COMPOUNDS

The present invention relates to substituted pyridines and derivatives thereof, and to a process for preparing these substituted pyridines. The invention also relates to the use of the substituted pyridines as intermediates in the production of pharmaceutical, chemical and agro-chemical products.

A number of routes are known for the synthesis of substituted pyridines. Okada et al (Okada et al., Heterocycles, 46, 129 (1997)) have shown that beta-trifiuorovinylamine reacts with various methylene compounds to give substituted 6- (trifluoromethyl)nicotinic acids and closely related compounds. Bagley et al (Bagley et al., J Chem Soc, Perkin Trans 1, 1663 (2002)) have added to the scope of the Bohhnann-Rahtz reaction (Bohlmann and Rahtz Chem Ber, 90, 2265 (1957)) and described the synthesis of a small range of 2, 6-disubstituted nicotinic esters and some of their derivatives. However, both of these syntheses are multi-step processes which start from commercially available materials and rely on harsh conditions for the final cyclisation namely a trifluoroacetic acid/benzene reflux (Okada et al., Heterocycles, 46, 129 (1997)) and a Lewis acid/toluene reflux (Bagley et al., J Chem Soc, Perkin Trans 1, 1663 (2002)).

The inventors have provided further substituted pyridines compounds. These compounds are prepared by a simplified process involving the mixing of commercially reagents in acetic acid followed by reflux. The compounds are useful as, or in the synthesis of, inter alia, pharmaceutical, nutraceutical or agricultural products.

According to a first aspect of the present invention there is provided a compound, or derivative thereof, of formula I

(I)

wherein R and R ¹ are the same or different and R is a fluorinated Cl-6 alkyl, COR ³ , CO ₂ R ³ , (CH ₂ )nCO ₂ R ³ or (CH ₂ )n0R ³ group optionally substituted by one or more of hydrogen, Cl-6 alkyl or Cl-6 haloalkyl;

R ¹ is NR ³ R ³ or hydrocarbyl optionally substituted by one or more of halogen (F, Cl, Br, I), CO ₂ R ⁴ , OR ⁴ , (CH ₂ )nOR ⁴ , (CH ₂ )nCO ₂ R ³ , NR ⁴ R ⁴ or optionally substituted Cl- 6 alkyl;

R ² is halogen, Cl-6 alkyl (preferably methyl or ethyl), NO ₂ , CN, S(O) ₂ R ³ , COR ³ , CO ₂ R ³ , (CH ₂ )nOR ³ , (CH ₂ )nCO ₂ R ³ or CONR ³ ₂ optionally substituted by one or more of halogen (F, Cl, Br, T), OR ⁴ , CN, Cl-6 alkyl, CO ₂ R ⁴ , (CH ₂ )nOR ⁴ , (CH ₂ )nCO ₂ R ³ or NR ⁴ R ⁴ ; wherein each saturated carbon in R ² is further optionally and independently substituted by O, =S, =NR ⁵ , NNR ⁵ ₂ or =NOR ⁵ ;

or R ¹ and R ² together form a partially saturated, unsaturated or fully saturated five or six membered ring containing zero to three heteroatoms which is further optionally fused to another partially saturated, unsaturated or fully saturated five or six membered ring to form a ring system containing zero to three heteroatoms, and each substitutable carbon atom in the optionally fused ring(s) or ring system(s) is optionally and independently substituted by one or more of halogen (Cl, I, F or Br), =0, =S, Cl-12 alkyl (e.g Cl-6 alkyl), Cl-12 haloalkyl, cyclohydrocarbyl, heterocyclyl, OR ³ , SR ³ , NR ³ ₂ , NO ₂ , CN, NR ³ COR ³ , NRCONR ³ ₂ , NRCOR ³ , NR ³ CO ₂ R ³ , S(O) ₂ R ³ , SONR ³ ₂ , S(O)R ³ , SO ₂ NR ³ ₂ , NR ³ S(O) ₂ R ³ , COR ³ , CO ₂ R ³ , (CH ₂ )nOR ³ , (CH ₂ )nCO ₂ R ³ or CONR ³ ₂ optionally substituted by one or more of halogen (F, Cl, Br, I), optionally substituted Cl-6 alkyl, CO ₂ R ⁴ , (CH ₂ )nOR ⁴ , (CH ₂ )nCO ₂ R ⁴ or NR ⁴ R ⁴ ;

R ³ which may be the same or different and is hydrogen, halogen (Cl, F, I or Br), CN, OR ⁵ , CO ₂ R ⁵ , (CH ₂ )IiNR ⁵ R ⁵ , NR ⁵ R ⁵ , (CH ₂ )nOH, C 1-6 alkyl (e.g methyl or ethyl), heterocyclyl or aryl;

R ⁴ which may be the same or different is hydrogen, halogen, CN, OR ⁵ , (CH ₂ )nNR ⁵ R ⁵ , NR ⁵ R ⁵ , optionally substituted Cl-12 alkyl (e.g Cl-6), heterocyclyl or aryl;

R ⁵ which may be the same or different is hydrogen, halogen (Cl, F, I or Br), Cl-6 alkyl or Cl-6 haloalkyl;

wherein n is 0 to 6, preferably 1, 2 or 3;

or a pharmaceutically acceptable salt, and other pharmaceutically acceptable derivatives thereof, and including the proviso that the compound is not methyl 2- methyl-6-(trifluoromethyl)-nicotinate, 2-methyl-6-(trifluoromethyl)nicotinic acid, 1- [2-methyl-6-(trifluoromethyl)pyridine-3-yl]ethanone; diethyl 6-methylpyridine-2,5- dicarboxylate, [2-methyl-6-(trifluoromethyl)pyridine-3-yl](phenyl)methanone or N- [7-(4-methoxyphenyl)-2-(trifluoromethyl)-l,6-naphthyridin-5- yl]propane-l ₃ 3- diamine.

For the purposes of this invention hydrocarbyl includes, but is not limited to, alkyl, alkenyl, alkynyl, vinyl, heterocyclyl, cyclohydrocarbyl, for example cycloalkyl, cycloalkenyl and moieties containing a combination thereof.

As used herein "alkyl" relates to both straight chain and branched alkyl radicals, for example, of 1 to 12 carbon atoms, e.g. 1, 2, 3, 4, 5, 6, 7, 8 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl. The term alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The alkyl group may be substituted with one or more halogen atoms, hi one class of compounds the halogen is fluorine and the alkyl group is mono-, di- or tri- fluoromethyl.

"Alkoxy" relates to both straight chain and branched alkyl radicals, for example, of 1 to 12 carbon atoms, e.g. 1, 2, 3, 4, 5, 6, 7, 8 carbon atoms containing one or more oxygen atoms or hydroxyl.

The term "alkenyl" means a straight or branched alkenyl radical of, for example, 2 to 12 carbon atoms, such as 2, 3, 4, 5 or 6 carbon atoms, and containing one or more carbon-carbon double bonds and includes but is not limited to ethylene, n-propyl-1- ene, n-propyl-2-ene, isopropylene etc.

"Alkynyl" relates to a straight or branched alkynyl radical of, for example, 2 to 12 carbon atoms, such as 2, 3, 4, 5 or 6 carbon atoms, and containing one or more triple bonds.

"Cyclohydrocarbyl" relates to a saturated, partly unsaturated or unsaturated 3 - 10, for example, 5, 6, 7, 8, 9 or 10, membered hydrocarbon ring, including cycloalkyl or aryl.

"Aryl" means an aromatic, for example, 6 -10 membered hydrocarbon containing one, e.g. 6C- 1OC, ring which is optionally fused to one or more saturated or unsaturated rings, including phenyl or phenyl substituted by an alkyl or alkoxy group in which alkyl and alkoxy are as described herein.

"Heteroaryl" means an aromatic, for example, 5-10 membered aromatic ring containing one or more heteroatoms selected from N, O or S, and containing one ring which is optionally fused to one or more saturated or unsaturated rings.

"Heterocyclyl" means, for example, a 3-10 membered, for example, 5, 6, 7, 8, 9 or 10, ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. The heterocyclyl system may contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl may be fully saturated, partially saturated or unsaturated.

"Ring" encompasses unsaturated or partially unsaturated rings but is usually a saturated ring, typically containing 5 to 13 ring-forming atoms, for example a 5- or 6- membered ring. The ring(s) may in turn be fused to one or more other rings, e.g the five or six membered ring may be fused to a further five or six membered ring, to form a ring system. The ring or ring system may be a cyclohydrocarbyl or heterocyclyl group.

Examples of cyclohydrocarbyl or heterocyclyl groups include but are not limited to cyclohexyl, cyclopentyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, cyclohexanone, cyclopentanone, dioxin, dioxane, dioxolane, dithiane, ditlήazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazne, phthalazine, piperazine, piperidine, pteridine, purine, putrescine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrolidine, pyrrole, pyrroline, quinoline, quinoxaline, quinazoline, quinnolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, trithiane, tropine.

Halogen means F, Cl, Br, or I.

In a preferred aspect of the invention R is fluorinated methyl or ethyl (preferably CF ₃ or CH ₂ F) or CO ₂ R ³ wherein R ³ is hydrogen or C 1-6 alkyl (preferably methyl or ethyl). Preferably still R is CF ₃ .

In a preferred aspect of the invention R ¹ is alkyl (preferably methyl), (CH ₂ )nCO ₂ R ³ , NR ³ R ³ , vinyl or aryl (preferably phenyl or pyridine) optionally substituted by one or more of halogen (preferably F or Cl); wherein R ³ is H or C 1-6 alkyl (preferably methyl); and wherein n is 1. Preferably still R ¹ is methyl, chloromethyl, NH ₂ , pyridine, phenyl, fluorophenyl or dimethylaminovinyl.

In a preferred aspect of the invention R ² is COR ³ , CO ₂ R ³ , (CH ₂ )nOR ³ , (CH ₂ )nCO ₂ R ³ , S(O) ₂ R ³ or C 1-6 alkyl (preferably methyl or ethyl) optionally substituted by CN, NH ₂ or OH; wherein each saturated carbon in R ² is further optionally and independently substituted by =0; wherein R ³ is hydrogen, Cl-6 alkyl (preferably methyl, ethyl or butyl), NH ₂ , CN, OH or aryl (preferably phenyl); and wherein n is 0, 1 or 2.

hi a preferred aspect of the invention R ¹ and R ² together are a group of formula II

wherein A and B are C and form a bicyclic fused ring system with the ring of formula I; W, X, Y or Z are independently selected from N, O, C or S; R ⁶ , R ⁷ , R ⁸ or R ⁹ are independently selected from hydrogen, halogen (Cl, I, F or Br), =0, =S, B(OR ¹² ) ₂ , Cl-12 alkyl (e.g Cl-6 alkyl), Cl-12 haloalkyl, cyclohydrocarbyl, heterocyclyl (preferably piperidine or piperazine), OR ¹² , SR ¹² , NR ¹² ₂ , NO ₂ , CN, NR ¹² COR ¹² , NRCONR ¹² 2, NRCOR ¹² , NR ¹² CO ₂ R ¹² , S(O) ₂ R ¹² , SONR ¹² ₂ , S(O)R ¹² , SO ₂ NR ¹² ₂ ,

NR ¹² S(O) ₂ R ¹² , COR ¹² , CO ₂ R ¹² , (CH ₂ )n0R ¹² , (CH ₂ )nCO ₂ R ¹² or CONR ¹² ₂ optionally substituted by one or more of halogen (F, Cl, Br, T), Cl-6 alkyl, CO ₂ R ¹³ , (CH ₂ )n0R ¹³ , (CH ₂ )nCO ₂ R ¹³ , NR ¹³ R ¹³ or heterocyclyl (preferably piperidine or piperazine) optionally substitiuted by NH ₂ ; wherein each saturated carbon in R ⁶ , R ⁷ , R ^s or R ⁹ is further optionally and independently substituted by -O, =S, =NR ¹⁴ , NNR ¹⁴ ₂ or =N0R ¹⁴ ; or wherein any two of R ⁶ , R ⁷ , R ⁸ or R ⁹ form a partially saturated, unsaturated or fully saturated optionally substituted five or six membered ring containing zero to three heteroatoms (e.g N);

wherein R ¹² which may be the same or different is hydrogen, halogen (Cl, F, I or Br), CN, OR ¹⁵ , CO ₂ R ¹⁵ , NR ¹⁵ R ¹⁵ , Cl-6 alkyl (e.g methyl or ethyl) or heterocyclyl (preferably piperidine or piperazine);

wherein R ¹³ which may be the same or different is hydrogen, halogen, CN, OR ¹⁶ , NR ¹⁶ R ¹⁶ , optionally substituted Cl-12 alkyl (e.g Cl-6);

R ¹⁴ , R ¹⁵ and R ¹⁶ are hydrogen or OH; and wherein n is 1 to 6, preferably 1 or 2.

R and R may together be optionally substituted pyridine, pyridazine, pyrimidine, pyrazine, pyran, quinoline, isoquinoline, quinazoline, pteridine, quinolizidine, indole, isoindole, indazole, purine or indolizidine. Preferably R ¹ and R ² together are substituted pyridine, pyrimidine, pyridazine or pyrazine. Preferably still R ¹ and R ² together are substituted pyridine or pyrimidine.

In a further preferred aspect of the invention one, two or three of W, X ₃ Y and Z is other than C. Preferably still one or two of W, X, Y or Z is O or N, preferably N.

In a yet further preferred aspect R ⁶ , R ⁷ , R ⁸ or R ⁹ are independently selected from =0, CN, halogen (Cl, Br or T), COR ¹² , CO ₂ R ¹² , NR ¹² R ¹² , B(OR ¹² ) ₂ , (CH ₂ )nCO ₂ R ¹² , Cl-6 alkyl (preferably methyl or ethyl), heterocyclyl (piperidine or piperazine) optionally substituted by one or more OfNR ¹³ R ¹³ or heterocyclyl (preferably piperidine);

wherein each saturated carbon in R ⁶ , R ⁷ , R ⁸ or R ⁹ is further optionally and independently substituted by =0, =S, =NR ¹⁴ or =N0R ¹⁴ ; wherein R ¹² is hydrogen, halogen (preferably Br), NR ¹⁵ R ¹⁵ , Cl-6 alkyl (preferably methyl), or heterocyclyl (preferably piperidine); wherein R ¹³ , R ¹⁴ and R ¹⁵ are hydrogen and wherein n is 1 or 2.

Ih a preferred aspect of the invention R and R are together a group of formula Ht

(III)

wherein A and B are C and form a bicyclic fused ring system with the ring of formula I; R ¹⁰ and R ¹¹ together optionally form a partially saturated, unsaturated or fully saturated optionally substituted six membered ring containing zero to three heteroatoms. Preferably still R 10 and R » 11 together are phenyl.

A compound according to the invention may be selected from the group consisting of

1 2 ethyl 2-methyI-6-(trifluoromethyl)nicotinate ethyl 2,6-bis(trifluoromethyI)nicotinate

4 methyl 2,6-bis(trifluoromethyl)nicotinate 2,6-bis(trifluoromethyl)nicotinic acid

6 ethyl 2-(chloromethyl)-6-(trifluoromethyl)nicotinate methyl 2-(chloromethyl)-6-(trifluoromethyl)nicotinate

7 8 2-(chloromethyl)-6-(trifluoromethyl)nicotinic acid ethyl 2-phenyl-6-(trifluoromethyl)nicotinate

10 methyl 2-phenyl-6-(trifluoromethyl)nicotinate 2-phenyl-6-(trifluoromethyl)nicotinic acid

ethyl 2-(4-fluorophenyl)-6-(trifluoromethyl)nicotinate

methyl 2-(4-fluorophenyl)-6-(trifluoromethyl)nicotinate

2-(4-fluorophenyl)-6-(trifluoromethyl)nicotinic acid ethyl 6-(trifluoromethyl)-2,2'-bipyridine-3-carboxylate

15 16 methyl 6-(trifluoromethyl)-2,2'-bipyridine-3-carboxylate 6-(trifluoromethyl)-2,2'-bipyridine-3-carboxylic acid

17 -methyl-6-(trifluoromethyl)nicotinamide ^•

18

^-(terf-butylJ-σ-methyl-θ-CtrifluoromethyOnicotinamicle

19 20

2-methyl-λ/-phenyl-6-(trifluoromethyl)nicotinamide 1-[2,6-bis(trifluoromethyl)pyridin-3-yl]ethanone

21 22

1-[2-phenyl-6-(trifluoromethyl)pyridin-3-yl]ethanone ethyl 2-amino-6-(trifluoromethyl)nicotinate

23

2-amino-6-(trifluoroinethyl)nicotinic acid 2-amino-6-(trifluoromethyl)nicotinamide

25

2-methyl-3-(methylsulfonyl)-6-(trifluoromethyl)pyridine

26

3-(methylsulfonyl)-2-phenyI-6-(trifluoromethyl)pyridine

3-(methylsulfonyl)-6-(trifluoromethyl)-2,2'-bipyridine ethyl 6-(difluoromethyl)-2-methylnicotinate

29

6-(difluoromethyl)-2-methylnicotinic acid

5-(ethoxycarbonyl)-6-methylpyridine-2-carboxylic acid

31 32 diethyl 6-aminopyridine-2,5-dicarboxylate 2-ethyl 5-methyl 6-aminopyridine-2,5-dicarboxylate

33 ethyl δ-amino-δ-CaminocarbonylJpyridine^-carboxylate

34 methyl 2-(2-methoxy-2-oxoethyl)-6-(trifluoromethyl)nicotinate

35 36

2-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one 2-(trifluoromethyl)-5,8-dihydroquinolin-7(6H)-one

-(trifiuoromethyl)-5H-indeno[1,2-b]pyridin-5-one ethyl 5-oxo-5/-/-indeno[1 ,2-;b]pyridine-2-carboxylate

39 methyl 2-[(E)-2-(dimethylamino)vinyl]-6-(trifluoromethyl)nicotinate

-(trifluoromethyI)-1 ,6-naphthyridin-5(6H)-one 5-chloro-2-(trifluoromethyl)-1 ,6-naphthyridine

42

6-(dimethylamino)-2-(trifluoromethyl)-1 ,6-naphthyridin-5(6H)-one

43

2-(trifluoromethyl)-7,8-dihydro-1 ,6-naphthyridin-5{6H)-one

44

8-bromo-2-(trifluoromethyl)-1 ,6-naphthyridin-5(6H)-one

45 -iodo-2-(trifluoromethyl)-1 ,6-naphthyridine

2-(trifluoromethyl)-1 ,6-naphthyridin-5-amine

47a

5-piperazin-1-y]-2-(trifluoromethyl)-1 ,6-naphthyridine

47b

5-(1 ,4-diazepan-1-yl)-2-(trifluoromethyl)-1 ,6-naphthyridine

48

5-hydrazino-2-(trifluoromethyl)-1 ,6-naphthyridine

W-piperidin-4-yl-2-(trifluoromethyl)-1 ,6-naphthyridin-5-amine

50

1-[2-(trifluoromethyl)-1 ,6-naphthyridin-5-yl]piperidin-4-amine

51

2-(trifluoromethyl)-1 ,6-naphthyridine-5-carbonitrile

52

1-[2-(trifluoromethyl)-1 ,6-naphthyridin-5-yl]methanamine

53

2-(trifluoromethyl)-1 ,6-naphthyridine-5-carboximidamide

54 55 -(trifluoromethyl)-1.δ-naphthyridine-δ-carboxylic acid 2-(trifluoromethyl)-1 ,6-naphthyridine-5-carbaldehyde

56

/V-hydroxy-2-(trifluoromethyl)-1,6-naphthyridine-5-carbox imidamide

57

2-(trifluoromethyl)-1 ,6-naphthyridine-5-carbothioamide

-bromo-5-chloro-2-(trifluoromethyl)-1,6-naphthyridine 8-bromo-5-iodo-2-(trifluoromethyl)-1,6-naphthyridine

8-bromo-2-(trifluoronnethyl)-1,6-naphthyridine-5-carbonit rile

8-bromo-2-(trifluoromethyl)-1 ,6-naphthyridin-5-amine

H ₂

8-bromo-5-hydrazino-2-(trifluoromethyl)-1 ,6-naphthyridine

8-bromo-2-(trifluoromethyl)-1 ,6-naphthyridine-5-carboxylic acid

8-bromo-2-(trifluoromethyl)-1,6-naphthyridine-5-carbaldeh yde

65 66 -(trifluoromethy])pyrido[2,3-d]pyrimidin-4(3H)-one 4-chloro-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine

67 68 -piperazin-1-y]-7-(trifluoromethyl)pyrido[2,3-<flpyrimidi ne 7-(trifluoromethyl)pyrido[2,3-c/lpyrimidin-4-amine

Ho

69 4-hydrazino-7-(trifluoromethyl)pyrido[2,3-c/lpyrimidine

70 λ/-piperidin-4-yl-7-(trifluoromethyl)pyrido[2,3-c(]pyrimidi n-4-amine

71

1-[7-(trifluoromethyi)pyrido[2,3-c(]pyrimidin-4-yl]piperi din-4-amine

72

4-iodo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine

73

7-(trifluoromethyl)pyrido[2,3-c(lpyrimidine-4-carbonitril e

1-[7-(trifluoromethyl)pyrido[2,3-c(]pyrimidin-4-yl]methan amine

75

7-(trifluoromethyl)pyrido[2,3-cflpyrimidine-4-carboximida rnide

7-(trifluoromethyI)pyrido[2,3-c(lpyrimidine-4-carboxylic acid

77

7-(trifluoromethyl)pyrido[2,3-<flpyrimidine-4-carbalde hyde

10

78

[7-(trifluoromethyl)pyrido[2,3-odpyrimidin-4-yl]boronic acid

79

7-(trifluoromethyl)pyrido[2,3-cflpyrimidine-4-carbothioam ide

ethyl 4-oxo-3,4-dihydropyrido[2,3-d]pyrirnidine-7-carboxylate

ethyl 4-chloropyrido[2,3-c(]pyrirnidine-7-carboxylate ethyl 4-cyano pyrido[2,3-c/]pyrimidine-7-carboxylate

7-(ethoxycarbonyl)pyrido[2,3-d]pyrimidine-4-carboxylic acid

ethyl 4-formylpyrido[2,3-o(]pyrimidine-7-carboxylate

ethyl 4-[amino(imino)methyl]pyrido[2,3-φyrimidine-7-carboxylate

ethyl 4-(aminocarbonothioyl)pyrido[2,3-c(lpyrimidine-7-carboxylate

ethyl 4-(aminomethyl)pyrido[2,3-c(]pyrimidine-7-carboxylate

88 89

[2-(trifIuoromethyl)-1 ,6-naphthyridin-5-yI]acetic acid 5-methyl-2-(trifluoromethyl)-1,6-naphthyridine

5-(bromomethyl)-2-(trifluoromethyl)-1,6-naphthyridine

91

3-[2-(trifluoromethyl)-1 ,6-naphthyridin-5-yl]propanoic acid

92

2-[2-(trifluoromethyl)-1,6-naphthyridin-5-yl]ethanamine

93

2-amino-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]ethan one

P-methyl-δ^trifluoromethyOpyridin-S-yllacetic acid

"Me F ₃ C" "N" "Me

95

3-ethyl-2-methyl-6-(trifluoromethyl)pyridine

3-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-3-oxopropane nitrile

97 98

[2-amino-6-(trifluoromethyl)pyridin-3-yl]methanol 2-amino-6-(trifluoromethyl)nicotinaldehyde

99 2-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[2,3--)]-1,6-nap hthyridine

7-(trifluoromethyl)-1 ,8-naphthyridine-2-carboxylic acid

101

7-(trif luoromethyl)-2H-pyrido[2,3-cOt1 ,3]oxazine-2,4(1 H)-dione

102

2-amino-7-(trifluoromethyl)-1 ,8-naphthyridine-3-carbonitrile

103

7-(trifluoromethyl)-1,8-naphthyridine-3-carbonitrile

104

7-(trifluoromethyl)-1.δ-naphthyridine-S-carboxylic acid

7-(trifluoromethyl)-1 ,8-naphthyridine-3-carbaldehyde 1 -[7-(trifluoromethyl)-1 ,8-naphthyridin-3-yl]methanamine

The compounds of the first aspect may be provided as a salt, preferably as a pharmaceutically acceptable salt of compounds of formula I. As used herein "pharmaceutically acceptable salts" is intended to mean salts which are compatible

with pharmaceutical administration. Examples of pharmaceutically acceptable salts

^■ of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, phosphoric, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric, hydrobromic, and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases. Examples of suitable inorganic bases for the formulation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases. Such bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are non- toxic and strong enough to form salts. Such organic bases are already well-known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; piperidine, N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.

Salts may be prepared in a conventional manner using methods well known in the art.

Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.

Where a compound of the invention contains an acidic function, a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation. The compounds of this invention may also exist in solvated or hydrated forms.

The invention also extends to a prodrug of the aforementioned compounds such as an ester or amide thereof. A prodrug is any compound that may be converted under physiological conditions or by solvolysis to any of the compounds of the invention or to a pharmaceutically acceptable salt of the compounds of the invention. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.

The present invention also provides derivatives including esters, amides, carbamates, carbonates, ureides, ureas, thioureas, hydantoins, thiohydantoins, diketopiperazines, solvates, hydrates, affinity reagents, peptides or prodrugs thereof

A hydrolysable ester of a compound of the formula (I) containing a hydroxy group ^' includes inorganic esters such as phosphate esters and acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break down to give the parent hydroxy group. Examples of acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters). Dialkylcarbamoyl and -V-^N-dialkylaminoethyty-N-alkylcarbamoyl (to give carbamates), N,N- dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino.

A suitable example of a hydrolysable amide of a compound of the formula (I) containing a carboxy group is, for example, N-C _1-6 alkyl amide or iV,JV-di-C _1-6 alkyl amide such as JV-methyl, N-ethyl, N-propyl, AζiV-dimethyl, iV-ethyl-N-methyl or N,N- diethyl amide.

According to a second aspect of the invention, there is provided a process for the manufacture of a compound of formula I which comprises reacting a compound of

formula IV with a compound of formula V or VI optionally in the presence of an ammonia source

('V) (V) (Vl)

wherein, R, R ¹ and R ² are as hereinbefore defined;

R ¹⁷ is hydrocarbyl preferably Cl-12 alkyl (e.g. Cl-6 alkyl);

X is O, NR ¹⁸ or NR ¹⁸ ₂ in protonated form and Y is NR ¹⁸ ₂ , wherein R ¹⁸ is hydrogen;

wherein when X is O the reaction must be carried out in the presence of a source of ammonia.

Preferably, the ammonia source is an ammonium ion.

The process according to the invention may be carried out in the presence of acid or base catalysis, in the presence of a solvent and/or in the presence of microwaves.

Preferably when X is NR ¹⁸ ₂ in protonated form R ¹ is NR ¹⁹ R ¹⁹ or OR ¹⁹ wherein R ¹⁹ is hydrogen or Cl-12 alkyl (e.g Cl-6 alkyl).

A further aspect of the invention provides an agent, for example, a pharmaceutical, nutraceutical, chemical or agrochemical agent comprising one or more compounds according to the invention.

The compounds according to the invention may be monomers for the preparation of polymers. Certain polyrαerisable compounds having polymerisable groups could be co-polymerised. Thus the agent may be a polymer or co-polymer.

The agent may be a dye. Alternatively, the agent may, for example, be a small molecule. Examples of small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids and amino acid analogs.

The synthesis of peptides is well known in the art. Solid phase peptide synthesis generally proceeds by initial attachment of a first (alpha)-amino protected amino acid to a solid support (typically a resin) at its carboxylic end via a linker. Resins with certain protected amino acids already attached are available from commercial sources or can be synthesised by known methods. The (alpha) protecting group is removed from the resin linked amino acid and a second (alpha) amino acid protected amino acid is coupled to the first amino acid using a coupling agent. Cycles of deprotection and coupling of protected amino acids continue until the desired peptide sequence is prepared. The reaction conditions (reagent, solvent, concentration, temperature, time etc) of deprotection of the alpha amino protecting group selected for synthesis preferably do not cleave a substantial amount of the growing peptide from the resin selected for synthesis. Potentially reactive groups on the side chains of protected amino acid synthetic peptide building blocks may also be protected, typically with protecting groups that are not that are not substantially removed by the reaction conditions selected for removal of the (alpha) amino protecting group. A variety of protecting groups, reaction conditions for deprotection, coupling agents, reaction conditions for coupling linkers, resins and conditions for cleavage of the peptide from the resin are known in the art. Details of solid phase peptide synthesis are given, for example, in Greene and Wut, protecting groups in Organic synthesis, Wiley Science (1984) and later editions; Atherton and Sheppard (1989) in solid- phase peptide synthesis, A Practical Approach, ERL Press at Oxford University Press; Barany et al., (1987) hit. J. Peptide Protein Res 30: 705-739.

The compounds, salts and agents of the invention can be incorporated into pharmaceutical, nutraceutical or agricultural/agrochemical compositions.

Pharmaceutical or nutraceutical compositions typically include the compound, salt or agent along with a pharmaceutically or nutraceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical or nutraceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered

saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troche or capsules, e.g., gelatin

capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.

Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, troches, capsules and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

hi one embodiment, the compounds may be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods

known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

Exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is furthermore understood that appropriate doses of a compound depend upon the potency of the compound with respect to the expression or activity to be modulated. When one or more of these compounds is to be administered to an animal (e.g., a human), a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

In a further aspect of the invention, there is provided a compound according to the invention for use as a medicament.

In a further aspect of the invention, there is provided a compound according to the invention for use as in agriculture.

The invention will now be described by way of reference to the following non- limiting examples.

EXAMPLE

General Procedure

The structure of all compounds was confirmed by ¹ H NMR (300 MHz) spectroscopy run on solutions in either deuterated chloroform or dimethylsulfoxide.

Preparation of Ethyl 2-Methyl-6-ftrifluoromethyl)nicotinate 1

Method A

A mixture of (3£)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (100 g, 0.595 mol, 1.1 eq.) (note:(3E)-4-Ethoxy-l,l,l-trifluorobut-3-en-2-one was made according to the procedure described in R. J. Andrew, J. M. Mellor, G. Reid Tetrahedron 2000, 56, 7255) , ethyl 3-oxobutanoate (70.4 g, 0.541 mol, 1.0 eq.), ammonium acetate (83.3 g, 1.08 mol, 2.0 eq.), and acetic acid (130 g, 2.17 mol, 4.0 eq.) was heated at reflux for 90 rnin and was then allowed to cool to room temperature. Water (300 mL) was added and the reaction mixture was extracted with dichloromethane (100 mL). The organic layer was separated, dried over magnesium sulphate, and the solvent was removed under reduced pressure to afford ethyl 2-methyl-6- (trifluoromethyl)nicotinate 1 (88.0 g, 70%) as a pale yellow oil, b.p. 56-62°C/0.25 mbar.

Method B

Ethyl 3-aminocrotonate (2.00 g, 15.5 mmol, 1.0 eq.) and (3£)-4-ethoxy- 1,1,1 - trifluorobut-3-en-2-one (2.60 g, 15.5 mmol, 1.0 eq.) were dissolved in glacial acetic acid (5 mL) and the resultant reaction mixture was heated at reflux for 1 h. The reaction was then allowed to cool to room temperature before being poured into water (100 mL) and extracted with hexane (50 mL). The organic layer was washed with water (2 x 20 mL), saturated aqeuous sodium bicarbonate (2 x 20 mL), and saturated aqueous sodium chloride (20 mL), and the solvent was removed under reduced pressure to afford ethyl 2-methyl-6-(trifluoromethyl)nicotinate 1 (2.59 g, 72%) as an oil.

Preparation of Ethyl 2,6-Bis(trifluoromethyl)nicotmate 2

F ₃ (

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (10 g, 60 mmol, 1.0 eq.), ethyl 4,4,4-trifluoro-3-oxobutanoate (11.04 g, 60 mmol, 1.0 eq.), ammonium acetate (9.26 g, 120 mmol, 2.0 eq.), and acetic acid (14.4 g, 240 mmol, 4.0 eq.) was heated at reflux for 1 h and was then allowed to cool to room temperature. Water was added, the organic layer was separated, dried over magnesium sulphate, and the solvent was removed under reduced pressure to afford ethyl 2,6-bis(trifluoromethyl)nicotinate 2.

Preparation of Ethyl 2-(Chloromethyl)-6-(trifluoromethyl)mcotinate 5

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (10 g, 60 mmol, 1.0 eq.), ethyl 4-chloro-3-oxobutanoate (9.80 g, 60 mmol, 1.0 eq.), ammonium acetate (9.24 g, 120 mmol, 2.0 eq.), and acetic acid (14.4 g, 240 mmol, 4.0 eq.) was heated at reflux for 6 h and was then allowed to cool to room temperature. Water (100 mL) was added and the reaction mixture was extracted with dichloromethane (2 x 50 mL). The organic layer was separated, dried over magnesium sulphate, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, hexane) to afford ethyl 2-(chloromethyl)-6- (trifluoromethyl)nicotinate 5; R _f 0.80 (1:4 ethyl acetate/hexane).

Preparation of Ethyl 2-Phenyl-6-(trifluoromethyl)nicotinate 8

A mixture of (3E)-4-ethoxy-l,l,l-trifiuorobut-3-en-3-one (50 g, 0.30 mol, 1.0 eq.), ethyl 3-oxo-3-phenylpropanoate (57.1 g, 0.30 mol, 1.0 eq.), and ammonium acetate (115 g, 1.5 mol, 5.0 eq.) in acetic acid (1.0 L) was heated at reflux overnight and then allowed to stand at room temperature for 1 week. Water (500 mL) was added and the reaction mixture was extracted with dichloromethane (2 ^χ 200 mL). The combined organic fractions were washed with water (3 x 100 mL), saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium

sulphate, and the solvent was removed under reduced pressure. The residue was purified by distillation (Kugelrohr, 130°C/l mbar) to afford ethyl 2-phenyl-6- (trifluoromethyl)nicotinate 8 (22.0 g, 25%) as an oil.

Preparation of σ-Methyl-iV-phenyl-β-ftrifluoromethvπnicotinamide 19

A mixture of (3£)-4-ethoxy- 1,1,1 -trifluorobut-3-en-3 -one (5.0 g, 0.03 mol, 1.0 eq.), 3-oxo-7V-phenylbutanamide (5.31 g, 0.03 mol, 1.0 eq.), ammonium acetate (4.02 g, 0.06 mol, 2.0 eq.), and acetic acid (18.0 g, 0.30 mol, 10.0 eq.) was heated at reflux overnight and then allowed to cool to room temperature. Water (50 mL) was added and the reaction mixture was extracted with hexane. The organic fraction was washed with saturated aqueous sodium chloride, dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica, hexane then 10% ethyl acetate in hexane) and then recrystallized from heptane/ethyl acetate to afford 2-methyl-N-phenyl-6- (trifluoromethyl)nicotinamide 19 (3.7 g, 44%) as a crystalline solid, m.p. 161.1- 1.61.4°C.

Preparation of l-f2,,6-Bisffaifluoromemyl)pyridin-3-yl1ethanone 20

20

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (5.0 g, 30 mmol, 1.0 eq.), l,l,l-trifluoropentane-2,4-dione (4.62 g, 30 mmol, 1.0 eq.), ammonium acetate (4.62

g, 60 mmol, 2.0 eq.), and acetic acid (18 g, 0.3 mol, 10 eq.) was heated at reflux for 2 h and was then allowed to cool to room temperature. Water was added and the reaction mixture was extracted with hexane. The organic fraction was dried over magnesium sulphate and the solvent was removed under reduced pressure to give 1- [2,6-bis(trifluoromethyl)pyridin-3-yl]ethanone 20.

Preparation of Methyl 2-r2-Methoxy-2-oxoethylV6-(trifluoromethvDm ^' cotinate 34

34

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (2.41 g, 14.4 mmol, 1.0 eq.), dimethyl 3-oxopentanedioate (2.50 g, 14.4 mmol, 1.0 eq.), and ammonium acetate (5.54 g, 72.0 mmol, 5.0 eq.) in acetic acid (20 mL) was heated at reflux overnight and then allowed to cool to room temperature. Water (50 mL) was added and the reaction mixture was extracted with hexane (20 mL) then dichloromethane (20 mL). The combined organic fractions were dried over magnesium sulphate and the solvent was removed under reduced pressure to give methyl 2-(2-methoxy-2- oxoethyl)-6-(trifluoromethyl)nicotinate 34 (0.95 g, 24%).

Preparation of 2-(Trifluoromethyl)-7,8-dihydroquinolin-5( ^' 6H)-one 35

35

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (5.0 g, 30 mmol, 1.0 eq.), cyclohexane-l,3-dione (3.36 g, 30 mmol, 1.0 eq.), ammonium acetate (4.62 g, 60 mmol, 2.0 eq.), and acetic acid (7.2 g, 120 mmol, 4.0 eq.) was heated at 10O ⁰ C for 2 h and was then allowed to cool to room temperature. Water was added and the reaction mixture was extracted with hexane. The organic fraction was dried over magnesium sulphate and the solvent was removed under reduced pressure to give 2- (trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one 35 and 2-(trifluoromethyl)-5,8- dihydroquinolin-7(6H)-one (1.90 g, 29%) as a 4:1 mixture of regioisomers.

Preparation of 2-(Trifluoromethyl)-l,6-naphthyridin-5f6H)-one 40

54% 40

A mixture of ethyl 2-methyl-6-(trifluoromethyl)mcotinate 1 (100 g, 0.43 mol, 1.0 eq.) and λζiV-drmethylformamide dimethyl acetal (53.6 g, .0.45 mol, 1.0 eq.) in N,N- dimethylformamide (300 mL) was heated at reflux overnight and then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was treated with 18% ammonia in methanol (500 mL) at 80°C for 2 h. The solvent was removed under reduced pressure and the residue was slurried with ethyl acetate to afford 2-(trifluoromethyl)-l ₃ 6-naphthyridin-5(6H)-one 40 (49.5 g, 54%) as a tan solid.

Preparation of 5-Cmoro-2-(1rifluoromethviyi,6-naphthyridme 41

40 41

2-(Trifluoromethyl)-l,6-naphthyridin-5(6H)-one 40 (15.0 g, 70.0 mmol) was heated at reflux with phosphorus oxychloride (50 mL, 0.54 mol) for 30 min and the reaction mixture was then slowly poured into water whilst the temperature of the reaction mixture was maintained between 20-30 ⁰ C. The aqueous phase was extracted with dichloromethane, the organic phase was washed with water (2 ^χ ), saturated aqueous sodium hydrogen carbonate, and saturated sodium chloride, dried over magnesium sulphate, and the solvent was removed under reduced pressure to afford 5-chloro-2- (trifluoromethyl)-l,6-naphthyridine 41 (15.0 g, 92%) as a solid, m.p. 90-90°C.

Preparation of 8-Bromo-2-(trifluoromethylVl,6-naυhthyridin-5( ^' 67J)-one 44

A solution of bromine (14.94 g, 93.4 mmol, 1.0 eq.) in acetic acid (10 mL) was added dropwise to a stirred solution of 2-(trifiuoromethyl)-l,6-naphthyridin-5(6/i)-one 40

(20.0 g, 93.4 mmol, 1.0 eq.) in acetic acid (200 mL) and upon complete addition, the reaction mixture was allowed to stir at room temperature for 30 min before being heated at reflux for 2 h. Once the reaction mixture had cooled to room temperature, water (200 mL) was added and the resultant precipitate was filtered off and air-dried. The product was then taken up in ethyl acetate, the organic phase was washed with water (2x), saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium

chloride, dried over magnesium sulphate, and the solvent was removed under reduced pressure to afford 8-bromo-2-(trifluoromethyl)-l,6-naphthyridin-5(6H)-one 44 (25.4 g, 93%) as a pale yellow solid, m.p. 223°C (dec).

Preparation of 8-Bromo-S-chloro-2-(trifluoromethyl)-l,6-naphthyridine 58

8-Bromo-2-(trifluoromethyl)-l,6-naphthyridin-5(6H)-one 44 (10.0 g, 70.0 mmol) was heated at reflux with phosphorus oxychloride (100 rnL, 1.08 mol) for 90 min and the reaction mixture was then slowly poured into water (400 mL) whilst the temperature of the reaction mixture was maintained between 20-30°C. The aqueous phase was extracted with dichloromethane, the organic phase was washed with water (2*), saturated aqueous sodium hydrogen carbonate, and saturated sodium chloride, dried over magnesium sulphate, and the solvent was removed under reduced pressure to afford 8-bromo-5-chloro-2-(trifluoromethyl)-l,6-naphthyridine 58 (10.2 g, 96%) as a tan solid, m.p. 59-6O ⁰ C.

Preparation of [2-Methyl-6-(trifluoromethyl)pyridin-3 -yl] (phenvpmethanone

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (5.0 g, 30 mmol, 1.0 eq.), l-phenylbutane-l,3-dione (4.87 g, 30 mmol, 1.0 eq.), ammonium acetate (4.62 g, 60 mmol, 2.0 eq.), and acetic acid (18 g, 0.3 mol, 10 eq.) was heated at reflux overnight and then allowed to cool to room temperature. Water was added and the reaction

mixture was extracted with dichloromethane. The organic fraction was dried over magnesium sulphate and the solvent was removed under reduced pressure to give [2- methyl-6-(trifluoromethyl)pyridin-3-yl](phenyl)methanone 33 (3.3 g, 42%).

Preparation of Diethyl 6-Methylpyridine-2,5-dicarboxylate

HO

A mixture of 4-ethoxy-2-oxobut-3-enoate (5.0 g, 29.0 mmol, 1.0 eq.) (note: for the synthesis of 4-ethoxy-2-oxobut-3-enoate see below), ammonium acetate (11.2 g, 0.145 mol), and ethyl 3-oxobutanoate (3.78 g, 29.0 mmol, 1.0 eq.) in acetic acid (50 mL) was heated at reflux for 1 h and then allowed to cool to room temperature. The reaction mixture was then poured into water (200 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with water (2 x 100 mL), saturated aqueous sodium hydrogen carbonate (2x), and saturated aqueous sodium chloride, dried over magnesium sulphate, and the solvent was removed under reduced pressure to afford diethyl 6-methylpyridine-2,5-dicarboxylate (2.80 g, 40%) as a dark oil.

Preparation of 4-Ethoxy-2-oxobut-3-enoate TG. Dujardin, S. Rossignol, E. Brown Synthesis 1998, 763)

O

Il ~, _/^ pyridine, DCM ,_,„ _nr . _c .

_Eto ^V ₊ EtQ^ -Tl ^ EtO^^^C0 ₂ Et

O 42% o

Ethyl vinyl ether (5.0 g, 69.0 mmol, 1.0 eq.) was added dropwise to a solution of ethyl chloro(oxo)acetate (9.42 g, 69.0 mmol, 1.0 eq.) and pyridine (5.47 g, 69.0 mmol, 1.0 eq.) in dichloromethane (100 mL) at 0°C under an atmosphere of argon. Upon complete addition, the reaction mixture was stirred at 0°C for 30 min and was then allowed to warm to room temperature. Water (100 mL) was added and the two phases were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (3 x 100 mL) and saturated aqueous sodium chloride, dried over magnesium sulphate, and the solvent was removed under reduced pressure to give ethyl 4-ethoxy-2-oxobut-3-enoate (5.0 g, 42%) as an orange oil and a 2:1 mixture of geometrical isomers.

Preparation of l-r2-Methyl-6-(trifluoromethyl)pyridin-3-yllethanone

A mixture of (3E)-4-ethoxy-l,l,l-trifluorobut-3-en-3-one (5.0 g, 30 mmol, 1.0 eq.), penta-2,4-dione (2.98 g, 30 mmol, 1.0 eq.), ammonium acetate (4.62 g, 60 mmol, 2.0 eq.), and acetic acid (7.2 g, 120 mmol, 4.0 eq.) was heated at reflux for 2 h and then allowed to cool to room temperature. Water was added and the reaction mixture was extracted with hexane. The organic fraction was dried over magnesium sulphate and the solvent was removed under reduced pressure to afford l-[2-mefhyl-6- (trifluoromethyl)pyridin-3-yl]ethanone (2.7 g, 40%).

Preparation of 2-Amino-6-( ^' trifluoromethyl)nicotinamide 24

A mixture of 3-amino-3-iminopropanamide hydrochloride (20.0 g, 0.145 mol), (3E)- 4-ethoxy-l,l,l-trifluorobut-3-en-2-one (24.4 g, 0.145 mol), and sodium acetate (39.5

g, 0.290 mol) was heated at reflux overnight. After being allowed to cool to room temperature, the mixture was partitioned between water (100 niL) and EtOAc (200 mL). The organic fraction was separated, washed with water (3 x 100 mL), saturated sodium bicarbonate solution, and brine, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was then allowed to form a slurry in isopropyl alcohol (50 mL), and the resultant precipitate was collected by filtration and dried to yield 2- amino-6-(trifluoromethyl)nicotmamide 24 as a pale yellow solid, mp 227-229 ⁰ C.

Preparation of 7-(TrifluoromethvDpyrido[2,3-dlpyrimidin-4-ol 65

A mixture of 2-amino-6-(trifluoromethyl)nicotinamide 2008952 (5.0 g, 24.0 mmol), trimethyl orthoformate (50 mL, 456 mmol), and p-toluenesulfonic acid (5 mg, catalytic) in methanol (50 mL) was heated at reflux overnight. After being allowed to cool to room temperature, the solvent was removed under vacuum. The residue was then allowed to form a slurry in ethyl acetate and the resultant precipitate was collected by filtration and dried to give 7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4- ol 65 (4.10 g, 78%) as a pale yellow solid, mp 268-269°C.