HERBICIOAL COMPOUNDS
The present invention relates to certain substituted heterobicyclic carboxylic acid derivatives, to processes for their preparation, herbicidal compositions comprising them, and their use in controlling plants or inhibiting plant growth.
Herbicidal 4-aminopicolinates are disclosed in WO01/51468. WO03/011853. WO2004/089906, WO2005/016887, WO2005/063721 and WO2006/062979.
WO2009/029735 discloses intermediates of the formula
o
which are stated to be useful in the preparation of herbicidal compounds.
This invention seeks to provide alternative herbicidal compounds.
In a first aspect, the invention provides compound having the formula (I):
1 .Y
(I)
or a salt or N-oxide thereof, wherein:
A is halogen, C2-C6 alkenyt optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^ ora mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^;
D is N or CR^:
1

X is O, S. N or NR*;
Y is CR^ CR^R^ N. NR^ O or S;
E is -(CR^R^)n-; n is 1, 2 or 3;
is a bond that is optionally single or double
Z is C(0)R^ C(S)R'°. or C(=NR'')R'';
each R^ is independently halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, di (C1-C3) alkylamino, cyano. C1-C3 alkyl. C1-C3 haloalkyi, C2-C3 alkenyl, C1-C3 alkoxy. C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 alkylsulphonyl, C2-C6 carboxyalkyi, carboxyl. C2-C6 alkoxycarbonyl, C2-C7 alkylcarbonyloxy or C6-C10 aryl optionally substituted by 1 to 3 groups R^;
each R^ is independently halogen, hydroxyl, nitro, amino, cyano, C1-C3 alkyl, C1-C3 haloalkyi, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulphonyl, C1-C3 alkylsulphonyloxy, C2-C6 carboxyalkyi, C2-C6 alkoxycarbonyl, C2-C7 alkylcarbonyloxy, C1-C3 alkylamino, or di(C1-C3 alkyl)amino;
R^ is hydrogen, halogen, C1-C3 alkyl. C1-C3 haloalkyi, C2-C4 alkoxyalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or cyclopropyl optionally substituted by 1 to 3 groups RR* is hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R'^. C2-C6 alkenyl optionally substituted by 1 to 3 groups R", C2-C6 alkynyl optionally substituted by 1 to 3 groups R'^ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R", C1-C6 acyl optionally substituted by 1 to 3 groups H\ C1-C6 alkoxycarbonyl optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^, C1-C6 alkylsulphonyl optionally substituted by 1 to 3 groups R^ or C6-C10 arylsulphonyl optionally substituted by 1 to 3 groups R^;
2

each of R^ and R'^ is independently hydrogen, halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxy, C6-C10 aryl optionally substituted by 1 to 3 groups R^, carboxyl, C1-C7 acyl, C2-C7 alkoxycarbonyl, or. taken together with the carbon atom to which they are attached, R^ and R^ form a C1-C6 alkenyl group optionally substituted by 1 to 3 groups R\ a carbonyl group, or a C3-C6 cycloalkyi group optionally substituted by 1 to 3 groups R';
each of R^ and R* is independently hydrogen, halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxy, C6-C10 aryl optionally substituted by 1 to 3 groups R^. carboxyl, C1-C7 acyl, C2-C7 alkoxycarbonyl, or R' represents an additional bond between the carbon atom to which it is attached and the adjacent ring atom or, taken together with the carbon atom to which they are attached, R^ and R^ form a C1-C6 alkenyl group optionally substituted by 1 to 3 groups R\ a carbonyl group, or a C3-C6 cycloalkyi group optionally substituted by 1 to 3 groups R^ or, when n is 2 or 3, taken together with the carbon atoms to which they are attached, any two R' and R® form a 5-or 6-membered saturated, unsaturated or aromatic ring , the ring optionally including 1 to 3 ring atoms which are independently selected from nitrogen, oxygen or sulphur and optionally substituted by 1 to 3 groups RR® is hydrogen, hydroxyl, C1-C10 alkoxy optionally substituted by C1-C6 alkoxy, C1-C6 alkoxy-Cl-C6alkoxy, phenyl. C5-C10 heteroaryl or C3-C10 heterocyclyl. C2-C10 alkenyloxy, C3-C8 cycloalkoxy optionally substituted by C1-C6 alkoxy or phenyl. C1-C6 alkylthio. amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, or (C1-C6 alkyl)(C1-C6 alkoxy )amino;
R^° is C1-C10 alkoxy optionally substituted by C1-C6 alkoxy or phenyl, C2-C10 alkenyloxy, C3-C8 cycloalkoxy optionally substituted by C1-C6 alkoxy or phenyl. C1-C6 alkylthio, amino, CI-C6 alkylamino, or di(C1-C6alkyl)amino;
R^' is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, amino. C1-C6 alkylamino. or di(C1-C6 alkyl)amino;
R^^ is hydrogen, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino, or di(Cl-C6 alkyl)amino;
each R^^ is independently cyano, hydroxyl, carboxyl, C3-C6 cycloalkyi, C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5
3

to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^ C1-C4 alkoxy; C1-C4 alkoxy(C1-C4)alkoxyi C1-C4 alkoxycarbonyl; or tri(C1-C4)alkylsilyl;
provided that
(i) when Y is NR^ X is N. Z is C(0)R^ D is N. E is -(CR^R^)n- R^ is alkyl or
haloalkyi. R' represents an additional bond to X, and R® is alkoxy, then R® is
other than H; (ii) when XEY is -N(R*)C(0)NH-. Z is not C{0)NH2, C(0)NHCH3 or C{0)N(CH3)2; (iii) the compound of formula (I) is not:
9-benzyl-9H-purine-2,6-dicarboxamide;
9-(2-hydroxyethyl)-2-(prop-1-enyi)-9H-purine-6-carboxamide;
9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide;
9-phenyl-2-(pyridin-3-yl)-9H-purine-6-carboxamide;
2-(3-hydroxyphenyl)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide;
2-(2-hydroxyphenyl)-9-(2-methoxyphenyl)-purine-6-carboxamide;
6-oxo-8-phenyl-2-(pyridin-3-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;
6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;
2-{3-hydroxyphenyl)-8-(2-methoxyphenyl)-6-oxo-5,6,7,8-tetrahydropteridine-4-
carboxamide;
2-chloro-9-phenyl-9H-purine-6-carboxylicacid;
2-chloro-9-methyl-9H-purine-6-carboxylic acid;
2-chloro-9-methyl-9H-purine-6-carboxylic acid ethyl ester;
2-chloro-9-ethoxycarbonylmethyl-9H-purine-6-carboxylic acid ethyl ester.
In a second aspect, the invention relates to a herbicidal composition comprising a compound of formula (I), wherein A is halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-6 haloalkyi optionally substituted by 1 to 3 groups R\ C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^ and D, X. E, Y and Z are as defined above without the provisos (i), (ii) and (iii) together with at least one agriculturally acceptable adjuvant or diluent.
4

In a third aspect, the invention relates to the use of a compound of formula (I), wherein A is halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ CI-6 haloalkyi optionally substituted by 1 to 3 groups R\ C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^ and D. X, E, Y and Z are as defined above without the provisos (i), (ii) and (iii) or composition as defined above as a herbicide.
In a fourth aspect, the invention relates to a method of controlling weeds in crops of useful plants, comprising applying to said weeds or to the locus of said weeds, or to said useful crop plants, a compound of formula (I), wherein A is halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-6 haloalkyi optionally substituted by 1 to 3 groups R\ C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^ a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^ and D, X. E, Y and Z are as defined above without the provisos (i), (ii) and (iii) or composition as defined above.
In a fifth aspect, the invention relates to a process for the preparation of compounds of formula (I).
In a sixth aspect, the invention relates to intermediates useful in the preparation of compounds of formula (I).
Tautomers
The compounds of formula (I) may exist as different geometric isomers, or in different tautomeric forms. This invention covers all such isomers and tautomers, and mixtures thereof in all proportions, as well as isotopic forms such as deuterated compounds. Zwitterionic forms are also covered. For example, compounds of formula (II) may exist in equilibrium with the zwitterionic forms (III) and (IV).
5

xX XX 1 jC
H ^
(II) (III) (IV)
Asymmetry
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and agrochemtcally acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated tfiat both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
"Alkyl", as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains e. g. of 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl.
"Alkenyl", as used herein, refers to an aliphatic hydrocarbon chain having at least one double bond, and preferably one double bond, and includes straight and branched chains e. g. of 2 to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methypropenyi.
"Alkynyl", as used herein, refers to an aliphatic hydrocarbon chain having at least one triple bond, and preferably one triple bond, and includes straight and branched chains e. g. of 2 to 6 carbon atoms such as ethynyl, propynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.
6

"Cycloalkyl", as used herein, refers to a cyclic, saturated hydrocarbon group having from 3 to 8 ring carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
"Alkoxy" as used herein refers to the group -0-alkyl, wherein aikyi is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, neo-pentoxy, n-hexyloxy, and isohexyloxy.
"Alkenyloxy" as used herein refers to the group -0-aikenyl, wherein alkenyl is as defined above.
"Cycloaikoxy" as used herein refers to the group -0-cycloalkyl, wherein cycloalkyl is as defined above. Examples of cycloaikoxy groups are cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
"Alkoxyalkyl" as used herein refers to the group I -alkyl-0-alkyl, where each alky! is, independently, as defined above.
'Alkoxyalkoxy" means a radical -Oalkyl-0-alkyl, wherein each alky! is, independently, as defined above.
"Alkyithio" as used herein refers to the group -S-alkyI, wherein alkyl is as defined above. Examples of Alkyithio groups are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, isopentylthio, neo-pentylthio, n-hexylthio, and isohexylthio.
"Haloalkylthio" means a radical -S-haloalkyI, where haloalkyi is as defined below.
"Alkyl sulphinyl" refers to the group -S{0)-alkyl, wherein alkyl is as defined above.
"Alkylsulphonyl" refers to the group -S(0)2-alkyl, wherein alkyi is as defined above. "Alkylsulphonyloxy" refers to the group -0-S(02)-alkyl, wherein alkyl is as defined above.
"Halogen", "halide" and 'halo" refer to iodine, bromine, chlorine and fluorine.
7

"HaloalkyI" as used herein refers to an alkyl group as defined above wherein at least one hydrogen atom has been replaced with a halogen atom as defined above. Examples of haloalkyi groups include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and trifluoromethyl. Preferred haloalkyi groups are fluoroalkyl groups {i.e. haloalkyi groups, containing fluorine as the only halogen). More highly preferred haloalkyi groups are perfluoroalkyi groups, i.e. alkyl groups wherein all the hydrogen atoms are replaced with fluorine atoms.
"Haloalkenyl" as used herein refers to an alkenyl group as defined above wherein at least one hydrogen atom has been replaced with a halogen atom as defined above.
"Haloalkoxy" refers to an alkoxy group as defined above wherein at least one of the hydrogen atoms on the alkyl moiety has been replaced with a halogen atom as defined above.
"Acyl" as used herein refers to the group -C(0)-alkyl or -C(0)H, wherein the alkyl group is as defined above. Examples of acyl groups are formyl, acetyl, pivaloyi etc.
"Alkoxycarbonyl" refers to the group -C(0)-0-alkyl, wherein the alkyl group is as defined above. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, i-propoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl and s-butoxycarbonyl etc.
"Alkylcarbonyloxy" refers to the group -OC(0)-alkyl, wherein alkyl is as defined above.
"Carboxyalkyl" refers to the group -alkyl-COOH, wherein alkyl is as defined above.
"Alkylamino" refers to the group -NH-alkyI, wherein alkyl is as defined above. Examples of alkylamino groups are methylamino, ethylamino, n-propylamino, i-propylamino etc.
"Dialkylamino" refers to the group -N(alkyl)alkyr, wherein alkyl and alkyl' are both alkyl groups as defined above which may be the same or different. Examples of dialkylamino groups are dimethylamino, diethylamino, di-n-propylamino, methylethylamino, methyisopropylamino, etc.
"Dialkylphosphonyl" refers to the group -P(0)(0-alkyl)(0-alkyl'), wherein alkyl and alkyl" are both alkyl groups as defined above which may be the same or different. Examples
8

of dialkylphosphonyl groups are dimethylphosphonyl, diethylphosphonyl, ethyl methyl phosphonyl etc.
"Alkylene" refers to a branched or linear divalent hydrocarbon radical. Examples of alkylene are methylene, 1,1-ethylene. 1,2-ethylene, 1,1-propylene. 1,2-propylene, 1,3-propylene and 2,2-propylene etc.
"Trialkylsilyl" refers to the group -Si(alkyl)3, wherein each alkyl is, independently, as defined above.
"Aryl" as used herein refers to an unsaturated aromatic carbocyclic group of from 6 to 10 carbon atoms having a single ring (e. g,, phenyl) or multiple condensed (fused) rings, at least one of which is aromatic (e.g., indanyl, naphthyl). Preferred aryl groups include phenyl, naphthyl and the like.
"Aryloxy" refers to the group -0-aryl, wherein aryl is as defined above. Preferred aryloxy groups include phenoxy, naphthyloxy and the like.
"ArylalkyI" refers to the group -alkyl-aryl, wherein aryl and alkyl are as defined above.
"Arylsulphonyl" refers to the group -S(0)2-aryl, wherein aryl is as defined above.
"Heteroaryl" refers to a ring system containing 5 to 10 ring atoms, at least one ring heteroatom and consisting either of a single aromatic ring or of two or more fused rings, at least one of which is aromatic. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of such groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl. Examples of bicyclic groups are benzothiophenyl, benzimidazolyl, benzothiadiazoiyi, methylenedioxyphenyl. quinolinyl, cinnolinyl, quinoxalinyl and pyrazolo{1,5-a]pyrimidinyl.
"Heteroaryloxy" refers to the group -0-heteroaryl, wherein heteroaryl is as defined above.
"Heterocyclyl" refers to a non-aromatic ring system containing 3 to 10 ring atoms, at least one ring heteroatom and consisting either of a single ring or of two or more fused
9

rings. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of such groups include pyrrolidinyl, imidazolinyl, pyrazolidinyl, piperidyl, piperazinyl, quinuclidinyl, morpholinyi, together with unsaturated or partially unsaturated analogues such as 4,5,6,7-tetrahydro-benzothiophenyl, chromen-4-onyl, 9H-fluorenyl, 3,4-dihydro-2H-benzo-l,4-dioxepinyl, 2,3-dihydro-benzofuranyl, piperidinyl, 1,3-dioxolanyl, 1,3-dioxanyl. 4,5-dihydro-isoxazolyl, tetrahydrofuranyl and morpholinyi.
"Optionally substituted" as used herein means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter. For most groups, one or more hydrogen atoms are replaced by the radicals listed thereafter. For halogenated groups, for example, haloalkyi groups, one or more halogen atoms are replaced by the radicals listed thereafter.
Salts
Suitable salts include those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium, and ammonium cations of the formula N*(R^^R^°R^^R^^) wherein R'^, R^, R^' and R" are independently selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxyalkyl. Salts of the compounds of Formula I can be prepared by treatment of compounds of Formula I with a metal hydroxide, such as sodium hydroxide, or an amine, such as ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine, morpholine, cyclododecylamine, benzylamine, or triisopropanolamine. Amine salts are often preferred forms of the compounds of Formula I because they are water-soluble and lend themselves to the preparation of desirable aqueous based herbicidal compositions.
Acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety.
Preferred values of A, D, E, X, Y, Z and R^ to R" are set out below.
10

In one embodiment. A is halogen. C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^. a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups
D is N or CR^;
X is O, S, N or NR";
Y is CR^ CR*R^ N. NR^ O or S;
Eis-(CR'RV; n is 1, 2 or 3;
is a bond that is optionally single or double
Z is C(0)R^ C(S)R'", or C(=NR")R'2;
each R' is independently halogen, hydroxyl. nitro, amino, C1-C3 alkylamino, di (C1-C3) alkylamino, cyano, C1-C3 alkyl, C1-C3 haloalkyi, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio. C1-C3 alkylsulphonyl, C2-C6 carboxyalkyi, carboxy, C2-C6 alkoxycarbonyl or C2-C7 alkylcarbonyloxy;
each R^ is independently halogen, hydroxyl, nitro, amino, cyano, C1-C3 alkyl, C1-C3 haloalkyi, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio. C1-C3 haloalkylthio, C1-C3 alkylsulphonyl, C1-C3 alkylsulphonyloxy, C2-C6 carboxyalkyi, C2-C6 alkoxycarbonyl, C2-C7 alkylcarbonyloxy, C1-C3 alkylamino, or di(C1-C3 alkyl)amino;
R^ is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyi, C2-C4 alkoxyalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, or cyclopropyl optionally substituted by 1 to 3 groups RR" is hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R'^, C2-C6 alkenyl optionally substituted by 1 to 3 groups R^^, C2-C6 alkynyl optionally substituted by 1 to 3 groups R^^ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups! R", C1-C6 acyl optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3
11

groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atonns and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^ or C1-C6 aikylsulphonyl optionally substituted by 1 to 3 groups R^
each of R^ and R® is independently hydrogen, halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxy, C6-C10 aryl optionally substituted by 1 to 3 groups R^, carboxyl, C1-C7 acyl, C2-C7 alkoxycarbonyl, or, taken together with the carbon atom to which they are attached. R' and R® form a C1-C6 alkenyl group optionally substituted by 1 to 3 groups R\ a carbonyl group, or a C3-C6 cycloalkyi group optionally substituted by 1 to 3 groups R^
each of R'' and R® is independently hydrogen, halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxy, C6-C10 aryl optionally substituted by 1 to 3 groups R^, carboxyl, C1-C7 acyl, C2-C7 alkoxycarbonyl, or R' represents an additional bond between the carbon atom to which it is attached and the adjacent ring atom or, taken together with the carbon atom to which they are attached, R^ and R* form a C1-C6 alkenyl group optionally substituted by 1 to 3 groups R\ a carbonyl group, or a C3-C6 cycloalkyi group optionally substituted by 1 to 3 groups R';
R^ is hydrogen, hydroxyl, C1-C10 alkoxy optionally substituted by C1-C6 alkoxy or phenyl, C2-C10 alkenyloxy, C3-C8 cycloalkoxy optionally substituted by C1-C6 alkoxy or phenyl, C1-C6 alkylthio, amino, C1-C6 alkylamino, ordi(C1-C6 alkyl)amino;
R^° is C1-C10 alkoxy optionally substituted by C1-C6 alkoxy or phenyl, C2-C10 alkenyloxy, C3-C8 cycloalkoxy optionally substituted by C1-C6 alkoxy or phenyl, C1-C6 alkyJthio, amino, C1-C6 alkylamino, ordi(Cl-C6alkyl)amino;
R'^ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, amino, C1-C6 alkylamino, or di(C1-C6 alkyl)amino;
R^^ is hydrogen, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino. or di(C1-C6 alkyl)amino;
each R^^ is independently cyano, hydroxyl, C3-C6 cycloalkyi, C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally
12

substituted by 1 to 3 groups R^ C1-C4 alkoxy; C1-C4 alkoxy(C1-C4)alkoxy; C1-C4 alkoxycarbonyl; or tri(C1-C4)alkylsilyl;
provided that
(i) when Y is NR^ X is N. Z is C(0)R^ D is N, E is -(CR'R'')n-, R^ is alky! or
haloalkyi, R' represents an additional bond to X, and R^ is alkoxy. then R° is
other than H; (ii) when XEY is -N(R'')C(0)NH-, Z is not C(0)NH2. C(0)NHCH3 or ClONiCHjh; (iii) the compound of formula (I) is not:
9-ben2yl-9H-purine-2,6-dicarboxamide;
9-{2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide;
9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide;
9-phenyl-2-(pyridin-3-yl)-9H-purine-6-carboxamide;
2-(3-hydroxyphenyl)-9-{2-methoxyphenyl)-9H-purine-6-carboxamide;
2-(2-hydroxyphenyl)-9-(2-methoxyphenyl)-purine-6-carboxamide;
6-oxo-8-phenyl-2-(pyridin-3-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;
6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;
2-(3-hydroxyphenyl)-8-(2-methoxyphenyl)-6-oxo-5,6,7,8-tetrahydropteridine-4-
carboxamide;
2-chloro-9-phenyl-9H-purine-6-carboxylicacid;
2-chioro-9-methyl-9H-purine-6-carboxylicacid;
2-chioro-9-methyl-9H-purine-6-carboxylic acid ethyl ester;
2-chloro-9-ethoxycarbonylmethyl-9H-purine-6-carboxylic acid ethyl ester.
A is preferably halogen, C2-C6 alkenyl, C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^, or a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^.
Examples of group A include 4-chloro-2-fluoro-3-methoxyphenyl, 4-chloro-3-dimethylamino-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, cyclopropyl and chioro.
More preferably. A is phenyl optionally substituted by 1 to 3 groups R^, or C3-C6 cycloalkyi (preferably cyclopropyl) optionally substituted by 1 to 3 groups R13

In an very preferred embodiment, A is cyclopropyl or trisubstituted phenyl, wherein the substituents are independently R^. More preferably, A is 2,3,4-trisubstituted phenyl, wherein the substituents are independently R^. More preferably, A is 4-chloro-2-fluoro-3-methoxyphenyl, or 4-chloro-3-dimethylamino-2-fluorophenyl. Most preferably, A is 4-chloro-2-fluoro-3-melhoxyphenyl.
Preferably, D is N, CH. CF, CCI, or CMe. More preferably, D is N or CH.
Preferably, n is 1 or 2. More preferably, n is 1.
Preferably X is O, S. or NR". More preferably, X is S or NR". Still more preferably, X is NR^
Examples of X are S, and NR".
Preferably, Y is CR^ CR^R®. N. or NR^ More preferably, Y is CR^ or CR^R^ Most preferably, Y is CR^
Preferably, Z is C(0)R^ and R^ is as defined above. More preferably. Z is C(0)R® and R^ is hydroxyl, C1-C6 alkoxy optionally substituted by C1-C6 alkoxy-C1-C6 alkoxy, C5-C10 heteroaryl or C3-C10 heterocyclyl, phenyl(C1-C2)alkoxy, (C1-C3)alkoxy(C1-C6)alkoxy or C3-C6 aikenyloxy.
Examples of group Z are C02CH2CH=CH2. C02CH2CH20Et, C02CH2CH20n-Bu, C02CH(CH3)CH20n-Bu, CO2CH2CH2OCH2CH2OCH3, C02i-Pr. C02n-Pr, COzn-octyl, C02CH{CH3)-n-pentyl, C02CH2(2-furanyl), C02CH2(2-telrahydrofuranyl), COzCHzPh, COzEt, C02Me and CO2H.
More preferably, Z is C(0)R®, wherein R' is hydroxyl, C1-C6 alkoxy, phenyl(C1-C2)alkoxy, or (C1-C3)alkoxy(C1-C6)alkoxy.
More preferably, Z is G(0)R® wherein R' is hydroxyl, C1-C6 alkoxy or phenyl(C1-C2)alkoxy. More preferably, Z is CO2H or C02Me. Most preferably, Z is C02Me.
Preferably, each R' is independently halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl. C1-C2 alkoxy, C1-C2 haloalkoxy, or C1-C3 alkoxycarbonyl;
14

Preferably, each R^ is independently halogen, C1-C2 aikyi, C1-C2 haloaikyi, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C3 alkylamino, or di(C1-C3 alkyl)amino. More preferably, each R^ is independently halogen, methoxy, or dimethylamino.
Preferably, R^ is hydrogen or halogen. More preferably, R^ is hydrogen, fluorine or chlorine. Most preferably, R^ is hydrogen.
Preferably, R" is hydrogen, C1-C2alkyl, C1-C2alkoxyC1-C2alkyl, carboxyC1-C2alkyl. C3-C6cycloalkylCl-C2alkyl, C1-C5acyl, C1-C3alkoxycarbonyl, phenylC1-C2alkyl. wherein the phenyl is optionally substituted by one to three groups R^, furanylCl-C2alkyl, wherein the furanyl is optionally substituted by one to three groups R^, pyridylC1-2alkyl, wherein the pyridyl is optionally substituted by one to three groups R^, C1-2alkylsulphonyl or phenylsulphonyl wherein the phenyl is optionally substituted by one to three groups R^
More preferably, R* is hydrogen, C1-C2alkyl, phenylC1-C2alkyl, furanylC1-C2alkyl or pyridylC1-2alkyl. More preferably, R"* is hydrogen, methyl or benzyl. Most preferably, R" is hydrogen.
Examples of R" are hydrogen, methyl and benzyl.
Preferably, each of R^ and R^ is independently selected from hydrogen, halogen, C1-4 alkyl optionally substituted by phenyl, C1-C4 haloaikyi, or phenyl optionally substituted by 1-3 groups R^ or, taken together, represent a C1-C4 alkylene group.
More preferably, each of R^ and R^ is independently selected from hydrogen, halogen, C1-4 alkyl. C1-C4 haloaikyi. or phenyl optionally substituted by 1-3 groups R^ or, taken together, represent a C1-C4 alkylene group. More preferably, each of R^ and R® is independently selected from hydrogen and C1-C4 alkyl, more preferably methyl.
Examples of R^ and R^ are hydrogen, methyl, or taken together are methylene.
Preferably, each of R^ is H or Me or represents an additional bond between the carbon atom to which it is attached and the adjacent ring atom or together with R® represents =0.
15

More preferably, each of R' represents an additional bond between the carbon atom to which it is attached and the adjacent ring atom. More preferably, R^ represents an additional bond to Y.
Preferably, R® is hydrogen, halogen, C1-6 alkyl, Cl-6 haloalkyi, or phenyl optionally substituted by 1-3 groups R^ or together with R^ represents =0.
More preferably, R^ is hydrogen, halogen, C1-6 alkyl, Cl-6 haloalkyi, or phenyl optionally substituted by 1-3 groups R^. More preferably, R' is selected from H and C1-C6 alkyl. More preferably, R° is hydrogen or methyl.
Examples of R® include hydrogen, methyl and phenyl.
In a particularly preferred embodiment, the compound of the invention has the formula (II)
N ^V^
A'-'^^N Z
(II)
wherein A, Z, R", R^ and R* have the values ascribed above. In this embodiment, it is preferred that A is phenyl optionally substituted by 1 to 3 groups R^ or cyclopropyl optionally substituted by 1 to 3 groups R\ In this embodiment, it is more preferred that A is phenyl optionally substituted by 1 to 3 groups R^. It is furthermore preferred that Z is C(0)R^ wherein R^ is selected from hydroxyl and C1-C6 alkoxy; that R" is H; that R^ is selected from H and C1-C6 alkyl, and that R* is selected from H and C1-C6 alkyl.
In an alternative, particularly preferred embodiment, the compound of the invention has the formula (III)
16

A N 2
(III) wherein A, Z, R^ and R* have the values ascribed above. In this embodiment, it is preferred that A is phenyl optionally substituted by 1 to 3 groups R^. It is furthermore preferred that 2 is C(0)R®, wherein R* is selected from hydroxyl and C1-C6 alkoxy; that R* is selected from H and C1-C6 alkyl, and that R* is selected from H and C1-C6 alkyl.
In an alternative, particularly preferred embodiment, the compound of the invention has the formula (IV)
A N z
(IV)
wherein A, Z, R^, R^, R^ and R® have the values ascribed above. In this embodiment, it is preferred that A is phenyl optionally substituted by 1 to 3 groups R^ or halogen. In this embodiment, it is more preferred that A is phenyl optionally substituted by 1 to 3 groups R^. It is furthermore preferred that Z is C(0)R', wherein R® is selected from hydroxyl and C1-C6 alkoxy; that R^ is H, fluor or chloro; that R" is H; that R^ is selected from H and C1-C6 alkyl; and that R* is selected from H and C1-C6 alkyl.
The compounds described below are illustrative of novel compounds of the invention.
Table 1 below provides 136 compounds designated compounds 1-1 to 1-136 respectively, of formula (1A) wherein Dis N and X is NH.
17

AX.
(1A)
TABLE 1
rnrnpniinHJ Substituent Values
Number A RL_B! ^
1-1 cyclopropyl H H CO2H
1-2 cyclopropyl H H C02Me
1-3 cyclopropyl Me H CO2H
1 -4 cyclopropyl Me H CQ2Me
1-5 cyclopropyl H Me CO2H
1-6 cyclopropyl H Me C02Me
1-7 cyclopropyl Me Me C02H
1-8 cyclopropyl Me Me C02Me
1-9 4-chlorophenyl H H CO2H
1-10 4-chlorophenyl H H C02Me
1-11 4-chlorophenyl Me H C02H
1-12 4-chlorophenyl Me H C02Me
1-13 4-chlorophenyl H Me C02H
1-14 4-chlorophenyl H Me CQ2Me
1-15 4-chlorophenyl Me Me CO2H
1-16 4-chlorophenyl Me Me C02Me
1-17 4-chloro-3-fluorophenyl H H CO2H
1-18 4-chloro-3-fluorophenyl H H COgMe
1-19 4-chloro-3-fluorophenyl Me H CQ2H
1-20 4-chloro-3-fluorophenyl Me H COgMe
1-21 4-chloro-3-fluorophenyl H Me COgH
1-22 4-chloro-3-fluorophenyl H Me C02Me
1-23 4-chloro-3-fluorophenyl Me Me CO2H
1-24 4-chloro-3-fluorophenyl Me Me COgMe
1-25 4-chloro-3-fluorophenyl H H C02Et
1-26 4-chloro-3-fluorophenyl H H COgn-Pr
1-27 4-chloro-3-fluorophenyl H H COgi-Pr
1-28 4-ch[oro-3-fluorophenyl H H C02CH2CH=CH2
1-29 4-chloro-3-fluorophenyl H H COzCHzCHzOMe
1-30 4-chloro-3-fluorophenyl H H COzCHzPh
1-31 4-chloro-3-fluorophenyl Me H COzEt
1-32 I 4-chloro-3-fluorophenyl I Me | H | COzO-Pr
18

r.nmpn..nH[ Substituent Values
Number A 51—5! ^
1-33 4-chloro-3-fluorophenyl Me H C02i-Pr
1-34 4-chloro-3-fluorophenyl Me H C02CH2CH=CH2
1-35 4-chloro-3-nuorophenyl Me H C02CH2CH20Me
1-36 4-chloro-3-fluorophenyl Me H C02CH2Ph
1-37 4-chloro-3-fluorophenyl H Me C02Et
1-38 4-chloro-3-fluorophenyl H Me C02n-Pr
1-39 4-chloro-3-fluorophenyl H Me C02i-Pr
1-40 4-chloro-3-fluorophenyl H Me C02CH2CH=CH2
1-41 4-chloro-3-fluorophenyl H Me C02CH2CH2QMe
1-42 4-chloro-3-fluorophenyl H Me CQ2CH2Ph
1-43 4-chloro-3-fluorophenyl Me Me C02Et
1-44 4-chloro-3-fluorophenyl Me Me C02n-Pr
1-45 4-chloro-3-fluorophenyl Me Me C02i-Pr
1-46 4-chloro-3-fluorophenyl Me Me C02CH2CH=CH2
1-47 4-chloro-3-fluorophenyl Me Me C02CH2CH20Me
1-48 4-chloro-3-fluorophenyl Me Me C02CH2Ph
1-49 4-chloro-3-fluorophenyl CI H CO2H
1-50 4-chloro-3-fluorophenyl CI H C02Me
1-51 4-chloro-3-fluorophenyl CI Me CO2H
1-52 4-chloro-3-fluorophenyl CI Me C02Me
1-53 4-chloro-3-fluorophenyl H Ph CO2H
1-54 4-chloro-3-fluorophenyt H Ph C02Me
1-55 4-chloro-3-fluorophenYl Me Ph CO2H
1-56 4-chloro-3-fluorophenyl Me Ph C02Me
1-57 4-chloro-3-fluorophenyl H CI CO2H
1-58 4-chloro-3-fluorophenyl H CI C02Me
1-59 4-chloro-3-fluorophenyl Me CI CO2H
1-60 4-chloro-3-fluorophenyl Me CI C02Me
4-chloro-2-fluoro-3-
1-61 methoxyphenyl H H CO2H
4-chloro-2-fluoro-3-
1-62 methoxyphenyl H H C02Me
4-chloro-2-fluoro-3-
1-63 methoxyphenyl Me H CO2H
4-chloro-2-fluoro-3-
1-64 methoxyphenyl Me H C02Me
4-chloro-2-fluoro-3-
1-65 methoxyphenyl H Me CO2H
4-chloro-2-fluoro-3-
1-66 methoxyphenyl H Me C02Me
4-chloro-2-fluoro-3-
1-67 methoxyphenyl Me Me CO2H
4-chloro-2-fiuoro-3-
1-68 methoxyphenyl Me Me COgMe
4-chloro-2-fluoro-3-
1-69 methoxyphenyl H H C02Et
4-chloro-2-fluoro-3-
1-70 I methoxyphenyl 1 H | H | C02n-Pr
19

rnmpn..nri| Substituent Values
Number A RL_5! ?
4-chloro-2-fluoro-3-
1-71 methoxyphenyl H H COai-Pr
4-chloro-2-fluoro-3-
1-72 methoxyphenyl H H C02CH2CH=CH2
4-chloro-2-fluoro-3-
1-73 methoxyphenyl i H H C02CH2CH20Me
4-chloro-2-fluoro-3-
1-74 methoxyphenyl H H C02CH2Ph
4-chloro-2-nuoro-3-
1-75 methoxyphenyl Me H COzEt
4-chloro-2-fluoro-3-
1-76 methoxyphenyl Me H COzO-Pr
4-chloro-2-fluoro-3-
1-77 methoxyphenyl Me H COzn-octyl
4-chloro-2-fluoro-3-
1-78 methoxyphenyl Me H COzi-Pr
4-chloro-2-fluoro-3-
1-79 methoxyphenyl Me H C02CH(Me)n-pentyl
4-chloro-2-fluoro-3-
1-80 methoxyphenyl Me H C02CH2CH=CHz
4-ch loro-2-f I uoro-3-
1-81 methoxyphenyl Me H COzCHzCHzOMe
4-chloro-2-fluoro-3-
1-82 methoxyphenyl Me H C02CH2CH20Et
4-chloro-2-fluoro-3-
1-83 methoxyphenyl Me H C02CH2CH20n-Bu
4-chloro-2-fluoro-3-
1-84 methoxyphenyl Me H C02CH(Me)CH20n-Bu
4-chloro-2-fluoro-3-
1-85 methoxyphenyl Me H COzCHzCHzOCHzCHzOMe
4-chloro-2-fluoro-3-
1-86 methoxyphenyl Me H C02CH2Ph
4-chloro-2-fluoro-3-
1-87 methoxyphenyl Me H C02CH2(2-furanyl)
4-chloro-2-fluoro-3- C02CH2(2-
1-88 methoxyphenyl Me H tetrahydrofuranyl)
4-chloro-2-fluoro-3-
1-89 methoxyphenyl H Me C02Et
4-chloro-2-fluoro-3-
1-90 methoxyphenyl H Me C02n-Pr
4-chloro-2-fluoro-3-
1-91 methoxyphenyl H Me C02i-Pr
4-chloro-2-fluoro-3-
1-92 methoxyphenyl H Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
1-93 methoxyphenyl H Me C02CH2CHzOMe
4-chloro-2-fluoro-3-
1-94 methoxyphenyl H Me C02CH2Ph
4-chloro-2-fluoro-3-
1-95 methoxyphenyl Me Me COzEt
4-chloro-2-fluoro-3-
1-96 I methoxyphenyl | Me | Me | COzn-Pr
20

r»n^P>-^..nH| Substituent Values
Number A 51 JB! 2
4-chloro-2-fluoro-3-
1-97 methoxyphenyl Me Me C02i-Pr
4-chloro-2-fluoro-3-
1-98 methoxyphenyl Me Me CQ2CH2CH=CH2
4-chloro-2-fluoro-3-
1-99 methoxyphenyl Me Me i C02CH2CH2QMe
4-chloro-2-fluoro-3-
1-100 methoxyphenyl Me Me C02CH2Ph
4-chloro-2-fluoro-3-
1-101 methoxyphenyl CI H CO2H
4-chloro-2-fluoro-3-
1-102 methoxyphenyl CI H COgMe
4-chloro-2-fluoro-3-
1-103 methoxyphenyl CI Me CO2H
4-chioro-2-fluoro-3-
1-104 methoxyphenyl CI Me C02Me
4-chloro-2-fluoro-3-
1-105 methoxyphenyl H Ph CO2H
4-chloro-2-fluoro-3-
1-106 methoxyphenyl H Ph C02Me
4-chloro-2-fluoro-3-
1-107 methoxyphenyl Me Ph CO2H
4-chloro-2-fluoro-3-
1-108 methoxyphenyl Me Ph C02Me
4-chloro-2-fluoro-3-
1-109 methoxyphenyl H CI CQ2H .
4-chloro-2-fluoro-3-
1-110 methoxyphenyl H CI CQ2Me
4-chloro-2-fluoro-3-
1-111 methoxyphenyl Me CI CO2H
4-chloro-2-fluoro-3-
1-112 methoxyphenyl Me CI C02Me
4-chloro-3-dimethylamino-2-
1-113 fluorophenyi H H CO2H
4-chloro-3-dimethylamino-2-
1-114 fluorophenyi H H C02Me
4-chloro-3-dimethylamino-2-
1-115 fluorophenyi Me H CO2H
4-chloro-3-dimethylamino-2-
1-116 fluorophenyi Me H CQ2Me
4-chloro-3-dimethyla m ino-2-
1-117 fluorophenyi H Me CO2H
4-chloro-3-dimethylamino-2-
1-118 fluorophenyi H Me C02Me
^ ;hloro-3-dimethylamino-2-
1-119 fluorophenyi Me Me CO2H
4-chloro-3-dimethylamino-2-
1-120 fluorophenyi Me Me C02Me
1-121 CI H H CO2H
1-122 CI H H CO^Me
Pri23 I CI I Me I H I CO2H
21

Compnundl Substituent Values
Number A _RL__5! ^
1-124 CI Me H COzMe
1-125 CI H Me CO2H
1-126 CI H Me COzMe
1-127 CI Me Me CO2H
1-128 CI Me Me COgMe
1-129 CI H CI CO2H
1-130 CI H CI COzMe
1-131 CI CI H CO2H
1-132 CI CI H COzMe
1-133 CI Me CI CQ2H
1-134 CI Me CI COzMe
1-135 CI CI Me CO2H
1-136 I CI I CI I Me I C02Me
136 compounds are described, designated compounds 2-1 to 2-136 respectively, of formula (1A) wherein D is Nl and X is NMe, and the values of A, R*, R° and Z are as defined in Table 1.
136 compounds are described, designated compounds 3-1 to 3-136 respectively, of formula (1 A) wherein D is N and X is NCHzOEt, and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 4-1 to 4-136 respectively, of formula (1A) wherein D is N and X is NCH2CO2H, and the values of A, R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 5-1 to 5-136 respectively, of formula (1 A) wherein D is N and X is NCH2(cyclopropyl), and the values of A, R^ R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 6-1 to 6-136 respectively, of formula (1A) wherein D is N and X is NCH2Ph, and the values of A, R^ R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 7-1 to 7-136 respectively, of formula (1 A) wherein D is N and X is NCH(Me)Ph, and the values of A, R^ R* and Z are as defined in Table 1.
22

136 compounds are described, designated compounds 8-1 to 8-136 respectively, of formula (1A) wherein D is N and X is NCH2(2-nitrophenyl), and the values of A. R^ R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 9-1 to 9-136 respectively, of formula {1A) wherein D is N and X is NCH2(4-fluorophenyl), and the values of A, R'^, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 10-1 to 10-136 respectively, of fomiula (1 A) wherein D is N and X is NCH2(4-methoxyphenyl), and the values of A, R^. R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 11-1 to 11-136 respectively, of formula (1A) wherein D is N and X is NCH2(2-furanyl), and the values of A. R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 12-1 to 12-136 respectively, of fomula (1A) wherein D is N and X is NCH2{5-trifluoromethylfuran-2-yl), and the values of A, R^. R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 13-1 to 13-136 respectively, of formula (1A) wherein D is N and X is NCHMe(4-pyridyl), and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 14-1 to 14-136 respectively, of formula (1A) wherein D is N and X is NCH2(3-chloropyrid-2-yl), and the values of A, R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 15-1 to 15-136 respectively, of formula (1A) wherein D is N and X is NCOMe, and the values of A, R^. R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 16-1 to 16-136 respectively, of formula (1A) wherein D is N and X is NCOCMes. and the values of A, R*, R* and Z are as defined in Table 1.
23

136 compounds are described, designated compounds 17-1 to 17-136 respectively, of formula (1 A) wherein D is N and X is NC02Me, and Vne values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 18-1 to 18-136 respectively, of formula (1 A) wherein D is N and X is NSOaMe, and the values of A, R^, R® and 2 are as defined in Table 1.
136 compounds are described, designated compounds 19-1 to 19-136 respectively, of formula (1 A) wherein D is N and X is NS02(4-methylphenyl), and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 20-1 to 20-136 respectively, of formula (1A) wherein D is N and X is O, and the values of A, R^, R® and Z are as defined in Table'1.
136 compounds are described, designated compounds 21-1 to 21-136 respectively, of formula (1A) wherein D is N and X is S, and the values of A, R^, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 22-1 to 22-136 respectively, of formula (1A) wherein D is CH and X is NH, and the values of A, R^, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 23-1 to 23-136 respectively, of formula (1A) wherein D is CH and X is NMe, and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 24-1 to 24-136 respectively, of formula (1 A) wherein D is CH and X is NCHaOEt. and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 25-1 to 25-136 respectively, of formula (1 A) wherein D is CH and X is NCH2CO2H, and the values of A, R^, R® and Z are as defined in Table 1.
24

136 compounds are described, designated compounds 26-1 to 26-136 respectively, of formula (1A) wherein D is CH and X is NCH2(cyclopropyl), and the values of A, R^ R' and Z are as defined in Table 1.
136 compounds are described, designated compounds 27-1 to 27-136 respectively, of formula (1A) wherein Dis CH and X is NCH2Ph, and the values of A, R^ R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 28-1 to 28-136 respectively, of formula (1A) wherein D is CH and X is NCH(Me)Ph, and the values of A, R*, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 29-1 to 29-136 respectively, of formula (1 A) wherein D is CH and X is NCH2(2-nitrophenyl), and the values of A, R*. R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 30-1 to 30-136 respectively, of formula (1 A) wherein D is CH and X is NCH2(4-fluorophenyl), and the values of A. R*. R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 31-1 to 31-136 respectively, of formula (1 A) wherein Dis CH and X is NCH2(4-methoxyphenyl), and the values of A, R^ R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 32-1 to 32-136 respectively, of formula (1A) wherein Dis CH and X is NCH2(2-furanyl), and the values of A, R°, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 33-1 to 33-136 respectively, of formula (1A) wherein Dis CH and X is NCH2(5-trifluoromethylfuran-2-yl), and the values of A. R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 34-1 to 34-136 respectively, of formula (1A) wherein D is CH and X is NCHMe(4-pyridyl). and the values of A, R^, R^ and Z are as defined in Table 1.
25

136 compounds are described, designated compounds 35-1 to 35-136 respectively, of formula (lA) wherein Dis CH and X is NCH2(3-chloropyrid-2-yl), and the values of A, R^, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 36-1 to 36-136 respectively, of fomiuia (1A) wherein Dis CH and X is NCOMe, and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 37-1 to 37-136 respectively, of formula (1A) wherein D is CH and X is NCOCMea, and the values of A, R*, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 38-1 to 38-136 respectively, of fomnula (1A) wherein D is CH and X is NCOjMe, and the values of A, R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 39-1 to 39-136 respectively, of formula (1 A) wherein D is CH and X is NSOaMe. and the values of A, R^ R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 40-1 to 40-136 respectively, of formula (1A) wherein D is CH and X is NS02(4-methylphenyl), and the values of A, R^, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 41-1 to 41-136 respectively, of formula (1A) wherein D is CH and X is O, and the values of A, R®, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 42-1 to 42-136 respectively, of formula (1A) wherein D is CH and X is S, and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 43-1 to 43-136 respectively, of formula (1A) wherein D is CF and X is NH, and the values of A, R^ R® and Z are as defined in Table 1.
26

136 compounds are described, designated compounds 44-1 to 44-136 respectively, of formula (1A) wherein D is CF and X is NMe, and the values of A, R^ R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 45-1 to 45-136 respectively, of formula (1A) wherein D is CF and X is O, and the values of A, R*, R* and Z are as defined in Table 1.
136 compounds are described, designated compounds 46-1 to 46-136 respectively, of formula (1A) wherein D is CF and X is S, and the values of A, R^ R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 47-1 to 47-136 respectively, of formula (1A) wherein D is CCI and X is NH, and the values of A, R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 48-1 to 48-136 respectively, of fonnula (1A) wherein D is CCI and X is NMe, and the values of A, R^, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 49-1 to 49-136 respectively, of formula (1A) wherein D is CCI and X is O, and the values of A, R^, R^ and Z are as defined in Table 1.
136 compounds are described, designated compounds 50-1 to 50-136 respectively, of formula (1A) wherein D is CCI and X is S, and the values of A, R^ R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 51-1 to 51-136 respectively, of formula (1A) wherein D is CMe and X is NH, and the values of A, R*, R® and Z are as defined in Table 1.
136 compounds are described, designated compounds 52-1 to 52-136 respectively, of formula (1A) wherein D is CMe and X is NMe, and the values of A, R^ R^ and Z are as defined in Table 1.
27

136 compounds are described, designated compounds 53-1 to 53-136 respectively, of formula (1A) wherein D is CMe and X is O. and the values of A, R^ R* and 2 are as defined in Table 1.
136 compounds are described, designated compounds 54-1 to 54-136 respectively, of formula (1A) wherein D is CMe and X is S, and the values of A, R^, R^ and 2 are as defined in Table 1.
Table 2 below provides 252 compounds designated compounds 55-1 to 55-252 respectively, of formula (IB) wherein D is N and X is NH.
(1B)
TABLE 2
Compound Substituent Values
Number A p? pS ps ^e 2
55-1 cyclopropyl H H H H CO2H
55-2 cyclopropyl H H H H COgMe
55-3 cyclopropyl H H Me H CO2H
55-4 cyclopropyl H H Me H COgMe
55-5 cyclopropyl Me H H H CO2H .
55-6 cyclopropyl Me H H H C02Me
55-7 cyclopropyl Me H Me H CO2H
55-8 cyclopropyl Me H Me H COgMe
55-9 4-chiorophenyl H H H H COgH
55-10 4-chlorophenyl H H H H COgMe
55-11 4-chlorophenyl H H Me H CO2H
55-12 4-chlorophenyl H H Me H COgMe
55-13 4-chlorophenyl Me H H H CO2H
55-14 4-chlorophenyl Me H H H COgMe
55-15 4-chlorophenyl Me H Me H CO2H
55-16 4-chlorophenyl Me H Me H C02Me
55-17 4-chloro-3-fluorophenyl H H H H CO2H
""55-18 ~T4-chloro-3-fluorophenyl I H | H | H | H I COgMe
28

Compound Substituent Values
Number A I RM RM R^ R^ Z
55-19 4-chloro-3-fluorophenyl H H Me H CO2H
55-20 4-chloro-3-fluorophenyl H H Me H C02Me
55-21 4-chloro-3-fluorophenyl Me H H H COgH
55-22 4-chloro-3-fluorophenyl Me H H H COgMe
55-23 4-chloro-3-fluorophenyl Me H Me H CO2H
55-24 4-chloro-3-fluorophenyl Me H Me H COgMe
55-25 4-chloro-3-fluorophenyl H H H H COgEt
55-26 4-chloro-3-fluorophenyl H H H H COgn-Pr
55-27 4-chloro-3-fluorophenyl H H H H COzi-Pr
55-28 4-chloro-3-fluorophenyl H H H H C02CH?CH=CH2
55-29 4-chloro-3-fluorophenyl H H H H C02CH2CH20Me
55-30 4-chloro-3-fluorophenyl H H H H C02CH2Ph
55-31 4-chloro-3-fluorophenyi H H Me H CQzEt
55-32 4-chloro-3-fluorophenyl H H Me H C02n-Pr
55-33 4-chloro-3-fluorophenyl H H Me H C02i-Pr
55-34 4-chloro-3-fluorophenyl H H Me H C02CH2CH=CH2
55-35 4-chloro-3-fluorophenyl H H Me H C02CH2CH20Me
55-36 4-chloro-3-fluorophenyl H H Me H COgCHzPh
55-37 4-chloro-3-fluorophenyl Me H H H C02Et
55-38 4-chloro-3-fluorophenyl Me H H H C02n-Pr
55-39 4-chloro-3-fluorophenyl Me H H H C02i-Pr
55-40 4-chloro-3-fluorophenyl Me H H H C02CH2CH=CH2
55-41 4-chloro-3-fluorophenyl Me H H H C02CH2CH20Me
55-42 4-chloro-3-fluorophenyl Me H H H C02CH2Ph
55-43 4-chloro-3-fluorophenyl Me H Me H COgEt
55-44 4-chloro-3-fluorophenyl Me H Me H COzn-Pr
55-45 4-chloro-3-fluorophenyl Me H Me H C02i-Pr
55-46 4-chloro-3-fluorophenyl Me H Me H C02CH2CH=CH2
55-47 4-chloro-3-fluorophenyl Me H Me H C02CH2CH20Me
55-48 4-chloro-3-fluorophenyl Me | H Me H COzCHzPh
55-49 4-chloro-3-fluorophenyl =0 H H CO2H
55-50 4-chloro-3-fluorophenyl =0 H H COgMe
55-51 4-chloro-3-fluorophenyl =0 Me H CO2H
55-52 4-chloro-3-fluorophenyl =0 Me H COzMe
55-53 4-chloro-3-fluorophenyl CH2CH2 H H CO2H
55-54 4-chloro-3-fluorophenyl CH2CH2 H H C02Me
55-55 4-chloro-3-fluorophenyl CH2CH2 Me H CO2H
55-56 4-chloro-3-fluorophenyl CH2CH2 Me H C02Me
4-chloro-2-fluoro-3-
55-57 methoxyphenyl H H H H CO2H
4-chloro-2-fluoro-3-
55-58 methoxyphenyl H H H H COzMe
4-ch loro-2-f I uoro- 3-
55-59 methoxyphenyl H H Me H CO2H
4-chioro-2-fluoro-3-
55-60 I methoxyphenyl I H I H | Me | H | C02Me
29

Compound Substituent Values
Number A I RM R° I R^ R^ Z
4-chloro-2-fluoro-3-
55-61 methoxyphenyl Me H H H CQ2H
4-chloro-2-fluoro-3-
55-62 methoxyphenyl Me H H H COzMe
4-chloro-2-fluoro-3-
55-63 methoxyphenyl Me H Me H CO2H
4-chloro-2-fluoro-3-
55-64 methoxyphenyl Me H Me H C02Me
4-chloro-2-fluoro-3-
55-65 methoxyphenyl H H H H COgEt
4-chloro-2-fluoro-3-
55-66 methoxyphenyl H H H H COgn-Pr
4-chloro-2-fluoro-3-
55-67 methoxyphenyl H H H H COgi-Pr
4-chloro-2-fluoro-3-
55-68 methoxyphenyl H H H H C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-69 methoxyphenyl H H H H COgCHgCHgOMe
4-chloro-2-fluoro-3-
55-70 methoxyphenyl H H H H C02CH2Ph
4-chloro-2-fluoro-3-
55-71 methoxyphenyl H H Me H COgEt
4-chloro-2-fluoro-3-
55-72 methoxyphenyl H H Me H C02n-Pr
4-chloro-2-fluoro-3-
55-73 methoxyphenyl H H Me H COzi-Pr
4-chloro-2-fluoro-3-
55-74 methoxyphenyl H H Me H C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-75 methoxyphenyl. H H Me H COzCHjCHzOMe
4-chloro-2-fluoro-3-
55-76 methoxyphenyl H H Me H COgCHzPh
4-chloro-2-fluoro-3-
55-77 methoxyphenyl Me H H H COzEt
4-chloro-2-fluoro-3-
55-78 methoxyphenyl Me H H H C02n-Pr
4-chloro-2-fluoro-3-
55-79 methoxyphenyl Me H H H COzi-Pr
4-chloro-2-fluoro-3-
55-80 methoxyphenyl Me H H H C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-81 methoxyphenyl Me H H H COzCHgCHgOMe
4-chloro-2-fluoro-3-
55-82 methoxyphenyl Me H H H CQ2CH2Ph
4-chloro-2-fluoro-3-
55-83 methoxyphenyl Me H Me H COgEt
4-chloro-2-fluoro-3-
55-84 methoxyphenyl Me H Me H COzn-Pr
4-chloro-2-f!uoro-3-
55-85 methoxyphenyl Me H Me H C02i-Pr
4-chloro-2-fluoro-3-
55-86 I methoxyphenyl | Me I H I Me I H I C02CH2CH=CH2
30

Compound | Substituent Values
Number A R' R° R^ R^ Z
4-chloro-2-fluoro-3-
55-87 methoxyphenyl Me H Me H C02CH2CH20Me
4-chloro-2-fluoro-3-
55-88 methoxyphenyl Me | H Me H C02CH2Ph
4-chloro-2-fluoro-3-
55-89 methoxyphenyl =0 H H CO2H
4-chloro-2-fluoro-3-
55-90 methoxyphenyl =0 H H C02Me
4-chloro-2-fluoro-3-
55-91 methoxyphenyl =0 Me H CO2H
4-chloro-2-fluoro-3-
55-92 methoxyphenyl =0 Me H C02Me
4-chloro-2-fluoro-3-
55-93 methoxyphenyl CH2CH2 H H CO2H
4-chloro-2-fluoro-3-
55-94 methoxyphenyl CH2CH2 H H C02Me
4-chloro-2-fluoro-3-
55-95 methoxyphenyl CH2CH2 Me H CO2H
4-chloro-2-fluoro-3-
55-96 methoxyphenyl CH2CH2 Me H C02Me
4-chloro-3-
dimethylamino-2-
55-97 fluorophenyl H H H H CO2H
4-chloro-3-
dimethylamino-2-
55-98 fluorophenyl H H H H COzMe
4-chloro-3-
dimethylamino-2-
55-99 fluorophenyl H H Me H CO2H
4-chloro-3-
dimethylamino-2-
55-100 fluorophenyl H H Me H C02Me
4-chloro-3-
dimethylamino-2-
55-101 fluorophenyl Me H H H CO2H
4-chloro-3-
dimethylamino-2-
55-102 fluorophenyl Me H H H C02Me
4-chloro-3-
dimethylamino-2-
55-103 fluorophenyl Me H Me H CO2H
4-chloro-3-
dimethylamino-2-
55-104 fluorophenyl Me H Me H COzMe
55-105 cyclopropyl Me Me H H CO2H
55-106 cyclopropyl Me Me H H C02Me
55-107 cyclopropyl Me Me Me H CO2H
55-108 cyclopropyl Me Me Me H COaMe
55-109 4-chlorophenyl Me Me H H CO2H
55-110 4-chlorophenyl Me Me H H COzMe
55-111 I 4-chlorophenyl I Me | Me I Me jH | CO2H
31

Compound Substituent Values
Number A I RM RM R^ I RM Z
55-112 4-chlorophenyl Me Me Me H COgMe
55-113 4-chloro-3-fluorophenyl Me Me H H CO2H
55-114 4-chloro-3-fluorophenyl Me Me H H C02Me
55-115 4-chloro-3-fluorophenyl Me Me Me H CO2H
55-116 4-chloro-3-fluorophenyl Me Me Me H COzMe
55-117 4-chloro-3-fluorophenyl Me Me H H C02Et
55-118 4-chloro-3-fluorophenyl Me Me H H COgn-Pr
55-119 4-chloro-3-fluorophenyl Me Me H H COai-Pr
55-120 4-chloro-3-fluorophenyl Me Me H H C02CH2CH=CH2
55-121 4-chloro-3-fluoraphenyl Me Me H H C02CH2CH20Me
55-122 4-chloro-3-fluorophenyl Me Me H H C02CH2Ph
55-123 4-chloro-3-fluorophenyl Me Me Me H C02Et
55-124 4-chloro-3-fluorophenyl Me Me Me H COan-Pr
55-125 4-chloro-3-fluorophenyl Me Me Me H COai-Pr
55-126 4-chloro-3-fiuorophenyl Me Me Me H C02CH2CH=CH2
55-127 4-chloro-3-fluorophenyl Me Me Me H C02CH2CH20Me
55-128 4-chloro-3-fluorophenyl Me Me Me H COgCHaPh
4-chloro-2-fluoro-3-
55-129 methoxyphenyl Me Me H H CO2H
4-chloro-2-fluoro-3-
55-130 methoxyphenyl Me Me H H COzMe
4-chloro-2-fluoro-3-
55-131 methoxyphenyl Me Me Me H CO2H
4-chloro-2-fluoro-3-
55-132 methoxyphenyl Me Me Me H C02Me
4-chloro-2-fluoro-3-
55-133 methoxyphenyl Me Me H H COzEt
4-chloro-2-fluoro-3-
55-134 methoxyphenyl Me Me H H COzn-Pr
4-chloro-2-fluoro-3-
55-135 methoxyphenyl Me Me H H C02i-Pr
4-chloro-2-fluoro-3-
55-136 methoxyphenyl Me Me H H C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-137 methoxyphenyl Me Me H H C02CH2CH20Me
4-chloro-2-fluoro-3-
55-138 methoxyphenyl Me Me H H C02CH2Ph
4-chloro-2-fluoro-3-
55-139 methoxyphenyl Me Me Me H COgEt
4-chloro-2-fluoro-3-
55-140 methoxyphenyl Me Me Me H COzn-Pr
4-chloro-2-fluoro-3-
55-141 methoxyphenyl Me Me Me H COgi-Pr
4-chloro-2-fluoro-3-
55-142 methoxyphenyl Me Me Me H C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-143 methoxyphenyl Me Me Me H C02CH2CH20Me
4-chloro-2-fluoro-3-
55-144 I methoxyphenyl | Me | Me | Me | H | C02CH2Ph
32

Compound Substituent Values
Number A | RM RM R^ I RM Z
4-chloro-3-
climethylamino-2-
55-145 fluorophenyl Me Me H H CO2H
4-chloro-3-
climethylamino-2-
55-146 fluorophenyl Me Me H H COgMe
4-chloro-3-
dimethylamino-2-
55-147 fluorophenyl Me Me Me H COgH
4-chloro-3-
dimethylamino-2-
55-148 fluorophenyl Me Me Me H COgMe
55-149 cyclopropyl H H Me Me CO2H
55-150 cyclopropyl H H Me Me COzMe
55-151 cyclopropyl Me H Me Me CO2H
55-152 cyclopropyl Me H Me Me COgMe
55-153 4-chlorophenyl H H Me Me CO2H
55-154 4-chlorophenyl H H Me Me C02Me
55-155 4-chlorophenyl Me H Me Me CO2H
55-156 4-chlorophenyl Me H Me Me COgMe
55-157 4-chloro-3-fluorophenyl H H Me Me CO2H
55-158 4-chloro-3-fluorophenyl H H Me Me C02Me
55-159 4-chloro-3-fluorophenyl Me H Me Me CO2H
55-160 4-chloro-3-fluorophenyl Me H Me Me COgMe
55-161 4-chloro-3-fluorophenyl H H Me Me COgEt
55-162 4-chloro-3-fluorophenyl H H Me Me C02n-Pr
55-163 4-chloro-3-fluorophenyl H H Me Me COgi-Pr
55-164 4-chloro-3-fluorophenyl H H Me Me C02CH2CH=CH2
55-165 4-chloro-3-fluorophenyl H H Me Me C02CH2CH20Me
55-166 4-chloro-3-fluorophenyl H H Me Me C02CH2Ph
55-167 4-chloro-3-fluorophenyl Me H Me Me C02Et
55-168 4-chloro-3-fluorophenyl Me H Me Me C02n-Pr
55-169 4-chloro-3-fluorophenyl Me H Me Me C02i-Pr
55-170 4-chloro-3-fluorophenyl Me H Me Me C02CH2CH=CH2
55-171 4-chloro-3-fluorophenyl Me H Me Me C02CH2CH20Me
55-172 4-chloro-3-fluorophenyl Me | H ~ Me Me C02CH2Ph
55-173 4-chloro-3-fluorophenyl =0 Me Me CO2H
55-174 4-chloro-3-fluorophenyl =0 Me Me C02Me
55-175 4-chloro-3-fluorophenyl CH2CH2 Me Me CO2H
55-176 4-chloro-3-fluorophenyl CH2CH2 Me Me C02Me
4-chloro-2-fluoro-3-
55-177 methoxyphenyl H H Me Me CO2H
4-chloro-2-fIuoro-3-
55-178 methoxyphenyl H H Me Me COgMe
4-chloro-2-fluoro-3-
55-179 methoxyphenyl Me H Me Me CO2H
4-chloro-2-fluoro-3-
I 55-180 I methoxyphenyl I Me | H | Me | Me | C02Me
33

Compound Substituent Values
Number A I RM RM RM RM Z
4-chloro-2-fluoro-3-
55-161 methoxyphenyl H H Me Me COaEt
4-chloro-2-fluoro-3-
55-182 methoxyphenyl H H Me Me C02n-Pr
4-chloro-2-fluoro-3-
55-183 methoxyphenyl H H Me Me COai-Pr
4-chloro-2-fluoro-3-
55-184 methoxyphenyl H H Me Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-185 methoxyphenyl H H Me Me C02CH2CH2QMe
4-chloro-2-fluoro-3-
55-186 methoxyphenyl H H Me Me COgCHzPh
4-chloro-2-fluoro-3-
55-187 methoxyphenyl Me H Me Me C02Et
4-chloro-2-fluoro-3-
55-188 methoxyphenyl Me H Me Me C02n-Pr
4-chloro-2-fluoro-3-
55-189 methoxyphenyl Me H Me Me COzi-Pr
4-chioro-2-fluoro-3-
55-190 methoxyphenyl Me H Me Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-191 methoxyphenyl Me H Me Me CO2CH2CH20Me
4-chloro-2-fluoro-3-
55-192 methoxyphenyl Me | H Me Me C02CH2Ph
4-chioro-2-fluoro-3-
55-193 methoxyphenyl =0 Me Me CO2H
4-chloro-2-fluoro-3-
55-194 methoxyphenyl =0 Me Me C02Me
4-chloro-2-fluoro-3-
55-195 methoxyphenyl CH2CH2 Me Me CO2H
4-chloro-2-fluoro-3-
55-196 methoxyphenyl CH2CH2 Me Me C02Me
4-chloro-3-dimethylamino-2-
55-197 fluorophenyl H H Me Me CO2H
4-chloro-3-dimethylamino-2-
55-198 fluorophenyl H H Me Me COgMe
4-chloro-3-dimethylamino-2-
55-199 fluorophenyl Me H Me Me CO2H
4-chloro-3-dimethylamino-2-
55-200 fluorophenyl Me H jyie Me COgMe
55-201 cyclopropyl Me Me Me Me CO2H
55-202 cyclopropyl Me Me Me Me C02Me
55-203 4-chlorophenyl Me Me Me Me COgH
55-204 4-chlorophenyl Me Me Me Me C02Me
55-205 4-chloro-3-fluorophenyl Me Me Me Me CO2H
55-206 4-chloro-3-fluorophenyl Me Me Me Me C02Me
55-207 I 4-chloro-3-fluorophenyl [ Me | Me | Me | Me | COgEt
34

Compound Substituent Values
Number A I RM RM RM RM Z
55-208 4-chloro-3-fluorophenyl Me Me Me Me CO;n-Pr
55-209 4-chloro-3-fluorophenyl Me Me Me Me COzi-Pr
55-210 4-chloro-3-fluorophenyl Me Me Me Me C02CH2CH=CH2
55-211 4-chloro-3-fluorophenyl Me Me Me Me COzCHgCHzOMe
55-212 4-chloro-3-fluorophenyl Me Me Me _ Me CO;CH2Ph
4-chloro-2-fluoro-3-
55-213 methoxyphenyl Me Me Me Me CO2H
4-chloro-2-fluoro-3-
55-214 methoxyphenyl Me Me Me Me C02Me
4-chloro-2-fluoro-3-
55-215 methoxyphenyl Me Me Me Me COzEt
4-chloro-2-fluoro-3-
55-216 methoxyphenyl Me Me Me Me C02n-Pr
4-chloro-2-fluoro-3-
55-217 methoxyphenyl Me lyie Me Me C02i-Pr
4-chloro-2-fluoro-3-
55-218 methoxyphenyl Me Me Me Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-219 methoxyphenyl Me Me Me Me C02CH2CH20Me
4-chloro-2-fluoro-3-
55-220 methoxyphenyl Me Me Me Me COzCHzPh
4-chloro-3-
ciimethylamino-2-
55-221 fluorophenyl Me Me Me Me CO2H
4-chloro-3-
dimethylamino-2-
55-222 fluorophenyl Me [Me Me | Me C02Me
55-223 4-chloro-3-fluorophenyl =0 =CH2 CO2H
55-224 4-chloro-3-fluorophenyl =0 =CH2 C02Me
55-225 4-chioro-3-fluorophenyl CH2CH2 =CH2 CO2H
55-226 4-chloro-3-fluorophenyl CH2CH2 =CH2 C02Me
4-chloro-2-fluoro-3-
55-227 methoxyphenyl =0 =CH2 CO2H
4-chloro-2-fluoro-3-
55-228 methoxyphenyl ^O =CH2 C02Me
4-chloro-2-fluoro-3-
55-229 methoxyphenyl CH2CH2 =CH2 COgH
4-chloro-2-fluoro-3-
55-230 methoxyphenyl CH2CH2 =CH2 COgMe
55-231 cyclopropyl Me Me =CH2 CO2H
55-232 cyclopropyl Me Me =CH2 C02Me
55-233 4-chlorophenyl Me Me =CH2 CO2H
55-234 4-chlorophenyl Me Me =CH2 COgMe
55-235 4-chloro-3-fluorophenyl Me Me =CH2 CQ2H
55-236 4-chloro-3-fluorophenyl Me Me =CH2 CQ2Me
55-237 4-chloro-3-fluorophenyl Me Me =CH2 C02Et
55-238 4-chloro-3-fluorophenyl Me Me =CH2 C02n-Pr
55-239 4-chloro-3-fluorophenyl Me Me =CH2 CQ2i-Pr
~55-240 I 4-chloro-3-fluorophenyl | Me | Me | =CH2 I C02CH2CH=CH2
35

Compound Substituent Values
Number A |"R^ RM RM RM Z
55-241 4-chloro-3-fluorophenyl Me Me =CH2 C02CH2CH20Me
55-242 4-chloro-3-fluorophenyl Me Me =CH2 C02CH2Ph
4-chloro-2-fiuoro-3-
55-243 methoxyphenyl Me Me =CH2 CO2H
4-chloro-2-fluoro-3-
55-244 methoxyphenyl Me Me =CH2 C02Me
4-chloro-2-fluoro-3-
55-245 methoxyphenyl Me Me =CH2 C02Et
4-chloro-2-fluoro-3-
55-246 methoxyphenyl Me Me =CH2 C02n-Pr
4-chloro-2-fluoro-3-
55-247 methoxyphenyl Me Me =CH2 C02i-Pr
4-chloro-2-fluoro-3-
55-248 methoxyphenyl Me Me =CH2 C02CH2CH=CH2
4-chloro-2-fluoro-3-
55-249 methoxyphenyl Me Me =CH2 C02CH2CH20Me
4-chloro-2-fluoro-3-
55-250 methoxyphenyl Me Me =CH2 C02CH2Ph
4-chloro-3-
dimethylamino-2-
55-251 fluorophenyl Me Me =CH2 CO2H
4-chloro-3-
dimethylamino-2-
55-252 I fluorophenyl | Me | Me | =CH2 I C02Me
252 compounds are described, designated compounds 56-1 to 56-252 respectively, of formula (IB) wherein D is N and X is NMe, and the values of A, R^ R^, R^, R® and Z are as defined in Table 2.
252 compounds are described, designated compounds 57-1 to 57-252 respectively, of formula (1B) wherein D is N and X is 0. and the values of A, R^ R^, R^, R® and Z are as defined in Table 2.
252 compounds are described, designated compounds 58-1 to 58-252 respectively, of formula (1B) wherein D is N and X is S, and the values of A, R^ R®, R^, R^ and Z are as defined in Table 2.
252 compounds are described, designated compounds 59-1 to 59-252 respectively, of formula (1B) wherein D is CH and X is NH, and the values of A, R^ R^ R^ R' and Z are as defined in Table 2.
36

252 compounds are described, designated compounds 60-1 to 60-252 respectively, of formula (1B) wherein D is CH and X is NMe, and the values of A. R^ R^, R', R* and Z are as defined in Table 2.
252 compounds are described, designated compounds 61-1 to 61-252 respectively, of formula (1B) wherein D is CH and X is O, and the values of A, R^ R^, R^ R® and 2 are as defined in Table 2.
252 compounds are described, designated compounds 62-1 to 62-252 respectively, of formula (1B) wherein D is CH and X is S, and the values of A, R^ R^ R^ R® and 2 are as defined in Table 2.
Table 3 below provides 172 compounds designated compounds 63-1 to 63-172 respectively, of formula (1C) wherein D is N and X is NH.
Rl R« X >'^
AX
(1C)
TABLE 3
Compound Substituent Values
Number A I RM R" I R*^ I RM 2
63-1 cyclopropyl H H H Me CO2H
63-2 cyclopropyl H H H Me COaMe
63-3 cyclopropyl H H Me Me CO2H
63-4 cyclopropyl H H Me Me COzMe
63-5 cyclopropyl Me H H Me CO2H
63-6 cyclopropyl Me H H Me COaMe
63-7 cyclopropyl Me H Me Me CO2H
63-8 cyclopropyl Me H Me Me COaMe
63-9 4-chlorophenyl H H H Me COgH
63-10 4-chlorophenyl H H H Me COzMe
63-11 4-chlorophenyl H H Me Me CO2H
~63-12 I 4-chlorophenyl I H | H I Me | Me | COaMe
37

Compound Substituent Values
Number A I RM R° R^' R^ Z
63-13 4-chlorophenyl Me H H Me CO2H
63-14 4-chlorophenyl Me H H Me C02Me
63-15 4-chlorophenyl Me H Me Me CQgH
63-16 4-chlorophenyl Me H Me Me C02Me
4-chloro-3-
63-17 fluorophenyl H H H H CO2H
4-chloro-3-
63-18 fluorophenyl H H H H COgMe
4-chloro-3-
63-19 fluorophenyl H H Me H CO2H
4-chloro-3-
63-20 fluorophenyl H H Me H COgMe
4-chloro-3-
63-21 fluorophenyl Me H H H CO2H
4-chloro-3-
63-22 fluorophenyl Me H H H COzMe
4-chloro-3-
63-23 fluorophenyl Me H Me H CO2H
4-chloro-3-
63-24 fluorophenyl Me H Me H COgMe
4-chloro-3-
63-25 fluorophenyl H H H Me CO2H
4-chloro-3-
63-26 fluorophenyl H H H Me COgMe
4-chloro-3-
63-27 fluorophenyl H H Me Me COgH
4-chloro-3-
63-28 fluorophenyl H H Me Me C02Me
4-chloro-3-
63-29 fluorophenyl Me H H Me CO2H
4-chloro-3-
63-30 fluorophenyl Me H H Me COgMe
4-chloro-3-
63-31 fluorophenyl Me H Me Me CO2H
4-chloro-3-
63-32 fluorophenyl Me H Me Me COgMe
4-chloro-3-
63-33 fluorophenyl H H H Me C02Et
4-chloro-3-
63-34 fluorophenyl H H H Me C02n-Pr
4-chloro-3-
63-35 fluorophenyl H H H Me C02i-Pr
4-chloro-3-
63-36 fluorophenyl H H H Me C02CH2CH=CH2
4-chloro-3-
63-37 fluorophenyl H H H Me C02CH2CH20Me
4-chloro-3-
63-38 fluorophenyl H H H Me C02CH2Ph
4-chloro-3-
63-39 fluorophenyl H H Me Me C02Et
~63"-40 I 4-chloro-3- I H | H | Me | Me | COgn-Pr
38

Compound Substituent Values
Number A I RM R" R^' I R^ . Z
fluorophenyl
4-chloro-3-
63-41 fluorophenyl H H Me Me CQzi-Pr
4-chloro-3-
63-42 fluorophenyl H H Me Me C02CH2CH=CH2
4-chloro-3-
63-43 fluorophenyl H H Me Me COzCHzCHgOMe
4-chloro-3-
63-44 fluorophenyl H H Me Me COzCHzPh
4-chloro-3-
63-45 fluorophenyl Me H H Me COzEt
4-chloro-3- ■
63-46 fluorophenyl Me H H Me CQzn-Pr
4-chloro-3-
63-47 fluorophenyl Me H H Me CQzi-Pr
4-chloro-3-
63-48 fluorophenyl Me H H Me C0zCHzCH=CH2
4-chloro-3-
63-49 fluorophenyl Me H H Me CQzCHzCHzOMe
4-chloro-3-
63-50 fluorophenyl Me H H Me COzCHzPh
4-chloro-3-
63-51 fluorophenyl Me H Me Me CQzEl
4-chloro-3-
63-52 fluorophenyl Me H Me Me COzn-Pr
4-chloro-3-
63-53 fluorophenyl Me H Me Me CQzi-Pr
4-chloro-3-
63-54 fluorophenyl Me H Me Me CQzCHzCH=CH2
4-chloro-3-
63-55 fluorophenyl Me H Me Me CQzCHzCHzOMe
4-chloro-3-
63-56 fluorophenyl Me | H Me Me COzCHzPh
4-chloro-3-
63-57 fluorophenyl =0 H Me COzH
4-chloro-3-
63-58 fluorophenyl =0 H Me COzMe
4-chloro-3-
63-59 fluorophenyl =0 Me Me COzH
4-chloro-3-
63-60 fluorophenyl =0 Me Me COzMe
4-chloro-3-
63-61 fluorophenyl CHgCHz H Me COzH
4-chloro-3-
63-62 fluorophenyl CHzCH; H Me COzMe
4-chloro-3-
63-63 fluorophenyl CHzCH; Me Me COzH
4-chloro-3-
63-64 fluorophenyl CHzCH? Me Me COzMe
4-chloro-2-fluoro-3-
63-65 I methoxyphenyl | H | H | H I H | COzH
39

rnrnpniinH I SubstJtuent Values
Number A R' R' R°' R^ Z
4-chloro-2-fluoro-3-
63-66 methoxyphenyl H H H H COaMe
4-chloro-2-fluoro-3-
63-67 methoxyphenyl H H Me H CO2H
4-chloro-2-fluoro-3-
63-68 methoxyphenyl H H Me H COaMe
4-chloro-2-fluoro-3-
63-69 methoxyphenyl Me H H H CO2H
4-chloro-2-fluoro-3-
63-70 methoxyphenyl Me H H H COgMe
4-chloro-2-fluoro-3-
63-71 methoxyphenyl Me H Me H CO2H
4-chloro-2-fluoro-3-
63-72 methoxyphenyl Me H Me H COaMe
4-chloro-2-fluoro-3-
63-73 methoxyphenyl H H H Me CO2H
4-chloro-2-fluoro-3-
63-74 methoxyphenyl H H H Me COzMe
4-chloro-2-fluoro-3-
63-75 methoxyphenyl H H Me Me CO2H
4-chloro-2-fluoro-3-
63-76 methoxyphenyl H H Me Me CQ2Me
4-chloro-2-fluoro-3-
63-77 methoxyphenyl Me H H Me CQ2H
4-chloro-2-fluoro-3-
63-78 methoxyphenyl Me H H Me COaMe
4-chloro-2-fluoro-3-
63-79 methoxyphenyl Me H Me Me CO2H
4-chloro-2-fluoro-3-
63-80 methoxyphenyl Me H Me Me COaMe
4-chloro-2-fluoro-3-
63-81 methoxyphenyl H H H Me C02Et
4-chloro-2-fluoro-3-
63-82 methoxyphenyl H H H Me C02n-Pr
4-chloro-2-fluoro-3-
63-83 methoxyphenyl H H H Me COgi-Pr
4-chloro-2-fluoro-3-
63-84 methoxyphenyl H H H Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
63-85 methoxyphenyl H H H Me COgCHgCHgOMe
4-ch loro-2-f I uoro-3-
63-86 methoxyphenyl H H H Me COjCHzPh
4-chloro-2-fluoro-3-
63-87 methoxyphenyl H H Me Me COgEt
4-chloro-2-fluoro-3-
63-88 methoxyphenyl H H Me Me COgn-Pr
4-chloro-2-fluoro-3-
63-89 methoxyphenyl H H Me Me COzi-Pr
4-chloro-2-fluoro-3-
63-90 methoxyphenyl H H Me Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
63-91 I methoxyphenyl | H | H [Me | Me | C02CH2CH20Me
40

Compound Substituent Values
Number A I RM RM R^' RM Z
4-chloro-2-fluoro-3-
63-92 methoxyphenyl H H Me Me C02CH2ph
4-chloro-2-fluoro-3-
63-93 methoxyphenyl Me H H Me C02Et
4-chloro-2-fluoro-3-
63-94 methoxyphenyl Me H H Me CQ2n-Pr
4-chloro-2-fluoro-3-
63-95 methoxyphenyl Me H H Me C02i-Pr
4-chloro-2-fluoro-3-
63-96 methoxyphenyl Me H H Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
63-97 methoxyphenyl Me H H Me C02CH2CH20Me
4-chloro-2-fluoro-3-
63-98 methoxyphenyl Me H H Me C02CH2Ph
4-chloro-2-fluoro-3-
63-99 methoxyphenyl Me H Me Me C02Et
4-chloro-2-fluoro-3-
63-100 methoxyphenyl Me H Me Me C02n-Pr
4-chloro-2-fluoro-3-
63-101 methoxyphenyl Me H Me Me C02i-Pr
4-chloro-2-fluoro-3-
63-102 methoxyphenyl Me H Me Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
63-103 methoxyphenyl Me H Me Me C02CH2CH20Me
4-chloro-2-fluoro-3-
63-104 methoxyphenyl Me | H Me Me C02CH2Ph
4-chloro-2-fluoro-3-
63-105 methoxyphenyl =0 H Me CO2H
4-chloro-2-fluoro-3-
63-106 methoxyphenyl =0 H Me COgMe
4-chloro-2-fluoro-3-
63-107 methoxyphenyl =0 Me Me CO2H
4-ch loro-2-f luo ro-3-
63-108 methoxyphenyl =0 Me Me C02Me
4-chloro-2-fluoro-3-
63-109 methoxyphenyl CH2CH2 H Me CO2H
4-ch loro-2-f I uoro-3-
63-110 methoxyphenyl CH2CH2 H Me C02Me
4-chloro-2-fluoro-3-
63-111 methoxyphenyl CH2CH2 Me Me CO2H
4-chloro-2-fluoro-3-
63-112 methoxyphenyl CH2CH2 Me Me C02Me
4-chloro-3-
dimethylamino-2-
63-113 fluorophenyl H H H Me CO2H
4-chloro-3-
dimethylamino-2-
63-114 fluorophenyl H H H Me C02Me
4-chloro-3-
dimethylamino-2-
63-115 fluorophenyl H H Me Me CO2H
"~63-116 I 4-chloro-3- |H |H | Me | Me | C02Me
41

Compound Substituent Values
Number A | RM R° I R^ I R^ Z
dimethylamino-2-
fluorophenyl
4-chloro-3-
dimethylamino-2-
63-117 fluorophenyl Me H H Me CO2H
4-chloro-3-
dimethylamino-2-
63-118 fluorophenyl Me H H Me COzMe
4-chloro-3-
dimethylamino-2-
63-119 fluorophenyl Me H Me Me CO2H
4-chloro-3-
dimethylamino-2-
63-120 fluorophenyl Me H Me Me C02Me
63-121 cyclopropyl Me Me H Me CO2H
63-122 cyclopropyl Me Me H Me COgMe
63-123 cyclopropyl Me Me Me Me CO2H
63-124 cyclopropyl Me Me Me Me C02Me
63-125 4-chlorophenyl Me Me H Me CO2H
63-126 4-chiorophenyl Me Me H Me COgMe
63-127 4-chlorophenyl Me Me Me Me CO2H
63-128 4-chlorophenyl Me Me Me Me C02Me
4-chloro-3-
63-129 fluorophenyl Me Me H H CO2H
4-chloro-3-
63-130 fluorophenyl Me Me H H C02Me
4-chloro-3-
63-131 fluorophenyl Me Me Me H CO2H
4-chloro-3-
63-132 fluorophenyl Me Me Me H C02Me
4-chloro-3-
63-133 fluorophenyl Me Me H Me CO2H
4-ch!oro-3-
63-134 fluorophenyl Me Me H Me C02Me
4-chloro-3-
63-135 fluorophenyl Me Me Me Me CO2H
4-chloro-3-
63-136 fluorophenyl Me Me Me Me COgMe
4-chloro-3-
63-137 fluorophenyl Me Me H Me COgEt
4-chloro-3-
63-138 fluorophenyl Me Me H Me COzn-Pr
4-chloro-3-
63-139 fluorophenyl Me Me H Me COzi-Pr
4-chloro-3-
63-140 fluorophenyl Me Me H Me C02CH2CH=CH2
4-chloro-3-
63-141 fluorophenyl Me Me H Me COzCHzCHzOMe
4-chloro-3-
63-142 fluorophenyl Me Me H Me COzCHzPh
~63-143 I 4-chloro-3- I Me | Me I Me | Me I C02Et
42

Compound Substituent Values
Number A R' R" R°' R^ Z
fluorophenyl
4-chloro-3-
63-144 fluorophenyl Me Me Me Me COan-Pr
4-chloro-3-
63-145 fluorophenyl Me Me Me Me COai-Pr
4-chloro-3-
63-146 fluorophenyl Me Me Me Me C02CH2CH=CH2
4-chloro-3-
63-147 fluorophenyl Me Me Me Me COaCHgCHaOMe
4-chloro-3-
63-148 fluorophenyl Me Me Me Me COaCHzPh
4-chloro-2-fluoro-3-
63-149 methoxyphenyl Me Me H H CO2H
4-chloro-2-fluoro-3-
63-150 methoxyphenyl Me Me H H COaMe
4-chloro-2-fluoro-3-
63-151 methoxyphenyl Me Me Me H COgH
4-chloro-2-fluoro-3-
63-152 methoxyphenyl Me Me Me H COzMe
4-chloro-2-fiuoro-3-
63-153 methoxyphenyl Me Me H Me CO2H
4-chloro-2-fluoro-3-
63-154 methoxyphenyl Me Me H Me COgMe
4-chloro-2-fluoro-3-
63-155 methoxyphenyl Me Me Me Me CO2H
4-chloro-2-fluoro-3-
63-156 methoxyphenyl Me Me Me Me COaMe
4-chloro-2-fluoro-3-
63-157 methoxyphenyl Me Me H Me C02Et
4-chloro-2-fluoro-3-
63-158 methoxyphenyl Me Me H Me C02n-Pr
4-chloro-2-fluoro-3-
63-159 methoxyphenyl Me Me H Me C02i-Pr
4-chloro-2-fluoro-3-
63-160 methoxyphenyl Me Me H Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
63-161 methoxyphenyl Me Me H Me CQ2CH2CH2QMe
4-chloro-2-fluoro-3-
63-162 methoxyphenyl Me Me H Me COgCHgPh
4-chloro-2-fluoro-3-
63-163 methoxyphenyl Me Me Me Me C02Et
4-chloro-2-fluoro-3-
63-164 methoxyphenyl Me Me Me Me C02n-Pr
4-chloro-2-fluoro-3-
63-165 methoxyphenyl Me Me Me Me C02i-Pr
4-chloro-2-fluoro-3-
63-166 methoxyphenyl Me Me Me Me C02CH2CH=CH2
4-chloro-2-fluoro-3-
63-167 methoxyphenyl Me_ Me Me Me C02CH2CH20Me
4-chloro-2-fluoro-3-
63-168 I methoxyphenyl | Me | Me I Me I Me | COzCHaPh |
43

Compound Substituent Values
Number A I R^ R" R"' R^ 2
4-chloro-3-
dimethylamino-2-
63-169 fluorophenyl Me Me H Me CO2H
4-chloro-3-
dimethylamino-2-
63-170 fluorophenyl Me Me H Me COgMe
4-chloro-3-
dimethylamino-2-
63-171 fluorophenyl Me Me Me Me CO2I-I
4-chIoro-3-
dimethylamino-2-
63-172 I fluorophenyl j Me I Me | Me I Me | COzMe
172 compounds are described, designated compounds 64-1 to 64-172 respectively, of formula (1C) wherein D is N and X is NMe, and the values of A, R^ R^ R^ R*' and Z are as defined in Table 3.
172 compounds are described, designated compounds 65-1 to 65-172 respectively, of formula (1C) wherein D is N and X is O, and the values of A, R^ R^ R®. R^' and Z are as defined in Table 3.
172 compounds are described, designated compounds 66-1 to 66-172 respectively, of formula (1C) wherein D is N and X is S, and the values of A, R^, R^, R^, R^' and Z are as defined in Table 3.
172 compounds are described, designated compounds 67-1 to 67-172 respectively, of formula (1C) wherein D is CH and X is NH, and the values of A. R^ R^ R^ R*' and Z are as defined in Table 3.
172 compounds are described, designated compounds 68-1 to 68-172 respectively, of formula (1C) wherein D is CH and X is NMe, and the values of A, R^ R^ R®. R*' and Z are as defined in Table 3.
172 compounds are described, designated compounds 69-1 to 69-172 respectively, of formula (1C) wherein D is CH and X is O. and the values of A, R^ R'', R', R^' and Z are as defined in Table 3.
44

172 compounds are described, designated compounds 70-1 to 70-172 respectively, of
formula (IC) wfierein D is CH and X is S, and the values of A. R^, R^ R^ R^' and Z are
as defined in Table 3.
Table 4 below provides 240 compounds designated compounds 71-1 to 71-240 respectively, of fomriula (ID) wherein D is N and X is NH.
R\ R' ,.
(1D)
TABLE 4
Compound Substituent Values
Number A I RM R" R^' I R^' I RM RM Z ~
71-1 cyclopropyl H H H H H H COgH
71-2 cyclopropyl H H H H H H COgMe
71-3 cyclopropyl H H H H H Me CO2H
71-4 cyclopropyl H H H H H Me COzMe
71-5 cyclopropyl H H H H Me Me CO2H
71-6 cyclopropyl H H H H Me Me COzMe
71-7 cyclopropyl H H H Me H H CO2H
71-8 cyclopropyl H H H Me H H COgMe
71-9 cyclopropyl H H H Me H Me COgH
71-10 cyclopropyl H H H Me H Me COgMe
71-11 cyclopropyl H H H Me Me Me CO2H
71-12 cyclopropyl H H H Me Me Me COaMe
71-13 cyclopropyl H H Me Me H H CO2H
71-14 cyclopropyl H H Me Me H H C02Me
71-15 cyclopropyl H H Me Me H Me CO2H
71-16 cyclopropyl H H Me Me H Me C02Me
71-17 cyclopropyl H H Me Me Me Me CO2H
71-18 cyclopropyl H H Me Me Me | Me C02Me
71-19 cyclopropyl H H Me Me =CH2 CO2H
71-20 cyclopropyl H H Me Me =CH2 COzMe
71-21 cyclopropyl H Me H H H I H CQ2H
71-22 I cyclopropyl |H iMelHIH |H |H | COgMe
45

Compound Substituent Values
Number A R^ I R" R^' R"' R^ I R^ Z
71-23 cyclopropyl H Me H H H Me COgH
71-24 cyclopropyl H Me H H H Me COgMe
71-25 cyclopropyl H Me H H Me Me CO2H
71-26 cyclopropyl H Me H H Me Me COgMe
71-27 cyclopropyl H Me H Me H H CO2H
71-28 cyclopropyl H Me H Me H H COgMe
71-29 cyclopropyl H Me H Me H Me CO2H
71-30 cyclopropyl H Me H Me H Me C02Me
71-31 cyclopropyl H Me H Me Me Me CO2H
71-32 cyclopropyl H Me H Me Me Me C02Me
71-33 cyclopropyl H Me Me Me H H CO2H
71-34 cyclopropyl H Me Me Me H H CO?Me
71-35 cyclopropyl H Me Me Me H Me CO2H
71-36 cyclopropyl H Me Me Me H Me C02Me
71-37 cyclopropyl H Me Me Me Me Me CO2H
71-38 cyclopropyl H Me Me Me Me | Me " C02Me
71-39 cyclopropyl H Me Me Me =CH2 CQ2H
71-40 cyclopropyl H Me Me Me =CH2 CQ2Me
71-41 cyclopropyl Me Me H H H I H CO2H
71-42 cyclopropyl Me Me H H H H C02Me
71-43 cyclopropyl Me Me H H H Me CO2H
71-44 cyclopropyl Me Me H H H Me COzMe
71-45 cyclopropyl Me Me H H Me Me CO2H
71-46 cyclopropyl Me Me H H Me Me C02Me
71-47 cyclopropyl Me Me H Me H H CO2H
71-48 cyclopropyl Me Me H Me H H C02Me
71-49 cyclopropyl Me Me H Me H Me CO2H
71-50 cyclopropyl Me Me H Me H Me C02Me
71-51 cyclopropyl Me Me H Me Me Me CO2H
71-52 cyclopropyl Me Me H Me Me Me C02Me
71-53 cyclopropyl Me Me Me Me H H CO2H
71-54 cyclopropyl Me Me Me Me H H C02Me
71-55 cyclopropyl Me Me Me Me H Me CQ2H
71-56 cyclopropyl Me Me Me Me H Me C02Me
71-57 cyclopropyl Me Me Me Me Me Me CO2H
71-58 cyclopropyl Me Me Me Me Me | Me C02Me
71-59 cyclopropyl Me Me Me Me =CH2 COgH
71-60 cyclopropyl Me | Me Me Me =CH2 C02Me
71-61 cyclopropyl =0 H H H I H CO2H
71-62 cyclopropyl =0 H H H H COgMe
71-63 cyclopropyl =0 H H H Me CO2H
71-64 cyclopropyl =0 H H H Me COzMe
71-65 cyclopropyl =0 H H Me Me CO2H
71-66 cyclopropyl =0 H H Me Me COgMe
~7T-67 I cyclopropyl I =0 I H | Me | H | H | CO2H
46

Compound Substituent Values
Number ~ A I RM RM R"' I R" R^ I R^ Z
71-68 cyclopropyl =0 H Me H H COaMe
71-69 cyclopropyl =0 H Me H Me CO2H
71-70 cyclopropyl =0 H Me H Me CQ2Me
71-71 cyclopropyl =0 H Me Me Me CO2H
71-72 cyclopropyl =0 H Me Me Me COaMe
71-73 cyclopropyl =0 Me Me H H CO2H
71-74 cyclopropyl =0 Me Me H H COaMe
71-75 cyclopropyl =0 Me Me H Me CO2H
71-76 cyclopropyl =0 Me Me H Me COaMe
71-77 cyclopropyl =0 Me Me Me Me CO2H
71-78 cyclopropyl =0 Me Me MelMe COaMe
71-79 cyclopropyl =0 Me Me =CH2 CQ2H
71-80 cyclopropyl =0 Me Me =CH? C02Me
4-chloro-3- I I
_7^81 fluorophenyl H H H H H H CO2H
4-chloro-3-
71-82 fluorophenyl H H H H H H C02Me
4-chloro-3-
71-83 fluorophenyl H H H H H Me COgH
4-chloro-3-
71-84 fluorophenyl H H H H H Me C02Me
4-chloro-3-
71-85 fluorophenyl H H H H Me Me CO2H
4-chloro-3-
71-86 fluorophenyl H H H H Me Me C02Me
4-chloro-3-
71-87 fluorophenyl H H H Me H H CO2H
4-chloro-3-
71-88 fluorophenyl H H H Me H H C02Me
4-chloro-3-
71-89 fluorophenyl H H H Me H Me CQ2H
4-chloro-3-
71-90 fluorophenyl H H H Me H Me COgMe
4-chloro-3-
71-91 fluorophenyl H H H Me Me Me CO2H
4-chloro-3-
71-92 fluorophenyl H H H Me Me Me COgMe
4-chloro-3-
71-93 fluorophenyl H H Me Me H H CO2H
4-chloro-3-
71-94 fluorophenyl H H Me Me H H COgMe
4-chloro-3-
71-95 fluorophenyl H H Me Me H Me CO2H
4-chloro-3-
71-96 fluorophenyl H H Me Ma H Me COgMe
4-chloro-3-
71-97 fluorophenyl H H Me Me Me Me CO2H
4-chloro-3-
71-98 fluorophenyl H H Me Me Me | Me COgMe
'7l"-99 I 4-chloro-3- I H | H | Me I Me | =CH2 I CO2H
47

Compntinri I SubstJtuent Values
Number A R' R" R'" R^' 1 RM R^ Z
fluorophenyl
4-chloro-3-
71-100 fluorophenyl H H Me Me =CH2 C02Me
4-chloro-3-
71-101 fluorophenyl H Me H H H H COgH
4-chloro-3-
71-102 fluorophenyl H Me H H H H COzMe
4-chloro-3-
71-103 fluorophenyl H Me H H H Me COgH
4-chioro-3-
71-104 fluorophenyl H Me H H H Me COzMe
4-chloro-3-
71-105 fluorophenyl H Me H H Me Me COgH
4-chloro-3-
71-106 fluorophenyl H Me H H Me Me COgMe
4-chloro-3-
71-107 fluorophenyl H Me H Me H H COgH
4-chloro-3-
71-108 fluorophenyl H Me H Me H H COaMe
4-chloro-3-
71-109 fluorophenyl H Me H Me H Me CO2H
4-chloro-3-
71-110 fluorophenyl H Me H Me H Me COgMe
4-chloro-3-
71-111 fluorophenyl H Me H Me Me Me CO2H
4-chloro-3-
71-112 fluorophenyl H Me H Me Me Me COzMe
4-chloro-3-
71-113 fluorophenyl H Me Me Me H H CO2H
4-chloro-3-
71-114 fluorophenyl H Me Me Me H H COzMe
4-chloro-3-
71-115 fluorophenyl H Me Me Me H Me COgH
4-chloro-3-
71-116 fluorophenyl H Me Me Me H Me COzMe
4-chloro-3-
71-117 fluorophenyl H Me Me Me Me Me CO2H
4-chloro-3-
71-118 fluorophenyl H Me Me Me Me | Me COzMe
4-chloro-3-
71-119 fluorophenyl H Me Me Me =CH2 CO2H
4-chloro-3-
71-120 fluorophenyl H Me Me Me =CH2 COzMe
4-chloro-3-
71-121 fluorophenyl Me Me H H H H CO2H
4-chloro-3-
71-122 fluorophenyl Me Me H H H H COgMe
4-chloro-3-
71-123 fluorophenyl Me Me H H H Me CO2H
4-chloro-3-
71-124 I fluorophenyl I Me | Me I H | H | H [Me I COgMe
48

Compound Substituent Values
Number A I RM R" I R^ I R^ | R^ } ^^ \ ^
4-chloro-3-
71-125 fluorophenyl Me Me H H Me Me CO2H
4-chloro-3-
71-126 fluorophenyl Me Me H H Me Me COzMe
4-chloro-3-
71-127 fluorophenyl Me Me H Me H H CG2H
4-chloro-3-
71-128 fluorophenyl Me Me H Me H H COzMe
4-chloro-3-
71-129 fluorophenyl Me Me H Me H Me CO2H
4-chloro-3-
71-130 fluorophenyl Me Me H Me H Me COzMe
4-chloro-3-
71-131 fluorophenyl Me Me H Me Me Me CO2H
4-chloro-3-
71-132 fluorophenyl Me Me H Me Me Me COzMe
4-chloro-3-
71-133 fluorophenyl Me Me Me Me H H CO2H
4-chloro-3-
71-134 fluorophenyl Me Me Me Me H H COzMe
4-chloro-3-
71-135 fluorophenyl Me Me Me Me H Me CO2H
4-chloro-3-
71-136 fluorophenyl Me Me Me Me H Me COzMe
4-chloro-3-
71-137 fluorophenyl Me Me Me Me Me Me COzH
4-chloro-3-
71-138 fluorophenyl Me Me Me Me Me | Me COzMe
4-chloro-3-
71-139 fluorophenyl Me Me Me Me =CHz COzH
4-chloro-3-
71-140 fluorophenyl Me | Me Me Me =CH2 COzMe
4-chloro-3-
71-141 fluorophenyl =0 H H H H COzH
4-chloro-3-
71-142 fluorophenyl =0 H H H H COzMe
4-chloro-3-
71-143 fluorophenyl =0 H H H Me COzH
4-chloro-3-
71-144 fluorophenyl =0 H H H Me COzMe
4-chloro-3-
71-145 fluorophenyl =0 H H Me Me COzH
4-chloro-3-
71-146 fluorophenyl =0 H H Me Me COzMe
4-chloro-3-
71-147 fluorophenyl =0 H Me H H COzH
4-chloro-3-
71-148 fluorophenyl =0 H Me H H COzMe
4-chloro-3-
71-149 fluorophenyl =0 H Me H Me COzH
4-chloro-3-
71-150 1 fluorophenyl j =0 I H 1 Me 1 H I Me 1 COgMe
49

Compound Substituent Values
Number A I R'l RM R^' I R^ I R^ I RM Z
4-chloro-3-
71-151 fluorophenyl =0 H Me Me Me COgH
4-chloro-3-
71-152 fluorophenyl =0 H Me Me Me COgMe
4-chloro-3-
71-153 fluorophenyl =0 Me Me H H CQgH
4-chloro-3-
71-154 fluorophenyl =0 Me Me H H CQ?.Me
4-chloro-3-
71-155 fluorophenyl =0 Me Me H Me CO2H
4-chloro-3-
71-156 fluorophenyl =0 Me Me H Me CO?Me
4-chloro-3-
71-157 fluorophenyl =0 Me Me Me Me CO2H
4-chloro-3-
71-158 fluorophenyl =0 Me Me Me | Me COgMe
4-chloro-3-
71-159 fluorophenyl =0 Me Me =CH2 CO^H
4-chloro-3-
71-160 fluorophenyl =0 Me Me =CH2 COgMe
4-chloro-2-fluoro-3-
71-161 methoxyphenyl H H H H H H CO2H
4-chloro-2-fluoro-3-
71-162 methoxyphenyl H H H H H H COgMe
4-chloro-2-fluoro-3-
71-163 methoxyphenyl H H H H H Me CO2H
4-chloro-2-fluoro-3-
71-164 methoxyphenyl H H H H H Me CO2M6
4-chloro-2-fluoro-3-
7_1-165 methoxyphenyl H H H H Me Me CO2H
4-chloro-2-fluoro-3-
71-166 methoxyphenyl H H H H Me Me CQ2Me
4-chloro-2-fluoro-3-
71-167 methoxyphenyl H H H Me H H CO2H
4-chloro-2-fluoro-3-
71-168 methoxyphenyl H H H Me H H COgMe
4-ch loro-2-f I uoro-3-
71-169 methoxyphenyl H H H Me H Me CO2H
4-chloro-2-fluoro-3-
71-170 methoxyphenyl H H H Me H Me COgMe
4-chloro-2-fluoro-3-
71-171 methoxyphenyl H H H Me Me Me CO2H
4-chloro-2-fluoro-3-
71-172 methoxyphenyl H H H Me Me Me C02Me
4-chloro-2-fluoro-3-
71-173 methoxyphenyl H H Me Me H H CO2H
4-chloro-2-fluoro-3-
71-174 methoxyphenyl H H Me Me H H C02Me
4-chloro-2-fluoro-3-
71-175 methoxyphenyl H H Me Me H Me CO2H
4-chloro-2-fluoro-3-
71-176 I methoxyphenyl I H | H I Me | Me I H | Me | CO?Me
50

r.r.rr^pnnnr\ I Substituent Values
Number A R' R" | R^' R° R' R^ Z
4-chloro-2-fluoro-3-
71-177 methoxyphenyl H H Me Me Me Me CO2H
4-chloro-2-fluoro-3-
71-178 methoxyphenyl H H Me Me Me | Me C02Me
4-chloro-2-fluoro-3-
71-179 methoxyphenyl H H Me Me =CH2 CO2H
4-chloro-2-fluoro-3-
71-180 methoxyphenyl H H Me Me =CH2 C02Me
4-chloro-2-fiuoro-3-
71-181 methoxyphenyl H Me H H H H CO2H
4-chloro-2-fluoro-3-
71-182 methoxyphenyl H Me H H H H COgMe
4-chloro-2-fIuoro-3-
71-183 methoxyphenyl H Me H H H Me CO2H
4-chloro-2-fluoro-3-
71-184 methoxyphenyl H Me H H H Me C02Me
4-chloro-2-fluoro-3-
71-185 methoxyphenyl H Me H H Me Me CO2H
4-chloro-2-fluoro-3-
71-186 methoxyphenyl H Me H H Me Me COzMe
4-chloro-2-fIuoro-3-
71-187 methoxyphenyl H Me H Me H H CO2H
4-chloro-2-fluoro-3-
71-188 methoxyphenyl H Me H Me H H COgMe
4-chloro-2-fluoro-3-
71-189 methoxyphenyl H Me H Me H Me CO2H
4-chloro-2-fluoro-3-
71-190 methoxyphenyl H Me H Me H Me COgMe
4-chloro-2-fluoro-3-
71-191 methoxyphenyl H Me H Me Me Me CO2H
4-chloro-2-fluoro-3-
71-192 methoxyphenyl H Me H Me Me Me C02Me
4-chloro-2-fluoro-3-
71-193 methoxyphenyl H Me Me Me H H CO2H
4-chloro-2-fluoro-3-
71-194 methoxyphenyl H Me Me Me H H C02Me
4-chloro-2-fluoro-3-
71-195 methoxyphenyl H Me Me Me H Me CO2H
4-chloro-2-fluoro-3-
71-196 methoxyphenyl H Me Me Me H Me C02Me
4-chloro-2-fluoro-3-
71-197 methoxyphenyl H Me Me Me Me Me CO2H
4-chloro-2-fluoro-3-
71-198 methoxyphenyl H Me Me Me Me | Me C02Me
4-chloro-2-fluoro-3-
71-199 methoxyphenyl H Me Me Me =CH2 CO2H
4-chloro-2-fluoro-3-
71-200 methoxyphenyl H Me Me Me =CH2 C02Me
4-chloro-2-fluoro-3- I
71-201 methoxyphenyl Me_ Me H H H H CO2H
4-chloro-2-fluoro-3-
71-202 I methoxyphenyl | Me | Me I H I H I H | H | CO?Me
51

Compound Substituent Values
Number A R' R" | R^' j R*^' R^ R^ Z
4-chloro-2-fluoro-3-
71-203 methoxyphenyl Me Me H H H Me CO2H
4-chloro-2-fluoro-3-
71-204 methoxyphenyl Me Me H H H Me COgMe
4-chloro-2-fluoro-3-
71-205 methoxyphenyl Me Me H H Me Me CO2H
4-chloro-2-fluoro-3-
71-206 methoxyphenyl Me Me H H Me Me C02Me
4-chloro-2-fluoro-3-
71-207 methoxyphenyl Me Me H Me H H CO2H
4-chloro-2-fluoro-3-
71-208 methoxyphenyl Me Me H Me H H C02Me
4-chloro-2-fluoro-3- |
71-209 methoxyphenyl Me Me H Me H Me CO2H
4-chloro-2-fluoro-3-
71-210 methoxyphenyl Me Me H Me H Me C02Me
4-chloro-2-fluoro-3-
71-211 methoxyphenyl Me Me H Me Me Me CO2H
4-chloro-2-fluoro-3-
71-212 methoxyphenyl Me Me H Me Me Me C02Me
4-chloro-2-fluoro-3- |
71-213 methoxyphenyl Me Me Me Me H H CO2H
4-chloro-2-fluoro-3-
71-214 methoxyphenyl Me Me Me Me H H C02Me
4-chloro-2-fluoro-3-
71-215 methoxyphenyl Me Me Me Me H Me CQ2H
4-chloro-2-fluoro-3-
71-216 methoxyphenyl Me Me Me Me H Me C02Me
4-chloro-2-fluoro-3-
71-217 methoxyphenyl Me Me Me Me Me Me CO2H
4-chloro-2-fluoro-3-
71-218 methoxyphenyl Me Me Me Me Me | Me C02Me
4-chloro-2-fluoro-3-
71-219 methoxyphenyl Me Me Me Me =CH2 CO2H
4-chloro-2-fluoro-3-
71-220 methoxyphenyl Me | Me Me Me =CH2 C02Me
4-chloro-2-fluoro-3- [
71-221 methoxyphenyl =0 H H H H CO2H
4-chloro-2-fluoro-3-
71-222 methoxyphenyl =0 H H H H CO^Me
4-chloro-2-fluoro-3-
71-223 methoxyphenyl =0 H H H Me CO2H
4-chloro-2-fluoro-3-
71-224 methoxyphenyl =0 H H H Me C02Me
4-chloro-2-fluoro-3-
71-225 methoxyphenyl =0 H H Me Me CO2H
4-chloro-2-fluoro-3-
71-226 methoxyphenyl =0 H H Me Me CQ2Me
4-chloro-2-fluoro-3-
71-227 methoxyphenyl =0 H Me H H CO2H
4-chloro-2-fluoro-3-
71-228 I methoxyphenyl I =0 I H | Me | H | H | COzMe
52

rnmpniinri I SubstJtuent Values
Number A R' | R^ | R^' | R" R^ R^ Z
4-chloro-2-fluoro-3-
71-229 methoxyphenyl =0 H Me H Me CO2H
4-chloro-2-fluoro-3-
71-230 methoxyphenyl =0 H Me H Me C02Me
4-chloro-2-fluoro-3-
71-231 methoxyphenyl =0 H Me Me Me CO2H
4-chloro-2-fluoro-3-
71-232 methoxyphenyl =0 H Me Me Me C02Me
4-chloro-2-fluoro-3-
71-233 methoxyphenyl =0 Me Me H H CO2H
4-chloro-2-fluoro-3-
71-234 methoxyphenyl =Q Me Me H H COgMe
4-chloro-2-fluoro-3-
71-235 methoxyphenyl =0 Me Me H Me CO2H
4-chloro-2-fluoro-3-
71-236 methoxyphenyl =0 Me Me H Me COzMe
4-chloro-2-fluoro-3-
71-237 methoxyphenyl =0 Me Me Me Me CO2H
4-chloro-2-fluoro-3-
71-238 methoxyphenyl =0 Me Me Me | Me C02Me
4-chloro-2-fluoro-3-
71-239 methoxyphenyl =0 Me Me =CH2 COgH
4-chloro-2-fluoro-3-
71-240 I methoxyphenyl | =0 | Me | Me I =CH2 I COgMe
240 compounds are described, designated compounds 72-1 to 72-240 respectively, of formula (ID) wherein D is N and X is NMe, and the values of A. R^ R^, R^ R^', R^ R^' and Z are as defined in Table 4.
240 compounds are described, designated compounds 73-1 to 73-240 respectively, of fomiula (ID) wherein D is N and X is O, and the values of A, R^ R^, R^, R^', R^ R®' and Z are as defined in Table 4.
240 compounds are described, designated compounds 74-1 to 74-240 respectively, of formula (ID) wherein D is N and X is S, and the values of A, R^ R®, R^ R^', R^ R^' and Z are as defined in Table 4.
240 compounds are described, designated compounds 75-1 to 75-240 respectively, of formula (ID) wherein D is CH and X is NH. and the values of A, R^ R^ R^ R'', R^ R^' and Z are as defined in Table 4.
53

240 compounds are described, designated compounds 76-1 to 76-240 respectively, of formula (ID) wherein D is CH and X is NMe, and the values of A, R^ R^ R^ R^*, R^ R*' and Z are as defined in Table 4.
240 compounds are described, designated compounds 77-1 to 77-240 respectively, of formula (ID) wherein D is CH and X is O, and the values of A, R*, R*, R^ R^', R*. R"' and Z are as defined in Table 4.
240 compounds are described, designated compounds 78-1 to 78-240 respectively, of formula (ID) wherein D is CH and X is S. and the values of A, R^ R^ R^ R^', R*, R*' and Z are as defined in Table 4.
Table 5 below provides 84 compounds designated compounds 79-1 to 79-84 respectively, of formula (1E) wherein D is N and X is NH.
R^ ,
(IE)
TABLE 5
Compound Substituen Values
Number A | R^ RM R^ Z
79-1 cyclopropyl H H H CO2H
79-2 cyclopropyl H H H COzMe
79-3 cyclopropyl H H Me CO2H
79-4 cyclopropyl H H Me COgMe
79-5 cyclopropyl Me H H CO2H
79-6 cyclopropyl Me H H COaMe
79-7 cyclopropyl Me H Me CO2H
79-8 cyclopropyl Me | H Me CQzMe
79-9 cyclopropyl =0 H CO2H
79-10 cyclopropyl =0 H COzMe
79-11 cyclopropyl =0 Me CQ2H
79-12 cyclopropyl =0 Me C02Me
"~79^13 I 4-chlorophenyl | H | H | H I CO2H
54

rnmpnnnH I Substituen Values
Number A R^; Rf Rf Z
79-14 4-chlorophenyl H H H COyMe
79-15 4-chlorophenyl H H Me CO2H
79-16 4-chlorophenyl H H Me COzMe
79-17 4-chlorophenyl Me H H CO2H
79-18 4-chlorophenyl Me H H COaMe
79-19 4-chlorophenyl Me H Me CO2H
79-20 4-chlorophenyl Me | H Me COzMe
79-21 4-chlorophenyl =0 H CO2H
79-22 4-chlorophenyl =0 H COgMe
79-23 4-chlorophenyl =0 Me CO2H
79-24 4-chlorophenyl =0 Me COaMe
4-chloro-3-
79-25 fluorophenyl H H H CQ2H
4-chloro-3-
79-26 fluorophenyl H H H COgMe
4-chloro-3-
79-27 fluorophenyl H H Me CO2H
4-chloro-3-
79-28 fluorophenyl H H Me C02Me
4-chloro-3-
79-29 fluorophenyl Me H H CO2H
4-chloro-3-
79-30 fluorophenyl Me H H C02Me
4-chloro-3-
79-31 fluorophenyl Me H Me CO2H
4-chloro-3-
79-32 fluorophenyl Me | H Me COzMe
4-chloro-3-
79-33 fluorophenyl =0 H CO2H
4-chloro-3-
79-34 fluorophenyl =0 H C02Me
4-chloro-3-
79-35 fluorophenyl =0 Me CO2H
4-chloro-3-
79-36 fluorophenyl =0 Me COzMe
4-chloro-2-fluoro-3-
79-37 methoxyphenyl H H H CO2H
4-chloro-2-fluoro-3-
79-38 methoxyphenyl H H H C02Me
4-chloro-2-fluoro-3-
79-39 methoxyphenyl H H Me CO2H
4-chloro-2-fluoro-3-
79-40 methoxyphenyl H H Me C02Me
4-chloro-2-fluoro-3-
79-41 methoxyphenyl Me H H CO2H
4-chloro-2-fluoro-3-
79-42 methoxyphenyl Me H H COgMe
4-chloro-2-fluoro-3-
79-43 methoxyphenyl Me H Me COgH
79-44 I 4-chloro-2-fluoro-3- I Me I H | Me I CQ2Me
55

r.nmpo..nri I ~ Substituen Values
Number A BL-B! ^ Z
methoxyphenyl
4-chloro-2-fluoro-3-
79-45 methoxyphenyl Me H CH2Ph CO2H
4-chloro-2-fluoro-3-
79-46 methoxyphenyl Me H CHzPh C02Me
4-chloro-2-fluoro-3- CH2(2,4-
79-47 methoxyphenyl Me H dimethoxyphenyl) CO2H
4-chloro-2-fluoro-3- " CH2(2.4-
79-48 methoxyphenyl Me | H dimethoxyphenyl) C02Me
4-chloro-2-fluoro-3-
79-49 methoxyphenyl =0 H CO2H
4-chloro-2-fluoro-3-
79-50 methoxyphenyl =0 H COzMe
4-chloro-2-fluoro-3-
79-51 methoxyphenyl =0 Me CO2H
4-chioro-2-fluoro-3-
79-52 methoxyphenyl =0 Me COzMe
4-chloro-3-
dimethylamino-2-
79-53 fluorophenyl H H H CO2H
4-chloro-3-
dimethylamino-2-
79-54 fluorophenyl H H H C02Me
4-chloro-3-
dimethylamino-2-
79-55 fluorophenyl H H Me COgH
4-chloro-3-
dimethylamino-2-
79-56 fluorophenyl H H Me COgMe
4-chloro-3-
dimethylamino-2-
79-57 fluorophenyl Me H H CO2H
4-chloro-3-
dimethylamino-2-
79-58 fluorophenyl Me H H C02Me
4-chloro-3-
dimethylamino-2-
79-59 fluorophenyl Me H Me CO2H
4-chloro-3-
dimethylamino-2-
79-60 fluorophenyl Me | H Me COgMe
4-chloro-3-
dimethylamino-2-
79-61 fluorophenyl =0 H CO2H
4-chloro-3-
dimethylamino-2-
79-62 fluorophenyl =0 H C02Me
4-chloro-3-dimethylamino-2-
79-63 fluorophenyl =0 Me CO2H
4-chloro-3-
79-64 I dimethylamino-2- | =0 | Me | C02Me
56

rompnnnH I Subs Jtueti Values
Number A R^ | R' R^; Z
fluorophenyl
79-65 cyclopropyl Me Me H CO2H
79-66 cyclopropyl Me Me H C02Me
79-67 cyclopropyl Me Me Me CO2H
79-68 cyclopropyl Me Me Me C02Me
79-69 4-chlorophenyl Me Me H CO2H
79-70 4-chlorophenyl Me Me H C02Me
79-71 4-chlorophenyl Me Me Me CO2H
79-72 4-chlorophenyl Me Me Me C02Me
4-chloro-3-
79-73 fluorophenyl Me Me H CO2H
4-chloro-3-
79-74 fluorophenyl Me Me H C02Me
4-chloro-3-
79-75 fluorophenyl Me Me Me CO2H
4-chloro-3-
79-76 fluorophenyl Me Me Me C02Me
4-chloro-2-fluoro-3-
79-77 methoxyphenyl Me Me H CO2H
4-chloro-2-fluoro-3-
79-78 methoxyphenyl Me Me H C02Me
4-chloro-2-fluoro-3-
79-79 methoxyphenyl Me Me Me CO2H
4-chloro-2-fluoro-3-
79-80 methoxyphenyl Me Me Me C02Me
4-chloro-3-
dimethylamino-2-
79-81 fluorophenyl Me Me H CO2H
4-chloro-3-
dimethylamino-2-
79-82 fluorophenyl Me Me H COaMe
4-chloro-3-
climethylamino-2-
79-83 fluorophenyl Me Me Me CO2H
4-chloro-3-
dimethylamino-2-
79-84 I fluorophenyl | Me (Me [Me | COzMe
84 compounds are described, designated compounds 80-1 to 80-84 respectively, of formula (1E) wherein D is N and X is NMe, and the values of A, R^ R^ R^ and 2 are as defined in Table 5.
84 compounds are described, designated compounds 81-1 to 81-84 respectively, of
formula (1E) wherein D is N and X is NCH2Ph, and the values of A, R*. R^ R^ and Z are
as defined in Table 5.
57

84 compounds are described, designated compounds 82-1 to 82-84 respectively, of formula (IE) wherein D is N and X is NCH2{2-nitrophenyl), and the values of A. R^ R\ R* and Z are as defined in Table 5.
84 compounds are described, designated compounds 83-1 to 83-84 respectively, of formula (1E) wherein D is N and X is NCH2(2,4-dimethoxyphenyl), and the values of A, R^ R^ R' and Z are as defined in Table 5.
84 compounds are described, designated compounds 84-1 to 84-84 respectively, of formula (IE) wherein D is N and X is NCH2(2-furanyl), and the values of A, R^ R', R° and Z are as defined in Table 5.
84 compounds are described, designated compounds 85-1 to 85-84 respectively, of formula (1E) wherein D is CH and X is NH, and the values of A, R^, R^, R^ and Z are as defined in Table 5.
84 compounds are described, designated compounds 86-1 to 86-84 respectively, of formula (1E) wherein D is CH and X is NMe, and the values of A, R^, R^, R® and Z are as defined in Table 5.
84 compounds are described, designated compounds 87-1 to 87-84 respectively, of formula (1E) wherein D is CH and X is NCHzPh, and the values of A, R^, R^, R* and Z are as defined in Table 5.
84 compounds are described, designated compounds 88-1 to 88-84 respectively, of formula (1E) wherein D is CH and X is NCH2(2-nitrophenyl), and the values of A, R^ R^ R^ and Z are as defined in Table 5.
84 compounds are described, designated compounds 89-1 to 89-84 respectively, of fonnula (IE) wherein D is CH and X is NCH2(2,4-dimethoxyphenyl), and the values of A, R^ R^ R* and 2 are as defined in Table 5.
84 compounds are described, designated compounds 90-1 to 90-84 respectively, of formula (IE) wherein D is CH and X is NCH2(2-furanyl), and the values of A, R^ R^ R^ and Z are as defined in Table 5.
58

Table 6 below provides 240 compounds designated compounds 91-1 to 91-240
respectively, of formula (IF) wherein D is N and X is NH.
(1F)
TABLE 6
Cnrnpniinri | Substituent Values
Number A R' R« | R' R"' R^ Z
91-1 cyclopropyl H_±! H H H COgH
91-2 cyclopropyl !J__H H H H CQzMe
91-3 cyclopropyl H_±! H H Me CO2H
91-4 cyclopropyl H^Jj H H Me C02Me
91-5 cyclopropyl !i_Jd H H i-Pr CO2H
91-6 cyclopropyl H_±| H H i-Pr COgMe
91-7 cyclopropyl H_ii H H CHgPh CO2H
91-8 cyclopropyl H-_JJ H H CHzPh C02Me
91-9 cyclopropyl H_Jj H H Ph CO2H
91-10 cyclopropyl H__H H H Ph COgMe
91-11 cyclopropyl H^Jj H Me H CO2H
91-12 cyclopropyl H__H H Me H C02Me
91-13 cyclopropyl H__y H Me Me CO2H
91-14 cyclopropyl H__H H Me Me C02Me
91-15 cyclopropyl H__H Me Me H CO2H
91-16 cyclopropyl !i_±! Me Me H COgMe
91-17 cyclopropyl HL__H Me Me Me CO2H
91-18 cyclopropyl H__±! Me Me Me C02Me
91-19 cydopropyl H Me H H H CO2H
91-20 cyclopropyl H Me H H H C02Me
91-21 cyclopropyl H Me H H Me CO2H
91-22 cyclopropyl H Me H H Me COzMe
91-23 cyclopropyl H Me H Me H CO2H
91-24 cyclopropyl H Me H Me H CQ2Me
91-25 cyclopropyl H Me H Me Me CO2H
91-26 cyclopropyl H Me H Me Me C02Me
91-27 cyclopropyl H Me Me Me H COgH
~91-28 I cyclopropyl I H | Me I Me | Me | H I C02Me
59

r.nmpn..nri I SubstJtuent Values
Number A R' R" R'" R"' R^ Z
91-29 cyclopropyl H Me Me Me Me COgH
91-30 cyclopropyl H Me Me Me Me COgMe
91-31 cyclopropyl Me Me H H H CO2H
91-32 cyclopropyl Me Me H H H CQ2Me
91-33 cyclopropyl Me Me H H Me CQ2H
91-34 cyclopropyl Me Me H H Me CQgMe
91-35 cyclopropyl Me Me H Me H COgH
91-36 cyclopropyl Me Me H Me H COgMe
91-37 cyclopropyl Me Me H Me Me COgH
91-38 cyclopropyl Me Me H Me Me COgMe
91-39 cyclopropyl Me Me Me Me H CQ;H
91-40 cyclopropyl Me__Me Me Me H COgMe
91-41 cyclopropyl Me Me Me Me Me CQ2H
91-42 cyclopropyl Me Me Me Me Me C02Me
91-43 cyclopropyl H Ph H Ph H CO2H
91-44 cyclopropyl H Ph H Ph H C02Me
91-45 cyclopropyl H Ph H Ph Me CO2H
91-46 cyclopropyl H Ph | H Ph Me C02Me
91-47 cyclopropyl H (CH2)4 H H CO2H
91-48 cyclopropyl H (CH2)4 H H COzMe
91-49 cyclopropyl H (CH2)4 H Me CO2H
91-50 cyclopropyl H | (CH2i4 H Me C02Me
91-51 cyclopropyl =0 H H H CO2H
91-52 cyclopropyl =0 H H H C02Me
91-53 cyclopropyl =0 H H Me CO2H
91-54 cyclopropyl =0 H H Me C02Me
91-55 cyclopropyl =0 H Me H CO2H
91-56 cyclopropyl =0 H Me H C02Me
91-57 cyclopropyl =0 H Me Me CO2H
91-58 cyclopropyl =0 H Me Me CQ2Me
91-59 cyclopropyl =0 Me Me H CQ2H
91-60 cyclopropyl =0 Me Me H C02Me
91-61 cyclopropyl =0 Me Me Me CQ2H
91-62 cyclopropyl =0 "Me | Me Me C02Me
91-63 cyclopropyl H | H "" =0 H CO2H
91-64 cyclopropyl H H =0 H C02Me
91-65 cyclopropyl H H =0 Me CO2H
91-66 cyclopropyl H H =0 Me C02Me
91-67 cyclopropyl H Me =0 H CO2H
91-68 cyclopropyl H Me =0 H C02Me
91-69 cyclopropyl H Me =0 Me CO2H
91-70 cyclopropyl H Me =0 Me C02Me
91-71 cyclopropyl Me Me =0 H C02H
91-72 cyclopropyl Me Me =0 H C02Me
91-73 I cyclopropyl I Me | Me | =0 | Me | CO2H
60

Compound Substituent Values
Number A R^ | R° R^ | R°' R^ Z
91-74 cyclopropyl Me | Me =0 Me C02Me
91-75 cyclopropyl fO =0 H CO2H
91-76 cyclopropyl fO =0 H COgMe
91-77 cyclopropyl fO =0 Me CO2H
91-78 cyclopropyl fO =0 Me COaMe
91-79 cyclopropyl fO =0 CHgPh CO2H
91-80 cyclopropyl =0 =0 CH2Ph COzMe
4-chloro-3-
91-81 fluorophenyl H_±! H H H CO2H
4-chloro-3-
91-82 fluorophenyl !±_jH H H H COsMe
4-chloro-3-
91-83 fluorophenyl H H H H Me COpH
4-chloro-3-
91-84 fluorophenyl H__h! H H Me COgMe
4-chloro-3-
91-85 fluorophenyl H__Jj H H i-Pr CO2H
4-chloro-3-
91-86 fluorophenyl !1_±! H H i-Pr COzMe
4-chloro-3-
91-87 fluorophenyl H__H H H CHzPh CO2H
4-chloro-3-
91-88 fluorophenyl H_±! H H CHzPh COzMe
4-chloro-3-
91-89 fluorophenyl !l_ij H H Ph CO2H
4-chloro-3-
91-90 fluorophenyl H_±! H H Ph COgMe
4-chloro-3-
91-91 fluorophenyl H__H H Me H CO2H
4-chloro-3-
91-92 fluorophenyl H___±! H Me H COgMe
4-chloro-3-
91-93 fluorophenyl H__H H Me Me COgH
4-chloro-3-
91-94 fluorophenyl H_±! H Me Me COgMe
4-chloro-3-
91-95 fluorophenyl HL_Jd Me Me H CO2H
4-chloro-3-
91-96 fluorophenyl H__t! Me Me H CQzMe
4-chloro-3-
91-97 fluorophenyl H_±! Me Me Me CO2H
4-chloro-3-
91-98 fluorophenyl !±__H Me Me Me C02Me
4-chloro-3-
91-99 fluorophenyl H Me H H H CO2H
4-chloro-3-
91-100 fluorophenyl H Me H H H COgMe
4-chloro-3-
91-101 fluorophenyl H Me H H Me CO2H
4-chloro-3-
91-102 I fluorophenyl I H | Me | H | H | Me | C02Me
61

rnmp^-H I Substituent Values
Number A R' R^ R^' R^' R^ Z
4-chloro-3-
91-103 fluorophenyl H Me H Me H CO2H
4-chloro-3-
91-104 fluorophenyl H Me H Me H C02Me
4-chloro-3-
91-105 fluoropher^yl H Me H Me Me CO2H
4-chloro-3-
91-106 fluorophenyl H Me H Me Me C02Me
4-chloro-3-
91-107 fluorophenyl H Me Me Me H CO2H
4-chloro-3-
91-108 fluorophenyl H Me Me Me H COzMe
4-chloro-3-
91-109 fluorophenyl H Me Me Me Me CO2H
4-chloro-3-
91-110 fluorophenyl H Me Me Me Me COgMe
4-chloro-3-
91-111 fluorophenyl Me Me H H H CO2H
4-chloro-3-
91-112 fluorophenyl Me Me H H H CQzMe
4-chloro-3-
91-113 fluorophenyl Me Me H H Me CO2H
4-chloro-3-
91-114 fluorophenyl Me Me H H Me C02Me
4-chloro-3-
91-115 fluorophenyl Me Me H Me H CO2H
4-chloro-3-
91-116 fluorophenyl Me Me H Me H COgMe
4-chloro-3-
91-117 fluorophenyl Me Me H Me Me CO2H
4-chloro-3-
91-118 fluorophenyl Me Me H Me Me C02Me
4-chloro-3-
91-119 fluorophenyl Me Me Me Me H CO2H
4-chloro-3-
91-120 fluorophenyl Me Me Me Me H C02Me
4-chloro-3-
91-121 fluorophenyl Me Me Me Me Me CO2H
4-chloro-3-
91-122 fluorophenyl Me Me Me Me Me C02Me
4-chloro-3-
91-123 fluorophenyl H Ph H Ph H CO2H
4-chloro-3-
91-124 fluorophenyl H Ph H Ph H COzMe
4-chloro-3-
91-125 fluorophenyl H Ph H Ph Me CO2H
4-chloro-3-
91-126 fluorophenyl H Ph | H Ph Me COpMe
4-chloro-3-
91-127 fluorophenyl H (CH2)4 H H CO2H
4-chloro-3-
91-128 I fluorophenyl I H | (CH2)4 I H I H | C02Me
62

r.nmpnMnH | SubstJtuent Values
Number A R^ R» | R^ R"' R' Z
4-chloro-3-
91-129 fluorophenyl H (CH,)4 H Me CO2H
4-chloro-3-
91-130 fluorophenyl H | (CHzj^ H Me COzMe
4-chloro-3-
91-131 fluorophenyl =0 H H H CO2H
4-chloro-3-
91-132 fluorophenyl =0 H H H COgMe
4-chloro-3-
91-133 fluorophenyl =0 H H Me CO2H
4-chloro-3-
91-134 fluorophenyl =0 H H Me COgMe
4-chloro-3-
91-135 fluorophenyl =0 H Me H CO2H
4-chloro-3-
91-136 fluorophenyl =0 H Me H COzMe
4-chloro-3-
91-137 fluorophenyl =0 H Me Me CO2H
4-chloro-3-
91-138 fluorophenyl =0 H Me Me C02Me
4-chloro-3-
91-139 fluorophenyl =0 Me Me H CO2H
4-chloro-3-
91-140 fluorophenyl =0 Me Me H C02Me
4-chloro-3-
91-141 fluorophenyl =0 Me Me Me CO2H
4-chloro-3-
91-142 fluorophenyl =0 Me | Me Me C02Me
4-chloro-3-
91-143 fluorophenyl H H =0 H CO2H
4-chloro-3-
91-144 fluorophenyl H H =0 H COgMe
4-chloro-3-
91-145 fluorophenyl H H =0 Me COgH
4-chloro-3-
91-146 fluorophenyl H H =0 Me COzMe
4-chloro-3-
91-147 fluorophenyl H Me =0 H COgH
4-chloro-3-
91-148 fluorophenyl H Me =0 H COgMe
4-chloro-3-
91-149 fluorophenyl H Me =0 Me CO2H
4-chloro-3-
91-150 fluorophenyl H Me =0 Me COgMe
4-chloro-3-
91-151 fluorophenyl Me Me =0 H CO2H
4-chloro-3-
91-152 fluorophenyl Me Me =0 H COgMe
4-chloro-3-
91-153 fluorophenyl Me Me =0 Me CO2H
4-chloro-3-
91-154 I fluorophenyl |_MgJ Me | =0 [Me | C02Me
63

Compound Substituent Values
Number A RJ \ R° R^' I R^' R' Z
4-chloro-3-
91-155 fluorophenyl fO =0 H CO2H
4-chloro-3-
91-156 fluorophenyl =0 =0 H C02Me
4-chloro-3-
91-157 fluorophenyl ^=0 =0 Me CO2H
4-chloro-3-
91-158 fluorophenyl fO =0 Me C02Me
4-chloro-3-
91-159 fluorophenyl =0 =0 CH2Ph CO2H
4-chloro-3-
91-160 fluorophenyl =0 =0 CH2Ph C02Me
4-chloro-2-fluoro-3-
91-161 methoxyphenyl H__H H H H CO2H
4-chloro-2-fIuoro-3-
91-162 methoxyphenyl H__JH H H H COzMe
4-chloro-2-fluoro-3-
91-163 methoxyphenyl H_JH H H Me CO2H
4-chloro-2-fluoro-3-
91-164 methoxyphenyl tL_Jd H H Me COaMe
4-chloro-2-fluoro-3-
91-165 methoxyphenyl H__H H H i-Pr CO2H
4-chloro-2-fluoro-3-
91-166 methoxyphenyl H__±! H H i-Pr COgMe
4-chioro-2-fluoro-3-
91-167 methoxyphenyl H__H H H CHaPh COgH
4-chloro-2-fluoro-3-
91-168 methoxyphenyl H___H H H CHgPh COgMe
4-chloro-2-fluoro-3-
91-169 methoxyphenyl H__H H H Ph CO2H
4-chloro-2-fluoro-3-
91-170 methoxyphenyl H__H H H Ph COgMe
4-chloro-2-fluoro-3-
91-171 methoxyphenyl H__H H Me H COzH
4-chloro-2-fluoro-3-
91-172 methoxyphenyl HL-Jd H Me H COzMe
4-chloro-2-fluoro-3-
91-173 methoxyphenyl HL_±! H Me Me CO2H
4-chloro-2-fluoro-3-
91-174 methoxyphenyl H__H H Me Me COzMe
4-chloro-2-fluoro-3-
91-175 methoxyphenyl H___H Me Me H CO2H
4-chloro-2-fluoro-3-
91-176 methoxyphenyl H__H Me Me H C02Me
4-chloro-2-fluoro-3-
91-177 methoxyphenyl tL-Jj Me Me Me CO2H
4-chloro-2-fluoro-3-
91-178 methoxyphenyl H_JH Me Me Me C02Me
4-chloro-2-fluoro-3-
91-179 methoxyphenyl H Me H H H CO2H
4-chloro-2-fluoro-3-
91-180 I methoxyphenyl | H | Me I H | H | H | COgMe
64

r^mpn..nH I Substituent Values
Number A R^ R» R^' R»' R^ Z
4-chloro-2-fluoro-3-
91-181 methoxyphenyl H Me H H Me CO2H
4-chloro-2-fluoro-3-
91-182 methoxyphenyl H Me H H Me C02lVle
4-chloro-2-fluoro-3-
91-183 methoxyphenyl H Me I H Me H CO2H
4-chloro-2-fluoro-3-
91-184 methoxyphenyl H Me H Me H C02Me
4-chloro-2-fluoro-3-
91-185 methoxyphenyl H Me 1 H Me Me CO2H
4-chloro-2-fluoro-3-
91-186 methoxyphenyl H Me 1 H Me Me COgMe
4-chloro-2-fluoro-3-
91-187 methoxyphenyl H Me Me Me H CO2H
4-chloro-2-fluoro-3-
91-188 methoxyphenyl H Me Me Me H C02Me
4-chloro-2-fluoro-3-
91-189 methoxyphenyl H Me Me Me Me COgH
4-chloro-2-fluoro-3-
91-190 methoxyphenyl H Me Me Me Me C02Me
4-chloro-2-fluoro-3-
91-191 methoxyphenyl Me Me H H H CO2H
4-chloro-2-fluoro-3-
91-192 methoxyphenyl Me Me H H H C02Me
4-chioro-2-fluoro-3-
91-193 methoxyphenyl Me Me H H Me CO2H
4-chloro-2-fluoro-3-
91-194 methoxyphenyl Me Me H H Me C02Me
4-chloro-2-fluoro-3-
91-195 methoxyphenyl Me Me H Me H CO2H
4-chloro-2-fluoro-3-
91 -196 methoxyphenyl Me Me H Me H C02Me
4-chloro-2-fiuoro-3-
91-197 methoxyphenyl Me Me H Me Me CQ2H
4-chloro-2-fluoro-3-
91-198 methoxyphenyl Me Me H Me Me C02Me
4-chloro-2-fluoro-3-
91-199 methoxyphenyl Me Me Me Me H CO2H
4-chloro-2-fluoro-3-
91-200 methoxyphenyl Me Me Me Me H C02Me
4-chloro-2-fluoro-3-
91-201 methoxyphenyl Me Me Me Me Me CO2H
4-chloro-2-fluoro-3-
91-202 methoxyphenyl Me__Me Me Me Me C02Me
4-chloro-2-fluoro-3-
91-203 methoxyphenyl H Ph H Ph H CO2H
4-chloro-2-fluoro-3-
91-204 methoxyphenyl H Ph H Ph H C02Me
4-chloro-2-fluoro-3-
91-205 methoxyphenyl H Ph H Ph Me CO2H
4-chloro-2-fluoro-3-
91-206 I methoxyphenyl I H | Ph | H | Ph | Me | COgMe
65

rnmpnnnH I SubstJtuent Values
Number A R' R^ | R^ R"" R' Z
4-chloro-2-fluoro-3-
91-207 methoxyphenyl H (CH?)4 H H COgH
4-chloro-2-fluoro-3-
91-208 methoxyphenyl H (CH2)4 H H C02Me
4-chloro-2-fluoro-3-
91-209 methoxyphenyl H (CH2)4 H Me COgH
4-chloro-2-fluoro-3-
91-210 methoxyphenyl H | (CHgU H Me COgMe
4-chloro-2-fluoro-3-
91-211 methoxyphenyl =0 H H H CO2H
4-ch loro-2-fl uoro-3-
91-212 methoxyphenyl =0 H H H COgMe
4-chloro-2-fluoro-3- '
91-213 methoxyphenyl =0 1 H H Me CO2H
4-chloro-2-fluoro-3-
91-214 methoxyphenyl =0 H H Me C02Me
4-chlGro-2-fluoro-3-
91-215 methoxyphenyl =0 H Me H CO2H
4-chioro-2-fluoro-3-
91-216 methoxyphenyl =0 H Me H COgMe
4-chloro-2-fluoro-3-
91-217 methoxyphenyl =0 H Me Me CO2H
4-chloro-2-fluoro-3-
91-218 methoxyphenyl =0 H Me Me COzMe
4-chloro-2-fluoro-3-
91-219 methoxyphenyl =0 Me Me H CO2H
4-chloro-2-fluoro-3-
91-220 methoxyphenyl =0 Me Me H COgMe
4-chloro-2-fluoro-3-
91-221 methoxyphenyl =0 Me Me Me CO2H
4-chloro-2-fluoro-3-
91-222 methoxyphenyl =0 Me | Me Me COzMe
4-chIoro-2-fluoro-3-
91-223 methoxyphenyl H H =0 H CO2H
4-chloro-2-fluoro-3-
91-224 methoxyphenyl H H =0 H COgMe
4-chloro-2-fluoro-3-
91-225 methoxyphenyl H H =0 Me CO2H
4-chloro-2-fluoro-3-
91-226 methoxyphenyl H H =0 Me COzMe
4-chloro-2-fluoro-3-
91-227 methoxyphenyl H Me =0 H CO2H
4-chloro-2-fluoro-3-
91-228 methoxyphenyl H Me =0 H C02Me
4-chloro-2-fluoro-3-
91-229 methoxyphenyl H Me =0 Me CO2H
4-chloro-2-fluoro-3-
91-230 methoxyphenyl H Me =0 Me C02Me
4-chloro-2-fluoro-3-
91-231 methoxyphenyl Me Me =0 H CO2H
4-chloro-2-fluoro-3-
91-232 I methoxyphenyl | Me | Me I =0 | H | COgMe
66

rnmpni.nH I SubstJtuent Values
Number A R^ j R" R^ 1 R^ R^ Z
4-chloro-2-fluoro-3-
91 -233 methoxyphenyl Me Me =0 Me COzH
4-chloro-2-fluoro-3-
91-234 methoxyphenyl Me | Me =0 Me COaMe
4-chloro-2-fluoro-3-
91-235 methoxyphenyl ^0 =Q H COzH
4-ch loro-2-fluoro-3-
91-236 methoxyphenyl fO =0 H C02Me
4-chloro-2-fluoro-3-
91-237 methoxyphenyl fO =0 Me CO2H
4-chloro-2-fluoro-3-
91-238 methoxyphenyl fO =0 Me COgMe
4-chloro-2-fluoro-3-
91-239 methoxyphenyl fO =0 CHzPh CO2H
4-chloro-2-fluoro-3-
91-240 I methoxyphenyl | =0 1 =0 | CHzPh | COaMe
240 compounds are described, designated compounds 92-1 to 92-240 respectively, of formula (IF) wherein D is N and X is NMe, and the values of A, R^ R^ R^", R®. R^'and Z are as defined in Table 6.
240 compounds are described, designated compounds 93-1 to 93-240 respectively, of formula (IF) wherein D is N and X is Ni-Pr. and the values of A, R^ R^ R^', R^, R^' and Z are as defined in Table 6.
240 compounds are described, designated compounds 94-1 to 94-240 respectively, of fomiula (IF) wherein D is N and X is NPh, and the values of A, R^ R^ R'', R^ R*' and Z are as defined in Table 6.
240 compounds are described, designated compounds 95-1 to 95-240 respectively, of formula (IF) wherein D is N and X is NCHzPh, and the values of A, R^ R^ R^', R^ R^' and Z are as defined in Table 6.
240 compounds are described, designated compounds 96-1 to 96-240 respectively, of formula (IF) wherein D is N and X is NCH2(2-nitrophenyl), and the values of A. R'*, R^, R'', R^ R®' and Z are as defined in Table 6.
240 compounds are described, designated compounds 97-1 to 97-240 respectively, of formula (IF) wherein D is N and X is NCH2(2-furanyl), and the values of A, R^, R', R^', R®, R^'and Z are as defined in Table 6.
67

240 compounds are described, designated compounds 98-1 to 98-240 respectively, of formula (IF) wherein D is CH and X is NH, and the values of A, R^ R^ R^', R^ R^'and Z are as defined in Table 6.
240 compounds are described, designated compounds 99-1 to 99-240 respectively, of formula (IF) wherein D is CH and X is NMe, and the values of A. R^ R^ R^, R®. R*' and Z are as defined in Table 6.
240 compounds are described, designated compounds 100-1 to 100-240 respectively, of formula (1F) wherein D is CH and X is Ni-Pr, and the values of A, R^ R^ R'', R^ R*' and Z are as defined in Table 6.
240 compounds are described, designated compounds 101-1 to 101-240 respectively, of formula (IF) wherein D is CH and X is NPh, and the values of A, R^ R^ R'', R^ R^' and 2 are as defined in Table 6.
240 compounds are described, designated compounds 102-1 to 102-240 respectively, of formula (IF) wherein D is CH and X is NCHzPh, and the values of A, R^ R^ R''. R®, R* and Z are as defined in Table 6.
240 compounds are described, designated compounds 103-1 to 103-240 respectively, of fonnula (IF) wherein D is CH and X is NCH2(2-nitrophenyl), and the values of A, R^ R^ R^', R^ R^and Z are as defined in Table 6.
240 compounds are described, designated compounds 104-1 to 104-240 respectively, of formula (IF) wherein D is CH and X is NCH2(2-furanyl), and the values of A, R^ R', R'', R^ R^'and Z are as defined in Table 6.
Table 7 below provides 108 compounds designated compounds 105-1 to 105-108 respectively, of formula (1G) wherein D is N and X is NH.
68

{1G)
TABLE 7
Compound Substituent Values
Number A R^ R" R^' R^' Z
105-1 cyclopropyl H H H H COgH
105-2 cyclopropyl H H H H C02Me
105-3 cyclopropyl H H H Me COgH
105-4 cyclopropyl H H H Me COaMe
105-5 cyclopropyl H H Me Me COgH
105-6 cyclopropyl H H Me Me COaMe
105-7 cyclopropyl H Me H H COzH
105-8 cyclopropyl H Me H H COgMe
105-9 cyclopropyl H Me H Me CO2H
105-10 cyclopropyl H Me H Me CQzMe
105-11 cyclopropyl H Me Me Me CQ2H
105-12 cyclopropyl H Me Me Me COaMe
105-13 cyclopropyl Me Me H H CO2H
105-14 cyclopropyl Me Me H H COzMe
105-15 cyclopropyl Me Me H Me CO2H
105-16 cyclopropyl Me Me H Me COaMe
105-17 cyclopropyl Me Me Me Me CO2H
105-18 cyclopropyl Me Me Me Me COaMe
105-19 cyclopropyl H Ph H Ph CO2H
105-20 cyclopropyl H Ph | H Ph C02Me
105-21 cyclopropyl H (CH2)4 H CO2H
105-22 cyclopropyl H | (CH2)4 H COgMe
105-23 cyclopropyl =0 I H H CO2H
105-24 cyclopropyl fO H H COgMe
105-25 cyclopropyl ^O H Me C02H
105-26 cyclopropyl fO H Me COgMe
105-27 cyclopropyl =0 Me Me COgH
105-28 cyclopropyl =0 ~~Me | Me COaMe
105-29 cyclopropyl H I H ~ =0 CO2H
105-30 cyclopropyl !1___H z^ COgMe
105-31 cyclopropyl H Me =0 CQ2H
"I05-32 I cyclopropyl I H | Me I =0 I C02Me
69

Compound Substituent Values
Number ~ A I R^ R" R^' j R"' Z
105-33 cyclopropyl Me Me =0 COgH
105-34 cyclopropyl Me | Me~ =0 COaMe
105-35 cyclopropyl ^O ^O COgH
105-36 cyclopropyl fO ^P COgMe
105-37 4-chioro-3-fluorophenvl H | H "~H | H COgH
105-38 4-chloro-3-fluorophenyl H H H H COgMe
105-39 4-chloro-3-fluorophenyl H H H Me COgH
105-40 4-chloro-3-fluorophenyl H H H Me COgMe
105-41 4-chloro-3-fluorophenvl H H Me Me COgH
105-42 4-chloro-3-fluorophenyl H H Me Me COgMe
105-43 4-chloro-3-fluorophenyl H Me H H COgH
105-44 4-chloro-3-fluorophenyl H Me H H COgMe
105-45 4-chloro-3-fluorophenyl H Me H Me COgH
105-46 4-chloro-3-fluorophenyl H Me H Me COgMe
105-47 4-chloro-3-fluorophenyl H Me Me Me COgH
105-48 4-chloro-3-fluorophenvl H Me Me Me COgMe
105-49 4-chloro-3-fluorophenvl Me Me H H COgH
105-50 4-chloro-3-fluorophenvl Me Me H H COgMe
105-51 4-chloro-3-fluorophenyl Me Me H Me COgH
105-52 4-chloro-3-fluorophenyl Me Me H Me COgMe
105-53 4-chloro-3-fluorophenyl Me Me Me Me COgH
105-54 4-chloro-3-fluorophenyl Me Me Me Me COgMe
105-55 4-chloro-3-fluorophenyl H Ph H Ph COgH
105-56 4-chloro-3-fluorophenyl H Ph | H Ph COgMe
105-57 4-chloro-3-fluorophenvl H (CH2)4 H COgH
105-58 4-chloro-3-fluorophenvl H | (CHg)^ H COgMe
105-59 4-chloro-3-fluorophenyl =0 I H H COgH
105-60 4-chloro-3-fluorophenyi ^O H H COgMe
105-61 4-chloro-3-fluorophenvl _^0 H Me COgH
105-62 4-chloro-3-fluorophenvl fO H Me COgMe
105-63 4-chloro-3-fluorophenvl ^O Me Me COgH
105-64 4-chloro-3-fluorophenyl =0 ~~Me \ Me COgMe
105-65 4-chloro-3-fluorophenvl H | H =0 COgH
105-66 4-chloro-3-fluorophenvl H__H =0 COgMe
105-67 4-chloro-3-fluorophenyl H Me =0 COgH
105-68 4-chloro-3-fluorophenvl H Me =0 COgMe
105-69 4-chloro-3-fluorophenyl Me Me =0 COgH
105-70 4-chloro-3-fluorophenyl Me | Me~ =0 COgMe
105-71 4-chloro-3-fluorophenyl ^O =0 COgH
105-72 4-chloro-3-fluorophenyl fO =0 COgMe
4-chloro-2-fluoro-3- I I
105-73 methoxyphenyi H H H H COgH
4-chloro-2-fluoro-3-
105-74 methoxyphenyi H H H H COgMe
4-chloro-2-fluoro-3-
105-75 I methoxyphenyi | H | H | H | Me | COgH
70

Compound Substituent Values
Number A i RM R° R'' R^' Z
4-chloro-2-fluoro-3-
105-76 I methoxyphenyl H H H Me COaMe
4-chloro-2-fluoro-3-
105-77 methoxyphenyl H H Me Me COaH
4-chioro-2-fluoro-3-
105-78 methoxyphenyl H H Me Me COgMe
4-chloro-2-fluoro-3-
105-79 methoxyphenyl H Me H H CO2H
4-ch loro-2-fluoro-3-
105-80 methoxyphenyl H Me H H COjMe
4-chloro-2-fluoro-3-
105-81 methoxyphenyl H Me H Me CO2H
4-chloro-2-fluoro-3-
105-82 methoxyphenyl H Me _H Me C02Me
4-chloro-2-fluoro-3-
105-83 methoxyphenyl H Me Me Me COgH
4-chloro-2-fluoro-3-
105-84 methoxyphenyl H Me Me Me C02Me
4-chloro-2-fluoro-3-
105-85 methoxyphenyl Me Me H H CO2H
4-chloro-2-fluoro-3-
105-86 methoxyphenyl Me Me H H C02Me
4-chloro-2-fluoro-3- I
105-87 methoxyphenyl Me 1 Me H Me CO2H
4-chloro-2-fluoro-3-
105-88 methoxyphenyl Me Me H Me C02Me
4-chloro-2-fluoro-3-
105-89 methoxyphenyl Me Me Me Me CO2H
4-chloro-2-fluoro-3-
105-90 methoxyphenyl Me Me Me Me C02Me
4-chioro-2-fluoro-3-
105-91 methoxyphenyl H Ph H Ph CO2H
4-chloro-2-fluoro-3-
105-92 methoxyphenyl H Ph | H Ph C02Me
4-chloro-2-fluoro-3-
105-93 methoxyphenyl H (CH2)4 H CO2H
4-chloro-2-fluoro-3-
105-94 methoxyphenyl H | (CH2)4 H COgMe
4-chloro-2-fluoro-3-
105-95 methoxyphenyl =0 H H CO2H
4-chloro-2-fluoro-3-
105-96 methoxyphenyl =0 H H C02Me
4-chloro-2-fluoro-3-
105-97 methoxyphenyl =0 H Me CO2H
4-chloro-2-fluoro-3-
105-98 methoxyphenyl =0 H Me C02Me
4-chloro-2-fluoro-3-
105-99 methoxyphenyl =0 Me Me CQ2H
4-chloro-2-fluoro-3-
105-100 methoxyphenyl fO Me | Me C02Me
4-chloro-2-fluoro-3- I
105-101 I methoxyphenyl | H | H | =0 | CO2H
71

Compound Substituent Values
Number ^A R^ R^ R^' | R^ Z
4-chloro-2-fluoro-3-
105-102 methoxyphenyl tl__H =0 COgMe
4-chloro-2-fluoro-3-
105-103 methoxyphenyl H Me =0 CO2H
4-chloro-2-fluoro-3-
105-104 methoxyphenyl H Me =0 COzMe
4-chloro-2-fluoro-3-
105-105 methoxyphenyl Me Me =0 COgH
4-chloro-2-fluoro-3-
105-106 methoxyphenyl Me | Me =0 CQzMe
4-chloro-2-fluoro-3-
105-107 methoxyphenyl fO =0 COgH
4-chloro-2-fluoro-3-
• 105-108 I methoxyphenyl | =0 | =0 | COgMe
108 compounds are described, designated compounds 106-1 to 106-108 respectively, of formula (1G) wherein D is N and X is NMe. and the values of A, R^, R^', R^ R'and Z are as defined in Table 7.
108 compounds are described, designated compounds 107-1 to 107-108 respectively, of formula (1G) wherein D is N and X is Ni-Pr, and the values of A, R^ R^', R^ R*' and Z are as defined in Table 7.
108 compounds are described, designated compounds 108-1 to 108-108 respectively, of formula (1G) wherein D is N and X is NPh, and the values of A, R^ R^', R^ R*' and Z are as defined in Table 7.
108 compounds are described, designated compounds 109-1 to 109-108 respectively, of formula (1G) wherein D is N and X is NCH2Ph, and the values of A, R^ R^, R^ R^' and Z are as defined in Table 7.
108 compounds are described, designated compounds 110-1 to 110-108 respectively, of formula (1G) wherein D is N and X is NCH2(2-nitrophenyl), and the values of A. R^, R'', R^ R'and Z are as defined in Table 7.
108 compounds are described, designated compounds 111-1 to 111-108 respectively, of formula (1G) wherein D is N and X is NCH2(2-furanyl), and the values of A, R^ R^', R®, R^'and Z are as defined in Table 7.
72

108 compounds are described, designated compounds 112-1 to 112-108 respectively, of formula (1G) whefein O is CH and X is NH. and the values of A, R^ R^', R^ R^' and Z are as defined in Table 7.
108 compounds are described, designated compounds 113-1 to 113-108 respectively, of formula (1G) wherein D is CH and X is Nl\/!e, and the values of A, R^, R^", R®, R^'and Z are as defined in Table 7.
108 compounds are described, designated compounds 114-1 to 114-108 respectively, of formula (1G) wherein D is CH and X is Ni-Pr, and the values of A, R^ R'', R^ R^'and Z are as defined in Table 7.
108 compounds are described, designated compounds 115-1 to 115-108 respectively, of formula (1G) wherein D is CH and X is NPh. and the values of A, R^ R^', R*. R^and Z are as defined in Table 7.
108 compounds are described, designated compounds 116-1 to 116-108 respectively, of formula (1G) wherein D is CH and X is NCH2Ph, and the values of A, R^ R^ R®, R*' and Z are as defined in Table 7.
108 compounds are described, designated compounds 117-1 to 117-108 respectively, of formula (1G) wherein D is CH and X is NCH2(2-nitrophenyl), and the values of A. R^ R^', R', R^'and Z are as defined in Table 7.
108 compounds are described, designated compounds 118-1 to 118-108 respectively, of formula (1G) wherein D is CH and X is NCH2(2-furanyl), and the values of A, R^ R^', R*, R" and Z are as defined in Table 7.
Table 8 below provides 210 compounds designated compounds 119-1 to 119-210 respectively, of formula (IN) wherein D is N and X is NH.
73

(1H)
TABLE 8
Compound Substituent Values
Number A R° R^ I R^ Z
119-1 cyclopropyl H H H CO2H
119-2 cyclopropyl H H H C02Me
119-3 cyclopropyl H H Me CO2H
119-4 cyclopropyl H H Me C02Me
119-5 cyclopropyl H H i-Pr CO2H
119-6 cyclopropyl H H i-Pr C02Me
119-7 cyclopropyl H H CHzPh COgH
119-8 cyclopropyl H H CHgPh C02Me
119-9 cyclopropyl H H Ph CO2H
119-10 cyclopropyl H H Ph C02Me
119-11 cyclopropyl H Me H CO2H
119-12 cyclopropyl H Me H C02Me
119-13 cyclopropyl H Me Me CO2H
119-14 cyclopropyl H Me Me C02Me
119-15 cyclopropyl Me H H CO2H
119-16 cyclopropyl Me H H C02Me
119-17 cyclopropyl Me H Me CO2H
119-18 cyclopropyl Me H Me C02Me
119-19 cyclopropyl Me Me H CO2H
119-20 cyclopropyl Me Me H C02Me
119-21 cyclopropyl Me Me Me CO2H
119-22 cyclopropyl Me | Me Me C02Me
119-23 cyclopropyl (CH2)4 H CO2H
119-24 cyclopropyl (CH2)4 H C02Me
119-25 cyclopropyl (CH2)4 Me CO2H
119-26 cyclopropyl (CH2)4 Me C02Me
119-27 cyclopropyl CH=CH-CH=CH H CO2H
119-28 cyclopropyl CH=CH-CH=CH H C02Me
119-29 cyclopropyl CH=CH-CH=CH Me COgH
~ri9-30 I cyclopropyl I CH=CH-CH=CH | Me | C02Me
74

Compound Substituent Values ~1
Number A R" | R"' R^ Z
119-31 cyclopropyl CH=CMe-CH=CH H COgH
119-32 cyclopropyl CH=CMe-CH=CH H COaMe
119-33 cyclopropyl CH=CMe-CH=CH Me COzH
119-34 cyclopropyl CH=CMe-CH=CH Me COgMe
119-35 cyclopropyl CH=CH-CMe=CH H CO2H
119-36 cyclopropyl CH=CH-CMe=CH H COaMe
119-37 cyclopropyl CH=CH-CMe=CH Me CO2H
119-38 cyclopropyl CH=CH-CMe=CH Me COgMe
119-39 cyclopropyl CH=CMe-CMe=CH H CO2H
119-40 cyclopropyl CH=CMe-CMe=CH H COzMe
119-41 cyclopropyl CH=CMe-CMe=CH Me CO2H
119-42 cyclopropyl CH=CMe-CMe=CH Me COzMe
119-43 cyclopropyl CMe=CMe-CH=CH H CO2H
119-44 cyclopropyl CMe=CMe-CH=CH H COgMe
119-45 cyclopropyl CMe=CMe-CH=CH Me CO2H
119-46 cyclopropyl CMe=CMe-CH=CH Me COzMe
119-47 cyclopropyl CH=CH-CMe=CMe H CO2H
119-48 cyclopropyl CH=CH-CMe=CMe H COaMe
119-49 cyclopropyl CH=CH-CMe=CMe Me CO2H
119-50 cyclopropyl CH=CH-CMe=CMe Me C02Me
119-51 cyclopropyl CH=CMe-CCI=CH H CO2H
119-52 cyclopropyl CH=CMe-CCI=CH H COaMe
119-53 cyclopropyl CH=CMe-CCI=CH Me CO2H
119-54 cyclopropyl CH=CMe-CCI=CH Me C02Me
119-55 cyclopropyl CH=CCI-CMe=CH H CO2H
119-56 cyclopropyl CH=CCI-CMe=CH H COzMe
119-57 cyclopropyl CH=CCI-CMe=CH Me CO2H
119-58 cyclopropyl CH=CCI-CMe=CH Me C02Me
119-59 cyclopropyl CH=CCI-CCI=CH H CO2H
119-60 cyclopropyl CH=CCI-CCI=CH H COgMe
119-61 cyclopropyl CH=CCI-CCI=CH Me COgH
119-62 cyclopropyl CH=CCI-CCI=CH Me COzMe
119-63 cyclopropyl C(N02)=CH-CH=CH H CO2H
119-64 cyclopropyl C(N02)=CH-CH=CH H COgMe
119-65 cyclopropyl C(N02)=CH-CH=CH Me CO2H
119-66 cyclopropyl C(N02)=CH-CH=CH Me C02Me
119-67 cyclopropyl CH=CH-CH=C(N02) H CO2H
119-68 cyclopropyl CH=CH-CH=C(N02) H COgMe
119-69 cyclopropyl CH=CH-CH=C(N02) Me CO2H
119-70 cyclopropyl CH=CH-Ct-I=C(N02) Me COgMe
119-71 4-chloro-3-fluorophenyl H IH H CO2H
119-72 4-chloro-3-fluorophenyl H H H C02Me
119-73 4-chloro-3-fluorophenyl H H Me CO2H
119-74 4-chloro-3-fluorophenyl H H Me C02Me
~Tl9-75 14-chloro-3-fluorophenyl | H I H I i-Pr | CO2H
75

Compound Substituent Values
Number A R^ R^' R^ Z
119-76 4-chloro-3-fluorophenyl H H i-Pr COgMe
119-77 4-chloro-3-fluorophenyl H H CHzPh CO2H
119-78 4-chloro-3-fluorophenyl H H CHzPh C02Me
119-79 4-chloro-3-fluorQphenyl H H Ph CO2H
119-80 4-chloro-3-fluorophenyl H H Ph COzMe
119-81 4-chloro-3-fluorophenyl H _jyie H COgH
119-82 4-chloro-3-fluorophenyl H Me H COzMe
119-83 4-chloro-3-fluorophenyl H Me Me CQ2H
119-84 4-chloro-3-fluorophenyl H Me Me COgMe
119-85 4-chloro-3-fluorophenyl Me H H CO2H
119-86 4-chloro-3-fluorophenyl Me H H COzMe
119-87 4-chloro-3-fluorophenyl Me H Me CO2H
119-88 4-chloro-3-fluorophenyl Me H Me COzMe
119-89 4-chloro-3-fluorophenyl Me Me H CO2H
119-90 4-chloro-3-fluorophenyl Me Me H COzMe
119-91 4-chloro-3-fluorophenyl Me Me Me CQ2H
119-92 4-chloro-3-fluorophenyl Me | Me Me C02Me
119-93 4-chloro-3-fluorophenyl i9h2k b CQ2H
119-94 4-chloro-3-fluorophenyl ICHz}^ H COzMe
119-95 4-chloro-3-fluorophenyl (CHy^ Me CO2H
119-96 4-chloro-3-fluorophenyl (CHz)^ Me COzMe
119-97 4-chloro-3-fluorophenyl CH=CH-CH=CH H CO2H
119-98 4-chloro-3-fluorophenyl CH=CH-CH=CH H C02Me
119-99 4-chloro-3-fluorophenyl CH=CH-CH=CH Me CO2H
119-100 4-chloro-3-fluorophenyl CH=CH-CH=CH Me COzMe
119-101 4-chloro-3-fluorophenyl CH=CMe-CH=CH H CO2H
119-102 4-chloro-3-fluorophenyl CH=CMe-CH=CH H C02Me
119-103 4-chloro-3-fluorophenYl CH=CMe-CH=CH Me CO2H
119-104 4-chloro-3-fluorophenyl CH=CMe-CH=CH Me COzMe
119-105 4-chloro-3-fluorophenvl CH=CH-CMe=CH H CO2H
119-106 4-chloro-3-fluorophenyl CH=CH-CMe=CH H CQzMe
119-107 4-chloro-3-fluorophenyl CH=CH-CMe=CH Me CO2H
119-108 4-chloro-3-fluorophenyl CH=CH-CMe=CH Me C02Me
119-109 4-chloro-3-fluorophenvl CH=CMe-CMe=CH H CO2H
119-110 4-chloro-3-fluorophenyl CH=CMe-CMe=CH H C02Me
119-111 4-chloro-3-fluorophenvl CH=CMe-CMe=CH Me COgH
119-112 4-chloro-3-fluorophenvl CH=CMe-CMe=CH Me COzMe
119-113 4-chloro-3-fluorophenyl CMe=CMe-CH=CH H CO2H
119-114 4-chloro-3-fluorophenyl CMe=CMe-CH=CH H COzMe
119-115 4-chloro-3-fluorophenvl CMe=CMe-CH=CH Me CO2H
119-116 4-chloro-3-fluorophenyl CMe=CMe-CH=CH Me COzMe
119-117 4-chloro-3-fluorophenvl CH=CH-CMe=CMe H CO2H
119-118 4-chloro-3-fluorophenyl CH=CH-CMe=CMe H COgMe
119-119 4-chloro-3-fluorophenyl CH=CH-CMe=CMe Me CO2H
~119-120 I 4-chloro-3-fluorophenyl I CH=CH-CMe=CMe | Me | COzMe
76

Compound , Substituent Values
Number A R" | R" R^ Z
119-121 4-chloro-3-fluorophenyl CH=CMe-CCI=CH H COgH
119-122 4-chloro-3-fluorophenyl CH=CMe-CCI=CH H COaMe
119-123 4-chloro-3-fluorophenyl CH=CMe-CCI=CH Me CO2H
119-124 4-chloro-3-fluorophenyl CH=CMe-CCI=CH Me COzMe
119-125 4-chloro-3-fluorophenyl CH=CCI-CMe=CH H CQ2H
119-126 4-chloro-3-fluorophenyl CH=CCI-CMe=CH H COgMe
119-127 4-chloro-3-fluorophenyl CH=CCI-CMe=CH Me CO2H
119-128 4-chloro-3-fluorophenyl CH=CCI-CMe=CH Me CQzMe
119-129 4-chioro-3-fluorophenyl CH=CCI-CCI=CH H COgH
119-130 4-chloro-3-fluorophenyl CH=CCI-CCI=CH H COgMe
119-131 4-chloro-3-fluorophenyl CH=CCI-CCI=CH Me CQ2H
119-132 4-chloro-3-fluorophenyl CH=CCI-CCI=CH Me COgMe
119-133 4-chloro-3-fluorophenyl C(N02)=CH-CH=CH H COgH
119-134 4-chloro-3-fluorophenyl C(N02)=CH-CH=CH H C02Me
119-135 4-chloro-3-fluorophenyl C(N02)=CH-CH=CH Me CO2H
119-136 4-chloro-3-fluorophenyl C(N02)=CH-CH=CH Me COgMe
119-137 4-chloro-3-fluorophenyl CH=CH-CH=C(N02) H CO2H
119-138 4-chloro-3-fluorophenyl CH=CH-CH=C(N02) H COgMe
119-139 4-chloro-3-fluorophenyl CH=CH-CH=C(N02) Me CO2H
119-140 4-chloro-3-fluorophenyl CH=CH-CH=C(N02) Me COgMe
4-chloro-2-fluoro-3- 1
119-141 methoxyphenyl H H H CO2H
4-chloro-2-fluoro-3-
119-142 methoxyphenyl H H H COgMe
4-chioro-2-fiuoro-3-
119-143 methoxyphenyl H H Me CO2H
4-chloro-2-fluoro-3-
119-144 methoxyphenyl H H Me COgMe
4-chloro-2-fluoro-3-
119-145 methoxyphenyl H H i-Pr CO2H
4-chloro-2-fluoro-3-
119-146 methoxyphenyl H H i-Pr COzMe
4-chloro-2-fluoro-3-
119-147 methoxyphenyl H H CH2Ph CO2H
4-chloro-2-fluoro-3-
119-148 methoxyphenyl H H CNgPh C02Me
4-chloro-2-fluoro-3-
119-149 methoxyphenyl H H Ph CO2H
4-chloro-2-fluoro-3-
119-150 methoxyphenyl H H Ph COgMe
4-chloro-2-fluoro-3-
119-151 methoxyphenyl H Me H CO2H
4-chloro-2-fluoro-3-
119-152 methoxyphenyl H Me H COgMe
4-chloro-2-fluoro-3-
119-153 methoxyphenyl H Me Me CO2H
4-chloro-2-fiuoro-3-
119-154 methoxyphenyl H Me Me C02Me
119-155 I 4-chloro-2-fluoro-3- | Me |H |H | CO2H
77

Compound Substituent Values
Number A R^ R"' R^ Z
methoxyphenyl
4-chloro-2-fluoro-3-
119-156 methoxyphenyl Me H H COzMe
4-chloro-2-fluoro-3-
119-157 methoxyphenyl Me H Me COgH
4-chloro-2-fluoro-3-
119-158 methoxyphenyl Me H Me COgMe
4-chloro-2-fluoro-3-
119-159 methoxyphenyl Me Me H COgH
4-chloro-2-fluoro-3-
119-160 methoxyphenyl Me Me H COgMe
4-chloro-2-fluoro-3-
119-161 methoxyphenyl Me Me Me CO2H
4-chloro-2-fluoro-3-
119-162 methoxyphenyl Me [Me Me COgMe
4-ch loro-2-f I uoro-3-
119-163 methoxyphenyl (CH2)4 H COgH
4-chloro-2-fluoro-3-
119-164 methoxyphenyl (CH2)4 H COzMe
4-chloro-2-fluoro-3-
119-165 methoxyphenyl (CH2)4 Me CO2H
4-chloro-2-fluoro-3-
119-166 methoxyphenyl (CH2)4 Me C02Me
4-chloro-2-fluoro-3-
119-167 methoxyphenyl CH=CH-CH=CH H CO2H
4-chloro-2-fluoro-3-
119-168 methoxyphenyl CH=CH-CH=CH |H | C02Me
4-chloro-2-fluoro-3-
119-169 methoxyphenyl CH=CH-CH=CH Me CO2H
4-chloro-2-fluoro-3-
119-170 methoxyphenyl CH=CH-CH=CH Me C02Me
4-chloro-2-fluoro-3-
119-171 methoxyphenyl CH=CMe-CH=CH H CO2H
4-chloro-2-fluoro-3-
119-172 methoxyphenyl CH=CMe-CH=CH H C02Me
4-chloro-2-f I uoro-3 -
119-173 methoxyphenyl CH=CMe-CH=CH Me CO2H
4-chloro-2-fluoro-3-
119-174 methoxyphenyl CH=CMe-CH=CH Me COaMe
4-chloro-2-fluoro-3-
119-175 methoxyphenyl CH=CH-CMe=CH H COgH
4-ch loro-2-fl uoro-3-
119-176 methoxyphenyl CH=CH-CMe=CH H COgMe
4-chloro-2-fluoro-3-
119-177 methoxyphenyl CH=CH-CMe=CH Me CO2H
4-chloro-2-f|uoro-3-
119-178 methoxyphenyl CH=CH-CMe=CH Me COgMe
4-chloro-2-fluoro-3-
119-179 methoxyphenyl CH=CMe-CMe=CH H COgH
4-chloro-2-f I uoro-3-
119-180 I methoxyphenyl | CH=CMe-CMe=CH | H | C02Me
78

rnmpnnnH I SubstJtuent Values J
Number j A R° j R°' I R^ I Z |
4-chloro-2-fluoro-3-
119-181 methoxyphenyl CH=CMe-CMe=CH Me CO2H
4-chioro-2-fluoro-3-
119-182 methoxyphenyl CH=CMe-CMe=CH Me COaMe
4-chloro-2-fluoro-3-
119-183 methoxyphenyl CMe-CMe-CH=CH H CO2H
4-chloro-2-fluoro-3-
119-184 methoxyphenyl CMe=CMe-CH=CH H COzMe
4-chloro-2-fluoro-3-
119-185 methoxyphenyl CMe=CMe-CH=CH Me CO2H
4-chloro-2-fluoro-3-
119-186 methoxyphenyl CMe=CMe-CH=CH Me COgMe
4-chloro-2-fluoro-3-
119-187 methoxyphenyl CH=CH-CMe=CMe H COgH
4-chloro-2-fluoro-3-
119-188 methoxyphenyl CH=CH-CMe=CMe H COgMe
4-chloro-2-fluoro-3-
119-189 methoxyphenyl CH=CH-CMe=CMe Me CO2H
4-chloro-2-fluoro-3-
119-190 methoxyphenyl CH=CH-CMe=CMe Me COgMe
4-chloro-2-fluoro-3-
119-191 methoxyphenyl CH=CMe-CCI=CH H CO2H
4-chloro-2-fluoro-3-
119-192 methoxyphenyl CH=CMe-CCI=CH H COzMe
4-chloro-2-fluoro-3-
119-193 methoxyphenyl CH=CMe-CCI=CH Me CO2H
4-chloro-2-fluoro-3-
119-194 methoxyphenyl CH=CMe-CCI=CH Me COzMe
4-chloro-2-fluoro-3-
119-195 methoxyphenyl CH=CCI-CMe=CH H CO2H
4-chloro-2-fluoro-3-
119-196 methoxyphenyl CH=CCI-CMe=CH H COzMe
4-chloro-2-fluoro-3-
119-197 methoxyphenyl CH=CCI-CMe=CH Me CO2H
4-chloro-2-fluoro-3-
119-198 methoxyphenyl CH=CCi-CMe=CH Me COgMe
4-chloro-2-fluoro-3-
119-199 methoxyphenyl CH=CCI-CCI=CH H CO2H
4-chloro-2-fluoro-3-
119-200 methoxyphenyl CH=CCI-CCI=CH H COzMe
4-chloro-2-fl uo ro-3-
119-201 methoxyphenyl CH=CCI-CCI=CH Me COgH
4-chloro-2-fluoro-3-
119-202 methoxyphenyl CH=CCI-CCI=CH Me COaMe
4-chloro-2-fluoro-3-
119-203 methoxyphenyl C(N02)=CH-CH=CH H CO2H
4-chloro-2-fluoro-3-
119-204 methoxyphenyl C(N02)=CH-CH=CH H COzMe
4-chloro-2-fluoro-3-
119-205 methoxyphenyl C(N02)=CH-CH=CH Me COgH
4-chloro-2-fluoro-3-
119-206 I methoxyphenyl I C(NO?)=CH-CH=CH | Me | COzMe
79

Compound Substituent Values
Number I A R^ I R"' I R^ I Z |
4-chioro-2-fluoro-3-
119-207 methoxyphenyl CH=CH-CH=C(N02) H CO2H
4-chloro-2-fluoro-3-
119-208 methoxyphenyl CH=CH-CH=C(N02) H COgMe
4-chloro-2-fluoro-3-
119-209 methoxyphenyl CH=CH-CH=C(NO?) Me CO2H
4-Ghloro-2-fluoro-3-
119-210 I methoxyphenyl | CH=CH-CH=C(N02) I Me I COgMe
210 compounds are described, designated compounds 120-1 to 120-210 respectively, of formula (1H) wherein D is N and X is NMe, and the values of A, R^ R^, R^ and Z are as defined in Table 8.
210 compounds are described, designated compounds 121-1 to 121-210 respectively, of formula (1H) wherein D is CH and X is NH, and the values of A, R^ R^, R^and Z are as defined in Table 8.
210 compounds are described, designated compounds 122-1 to 122-210 respectively, of formula (1H) wherein D is CH and X is NMe, and the values of A. R^ R*, R^'and Z are as defined in Table 8.
Table 9 below provides 72 compounds designated compounds 123-1 to 123-72 respectively, of formula (U) wherein D is N.
AX
(U) 80

TABLE 9
rnmpnnnH i Substituept Values
Number A R^ R°' R^ Z
123-1 cyclopropyl H H H COgH
123-2 cyclopropyl H H H COgMe
123-3 cyclopropyl H H Me CO2H
123-4 cyclopropyl H H Me COaMe
123-5 cyclopropyl H Me H CO2H
123-6 cyclopropyl H Me H COaMe
123-7 cyclopropyl H Me Me COgH
123-8 cyclopropyl H Me Me C02Me
123-9 cyclopropyl Me H H CO2H
123-10 cyclopropyl Me H H COaMe
123-11 cyclopropyl Me H Me COgH
123-12 cyclopropyl Me H Me COgMe
123-13 cyclopropyl Me Me H CO2H
123-14 cyclopropyl Me Me H COgMe
123-15 cyclopropyl Me Me Me COgH
123-16 cyclopropyl Me | Me Me C02Me
123-17 cyclopropyl (CH2)4 H CO2H
123-18 cyclopropyl (CH2)4 H COzMe
123-19 cyclopropyl (CH2)4 Me CO2H
123-20 cyclopropyl (CH2)4 Me C02Me
123-21 cyclopropyl CH=CH-CH=CH H CO2H
123-22 cyclopropyl CH=CH-CH=CH H COzMe
123-23 cyclopropyl CH=CH-CH=CH Me COgH
123-24 cyclopropyl CH=CH-CH=CH Me C02Me
123-25 4-chloro-3-fluorophenyl H IH H CO2H
123-26 4-chloro-3-fluorophenyl H H H COzMe
123-27 4-chloro-3-fluorophenyl H H Me CO2H
123-28 4-chloro-3-fluorophenyl H H Me COaMe
123-29 4-chloro-3-fluorophenyl H Me H CO2H
123-30 4-chloro-3-fluorophenyl H Me H COgMe
123-31 4-chloro-3-fluorophenyl H Me Me CO2H
123-32 4-chloro-3-fluorophenyl H Me Me C02Me
123-33 4-chloro-3-flLiorophenyl Me H H CO2H
123-34 4-chloro-3-fluorophenvl Me H H C02Me
123-35 4-chloro-3-fluorophenyl Me H Me CO2H
123-36 4-chloro-3-fluorophenyl Me H Me COgMe
123-37 4-chloro-3-fluorophenyl Me Me H CO2H
123-38 4-chloro-3-fluorophenyl Me Me H COzMe
123-39 4-chloro-3-fluorophenyl Me Me Me CO2H
123-40 4-chloro-3-fluorophenyl Me | Me Me COgMe
123-41 4-chioro-3-fluorophenyl (CHg)/! H CO2H
123-42 4-chloro-3-fluorophenyl (CH2)4 H COzMe
123-43 4-chloro-3-fluorophenyl (CH2)4 Me CO2H
123-44 I 4-chloro-3-fluorophenyl | (CH2)4 I Me I C02Me
81

r-nrnpniinrt I SubstJtuent Values
Number A R^ I R°' R^ | Z
123-45 4-chloro-3-fluorophenyl CH=CH-CH=CH H COgH
123-46 4-chloro-3-fluorophenvl CH=CH-CH=CH H COzMe
123-47 4-chloro-3-fluorophenvl CH=CH-CH=CH Me COgH
123-48 4-chloro-3-fluorophenyl CH=CH-CH=CH Me COzMe
4-chloro-2-fluoro-3-
123-49 methoxyphenyl H H H CO2H
4-chloro-2-fluoro-3-
123-50 methoxyphenyl H H H COgMe
4-chloro-2-fluoro-3-
123-51 methoxyphenyl H H Me COgH
4-chloro-2-fluoro-3-
123-52 methoxyphenyl H H Me COgMe
4-chloro-2-fluoro-3-
123-53 methoxyphenyl H Me H COgH
4-chloro-2-fluoro-3-
123-54 methoxyphenyl H Me H COzMe
4-chloro-2-fluoro-3-
123-55 methoxyphenyl H Me Me COgH
4-chloro-2-fluoro-3-
123-56 methoxyphenyl H Me Me C02Me
4-chloro-2-fluoro-3-
123-57 methoxyphenyl Me H H CO2H
4-chloro-2-fluoro-3-
123-58 methoxyphenyl Me H H C02Me
4-chloro-2-fluoro-3-
123-59 methoxyphenyl Me H Me CO2H
4-chloro-2-fluoro-3-
123-60 methoxyphenyl Me H Me COzMe
4-chloro-2-fluoro-3-
123-61 methoxyphenyl Me Me H CO2H
4-chloro-2-fluoro-3-
123-62 methoxyphenyl Me Me H C02Me
4-chloro-2-fluoro-3-
123-63 methoxyphenyl Me Me Me CO2H
4-chloro-2-fluoro-3-
123-64 methoxyphenyl Me | Me Me COgMe
4-chloro-2-fluoro-3-
123-65 methoxyphenyl (CHa)^ H CO2H
4-chloro-2-fluoro-3-
123-66 methoxyphenyl (CH2)4 H C02Me
4-chloro-2-fluoro-3-
123-67 methoxyphenyl (CH2)4 Me CQ2H
4-chloro-2-fluoro-3-
123-68 methoxyphenyl (CH2)4 Me CQ2Me
4-chloro-2-fluoro-3-
123-69 methoxyphenyl CH=CH-CH=CH H CO2H
4-chloro-2-fluoro-3-
123-70 methoxyphenyl CH=CH-CH=CH H COzMe
4-chloro-2-fluoro-3-
123-71 methoxyphenyl CH=CH-CH=CH Me COgH
~T23-72 I 4-chloro-2-fluoro-3- | CH=CH-CH=CH | Me I C02M^
82

rnmpnnnH I SubstJtuent Values
Number A R' I R^' R^ Z
methoxyphenyl
72 compounds are described, designated compounds 124-1 to 124-72 respectively, of formula (1J) wherein D is CH, and the values of A, R^. R^ R^' and Z are as defined in Table 9.
Table 10 below provides 96 compounds designated compounds 125-1 to 125-96 respectively, of formula (1K) wherein D is N.
f
(1K)
TABLE 10
nnmpn.ind I Substituent Values
Number A R° I '^'' I ^
125-1 cyclopropyl H H CO2H
125-2 cyclopropyl H H C02Me
125-3 cyclopropyl H Me CO2H
125-4 cyclopropyl H Me C02Me
125-5 cyclopropyl Me H CO2H
125-6 cyclopropyl Me H C02Me
125-7 cyclopropyl Me Me CO2H
125-8 cyclopropyl Me | Me C02Me
125-9 cyclopropyl (CH2)4 CO2H
125-10 cyclopropyl (CH2)4 C02Me
125-11 cyclopropyl CH=CH-CH=CH CO2H
125-12 cyclopropyl CH=CH-CH=CH C02Me
125-13 cyclopropyl CH=CMe-CH=CH CO2H
125-14 cyclopropyl CH=CMe-CH=CH COgMe
125-15 cyclopropyl CH=CH-CMe=CH CO2H
125-16 cyclopropyl CH=CH-CMe=CH COgMe
"T25-I7 I cyclopropyl I CH=CMe-CMe=CH | CO2H
83

r.nmpn,.nri| Substituent Values
Number A R' I R" Z
125-18 cyclopropyl CH=CMe-CMe=CH C02Me
125-19 cyclopropyl CMe=CMe-CH=CH CO?H
125-20 cyclopropyl CMe=CMe-CH=CH C02Me
125-21 cyclopropyl CH=CH-CMe=CMe CQzH
125-22 cyclopropyl CH=CH-CMe=CMe COaMe
125-23 cyclopropyl CH=CMe-CCI=CH CQ2H
125-24 cyclopropyl CH=CMe-CCI=CH COaMe
125-25 cyclopropyl CH=CCI-CMe=CH CQ2H
125-26 cyclopropyl CH=CCI-CMe=CH COaMe
125-27 cyclopropyl CH=CCI-CCI=CH CO2H
125-28 cyclopropyl CH=CCI-CCI=CH COaMe
125-29 cyclopropyl C(NQ2)=CH-CH=CH CO2H
125-30 cyclopropyl C(N02)=CH-CH=CH COaMe
125-31 cyclopropyl CH=CH-CH=C(NQ2) CQ2H
125-32 cyclopropyl CH=CH-CH=C(NQ2) CQ2Me
125-33 4-chloro-3-fiuorophenyl H I "^ ^^^^
125-34 4-chloro-3-fluorophenyl H H C02Me
125-35 4-chloro-3-fluorophenyl H Me CO2H
125-36 4-chloro-3-fluorophenyl H Me COaMe
125-37 4-chloro-3-fluorophenyl Me H CO2H
125-38 4-chioro-3-fluorophenyl Me H COgMe
125-39 4-chloro-3-fluorophenyl Me Me CO2H
125-40 4-chloro-3-fluorophenyl Me | Me COaMe
125-41 4-chloro-3-fluorophenyl (CH2)4 COgH
125-42 4-chloro-3-fluorophenyl (CH2)4 C02Me
125-43 4-chloro-3-fluorophenyl CH=CH-CH=CH CO2H
125-44 4-chloro-3-fluorophenyl CH=CH-CH=CH C02Me
125-45 4-chloro-3-fluorophenyl CH=CMe-CH=CH CO2H
125-46 4-chloro-3-fluorophenyl CH=CMe-CH=CH C02Me
125-47 4-chloro-3-fluorophenyl CH=CH-CMe=CH CO2H
125-48 4-chloro-3-fluorophenyl CH=CH-CMe=CH C02Me
125-49 4-chloro-3-fluorophenyl CH=CMe-CMe=CH CO2H
125-50 4-chloro-3-fluorophenyl CH=CMe-CMe=CH CQ2Me
125-51 4-chloro-3-fluorophenyl CMe^CMe-CH=CH CO2H
125-52 4-chloro-3-fluorophenyl CMe=CMe-CH=CH COaMe
125-53 4-chloro-3-fluorophenyl CH=CH-CMe=CMe CQ2H
125-54 4-chloro-3-fluorophenyl CH=CH-CMe=CMe COaMe
125-55 4-chloro-3-fluorophenyl CH=CMe-CCI=CH CO2H
125-56 4-chloro-3-fluorophenyl CH=CMe-CCI=CH COaMe
125-57 4-chloro-3-fluorophenyl CH=CCI-CMe=CH CO2H
125-58 4-chloro-3-fluorophenyl CH=CCI-CMe=CH C02Me
125-59 4-chloro-3-fluorophenyi CH=CCI-CCI=CH CO2H
125-60 4-chloro-3-fluorophenyl CH=CCI-CCI=CH COaMe
125-61 4-chloro-3-fluorophenyl C(N02)=CH-CH=CH CO2H
~125-62 I 4-chloro-3-fluorophenyl I C(NOy)=CH-CH=CH | COaMe
84

r.nmpn..nri| Substituent Values
Number A R^ I R" Z
125-63 4-chloro-3-fluorophenyl CH=CH-CH=C(N02) CO2H
125-64 4-chloro-3-fluorophenyl CH=CH-CH=C(N02) C02Me
4-chloro-2-fluoro-3-
125-65 methoxyphenyl H H COgH
4-chloro-2-fluoro-3-
125-66 methoxyphenyl H H C02Me
4-chloro-2-fluoro-3-
125-67 methoxyphenyl H Me CO2H
4-chloro-2-fluoro-3-
125-68 methoxyphenyl H Me C02Me
4-chloro-2-fluoro-3-
125-69 methoxyphenyl Me H CO2H
4-chloro-2-fluoro-3-
125-70 methoxyphenyl Me H COgMe
4-chloro-2-fluoro-3-
125-71 methoxyphenyl Me Me CO2H
4-ch!oro-2-fluoro-3-
125-72 methoxyphenyl Me | Me C02Me
4-chloro-2-fluoro-3-
125-73 methoxyphenyl (CH2)4 CO2H
4-chloro-2-fluoro-3-
125-74 methoxyphenyl (CH2)4 C02Me
4-chloro-2-fluoro-3-
125-75 methoxyphenyl CH=CH-CH=CH CO2H
4-chloro-2-fluoro-3-
125-76 methoxyphenyl CH=CH-CH=CH C02Me
4-chloro-2-fluoro-3-
125-77 methoxyphenyl CH=CMe-CH=CH CO2H
4-chloro-2-fluoro-3-
125-78 methoxyphenyl CH=CMe-CH=CH COzMe
4-chloro-2-fluoro-3-
125-79 methoxyphenyl CH=CH-CMe=CH CO2H
4-chloro-2-fluoro-3-
125-80 methoxyphenyl CH=CH-CMe=CH C02Me
4-chloro-2-fluoro-3-
125-81 methoxyphenyl CH=CMe-CMe=CH CO2H
4-chloro-2-fluoro-3-
125-82 methoxyphenyl CH=CMe-CMe=CH COgMe
4-chloro-2-fluoro-3-
125-83 methoxyphenyl CMe=CMe-CH=CH CO2H
4-chloro-2-fluoro-3-
125-84 methoxyphenyl CMe=CMe-CH=CH COzMe
4-chloro-2-fluoro-3-
125-85 methoxyphenyl CH=CH-CMe=CMe CO2H
4-chloro-2-fluoro-3-
125-86 methoxyphenyl CH=CH-CMe=CMe C02Me
4-chloro-2-fluoro-3-
125-87 methoxyphenyl CH=CMe-CCI=CH CO2H
4-chloro-2-fluoro-3-
125-88 methoxyphenyl CH=CMe-CCI=CH C02Me
125-89 I 4-chloro-2-fluoro-3- I CH=CCI-CMe=CH | CO2H
85

r.nmpn.,nri| Substituent Values
Number A R" I R"' Z
methoxyphenyl
4-chloro-2-fluoro-3-
125-90 methoxyphenyl CH=CCI-CMe=CH COgMe
4-chloro-2-fluoro-3-
125-91 methoxyphenyl CH=CCI-CCI=CH CO2H
4-chloro-2-fluoro-3-
125-92 methoxyphenyl CH=CCI-CCI=CH COzMe
4-chloro-2-fluoro-3-
125-93 methoxyphenyl C(N02)=CH-CH=CH CO2H
4-chloro-2-fluoro-3-
125-94 methoxyphenyl C(N02)=CH-CH=CH COzMe
4-chloro-2-fluoro-3-
125-95 methoxyphenyl CH=CH-CH=C(N02) CO2H
4-chloro-2-fluoro-3-
125-96 I methoxyphenyl [ CH=CH-CH=C(N02) | COzMe
96 compounds are described, designated compounds 126-1 to 126-96 respectively, of formula (IK) wherein D is CH, and the values of A, R*, R* and Z are as defined in Table 10.
Table 11 below provides 36 compounds designated compounds 127-1 to 127-36 respectively, of formula (1L) wherein D is N and X is NH.
(1L) TABLE 11
Compound Substituent Values
Number "A TR^ VZ
127-1 Ci ""H CO2H
127-2 ci ""H COzMe
127-3 ci H CO/Pr
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127-4 Tcl TMe I CO2H
127-5 Ci Me CO^Me
127-6 ci Me COT^Pr
127-7 cyclopropyl H CO2H
127-8 cyclopropyl H COzMe
127-9 cyclopropyl H COTPr
127-10 cyclopropyl Me CO^H
127-11 cyclopropyl Me C02Me
127-12 cyclopropyl Me CO?Pr
127-13 4-chlorophenyl H CO^H
127-14 4-chlorophenyl H COjMe
127-15 4-chlorophenyl H CO^Pr
127-16 4-chlorophenyi Me CO^H
127-17 4-chlorophenyl Me COjMe
127-18 4-chlorophenyl Me CO^Tr
127-19 4-chloro-3-fluorophenyl H CO2H
127-20 4-chloro-3-fluorophenyl H CO^Me
127-21 4-chloro-3-fluorophenyl H COTVr
127-22 4-chloro-3-fluoropheny] Me CO2H
127-23 4-chloro-3-fluorophenyl Me CO^Me
127-24 4-chloro-3-fluorophenyl Me CO?Pr
127-25 4-chloro-2-fluoro-3-methoxyphenyl H CO2H
127-26 4-chloro-2-fluoro-3-methoxyphenyl H CO^Me
127-27 4-chloro-2-fluoro-3-methoxyphenyl H COTPr
127-28 4-chloro-2-fluoro-3-methoxyphenyl Me CO2H
127-29 4-chloro-2-fluoro-3-methoxyphenyl Me ^O^Me
127-30 4-chloro-2-fluoro-3-methoxyphenyl Me COTPr
127-31 4-chloro-3-dimethylamino-2-fluorophenyl H CO^H
127-32 4-chloro-3-dimethylamino-2-fluorophenyl H CO^Me
127-33 4-chloro-3-dimethylamino-2-fluorophenyi H CO^Pr
127-34 4-chloro-3-dinnethylamino-2-fluorophenyl Me CO2H
127-35 4-chloro-3-dinnethylamino-2-fluorophenyl Me C02Me
127-36 4-chloro-3-dimethylamino-2-fluorophenyl Me CO/'Pr
87

36 compounds are described, designated compounds 128-1 to 128-36 respectively, of formula (1L) wherein D is N and X is NMe, and the values of A, R® and Z are as defined in Table 11.
36 compounds are described, designated compounds 129-1 to 129-36 respectively, of formula (1L) wherein D is N and X is NCHzPh, and the values of A, R* and Z are as defined in Table 11.
36 compounds are described, designated compounds 130-1 to 130-36 respectively, of formula (1L) wherein D is N and X is NCH2(2-nitrophenyl), and the values of A, R^ and Z are as defined in Table 11.
36 compounds are described, designated compounds 131-1 to 131-36 respectively, of formula (1L) wherein D is N and X is NCH2(2,4-dimethoxyphenyl), and the values of A. R® and Z are as defined in Table 11.
36 compounds are described, designated compounds 132-1 to 132-36 respectively, of fonnula (1L) wherein D is N and X is NCH2(2-furanyl), and the values of A, R* and Z are as defined in Table 11.
36 compounds are described, designated compounds 133-1 to 133-36 respectively, of formula (1L) wherein D is CH and X is NH, and the values of A, R® and Z are as defined in Table 11.
36 compounds are described, designated compounds 134-1 to 134-36 respectively, of formula (1L) wherein D is CH and X is NMe, and the values of A, R* and Z are as defined in Table 11.
36 compounds are described, designated compounds 135-1 to 135-36 respectively, of formula (1L) wherein D is CH and X is NCHzPh, and the values of A, R® and Z are as defined in Table 11.
36 compounds are described, designated compounds 136-1 to 136-36 respectively, of formula (1L) wherein D is CH and X is NCH2(2-nitrophenyl), and the values of A, R® and Z are as defined in Table 11.
88

36 compounds are described, designated compounds 137-1 to 137-36 respectively, of formula (1L) wherein D is CH and X is NCH2(2,4-dimethoxyphenyl), and the values of A, R® and Z are as defined in Table 11.
36 compounds are described, designated compounds 138-1 to 138-36 respectively, of formula (1L) wherein D is CH and X is NCH2(2-furanyl), and the values of A, R® and Z are as defined in Table 11.
General methods for the production of compounds of formula (I) are described below. Unless otherwise stated in the text, the substituents A, D, E, R^, R^, R^ R^ X, Y and Z, and the number n are as defined hereinbefore. The abbreviation LG as used herein refers to any suitable leaving group. Preferred leaving groups are halogen, sulphonate (preferably tosylate), and sulphone groups. The groups R' as used herein are optional substituents and are, independently of each other, alkyl or substituted alkyl groups. The abbreviation M as used herein refers to a metal or metalloid derivative. Preferred groups M are boronic acids and esters, trialkylstannanes and halomagnesium species (Grignard reagents).
Compounds of formula (I) in which Y is a carbon atom and n = 1 may be prepared from compounds of formula (A) as shown in reaction scheme 1.
Reaction Scheme 1
xY - .xi
A N Z A N Z
(A) (1)
For example a compound of formula (I), in which X is an oxygen atom, may be prepared by reacting a pyridone or pyrimidone in the presence of a suitable base (for example an organic base, such as triethylamine), optionally in a suitable solvent, as described in, for example, Chem. Pharm. Bull.. 1982. 30(7). 2417.
Compounds of formula (A) may be prepared from compounds of formula (B) as shown in reaction scheme 2.
89

Reaction Scheme 2
vu XH ^^R
XX —" .-XX
A-^ ^N'^ ^2 A N 2
(B) (A)
For example, a compound of formula (A) may be prepared from a compound of formula (B) in which LG is a halogen atom or sulphonate by Sonogashira reaction with an alkyne of formula (C) in the presence of a copper source (for example, a copper(l) salt, such as copper(l) iodide), a palladium catalyst (for example bis(triphenylphosphine)palladium(ll) dichloride) and a suitable base (for example an organic base, such as triethylamine), optionally in a suitable solvent, as described in, for example, Chem. Pharm. Bull., 1982, 30(7), 2417; as shown in reaction scheme 3.
Reaction Scheme 3
XH XH ^R*
1 1 ' ^ —^ IT
(B) (C)
(A)
Alternatively (see reaction scheme 4) a compound of formula (A) may be prepared from a compound of formula (B) in which LG is a halogen atom or sulphonate by reaction with a suitable metal or metalloid alkyne derivative (D) (for example a boronic acid or ester, a trialkyltin derivative, a zinc derivative or a Grignard reagent) in the presence of a suitable base (for example an inorganic base, such as potassium phosphate or caesium fluoride), a metal source (for example a palladium source, such as Pd(OAc)2) and, optionally, a ligand for the metal (for example a phosphine ligand, such as PCya.HBF,,) in a suitable solvent (for example a single solvent, such as dimethylformamide, or a mixed solvent system, such as a mixture of dimethoxyethane and water or toluene and water). The metal catalyst and ligands may also be added as a single, pre-formed, complex (for example a palladium/phosphine complex, such as bis(triphenylphosphine)palladium dichloride or (1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride
90

dichloromethane adduct). Such reactions are well known in the literature and are described in, for example. WO2009/046090.
Reaction Scheme 4
XH XH ^R"
JL LG /R' JL J^
(B) (D) (A)
Compounds of formula (B) may be prepared as described in, for example, WO2009/081112.
Alternatively, compounds of formula (A1), which are compounds of formula A in which R' is a hydrogen atom, may be prepared from compounds of formula (E) as shown in reaction scheme 5.
Reaction Scheme 5
XH O XH
(E) (A1)
There are many ways in which this transformation may be performed known in the
literature, for example as described in Synlett., 1996, 521; Tetrahedron Lett., 1972, 36,
3769; J. Org. Chem., 2000. 65, 1889.
Compounds of formula (E) may be prepared as described in, for example,
WO2009/046090.
Alternatively, compounds of formula A may be prepared from compounds of formula (F) as shown in reaction scheme 6.
Reaction Scheme 6
91

XH Q ^^ ^^^
(F) (A)
This transformation may be performed, for example, as described in J. Org. Chem., 1982, 47. 1837.
Compounds of formula (F) may be prepared as described in, for example, WO2009/046090.
Alternatively, compounds of formula (E) and formula (F) may be prepared from compounds of formula (G), as shown in reaction scheme 7.
Reaction Scheme 7
XH rj^^ XH O
fiT N ^Z A N Z
(G) (E)or(F)
For example, a compound of formula (E) or (F) may be prepared by the reaction of a compound of formula (G) with ozone in a suitable solvent, for example dichloromethane, followed by in situ treatment of the resulting ozonide with a suitable reducing agent, for example triphenylphosphine or dimethyl sulphide.
Alternatively, a compound of formula (G) may be treated with metallic oxidising agents, for example, osmium tetroxide and sodium periodate, optionally in the presence of a further stoichiometric oxidant, for example, an amine A/-oxide such as N-methylmorpholine A/-oxide, to produce a compound of formula (E) or (F).
Compounds of formula (G) are described in, for example, WO2009/081112.
92

Compounds of formula (I) may also be prepared from compounds of formula (B), as shown in reaction scheme 8.
Reaction Scheme 8
A N Z A^ ^N'^ ^Z
(B) (1)
For example, a compound of formula (I) in which Y is a carbon atom and n = 1 may be prepared from a compound of formula (B) by reaction with an allenyl metal or metalloid reagent (H) (for example an allenyl stannane or allenyl boronic acid) in the presence of a suitable base (for example an inorganic base, such as potassium phosphate or caesium fluoride), a metal source (for example a palladium source, such as Pd(0Ac)2) and, optionally, a ligand for the metal (for example a phosphine ligand, such as PCy3.HBF4) in a suitable solvent (for example a single solvent, such as dimethylfomiamide, or a mixed solvent system, such as a mixture of dimethoxyethane and water or toluene and water). The metal catalyst and ligands may also be added as a single, pre-formed, complex (for example a palladium/phosphine complex, such as bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane adduct), as shown in reaction scheme 9.
Reaction Scheme 9
XH /
A ^N ^Z
(B) (H)
(1)
Alternatively, as shown in reaction scheme 10, a compound of formula (I) in which Y is a carbon atom and n = 1 may be prepared from a compound of formula (B) in which LG is a halogen atom or sulphonale by Sonogashira reaction with an alkyne of formula (C) in the presence of a copper source (for example, a copper(l) salt, such as copper(l) iodide), a palladium catalyst (for example bis(triphenylphosphine)palladium(ll)
93

dichloride) and a suitable base (for example an organic base, such as triethylamine), optionally in a suitable solvent, as described in, for example, Chem. Pharm. Bull., 1982, 30(7), 2417.
Reaction Scheme 10
XH /
A * ^ — XX
(B) (C)
(1)
Compounds of formula (I) in which Y is carbon may also be prepared from compounds of formula (J), as shown in reaction scheme 11.
Reaction Scheme 11
II I " 1 A
(J) (1)
For example a compound of formula (J) may be treated with a suitable base (for example an inorganic base, such as sodium acetate), a metal source (for example a palladium source, such as Pd(0Ac)2) and, optionally, a ligand for the metal (for example a phosphine ligand, such as PCya.HBF^) in a suitable solvent (for example dimethylacetamide). The metal catalyst and ligands may also be added as a single, pre¬formed, complex (for example a palladlum/phosphine or palladium/AZ-heterocyclic carbene complex, such as a PEPPSI complex). Such methods are described in, for example, J. Chem. Soc, Perkin 1,1979, 771; Tetrahedron Lett., 1987. 28(44), 5291.
Compounds of formula (J) may be prepared from compounds of formula (K), in which LG and LG' may be the same or different leaving groups, by reaction with a nucleophile of formula (L), optionally in the presence of a base (for example an organic base, such
94

as triethylamine, or an inorganic base, such as potassium carbonate), in a suitable solvent, for example dichloroethane. as shown in reaction scheme 12.
Reaction Scheme 12
LG' I
(K) (L)
(J)
Compounds of formula (K) may be prepared using methods known in the literature, for example as described in WO2009/081112.
Alternatively, compounds of formula (J) may be prepared from compounds of formula (B) by reaction with suitable alkylating agents of formula (M), as shown in reaction scheme 13.
Reaction Scheme 13
XH I
A N ^Z
(B) (M)
(J)
Compounds of formula (I) in which Y is carbon may also be prepared from compounds of formula (N), as shown in reaction scheme 14.
95

Reaction Scheme 14
1 1 ^' —' XX
A'^ ^N^ ^Z A N Z
(N) (1)
For example a compound of formula (I) may be prepared by treating a compound of
formula (N) with an olefin metathesis catalyst, for example a ruthenium or molybdenum
complex. such as 1,3-bis-(2,4,6-trimethylphenyl)-2-
(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexylphosphine)ruthenium.
Compounds of formula (N) may be prepared from compounds of formula (J), as shown in reaction scheme 15.
Reaction Scheme 15
1 I \A A A A i
A N Z A-^ ^N ^Z
''' (N)
For example, such a transformation may be carried out by reaction with a metal or metalloid derivative of formula (O) (for example a boronic acid, boronate ester or stannane) in the presence of a base {for example an inorganic base, such as potassium phosphate or caesium fluoride, or an organic base, such as triethylamine), a metal source (for example, a palladium source such as Pd2(dba)3) and, optionally, a ligand for the metal (for example a phosphine ligand. such as X-Phos) in a suitable solvent (for example a single solvent, such as acetonitrile, or a mixed solvent system, such as a mixture of dimethoxyethane and water). The metal catalyst and ligands may also be added as a single, pre-formed, complex (for example a palladium/phosphine complex, such as palladium tetrakis(triphenylphosphine), bis(triphenylphosphine)palladium
96

dichloride or [1,1"-bis(cliphenylphosphino)ferrocene] palladium dichloride), as shown in reaction scheme 16.
Reaction Scheme 16
X n ^ fi
1 + 11 1 0
(O)
(>J) (N)
Alternatively, compounds of formula (N) may be prepared from compounds of formula (P) by reaction with a nucleophile of formula (L), optionally in the presence of a base (for example an organic base, such as triethylamine, or an inorganic base, such as potassium carbonate), in a suitable solvent, for example dichloroethane, as shown in reaction scheme 17.
Reaction Scheme 17
R' R«-^r^^R'
I II R--~^r f^' ^ fl
?i T'^^''' ■*" J) " JL X
A ^N ^Z 11
(L) A-^N^^Z '
(P)
(N)
Compounds of formula (P) may be prepared from compounds of formula (K), in which LG" is a leaving group or the precursor to a leaving group (for example an alkylthio group that can be converted into an alkylsulphonyl leaving group by oxidation), as shown in reaction scheme 18.
97

Reaction Scheme 18
1 \ H
A N Z A'^^N'^^Z
(K)
(P)
For example, such a transformation may be carried out by reaction witli a metal or metalloid derivative of formula (O) (for example a boronic acid, boronate ester or stannane) in the presence of a base (for example an inorganic base, such as potassium phosphate or caesium fluoride, or an organic base, such as triethylamine), a metal source (for example, a palladium source such as Pd2(dba)3) and, optionally, a ligand for the metal (for example a phosphine ligand, such as X-Phos) in a suitable solvent (for example a single solvent, such as acetonitrile, or a mixed solvent system, such as a mixture of dimethoxyethane and water). The metal catalyst and ligands may also be added as a single, pre-formed, complex (for example a palladium/phosphine complex, such as palladium tetrakis(triphenylphosphine), bis(triphenylphosphine)palladium dichloride or [1,r-bis(diphenylphosphino)ferrocene] palladium dichloride). as shown in reaction scheme 19.
Reaction Scheme 19
A N ^ A'^ ^N ^Z
(0)
(«) (P)
Compounds of formula (N) may also be prepared from compounds of formula (G) by reaction with suitable alkylating agents of formula (M), as shown in reaction scheme 20.
98

Reaction Scheme 20
(M) A^^N^'^^Z
(G)
(N)
Compounds of formula (I) in which X is NH, Y is carbon and n = 1 may be prepared from compounds of formula (Q), as shown in reaction scheme 21.
Reaction Scheme 21
(Q) (1)
For example, an azide of formula (Q) may be heated in an inert solvent (for example a haloarene such as dibromobenzene) to produce a compound of formula (I), for example as described in Chem. Pharm. Bull., 1982, 30(7), 2417.
Alternatively an azide of formula (Q) may be converted to a compound of formula (I) by photolysis in a suitable solvent (for example, trifluoroacetic acid), for example as described in Chem. Pharm. Bull., 1989, 37(11), 2933.
Compounds of formula (Q) may be prepared from compounds of formula (P), as shown in reaction scheme 22.
Reaction Scheme 22
J!X JLX
A-^N^Z A--^K^Z
(P) 1°)
99

For example, a compound of formula (Q) may be prepared by treating a compound of formula (P) with a source of azide (for example an inorganic azide, such as sodium azide) in a suitable solvent (for example, ethanol or dimethylformamide).
Alternatively, compounds of formula (Q) may be prepared from compounds of formula (R), as shown in reaction scheme 23.
Reaction Scheme 23
N /R'
A A XX '°
(R)
(Q)
For example, such a transformation may be carried out by reaction with a metal or
metalloid derivative of formula (O) (for example a boronic acid, boronate ester or
stannane) in the presence of a base (for example an inorganic base, such as potassium
phosphate or caesium fluoride, or an organic base, such as triethylamine), a metal
source (for example, a palladium source such as Pd2(dba)3) and, optionally, a ligand for
the metal (for example a phosphine ligand, such as X-Phos) in a suitable solvent (for
example a single solvent, such as acetonitrile, or a mixed solvent system, such as a
mixture of dimethoxyethane and water). The metal catalyst and ligands may also be
added as a single, pre-formed, complex (for example a palladium/phosphine complex,
such as bis(triphenylphosphine)palladium dichloride or [1,1'-
bis(diphenylphosphino)ferrocene] palladium dichloride), as shown in reaction scheme 24.
Reaction Scheme 24
(O)
JH ^Y
AXA' —^ XX
A-^^N^^Z A'^ ^N^ ^Z
(^) (X)
Alternatively, compounds of formula (X) may be prepared by reduction of compounds of formula (Z), as shown in reaction scheme 37.
Reaction Scheme 37
xX —' .^.
A-^ ^N'^ ^Z A N Z
(Z) (X)
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For example, this transformation may be acfiieved by the reaction of a compound of formula (2) with a suitable reducing agent, for example a metal hydride such as sodium borohydride.
Compounds of formula (Z) in which Y is carbon and n = 1 may be prepared from compounds of formula (A), as shown in reaction scheme 38.
Reaction Scheme 38
A N Z A^^N^^Z
(A) (Z)
For example, a compound of formula (Z) may be prepared by treating a compound of formula (A) with a metal salt (for example a gold or mercury salt, such as mercury (II) sulphate) optionally in the presence of an acid (for example an inorganic acid such as sulphuric acid).
Compounds of formula (Z) may also be made by oxidation of compounds of formula (X), as shown in reaction scheme 39.
Reaction Scheme 39
xX — XX.
A'^ ^N-^ ^2 A N Z
(X) (Z)
For example, a compound of formula (Z) may be prepared by treating a compound of formula (X) with an oxidising agent, using methods that are well known in the literature.
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Compounds of formula (Z) in which Y is a carbon and n=1 may be prepared from compounds of formula (B) by reaction with a siiyi enol ether (AA), as shown in reaction scheme 40.
Reaction Scheme 40
A N Z
(B) (AA)
(Z)
For example a compound of formula (Z) may be prepared by reacting a silyl enol ether (AA) with a compound of formula (B) in the presence of a metal source (for example a palladium source such as Pd2(dba)3), a second metal (for example a zinc salt, such as zinc difluoride) and, optionally, a ligand for the metal (for example a phosphine ligand, such as S-Phos) in a suitable solvent (for example dimethyl formamide), as described in, for example, Tetrahedron Lett., 2007, 48, 1213.
Compounds of formula (I) may be prepared from compounds of formula (X), as shown in reaction scheme 38.
Reaction Scheme 41
XH P/
A^z XI
(X) (1)
For example, a compound of formula (I) may be prepared by treating a compound of formula (X) as described in, for example, J. Het. Chem., 1996, 33. 229.
Compounds of formula (I) in which X is nitrogen may be prepared from compounds of formula (Z) in which X is nitrogen, as shown in reaction scheme 42.
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Reaction Scheme 42
A^ ^N ^2 A N Z
(Z) (1)
For example, a compound of fomiula (I) may be prepared by treating a compound of formula (Z) with an acid (for example an organic acid, such as para-toluene sulphonic acid) as described in, for example, J. Orq. Chem., 2007, 72(13), 4596 and WO2004/000843.
Compounds of formula (I) may be prepared from compounds of formula (BB), as shown in reaction scheme 43.
Reaction Scheme 43
X.-rr.R f"^^
X XX
LU N Z A N Z
(BB) (1)
For example, a compound of formula (I), in which A is a ring linked to the bicyclic ring system through a nitrogen atom, may be prepared by reaction of a compound of formula (BB) with A-H (for example pyrrole), optionally in the presence of a suitable base (for example an amine base, such as triethylamine), in a suitable solvent (for example an alcohol, such as methanol) ~ see reaction scheme 44 below. The reaction may be performed at ambient temperature or preferably, at an elevated temperature. This transformation may also be performed in the presence of a suitable metal (for example palladium) catalyst, optionally complexed by any suitable ligands (for example phosphine ligands, such as Josiphos).
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Reaction Scheme 44
/^ NH
(BB) (1)
In a second example (see reaction scheme 45) a compound of fomiula (1), in which A is a group attached through a carbon atom, may be prepared by reacting a suitable metal or metalloid derivative A-M (for example a boronic acid or ester, a trialkyltin derivative, a zinc derivative or a Grignard reagent) with a compound of formula (BB) in the presence of a suitable base (for example an inorganic base, such as potassium phosphate or caesium fluoride, or an organic base, such as triethylamine), a metal source (for example a palladium source such as Pd2(dba)3) and, optionally, a ligand for the metal (for example a phosphine ligand, such as X-Phos) in a suitable solvent (for example a single solvent, such as acetonitrile, or a mixed solvent system, such as a mixture of dimethoxyethane and water). The metal catalyst and ligands may also be added as a single, pre-formed, complex (for example a palladium/phosphine complex, such as palladium tetrakis(triphenylphosphine), bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride).
Reaction Scheme 45
AX XX
LG ^N^ ^Z A-^^N ^Z
(BB) (1)
As an additional example, a compound of formula (I) in which A is an alkenyl group may be prepared using a Heck reaction in which the group A component containing the double bond may be reacted with a compound of formula (AA) in the presence of a suitable metal catalyst (for example a palladium derivative, such as palladium acetate), optionally with a suitable ligand for the metal, and a suitable base (for example an inorganic base, such as potassium phosphate) in a suitable solvent (for example N-methylpyrroiidone), as shown in reaction scheme 46.
no

Reaction Scheme 46
5
3=^^ f^
{ R'- / ;Y
^ 0^^^^
u. . Z R.,>^N^Z
(BB) (1)
Alternatively, compounds of formula (I) may be prepared from compounds of formula (CC), wherein M represents a suitable metal or metalloid derivative (for example a boronic acid or ester, a trialkyltin group, a suitably substituted silyl group, a zinc derivative or a magnesium halide), by reaction with a compound A-LG - see reaction scheme 47 below.
Reaction Scheme 47
?i I "^ Y'l^
(CC) (1)
For example, a compound of fomnula (I) may be prepared from a compound of formula (CC) in which M is a boronic acid group by reaction with a compound A-LG in the presence of a metal catalyst (for example a palladium derivative such as Pd2(dba)3), optionally with a suitable ligand (for example a phosphine such as X-Phos) and a base (for example an inorganic base, such as potassium phosphate or caesium fluoride) in a suitable solvent.
Compounds of formula (CC) may be prepared from other compounds of formula (CC) using a transmetallation reaction. For example, a compound of formula (CC) wherein M is a boronic acid may be prepared from a compound of formula (CC) where M is a magnesium halide by reaction with a trialkylboronate, followed by hydrolysis (for example under acidic conditions).
Alternatively compounds of formula (CC) may be prepared from compounds of formula (BB) (reaction scheme 48).
Ill

Reaction Scheme 48
X.rr:R X-rrtE
IX AX
LG N Z M N Z
(BB) <^^)
For example, a compound of formula (CC) wherein M is a boronate ester or a trialkylstannane may be prepared from a compound of formula (BB) by treating it witli a suitable M-containing reagent (for example pinacolborane, bispinacolatodiboron, hexa-alkyldi-tin) in the presence of a metal catalyst (for example a palladium species, such as bis(diphenylphosphine)palladium dichloride) in a suitable solvent (for example dioxane).
Alternatively, a compound of fomiula (CC) where IVI is a magnesium halide may be prepared from a compound of formula (BB) by treatment with a suitable Grignard reagent (for example an isopropylmagnesium halide such as isopropylmagnesium chloride) in a suitable solvent.
Compounds of formula (BB) may be prepared from compounds of formula (DD), in which LG' is a leaving group and may be the same as or different to LG, as shown in reaction scheme 49.
Reaction Scheme 49
JuC' —' XJ^
(DD) (BB)
For example a compound of formula (BB) in which Z is CO2R' may be prepared from a compound of formula (DD) by reaction with an alcohol R'OH and carbon monoxide in the presence of a suitable metal catalyst (for example a palladium reagent, such as bis(triphenylphosphine)palladium dichloride) and a suitable base (for example an organic base, such as triethylamine), see reaction scheme 50. It may conveniently be conducted under an atmosphere of carbon monoxide gas at atmospheric or raised pressure.
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Reaction Scheme 50
11 ^ 9 1^
(DD) (88)
Compounds of formula (DD) in which LG and LG' are the same, may be prepared from compounds of formula (EE) by reaction with a suitable reagent (for example a phosphoryl halide or sulphonyl anhydride) as shown in reaction scheme 51.
Reaction Scheme 51
X AX
MU N OH LG N LG'
(EE) (DD) •
For example, a compound of formula (DD) in which LG and LG* are halogen atoms may be prepared by reaction of a compound of fonnula (EE) with a halogenating agent (for example a phosphoryl halide such as phosphorus oxychloride) in the presence of a suitable base (for example an organic base, such as /\/,A/-diethylaniline).
Compounds of formula (EE) may be prepared from compounds of formula (FF), in which G is a leaving group or an amine and J is an alkoxy or amino group, as shown in reaction scheme 52.
Reaction Scheme 52
L^ Y 1 ;Y
'X ~~ Xx
(FF) (EE)
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For example, as shown in reaction scheme 53, a compound of formula (EE) in which D is a nitrogen atom, may be prepared by the reaction of a compound of formula (FF) in which G and J are both NH?, with a chloroformate in the presence of a base (for example an organic base, such as pyridine), as described in, for example. Nucleosides and Nucleotides, 1994, 13{5), 1135.
Reaction Scheme 53
(FF) (EE)
Compounds of formula (FF) are known in the literature, or may be made using procedures known in the literature.
Compounds of formula (I) may be prepared from different compounds of formula (I) by the conversion of any of the substituents A, D, E, X, Y and Z, into a different group A, D, E, X, Y and Z, using techniques well known to the skilled man.
For example, an unsaturated group A (for example an alkene or cycloalkene) may be reduced to form a saturated group (for example an alkyl or cycloalkyi group). When A is an unsaturated ring it may be oxidised to form an aromatic ring under standard conditions.
A second example is the conversion of a compound in which A is a halogen atom (for example, chlorine) into a compound in which A is a substituted phenyl ring. Such a conversion may be performed by reacting a suitable metal or metalloid derivative A-M (for example a boronic acid or ester, a trialkyltin derivative, a zinc derivative or a Grignard reagent) with a compound of formula (I) in which A = CI in the presence of a suitable base (for example an inorganic base, such as potassium phosphate or caesium fluoride, or an organic base, such as triethylamine), a metal source (for example a palladium source such as Pd2(dba)3) and, optionally, a ligand for the metal (for example a phosphine ligand, such as X-Phos) in a suitable solvent (for example a single solvent, such as acetonitrile, or a mixed solvent system, such as a mixture of dimethoxyethane and water). The metal catalyst and ligands may also be added as a single, pre-formed,
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complex (for example a palladium/phosphine complex, such as palladium tetrakls(triphenylphosphine), bis(triphenyiphosphine)palladium dichloride or [1,1'-bis(diphenyiphosphino)ferrocene] palladium dichloride).
A further example is the conversion of a compound in which D is C-Halogen (for example C-Br or C-CI) into a compound in which D is a carbon atom attached to a carbon-based group, for example an alkyl or alkenyl group. Such a transformation may be carried out by reaction with a metal or metalloid derivative of the alkyl or alkenyl group (for example a boronic acid or boronate ester) in the presence of a base (for example an inorganic base, such as potassium phosphate or caesium fluoride, or an organic base, such as triethylamine), a metal source (for example a palladium source such as Pd2(dba)3) and, optionally, a ligand for the metal (for example a phosphine ligand, such as X-Phos) in a suitable solvent (for example a single solvent, such as acetonitrile, or a mixed solvent system, such as a mixture of dimethoxyethane and water). The metal catalyst and ligands may also be added as a single, pre-formed, complex (for example as a palladium/phosphine complex, such as palladium tetrakis(triphenylphosphine), bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride).
A further compound of formula (I) may be prepared from a compound of formula (I) in which R" is H by reaction with a suitable reagent R''-LG in which LG is a leaving group such as a halogen atom. Examples of such reagents R*-LG are alkyl halides and acid anhydrides. See reaction scheme 54.
Reaction Scheme 54
(1) (1)
In an additional example a compound of formula (I) in which Z is a carboxylic acid may be prepared from a compound of formula (I) in which Z is a carboxylate ester, by hydrolysis under basic or acidic conditions, for example by treatment with aqueous sodium hydroxide. Alternatively this transformation may be achieved by treatment of the
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ester with a nucleophile (for example an alkyl thiolate) in a suitable solvent (both shown schematically in reaction scheme 55 below).
Reaction Scheme 55
?l^l^ " ^^^A^
(1) (1)
A compound of fomnula (I) in which Z is a carboxylate ester may be prepared directly from a compound of formula (I) in which Z is a carboxylic acid by esterification under standard conditions, for example by treatment with an alcohol R'OH and an acid catalyst (for example, thionyl chloride). Alternatively, this transformation may be achieved by first preparing an activated derivative of the acid group (for example an acyi halide) followed by reaction with an alcohol.
Other derivatives of the acid group in compounds of formula (I) in which Z is a carboxylic acid may be prepared by standard methods found in the literature. For example a compound of formula (I) in which Z is an amide group may be prepared from a compound of formula (I) in which Z is a carboxylic acid by treatment with a suitable coupling reagent (for example a carbodiimide such as dicyclohexylcarbodiimide) and an amine R'aNH, optionally with a additive (for example dimethylaminopyridine), in a suitable solvent (for example dimethylformamide). Alternatively, this transformation may be performed by first preparing an activated derivative of the carboxylic acid group (for example an acyl halide such as an acid chloride), and then treating the activated derivative with an amine R'2NH. Again, both transformations are shown schematically in reaction scheme 56 below.
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Reaction Scheme 56
AA 1 1
(1) (1)
Compounds of formula (Z) in which Y is a carbon may be prepared from compounds of formula (GG) by reaction with an oxidising agent, as shown in reaction scheme 57.
Reaction Scheme 57
XH ^'K' R\.^^0
I XH ^^
(GG)
(Z)
For example a compound of formula (Z) may be prepared by reacting an alkene (GG) with ozone followed by a reducing agent, for example dimethyl sulphide.
Compounds of formula (GG) may be prepared from compounds of formula (B) by reaction with an organometallic reagent (HH), as shown in reaction scheme 58.
Reaction Scheme 58
AA. ^A- AX;
(B) (HH)
(GG)
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For example a compound of formula (GG) may be prepared by reacting an organometallic reagent, for example an organostannane or organoboron reagent, (HH) with a compound of formula (B) in the presence of a metal source (for example a palladium source such as Pd2(dba)3), and, optionally, a ligand for the metal (for example a phosphine ligand, such as S-Phos) in a suitable solvent (for example dimethyl formamide).
Compounds of formula (Z) in which Y is a carbon may also be prepared from compounds of formula (JJ) by hydrolysis, as shown in reaction scheme 59.
Reaction Scheme 59
A N ^Z
(JJ)
(Z)
For example a compound of formula (Z) may be prepared by reacting an alkene (GG) with ozone followed by a reducing agent, for example dimethyl sulphide.
Compounds of formula (JJ) may be prepared from compounds of formula (B) by reaction with an organometallic reagent (KK), as shown in reaction scheme 60.
Reaction Scheme 60
A: * ■/" — J5C'
A ^N ^Z
(B) (KK)
(JJ)
For example a compound of formula (JJ) may be prepared by reacting an organometallic reagent, for example an organostannane or organoboron reagent, (KK) with a compound of formula (B) in the presence of a metal source (for example a
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palladium source such as Pcl2(dba)3), and, optionally, a ligand for the metal (for example a phosphine ligand. such as S-Phos) in a suitable solvent (for example dimethyl forma mide).
Compounds of formula (1) may be prepared from compounds of formula (LL) by reaction with a suitable bifunctional reagent (MM), as shown in reaction scheme 61.
Reaction Scheme 61
.AX ■ '-■"• — XX
(LL) (MM) (1)
For example a compound of formula (1) may be prepared by reacting a compound of formula (LL) with an aldehyde or a bis acid chloride, optionally in the opresence of an acid, such as toluene sulphonic acid, or a base, such as triethylamine.
Compounds of formula (LL) may be prepared from compounds of formula (B) as shown in reaction scheme 62.
Reaction Scheme 62
(B) (LL)
For example, a compound of formula (LL) in which Y is a heteroatom may be prepared by treating a compound of formula (B) with a nucleophile of formula (NN), as shown in reaction scheme 63,
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Reaction Scheme 63
^^ XH
A N Z A-^^N^^Z
(NN)
(B) (LL)
As an example a compound of formula (LL) may be prepared from a compound of formula (B) and a nucleophile of formula (NN) by treatment with a suitable catalyst (for example a metal catalyst, such as a palladium source) and optionally a suitable ligand (for example a phosphine ligand, such as Josiphos) in a suitable solvent.
One skilled in the art will realise that it is often possible to alter the order in which the transformations described above are conducted, or to combine them in alternative ways to prepare a wide range of compounds of formula (I). All such variations are contemplated within the scope of the invention.
The skilled man will also be aware that some reagents will be incompatible with certain values or combinations of the substituents A, D, E, X, Y and 2, and the number n as defined herein, and any additional steps, such as protection and/or deprotection steps, which are necessary to achieve the desired transformation will be clear to the skilled man.
Compounds of formula (I) may be used in unmodified form, i.e. as obtainable from synthesis, but preferably are formulated in any suitable manner using formulation adjuvants, such as carriers, solvents and surface-active substances, for example, as described hereinafter.
The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, suspension concentrates, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a waler-miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. from the Manual on Development and Use of FAO Specifications for Plant Protection Products, 5th Edition,
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1999. The formulations can be in the form of concentrates which are diluted prior to use, although ready-to-use formulations can also be made. The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
The formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof. The active ingredients can also be contained in very fine microcapsules consisting of a polymer. Microcapsules usually have a diameter of from 0.1 to 500 microns. Typically, they will contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other known polymers. Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
The formulation adjuvants that are suitable for the preparation of compositions according to the invention are known per se. As liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, A/,/\/-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate. diproxitol, alkylpyrrolidone, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene. ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone. glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl
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myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, /n-xylene, n-hexane, n-octyiamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol (PEG), propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene. toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, amyl acetate, methanol, ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, A/-methyl-2-pyrrolidone and the like. Water is generally the carrier of choice for diluting the concentrates. Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances, as described, for example, in CFR 180.1001. (c) & (d).
A large number of surface-active substances may advantageously be used in the formulations, especially in those formulations designed to be diluted with a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyi esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryttrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di-alkylphosphate esters; and also further substances described e.g. in "McCutcheon's Detergents and Emulsifiers Annual" MC Publishing Corp., Ridgewood New Jersey, 1981.
Further adjuvants that can usually be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants. foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances,
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wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and also liquid and solid fertilisers.
The compositions according to the invention can additionally include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the invention is generally from 0.01 to 10%, based on the spray mixture. For example, the oil additive can be added to the spray tank in the desired concentration after the spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, such as AMIGO® (Rhone-Poulenc Canada Inc.), alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. A preferred additive contains, for example, as active components essentially 80% by weight alkyl esters of fish oils and 15% by weight methylated rapeseed oil, and also 5% by weight of customary emulsifiers and pH modifiers. Especially preferred oil additives comprise alkyl esters of Cg-aa fatty acids, especially the methyl derivatives of C,2.18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid, being of importance. Those esters are known as methyl laurate (CAS-111-82-0), methyl palmitate (CAS-112-39-0) and methyl oleate (CAS-112-62-9). A preferred fatty acid methyl ester derivative is Emery® 2230 and 2231 (Cognis GmbH). Those and other oil derivatives are also known from the Compendium of Herbicide Adjuvants, 5th Edition, Southern Illinois University, 2000. Another preferred adjuvant is Adigor® (Syngenta AG) which is a methylated rapeseed oil-based adjuvant.
The application and action of the oil additives can be further improved by combination with surface-active substances, such as non-ionic, anionic or cationic surfactants. Examples of suitable anionic, non-ionic and cationic surfactants are listed on pages 7 and 8 of W097/34485. Preferred surface-active substances are anionic surfactants of the dodecylbenzylsulfonate type, especially the calcium salts thereof, and also non-ionic surfactants of the fatty alcohol ethoxylate type. Special preference is given to ethoxylated C12.22 fatty alcohols having a degree of ethoxylation of from 5 to 40. Examples of commercially available surfactants are the Genapol types (Clariant AG). Also preferred are silicone surfactants, especially polyalkyl-oxide-modified heptamethyltriloxanes which are commercially available e.g. as Silwet L-77®, and also perfluorinated surfactants. The concentration of the surface-active substances in relation to the total additive is generally from 1 to 30% by weight. Examples of oil
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additives consisting of mixtures of oil or mineral oils or derivatives thereof with surfactants are Edenor ME SU®, Turbocharge® (Syngenta AG, CH) or ActipronC (BP Oil UK Limited, GB).
If desired, it is also possible for the mentioned surface-active substances to be used in the formulations on their own, that is to say without oil additives.
Furthermore, the addition of an organic solvent to the oil additive/surfactant mixture may contribute to an additional enhancement of action. Suitable solvents are, for example, Solvesso® (ESSO) or Aromatic Solvent® (Exxon Corporation). The concentration of such solvents can be from 10 to 80% by weight of the total weight. Oil additives that are present in admixture with solvents are described, for example, in US-A-4,834,908. A commercially available oil additive disclosed therein is known by the name MERGE® (BASF Corporation). A further oil additive that is preferred according to the invention is SCORE®(Syngenta Crop Protection Canada).
In addition to the oil additives listed above, for the purpose of enhancing the action of the compositions according to the invention it is also possible for formulations of alkylpyrrolidones (e.g. Agrimax®) to be added to the spray mixture. Formulations of synthetic lattices, e.g. polyacrylamide, polyvinyl compounds or poly-1-p-menthene (e.g. Bond®, Courier® or Emerald®) may also be used. It is also possible for solutions that contain propionic acid, for example Eurogkem Pen-e-trate®, to be added to the spray mixture as action-enhancing agent.
Herbicidal compositions of the invention generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, compounds of formula (I) and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ dilute formulations.
Examples of preferred formulation types and their typical compositions are given below (% is percent by weight). Wettable powders as described herein are one particularly preferred type of formulation for use in the invention. In other preferred embodiments, in particular where the compound/composition/formulation of the invention is intended for use on turf, granular (inert or fertiliser) formulations as described herein are particularly suitable.
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Emulsifiable concentrates:
active ingredient: 1 to 95%, preferably 60 to 90%
surface-active agent: 1 to 30%. preferably 5 to 20%
liquid carrier: 1 to 80%. preferably 1 to 35%
Dusts:
active ingredient: 0.1 to 10%, preferably 0.1 to 5%
solid carrier: 99.9 to 90%, preferably 99.9 to 99%
Suspension concentrates:
active ingredient: 5 to 75%. preferably 10 to 50%
water: 94 to 24%. preferably 88 to 30%
surface-active agent: 1 to 40%, preferably 2 to 30%
Wettable powders:
active ingredient: 0.5 to 90%, preferably 1 to 80%
surface-active agent: 0.5 to 20%. preferably 1 to 15%
solid carrier; 5 to 95%, preferably 15 to 90%
Granules:
active ingredient: 0.1 to 30%. preferably 0.1 to 15%
solid carrier: 99.5 to 70%, preferably 97 to 85%
The following Examples further illustrate, but do not limit, the invention.
Formulation Examples for herbicides of formula (I) (% =% by weight)
F1. Emulsifiable concentrates a) b) c) d)
active ingredient 5% 10% 25% 50%
calcium dodecyibenzenesulfonate 6% 8% 6% 8%
castor oil polyglycol ether 4% - 4% 4%
(36 mol of ethylene oxide)
octylphenol polyglycol ether - 4% - 2%
(7-8 mol of ethylene oxide)
A/-methyI pyrrolidone - - 10% 20%
arom. hydrocarbon mixture 85% 78% 55% 16%
(C9-C12)
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Emulsions of any desired concentration can be obtained from such concentrates by dilution with water.
F2. Solutions a) b) c) d)
active ingredient 5% 10% 50% 90%
1 -methoxy-3-(3-methoxy-
propoxy)-propane - 20% 20%
polyethylene glycolMW 400 20% 10%
NMP - - 30% 10%
arom. hydrocarbon mixture 75% 60%
(C9-C12)
The solutions are suitable for use in the form of microdrops.
F3. Wettable powders a) b) c) d)
active ingredient 5% 25% 50% 80%
sodium lignosulfonate 4% - 3%
sodium lauryl sulphate 2% 3% - 4%
sodium diisobutylnaphthalene-
sulfonate - 6% 5% 6%
octylphenol polyglycol ether - 1% 2%
(7-8 mol of ethylene oxide)
highly dispersed silicic acid 1% 3% 5% 10%
kaolin 88% 62% 35%
The active ingredient is mixed thoroughly with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders which can be diluted with water to give suspensions of any desired concentration.
F4. Coated granules a) b) c)
active ingredient 0.1% 5% 15%
highly dispersed silicic acid 0.9% 2% 2%
inorganic carrier 99.0% 93% 83%
(diameter 0.1 -1 mm)
e.g. CaCOa or SiOj
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The active ingredient is dissolved in methylene chloride and applied to the carrier by spraying, and the solvent is then evaporated off in vacuo.
F5. Coated granules a) b) c)
active ingredient 0.1% 5% 15%
polyethylene glycol MW 200 1.0% 2% 3%
highly dispersed silicic acid 0.9% 1% 2%
inorganic carrier 98.0% 92% 80%
(diameter 0.1 -1 mm)
e.g. CaCOa or Si02
The finely ground active ingredient is uniformly applied, in a mixer, to the carrier moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
F6. Extruder granules a) b) c) d)
active ingredient 0.1% 3% 5% 15%
sodium lignosulfonate 1.5% 2% 3% 4%
carboxymethylcellulose 1.4% 2% 2% 2%
kaolin 97.0% 93% 90% 79%
The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
n. Dusts a) b) c)
active ingredient 0.1% 1% 5%
talcum 39.9% 49% 35%
kaolin 60.0% 50% 60%
Ready-to-use dusts are obtained by mixing the active ingredient with the carriers and grinding the mixture in a suitable mill.
F8. Suspension concentrates a) b) c) d)
active ingredient 3% 10% 25% 50%
ethylene glycol 5% 5% 5% 5%
nonylphenol polyglycol ether
(15 mol of ethylene oxide) - 1% 2%
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sodium lignosulfonate 3% 3% 4% 5%
carboxymethylcellulose 1% 1% 1% 1%
37% aqueous formaldehyde
solution 0.2% 0.2% 0.2% 0.2%
silicone oil emulsion 0.8% 0.8% 0.8% 0.8%
water 87% 79% 62% 38%
The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired concentration can be obtained by dilution with water.
Compounds of the invention (as well as mixtures and/or formulations containing the same) find utility as herbicides, and may thus be employed in methods of controlling plant growth. Such methods involve applying to the plants or to the locus thereof a herbicidally effective amount of said compound, or composition comprising the same (or mixture as described hereinafter). The invention thus also relates to a method of inhibiting plant growth which comprises applying to the plants or to the locus thereof a herbicidally effective amount of a compound of formula (I), composition, or mixture of the invention. In particular the invention provides a method of controlling weeds in crops of useful plants, which comprising applying to said weeds or the locus of said weeds, or to said crop of useful plants, a compound of formula I or a composition or mixture containing the same.
The term "locus" as used herein includes not only areas where weeds may already be growing, but also areas where weeds have yet to emerge, and also to areas under cultivation with respect to crops of useful plants. Areas under cultivation include land on which the crop plants are already growing and land intended for cultivation with such crop plants.
A compound, composition, and/or mixture of the invention may be used in a pre-emergence application and/or in a post-emergence application in order to mediate its effect.
Crops of useful plants in which compounds of formula (I), as well as formulations and/or mixtures containing the same, may be used according to the invention include perennial crops, such as citrus fruit, grapevines, nuts, oil palms, olives, pome fruit, stone fruit and rubber, and annual arable crops, such as cereals, for example barley and wheat, cotton,
128

oilseed rape, maize, rice, soy beans, sugar beet, sugar cane, sunflowers, ornamentals and vegetables, especially cereals and maize.
Compounds of formula (I), formulations and/or mixtures containing the same may also be used on turf, pasture, rangeland, rights of way etc. In particular they may be used on golf-courses, lawns, parks, sports-fields, race-courses and the like,
Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-. GS-, EPSPS-, PPO- and HPPD-inhibitors and synthetic auxins) by conventional methods of breeding or by genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer rape (canola). Examples of crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®.
Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle). Examples of Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds). The Bt toxin is a protein that is formed naturally by Bacillus thuringiensis soil bacteria. Examples of toxins, or transgenic plants able to synthesise such toxins, are described in EP-A-451 878, EP-A-374 753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529. Examples of transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Card® (maize). NuCOTIN33B® (cotton). Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and PnDtexcta®. Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding ("stacked" transgenic events). For example, seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
Crops are also to be understood as being those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavour).
129
%

The term "weeds" as used herein means any undesired plant, and thus includes not only agronomically important weeds as described below, but also volunteer crop plants.
Compounds of formula (I) may be used against a large number of agronomically important weeds. The weeds that may be controlled include both monocotyledonous and dicotyledonous weeds, such as, for example, Alisma spp, Leptochloa chinensis, Slellaria, Nasturtium, Agrostis, Digitaria, Avena, Setaria, Sinapis, Lolium, Solanum, Echinochloa, Scirpus, Monochoria, Sagittaria, Bromus, Alopecurus, Sorghum, Rottboeltia, Cyperus and especially Cyperus iria, Abutilon, Sida, Xanthium, Amaranthus, Chenopodium, Ipomoea, Chrysanthemum, Galium, Viola, Veronica, Bidens, Euphorbia,Ischaemum, Polygonum, Helianthus, Panicum, Eriochloa, Brachiaria, Cenchrus, Commelina, Spermacoce, Senna, Tridax, RIchardia, Chamaesyce, and Conyza spp..
The rates of application of compounds of formula (I) may vary within wide limits and depend on the nature of the soil, the method of application (pre- or post-emergence; seed dressing; application to the seed furrow; no tillage application etc.), the crop plant, or weed to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. The compounds of formula I according to the invention are generally applied at a rate of from 10 to 2000 g/ha, especially from 25 to 1000 g/ha.
Any method of application to weeds/crop of useful plant, or locus thereof, which is routinely used in agriculture may be used, for example application by spray or broadcast method typically after suitable dilution of a compound of formula (I) (whether said compound is formulated and/or in combination with one or more further active ingredients and/or safeners, as described herein).
The compounds of formula (I) according to the invention can also be used in combination with other active ingredients, e.g. other herbicides, and/or insecticides, and/or acaricides, and/or nematocides, and/or molluscicides. and/or fungicides, and/or plant growth regulators. Such mixtures, and the use of such mixtures to control weeds and/or undesired plant growth form yet further aspects of the invention. For the avoidance of doubt, mixtures of invention also include mixtures of two or more different compounds of formula (I).
130

Where a compound of formula (I) is combined with at least one additional herbicide, the
following mixtures of the compound of formula (I) are particularly preferred. Compound
of formula (I) + acetochlor, compound of formula (I) + acifluorfen, compound of formula
(1) + acifluorfen-sodium, compound of formula (I) + aclonifen, compound of formula (I) +
acrolein, compound of formula (I) + alachlor, compound of formula (I) + alloxydim,
compound of formula (I) + allyl alcohol, compound of formula (I) + ametryn, compound
of formula (I) + amicarbazone, compound of formula (I) + amidosulfuron, compound of
formula (I) + aminocyclopyrachlor, compound of formula (I) + aminopyralid, compound of
formula (I) + amitrole, compound of formula (I) + ammonium sulfamate, compound of
formula (I) + anilofos, compound of formula (I) + asulam, compound of formula (I) +
atrazine, formula (I) + aviglycine, formula (I) + azafenidin, compound of formula (I) +
azimsuifuron, compound of formula (I) + BCPC, compound of formula (!) + beflubutamid,
compound of formula (I) + benazolin, fomiula (I) + bencarbazone, compound of formula
(I) + benfluralin, compound of formula (I) + benfuresate, compound of formula (I) +
bensulfuron, compound of formula (I) + bensulfuron-methyl, compound of formula (I) +
bensulide, compound of formula (I) + bentazone, compound of formula (I) +
benzfendizone, compound of formula (I) + benzobicyclon, compound of formula (I) +
benzofenap, compound of formula (I) + bifenox, compound of formula (I) + bilanafos,
compound of formula (I) + bispyribac, compound of formula (I) + bispyribac-sodium.
compound of formula (I) + borax, compound of formula (I) + bromacil, compound of
formula (I) + bromobutide, formula (I) + bromophenoxim, compound of formula (I) +
bromoxynil, compound of formula (I) + butachlor, compound of formula (I) + butafenacil,
compound of formula (I) + butamifos, compound of formula (I) + butralin, compound of
formula (I) + butroxydim, compound of formula (I) + butylate, compound of formula (I) +
cacodylic acid, compound of formula (I) + calcium chlorate, compound of formula (I) +
cafenstrole, compound of formula (I) + carbetamide, compound of formula (I) +
carfentrazone, compound of formula (I) + carfentrazone-ethyl, compound of formula (I) +
CDEA, compound of formula (I) + CEPC, compound of fonnula (I) + chlorflurenol,
compound of formula (I) + chlorflurenol-methyl, compound of formula (I) + chloridazon,
compound of formula (I) + chlorimuron, compound of formula (I) + chlorimuron-ethyl,
compound of formula (I) + chloroacetic acid, compound of formula (I) + chlorotoluron,
compound of formula (1) + chlorpropham, compound of formula {1} + chlorsulfuron,
compound of formula (I) + chlorthal, compound of formula (I) + chlorthal-dimethyl,
compound of formula (1) + cinidon-ethyl, compound of formula (I) + cinmethylin,
compound of formula (1) + cinosulfuron, compound of formula (I) + cisanilide, compound
of formula (I) + clethodim, compound of formula (I) + clodinafop, compound of formula (I)
+ clodinafop-propargyl, compound of formula (I) + clomazone, compound of formula (I) +
131

clomeprop, compound of formula (I) + clopyralid, compound of formula (I) +
cloransulam, compound of formula (I) + cloransulam-methyl, compound of formula (I) +
CMA, compound of formula (I) + 4-CPB, compound of formula (I) + CPMF, compound of
formula (I) + 4-CPP, compound of formula (I) + CPPC, compound of formula (I) + cresol,
compound of formula (I) + cumyluron, compound of formula (I) + cyanamide, compound
of formula (I) + cyanazine, compound of formula (I) + cycloate, compound of formula (I)
+ cyclosulfamuron, compound of formula (I) + cycloxydim, compound of formula (I) +
cyhalofop, compound of formula (I) + cyhalofop-butyl. compound of formula (I) + 2,4-D,
compound of formula (I) + 3,4-DA, compound of formula (I) + daimuron, compound of
formula (I) + dalapon, compound of formula (I) + dazomet, compound of formula (I) +
2,4-DB, compound of formula (I) + 3,4-DB, compound of formula (I) + 2.4-DEB,
compound of formula (I) + desmedipham, formula (I) + desmetryn, compound of formula
(I) + dicamba, compound of formula (I) + dichlobenil, compound of formula (I) + ortho-
dichlorobenzene, compound of formula (I) + para-dichlorobenzene, compound of
formula (I) + dichlorprop, compound of formula (I) + dichlorprop-P. compound of fonnula
(I) + diclofop, compound of formula (I) + diclofop-methyl, compound of formula (I) +
diclosulam, compound of formula (I) + difenzoquat, compound of formula (I) +
difenzoquat metilsulfate, compound of formula (I) + diflufenican, compound of formula (I)
+ diflufenzopyr, compound of formula (I) + dimefuron, compound of formula (I) +
dimepiperate, compound of formula (I) + dimethachlor, compound of formula (I) +
dimethametryn, compound of fomiula (I) + dimethenamid, compound of formula (I) +
djmethenamid-P, compound of formula (I) + dimethipin, compound of formula (I) +
dimethylarsinic acid, compound of formula (I) + dinitramine. compound of formula (I) +
dinoterb, compound of formula (I) + diphenamid, formula (I) + dipropetryn, compound of
formula (I) + diquat, compound of formula (I) + diquat dibromide, compound of formula
(I) + dithiopyr, compound of formula (I) + diuron, compound of formula (I) + DNOC,
compound of formula (I) + 3,4-DP. compound of formula (I) + DSMA, compound of
formula (I) + EBEP. compound of formula (I) + endothal, compound of formula (I) +
EPTC, compound of formula (I) + esprocarb, compound of fomiula (I) + ethalfluralin,
compound of formula (I) + ethametsulfuron, compound of formula (I) + ethametsulfuron-
methyl, formula (I) + ethephon, compound of formula (I) + ethofumesate, compound of
formula (I) + ethoxyfen, compound of formula (I) + ethoxysulfuron, compound of formula
(I) + etobenzanid, compound of formual (I) + fenoxaprop, compound of formula (I) +
fenoxaprop-P, compound of formula (I) + fenoxaprop-ethyl, compound of formula (I) +
fenoxaprop-P-ethyl, compound of formula (1) + fentrazamide, compound of formula (I) +
ferrous sulfate, compound of fonmula (I) + flamprop-M, compound of formula (I) +
flazasulfuron, compound of formula (I) + florasulam, compound of formula (I) + fluazifop.
132

compound of formula (I) + fluazifop-butyl, compound of formula (I) + fluazifop-P,
compound of formula (!) + fluazifop-P-butyl, formula (I) +. fluazolate. compound of
formula (I) + flucarbazone, compound of formula (I) + flucarbazone-sodium, compound
of formula (I) + flucetosulfuron, compound of formula (I) + fluchloralin, compound of
formula (I) + flufenacet, compound of formula (I) + flufenpyr, compound of formula (I) +
flufenpyr-ethyl, formula (I) + flumetralin. compound of formula (I) + flumetsulam,
compound of formula (I) + flumiclorac, compound of formula (I) + flumiclorac-pentyl,
compound of formula (I) + flumioxazin, formula (I) + flumipropin, compound of formula (I)
+ fluometuron, compound of formula (I) + fluoroglycofen, compound of fonnula (I) +
fluoroglycofen-ethyl, fomiula (I) + fluoxaprop, formula (I) + flupoxam, formula (I) +
flupropacil, compound of formula (I) + flupropanate, compound of formula (I) +
flupyrsulfuron, compound of formula (I) + flupyrsulfuron-methyl-sodium, compound of
formula (!) + flurenol, compound of formula (I) + fluridone, compound of formula (I) +
flurochloridone, compound of formula (I) + fluroxypyr, compound of formula (I) +
flurtamone. compound of formula (I) + fluthiacet, compound of formula (I) + fluthiacet-
methyl, compound of formula (I) + fomesafen, compound of formula (1) + foramsulfuron,
compound of formula (I) + fosamine, compound of formula (I) + glufosinate, compound
of formula (I) + glufosinate-ammonium. compound of formula (I) + glyphosate,
compound of formula (I) + halosulfuron, compound of formula (I) + halosulfuron-melhyl,
compound of formula (I) + haloxyfop, compound of formula (I) + haloxyfop-P, compound
of formula (I) + HC-252, compound of formula (I) + hexazinone, compound of formula (I)
+ imazamethabenz, compound of formula (I) + imazamethabenz-methyl, compound of
fonnula (I) + imazamox, compound of formula (I) + imazapic, compound of formula (I) +
imazapyr, compound of formula (I) + imazaquin, compound of formula (I) + imazethapyr,
compound of formula (I) + imazosulfuron, compound of formula (I) + indanofan,
compound of formula (I) + iodomethane, compound of formula (I) + iodosulfuron,
compound of formula (I) + iodosulfuron-methyl-sodium, compound of fonnula (I) +
ioxynil, compound of formula (I) + isoproturon, compound of formula (I) + isouron,
compound of formula (I) + isoxaben, compound of formula (I) + isoxachlortole,
compound of formula (I) + isoxaflutole, formula (I) + isoxapyrifop, compound of formula
(I) + karbutilate, compound of formula (I) + lactofen, compound of formula (I) + lenacil,
compound of formula (I) + linuron, compound of formula (1) + MAA, compound of
formula (I) + MAMA, compound of formula (I) + MCPA, compound of formula (I) +
MCPA-thioethyl, compound of formula (I) + MCPB. compound of formula (I) +
mecoprop, compound of formula (I) + mecoprop-P. compound of formula (I) +
mefenacet, compound of formula (I) + mefluidide, compound of formula (I) +
mesosulfuron, compound of formula (I) + mesosulfuron-methyl, compound of formula (I)
133

+ mesotrione, compound of formula (I) + metam, compound of formula (I) + metamifop,
compound of formula (I) + metamitron, compound of formula (I) + metazachlor,
compound of fomiula (I) + methabenzthiazuron, formula (I) + methazole, compound of
formula (I) + methylarsonic acid, compound of formula (I) + methyldymron, compound of
formula (1) + methyl isothiocyanate, compound of formula (I) + metobenzuron, formula (I)
+ metobromuron, compound of formula (I) + metolachlor, compound of formula (I) + S-
melolachlor, compound of formula (I) + metosulam, compound of formula (I) +
metoxuron, compound of formula (I) + metribuzin, compound of formula (I) +
metsulfuron, compound of formula (I) + metsulfuron-methyl, compound of formula (I) +
MK-616, compound of formula (I) + molinate, compound of formula (1) + monolinuron,
compound of formula (l)+ MSMA, compound of formula (I) + naproanilide, compound of
fonnnuia (I) + napropamide, compound of formula (I) + naptalam, formula (I) + NDA-
402989, compound of formula (I) + neburon, compound of formula (I) + nicosulfuron,
formula (I) + nipyraclofen, fonnula (I) + n-methyl glyphosate, compound of formula (I) +
nonanoic acid, compound of formula (I) + norflurazon. compound of formula (I) + oleic
acid (fatty acids), compound of formula (I) + orbencarb, compound of formula (I) +
orthosulfamuron, compound of formula (I) + oryzalin, compound of formula (I) +
oxadiargyl, compound of formula (I) + oxadiazon, compound of formula (I) +
oxasulfuron, compound of formula (I) + oxaziclomefone, compound of formula (I) +
oxyfluorfen, compound of formula (I) + paraquat, compound of formula (I) + paraquat
dichloride, compound of formula (I) + pebulate, compound of formula (I) +
pendimethalin, compound of formula (I) + penoxsulam, compound of formula (I) +
pentachlorophenol, compound of formula (I) + pentanochlor, compound of formula (I) +
pentoxazone, compound of formula (1) + pethoxamid, compound of formula (I) +
petrolium oils, compound of formula (I) + phenmedipham. compound of formula (I) +
phenmedipham-ethyl, compound of formula (I) + picloram, compound of formula (I) +
picolinafen, compound of formula (I) + pinoxaden, compound of formula (I) +
piperophos. compound of formula (I) + potassium arsenite, compound of formula (I) +
potassium azide, compound of formula (I) + pretilachlor, compound of formula (I) +
primisulfuron. compound of formula (I) + primisulfuron-methyl, compound of formula (I) +
prodiamine, compound of formula (I) + profluazoi, compound of fomnula (I) + profoxydim,
formula (I) + prohexadione-calcium, compound of formula (I) + prometon, compound of
formula (1) + prometryn, compound of formula (I) + propachlor, compound of formula (I)
+ propanil, compound of formula (I) + propaquizafop, compound of formula (I) +
propazine, compound of formula (I) + propham, compound of formula (I) + propisochlor,
compound of formula (I) + propoxycarbazone, compound of formula (I) +
propoxycarbazone-sodium, compound of formula (I) + propyzamide. compound of
134

formula (I) + prosulfocarb, compound of formula (I) + prosulfuron, compound of formula
(I) + pyraclonil, compound of formula (1) + pyraflufen, compound of formula (I) +
pyraflufen-ethyl, formula (I) + pyrasuifotole, compound of formula (I) + pyrazoiynate,
compound of formula (I) + pyrazosulfuron, compound of formula (I) + pyrazosulfuron-
ethyl, compound of formula (I) + pyrazoxyfen, compound of formula (I) + pyribenzoxim,
compound of formula (I) + pyributicarb, compound of formula (I) + pyridafol, compound
of formula (I) + pyridate, compound of formula (I) + pyriftalid, compound of formula (I) +
pyriminobac, compound of formula (I) + pyriminobac-methyl, compound of formula (I) +
pyrimisulfan, compound of formula (1) + pyrithiobac, compound of formula (I) +
pyrithiobac-sodium, formula (I) + pyroxasulfone, formula (I) + pyroxulam, compound of
formula (I) + quinclorac, compound of formula (1) + quinmerac, compound of formula (1)
+ quinoclamine, compound of formula (I) + quizalofop, compound of formula (I) +
quizalofop-P, compound of formula (I) + quizalofop-ethyl, compound of formula (1) +
quizalofop-P-ethyl, compound of formula (I) + rimsulfuron, compound of formula (1) +
saflufenacil. compound of formula (1) + sethoxydim, compound of formula (I) + siduron,
compound of formula (I) + simazine, compound of formula (I) + simetryn, compound of
formula (I) + SMA, compound of formula (I) + sodium arsenite, compound of formula (1)
+ sodium azide, compound of formula (I) + sodium chlorate, compound of formula (1) +
sulcotrione, compound of formula (I) + sulfentrazone, compound of formula (I) +
sulfometuron, compound of formula (I) + sulfometuron-methyl, compound of formula (I)
+ sulfosate, compound of formula (1) + sulfosulfuron, compound of formula (1) + sulfuric
acid, compound of formula (1) + tar oils, compound of formula (I) + 2,3,6-TBA. compound
of formula (I) + TCA. compound of formula (I) + TCA-sodium, fonnula (1) + tebutam,
compound of formula (I) + tebuthiuron, formula (1) + tefuryltrione, compound of formula 1
+ tembotrione, compound of formula (I) + tepraloxydim, compound of formula (I) +
terbacil, compound of formula (I) + terbumeton, compound of formula (I) +
terbuthylazine, compound of formula (I) + terbutryn, compound of formula (I) +
thenylchlor, compound of formula (I) + thiazafluron, compound of formula (I) + thiazopyr,
compound of formula (1) + thifensulfuron, compound of formula (1) + thiencarbazone,
compound of formula (I) + thifensulfuron-methyl, compound of formula (I) + thiobencarb,
compound of fonnula (I) + tiocarbazil, compound of formula (I) + topramezone,
compound of formula (I) + tralkoxydim, compound of formula (I) + tri-allate, compound of
formula (I) + triasulfuron, compound of formula (1) + triaziflam, compound of formula (I) +
tribenuron, compound of formula (I) + tribenuron-methyl, compound of formula (I) +
tricamba, compound of formula (I) + triclopyr, compound of formula (I) + trietazine,
compound of formula (I) + trifloxysulfuron, compound of formula (I) + trifloxysulfuron-
sodium, compound of formula (I) + trifluralin, compound of formula (I) + trifiusulfuron,
135

compound of formula (I) + triflusulfuron-methyl, compound of formula (I) + trifop, compound of formula (1) + trifop-methyl, compound of formula (!) + trihydroxytriazine. compound of formula (I) + trinexapac-ethyl, compound of formula (I) + tritosulfuron, compound of formula (I) + [3-[2-chloro-4-fluoro-5-(1-methyl-6-lrifluoromethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl ester (CAS RN 353292-31-6), compound of formula (I) + 4-hydroxy-3-[[2-[(2-methoxy8thoxy)methyl]-6-(trifluoromethyl)-3-pyridinyl]carbonyl]-bicyclo[3.2.1)oct-3-en-2-one (CAS RN 352010-68-5), compound of formula (I) + 4-hydroxy-3-[[2-(3-methoxypropyl)-6-(difluoromethyl)-3-pyridinyl]carbonyl]-bicyclo[3.2.1]oct-3-en-2-one, and compound of formula (I) + 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-melhoxyphenyl)-pyridine-2-carboxylic acid (CAS RN 943832-60-8).
Whilst two-way mixtures of a compound of formula (I) and another herbicide are explicitly disclosed above, the skilled man will appreciate that the invention extends to three-way, and further multiple combinations comprising the above two-way mixtures.
In preferred embodiments a compound of formula (I) is combined with an acetolactate synthase inhibitor, (e.g. one or more of florasulam, metsulfuron, thifensulfuron, tribenuron, triasulfuron, flucarbazone, flupyrsulfuron, iodosulfuron, mesosulfuron, propoxicarbazone, sulfosulfuron, pyroxsulam and tritosulfuron, as well as salts or esters thereof), a synthetic auxin herbicide [e.g. one or more of aminocyclopyrachlor, aminopyraiid, clopyralid, 2,4-D, 2,4-DB, dicamba, dichlorprop, fluroxypyr, MCPA, MCPB, mecoprop, mecoprop-P and 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylic acid (CAS RN 943832-60-8)], an ACCase-inhibiting herbicide (e.g. one or more of phenylpyrazolin; pinoxaden; an aryloxyphenoxypropionic herbicide such as clodinafop. cyhalofop, diclofop, fenoxaprop, fluazifop, haloxyfop, quizalofop, trifop and mixtures thereof, as well as the isomers thereof, for example. fenoxaprop-P, fluazifop-P, haloxyfop-P, quizalofop-P; and a cyclohexanedione herbicide such as alloxydim, butroxydim, clethodim, cycloxydim, profoxydim, sethoxydim, tepraloxydim and tralkoxydim, as well as salts or esters thereof), an auxin transport inhibitor such as a semicarbazone (e.g. diflufenzopyr, in particular the sodium salt) or phthalamate compound (e.g. naptalam), and/or an EPSPS inhibitor such as glyphosate.
Particularly preferred mixture partners for compounds of formula (I) are: florasulam, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, thifensulfuron, triasulfuron, tribenuron-methyl or pyroxsulam; dicamba, fluroxypyr, MCPA, mecoprop, mecoprop-P or 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-
136

carboxylic acid (CAS RN 943832-60-8); clodinafop-propargyl, cyhalofop-butyl. diclofop-methyl, fenoxaprop-ethyl, fenoxaprop-P-ethyl, fluazifop-butyl, fluazifop-P-butyl, haloxyfop-methyl, haloxyfop-P-methyl, pinoxaden, propaquizafop, quizalofop-ethyl, quizalofop-P-ethyl, tralkoxydim. trifop-methyl, diflufenzopyr-Na, napfalam. and glyphosate.
For the avoidance of doubt, even if not explicitly stated above, the mixing partners of the compound of formula (I) may also be in the form of any suitable agrochemically acceptable ester or salt, as mentioned e.g. in The Pesticide Manual, Thirteenth Edition, British Crop Protection Council, 2003.
The mixing ratio of the compound of formula (I) to the mixing partner is preferably from 1:100 to 1000:1.
The mixtures can advantageously be used in the above-mentioned formulations (in which case "active ingredient" relates to the respective mixture of compound of formula (I) with the mixing partner).
The compounds of formula (I) according to the invention can also be used in
combination with one or more safeners. Likewise, mixtures of a compound of formula (I)
according to the invention with one or more further active ingredients, in particular with
one or more further herbicides, can also be used in combination with one or more
safeners. Where a compound of formula (I) is combined with a safener, the following
combinations of the compound of formula (I) and the safener are particularly preferred.
Compound of formula (I) + AD 67 (MON 4660), compound of formula (I) + benoxacor,
compound of formula (I) + cloquintocet-mexyl, compound of formula (1) + cyometrinil and
a compound of formula (I) + the corresponding (Z) isomer of cyometrinil, compound of
formula (I) + cyprosulfamide (CAS RN 221667-31-8), compound of formula (I) +
dichlormid, compound of formula (I) + fenchlorazole-ethyi, compound of formula (I) +
fenclorim, compound of formula (I) + flurazole, compound of formula (I) + fluxofenim,
compound of formula (I) + furilazole and a compound of formula (I) + the corresponding
R isomer or furilazome, compound of formula (1) + isoxad if en-ethyl, compound of
formula (I) + mefenpyr-diethyl, compound of formula (I) + oxabetrinil, compound of
formula (I) + naphthalic anhydride (CAS RN 81-84-5), compound of formula (I) + N-
isopropyl-4-{2-mefhoxy-benzoylsulfamoyl)-benzamide (CAS RN 221668-34-4) and a
compound of formula (I) + N-(2-methoxybenzoyl)-4-
[(methylaminocarbonyl)amino]benzenesulfonamide.
137

Particularly preferred safeners for use in the invention are cloquintocet-mexyl, cyprosulfamide, fenchlora2ole-ethyl, mefenpyr-diethyl and N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide. The safeners of the compound of formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, 13'^ Edition supra. The reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium, magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium salt thereof as disclosed in WO02/34048, and the reference to fenchlorazole-ethyl also applies to fenchlorazole, etc.
Preferably the mixing ratio of compound of formula (I) to safener is from 100:1 to 1:10, especially from 20:1 to 1:1.
The mixtures can advantageously be used in the above-mentioned formulations (in which case "active ingredient" relates to the respective mixture of compound of formula (I) with the safener).
Preferred mixtures of a compound of formula (I) with further herbicides and safeners include: a compound of formula (I) + pinoxaden + cloquintocet-mexyl, a compound of fomnula (I) + clodinafop + cloquintocet-mexyl, and a compound of formula (I) + clodinafop-propargyl + cloquintocet-mexyl.
Various aspects and embodiments of the present invention will now be illustrated in more detail by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention.
For the avoidance of doubt, where a literary reference, patent application, or patent, is cited within the text of this application, the entire text of said citation is herein incorporated by reference.
EXAMPLES
EXAMPLE 1 Synthesis of 2-(4-chioro-3-dimethylamino-2-fluorophenyl)-4-
methoxycarbonyl-6*methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound
1-118)
138

NHj /
fl ^1 f^ CO^Me
I cr Y^ ^F
NMe, I
^ NMej
A solution of 4-amino-5-chloro-2-(4-chloro-3-dimethylamino-2-fluorophenyl)-6-methoxycarbonylpyrimidine (prepared as described in WO2007/082076) (585 mg, 1.63 mmol), allenyltributyistannane (0.58 ml, 2.0 mmol) and tetrakis(triphenylphosphine) palladium (376 mg, 0.326 mmol) in dimethyl sulphoxide (11 ml) was heated in a microwave reactor at 170 °C for 40 minutes, then allowed to cool. A saturated solution of potassium fluoride in methanol (24 ml) was added and the resulting mixture stirred at ambient temperature for 2 hours, then allowed to stand for a further 16 hours. The mixture was filtered through Celite®, the solid washed with methanol and the filtrate evaporated under reduced pressure. The residue was extracted with ether and ethyl acetate and the combined organic extracts washed with brine, dried over magnesium sulphate, filtered and absorbed onto silica. Purification using a FractionLynx hpic provided 2-(4-chloro-3-dimethylamino-2-fluorophenyl)-4-methoxycarbonyl-6-methyi-7H-pyrrolo[2,3-d)pyrimidine as a yellow gum (45 mg, 8%). Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 8 9.90 (1H, br s), 7.70 (1H, t), 7.20 (1H, dd), 6.80 (1H, m), 4,10 (3H, s), 2.90 (6H, s), 2.40 (3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 12.
TABLE 12 Compounds made according to the method described in Example 1 above.
Compound I Name I Structure I ^H NMR (400 MHz,
Number CDCI3) 5
139

1-66 I 2-(4-chloro-2- I 7 p-SO (1H. br s),'
fluoro-3- ^f^ ^-^^ ^^^' *^' ^-^^
methoxyphenylH- N^"'^^ (1H, t), 6.80 (1H,
methoxycarbonyl- /N. J-^ .^y-^ m). 4.10 (3H, s),
({^^ N COjMe
6-methyl-7H- 11 I 4.00 {3H. s), 2.50
pyrrolo[2,3- ci^'^r^^F (3H, s) ppm
., . ... OMe
d]pyrimicline
EXAMPLE 2 Alternative synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-
methoxycarbonyi-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-66)
2.1 Preparation of 5-chloro-2-(4-chloro-2-fluoro-3-methoxvphenvl)-6-m ethoxvca rbonyl-4-thiomet hyl-pvri m id i ne
f SMe
II 1 fl ^^ "^ COjMe
I cr ^f"^ ^F
OMe I
OMe
Sodium methanethiolate (290 mg, 4.1 mmol) was added to a solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-dichloro-6-methoxycarbonyl-pyrimidine (prepared as described in WO2009/081112) (1.00 g. 2.73 mmol) in methanol (20 ml) and the resulting mixture stirred at ambient temperature for 1 hour, then evaporated under reduced pressure. The residue was extracted with ethyl acetate and the extract washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to provide 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-4-thiomethyl-pyrimidine as pale yellow solid (800 mg, 77%). Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 6 7.80 (1H. t). 7.20 (1H. dd). 4.05 (3H. s), 4.00 (3H. s). 2.70 (3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 13.
140

TABLE 13 Compounds made according to the method described in Example 2.1 above.
Name | Structure Melting point "C
5-Chloro-2- |Me 74-75
cyclopropyi-6- N^'^^V^^'
methoxycarbonyl- J! .^;>L
r—r N COjMe
4-thiomethyl- V
pyrimidine
2.2 Preparation of (Z)-2-(4-chloro-2-flLioro-3-methoxvphenYn-6-methoxvcarbonvl-5-(prop-1-envl)-4-thiomethvl-pyrimidine
SMe
I SMe
I (l ^T ^ COjMe
I cr Y^ F
OMe I
OMe
A mixture of 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-4-thiomethyl-pyrimidine (200 mg, 0.56 mmol), c/s-propenyl boronic acid (72 mg, 0.84 mmol), [1,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (46 mg, 0.056 mmol), caesium fluoride (170 mg, 1.12 mmol), dimethoxyethane (2.4 ml) and water (2.4.ml) was heated in a microwave reactor at 150 °C for 20 minutes, then allowed to cool. Water was added and the resulting mixture extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, using hexanerethyl acetate (4:1) as eluent. to provide (Z)-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-5-(prop-1-eny|)-4-thiomethyl-pyrimidine as a pale yellow solid (100 mg, 49%).
Characterising data for the compound are as follows:
'H NMR (400 MHz. CDCl3)5 7.90 (1H, t), 7.30 (1H, dd), 6.30 (1H. d), 6.10 (1H, m), 4.00 (3H, s). 3.90 (3H. s), 2.60 (3H. s), 1.60 (3H, d) ppm.
141

Further examples of compounds that were prepared using this method are listed below in Table 14,
TABLE 14 Compounds made according to the method described in Example 2.2 above.
Name I Structure I 'H NMR (400 MHz,
CDCI3) 6
2-Cyclopropyl-5- ¥^ 6.68 (1H, m), 6.55
ethenyl-6- N^^W'^^ (2H. m). 3.90 (3H,
methoxycarbonyl- Jl ^ji s), 2.50 (3H, s),
4-thiomethyl- V 2.23 (1H. m), 1.20
pyrimidine (2H, m). 1.08 (2H,
m) ppm
2.3 Preparation of (Z)-4-azido-2-(4-chloro-2-fluoro-3-methoxvDhenvn-6-methoxvcarbonvl-5-/prop-1-envl)-pvrimidine
SMe
|l I f| ^1 "^ COjMe
I cr y^ ^F
OMe I
OMe
3-Chloroperben20ic acid (168 mg, 1.0 mmol) was added to a stiaed suspension of (Z)-2-(4-chloro-2-fiuoro-3-methoxyphenyl)-6-methoxycarbonyl-5-(prop-1-enyl)-4-thiomethyl-pyrimidine (100 mg, 0.39 mmol) in dichloromethane and stirring continued for 2 hours. The reaction mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was dissolved in methanol (5 ml) and sodium azide (255 mg, 3.0 mmol) added. The resulting mixture was stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue was suspended in dichloromethane, washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, using hexane.ethyl acetate (4:1) as eluent. to provide (Z)-4-azido-2-(4-
chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-5-(prop-1-enyl)-pyrimidine as a pale yellow oil (80 mg, 81%).
142

Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 8 7.80 (1H, t), 7.30 (1H. m). 6.30 (1H, dd), 6.00 (1H, m), 4.00
{2x3H, s), 1.60(3H, d)ppm.
Further examples of compounds that were prepared using this method are listed below in Table 15.
TABLE 15 Compounds made according to the method described in Example 2.3 above.
Name I Structure Melting Point °C '
4-Azido-2- ^z 120-130 (dec.)
cyclopropyl-5- fg-^^'^^-^^
ethenyi-6- 1 J^
rr—t^ N COjMe
methoxycarbonyl- \/ pyrimidine
2.4 Preparation of 2-(4-chloro-2-fluoro-3-methoxvphenyl)-4-methoxvcarbonvl-6-methvl-7H-pvrrolof2.3-d1pvrimldine (Compound 1-66)
fi ^^r^N'''^CO.Me *" ^^>^ yl^ ^j::^^
III fl ^7 N COjMe
I or ^Y "^
OMe I
OMe
A solution of (Z)-4-a2ido-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-5-(prop-l-enyl)-pyrimidine (80 mg, 0.21 mmol) in 1.2-dichloroben2ene (3 ml) was heated at 156 °C for 1 hour, then allowed to cool. The reaction mixture was filtered through a silica column, eluting first with hexane, then with hexane.ethyl acetate (3:2) to provide the crude product, which was further purified by automated flash chromatography (Presearch Combifiash Rf) on silica, with hexane, then ethyl acetate in hexane (0-40% gradient) to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (20 mg, 27%). Characterising data for the compound are as follows:
143

'H NMR (400 MHz, CDCI3) 8 9.30 (1H. br s). 7.80 (1H. t), 7.20 (1H, t). 6.80 (1H. m), 4.10 (3H, s). 4.00 (3H, s), 2.50 (3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 16.
TABLE 16 Compounds made according to the method described in Example 2.4 above.
Compound Name [ Structure I Melting Point °C
Number
~U2 2-Cyclopropyl-4- W~\ 162-165
methoxycarbonyl- N''''^N/
7H-pyrrolo[2,3- J\ J
., . ... r-T^ ^N^ ^COjMe
d]pynmidine \/
EXAMPLE 3 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-
methoxycarbonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-64)
3.1 Preparation of 5-chloro-2-(4-chloro-2-fluoro-3-methoxvphenvl)-6-methoxvcarbonvl-4-(prop-2-enylamino)-pvrimidine
HI f^ ^==>]r N ^COjMe
I cr y^ ^F
OMe I
OMe
A solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-dichloro-6-
methoxycarbonylpyrimidine (prepared as described in WO2009/081112) (364 mg, 1,0 mmol), allylamine (0.15 ml. 2.0 mmol) and triethylamine (0.26 ml, 2.0 mmol) in dichloroethane (3.5 ml) was stirred at ambient temperature for 4 hours. Water was added and the mixture extracted with dichloromethane. The organic extract was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, using ethyl acetate in hexane (20% to 40%
144

gradient) as eluent to provide 5-chioro-2-(4-chloro-2-fluoro-3-methoxypiienyi)-6-methoxycarbonyl-4-(prop-2-enylamino)-pyrimidine as a yellow solid (330 mg, 85%). Characterising data for the compound are as follows:
'H NIVIR (400 MHz. CDCI3) 5 7.70 (1H, t), 7.20 (1H, dd). 6.00 (1H, m), 5.80 (1H. br s). 5.30 (2H, qd), 4.30 (2H, m), 4.00 (2x 3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 17.
TABLE 17 Compounds made according to the method described in Example 3,1 above.
Name I Structure I 'H NIVIR (400 MHz,
CDCI3) 5
5-Chloro-2-(4-chloro-2-fluoro-3- \^,-^\^ 7.70 (1H, t), 7.20 (1H.
methoxyphenyl)-6- 1^ Q dd). 5.90 (1H, m). 5.30
methoxycarbonyl-4-(/S/-methyl- Vi | (1H. m). 5.20 (1H. m).
A/-prop-2-enyl-amino)- f^'^^JY^^N^^co^Me 4.30 (2H, d). 4.00 (2x
pyrimidine /^X^^JJ^P 3H, S). 3.30 (3H, s)
owe PP"'
5-Chloro-2-(4-chloro-2-fiuoro-3- ^^'^^j.^Vj^/^.^ 7.70 (1H, t), 7.30 (5H.
methoxyphenyl)-6- l[ >J X a "i). 7.20 (1H, dd). 6.00
methoxycarbonyl-4-(A/- i| T (1H. m). 5.30 (2H. q),
phenylmethyl-A/-prop-2-enyl- f|''^^^^^=:>r^^^N''''^C02Me 5.00 (2H, s). 4.30 (2H.
amino)-pyrimidine X^-^NS^^SJ^P d). 4.00 (2x 3H. s) ppm
OMe
4-(But-1 -en-3-ylamino)-5- j 7.70 (1H. t), 7.20 (1H,
chloro-2-(4-chloro-2-fluoro-3- HN'^'^^ dd). 5.90 (1H, dq). 5.60
methoxyphenyi)-6- 1 ^a (1H. br s). 5.20 (2H, qd),
methoxycarbonyl-pyrimidine l| I 5.00 (1H. m). 4.00 (2x
rj'^^Y'^'^ ^^s"^® 3H, s). 1.40 (3H. d) ppm
OMe
I I
145

"N^^m^ I Structure I 'H NMR (400 MHz,
CDCI3) 5
5-Chloro-2-(4-chloro-2-fluoro-3- ^^^ 7.60 (1H, t). 7.40 (5H,
methoxyphenyl)-6- [IJ m), 7.20 (1H, dd), 6.10
methoxycarbonyl-4-(1- | (1H, m), 6.00 (2H, br s).
phenylprop-2-en-1-ylamino)- HN^''^^^ 5.30 (2H, dd), 4.00 (2x
pyrimidine N^'^V^^' ^^' ^^ ^^"^
OMe
5-Chloro-2-(4-chloro-2-fluoro-3- /^\^ 7.81 (1H. t), 7.26'~(THr
methoxyphenyl)-6- I n dd) 5.98 (1H, m), 5.37
methoxycarbonyM-(prop-2- || (1H, dq), 5.20 (1H. d),
enylthio)-pyrimidine rf^'^^^'V^^N^^co^Me 4.04 (3H, s), 4.02 (3H,
a^-^^y^f s). 3.97 (2H. d) ppm
OMe
"5-Chloro-2-(4-chloro-2-fluoro-3- HN^^V^^ 7.70 (1H,t), 7.20 (iH.d),
methoxyphenyl)-4-{2.2- Jf /^^ 5.80 (1H, dd), 5.70 (1H,
dimethyl-but-3-en-1-ylamino)-6- ll | br s). 5.20 (2H, m), 4.00
methoxycarbonyl-pyrimidine K''''^^^V'''^N'''^C02Me (2x 3H. s), 3.50 (2H, d),
c./'k^^P 1.10 (6H.S) ppm
OMe
~5-Chloro-2-cyclopropyl-6- ^^iP^"^^ 5.90 (1H, m) 5.60 (1H, br"
methoxycarbonyl-4-(prop-2- 1^ ^i s), 5.20 (2H, m), 4.10
enylamino)-pyrimidine I*! T (2H, m), 4.00 (3H, s),
ry^'^N^^co^Me 2.10 (1H, m), 1.10 (2H,
m), 0.90 (2H, m) ppm
5-Chloro-2-cyclopropyl-6- jp^ 8.10 (1H, d), 7.61. (2H,
methoxycarbonyl-4-(2- (■'''W'^^^NH I^)- ^-^^ (1H, t). 6.46
nitrophenyl-methylamino)- K^ .J\/C' (''^' ^' *)• ^^^ (^^' ^^'
pyrimidine jj T 3.96 (3H, s). 2.10 (1H.
^—r-'^^N cOjMe quintet). 0.99 (4H. d)
ppm
146

"Name I Structure PH NMR (400 MMz^
CDCI3) 5
4-(2-Amino-1.2-diphenyl- ^ 7.29 (3H, m), 7.23 (3H,
ethylamino)-5-chloro-2- ^'^^f-^NH ^)- ^H (2H, d), 7.03
cyclopropyl-6-methoxycarbonyl- Ph ^,jL.ci {2H, m), 6.70 (1H, br d),
pyrimidine 1 X ^'^^ ^^^' ^^' ^'^^ ^^^'
^—T^^^N'^^^co.Me m). 3.95 (3H, s). 1.95
(1H, quintet). 0.98 (1H,
m), 0.89 (1H. m). 0.75
(1H. m), 0.49 (1H, m)
ppm
(NH2 not observed)
4-(fraA7S-2-Amino- V\^ 7^86 (1H, br s). 7.20
cyclohexylamino)-5-chloro-2-(4- L ^L ^^^' '^'^^' ^"^^ ^^^' ^^ ^^'
chloro-2-fluoro-3- I T 4.16 (1H, br s), 4.00
methoxyphenyl)-6- "'"^ Yl^l^^' ^^^' ^^' ^'^^ ^^^- ^^'
methoxycarbonyl-pyrimidine /^^^^^v-^M^^^^r, M 2.74 (1H, br s), 2.03 (3H,
Jl J^ m), 1.72 (3H. m). 1.34
I (4H, m) ppm
OMe
5-Chloro-2-(4-chloro-2-fluoro-3^ P^^^i^^^Sw 7.70 (1H, dd). 7.36 (4H.
methoxyphenyl)-6- 'L xJ Jk ci "i)- ^-33 (1H, m), 7.20
methoxycarbonyl-4- ^ j (1H. dd). 6.04 (1H, br t),
phenylmethylamino-pyrimidine rj'''^^^=>T^^'^N^'^cOjMe 4.81 (2H, d), 4.01 (3H,
ci^-kiSJ^P s). 4.00 (3H. s) ppm
OMe
5-Chloro-2-(4-chloro^-fluoro'3^ no-s,,/\^/ 7.69 (1H, dd), 7.21 (1H,
methoxyphenyl)-4-[/V-(2- jf ci ^1). 3.98 (2x3H. s), 3.95
hydroxyethyl)-A/-methyl-amino)- j( | (2H, m). 3.89 (2H. m).
6-methoxycarbonyl-pyrimidine ^^''^^^Y^'^N'^'^co^Me 3.43 (3H, s), 2.81 (1H, br
c,->Y^F s) ppm
OMe 147

_____ I structure I ^H NWIR (400 MHz,
CDCI3) 5
"4-(3-Amino-butan-2-yl-amirio)- I 7.69 (1H, dd), 7.20(1 H,
5-chloro-2-(4-chloro-2-fluoro-3- '^''^N^^NH dd), 6.33 (1H, br s). 4.30
methoxyphenyl)-6- ' JL xi (1H. m). 3.99 (2x3H. s),
methoxycarbonyl-pyrimidine l| I 3.12 (1H, m), 1.19 {3H,
Ij'^^Y'^N cOjMe d), 1.16 (3H, d) ppm
OMe
"5-Chloro-2-(4-chloro-2-fluoro^ 9^ 7.73 (1H, dd), 7.28 (1H,~
methoxyphenyl)-4-(2.4- ^-'''^^is/^NH d), 7.22 (1H, dd), 6.49
dimethoxyphenyl-methylamino)- J^^ .Jk. ^ci (1H, s), 6.44(1H, d),
6-methoxycarbonyl-pyrimidine l( I 6.30 (1H, brt). 4.72 (2H,
rj^'^^^Y^^N'^ ^°2^^ d), 4.02 (3H, s), 3.97
C,/\J:^^F (3H. s), 3.88 (3H, s),
OMe 3.80 (3H, s) ppm
3.2 Preparation of 2-(4-chloro-2-fluoro-3-methoxvphenvl)-4-methoxvcarbonvl-5-methvl-7H-pvrrolof2.3-dlpvrinnidine (Compound 1-64)
[I I f| ^[ N X02Me
OMe I
OMe
A mixture of 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-4-(prop-2-enylamino)-pyrimidine (200 mg, 0.52 mmol), [1,3-bis(2,6-diisopropyiphenyl)imidazoi-2-ylidene](3-chloropyridyl)palladium(ll) dichloride (36 mg, 0.052 mmol), sodium acetate (64 mg, 0.78 mmol) and dimethyl acetamide (4 ml) was heated in a microwave reactor at 150 °C for 30 minutes, then allowed to cool, water added and the mixture extracted with ethyl acetate. The organic extract was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with
148

ethyl acetale in hexane (20% to 40% gradient) as eluenl, to provide 2-(4-chloro-2-fluoro-
3-methoxyphenyI)-4-methoxycarbonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow
solid (106 mg, 59%).
Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 5 7.78 (1H, t), 7.30 (1H, dd). 7.23 (1H, br s), 4.10 (3H, s),
4.03 (3H, s), 2.45 (3H, s) ppm (NH not observed).
Further examples of compounds that were prepared using this method are listed below in Table 18.
TABLE 18 Compounds made according to the method described in Example 3.2 above.
Compound j Name [Structure I ^H Nf\/IR (400 IVIHz,
Number CDCI3) S
2-64 2-(4-Chloro-2-fluoro-3' \ 7.80 (1H, t), 7.20
methoxyphenyl)-5.7- jC\-^ ^''^' ^^^' ^ ""^ ^'"^•
dimethyl-4- I'l^'l'^ ^^' '*'^° ^^^' ^^' "^'^^
methoxycarbonyl-7H- l^^^r'^N^^cOjivie (3H, s), 3.90 (3H, s).
pyrrolo[2,3-d]pyrimidine J! ^JL 2.50 (3H, s) ppm
OMe
6-64 2-(4-Chloro-2-fluoro-3- 1F\IIZ 7.85 (1H, t), 7.30
methoxyphenyl)-4- \^ ^/^"^ ^^^' ^^' ^'^^ ^^^'
methoxycarbonyl-5- N'^'W^^ ^^' ^'^^ ^^^' ^^' ^'^^
methyl-7-phenylmethyl- J\ ^\ (3H. s), 4.03 (3H, s),
7H-pyrrolo[2.3- fll ^ ^'^^ 2.40 (3H. s) ppm
djpyrimidine ci^^^y^^^F
OMe
1-68 2-(4-Chloro-2-fluoro-3- 7 8.70 (1H, br s), 7.80
methoxyphenyl)-5,6- 7"V^ ^^^' *^' ^'^^ ^^^'
dimethyl-4- N^^^^^^ " dd), 4.10 (3H, s),
methoxycarbonyl-7H- ^-^Ss^^A.-^^ 4.00 (3H, s), 2.50
pyrrolo[2,3-d]pyrimidine II 1^ (3H, s), 2.40 (3H. s)
I ppm
OMe 149

Compound I Name [ Structure I ^H NMR (400 MHz^
Number CDCI3) 5
1-108 2-(4-Chloro-2-fluoro-3- T^ "Q^ioTTHTbf^W^
methoxyphenyl)-4- \__/ (1H, t). 7.50 (5H. m).
methoxycarbonyl-5- ^^i^ / 7.20 (1H, dd), 4.10
methyl-6-phenyl-7H- T V^ {3H, s), 4.00 (3H, s),
pyrrolo{2.3-d]pyrimidine || 2.50 (3H. s) ppm
OMe
21-64 2-(4-Chloro-2-fluoro-3^ s—A 7.80 (1H, t), 7.30
methoxyphenyl)-4- N^^W*^ (1H. dd), 6.00(1H,
methoxycarbonyl-5- ^.^^ ]! A^^ m), 4.00(2x3H, s),
methyl-thieno[2.3- |l jT "^ ^^'"^ 2.60 (3H. s) ppm
djpyrimidine a^'^^^^^^F
OMe
71-180 2-(4-Chloro-2-fluoro-3- ^^^^ 7.60 (1H. t). 7.20
methoxyphenyl)-6.6- "V J" (1H, dd). 5.70(1 H.
dimethyl-4- 'll^l'^^ ^'^ ^^' ^^° ^^^' ^^•
methoxycarbonyl-5- f^^=^>,^^N^^co Me ^'^^ ^^^' ^^' ^'^^
methylene-5,6,7,8- JL JL ' (3H, s), 3.20 (2H, d).
tetrahydro-pyridoI2.3- ° | "" ' 1.20 (6H. s) ppm
OMe
djpyrimidine
1-124 2-Chloro-4- HN—A 7.40 (1H. s) 4.00
methoxycarbonyl-5- N^'W'^ ^^'^' ^^ ^'^^ ^^"^^ ^^
methyl-7H-pyrrolo[2.3- JP J. ppm (NH not
djpynmidine ' observed) (nmr run
in CD3OD)
T4 2-Cyclopropyl-4- HN—A 10.20 (1H. brs).
methoxycarbonyl-5- N^'^^V'^ 7.20 (1H, S), 4.00
mefhyJ-7H-pyrrolo[2.3- ]j^ ^J^ (3H. s), 2.40 (1H,
djpyrimidine S/ ^ ^^'^^ m), 2.35 (3H. s).
1.20 (4H.m) ppm
150

EXAMPLE 4 Synthesis of 2-(4-chloro-3-fluorophenyl)-5,6-dimethyl-4-
methoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-24)
4.1 Preparation of 2.5-dichloro-6-methoxvcarbonvl-4-(prop-2-envlamino)-pvrimidine
A solution of 6-metlioxycarbony-2,4,5-trichloropyrimidine (prepared as described in WO2009/081112) (1000 mg, 4.0 mmol), allylamine (0.45 ml, 6.0 mmol) and triethylamine (1.1 ml, 8.0 mmol) in dimethoxyethane (10 ml) was stirred at ambient temperature for 2 hours. Water was added and the mixture extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, using ethyl acetate in hexane (0% to 40% gradient) as eluent to provide 2,5-dichloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyrimidine as an off-white solid (1000 mg, 87%). Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 6 6.00 (2H. br m), 5.30 (2H, m), 4.20 (2H. m), 4.00 (3H. s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 19.
TABLE 19 Compounds made according to the method described in Example 4.1 above.
Name I Structure I 'H NMR (400 MHz,
CDCI3) 5
4-(But-1-en-3-ylamino)-2,5- j 5.90 (1H, dq). 5.80 (1H.
dichloro-6-methoxycarbonyl- HN"''^^ ^r s). 5.30 (1H, d), 5.20
pyrimidine ^^Lv^^ ^^^' ^^^' ^-^^ ^^^' '^^•
jl T 4.00(3H, s), 1.40(3H, d)
Q'^'^N'^^cOjMe ppm
151

Name I Structure I ^H NMR (400 MHz,
CDCIj) 8
2,5-Dichloro-4-(2-furanyl- /^/^Sw 7.40 (1H. s), 6.36 (2H.
methylamino)-6- \^l I ci m), 6.19 (1H, br t). 4.72
N ^^1^
methoxycarbonyl-pyrimidine l| I {2H, d). 3.97 (3H, s) ppm
4-Cyclopropylmethylamino-2.5- .X^^j,, 5.98 (1H, br s), 3.97 (3H,
dichloro-6-methoxycarbonyl- V j[ ^^ s), 3.39 (2H, dd), 1.11
pyrimidine I | (1H. m). 0.63 (2H, m).
ci'^''^N^'^cOjMe 0.32 (2H. m) ppm
Ts-Dichloro-e- I^^^^^^P^SJH 7.37 (5H, m), 6.14 (1H,
methoxycarbonyl-4- (I J J. ci br t), 4.73 (2H, d). 3.97
phenylmethylamino-pyrimidine || T (3H, s) ppm
CI'''''^N''''^C02Me
2.5-Dichloro-6- p 8.13 (1H, dd). 7.76 (1H,
methoxycarbonyl-4-(2- f^^^=^y^^^NH ^d)- ^-67 (1H, d), 7.52
nitrophenyl-methylamino)- l!^J J'x/Ci (1H. td). 6.87 (1H, br t),
pyrimidine jj T 5.01 (2H, d), 3.95 (3H,
ci-'''^N''''^co,Me s) ppm
4-{3-Chloropyrid-2-yl- 9 8.64 (1H, br t), 8.43 (1H,
methylamino)-2,5-dichloro-6- C''W,''''^^NH ^d), 7.91 (1H, m), 7.33
methoxycarbonyl-pyrimidine S. ^N ^JL ^CI (1H, dd), 4.74 (2H. d),
Jl T 3.86 (3H. s) ppm (nmr
ci'^'^N cOjMe run in dg-DIVISO)
4-(2-Amino-1.2-diphenyl- ^ 7.24 (6H, m), 7.05 (2H,
ethylamino)-2,5-dichloro-6- "''^"V^NH d), 6.99 (2H. d), 5.37
methoxycarbonyl-pyrimidine PH JL xi (1H, t), 4.42 (1H. m),
j\ \ 3.96 (3H, s) ppm
ci^^N cOjMe (NH and NH? not
observed)
4.2 Preparation of 2-(4-chloro-3-fluorophenyl)-5,6-dimethyl-4-methoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-24)
152

1 C, ^ XX
CI N COjMe Cr N^
F
A mixture of 4-(but-1-en-3-ylamino)-2,5-dichloro-6-methoxycarbonyl-pyrimidine (276 mg, 1.0 mmol), 4-chloro-3-fluorophenylboronic acid (210 mg, 1.2 mmoi), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), tri-t-butylphosphine tetrafluoroboric acid complex (29 mg, 0.10 mmol), caesium carbonate (652 mg, 2.0 mmol), dioxane (6 ml) and dimethylformamide (2 ml) was heated in a microwave reactor at 150 "C for 20 minutes, then allowed to cool. Dichloromethane was added and the mixture washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 40% gradient) as eluent, followed by further purification using a FractionLynx hpic, to provide 2-(4-chloro-3-fluorophenyl)-5,6-dimethyl-4-methoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (49 mg, 15%).
Characterising data for the compound are as follows:
^H NMR (400 MHz. CDCI3) 5 8.47 (1H, br s), 8.28 (1H, dd). 8.23 (1H. dd), 7.46 (1H, dd), 4.09 (3H, s), 2.46 (3H, s), 2.32 (3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 20.
TABLE 20 Compounds made according to the method described in Example 4.2 above.
Compound I Name I Structure I ^H NMR (400 MHz,
Number CDCI3) 8
1-20 2-(4-Chloro-3- HN—^ 8.70 (1H, br s), 8.30
fluorophenyl)-4- N^'^W''^ C^' ^'^^^ ^-^^ <'"^'
methoxycarbonyl-5- ^^^^ 11 J^ dd), 7.50 (1H, t),
methyl-7H-pyrrolo[2,3- fl "] ^ ^°'^^ ^-20 C^^- "!)■ ^.10
djpyrimidine ci'^^v^ (3H, s), 2.40 (3H. s)
I I F
153

Compound Name j Structure I 'H NMR (400 MHz,
Number CDCI3) 5
ppm
1-116 2-(4-Chloro-3- ^T~\ 10.60 {1H, br s),
dimethylamino-2- N^'W^^ ^'^^ ^^^ *^' ^'^^
fluorophenyl)-4- ^-^ JL <:i^ ^'"^" ^'^^' ^'^^ ^'"^■
methoxycarbonyl-5- (l I "^ ^°'^^ ^'^ ^^" ^'^^ ^^^' ^^'
methyl-7H-pyrrolo[2,3- a'^^'y^^F 2.90 (6H, s), 2.40
d]pyrimidine ^^^z (3H, s) ppm
1-120 2-{4-Chloro-3- 7 9.70 (1H. br s), 7.70"
dimethylamino-2- T'A^. ^^^' *^' ^'^^ ^^^' ^^'
fluorophenyl)-5,6- N^'W^ 4.10 {3H, s), 2.90
dimethyl-4- ^^^ JL JL^ (6H, s), 2.30 (3H, s).
rj ^^ N C02Me
methoxycarbonyl-7H- II 1^ 2.25 (3H. d) ppm
pyrrolo[2,3-d]pyrimidine ^' | '^
22-20 6-(4-Chloro-3- HN—^" 8.40 (1H, br s). 7.90
fluorophenyl)-4- r^^ (''^' ^^^' '^•^° ^^^■
methoxycarbonyl-3- ^ Jl JL m). 7.40 (1H, t), 7.10
methyl-1H-pyrrolo[3,2- fl T ^ ^^'"^^ (1H, br s). 4.10 (3H,
cjpyridine ci'^'^Y^ s), 2.40 (3H, s) ppm
F
EXAMPLE 5 Synthesis of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-
methoxycarbonyl-3-methyl-1H>pyrrolo[3,2-c]pyricline (Compound 22-64)
5.1 Preparation of 2,5-dichloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine
jiSr" —^ [TV'
154

A solution of 6-methoxycarbonyl-2,4,5-trichloro-pyridine (1000 mg, 4.0 mmol), allylamine (240 mg, 4.8 mmol) and triethylamine (1.1 ml, 8.0 mmol) in dimethylformamide (10 ml) was heated at 100 "C for 3 hours, allowed to cool to ambient temperature, water added and the mixture extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, using ethyl acetate in hexane (20% to 40% gradient) as eluent to provide 2,5-dichloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine as an off-white solid (680 mg, 65%).
Characterising data for the compound are as follows:
'H NMR (400 MHz. CDCI3) 5 6.60 (1H. s), 5.90 (1H, m). 5.40 (1H, br s), 5.30 (2H, m), 4.00 (3H, s), 3.90 (2H. m) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 21.
TABLE 21 Compounds made according to the method described in Example 5.1 above.
Name I Structure I 'H NMR (400 IVIHz,
CDCI3) 8
2,5-Dichloro-4-(furan-2- ~/^^^^^^^^ 7.42 (m. 1H). 6.72
ylmethylamino)-6- \^o JL ci (s. tH). 6.37 (m,
methoxycarbonyl- (l I '"^)' ^■^'^ ^'^' '"^)-
pyridine ci'^'^N'^'^cOjMe 5.55 (br. s, 1H). 4.44
(d. 2H). 3.96 (s, 3H)
ppm
5.2 Preparation of 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine
(1 ^1 ^ COjMe
OMe
155

A mixture of 2,5-dichloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine (260 mg, 1.0 mmol). 4-chloro-2-fluoro-3-methoxyphenylboronic acid 1,3-propanediol ester (290 mg, 1.2 mmol). [1.1'-bis(diphenytphosphino)-ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (82 mg, 0.1 mmol) and caesium fluroide (300 mg, 2.0 mmol), dimethoxyethane (7 ml) and water (7 ml) was heated in a microwave reactor at 140 "C for 40 minutes, allowed to cool to ambient temperature and dichloromethane added. The resulting mixture was washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, using ethyl acetate:hexane (1:4) as eluent to provide 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine as a colourless oil (110 mg, 29%). Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 8 7.60 (1H, t), 7.20 (1H, dd). 7.00 (1H, s), 5.90 (1H, m), 5.20 (3H, m), 4.00 (8H, m) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 22.
TABLE 22 Compounds made according to the method described in Example 5.2 above.
Name i Structure I 'H NMR (400 IMHz,
CDCI3) 8
5-Chloro-2-(4-chloro-2- /^^^j^^^m 7.64 (1H, t), 7.41
fluoro-3- \^l "T CI CH. s), 7.25 (1H,
methoxyphenyl)-4- f\ T m), 7.17 (1H, m),
(furan-2- ri'^^^^V'^^N'^'^co^Me 6.37 (1H, m), 6.34
ylmethylamino)-6- ^^J\<:^. (1H, m), 5.49 (1H,
methoxycarbonyl- ^f^^ m), 4.50 (2H, d),
pyridine 4.00 (3H, s), 3.99
(3H, s) ppm
5-Chloro-2-(4-chloro-3- '/^P^^H 8.17 (2H, m), 7.46
fluorophenyl)-4-(furan- \_^l J. ci CH, m), 7.40 (1H,
2-ylmethylamino)-6- || | d), 6.35 (2H, m),
methoxycarbonyl- fr'''^^^V''^'^^^^^^^°?'^« 6.02 (1H, br t), 4.83
pyrimidine ci^^'^T ^^^' ^'^' ^'^^ ^^^' ^^
F ppm
156

Name ' I Structure | 'H NWIR (400 MHz,
CDCI3) 8
5-Chloro-2-{4-chloro-3- ,^^^M\ 8.14 (2H, m), 7.45
fluorophenyl)-4- JL ci CH, dd), 5.83 (1H,
cyclopropylmethylamin || br t), 4.02 (3H, s),
0-6-methoxycarbonyl- fT^^^^^^^Y^^^^^^z"^^ 3.50 (2H, dd), 1.18
pyrimidine ci^'^r^ ^^^' '^^' °'^^ ^^^'
I m), 0.35 (2H, m)
ppm
5-Chloro-2-(4-chloro-3- /^3^^^^NI] 8.14 (2H, m). 7.45
fluorophenyl)-6- (I J ^1 ci (1H. t), 7.39 (4H. m),
methoxycarbonyl-4- I j 7.34 (1H, m), 6.05
phenylmethylamino- ||^''^^^^V'''^N'''^cOjMe (1H, br t), 4.84 (2H.
pyrimidine ^A^^x?>' d), 4.02 (3H, s) ppm
F
5-Chloro-2-(4-chloro-3- W2 8.12 (3H, m), 7.70
fluorophenyl)-6- r^''Wx^^NH CH, dd). 7.63 (1H.
methoxycarbonyl-4-(2- ^L^ -'^^Vv^^ *^^' ^'^^ ^^^' '^)'
nitrophenyl- jj T 6.62 (1H, br t). 5.14
methylamino)- ff^^Y^^'^ ^°''^* ^^"^^ ^^' ^'^^ ^^'^' ^^
pyrimidine ci'^^^r '^^"^
F
5-Chloro-2-(4-chloro-3- V 8.55 (1H, dd). 8.22
fluorophenyl)-4-(3- f'^W^^NH (2H. m), 7.78 (1H,
chloropyrid-2-yl- ll^^ii J\^ci dd), 7.65 (1H, br t),
methylamino)-6- jj jT 7.48 (1H, dd), 7.28
methoxycarbonyl- fT^^^^I^^'^ ^°^^^ ^^^' ^^' ^'^^ ^^^'
pyrimidine ci^^^r ^^' ^'^^ ^^^' ^^ ^'^'^
F
\ L
157

Name { Structure I ^H NMR (400 MHz,
CDCI3) 6
4-{2-Amino-1.2- ^ 7.42 (1H. dd), 7.24
diphenyl-ethylannino)-5- "'"^N^^NH (^^' '^^' ^-^^ (^^^•
chloro-2-(4-chloro-2- in ^1 a m). 6.95 (2H, m),
fluoro-3- || I 5.43 (1H, m), 4.45
methoxyphenyl)-6- rj^^^s^^^N^^^cOjMe (1H. m), 3.97 (3H,
methoxycarbonyl- ci-'-'^r^^^F ^^" ^-^^ ^^^' ^^ PP*^
pyrimidine o^e (NH and NH2 not
observed)
5-Chloro-2-(4-chlorb-2- p 8.13 (1H, m), 7.75"
fluoro-3- r'^^''^^^IH (1H. m). 7.69 (1H,
methoxyphenyl)-6- i!^^ Jk^ci m), 7.61 (1H, t). 7.49
methoxycarbonyl-4-(2- 1 1 ^'"^' "^^' ^'^^ (^^•
nitrophenyl- rl'^^V'^^N'^^^^co^Me dd), 6.71 (1H. br t).
methylamino)- a-^'^r^f 5''° (^H, d). 4.01
pyrimidine OMe (3H, s), 3.97 (3H, s)
ppm
5-Chloro-2-{4-chloro-2- " ^^^NII 7.70 (1H, dd), 7.20"
fluoro-3- V jr ^ (1H. dd), 5.84 (1H,
methoxyphenyl)-4- fl "j br t), 3.99 (2x 3H,
cyciopropylmethylamin fr'''^^^^^V'''^N''''^C02Me s). 3.45 (2H, m),
o-6-methoxycarbonyl- n'-^'^^r'^^^F ^'^^ ^^^' '^^' ^'^^
pyrimidine ^^^ (2H, m), 0.33 (2H,
m)ppm
\ \
5.3 Preparation of 6-(4-chloro-2-fiuoro-3-methoxyphenyl)-4-methoxycarbonyl-3-methyl-1 H-pyrrolo[3,2-c]pyridine (Compound 22-64)
158

II 1 fl ^f "^ COJMe
I cr ^f^ ^F
OMe I
OMe
A mixture of 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine (110 mg. 0.286 mmol), tris{dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), tri-t-butylphosphine tetrafluoroboric acid complex (8 mg, 0.028 mmol), caesium carbonate (186 mg, 0.57 mmol), dioxane (3.5 ml) and dimethylformamide (1 ml) was heated in a microwave reactor at 150 °C for 20 minutes, then allowed to cool and ethyl acetate added. The resulting mixture was washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 40% gradient) as eluent, to provide 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-3-methyl-1H-pyrrolo[3,2-cjpyridine as an off-white solid (35 mg, 35%). Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 8 8.60 (1H, br s), 7.90 (1H, d), 7.80 (1H, t), 7.20 (1H, dd), 7.10 (1H, m), 4.10 (3H, s), 4.00 (3H. s), 2.40 (3H, s) ppm.
EXAMPLE 6 Synthesis of 2-cyclopropyl-4-methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-6)
6.1 Preparation of 4-amino-2-cyclopropyl-6-methoxycarbonyl-5-(2-methylprop-2-enyO-pyrimidine
A mixture of 4-amino-5-chloro-2-cyclopropyl-6-methoxycarbonylpyrimidine (prepared as described in WO2010/092339; 227 mg, 1.0 mmol), (1-tributylstannyl)-2-methyl-prop-2-
159

ene (414 mg, 1.2 mmol), bis-(tri-t-butylphosphine)pallaclium (26 mg, 0.05 mmol) and
degassed dimethylformamide (10 ml) was heated in a microwave reactor at 160 °C for
20 minutes, then allowed to cool and ethyl acetate added. The mixture was washed with
water and brine, dried over magnesium sulphate, filtered and evaporated under reduced
pressure. The residue was purified by automated flash chromatography (Presearch
Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 40% gradient) as eiuent, to
provide 4-amino-2-cyclopropyl-6-methoxycarbonyl-5-(2-methylprop-2-enyl)-pyrimidine
as a white solid (210 mg, 85%).
Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 8 5.10 (2H, br s), 4.90 (1H, m), 4.80 (1H. m), 3.90 (3H. S),
3.40(2H, s). 2.10(1H, m), 1.70 (3H,s), 1.00 (4H, m) ppm.
Further examples of compounds that were prepared using this method are listed below
in Table 23.
TABLE 23 Compounds made according to the method described in Example
6.1 above. Characteristic data is ^H NMR (400 IVIHz, CDCI3) 5 or mass
ion.
Name Structure Characteristic data
4-Amino-2-(4-chloro-2- ,,^ <^^ MH* 365, 367
NH2 ^<^
fluoro-3- 1^ I
methoxyphenyl)-6- [| T
methoxycarbonyl-5-(2- jj'''''^^^^V''''^N''''^C02Me
methylprop-2-enyl)- /-^V-:?^
pyridine ^^
4-Amino-2^-chloro-2- ^^ -^^y^ 7.64 (1H. dd), 7.22
fluoro-3- JP 1 (1H, d), 5.34 (2H, br
methoxyphenyl)-6- fl J^ s), 4.97 (1H. s), 4.85
methoxycarbonyl-5-(2- fj'''''^^^^Y''^N^^^^^^cOjMe (1H. s), 4.00 (3H, s),
methylprop-2-enyl)- yK^^:^^^ 3.96 (3H, s), 3.50
pyrimidine ^^^ (2H, s), 1.78 (3H. s)
ppm
160

Name TStruicfUfF Characteristic data
2-(4-Chloro-3- ^V'^^NH ^V^ 8.20 (2H. m), 7.45
fluorophenyl)-4-(furan- \^l JL J ^^^' ^^^' ^'^^ ^^'^'
2-ylmethylamino)-6- 'u j[^ d), 6.33 (1H, m).
methoxycarbonyl-5-(2- r|'''^^V''^N^^^^C0jMe 6.27 {1H, m), 5.60
methylprop-2-enyl)- ci'^'^-T (1H, br t). 4.95 (1H,
pyrimidine ^ m), 4.80 (3H, m),
3.98 (3H, s), 3.49
(2H. s), 1.73 (3H, s)
ppm
2-(4-Chloro-3- Wz 8.11 (3H, m), 7.69
fluorophenyl)-6- (^''W^^NH %^ (1H. dd). 7.59 (1H,
methoxycarbony!-5-(2- (IJ JLJ t), 7.45 {2H. m). 6.18
methylprop-2-enyl)-4- jj T Error! Hyperlink reference not valid. t), 5.10 (2H.
(2-nitrophenyl- fT^^^Y^^'^ ^°'^^ ^^' ^'^^ ^^^' ^^' ^'^^
methylamino)- CI^^'^Y^ C^. S), 3.96 (3H,
pyrimidine { s), 3.44 (2H, s), 1.72
(3H, s)ppm
~2-Cyclopropyi-6- W2 8.06 (1H, d). 7.59
methoxycarbonyl-5-(2- ('''^WJ^^^^NH'^^^V^ (2H, m), 7.44 (1H.
methylprop-2-enyl)-4- [IJ jCJ m), 5.97 (1H, br t),
(2-nitrophenyl- | T 4.90 (3H, m), 4.75
methylamino)- \7^^^^ ^°^^ (1H, s), 3.91 (3H. s),
pyrimidine 3.36 (2H, s), 2.09
(1H. m), 1.59 (3H,
s), 0.95 (4H, m)
ppm
2-(4-Chloro-2-fluoro-3- W2 MH* 501,503
methoxyphenyl)-6- r^^5^T-''''~^NH ^^^^V^
methoxycarbonyl-5-(2- \^ •--*^\ ^
methylprop-2-enyl)-4- || T
(2-nitrophenyl- fr''^^^V'''^N^'^C0jMe
methylamino)- J,,^''^\J^=^P
pyrimidine ^^^
161

Name I Structure Characteristic data
~2-(4-Chloro-2-fluoro-3- .^^^^,, <;^!^ 7.72 (1H. dd), 7.20
methoxyphenylH- V j" 1 (1H, dd), 5.45 {1H,
cyclopropylmethylamin ii T br t), 4.99 (1H. m),
o-6-methoxycarbonyl-5- |r'^^^^^Y'''^'^'^'^C02Me 4.90 (1H, m), 3.99
(2-methylprop-2-enyl)- ^^K^^ (3H. s), 3.97 (3H,
pyrimidine j^^^ s), 3.50 (2H, s), 3.40
(2H. m). 1.76 (3H, s). 1.10 (1H. m). 0.54 (2H, m), 0.25 (2H, m) ppm
2-(4-Chloro-2-fluoro-3-" ,^^^V^^NH ^V^ ^-^^ (1H, dd), 7.32
methoxyphenyl)-6- [I J J\ J ^^^' '^^' ''"'^ ^'"^•
methoxycarbonyl-5-(2- w J^ dd), 5.61 (1H, br t),
methylprop-2-enyl)-4- |j''^^^*=^T^^^N'^^C0jMe 4.92 {1H, m). 4.78
phenylmethylamino- .,A^x;:fJ\^ (3H, m), 3.99 {3H,
pyrimidine ^^^ s), 3.96 (3H. s). 3.49
(2H, s), 2.73 (3H, s)
ppm
I I
^^
6.2 Preparation of 2-cyclopropyl-4-metlioxycarbonyi-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-6)
ju^ —' JCX
Ozone was bubbled through a solution of 4-amino-2-cyclopropyl-6-methoxycarbonyl-5-(2-methylprop-2-enyl)-pyrimidine (190 mg, 0.77 mmol) in dichloromethane (40 ml) at -78 "C until a blue colour persisted in the reaction vessel. Oxygen was then bubbled through the reaction mixture until the blue colour disappeared, dimethyl sulphide (2 ml) was added and the mixture was allowed to warm to room temperature and stirred for 3 hours The solution was evaporated under reduced pressure and the residue purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate
162

in hexane (0% to 40% gradient) as eluent, followed by further purification using a
FractionLynx hpic, to provide 2-cyclopropyl-4-methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-
djpyrimidine as a pale yellow solid (29 mg, 16%).
Characterising data for the compound are as follows:
^H NMR (400 MHz. CDCI3) 8 8.80 (1H. br s). 6.70 (1H, s), 4.10 (3H, s), 2.50 (3H, s), 2.40
(1H, m). 1.10(4H. m)ppm.
Further examples of compounds that were prepared using this method are listed below
in Table 24.
TABLE 24 Compounds made according to the method described in Example
6.2 above. Characteristic data is melting point (°C) or ^H NMR (400
MHz, CDCI3) 5
Compound Name Structure Characteristic data
Number
5-66 2-(4-Chloro-2-fluoro-3- r>-^^^\ 7 "^
methoxyphenyl)-?- ^ ^
cyclopropylmethyl-4- N^'^^^^ip
methoxycarbonyl-6- ^-''55?^/^ ^^^^
^ ' fl M^ COjMe
methyl-7H-pyrrolo[2,3- II ]^
djpyrimidine a y F
OMe
6-66 2-(4-Chloro-2-fluoro-3- r--^v. '. 7.86 (1H, dd), 7.27
methoxyphenyl)-4- \:P=J^'i''~C ^^^' '^^' ^'^^ ^^'^■
methoxycarbonyl-6- N'^'^V'^ '^^' ^'^^ ^'^^' ^^'
methyl-7-phenylmethyl- ^^^ Tl ^\ 5.57 (2H, s), 4.09
7H-pyrrolo[2.3- flj^'^ ^'^^ ^^^' ^^' "^'^^ ^^^' ^^'
d]pyrimidine ci''''^r'^^F 2.44 (3H. s) ppm
OMe
~8^6 2-Cyclopropyl-4- W^ 8.20 (1H, m). 7.44
methoxycarbonyl-6- /f\v---\ / (^^' "^^' ^'^^ ^'^^•
methyl-7-(2- \^:J^ f\. s). 6.39 (1H. m),
nitrophenylmethyl)-7H- N^'W'^ 5.82 (2H, s), 4.08
pyrrolo[2,3-d]pyrimidine II JL (3H, s). 2.39 (1H,
v—r^ N C0,Me
V quintet). 2.32 (3H.
s). 1.05 (2H, m). 163

Compound Name Structure Characteristic data
Number
0.98 (2H, m) ppm
8-22 2-(4-Chloro-3- M 8.26 (3H, m). 7.46
fluorophenylH- //K-^x / ^^^' ^^' ^'^^ (''^'
methoxycarbonyl-6- \i=^ f\. ^)' ^-^^ C"^- ^^^
methyl-7-(2- N-^W^^ 6.00 (2H. s). 4.13
nitrophenylmethyl)-7H- ^^. JL J. (3H, s), 2.40 (3H, s)
({'^^ H COjMe
pyrrolo[2,3-d]pyrimidine || J ppm
8-66 2-(4-Chloro-2-fluoro-3- W, 198
melhoxyphenyl)-4- //V-^ /
methoxycarbonyl-6- \:s=^ /* v^
methyl-7-(2- N^W'^
nitrophenylmethyl)-7H- ^^ Jl ,^JL
pyrrolo[2,3-cl]pyrimidine H I
OMe
1-66 2-(4-chloro-2-fluoro-3- 7 9.30 (1H, br s), 7.80
methoxyphenyl)-4- ^f\ ^^^' *^' ^'^^ ^''^' *^'
methoxycarbonyl-6- N'''''^=Y ^-^^ C^- '^)' ^''^
methyl-7H-pyrrolo[2,3- .^^^ >\ <^ (3H, s). 4.00 (3H. s),
djpyrimidine II ]^ 2.50 (3H, s) ppm
OMe
22-66 6-(4-Chloro-2-fluoro-3- 7 8.04 (1H, s), 7.26
methoxyphenyl)-4- ^f^ ^''^' '^^' ^''^ ^'"^■
methoxycarbonyl-2- (i^^^ '^^' ^'^^ ^^'^' "^"^ ^^'
methyl-1H-pyrrolo[3,2- /^^^^^^ ^:^ 6.86 (1H, s), 4.11
cjpyridine II 1^ (3H. s), 3.92 (3H, s),
^' J^*' 2.58 (3H. s) ppm
OMe
164

EXAMPLE 7 Synthesis of 7-carboxymethyl-2-{4-chloro-3-fluorophenyl)-4-
methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 4-22)
Ozone was bubbled through a solution of 2-(4-chloro-3-fluorophenyl)-4-(2-furanylmethylamino)-6-methoxycarbonyl-5-(2-methylprop-2-eny!)-pyrimidine (150 mg, 0.36 mmol) in dichloromethane (40 ml) at -78 "C until a blue colour persisted in the reaction vessel. Oxygen was then bubbled through the reaction mixture until the blue colour disappeared, dimethyl sulphide (2 ml) was added and the mixture was allowed to warm to room temperature and stirred for 3 hours The solution was evaporated under reduced pressure and the residue purified using a FractionLynx hpic, to provide 7-carboxymethyl-2-(4-chloro-3-fiuorophenyl)-4-methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-djpyrimidine as a yellow solid (5 mg, 4%). Characterising data for the compound are as follows:
^H NMR (400 MHz. CD3OD) 6 8.34 (2H, m) 7.53 (1H, t) 6.74 (1H, s) 4.96 (2H, s) 3.97 (3H. s) 2.52 (3H, s) ppm (CO2H not obsen/ed).
EXAMPLE 8 Synthesis of 2-chloro-4-methoxycarbonyl-7H-pyrrolo[2,3-
d]pyrlmidine (Compound 1-122) and 4-carboxy-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-121)
8.1 Preparation of 4-amino-2-chloro-5-(2-ethoxyethenyl)-6-methoxycarbonyl-pyrimidine
NH ^*°rr' —- -^
165

A mixture of 4-amino-2-chloro-6-iodo-6-methoxycarbonyl-pyr(midine (prepared as described in WO2009/046090; 475 mg, 1.5 mmol). 2-ethoxy-(1-tributylstannyl)-ethene (650 mg. 1.8 mmol), bis-(tri-t-butylphosphine)palladium (38 mg, 0.07 mmol) and degassed dimelhyiformamide (15 ml) was heated in a microwave reactor at 160 "C for 20 minutes, then allowed to cool and ethyl acetate added. The mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 40% gradient) as eiuent, to provide 4-amino-2-chloro-5-(2-ethoxyethenyl)-6-methoxycarbonyl-pyrimidine as an off-white solid (154 mg, 39%).
Characterising data for the compound are as follows:
'H NMR (400 MHz, COCfa) 8 6.30 (1H. d), 5.60 (2H, br s), 5.40 (1H, d). 4.00 (2H, q). 3.90 (3H,s), 1.30(3H, t)ppm.
Further examples of compounds that were prepared using this method are listed below in Table 25.
TABLE 25 Compounds made according to the method described in Example 8.1 above.
Name I Structure I 'H NMR (400 MHz,
CDCIj) 6
4-Amino-2-(4-chloro-2- ^Eto. 7.60 (1H, t), 7.20
fluoro-3- Jf ' Ij (1H, dd). 6.30 (1H,
methoxyphenyl)-5-(2- 'u ^^ d). 5.60 (2H. br s),
ethoxyethenyl)-6- rr^^^V'^N^^co^Me 5.50 (1H, d), 4.10
methoxycarbonyl- o-^^-r^^^^ ^^^' ^^' ^'^^ ^^^' ^^'
pyrimidine ^^^ 3.90 (3H, s). 1.30
(3H, q) ppm
2-(4-Chloro-2-fluoro-3- /v;^^,.-^ Etc MH* 461.463
methoxyphenyl)-5-(2- \^o >L j)
ethoxyethenyl)-4-(2- f| |
furanylmethylamino)-6- fr'''^^V^^N''^C0jMe
methoxycarbonyl- n^^'^^^^^^^'^
pyridine T^^
1— . I
166

Name I Structure I 'H NMR (400 MHz,
CDCI3) 6
2-(4-Chloro-3- y^i^^^^^Nif°> MH* 432.434
fluorophenyl)-5-(2- \_] J\ J
ethoxyethenyl)-4-(2- ^| T
furanylmethylamino)-6- rj^V'^'^N'^'^cOjivie
methoxycarbonyl- /\j^
pyrimidine l
2-(4-Chloro-3- ^^^^'OvT 8.19 {2H, m), 7.43
fluorophenylH- V T ]| (1H, dd), 6.35 (1H,
cyclopropylmethylamin ij d), 5.72 (1H, br t),
o-5-(2-ethoxyethenyl)- rj^'^^^Y^^'^^^^^co^Me 5.40 (1H. d), 3.99
6-methoxycarbonyl- a^"^r ^^^' ^^' ^'^^ ^^^' ^^'
pyrimidine I 3.49 (2H. m), 1.31
(3H, t). 1.14 (IH.m),
0.60 (2H, m), 0.32
(2H, m) ppm
2-(4-Chloro-3- P^^PSif^ 8.17 (2H, m). 7.39
fluorophenyl)-5-(2- |l ^ JC J ^^^' '^^' ^'^^ ^^^'
ethoxyethenyl)-6- 1\ "] d). 5.94 (1H, br t),
methoxycarbonyl-4- rr'''^^==Y'^'^^^^^c02Me 5.40 (1H, d), 4.83
pfienylmethylamino- i^'^N^^ ^'^^' ^)' ^-^^ ^^^'
pyrimidine J s). 3.87 (2H, q),
1.13 (3H.t) ppm
2-(4-Chloro-3- pi 8.08 (3H, m). 7.72
fluorophenyl)-5-(2- I^^WY^'^NH'^^ ('"^• ^d), 7.59 (1H,
ethoxyethenyl)-6- IIJ J'xJ' "^)" '''*'* (^'^' "^)'
methoxycarbonyl-4-(2- j) jT 6.41 (1H. br t), 6.36
nitrophenyl- fj'^^=Y^'^'^^^^c°»'^« (1H, d), 5.39 (1H. d),
methylamino)- ci^^^T ^"^^ ^^^' ^^' ^'^^
pyrimidine J (2H. q), 3.94 (3H, s)
1.28 (3H.t) ppm
167

Name ~~ I Structure PH NMR (400 MHz,
CDCIj) 5
2-(4-Chloro-3- 9 8.49 (1H, d), 8.26
fluorophenyl)-4-(3- r'"'^^V^^NH'°N C'^- "^)- '^•'^^ C^-
chloropyrid-2-yl- l[^.i JQJ ^)' ^'^^ (1H, br q).
methylamino)-5-(2- jj T 7.46 (1H, t), 7.22
ethoxyethenyl)-6- fT^^^^^I^^ ^°^^^ ^^^' '^^' ^-^^ (''^•
mefhoxycarbonyl- ci^''^T^ ^)' ^•'*^ C'^- ^)' "^-^^
pyrimidine J (2H, d). 4.00 (2H, q),
3.99 (3H, s), 1.21
(3H, t) ppm
2-Cyclopropyl-5-(2- W2 8.07 (1H, m), 7.64
ethoxyethenyl)-6- J^''W^^NH'°^ C^^- "I)- '^■56 (1H.
methoxycarbonyl-4-(2- 'L^ •■^z '^^' ^'^^ ^^^' '^^■
nitrophenyl- "ll | 6.28 (1H, d). 6.22
methylamino)- V/ ^°^"^ (1H, brt), 5.35 (1H,
pyrimidine d), 4.96 (2H, d),
3.91 (3H, s), 3.49 (2H. m), 2.09 (IH. m), 1.20(3H, t). 0.91 (4H, m) ppm
8.2 Preparation of 2-chloro-4-methoxycarbonyl-7H-pyn'olo[2,3-d]pyrimidine (Compound 1-122) and 4-carboxy-2-chloro-7H-pyn'olo[2,3-d]pyrimidine (Compound 1-121)
XX — IX • IX
CI-'^N^^^CO.Me CK N^ CO.Me cK N CO,H
A mixture of 4-amino-2-chloro-6-(2-ethoxyethenyl)-6-methoxycarbonyi-pyrimidine (120 mg, 0.47 mmol) and hydrochloric acid (2N: 5 ml) was heated at reflux for 3 hours, cooled to ambient temperature and evaporated' under reduced pressure, The residue was purified using a FractionLynx hpic, to provide 2-chloro-4-melhoxycarbonyl-7H-pyrroio[2,3-d]pyrimidine (24 mg, 24%). Characterising data for the compound are as follows: MH*212. 214.
168

Also isolated was 4-carboxy-2-chloro--7H-pyrrolo[2,3-d]pyrimicline as an off-white solid
(61 mg. 66%)
Characterising data for the compound are as follows:
'H NMR (400 MHz. dg-DMSO) 6 7.50 (1H, d). 6.80 (1H, d), 6.50 (1H. m) ppm (CO2H not
observed).
Further examples of compounds that were prepared using this method are listed below in Table 26.
TABLE 26 Compounds made according to the method described in Example 8.2 above.
Compound I Name I Structure I ^H NMR (400 MHz^
Number CDCI3) 5
Tei 4-Carboxy-2-(4-chloro- HN—A 7.90 (1H. t). 7.80
2-fluoro-3- N'^'W^ ^^^' "^)' ^-^^ (''^■
methoxyphenyl)-7H- JB A^ m), 6.90 (1H, m),
pyrrolo[2,3-d]pyrimidine l| I ' 4.00 (3H, s) ppm
CI'''''Y^^^^F (NH and CO2H not
oMe observed)
5-18 2-(4-Chloro-3- l>^^^^^^ 8.38 (2H, m), 7.55
fluorophenyl)-7- jr\ (1H, d). 7.52 (1H,
cyclopropylmethyl-4- Vl^l^^ ^^^' ^'^^ ^^^' ^^'
methoxycarbonyl-7H- (/^^^V^^i^^^^^co^Me '^^^ <^^' ^^' ^'^^
pyrrolo[2,3-d]pyrimidine JL J ' (3H, s), 1.22 (1H.
^ I m). 0.69 (2H. m).
F
0.51 (2H, m) ppm
6-18 2-(4-Chloro-3- lr\IZ ^^ (2H, m), 7.52
fluorophenyl).4- \=:sJ^^f'\ ^^'^' ^^^' ^'^^ ^^^'
methoxycarbonyl-7- N'^'^ST '^^' ^'^^ ^^^' '^^'
phenylmethyl-7H- J\ ^\ 7.07 (1H. d), 5.58
pyrrolo[2,3-d]pyrimidine (| jT "^ ^^^^ (2H, s), 4.12 (3H. s)
a^''^^'^^ ppm
F 169

Compound [Name I Structure | ^H NMR (400 MHz,
Number CDCI3) 8
Ti 4-Carboxy-2- Wi 8^08 (1H, d), 7.56
cyclopropyl-7-(2- f\--\ ^^^' ^^' '^'^^ ^^^' ^^■
nitrophenyl-methyl)-7H- \^ f~^ 7.42 (1H. br s). 6.75
pyrrolo[2,3-d]pyrimidine N^''W^ CH. br s), 6.67 (1H,
XJ\ m). 5.70 (2H. s).
V 4.08 (1H, brs), 2.13
(1H, m), 0.89 (4H, m) ppm (nmr run in de-DMSO)
T2 2-Cyclopropyl-4- W, 8.13 {1H, d), 7.48
methoxycarbonyl-7-(2- yT'^y.-v (2H, m). 7.31 (1H,
nitrophenyl-methyl)-7H- \^:J^ f"^ d). 7.03 (1H. d).
pyrrolo[2,3-djpyrimidine N'^^^^ ^-^^ ('"^' ^^)' 5-^''
I J (2H. s), 4.07 (3H.
r—r N COjMe
V S). 2.45 (1H.
quintet), 1.12 (2 H, m). 1.05 (2H. m) ppm
8-18 2-(4-Chloro-3- Wi O2 (2H, m), 8.17
fluorophenylH- f/S^-^ ^^^' ^'^^' '^'^^ ^^^' '
methoxycarbonyl-7-(2- V^ f'A ^^' ^''^ (''^" ^^■
nitrophenyl-methyl)-7H- N'^'W''^ 7.00 (1H, m). 5.98
pyrrolo[2.3-d]pyrimidine ^^ 1 JL {2H. s), 4.13 (3H. s)
ppm
F
11-18 2-(4-Chloro-3- ^^5;v_^ 8.40 (2H. m). 7.52
fluorophenyi)-7-(2- ^o f~\ O'^- ^^)' ^-^^ C'^'
furanyi-methyl)-4- N'^'W^ ^)' ^'^^ C^- '^)'
methoxycarbonyl-7H- ^/\^ JL ^^ ^-^^ ^^'^' ^^' ^'^^
pyrrolo[2,3-d]pyrimidine jT jT ^ ^°'^^ C^^- ^)' ^-^^ (1H.
ci'^^Y^ m). 5.54 {2H, s).
t .
170

Compound I Name I Structure I ^H NMR (400 MHz.
Number CDCI3) 5
4.11 (3H, s) ppm
14118 2-(4-Chloro-3- P MH* 431,433.435
fluorophenyl)-7-(3- /T^v-—chloropyrid-2-yl- \^/ ,N—^
methyl)-4- N^'W'^
methoxycarbonyl-7H- jO ^^X
pyrrolo[2,3-cl]pyrimidine l| J
F
12^62 6-(4-Chloro-2-fluoro-3- ^^^\ZZ 7.98 (1'H, S), 7.83
methoxyphenyl)-1-(2- '^o f^ (1H, t). 7.37 (2H, m),
furanyl-methylM- r^^^ ^'^^ ^""^^ ^^'^' ^ ^^
methoxycarbonyl-IH- ^ Ji JL (1H, d), 6.34 (2H, s),
pyrrolo[3.2-c]pyridine 1 T "^ ^^'^^ ^-^^ ^^^' ^^' ^'^^
ci''^N=^^^F (3H, s), 4.00 (3H, s)
OMe ppm
I I 1
EXAMPLE 9 Synthesis of 2-chloro-7-(2-furanylmethyl)-4-methoxycarbonyl-6-methyl-7H-pyrrolol2,3-cllpyrimidine (Compound 11-126)
9.1 Prepa ration of 2-chloro-4-(2-furanylmethylamino)-5-iodo-6-methoxycarbonyl-pyrimidine
A solution of 2,4-dichloro-5-iodo-6-methoxycarbonyl-pyrimidine (prepared as described in WO2009/046090: 1.0 g, 3.0 mmol), furfurylamine (0,44 g, 4.5 mmol) and trietiiylamine (0.83 mi, 6.0 mmol) in dichloromethane (10 ml) was stirred at ambient temperature for 1 hour. Dichloromethane was added, the resulting solution washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The
171

residue was purified by automated flash chromatography (Presearch Combiflash Rf) on
silica, with ethyl acetate in hexane (0% to 40% gradient) as eluent. to provide 2-chloro-
4-(2-furanylmethylamino)-5-iodo-6-methoxycarbonyl-pyrimidine as a white solid (898
mg. 76%).
Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 8 7.40 (1H, d), 6.30 (2H, m), 6.20 (1H, br s), 4.70 (2H, d),
4.00 (3H, s) ppm.
9.2 Preparation of 2-chloro-7-(2-furanylmethyl)-4-methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 11-126)
OX- ^xi
A mixture of 2-chloro-4-(2-furanylmethylamino)-5-iodo-6-methoxycarbonyl-pyrimidine (377 mg, 0.96 mmol), (l-tributylstannyl)-allene (378 mg, 1.15 mmol), bis-(tri-t-butylphosphine)palladium (24 mg, 0.05 mmol) and degassed dimethylformamide (9 ml) was heated in a microwave reactor at 160 °C for 20 minutes, then allowed to cool and ethyl acetate added. The mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 40% gradient) as eluent, followed by further purification using a FractionLynx hpic, to provide 2-chloro-7-(2-furanylmethyl)-4-methoxycarbonyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid (75 mg, 26%). Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 6 7.30 (1H, m), 6.80 (1H. m). 6.20 (2H, m). 5.40 (2H, s), 4.10 (3H,s), 2.50 (3H,s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 27.
TABLE 27 Compounds made according to the method described in Example 9.2 above.
172

Compound I Name [ Structure I 'H NMR (400 MHz,
Number CDCI3) 5
1-126 2-Chloro-4- 7 6.80 (1H, s), 5.70
methoxycarbonyl-6- "f~\ ^""^^ ^'' ^^' ^'^^ ^^'^■
methyl-7H-pyrrolo[2.3- N^'^^^Y ^)' ^'^^ (^'^' ^^ PP"^
dlpyrimidine J\ -:^K.
' or ^N COjMe
EXAMPLE 10 Synthesis of 6-chloro-4-methoxycarbonyl-1H-pyrrolo[3,2-c]pyridine (Compound 22-122)
10.1 Preparation of 4-nnethoxycarbonyl-5-oxy-1H-pyrrolo[3,2-c]pyridine
N COjMe I
o" A mixture of 4-methoxycarbonyl-1H-pyrrolo[3,2-c]pyridine (0.50 g, 2.6 mmol), 3-chloroperoxybenzoic acid (0.82 g, 2.8 mmol) and chloroform (10 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with methanol in dichloromethane (0% to 10% gradient) as eluent to provide 4-methoxycarbonyl-5-oxy-1H-pyrrolo[3,2-cjpyridine as an orange foam (220 mg, 40%). Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 5 12.93 (1H. s). 8.02 (1H. d), 7.55 (2H, m), 6.56 (1H, m), 4.03 (3H, s) ppm.
10.2 Preparation of 6-chloro-4-methoxycarbonyl-1 H-pyrrolo[3,2-c]pyridine (Compound
22-122)
HN—TV
N* CO^Me y\ xj:^
( Cr N COjMe
o' A solution of 4-methoxycarbonyl-5-oxy-1H-pyrrolo[3,2-c]pyridine (220 mg, 1.15 mmol) in phosphorous oxychloride (5 ml) was heated at reflux for 4 hours, then allowed to cool to ambient temperature. The mixture was concentrated under reduced pressure, ice
173

added and the resulting mixture extracted witfi dichloromethane. The combined organic
extracts were evaporated under reduced pressure and the residue purified using a
FractionLynx hpic, to provide 6-chloro-4-melhoxycarbonyl-1H-pyrroio[3,2-c]pyridine as a
white solid (24 mg. 10%).
Characterising data for the compound are as follows:
'H NMR (400 MHz, CD3OD) 5 7.63 (1H, s), 7.55 (1H. d), 7.08 (1H, m), 4.60 (1H, br s),
4.02 (3H, s) ppm.
EXAMPLE 11 Synthesis of 3,6-dichloro-4^Ci T'A
I Cr N COjMe
O"
A solution of 3-chloro-4-methoxycarbonyl-5-oxy-1H-pyrrolo[3,2-c]pyridine (520 mg, 5.5 mmol) in phosphorous oxychloride (20 ml) was heated at reflux for 4 hours, then allowed to cool to ambient temperature. The mixture was concentrated under reduced pressure, warm water added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure and the residue purified using a FractionLynx hpic, to provide 3,6-dichloro-4-methoxycarbonyl-1H-pyrrolo[3,2-c)pyridine as a white solid (23 mg, 4%). Characterising data for the compound are as follows:
^H NMR (400 MHz. de-DMSO) 5 7.86 (1H, s), 7.69 (1H, s), 3.94 (3H, s) ppm (NH not observed).
EXAMPLE 12 Synthesis of 6-chloro-4-methoxycarbonyl-3-methyl-1 H-pyrrolo[3,2-cjpyridine (Compound 22-124)
12.1 Preparation of 5-bromo-2-chloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine
175

Triethylamine (4.1 ml. 30 mmol). followed by allylamine (0.84 g, 14.7 mmol), were added to a solution of 5-bromo-2,4-dichloro-6-methoxycarbonyl-pyridine (4.20 g, 14.7 mmol) in anhydrous dimethylformamide (50 ml). The resulting reaction mixture was heated at 100 °C for 2 hours, then allowed to cool to ambient temperature and evaporated under reduced pressure to yield an orange coloured oil which was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in isohexane (0% to 70% gradient) as eluent to provide 5-bromo-2-chloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine as a white solid (2.44 g, 54%). Characterising data for the compound are as follows:
^H NMR (400 MHz. CDCI3) 5 6.53 (1H, s). 5.96-5.85 (1H, m). 5.45 (1H, br s), 5.32 (1H. s), 5.28 (1H, d), 3.97 (3H, s). 3.92 (2H, m) ppm.
12.2 Preparation of 6-chloro-4-methoxycarbonyl-3-methyl-1 H-pyrrolo[3,2-c]pyridine (Compound 22-124)
Jl T ' fpY
Cr N COjMe
Tetrakis(triphenylphosphine) palladium(O) (1.06 g, 0.91 mmol), followed by degassed dimethylformamide (100 ml), were added to a mixture of 5-bromo-2-chloro-6-methoxycarbonyl-4-(prop-2-enylamino)-pyridine (5.57 g, 18.3 mmol) and finely ground sodium acetate (2.26 g, 27.4 mmol) The mixture was purged with nitrogen and then heated at 105 °C under an atmosphere of nitrogen for 20 hours. Additional tetrakis(triphenylphosphine) palladium(O) (1.06 g, 0.91 mmol) was added and heating continued for a further 24 hours. The reaction mixture was allowed to cool to ambient temperature, poured into water and the resulting mixture extracted with diethyl ethyl. The combined organic phases were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to yield a yellow solid, which was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in isohexane (0% to 80% gradient) as eluent to provide 6-chloro-4-methoxycarbonyl-3-methyl-1H-pyrrolo[3,2-cJpyridine as a yellow solid (1.92 g, 47%). Characterising data for the compound are as follows:
^H NMR (400 MHz, CD3OD) 5 7.51 (1H. s), 7.28 (1H. s), 4.00 (3H. s), 2.33 (3H, s) ppm (NH not observed).
176

EXAMPLE 13 Alternative synthesis of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-
methoxycarbonyl-3-methyl-1 H-pyrroio[3,2-c]pyridine (Compound 22-64)
HN—A
HN—A ^/^^5^v/
cr ^N co,Me ^.^^^'^-^..^^^y^^
OMe
A mixture of 6-chloro-4-methoxycarbonyl-3-methyl-1H-pyrrolo[3,2-c]pyridine (1.00 g, 4.45 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid 1,3-propanediol ester (1.42 g, 5.8 mmol), [1,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (182 mg, 0.22 mmol) and caesium fluoride (1.35 g, 8.9 mmol), dimethylformamide (12 ml) and water (4 ml) was heated in a microwave reactor at 115 °C for 3 hours, allowed to cool to ambient temperature and water added. The resulting mixture was extracted with dichloromethane and the combined organic extracts dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in isohexane (0% to 60% gradient) to provide 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-3-methyl-1 H-pyrrolo[3,2-c]pyridine as a beige solid (595 mg, 38%).
Characterising data for the compound are as follows:
^H NMR (400 MHz, CD3OD) 6 7.85 (1H, d), 7.65 (1H, t), 7.33 (2H, m), 4.03 (3H, s). 3.99 (3H, s), 2.37 (3H. s) ppm (NH not observed).
Further examples of compounds that were prepared using this method are listed below
in Table 28.
TABLE 28 Compounds made according to the method described in Example 13
above. Characteristic data is melting point (°C), ^H NMR (400 MHz,
CDCI3) S or mass ion
177

"Compound j Name 1 Structure j Characteristic data
Number
T22 2-(4-Chloro-3- y 8.90 (1H, br s). 8.30
fluorophi3nyl)-4- *^f~\ ^'^^' '^^' '^■^^ ^^^' ^^'
methoxycarbonyl-6- N''''^^^ 6.80 (1H, S), 4.10
methyl-7H-pyrrolo[2,3- r^^^^^jv^^ ^^ (^^' ^)' ^-^^ ^^^' ^^
cl]pyrimidine Jl ! ppm
F
~TU22 2-(4-Chloro-3- ^^^%~Z^ / MH* 400,402
fluorophenyl)-7-(2- ^o f^
I furanylmethyl)-4- N'^'W/'^
methoxycarbonyl-6- ^.^^ Jl J^
methyl-7H-pyrrolo[2,3- | j ^
d]pyrimicline a^'^^^r^
11-66 2-(4-Chloro-2-fluoro-3- PvIIT / ^
methoxyphenyl)-7-(2- ^o 5^—Vv
furanylmethyl)-4- N'^'^V''^
methoxycarbonyl-6- ^.^.^^ II Jl
methyl-7H-pyrralo[2,3- jfj^ "" ''°''"
d]pyrimidine CI'''^^Y'''^F
OMe
'22^«2 6-(4-Chloro-2-fluoro-3- HN—^ 7.97 (1H. m), 7.70
methoxyphenyl)-4- (^""^V"^ ^^'^' *^' ^"^^ ^^^' ^^'
methoxycarbonyl-1H- ^^^ Jj^ J^ . 7.32 (1H. dd), 7.11
pyrrolo(3.2-c]pyridine Jj jT ^ ^°''^* (1H. d).4.60{1H. br
o-'^'^Y^^ s). 4.05 {3H, s), 3.98
o*^^ (3H. s) ppm (nmr run
in CD3OD)
178

EXAMPLE 14 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5,8-climethyl-4-methoxycarbonyl-5,6,7,8.tetrahydropteridine (Compound 92-164)
1 JL 1 I
A solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-clichloro-6-methoxycarbonyl-pyrimidine (prepared as described in WO2009/081112: 1.50 a. 4.15 mmolV N. N'-dimethyl-ethane-1,2-diamine (O.S.ml, 4.1 mmol) and triethylamine (0.6 ml, 4.2 mmol) in dichloromethane (20 ml) was stinred at ambient temperature for 45 minute and then evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with methanol in dichloromethane (0% to 10% gradient)as eluent, followed by further purification using a FractionLynx hpic, to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5,8-dimethyl-4-methoxycarbonyl-5,6,7,8-tetrahydropteridine as a white solid (310 mg, 20%). Characterising data for the compound are as follows: M.p. 97 °C;
'H NMR (400 MHz. CDCI3) 8 7.68 (1H, dd), 7.16 (1H, m), 3.97 (3H, s), 3.96 (3H, s), 3.54 (2H, m). 3.42 (2H, m), 3.23 (3H, s), 2.88 (3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 29.
TABLE 29 Compounds made according to the method described in Example 14 above.
179

Compound I Name i Structure Wielting point ("C)
Number
93-166 2-(4-Chloro-2-fluoro-3- j 135
methoxyphenyl)-5,8- ''^^1''''^
diisopropyl-4- ^^^^^'^-v^
methoxycarbonyl- ^^:s^ JI .XA^ '
(\^^ N COjMe
5.6,7.8- Jl
CI ^I F
tetrahydropteridine |
OMe
95-168 2-(4-Chloro-2-fluoro-3- p^/\^/\ 146
methoxyphenyl)-5,8- ^^^v./'^-vx^'''^
dibenzyl-4- 11 -I
methoxycarbonyl- N I
5,6,7,8- a^^^Y^f
tetrahydropteridine
EXAMPLE 15 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5,8-diphenyl-4-methoxycarbonyl-5,6,7,8-tetrahydropteridlne (Compound 94-170)
15.1 Preparation of 5-chloro-2-(4-chloro-2-fiuoro-3-methoxyphenyi)-4-(N. N'-diphenyl-2-amino-ethylamino)-6-methoxycarbonyl-pyrimidine
H
CI ^N^ ^x\ ^Ph
fi ^Y'^ N'^'^COjMe ^ ^''^s^ ^'^ <^^
I cr y^ F
OMe I
OMe
A mixture of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4.5-dichloro-6-methoxycarbonyl-pyrimidine (prepared as described in WO2009/081112; 360 mg. 1.0 mmol). tris(diben2ylideneacetone)dipalladium(0) (90 mg, 0.10 mmol). Xanlphos (60 mg, 0.10 mmol), sodium carbonate (130 mg, 1.2 mmol), water (10 drops) and dimethoxyethane (5 ml) was heated in a microwave reactor at 140 'C for 75 minutes, then allowed to cool and ethyl acetate added. The mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with
180

ethyl acetate in hexane (10% to 40% gradient) as eluent, to provide 5-chloro-2-(4-
chloro-2-fluoro-3-methoxyphenyl)-4-(N, N'-diphenyl-2-amino-ethylamino)-6-
methoxycarbonyl-pyrimidine as a solid (100 mg, 19%). Characterising data for the compound are as follows: MH* 541, 543, 545;
15.2 Preparation of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5.8-diphenyl-4-methoxycarbonyl-5,6,7,8-tetrahydropteridine (Compound 94-170)
OMe OMe
A mixture of 5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-(N, N'-diphenyl-2-amino-
ethylamino)-6-methoxycarbonyl-pyrimidine (190 mg. 0.35 mmol),
tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.035 mmol), Xantphos (20 mg, 0.035 mmol), sodium carbonate (50 mg, 0.46 mmol), water (10 drops) and dimethoxyethane (4 ml) was heated in a microwave reactor at 140 "C for 75 minutes, then allowed to cool and ethyl acetate added. The mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (10% to 30% gradient) as eluent, followed by further purification using a FractionLynx hpic, to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5,8-diphenyl-4-methoxycarbonyl-5,6,7,8-tetrahydropferidine as a yellow solid (4 mg, 2%). Characterising data for the compound are as follows:
'H NMR (400 MHz. CDCI3) 8 7.68 (1H, m), 7.56 (1H. m), 7.45 (3H, m), 7.30 (4H, m), 7.16 (1H, dd), 7.09 (2H, d), 3.95 (3H, s), 3.94 (3H, s), 3.32 (2H, m). 3.06 (2H, m) ppm.
Further examples of compounds that were prepared using this method are listed below
in Table 30.
TABLE 30 Compounds made according to the method described in Example
15.2 above. Characteristic data is melting point {"C) or ^H NMR (400
MHz, CDCI3) 8
181

Compound I Name I Structure Characteristic data
Number
91-44 2-cyclopropyl-6,7- ^ 7.41 (1H, m). 7.15
diphenyl-4- HN^'^Y^''^ ^^^' "i)- ^-^2 (2H,
methoxycarbonyl- J-"-.^^^ ^^- ^'^^ ^^^' ^^' ^'^^
5,6.7,8- j\ jT (1H. brs).4.87
tetrahydropteridine ^—T^^^N^^co^we (2H, m), 3.95 (3H,
s), 2.12(1H, m).
0.90 (4H, m) ppm
91-184 2-(4-ChlDro-2-fluoro-3- j TIO
methoxyphenyl)-6,7- HN'''^^Y^
dimethyl-4- X^ NH
methoxycarbonyl- l| I
5,6.7,8- Ij^'^V^^N^^co.Me
tetrahydropteridine ^I/'\^;?:^^P
OMe
91-203 4-Carboxy-2-(4-chloro^ ^ 230
2-fluoro-3- HN^^Y^''^
methoxyphenyl)-6,7- JL NH
diphenyl-5,6.7.8- \\ I
tetrahydropteridine fl^f'^'^ ^^^"^
OMe
91-204 2-(4-Chloro-2-fluoro-3^ ^ 7.77 (1H, m). 7.66
methoxyphenyl)-6.7- HN^^^Y^^*" (1H, dd), 7.21 (3H,
diphenyl-4- I L m), 7.14(4H. m),
methoxycarbonyl- || 1 6.83 (2H, d), 6.79
5.6,7,8- rj^^==Y^^N^^^^co,Me (2H, d), 5.92 (1H, br
tetrahydropteridine CI'''''^Y^^F ^)' ^^^ (^H, m).
Le 4.01 (3H.s).3.96
(3H, s) ppm
182

Compound Name Structure Characteristic data
Number
91-207 (5aR,9aR)-4-Carboxy- ^^\ 236
2-(4-chloro-2-fluoro-3- ^^ J
methoxyphenyl)- i |
5.5a,6,7,8.9,9a.10-oc Yl ^^
tahydro- ./^^^^./\ <=^^^
benzo[g]pteridine Jl J^^
OMe
106-74 2-(4-Chloro-2-fluoro-3- Sf?^^N ^
m6(hoxyphenyl)-4- 1^ 5
methoxycarbonyl-8- 11 T
methyl-7,8-dihydro-6H- j^''''^^^Y''^^N'^^^^cOjMe
pyrimido[5,4- 0/"^^^?
b][1.4]oxazine ^^^
EXAH/IPLE 16 Synthesis of 8-benzyl-2-(4-chloro-2-fiuoro-3-methoxyphenyl)-4-methoxycarbonyl-5,6,7,8-tetrahydropteridine (Compound 95-162)
f| ^^ N COjMe rp ^V^ ^N COjMe
OMe OMe
Hydrochloric acid (2N; 3 drops) and palladium (5% on carbon; 32 mg) moistened with water (3 drops) were added to a solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5,8-dibenzyl-4-melhoxycarbonyl-5.6,7,8-tetrahydropteridine (prepared as described in example 14; 190 mg, 0.36 mmol) in methanol (10 ml). The mixture was hydrogenated under 4 bar of hydrogen for 6 hours then filtered through Celite®, the filtrate evaporated under reduced pressure and the residue purified using a FractionLynx hpic, to provide 8-benzyl-2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-5,6,7,8-tetrahydropteridine as a yellow solid (30 mg, 19%). Characterising data for the compound are as follows:
183

^H NMR (400 MHz, CDCI3) 5 7.70 (1H, t), 7.60 (1H, br s). 7.30 (5H. m), 7.10 (1H. d). 5.00 (2H. s), 4.00 (3H. s), 3.95 {3H, s). 3.50 (4H, s) ppm.
EXAMPLE 17 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-
methoxycarbonyl-5,10-dihydro-ben2o[g]ptericline (Compound 119-168)and2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-benzo[g]pterJdine (Compound 125-76)
17.1 Preparation of 4-(2-amino-phenylamino)-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-pyrimidine
\^ i' i
OMe Cr ^r^ F
OMe
2-Amino-aniline (0.13 g. 1.2 mmol), followed by triethylamine (0.15 ml, 1.3 mmoi), were added to a solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-dicliloro-6-methoxycarbonyl-pyrimidine (prepared as described in WO2009/081112; 365 mg, 1.0 mmol) in dimethylsulphoxide (6 ml) was heated at 90 °C for 3 hours, then allowed to cool to ambient temperature. The mixture was poured into waterand the dark yellow solid removed by filtration and washed with cold dichloromethane to provide 4-(2-amino-phenylamino)-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-pyrimidine as a yellow solid (400 mg, 92%). Characterising data for the compound are as follows: M.p. 162-164°C;
'H NMR (400 MHz, CDCI3) 8 7.62 (1H, t), 7.59 (1H, d), 7.4(1H, br s), 7.17 (IN, d), 7.12 (1H, t). 6.90 (2H, dd), 4.03 (3H, s), 3.97 (3H. s), 3.70 (2H. br s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 31.
TABLE 31 Compounds made according to the method described in Example 17.1 above.
184

Name Structure Melting point
4-(2-Amino- ^^^/NH^ 164-168
phenylamino)-5-chloro- i II
2-cyclopropyl-4- 'i"^
methoxycarbonyl- M'"'^^^
pyrimidine jl ^;Jt^
17.2 Preparation of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-5,10-dihydro-benzo[g]pteridine (Compound 119-168) and 2-(4-cliloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-benzo[g]pteridine (Compound 125-76)
a: X} f}
OMe OMe OMe
A mixture of 4-(2-amino-phenylamino)-5-chloro-2-(4-chloro-2-fluoro-3-metlioxyplienyl)-4-
methoxycarbonyl-pyrimidine (170 mg, 0.4 mmol),
tris(dibenzyiideneacetone)dipalladium(0) (25 mg, 0.03 mmol), Xantphos (45 mg, 0.08 mmol), sodium carbonate (70 mg, 0.65 mmol), water (5 drops) and dimetfioxyethane (3 ml) was heated in a microwave reactor at 150 °C for 60 minutes, then allowed to cool to ambient temperature. The mixture was evaporated under reduced pressure and the residue dissolved in water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica, with 20 % ethyl acetate in hexane as eluent, to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-5.10-dihydro-ben2o[g]pteridine as a yellow solid (50 mg. 32%).
Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 5 8.70 (1H, br s). 7.48 (1H, t). 7.14 (1H, d), 6.88 (1H, br s), 6.62 (1H, t), 6.58 (1H, t), 6.34 (1H, d). 6.14 (1H, d). 3.97 (3H. s), 3.92 (3H, s) ppm.
185

Also isolated was 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbony!-
benzofgjpteridine as a yellow solid (20 mg. 13%).
Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) S 8.40 (2H. t), 8.30 (1H. t). 8.18 (1H, t), 8.00 (1H, t). 7.35
(1H. d). 4.25 (3H, s), 4.10 (3H, s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 32.
TABLE 32 Compounds made according to the method described in Example 17.2 above.
Compound Name Structure IMeiting point
Number "C
119-28 2-Cyclopropyl-4- ^^N 217-219
methoxycarbonyl-5,10- JL JJ
dihydro- 1 (
benzo[g]pteridine N ^^^Y'^
EXAMPLE 18 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-7,9-dibenzyl-6-methoxycarbonyl-8-methyl-8,9-dihydro-7H-purine (Compound 81-46)
18.1 Preparation of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-di(ben2ylamino)-6-methoxycarbonyl-pyrimidine
OMe OMe
A mixture of 4-benzylamino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-pyrimidine (prepared as described in example 3.1; 330 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.075 mmol), Xantphos (50
186

mg. 0.075 mmol), sodium carbonate (95 mg, 0.90 mmol), water (10 drops) and
dimethoxyethane (5 ml) was heated in a microwave reactor at 140 °C for 75 minutes,
tlien allowed to cool and ethyl acetate added. The mixture was washed with water and
brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure.
The residue was purified by automated flash chromatography (Presearch Combiflash
Rf) on silica, with ethyl acetate in hexane (10% to 30% gradient) as eluent, to provide 2-
(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-di(benzylamino)-6-methoxycarbonyl-pyrimidine
as a solid (100 mg, 26%).
Characterising data for the compound are as follows:
'H NMR (400 MHz. CDCI3) 8 7.70 (1H, dd), 7.30 (6H, m). 7.23 (5H, m), 6.28 (1H, br t),
5.88 (1H.br t), 4.74 (2H, d). 4.15 (2H. d), 3.99 (3H, s). 3.87 (3H. s) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 33.
TABLE 33 Compounds made according to the method described in Example 18.1 above.
Name I Structure | ^H NIVIR (400 MHz,
CDCI3) 8
2-(4-Chloro-2-fluoro-3- "P ~ 7.72 (1H, dd). 7.31
methoxyphenyl)-4.5- jfjO!! « jCX C'^' '^)' '^■^^ C"^-
bis(2,4- /^AJk ^ m). 7.05 (1H. d),
dimethoxyphenyl- C.A^P 6.63 (1H. br t), 6.45
methylamino)-6- °>^ (2H. m), 6.40 (2H.
methoxycarbonyl- m), 6.08 (1H, t), 4.72
pyrimidine (2H, d), 4.03 (2H, d),
4.01 (3H. s), 3.86
(3H. s), 3.80 (3H. s).
3.79 (3H. s), 3.78
(3H, s), 3.63 (3H. s)
ppm
2-(4-Chloro-3- '^^^P^» j^ 8.13 (2H, dd). 7.41
fluorophenyl)-4,5- k?^ N/W^'^\>^ (1H, dd), 7.30 (8H,
di(ben2ylamino)-6- jj^Y^'' "^O'-^^ "^^^ ''■^° ^^^' ^^■
methoxycarbonyl- o-''^^ 6.18 (1H, br t). 5.92
pyrimidine f (1H, br t). 4.78 (2H,
d). 4.13 (2H.d), 3.87
1 _1
187

"Name I Structure I ^H NMR (400 MHz,
CDCI3) 8
(3H, s) ppm
2-(4-Chloro-2-fluoro-3- P 7.78 (1H, dd), 7.33
methoxyphenyl)-4.5- JJf X^S^^Xj ('"^' ^^^' ^''^ ^''^•
bis(2.4- "^ /^AA^i^ m). 7.04 (1H, dd).
dimethoxyphenyl- a^^N**^F ^^'^ ^^^' ^''*^' ^'^^
methylamino)-6-(n- o'*' (4H, m). 6.09 (1H, br
propoxycarbonyl)- t), 4.74 (2H. d), 4.50
pyrimidine (2H. d), 4.22 (2H,
m). 4.01 (3H, s), 3.86 (3H, s), 3.80 (3H, s), 3.79 (3H. s). 3.78 (3H, s), 1.79 (2H. m), 1.00 (3H. t) ppm
18.2 Preparation of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-7,9-dibenzyl-6-methoxycarbonyl-8-methyl-8,9-dihydro-7H-purine (Compound 81-46)
H f \ Ph
A solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-di(benzylamino)-6-methoxycarbonyl-pyrimidine (100 mg, 0.20 mmol) and acetaldehyde (0.02 ml; 0.36 mmol) in ethanol (5 ml) was heated at reflux for 6 hours, then allowed to cool and evaporated under reduced pressure. The residue was purified using a FractionLynx hpic, to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-7,9-dibenzyl-6-methoxycarbonyl-8-methyl-8,9-dihydro-7H-purine as a yellow oil (28 mg, 27%). Characterising data for the compound are as follows:
188

'H NMR (400 MHz, CDCI3) S 7.69 (1H, dd), 7.25 (8H, m). 7.16 (1H. d), 7.10 (2H, d), 5.24 (1H, q). 5.19 (2H. dd), 4.56 (1H, d). 4.37 (1H, d), 3.98 (3H, s), 3.81 (3H. s). 1.39 (3H, d) ppm.
Further examples of compounds that were prepared using this method are listed below in Table 34.
TABLE 34 Compounds made according to the method described in Example 18.2 above.
Compound I Name I Structure ^H NMR (400 IWHz,
Number CDCI3) S
"83^48 2-(4-Chloro-2-fluoro-3- '~T'' ^°"e 7.68 (1H. dd). 7.22
methoxyphenyl)-7,9- MKT-^^'^}''^ >=/ ^'"^' ^^^' ''"'^ ^'"^•
bis(2,4- v^" oMe d), 6.92 (1H, d),
dimethoxyphenyl- (l^"^ ^''^ ^'^^ ^^^' '^^' ^'^^
methyl)-6- "^L^' ^^^' '^^' ^''^ ^''^•
methoxycarbonyl-8- q), 5.14 (1H, d), 4.96
methyl-8.9-dihydro-7H- (1H, d), 4.34 (2H,
purine dd). 3.98 (3H, s).
3.84 (3H. s). 3.79 (3H, s). 3.76 (3H. s) 3.67 (3H. s). 3.48 (3H, s), 1.47 (3H.d) ppm
EXAIMPLE 19 Synthesis of 2-(4-chioro-3-fluorophenyl)- 5,8-dibenzyl-6,7-dioxo<4-methoxycarbonyl-5,6,7,8-tetrahydropteridine (Compound 95-160)
o
F 189

A solution of 2-(4-chloro-3-fluorophenyl)-4,5-di(benzylamino)-6-methoxycarbonyl-pyrimidine (prepared as described in example 18.1; 60 mg, 0.13 mmol) in dichlorobenzene (4 ml) was added to a stirred solution of oxalyl chloride (0.02 ml; 0.18 mmol) in dichlorobenzene (2 ml) at 60 °C. The reaction mixture was heated at 160 °C for 1 hour, then allowed to cool and ethyl acetate added. The mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (10% to 40% gradient) as eluent, to provide 2-(4-chloro-3-fluorophenyl)-5,8-dibenzyl-6.7-dioxo-4-methoxycarbonyl-5,6,7.8-tetrahydropteridine as a yellow solid (46 mg, 54%). Characterising data for the compound are as follows: M.p. 211 °C;
^H NMR (400 MHz, CDCI3) 6 8.12 (2H, m), 7.55 (3H. m), 7.30 (6H, m), 7.06 (2H, dd), 5.72 (2H, s), 5.48 (2H, s). 3.57 (3H. s) ppm.
EXAMPLE 20 Synthesis of 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrido[2,3-d]pyrimidine (Compound 123-49)
20.1 Preparation of 2-chloro-4-(2-furanyl)-pyrido[2,3-d]pyrimidine
N-^ 1 J
II I >\ -A^^O.
cr ^N XI U //
A mixture of 2,4-dichloro-pyrido[2,3-d]pyrimidine (200 mg, 1.0 mmol), 2-(tributylstannyl)-furan (0.35 ml, 1.1 mmol), bis-(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol) and degassed dimethylformamide (10 ml) was heated in a microwave reactor at 60 "C for 20 minutes, then allowed to cool and ethyl acetate added. The mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with methanol in dichloromethane (0% to 10% gradient) as eluent. to provide 2-chloro-4-(2-furanyl)-pyrido[2,3-d]pyrimidine as a yellow solid (217 mg, 94%). Characterising data for the compound are as follows:
190

'H NMR (400 MHz. CDCI3) 5 9.40 (1H. dd). 9.30 (1H. m). 7.80 (1H, m), 7.70 (1H. m), 7.60 (1H, dd), 6.70 (1H, m) ppm.
20.2 Preparation of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-(2-furanyl)-pyrido[2.3-djpyrimidine
ILy c^S^^^^F ^^
OMe
A mixture of 2-chloro-4-(2-furanyl)-pyrido[2,3-d]pyrimidine (217 mg, 0.94 mmol). 4-chloro-2-fluoro-3-methoxyphenylboronic acid 1,3-propanedioi ester (275 mg, 1.1 mmol), [1,1'-bis{diphenyiphosphino)-ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (77 mg, 0.09 mmol) and caesium fluoride (283 mg, 1.9 mmol), dimethoxyethane (5 ml) and water (5 ml) was heated in a microwave reactor at 140 °C for 20 minutes, allowed to cool to ambient temperature and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with methanol in dichloromethane (0% to 10% gradient) to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-(2-furanyl)-pyrido[2,3-d]pyrimidine as a brown solid (137 mg, 39%). Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 5 9.40 (1H, dd), 9.30 (1H, m). 8.10 (1H, t), 7.90 (1H, m). 7.80 (1H, m), 7.70 (1H, dd), 7.30 (1H, dd), 6.70 (IN, m), 4.00 (3H, s) ppm.
20.3 Preparation of 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrido[2,3-d]pyrimidine (Compound 123-49)
191

OMe OMe
Ozone was bubbled through a solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-(2-furanyl)-pyrido[2,3-cl]pyrimidine (137 mg, 0.37 mmol) in dichloromethane (40 ml) at -78 °C until a blue colour persisted in the reaction vessel. Oxygen was then bubbled through the reaction mixture until the blue colour disappeared, dimethyl sulphide (2 ml) was added and the mixture was allowed to warm to room temperature and stirred for 1 hour. The solution was evaporated under reduced pressure to provide 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrido[2,3-d]pyrimidine. Characterising data for the compound are as follows: [M-H]- 332. 334
EXAMPLE 21 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4.
methoxycarbonyl-pyrido[2,3-d]pyrimidine (Compound 123-50)
11 XX
f| ^^ N COjH rp ^p N CO^Me
or Y^ ^F cr Y^ F
OMe OMe
Trimethylsilyldiazomethane (2M in hexane; 0.48 ml, 0.89 mmol) was added to a stirred solution of 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrido[2,3-d]pyrimidine (prepared as described in example 20; 267 mg, 0.80 mmol) in methanol (5 ml) and dichloromethane (20 ml) and the reaction mixture stirred at ambient temperature for 30 minutes. Glacial acetic acid (0.1 ml) was added, the mxture evaporated under reduced pressure and the residue dissolved in ethyl acetate. The solution was washed with water, aqueous sodium hydrogen carbonate and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with methanol in
192

dichloromethane (0% to 10% gradient) to provide 2-(4-chloro-2-fluoro-3-
methoxyphenyl)-4-nnethoxycarbonyi-pyrido[2,3-d]pyrimidine as a brown solid (25 mg,
9%).
Characterising data for the compound are as follows:
M.p. 160-162 X;
'H NMR (400 MHz, CDCI3) 5 9.37 (1H, m), 9.12 (1H, dd). 8.06 (1H. dd). 7.70 (1H. dd),
7.33 (1H, dd), 4.17 (3H, s), 4.07 (3H, s) ppm.
EXAMPLE 22 Synthesis of 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1-63)
^ ^^ N CO^Me K^ ^^ N CO^H
OMe OMe
A mixture of 2-(4-chloro-2-fluoro-3-methoxyphenyI)-4-methoxycarbonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared as described in example 5; 260 mg, 0.75 mmol), sodium hydroxide (80 mg, 2.0 mmol), tetrahydrofuran (30 ml) and water (20 ml) was stirred at ambient temperature for 3 hours and then allowed to stand for 12 hours. The reaction mixture was acidified to pH 1-2 and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure to provide 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (88 mg, 35%). Characterising data for the compound are as follows:
^H NMR (500 MHz, dg-DMSO) 8 12.40 (1H, s), 7.80 (1H, t), 7.60 (1H, br s), 7.40 (1H, d), 4.00 (3H, s). 2.30 (3H, s) ppm (CO2H not observed).
Further examples of compounds that were prepared using this method are listed below
in Table 35.
TABLE 35 Compounds made according to the method described in Example 22
above. Characteristic data is melting point ("C) or ^H NMR (400 MHz,
CDCI3) 6
193

Compound I Name I Structure Characteristic data
Number
T3 4-Carboxy-2- ^T~\ 204 (dec.)
cyclopropyl-S-methyl- N'^^^V'^
7H-pyrrolo[2,3- Jl jL
d]pyrimicline \/
1-65 4^Carboxy-2-(4-chloro- / 7.80 (1H, t), 7.40
2-fluoro-3- '^l''^ (1H, d). 6.60 (1H, s).
methoxyphenyl)-6- N'^'W^^ 4.00 (3H, 5), 2.50
methyl-7H-pyrrolo[2,3- ^^^^^ -s^ (3H. s) ppm (NH and
d]pyrimidine 11 J^ CO2H not observed)
° I "^ (nmr run in de-
DMSO)
T21 4-Carboxy-2-(4-chloro- r>--^^^\ 7 8.23 (1H, dd), 8.16~
3-fluorophenyl)-7- ^ J^"^ (1H, dd). 7.71 (1H.
cyclopropylmethyl-6- N^'^^Y ^^' "705 (1H. s), 4.34
methyl-7H-pyrrolo[2.3- ,/%^N^CO,H ^^^' "^^^ ^'^^ ^^'^•
djpyrimidine Jl ^ ^ s), 1.36 (1H, m),
° 1^ 0.60 (4H, m) ppm
(CO2H not observed) (nmr run in CD3OD)
~5^65 4-Carboxy-2-(4-chloro- r-^^ ^ T 7.86 (1H. dd), 7.29~
2-fluoro-3- ^ J~\ (1H, m), 7.01 (1H.
methoxyphenyl)-7- N-^"^^ S), 4.22 (2H, d), 4.00
cyclopropylmethyl-6- ^^^5^.^^ -^V (3H, s). 2.63 (3H, s).
methyl-7H-pyrrolo[2,3- J Ji. ' "I-26 (1H, m), 0.56
d]pyrimidine ^' ]^ "^ (4H. m) ppm (CO2H
not observed)
I I \ I
194

Compound Name I Structure Characteristic data
Number
6-17 4-Carboxy-2-(4-chloro- iP^ZIT 8.51 (1H, dd), 8.43
3-fluorophenyl)-7- Vr^^^r'A ^^^' ^^^' ^'^^ ^^^'
phenylmethyl-7H- N^'W^ ^^' ^'^^ ^^^' ^^' ^'^^
pyrrolo[2.3-d]pyrimidine ^^^ Ij^ ^J^ (1H, t). 7.36 (4H. m),
||^]^'^ CO,H ggg ^^^ ^j gg
CI^'Y^^ 2(2H. S) ppm (CO2H
F not observed) {nmr
run in de-DMSO)
6-21 4-Carboxy-2-(4-chloro- yP^ZI^ / 8.28 (2H, t). 7.51
3-fluorophenyl)-6- \^=J^f\, ^^ ^' '^' ^'^^ ^^^' '^^■
methyl-7-phenylmethyl- N^'W'^ 7.14 (2H, d). 7.03
7H-pyrrolo[2,3- ^\ J'L^^ (1H. s), 5.60 (2H,
djpyrimidine fl |^ "^ ^°^" s), 2.45 (3H. s) ppm
01^^"^!^ (CO2H not observed)
F
6-65 4-Carboxy-2-(4-chloro- y^-'^v^ ^^^ 165
2-fluoro-3- X-sJ^ /^"^
methoxyphenyl)-6- N''''^V'^
methyl-7-phenylmethyl- ^^ II J^
7H-pyrrolo[2.3- I
d]pyrimidine a''''^N''''^F
OMe
TS 4-Carboxy-2- W2 8.12 (1H, d), 7.52
cyclopropyl-6-methyl-7- yTNs,-^ / (2H. m), 6.69 (1H,
(2-nitrophenyl-methyl)- \^ f^ s), 6.35 (1H, d),
7H-pyrrolo[2,3- N^^^^Y ^'^^ (2H. m). 2.27
djpyrimidine JL-J^ (3H, s), 2.15 (1H,
r—r N CO,H
V quintet), 0.88 (4H,
m) ppm (CO2H not observed) (nmr run
in de-DMSO)
I -J 1
195

Compound I Name I Structure I Characteristic data
Number
8-17 4-Carboxy-2-(4-chloro- Wz 8.35 (1H. dd), 8.27
3-fluorophenyl)-7-(2- //K-^ (1H, dd), 8.09 {1H.
nitrophenyl-methyl)-7H- \:^ f^\ dd), 7.83(1 H, d).
pyrrolo[2,3-d]pyrimidin8 N^'^W^ ^-^^ C ^' 0.7-59
l!^^ (1H.m).7.51(1H,
Jl J " m),6.98(lH.d).
o^^^^ 6.89(1H, d). 5.92
^ (2H, s) ppm (CO2H
not observed) (nmr
run in de-DMSO)
^21 4-Carboxy-2-(4-chloro- W, 8.18 (3H. m), 7.60
3-fluorophenyl)-6- //K^^ / (1H, t), 7.51 (2H. m),
methyl-7-(2- \^ f"^ 6.70(1H. s), 6.39
nitrophenyl-methyl)-7H- N-'^W^ (1H, dd), 5.87 (2H.
pyrrolo[2,3-d]pyrimidine ^^.^ Jl ,^JL s). 2.29 (3H, s) ppm
fT "^=V^ N^ ^CO,H
Jl J (CO2H not observed)
CI ^p (nmr run in dg-
^ DMSO)
8-65 4-Carboxy-2-(4-chloro- T^^ 187
2-fluoro-3- /TV-X /
methoxyphenyl)-6- \:s=^ T\.
methyl-7-(2- N^^^
nitrophenyl-methyl)-7H- -^ JO ^A^
<\^^ N COjH
pyrrolo[2,3-d]pyrimidine l| I
OlVIe 196

Compound Name Structure Characteristic data
Number
11-21 4-Carboxy-2-(4-chloro- ^^^^\Z^ / 8.41 (1H. dd), 8.34
3-fluorophenyl)-7-(2- '^o /^"A (1H, d). 7.69 (1H, t).
furanyl-methyl)-6- N'^W'^ ^-^^ ^'"^' '^)' ^-^^
methyl-7H-pyrroio[2,3- /\.Jv.-^^ (1H. br s), 6.40 (1H.
djpyrimidine |l T ^ ^°'" m), 6.36 (1H, m),
Cl-^N^ 5.55 (2H, s), 2.50
F (3H. s) ppm (CO2H
not observed)
(nmr run in de-
DMSO)
12-63 4-Carboxy-2-(4-chloro- ^^^^\I^ "^
2-fluoro-3- /-o f"^
nnethoxyphenyl)-7-(5- ^i^ u^^^^f
trifluoromethyl-furan-2- ^.^^ Jl JL
yl-methyl)-5-methyl-7H- jT j^ '^ ^^'^
pyrroloI2,3-d]pyrimidine CI'''^V''^F
OMe
14-17 4-Carboxy-2-(4-chloro- ?i 8.41 (1H, d). 8.28
3-fluorophenyl)-7-(3- /Txs-^X (2H, m). 8.02 (1H,
chloropyrid-2-yl- \^N f^ s). 7.76 (1H, dd),
methyl)-7H-pyrrolo[2.3- N^W^ 7-62 (1H, m), 7.53
dlpyrimidine ^^ JL JL (IH. m). 7.29(1H,
(T^r N co,H
II J m). 5.84 (2H. s)
ci^^p ppm (CO2H not
^ observed)
22-63 4-Carboxy-6-(4-chloro- HN—^ 11.66 (IH, s), 7.91
2-fluoro-3- r'^^V'^ (IH. m). 7.86(1H,t),
methoxyphenyl)-3- ^ Jl JL 7.44 (2H. m), 3.95
methyl-1H-pyrrolo[3.2- J T "^ ^^'^ (3H, s). 2.34(3H. s)
cjpyridine CI-'-'^^V^'^F ppm (CO2H not
o"^^ observed) (nmr run
in de-DMSO)
197

Compound Name Structure Characteristic data
Number
91-183 4-Carboxy-2-{4-chloro- j 8.10 (1H, brs). 7.65
2-fluoro-3- HN-^Y^ ^^^' *^' ^'^^ ^^^" ^^
methoxyphenyl)-6.7- Jk,^/NH s), 7.34 (1H, dd),
dimethyl-5,6,7.8- jj T 3.90 (3H, s), 3.62
tetrahydropteridine fT'^^Y'^'^ ^°'" (2H. m), 1.10 (2x
c^'^-'^-^-f^^f 3H, s) ppm (CO2H
OMe not observed) (nmr
run in de-DMSO)
92-163 4-Carboxy-2-(4-chloro- SvP^N "^
2-fluoro-3- X N
methoxyphenyl)-5,8- jj
dimethyl-5,6,7,8- fr''^^^==?i''^^N'^^cOjH
tetrahydropteridine ri-'-'''^s;?^^^c
OMe
93-165 4-Carboxy-2-(4-ch(oro- j 125
2-fluoro-3- -^^N'^
methoxyphenyl)-5,8- N'^'^V^'^N^
diisopropyl-5,6,7,8- ^.^ ]1 J^ I
fl ^T N C0,H
tetrahydropteridine Jj I
CI'''''^j'''''^F OMe
I I 1 \
EXAMPLE 23 Synthesis of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-
ethoxycarbonyl-3-methyl-1H-pyrrolo[3,2-c]pyridine (Compound 22-75)
XX XX
OMe OMe
198

1-Hydroxy-3-isothionato-1.1,3,3-tetrabutyl-distannoxane (16 mg, 0.029 mmol) was added to a suspension of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methOKycarbonyl-3-methyl-1H-pyrrolo[3,2-c]pyridine (prepared as described in example 5; 200 mg, 0.58 mmol) in toluene (5 ml). Ethanol (0.67 ml, 11.5 mmol) was added and the resulting mixture heated in a microwave reactor at 170 "C for 1 hour, then cooled and ethyl acetate and water added. The organic phase was evaporated under reduced pressure and the residue purified using a FractionLynx hpic, to provide 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-ethoxycarbonyl-3-methyl-1H-pyrrolo[3,2-c]pyridine (98 mg, 47%). Characterising data for the compound are as follows:
'H NMR (400 MHz. CDCI3) 5 8.50 (1H, br. s), 7.87 (1H. m), 7.84 (1H, d). 7.26 (1H. m). 7.16 (1H, m), 4.55 (2H, q), 3.99 (3H, s). 2.42 (3H, s), 1.49 (3H, t) ppm.
Further examples of compounds that were prepared using this method are listed below
in Table 36.
TABLE 36 Compounds made according to the method described in Example 23
above. Characteristic data is melting point ("C) or ^H NMR (400 MHz,
CDCI3) 6
Compound Name Structure Characteristic data
Number
1-75 2^<4^€hio7o-2-fluoro-3- HN—A 172-174
methoxyphenyl)-4- N^''^55>r~^
ethoxycarbonyl-5- • ^.^^ ]l A^^
methyl-7H-pyrrolo[2.3- | ^
d]pyrimidine CI^^N^-'^F
OMe
TTT 2-(4-Chloro-2-fluoro-3- HN—A ^64 (1H, br s), 7,82'
methoxyphenyi)-5- N'^'^W'^ (1H. dd), 7.28 (1H,
methyl-4-(n- ^^:^ J\ ■J^ „ m), 7.22 (1H. m),
(f ^7 N COj oclyl
octyloxycarbonyl)-7H- Jl ,JL '^•^^ (2H. t), 4.03
pyrrolo[2,3-d]pyrimidine ^' \ ^ (3H. s), 2.43 (3H, d),
OMe
1.85 (2H. quintet),
1.48 (2H, m), 1.30
(8H, m). 0.89 (3H, t)
ppm
199

Compound Name Structure I Characteristic data
Number
1-78 2-(4-Chloro-2-fluoro-3- T~A 154-156
methoxyphenyl)-4- N^'^^Y"
isopropoxycarbonyl-5- ^^^ 11 J^^
methyl-7H-pyrrolo(2.3- (l jT '^ ^°''^'
d]pyrlmidine ci""^ ^F
OMe
1-79 2-{4-Chloro-2-fluoro-3- T^T 9.43 (1H. br s), 7.86
metiioxyphenyl)-4- 1 JL ^'"^' ^^^' '"'^^ (''^•
(hept-2-yloxycarbonyl)- X^X^"^ co,cH(MexcH,).Me ^^^ ^ 22 (1H, t). 5.32
5-methyl-7H- ° il/' <''^' f")' ^^^ (2^^-
pyrrolo[2.3-d]pyrimidine s), 2.44 {3H, s), 1.85
(1H, m). 1.69 (1H,
m), 1.47 (3H, d),
1.35 (3H, m). 0.90
(3H, m) ppm
1-80 2-(4-Chloro-2-fluoro-3- T\l 10.55 (1H. br s).
methoxyphenyl)-5- ?l'|^ ^'^^ ^''^' ^^^' ^'^^
methyl-4-(prop-2- ^^'"'^^^^U'^^CO.CH^CH^CH, (IH, m), 7.22 (1H,
enyloxycarbonyl)-7H- a^^^r^^e m), 6.10 (1H, m),
pyrroioI2.3-d]pyrimidine "^^ 5.51 (1H, dd), 5.36
(IH, dd), 5.01 (2H.
m). 4.04 (3H. s).
2.44 (3H, s) ppm
1-82 2-(4-Chloro-2-fliJoro-3- T\~ 9.24 (IH, br s), 7.82
methoxyphenyl)-4-[(2- fl'^S'^ ^'"^" ^^' ^'^^ ^^^'
ethoxy)- JJ-^^V-^N-^^CO^CH^JJOEI m), 7.22 (IH, m),
ethoxycarbonyl]-5- CI^^^N^^'' ^'^^ ^^^' '^^' "^'^^
methyl-7H-pyrroio[2,3- o«« (3H, s), 3.85 (2H,
d]pyrinnidine m), 3,61 (2H, q),
2.43 (3H, s), 1.24 (3H. t) ppm
200

Compound Name I Structure I Characteristic data
Number
1-83 4-[(2-n-Butoxyy l'~\ 9.39 {1H, br s). 7.82
ethoxycarbony|]-2-(4- Tl'^Y^ ^'"^' ^^^' ^"^^ ^''^•
chloro-2-fluoro-3- rr^'^=ir^'^tr^coj,cH,)firBu m), 7.21 (IH, m),
methoxyphenyl)-5- a-^'^f^p 4.63 (2H. m), 4.02
methyl-7H-pyrrolo[2.3- °"' {3H. s). 3.85 (2H.
djpyrimidine m), 3.53 (2H, t), 2.44
{3H, s), 1.60 (2H.
m), 1.37 (2H,
sextet), 0.91 {3H, t)
ppm
1-84 4-((1-n-Butoxy)-prop-2- T\I 9.80 (IH, br s). 7.84
yloxycarbonyl].2-(4- JlJL ^''^' ^^^' ^'^^ ^'"^■
chloro-2-fluoro-3- jCk '" cofi^^^^P^^ m), 7.20 (IH, t), 5.49
methoxyphenyl)-5- ° Xe "^ (^^' sextet). 4.02
methyl-7H-pyrrolo[2.3- (3H. s), 3.68 (2H,
d]pyrimidine ddd), 3.53 (2H. m),
2.42 (3H. d), 1.56
(2H. m), 1.49 (3H.
d), 1.37 (2H, sextet),
0.90 (3H, s) ppm
T85 2-(4-Chloro-2-fltioro-3- T\^ 10.05 (1H, br s).
methoxypheny|)-4-{2- XJL ^^^ ^^^' ^^^' '^'^^
[(2-methoxy)-ethoxy]- jQ^ "" CO,C»,,«CH,,OM. (^H, m), 7.19 (1H. t),
ethoxycarbonyl}-5- " X. ' ^-^^ (2H. m), 4.04
methyl-7H-pyrrolo[2.3- (3H, s). 3.93 (2H,
djpyrimidine m), 3.75 (2H, m),
3.59 (2H. m), 3.39
(3H. s). 2.41 (3H, d)
ppm
1-86 4-8enzyloxycarbonyl-2- HN-A 10.20 (IH. br s),
(4-chloro-2-fluoro-3- N'^W'^ 7.81 (1H. dd), 7.53
methoxyphenyl)-5- I^^^^Y^'' co,CH,Ph ^^H. m). 7.40 (3H
methyl-7H-pyrrolo[2.3- Jl JL ' ' m), 7.29 (1H. dd)
cr ^Y ^F
d]pyrimidine i^^ 7.19 (IH. m), 5.5'
(2H, s), 4.04 (3H. s' 201

Compound fName Structure Characteristic data
Number
TST 2-(4-Chloro-2-fluoro-3- T^Vl 9.40 (1H. br s). 7.81
methoxyphenyl)-4-(2- 1^1^ ^^^' ^^^' '''^^ ^'"^'
furanyl- r^^^^" '=°'<^"'<^-'"'«"*" d), 7.28 (1H, m),
methoxycarbonyt)-5- a^^^f 7 20 (1H, m). 6.59
OMe
methyl-7H-pyrrolo[2.3- (1H, m). 6.40 (1H,
djpyrimidine m), 5.46 (2H. s),
4.03 (3H. s). 2.33
{3H, d) ppm
T88 2^(4-Chloro-2-fluoro-3- TyJ 9^49 (iHTbr s). 7.82
methoxyphenyl)-5- ^^ jOC C^- ^^)' ''•28 CH,
methyl-4- „JyK m). 7.20(1 H, t), 4.55
(tetrahydrofuran-2-yl- °^ {1H, dd), 4.46 (1H,
methoxycarbonyl)-7H- m), 4.35 (1H, m).
pyrrolo[2,3-d]pyrimidine 4.04 (3H. s), 3.96
(1H, m), 3.84 (1H,
m). 2.42 {3H. s).
2.10 (1H. m), 1.90
{2H. m). 1.80 (1H.
m) ppm
22-77 6^(4^loro-2-fluoro-3- HN—^ 8.40 (IH. br s). 7.88~
methoxyphenyl)-3- f^^^J^ ^^H, m). 7.26 {1H,
methyl)-4-(n- ^^'^JL<^ „ dd), 7.16(1H. m),
octyloxycarbonyl)1H- Jl^^ 4.48 (2H, t), 3.99
pyrrolo[3.2-c]pyridine *^' | ^ {3H, s), 2.42 {3H. s),
OMe
1.85 {2H,m), 1.49
{2H, m), 1.32 (BH,
m), 0.89 (3H. m)
ppm
22-78 6-(4-Chloro-2-fluoro-3- HN—A 8.35 (1H. s).'7.86
methoxyphenylH- r^^==>r ^'^^' ^^' ^^® ^^^'
isopropoxycarbonyl-3- ^..^^ jl -I m), 7.14 (1H, m),
methyl-1H-pyrrolo[3,2- || | ^ ^°'^' 5.41 (IH, sept), 3.98
clpyridine CI^'^^Y^^^F (3H, s), 2.42 (3H. s'
OMe and 1.48 (6H, d
202

Compound i Name I Structure Characteristic data
Number
, _____
1Z^79 6-(4-Chloro-2-fluoro-3- T\^ 8^7 (1H, br s), 7.89
methoxyphenyl)-4- JljL ^^^' ^^' ^'^^ (^^•
(hept-2-yloxycarbonyi)- jTX^''^ co,cH(MexcHAMe ^^ ^23 (1H, dd),
3-methyl-1H- "'L/' ^''2 CH, m), 5.31
pyrrolo[3,2-c]pyridine (1H, m). 3.97 (3H.
s), 2.41 (3H. s), 1.85
(1H, m), 1.66 (1H.
m), 1.49 (2H. m),
1.45 (3H. d). 1.33
(4H, m), 0.90 (3H,
m) ppm
22-80 6-(4-Chloro-2-fluoro-3- T\l 8.47 (1H, br s), 7.88
methoxyphenyl)-3- III (1H, m), 7.85 (1H,
methyl-4-(prop-2- rj-''^V'^N**^co,cH,cH-cH, d), 7.26(1 H, m),
enyloxycarbonyl)-1H- Q'^^'^F 7.16 (1H, m), 6.13
pyrrolo[3.2-c]pyridine °**' (1H. m), 5.50 (1H,
dd). 5.34(1 H,dd),
4.98 (2H. m), 3.99
(3H, s). 2.42 (3H, s)
ppm
22-82 6-(4-Chloro-2-fluoro-3- TAT 8.50 (1H, brs). 7.86
methoxyphenyl)-4-[(2- fll^ (2H, m), 7.26 (1H,
ethoxy)- r|''''=5Y'^N*'*^co,(CH,),oEi m), 7.13 (1H, m),
ethoxycarbonyl]-3- ci-^'^f^F 4.63 (2H, m). 3.99
methyl-1H-pyrrolo[3,2- owe (3H, s). 3.86 (2H.
c]pyridine m), 3.62 (2H, q),
2.41 (3H,s), 1.24
(3H. t) ppm
22-83 4-[(2-n-Butoxy)- T\I ~ 8.55 (1H, br s). 7.85
ethoxycarbonyl]-6-(4- (|Y^ (2H, m), 7.26 (1H,
chloro-2-fluoro-3- IJ'''^V'^N^^^^^^CO^CH,),O"BU m), 7.12 (1H, m),
methoxyphenyl)-3- a-^^S^^^^F 4.63 (2H. m), 3.99
methyl-1H-pyrrolo[3,2- °"' (3H. s), 3.85 (2H,
203

PCT/GB2010/001890
Compound Name Structure Characteristic data
Number
cjpyridine m), 3.55{2H, m),
2.40 <3H,s), 1.59 {2H, m), 1.43-1.32 (2H, m). 0.91 (3H, t) ppm
22-84 4-[(1-n-Buloxy}-prop^ T^V^^^ 8.68 (1H. brs), 7.65
yloxycarbonyl]-6-(4- XJL (2H.m). 7.23(1 H,
chloro-2-fluoro-3- jCC"'" CO,CH,M.,C«,O^ dd). 7.09(1 H. S).
methoxyphenyJ)-3- " Xe ' 6.49 (1H, m), 3.98
methyl-1H-pyrrolo[3,2- {3H, s), 3.68 (2H.
cjpyridine m), 3.55 (2H, m),
2.39 (3H,s), 1.57
(2H, m), 1.48(3H,
d), 1.38(2H, m).
0.90 (3H. t) ppm
I 22-85 6-(4-Chtoro-2-fluoro-'3^ T\— 8.63(IH, brs), 7.83~
methoxyphenyl)-4-{2- XjL {2H, m), 7.24(1 H,
((2-methoxy)-ethoxy]- jQ/'" CO,C«,,P' '^^ (^H, m).
methyl-1H-pyrrolol3.2- Jl JL ' ' 7.26 (1H, m), 7.13
cr y"^ F
clpyridine J,^^ (IH, m), 5,53 (2H.
s). 3.99 (3H, s), 2.31 (3H, s) ppm
204

Compound Name Structure Characteristic data
Number
22-87 6-(4-Chloro-2-fluoro-3- T\l 8.52 (1H, brs). 7.86
methoxyphenyl)-4-(2- J|J~ (2H, m). 7.45 (1H.
furanyl- (rY^"^ co,cH,(24urany«) m), 7.26 (1H, m),
methoxycarbonyl)-3- a-'^-^F 7.13 (1H. m). 6.55
OMe
methyl-1H-pyrrolo[3,2- (1H. m). 6.39 (1H.
cjpyridine m), 5.47 (2H, s),
3.98 (3H. s), 2,33 (3H, s) ppm
22-88 6-(4-Chloro-2-fluoro-3- T\~~ 8.71 (1H, brs), 7.84
methoxyphenyl)-3- .^ jOC ^2H. m), 7.24 (1H,
methyl-4- CKW*S dd), 7.06 (1H, S),
(tetrahydrofuran-2-yl- °^' 4.55 (1H, m), 4-41
methoxycarbonyl)-1 H- (2H. m), 3.97 (4H,
pyrrolo[3,2-c]pyridine m). 3.86 (1H, m),
2.36 (3H, s). 2.03
(3H. m). 1.80(1H,
m)ppm
h^ 5-Chloro-2-{4-chloro-2- 9^^ 7.80 (1H, t), 7.30
fluoro-3- iTl^^^" (1H, m),7.20(1H,
methoxyphenyl)-4-(2.4- M^QA^ N'^'W^" m). 6.50 (1H. m).
dimethoxyphenyl- ^^^ I J. 6.40 (1H, dd). 6.30
methylamino)-6-(n- II I (1H, brs). 4.70(2H,
propoxycarbonyl)- ^' |^ ^ d), 4.30 (2H. t), 4.10
OMe
pyrimidine (3H, s), 3.90 (3H, s),
3.80 (3H,s), 1.80 (2H, sept). 1.00 (3H,
t)ppm
I I . I .
EXAMPLE 24 Synthesis of 2'(4-chloro-2-fluoro-3-methoxyphenyl)-4-
methoxycarbonyl-5.methyl-7-methylsulphonyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 18-64)
205

3.f
1^ ^^ N CO^Me ff ^A "^ COjMe
OMe OMe
Triethylamine (0.26 ml, 1.9 mmol) was added to a suspension of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared as described in example 3; 350 mg, 1.0 mmol) in dichloromethane (12 ml) and the resulting mixture cooled to 0 °C. After stirring for lOmins, methanesulphonyl chloride (0.12 ml, 1.5 mmol) was added and the reaction mixture stirred for 10 minutes at 0 °C, then warmed to ambient temperature and stirred for a further 1 hour. The reaction mixture was evaporated under reduced pressure and the residue purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in isohexane (10% to 40% gradient) as eluent, followed by further purification using a FractionLynx hpic, to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-5-methyl-7-methylsulphonyl-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid (151 mg, 35%). Characterising data for the compound are as foltows:
^H NMR (400 MHz, CDCI3) 6 8.00 (1H, m), 7.60 (1H, m), 7.30 (1H, m), 4.10 (3H, s), 4.00 (3H, s), 3.70 (3H, s). 2.40 (3H, s) ppm.
EXAMPLE 25 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-7-ethoxymethyl-4-methoxycarbonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 3-64) and 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-7-ethoxymethyl-5-methyl-7H-pyrrolo[2,3-djpyrimidine (Compound 3-63)
HN-A EtO^A ElO—°"® OMe OMe
2-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-5-methyl-7H-pyrroio[2,3-djpyrimidine (prepared as described in example 3; 175 mg, 0.5 mmol) was added to a
206

stirred suspension of potassium t-butoxide (112 mg. 1.0 mmol) in tetrahydrofuran (10
ml) at ambient temperature. After stirring for 15mins, chloromethyl ethyl ether (0.09 ml,
1.0 mmol) was added and the reaction mixture stirred for 3 hours, evaporated under
reduced pressure and the residue purified using a FractionLynx hpic, to provide 2-(4-
chloro-2-fluoro-3-methoxyphenyl)-7-ethoxymethyi-4-methoxycarbonyl-5-methyl-7H-
pyrrolo[2,3-d]pyrimidine as an off-white solid (71 mg, 35%).
Characterising data for the compound are as follows:
M.p. 107-108 X;
'H NMR (400 MHz, CDCI3) 5 7.80 (1H, t). 7.30 (1H. m). 7.20 (1H. m), 5.70 (2H, s), 4.10
{3H. s), 4.00 (3H, s), 3.50 (2H. q). 2.50 (3H, s), 1.20 (3H, t) ppm.
Also isolated was 4-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-7-ethoxymethyl-5-
methyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (38 mg, 19%).
Characterising data for the compound are as follows:
M.p. 112-114 X (dec);
'H NMR (500 MHz, dg-DMSO) 5 7.80 (1H, t), 7.60 (1H, br s), 7.40 (IN, d), 5.60 (2H. s),
3.90 (3H, s), 3.40 (2H, q), 2.30 (3H, s), 1.00 (3H, t) ppm (CO2H not observed).
Further examples of compounds that were prepared using this method are listed below
in Table 37.
TABLE 37 Compounds made according to the method described in Example 24
above. Characteristic data is melting point ("C) or ^H NMR (400 IVIHz,
CDCI3) 5
Compound Name Structure Characteristic data
Number
~&^63 7-Benzyl-4-carboxy^ ^T^^ZZ 7.90 (1H, t), 7.30
(4-chloro-2-fluoro-3- \-=:J^^~\ ^^^' "^^- ^'^^ ^^^■
methoxyphenyl)-5- N''''^=V'^— ^^' ^'^^ ^^^' ^^' ^'^^
methyl-7H-pyrrolo[2,3- ^^^ J\ \^ (3H, s) ppm (CO2H
d]pyrimtdine H T "^ ^ ^" not observed) (nmr
ci'''''^ir'''^^F run in de-DMSO)
OMe 207

Compound I Name Structure Characteristic data
Number
6-64 7-Benzyl-2-(4-chloro-2- lr\~Z 7.90 (IH, t), 7.80
fluoro-3- XrpJ^^f'^ ^^^- ^^' ^^° ^^^■
methoxyphenyl)-4- /^/^ dd). 7.30 (5H, m),
methoxycarbonyl-5- J\ J^ 5.50 (2H, s), 4.10
methyl-7H-pyrrolo[2.3- (l |^ "^ ^^'"^^ ^^^' ^^' '*-°° ^^^' ^^•
djpyrimidine a'^'^|*^^^F 2.30 (3H, s) ppm
OMe
7-63 4<^arboxy-2-{4-chloro- ~~ 7 iTs
2-fluoro-3- ^/"^N
methoxyphenyl)-5- ^^^^^"^ Jl \.^
methyl-7-(1-phenyl- fl j
ethyl)-7H-pyrrolo[2.3- rj-^'^^^V^'^N^^'^co^H
dlpyrimidine .-^^-^^^
OMe
7-64 2-(4-Chloro-2-fluoro-3- ~~ 1 7.83 (IH, dd), 7.32
methoxyphenylH- ^ /"^N ^^*^' '"^' ^"^^ ^'"^'
methoxycarbonyl-5- ^=^ /" V.^ m). 7.16 (1H, s),
methyl-7-(1-phenyl- n J^ 6.31 (IH, q), 4.06
ethyl)-7H-pyrrolo[2.3- fj^^^^^V^^'^^co.Me (3H, s). 4.03 (3H, s),
dlpyrimidine /%;?^ 2.40 (3H, s), 1.91
Le (3H.d)ppm
8-63 4-Carboxy-2-(4-chloro- 'Wz 165
2-fluoro-3- /TV^
methoxypheny|)-5- \^ /""^
methyl-7-(2- N^W^
nitrophenyl-methyl)-7H- ^-v. Jl .^^JL
r « , fT '^V'"^ N CO,H
pyrrolo[2,3-d]pyrimidine l| I
OMe 208

Compound Name I Structure Characteristic data
Number
8-64 2-(4-Chloro-2-fluoro-3- Jo, 8.13 (1H, d). 7.80~
methoxyphenyl)-4- /fNy—v C"^- ^^)' '^•^2 (1H.
methoxycarbonyl-5- \=s^ /'"^ '^)' ^"^^ (""^^ '^)'
methyl-7-(2- ^,^'^/^ 7.25 (2H. m). 7.10
nitrophenyl-methylHH- ^^^ JB JL (1H, m), 5.88 (2H,
ff "^^r N CO,IVle
pyrrolo[2,3-d]pyrimidine l( I s), 4.09 (3H, s), 4.01
ct^'^^^F (3H, s). 2.44 (3H. s)
o"^^ ppm
"9^ 4-Carboxy-2-(4-chloro- /P^VZT ^
2-fluoro-3- ^""X^ ^^~~methoxyphenyl)-7-(4- N^^^^^V'^
fluorophenyl-methyl)-5- 11 J,
methyl-7H-pyrrolo[2,3- ll 1^ ^ ^°'^
d]pyrimidine CI^''^N-'^^F
OMe
10-63 4-Carboxy-2-(4-chloro- /P^VZZ ^^^^
2-fluoro-3- MBO—-\^^ f'~methoxyphenyl)-7-(4- H''^^^
methoxyphenyl- ^^^^ II A^
methyl)-5-methyl-7H- fl 1^ ^ ^°'"
pyrrolo[2,3-d]pyrimidine ci'^^r'^F
OMe
12-64 2-(4-Chloro-2-fluoro-3- ^^^%Z^ ^
methoxyphenyl )-4- 3^o T""^
methoxycarbonyl-5- F3C N''''^^^V'^
methyl-7-(5- ^^^ ]) JL
trifluoromethylfuran-2- I
yl-methyl)-7H- ci''''^r^'^F
pyrrolo[2,3-d]pyrimidine °'*^s
\ I I
209

Compound Name Structure Characteristic data
Number
16-64 7-t-Butylcarbonyl-2-(4- j '^ 147-149
chloro-2-fluoro-3- 7-^
methoxyphenyl)-4- / ^..^
methoxycarbonyl-5- Vi |
methyl-7H-pyrrolo[2,3- rr'^^^^^^^j^'^^N^'^cOjMe
dlpyrimidine ^^.^^^^
OMe
17-63 4-Carboxy-2-(4-chloro- P 155-157
2-fluoro-3- o-^
methoxyphenyl)-7- / \_^
methoxycarbonyl-5- 'I'l j
methyl-7H-pyrrolof2,3- ^'^^^^^-^^YT^CO^H
dlpyrimidine ^^A^^^A^^
OMe
17-64 2-{4-Chioro-2-fluoro-3- P 204-205
methoxyphenyl)-4.7- O'x
di(methoxycarbonyl)-5- / yy
methy(-7H-pyrrolo[2,3- i'l ^'^
djpyrimidine fr'''^^^=^r■''^N'''^^C02Me
OMe
19-63 4-Carboxy-2-(4-chloro- %J^ 8.20 {2H, d), 7.90
2-fluoro-3- f Y^\ (1H, t). 7.70 (1H, s).
methoxyphenyl)-5- ^^ I \ 7.20 (3H, m). 4.00
methyl-7-{4- fl^ll ^^^' ^^' ^'^^ ^'^^' ^^'
methylphenyi- fT^^^^^^^if^N^^^co^H 2.40 (3H, s) ppm
suiphonyl)-7H- J\ ^^j^J^ (CO2H not observed)
pyrrolo[2,3-d]pyrim(dine I ,
OMe
210

Compound Name Structure Characteristic data
Number
36-64 6-(4-Chloro-2-fluoro-3- ~9 8.93 (1H, s), 7.71
methoxyphenyl)-4- -^ (1H, t), 7.35 (1H, d),
methoxycarbonyl-3- 1 V_ 7.26 (1H. dd), 4.05
methyl-1- |l |^ ^^^' ^^' ^'^"^ ^^^' ^^'
methylcarbonyl-IH- rj^^'^^^^Ss^^^N^^^cOjMe 2.66 (3H. s), 2.37
pyrrolo[3,2-c]pyridine ,/V..o::s5^ (3H, s) ppm
CI l*^ F
OMe
37-64 1-t-Butylcarbonyl-6-(4- i P 9^00 (1H. m), 7.71
chloro-2-fluoro-3- r^ (1H, t), 7.66 (1H, s).
methoxyphenyl)-4- / \ 7.25 (1H, m), 4.05
methoxycarbonyl-3- || | (3H, s). 4.01 (3H, s).
methyl-1H-pyrrolo[3,2- |r''^^=Y^N'^^co,Me 2.38 (3H, s), 1.53
clpyridine ^X^^i^-^ (9H, s) ppm
cr Y^ F
OMe
38-64 6-(4-Chloro-2-fluoro-3- ~9 8^09 {1H, s). 7.76
methoxyphenyl)-1.4- o-A (1H, t), 7.54 (1H, s).
di(methoxycarbonyl)-3- 1 V_ 7.28 (1H, m), 4.09
methyl-1H-pyrroloI3,2- I) 1^ (3H, s), 4.06 (3H, s).
clpyridine |r''^^^>r^^N^^^C0jMe 4.01 (3H, s), 2.36
Ji^^x^k, {3H. s)ppm
CI y^ F
OMe
40-64 6-(4-Cliloro-2-fluoro-3- ^J^ 8.49 (1H, d). 7.89
methoxyphenylH- J T'^^ (2H. d), 7.74 (2H.
methoxycarbonyl-3- ^— / V_ m), 7.37 (3H, m).
methyi-1-{4- [l |^ ^'^^ ^^^' ^^' '*-°°
methylphenyl- ^r^'^^^^^f^'^tT^coj^e (3H. s). 2.37 (3H, s).
sulphonyl)-1H- ^^^^^^;^^ 2.32 (3H, s) ppm
pyrrolo[3,2-c]pyridine I (nmr run in CD3OD)
I \ I
211

EXAMPLE 26 Synthesis of 2-(4-chloro-2-fluoro-3-methoxyphenyi)-9-(2,4-
dimethoxyphenylmethyl)-6-{n-propoxycarbonyl)-8-methyl-9H-purine (Compound 131-30)
pMe
OMe I
c-A^^ AA
I cr Y^ F
OMe I
OMe
A solution of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-bis(2,4-
dimethoxyphenylmethylamino)-6-(n-propoxycarbonyl)-pyrimicline (prepared as described in example 23; 654 mg, 1.24 mmol) and trifluoroacetic acid (5 ml) in dichloromethane (10 ml) was stirred at ambient temperature for 5 hours, then evaporated under reduced pressure and the residue purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 100% gradient) as eiuent. A solution of the purified material, acetaldehyde (2 ml) and camphor sulphonic acid (35 mg, 0.15 mmol) in dioxane (3 ml) was heated at 100 "C for 30 minutes, then allowed to cool and evaporated under reduced pressure. The residue was purified using a FractionLynx hpic, to provide 2-(4-chloro-2-fluoro-3-methoxyphenyl)-9-(2,4-dimethoxyphenylmethyl)-6-(n-propoxycarbonyl)-8-methyl-9H-purine as an off-white solid (2mg, 1%).
Characterising data for the compound are as follows:
'H NMR (400 MHz. CDCI3) 5 7.90 (1H, t), 7.30 (1H, m), 7.20 (1H, d), 6.40 (2H, m). 5.40 (2H, S), 4.50 (2H, t), 4.00 (3H, s), 3.80 (3H, s), 3.70 (3H. s), 2.70 (3H. s). 1.90 (2H, m), 1.00 (3H, t) ppm.
EXAMPLE 27 Synthesis of 9-benzy|.6-carboxy-2-(4-chioro-2-fluoro-3. methoxyphenyl)-9H-purine (Compound 129-25)
27.1 Preparation of 9-benzyl-2,6-dichloro-9H-purine
212

xX —' ^ I
Potassium carbonate (2.07 g, 15 mmol) was added to a solution of 2,6-dichloro-9H-purine (945 mg, 5.0 mmol) in dimethylformamide (20 ml) and the mixture stirred at ambient temperature for 30 minutes. Benzyl bromide (1.2 ml. 10 mmol) was added and the mixture stirred overnight. Water was added and the resulting mixture extracted with ethyl acetate. The comined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane [10% to 80% gradient) as eluent, to provide Q-benzyl-2,6-dichloro-9H-purine as a white solid (876 mg, 94%). Characterising data for the compound are as follows: 'H NMR (400 MHz, CDCis) 8 8.10 (1H, s). 7.40 (5H, m), 5.40 (2H. s) ppm.
27.2 Preparation of 9-benzyi-2-chloro-6-trimethylstannyl-9H-purine
Palladium acetate (112 mg, 0.5 mmol) was added to a mixture of 9-benzyl-2,6-dichloro-9H-purine (1,4 g, 5.0 mmol), hexamethylditin (1.64 g, 5.0 mmol), 1,4-bis(diphenylphosphino)-butane (215 mg, 0.5 mmol) and dioxane (50 ml) and the resulting mixture heated at 110 °C for 4 hours. The reaction mixture was allowed to cool to ambient temperature, evaporated under reduced pressure and ethyl acetate added. The solution was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 100% gradient) to provide 9-benzyl-2-chloro-6-trimethylstannyl-9H-purine as a white solid (907 mg, 44%). Characterising data for the compound are as follows:
213

^H NMR (400 MHz, CDCI3) 5 7.90 (1H, s), 7.30 (5H, m), 5.40 (2H, s), 0.50 (9H, t) ppm. 27.3 Preparation of 9-benzyl-2-chloro-6-(2-furanyl)-9H-purine
Ph—\ N—^
Cr ^N SnMej U /?
A mixture of 9-benzyl-2-chloro-6-trimethylstannyl-9H-purine (247 mg, 0.60 mmol), 5-bromofuran (105 mg, 0.72 mmol), [1,1'-bis(cliphenylphosphino)-ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (49 mg, 0.06 mmol) and caesium fluoride (181 mg. 1.2 mmol), dimethoxyethane (3 ml) and water (3 ml) was heated in a microwave reactor at 140 °C for 20 minutes, allowed to cool to ambient temperature and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 100% gradient) to provide 9-benzyl-2-chloro-6-(2-furanyl)-9H-purine as a brown oil (79 mg, 42%). Characterising data for the compound are as follows:
'H NMR (400 MHz, CDCI3) 5 8.00 (1H, s), 7.90 (1H, d), 7.80 (1H, d), 7.40 (5H, m), 6.70 (IH.dd), 5.40 (2H,s) ppm.
27.4 Preparation of 9-benzy|-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(2-furanyl)-9H-purine
Ph-—U__j/ cr ^Y F
OMe 214

A mixture of 9-ben2yl-2-chloro-6-(2-furanyl)-9H-purine (79 mg, 0.25 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid 1,3-propanediol ester (69 mg, 0.28 mmol), [1,1'-bis(diphenylphiosphino)-ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (20 mg, 0.025 mmol), caesium fluoride (76 mg, 0.5 mmol), dimethoxyethane (1.5 ml) and water (1.5 ml) was heated in a microwave reactor at 140 °C for 20 minutes, allowed to cool to ambient temperature and extracted with dichloromethane. The organic extract was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 100% gradient) to provide 9-benzyl-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(2-furanyl)-9H-purine as a yellow solid (80 mg, 72%). Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 8 8.10 (1H, s), 7.90 (1H, m), 7,85 (1H, d), 7.80 (1H, m). 7.40 (5H. m), 7.30 (1H, dd), 6.70 (1H, m). 5.50 (2H, s), 4.10 (3H, s) ppm.
27.5 Preparation of 9-benzyl-6-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-9H-purine (Compound 129-25)
Ph—\ Ph^^
ci-''^^r'''^F ci'''''^r'''''^F
OMe OMe
Ozone was bubbled through a solution of 9-benzyl-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(2-furanyl)-9H-purine (80 mg, 0.19 mmol) in dichloromethane (40 ml) at -78 "C until a blue colour persisted in the reaction vessel. Oxygen was then bubbled through the reaction mixture until the blue colour disappeared, dimethyl sulphide (4 ml) was added and the mixture was allowed to warm to room temperature and stirred for 4 hours. The solution was evaporated under reduced pressure to provide 9-benzyl-6-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-9H-purine (78 mg, 100%). Characterising data for the compound are as follows: [M-H]" 411,413.
215

EXAMPLE 28 Synthesis of 9-benzyl-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycarbonyl-9H-purine (Compound 129-26)
Ph-—\ Ph-"^
JO" X)"
ry , XX
OMe OMe
Trimethylsilyldiazomethane (2M in hexane; 0.11 ml, 0.23 mmol) was added to a stirred solution of 9-benzyl-6-carboxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-9H-purine (prepared as described in example 27; 78 mg, 0.19 mmol) in methanol (1 ml) and dichloromethane (4 ml) and the reaction mixture stirred at ambient temperature for 30 minutes. Glacial acetic acid (0.1 ml) was added, the mxture evaporated under reduced pressure and the residue dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by automated flash chromatography (Presearch Combiflash Rf) on silica, with ethyl acetate in hexane (0% to 100% gradient) to provide 9-ben2yl-2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-methoxycart)onyl-9H-purine as a white solid (31 mg, 38%).
Characterising data for the compound are as follows:
^H NMR (400 MHz, CDCI3) 6 8.28 (1H, s), 7.91 (1H, t). 7.39 (5H, m), 7.29 (1H, d), 5.52 (2H, s), 4.14 (3H, s), 4.05 (3H, s) ppm.
EXAMPLE 29 Pre>emergence biological efficacy
Seeds of Alopecurus myosuroides (ALOMY), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Solanum nigrum (SOLNI), Amaranthus retroflexus (AMARE) and Ipomoea hederaceae (IPOHE) were sown in standard soil in pots. After cultivation for one day under controlled conditions in a glasshouse (at 24/16°C, day/night; 14 hours light; 65 % humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone / water (50:50) solution containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5) to give a final dose of 1000 g/ha of test compound.
216

The test plants were then grown under controlled conditions in the glasshouse (at 24/1 e^C, day/night; 14 hours light; 65 % humidity) and watered twice daily. After 13 days the test was evaluated (100 = total damage to plant; 0 = no damage to plant). Results are shown below in Table 38.
TABLE 38 Percentage damage caused to weed species by compounds of the invention when applied pre-emergence.
Compound Rate Species
Number (g/ha) "SOLNI I AMARE I SETFA I ALOMY 1 ECHCG | IPOHE
^2 1,000 50 30 0 0 0 20
1^3 1,000 20 50 W~ 0 0 100
174 1,000 90 90 30 10 30 60
1^6 1,000 0 ~0 0 6 0 0
1^20 1,000 0 50 0 0 O" 0
1^22 1,000 0 0 0 6 0 0
r24 1,000 0 0 0 6 0 0
1^61 1,000 ^^^ ~ 0 0 0 " 0
1^63 1,000 90 70 10 30 20 80
1^64 1,000 70 Too To 20 30 100
1^65 1.000 0 0 6 0 0 0
1^66 TjOOO Too Too 70 20 40 90
^68 1,000 0 0 0 0 0 0
^75 1,000 0 0 0 0 0 0
1^77 1,000 To 0 To 6 0 0
V78 1,000 40 50 0 0 0 20
1^79 1,000 0 0 0 0 0 0
TiO 1,000 0 0 0 0 0 0
^83 1.000 30 40 0 0 0 20
1^84 1,000 40 20 To To To 70
V85 1,000 70 Too 0 20 0 To
T^ie 1,000 To" ^^^^^ o o o o
^87 1.000 20 To 0 0 0 10
T^88 1,000 20 To 0 0 To To
vT08 1.000 0 0 0 0 0 0
217

1-116 I i^OOO I 0 I 0 I 0 \ 0 [ 0 I 0
' 1-118 1.000 70 40 20 6 T6 40
1-120 1,000 0 0 0 0 0 6
1-121 Tw 0 0 0 0 6 0
1-126 1,000 0 0 0 6 0 0
^^64 1,000 40 30 0 0 0 50
3^63 1.000 50 TOO 0 0 0 20
3^64 1.000 0 0 ' 0 0 0 0
M8 1,000 0 6 0 0 0 0
5^21 1,000 40 Too 10 10" 0 30
5^65 1,000 0 0 0 0 0 0
S^66 1,000 0 0 0 0 0 0
eTr 1,000 o o o o o o^'
6^18 T^OOO 0 0 0 0 0 0
&^21 250 0 0 6 0 0 0
6^63 1,000 0 0 0 0 0 0
6^64 rOOO 50 50 0 ~0 ~0 30
6^^65 1.000 0 0 0 0 0 0
6^ 1,000 " 20 To 0 0 0 0
^63 1,000 0 0 0 0 0 0
8^1 1,000 0 0 0 0 0 0
8^2 1,000 0 0 0 6 0 0
8^ 1,000 0 6 0 0 0 0
8^6 1.000 0 6 0 0 0 0
S^TT 1,000 0 0 0 6 0 0
8^T8 1,000 0 6 0 0 0 0
8^21 1.000 0 ^^ 20 0 0 0
V 8-63 1.000 40 To 0 0 0 30
8^65 1,000 0 6 0 0 0 0
8^^66 1,000 To To 0 0 0 0
9^63 1,000 To 20 0 0 0 0
10-63 1,000 0 6 0 0 0 0
11-18 1,000 0 0 0 6 0 0
11-21 1,000 0 0 0 6 0 0
11-66 " 1,000 6 0 0 0 0 0
11-126 1,000 0 0 0 0 0 0
218

12-63 I 1.000 I 0 I 60 I 20 1 0 I 0 I TO
12-64 1.000 0 0 0 0 0 0
14-17 1,000 0 0 0 0 0 0
16-64 1.000 0 6 0 0 0 0
17-63 1,000 90 100 20 20 20 100
17-64 1,000 0 0 0 0 0 0
18-64 1.000 0 0 0 0 0 0
19-63 1.000 6 0 0 0 0 0
21-64 1.000 6 0 0 d 0 6
22-20 1,000 60 Too 0 20 20 80
22-62 1.000 20 20 0 0 0 50
22-63 1.000 60 20 6 0 0 70
22-64 1,000 80 90 20 10 70 60
22-66 1,000 6 0 O" 0 0 0
22-75 1,000 80 70 0 10 10 90
22-71 1,000 80 20 20 10 0 90
22-78 1,000 To 20 0 0 0 0
22^79 1.000 50 10 20 To 10 30
22^80 1,000 60 40 20 20 20 50
22^^82 1,000 90 70 0 10 20 90
22^83 T^OOO 80 0 10 20 20 80
22-84 1,000 70 40 To 20 20 80
22-86 T^ooo Too Too To To To so
22-86 riooo To 6 0 0 0 6
22^87 1,000 70 20 To To To 80
22^88 1.000 Too Too ~To To 0 50
22-122 T^OOO 0 6 0 0 0 0
22^T24 1,000 Too Too 30 70 20 100
22-132 1,000 To 0 0 6 0 40
32-62 1,000 80 80 20 30 30 20
3fr^64 1,000 50 ~ 0 0 0 20
37-64 T^OOO 0 0 0 0 6 0
38-64 1.000 0 0 0 0 0 0
40-64 T7600 40 0 To 0 To 0
71-18'0 500 0 0 0 0 0 6
81-46 1,000 0 6 0 0 0 6
219

83-48 I 1,000 I 0 1 0 1 0 I 0 I 0 I 0
91-44 1,000 30 70 0 30 10 20
91-184 1,000 0 0 0 0 0 0
91-203 1,000 20 6 6 0 0 10
91-204 1,000 To 20 0 0 0 0
91-207 1,000 To 20 To 0 0 0
92-163 1,000 0 0 0 0 0 0
92-164 1,000 0 6 6 0 0 0
93-165 1,000 0 0 0 0 0 10
93-166 1.000 0 0 0 0 0 0
95-160 250 0 0 0 0 0 0
95-162 1,000 0 0 0 10 0 40
95-168 1.000 0 0 6 0 0 0
106-74 1,000 0 0 0 0 0 0
119-28 T^OOO 0 0 0 0 0 0
119-168 1,000 0 0 0 ~0 0 6
123-50 1,000 0 0 0 0 0 0
125-76 1,000 70 80 20 10 20 60
EXAMPLE 30 Post-emergence biological efficacy
Seeds of Alopecurus myosuroides (ALOMY), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Solanum nigrum (SOLNi), Amaranthus retroflexus (AMARE) and Ipomoea hederaceae (IPOHE) were sown in standard soil in pots. After cultivation for 8 days under controlled conditions in a glasshouse (at 24/16°C, day/night; 14 hours light; 65 % humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone / water (50:50) solution-containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate. CAS RN 9005-64-5) to give a final dose of 500 or 1000 g/ha of test compound.
The test plants were then grown on under controlled conditions in a glasshouse (at 24/16°C. day/night; 14 hours light; 65 % humidity) and watered twice daily. After 13 days the test was evaluated (100 = total damage to plant; 0 = no damage to plant). Results are shown below in Table 39.
220

TABLE 39 Percentage damage caused to weed species by compounds of the
invention wfien applied post-emergence
Compound Rate Species
Number (g/ha) "SOLNI I AMARE I SETFA | ALOMY I ECHCG I IPOHE
V2 1,000 90 90 90 10 70 100
V3 1,000 80 100 0 0 6 50
r4 1^000 90 Too 80 10 70 70
Te 1,000 0 0 0 0 o o
r^20 rOOO 70 70 0 0 Q~~~ 60
V^ tOOO 30 20 T0~~ To 0 40
1^24 T^ooo """so To 0 0 0 20
1^61 1,000 70 Too 40 To 2o~ 7o
1^63 1,000 Too Too 60 40 60 70
^64 TioOO ~80 Too 70 20 70 70
T^5 1,000 60 40 To 0 40 60
^66 1.000 Too Too 80 80 80 80
V68 Tlooo 30 To 0 6 To 60
TTS tOOO 70 40 0~~ 0 0 70
T^TT tOOO 70 To To 6 0 40
T78 1,000 60 0 0 0 0 70
T79 1,000 To To 0 0 6 20
1^80 T^OOO 80 60 0 0 To 40
V83 1.000 70 70 To 0 To 40
^84 T^OOO 70 60 To TO 0 40
V85 1.000 90 Too 40 To 60 40
V86 1,000 60 40 To 0 0 30
V87 1.000 90 Too To 0 6 50
V88 1.000 70 50 40 To To 50
1-108 ' 1,000 30 0 0 6 0 50
■Pne T^ooo 40 50 20 6 0 50
1-118 1,000 80 Too 70 To 50 50
r^T20 1,000 20 To o 6 6 20
1-121 1.000 To 0 0 0 0 0
1-126 1,000 0 0 0 0 0 0
— 1.^.- J ! L I I _J
221

2^64 I 1,000 I 60 I 30 ! 0 I 0 \ 0 I 40
3^^3 1,000 80 80 To 0 10 60
3^64 1.000 40 To 0 0 0 70
S^Ts 1.000 20 0 0 0 0 0
5^21 1,000 50 70 To To To 30
5^i5 1,000 20 To 20 0 0 10
5^^66 1,000 20 0 20 ~\b To 0
6^T7 1,000 40 20 6 0 0 0
6^T8 1.000 40 0 0 0 0 20
6^21 250 To 0 0 lb 0 To
6^^3 T";000 70 80 50 10 40 60
6^64 1.000 70 20 0 0 0 50
6^65 1.000 80 20 6 0 0 40
6^66 1,000 80 40 10 0 0 40
7^63 TiOOO 60 20 To 0 0 To
8^1 1,000 3iO 0 6 0 To 40
8^^2 1.000 20 0 0 6 0 20
8^^5 riooo 0 0 0 0 0 0
8^€ 1,000 20 20 0 0 0 50
8^17 TioOO 50 20 0 0 " 0 50
8^18 TiOOO 30 0 0 0 0 20
8^5T 1.000 20 0 0 To 0 To
a^63 riooo 80 TO 20 To 50 60
8^65 1,000 To 0 20 6 0 To
8^66 tOOO 30 0 0 0 0 To
9^63 T^OOO 60 20 0 0 0 40
10-63 1.000 20 To 0 6 0 20
11-18 T^OOO 50 0 0 0 0 20
11-21 T^OOO 50 0 0 6 0 20
11-66 1,000 50 20 To To 20 30
11-126 1,000 20 0 6 0 0 0 '
12-63 1,000 70 30 0 0 0 50
12-64 tOOO 30 20 30 10 To 50
14-17 1,000 40 6 6 0 0 To
16-64 T^OO 60 To 0 6 0 70
17-63 1.000 90 90 60 30 60 70
I 1 . I J . I I 1 i
222

17-64 I 1,000 I 20 I 0 I 0 I 0 | 0 I 0
iai4 1^000 40 20 30 10 10 40
19-63 1^000 70 50 0 0 0 60
21-64 1^000 70 80 0 0 10 40
22-20 ITOOO 80 100 60 50 70 70
22-62 1,000 70 80 20 0 50 60
22-63 1,000 80 70 90 40 70 70
22-64 T^OOO 90 100 70 50 80 70
22-66 TJOOO 40 20 0 6 0 40
22-75 1^000 90 80 50 10 20 60
22-77 1^000 90 70 0 10 0 30
22^78 i^^OOO 60 0 0 0 0 70
22-79 1,000 70 40 10 10 0 40
22-80 1,000 90 70 20 10 10 50
22-82 TfiOd 90 80 40 20 20 40
22-83 T^OOO 90 90 40 20 20 60
22-84 1,000 90 80 30 20 20 40
22-85 TioOO 90 90 20 30 20 40
22-86 1,000 70 40 0 10 To 40
22-87 T^OOO 90 80 40 20 10 70
22-88 ITOOO 90 80 40 3i0 20 60
22-122 TioOO 20 60 0 0 0 10
22-124 TioOO 90 80 40 30 20 80
22-132 1^000 60 50 6 0 0 50
32-62 rOOO 80 80 40 10 50 70
36-64 TJOOO 80 70 10 0 0 70
37-64 T^OOO 50 0 0 0 0 40
38-64 1^000 10 0 10 10 0 20
40-64 1.000 60 0 0 0 0 50
71-180 500 20 0 0 0 0 40
81-46 T^OOO 10 0 To 0 6 0
83-48 1,000 20 0 20 20 20 10
91-44 1,000 90 70 50 20 50 60
91-184 1,000 50 20 ~0 0 30 70
91-203 1.000 40 To To 0 0 10
91-204 1,000 80 50 6 0 0 40
I 1 I I .—I I ! I I
223

91-207 I 1,000 I 70 I 20 I 0 I 0 I 0 | 60
92-163 1,000 To 6 10 To To To
92-164 1,000 To 0 0 6 0 0
93-165 1.000 30 20 30 10 20 20
93-166 1,000 10 0 30 20 To To
95-160 250 30 20 40 10 To 20
95-162 1,000 40 70 6 10 0 30
95-168 1,000 To 0 0 0 0 To
106-74 1.000 0 0 0 6 0 0
119-28 1,000 20 20 0 6 0 To
119-168 1,000 30 10 0 6 0 40
123-50 1,000 20 0 To 0 10 10
125-76 1.000 90 100 80 10 70 80
224

CLAIMS
1. A compound having the formula (I):
AX.
(I)
or a salt or N-oxide thereof, wherein:
A is halogen, C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^ or a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^-
D is N or CR^;
X is O, S, N or NR*;
Y is CR^ CR*R^ N. NR^ O or S;
E is -(CR'R«).-; n is 1, 2 or 3;
is a bond that is optionally single or double
Z is C{0)R^ C(S)R'°. or C(=NR^^)R";
each R^ is independently halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, di (C1-C3) alkylamino, cyano, C1-C3 alkyl, C1-C3 haloalkyi, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 alkylsulphonyl, C2-C6
225

carboxyalkyi, carboxyl, C2-C6 alkoxycarbonyl, C2-C7 alkylcarbonyloxy or C6-C10 ary) optionally substituted by 1 to 3 groups R^;
each R^ is independently tiaiogen, hydroxyl, nitro, amino, cyano, C1-C3 alkyl, C1-C3 haioalkyl. C1-C3 alkoxy. C1-C3 haloalkoxy. C1-C3 aikylthio, C1-C3 haloalkylthio. C1-C3 alkylsulpnoyl. C1-C3 alkylsulphonyioxy, C2-C6 carboxyalkyi, C2-C6 alkoxycarbonyl, C2-C7 alkylcarbonyloxy, C1-C3 alkylamino, ordi(Cl-C3alkyl)amino;
R^ is hydrogen, halogen, C1-C3 alkyl , C1-C3 haioalkyl, C2-C4 alkoxyalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl or cyclopropyl optionally substituted by 1 to 3 groups R^
R" is hydrogen. C1-C6 alkyl optionally substituted by 1 to 3 groups R^^ C2-C6 alkenyl optionally substituted by 1 to 3 groups R^^, C2-C6 alkynyl optionally substituted by 1 to 3 groups R", C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R", C1-C6 acyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxycarbonyl optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^, C1-C6 alkylsulphonyl optionally substituted by 1 to 3 groups R' or C6-C10 arylsulphonyl optionally substituted by 1 to 3 groups R^;
each of R^ and R^ is independently hydrogen, halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxy, C6-C10 aryl optionally substituted by 1 to 3 groups R^, carboxyl, C1-C7 acyl, C2-C7 alkoxycarbonyl, or, taken together with the carbon atom to which they are attached, R^ and R® form a C1-C6 alkenyl group optionally substituted by 1 to 3 groups R\ a carbonyl group, or a C3-C6 cycloalkyi group optionally substituted by 1 to 3 groups R^
each of R^ and R* is independently hydrogen, halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-C6 alkoxy, C6-C10 aryl optionally substituted by 1 to 3 groups R^. carboxyl, C1-C7 acyl, C2-C7 alkoxycarbonyl, or R^ represents an additional bond between the carbon atom to which it is attached and the adjacent ring atom or, taken together with the carbon atom to which they are attached, R^ and R^ form a C1-C6 alkenyl group optionally substituted by 1 to
226

3 groups R', a carbonyl group, or a C3-C6 cycloalkyi group optionally substituted by 1 to 3 groups R' or, when n is 2 or 3, taken together with the carbon atoms to which they are attached, any two R' and R* form a 5- or 6-memberecl saturated, unsaturated or aromatic ring, the ring optionally including 1 to 3 ring atoms which are independently selected from nitrogen, oxygen or sulphur and optionally substituted by 1 to 3 groups R^;
R^ is hydrogen, hydroxyl, C1-C10 alkoxy optionally substituted by C1-C6 alkoxy, C1-C6alkoxy-C1-C6alkoxy, phenyl, C5-C10 heteroaryl or C3-C10 heterocyciyi, C2-C10 alkenyloxy, C3-C8 cycloalkoxy optionally substituted by C1-C6 alkoxy or phenyl, C1-C6 alkylthio. amino, C1-C6 alkylamino, or di(C1-C6 alkyl)amino;
R^° is C1-C10 alkoxy optionally substituted by C1-C6 alkoxy or phenyl, C2-C10 alkenyloxy, C3-C8 cycloalkoxy optionally substituted by C1-C6 alkoxy or phenyl, C1-C6 alkylthio. amino, C1-C6 alkylamino, or di{C1-C6 alkyl)amino:
R'^ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, amino, C1-C6 alkylamino, ordi(C1-C6 alkyl)amino;
R^^ is hydrogen, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 alkylthio, amino. C1-C6 alkylamino, or di(C1-C6 alkyl)amino;
each R" is independently cyano, hydroxyl, carboxyl. C3-C6 cycloalkyi, C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^, C1-C4 alkoxy; C1-C4 alkoxy(C1-C4)alkoxy; C1-C4 alkoxycarbonyl; ortri{C1-C4)alkylsiiyl
provided that
(i) when Y is NR^ X is N, Z is C(0)R^ D is N, E is -iCR'R\-, R^ is alkyl or
haloalkyi, R^ represents an additional bond to X, and R® is alkoxy, then R®
is other than H; (ii) when XEY is -N(R')C(0)NH-. Z is not C(0)NH2. C(0)NHCH3 or
C(0)N(CH3)2; (iii) the compound of formula (I) is not:
9-benzyl-9H-purine-2.6-dicarboxamide;
9-(2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide;
227

9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamicle;
9-phenyl-2-(pyridin-3-yl)-9H-purine-6-carboxamicle;
2-(3-hydroxyphenyl)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide;
2-(2-hydroxyphenyl)-9-(2-methoxyphenyl)-purine-6-carboxamide;
6-oxo-8-phenyl-2-(pyridin-3-yl)-5,6,7.8-tetrahydropteridine-4-
carboxamide;
6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-
carboxamide;
2-(3-hydroxyphenyl)-8-(2-methoxyphenyl)-6-oxo-5,6,7,8-
tetrahydropteridine-4-carboxamide;
2-chloro-9-phenyl-9H-purine-6-carboxylicacid;
2-chloro-9-methyl-9H-purine-6-carboxylicacid;
2-chloro-9-methyl-9H-purine-6-carboxylic acid ethyl ester;
2-chloro-9-ethoxycarbonylmethyl-9H-purine-6-carboxylic acid ethyl ester.
2. A compound according to claim 1, wherein A is halogen, C2-C6 alkenyl, C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^ or a mono or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulphur optionally substituted by 1 to 3 groups R^.
3. A compound according to claim 1 or claim 2 wherein A is halogen, a phenyl ring optionally substituted by 1 to 3 groups R^, or cyclopropyl optionally substituted by 1-2 groups R', and R^ and R^ are as defined in claim 1.
4. A compound according to any one of claims 1 to 3 wherein D is N, CH, CF, CCI orCMe.
5. A compound according to claim 4 wherein D is N or CH.
6. A compound according to any preceding claim, wherein X is NR'' and R" is as defined in claim 1.
7. A compound according to any preceding claim wherein Y is CR^ or CR^R® and R^ and R^ are as defined in claim 1.
228

8. A compound according to any preceding claim wherein Z is C{0)R^ and R9 is as defined in claim 1.
9. A compound according to any preceding claim, wherein n is 1, R^ represents an additional bond to Y, and R* is selected from H and C1-C6 a!lY^. aA^, oA^,
NWe? OMe OKte
> t I
a-^'Y^'^ ci'''^«==^F c.^'^Y*^''
OMe OMs OMe
« f »
x^ r,^ M
ff^y^N^CO^Me |PY'^'^^°'"* rr^V^N^^CO,Me
c) Y^ F CI y F CI y F
OMe OMe OMe
X^ ^ ^
frV^AcO^M. ipY^N^CO^Me ipY^N^CCMe
F F NMe,
rr'''^*=Y''^N^'^CO,Me fl ^f CO^Me
NMB, QP OMe
13. A herbicidal composition comprising a compound of formula I wherein A is
(i) halogen, C1-C6 alky! optionally substituted by 1 to 3 groups R\ C1-6 haloalkyi optionally substituted by 1 to 3 groups R\ C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R', C6-C10 aryl optionally substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to
230

10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur
optionally substituted by 1 to 3 groups R^, or
(il) as defined in any one of claims 1 to 12,
and D, X, E, Y and Z are as defined in any one of claims 1 to 12,
without the provisos (i). (ii) and (iii) of claim 1, together with at least one
agriculturally acceptable adjuvant or diluent.
14. A composition according to claim 13 which comprises a further herbicide in addition to the compound of formula (I).
15. A composition according to claim 13 or 14 which comprises a safener.
16. Use of a compound of formula I wherein A is
(i) halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-6 haloalkyi
optionally substituted by 1 to 3 groups R\ C2-C6 alkenyl optionally substituted
by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups RC1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally
substituted by 1 to 3 groups R^, a mono- or bicyclic heteroaryl group having 5 to
10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur
optionally substituted by 1 to 3 groups R^, or
(ii) as defined in any one of claims 1 to 12,
and D, X, E, Y and 2 are as defined in any one of claims 1 to 12,
without the provisos (i), (ii) and (iii) of claim 1,
or a composition as defined in any one of claims 13 to 15 as a herbicide.
17. A method of controlling weeds in crops of useful plants, comprising applying to
said weeds or to the locus of said weeds, or to said useful crop plants, a
compound of formula I wherein
A is
(i) halogen, C1-C6 alkyl optionally substituted by 1 to 3 groups R\ C1-6 haloalkyi optionally substituted by 1 to 3 groups R\ C2-C6 alkenyl optionally substituted by 1 to 3 groups R\ C3-C8 cycloalkyi optionally substituted by 1 to 3 groups R\ C1-C6 alkylthio optionally substituted by 1 to 3 groups R\ C6-C10 aryl optionally substituted by 1 to 3 groups R^ a mono- or bicyclic heteroaryl group having 5 to 10 ring atoms and at least one ring atom which is nitrogen, oxygen or sulfur optionally substituted by 1 to 3 groups R^ or
231

(ii) as defined in any one of claims 1 to 12,
and D, X, E, Y and Z are as defined in any one of claims 1 to 12.
without the provisos (i), (ii) and (iii) of claim 1,
or a composition as claimed in any one of claims 13 to 15.
OF ANANtTAND ANANO ADVOCATES AGENTS FOR THE APPUCANTS
232