmosphere (80 psi) for 1 hour. The reaction mixture was filtered through a Celite pad then evaporated to yield the title compound as a pale green solid (218 ing, 100 %). Taken on without further purification due to stability concerns.

Preoaration 67
(2.6-Dibromo-3-nittO-Pvridin-4-vl~-carbam ic acid ethyl ester

A solution of ethyl chloroformate (5.95 g) in anhydrous 2-methyl THE (50 ml) was added drop-wise to a solution of 2.6-dibromo-3-nitro-pyridin-4-yiamine (15,00 g) and triethylamine (10.1 g) in anhydrous 2-methyl TH~ (100 ml) at 0 00 keeping the ~ddi~ion rate such that the reaction temperature did not rise above 5 ~C. The reaction mixture was allowed to warm to i-oom temperature then left to stir under nitrogen tar 1 hour. A further portion of ethyl ohloroformate (0.54 g) was added and the mixture was left to stir for a further 1 hour. Water (50 ml) was added and the layers separated. The aqueous layer was extracted with LOAc (50 ml) and the combined organics were dried (MgSO4) and evaporated to a brown solid. This solid was pre-absorbed onto silica (--19 g) then columned on Isco Companion on a silica column (330 g, Redisep), eluting with EtOAc:heptane. The gradient was kept isocractic at 10:90 for 1 column volume (CV). then increased linearly from 10:90 to 30:70 over 6 CVs. This provided the title compound (12.6 g) as a pale yellow foamy solid.

1H NMR (400 MHz, CHLOROFORM-d) ~ ppm 1.36 (t, Jz7.10 Hz, 3 H), 4.26 (q, ~7.10 Hz, 2 H), 7.95 (br, s, I H), 8.59 (s, I H), LOMS R~ = 3.22 m/z 368, 370, 372 [MHIJ~

Preqaration 68
(2,6-Dibromo-3-nitro-pvridin-4-vfl-(6-methvl-pvridin-3-vlmethyl)-carbam ic acid ethyl ester

Potassium carbonate (7.95 g) was added to a stirred solution of (2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (10.62 g) in acetone (100 ml). 5-(chloromethyl)-2-methylpyridine (4.89 g) was then added, followed by sodium iodide (5.18 g). The mixture was left to stir under nitrogen for 18 hours. The reaction mixture was filtered, concentrated in vacua, and then partitioned between ethyl acetate (100 ml) and water (100 ml). The organics were dried (MgSO4) and evaporated to a dark purple gum, which was columned on Isco Companion on a silica column (330 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 40:60 to 80:20 over 6 column volumes. This provided the title compound (8.5 g) as a green gum which solidified to a pale green solid on standing.

1K NMR (400 MHz, CHLORCFORM-~ ~ ppm 1.24 (t, .J=7.10 Hz, 3 H) 2.59 (s, 3 K) 4.19 (q, J~7.10 Hz, 2
H) 4.79 (s, 2 K) 7.17 (s, 1 K) 7.19 (d, J~8.20 Hz, 1 H) 7.57 (dd, Lk=8.20, 2.34 Kx, 1 H) 8.38 (d, J=2.34 Hz,
I H), LOMS R~ = 2.44 m/x 473, 475, 477 (MHJ'

Preparation 69
(2-Am ino-6-bromo-3-nitro-pvridin-4-vl')-(6-methvl-pvridin-3-vlmethvl)-carbamio acid ethyl ester

(2,6-Dibromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (6.00 g) was dissolved iii 2-tnethyltetrahydrofuran (60 ml). The solution was split equally into 3 sealable vessels (Biotage, 10-20 ml). Aqueous ammonia solution (0.88 g cm3, 20 ml) was added to each vial (60 ml total). The vials were sealed then the bi-phasic mixtures were left to stir vigorously at room temperature

overnioht. The three reaction mixtures were combined and transferred to a separating lunnel. Ethyl acetate (120 ml) and water (120 ml) were added. The phases were separated then the organics were washed with brine (100 ml). The organics were dried (MqSO4) then evaporated to a brown gum. The gum was re-dissolved in diethkA ether, then evaporated to proAde the title compound (5.4 g) as a foamy yeilow solid.

1H NMR (400 MHz, CHL0RCFORM-c~ ~ p~j~Ti 1.16- 1.27 (in, 3 H) 2.58 (a, 3 H) 4.10- 4.21 (in, 2 i-I) ~.37
(s, 2 H~ 6.34 (s, 2 H) 6.61 (s. 1 H) 7.113 (d, ,J~8.i9 E-lz, 1 k-I) 7.66 (s, 1 K) 8.41 (d, J=2.34 Hz, I H), LOMS
R~= 1.94 mfz 412 LMHI*

Preparation 70

F2-Amino-6-f4-methvl-oxazol-2-vl)-3-nitro-ovridin-4-vW(6-methvl-pvridin-3-vlmethvl)-carbam ic acid ethyl

ester

Butyl lithium (1.6 M in hexane, 366 jjl) was added drop-wise to a stirred solution of 4-methyloxazole (41 mg) in TKF (0.5 ml) in a ReachVial at -78 0C (dry iceiacetone bath). The solution was stirred at this temperature far 10 minutes then a solution at zinc chloride (199 mg) in TKF (1 ml) was added drop-wise. The solution was stirred for 15 minutes at - 78 0C then the cooling bath removed and the reaction mFxture allowed to warm to room temperature. This zinc oxazole solution was then added via syringe to a pre-sealed and nitrogen purged microwave vial (Biotage, 0.5-2.0 ml) containing (2-Amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pynidin-3-ylmethyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine) dichloride (34 mg). The vial was heated under microwave irradiation (Biotage, Initiator 8) for 15 minutes at 60 0C. The reaction mixture was then partitioned between ethyl acetate (10 ml) and a saturated aqueous solution of ammonium chloride (10 ml). The layers were separated and the aqueous extracted with ethyl acetate (10 ml). The combined organics were washed with brine (10 ml) then dried (MgSO4) and evaporated. The crude was columned on Isco Companion on a silica column (12 g, Redisep), eluting with ethyl acetate for 4 column volumes (CV), then the gradient increased linearly from 0 - 5 % methanol in ethyl acetate over. 10 CV. This provided the title compound (69 mg)as a yellow gum.

11-I NMR (400 MHz, CHLOROFORM-ci9 ~ ppm 1.11 - 1.25 (in, 3 H) 2.28 (s, 3 H) 2.56 (s, 3 K) 4.13 - 4.23
(in, 2 H) 4.96 (s, 2 H) 6.37 (s, 2 H) 7.16 (d, J=7.80 Hz, 1 H) 7.26 (s, 1 K) 7.53 (s, 1 H) 7.65 - 7.78 (in, 1 K)
8.43 (s,1 H~, LOMS R~ = 1.86 m/x 413 ~MH]~

Preparation 71
5-Ethyl-oxazole

Ethyl-5-ethyloxazole-4-carboxylate (3.5g) was dissolved in ethanol (45 ml) and a solution of sodium hydroxide (2.07g) in water (18 ml) added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was reduced to —20 ml, and then concentrated hydrochloric acid added to give a pH of

—1-2. The reaction mixture was extracted with Ci-bCl~ 3x3Ornl. The combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered and evaporated to give a pale yellow Saud. This was taken up in quinoline (3 nil) and 100mg of copper (II) oxide was added, The reaction was then heated (oil balb 160 CC) under slightly reduced pressure and a clear liquid distilled over at —60 — 70 ~C. This provided the title compound (790 mg} as a clear oil.

1H NMR (400 MHz, CI-kLOROFCRM-dl Sppm 1.2 (~, 3 H), 2.6 (q, 2 H), 6.65 (s, 1 K), 7.7 (s, 1 H)

Preperation-72

T2-Am ino-6-(5-ethyl-oxazol-2-vl)-3-nitro-pvridin-4- ~AV(6-nj~!~lj~ridin-3-vlmethvl)-carbamic acid ethyl
ester

The title compound was prepared following the Example in preparation 70, using 5-ethyl-oxazole (47 ing)
and (2-am ino-6-bromo-3-nitro-pyridin-4-yl)-(6-m ethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100
mg}, giving the product (79 ing) as a yellow gum.

1H NMR (400 MHZ, OKLOROFORM-o9 ~ ppm 1.13- 1.25 (in, 3 H) 1.33 (t, J=7.61 Hz, 3 H) 2.56 (s, 3K)
2.80 (q, J=7.41 Hz, 2 H) 4.13 - 4.22 (in, 2 H) 4.96 (s, 2 K) 6.31 - 6.45 (in, 2 H) 6.97 (5, 1 K) 7.16 (d,

d=7.80 Hz, I K) 7.26 (s, 1 K) 7.63 -7.79 (in, I H) 8.43 (s, 1 K), LCMS Rt= 2.16 m/z 427 [MH)~

Pre~aration 73
5-lsopropyl-oxazole-4-carboxvlic acid ethyl ester

Ethyl isocyanoacetate (4.52 9) was added drop-wise to a stirred suspension of KOtBu in THE (35 ml) at 0 0C under nitrogen. After complete addition, the dark brown solution was stirred for 30 minutes and then a solution of isobutyryl chloride (2.1 ml) in THE (15 ml) added drop-wise, keeping the temperature below
—100C. The reaction was stirred for 1 hour then evaporated to dryness. The residue was treated with acetic acid (1.14 ml) and water (25 ml), and then extracted with ether (3x30m I). The combined ether extracts were washed with saturated brine, dried over sodium sulfate, filtered and evaporated to give a brown oil that was purified by column chromatography, eluting with 1%MeOH in dichloromethane. This gave the title compound (1.91 g) as a colourless oil.

1H NMR (400 MHz, CHLOROFORM-o~ ~ ppm 1.25 (d, 6 K), 1.38 (t, 3 K), 3.8 (in, 1 H), 4.35 (q, 2 K), 7.7 (s, 1 H), LRMS m/x (API) 184 fMI-134, 367 l2MH1~

Precaration 74
5-isopropyl-oxazole

5-lsopropyl-oxazole-4-carboxylic acid ethyl ester (1.89 g) was taken up in a solution of 1 N sodium hydroxide (10 ml) and ethanol (0.5 ml) and the mixture stirred at room temperature for 16 hours. A solution of iN HCI (approx 9 nIl) was added and the mixture stirred for a few minutes. A white solid crystallized out and was collected by filtration. After drying, this solid was taken up in quinoline (3 ml) and
topper oxide (120 nig) added. The reaction was heated under vacuum, slowly increasing the oil bath temperature to ~.170CC. A clear liquid dist;iled out gYving a mixture of the desired product and quinoline. This oil was then re-distilled at lower pressure (—lSOrnBar) and temperature (70 ~C) providing the title compound (260 mg) as a clear o;l.

1 K NMR (400 MHz, CHLOROFORM-a) 5 ppm ~l.24 (d, 6 H), 2.96 (in, 1 H), 6.7 (s, 1 K), 7.7 (s, 1 H)

Preparation 75

r2-Ainino-6-(5-isooropvl-oxazol-2-vn-3-nitro-pvridin-4-v13-(6-in eihvl-pvridin-3-vlmethvl'i-carbain ic acid ethyl ester

The title compound was prepared following the Example in preparation 70, using 5-isopropyl-oxazole (54 mg} and (2-amino-6-broino-3-nitrc-pyridin-4-yQ-(6-mehl-nyl-py~idin-3-ylinethyl)-carbamic acid ethyl ester (100mg), giving the product (48 ing) as a yellow gum.

iN NMR (400 MHz, CKLOROFORM-~ S ppm 1.13 - 1.26 (in, 3 K) 1.34 (d, ~6.63 Hz, 6 H) 2.56 (s, 3 K)
3.04- 3.15 (in, 1 K) 4.10 -4.23 (in, 2 1-I) 4.96 (s, 2 H) 6.39 (s, 2 H) 6.94 (s, 1 K) 7.16 (d, J=7.80 Hz, 1 K)
7.21 (s, 1 1-1) 7.63 - 7.76 (in, 1 H) 8.43 (s, I K), LCMS ft 2.30 mU 441 (MHI~

Preparation 76
r2-Am ino-6-(4.5-diin ethyl-oxazol-2-vfl-3-nitro-pvrid(n-4-vll-(6-inethvl-ovridin-3-vlmethvl)-carbamic acid
ethyl ester

The title compound was prepared following the Example in preparation 70, using {5-diinethyl-oxazole (47 mg) and (2-am ino-6-bromo-3-nitro-pyridin-4-yl)-(6-in ethyl-pyridin-3-ylinethyl)-carbamic acid ethyl ester (100 mg), giving the product (75 ing) as a yeflow gum.

1K NMR (400 MKz, CKLOROFORM-d) S ppm 1.03- 4.26 (in, 3 K) 2.19 (s, 3 K) 2.37 (s, 3 K) 2.56 (s, 3 K)
4.09 - 4.26 (in, 2 k-I) 4.95 (s, 2 1-1) 6.40 (s, 2 I-i) 7.16 (d, J=7.S0 Hz, 1 H) 7.21 (s, 1 H) 7.62 - 7.83 (in, 1 i-I)
8.42 (s, 1 H), LOMS R1= 2.12 in/z 427 [MKJ~

Preparation 77

Oxazol-4-vl-in ethanol

DIBAL-H (56 ml of a 1.0 M solution in toluene) was added drop-wise over 15 minutes to a solution of oxazole-4-carboxylic acid ethyl ester (7.50 g, 53.1 mmol) in THE (140 ml) at -78 ~C. The resulting solution was stirred at -78 OQ for 30 mm and then further D]BAL-H (56 mL of a 1.0 M solution in toluene, 56.0 mmol) was added over 15 minutes. The reaction was then left to slowly warm from -78 0C to room temperature for 16 hours. The resulting bright yellow solution was cooled to 0 0C in an ice bath and Na2SO4.10 K20 (15.9 § - equal weight to OIBAL-l-i added) was added in small portions (CARE - slow addition to prevent exotherm) to cause precipitation of aluminium salts. The mixture was left to warm to

room temperature and after stirring; ~or 90 rriins the resulting suspension was filtered through a layer ci cefite, The ceite plug was rinsed with dichlorometnane (3 x 100 mL) arid methanol (2 x 100 inL) and the filtrates wore combined. The solvent was removed gander reduced pressure, providing tne title compound (4.8 g~) as a brov~n oil.

114 ~MR (400 MI-lz, CHLOROFORM-~ 8 ppm 4.60 (s, 2 H), 7.6 (o, 1 H), 7.9 (s, I H)

Preparation 78
4-Methoxvmethvl-oxazole

Oxazo!-4-yJ-methanol (750 mg) was dissolved in anhydrous TI-IF (38 inL) and the solution cooled to 0 0C. Sodium hydride (365 ing, 9.1 minol) was then added in small portions over 4 minutes, and after complete addition, the reaction was warmed to room temperature for 30 minutes. The reaction was re-cooled to 0 "C and inethyltosylate (2.11 g) added In small portions. After complete addition the reaction was warmed to room temperature and stirred for 16 hours. The crude reaction mixture was pre-absorbed onto silica gel and then purified by ISCO combi-flash chromatography (SiO2; gradient elution of MeOK, 2 to 5% in DCM, f% NH3~ to afford the title compound (473 mg~ as a pale yellow liquid.

Il-I M~AR (400 MHz, CHLQROFORM-c~ 8 ppm 3.41 (s, 3 1-i), 4.40 (5, 2 H), 7.61 (s,1 1-1), 7.85 (s, I H)

Preparation 79
~2-Amino-6-(4-m ethoxvmethvl-oxazol-2-vl)-3-nitro-pVr]din-4-vll-l'6-inethvl-pyridin-3-vlmethvl)-carbainic
acid ethyl ester

The tille compound was prepared following the Example in preparation 70, using 4-inethoxymethyl-cxazole (110 mg), (2-arnino-6-broino-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylinethyl)-carbainic acid ethyl ester (200 ing) and palladium bis(triphenylphosphine) dichloride (68 ing), giving the product (107 mg) as a yellow gum.

1 H NMR (400 MHz, CHLOROFOF~M-~ 8 ppm 4.11 - 1.29 (in, 3 H) 2.54 (s, 3 H) 3.47 (s, 3 K) 4.09 - 4.24
(in, 2 H) 4.49 (s, 2 H) 4.96 (s, 2 H) 6.34 (s, 2 H) 7.13 (d, J~7.81 Hz, 1 H) 7.32 (s, 1 H) 7.63 - 7.72 (in, 1 K)
7.76 (s, 1 H) 8.42 (s, I K), LCMS R~ 1.62 rnlz 443 [MH]+

Prepara~Ion 80
(2-Amino-3-nitro-6-thiazol-2-vl-pvridin-4-vl)-(6-methvl-pvridin-3-vlmethvfl-carbainic acid ethyl ester

The title compound was prepared following the Example in preparation 70, using thia~ole (42 ing) and (2-am ino-6-broino-3-nitro-pyridin-4-yl)-(6-metliyl-pyridin-3-ylinethyl)-carbainic acid ethyl ester (100 ing), giving the product (79 mg) as a yellow gum.

tH NMR (400 MHz, CHLOROFORM-a) S ppm 1.05 - 1.30 iTh, 3 H) 2.56 (s, 3 H) 4.07 - 4.25 (in, 2 H) 4.99
~s, 2 Hi 6.25 is, 2 H) 7.16 (d, ~7.80 Hz, 1 H) 7.46 (s. 1 H) 7.54 (d, ~3.12 Hz, 1 H) 7.64 - 7.84 (in, 1 H)
7.95 (d, J=3.12 Hz, 1 H) 8.35 - 8.50 (in. 1 H), LCMS ~ = 2.11 ni/z 415 LMHI~

Preoaration 131
2-Chloro-3-oxo-oentanoic acid ethyl ester

Suiphuryl chloride (6.50 ml) was added drop-wise to ethyl propionyl acetate (11.70 g) at i~oom temperature arid the reaction stirred for 16 hours. The Teaction mixture was placed under vacuum for an hour to remove highly volatile material, then the residue was distilled under 'high' vacuum to give an oil that d'stilled at 75-790C with a vacuum of SMbar (~= 4.5mm Hg), thus providing the title compound (13.54 g) as a clear oil.

1K NMR (400MHz, CHLOROFORM-~ 8ppin 1.11 (t, 3K), 1.31 (t, 3 H), 2.75 (q, 2K), 4.25 (q, 2K), 4.80 (s, I K)

Prepai~ation 82
4-Ethyl-oxazole-5-carboxvlic acid ethyl ester

2-Chloro-3-cxo-pentanoic acid ethyl ester (13.5 g) was dissolved In 75in1 of 95% formic acid. Ainmoniuin forinate (27.6 g} was added and the reaction heated at ref lux under nitrogen for 6 hours. After cooling to room temperature the reaction mixture was evaporated and the residue extracted with ether (3 x 50 ml). Combined ether extracts were washed with waler and brine, dried (MgSO4, filtered and evaporated to give a crude oil (9 g). The oil was purified by chromatography on silica gel, eluting with 0K2C12/MeOK 99:1, providing the title compound (3.779) as a pale brown oil.

1K NMR (403 MHz, CKLOROFORM-c~ B ppm 1.25 (t, 3 H), 1.41 (t, 3 K), 2.90 (q, 2 H), 4.41 (q, 2 H), 7.85 (s, I H)

Preparation 83
4-Ethyl-oxazole-5-carboxvlic acid

4-Ethyl-oxazole-5-carboxylic acid ethyl ester (4.6 g) was stirred in a solution of iN NaOH (25 ml) and ethanol (1 ml). The reaction mixture was then stirred at room temperature far 16 hours. Diethyl ether (25 ml) was added, and then the aqueous layer separated and acidified with iN MCI (26 ml). A yellow Solid formed that was collected by filtration, washed with water, then with n-pentane, providing the title compound (2.6 g) as a white Solid.

1K NMR (400 MHz, CHLOROFORM-o~ S ppm 1.30 (t, 3 K), 2.95 (q, 2 K), 8.0 (s, 1 H)

Preparation 84


4-Ethvl-oxazole

4-Ethy~-oxazote-5-carboxy~c acid (1.2 ~) was taken up in ~uinoiirie (3 ml) and CuO (50 mg) added. The reaction was then heated to 21 5~20CC and a colow'less dis§lale was colected, Thus providing the title compound (621 mg) as a cloudy oil.

1K NMR (400 MHz, CHLOROFORM-d) ~ pom 1.21 tt, 3 H), 2.55 (q, 2 H), 7.4 (s, 1 K), 7.8 (s, 1 K)

Preparation 135

f2-Ainino-6-(4-ethvl-oxazol-2-vl'~-3-nitro-ovridin-4-vlk6-m ethvl-pvridin-3-ylinethvl)-carbarnic acid ethyl

ester

The title compound was prepared following the Example in preparation 70, using 4-ethyl-oxazole (47 ing)
and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-inethyl-pyridin-3.yirnethyl)-carbamic acid ethyl ester (100
ing), giving the product (74 mg) as a yellow gum.

1K NMR (400 MHz, CHLOROFORM-cl) B ppm 1.09-1.22 (in, 3 H) 1.25 (t, J=7.42 Hz, 3 H) 2.50 (s, 3M)
2.56- 2.68 (in, 2 H) 4.04 - 4.21 (in, 2 H) 4.92 (s, 2 H) 6.33 (s, 2 1-1) 7.10 (d, J=7.81 Hz, 1 H) 7.23 (s, 1 K)

7.46 - 7.49 (in, 1 K) 7.59 - 7.69 (in, I K) 8.39 {s, 1 K), LCMS R1 = 2.07 mlz 427 [MH]+

Preoaration 86

1 -Bromo-3-methvl-butan-2-one

A solution of 3-methyl-2-butanone (5 g) in methanol (55 mL) was cooled to -30 0C. Bromine (2.97 uL) was then added dropwise, and once the addition was complete, the reaction was allowed to warm to room temperature and stirred for 3.5 hours. The reaction was then poured into water (100 inL) and extracted with diethyl ether (2 x 100 inL), the combined extracts were dried (MgSO4), filtered and concentrated. Upon standing the oily residue formed two layers as two different oils which were separated. The bottom layer was retained, thus providing the title compound (5.149) as a pale golden oil.

1K NMR (400 MHz, CHLOROFORM-c~ S ppm 1.15 (d, 6 K), 2.95 (in, I H), 3.95 (s, 1 H)

Preoaration 87
4-Isoproovl-oxazole

1-Broino-3-inethyl-butan-2-one (1.0 g) was added to formamide (3.0 ml) and the reaction mixture heated to 110 0C for 6 hours. After cooling to room tein~erature the reaction mixture was diluted with a 40% solution of potassium hydroxide (10 ml), stirred for a few minutes and then extracted with diethyl ether (3 x 10 ml). The ether extracts were combined and carefully evaporated. The resultant brown mobile oil was

—'tnturated with n-penrane and the solvent decanted. This process ~vas repeated ~x 2), and [hen iesio'ual pentane evaporated, to pro Ade the title compound t65 ng) as a light brohvn oil.

1K NMR (400 MHz, CHLOROFORM-a) B ppm 1.30 (d, S H), 285 fin, i H), 4.41 (q, 2 H), 7.35 (s, 1 H).
7.80(s,1 I-I)

Preparation-88
[2-Am ino-6-~4-isooroovl-oxazol.2-vO-3-nhro-ovdin-4-vfl-(6-me~-vridin-s-vlmethvl)-carbam ic acid ethyl ester

The title coin pouno was prepared following the Example in preparation '70, using 4-isopropyl-oxazole (54 mg} and (2-amino-6-broin o-3-nitro-pyridin-4-yl)-%m ethyf-pyndfn-3-ylinethyl)-carbamic acid ethyl ester (100 mg), giving the product (71 mg) as a yellow gum.

1K NMR (400 MHz, CHLOROFORM-a) 5 ppm 1.10 - 1.22 (in, 3 H) 1.27 (d. J=6.64 Hz, 6 K) 2.50 (s, 3 H)
2.82 - 2.97 (in, I K) 3.96 -4.27 (in, 2 K) 4.92 (s, 2 1-1) 6.34 (s, 2 H) 7.10 (d, ,h7.81 Hz, 1 K) 7.23 (s, 1 K)
7.45 (s, 1 H) 7.59 - 7.70 (in, I H) 8.39 (s, I I-?), LOMS ft = 2.23 ni/z 441 [MKf

Preparation 89
Benzvl-(2,8-dibrorno-3-nitrc-pvridin-4-vl~-carbamic acid ethyl ester

Potassium carbonate (5.57 9) was added to a stirred solution of (2,6-dibroino-3-nitro-pyridin-4-yl)-carbainic acid ethyl ester (7.44 g) in acetone (100 ml) Then benzyl bromide (2.87 ml) was added, followed by sodium iodide (3.63 g). The mixture was left to stir under nitrogen for 36 hours. The reaction mixture was filtered to remove precipitated white solids, concentrated in vacua, and then partitioned between ethyl acetate (100 ml) and water (100 ml). The organics were dried (MgSO4) and evaporated to a yellow oil. This crude oil was adsorbed onto silica gel and then purified by chromatography on Isco Companion on a silica column (80 g, Redisep) eluting with EtOAO:heptane, increasing the gradient linearly from 10:90 to 50:50. This provided the title compound (7.50 g) as a yellow oil.

IH NMR (400 MHZr CHLOROFORM-a) 6 ppm 1.20 (t, 3 H), 4.18 (q, 2 H), 4.8 (br, s, 2 K), 7.0 (s, I H), 7.20 (in, 2 H), 7.35 (in, 3 K), LRMS mlz (API) 458.460, 462 [MI-l]~

Preparation 90
(2-Am ino-6-bromo-3-nitro-ovridin-4-yl)-benzvl-carbamic acid ethyl ester

Benzyl-(2,6-dibromo-3-nltro-pyridin-4-yl)-carbamic acid ethyl ester (7.50 g) was dissolved in 2-methyl-tetrahydrofuran (15 ml) and the solution placed in a sealable vessel. Concentrated aqueous ammonia solution (15 ml) was added and the vial was then sealed and the bi-phasic mixture left to stir vigorously at room temperature for 36 hours. The reaction mixture was then transferred to a separating funnel and ethyl acetate (120 ml) and water (120 ml) were added. The phases were separated, and then the

The title compound was prepared following The Example in preparation 70, using diinethyl-oxazol-4-ylinethyi-arnine (128 ing), (2-amino-6-broino-3-nitro-pyridin-4.yD-benzyl-carbainic acid ethyl ester (200
organ5cs washed with brine (400 mi), dKed (MaSO4), and evaoorated to a yellow oil. Upon standing, a yellow solid crystallised. This was coUected by hltraton and washed with pentane, providing the title compound (6.64 g) as a yellow solid.

1K I'DMR (400 MHz, CHLOROFOFIM-o~ 3ppm 1.21 It, 3 'riD, 449 (q, 2 H), 4.62 (br, s,2 H). 6.25 (br, 5,2 H), 6.55 (s, 1 H), 7.20-7.35 (in, 5 H), LRMS in/z (API) 393, 307 [Mi-v

Precaration 91
t2-Arnino-6-(4-methoxvrnethvl-oxazol-2-vO-3-n itro-ovridH-4-V!I-bsnztd-carbainic acid ethyl ester

The title compound was prepared following The Example in preparation 70, using 4-inethoxyinethyl-oxazole (114 mg)1 (2-amino-6-broino-3-nitro-pyridin-4-yI)-benzyi-carbainnic acid ethyl ester (200 ing) and palladium bis(triphenylphosphine) dichloride (71 ing), gving the product (160 ing) as a yellow gum.

1K NMR (400 MHz, CHLOROF0RM-o~ '3 ppm 1.20 (t. k7.03 Hz, 3 H) 3.46 (s, 3 H) 4.12- 4.22 (in, 2 K)
4.47 (s, 2 H) 4.92 - 5.03 (in, 2 H) 6.32 (s, 2 H) 7.26 - 7.35 Cm. 6 H) 7.74 (s, 1 1-1), LCMS R~ 3.08 in/z 428[MH]~

Prenaration 92

Dimethvi-oxazol.4-vlin ethyl-amine

Thionyl chloride (5.51 ml) was added dropwise to a cooled solution (0 0C) of oxazol-4-yl-inethanol (1.51 g) in dichloromethane (50 ml) over 5 minutes. The resulting cloudy solution was stirred for 5 minutes at room temperature and then heated to refiux. On heating the solution became clear and a deep yellow colour. After 10 minutes at reflux the solution was allowed! to cool to room temperature and the excess thionyl chloride and solvent were then removed under reduced pressure to afford the corresponding chloride compound that was used without further purification.
Dimethylainine (38 ml of a 2.0 M solution in 11-IF) was cooled La 0 "C in an ice-bath and a solution of the chloride (1.74 g) in dry TI-iF (50 ml) was added in small portions over 10 inins. The resulting suspension was then left to react for 16 hours. The solvent was removed to afford a dark brown/black solid that was then pre-absorbed onto silica and purified by 15CC' combi-flash chromatography on silica gel eluting with 5 to 15% MeOl-I in dichloromethane with 10% NH3. This provided the 1*14 compound (335 ing) as a dark brown viscous oil.

li-I NMR (400 MHz, CHLOROFORM-c?) a ppm 2.35 (s, 6K), 3.50(s,2 H), 7.62 (s, 1 K), 7.85 (s, 1 K)

Frenaration 93

[2-Am ino-8-(4-diin ethvlaininoniethvl-oxazol-2-vB-3-nitro-pvrjdin-4-vll-benzvl-carbamic acid ethyl ester
mg) and palladium 'ois(triphenyiphosphine) dichlorica (73 mg). giving the product (99 trig) as a yeilcw gum.

1K NMR (400 MHz, CHLOROFORM-d) S ppm 1.20 (t. ~M703 Hz, 3 H) 2.32 (s, 6 H) 3.49 (s, 2 H) 4.13 -

4.23 (in, 2K) 4.92 5.03 (in, 2 H) 6.33 (s, 2 H) 7.23 - 7.36 (in, S H) 7.63 (s. 1 H), LOMS R~ 1.86 in/z 441

Preoarat'cn 94
2-Aniino-3-nitro-6-Jl -('2-triineth v!silanvl-ethoxvrn ethx'l)-i H-11nii6ao~-2-vl1-pvridir-4-vI~benzvl-carbamic

acid ethyl ester

The title compound was prepared following The Example in preparation 70, using 1-(2-triinethylsilanyl-ethoxyrneth~4)~-I 1-1-imidazole (201 mg), (2-am inc-6-biromo-3-nitro-pyrid!in-4-yl)-benzyl-carbamic acid ethyl ester (200 ing) and pailadiuin bis(triphenylphosphine) dichloride (71 ing), giving the product (174 ing) as a yellow gum.

1K NML4 (400 MHz, CHLOROFORM-c?) 5 ppm -0.04 (s, 9 H) 0.87 - 0.94 (in, 2 1-I) 1.19 (t, J=7.03 Hz, 3 K)
3.49 -3.59 (in, 21-1)4.10-4.22 (in, 2K) 4.98 (s, 2 H)' 5.93 (s. 2 H) 6.18 (s, 2 H) 7.18 (s, 1 H) 7.23 (s, 1 K)
7.28 - 7.38 (in, 5 H) 7.53 (s, 1 H)

Preparation 95
(2-Ainino-6-rnethvlsulfanvl-3-nitro-ovridin-4-vll-benzvl-carbamic acid ethyl ester

Sodium methanethiolate (180 mg) was added portion-wise to a stirred suspension of (2-ainino-6-chloro-3-rtitro-pyridin-4-y~-benzyl-carbainic acid ethyl ester (300mg) in inethanol:THI (3:1, 4 ml). The mixture was sealed in a ReactiVial then left to stir at room temperature for 2 hours. The reaction mixture was diluted with methanol then pre-absorbed directly onto silica gel. The crude was columned on Isco Companion on a silica column (12g. Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 30:70 to 50:50 over '6 column volumes. The desired fractions were combined and evaporated to provide the title compound (297 mg) as a yellow gum.

1K NMR (400 MHz, METHANOL-c?4) S ppm 1.04-122 (in, 3 H)243 (s, 3K) 3.96-4.24 (in, 2 H),4.35 -
4.55 (in, I H) 5.03 -5.17 (in, 1 H) 6.13 (s, 2 H) 7.12-7.47 (in', 6 H), LOMS R1= 3.29 m/z 363 [MKV

Preparation 96
[2-Am ino-6-(2-fluoro-phenyl'l-3-nitro-nvridin-4-vll-benzvl-carbam ic acid ethyl ester

2-Fluoro-phenylboronic acid (34 ing), copper (I) thiophene-2-carboxylate (79 ing) and palladium bis(triphenylphosphine) dichloride (19 ing) were added to a microwave vial. The vial was then flushed with nitrogen and sealed. A solution of (2-amino-6-rnethylsullanyl-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (42 ing) in anhydrous THF (0.5 ml) was then added to the vial and the mixture heated
under microwave irradiation (GEM) for 10 minutes at 102 "C'4 The reaction mixture was then diluted with methanol and filtered through Arbocel directly onto a cation-exchange cartridge (Bakerbond, sulphonic acid bonded-phase, ig). The cartridge was washed with methanci (2 x S ml) to remove impurities and then the product was released by eluting with ammonia in methanol (2 PA, 5 ml). Tha.desired fractions were conabir.ed and evaporated to yield the tile compound (31 mg) as a yellow gum.

1K NMR (403 MHz, CHLOROFORM-c?) Sppm 1.03 - 1.31 (in, 3 H) 4.16 (s, 2 H) 4.91 (br. s., 1 H) 6.20 (s,
2 H) 6.35 (s, 1 H) 7.07 (dd, .1=11.71, 8.20 liz, I H) 7.16-7.22 (in, I H)' 7.21 - 7.42 (in, 7 H) 7.84- 7.93
(in, 1 H), LOMS R~ = 3.50 in/z 411 [MH]4

Prejoaration 97
12-Amino-6-(3-fluoro-phenvl)-3-nitro-pvridin-4-vll-benzvi-carbarn ic acid ethyl ester

The title compound was prepared following the Example in preparation 95 using 3-fluoro-phenylboronic acid, providing the product (18 ing) as a yellow gum.

1K NMR (400 MHz, CHLOROFORM-c~ S ppm 1.08 - 1.35 (in, 3 H) 4.19 (s, 2 H) 5.29 (br. s., 2 H) 6.29 (s,
2 H) 6.65 (s, I H) 7.04- 7.17 (in, 1 K) 7.28 - 7.40 (in, 7 H)' 7.43 -7.55 (in, 1 H), LCMS R~ = 3.53 in/z 411
[MH]+

Prenaration 98
[2-Am ino-6-(4-fluoro-phenvl i-3-nitro-pvridin-4-vll-benzvl-carbam ic acid ethyl ester

The title compound was prepared following the Example in preparation 96 using 4-fluoro-phenylboronic acid, providing the product (28 mg) as a yellow gum.

1K NMR (400 MHz, CKLOROFORM-d) 6ppm 1.19 (s, 3 H) 4.19 (s, 2 I-I) 5.33 (br. s., 2 H) 6.31 (s, 2 H)
6.63 (s, 1 H) 7.03 - 7.13 (in, 2 H) 7.29- 7.38 (in, 5 H) 7.68 - 7.77 (in, 2 K). LCMS FI~ 3.52 in/z 411 [MH]+

Preoaration 99

(2-Am ino-6-methoxv-3-nitro-pyridin-4-yl)-benzvl-carbarnic acid ethyl ester

Sodium hydride (9 ing) was dissolved carefully in methanol (0.5 ml) and this solution then added to a solution of (2-arnino-6-broino-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 ing) in THF (0.5 ml) at room temperature. The reaction was stirred under nitrogen for 2 hours then the solution preabsorbed directly onto silica gel. The mixture was purified by chromatography on an Isco Companion, eluting with ethyl acetate:heptane, increasing the gradient linearly from 20:80 to 60:40 over several column volumes. The desired fractions were combined and evaporated to provide the title compound (23 ing) as a yellow gum.

Il-I NMR (400 MHz. GHLORCEOHM% S porn 1.15 (s, 3 8) 3.34 (a, 3 W 3.97 - 4.32 fin, 2 H) 4.42 (d, ~1=i5.05 Hz. 1 H) 521 (d, .1=15.05 Hz, 1 H) 5.77 (s, 1 8) 5.61 (ba a, 2 8) 7.23 - 7.33 (11, 5 H), LOMS R~ = 3.19 miz 347 [ftP-I]t

Preparaton 11110

(2-Arnino-6-ethoxv-3-nilro-pyridTh-4-W)-benzvl-oerbain 'c acid ethyl ester

The title compound was prepared following the exam pie in preparation 09 using ethanol and g:ving the product (31 ing) as an off-white solid.

1K NMR (40Q MHz, CHLOROFORM-cD 5 ppm 1.10-128 (in, 38) 1.3~ (t, .1=7.03 Hz, 3 1-1) 3.97-4.32
(in, 4 1-1) 4.43 (d, .1=15.83 Hz, 1 H) 5.20 (d, ~N15.83 Hz, 1 H) 5.70 - 5.86 (at, 1 H) 6.61 (br. s., 2 H) 7.25 -

7.36 (in, 5 H), LCMS lIt = 3.36 ink 361 JMH]4

Prenaration 101
(2-Amino-6-propoxy-3-nitro-oyridin-4-vll-benzvl-carbarnic acid ethyl ester

The title compound was prepared foltowing the Example in preparation 99 using propanol and giving the product (30 mg) as an off-white solid.

1K NMR (400 MHz, GHL0ROFORM-c~ S ppm 0.95 (t .1=7.42 Hz, 3 H) 1.07 - 1.33 (in, 3 H) 1.62 - 1.79
(ni, 2 H) 3.95-4.29 (in, 4 K) 4.44 (d, .1=15.63 Hz, 1 H) 5.20 (d, .1=15.63 Hz, 1 K) 5.67-5.90 (in, 1 1-1) 6.61
(br. s., 2 H) 7.25 - 7.41 (in, 5 H), LCMS R = 3.51 mlz 375 [MK]~

Preparation 102
(2-Am ino-6-methvlainino-3-nitro-pvridin-4-vfl-benzvl-carbamic acid ethyl ester

Methylamine (40% solution in water) (0.055 ml) was added to a solution of (2-ainino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 ing) in THF (0.5 ml) at room temperature. The reaction was stirred under nitrogen for 16 hours then the solution pre-absorbed directly onto silica gel. The mixture was purified by chromatography on an Isco Companion, eluting with eThyl acetate:heptane, increasing the gradient linearly from 20:80 to 60:40 over several column volumes. The desired fractions were combined and evaporated to provide the title compound (30 ing) as a yellow gum.

1K MMII (400MHz, CHLOROFORM-tX Sppin 1.04-1.40 (in, 3 H)2.82 (S,3 H) 3.97 4.33 (in, 3 H)4.75
- 5.04 (in, 1 H) 5.22-5.49 (in, 2 H) 6.79 (br. s., 2 K) 7.28 - 7.39 (in, 5 H), LCMS R~= 2.83 m/z 346 LMH)~

Preparation 103
{2-Aniino-6-ethylamino-3-nitro-nvridin-4-vl)-benzvl-carbain ic acid ethyl ester

The title compound was prepared followitrg the Example ri preparahort t02 us,ng ethyiainrne (70% solution in water) (0.051 inO and giving the product (35 rng) as a yellow gum.

1K NMR (dO0 MHz, CHLOROFORM-c) S ppm 1 05 - 1.37 (in, 6 H) 3.23 (s. 2 H) 393 - 4.35 (in, 3 H) 4.13" (s, 1 H) 5 17- 552 (in, 2 H) 6.75 (br s., 2 H) 7.29 - 7.42 ~ni, S H> LOMS P1 3.0 mx 360 [MH]+
Precaration 10"

(2-Amino-6-oropvlamino-3-nitro-pvridin-4-v~-ben~yJ.ca,tainic acd ethyl ester

The title compound was prepared following the e~ainpie in preparation 102 using n-propylarnine (0.052 ml) and gMn9 the product (35 mg) as a yellow ~uin.

li-I NMR (400 MHz, CHLOROFORM-c?) 8 ppm 0.91 (t, .1=7.42 Hz, 3 H) 1.06 1-38 (in, 3 H) 1.44 - 1.55
(in, 2 H) 3.14 (s, 2 H} 3.93 - 4.30 (in, 3 H) 4.75 - 5.07 (in, I H) 5.22 - 5.48 (in, 2 H) 6.77 (br. s., 2 H) 7.28 -
7.37 (in, 5 H), LCMS R~= 3.16 m/z 374 [MH]+

Preoaration 105

(2-Ainino-6-butvlamino-3-nitro-r~vridin-4-vfl-benzvl-carbamic acid ethyl ester

The title compound was prepared following the Example in preparation 102 using n-butylamine (0.063 ml) and giving the product (39 mg) as a yellow gum.

1H NMR (400 MHz, CHLOROFORM-cO 8 ppm 0.92 (~, .1=7.42 Hz, 3 H) 1.12 - 1.37 (in, S H) 1.41 - 1.51
(in, 2 H) 3.17 (s, 2 H) 3.98 - 4.31 (in, 3 K) 4.84 Cs, 1 H) 5.26- 5.47 (in, 2 H') 6.75 (br. s., 2 H) 7.28 - 7.36
(in, 5 K), LCMIS R1 = 3.31 mfz 388 [MH]+

Preoaration 106

f2-Amino-6-(2-inethoxv-ethylamino)-3-nitro-ovridin-4-vrl-benzvi-carbam ic acid ethyl ester

The title compound was prepared following the Example in preparation 102 using 2-methoxyethylamine (1.0 ml) and (2-arnino-6-broino-3-nitro-pyridin-4-yl)-benzyl-carbam]c acid ethyl ester (150 mg), giving the product (121 mg) as a yellow gum.

1K NMR (400 MHz, DMSO-d6) S ppm t21 ~t, 3 1-1), 3.35 (s, 3 K), 3.45 (3m 4 I-i), 4.20 (q, 2 H), 5.25 (br, s,
2 H), 7.20-7.36 (in, 5 H), LRMS m/z (API) 390 ~MK]~, 388 (Mi-If

Prer,aration 107

('2.6-Dibromo-3-nitro-pvridin-4-yl~-(6-tri~luoromethyl-~-vlmethvl~-carbamic acid ethyl ester

The title compound was prepared following the Example in preparation 68 using potassium carbonate (1.50 g), (2,6-dibromo-3-nitro~pyridin-4-yl)-carbamic acid ethyl ester (2.0 g} in acetone (40 ml), 5-

(chiorornet~yi)-2-trifluoromeu~ypyridine (1 06 g) ~nd sodium iodide (ID.98 g). This gave The product (2.79 g) as a yellow oil.

1 H NMR (400 MHz, DMSO.d6) ~ ppm 1.20 ~t, 3 H> 4.20 (q, 2 H), 4.85 (s. 2 H~, 7.28 (s, 1 H), 7.71 (0,1 H),

7.88 (dd, I H). &6~ (d, I H)

Prep~raticn 108

(2-Amino-6-broino-3-nitro-pyridin-4-yfl-(~-~rifli.porornetlwl-pvridir',-3-vlmethvfl-cari~am ic acid ethyl ester

The title compound was prepared following the Example in preparation 69' using (2,6-dibroino-3-nitro-p~rWin-4-yl)-~6-trifiuoroinethyl-pyridin-3-ylmethyl)-carbainic acid ethyl ester (2.75 g)~ aqueous ammonia (11 ml), and 2-methyl-THF (11 ml). This gave the product (1.92 g) as a yeLlow oil.

1K NMR (400 MHz, DMSO-d6) 8 ppm 1.21 (t, 3 H). 4.11 (q, 2 H), 4.95 (br, s,2 H), 6.41 (br, s,2 K), 6.60 (s, 1 H), 7.85 (d', 1 l-{), 7.95 (in, I 1-1), 8.65 (in, 1 H)

Prep~rati0n 109
(3-Cyano-benzvl)-(2,6-dibroino-3-nitro-nwidin-4-vl~I-carbainic acid' ethivl ester

The title compound was prepared following the Example in preparation 68 using potassium carbonate (1.50 g}, (2,6-dibromo-3-nitro-pyridin-4-yl)-carbarnic acid ethyl ester (2.0 g) in acetone (40 ml), 3-chloromethyl-benzonitrile (0.82 g) and sodium iodide (0.98 g). This gave the product (2.62 g) as a yellow oil.

1K NMR (400 MHz, DMSO-d6) ~ ppm 1.20 (t, 3 K), 4.15 (q, 2 i-I), 4.80 (br, s, 2 K), 7.15 (s, 1 H), 7.5 (in, 2
1-1), 7.61 (in, 1 H), 7.65 (in, 1 H)

Preperation 110
(2-Amino-6-broino-3-nitro-pyrjdjn-4-yl~-(3-cVano-benzVPi-carbam ic acid ethyl ester

The title compound was prepared following the Example in preparation 68 using (3-cyano-benzyl)-(2,6-dibromo-3-nitro-pyridln-4-yl)-carbainlc acid ethyl ester (2.32 g), aqueous ammonia (10.2 ml), 'and 2-rnethyl-TKF (10.2 ml). This gave the product (1.51 g) as a yellow solid.

1K NMR (400 MHz, DMSO-d8) 8 ppm 1.20 (t, 3 H), 4.21 (q, 2 H), 4.95 (br, s, 2 K), 6.35 (br, s, 2 K), 6.59 (s, I H), 7.5 (in, I H), 7.6 (in, 3 H)

Preparation 111
(2-Am lno-3-nitro-6-oxazol-2-yl-ovridin-4-vl)-(6-trifluoroin ethvl-ovridin-3-vlmethvfl.carbamic acid ethyl ester

The title compound was prepared foffc'w[ng the Example in prep~raUsn 70, using o~azols (30 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(a-trifluoroinethyl-pyridirvs-yimethvn-carbaimic acid ethyl ester (100 mg) and palladium bis(tripheriylphosphine) dichIOfide (30 mg), gDing the product (61 mg~ as a yellow solid

1K NMR (400 lViHz. CHLOROFORM-a) S ppm 1.10 - 1.31 (in 3 H~ 4.02 - 4.30 (in, 2 H) 5.07 (s, 2 K) 6.39

(s, 2 H) 7.32 (s. 1 H) 7.35 (.9, 1 H) 7.69 (d. ~7,82 Hz, 1 H) 7.34 (s, I H) 3.01 (d, 3=5.47 Hz, 1 Fl) 8.70 (s,

1 K), LOMS R~ = 3.02 miz 453 [MH]+

Preperation- 112

ic acid

ethyl ester
The title compound was prepared following the Example in preparation 70, using 4-methyl-oxazole (36 ing> (2-am ino-6-bromo-3-nitro-pyridin-4-yl)-(e-tritluoroinethyl-pyridin-3-ylrnethyl)-carbarn ic acid ethyl ester (100 ing) and palladium bis(triphenylphosphine) dichloride (30 ing), giving the product (44 mg) as a yellow solid.

1K NMR (400 MHz, CHLOROFORM-a) S ppm ~.10 - 1.25 (in, 3 H) 228 (5, 3 H) 4.09 - 4.25 (in, 2 K) 5-06

~s, 2 i-f) 6.41 (s, 2 H) 7.25 (s, 1 H) 7.55 (d, 3=t.l1 Hz, 1 K) 7.69 (d, .1=8.21 Hz, I H) 8.01 (d, .1=7.03 Hz, 1

K) 8.70 (s. 1 lid), LCMS R1 = 3.13 in/z 467 [MH]+

Preparation 113
I2-Ainino-3-nitro-6-oxazol-2-vl-pvridin-4-vl)-(3-cvano-benzvl)-carbamic acid ethyl ester

The title compound was prepared following the Example in preparation 70, using oxazofe (33 ing), (2-ainino-6-bromo-3-nitro-pyridin-4-y~-(3-cyano-benzyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine) dichloride (33 ing), giving the product (67 rag) as a yellow solid.

1K NMR (400MHz, CHLOROFORM-a) Sppm 120(1, 3=7.03 Hz, SN) 4.17 (s, 2K) 4.99 (s, 2 H) 6.36 (s,
2 H) 7.26 (s, 1 H) 7.34 (s, 1 H) 7.46 (1, 3=7.62 Hz, 1 H) 7.59 (d, 3=7.42 F-fz, 1 H) 7.62 - 7.68 (in, 2 H) 7.82
(s, 1 K), LOMS R1 = 2.93 in/z 409 [MI-It

Preparation 114
f2-Amino-5-(4-inethyf-oxazol-2-vfl-3-nhtro-pyridin-4-v1J-(3-GYaflO-beflZVl)-carbainic acid ethyl ester

The title compound was prepared following the Example in preparation 70, using 4-inethyl-oxazole (40 ing), (2-ainino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano-benzyl)-carbarnio acid ethyl ester (100 ing) and palladium bis(triphenylphosphine) dichloride (30 nig), giving the product (65 mg) as a yellow solid.

1K AR (400 MHz, CHLGROR)RM-c'~ i ppm 1.10 - 1.25 ~rn, 3 H) 2.2.8 (S. 3 H) 4.10-4.23 (rri, 2 H) 4.99
(s, 2 H) 6.39 (s. 2 H) 7.20 Cs, 1 H) 7.46 ~t, Jz7.62 LIz, 1 H) 7.54 (d, .1=117 Hz, I I-I) 7.~O (d, ~7.42 Hz, 1

H) 7.63- 7.69 (in. 2 H), LOMS R~ = 3.04 m/z 423 ~f Mi-Ilt

Preparation 115

4-Am no-i -benzvl-6-brom 0-I .3-dihydro-irn~dazo[4.5-C1rvridin-2-cne (2-Amino-6-bromo-3-nitro-pyridin-4-yl)-benzyi-carbainic acid ethyl ester (50mg. 0.13mm ci) was dissolved in AcOK (3m I). Fe powder ~43mg, 0.76mmol) was added and d~e mixture was vigorously stirred at room temperature for 24h. The reaction mixture diluted w~th EtOAc (20m~ and water (lOini). The mixture was filtered through celite, washing through with EtOAc (20m1). The layers were separated and the organic layer was washed with water (lOmi), sat. NaHCO3 ta~ (2xIOml) and brine (lOmI), dried over MgSO4 and concentrated it, vacua. The crude was trituratecf in pentane, filtered and dried in vacua at 400C to give the title compound (15mg) as a beige solid.

'H NMR (d6-DM.SO) 5 10.47 (br s, 1 H), 7.36-7.26 (in, 5H), 6.70 (s, 1K), 6.05 (br s, 2K), 4.94 (s, 2H); LRMS (APCJ and ~S) mlz 319/321 ~MH]4.

Preparation 116

Benzvl-(2,3-diam ino-6-oyrazol-1 -yl-r~vridin-4-vl~-carbam ic acid ethyl ester

(2-Amino-3-nitro-6-pyrazol-1-yl-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (65,4mg, 0.l7lmmol) was dissolved in methanol (5mL) and hydrogenated over Raney Nickel (25mg) at room temperature, 8opsi for 1 hour. The reaction mixture was filtered through a short plug of Arbocel and the filtrate was then evaporated ir~ vacua to afford 58mg of the title compound as a brown residue.

'K NMR (CDCl3) 5 1.15 (in, 3K), 2.90 (s br, 2K), 3.50 (m, 2H), 4.12 (4, 2K), 4.20 (s br, 2H), 6.28 (5 br, 1 K), 7.10 (s br, 11-1), 7.20-7.35 (in, 5K), 7.65 (s, 1K), 8.30 (s, 1K). LF~MS (ES~) m/z 353 (MH~).

Preoaration 117
(2-Am ino-3-nitro-6-rl .2,4ltriazol.1 -vl-ovridin-4-vfl-benzyl-carbamic acid ethyl ester

The title compound was prepared following the Example in preparation 116.
~H NMR (ODdS) lii 1.20 (t, 3K), 4.19 (quart, 2K), 5.00 (s br, 2K), 6.37 (s br, 2H), 7.09 (s, 1K), 7.27-7.37 (in, SM), 8.03 (s, 1K), 9.00 (s, 1K). LRMS (ES4) m/z 334 (MU4).

PreQaration 118'

(a) (2-An,ino-3-nitro-6-E1 ,2.3ltriazol-2-Vl-Dvridin-4-vl'p-benzvl-carbamic acid ethyl ester and (bh (2-Amino-
3-nitro-6-f 1 ,2,3ltriazol-1 -vl-pvridin-4-vlY-benzvl-carbam ic acid ethyl ester

(2-Am ino-6-cbloro-3-nitro-pyridin-4-yl)-benzyl-carbamic ac~d ethyl ester (100mg, O2BSrnrncl) was dissolved in acetonitrile (lOin.) and 1,2,3-triazole (39.4mg, 0.S7Oinmol), followed by potassium carbonate (78.8mg, 0.S7Ommol) were added. The yellow solution was stirred at 700C for 18 hours under an atmosphere of nitrogen. The resulting dark orange reaction mixture was evaporated in vacua and the residue was dissolved in EtOAc and extracted with water. The organFc extracts were combined, dried over anhydrous magnesium sulphate and concentrated in vacua. The 2 structural' isomers were isolated by autopurification (chiralpak column, 60:50 inethanol:ethanol) to afford 4.8.1mg of (a)) (2-Aniine-3-nitro-6-(1 ,2,3]triazol-2-yl-pyridin-4-yl)-benzyl-carbamic acid ethyl ester and 34.9mg of (b~~ (2-Arnino-3-nitro-6-[1,2,3}triazol-t-yl-pyridin-4-yQ-benzyl-carbamic acid ethyl ester both as yeiHow solids.

'H NMR (CDCI3) (at) El 1.19 (t, 38), 4.18 (d, 2K), 5.00 (s br, 28), 6.62 (s br, 28), 7.25-7.36 (in, 6K), 7.87 (s, 18). LRMS (ES') mJz 384 (MM').

H NMR (GDCI3) (b/) U 1.21 (t, 3K), 4.20 (q, 2K), 5.02 (s br, 2K), 6.35 (s br, 2K), 7.24-7.40 (in, 61-1), 7.77 (s, 18), 8.40 (d, 1K). LRMS (ES') rn/z 384 (MK').

Preparation 119
f2-Amino-6-(4-fluoro-pvrazol-1-vl)- 3-nitro-ovridin-4-vll-benzvl-carbarnic acid ethyl ester

(2-Arnino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (lOOmgh 0.28Smmol), 4-fkjoropyrazole (24.5mg, 0.2BSmmoI) and potassium carbonate (118mg 0.855mm 01) were stirred together in 5mL of acetonitrile, under nitrogen. Heated the reaction to ref lux for 3 hours and then allowed to cool to ambient temperature over night.
The solvent was evaporated and the dichloroinethane soluble portion of the residue was pvrili?d by chromatography on silica, eluted with 1% methanol In dichloromethane. Combined and evaporated fractions containing clean material with an Rt of 0.66 in same eluent to give the title compound (1 06mg) as a yellow gum.

'H NMR (CDCI3, 400MHz) 0 1.20 (broad singlet, 3K), 4.17 (broad singlet, 2K), 4.95 (broad doublet, 2K)
6.38 (broad sInglet 21-1) 7.15 (a, 18)7.35 (in, 5K) 7.58 (d, 1H) 8.23 (d,1K).

LRMS (ES+) m/z 401 (MH.i-)

The following compounds were prepared using an identical method to that described in Preparation 119.
Preperaticn 120

~2-Am ino-6-43.5-dimethvl-oyrazot-1 -vl'~-3-n~ro-ovri~in-4-yl1-benzvi-oarbarnic acid ethyl ester.

'H NMR (CD'C13, 400MHz) 6 1.19 (broad sThglet. 3I-t~, 2.24 (s, 3'i{i 2.62 ~s3'l-i) 4A'6 (broad singlet, 21-i),
4.94 (broa&doublet. 2H) 5.98 (s, 1K) 6.36 (broad ~ing~et, 2H~ 7.21 {~1H) 7.32 (in, 5H). LRMS (ES+) mlz

411 (MK+).
- Preparation 121

12-Amino-6-(4-methvl-pvrazol-1 -vb-3-nitro-pvrid.in-4-vl~-benzvl-carbam ic acid eth.ul ester.

'H NMR (CDC~3, 400M1-lz) 0 1.20 (broad singlet, 3H), 2.14 (s, 3K) 4.16 (broad singlet, 2K), 4.95 (broad
doubie~, 2K) 6.39 (broad singlet. 21-I) 716 (s,1I-f) 7.36 (in, 5K). 7.53 (s, 1 H) 8.15 (s,IH). LRMS (ES±) mlz
397(MH+)

Preaaration 122
F2-Amino-6-(3-trifluoromethvl -pvrazol-1 -vl)-3-nitro-pvrid~n-4-vl1-benzvl-carbam ic acid ethyl ester.

~H NMR (CDCI~, 400MHz) 6 1.22 (broad singlet, 3K), 4.20 (bread singles, 2K), 5.00 (broad doublet, 2K),
6.33 (broad singlet, 2K) 6.69 (d, 1K), 7.22 (siK), 7.35 (in, 51-I), 8.45 (dIK). LRM'S (ES+) m/z 451 (MH+)

Preparation 123

[2-Ainino-6-(5-methvl-3-trifluoromethvl-pvrazol-l -vl~-3-nitro-pvridin-4-vl1-benzvl-carbamic acid ethyl ester.

'K NMR (CDCI5, 400MHz) 0 1.22 (broad singlet, 31-I), 2.69 (s, 3K), 4.20 (broad singleL 2H), 5.00 (broad,
2K), 6.29 (broad singlet, 21-I), 6.41 (s, 1K), 7.19 (s,1K), 7.33 (in, SI-I). LRMS (ES+) rn/z465 (MK+).

Preparation 124
{2-Amino-6-F4-(2-hydroxv-ethyl)-pyrazol-1 -vll-3-nitro-pvridin-4-yll-benzvl-carbam ic acid ethyl ester.

1H NMR (ODd3, 400MHz) 0 1.20 (broad singlet, 3H), 2.78 (t, 2K), 3.85 (q, 2K) 4.18 (broad singlet, 2K),
4.98 (broad, 2K), 6.37 (broad singlet, 2K), 7.17 (s,1J-I), 7.33 (in, 5K), 7.61 (s, 1K), 8.28 (s, 1K). LRMS
(ES÷) m/w 427 (MH+)

Preparation 125
1 -Benzyl-4-benzvlam ino-2-oxo-2,3-dihydro-1 H-imidazo[4,5-clpvridine-6-carboxvlic acid-(1 -hydroxyimino
ethvl~-amide

CDI (52 mg, 0.32 mmcl) was added to a solution of 1-benzyl-4-benzylamino-2-oxo-2A3-dihvdro.1H-imidazoE4.5-clpyridine-5-carboxvlic acid (30 mg, 0.21 mmcl) and Hunnigs base (33 i'J. 0.54 mmcl) in dry OME in a ReactVial. The vial was sealed and the mxture was stired at room temperaUre for 15 minutes. N-Hydroxyacetamidine (24 mg, 0.32 mmcl) '~sas added and mixture heated to 60 ~C io an aluminium block The mixture was left to stir at this temperature for 3 hrs then aiiotved to cool and concentrated in vacuo. The residue was partitioned between EtOAc (13 ml) and water (5 mO. The layers were separated and the organic phase was washed with brIne (5 ml). At this point, some solid precipitated and was left inside the senarating funnel. This was washed into The organic phase with MeO[-{ then the organics were dried ('MgSO4) and evaporated to yield the final product as a white solid (120 ing, 130 %). Material probably contains inorganic material, but taken on with a view to purification after next step.

'H NM6C'DSOPIJ 1.94 (s, 3K) 4.54 (s, 2H) 5.16 (s, 2K) 7.16 - 7.46 (in, IlK).

LCMS R~ = 3.47 mfz 431 (MI-i)'

Prenaration 126

N2.N2-Dibenzvl-6-broma-3-nitro-rivridine-2,4-diam me

2,6-Ijibromo-4-amino-5-nitro-pyridine (3.52 g) was dissolved in 2-methyl THE (40 ml) and the solution was cooled to <5 ~C in an ice bath. A solution of dibeozylainine (2.39 ml) and triethylamine (2.48 ml) in 2-methyl THE (20 ml) was added drop-wise to the dibromiopy~idine solution and the reaction mixture allowed to warm to RT and left to stir under nitrogen for 16h. Additioriai dibenzylamine (684 p1) and triethylamine (496 Wi) was added and the mixture was left to stir at RT for a further 6 hours, then further dibenzylarnine (684 p1) and triethyl~mine (496 p1) was added and the mixture was Left to stir at fIT for an additional ISh.
The mixture was transferred to a separating funnel them water (60 ml) added. Layers were separated and the aqueous then re-extracted with EtOAc (SOmI). The combined organics were dried (MgSO4 and evaporated to an orange gum. The gum was crystallised from MeO'K:water (90:10, -200 ml) to give a solid that was filtered and washed with MeOi-t:water (90:10) Then dried under vacuum to yield the title compound as an orange crystalline solid (3.6 g).

1K NMR (COCIa, 400MHz) 04.45 (a, 4K), 5.95 (Lw, s,2K), '6.22 (a, 1K), 7.05-7.15 (in, 4K),7.21-7.35 (in,
6K). LOMS R~ = 3.73 mlz 415 [MKJ'

Preuaration 127
N2,N2-Dibenzvl-6-bromo-N4-(6-methvl-pvridin-3-vlmethvl%3-nitropvridine-2,4-diamine

Potassium tert-butoxide (448 ing) was added portion-wise to a cooled solution (-18 0C - salt/ice bath) of N2,N2-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamine (1500 mg, 3.63 ramol) in TKF (40 ml) under
nitrogen. The solution changed from yellow to deep re&oranga en addition ot base. The solution was left to stir in the cooling bath for 5 minutes.

5-Bromometh~A-2-methyl-pyridine hydrobrom:de (1160 ing) was partihoned between saturated NaHCO3 solution (20 ml) and 2-Me THF (20 ml). The phases were separated and the aqueous was re-extracted with 2-Me THF (20 nit). The combined organics were dried (MgSO4) then added drop-wise tc the &ninopyridine and KOtBu mixture drop-wise via a dinpprng funnel The colour changed from red/orange to yellow/orange.The mointure was left to warm slowly to RT in the cooflng bath then left to stir at RT under nitrogen for 4Gb. The reaction mixture was cooled back down to -18 tQ doe/salt !~ath) then KOtBo (102 mg) was added fo'lowed by tetra-n-butylammonturn iodide ('370 rrg). The cooling bath was removed and the mixture allowed to warm to RT then stilTed for a further 4h. The reaction mixture was pine-absorbed directly onto silica then columned on Isco Companion on a silica column (80 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 40:60 to 80:20 over 10 column volumes. The desired iractions were combined and evaporated to give the title compound as a yellow solid (0.99 g).

'H NMR (CDCI3, 400MHz) El 2.58 (s, 3K), 4.38 (d, 2)-fl, 4.45 (s, 4K), 619 (s, fl-I) 7.05-7.15 (in, 4K), 7.18 (d, 1K), 7.21-7.35 (in, 6K), 7.49 (dd, 1K), 7.99 (t, 1K). 8.42 (d, 11-f). LOMS B, = 3.12 m/z 520 [MK]~

Preparation 128

N2, N2-Dibenzvl-N4-(6-methvl-pvridin-3-vlmethylt-3-nitro-6-oxazol-2-vl-pvridine-2,4-diamine

Butyl Lithium (2.9 ml) was added drop-wise to a stirred solution of oxazole (0.251 ml) in THF (5 ml) at -78 00 (dry ice/acetone bath), keeping the addition rate such Ihat the reaction temperature did not go above -

60 ~C. The solution was stirred at this temperature for 10 minutes then a solution of zinc chloride (1.56 g) in THF (7 ml) was added drop-wise. The solution was stirred for 15 minutes at -78 00 then the cooling bath removed and the reaction mixture allowed to warm to RT. An aliquot (1.2 ml) of the zinc oxazole solution was added via a syringe to a pre-sealed and nitrogen purged microwave vial (Biotage, 0.5-2.0 ml) containing N2,N2-dibenzyl-6-bromo-N4-(6-methyl-pyridin-3-ytmnethyl)-3-nitropyridine-2,4-diamine (90 mg) and palladium bis(triphenylphosphine) dichloride (24 ing). The vial was heated under microwave irradiation (Biotage, Initiator 8)for 15 minutes at 130 0C. Nine further aliquots of the zinc oxa.zole solution were reacted with the broinopyridine in the microwave in an analogous fashion.
All of the reaction mixtures were combined and concentrated in vacuo to a brown gum. The gum was partitioned between EtOAc (20 ml) and 2M ammonia solution (20 ml). The aqueous was re-extracted with EtOAc (20 ml), and the combined organics washed with brine (20 ml), then dried (MgSO4) and evaporated to a brown gum. The crude was purified on Isco Companion on a silica column (120 g, Redisep), elufing with EtOAc:heptane, increasing the gradient linearly from 80:20 to 100:0 over 6 column volumes then isocratic at 100 % EtOAc for 18 column volumes. The desired fractions were combined and evaporated to give the title compound as a yellow foamy solid (0.43 g).
'H NMR (ODd3, AOOMHz~ LI 2.60 (5, 3K), 4.55 (d. 2Ht 4.60 (s, 41), 699 (s, 1½) 7,05-7.15 (rti, 4K), 7.20-7.22 (d, 2K), 7.22-7.35 (in, 61-1), 7.59 (dd, iHt 7.79 y~ IN). 3.09 (t, ill), 6.55 (d, TN). LCMS P1 2.87 m/z 507 [MH]4

Preparation 129

N2.N2-Dibenzyl-N4-(6-methvj-pvridin-3-ylrnethyl)-6.oxazei.2-yl-pyridlne-2,3.4-trigm me
N2,2-Dibenzyf-N4-(Gmethyl-pyridin-3-yimethyfl-3-nitro-6-oxazoN.2-yi-pyrioine-2A-diam me (425 mg) was dissolved in THF (60 ml) then MeOl-! (60 ml) added.. The solution was hydrogenated over Raney nickel (40 ing) under a hydrogen atmosphere (80 psi) for lh. The reaction mixture was filtered through a Celite pad then evaporated Ito yield the title compound as a crude yellow gum which was used directly in the next step.

LCMS R~ = 2.42 m/z 477 IMKP

Preparation 130

(2.6-Dichloro-3-nitro-pyridin-4-vl~-car'oamic acid ethyl ester

A solution of ethyl chloroformate (2.75 ml) in 2-methyl THF (10 ml) was added drop-wise to a cooled (ice bath) solution of 2,6-dichloro-4-amino-5-nitro-pyridine (5.00 g) and triethylamine (4.02 ml) in 2-methyl THF (50 ml). The rate of addition was such that the reaction temperature did not rise above 5 0C A precipitate formed on addition of the ethyl chioroformate. The suspension was allowed to warm to RT then left to stir under nitrogen for 1 Gh. The suspension was transferred to a separating funnel and water (50 ml) added. The layers were separated and the organics were washed with brine (50 ml) then dried (MgSO4 and evaporated to an orange gum which solidified to a yellow solid on standing. The solid was re-crystallised from MeOl-itwater (70:30) providing the title compound as white needles that were collected by filtration (6.7 g).

'H NMR (CDCl~, 400MHz) 0 1.25 (t, 31-1), 4.31 (q, 2K), 8.10 (tar, s, 1 I-I), 8.40 (s, 1K). LOMS B, = 4.16 m/z 280 IMI-Ir

Preparation 131
Benzvl-(2,6-dichloro-3-nitro-pvridin-4-vJ)-carbamic acid ethyl ester

Benzyl bromide (2.33 ml) was added drop-wise to a stirred suspension of (2,6-dichloro-3-nitro-pyridini4-yp-carbarnic acid ethyl ester (4.57 g) in acetonitrile (40 ml). The mixture was left to stir at RT under nitrogen for iSh. The mixture was concentrated in vacuo then partitioned between EtOAc (SO ml) and water (50 mU. The layers were separated and the organics were washed with saturated NH,~Cl (50 ml), water (50 ml) and brine (50 ml). The organics were dried (MgSO4) and evaporated to a yellow oil. This

material was prs-absorbed onto silica then columned on lsc..~ Companion on a silica column (330 g, Redisep) eluting wrth EtOAc:heptane, isocratfo at 10:00 for I column vol~.~me (CV) then increasing the oradient irorn 10:93 to 30:70 over 6 CVs. The desired fractms were cembiried and evai~crated to provkde the titie compound as a yaliow oil (6.05 g).

'I-I t~MR (CDCI3, 400MHz) LI 1.25 (t, 3K), 4.19 (q, 2H~. 4.81 (s, 2ii-i), 638 (s, 1K), '7.20-7.213 (in, 2)-i), 7.30-7.40 (in, 3K). LOMS B, = 3.62 m/z 372 tM1-l~

Preoaration t32
(2-Amino-6-chloro-3-nitro-pyridin-4-yi)-benzyf-carbam ic acid ethyl ester

Benzyl-(2,6-dichloro-3-nitro-pyridin-4-yl)-carbarnic acid ethyl ester (500 ing) was dissolved in TKF (3 ml) in a ReactiVial. Ammonia (7M in MeOK, 1 ml) was added, the vial was sealed, and the reaction left to stir at AT for 48h. The reaction mixture was then pre-absor'oed directly onto silica and columned on Isco Companion on a silica column (40 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 10:90 to 40:60 over 10 column volumes. The desired fractions were combined and evaporated to provide the title compound as a yellow gum which solidified on scratching (305 mg)

1H NMR (00013, 400MHZ) LI 1.05 (t, 3K), 4.02 (q, 2K), 4.87 (tar, s, 2K), 6.58 (s, 1K), 7.20'-7.36 (in, 5K),
7.61 (br, s, 1K). LOMS B, = 3.24 m/z 351 [MH]+

Preparation 1133
t2-Amino-6-(2-methoxv-ethoxv)-3-nitro-pvrldin-4-vl1-benz~,l-carbam ic acid ethyl ester

Sodium hydride (21 mg) was added portion-wise to 2-in ethoxyethanol (0.5 ml). The resultant solution was
added drop-wise to a solution of (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester
(100 mg) in TKF (1.0 ml). The reaction mixture changed from yellow to deep red/orange solution and was
left to stir at RT for lh. The orange mixture was concentrated in vacuo then partitioned between EtOAc
(10 ml) and saturated NI-14C1 solution (10 ml). The layers were separated and the organics were washed
with water (10 ml) and brine (10 ml) then dried (MgSO4 and evaporated to provide the title compound as
a crude yellow gum (111 mg). This was used directly in the next step with no further purification.

LOMS At = 3.13 m/z 391 [MH]+

Preparation 134

4-benzylarnino-3-nitro-pyridin-2-ol
4-chloro-3-nitro-2-pyridone (Eg, 23 SSmmol) was suspenied in 1 EOmL of acetonitrie then benzylamine (3.iSmL. 28.SSmmol) was added followed by potassium carbonate (4g. 28.SSmmol) and the mixture was stirred at 600C overnight. The solvent was removed in vacuo and the residue was suspende~ in water
~200mL). A solution of KGI 2M was added until pH-fl. The precipitate was fdtered and dried in. vccuo to give 4.75g of The title compound as a beige solid. A second crop from the mother hquids provided 1.4g of the title compound.
'H NMR (dO DM60) '2:11.20 (s broad, 11-fl, 9.35 (t, 1k) 7.40-7.20 (rn SM), 5,85 (d, 1K), 4.60 (d, 2k). LAMS {ES4J m/z 246 WIN]4

Preparafion 135

Benzvl-(2-chloro-3-nitro-ovridin-4-vl)-amine

4-benzy[amino-3-rtitro-pyridin-2-ol (6.15g. 25.O7mmOi) was suspended in lOOrnL of acetonitrile then phosphorus oxychioride (l2mL, 125.4Ommol) was added foflowed by tetraethyl am monium chloride
(4.15g. 25.O7mmol) and the mixture was stirred at 85CC overnight The solvent was removed in vacuo and the residue was suspended in water (300mL) and extracted with dichloromethane (2x200mL). The
organic layer was dried over magnesium sulfate and The solvent was removed in vacuo to give 5.9g of the title compound as a yellow solid.

'H NMR (CDCV3) El: 8.0 (d, iN), 7.40-7.20 (in, SHy, 6.9 (s broad, 1K). 6.60 (d, 1K), 4.5 (d, 2K).
LAMS (ES4) miz 264 [NIH]4

Preparation 135

N-2.N-2.N-4,tribenzvl-3-nitro-pvridine-2.4-diam me

Benzyl-(2-chlcro-3-nitro-pyridin-4-yl)-amine (3.95g, 14.S9mmol) was suspended in 5OmL of acetonitrile then dibenrylamine (2.9mL, 14.9gmmol) was added followed by potassium carbonate (2g, 14.99mmol) and the mixture was stirred at 800C overnight The solvent was removed in vacuo and The residue was suspended in water (iOOmL) and extracted with ethyl acetate (2xlOOmL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuc. The crude residue was purified by column chromatography on silica gel using 15% ethyl acetate in pentarie to give fig of the title compound as a yellow oil.

'K NMR (dfl DM60) 0: 8.1 (s broad, 1K), 7.9 (d, 11-1), 7.40-7.10 (in, 15K), 6.10 (d, 1K), 4.55 (s, 4K), 4.5 (d, 2H).

LRMS (ES4~) m/z 425 [MN]4

Preoaration 137

N-2.N-2.N-4.tribenzvl-pvridine-2.3,4-triamine


N-2,N-2tJ-4,fribenzyl-3-nilxo-pyridine.2,zi-diamirvs 6g. t-t iThtm&) was suspended in lEOrnL of ethanol and Raney nickel (1 2g. 20% weight) was added, then tne mixture was stirred at room temperature under 50 psi of hydrogen for 3 hours. After complet~on, the mixture was filtered through arbocel and the solvdnt was removed in vacua to give Sg of the title compound as a pale purple gum.

1H NMR (CDCI~) LI: 7.30 (d, 1K), 7.40-7.15 (in, 15K). 6.35 Cd. 1K). 4.35 ~d, 2K. 4.15 (s, 4H).3.5-3.25 broad, 2K).

LRMS (051 in/z 395 [MH]4

Prenaration 138

1 -benzvl-4-dibenzylamino-1 .3-dihydro-im idazof4.5,clovridine-2-one

N-2,N-2,N-4,tribenzyl-pyridine-2,3,4-triamine (5g. 12.B7mmoi) was dissolved in lOOmL of acetonitrile then 1,1'-carbonyldiimidazole (3g, 19.7Olmol} was added and the reaction was stirred at 800C overnight. The mixture was cooled down to room temperature and the precipitate was filtered and washed with acetonitrile then dried in vacuo to give 4.3g of the title compound as a light purple solId.

'I-I NMR (d6 DM50) LI: 10.9 (s, 1K), 7.75 (d, 4K), 7.40-7.10 (in, 15K), 6.70 (d, iN), 4.9 (s, 2K), 4.6 (s, 41-I).

LRMS (ESI m/z 421 [MK]~

Preparation 139

1 -benzvl-7-bromo-4-dibenzvlamino- 1 ,3-dihvdro-iinidazol4.5,clnvridine-2-one

11 -benzyl-4-dibenzylamino-1 ,3-dihydro-im idazo~4,5,C1pyricline-2-one (1 g, 2.4mmol) was suspended
2OrnL of acetic acid then sodium acetate (195mg, 2.4mrnol) was added tollowed by bromine (456mg, 2.BSmmol) dropwise. The mixture was stirred at room temperature for 15 minutes. A heavy precipit~te was formed. The mixture was diluted in water (SGmL) and the solid was filtered and washed with waterY2lt was then diluted in ethyl acetate (2OmL), dried over magnesium sulfate and the solvent was removediin vacuo to give I .29g of the title compound as a light orange solid.

'H NMR (dG DM50) 0:11.5 (s, 1K), 7.85 (s, 1K), 7.40-7.10 (in, 15K), 5.30 (s, 2K), 4.55 (s, 41-9.
LRMS (ESj mfz 499,501 [MH]+

Preparation 140

1 -benzvl-4-dibenzvlamino-2-oxo-2,3-dihvdro-1 H-imidazof4. 5,clovridine-7-carboxvlic acid methyl ester

(1,1 'bis(d phenyiphosphino)ten ocene) dichioro palladium (82mg, ~2 I rn mom) and the mixhii e was stirred at 100CC under lOOpsi of CO overnight. The mixture was cooled down to room temperature, filtered through Arbocel and washed with methanol. The solven: was removed in vacuc and the, residue was purified by column chromatography on silica gel using 1% of methanol n dchloromethane to~giv~e 21mg of th.e title compound as a white solid.

'H NMR (00013) 12: 8.4 (s, 1K). 8.0 (S broad, 1K). 7.40-7.00 (in, 15K), 545 (5, 2K), 4.80 (s, 4K), 3.7~s, 3K).

LRMS (ES") mlz 479 [MHf~

Precaration 141

1 -benzvl-4-dibenzvlamino-2-oxo-2.3-dihydro-1 H-imidazoF4~5.C1ovridin e-7-carbox\'lic acid

cvclopro~vlmethvl-am ide

1 -benzyl-4-dibenzylamino-2-oxo-2,3-dihydro-1l K-imidazo[4,5,cjpyridine-7-carboxylic acid methyl ester (50mg, 0.1 mmcl) was suspended in 2mL of (aminornehtyl) cyclopropane and the mixture was stirre&at 1200C overnight. The excess of amine was removed in vacuo and the gum was partitioned in water (2OmL) and ethyl acetate (5OmL), the organic layer was isolated, dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 5% M methanol in dichioromethane to give 10mg of the title compound as a yellow gum.

LAMS (ES4) ni/z 518 IMH~

Preperation-142
6-Chloro-2,4-dihvdroxv-5-methvi-nvridine

Malonyl dichioride (log, 7lmmol) and propionitrile (12mL4 were combined and stirred at room temperature for 16h under a nitrogen atmosphere. To the resulting heterogenous mixture was added 5OmL dioxan, and the resulting precipitate was collected by filtration and washed with cold dioxan. The collected solid was dissolved in a few mL's of methanol and precipitated once more with dioxan. The solid was collected by filtration, washed with dioxan and dried in vacuo to give the title compound as a white solid (6g, 53%).

LAMS: (ES4) m/z 160 JMKIj4.

Preoaration 143

6-Chloro-2.4-dihvdroxy-5-methvl-3-nitro-~yridine

6-Chloro-2,4-dihydroxy-5-methyl-pyridine (500mg, 3.1 mmol) was taken up in acetic acid (lmL), cooled ito

0~C and nitric acid added (4mL) dropwise with stirring. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to room temperature over 16h. Ice was added jto

the tixture to provide a precipitate, which was collected by filtrahort and tied la vacua to give the title compound as a yellow solid (180mg, 28%).

LRMS: (ES+) m/z 205 [MI-l)±

Prenaratiori 144

Diohenvi mejonate

MaLonic acid (1 ig, t06mmol) was mixed with phenol (20g. 2l2mmol) at 0~C under nitrogen and phosphorus oxychlcride (11 .SmL, l23mmol) was added drop'uise to the solid mixture. The resulting mixture was stirred at 000 for Smins, and then heated at reflux for 5h, causing the solid to melt and an orange solution to form. The reaction was ocoled to room temperature, and Then poured onto IOOinL water and extracted with diethyl ether (3x 75mL). The combined organics were washed with brine, dried over MgSO4, concentrated in vacuo to an orange oil of the title compound. (27g. 99%).

'HNMR (CDCl~, 400MHz) 3.86 (s, 2K), 7.17 (in, 41-F), 7.27 (m, 2H), 7.41 (in, 4K). LRMS (ES) m/z 257 [MH]+

Precaration 145
Cvclopentanone-tert-butvl mine

Cyolopentanone (13.Srnt., ISOinmol) and tert-butylainine (47.4rnL, 4SOininol) were combined in llOinL diethyl ether under a nitrogen atmosphere and were then cooled to ~55~C in a dry ice/acetonitrile bath. Titanium tetrachloride (8.2mL, 7Sminol) was taken up in 7OinL pentane and added dropwise to the above solution, being careful to maintain the temperature at —40CC. the reaction was then stirred at —40CC for Oh and was then allowed to warm to room temperature overnight. The reaction mixture was filtered throUgh a short plug of celite and washed with diethyl ether. The filtrate was evapor&led in vacuo to yield 1 5.9g (76%) of the title product as a clear oil.

'1-INMA (COOS, 400MHz) 1.26 (s, 9K), 1.67 (in, 28), 1.82 (in, 2K), 2.29 (t, 2K), 2.36 (t, 2K).

Preparation 146
6.7-Dihvdro-51-l-[1 Invridine-2.4-diol

Cyclopentanone-tert-butyl imine (2.78g, 2OmmoI) and diphenyl malonate (5.12g. 2Oinmol) were combined in 4QmL triglyme and heated at 1000 for 4h, and then at 2000 far 2h. The reaction was Then allowed to cool to room temperature before pouring into 200mL diethyl eTher and storing in the freezer in a sealed flask for 4days. The resulting precipitate was filtered, washed with diethyl ether and dried in vacuo to yield the title compound (1 .45g, 50%) as a light brown soLid.

'KNMR (CD3OD, 400MHz) 2.12 (in, 2K), 2.70 (t. 2K), 2.82 (t, 28), 5.64 (s. 1K).

Preparation 147

5,6-Dimethvl-ovridin-2.4-dol

5,6-lJimethvl-4-hydroxy-2-oxo-2H-pyran ~J ~hem. Soc Ferlin Trans 1, 1930, 227Z~ (1 0g. Ylmmol) was dissolved in SGmL of dioxan and 33mL of 0.83 NK~ sotutiori and the mtxture ref luxed for Sb. The resulting suspension was then allowed to cool to room temperature overnight, filtered and the solid collected and dried in vacuo to provide the title compound as a white ciystalline sofid (6.Sg). The filtrate was concentrated to approximately lOmL in vacuo, and a second crop of solid collected by filtration (1.Og). Both crops were combined and used in the ne~d synthetic step.
1j~~ NMR (DM50, 400MHZ): 6 1.77 (s, 3K), 2.06 (s, 3K)', 5,42 (s, 1K). LRMS in/a (AFCI4') 140 [MH]+.

Preparation 148

5,6-Dim ethvl-3-n 'tin -pvridin-2,4-diol

5,6-Dimethyi-pyridin-2,4-diol (6.5g. 47mmol) was stirred in 3OmL sulphuric acid and then cooled to 000 in an ice bath. Fuming nitric acid (lOmL) was added drcpwise, and the mixture allowed to stir for lh after complete addition. The reaction mixture was poured onto crushed ice and the resulting yellow solid collected by filtration to give the title compound (3.Qg, 46%).

'K NMfl (MeOD, 400MHZ): 52.04 (s, 31-1), 2.31 (s, 3K).
LRMS m/z (APCl~) 185 [MKf.

Preoaration 149

2,4-Dichloro-S.6-Dim ethvl-3-nitro-pvridine

5,6-Dimethyl-3-nitro-pyridin-2,4-diol (3.9g. 21mmol) was dissolved in acetonitrile (l5OmL) and firstly tetraethylammonium chloride (7.lg, 42mmol) and then phosphorus oxychloride {19.9mL, 2iOinmol) were added and the whole heated at 700 for 16h. The reaction mixture was poured into crushed ice and extracted with DOM (2x3OmL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a brown solid. This solid was taken up in 2mL DOM and filtered through a short plug of silica gel eluting with 2:1 pentane:EtOAc. The filtrate was then evaporated to afford the title compound as a light brown solid (3.59, 75%).

'K NMR (00013, 400MHz): 62.61 (s, 3K), 2.41 (s, 3H)

Preoaration 150

Benzvl-(2-chloro-5,6.dimethvl-3-nitro-pvridin-4-vl)-amine

2,4-Dichloro-5,6-Dimethyl-3-nitro-pyridine (2g, 9mmol) was dissolved in acetonitrile (lOOmL) and benzylamine (1.OmL, 9.Smmol). Potassium carbonate (1.Sg, 9.Smmol) was added in one portion, and the whole was heated at 5500 for I6h. The reaction mixture was diluted with EtOAc and washed with 5OmL water. The aqueous was re-extracted with EtOAc, the organics were combined and then dried over

'MgSO4 and evaporated to a dark red residue. This resdue was purified by o&umn chromatography on silica ge! using 8:1 pentane:EIOAc as eluant ~c afford the title compound as a bright orange solid (1.2g.
45%).

1K NMR (CDCI3, 400MHz): 6 2.09 (s, SH), 2.47 (s, 3H), ti.254,27 (d, 2K), 4.52 (bell-tX 7.23-7.30 (in,

2K), 7.35-7.41 (in, 3K)

LRMS in/z (APOIt 292 [MIff.

Preparation 151

N2.N2-Diallvl-N4-benzvl-5,6-dimet'nv]-3-nitro-pvridine-2.4-diam inc

Benzyl-(2-chloro-5,6-dimethyl-3-nitro-pyridin-4-yl)-amine (1 .2g, 41 inniot) was disso]ved in ethoxyethanol (6OmL) and diisopropylethylamine (1 .ImL, 6.2mm ci) and diallylainine (0.7GinL, 6.2minol} added in one portion. The reaction mixture was heated in a sealed vessel at 10000 overnight, and then concentrated in vacuo to an orange residue. This residue was purified directly by column chrdmatography on silica gel, using a gradient of 8:1—*1:1 pentane:EtOAc as eluant to provide the title comipound as a bright orange oil (938mg, 65%).

'b-i NMR (CD%, 400MHz): 62.16 (s, 3K), 2.34 (s, 3K), 3.90-3.92 (ci, 41-f), 4.33-4.34 (d, 21-1), 5.13-5.21 (in, 41-1), 5.77-5.87 (in, 2K), 6.37-6.40 (bt, 1K), 7.35-7.28 (in, 5K).

LRMS ink (APOP') 353 [MHf

Precaration 152

N2.N2-DialIvl-N4-benzvl-5.6-dimetl-M-pvridina-2.3,4-triamine

N2,N2-lDiallyJ-N4-benzyl-5,6-dimethyl-3-nitro-pyridine-2,4-diamine (628mg, 2.4mmol} was dissolved in ethanol (l5mL) and 2N HOI (l5mL) and iron powder (527mg, 9.Smmol) was added in one portion. The reaction mixture was heated at 7000 for 2h, and then cooled to room temperature and poured into SGmL water. The resulting solution was neutralised with IN NaQH solution to give a dark green suspension, which was extracted with EtOAc (2x25mL) and the combined organics were dried over MgSO4, filtered and evaporated to give the title compound as a dark green oil (559mg, 74%).

'H NMR (CDCI3, 400MHz): 8 1.95 (a, 3K), 2.32 (s, 31-9,3.73-3.74 (ci, 41-I), 4.21 (s, 2K), 5.07-5.23 (in, 4K), 5,86-5.96 (in, 2K), 726-7.32 (in, 5K). LRMS m/z (APCI) 323 [MH]+

Prenaration 153

1-Benzvl-4-diallvlamino-6.7-dimethvl-1 ,3-dihydro-imidazor4,5-clpvridin-2-one

N2,N2-DiallyI-N4-benzyl-5,6-dimethyl-pyridine-2,3,4-triamine (559mg, 1.7rnmol) was taken up in acetonitrile (5OinL), and 1,1 -carbonyldilmidazole (2.8g, l7mmol) was added in one portion, and the whole refluxed for 2h. The reaction mixture was allowed to cool to room temperature, and was then

concentrated ~n vacric and purified directly by column chr~rnatograph':~ on silica gel using a gradient of 8:
-44:1 pentane:EtOAc as etuant to afford the title compound as a white soi& (258, 5~%).

'H NMR (ODd3, ~QMH~: ~ 2.12 (s, 3K), 2.34 (s, 3K:, 3.9~-4.01 (dt, 4K). 5.25-5.28 (in. 4K), 5.34-5.4( (d, 2K). 6.01-6.10 (in, 21-I), 7.11-'7.t3 (ci, 2H), 7.24-7.32 (in, 31-I). 7.66(bs, 1K). LRMS m/z (ESCl~) 34t

[MH]+

PREperation- 154

4-Methyl-3-oxo-pentanoio acid

Ethyl isobutyrylacetiC acid (21g, I32mmol) was taken up in a f.5M sodium hydroxide solution (15g ir 250mL water) and stirred at room temperature over ISh. The solution was cooled to 00C ~ an ice batf and was ~ien acidified with 35mL conc. Hydrochloric acid to pH 1-2. The resulting soiuUon was saturatec with sodium chloride and was then extracted with ethyl acetate (3x 300inL). The combined extracts were dried over sodium 5ullate and then filtered and concentrated in vacuo to give the title compound as ~ clear oil (16.4g. 95%).

1HNMR (CDCl~, 400MHZ, approx. 4:1 mixture of keto and eno! tautomers) 0(major keto form) 1.15-1.16 (ci, 6H), 2.75-2.71 (in IH), 3.56 (s, 2K).

Preparation 155

4-Kvdroxy-3-isobutvrvl-6-isopropvl-rpvran-2-ane

4-Methyl-3-oxo-pent~floiO acid (16.4g, l26mmol) was taken up in TKF (200mL) at room temperature

under a nitrogen atn~O5phere, and 1,1-carbonylduimidazole (22.4~, l3Smmo) was added in one portion. The reusiting yellow solution was stirred at room temperature for 16h, and then concentrated in vacuo and the residue diluted with 0CM (200mL). The solution was washed with 2N HOI (100mb) and water (lOOmL) and the aqueous was re-extracted with DCM (5OmL). The combined orgartics were dried over sodium sulfate arid were then concentrated it, vacuo to give the title compound as a yellow oil (11.7g, 80%).

1KNMR (COd3, 400MHZ) 01.16-1.18 (ci, 6K), 1.25-1.27 (d, 6K), 2.71-2.74 (in, 1K), 3.94..3.97 (in, 1K),
5.92 {s, 1K). LRMS (APCl+) mlz 225 IMKJ-iPreparation 156

4-Hvdroxv-6-isor,ropvl-pvran-2-one

4~Kydroxy~3~isobuty(Y3-6-i5OPropYl-pyran-2-one (11 .7g, S2mmol) was taken up in conc. Sulfuric acid (4OmL) and stirred ~t 130~G for ISm ins. The dark oil obtained was left to cool to room temperature and was then cooled further to 0~C in an ice bath before the addition of 200mL crushed ice with stirring. The resulting solution was extracted with ethyl acetate (3x200mL) and the combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to a light brown oil that was purified by column

chromatography usir~ a gradient of pentane in ethyl acetate ~3:1 —* 30:70 as eluant to provide the title compound as a light brown oil which solidified on standing (6.Ig, 77%).

'KNMR (CDCl~, 400MHz) 0 1.20-1.22 (d, 6K, 2.70-2.30 (in, 1H), 5.58 {s, 18), 5.99 (5, 18). LRMS (APCh) m/z 155 ~MI-lJ+

Preperation 157

Ethvl-2.4-diam!nobenzv~-6-methvl-3-carboxvlate

Ethyl-2,4-dichloro-6-methy~-3-carboxy1ate (100 mg, 0.43 rnmol) was di~soived in acetonitrile (2 ml) and treated firstly w~th triethytamine (240 01, 1.70 mmol) and then with benzylamine (112 01, 1.02 mmol) and the reaction mixture stirred at 40 0C for 18 hours undernitrogen. After cooling to room temperature, the reaction was poured into water and the mixture extracted with ethyl acetate (3 x 5 ml). Combined organics were dried (MgSO4, and evaporated to give a crude oil that was purified by column chromatography on silica eel, eluting with pentane : ethyl acetate, 20:1 toS: 1. The title compound was obtained as a clear oil, (98 mg, 61%).
'8-NMR (COOl3, 400MHz): l~J 1.21 (t, 38), 2.25 (s, 31-1), 4.29 (q, 2H), 4.40, (d, 2K), 4.78, (d, 2K), 5.81 (5, 28), 7.21-7.42 (in, 108), 8.10 (brs, 1K), 8.30 (bra, 1 K). L~MS rn~z (ESI) 376 [MHV

Preparation 158

2,4-Diaminobenzvl-6-methvl-3-carboxvlic acid

Ethyl-2,4-diaminobenzyl-6-methyl-3-carboxylate (40mg, 0.11 mind) was dissolved in methanol (1 ml)

and treated with. a 2N solution of sodium hydroxide (60 01, 0.12 minol) and the reaction mixture stirred at 6500 for 5 hours under nitrogen. After cooling to room temperature, the Teaction was poured into water, the p1-I adjusted to 6-7 using 2N hydrochloric acid, and the mixture extracted with ethyl acetate (3 x 5 ml). Combined organics were dried (MgSO4), and evaporated to provide the title compound as an oft-white solid, (37 ing, quant).
1H-NMR (DMSO, 400MHz): 1112.22(5, 3K), 4.59, (d, 2K), 4.64, (d, 2K), 6.20 (5, 2K), 7.20-7.39 (in, 10K). LRMS m/z (ESI) 348 (MH1~, 346 fM-Ky

Prenaration 159
6-Benzvlamino-9-benzvl-2-methvl-8-oxo-8,9-dihvdro-7H-ourine and 4-Benzvlam ino-9-benzyl-6-methyl-8-
oxo-8.9-dihvdro-7H-purine

(Formula Rmeoved)

2,4-Diaminobenzyl-6-methyl-3-carboxyhc acid (30 rng 0.09 mmoU, d~pt~ertylphosphoryl az~de (25 mg.
0.09 in~ol) and triethylamine (14 01, 010 nimol) were combined in [duane and the reaction heated at

111 ~C for 16 hours under nitrogen. After cooling to room :emperature, The reaction was poured into water and the mixture extracted with etnyl acetate (3 x 5 ml). Combineu organics were dried {M~SO4~, o give a crude oil that was purified by column chromatography on silica gel. eiu~ting with perttanc-. eth~tl acetate~ 1 :1, providing the separate title compounds both as clear oils, (10 rile (1). 11 mg~ll),68% combined yield).

(ESI) 354 fMK1~; (II) p2.39 (5, 3K), 4.39, (d, 2K), 5.01, (s, 28), 6.19 (5. 28), 7.15-7.39 (in, lOi-l). LRMS in/z (ESI) 354 ~MH)~

Preparation1 60
1 -Benzyl-2-bromo-f K-in idazole-5-iodo-4-carbonitrile

5-Amino-i -berrzyl-2-bromo-1 I-I-imidazole-4-carbonitriie (50 rrtg, 0.18 mrnol) was dissolved in dilodomethane (11 ml) and the mixture heated to 100 00. Isoamyl nitrite (97 01, 0.72 inmol) was then added dropwise via syringe to the heated reaction mixture. Gas evolution was observed. Following 30 minutes the reaction was allowed to cool to room temperature and solvents were removed under high vacuum. The remaining crude red residue was purified by column chromatography over silica gel elutinQ with 100% pentane to 7 :3 pentane : ethyl acetate. This provided the title compound as a ye how oil (40 mg, 60%).

I
8-NMR (ODds, 400MHz): [I 5.22 (5, 2H), 6.71 (s, 28), 7.09 (in, 2K), 7.26-7.40 (in, al-I). LRMS m12
388/390 tMH]~

Precaration161
1 -Benzvl-2-bromo-5-f4-hvdroxvbut-1 -vne)-1 8-in idazo!e-4-carboonitrite (I) and 2-(4~Am ino-1-benzvl~2-
bromo-1 H-imidazor4.5-c~gsyridin-6-vl)-ethanol (I Pi

1-Benzyl-2-bromo-IH-imidazole-5-iodo-4-carbonitrile (39 mg, 0.1 mrriol) was dissolved in acetonitrile~(1 ml) and the mixture treated with triethylamine (20 0!, 0.15 mino!), Pd(PhCN)2C12 (3.8 mg, 0.01 minol), and but-1-yn-4-ol (9 01, 0.12 minol). The reaction was then heated in a sealed tube at 100 ~'C for2 hou~sWfhe reaction was allowed to cool to room temperature and solvents were removed under vacuum. A 7N solution of arnin onia in methanol was then added to the remaining crude brown residue and the reaction heated in a sealed tube at 120 0C for 18 hours. Volatile components were then removed under vacuum providing a crude brown oil. LRMS of this material showed that the major component was the cyclised material (II), rn/z (ES!) 347/349 [MH]+. This oil was then purified by column chromatography over silica gel eluting with 10% pentane in ethyl acetate, providing the title compound (I) as a yellow oil (6 mg Compound (11) was not recovered from the silica g~l column.
1K-NMR (00013, 400MHz): (1) ~112.75 (t, 2H), 3.71~ ~l. 2iA~, ~5.2 (s, 2H), 7.18 {n~, 2H). 7.22-7.33 (in, 3K).
LRMS rnlz (ESI) 330/332 [MH]+

I -~enzvl-5j-but-4-hydroxv-2-~eto-1 -yi~-i Wmkiazole-2-m c-Thox~4-carbonftrif a 1-'Benzyl-2-bTomo-5-(4-hydroxybut~1-yne)-il-i-imidazcle..4.ca~:bartA~riie (~3 mg~ 0.02 mrnol) was d;ssorved in methanol (1 ml) and the mixture treated with sodkirn rnefhoxide (if .mg, xs). The recodon was then heated at 65 0C for 12 hours. the reaction was allowed to cool to room temperature and solvenis were rernov'ed under vacuum. A 2N solution of hydrochloric acid was then added to the remaining crude residue and the reaction stirred at room temperature for 2 hours. Vo~a~iIe components were then removed under vacuum providing a crude white solid containing mostly the title compound,

LRMS mlz (ESI) 300 [MH]+.

Preoaration 163
2.6-Dichloro-4-(N-nitro'iamino~ovridine

2,6-Dich[oro-4-amino pyridine (1.589) was taken up hi sulluric acid ~20mL~ at O~C under a nitrogen atmosphere and nitric acid (2.5mL) added dropwise. After 30mins, the reaction turned to an orange colour and was poured slowly into ice water. The precipitate was filtered, washed with water and then dissolved in eThyl acetate. The organic solution was then dried over MgSO4, filtered and evaporated in vacuo to give the title compound (1 .7g) as a yellow solid.

1j] NMR (COd3, 400MHZ) 5 7.40 (s, 28), 10.4 (s, li-I).

Preparation 164
2,6-Dich[oro-4-amino-&-n~tro-pyridine

2,6-Dlchloro-4-(N-nitro)ainino-pyridine (1.7g) Was taken up in sulfuric acid {lOmL) and heated at 9000 for
3Dm ins. The readion mixture was cooled to room temperature, then poured into ice water to produce a precipitate. The yellow solid was filtered off, c~lected, dissolved in ethyl acetate and then washed with an aqueous Na2CQ3 solution. The organics were then further washed with brine, then dried over,MgSO4, filtered and evaporated in vacuo to give the title compound (lA5g) as a yellow solid.

'H NMR (COd3, 400MHZ) IJ 6.70 (s,28), 6.70 (s, 1K). LRMS (ES+) m,~209 IMH]+

Preparation 165
2,6-Oibromo-4-amino-s-nitro-pvridine

2,6-Drchloro.4-amino-5-nrtro-pyndine (2g~ Was taken up ~ri a 33% solution of HIBr in acetic ac~i (2OrnL) and heated at ~0~C in a Teflon-lined bomb for 72ii. The reacton mixture was cooled to room terriperacure, poured into ice water to produce a precipitate. The resuifng sc'id was filtered off, co2lected, .dissolv~d in ethyl acetate end then washed with an aqueous K~C0~ solufon. The organics were then further washed wrth brine, then dr:ed over MgSC~, filtercd and evaporated ~n vacuo to give the t~tle compound (2g) as a pale yellow solid.

'I-I NMR (CDCl~, 400['AKz~ 0 5.60 (S. 21-1), 6.90 (s, tt-~. LRMS (ES+) ni/z 295, 297, 299 ~e~wi~-,Preoararion166
2.6-Dibromo-4-chloro-5-nitro-pvridine

2,6-Oibromo-4-amino-5-nitro-pyridine (3g) was taken up in concentrated hydrochloric acid (2OmL) and cooled to 00C. Sodium nitrite (3.5g) was added and the reaction mixture was allowed to stir at O~C for lh. The ice bath was removed and the reaction allowed to warm to room temperature over 3h, and was then quenched by the addition of ethyl acetate (5OmL) and water (lOOmL). The organic layer was separated, dried over MgSO4 and filtered and evaporated in vacue to a pale yellow oil, which was purified by column chromatography using 35:1 pentane:EtOAc as eluant to give the title compound (2.2g) as a white solid.

~H NMR (COOl3, 400MHz) 0 7.65 (s, 18).

Preparation 167
N-2,N-4-Oibenzyl-6-bromo-3-nitro-pvridine-2,4-diam me

2,6-Dibromo-4-an~ino-5-nitro-pyridine (1 .53g~ Was taken up in THF (2OmLY and firstly solid K2C03 (100mg) and then benzylamine (1.lmL) were added in one portion each. The reaction mixture was then heated at 7000 for 1 6h. The solvent was removed in vaouo, and the crude residue was purified by column chromatography on silica gel using 10% ethyl acetate in pentane as the eluant to give the title compound (1 .2g) as a yellow oil.

'I-I NMR (COCl~, 400MHz) El 4.46 (d, 2H), 4.78 (d, 21-i), 6.20 (s, 1K), 7.20-7.41 (in, 108), 9.41 (s, 1K),

9.50 (s, 18). LRMS (ES+) m/z 413, 415 [MKIl+

Preparation 168
4,6-Bis-benzvlam ino-5-nitro-pvridine-2-carboxvli acid methyl ester

N-2,N-4-Dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamine (Ig) Was taken up in a mixture of methanol and DMF (2:1, I5mL), and firstly triethylamine (0.7mL), then triphenyiphosphine (30mg). and finally palladium acetate (27mg) was added and the mixture was heated at 6000 and I Oopsi carbon monoxide pressure for

1 6h. The react~on mixture was cooled to rc~m Temperature. fihered thn~Jgt' a short plug of kbooel and evaporated in vacuo to give a yellow residue. This residue was pLrit~ed by column chromatography on silica gel using a gradient of 8:I--~ 2:1 pentane in ethyl acetate as the e~uant to give the ~ttle compound (0.5g~ as a pale yellow solid.

1H NMR (CDCl~. 400fQlHz) El 3.91 (s, 2K), 4.58 (s, 1H), 4.85 (d, 2I-~), 6.85 (s, 1H), 7.05-7.25 (in, lOU), 9.3 (f, 1K), 9.65 (t, 1K). LRMS (ES+) m/z 393 [MKI±

Preparation t69
5-Amino-4,6-benzylam ino-ovridin-2-carboxvlic acd maThyi ester

4,6-Bis-benzyiamino-5-nitro-pyridine-2-carboxyli acid methyl ester (800mg) Was taken up in methanol (3OmL), and Raney nickel (80mg) was added in one portion and the mixture was stirred at room temperature for 3h under 6opsi hydrogen pressure. The reaction mixture was filtered through a short plug of Arbocel and the filtrate was evaporated in vacuo to give a yellow residue of the fitle compound (0.75g) which was used with no further purification.

LFIMS (ES+) m/z 363 (MHJ+

Preparation 170

1-Benzvl-4-benzvlamino-2-oxo-2.3-dihvdro-1 K-imidazof4.5-c~pvridine-6-carboxvlic acid methyl ester

5-Amino-4,6-l3enzylamino-pyridin-2-carboxylic acid methyl ester (0.75g) Was taken up in acetonitrile
(4OmL), and 1,1-carbonyldilmidazole (500mg) added in one portion and the mixture heated at 8000 for
6h. The reaction mixture was evaporated in vacuo to give a residue whiich was purified by column
chromatography on siflca gel using 1:1 pentane in elhyl acetate as the eluant to give the title compound
(1 00mg) as a white solid.

'K NMR (d6-OMSO, 400MHz) El 3.75 (s, 3K), 4.45 (d, 2K), 4.98 (s, 2H), 6.48 (t, 1K), 7.18. Cs, 1K), 7.22-
7.47 (in, 10K). LFIMS (ES.r-) mIx 389 IMH)+

Preisaration 171
I -Benzvl-4-benzvlamino-2-oxo-2.3-dihvdrof4,5-cTrrvridine-6-carboxvlic acid

1 -Benzyl-4-benzylainino-2-oxo-2,3-dihydro-1 H-in idazot4,5-clpyridine-6-carboxylic acid methyl ester
(0.03g) Was taken up in methanol (lmL), and iN NaCH solution (2mL) and the mixture was stirred at
400. After 2h, 2mL of 2N HOl was added, which caused a solid to precipitate out. This solid was filtered

off and dried in vacuo to give the title compound (25mg) as a white solid.

1H NMR (CDCl3, 400MHz) El 4.30 (a, 2H) 4.90 (a, 2K), 7 '~0-T35 (in, Vt H), 10,80 (s, 1H). LRMS (ES+)

m!z 375 ~tAH]~

Precaration 172
I -~enzvl-4-benzylainino-2-oxo-2,3-'jih~dro-I H-irridazo~4~5. &fovridine-6-carbo~vlic acid
cycloorooylrnethvlam ide

I -Benzyl-4-benzyiamfno-2-oxo-2,3-dihydro-1 N-irnidazo~4,5-C1pyridine-6-carboxylic acid methyl ester (0.05g) Was taken up in cyclopropylinethylarnine (1 mL) and heated in a ReactiVial at 8000 for 3h. The solvent was removed in vacuo and diethyl ether was added wh~ch caused a solid to precipitate out. This sofld was filtered off and dried in vacuo to give 40mg of a white solid. This solid was purified by preparative KPLC using mixtures of acetonitrile, water and die~.hylamine as the eluant to give the title compound as a white solid (18mg).

'K NMR (CDCl~, 400MHz) El 0.22 (q, 21-1), 0.55 (q, 2K), 1.05 (in, Il-I), 3.22 (t, 28), 4.35 (d, 2K), 4.90 (s, 2K), 5.90 (t, 1K), 710-7.35 (in, ilK), 7.85 (t, 18). LRMS (ES÷) m/z 428 {MH]~±

Precarafon 173

4-Bromo-2-chloro-6-irifluoromethvl-pvridini-3-vlain me

6-Thfluoromethyl-pyridin-3-ylamine (150g. 92Sininol) was suspended in 500m1 acetonitrile. Added to the solution was N-Chlorosuccinimide (l24~, 925inmo1) and the mixture heated at 8000 for 2h after which Nbromosuccinimide (165g, 925mmo1) was added and the mixture heated at 8000 for a further 3h. The ~ was cooled to ambient temperature, concentrated in ~iacuo and triturated in lOOmI diethyl ether, removing the precipitate by fiJtration. The resulting filtrate was concentrated in vacuo and purified by column chromatography on silica, eluting with Hept:EtQAc, 4:1 to give the title compound as a dark red oil (220g.
88%).

'H NMR (CDCl~) El 4.90 (bs, 2H), 7.67(s, il-I); LRMS (ES) m/z 275/277 [MH]÷

Preparation 174

N*4*.Benzvl~2~chloro.6.trifluoromethvl.pvridine.3.4~diamine

4-Bromo-2-chloro-6-trifluoroinethyl-pyridin-3-ylamine (84g. 300mmol) was stirred in 50Dm I DM50 in the presence of ceesium fluoride (46.3g, 3O5mmol) and benzyiarnine (66.6m(, SlOmmol). The resulting brown suspension was heated at 15000 for 16h. Added to the cooled suspension was iSOOinI water and the mixture extracted with 2 x SOOmI diethyl ether. The combined organic extracts were dried (MgSO4), concentrated in vacua and purified by column chromatography on silica, eluting with Kept:EtOAo, 4:1 to

2:1 to give the title compound (15.8g, 17%) as a pale bro~'n solid. The undesired isomer was similarly isolated as a brown oil (5i.Og, 48%).

~l-1 NMR (COCI3) 5 3.75(bs, 2K), 4.39-2..4t(d. 2K), 453(bs. 1K), 5.85(s, il-I), 7.34-7.40(m, 5H); LAMS (ES) rn/z 302 [MH]+.

Prenaration 175

4,6-dihvdroxv-2-trifluoromethvl-nicotinio acid ethyl ester

In a three necked flask, potassium tert-butoxide (5.8g. 51 .9mmol) was suspended in lOOmL of tetrahydrofuran and a solution of diethyl-1 ,3-acetonedicarboxylate (lOg, 49.Smmol) in 3OmL of tetrahydrofuran was slowly added. Once the addition was complete, the mixture was stirred at room temperature for 30 minutes. In a second three necked flask set up with a gas outlet linked to the first three necked flask, 2,2,2-Irifluoroacetainide (l1.2g, 98.9inmol) was dissolved in 8OmL of pyridine and a premixed solution of trifluoroacetic anhydride (20.8g, 98.9mmol) in 3OinL of pyridine was added slowly, the gas formed (2,2,2-trifluoroinethylacetonitrile) was directly bubbled through the first three necked flask. Once the addition was complete, the mixture in the second three necked flask was stirred at room temperature for 30 minutes then the solvent was removed in vacuo and the residue was poured into lOOmL of a 4M HOl. The mixture was extracted with l5OmL of ethyl acetate. The organic layer was isolated, dried over magnesium sulfate and the solvent was removed' in vacuo. The residue was tritur~ted in dichloromethane and the precipitate was filtered to give 3g of the title compound as a solid.
NMR (MeOD): 12.5 (s. 1K), 12.4 (s broad, 1K), 7.1 (s, 11-1), 5.05 (q, 2H), 2.05 (t, 3K).

LRMS (ES~) in/z 252 [MH]+

Pre~a ration 176

4,6-dihvdroxv-5-nitro-2-trifluoromethvl-nicotinio acid ethyl ester

4,6-dihydroxy-2-trilluoromethyl-nicotinic acid ethyl ester (ig, 3.9mm ol) was dissolved in 1 Om L of concentrated sulfuric acid and 2inL of fuming nitric acid was added dropwise at room temperature. Once
lf the addition was complete, the mixture was stirred at room teinperalure for 30 minutes. The inixture~tas
then poured into crushed ice and the white precipitate was collected, dissolved in 5OmL of ethyl acetate, washed with 5OmL of water and 5OmL of brine, dried over magnesium sulfate and the solvent was removed in vacuoto give 1.lg of the title compound as a white solid.

'H NMR (d6 DMSO) : 4.25 (q, 2K), 1.20 (t, 3K).

Preparation 177

6-trifluoroinethvl-pvridine-2.4-diol

4,6-dihydroxy-2-trifluoromethyl-nmcotinic acid ethyl ester ij5g 59.7minol~ was dissolved Tn 2~OmL of

concentrated HC~ and the mixture was stirred at 115'D0 for 3 days. The mixture was cooled down to 000 and 0.88 ammonia was added until pH 7, The solid formed was (iterec.. washed with water. azeotroped with toluene and dried 1 vacuo to give 9g of the tile conpoun~ as a white sol~d

'H NMR @6 DMSO) : 6.7 fs, 1K), 6.1 (s, 1K)

LRMS (ES~) nifz 180 [MH]4

Pre~aration 178

(2-Am in o-3-nitro-6-vinyl-oyridin-4-vi'j-(6-m ethvl-~widin-3-vlme~hvfl-carbani ic acid ethyl ester

(2-Am ino-6-chioro-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl es~er (71 5mgs I
1.95Smmols), potassium vinyltrifluoroborate (4~5mgs / ao98mrnots), [1,1w-
Bis~dipheny1phosphino)ferrocene]dichloropalladium (I l).CK2CI2 ~9Qm gs / 0.1 1 romols) and triethylam me
(0.2Smls 1 2.Ommols) were combined in iPrOK (aomls) and heated at 5000 under N2 for 24hrs.
Preadsorbed directly onto silica and purified by column chromatography to give title compound .(27Omgs)
as a purple resin

'K NMR (CD300, 400MHz) El 1.15-1.20 (mult, 31-i), 2.50 (s, 3K), 4.05-4.15 (mult, 21-1), 4.90-4.95 (mult, 2K), 5.60 (d, 1K), 6.20-6.30 (mult, 1K); 6.55-665 (mull, 2K), 7.20-7.25 (ci! 1K), 7.70 (mutt / 1K). 8.35 (s!
1H); LRMS (ES) ink 358 [MHJ+.

Prepairation 179
(2-Am ino-6-forrnvl-3-nitro-Dvridin-4-vl)-(6-methvl-Dvridin-3-vlm eThyl~-carbam ic acid ethyl ester (2-Amino-3-nitro-6-vinyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylrnethyl)-carbamic acid ethyl ester (27Omgs / 0.7SSmmols) was dissolved in acetone (Sm Is) I water (Smis) and osmium tetroxide (2.5%wt in tBuOH) (0.lOmls I 0.OOBmmols) was added. Stirred for 5mins to give brown solution then added sodium metaperiodate (500mgs / 3.47mmols).Orange suspension stirred for ihour. Partitioned between EtOAc (lOOmIs) and sodium thiosuifate pentahydrate (20%wt in K20) (5Omls). Organic collected, washed with brine, dried over Na2SO4, filtered and concentrated to a brown resin. Purification by co[umn chromatography eluting with EtOAc gave the title compound (22Omgs) as a yellow oil.

'H NMR (CDCI3, 400MHz) El 1.15-1.20 (mult, 3H), 2.55 (s, 3K), 4.10-4.20 (mult, 2K), 4.95 (5, 2H), 6.06-6.15 (brs, 2K), 7.05 (s, 1H);7.10-7.15 (d, lI-f), 7.60 (df 1K), 8.35-8.40 (sflK), 9.75(5/1H); LRMS(AP) m/z 360 LMH]4.

Preparation 180

(2-Amino-3-nitro-6-oxazol-5-vl-pvridin-4-vl)-(6-methvl-pvridin-3-vlmethvfl-carbam ic acid ethyl ester
acid etn~i es.er (i 90mgs I 0.S29inmois) was dissolved in MeCM-i (Smis). Added (4-tcly~sulphonyi)rnethylisocyanide (1 24mgs /
0.634mmois) followed by anhydious potassium carbonate ~200mgs 1A5nm~ols). Stirred under N~ for lhr then concentrated in vacuo. Parttioned between EtOAc (tQOrnls) and H20 {SOmls}. Organic collected, washed with brine. dii&d over Na2SO4, filtered and cor~ceritrated ~o a biacit resir~. 'Purif,oaV~on by column chromatography eluting with 90:10 DCM/MeOH gave the title compound (1 35rngsy as a crud" brown solid.

LRMS (ES) m/z 399 (MH44.

Bio)o~ical data
The abifity ol the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and polymorphs to modulate TLR7 receptor activity is demonstrated by a 'Pi3IJKCV rep icon bioassay as detailed below, in which the following abbreviations may be used:
EMCV: Encephalomyocarditis virus
IRES: Internal ribosmomal entry site
Huh: Huh-? human hepatoma cell line 7 (parental cells used to generate KCV replicon cell lines) luc: luciferase
ubi: ubiquitin
nee: neomycin
ET: glutarnic acid, threonine (cell culture adaptive mutations in the replicon used in the assay) RPMI-FCS: Roswell Park Memorial Institute (cell culture medium for PBL) - Foetal Calf Serum PBL: peripheral blood lymphocytes

POL contain as a subpopulation plasmacytoid dendritic cells which are the natural interferon producing cells during an infection and as such are an excellent model in which to profile interferon inducers. As an extremly sensitive antiviral bioassay, supematant taken from PBL is assayed for antivira! activity in the 4-ICV rephcon system. ArmtMral EC5O values are defined as the concentration of a test compound applied to PBL that results in a 50% reduction of HCV replicon [evels on transfer of a defined amount of PBL cullure medium to a KCV replicon containing cell line. A[though KCV replicon containing cells are fully responsive to PBL conditioned medium they do not respond directly to known TLR agonists such as Resiquimod and ~miquimod.

The HCV replicon (Huh-5-2[1389luc-ubi-neo-NS3-3'/ET]) is an in vitro model of HCV replication in which the luciferase reporter is incorporated into HCV sequences and stably maintained in the human hepatoina cell line Kuh-7. The firelly luciferase reporter is expressed as a luciferase-ubiquitin-neomycin phosphotransferase fusion protein which is cleaved by host proteases to release luciferase. The replicon also contains an internal EMCV IRES, which drives translation of HCV N53-5B polyprotein, which harbour cell culture adapted mutations to permit high cloning efficiency. The luciferase output has been

shown to be directly proportional to the level of I-ICy RNA present in the host cell. Firefly luciferase activity is detected using a Bright~GloTM Luciferase Assay System manufactured by Proinega.

Typically. 1 — 3 mg of test compound is dissolved in 1 00%(v/v} DM50 to a final concentration of usually 1, 4 or 10 mM, or higher depending on the starting concentration required in time assay. An initial 3 fold serial dilution series of compounds in 100% DM50 is prepared from stocks. The dilution series is then further diluted 100 fold with complete RPMI — ECS. The final concentration of DMSO In the assay is thus 0.1% and that of the test compound is 1/1 000 in the 100% DMSO dilution series.
PBL are prepared seeded at 5x105 /wellI9OlIl into the previously prepared compound containing assay plates (96 well clear bottomed TC grade) arid incubated for 24h.

LucUbiNee HCV replicon cells are seeded at ~ /well/SOi.il. These are incubated for 24h. After 24h, lOpI of medium is transferred from the PBL assay plates to time I-IGV replicon plates and incubated for a further 48h.
(Table Removed)

It is desirable that the compounds of the invention have selectivity for the TLR7 receptor over one or more other known Toll-like Receptors. It is also desirable that the compounds of the invention have selectivity for the TLR7 receptor over one or more cellular kineses and/or one or more pulinergic receptors such as adenosine or phosphodiesterase receptors.

Examples 1, 2, 12 and 15 were tested and found to be selective for the TLR7 receptor over all other known Toll-like Receptors.

In addition, Examples 1, 2, 12 and 15 were tested and found to be selective for the TLR7 receptor over the following targets: MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase), COKi (cyclin-dependent kinase-1), CDK2 (cyclin-dependent kinase-2) JNK (stress-activated protein kinase), MSK (mitogen and stress-activated protein kinase), MSK-1, SGK, AMPK, MLCK, CHK-2 and phosphodiesterase enzymes PDE3, PDE4 and POES.
In addition, Examples 12 and 15 were tested an~ round to be selective tar The TL~7 receptor over MAP (initogen-activated protein iinase).

Furthermore, Example 15 was tested and found to be selective for the TL~R7 receptor over all known adenosine receptors Al, A2a, A2b and A3.

WE CLAIM:
1. A compound of formula (!)
(Formula Removed)
or a pharmaceutically acceptable salt or solvate of said compound or tauiomer, wheTein
(a) Y is a direct bond, and R3 is selected from aryl, (C1-C6)a!kyl and -(C1-C4alkylene-O-tC1-C4alkyl; or
(b) Y is (C14)Elkylene, and R3 is selected from sryl, (C3-C7)cycloalkyl and a 3 to 10-membered
heterocycly!;
Z is an oxygen or is absent;
R1 is selected from H, halo, OH, CN, (C1-C6)alkyl, (C3-C7)cycloalkyf, ((C1-C6)alkoxy,
-NHS02R6, -NR6R7, -C(0)R6, -C02RB, -C(0)NReRT, -C(0)NR&S02R8, aryl and 3 to 10-membered
heterocyclyl;
R2 is selected from H, halo, OH, ((C1-C6)alkyl, (C3-C7)cycloalky], ((C1-C6)alkoxy, -NRBR7, -C02R6, -C(0)NRsR7, -C{0)NR6S02Rar and 3 to 10-membered heterocyclyl; or
R1 and R2 may be joined to form a (C2-C5)alkylene link, said link optionally incorporating 1 or 2 heteroatoms each independently selected from Nr O and S;
R5 is absent and R4 is selected from H, (C3-C7}cyctoalkyl, aryl, -(CH2aryl, -C(0)R9, -C02R9, -(C1-C6)alkylene-O-C(O)R9, -(C1-C6) alkylene-Q-COaR9), -C(0)NR9R1D, -(C1-C6)alkylene-O-C(O)NR8R1° and -(C1-C6)alkylene-O-P(O)(OH)2; or
R4 is absent and R5 is selected from R9, -C(0)R9, -C02R9, -(C1-C6)alkylene-O-C(O)R9, -(C1-C6)alky]ene-O-C02R9, -C(0)NR9R1D, -(C1-C6)alkylene-O-C(0)NR9R1D and -(C1-C6)alkylene-O-P(0)(0H)2;
R6 and R7 are each independently selected from H, (C1-C6)alkyl, (C3-C7)cycloalkyl, and -(C1-C6)alkylene{C3-C7)cycloalkyl; or R6 and R7 taken together with the nitrogen to which they are attached form a 3 to 6 membered saturated heterocycle optionally containing a further one or two heteroatoms selected from N, O and S;
R6 is selected from (C1-C6)alkyl, (C3-C7)cyclaalkyi and phenyl;
R9 and R10 are each independently selected from H, (C1-C6)alkyl, ((C1-C6)cycloalkyl, aryl,
-(CH2)aryl and 3 to 10-membered heterocyclyl; or Ra and R15, taken together with the nitrogen to which
they are attached', form a 3 to 10-membered heterocyclyl group;
R11 and R12 are independently selected from H and (C1-C6)aSkyl; or R11 and R12 together with the M to which they are attached form a 3 to 6 membered saturated heterocyclyl optionally containing a further one or two heteroatoms sefected from N, O and S;
said alkyl, cycloalkyi, alkoxy, aryl and heterocyclyl groups being optionally substituted by one or more atoms or groups independently selected from halo, OH, oxo, CF3, CN, ((C1-C6)Jalky), (C3-C7)cycloalkyl, (C1-C6)alkoxy, -(C1-C6)aSkylene-O-(C1-C6)alkyl, -(C1-C6)ar.kylene-0Hs -NR11R12, -(C1-C6)alkylene-NRi1R12, aryl and 3 to 10-membered heterocyclyl;
with the proviso thai when R1 and R2 are H, and Z and R5 are absent, then (a)R4 is not methyl when Y-R3 is ethyl; and (b)R* is not H or methyl when Y-R3 is methyl.
2. A compound according to claim 1 wherein R1 is sefected from
(a)H;
(b) CN;
(c) halo
(d ) (C1-C6)alkyl optionally substituted by one to three halo atoms;
(e) tetrahydrofuranoxy;
(f) (C1-C6)alkyI substituted by a 3 to 6 membered saturated heterocycyl containing 1 to 3 hetero atoms independently selected from N, O and S wherein said heterocyclyl is optionally substituted by one to three groups independently selected from CF31 (C1-C6)alkyl, (C1-C6)a!koxy and -{C1-C6)a[kytene-O-(C1-C6)alkyl; (g)(C1-C6)alkylene-(C1-C6)alkyl; {h)-(C1-C4)alkyJene-N(H)-(CrC4)alkylene-O-(C1-C4)a]kyl;
{i) (CrCB)alkoxy optionafly substituted by OH or cyctopropyl;
(j) (C3-C7)cycloa!kyl;
(k) -{C1-C4)alkylene(C3-C7)cycroalkyl;
(I) -C(0)NR°R7;
(m) -C0aR6;
(n}-C(0)R6;
{o) a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms
and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl
comprising 1 to 3 nitrogen atoms, said 5 and 6 membered aromatic rjeterocyo'yl being optionally
substituted fay one to three atoms or groups independently selected from halo, OH, CF3,(C1-C6)alkyl(C1-C6)
C6)alkoxy, -((C1-C6)alkyleneO-(C1-C6)alky, -(C1-C3)alky-OH r NR11R12 and -(C1-C6)alkylene-
NR11R12;
(p) phenyl optionally substituted by 1 to 3 halo atoms;
(q) -NR6R7;
(O-NH-(C1-C6)alkylene-O-(C1-C6)ealkyl;
wherein
R6, R\ Rt1 ami R12 are as defined in claim 1.
3. A compound according to claims 1 or 2 wherein R1 is selected from
(a)H;
(b)CN;
(c)halo
(d ) {C1-C6)a'kyl optionally substituted by one to three halo atoms;
(e) tetrahydrofuranoxy;
(f) (C1-C6}alkyl substftuted by morpholine, piperazine or pyrrolodine which are optionally substituted by one or two methyl groups;
{h) -(C1-C4)a1kylene-N(HHC1-C4)alkylene-O-(C1-C4)alkyl;
(i) (C1-C4)alkoxy optionally substituted by OH or cyclopropyl;
(J) (C3-C7)cyc!oafkyl;
(k)-(CR94)alkylene(C3-C7)cycloalky);
(!) -C(O)NR6R7;
{m) -CO2R6;
(n)-C(0)R6;
(o) a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ri) 1 to 2 nitrogen atoms
and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl
comprising 1 to 3 nitrogen atoms, said 5 and 6 membered aromatic heterocyclyl being optionally
substituted by one to three atoms or groups independently selected from halo,. OH, CF3, (C1-C6)alkyl, (d-
C6)alkoxyt (C1-C6alkylene-O-C1-C6alkyl, -(C1-C6)atkylene-OH , -NR1V2 and -(C1-C6alkylene-
NR11R12;
(p) phenyl optionally substituted by 1 to 3 halo atoms;
(q) -NR6R7;
(r) -NH-(C1-C4)al kylene-O-(C1-C6)alkyl;
wherein
R5, R7, R11 and R12 are as defined in claim 1.
4. A compound according to any one of the preceding claims wherein R1 is selected from methyl or
ethyl substituted by one to three fluoro atoms; cyciopropyS; -C1-C6alkylene-O-C1-C6 alkyl (C1-C4)alkoxy
optionally substituted by OH or cyclopropyl; -COCH3; -CH2OCH3; and -CO2CH3.
5. A compound according to any one of the preceding claims wherein the R1 is cyciopropyl or CF3.
6. A compound according to any of claims 1 to 3 wherein R1 is a 5 membered aromatic heterocyclyl comprising (i) 1 So 4 ni-rogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen cr sulphur atom, or (Hi) 1 oxygen or sulphur atom, said 5 membered aromatic heterocyclyl being optionairy substituted by one to three atoms or groups Independently selected from halo, CH, CF3, (C1C6)alkyl, (C1-C6)alkoxy, -{C1C3)akyIene-O-(C1-C4alkyl, -(C1-C4)alky!ens-OH -NR11R12 and -(C1-C3)alky!3ne-NR11R12, wherein R11 and R12 are as defined in claim 1.
7. A compound according to claim 6 wherein the R1 is selected from imadazolyl,. oxazolyl, oxadiazolyl, triazole, pyrazole and thiazole, alS of which are optionally substituted by by one to three atoms or groups independently selected from halo, OH, CF3, (C1-C6)alkyl, (C1-C6)aikoxyl -(C1-C6alkylene-O-C1-C6-alkyl, -(C1-C4)alkyiene-OH and -(C1-C6)alkylene-NR11R12, wherein R11 and R12 are as defined in claim 1.
8. A compound according to claim 7 wherein the R' is selected from unsubstituted oxazolyl, triazole, pyrazole and thiazole.
9. A compound according to claim 8 wherein the R1 is oxazolyl.
10. A compound according to any one of the preceding claims wherein R2 is selected from (a)H;

(b) halo
(c) (C1-C6)alkyl optionally substituted by one to three halo atoms;
(d) tetrahydrofuranoxy;
(e) (C1-C6)alkyl substituted by a 3 to 6 membered saturated heterocycyl containing 1 to 3 hetero atoms independently selected from N, O and S wherein said heterocyclyl is optionally substituted by one to three groups independently selected from CF3, (C1-C6)alkyi, (C1-C6)afkoxy and -(C1-C6)alky;ene-O-(C1-C6)alkyl;

(f) -(C1-C4)alkylene-O-(C1-C6)alkyl;
(g) -{C1-.C4)alkylene-N(H)-(C1-C4)alky[ene-O-(C1-C4)alky[; (h) (C1-C6}alkoxy optionally substituted by OH or cyciopropyl; (i) (C3-C7)cycbalkyl;
(j) -(CrC<,)aIkylene(C3-C7)cycloalkyl;
(k) -C(0)NR6R7;
(l}-CO2R6;
(m)-C(0)R5;
(n) a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms
and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl
comprising 1 to 3 nitrogen atoms, said 5 and 6 membered aromatic heterocyclyl being optionally
substituted by one to threeatoms or groups independently selected from halo, OH, CF3, (C1-C6)alkyl, (
C6)alkoxy -(C1-C6alkylene-O-(C1-C6)alkyl, -(C1-C6)a1kyiene-0H , -MR11R'2 and -(C1-C6)alkylene-
(o) phenyl optionally substituted by 1 to 3 halo atoms;
(p) -NR6R7;
(q) -NH-(C1-C4)alkylene-O-(C1-C6)alkyl;
wherein
R6, R7, R11 and R12 are as defined in claim 1.
11. A compound according to any one of the preceding claims wherein R2 is H or methyl.
12. A compound according to any one of the preceding claims wherein R2 is H.
13. A compound according to any one of the preceding claims wherein Z is absent.
14. A compound according to any one of the preceding claims wherein Y is methylene; and R3 is selected from aryl; a 5 membered aromatic heterocyclyl! comprising (i} 1 to 4 nitrogen atoms, or (ii) 1 to 2 nilrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; and a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms; said aryl and aromatic heterocycle being optionally substituted by one to three atoms oir groups independently selected from halo, OH, oxo, CF3, CN, (C1-C6)alkyl, (C3-C7)cyc]oalkyl, (C1-C6alkoxy, -(C1-C6)alkylene-O-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -NR11R12, -(C1-C6)alkylene-NR1tR1z aryl and 3 So 10-membered heterocyclyl,
wherein R11 and R1Z are as defined in claim 1.
15. A compound according to any one of the preceding claims wherein Y is methylene; and R3 is selected from phenyl, pyridyl, pyrimidyl, pyrfdizinyl and pyrazinyl each of which are optionally substituted by one to three atoms or groups independently selected from halo, (CH2lkyl, (C1-C4)alkoxy and CF3.
16. A compound according to any one of the preceding claims wherein Y is methylene; and R3 is selected from phenyi, pyridin-3-yl and 6-methyl-pyridin-3-yl.
17. A compound according to any one of the preceding claims wherein R5 is absent; and R4 is selected from -C1-C6alkylene-O-C(0)R9, -{C1-C6alkylene-O-COaR9,
-(C1-C6)alkylene-O-C(0)NR9R1D and -{C1-C6alkylene-O-P(O)OH)2, wherein R9 and R10 are as defined in claim 1.
18. A compound according to any one of the preceding claims wherein R4 is H and R5 is absent.
19. A compound according to any one of claims 1 to 16 wherein R is absent; and R5 is selected from -(C1-C6)alkylene-O-C(0)R9, -(C1-C6)alkylen e-O-CO2R9),
-(C1-C6)alkylene-O-C(0)NR9R'10 and -C1-C6alkylene-O-P(O)(OH)2, wherein R9 and R10are as defined in claim 1.
20. A compound according to claim 1 wherein
Y is methylene;
R1 is selected from CF3; cyclopropyl; and oxazofe;
R2isH;
R3 is selected from phenyl, pyridin-3-yl and 6-metfiyl-pyridin-3-yl.
R4 is H; and
R5 is absent.
21. A compound of formula (Ic)
(Formula Removed)
or a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.
wherein
Y is a methylene;
R1 and R2 are each independently selected from H, halo, OH, (C1-C6)alkylo, {C3-C7)cycloalkyl,
(C1-C6 alkoxy, -NR6R7, -C02R6, -C(0)NRsR7, -C{O}NR6SO2RB, aryl and 3 to 10-membered heterocyclyl;
or
R1 and R2 may be joined to form a (C2-C5)alkylene link, said link optionally incorporating 1 or 2
heteroafcoms each independently selected from N, O and S; ,
R3 is selected from (C1-C6alkyl, (C3-C7)cycloalkyl, aryl and 3 to 10-membered heterocyclyl;
R4 is selected from R9, -C(O)R9, -Co2R9 and -C(o)NR9R11 and R5 is absent; or
R5 is selected from R9, -C(0)R9, -C02R9 and -C(0)NR9R10, and R4 is absent;
R6 and R7 are each independently selected from H and C1-C6alkyi;
R5 is selected from (C1-C6)aIkyl, {C3-C7)cycloalkyl and phenyl;
R9 and R10 are each independently selected from H, (C1-C6alkyl (C3-C7)cycloalkyl, aryl, -(CH2}aryl and 3 to 10-membered heterocyclyl; or
R and R10 taken together with the nitrogen lo which they are attached:, form a 3 to 10-membered. heterocyclyS group;
said alkyl, cydbalkyl, alkoxy, aryl and heterocyclyl. groups being optionally substitued! by one or more groups independently selected from halo. OH, oxo, CF3. CM, (C1-C6}alkyl, {C3-C7)cycloalkyl, (C1-C6)aikoxy, -(C1-C6)alkylene-O-(C1-C6}alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, aryl and 3 to 10-membered heterocyclyl;
with the proviso that when R1 and Rz are H; Z and R5 are absent, then (a)R* is not methyt when Y-R3 is ethyl; and (b)R4 is not H or methyl when Y-R3 is methyl.
22. A compound according to claim 21 wherein R1 and R2 are each independently selected from H, (C1-C6alkyS, (C3-C7)cycl.oalkyl, -CO2H, -CO2(C1-C6}alkyl and -C(O)NH(C1-C6)aikyleneC1-C7)cycloalkyl; or R1 and R2 may be joined to form a (C2-C5)alkylene fink.
23. A compound according to claim 22 wherein R1 is selected from H, methyl, n-propyl, isopropyl, cyclopropyl, -CO2H, -CO2CH3 and -C(0}NH(CH2)cycfopropyl; and R2 is selected from HI and! methyl; or R1 and R2 may be joined to form a Cs-alkylene link.
24. A compound according to claims 21 to 23 wherein R3 is aryl, which is optionally substitued by one or more groups independently selected from halo, OH, oxo,. CF3, CM, (C1-C6alkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl,
-NH{C1-C6)aikyl, -N(C1-C6alkyl)2, aryl and 3 to 10-membered heterocyclyl.
25. A compound according to claim 24 wherein R3 is phenyl, which is optionally substitued by one or more groups independently selected from halo and CF3.
26. A compound of formula (l) according to claim "l which is selected from 4-Amino-1-benzyl-6-cyclopropyI-1,3-dihydro-imidazo[4,5-cJpyridin-2-one; 4-Amino-1-benzyl-6-oxazol-2-yl-1>3-dihydro-imidazo[4r5-c]pyridin-2-one;and 4-Amino-1-benzyl-6-trifluoromethyl-1,3-dihydro-imidazd[4,5-clpyridine-2-one; or pharmaceutically acceptable salts or solvates of said compound.
27. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of the preceding claims, or a pharmaceutically acceptable salt or solvate of said compound, together with one or more pharmaceutically acceptable excipients.
28. A. pharmaceutical composition according to claim 27 including one or mere additional therapeutic agents.
29. A pharmaceutical composition according to claim 28 wherein the additional therapeutically active-agent or agents are selected from inhibitoR5 of HCV NS3A protein, HCV NS5A protein,, HCV NS4B protein, HCV polymerase, HCV metallqprotease, HCV serine protease, HCV helicase and; p7 protein.
30. A compound of formula (I) as defined in any one of claims 1 to 26 cr a pharmaceutically acceptable salt or solvate of said compound for use as a medicament,
31. A compound of formula (I) as defined in as claimed in any one of ciaims 1 to 26 or a pharmaceutically acceptable salt or solvate of said compound for the treatment of a disorder or condition in which modulation of the TLR7 receptor is implicated.
32. A compound of claim 31 wherein the disorder or condition is viral infection selected from adenovirus, herpes virus, poxvirus, orthomyxovirus, paramyxovirus, coronavirus, papovavirus, papillomavirus, hepadnavirus, flavivirus, retrovirus and filovirus.
33. A compound of claim 31 wherein the disorder or condition is hepatitis C.
34. Use of a compound of formula (1) as defined in as Claimed in any one of claims 1 to 26 or a pharmaceutically acceptable salt or solvate of said compound in the preparation of a medicament for the treatment of a disorder or condition in which modulation of the TLR7 receptor is implicated.
35. A method of treatment of a disorder or condition where modulation of TLR7 receptor is implicated in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (1) as defined in any one of claims 1 to 26or a pharmaceutically acceptable salt or solvate of said compound.
36. A process for preparing a compound of formula (I)
(Formula Removed)
wherein in each of formulae I, XVIII, XVII la, XIX, XlXa, XXa, XXb, XIV, XV, LIV and LXIII, Y-R3 is as defined in claim 14, R1 is as defined in claim 2, R2 is as defined in claim 10, PG1 and PG2 are nitrogen protecting agents and R13 is (C1-C6)alkyl,
said process comprising
(a) Reaction of a compound of formula (XVIII) or (XVIIla) with a carbonyl donating agent
(Formula Removed)
to form a corresponding compound of formula (XIX) or (XlXa)
(Formula Removed)
then subsequent deprotection of the compound of formula (XIX) or (XlXa); or
(b) reduction of a compound of formula (XXa)
(Formula Removed)
to form a compound of formula (XXb)
(Formula Removed)
and then cyclisation of the compound of formula (XXb) by treatment with a protic acid; or (C) reduction of a compound of formula (XIV)
(Formula Removed)
to form a compound of formula (XV)
(Formula Removed)
and then cyclisation of a compound of formula (XV) in the presence of a carbonyl moiety; or
(e) cyclisation of a compound of formula (L!V) in the presence of diphenylphosphonyl azide to a corresponding compound of formula (XIXA) hereabove and then subsequent deprotection of the amino protection group
(Formula Removed)
(f) hydrolysis of a compound of formula (LXfll)

(Formula Removed)
37. A compound of formulae XVlll, XVilla, XIX, XlXa, XXa, XXb, XIV, XV, LIV and LXIIl,
wherein Y-R3 is as defined in claim 14, R1 is as defined in claim 2, R2 is as defined in claim 10, PG1 and
PG2are nitrogen protecting agents and R13 is (C-alkyl.
38. A compound of formulae XVlll, XVllla, XIX, XlXa, XXar XXb, XIV, XV, LIV and LXIIl, wherein Y-R3 is as defined in claims 15 or 16, R1 is as defined in any one of claims 4 to 6, R2 is H or methyl, PG1
and PG2 are nitrogen protecting agents and R13 is (C1-.8)alkyl.