OA19408A

OA19408A - Herbicidal compounds.

Info

Publication number: OA19408A
Application number: OA1202000075
Authority: OA
Inventors: James Nicholas Scutt; Nigel James Willetts; Ravindra SONAWANE; Mangala Phadte; Sandeep Reddy KANDUKURI; Swarnendu SASMAL; Sarah Armstrong; Andrea MCGRANAGHAN; Sean NG
Original assignee: Syngenta Participations Ag
Priority date: 2017-08-17
Filing date: 2018-08-16
Publication date: 2020-07-31

Abstract

Compounds of the formula (I) wherein the substituent « are as defined m » claim 1, useful as a pesticides, especially as herbicides.

Description

The présent invention relates to herbicidally active pyridazine denvatives, as well as to processes and intermediates used for the préparation of such dérivatives. The invention further extends to herbicidal compositions comprising such dérivatives, as well as to the use of such compounds and compositions for controlling undesirable plant growth: in particular the use for controlling weeds, in crops of useful plants.

The présent invention is based on the finding that pyridazine dérivatives of Formula (I) as defined herein, exhibit surprisingly good herbicidal activity. Thus, according to the présent invention there is provided a compound of formula (I) or an agronomically acceptable sait or zwitterionic species thereof:

wherein

R¹ is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl, 02-Cealkenyl, C2Cealkynyl, Cs-Cecycloalkyl, Ci-Cshaloalkyl, -OR⁷, -OR^15a, -N(R⁶)S(O)2R¹⁵, -N(R⁶)C(O)R¹⁵, N(R⁶)C(O)OR¹⁵, -N(R⁶)C(O)NR¹⁶R¹⁷, -N(R⁶)CHO, -N(R^7a)₂ and -S(O)rR¹⁵;

R² is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl and Ci-Cehaloalkyl;

and wherein when R¹ is selected from the group consisting of -OR⁷, -OR^15a, -N(R⁶)S(O)2R¹⁵, N(R⁶)C(O)R¹⁵, -N(R⁶)C(O)OR¹⁵, -N(R⁶)C(O)NR¹⁶R¹⁷, -N(R⁶)CHO, -N(R^7a)2 and -S(O)rR¹⁵, R² is selected from the group consisting of hydrogen and Ci-Cealkyl; or

R¹ and R² together with the carbon atom to which they are attached form a Cs-Cecycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O;

Q is (CR^1aR^2b)_m;

m is 0, 1, 2 or 3;

each R^1a and R^2b are independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl, Ci-Cehaloalkyl, -OH, -OR⁷, -OR^15a, -NH2, -NHR⁷, -NHR^15a, -N(R⁶)CHO, -NR^7bR^7cand -S(O)rR¹⁵; or each R^1a and R^2b together with the carbon atom to which they are attached form a C₃Cecycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O;

R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR¹⁵, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, Ci-Cealkoxy, C3Cecycloalkyl and -N(R⁶)2;

each R⁶ is independently selected from hydrogen and Ci-Csalkyl;

each R⁷ is independently selected from the group consisting of Ci-Cealkyl, -S(O)2R¹⁵, -C(O)R¹⁵, -C(O)OR¹⁵ and -C(O)NR¹⁶R¹⁷;

each R^7a is independently selected from the group consisting of -S(O)2R¹⁵, -C(O)R¹⁵, -C(O)OR¹⁵-C(O)NR¹⁶R¹⁷and -C(O)NR⁶R^15a;

R^7b and R^7c are independently selected from the group consisting of Ci-Cealkyl, -S(O)2R¹⁵, C(O)R¹⁵, -C(O)OR¹⁵, -C(O)NR¹⁶R¹⁷ and phenyl, and wherein said phenyl is optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different; or

R^7b and R^7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and

A is a 6-membered heteroaryl, which comprises 1, 2, 3 or 4 nitrogen atoms and wherein the heteroaryl may be optionally substituted by 1, 2, 3 or 4 R⁸ substituents, which may be the same or different, and wherein when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NRi®R¹⁷, Ci-Cealkyl, C1Cehaloalkyl, Cs-Cecycloalkyl, Cs-Cehalocycloalkyl, Cs-Cecycloalkoxy, 02-Cealkenyl, C2Cehaloalkenyl, C2-C₆alkynyl, Ci-C₃alkoxyCi-C3alkyl-, hydroxyCi-Cealkyl-, Ci-C₃alkoxyCiC₃alkoxy-, Ci-Cehaloalkoxy, Ci-C₃haloalkoxyCi-C₃alkyl-, C₃-C₆alkenyloxy, C₃-C₆alkynyloxy, NCs-Cecycloalkylamino, -C(R⁶)=NOR⁶, phenyl, a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6- membered heteroaryl, which comprises 1,2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1,2 or 3 R⁹substituents, which may be the same or different;

or when A is substituted by 3 or 4 substituents, each R⁸ is independently selected from the group consisting of halogen, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, C1Cealkyl and Ci-Cehaloalkyl; and each R⁹ is independently selected from the group consisting of halogen, cyano, -OH, -N(R⁶)2, Ci-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl and Ci-C4haloalkoxy;

X is selected from the group consisting of Ca-Cecycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1,2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R⁹, and wherein the aforementioned CR¹ R², Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties;

n is 0 or 1;

Z is selected from the group consisting of -C(O)OR¹⁰, -CH2OH, -CHO, -C(O)NHOR¹¹, C(O)NHCN, -OC(O)NHOR¹¹, -OC(O)NHCN, -NR⁰C(O)NHOR¹¹, -NR⁶C(O)NHCN, C(O)NHS(O)2R¹², -OC(O)NHS(O)2R¹², -NR⁶C(O)NHS(O)2R¹², -S(O)2OR¹°, -OS(O)2OR¹°, NR⁶S(O)2OR¹⁰, -NR⁶S(O)OR¹°, -NHS(O)2R¹⁴, -S(O)OR¹⁰, -OS(O)OR¹°, -S(O)2NHCN, S(O)₂NHC(O)R¹⁸, -S(O)2NHS(O)2R¹², -OS(O)2NHCN, -OS(O)2NHS(O)₂R¹²,

OS(O)₂NHC(O)R¹⁸, -NR^sS(O)2NHCN, -NR⁶S(O)2NHC(O)R¹⁸, -N(OH)C(O)R¹⁵, -ONHC(O)R¹⁵, -NR⁶S(O)₂NHS(O)₂R¹², -P(O)(R¹³)(OR¹⁰), -P(O)H(OR¹⁰), -OP(O)(R¹³)(OR¹⁰),

NR⁶P(O)(R¹³)(OR¹⁰) and tetrazole;

R¹⁰ is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different;

R¹¹ is selected from the group consisting of hydrogen, Ci-Cealkyl and phenyl, and wherein said phenyl is optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different;

R¹² is selected from the group consisting of Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OH, N(R⁶)2 and phenyl, and wherein said phenyl is optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different;

R¹³ is selected from the group consisting of -OH, Ci-Cealkyl, Ci-Cealkoxy and phenyl;

R¹⁴ is Ci-Cehaloalkyl;

R¹⁵ is selected from the group consisting of Ci-Cealkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹ substituants, which may be the same or different;

R^15a is phenyl, wherein said phenyl is optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different;

R¹⁶ and R¹⁷ are independently selected from the group consisting of hydrogen and Ci-Cealkyl; or

R¹⁶ and R¹⁷ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S;

R¹⁸ is selected from the group consisting of hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -N(R⁶)2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹substituents, which may be the same or different;

and r is 0, 1 or 2.

According to a second aspect of the invention, there is provided an agrochemical composition comprising a herbicidally effective amount of a compound of Formula (I) and an agrochemicallyacceptable diluent or carrier. Such an agricultural composition may further comprise at least one additional active ingrédient.

According to a third aspect of the invention, there is provided a method of controlling or preventing undesirable plant growth, wherein a herbicidally effective amount of a compound of Formula (I), or a composition comprising this compound as active ingrédient, is applied to the plants, to parts thereof or the locus thereof.

According to a fourth aspect of the invention, there is provided the use of a compound of formula (I) as a herbicide.

According to a fifth aspect of the invention, there is provided a process for the préparation of compounds of formula (I).

As used herein, the term halogen or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.

As used herein, cyano means a -CN group.

As used herein, hydroxy means an -OH group.

As used herein, nitro means an -NO2 group.

As used herein, the term Ci-Cealkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molécule by a single bond. Ci-C4alkyl and C1C2alkyl are to be construed accordingly. Examples of Ci-Cealkyl include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (f-butyl).

As used herein, the term Ci-Cealkoxy refers to a radical of the formula -OR_a where Ra is a C1Cealkyl radical as generally defined above. Ci-C4alkoxy is to be construed accordingly. Examples of C14alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and t-butoxy.

As used herein, the term Ci-Cehaloalkyl refers to a Ci-Cealkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Ci-C4haloalkyl is to be construed accordingly. Examples of Ci-Cehaloalkyl include, but are not limited to chloromethyl, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

As used herein, the term C2-C6alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (^-configuration, having from two to six carbon atoms, which is attached to the rest of the molécule by a single bond. C2-C4alkenyl is to be construed accordingly. Examples of C2-Cealkenyl include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl) and but-1-enyl.

As used herein, the term “C2-C6haloalkenyl” refers to a C2-C6alkenyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Examples of C2-C6haloalkenyl include, but are not limited to chloroethylene, fluoroethylene, 1,1-difluoroethylene, 1,1-dichloroethylene and 1,1,2-trichloroethylene.

As used herein, the term C2-C6alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molécule by a single bond. C2-C4alkynyl is to be construed accordingly. Examples of C2-Cealkynyl include, but are not limited to, prop-1-ynyl, propargyl (prop-2-ynyl) and but-1-ynyl.

As used herein, the term Ci-Cehaloalkoxy refers to a Ci-Cealkoxy group as defined above substituted by one or more of the same or different halogen atoms. Ci-C4haloalkoxy is to be construed accordingly. Examples of Ci-Cehaloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy and trifluoroethoxy.

As used herein, the term Ci-CshaloalkoxyCi-Caalkyl refers to a radical of the formula R_b-O-R_awhere Rb is a Ci-Cshaloalkyl radical as generally defined above, and R_a is a Ci-Csalkylene radical as generally defined above.

As used herein, the term Ci-CsalkoxyCi-Csalkyl refers to a radical of the formula R_b-O-R_a-where R_b is a Ci-Csalkyl radical as generally defined above, and R_a is a Ci-Csalkylene radical as generally defined above.

As used herein, the term Ci-CsalkoxyCi-Csalkoxy- refers to a radical of the formula R_b-O-R_aO- where Rb is a Ci-Csalkyl radical as generally defined above, and R_a is a Ci-Csalkylene radical as generally defined above.

As used herein, the term Cs-Cealkenyloxy refers to a radical of the formula -OR_a where Ra is a Cs-Cealkenyl radical as generally defined above.

As used herein, the term Cs-Cealkynyloxy refers to a radical of the formula -OR_a where R_a is a Cs-Cealkynyl radical as generally defined above.

As used herein, the term “hydroxyCi-Cealkyl” refers to a Ci-Csalkyl radical as generally defined above substituted by one or more hydroxy groups.

As used herein, the term Ci-Cealkylcarbonyl refers to a radical of the formula -C(O)R_a where R_a is a Ci-Cealkyl radical as generally defined above.

As used herein, the term Ci-Cealkoxycarbonyl refers to a radical of the formula -C(0)0R_a10 where R_a is a Ci-Cealkyl radical as generally defined above.

As used herein, the term “aminocarbonyl” refers to a radical of the formula -C(O)NH2.

As used herein, the term Ca-Cecycloalkyl refers to a stable, monocyclic ring radical which is saturated or partially unsaturated and contains 3 to 6 carbon atoms. C3-C4cycloalkyl is to be construed accordingly. Examples of Cs-Cecycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, 15 cyclopentyl and cyclohexyl.

As used herein, the term Cs-Cehalocycloalkyl refers to a Cs-Cecycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. C3-C4halocycloalkyl is to be construed accordingly.

As used herein, the term Cs-Cecycloalkoxy refers to a radical of the formula -OR_a where R_a is a 20 Cs-Cecycloalkyl radical as generally defined above.

As used herein, the term “N-Cs-Cecycloalkylamino” refers to a radical of the formula -NHR_awhere R_a is a Cs-Cecycloalkyl radical as generally defined above.

As used herein, except where explicitly stated otherwise, the term heteroaryl refers to a 5- or 6membered monocyclic aromatic ring which comprises 1,2, 3 or 4 heteroatoms individually selected from 25 nitrogen, oxygen and sulfur. The heteroaryl radical may be bonded to the rest of the molécule via a carbon atom or heteroatom. Examples of heteroaryl include, furyl, pyrrolyl, imidazolyl, thienyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.

As used herein, except where explicitly stated otherwise, the term heterocyclyl or heterocyclic refers to a stable 4- to 6-membered non-aromatic monocyclic ring radical which comprises 1, 2, or 3 30 heteroatoms individually selected from nitrogen, oxygen and sulfur. The heterocyclyl radical may be bonded to the rest of the molécule via a carbon atom or heteroatom. Examples of heterocyclyl include, but are not limited to, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dihydroisoxazolyl, dioxolanyl, morpholinyl or δ-lactamyl.

The presence of one or more possible asymmetric carbon atoms in a compound of formula (I) means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms. Also atropisomers may occur as a resuit of restricted rotation about a single bond. Formula (I) is intended to include ail those possible isomeric forms and mixtures thereof. The présent invention includes ail those possible isomeric forms and mixtures thereof for a compound of formula (I). Likewise, 40 formula (I) is intended to include ail possible tautomers (including lactam-lactim tautomerism and ketoenol tautomerism) where présent. The présent invention includes ail possible tautomeric forms for a compound of formula (I). Similarly, where there are di-substituted alkenes, these may be présent in E or Z form or as mixtures of both in any proportion. The présent invention includes ail these possible isomeric forms and mixtures thereof for a compound of formula (I).

The compounds of formula (I) will typically be provided in theform of an agronomically acceptable sait, a zwitterion or an agronomically acceptable sait of a zwitterion. This invention covers ail such agronomically acceptable salts, zwitterions and mixtures thereof in ail proportions.

For example a compound of formula (I) wherein Z comprises an acidic proton, may exist as a zwitterion, a compound of formula (l-l), or as an agronomically acceptable sait, a compound of formula (l-ll) as shown below:

wherein, Y represents an agronomically acceptable anion and j and k represent integers that may be selected from 1,2 or 3, dépendent upon the charge of the respective anion Y.

A compound of formula (I) may also exist as an agronomically acceptable sait of a zwitterion, a compound of formula (l-lll) as shown below:

wherein, Y represents an agronomically acceptable anion, M represents an agronomically acceptable cation (in addition to the pyridazinium cation) and the integers j, k and q may be selected from 1, 2 or 3, dépendent upon the charge of the respective anion Y and respective cation M.

Thus where a compound of formula (I) is drawn in protonated form herein, the skilled person would appreciate that it could equally be represented in unprotonated or sait form with one or more relevant counter ions.

In one embodiment of the invention there is provided a compound of formula (l-ll) wherein k is 2, j is 1 and Y is selected from the group consisting of halogen, trifluoroacetate and pentafluoropropionate. In this embodiment a nitrogen atom in ring A may be protonated or a nitrogen atom comprised in R¹, R², Q or X may be protonated (for example see compound A234 or A235 in table A). Preferably, in a compound of formula (l-ll), k is 2, j is 1 and Y is chloride, wherein a nitrogen atom in ring A is protonated.

Suitable agronomically acceptable salts of the présent invention, represented by an anion Y, include but are not limited chloride, bromide, iodide, fluoride, 2-naphthalenesulfonate, acetate, adipate, methoxide, ethoxide, propoxide, butoxide, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butylsulfate, butylsulfonate, butyrate, camphorate, camsylate, caprate, caproate, caprylate, carbonate, citrate, diphosphate, edetate, edisylate, enanthate, ethanedisulfonate, ethanesulfonate, ethylsulfate, formate, fumarate, gluceptate, gluconate, glucoronate, glutamate, glycérophosphate, heptadecanoate, hexadecanoate, hydrogen sulfate, hydroxide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methanedisulfonate, methylsulfate, mucate, myristate, napsylate, nitrate, nonadecanoate, octadecanoate, oxalate, pelargonate, pentadecanoate, pentafluoropropionate, perchlorate, phosphate, propionate, propylsulfate, propylsulfonate, succinate, sulfate, tartrate, tosylate, tridecylate, triflate, trifluoroacetate, undecylinate and valerate.

Suitable cations represented by M include, but are not limited to, metals, conjugate acids of amines and organic cations. Examples of suitable metals include aluminium, calcium, césium, copper, lithium, magnésium, manganèse, potassium, sodium, iron and zinc. Examples of suitable amines include allylamine, ammonia, amylamine, arginine, benethamine, benzathine, butenyl-2-amine, butylamine, butylethanolamine, cyclohexylamine, decylamine, diamylamine, dibutylamine, diethanolamine, diethylamine, diethylenetriamine, diheptylamine, dihexylamine, diisoamylamine, diisopropylamine, dimethylamine, dioctylamine, dipropanolamine, dipropargylamine, dipropylamine, dodecylamine, ethanolamine, ethylamine, ethylbutylamine, ethylenediamine, ethylheptylamine, ethyloctylamine, ethylpropanolamine, heptadecylamine, heptylamine, hexadecylamine, hexenyl-2amine, hexylamine, hexylheptylamine, hexyloctylamine, histidine, indoline, isoamylamine, isobutanolamine, isobutylamine, isopropanolamine, isopropylamine, lysine, meglumine, methoxyethylamine, methylamine, methylbutylamine, methylethylamine, methylhexylamine, methylisopropylamine, methylnonylamine, methyloctadecylamine, methylpentadecylamine, morpholine, Ν,Ν-diethylethanolamine, N-methylpiperazine, nonylamine, octadecylamine, octylamine, oleylamine, pentadecylamine, pentenyl-2-amine, phenoxyethylamine, picoline, piperazine, piperidine, propanolamine, propylamine, propylenediamine, pyridine, pyrrolidine, sec-butylamine, stearylamine, tallowamine, tetradecylamine, tributylamine, tridecylamine, trimethylamine, triheptylamine, trihexylamine, triisobutylamine, triisodecylamine, triisopropylamine, trimethylamine, tripentylamine, tripropylamine, tris(hydroxymethyl)aminomethane, and undecylamine. Examples of suitable organic cations include benzyltributylammonium, benzyltrimethylammonium, benzyltriphenylphosphonium, choline, tetrabutylammonium, tetrabutylphosphonium, tetraethylammonium, tetraethylphosphonium, tétraméthylammonium, tetramethylphosphonium, tetrapropylammonium, tetrapropylphosphonium, tributylsulfonium, tributylsulfoxonium, triethylsulfonium, triethylsulfoxonium, trimethylsulfonium, trimethylsulfoxonium, tripropylsulfonium and tripropylsulfoxonium.

Preferred compounds of formula (I), wherein Z comprises an acidic proton, can be represented as either (l-l) or (l-ll). For compounds of formula (l-ll) emphasis is given to salts when Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, pentafluoropropionate, triflate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1. Preferably, Y is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate and nitrate, wherein j and k are 1. For compounds of formula (l-ll) emphasis is also given to salts when Y is carbonate and sulfate, wherein j is 2 and k is 1, and when Y is phosphate, wherein j is 3 and k is 1.

Where appropriate compounds of formula (I) may also be in the form of (and/or be used as) an N-oxide.

Compounds of formula (I) wherein m is 0 and n is 0 may be represented by a compound of formula (l-la) as shown below:

(l-la) wherein R¹, R², R³, R⁴, R⁵, A and Z are as defined for compounds of formula (I).

Compounds of formula (I) wherein m is 1 and n is 0 may be represented by a compound of formula (l-lb) as shown below:

(l-lb) wherein R¹, R², R^1a, R^2b, R³, R⁴, R⁵, A and Z are as defined for compounds of formula (I).

Compounds of formula (I) wherein m is 2 and n is 0 may be represented by a compound of formula (l-lc) as shown below:

wherein R¹, R², R^1a, R^2b, R³, R⁴, R⁵, A and Z are as defined forcompounds of formula (I).

Compounds of formula (I) wherein m is 3 and n is 0 may be represented by a compound of formula 5 (l-ld) as shown below:

wherein R¹, R², R^1a, R^2b, R³, R⁴, R⁵, A and Z are as defined for compounds of formula (I).

The following list provides définitions, including preferred définitions, for substituents n, m, r, A, Q, X, Z, R¹, R², R^1a, R^2b, R², R³, R⁴, R⁵, R⁶, R⁷, R^7a, R^7b, R^7c, R⁸, R⁹, R¹⁰, R¹¹, R¹². R¹³. R¹⁴. R¹⁵. ^R15a. R¹⁶, R¹⁷ and R¹⁸ with reference to the compounds of Formula (I) according to the invention. For any one of these substituents, any of the définitions given below may be combined with any définition of any other substituent given below or elsewhere in this document.

R¹ is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl, C2-Csalkenyl, C2-Cealkynyl, Cs-Cscycloalkyl, Ci-Cehaloalkyl, -OR⁷, -OR^15a, -N(R⁶)S(O)2R¹⁵, -N(R⁶)C(O)R¹⁵, -N(R⁸)C(O)OR¹⁵, N(R^S)C(O)NR¹⁶R¹⁷, -N(R⁶)CHO, -N(R^7a)2 and -S(O)rR¹⁵. Preferably, R¹ is selected from the group consisting of hydrogen, halogen, Ci-Csalkyl, Ci-Cefluoroalkyl, -OR⁷, -NHS(O)2R¹⁵, -NHC(O)R¹⁵, 20 NHC(O)OR¹⁵, -NHC(O)NR¹⁶R¹⁷, -N(R^7a)2 and -S(O)rR¹⁵. More preferably, R¹ is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl, Ci-Cefluoroalkyl, -OR⁷ and -N(R^7a)2. Even more preferably, R¹ is selected from the group consisting of hydrogen, Ci-Cealkyl, -OR⁷ and -N(R^7a)2. Even more preferably still, R¹ is hydrogen or Ci-C6alkyl. Yet even more preferably still, R¹ is hydrogen or methyl. Most preferably R¹ is hydrogen.

R² is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl and Ci-Cehaloalkyl. Preferably, R² is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl and CiCefluoroalkyl. More preferably, R² is hydrogen or Ci-Cealkyl. Even more preferably, R² is hydrogen or methyl. Most preferably R² is hydrogen.

Wherein when R¹ is selected from the group consisting of-OR⁷, -OR^15a, -N(R⁶)S(O)2R¹⁵, -N(R⁶)C(O)R¹⁵,

-N(R⁶)C(O)OR¹⁵, -N(R⁶)C(O)NR¹⁶R¹⁷, -N(R⁶)CHO, -N(R^7a)2 and -S(O)rR¹⁵, R² is selected from the group consisting of hydrogen and Ci-Cealkyl. Preferably, when R¹ is selected from the group consisting of -OR⁷, -NHS(O)2R¹⁵, -NHC(O)R¹⁵, -NHC(O)OR¹⁵, -NHC(O)NR¹⁶R¹⁷, -N(R^7a)₂ and -S(O)_rR¹⁵, R² is selected from the group consisting of hydrogen and methyl.

Alternatively, R¹ and R² together with the carbon atom to which they are attached form a Cs-Cecycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O. Preferably, R¹ and R² together with the carbon atom to which they are attached form a C3Cecycloalkyl ring. More preferably, R¹ and R² together with the carbon atom to which they are attached form a cyclopropyl ring.

In one embodiment R¹ and R² are hydrogen.

In another embodiment R¹ is methyl and R² is hydrogen.

In another embodiment R¹ is methyl and R² is methyl.

Q is (CR^1aR^2b)m.

m is 0, 1, 2 or 3. Preferably, m is 0,1 or 2. More preferably, m is 1 or 2. Most preferably, m is 1.

Each R^1a and R^2b are independently selected from the group consisting of hydrogen, halogen, C1Cealkyl, Ci-Cehaloalkyl, -OH, -OR⁷, -OR^15a, -NH2, -NHR⁷, -NHR^15a, -N(R⁶)CHO, -NR^7bR^7cand -S(O)rR¹⁵. Preferably, each R^1a and R^2b are independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl, Ci-Cefluoroalkyl, -OH, -NH₂ and -NHR⁷. More preferably, each R^1a and R^2b are independently selected from the group consisting of hydrogen, Ci-Cealkyl, -OH and -NH2. Even more preferably, each R^1a and R^2b are independently selected from the group consisting of hydrogen, methyl, -OH and -NH2. Even more preferably still, each R^1a and R^2b are independently selected from the group consisting of hydrogen and methyl. Most preferably R^1a and R^2b are hydrogen.

In another embodiment each R^1a and R^2b are independently selected from the group consisting of hydrogen and Ci-Cealkyl.

Alternatively, each R^1a and R^2b together with the carbon atom to which they are attached form a C3Cscycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O. Preferably, each R^1a and R^2b together with the carbon atom to which they are attached form a Cs-Cecycloalkyl ring. More preferably, each R^1a and R^2b together with the carbon atom to which they are attached form a cyclopropyl ring.

R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)rR¹⁵, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, Ci-Cealkoxy, Ca-Cecycloalkyl and -N(R⁶)2. Preferably, R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, Ci-Cealkoxy, Cs-Cecycloalkyl and -N(R⁶)2. More preferably, R³, R⁴5 and R⁵ are independently selected from the group consisting of hydrogen, Ci-Cealkyl and Ci-Cealkoxy.

Even more preferably, R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen and Ci-Cealkyl. Even more preferably still, R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen and methyl. Most preferably, R³, R⁴ and R⁵ are hydrogen.

Each R⁶ is independently selected from hydrogen and Ci-Cealkyl. Preferably, each R⁶ is independently selected from hydrogen and methyl.

Each R⁷ is independently selected from the group consisting of Ci-Cealkyl, -S(O)2R¹⁵, -C(O)R¹⁵, C(O)OR¹⁵ and -C(O)NR¹⁶R¹⁷. Preferably, each R⁷ is independently selected from the group consisting 15 of Ci-Cealkyl, -C(O)R¹⁵ and -C(O)NR¹⁶R¹⁷. More preferably, each R⁷ is Ci-Cealkyl. Most preferably, each R⁷ is methyl.

Each R^7a is independently selected from the group consisting of -S(O)2R¹⁵, -C(O)R¹⁵, -C(O)OR¹⁵ C(O)NR¹⁶R¹⁷and -C(O)NR⁶R^15a. Preferably, each R^7a is independently -C(0)R¹⁵ or-C(O)NR¹⁶R¹⁷.

R^7b and R^7care independently selected from the group consisting of Ci-Cealkyl, -S(O)2R¹⁵, -C(O)R¹⁵, C(O)OR¹⁵, —C(O)NR¹⁶R¹⁷ and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹substituents, which may be the same or different. Preferably, R^7b and R^7c are independently selected from the group consisting of Ci-Cealkyl, -C(O)R¹⁵ and -C(O)NR¹⁶R¹⁷. More preferably, R^7b and R^7care 25 Ci-Cealkyl. Most preferably, R^7band R^7care methyl.

Alternatively, R^7b and R^7c together with the nitrogen atom to which they are attached form a 4- to 6membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S. Preferably, R^7b and R^7c together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom 30 individually selected from N and O. More preferably, R^7b and R^7c together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.

A is a 6-membered heteroaryl, which comprises 1, 2, 3 or 4 nitrogen atoms and wherein the heteroaryl 35 may, where feasible, be optionally substituted by 1, 2, 3 or 4 R⁸ substituents, which may be the same or different.

Preferably, A is a 6-membered heteroaryl, which comprises 1, 2, 3 or 4 nitrogen atoms and wherein the heteroaryl may, where feasible, be optionally substituted by 1 or 2 R⁸ substituents, which may be 40 the same or different.

More preferably, A is a 6-membered heteroaryl, which comprises 1 or 2 nitrogen atoms and wherein the heteroaryl may be optionally substituted by 1 or 2 R⁸ substituents, which may be the same or different.

Further more preferably, A is selected from the group consisting of formula A-l to A-VI11 below

wherein the jagged line defines the point of attachment to the remaining part of a compound of Formula (I) and p is 0, 1 or 2.

Even more preferably, A is selected from the group consisting of formula A-l to A-VII below

Even more preferably still, A is selected from the group consisting of formula A-l to A-V below

A-V wherein the jagged line defines the point of attachment to the remaining part of a compound of Formula (I) and p is 0, 1, or 2.

Yet, even more preferably still, A is selected from the group consisting of formula A-l to A-V and p is 0 or 1.

Most preferably, A is selected from the group consisting of formula A-l to A-V and p is 0.

When A is substituted by 1 or 2 substituents each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, C3Cehalocycloalkyl, Cs-Cecycloalkoxy, C2-Cealkenyl, C2-Cehaloalkenyl, C2-Cealkynyl, Ci-C₃alkoxyCi15 C₃alkyl-, hydroxyCi-Cealkyl-, Ci-C₃alkoxyCi-C₃alkoxy-, Ci-Cehaloalkoxy, Ci-C₃haloalkoxyCi-C₃alkyl-, C₃-Cealkenyloxy, C₃-C₆alkynyloxy, N-Cs-Cecycloalkylamino, -C(R⁶)=NOR⁶, phenyl, a 3-to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R⁹20 substituents, which may be the same or different.

Preferably, when A is substituted by 1 or 2 substituents each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, -NR^SS(O)2R¹⁵, C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, C₃25 Cehalocycloalkyl, C₃-C₆cycloalkoxy, 02-Cealkenyl, C2-C₆haloalkenyl, C2-C₆alkynyl, Ci-C₃alkoxyCiC₃alkyl-, hydroxyCi-Cealkyl-, Ci-C₃alkoxyCi-C₃alkoxy-, Ci-Cehaloalkoxy, Ci-C₃haloalkoxyCi-C₃alkyl-, C₃-C₆alkenyloxy, C₃-C₆alkynyloxy, -C(R⁶)=NOR⁶, phenyl and a 5- or 6- membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl or heteroaryl are optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or different.

More preferably, when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁸R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-C₆alkyl, Ci-Cehaloalkyl, C₃-Cecycloalkyl, C15 C₃alkoxyCi-C₃alkyl-, hydroxyCi-Cealkyl-, Ci-C₃alkoxyCi-C₃alkoxy-, Ci-Cehaloalkoxy, phenyl and a 6membered heteroaryl, which comprises 1 or 2 nitrogen atoms, and wherein said phenyl or heteroaryl are optionally substituted by 1 or 2 R⁹ substituents, which may be the same or different.

Even more preferably, when A is substituted by 1 or 2 substituents, each R⁸ is independently selected 10 from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-Cealkyl, Ci-Cehaloalkyl, C3Cecycloalkyl, hydroxyCi-Cealkyl-, Ci-Cehaloalkoxy and a 6- membered heteroaryl, which comprises 1 or 2 nitrogen atoms, and wherein said heteroaryl is optionally substituted by 1 R⁹ substituent.

Even more preferably still, when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-Cealkyl and Ci-Cehaloalkyl.

Further more preferably still, when A is substituted by 1 or 2 substituents, each R⁸ is independently 20 selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, -OH, -OMe, -S(O)2Me, C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH₂, -C(O)NHMe, -C(O)N(Me)₂, methyl and trifluoromethyl.

Most preferably, when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, -OMe, -S(O)2Me, -C(O)NHMe, 25 C(O)N(Me)2, methyl and trifluoromethyl.

In one embodiment, when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of halogen, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-C6alkyl, Ci-C6haloalkyl, Cs-Cecycloalkyl, 30 hydroxyCi-Cealkyl-, and a 6- membered heteroaryl, which comprises 2 nitrogen atoms, and wherein said heteroaryl is optionally substituted by 1 R⁹ substituent. Preferably, when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, -OH, -OMe, -S(O)₂Me, -C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH₂, -C(O)NHMe, -C(O)N(Me)₂, -S(O)₂NHMe, methyl, trifluoromethyl, cyclopropyl, hydroxymethyl- and 6-chloropyridazin-3-yl.

Alternatively when A is substituted by 3 or 4 substituents, each R⁸ is independently selected from the group consisting of halogen, —NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, C1Cealkyl and Ci-Cehaloalkyl. Preferably, each R⁸ is independently selected from the group consisting of -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, Ci-C6alkyl and Ci-C₆haloalkyl. More preferably, each R⁸ is 40 independently selected from the group consisting of -NH2, -NHR⁷, -OR⁷, Ci-Cealkyl and Ci-CehaloalkyL

Even more preferably still, each R⁸ is independently selected from the group consisting of Ci-Cealkyl and Ci-Cehaloalkyl.

Each R⁹ is independently selected from the group consisting of halogen, cyano, -OH, -N(R⁶)2, Ci-C4alkyl, 5 Ci-C4alkoxy, Ci-C4haloalkyl and Ci-C4haloalkoxy. Preferably, each R⁹ is independently selected from the group consisting of halogen, cyano, -N(R⁶)2, Ci-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl and CiC4haloalkoxy. More preferably, each R⁹ is independently selected from the group consisting of halogen, Ci-C4alkyl, Ci-C4alkoxy and Ci-C4haloalkyl. Even more preferably, each R⁹ is independently selected from the group consisting of halogen and Ci-C4alkyl.

X is selected from the group consisting of Cs-Cecycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1,2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1,2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 15 substituents, which may be the same or different, selected from R⁹, and wherein the aforementioned

CR¹R², Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties.

Preferably, X is selected from the group consisting of phenyl and a 4- to 6- membered heterocyclyl, 20 which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said phenyl or heterocyclyl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R⁹, and wherein the aforementioned CR¹R², Q and Z moieties may be attached at any position of said phenyl or heterocyclyl moieties.

More preferably, X is a 4- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and wherein said heterocyclyl moieties is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R⁹, and wherein the aforementioned CR¹ R², Q and Z moieties may be attached at any position of said heterocyclyl moiety.

In one embodiment, X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR¹ R², Q and Z moieties may be attached at any position of said heterocyclyl moiety. Preferably, X is a 5-membered heterocyclyl, which comprises 1 heteroatom, wherein said heteroatom is N, and wherein the aforementioned CR¹ R² and Q moieties are attached adjacent to the N atom and the Z moiety is attached to the N atom.

In another embodiment, X is phenyl optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R⁹, and wherein the aforementioned CR¹ R², Q and Z moieties may be attached at any position of said phenyl moiety. Preferably, X is phenyl and the aforementioned CR¹ R²and Q moieties are attached in a postion para to the Z moiety.

n is 0 or 1. Preferably, n is 0.

Z is selected from the group consisting of -C(0)0R¹°, -CH2OH, -CH0, -C(O)NHOR¹¹, -C(O)NHCN, OC(O)NHOR¹¹, -OC(O)NHCN, -NR⁶C(0)NH0R¹¹, -NR⁶C(0)NHCN, -C(O)NHS(O)2R¹², OC(O)NHS(O)2R¹², -NR⁶C(O)NHS(O)2R¹², -S(O)2OR¹⁰, -OS(O)2OR¹⁰, -NR⁶S(O)2OR¹⁰, -NR⁶S(O)OR¹⁰, 5 -NHS(O)2R¹⁴, -S(O)OR¹⁰, -OS(O)OR¹°, -S(O)2NHCN, -S(O)₂NHC(O)R¹⁸, -S(O)2NHS(O)2R¹², OS(O)2NHCN, -OS(O)₂NHS(O)₂R¹², -OS(O)2NHC(O)R¹⁸, -NR⁶S(O)2NHCN, -NR⁶S(O)2NHC(O)R¹⁸, N(0H)C(0)R¹⁵, -0NHC(0)R¹⁵, -NR⁶S(O)2NHS(O)₂R¹², -P(O)(R¹³)(OR¹°), -P(O)H(OR¹°), OP(O)(R¹³)(OR¹⁰), -NR⁶P(O)(R¹³)(OR¹⁰) and tetrazole.

Preferably, Z is selected from the group consisting of -C(O)OR¹⁰, -C(O)NHOR¹¹, -OC(O)NHOR¹¹, NR⁶C(O)NHOR¹¹, -C(O)NHS(O)2R¹², -OC(O)NHS(O)2R¹², -NR^sC(O)NHS(O)2R¹², -S(O)2OR¹⁰, OS(O)2OR¹⁰, -NR⁶S(O)2OR¹°, -NR⁶S(O)OR¹⁰, -NHS(O)2R¹⁴, -S(O)OR¹⁰, -OS(O)OR¹⁰, S(O)2NHC(O)R¹⁸, -S(O)2NHS(O)2R¹², -OS(O)2NHS(O)₂R¹², -OS(O)2NHC(O)R¹⁸, -NR⁶S(O)2NHC(O)R¹⁸, -N(OH)C(O)R¹⁵, -ONHC(O)R¹⁵, -NR⁶S(O)₂NHS(O)₂R¹², -P(O)(R¹³)(OR¹⁰), -P(O)H(OR¹⁰), 15 OP(O)(R¹³)(OR¹⁰) and -NR⁶P(O)(R¹³)(OR¹°).

More preferably, Z is selected from the group consisting of -C(O)OR¹⁰, -C(O)NHOR¹¹, C(O)NHS(O)2R¹², -S(O)2OR¹°, -OS(O)2OR¹⁰, -NR⁶S(O)2OR¹⁰, -NHS(O)₂R¹⁴, -S(O)OR¹⁰ and P(O)(R¹³)(OR¹⁰).

Even more preferably Z is selected from the group consisting of -C(O)OR¹⁰, -C(O)NHS(O)2R¹², S(O)2OR¹⁰, and -P(O)(R¹³)(OR¹°).

Even more preferably still Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, 25 C(O)OCH₂CH₃, -C(O)OCH(CH₃)₂, -C(O)OC(CH₃)₃, -C(O)OCH₂C₆H₅, -C(O)OCeH₅, -C(O)NHS(O)₂CH₃, S(O)₂OH, -P(O)(OH)( OCH₂CH₃) and -P(O)(OCH₂CH₃)(OCH₂CH₃).

Most preferably Z is -C(O)OH or -S(O)₂OH.

In one embodiment Z is selected from the group consisting of -C(O)OR¹⁰, -CH2OH, -C(O)NHOR¹¹, C(O)NHCN, -C(O)NHS(O)2R¹², -S(O)2OR¹°, -OS(O)2OR¹⁰, -NR^sS(O)2OR¹°, -NHS(O)2R¹⁴, P(O)(R¹³)(OR¹⁰) and tetrazole. Preferably, Z is selected from the group consisting of -C(O)OH, C(O)OCH₃, -C(O)OCH₂CH₃, -C(O)OCH(CH₃)₂, -C(O)OC(CH₃)₃, -C(O)OCH₂C₆H₅, -C(O)OC_sH₅, CH₂OH, -C(O)NHOMe, -C(O)NHCN, -C(O)NHS(O)₂N(Me)₂, -C(O)NHS(O)₂Me, -C(O)NHS(O)₂CH₃, 35 S(O)₂OH, -OS(O)₂OH, -NHS(O)₂OH, -NHS(O)₂CF₃, -P(O)(OH)(OH), -P(O)(OCH₃)(OCH₃), P(O)(OH)(OCH₃), -P(O)(OH)(OCH₂CH₃), -P(O)(OCH₂CH₃)(OCH₂CH₃) and tetrazole.

R¹⁰ is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or 40 different. Preferably, R¹⁰ is selected from the group consisting of hydrogen, O-Cealkyl, phenyl and benzyl. More preferably, R¹⁰ is selected from the group consisting of hydrogen and Ci-CealkyL Most preferably, R¹⁰ is hydrogen.

R¹¹ is selected from the group consisting of hydrogen, Ci-Cealkyl and phenyl, and wherein said phenyl 5 is optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or different. Preferably,

R¹¹ is selected from the group consisting of hydrogen, Ci-Cealkyl and phenyl. More preferably, R¹¹ is selected from the group consisting of hydrogen and Ci-CealkyL Even more preferably, R¹¹ is Ci-Cealkyl. Most preferably, R¹¹ is methyl.

R¹² is selected from the group consisting of Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OH, -N(R⁶)2 and phenyl, and wherein said phenyl is optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different. Preferably, R¹² is selected from the group consisting of Ci-Cealkyl, Ci-Cshaloalkyl, CiCealkoxy, -OH, -N(R⁶)z and phenyl. More preferably, R¹² is selected from the group consisting of CiCealkyl, Ci-Cehaloalkyl and -N(R⁶)2. Even more preferably, R¹² is selected from the group consisting of methyl, -N(Me)2 and trifluoromethyl. Most preferably, R¹² is methyl.

R¹³ is selected from the group consisting of -OH, Ci-Cealkyl, Ci-Cealkoxy and phenyl. Preferably R¹³ is selected from the group consisting of -OH, Ci-Cealkyl and C-i-Cealkoxy. More preferably, R¹³ is selected from the group consisting of —OH and Ci-Cealkoxy. Even more preferably, R¹³ is selected from the group consisting of-OH, methoxy and ethoxy. Most preferably, R¹³ is -OH.

R¹⁴ is Ci-Cehaloalkyl. Preferably, R¹⁴ is trifluoromethyl.

R¹⁵ is selected from the group consisting of Ci-Cealkyl and phenyl, and wherein said phenyl is optionally 25 substituted by 1,2 or 3 R⁹ substituents, which may be the same or different. Preferably, R¹⁵ is selected from the group consisting of Ci-Cealkyl and phenyl. More preferably, R¹⁵ is Ci-OealkyL Most preferably R¹⁵ is methyl.

R^15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹ substituents, which may be 30 the same or different. Preferably, R^15a is phenyl optionally substituted by 1 R⁹ substituent. More preferably, R^15a is phenyl.

R¹⁶ and R¹⁷ are independently selected from the group consisting of hydrogen and Ci-Cealkyl. Preferably, R¹⁶ and R¹⁷ are independently selected from the group consisting of hydrogen and methyl. 35

Alternatively, R¹⁶ and R¹⁷ together with the nitrogen atom to which they are attached form a 4- to 6membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S. Preferably, R^1S and R¹⁷ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N and O. More preferably, R¹⁶ and R¹⁷ together with the nitrogen atom to which they are attached form an pyrrolidyl, oxazolidinyl, imidazolidinyl, piperidyl, piperazinyl or morpholinyl group.

R¹⁸ is selected from the group consisting of hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -N(R⁶)2 5 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or different. Preferably, R¹⁸ is selected from the group consisting of hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -N(R⁶)₂ and phenyl. More preferably, R¹⁸ is selected from the group consisting of hydrogen, Ci-Cealkyl and Ci-Cehaloalkyl. Further more preferably, R¹⁸ is selected from the group consisting of Ci-Cealkyl and Ci-CehaloalkyL Most preferably, R¹⁸ is methyl or trifluoromethyl.

r is 0, 1 or 2. Preferably, r is 0 or 2.

In a set of preferred embodiments, in a compound according to Formula (I) of the invention,

R¹ is hydrogen or Ci-Cealkyl;

R² is hydrogen or methyl;

Q is (CR^1aR^2b)_m;

m is 0,1 or 2;

R^1a and R^2b are independently selected from the group consisting of hydrogen, Ci-Cealkyl, -OH and NH₂;

R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen and Ci-Cealkyl;

each R⁶ is independently selected from hydrogen and methyl;

each R⁷ is Ci-Cealkyl;

A is a 6-membered heteroaryl, which comprises 1 or 2 nitrogen atoms and wherein the heteroaryl may be optionally substituted by 1 or 2 R⁸ substituents, which may be the same or different;

each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, N(R⁷)2, -OH, -OR⁷, -S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)₂NR¹⁶R¹⁷, CiCealkyl and Ci-Cehaloalkyl;

n is 0;

Z is selected from the group consisting of -C(O)OR¹⁰, -C(O)NHS(O)2R¹², -S(O)2OR¹⁰, and 30 P(O)(R¹³)(OR¹⁰);

R¹⁰ is selected from the group consisting of hydrogen, Ci-Cealkyl, phenyl and benzyl;

R¹² is selected from the group consisting of Ci-Cealkyl, Ci-Cehaloalkyl and -N(R⁶)₂;

R¹³ is selected from the group consisting of-OH and Ci-Cealkoxy;

R¹⁵ is Ci-Cealkyl;

R¹⁶ and R¹⁷ are independently selected from the group consisting of hydrogen and methyl; and r is 0 or 2.

More preferably,

R¹ is hydrogen or methyl;

R² is hydrogen or methyl;

Q is (CR^1aR^2b)_m;

m is 1 or 2;

R^1a and R^2b are independently selected from the group consisting of hydrogen and methyl;

R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen and methyl;

A is selected from the group consisting of formula A-l to A-V and p is 0, 1, or 2;

each R⁸ is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, OH, -OMe, -S(O)₂Me, -C(O)OMe, -C(O)OH, -C(0)Me, -C(O)NH₂, -C(O)NHMe, -C(O)N(Me)₂, methyl and trifluoromethyl;

n is 0; and

Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, 10 C(O)OC(CH₃)₃, -C(O)OCH2CeH5, -Ο(Ο)ΟΟ₆Η5, -C(O)NHS(O)₂CH₃, -S(O)₂OH, -P(O)(OH)( OCH2CH3) and -P(O)(OCH2CH₃)(OGH2CH3).

In a further set of preferred embodiments, the compound according to Formula (I) is selected from a compound of Formula (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g), (l-h), (l-j) or (l-k),

wherein in a compound of Formula (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g), (l-h), (l-j) or (l-k), p is 0, 1 or 2;

each R⁸ is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, OH, -OMe, -S(O)₂Me, -C(O)OMe, -C(O)OH, -C(0)Me, -C(O)NH₂, -C(O)NHMe, -C(O)N(Me)₂, methyl and trifluoromethyl; and

Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, C(O)OC(CH₃)3, -C(O)OCH₂C6H₅, -C(O)OC₆H₅, -C(O)NHS(O)₂CH₃, -S(O)₂OH, -P(O)(OH)( OCH2CH3) and-P(O)(OCH₂CH3)( OCH2CH3).

In a further more preferred set of embodiments, the compound according to Formula (I) is selected from a compound of Formula (l-m), (l-n), (l-p), (l-q), (l-r), (l-s), (l-t), (l-u), (l-v) or (l-w),

wherein in a compound of Formula (l-m), (l-n), (l-p), (l-q), (l-r), (l-s), (l-t), (l-u), (l-v) or (l-w), Zis -C(O)OH or -S(O)₂OH.

In another preferred set of embodiments, the compound according to Formula (I) is selected from a 10 compound of Formula (l-aa), (l-bb), (l-cc), (l-dd) or (l-ee),

(l-ee) wherein in a compound of Formula (l-aa), (l-bb), (l-cc), (l-dd), or (l-ee), p is 0, 1 or 2;

each R⁸ is independently selected from the group consisting of chloro, fluoro, cyano, -NH2, -N(Me)2, OH, -OMe, -S(O)₂Me, -C(O)OMe, -C(O)OH, -C(O)Me, -C(O)NH₂, -C(O)NHMe, -C(O)N(Me)₂, methyl and trifluoromethyl; and

Z is selected from the group consisting of -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, C(O)OC(CH₃)₃, -C(O)OCH₂C6H5, -C(O)OCeH5, -C(O)NHS(O)₂CH3, -S(O)₂OH, -P(O)(OH)( OCH2CH3) and -Ρ(Ο)(ΟΟΗ₂ΟΗ₃)( OCH₂CH₃).

In one set of embodiments, the compound according to Formula (I) is selected from a compound A1 to A251 listed in Table A.

In another more preferred set of embodiments, the compound according to Formula (I) is selected from a compound of Formula (l-ff), (l-gg), (l-hh), (l-jj) or (l-kk),

wherein in a compound of Formula (l-ff), (l-gg), (l-hh), (l-jj) or (l-kk), Z is -C(O)OH or -S(O)2OH.

There is also provided a process for the préparation of compounds of formula (I):

Wherein Q, Z, X, n, R¹, R², R³, R⁴, R⁵ and A are as defined herein;

comprising (i) either (a) reacting a compound of formula (H)

A—Hal formula (H) wherein

A is as defined herein and Hal is a halogen or pseudo halogen, with a compound of formula (J)

formula (J) wherein

R³, R⁴ and R⁵ are as defined herein and M’ is an organostannane or an organoborane (e.g organoboronic acid, organoboronic ester or organotrifluoroborate), in the presence of a palladium catalyst, to give a compound of formula (X)

formula (X) or (b) reacting a compound of formula (K)

1Q formula (K) wherein R³, R⁴ and R⁵ are as defined herein and Hal is a halogen or pseudo halogen, with a compound of formula (L)

A—M' formula (L) wherein

A is as defined herein and M’ is an organostannane or an organoborane (e.g organoboronic acid, organoboronic ester or organotrifluoroborate), in the presence of a palladium catalyst, to give a compound of formula (X);

(ii) reacting a compound of formula (X) with an alkylating agent of formula (W)

formula (W) wherein R¹, R², Q, X, Z and n are as defined herein, and LG is a suitable leaving group, in an inert solvent or mixture of inert solvents, at a température of from -78 °C to 150 °C, to give a compound of formula (I);

(iii) optionally, partially orfully hydrolysing a compound of formula (I) in the presence of a suitable acid.

According to the invention there is also provided the use of a compound of formula (J) as defined herein, 10 in a process for the manufacture of a compound of formula (I) as defined herein. Preferably, in a compound of formula (J) M’ is an organostannane, organoboronic acid, organoboronic ester or organotrifluoroborate. More preferably, in a compound of formula (J) M’ is an organostannane. Most preferably, in a compound of formula (J) M’is tributylstannane.

In another embodiment of the invention there is also provided the use of a compound of formula (X) as defined herein, in a process for the manufacture of a compound of formula (I) as defined herein. Preferably, the compound of formula (X) is selected from the group consisting of 2-pyridazin-4ylpyrimidine, 4-pyridazin-4-ylpyrimidine, 3-pyridazin-4-ylpyridazine, 2-pyridazin-4-ylpyrazine and 4pyridazin-4-ylpyridazine.

According to the invention there is also provided novel intermediates of formula (X), wherein a compound of formula (X) selected from the group consisting of 2-pyridazin-4-ylpyrimidine, 4-pyridazin4-ylpyrimidine, 3-pyridazin-4-ylpyridazine and 2-pyridazin-4-ylpyrazine.

It should be understood that compounds of Formula (I) may exist/be manufactured in ‘procidal form’, wherein they comprise a group ‘G’. Such compounds are referred to herein as compounds of Formula (l-IV).

G is a group which may be removed in a plant by any appropriate mechanism including, but not 30 limited to, metabolism and Chemical dégradation to give a compound of Formula (l-l), (l-ll) or (l-lll) wherein Z contains an acidic proton, for example see the scheme below:

Whilst such G groups may be considered as ‘procidal’, and thus yield active herbicidal compounds once removed, compounds comprising such groups may also exhibit herbicidal activity in their own right.

In such cases in a compound of Formula (l-IV), Z-G may include but is not limited to, any one of (G1) to (G7) below and E indicates the point of attachment to the remaining part of a compound of Formula (I):

O O w // \ G (G2)

(G5)

O O w //

S G

O “t «33)

% (G6) .G eX|^o

G (G7)

In embodiments where Z-G is (G1) to (G7), G, R¹⁹, R²⁰, R²¹, R²² and R²³ are defined as follows:

G is Ci-Csalkyl, C2-C6alkenyl, C2-C6alkynyl, -C(R²¹R²²)OC(O)R¹⁹, phenyl or phenyl-Ci-C4alkyl-, wherein said phenyl moiety is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, Ci-Cealkyl, Ci-Cehaloalkyl or Ci-Cealkoxy.

R¹⁹ is Ci-Cealkyl or phenyl,

R²⁰ is hydroxy, Ci-Cealkyl, Ci-Cealkoxy or phenyl,

R²¹ is hydrogen or methyl,

R²² is hydrogen or methyl, R²³ is hydrogen or Ci-Cealkyl.

The compounds in Tables 1 to 27 below illustrate the compounds of the invention. The skilled person would understand that the compounds of formula (I) may exist as an agronomically acceptable sait, a zwitterion or an agronomically acceptable sait of a zwitterion as described hereinbefore.

Table 1:

This table discloses 53 spécifie compounds of the formula (T-1):

Wherein m, Q, R³, R⁴, R⁵ and Z are as defined in Table 1, R¹ and R² are hydrogen and n is 0.

Compound number	R³	R⁴	R⁵	Z	m	Q
1.001	H	H	H	-C(O)OH	0	-
1.002	H	H	H	-C(O)OMe	0	-
1.003	H	H	H	-C(O)NHOMe	0	-
1.004	H	H	H	-OC(O)NHOMe	0	-
1.005	H	H	H	-NHC(O)NHOMe	0	-
1.006	H	H	H	-NMeC(O)NHOMe	0	-
1.007	H	H	H	-C(O)NHS(O)₂Me	0	-
1.008	H	H	H	-OC(O)NHS(O)₂Me	0	-
1.009	H	H	H	-NHC(O)NHS(O)₂Me	0	-
1.010	H	H	H	-NMeC(O)NHS(O)₂Me	0	-
1.011	H	H	H	-S(O)₂OH	0	-
1.012	H	H	H	-OS(O)₂OH	0	-
1.013	H	H	H	-NHS(O)₂OH	0	-
1.014	H	H	H	-NMeS(O)₂OH	0	-
1.015	H	H	H	-S(O)OH	0	-
1.016	H	H	H	-OS(O)OH	0	-
1.017	H	H	H	-NHS(O)OH	0	-
1.018	H	H	H	-NMeS(O)OH	0

Compound number	R³	R⁴	R⁵	Z	m	Q
1.019	H	H	H	-NHS(O)₂CF₃	0	-
1.020	H	H	H	-S(O)₂NHC(O)Me	0	-
1.021	H	H	H	-OS(O)₂NHC(O)Me	0	-
1.022	H	H	H	-NHS(O)₂NHC(O)Me	0	-
1.023	H	H	H	-NMeS(O)₂NHC(O)Me	0	-
1.024	H	H	H	-P(O)(OH)(OMe)	0	-
1.025	H	H	H	-P(O)(OH)(OH)	0	-
1.026	H	H	H	-OP(O)(OH)(OMe)	0	-
1.027	H	H	H	-OP(O)(OH)(OH)	0	-
1.028	H	H	H	-NHP(O)(OH)(OMe)	0	-
1.029	H	H	H	-NHP(O)(OH)(OH)	0	-
1.030	H	H	H	-NMeP(O)(OH)(OMe)	0	-
1.031	H	H	H	-NMeP(O)(OH)(OH)	0	-
1.032	H	H	H	-tetrazole	0	-
1.033	H	H	H	-S(O)₂OH	1	CH(NH₂)
1.033	H	H	H	-C(O)OH	1	CH(NH₂)
1.035	H	H	H	-S(O)₂OH	2	CH(OH)CH₂
1.036	H	H	H	-C(O)OH	2	CH(OH)CH₂
1.037	H	H	H	-S(O)₂OH	1	CH(OH)
1.038	H	H	H	-C(O)OH	1	CH(OH)
1.039	H	H	H	-C(O)NHCN	0	-
1.040	H	H	H	-OC(O)NHCN	0	-
1.041	H	H	H	-NHC(O)NHCN	0	-
1.042	H	H	H	-NMeC(O)NHCN	0	-
1.043	H	H	H	-S(O)₂NHCN	0	-
1.044	H	H	H	-OS(O)₂NHCN	0	-
1.045	H	H	H	-NHS(O)₂NHCN	0	-
1.046	H	H	H	-NMeS(O)₂NHCN	0	-
1.047	H	H	H	-S(O)₂NHS(O)₂Me	0	-
1.048	H	H	H	-OS(O)₂NHS(O)₂Me	0	-
1.049	H	H	H	-NHS(O)₂NHS(O)₂Me	0	-
1.050	H	H	H	-NMeS(O)₂NHS(O)₂Me	0	-
1.051	H	H	H	-P(O)H(OH)	0	-
1.052	H	H	H	-N(OH)C(O)Me	0	-
1.053	H	H	H	-ONHC(O)Me	0	-

Table 2:

This table discloses 49 spécifie compounds of the formula (T-2):

Wherein m, Q, R³, R⁴, R⁵ and Z are as defined in Table 2, R¹ and R² are hydrogen and n is 0.

Compound number	R³	R⁴	R⁵	Z	m	Q
2.001	H	H	H	-C(O)OH	1	ch₂
2.002	H	H	H	-C(O)OMe	1	ch₂
2.003	H	H	H	-C(O)NHOMe	1	ch₂
2.004	H	H	H	-OC(O)NHOMe	1	ch₂
2.005	H	H	H	-NHC(O)NHOMe	1	ch₂
2.006	H	H	H	-NMeC(O)NHOMe	1	ch₂
2.007	H	H	H	-C(O)NHS(O)₂Me	1	ch₂
2.008	H	H	H	-OC(O)NHS(O)₂Me	1	ch₂
2.009	H	H	H	-NHC(O)NHS(O)₂Me	1	ch₂
2.010	H	H	H	-NMeC(O)NHS(O)₂Me	1	ch₂
2.011	H	H	H	-S(O)₂OH	1	ch₂
2.012	H	H	H	-OS(O)₂OH	1	ch₂
2.013	H	H	H	-NHS(O)₂OH	1	ch₂
2.014	H	H	H	-NMeS(O)₂OH	1	ch₂
2.015	H	H	H	-S(O)OH	1	ch₂
2.016	H	H	H	-OS(O)OH	1	ch₂
2.017	H	H	H	-NHS(O)OH	1	ch₂
2.018	H	H	H	-NMeS(O)OH	1	ch₂
2.019	H	H	H	-NHS(O)₂CF₃	1	ch₂
2.020	H	H	H	-S(O)₂NHC(O)Me	1	ch₂
2.021	H	H	H	-OS(O)₂NHC(O)Me	1	ch₂
2.022	H	H	H	-NHS(O)₂NHC(O)Me	1	ch₂
2.023	H	H	H	-NMeS(O)₂NHC(O)Me	1	ch₂
2.024	H	H	H	-P(O)(OH)(OMe)	1	ch₂
2.025	H	H	H	-P(O)(OH)(OH)	1	ch₂
2.026	H	H	H	-OP(O)(OH)(OMe)	1	ch₂

Compound number	R³	R⁴	R⁵	Z	m	Q
2.027	H	H	H	-OP(O)(OH)(OH)	1	ch₂
2.028	H	H	H	-NHP(O)(OH)(OMe)	1	ch₂
2.029	H	H	H	-NHP(O)(OH)(OH)	1	ch₂
2.030	H	H	H	-NMeP(O)(OH)(OMe)	1	ch₂
2.031	H	H	H	-NMeP(O)(OH)(OH)	1	ch₂
2.032	H	H	H	-tetrazole	1	ch₂
2.033	H	H	H	-S(O)₂OH	2	CH₂CH(NH₂)
2.034	H	H	H	-C(O)OH	2	CH₂CH(NH₂)
2.035	H	H	H	-C(O)NHCN	1	ch₂
2.036	H	H	H	-OC(O)NHCN	1	ch₂
2.037	H	H	H	-NHC(O)NHCN	1	ch₂
2.038	H	H	H	-NMeC(O)NHCN	1	ch₂
2.039	H	H	H	-S(O)₂NHCN	1	ch₂
2.040	H	H	H	-OS(O)₂NHCN	1	ch₂
2.041	H	H	H	-NHS(O)₂NHCN	1	ch₂
2.042	H	H	H	-NMeS(O)₂NHCN	1	ch₂
2.043	H	H	H	-S(O)₂NHS(O)₂Me	1	ch₂
2.044	H	H	H	-OS(O)₂NHS(O)₂Me	1	ch₂
2.045	H	H	H	-NHS(O)₂NHS(O)₂Me	1	ch₂
2.046	H	H	H	-NMeS(O)₂NHS(O)₂Me	1	ch₂
2.047	H	H	H	-P(O)H(OH)	1	ch₂
2.048	H	H	H	-N(OH)C(O)Me	1	ch₂
2.049	H	H	H	-ONHC(O)Me	1	ch₂

Table 3:

This table discloses 49 spécifie compounds of the formula (T-3):

(T-3) wherein m, Q, R³, R⁴, R⁵ and Z are as defined in Table 3, R¹ and R² are hydrogen and n is 0.

Compound number	R³	R⁴	R⁵	Z	m	Q
3.001	H	H	H	-C(O)OH	2	CH₂CH₂
3.002	H	H	H	-C(O)OMe	2	ch₂ch₂
3.003	H	H	H	-C(O)NHOMe	2	ch₂ch₂
3.004	H	H	H	-OC(O)NHOMe	2	ch₂ch₂
3.005	H	H	H	-NHC(O)NHOMe	2	ch₂ch₂
3.006	H	H	H	-NMeC(O)NHOMe	2	ch₂ch₂
3.007	H	H	H	-C(O)NHS(O)₂Me	2	ch₂ch₂
3.008	H	H	H	-OC(O)NHS(O)₂Me	2	ch₂ch₂
3.009	H	H	H	-NHC(O)NHS(O)₂Me	2	ch₂ch₂
3.010	H	H	H	-NMeC(O)NHS(O)₂Me	2	ch₂ch₂
3.011	H	H	H	-S(O)₂OH	2	ch₂ch₂
3.012	H	H	H	-OS(O)₂OH	2	ch₂ch₂
3.013	H	H	H	-NHS(O)₂OH	2	ch₂ch₂
3.014	H	H	H	-NMeS(O)₂OH	2	ch₂ch₂
3.015	H	H	H	-S(O)OH	2	ch₂ch₂
3.016	H	H	H	-OS(O)OH	2	ch₂ch₂
3.017	H	H	H	-NHS(O)OH	2	ch₂ch₂
3.018	H	H	H	-NMeS(O)OH	2	ch₂ch₂
3.019	H	H	H	-NHS(O)₂CF₃	2	ch₂ch₂
3.020	H	H	H	-S(O)₂NHC(O)Me	2	ch₂ch₂
3.021	H	H	H	-OS(O)₂NHC(O)Me	2	ch₂ch₂
3.022	H	H	H	-NHS(O)₂NHC(O)Me	2	ch₂ch₂
3.023	H	H	H	-NMeS(O)₂NHC(O)Me	2	ch₂ch₂
3.024	H	H	H	-P(O)(OH)(OMe)	2	ch₂ch₂
3.025	H	H	H	-P(O)(OH)(OH)	2	ch₂ch₂
3.026	H	H	H	-OP(O)(OH)(OMe)	2	ch₂ch₂
3.027	H	H	H	-OP(O)(OH)(OH)	2	ch₂ch₂
3.028	H	H	H	-NHP(O)(OH)(OMe)	2	ch₂ch₂
3.029	H	H	H	-NHP(O)(OH)(OH)	2	ch₂ch₂
3.030	H	H	H	-NMeP(O)(OH)(OMe)	2	ch₂ch₂
3.031	H	H	H	-NMeP(O)(OH)(OH)	2	ch₂ch₂
3.032	H	H	H	-tetrazole	2	ch₂ch₂
3.033	H	H	H	-S(O)₂OH	3	CH₂CH₂CH(NH₂)
3.034	H	H	H	-C(O)OH	3	CH₂CH₂CH(NH₂)
3.035	H	H	H	-C(O)NHCN	2	ch₂ch₂
3.036	H	H	H	-OC(O)NHCN	2	ch₂ch₂
3.037	H	H	H	-NHC(O)NHCN	2	ch₂ch₂
3.038	H	H	H	-NMeC(O)NHCN	2	ch₂ch₂

Compound number	R³	R⁴	R⁵	Z	m	Q
3.039	H	H	H	-S(O)₂NHCN	2	CH₂CH₂
3.040	H	H	H	-OS(O)₂NHCN	2	ch₂ch₂
3.041	H	H	H	-NHS(O)₂NHCN	2	ch₂ch₂
3.042	H	H	H	-NMeS(O)₂NHCN	2	ch₂ch₂
3.043	H	H	H	-S(O)₂NHS(O)₂Me	2	ch₂ch₂
3.044	H	H	H	-OS(O)₂NHS(O)₂Me	2	ch₂ch₂
3.045	H	H	H	-NHS(O)₂NHS(O)₂Me	2	ch₂ch₂
3.046	H	H	H	-NMeS(O)₂NHS(O)₂Me	2	ch₂ch₂
3.047	H	H	H	-P(O)H(OH)	2	ch₂ch₂
3.048	H	H	H	-N(OH)C(O)Me	2	ch₂ch₂
3.049	H	H	H	-ONHC(O)Me	2	ch₂ch₂

Table 4:

This table discloses 53 spécifie compounds of the formula (T-4):

wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 1, R¹ and R² are hydrogen and n is 0.

Table 5:

This table discloses 49 spécifie compounds of the formula (T-5):

(T-5) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 6:

This table discloses 49 spécifie compounds of the formula (T-6):

(T-6) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and n is 0.

Table 7:

This table discloses 53 spécifie compounds of the formula (T-7):

Table 8:

This table discloses 49 spécifie compounds of the formula (T-8):

wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 9:

This table discloses 49 spécifie compounds of the formula (T-9):

wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and n is 0.

Table 10:

This table discloses 53 spécifie compounds of the formula (T-10):

(T-10) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 1, R¹ and R² are hydrogen and n is 0.

Table 11:

This table discloses 49 spécifie compounds of the formula (T-11):

(T-11) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 12:

This table discloses 49 spécifie compounds of the formula (T-12):

(T-12) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and n is 0.

Table 13:

This table discloses 53 spécifie compounds of the formula (T-13):

Table 14:

This table discloses 49 spécifie compounds of the formula (T-14):

Table 15:

This table discloses 49 spécifie compounds of the formula (T-15):

Table 16:

This table discloses 53 spécifie compounds of the formula (T-16):

(T-16) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 1, R¹ and R² are hydrogen and n is 0.

Table 17:

This table discloses 49 spécifie compounds of the formula (T-17):

(T-17) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 18:

This table discloses 49 spécifie compounds of the formula (T-18):

(T-18) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and n is 0.

Table 19:

This table discloses 53 spécifie compounds of the formula (T-19):

(T-19) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 1, R¹ and R² are hydrogen and n is 0.

Table 20:

This table discloses 49 spécifie compounds of the formula (T-20):

(T-20) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 21:

This table discloses 49 spécifie compounds of the formula (T-21):

(T-21) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and is 0.

Table 22:

This table discloses 53 spécifie compounds of the formula (T-22):

(T-22) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 1, R¹ and R² are hydrogen and 15 is 0.

Table 23:

This table discloses 49 spécifie compounds of the formula (T-23):

(T-23) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 24:

This table discloses 49 spécifie compounds of the formula (T-24):

(T-24) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and n is 0.

Table 25:

This table discloses 53 spécifie compounds of the formula (T-25):

(T-25) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 1, R¹ and R² are hydrogen and n is 0.

Table 26:

This table discloses 49 spécifie compounds of the formula (T-26):

(T-26) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 2, R¹ and R² are hydrogen and n is 0.

Table 27:

This table discloses 49 spécifie compounds of the formula (T-27):

(T-27) wherein m, Q, R³, R⁴, R⁵ and Z are as defined above in Table 3, R¹ and R² are hydrogen and n is 0.

The compounds of the présent invention may be prepared according to the following schemes in which the substituents n, m, r, A, Q, X, Z, R¹, R², R^1a, R^2b, R², R³, R⁴, R⁵, R⁶, R⁷, R^7a, R^7b R^7c, R⁸. R⁹. rw, ru R12 ris R14 ris Risa, pie ri? _anc] Ris _{are as} defined hereinbefore unless explicitly stated otherwise. The compounds of the preceeding Tables 1 to 27 may thus be obtained in an analogous manner.

The compounds of formula (I) may be prepared by the alkylation of compounds of formula (X), wherein R³, R⁴, R⁵ and A are as defined for compounds of formula (I), with a suitable alkylating agent of formula (W), wherein R¹, R², Q, X, n and Z are as defined for compounds of formula (I) and LG is a suitable leaving group, for example, halide or pseudohalide such as triflate, mesylate or tosylate, in a suitable solvent at a suitable température, as described in reaction scheme 1. Example conditions include stirring a compound of formula (X) with an alkylating agent of formula (W) in a solvent, or mixture of solvents, such as acetone, dichloromethane, dichloroethane, /V,A/-dimethylformamide, acetonitrile, 1,4-dioxane, water, acetic acid or trifluroacetic acid at a température between -78°C and 150°C. An alkylating agent of formula (W) may include, but is not limited to, bromoacetic acid, methyl bromoacetate, 3bromopropionoic acid, methyl 3-bromopropionate, 2-bromo-N-methoxyacetamide, sodium 2bromoethanesulphonate, 2,2-dimethylpropyl 2-(trifluoromethylsulfonyloxy)ethanesulfonate, 2-bromo-Nmethanesulfonylacetamide, 3-bromo-N-methanesulfonylpropanamide, dimethoxyphosphorylmethyl trifluoromethanesulfonate, dimethyl 3-bromopropylphosphonate, 3-chloro-2,2-dimethyl-propanoic acid and diethyl 2-bromoethylphosphonate. Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods. Compounds of formula (I) which may be described as esters of N-alkyl acids, which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent, for example, aqueous hydrochloric acid or trimethylsilyl bromide, in a suitable solvent at a suitable température between 0°C and 100°C.

Reaction scheme 1

Additonally, compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein 5 R3 R4 R5 _anc| a _{are as} defined for compounds of formula (I), with a suitably activated electrophilic alkene of formula (B), wherein Z is -S(O)2OR¹⁰, -P(O)(R¹³)(OR¹⁰) or-C(O)OR¹⁰ and R¹, R², R^1a, R¹⁰ and R¹³ are as defined for compounds of formula (I), in a suitable solvent at a suitable température. Compounds of formula (B) are known in the literature, or may be prepared by known methods. Example reagents include, but are not limited to, acrylic acid, methacrylic acid, crotonic acid, 3,3-dimethylacrylic 10 acid, methyl acrylate, ethene sulfonic acid, isopropyl ethylenesulfonate, 2,2-dimethylpropyl ethenesulfonate and dimethyl vinylphosphonate. The direct products of these reactions, which may be described as esters of N-alkyl acids, which include, but are not limited to, esters of carboxylic acids, phosphonic acids, phosphinic acids, sulfonic acids and sulfinic acids, may be subsequently partially or fully hydrolysed by treament with a suitable reagent in a suitable solvent at a suitable température, as 15 described in reaction scheme 2.

Reaction scheme 2

formula (X) formula (I), wherein m=1, n=0 and

Z=S(O)₂OR¹°, P(O)(R¹³)(OR¹⁰),

C(O)OR¹⁰ formula (I), wherein m=1, n=0 and

Z=SO₃H, P(O)(R¹³)(OH)_;

C(O)OH

In a related reaction compounds of formula (I), wherein Q is C(R^1aR^2b), m is 1, 2 or 3, n=0 and Z is 20 S(O)2OH, -OS(O)2OH or -NR⁶S(O)2OH, may be prepared by the reaction of compounds of formula (X), wherein R³, R⁴, R⁵ and A are as defined for compounds of formula (I), with a cyclic alkylating agent of formula (E), (F) or (AF), wherein Y^a is C(R^1aR^2b), O or NR⁶and R¹, R², R^1a and R^2b are as defined for compounds of formula (I), in a suitable solvent at a suitable température, as described in reaction scheme 3. Suitable solvents and suitable températures are as previously described. An alkylating agent of formula (E) or (F) may include, but is not limited to, 1,3-propanesultone, 1,4-butanesultone, ethylenesulfate, 1,3-propylene sulfate and 1,2,3-oxathiazolidine2,2-dioxide. Such alkylating agents and related compounds are either known in the literature or may be prepared by known literature methods.

Reaction scheme 3

formula (I), wherein m is 1, 2 or 3, n=0 and Z= SO₃H, OSO₃Hor

NR⁶SO₃H formula (F), Where m=2 and n=0 or O

O—s=o

R^2b

R

formula (AF) Where m=1 and n=0

A compound of formula (I), wherein m is 0, n is 0 and Z is -S(O)2OH, may be prepared from a compound of formula (I), wherein m is 0, n is 0 and Z is C(O)OR¹⁰, by treatment with trimethylsilylchlorosulfonate 10 in a suitable solvent at a suitable température, as described in reaction scheme 4. Preferred conditions include heating the carboxylate precursor in neat trimethylsilylchlorosulfonate at a température between 25°C and 150°C.

Reaction scheme 4

formula (I), wherein m=0, n=0 and Z=C(O)OR¹⁰ formula (I), wherein m=0, n=0 and Z=SOsH

Furthermore, compounds of formula (I) may be prepared by reacting compounds of formula (X), wherein 5 R³, R⁴, R⁵ and A are as defined for compounds of formula (I), with a suitable alcohol of formula (WW), wherein R¹, R², Q, X, n and Z are as defined for compounds of formula (I), under Mitsunobu-type conditions such as those reported by Petit et al, Tet. Lett. 2008, 49 (22), 3663. Suitable phosphines include triphenylphosphine, suitable azodicarboxylates include diisopropylazodicarboxylate and suitable acids include fluoroboric acid, triflic acid and bis(trifluoromethylsulfonyl)amine, as described in reaction 10 scheme 5. Such alcohols are either known in the literature or may be prepared by known literature methods.

Reaction scheme 5

Acid, PhsP

Compounds of formula (I) may also be prepared by reacting compounds of formula (C), wherein Q, Z, X, n, R¹, R², R³, R⁴, R⁵ and A are as defined for compounds of formula (I), with a hydrazine of formula (D) in a suitable solvent or mixture of solvents, in the presence of a suitable acid at a suitable température, between -78°C and 150°C, as described in reaction scheme 6. Suitable solvents, or 20 mixtures thereof, include, but are not limited to, alcohols, such as methanol, éthanol and isopropanol, water, aqueous hydrochloric acid, aqueous sulfuric acid, acetic acid and trifluoroacetic acid. Hydrazine compounds of formula (D), for example 2,2-dimethylpropyl 2-hydrazinoethanesulfonate, are either known in the literature or may be prepared by known literature procedures.

Reaction scheme 6

R' = H, Ci-C4alkyl, Ci-C4alkylcarbonyl

Compounds of formula (C) may be prepared by reacting compounds of formula (G), wherein R³, R⁴, R⁵5 and A are as defined for compounds of formula (I), with an oxidising agent in a suitable solvent at a suitable température, between -78°C and 150°C, optionally in the presence of a suitable base, as described in reaction scheme 7. Suitable oxidising agents include, but are not limited to, bromine and suitable solvents include, but are not limited to alcohols such as methanol, éthanol and isopropanol. Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium 10 bicarbonate, potassium carbonate and potassium acetate. Similar reactions are known in the literature (for example Hufford, D. L; Tarbell, D. S.; Koszalka, T. R. J. Amer. Chem. Soc., 1952, 3014). Furans of formula (G) are known in the literature or may be prepared using literature methods. Example methods include, but are not limited to, transition métal cross-couplings such as Stille (for example Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions, Vol. 50. 1997, and Gazzard, L. et al. J. Med. Chem., 15 2015, 5053), Suzuki-Miyaura (for example Ando, S.; Matsunaga, H.; Ishizuka, T. J. Org. Chem. 2017, 1266-1272, and Ernst, J. B.; Rakers, L.; Glorius, F. Synthesis, 2017, 260), Negishi (for example Yang, Y.; Oldenhius, N. J.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 615, and Braendvang, M.; Gundersen, L. Bioorg. Med. Chem. 2005, 6360), and Kumada (for example Heravi, Μ. M.; Hajiabbasi, P. Monatsh. Chem., 2012, 1575). The coupling partners may be selected with reference to the spécifie 20 cross-coupling reaction and target product. Transition métal catalysts, ligands, bases, solvents and températures may be selected with reference to the desired cross-coupling and are known in the literature. Cross-coupling reactions using pseudo halogens, including but not limited to, triflates, mesylates, tosylates and anisoles, may also be achieved under related conditions.

Reaction scheme 7

Oxidising agent Base

R'OH

A R⁴

formula (C)

R' = H, Ci-C₄alkyl, Ci-C4alkyl carbonyl

In another approach a compound of formula (I), wherein Q, Z, X, n, R¹, R², R³, R⁴, R⁵ and A are as defined for compounds of formula (I), may be prepared from a compound of formula (R) and an oxidant, in a suitable solvent at a suitable température, as outlined in reaction scheme 8. Example oxidants include, but are not limited to, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachloro-p-benzoquinone, 5 potassium permanganate, manganèse dioxide, 2,2,6,6-tetramethyl-1-piperidinyloxy and bromine.

Related reactions are known in the literature.

Reaction scheme 8

formula (R) formula (I)

A compound of formula (R), wherein Q, Z, X, n, R¹, R², R³, R⁴, R⁵ and A are as defined for compounds of formula (I), may be prepared from a compound of formula (S), wherein Q, Z, X, n, R¹, R², R³, R⁴ and R⁵ are as defined for compounds of formula (I), wherein and an organometallic of formula (T), wherein M” includes, but is not limited to, organomagnesium, organolithium, organocopper and organozinc 15 reagents, in a suitable solvent at a suitable température, optionally in the presence of an additonal transition métal additive, as outlined in reaction scheme 9. Example conditions include treating a compound of formula (S) with a Grignard of formula (T), in the presence of 0.05-100 mol% copper iodide, in a solvent such as tetrahydrofuran at a température between -78°C and 100°C. Organometallics of formula (T) are known in the literature, or may be prepared by known literature methods. Compounds 20 of formula (S) may be prepared by analogous reactions to those for the préparation of compounds of formula (I) from a compound of formula (XX).

Reaction scheme 9

formula (S)

Biaryl pyridazines of formula (X) are known in the literature or may be prepared using literature methods. Example methods include, but are not limited to, the transition métal cross-coupling of compounds of formula (H) and formula (J), or alternatively compounds of formula (K) and formula (L), in which compounds of formula (J) and formula (L), wherein M’is eitheran organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, as outlined in reaction scheme 10. Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate. Such cross-couplings include Stille (for example Sauer, J.; Heldmann, D. K. Tetrahedron, 1998, 4297), Suzuki-Miyaura (for example Luebbers, T.; Flohr, A.; Jolidon, S.; David-Pierson, P.; Jacobsen, H.;

Ozmen, L.; Baumann, K. Bioorg. Med. Chem. Lett., 2011, 6554), Negishi (for example Imahori, T.; Suzawa, K.; Kondo, Y. Heterocycles, 2008, 1057), and Kumada (for example Heravi, Μ. M.; Hajiabbasi, P. Monatsh. Chem., 2012, 1575). The coupling partners may be selected with reference to the spécifie cross-coupling reaction and target product. Transition métal catalysts, ligands, bases, solvents and températures may be selected with reference to the desired cross-coupling and are known in the literature. Compounds of formula (H), formula (K) and formula (L) are known in the literature, or may be prepared by known literature methods.

Reaction scheme 10 formula (H)

A—Hal +

formula (J)

formula (X)

formula (L) formula (K) formula (X)

An compound of formula (J), wherein M’ is either an organostannane, organoboronic acid or ester, organotrifluoroborate, organomagnesium, organocopper or organozinc, may be prepared from a compound of formula (XX), wherein R³, R⁴ and R⁵ are as defined for compounds of formula (I), by metallation, as outlined in reaction scheme 11. Similar reactions are known in the literature (for example 20 Ramphal et al, WO2015/153683, Unsinn étal., Organic Letters, 15(5), 1128-1131; 2013, Sadler et al.,

Organic & Biomolecular Chemistry, 12(37), 7318-7327; 2014. Alternatively, an organometallic of formula (J) may be prepared from compounds of formula (K), wherein R³, R⁴, R⁵ are as defined for compounds of formula (I), and Hal is defined as a halogen or pseudo halogen, for example triflate, mesylate and tosylate, as described in scheme 11. Example conditions to préparé an compound of formula (J) wherein 25 M' is an organostannane, include treatment of a compound of formula (K) with lithium tributyl tin in an appropriate solvent at an appropriate température (for example see WO 2010/038465). Example conditions to prépare compound of formula (J) wherein M’ is an organoboronic acid or ester, include treatment of a compound of formula (K) with bis(pinacolato)diboron, in the presence of an appropriate transition métal catalyst, appropriate ligand, appropriate base, in an appropriate solvent at an appropriate température (for example KR 2015135626). Compounds of formula (K) and formula (XX) are either known in the literature or can be prepared by known methods.

In another approach, an organometallic of formula (J), in which M’ is either an organostannane or organoboronic acid or ester, may be prepared from a compound of formula (N) and a compound of formula (O), wherein R³, R⁴ and R⁵ are as defined for compounds of formula (I), as outlined in reaction scheme 12. Examples of such a reaction are known in the literature, for example, Helm et al., Org. and Biomed. Chem., 2006, 4 (23), 4278, Sauer et al., Eur. J. Org. Chem., 1998, 12, 2885, and Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A., Angew. Chem. Int. Ed., 2005, 3889. Compounds of formula (N) and formula (O) are known in the literature.

Reaction scheme 12

formula (O)

formula (J) formula (N)

Compounds of formula (X), wherein R³, R⁴, R⁵ and A are as previously defined, may be prepared from 20 compounds of formula (P) and formula (O), in an appropriate solvent, at an appropriate température, as outlined in reaction scheme 13. Examples of such a reaction are known in the literature, for example, Sauer et al., Eur. J. Org. Chem., 1998, 12, 2885. Compounds of formula (P) are known in the literature, or may be prepared by known methods.

Reaction scheme 13

formula (P) formula (O) formula (X)

In a further approach a compound of formula (X), wherein R³, R⁴, R⁵ and A are as defined for compounds of formula (I), may be prepared from compounds of formula (C) and hydrazine, in an appropriate solvent, 5 at an appropriate température, as outlined in reaction scheme 14. This reaction may also optionally be performed in the presence of an acid, for example aqueous sulfuric acid or aqueous hydrochloric acid. Similar reactions are known in the literature (for example DE 102005029094, and Chen, B.; Bohnert, T.;

Zhou, X.; Dedon, P. C. Chem. Res. ToxicoL, 2004, 1406). Compounds of formula (C) may be prepared as previously outlined.

Reaction scheme 14

A R⁴

formula (C)

R' = H, Ci-C₄alkyl, Ci-C4alkylcarbonyl

The compounds according to the invention can be used as herbicidal agents in unmodified form, 15 but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, waterdispersible tablets, effervescent pellets, emulsifiable concentrâtes, microemulsifiable concentrâtes, oilin-water émulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule 20 suspensions, emulsifiable granules, soluble liquids, water-soluble concentrâtes (with water or a watermiscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. from the Manual on Development and Use of FAO and WHO Spécifications for Pesticides, United Nations, First Edition, Second Révision (2010). Such formulations can either be used directly or diluted prior to use. The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological 25 organisms, oil or solvents.

The formulations can be prepared e.g. by mixing the active ingrédient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or émulsions. The active ingrédients can also be formulated with other adjuvants, such as finely divided solids, minerai 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 ingrédients can also be contained in very fine microcapsules. Microcapsules contain the active ingrédients in a porous carrier. This enables the active ingrédients to be released into the 5 environment in controlled amounts (e.g. slow-release). Microcapsules usually hâve a diameter of from 0.1 to 500 microns. They contain active ingrédients in an amount of about from 25 to 95 % by weight of the capsule weight. The active ingrédients 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 can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, 10 polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyuréthane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art. Alternatively, very fine microcapsules can be formed in which the active ingrédient 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 préparation of the compositions according to the invention are known perse. 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, butylène carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p20 diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, A/,A/-dimethylformamide, dimethyl sulfoxide, 1,4dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol 25 methyl ether, gamma-butyrolactone, glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, 30 oleylamine, o-xylene, phénol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, minerai oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, éthanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, 35 hexanol, octanol, ethylene glycol, propylene glycol, glycerol, A/-methyl-2-pyrrolidone and the like.

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.

A large number of surface-active substances can advantageously be used in both solid and 40 liquid formulations, especially in those formulations which can 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 5 tridecylalcohol ethoxylate; soaps, such as sodium stéarate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stéarate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di10 alkylphosphate esters; and also further substances described e.g. in McCutcheon's Détergents and

Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).

Further adjuvants that can 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, 15 corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.

The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a minerai oil, alkyl esters of such oils or mixtures of such oils and oil dérivatives. The amount of oil additive in the composition according to the invention is generally from 20 0.01 to 10 %, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise minerai oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl dérivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of 25 C8-C22 fatty acids, especially the methyl dérivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil dérivatives are known from the Compendium of Herbicide Adjuvants, 10^th Edition, Southern Illinois University, 2010.

The herbicidal compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 30 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. The inventive compositions generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, of compounds of the présent invention 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 35 products may preferably be formulated as concentrâtes, the end user will normally employ dilute formulations.

The rates of application vary within wide limits and dépend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general 40 guideline compounds may be applied at a rate of from 1 to 2000 l/ha, especially from 10 to 1000 l/ha.

Preferred formulations can hâve the following compositions (weight %):

5	Emulsifiable concentrâtes: active ingrédient: surface-active agent: liquid carrier:	1 to 95 %, preferably 60 to 90 % 1 to 30 %, preferably 5 to 20 % 1 to 80 %, preferably 1 to 35 %
10	Dusts: active ingrédient: solid carrier:	0.1 to 10 %, preferably 0.1 to 5 % 99.9 to 90 %, preferably 99.9 to 99 %
15	Suspension concentrâtes: active ingrédient: water: surface-active agent:	5 to 75 %, preferably 10 to 50 % 94 to 24 %, preferably 88 to 30 % 1 to 40 %, preferably 2 to 30 %
20	Mettable powders: active ingrédient: surface-active agent: solid carrier:	0.5 to 90 %, preferably 1 to 80 % 0.5 to 20 %, preferably 1 to 15 % 5 to 95 %, preferably 15 to 90 %
25	Granules: active ingrédient: solid carrier:	0.1 to 30 %, preferably 0.1 to 15 % 99.5 to 70 %, preferably 97 to 85 %

The composition of the présent may further comprise at least one additional pesticide. For example, the compounds according to the invention can also be used in combination with other herbicides or plant growth regulators. In a preferred embodiment the additional pesticide is a herbicide 30 and/or herbicide safener.

Thus, compounds of Formula (I) can be used in combination with one or more other herbicides to provide various herbicidal mixtures. Spécifie examples of such mixtures include (wherein “I” represents a compound of Formula (I)):-1 + acetochlor; I + acifluorfen (including acifluorfen-sodium); I + aclonifen; I + alachlor; I + alloxydim; I + ametryn; I + amicarbazone; I + amidosulfuron; I + 35 aminocyclopyrachlor ; I + aminopyralid; I + amitrole; I + asulam; I + atrazine; I + bensulfuron (including bensulfuron-methyl); I + bentazone; I + bicyclopyrone; I + bilanafos; I + bifenox; I + bispyribac-sodium; I + bixlozone; I + bromacil; I + bromoxynil; I + butachlor; I + butafenacil; I + cafenstrole; I + carfentrazone (including carfentrazone-ethyl); cloransulam (including cloransulam-methyl); I + chlorimuron (including chlorimuron-ethyl); I + chlorotoluron; I + cinosulfuron; I + chlorsulfuron; I + cinmethylin; I + elaeyfos; I + 40 clethodim; I + clodinafop (including clodinafop-propargyl); I + clomazone; I + clopyralid; I + cyclopyranil;

I + cyclopyrimorate; I + cyclosulfamuron; I + cyhalofop (including cyhalofop-butyl); I + 2,4-D (including the choline sait and 2-ethylhexyl ester thereof); I + 2,4-DB; I + daimuron; I + desmedipham; I + dicamba (including the aluminum, aminopropyl, bis-aminopropylmethyl, choline, dichloroprop, diglycolamine, dimethylamine, dimethylammonium, potassium and sodium salts thereof); I + diclofop-methyl; I + diclosulam; I + diflufenican; I + difenzoquat; I + diflufenican; I + diflufenzopyr; I + dimethachlor; I + 5 dimethenamid-P; I + diquat dibromide; I + diuron; I + esprocarb; I + ethalfluralin; I + ethofumesate; I + fenoxaprop (including fenoxaprop-P-ethyl); I + fenoxasulfone; I + fenquinotrione; I + fentrazamide; I + flazasulfuron; I + florasulam; I + florpyrauxifen; I + fluazifop (including fluazifop-P-butyl); I + flucarbazone (including flucarbazone-sodium);; I + flufenacet; I + flumetralin; I + flumetsulam; I + flumioxazin; I + flupyrsulfuron (including flupyrsulfuron-methyl-sodium);; I + fluroxypyr (including fluroxypyr-meptyl);; I + 10 fluthiacet-methyl; I + fomesafen; I + foramsulfuron; I + glufosinate (including the ammonium sait thereof);

I + glyphosate (including the diammonium, isopropylammonium and potassium salts thereof); I + halauxifen (including halauxifen-methyl); I + halosulfuron-methyl; I + haloxyfop (including haloxyfopmethyl); I + hexazinone; I + hydantocidin; I + imazamox; I + imazapic; I + imazapyr; I + imazaquin; I + imazethapyr; I + indaziflam; I + iodosulfuron (including iodosulfuron-methyl-sodium); I + iofensulfuron; I 15 + iofensulfuron-sodium; I + ioxynil; I + ipfencarbazone; I + isoproturon; I + isoxaben; I + isoxaflutole; I + lactofen; I + lancotrione; I + linuron; I + MCPA; I + MCPB; I + mecoprop-P; I + mefenacet; I + mesosulfuron; I + mesosulfuron-methyl; I + mesotrione; I + metamitron; I + metazachlor; I + methiozolin; I + metobromuron; I + metolachlor; I + metosulam; I + metoxuron; I + metribuzin; I + metsulfuron; I + molinate; I + napropamide; I + nicosulfuron; I + norflurazon; I + orthosulfamuron; I + oxadiargyl; I + 20 oxadiazon; I + oxasulfuron; I + oxyfluorfen; I + paraquat dichloride; I + pendimethalin; I + penoxsulam; I + phenmedipham; I + picloram; I + picolinafen; I + pinoxaden; I + pretilachlor; I + primisulfuron-methyl; I + prodiamine; I + prometryn; I + propachlor; I + propanil; I + propaquizafop; I + propham; I + propyrisulfuron, I + propyzamide; I + prosulfocarb; I + prosulfuron; I + pyraclonil; I + pyraflufen (including pyraflufen-ethyl): I + pyrasulfotole; I + pyrazolynate, I + pyrazosulfuron-ethyl; I + pyribenzoxim; I + 25 pyridate; I + pyriftalid; I + pyrimisulfan, I + pyrithiobac-sodium; I + pyroxasulfone; I + pyroxsulam ; I + quinclorac; I + quinmerac; I + quizalofop (including quizalofop-P-ethyl and quizalofop-P-tefuryl),; I + rimsulfuron; I + saflufenacil; I + sethoxydim; I + simazine; I + S-metoIachlor; I + sulcotrione; I + sulfentrazone; I + sulfosulfuron; I + tebuthiuron; I + tefuryltrione; I + tembotrione; I + terbuthylazine; I + terbutryn; I + thiencarbazone; I + thifensulfuron; I + tiafenacil; I + tolpyralate; I + topramezone; I + 30 tralkoxydim; I + triafamone; I + triallate; I + triasulfuron; I + tribenuron (including tribenuron-methyl); I + triclopyr; I + trifloxysulfuron (including trifloxysulfuron-sodium); I + trifludimoxazin; I + trifluralin; I + triflusulfuron; I + tritosulfuron; I + 4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2pyridyl]imidazolidin-2-one; I + 4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one;

I + 5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one; I + 4-hydroxy-135 methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one; I + 4-hydroxy-1,5-dimethyl-3-[1-methyl-5(trifluoromethyl)pyrazol-3-yl]imidazolidin-2-one; I + (4R)1-(5-tert-butylisoxazol-3-yl)-4-ethoxy-5-hydroxy3-methyl-imidazolidin-2-one; I + 3-(2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4carbonyl]bicyclo[3.2.1]octane-2,4-dione; I + 2-(2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4carbonyl]-5-methyl-cyclohexane-1,3-dione; I + 2-(2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine40 4-carbonyl]cyclohexane-1,3-dione; I + 2-(2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4carbonyl]-5,5-dimethyl-cyclohexane-1,3-dione; I + 6-(2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo19408 pyridazine-4-carbonyl]-2,2,4,4-tetramethyl-cyclohexane-1,3,5-trione; I + 2-[2-(3,4-dimethoxyphenyl)-6methyl-3-oxo-pyridazine-4-carbonyl]-5-ethyl-cyclohexane-1,3-dione; I + 2-[2-(3,4-dimethoxyphenyl)-6methyl-3-oxo-pyridazine-4-carbonyl]-4,4,6,6-tetramethyl-cyclohexane-1,3-dione; I + 2-[6-cyclopropyl-2(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5-methyl-cyclohexane-1,3-dione; I + 3-[6cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione; I + 2[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-5,5-dimethyl-cyclohexane-1,3dione; I + 6-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4-carbonyl]-2,2,4,4-tetramethylcyclohexane-1,3,5-trione; I + 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxo-pyridazine-4carbonyl]cyclohexane-1,3-dione; I + 4-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxo-pyridazine-4-carbonyl]2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione and I + 4-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]-2,2,6,6-tetramethyl-tetrahydropyran-3,5-dione.

The mixing partners of the compound of Formula (I) may also be in the form of esters or salts, as mentioned e.g. in The Pesticide Manual, Fourteenth Edition, British Crop Protection Council, 2006.

The compound of Formula (I) can also be used in mixtures with other agrochemicals such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.

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 ingrédient relates to the respective mixture of compound of Formula (I) with the mixing partner).

Compounds of Formula (I) of the présent invention may also be combined with herbicide safeners. Preferred combinations (wherein “I” represents a compound of Formula (I)) include:- I + benoxacor, I + cloquintocet (including cloquintocet-mexyl); I + cyprosulfamide; I + dichlormid; I + fenchlorazole (including fenchlorazole-ethyl); I + fenclorim; I + fluxofenim; l+ furilazole I + isoxadifen (including isoxadifen-ethyl); I + mefenpyr (including mefenpyr-diethyl); I + metcamifen; I + N-(2methoxybenzoyl)-4-[(methylaminocarbonyl)amino] benzenesulfonamide and I + oxabetrinil.

Particularly preferred are mixtures of a compound of Formula (I) with cyprosulfamide, isoxadifen (including isoxadifen-ethyl), cloquintocet (including cloquintocet-mexyl) and/or N-(2-methoxybenzoyl)-4[(methyl-aminocarbonyl)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, 14^th Edition (BCPC), 2006. The reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium, magnésium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium sait thereof as disclosed in WO 02/34048, 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 ingrédient relates to the respective mixture of compound of Formula (I) with the safener).

The compounds of Formula (I) of this invention are useful as herbicides. The présent invention therefore further comprises a method for controlling unwanted plants comprising applying to the said plants or a locus comprising them, an effective amount of a compound of the invention or a herbicidal composition containing said compound. ‘Controlling’ means killing, reducing or retarding growth or preventing or reducing germination. Generally the plants to be controlled are unwanted plants (weeds). ‘Locus’ means the area in which the plants are growing or will grow.

The rates of application of compounds of Formula (I) may vary within wide limits and dépend on the nature of the soil, the method of application (pre-emergence; post-emergence; application to the seed furrow; no tillage application etc.), the crop plant, the weed(s) to be controlled, the prevailing climatic conditions, and other factors govemed 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 50 to 1000 g/ha.

The application is generally made by spraying the composition, typically by tractor mounted sprayer for large areas, but other methods such as dusting (for powders), drip or drench can also be used.

Useful plants in which the composition according to the invention can be used include crops such as cereals, for example barley and wheat, cotton, oilseed râpe, sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.

Crop plants can also include trees, such as fruit trees, palm trees, coconut trees or other nuts. Also included are vines such as grapes, fruit bushes, fruit plants and vegetables.

Crops are to be understood as also including those crops which hâve been rendered tolérant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPG-, ACCase- and HPPD-inhibitors) by conventional methods of breeding or by genetic engineering. An example of a crop that has been rendered tolérant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer râpe (canola). Examples of crops that hâve been rendered tolérant 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 hâve been rendered résistant to harmful insects by genetic engineering methods, for example Bt maize (résistant to European corn borer), Bt cotton (résistant to cotton boll weevil) and also Bt potatoes (résistant 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 résistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®. Plant crops or seed material thereof can be both résistant to herbicides and, at the same time, résistant to insect feeding (stacked transgenic events). For example, seed can hâve the ability to express an insecticidal Cry3 protein while at the same time being tolérant to glyphosate.

Crops are also to be understood to include 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).

Other useful plants include turf grass for example in golf-courses, lawns, parks and roadsides, or grown commercially for sod, and ornamental plants such as flowers or bushes.

Compounds of Formula (I) and compositions of the invention can typically be used to control a wide variety of monocotyledonous and dicotyledonous weed species. Examples of monocotyledonous 5 species that can typically be controlled include Alopecurus myosuroides, Avena fatua, Brachiaria plantaginea, Bromus tectorum, Cyperus esculentus, Digitaria sanguinalis, Echinochloa crus-galli, Lolium perenne, Lolium multiflorum, Panicum miliaceum, Poa annua, Setaria viridis, Setaria faberi and Sorghum bicolor. Examples of dicotyledonous species that can be controlled include Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Euphorbia heterophylla, 10 Galium aparine, Ipomoea hederacea, Kochia scoparia, Polygonum convolvulus, Sida spinosa, Sinapis arvensis, Solanum nigrum, Stellaria media, Veronica persica and Xanthium strumarium.

Compounds/compositions of the invention are particularly useful in non-selective burn-down applications, and as such may also be used to control volunteer or escape crop plants.

Various aspects and embodiments of the présent invention will now be illustrated in more detail 15 by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention.

EXAMPLES

The Examples which follow serve to illustrate, but do not limit, the invention.

Formulation Examples

Wettable powders	a)	b)	c)
active ingrédients	25%	50 %	75 %
sodium lignosulfonate	5%	5%	-
sodium lauryl sulfate	3%	-	5 %
sodium diisobutylnaphthalenesulfonate	-	6%	10%
phénol polyethylene glycol ether	-	2 %	-
(7-8 mol of ethylene oxide)
highly dispersed silicic acid	5%	10%	10%
Kaolin	62%	27 %	-

The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.

Emulsifiable concentrate active ingrédients 10% octylphenol polyethylene glycol ether 3 % (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3 %

4% castor oil polyglycol ether (35 mol of ethylene oxide)

Cyclohexanone xylene mixture

30% 50%

Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

Dusts	a)	b)	c)
Active ingrédients	5%	6%	4%
Talcum	95%	-	-
Kaolin	-	94%	-
minerai filler	-	-	96%

Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.

Extruder granules

Active ingrédients 15% sodium lignosulfonate 2 % carboxymethylcellulose 1 %

Kaolin 82 %

The combination 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.

Coated granules

Active ingrédients 8 % polyethylene glycol (mol. wt. 200) 3 %

Kaolin

89%

The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

Suspension concentrate active ingrédients 40 % propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6 %

Sodium lignosulfonate 10% carboxymethylcellulose 1 % silicone oil (in the form of a 75 % émulsion in water) 1 %

Water 32 %

The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water.

Slow Release Capsule Suspension parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamerand 51.6 parts ofwater until the desired particle 5 size is achieved. To this émulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.

The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingrédients. The medium capsule diameter is 8-15 microns.

The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

List of Abbreviations:

15	Boc	= ferf-butyloxycarbonyl
	br	= broad
	CDCb	= chloroform-d
	CD3OD	= methanol-d
	°C	= degrees Celsius
20	D2O	= water-d
	DCM	= dichloromethane
	d	= doublet
	dd	= double doublet
	dt	= double triplet
25	DMSO	= dimethylsulfoxide
	EtOAc	= ethyl acetate
	h	= hour(s)
	HCl	= hydrochloric acid
	HPLC	= high-performance liquid chromatography (description of the apparatus and the
30	methods used for HPLC are given below)
	m	= multiplet
	M	= molar
	min	= minutes
	MHz	= mega hertz
35	mL	= millilitre
	mp	= melting point
	ppm	= parts per million
	q	= quartet
	quin	= quintet
40	rt	= room température
	s	= singlet

t

THF

LC/MS = triplet = tetrahydrofuran = Liquid Chromatography Mass Spectrometry

Préparative Reverse Phase HPLC Method:

Compounds purified by mass directed préparative HPLC using ES+/ES- on a Waters FractionLynx Autopurification System comprising a 2767 injector/collector with a 2545 gradient pump, two 515 isocratic pumps, SFO, 2998 photodiode array (Wavelength range (nm): 210 to 400), 2424 ELSD and QDa mass spectrometer. A Waters Atlantis T3 5micron 19x10mm guard column was used with a Waters 10 Atlantis T3 OBD, 5micron 30x100mm prep column.

Ionisation method: Electrospray positive and négative: Cône (V) 20.00, Source Température (°C) 120,

Cône Gas Flow (L/Hr.) 50

Mass range (Da): positive 100 to 800, négative 115 to 800.

The préparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:

Time (mins)	Solvent A (%)	Solvent B (%)	Flow (ml / min)
0.00	100	0	35
2.00	100	0	35
2.01	100	0	35
7.0	90	10	35
7.3	0	100	35
9.2	0	100	35
9.8	99	1	35
11.35	99	1	35
11.40	99	1	35

515 pump Oml/min Acetonitrile (ACD)

515 pump 1ml/min 90% Methanol/10% Water (make up pump)

Solvent A: Water with 0.05% Trifluoroacetic Acid

Solvent B: Acetonitrile with 0.05%> Trifluoroacetic Acid

Préparation Examples

Example 1: Préparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate A1

O

Step 1 : Préparation of tributyl(pyridazin-4-yl)stannane

To a solution of lithium diisopropylamide (1M solution in tetrahydrofuran, 125 mL) at -78°C under nitrogen was added a solution of pyridazine (10g) and tri-n-butyltin chloride (44.6g) in THF (100 mL) drop wise. The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was warmed to room température and quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3*150 mL). The organic layer was dried over sodium sulfate, concentrated and purified by chromatography on silica eluting with 30% ethyl acetate in hexanes to afford tributyl(pyridazin-4-yl)stannane as a pale brown liquid.

¹H NMR (400MHz, CDCb) 9.17 (t, 1H) 9.02 (dd, 1H) 7.54 (dd, 1H) 1.57-1.49 (m, 6H) 1.37-1.29 (m, 6H) 1.19-1.13 (m, 6H) 0.92-0.86 (m, 9H).

Step 2: Préparation of 2-pyridazin-4-ylpyrimidine

A solution of 2-bromopyrimidine (2.50g) and tributyl(pyridazin-4-yl)stannane (5.80g) in tetrahydrofuran (25 mL) was degassed with argon for 20 min. Tetrakis (triphenylphosphine) palladium (0) (1.80g) was added to the reaction mixture at room température and then irradiated in a microwave at 120°C for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (100 mL). The organic layer was concentrated and purified by chromatography on silica eluting with 80% ethyl acetate in hexanes to give 2-pyridazin-4-ylpyrimidine as a beige solid.

¹H NMR (400MHz, CDCb) 10.17 (dd, 1H) 9.39 (dd, 1H) 8.92 (d, 2H) 8.43 (dd, 1H) 7.39 (t, 1H).

Step 3: Préparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate A1

A mixture of 2-pyridazin-4-ylpyrimidine (0.120g) and sodium 2-bromoethanesulfonate (0.196g) was stirred in water (2.3 mL) at 100°C for 42 hours. The reaction mixture was concentrated and purified by préparative reverse phase HPLC to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate as a beige solid.

¹H NMR (400MHz, D₂O) 10.19 (d, 1H) 9.84 (d, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.27-5.18 (m, 2H) 3.71-3.63 (m, 2H).

Example 2: Préparation of 4-pyridazin-4-yipyrimidine

A microwave vial was charged with tributyl(pyridazin-4-yl)stannane (0.387g), 4-chloropyrimidine (0.100g), palladium (0) tetrakis(triphenylphosphine) (0.101g), césium fluoride (0.265g), cuprous iodide (0.00665g) and 1,4-dioxane (4.37 mL) and heated to 140°C under microwave conditions for 1 hour. The reaction mixture was concentrated and purified by chromatography on silica eluting with a gradient from 0 to 70% acetonitrile in dichloromethane to give 4-pyridazin-4-ylpyrimidine as an orange solid.

¹H NMR (400MHz, CDCb) 9.90-9.83 (m, 1H) 9.41 (dd, 2H) 8.97 (d, 1H) 8.21-8.13 (m, 1H) 7.89 (dd, 1H).

Example 3: Préparation of methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide A2

/=N v—n

Methyl bromoacetate (0.755g) was added drop wise to a solution of 2-pyridazin-4-ylpyrimidine (0.505g) in acetone (6.4mL) and heated at 60°C for 24 hours. The reaction mixture was concentrated and the residue triturated with dichloromethane. The resulting solid was filtered, washed with acetone and dried to give methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide as a brown solid.

¹H NMR (400MHz, D₂O) 10.22 (d, 1H) 9.84 (d, 1H) 9.30 (dd, 1H) 9.01 (d, 2H) 7.66 (t, 1H) 5.84 (s, 2H) 3.79 (s, 3H).

Example 4: Préparation of (4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methanesulfonate A3

Methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide (0.420g) was stirred in trimethylsilyl chlorosulfonate (4.96g) at 80°C for 66 hours. The reaction mixture was carefully quenched with water, concentrated and purified by préparative reverse phase HPLC to give (4-pyrimidin-2-ylpyridazin-1-ium1-yl)methanesulfonate as a pale brown solid.

¹H NMR (400MHz, D2O) 10.26 (brs, 1H) 9.94 (brd, 1H) 9.27-9.39 (m, 1H) 8.96-9.14 (m, 2H) 7.56-7.73 (m, 1H) 5.97 (s, 2H).

Example 5: Préparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A6

To a solution of 2-pyridazin-4-ylpyrimidine (0.200g) in 1,4-dioxane (3.79mL) was added 1,3propanesultone (0.189g). The mixture was stirred at 90°C for 44 hours. The resulting solid was filtered 5 off and washed with acetone. The solid was purified by préparative reverse phase HPLC to give 3-(4pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate.

¹H NMR (400MHz, D₂O) 10.18 (d, 1H) 9.80 (d, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.01 (t, 2H) 2.98 (t, 2H) 2.53 (quin, 2H).

Example 6: Préparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2trifluoroacetate A9

Step 1 : Préparation of 2-pyridazin-4-ylpyrazine

A mixture of tributyl(pyridazin-4-yl)stannane (3.87g), 2-chloropyrazine (1.00g), palladium (0) tetrakis(triphenylphosphine) (1.03g) and 1,4-dioxane (43.7 mL) was heated to 140°C under microwave conditions for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 50% acetonitrile in dichloromethane to give 2-pyridazin-4-ylpyrazine as an off white solid.

¹H NMR (400MHz, CDCh) 9.87 (dd, 1H) 9.39 (dd, 1H) 9.19 (d, 1H) 8.81-8.75 (m, 1H) 8.72 (d, 1H) 8.11 (dd, 1H).

Step 2: Préparation of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide

Methyl 3-bromopropanoate (0.518 mL) was added to a solution of 2-pyridazin-4-ylpyrazine (0.250g) in acetonitrile (15.8 mL). The reaction mixture was heated to 80°C for 24 hours. The reaction mixture was concentrated and the residue taken up in water and washed with dichloromethane. The aqueous phase was concentrated to give crude methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide (as a

1:1 mixture with 3-(5-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide) as a brown gum, which was used crude in subséquent reactions.

Step 3: Préparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate A9 The crude mixture of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide (0.515g) and conc. hydrochloric acid (11.1 mL) was heated to 80°C for 4 hours. The reaction mixture was cooled and allowed to stand overnight. The reaction mixture was concentrated and purified by préparative reverse phase HPLC to give 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate as a brown gum.

¹H NMR (400MHz, CDsOD) 10.28 (d, 1H) 10.00 (d, 1H) 9.62 (d, 1H) 9.28 (dd, 1H) 8.96-8.93 (m, 1H) 8.90 (d, 1H) 5.19-5.12 (t, 2H) 3.28 (t, 2H).

Example 7: Préparation of 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate A11

Q

Step 1: Préparation of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate

Boc-hydrazide (1.00g) was added to a solution of 2,2-dimethylpropyl ethenesulfonate (1.35g) in methanol (10.1 mL) and heated to 70°C for 24 hours. The reaction was concentrated to give 2,2dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate as a thick yellow liquid.

¹H NMR (400MHz, CDCh) 3.90 (s, 2H) 3.38-3.30 (m, 4H) 1.50-1.43 (s, 9H) 1.00-0.97 (s, 9H).

Step 2: Préparation of [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride

A mixture of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate (1.00g) and 3M methanolic hydrogen chloride (24.2 mL) was heated to 70°C for 7 hours. The reaction mixture was concentrated to give [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride as a pink gum that solidified on standing.

¹H NMR (400MHz, CD₃OD) 3.95 (s, 2H) 3.59-3.53 (m, 2H) 3.44-3.39 (m, 2H) 1.00 (s, 9H) sample contained ~20% methanol and was used as such.

Step 3: Préparation of 4-(3-furyl)pyridazine

To a mixture of 4-bromopyridazin-1-ium bromide (2.50g), sodium carbonate (2.2g), degassed toluene 5 (17.3 mL) and 1,T-bis(diphenylphosphino)ferrocenepalladium (II) dichloride (0.634g) was added a solution of 3-furylboronic acid (1.00g) in éthanol (17.3 mL). The mixture was heated to 80°C under nitrogen atmosphère for 24 hours. The reaction mixture was filtered through celite and concentrated. The residue was partitioned between water and dichloromethane then extracted with further dichloromethane. The combined organic layers were washed with brine and dried with magnésium 10 sulfate. The concentrated filtrate was purified on silica eluting with a gradient of 0-100% ethyl acetate in iso-hexane to give 4-(3-furyl)pyridazine as a dark red semi-solid.

¹H NMR (400 MHz, CD₃OD) 9.45 (s, 1H) 9.03-9.16 (m, 1H) 8.36 (s, 1 H) 7.86 (dd, 1 H) 7.71 (t, 1 H) 7.04 (d, 1H).

Step 4: Préparation of 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine

A mixture of 4-(3-furyl)pyridazine (0.025g) and sodium bicarbonate (0.14g) in methanol (0.5 mL) was cooled to -10°C and bromine (0.069g) was added drop wise. After 30 minutes the reaction was quenched with 1:1 sat. aqueous sodium bicarbonate and 1M aqueous sodium thiosulfate (3 mL). The 20 aqueous layer was extracted with ethyl acetate. The organic layer was concentrated to give crude 4(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine.

¹H NMR (400 MHz, CD3OD) 9.42-9.41 (m, 1H) 9.20-9.19 (m, 1H) 7.85 (dt, 1H) 7.02-6.94 (m, 1H) 6.085.77 (m, 2H) 3.46 (d, 3H) 3.42 (d, 3H).

Step 5: Préparation of 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate A11

A mixture of 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine (0.500g) and [2-(2,2dimethylpropoxysulfonyl)ethylamino]ammonium chloride (0.658g) was heated in aqueous 3M hydrochloric acid (12mL) at 60°C for 2 hours. The reaction mixture was concentrated and purified by préparative reverse phase HPLC to give 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate as a 30 brown solid.

¹H NMR (400MHz, D2O) 9.80-9.97 (m, 2H) 9.62-9.75 (m, 1H) 9.35-9.50 (m, 1H) 8.97 (dd, 1H) 8.19-8.42 (m, 1H) 5.20-5.29 (m, 2H) 3.59-3.73 (m, 2H).

Example 8: Préparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride A29

OH =N ’N^ /

---^N Cl

A column packed with ion exchange resin (5.84g, Discovery DSC-SCX) was washed with water (3 column volumes). The 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (0.292g) dissolved in a minimum amount of water was loaded onto the column. The column was first eluted with water (3 column volumes) and then eluted with 2M hydrochloric acid (3 column volumes). The collected washings were concentrated to give 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a yellow solid.

¹H NMR (400MHz, D₂O) 10.03 (d, 1H) 9.80 (d, 1H) 9.35 (d, 1H) 9.05 (dd, 1H) 8.87-8.82 (m, 1H) 8.76 (d, 1 H) 5.08 (t, 2H) 3.22 (t, 2H).

Example 9: Préparation of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate chloride A30

A column packed with ion exchange resin (1.6g, Discovery DSC-SCX) was washed with methanol (3 column volumes). The 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (0.081g) dissolved in a minimum amount of methanol was loaded onto the column. The column was first eluted with methanol (3 column volumes) and then eluted with 3M methanolic hydrochloric acid (3 column volumes). The collected washings were concentrated to give methyl 3-(4-pyrazin-2-ylpyridazin1-ium-1-yl)propanoate chloride as a blue gum.

¹H NMR (400MHz, CD3OD) 10.30-10.26 (m, 1H) 10.04-10.00 (m, 1H) 9.66-9.64 (m, 1H) 9.33-9.30 (m, 1H) 8.97-8.93 (m, 1H) 8.91-8.88 (m, 1H) 5.25-5.14 (m, 2H) 3.71-3.68 (m, 3H) 3.35-3.27 (m, 2H).

Example 10: Préparation of isopropyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2trifluoroacetate A81

Sodium iodide (0.24g) and isopropyl 3-chloropropanoate (0.357g) were added to a solution of 2pyridazin-4-ylpyrimidine (0.25g) in acetonitrile (6 mL) and heated at 80°C for 25 hours. The reaction mixture was concentrated and purified by préparative reverse phase HPLC to give isopropyl 3-(4pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate as a brown gum.

¹H NMR (400 MHz, CD₃OD) 10.29-10.43 (m, 1H) 10.02 (d, 1H) 9.36-9.49 (m, 1H) 9.04-9.18 (m, 2H)

7.63-7.76 (m, 1H) 5.10-5.24 (m, 2H) 4.92-5.04 (m, 1H) 3.14-3.41 (m, 2H) 1.12-1.25 (m, 6H).

Example 11: Préparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide A107

A mixture of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate (0.2g), concentrated hydrogen bromide (1 mL, 48 mass%) and water (5 mL) was heated to 80°C for 4 hours and left to cool overnight. After a further 4 hours heating at 80°C the reaction mixture was concentrated and the resulting yellow gum was triturated with acetone to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)propanoic acid bromide as a cream solid.

¹H NMR (400MHz, D2O) 10.16 (d, 1H) 9.86 (d, 1H) 9.21-9.15 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H).

Example 12: Préparation of 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-suIfonate A134

Step 1: Préparation of methyl 2-(2,2-dimethylpropoxysulfonyl)acetate

Methyl 2-chlorosulfonylacetate (0.5g) was added drop wise to a cooled (ice bath) solution of 2,2dimethylpropan-1-ol (0.306g) and pyridine (0.284 mL) in dichloromethane (14.5 mL). The reaction mixture was stirred cold for a further 2 hours then partitioned with aqueous sat. ammonium chloride. The aqueous phase was extracted with further dichloromethane (x2). The combined organic extracts were concentrated and passed through a plug of silica eluting with diethyl ether. The filtrate was concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)acetate as a yellow liquid.

¹H NMR (400MHz, CDCb) 4.11 (s, 2H) 4.00 (s, 2H) 3.84 (s, 3H) 1.01 (s, 9H).

Step 2: Préparation of methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate

A mixture of sodium hydride (60% in minerai oil, 0.039g) in tetrahydrofuran (4.46 mL) was cooled (ice bath) to 0°C under nitrogen atmosphère. To this was added a solution of methyl 2-(2,2dimethylpropoxysulfonyl)acetate (0.2g) in tetrahydrofuran (1.78 mL) and stirred at this température for 5 minutes, lodomethane (0.067 mL) was added and the reaction was allowed to warm to room température and stirred for 1 hour. The reaction mixture was partitioned between 2M hydrochloric acid and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (x2). The combined organic extracts were dried with magnésium sulfate and concentrated to give methyl 2-(2,2dimethylpropoxysulfonyl)propanoate as a yellow liquid.

¹H NMR (400MHz, CDCb) 4.12-4.09 (m, 1H) 3.97 (d, 2H) 3.83 (s, 3H) 1.69 (d, 3H) 0.99 (s, 9H).

Step 3: Préparation of 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate

To a cooled (ice bath) solution of methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate (1g) in dichloromethane (126 mL) was added dropwise, under nitrogen atmosphère, diisobutylaluminum hydride (1M in dichloromethane, 10.5 mL) maintaining the température below 5°C during the addition. The reaction mixture was stirred at 0°C for 1 hour. Propan-2-ol (12.6 mL) was added and the reaction mixture was stirred at 0°C for 1 hour and then allowed to warm to room température. The reaction mixture was partitioned between 2M aqueous hydrochloric acid and dichloromethane. The organic phase was dried with magnésium sulfate, concentrated and chromatographed on silica using a gradient from 0 to 100% EtOAc in isohexane to give 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate as a colourless liquid.

¹H NMR (400MHz, CDCb) 4.03-3.84 (m, 4H) 3.43-3.33 (m, 1H) 2.60-2.52 (m, 1H) 1.45 (d, 3H) 1.00 (s, 9H).

Step 4: Préparation of 1-hydroxypropane-2-sulfonic acid

HO

A mixture of 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate (0.25g) and 6M aqueous hydrochloric acid (9.51 mL) was heated to 95°C for 4 hours. The reaction mixture was cooled and concentrated by freeze drying.

¹H NMR (400MHz, D₂O) 3.88-3.78 (m, 1H) 3.56-3.47 (m, 1H) 2.98-2.89 (m, 1 H) 1.18 (d, 3H).

Step 5: Préparation of 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A134

To a cooled (ice bath) solution of 2-pyridazin-4-ylpyrimidine (0.1g) in dry acetonitrile (6.32 mL) was added 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (0.131 mL) and the reaction mixture was stirred at room température for 15 minutes. To this mixture was added triphenylphosphine (0.332g) and a solution of 1-hydroxypropane-2-sulfonic acid (0.133g) in acetonitrile (0.5mL), followed by drop wise addition of diisopropyl azodicarboxylate (0.25 mL). The reaction mixture was heated at 80°C for 170 hours. The reaction mixture was concentrated and partitioned between water and diethyl ether. The aqueous layer was concentrated and purified by préparative reverse phase HPLC to givel5 (4-pyrimidin-2-ylpyridazin-1 -ium-1 -yl)propane-2-sulfonate as a white solid.

¹H NMR (400MHz, D₂O) 10.20-10.18 (m, 1H) 9.81 (dd, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.105.07 (m, 2H) 3.84-3.74 (m, 1H) 1.39 (d, 3H).

Example 13: Préparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,210 trifluoroacetate A40

To a mixture of 2-pyridazin-4-ylpyrimidine (0.5g) in water (10 mL) was added but-2-enoic acid (0.816g).

The mixture was heated at reflux for 40 hours. The reaction mixture was concentrated and the resulting 15 solid was triturated with tert-butylmethylether and acetone. The solid was purified by préparative reverse phase HPLC to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate.

¹H NMR (400MHz, D₂O) 10.22 (d, 1H) 9.92 (d, 1H) 9.18-9.26 (m, 1H) 8.99-9.05 (m, 2H) 7.68 (t, 1H)

5.49-5.60 (m, 1H) 3.39 (dd, 1H) 3.10-3.21 (m, 1H) 1.71 (d, 3H).

Example 14: Préparation of 2-(3-methyI-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate

A88

O /

Step 1: Préparation of tributyl-(3-chloro-6-methoxy-pyridazin-4-yl)stannane

A solution of lithium diisopropylamide (1M in tetrahydrofuran, 1.7 mL) was cooled to -78°C. To this was added a solution of 3-chloro-6-methoxy-pyridazine (0.2g) in tetrahydrofuran (2 mL) whilst maintaining the température below -70°C. The resulting mixture was stirred at -78°C for 40 minutes. To this was slowly added tri-n-butyltin chloride (0.47 mL) at -78°C over a period of 10 minutes, then stirring was continued at -78°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (50 mL). The aqueous layer was extracted with further ethyl acetate (50 mL). The 5 combined organic layers were dried over sodium sulphate, concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give crude tributyl-(3-chloro-6-methoxypyridazin-4-yl)stannane (HPLC rétention time 2.07min) in a 2:1 ratio with the isomer tributyl-(6-chloro3-methoxy-pyridazin-4-yl)stannane (HPLC rétention time 1.79min).

Step 2: Préparation of 3-chloro-6-methoxy-4-pyrimidin-2-yl-pyridazine

A solution of the crude tributyl-(3-chloro-6-methoxy-pyridazin-4-yl)stannane (15.2g) in 1,4-dioxane (304 mL) was degassed with nitrogen for 20 minutes. To this was added cuprous iodide (1.02g), tris(dibenzylideneacetone)dipalladium(0) (1.65g) and triphenylphosphine (0.763g) and again degassed 15 for 20 minutes. After the addition of 2-bromopyrimidine (6.13g) the reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled, concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give a mixture of isomers 3-chloro-6-methoxy4-pyrimidin-2-yl-pyridazine and 6-chloro-3-methoxy-4-pyrimidin-2-yl-pyridazine, as an off-white solid, which was used crude in the next step.

Step 3: Préparation of 6-methoxy-3-methyl-4-pyrimidin-2-yl-pyridazine

To a solution of crude 3-chloro-6-methoxy-4-pyrimidin-2-yl-pyridazine (1.5g) in 1,4-dioxane (45 mL), under a nitrogen atmosphère, was added methylboronic acid (1.2g) and [1,T25 bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.49g). The mixture was degassed with nitrogen for 15 minutes then heated to 100°C. Césium carbonate (4.4g) was added over 5 minutes and the mixture heated at 100°C for 3 hours. The reaction mixture was cooled, concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give 6methoxy-3-methyl-4-pyrimidin-2-yl-pyridazine.

¹H NMR (400MHz, CDCb) 8.91 (d, 1H) 8.82-8.99 (m, 1H) 7.52 (s, 1H) 7.37 (t, 1H) 4.17 (s, 3H) 2.88 (s, 3H).

Step 4: Préparation of 6-methyl-5-pyrimidin-2-yl-pyridazin-3-ol

A mixture of 6-methoxy-3-methyl-4-pyrimidin-2-yl-pyridazine (0.5g) in concentrated hydrogen bromide (10 mL, 48 mass%) was heated at 80°C for 16 hours. The reaction mixture was cooled, concentrated and azeotroped with toluene (2x30 mL) to give crude 6-methyl-5-pyrimidin-2-yl-pyridazin-3-ol which was used in the next step without further purification.

Step 5: Préparation of 6-chloro-3-methyl-4-pyrimidin-2-yl-pyridazine

A mixture of 6-methyl-5-pyrimidin-2-yl-pyridazin-3-ol (0.025g) in phosphorus oxychloride (0.25 mL) was heated at 80°C for 3 hours. The reaction mixture was concentrated and the residue was diluted with ice cold water (2 mL) and neutralised with sodium bicarbonate solution. The aqueous was extracted with ethyl acetate (2x15 mL). The combined organic layers were dried over sodium sulphate and concentrated to give 6-chloro-3-methyl-4-pyrimidin-2-yl-pyridazine, which was used in the next step without further purification.

¹H NMR (400MHz, CDCb) 8.94 (d, 2H) 8.13 (s, 1H) 7.41 (t, 1H) 3.03 (s, 3H).

Step 6: Préparation of 3-methyl-4-pyrimidin-2-yl-pyridazine

To a solution of 6-chloro-3-methyl-4-pyrimidin-2-yl-pyridazine (0.37g) in éthanol (15 mL) was added triethylamine (0.24g) and 10% palladium on carbon (0.035g). The mixture was hydrogenated under balloon pressure for 1 hour. The reaction mixture was diluted with éthanol (10 mL) and filtered through celite, washing through with further éthanol (2x20 mL). The filtrate was concentrated and chromatographed on silica using a gradient from 0 to 100% ethyl acetate in isohexane to give 3-methyl4-pyrimidin-2-yl-pyridazine as a white solid.

¹HNMR (400MHz, CDCI₃) 9.25 (d, 1H) 8.93 (d, 2H) 8.02 (d, 1H) 7.38 (t, 1H) 3.04 (s, 3H).

Step 7: Préparation of 2-(3-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate A88

A mixture of 3-methyl-4-pyrimidin-2-yl-pyridazine (0.125g) and sodium 2-bromoethanesulfonate (0.153g) in water (2.5 mL) was heated at reflux for 18 hours. The reaction mixture was concentrated and purified by préparative reverse phase HPLC to give 2-(3-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1- yl)ethanesulfonate, A88.

¹H NMR (400MHz, D₂O) 9.76 (d, 1H) 9.69-9.88 (m, 1H) 9.02 (d, 1H) 8.77 (d, 1H) 7.69 (t, 1H) 5.21 (t, 2H) 3.71 (t, 2H) 2.94 (s, 3H).

Example 15: Préparation of 3-bromo-M-methylsulfonyl-propanamide

To a solution of methanesulfonamide (0.5g) in toluene (25.8 mL) was added 3-bromopropionyl chloride (1.77g) drop wise at room température. The reaction mixture was heated at 110°C for 4 hours. The reaction was cooled in ice and the resulting solid was filtered and washed with cold toluene to give 3bromo-/V-methylsulfonyl-propanamide as a colourless solid.

¹H NMR (400MHz, CDCh) 8.28 (br s, 1 H) 3.62 (t, 2H) 3.34 (s, 3H) 2.94 (t, 2H).

Example 16: Préparation of 2-hydroxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1 sulfonate A143

A mixture of 2-pyridazin-4-ylpyrimidine (0.3g), water (6 mL) and sodium 3-chloro-2-hydroxy-propane-1sulfonate (0.45g) was heated at reflux for 3 days. The reaction mixture was concentrated and the resulting solid was washed with t-butylmethyl ether and acetone. The solid was purified by préparative 25 reverse phase HPLC to give 2-hydroxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate, A143.

¹H NMR (400MHz, D₂O) 10.24 (d, 1H) 9.80 (d, 1H) 9.25 (dd, 1H) 9.04 (d, 2H) 7.68 (t, 1H) 5.21 (dd, 1H) 4.93 (dd, 1H) 4.64-4.71 (m, 1H) 3.19-3.36 (m, 2H).

Example 17: Préparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2trifluoroacetate A125

3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride (0.119g) was stirred in 2,2,2- trifluoroacetic acid (4 mL) at room température for two hours. The reaction mixture was concentrated and freeze dried to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate, A125, as a pale yellow gum, which solidified on standing.

¹H NMR (400MHz, D₂O) 10.18-10.13 (m, 1H) 9.87-9.82 (m, 1H) 9.20-9.14 (m, 1H) 8.98 (d, 2H) 7.63 (s, 1H) 5.10 (s, 2H) 3.24 (t, 2H).

Example 18: Préparation of 3-methyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2trifluoroacetate A131

OH F

A mixture of 2-pyridazin-4-ylpyrimidine (1g), 3,3-dimethylacrylic acid (1.96g), 2,2,2-trifluoroacetic acid 15 (5 mL) and water (5 mL) was heated at 100°C under microwave conditions for 18 hours. The reaction mixture was concentrated and the resulting solid was washed with diethyl ether (5x10 mL). The solid was purified by préparative reverse phase HPLC to give 3-methyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)butanoic acid 2,2,2-trifluoroacetate, A131.

¹H NMR (400MHz, D2O) 10.18 (m, 1H) 9.97 (m, 1H) 9.21 (m, 1H) 8.98 (m, 2H) 7.61 (m, 1H) 3.36 (s, 20 2H) 1.94 (s, 6H).

Example 19: Préparation of 5-methylsulfonyl-2-pyridazin-4-yl-pyrimidine

Step T. Préparation of 5-chloro-2-pyridazin-4-yl-pyrimidine

A solution of 2,5-dichloropyrimidine (6g) in 1,4-dioxane (60 mL) was degassed with nitrogen for 20 minutes.

To this was added tributyl(pyridazin-4-yl)stannane (14.87g), tetrakis(triphenylphosphine)palladium(0) (4.66g) and the mixture heated at 110°C for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3x100 mL). The orgamc layers were concentrated and chromatographed on silica eluting with 75% ethyl acetate in hexanes to give 5chloro-2-pyridazin-4-yl-pyrimidine as a pinkish solid.

¹H NMR (400MHz, CDCb) 10.12 (dd, 1H) 9.38 (dd, 1H) 8.86 (s, 2H) 8.38 (dd, 1H)

Step 2: Préparation of 5-methylsulfonyl-2-pyridazin-4-yl-pyrimidine

To a solution of 5-chloro-2-pyridazin-4-yl-pyrimidine (0.8g) in A/,/\/-dimethylformamide (8 mL) was added sodium methanesulfinate (1g) and the mixture heated at 100°C for 18 hours. The reaction mixture was cooled to room température and poured into ice cold water (50 mL). The resulting solid was filtered and dried to give 5-methylsulfonyl-2-pyridazin-4-yl-pyrimidine as a white solid.

¹H NMR (400MHz, de-DMSO) 10.01-10.10 (m, 1H) 9.45-9.60 (m, 3H) 8.46-8.55 (m, 1H), 3.48 (s, 3H).

Example 20: Préparation of W,/V-dimethyl-2-pyridazin-4-yl-pyrimidin-5-amine

To a mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (0.035g) in dimethylamine (40 mass% in water, 1 mL) in a microwave vial was added A/,A/-diisopropylethylamine (0.16 mL). The mixture was heated under microwave conditions at 150°C for 6 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (15 mL). The aqueous layer was extracted with further ethyl acetate (30 mL). The organic layers were dried over sodium sulfate and concentrated to give A/,/V-dimethyl-2-pyridazin4-yl-pyrimidin-5-amine as a yellow solid.

¹H NMR (400MHz, CDCb) 10.05 (s, 1H) 9.24 (d, 1H) 8.30 (s, 2H) 8.25 (dd, 1H) 3.12 (s, 6H).

Example 21: Préparation of 2-pyridazin-4-ylpyrimidine-5-carbonitrile

A mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (2g), zinc cyanide (0.75g), zinc (0.068g), tris(dibenzylideneacetone)dipalladium(0) (0.98g) and dicyclohexyl-[2-(2,4,6triisopropylphenyl)phenyl]phosphane (0.99g) in Λ/,/V-dimethylacetamide (16 mL) was heated at 120°C under nitrogen atmosphère for 12 hours. After cooling, the reaction was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 2-pyridazin-4-ylpyrimidine-5-carbonitrile as a yellow solid.

¹H NMR (400MHz, CDCb) 10.19-10.20 (m, 1H) 9.50 (d, 1H) 9.19 (s, 2H) 8.47-8.49 (m, 1H).

Example 22: Préparation of 5-cyclopropyl-2-pyridazin-4-yl-pynmidine

A mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (0.05g), tricyclohexylphosphane (0.007g), cyclopropylboronic acid (0.045g), tris(dibenzylideneacetone)dipalladium(0) (0.024g) and potassium phosphate (0.07g) in dioxane (0.5 mL) was heated at 120°C under nitrogen atmosphère for 4 hours. The reaction was concentrated and chromatographed on silica eluting with 60% ethyl acetate in cyclohexane to give 5-cyclopropyl-2-pyridazin-4-yl-pyrimidine as a yellow solid.

¹H NMR (400MHz, CDCb) 10.00-10.21 (m, 1H) 9.27-9.40 (m, 1H) 8.54-8.67 (m, 2H) 8.35-8.46 (m, 1H) 2.14-2.22 (m, 1H) 1.18-1.24 (m, 2H) 0.87-0.93 (m, 2H).

Example 23: Préparation of 1-(2-pyridazin-4-ylpyrimidin-5-yl)ethanone

Step 1: Préparation of 5-(1-ethoxyvinyl)-2-pyridazin-4-yl-pyrimidine

A mixture of 5-chloro-2-pyridazin-4-yl-pyrimidine (1g), tributyl(1-ethoxyvinyl)stannane (2.062g), palladium(ll)bis(triphenylphosphine) dichloride (0.368g) in Λ/,/V-dimethylformamide (10 mL) was heated at 70°C for 16 hours. After cooling the reaction was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanesto give 5-(1-ethoxyvinyl)-2-pyridazin-4-yl-pyrimidine as a yellow solid. ¹H NMR (400MHz, CDCb) 10.17 (s, 1H) 9.36-9.47 (m, 1H) 9.09 (s, 2H) 8.87 (s, 1H) 4.83-4.88 (m, 1H) 4.46-4.49 (m, 1H) 3.97-4.04 (m, 2H) 1.45-1.51 (m, 3H).

Step 2: Préparation of 1-(2-pyridazin-4-ylpyrimidin-5-yl)ethanone

A solution of 5-(1-ethoxyvinyl)-2-pyridazin-4-yl-pyrimidine (0.4g), acetone (4 mL) and 2M aqueous hydrochloric acid (0.88 mL) was heated at 65°C for 18 hours. After cooling the reaction was partitioned between water and ethyl acetate. The organic layer was washed further with water and brine. The organic layer was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 1-(2-pyridazin-4-ylpyrimidin-5-yl)ethanone.

¹H NMR (400MHz, CDCb) 10.15 (s, 1H) 9.41 (d, 1H) 8.88 (s, 2H) 8.42-8.44 (m, 1H) 2.10 (s, 3H).

Example 24: Préparation of N,N-dimethyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide

Step 1 : Préparation of methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate

To a solution of 2-pyridazin-4-ylpyrimidine-5-carbonitrile (0.52g) in methanol (5.2 mL) was added a solution of potassium hydroxide (0.023g) in water (5.2 mL) at 0°C. After stirring at 0°C for 90 minutes the reaction mixture was acidified with acetic acid to pH 3. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (2x200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate as a brown solid.

¹H NMR (400MHz, CDCh) 10.22 (s, 1H) 9.41-9.46 (m, 3H) 8.50 (dd, 1H) 4.05 (s, 3H).

Step 2: Préparation of /V,A/-dimethyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide

A mixture of methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate (0.02g) and /V-methylmethanamine (2 mL) in a sealed vial was heated at 85°C for 2 hours. The reaction mixture was concentrated to give N,Ndimethyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide as a white solid.

¹HNMR (400 MHz, D₂O) 9.82-9.88 (m, 1H) 9.28-9.32 (m, 1H) 8.98 (s, 2H) 8.42-8.44 (m, 1H) 2.98-3.02 (m, 6H).

Example 25: Préparation of N-methyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide

A mixture of methyl 2-pyridazin-4-ylpyrimidine-5-carboxylate (0.02g) and methylamine in methanol (2M solution, 0.2 mL) in a sealed vial was heated at 100°C for 2 hours. The reaction mixture was concentrated to give A/-methyl-2-pyridazin-4-yl-pyrimidine-5-carboxamide as a brown solid.

¹H NMR (400 MHz, CD₃OD) 10.05-10.20 (m, 1H) 9.40-9.45 (m, 1H) 9.27-9.39 (m, 2H) 8.66 (dd, 1H) 2.99 (s, 3H).

Example 26: Préparation of (2-pyridazin-4-ylpyrimidin-4-yl)methanol

Step 1: Préparation of 2-pyridazin-4-ylpyrimidine-4-carbonitrile

A solution of 2-chloropyrimidine-4-carbonitrile (4.89g) in tetrahydrofuran (50 mL) was degassed with nitrogen for 30 minutes. To this was added tributyl(pyridazin-4-yl)stannane (12.9g) and tetrakis(triphenylphosphine)palladium(0) (4.06g) and the reaction mixture was heated at 110°C for 12 hours. After cooling the reaction was partitioned between water and ethyl acetate and extracted with further ethyl acetate (2x200 mL). The combined organic layers were dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give 2pyridazin-4-ylpyrimidine-4-carbonitrile as a brown solid.

¹H NMR (400MHz, CDCI3) 10.17 (dd, 1H) 9.46 (dd, 1H) 9.09-9.20 (m, 1H) 8.36-8.53 (m, 1H) 7.72 (d, 1H).

Step 2: Préparation of methyl 2-pyridazin-4-ylpyrimidine-4-carboxylate

To a solution of 2-pyridazin-4-ylpyrimidine-4-carbonitrile (2.7g) in methanol (27 mL) was added a solution of potassium hydroxide (0.55g) in water (27 mL) at 0°C. After stirring at 0°C for 90 minutes the reaction mixture was acidified with acetic acid to pH 3. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (2x200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 2-pyridazin-4-ylpyrimidine-4-carboxylate as a brown solid.

¹H NMR (400MHz, CDCb) 10.24 (s, 1H) 9.44 (dd, 1H) 9.17 (d, 1H) 8.53 (dd, 1H) 8.06 (d, 1H)4.11 (s, 3H).

Step 3: Préparation of (2-pyridazin-4-ylpyrimidin-4-yl)methanol

To a solution of methyl 2-pyridazin-4-ylpyrimidine-4-carboxylate (0.05g) in methanol (0.5 mL) under a nitrogen atmosphère was added sodium borohydride (0.018g) slowly, keeping the reaction température below 20°C. The mixture was stirred for 16 hours at room température. The reaction mixture was quenched with water and extracted with ethyl acetate (3x30 mL). The aqueous layer was further extracted with 10% isopropanol in chloroform (100 mL). The combined organic layers were dried over sodium sulfate, concentrated and chromatographed on silica eluting with 20-100% ethyl acetate in hexanes to give (2-pyridazin-4-ylpyrimidin-4-yl)methanol as a yellow solid.

¹H NMR (400MHz, de-DMSO) 10.00 (s, 1H) 9.45 (d, 1H) 9.02 (d, 1H) 8.40-8.44 (m, 1H) 7.68 (d, 1H) 4.70 (d, 2H).

Example 27: Préparation of 2-methyl-1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2sulfonate A114

Step 1: Préparation of methyl 2-(2,2-dimethylpropoxysulfonyl)-2-methyl-propanoate

To sodium hydride (60% in minerai oil, 0.392g), under a nitrogen atmosphère and cooled in an ice bath, was added tetrahydrofuran (22.3 mL) followed by a solution of methyl 2-(2,2dimethylpropoxysulfonyl)acetate (1g) in tetrahydrofuran (8.92 mL). The reaction mixture was stirred at this température for 5 minutes and then iodomethane (0.694 mL) was added. The ice bath was removed and the reaction mixture was stirred at room température for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)-2-methyl-propanoate as a yellow liquid.

¹H NMR (400MHz, CDCb) 3.95 (s, 2H) 3.82 (s, 3H) 1.71 (s, 6H) 0.98 (s, 9H).

Step 2: Préparation of 2,2-dimethylpropyl 1-hydroxy-2-methyl-propane-2-sulfonate

Diisobutylaluminum hydride (1M in dichloromethane, 6.62 mL) was added drop wise to a cooled (ice bath) solution of methyl 2-(2,2-dimethylpropoxysulfonyl)-2-methyl-propanoate (0.668g) in dichloromethane (79.4 mL) under a nitrogen atmosphère, maintaining the température below 5°C during 5 the addition. The reaction mixture was stirred at 0°C for 1 hour. Propan-2-ol (7.94 mL) was added to the reaction mixture and stirring continued at 0°C for a further hour, then it was allowed to warm to room température. The reaction mixture was diluted with dichloromethane and washed with 2M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, concentrated and chromatographed on silica eluting with 0-100% ethyl acetate in hexanes to give 2,2-dimethylpropyl 110 hydroxy-2-methyl-propane-2-sulfonate as a clear colourless liquid.

¹H NMR (400MHz, CDCb) 3.94 (s, 2H) 3.80 (d, 2H) 2.53 (t, 1H) 1.46 (s, 6H) 1.00 (s, 9H).

Step 3: Préparation of 1-hydroxy-2-methyl-propane-2-sulfonic acid

HO

o ^OH

A mixture of 2,2-dimethylpropyl 1-hydroxy-2-methyl-propane-2-sulfonate (0.393g) and 6M aqueous hydrochloric acid (14.0 mL) was heated to 95°C for 4 hours. The reaction mixture was cooled and concentrated. The residue was taken up in acetonitrile, dried over magnésium sulfate and concentrated to give 1-hydroxy-2-methyl-propane-2-sulfonic acid as a colourless gum.

¹H NMR (400MHz, D₂O) 3.93-3.86 (m, 2H) 1.15-1.08 (m, 6H).

Step 4: Préparation of 2-methyl-1-(trifluoromethylsulfonyloxy)propane-2-sulfonate

A mixture of 2,6-dimethylpyridine (0.278g) and 1-hydroxy-2-methyl-propane-2-sulfonic acid (0.200g) in dichloromethane (2.33 mL) was cooled to 0°C in an ice bath. Trifluoromethylsulfonyl 25 trifluoromethanesulfonate (0.403g) was added dropwise and the reaction mixture was stirred cold for 15 minutes then allowed to warm to room température. The reaction mixture was quenched with water and extracted with dichloromethane (x3). The combined organic extracts were dried over magnésium sulfate and concentrated to give 2-methyl-1-(trifluoromethylsulfonyloxy)propane-2-sulfonate as a brown gum.

¹H NMR (400MHz, CDCb) 4.09 (s, 2H) 1.77 (s, 6H).

Step 5: Préparation of 2-methyl-1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A114

A mixture of 2-pyridazin-4-ylpyrimidine (0.040g), 2-methyl-1-(trifluoromethylsulfonyloxy)propane-2sulfonate (0.072g) and 1,4-dioxane (2.0 mL) was heated to 90°C overnight. The reaction mixture was cooled, concentrated and purified by préparative reverse phase HPLC to give 2-methyl-1-(4-pyrimidin5 2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate A114 as a white solid.

¹H NMR (400MHz, D₂O) 10.17-10.12 (m, 1H) 9.75-9.71 (m, 1H) 9.15 (dd, 1H) 8.97 (d, 2H) 7.61 (t, 1H)

5.04 (s, 2H) 1.37 (s, 6H).

Example 28: Préparation of ethoxy-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]phosphinate 10 A113

To a mixture of 2-pyridazin-4-ylpyrimidine (0.5g) in acetonitrile (10 mL) was added 1-bromo-215 diethoxyphosphoryl-ethane (0.929g). The mixture was heated at reflux for 24 hours. The reaction was concentrated and the residue washed with ethyl acetate and acetone. The residue was purified by préparative reverse phase HPLC (trifluoroacetic acid was présent in the eluent) to give 1-(2diethoxyphosphorylethyl)-4-pyrimidin-2-yl-pyridazin-1-ium, A124.

¹H NMR (400MHz, D₂O) 10.26 (d, 1H) 9.89 (d, 1H) 9.27 (dd, 1H) 9.00-9.06 (m, 2H) 7.69 (t, 1H) 5.1120 5.23 (m, 2H) 4.03-4.15 (m, 4H) 2.84 (dt, 2H) 1.21 (t, 6H).

Step 2: Préparation of ethoxy-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]phosphinate A113

A mixture of 1-(2-diethoxyphosphorylethyl)-4-pyrimidin-2-yl-pyridazin-1-ium (0.2g) in 2M aqueous hydrochloric acid (4 mL) was heated at 60°C for 4 hours. The reaction was concentrated and purified 25 by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give ethoxy-[2-(4pyrimidin-2-ylpyridazin-1 -ium-1 -yl)ethyl]phosphinate, A113.

¹H NMR (400MHz, D2O) 10.22 (d, 1H) 9.86 (d, 1H) 9.23 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 5.06 (dt, 2H) 3.85 (quin, 2H) 2.44-2.53 (m, 2H) 1.13 (t, 3H).

Example 29: Préparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride A138

Step 1: Préparation of 3-pyridazin-4-ylpyridazine

A microwave vial, under nitrogen atmosphère, was charged with tributyl(pyridazin-4-yl)stannane (0.697g), 3-bromopyridazine (0.25g), palladium (0) tetrakis(triphenylphosphine) (0.185g) and 1,4dioxane (7.86 mL) and heated at 140°C in the microwave for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 50% acetonitrile in dichloromethane to give 3-pyridazin-4-ylpyridazine as an orange solid.

1H NMR (400MHz, CDCb) 9.94-9.89 (m, 1H) 9.42 (dd, 1H) 9.35 (dd, 1H) 8.24 (dd, 1H) 8.09 (dd, 1H) 7.79-7.72 (m, 1H).

Step 2: Préparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate A182

A mixture of 3-pyridazin-4-ylpyridazine (0.25g), water (15 mL) and 3-bromopropanoic acid (0.363g) was heated at 100°C for 25 hours. The mixture was concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 3-(4-pyridazin-3-ylpyridazin-1-ium-1yl)propanoic acid 2,2,2-trifluoroacetate, A182.

1H NMR (400MHz, D₂O) 10.11 (d, 1H) 9.88 (d, 1H) 9.32 (dd, 1H) 9.10 (dd, 1H) 8.50 (dd, 1H) 7.99 (dd, 20 1H) 5.13 (t, 2H) 3.26 (t, 2H) (one CO2H proton missing).

Step 3: Préparation of 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride A234

A mixture of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoicacid 2,2,2-trifluoroacetate (6.56g) and 2M aqueous hydrochloric acid (114 mL) was stirred at room température for 3 hours. The mixture was concentrated and the residue was taken up in a small amount of water and freeze dried. The resulting glassy yellow solid was stirred in acetone (105 mL) overnight. The solid material was collected by filtration, washed with further acetone and dried under vacuum to give 3-(4-pyridazin-1-ium-3ylpyridazin-1-ium-1-yl)propanoic acid dichloride, A234, as a beige solid.

1H NMR (400MHz, D2O)10.11 (d, 1H) 9.88 (d, 1H) 9.36 (brd, 1H) 9.10(dd, 1H) 8.48-8.56 (m, 1H)7.928.07 (m, 1H) 4.98-5.20 (m, 2H) 3.18-3.32 (m, 2H) (one CO₂H proton missing)

Step 4: Préparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride A138

A mixture of 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride (0.541g) and 2propanol (10 mL) was heated at 90°C. Water was added drop wise until a clear solution was obtained, this took ~0.8 mL. To this was added further hot 2-propanol (10 mL) and the solution left to cool. Filtered off the precipitate and washed with cold 2-propanol and acetone and dried under vacuum to give 3-(4pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride, A138, as a beige solid.

1H NMR (400 MHz, D₂O) 10.11 (d, 1H) 9.87 (d, 1H) 9.32 (dd, 1H) 9.12-9.08 (m, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.12 (t, 2H) 3.24 (t, 2H) (one CO2H proton missing)

EXAMPLE 30: Préparation of 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride A213

Step 1: Préparation of 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate A5

A mixture of 3-pyridazin-4-ylpyridazine (0.41g), sodium 2-bromoethanesulfonic acid (0.656g) and water (7.78 mL) was heated at 100°Cfor 17 hours. The reaction mixture was cooled, filtered through a syringe filter and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to 5 give 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate as a yellow solid.

1H NMR (400MHz, D₂O) 10.15 (d, 1H) 9.87 (d, 1H) 9.33 (dd, 1H) 9.12 (dd, 1H) 8.52 (dd, 1H) 7.99 (dd, 1H) 5.32-5.19 (m, 2H) 3.73-3.65 (m, 2H)

Step 2: Préparation of 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride A213

A solution of 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate (0.2g) and 2M aqueous hydrochloric acid (5 mL) was stirred at room température for 2 hours. The mixture was concentrated and the residue was taken up in a small amount of water and freeze dried to give 2-(4-pyridazin-1-ium3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride as a cream glass like solid.

1H NMR (400MHz, D2O) 10.13 (d, 1H) 9.86 (d, 1H) 9.35 (dd, 1H) 9.11 (dd, 1H) 8.57 (dd, 1H) 8.05 (dd,

1H) 5.27-5.21 (m, 2H) 3.71-3.64 (m, 2H) (one NH proton missing)

Example 31: Préparation of 4-pyridazin-4-ylpyrimidin-2-amine

A microwave vial, under nitrogen atmosphère, was charged with tributyl(pyridazin-4-yl)stannane (3.42g), 20 4-pyridazin-4-ylpyrimidin-2-amine (0.727g), palladium (0) tetrakis(triphenylphosphine) (0.892g), N,Ndiisopropylethylamine (1.35 mL) and 1,4-dioxane (38.6 mL) and heated to 140°C in the microwave for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 70% acetonitrile in dichloromethane to give 4-pyridazin-4-ylpyrimidin-2-amine as a beige solid.

1H NMR (400MHz, de-DMSO) 9.82 (dd, 1H) 9.41 (dd, 1H) 8.47 (d, 1H) 8.22 (dd, 1H) 7.38 (d, 1H) 6.98 25 (brs, 2H)

Example 32: Préparation of 2-pyridazin-4-ylpyrimidin-4-ol

To a mixture of 2-pyridazin-4-ylpyrimidin-4-amine (0.1g) and acetic acid (1 mL) was added a solution of sodium nitrite (0.12g) in water (1 mL) drop wise at room température. The mixture was heated to 90°C for 30 minutes. The reaction mixture was concentrated and the resulting solid washed with water and t-butylmethylether to give 2-pyridazin-4-ylpyrimidin-4-ol.

1H NMR (400MHz, de-DMSO) 12.39-13.52 (m, 1H) 9.82-9.86 (m, 1H) 9.46 (d, 1H) 8.37 (d, 1H) 8.30 (d, 1H) 6.64 (d, 1H)

Example 33: Préparation of 4-methyl-5-pyrimidin-2-yl-pyridazine

Step 1 : Préparation of 2-(5-methyl-1,4-dihydropyridazin-4-yl)pyrimidine

A solution of 2-pyridazin-4-ylpyrimidine (2g) in tetrahydrofuran (20 mL), under nitrogen atmosphère, was cooled to 0°C and to this was added méthylmagnésium chloride (3M in tetrahydrofuran, 8.4 mL). The reaction mixture was allowed to warm to room température and stirred for 16 hours. The reaction mixture was partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine (2x), dried over anhydrous sodium sulfate and concentrated to give crude 2-(5methyl-1,4-dihydropyridazin-4-yl)pyrimidine, which was used without further purification

Step 2: Préparation of 4-methyl-5-pyrimidin-2-yl-pyridazine

To a solution of 2-(5-methyl-1,2-dihydropyridazin-4-yl)pyrimidine (1g) in dichloromethane (20 mL), under nitrogen atmosphère, was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.61g) and the mixture stirred at room température for 16 hours. The reaction mixture was concentrated and purified on silica using 20% methanol in dichloromethane as eluent. The resulting solid was triturated with ethyl acetate to give 4-methyl-5-pyrimidin-2-yl-pyridazine.

1H NMR (400MHz, de-DMSO) 9.54 (m, 1H) 9.28-9.31 (m, 1H) 9.02-9.07 (m, 2H) 7.60-7.68 (m, 1H) 2.62 (s, 3H)

Example 34: Préparation of 3-[4-(5-chloro-6-oxo-1H-pyrimidin-2-yl)pyridazin-1-ium-1yl]propanoic acid 2,2,2-trifluoroacetate A161

Step 1: Préparation of ethyl bromide

3-[4-(5-chloro-4-methoxy-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoate

To a mixture of 5-chloro-4-methoxy-2-pyridazin-4-yl-pyrimidine (0.4g) in acetonitrile (4 mL), under nitrogen atmosphère, was added ethyl 3-bromopropanoate (0.346 mL). The mixture was heated at 60°C for 48 hours and concentrated to give crude ethyl 3-[4-(5-chloro-4-methoxy-pyrimidin-210 yl)pyridazin-1-ium-1-yl]propanoate bromide, which was used without further purification.

Step 2: Préparation of 3-[4-(5-chloro-6-oxo-1H-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoic acid;2,2,2trifluoroacetate A161

A mixture of ethyl 3-[4-(5-chloro-4-methoxy-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoate (0.88g) and 15 2M aqueous hydrochloric acid (8.8 mL) was stirred at room température overnight. The mixture was concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 3-[4-(5-chloro-6-oxo-1H-pyrimidin-2-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2trifluoroacetate.

1H NMR (400MHz, D₂O) 9.95 (s, 1H) 9.87 (d, 1H) 9.00 (dd, 1H) 8.44 (s, 1H) 5.09 (t, 2H) 3.22 (t, 2H) 20 (one NH proton and one CO2H proton missing)

Example 35: Préparation of 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate

A184

Step 1 : Préparation of 2,2-dimethylpropyl methanesulfonate

A solution of triethylamine (8.1 mL) and 2,2-dimethylpropan-1-ol (2.3g) in dichloromethane (40 mL) was cooled to 0°C in an ice/acetone bath. To this was added methanesulfonyl chloride (2.2 mL) drop wise. The reaction mixture was stirred cold for 2 hours and washed with aqueous ammonium chloride. The organic layer was concentrated and the residue dissolved in ether. The ether solution was passed through a plug of silica eluting with further ether. Concentration of the ether filtrate gave 2,2dimethylpropyl methanesulfonate as a light yellow liquid.

1H NMR (400MHz, CDCh) 3.90-3.85 (m, 2H) 3.01 (s, 3H) 1.00 (s, 9H)

Step 2: Préparation of 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate

A solution of 2,2-dimethylpropyl methanesulfonate (1.75g) in tetrahydrofuran (22.1 mL) was cooled to 78°C under nitrogen atmosphère. To this was added drop wise n-butyllithium (2.5 mol/L in hexane, 5.1 mL). The reaction mixture was gradually warmed to -30°C over 2 hours and acetone (7.73 mL) was added. The reaction mixture was warmed to room température and stirred for a further 1.5 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate (x3). The combined organic extracts were dried with magnésium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in iso-hexane to give 2,2-dimethylpropyl 2-hydroxy-2-methylpropane-1-sulfonate as a colourless liquid.

1H NMR (400MHz, CDCh) 3.90 (s, 2H) 3.32 (s, 2H) 2.79 (brs, 1H) 1.44 (s, 6H) 0.99 (s, 9H)

Step 3: Préparation of 2-hydroxy-2-methyhpropane-1-sulfonic acid

A mixture of 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate (1.84g) and 6M aqueous hydrochloric acid (32.8 mL) was heated at 95°C for 4 hours. The reaction mixture was cooled to room température and freeze dried overnight to give 2-hydroxy-2-methyl-propane-1-sulfonic acid as an off white solid.

1H NMR (400 MHz, D₂O) 2.99 (s, 2H) 1.24 (s, 6H) (one OH proton and one SO3H proton missing)

Step 4: Préparation of 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A184

A mixture of 2-pyridazin-4-ylpyrimidine (0.507g) in dry acetonitrile (32.1 mL) was cooled in an ice bath.

To this was added l,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (0.663 mL) and the reaction mixture stirred at room température for 15 minutes. To this was added triphenylphosphine (1.68g) and a solution of 2-hydroxy-2-methyl-propane-1-sulfonic acid (0.741g) in dry acetonitrile (0.5 mL) followed by drop wise addition of diisopropyl azodicarboxylate (1.26 mL, 1.30 g). The reaction mixture was then heated at 80°C for 144 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1sulfonate as a yellow solid.

1H NMR (400MHz, CD3OD) 10.41-10.35 (m, 1H) 10.05-9.99 (m, 1H) 9.31 (dd, 1H) 9.12 (d, 2H) 7.67 (t, 1H) 3.67 (s, 2H)2.10(s, 6H)

Example 36: Préparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A181

Step 1: Préparation of 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate

A solution of 2,2-dimethylpropyl methanesulfonate (2g) in tetrahydrofuran (25 mL) was cooled to -78°C under nitrogen atmosphère and n-butyllithium (2.5 mol/L in hexane, 5.8 mL) was added drop wise. The reaction mixture was gradually warmed to -30°C over 1 hour and acetaldehyde (6.8 mL) was added. The reaction mixture was warmed to room température and stirred for a further 2.5 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate (x3). The combined organic extracts were dried with magnésium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in iso-hexane to give 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate as a yellow liquid.

1H NMR (400MHz, CDCb) 4.47-4.34 (m, 1H) 3.96-3.87 (m, 2H) 3.25-3.17 (m, 2H) 3.01 (brs, 1H) 1.34 (d, 3H) 1.00 (s, 9H)

Step 2: Préparation of 2-hydroxypropane-1-sulfonic acid °\\ ^OH

HO

A mixture of 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate (1.35g) and 6M aqueous hydrochloric acid (32.8 mL) was heated at 95°C for 4 hours. The reaction mixture was cooled to room température and freeze dried overnight to give 2-hydroxypropane-1-sulfonic acid as a brown solid.

1H NMR (400 MHz, D₂O) 4.17-4.06 (m, 1H) 2.99-2.85 (m, 2H) 1.16 (d, 3H) (one OH proton and one SO3H proton missing)

Step 3: Préparation of 2-(trifluoromethylsulfonyloxy)propane-1-sulfonic acid

To a mixture of 2-hydroxypropane-1-sulfonic acid (0.2g) in dichloromethane (2.57 mL) was added 2,6dimethylpyridine (0.33 mL) and the resulting mixture was cooled to 0°C. To this was added drop wise trifluoromethylsulfonyl trifluoromethanesulfonate (0.264 mL) and stirring continued at this température for 15 minutes. Cooling was removed and the reaction mixture was stirred at room température for a further hour. The reaction mixture was quenched with water and extracted with dichloromethane (x3). The combined organic extracts were dried with magnésium sulfate and concentrated to give 2(trifluoromethylsulfonyloxy)propane-l-sulfonic acid as a brown gum, ~50% purity. The product was used immediately in subséquent reactions without further purification.

1H NMR (400MHz, CDCb) product peaks only 5.57-5.41 (m, 1H) 4.18-3.98 (m, 1H) 3.58-3.35 (m, 1H) 1.76-1.65 (m, 3H) (one SO₃H proton missing)

Step 4: Préparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A181

A mixture of 2-pyridazin-4-ylpyrimidine (0.15g), 2-(trifluoromethylsulfonyloxy)propane-1-sulfonate (0.55g) and 1,4-dioxane (7.8 mL) was heated at 90°C for 24 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1sulfonate as a yellow solid.

1H NMR (400MHz, CD₃OD) 10.43-10.37 (m, 1H) 9.93 (dd, 1H) 9.34 (dd, 1H) 9.11 (d, 2H) 7.68 (t, 1H)

5.66-5.53 (m, 1H) 3.66 (dd, 1H) 3.43 (dd, 1H) 1.83 (d, 3H)

Example 37: Préparation of 2-(4-pyrimidin-2-ylpyridazin-1 -ium-1 -yl)ethanol 2,2,2-trifluoroacetate A195

Step 1 : Préparation of 2-(4-pyrimidin-2-ylpyridazin-1 -ium-1 -yl)ethyI sulfate A194

A mixture of 2-pyridazin-4-ylpyrimidine (0.2g), 1,2-dichloroethane (3.8 mL) and 1,3,2-dioxathiolane 2,2dioxide (0.198g) was stirred at room température for 22 hours. The resulting precipitate was filtered off and washed with dichloromethane to give a mixture of regio-isomers. This mixture was triturated with 10 water and filtered to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl sulfate as a pale grey solid.

1H NMR (400 MHz, D₂O) 10.28 (d, 1H) 9.87 (d, 1H) 9.29 (dd, 1H) 9.07 (d, 2H) 7.72 (t, 1H) 5.18-5.28 (m, 2H) 4.62-4.72 (m, 2H)

Step 2: Préparation of 2-(4-pyrimidin-2-ylpyridazin-1 -ium-1 -yl)ethanol 2,2,2-trifluoroacetate A195

A mixture of crude 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl sulfate (0.25g, mixture of regio-isomers) and 2M aqueous hydrochloric acid (5 mL) was heated at 80°C for 12 hours. The reaction mixture was concentrated, washed with cyclohexane and ferf-butylmethylether and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 2-(4-pyrimidin-2-ylpyridazin-1 -ium-1 yl)ethanol 2,2,2-trifluoroacetate.

1H NMR (400 MHz, D₂O) 10.25 (d, 1H) 9.81 (d, 1H) 9.26 (dd, 1H) 9.05 (d, 2H) 7.70 (t, 1H) 4.94-5.08 (m, 2H) 4.17-4.22 (m, 2H)

Example 38: Préparation of 3-[4-(5-carbamoylpyrazin-2-yl)pyridazin-1-ium-1-yl]propanoic acid

2,2,2-trifluoroacetate A202

A mixture of ethyl 3-[4-(5-cyanopyrazin-2-yl)pyridazin-1-ium-1-yl]propanoate bromide (0.33g) and 2M aqueous hydrochloric acid (5 mL) was stirred at room température for 40 hours. The reaction mixture was concentrated, washed with cyclohexane and tert-butylmethylether and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 3-[4-(5-carbamoylpyrazin-2yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate.

1H NMR (400 MHz, D₂O) 10.18 (d, 1H) 9.92 (d, 1H) 9.51 (d, 1H) 9.43 (d, 1H) 9.20 (dd, 1H) 5.18 (t, 2H) 3.31 (t, 2H) (two NH protons and one CO2H proton missing)

Example 39: Préparation of [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)propyl]ammonium 2,2,2-trifluoroacetate A201

Step 1: Préparation of [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride

To a mixture of (2S)-2-amino-4-bromo-butanoic acid (0.2g) in dry methanol (4 mL) at 0°C, under nitrogen atmosphère, was added thionyl chloride (0.392g) drop wise. The reaction mixture was stirred overnight at room température and concentrated to give crude [(1S)-3-bromo-1-methoxycarbonylpropyl]ammonium chloride as an orange gum, which was used without further purification.

Step 2: Préparation of methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate

Crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride was stirred in dichloromethane (4 mL) and a solution of sodium hydrogen carbonate (0.28g) in water (4 mL) was added. The mixture was cooled to 0°C and benzyl carbonochloridate (0.225g) was added. The reaction mass was warmed to room température and stirred for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in cyclohexane to give methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate.

1H NMR (400MHz, CDCb) 7.30-7.40 (m, 5H) 5.37-5.43 (m, 1H) 5.13 (s, 2H) 3.78 (s, 3H) 3.42-3.46 (m, 2H) 2.25-2.49 (m, 2H)

Step 3: Préparation of methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)butanoate iodide

To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate (0.1g) in dry acetone (2 mL), under nitrogen atmosphère, was added sodium iodide (0.054g). The reaction mixture was stirred at room température overnight. To this was added 2-pyridazin-4-ylpyrimidine (0.048g) and the mixture heated at reflux for 16 hours. The reaction mixture was concentrated and the crude methyl (2S)-2(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide was used in the next step without further purification.

Step 4: Préparation of [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2trifluoroacetate A201

A mixture of methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide (0.5g) and concentrated hydrochloric acid (4.9 mL) was heated at 80°C for 30 minutes. The reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate (3x20 mL). The aqueous layer was purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2trifluoroacetate.

1H NMR (400 MHz, D₂O) 10.26 (d, 1H) 9.90 (d, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 5.17 (t, 2H) 4.09 (dd, 1H) 2.76-2.79 (m, 2H) (Three NH protons and one CO2H proton missing)

Example 40: Préparation of [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)propyl]ammonium 2,2,2-trifluoroacetate A207

Step 1: Préparation of [(1R)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride

To a mixture of [(1R)-3-bromo-1-carboxy-propyl]ammonium bromide (0.1g) in dry methanol (2 mL) at 0°C, under nitrogen atmosphère, was added thionyl chloride (0.083 mL) drop wise. The reaction mixture was stirred overnight at room température and concentrated to give crude [(1S)-3-bromo-1methoxycarbonyl-propyl]ammonium chloride as a yellow solid, which was used without further purification.

Step 2: Préparation of [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)propyl]ammonium bromide chloride

To a mixture of 2-pyridazin-4-ylpyrimidine (0.1g) in acetonitrile (3.16 mL) was added [(1R)-3-bromo-119408 methoxycarbonyl-propyljammonium chloride (0.16g) The mixture was heated at reflux for 12 hours. The reaction mixture was concentrated to give crude [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2ylpyridazin-1-ium-1-yl)propyl]ammonium bromide as a dark brown gum, which was used without further purification.

Step 3: Préparation of [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2trifluoroacetate A207

A mixture of [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium bromide (0.5g) and 2M aqueous hydrochloric acid (7.29 mL) was heated at 80°C for 2 hours. The 10 reaction mixture was concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)propyl]ammonium 2,2,2-trifluoroacetate.

1H NMR (400 MHz, D₂O) 10.22 (s, 1H) 9.87 (d, 1H) 9.24 (d, 1H) 8.99-9.04 (m, 2H) 7.66 (t, 1H) 5.16 (t, 2H) 4.17 (dd, 1H) 2.69-2.85 (m, 2H) (Three NH protons and one CO2H proton missing)

Example 41: Préparation of hydroxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A205

Step 1: Préparation of 1-(diethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium 2,2,220 trifluoroacetate A230

To a solution of diethoxyphosphorylmethanol (0.2g) in dichloromethane (3.57 mL) at -78°C, under nitrogen atmosphère, was added A/,A/-diisopropylethylamine (0.244 mL) followed by 25 trifluoromethylsulfonyl trifluoromethanesulfonate (0.24 mL). The reaction was warmed slowly to 0°C over 2 hours. To this mixture was added a solution of 2-pyridazin-4-ylpyrimidine (0.188g) in dichloromethane (3.57 mL) and the reaction was stirred at room température for 2 hours. The reaction mixture was quenched with water, diluted with éthanol, concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 1-(diethoxyphosphorylmethyl)-419408 pyrimidin-2-yl-pyridazin-1 -ium 2,2,2-trifluoroacetate as a brown gum.

1H NMR (400MHz, de-DMSO) 10.39-10.35 (m, 1H) 10.01 (d, 1H) 9.47 (dd, 1H) 9.22 (d, 2H) 7.84 (t, 1H) 5.78 (d, 2H) 4.24-4.13 (m, 4H) 1.27 (t, 6H)

Step 2: Préparation of hydroxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A205 To a mixture of 1-(diethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium 2,2,2-trifluoroacetate (0.17g) in dry acetonitrile (7.42 mL) at room température, under nitrogen atmosphère, was added bromo(trimethyl)silane (0.049 mL). After stirring overnight further bromo(trimethyl)silane (0.049 mL) was added After stirring overnight again a final portion of bromo(trimethyl)silane (0.049 mL) was added.

After stirring overnight the reaction mixture was quenched with water and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give hydroxy-[(4-pyrimidin-2-ylpyridazin-1ium-1-yl)methyl]phosphinate as an off white solid.

1H NMR (400 MHz, D2O) 10.16-10.13 (m, 1H) 9.72-9.68 (m, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (d, 2H) (one OH proton missing)

Example 42: Préparation of [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)ethyl]ammonium 2,2,2-trifluoroacetate A208

Step 1: Préparation of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)propanoate

To a mixture of 2-pyridazin-4-ylpyrimidine (0.05g) in dry acetonitrile (1 mL) was added terf-butyl N-[(3S)25 2-oxooxetan-3-yl]carbamate (0.071g) and the reaction mixture was stirred at room température for 48 hours. Concentration of the reaction mixture gave crude (2S)-2-(tert-butoxycarbonylamino)-3-(419408 pyrimidin-2-ylpyridazin-1 -ium-1 -yl)propanoate, which was used without further purification.

Step 2: Préparation of [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]ammonium 2,2,2trifluoroacetate A208

A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate (0.4g) and 2M aqueous hydrochloric acid (10 mL) was stirred at room température for 18 hours. The reaction mixture was concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1 -ium-1 -yl)ethyl]ammonium 2,2,2-trifl u oroacetate.

1H NMR (400 MHz, D₂O) 10.26 (s, 1H) 9.94 (d, 1H) 9.31-9.34 (m, 1H) 9.04 (dd, 2H) 7.69 (t, 1H) 5.48 (d, 2H) 4.75 (t, 1H) (Three NH protons and one CO2H proton missing)

Example 43: Préparation of W-methyl-2-pyridazin-4-yl-pyrimidine-5-sulfonamide

Step T. Préparation of 2-chloro-A/-methyl-pyrimidine-5-sulfonamide

Cooled a solution of 2-chloropyrimidine-5-sulfonyl chloride (0.05g) in tetrahydrofuran (1 mL) at -78°C, under nitrogen atmosphère, and added methanamine (2M in tetrahydrofuran, 0.117 mL) followed by A/,/V-diisopropylethylamine (0.065 mL). The reaction was stirred for 20 minutes and quenched with ice cold water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were concentrated to give crude 2-chloro-/\/-methyl-pyrimidine-5-sulfonamide.

1H NMR (400MHz, de-DMSO) 9.10 (s, 2H) 7.96-8.00 (m, 1H) 2.54 (d, 3H)

Step 2: Préparation of/V-methyl-2-pyridazin-4-yl-pyrimidine-5-sulfonamide

A microwave vial, under nitrogen atmosphère, was charged with tributyl(pyridazin-4-yl)stannane (0.64g), 2-chloro-/\/-methyl-pyrimidine-5-sulfonamide (0.3g), palladium (0) tetrakis(triphenylphosphine) (0.167g) and 1,4-dioxane (4.5 mL) and heated at 130°C in the microwave for 30 minutes. The reaction mixture was concentrated and triturated with tert-butylmethylether to give /V-methyl-2-pyridazin-4-yl-pyrimidine5-sulfonamide as a black solid.

1H NMR (400MHz, de-DMSO) 10.03-10.04 (m, 1H) 9.53-9.54 (m, 1H) 9.35 (s, 2H) 8.49-8.51 (m, 1H)

8.04-8.05 (m, 1H) 2.58 (d, 3H)

Example 44: Préparation of 2-(6-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate A212

Step 1 : Préparation of 3-methyl-5-pyrimidin-2-yl-1 H-pyridazin-6-one

To a mixture of 5-bromo-3-methyl-1H-pyridazin-6-one (0.1g) in degassed 1,4-dioxane (2 mL), under nitrogen atmosphère, was added tributyl(pyrimidin-2-yl)stannane (0.234g), dichloropalladium triphenylphosphane (0.038g) and cuprous iodide (0.02g) and the mixture heated at 130°C for 2 hours. The reaction mixture was diluted with 1,4-dioxane, filtered, using a syringe filter, to remove insoluble material and purified on silica using a gradient from 0 to 10% methanol in dichloromethane to give 3methyl-5-pyrimidin-2-yl-1H-pyridazin-6-one as a white solid.

1H NMR (400MHz, de-DMSO) 12.90-13.20 (br s, 1H) 8.92-8.93 (m, 2H) 7.68 (s, 1H) 7.53-7.54 (m, 1H) 2.31 (s, 3H)

Step 2: Préparation of 3-chloro-6-methyl-4-pyrimidin-2-yl-pyridazine

A mixture of 3-methyl-5-pyrimidin-2-yl-1H-pyridazin-6-one (1.93g) and phosphorus oxychloride (1.93 mL) was heated at 100°C for 3 hours. After cooling, the reaction mixture was concentrated, poured onto ice and basified with a cold aqueous sodium bicarbonate solution to pH 8. The aqueous was extracted with ethyl acetate (2x150 mL). The combined organic layers were washed with water (2x40 mL), dried over sodium sulphate and concentrated to give 3-chloro-6-methyl-4-pyrimidin-2-yl-pyridazine.

1H NMR (400MHz, CDCb) 8.94-8.95 (m, 2H) 7.78 (s, 1H) 7.42-7.44 (m, 1H) 2.80 (s, 3H)

Step 3: Préparation of 3-methyl-5-pyrimidin-2-yl-pyridazine

Triethylamine (1.32 mL) was added to a solution of 3-chloro-6-methyl-4-pyrimidin-2-yl-pyridazine (1.5g) in a mixture of éthanol (40 mL) and ethyl acetate (10 mL). This mixture was degassed with nitrogen and % palladium on carbon (0.2g) was added. This mixture was hydrogenated under a balloon atmosphère of hydrogen for 1 hour at room température. Further catalyst (0.2g) was added and hydrogénation continued for an additional 3 hours. The reaction mixture was diluted with éthanol (50 mL) and filtered through Celite, washing with éthanol (2x40 mL). The filtrate was concentrated and purified on silica using a gradient from 0 to 10% methanol in dichloromethane to give 3-methyl-5pyrimidin-2-yl-pyridazine as a white solid.

1H NMR (400MHz, CDCI₃) 9.97 (d, 1H) 8.89 (d, 2H) 8.27 (d, 1H) 7.35-7.38 (m, 1H) 2.82 (s, 3H)

Step 4: Préparation of 2-(6-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate A212

A mixture of 3-methyl-5-pyrimidin-2-yl-pyridazine (0.8g) and sodium 2-bromoethanesulfonate (1.078g) in water (16 mL) was heated at 120°C for 24 hours. The reaction mixture was concentrated, washed with ferf-butylmethylether and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give 2-(6-methyl-4-pyrimidin-2-yl-pyridazin-1-ium-1-yl)ethanesulfonate.

1H NMR (400 MHz, D2O) 10.00 (d, 1H) 9.08 (d, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.16 (t, 2H) 3.68 (t, 2H)

3.12 (s, 3H)

Example 45: Préparation of dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)acetyl]azanide A214

Step 1 : Préparation of 2-bromo-/V-(dimethylsulfamoyl)acetamide

To a solution of dimethylsulfamide (0.5g) and 4-(dimethylamino)pyridine (0.541g) in dichloromethane (19.9 mL) at 0°C was added bromoacetyl bromide (0.903g) drop wise. The reaction was slowly warmed to room température and stirred for 24 hours. The reaction was partitioned with 0.5M aqueous hydrochloric acid. The organic layer was dried over magnésium sulfate and concentrated to give crude 2-bromo-N-(dimethylsulfamoyl)acetamide as a pale yellow oil. The product was used without further purification.

Step 2: Préparation of dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetyl]azanide A214 To a solution of 2-pyridazin-4-ylpyrimidine (0.15g) in acetonitrile (10 mL) was added 2-bromo-/V(dimethylsulfamoyl)acetamide (0.21g) and the mixture heated at 80°C for 16 hours. The resulting precipitate was filtered, washed with acetonitrile (2x20 mL) to give dimethylsulfamoyl-[2-(4-pyrimidin-2ylpyridazin-1-ium-1-yl)acetyl]azanide as a light green solid.

1H NMR (400 MHz, de-DMSO) 10.36 (s, 1H) 10.06-10.10 (m, 1H) 9.56-9.62 (m, 1H) 9.18-9.22 (m, 2H) 7.82-7.86 (m, 1H) 5.88-5.94 (m, 2H) 2.80-2.86 (m, 6H)

Example 46: Préparation of N-(2-bromoethyl)-1,1,1-trifluoro-methanesulfonamide

A mixture of 2-bromoethanamine bromide (1g) and A/,A/-diisopropylethylamine (1.42g) was stirred in dichloromethane (24.5 mL) at 0°C until the reaction became homogeneous. Trifluoromethanesulfonic anhydride (1.55g) was added drop wise and stirred at 0°C for 3 hours. The reaction mixture was concentrated and partitioned between 1M aqueous hydrochloric acid and diethyl ether. The organic layer was washed with water, 1M aqueous hydrochloric acid and brine, dried over magnésium sulfate and concentrated to afford A/-(2-bromoethyl)-1,1,1-trifluoro-methanesulfonamide as a pale yellow oil. 1H NMR (400MHz, CDCb) 5.44 (br. s., 1H) 3.71 (q, 2H) 3.53 (t, 2H).

Example 47: Préparation of 2-bromo-N-methoxy-acetamide

To a suspension of methoxyamine hydrochloride (0.248g) and /V,/V-diisopropylethylamine (2.29 mL) in tetrahydrofuran (10 mL) at 0°C was added 2-bromoacetyl bromide (0.5g) drop wise. The reaction mixture was warmed to room température and stirred for 2 hours. The reaction mixture was concentrated and purified on silica using 2:1 iso-hexane:ethyl acetate to give 2-bromo-/V-methoxyacetamide as a pale yellow liquid.

1H NMR (400MHz, CDCb) 4.48 (s, 2H) 4.24-4.28 (m, 1H) 3.88-3.92 (m, 3H)

Example 48: Préparation of 3-bromo-N-cyano-propanamide

O

To a stirred solution of cyanamide (0.5g) in water (10 mL) and tetrahydrofuran (10 mL) at 0°C was added sodium hydroxide (1.427g). After 10 minutes at 0°C a solution of 3-bromopropanoyl chloride (1.27 mL) in tetrahydrofuran (5 mL) was added drop wise. The resulting reaction mixture was stirred at room température for 3 hours. Water was added and the mixture was extracted with dichloromethane (2x75 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3bromo-/V-cyano-propanamide as a light yellow liquid.

1H NMR (400 MHz, de-DMSO) 12.40 (brs, 1H) 3.54-3.70 (m, 2H) 2.80-2.94 (m, 2H)

Example 49: Préparation of yl)butyl]ammonium dichloride A211

[(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-

Step 1 : Préparation of dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate

To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)pentanedioate (0.3g) in acetonitrile (6 mL), under nitrogen atmosphère, was added 4-dimethylaminopyridine (0.028g). The mixture was cooled to 0°C and di-tert-butyl dicarbonate (0.264g) was added. The reaction was allowed to warm to room température and stirred for 18 hours. The reaction mixture was partitioned between water and ethyl acetate (80 mL) and extracted with further ethyl acetate (80 mL). The combined organic layers were washed with 10% aqueous citric acid, followed by saturated sodium bicarbonate solution and brine. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica using ethyl acetate in cyclohexane to give dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate as a colourless gum.

1H NMR (400MHz, CDCb) 4.95 (dd, 1H) 3.73 (s, 3H) 3.68 (s, 3H) 2.36-2.54 (m, 3H) 2.15-2.23 (m, 1H)

1.50 (s, 18H)

Step 2: Préparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate

Cooled a solution of dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate (0.28g) in diethyl ether (5.6 mL), under nitrogen atmosphère, to -78°C and added slowly diisobutylaluminum hydride (1M in Toluene, 0.82 mL). The reaction was stirred at -78°C for 10 minutes, then quenched with water (0.094 mL) and stirred for a further 30 minutes. After warming to room température solid sodium sulfate was added. The mixture was filtered through Celite, washed with tert-butylmethylether and the filtrate concentrated to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate.

1H NMR (400MHz, CDCb) 9.78 (s, 1H) 4.90 (dd, 1H) 3.73 (m, 3H) 2.45-2.66 (m, 3H) 2.11-2.28 (m, 1H) 1.42-1.63 (m, 18H)

Step 3: Préparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate

Cooled a solution of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate (0.2g) in dry methanol (4 mL), under nitrogen atmosphère, to 0°C and added sodium borohydride (0.025g) portion wise and stirred for 2 hours. The reaction mixture was concentrated and purified on silica using ethyl acetate in cyclohexane to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate as a colourless gum.

1H NMR (400MHz, CDCb) 4.90 (dd, 1H) 3.74-3.67 (m, 5H) 2.30-2.20 (m, 1H) 1.99-1.89 (m, 1H) 1.681.41 (s, 20H) (one OH proton missing)

Step 4: Préparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate

100

Cooled a solution of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate (4g) in dry tetrahydrofuran (40 mL) to 0°C and added carbon tetrabromide (5.728g). To this was added drop wise a solution of triphenylphosphine (4.576g) in tetrahydrofuran (40 mL). The reaction was allowed to warm to room température and stirred for 24 hours. The reaction mixture was concentrated and purified on silica using ethyl acetate in cyclohexane to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromopentanoate.

1H NMR (400MHz, CDCb) 4.88 (dd, 1H) 3.73 (s, 3H) 3.38-3.50 (m, 2H) 2.24-2.27 (m, 1 H) 1.85-2.12 (m, 3H) 1.51 (s, 18H)

Step 5: Préparation of [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)butyl]ammonium 2,2,2-trifluoroacetate

To a mixture of 2-pyridazin-4-ylpyrimidine (0.4g) in acetonitrile (12.6 mL) was added methyl (2S)-2[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate (1.141g) and the reaction mixture was heated at reflux for 12 hours. The reaction mixture was concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent which led to the loss of the BOC-protecting groups) to give [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium 2,2,2trifluoroacetate.

1H NMR (400 MHz, D₂O) 10.22 (d, 1H) 9.80-9.86 (m, 1H) 9.20-9.27 (m, 1H) 8.99-9.06 (m, 2H) 7.667.73 (m, 1H) 4.90-5.01 (m, 2H) 4.20 (t, 1H) 3.76-3.84 (m, 3H) 2.20-2.40 (m, 2H) 1.97-2.18 (m, 2H) (NH protons are missing)

Step 6: Préparation of [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium dichloride A211

101

A mixture of [(1 S)-1 -methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1 -ium-1 -yl)butyl]ammonium;2,2,2trifluoroacetate (0.1g) and 4M aqueous hydrochloric acid (0.78 mL) was heated at 60°C for 14 hours. The reaction mixture was concentrated to give [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1yl)butyl]ammonium dichloride.

1H NMR (400 MHz, D₂O) 10.24 (dd, 1H) 9.87 (dd, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 4.99 (t, 2H) 4.08 (t, 1H) 2.23-2.44 (m, 2H) 2.00-2.16 (m, 2H) (three NH protons and one CO2H proton missing)

Example 50: Préparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride A26

Step 1: Préparation of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate

A54

A mixture of methyl 3-bromopropanoate (1.58g), 2-pyridazin-4-ylpyrimidine (0.5g) in acetonitrile (31.6 15 mL) was heated at 80°C for 24 hours. The reaction mixture was cooled, concentrated and partitioned between water (10 mL) and dichloromethane (20 mL). The aqueous layer was purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give methyl 3-(4-pyrimidin-2ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate as an orange gum.

¹H NMR (400MHz, D₂O) 10.15 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.98 (d, 2H) 7.63 (t, 1H) 5.12 (t, 2H) 20 3.59 (s, 3H) 3.25 (t, 2H) ¹H NMR (400MHz, CD3OD) 10.43-10.32 (m, 1H) 10.04 (d, 1H) 9.43 (dd, 1H) 9.12 (d, 2H) 7.65 (t, 1H)

5.18 (t, 2H) 3.70 (s, 3H) 3.36-3.27 (m, 2H)

Step 2: 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride A26

A mixture of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate;2,2,2-trifluoroacetate (0.392g) and conc. hydrochloric acid (7.66 mL) was heated at 80°C for 3 hours. The reaction mixture was cooled, concentrated and triturated with acetone to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a beige solid.

102 ¹H NMR (400MHz, D₂O) 10.16 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO2H proton missing) ¹H NMR (400MHz, CD3OD) 10.43-10.32 (m, 1H) 10.02 (d, 1H) 9.36 (dd, 1H) 9.09 (d, 2H) 7.68 (t, 1H)

5.16 (t, 2H) 3.29-3.21 (m, 2H) (one CO2H proton missing)

Example 51: Préparation of methoxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate

A245

Step 1 : Préparation of dimethoxyphosphorylmethyl trifluoromethanesulfonate

A solution of dimethoxyphosphorylmethanol (1g) in dichloromethane (20 mL) was cooled to -78°C and 2,6-Lutidine (1.32 mL) followed by trifluoromethylsulfonyl trifluoromethanesulfonate (1.91g) was added. The resulting reaction mixture was allowed to warm to room température and stirred for 1 hour. The 15 reaction mixture was poured into water and extracted with dichloromethane (50 mL). The organic layer was washed with 1M aqueous hydrochloric acid (50 mL), dried over anhydrous sodium sulfate and concentrated to give dimethoxyphosphorylmethyl trifluoromethanesulfonate as a pale yellow liquid. 1H NMR (400 MHz, de-DMSO) 4.82 (d, 2H) 3.78 (s, 3H) 3.74 (s, 3H)

Step 2: Préparation of 1-(dimethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium trifluoromethanesulfonate A238

To a stirred solution of 2-pyridazin-4-ylpyrimidine (0. 6g) in acetonitrile (15 mL) was added dimethoxyphosphorylmethyl trifluoromethanesulfonate (1.549g) at room température. The resulting 25 reaction mixture was stirred at room température for 16 hours. The reaction mixture was concentrated and the obtained residue was partitioned between water (75 mL) and dichloromethane (75 mL). The aqueous layer was washed with further dichloromethane (75 mL), concentrated and purified by Reverse Phase chromatography using 100% water (note: no added trifluoroacetic acid) to give 1(dimethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium trifluoromethanesulfonate as a brown 30 liquid

103

1H NMR (400 MHz, D₂O) 10.37 (d, 1H) 10.00 (d, 1H) 9.48-9.42 (m, 1H) 9.23-9.20 (m, 2H) 7.83 (t, 1H)

5.82 (d, 2H) 3.83 (s, 3H) 3.82-3.78 (m, 3H)

Step 3: Préparation of methoxy-[(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methyl]phosphinate A245

To a stirred solution of 1-(dimethoxyphosphorylmethyl)-4-pyrimidin-2-yl-pyridazin-1-ium trifluoromethanesulfonate (0.1g) in dichloromethane (10 mL) was added bromotrimethylsilane (0.097 mL) at room température. The reaction mixture was stirred at room température for 2 hours. The reaction was concentrated and the residue was dissolved in water (25 mL) and washed with dichloromethane (2x25 mL). The aqueous layer was concentrated and purified by préparative reverse phase HPLC (trifluoroacetic acid is présent in the eluent) to give methoxy-[(4-pyrimidin-2-ylpyridazin-1ium-1-yl)methyl]phosphinate as a light brown solid.

1H NMR (400 MHz, D2O) 10.19-10.15 (m, 1H) 9.73-9.69 (m, 1H) 9.25-9.20 (m, 1H) 9.01 (d, 2H) 7.687.62 (m, 1H) 5.19 (d, 2H) 3.61 (d, 3H)

Additional compounds in Table A (below) were prepared by analogues procedures, from appropriate starting materials. The skilled person would understand that the compounds of Formula (I) may exist as an agronomically acceptable sait, a zwitterion or an agronomically acceptable sait of a zwitterion as described hereinbefore. Where mentioned the spécifie counterion is not considered to be limiting, and the compound of Formula (I) may be formed with any suitable counter ion.

NMR spectra contained herein were recorded on either a 400MHz Bruker AVANCE III HD equipped with a Bruker SMART probe unless otherwise stated. Chemical shifts are expressed as ppm downfield from TMS, with an internai reference of either TMS or the residual solvent signais. The following multiplicities are used to describe the peaks: s = singlet, d = doublet, t = triplet, dd = double doublet, dt = double triplet, q = quartet, quin = quintet, m = multiplet. Additionally br. is used to describe a broad signal and app. is used to describe and apparent multiplicity.

Additional compounds in Table A were prepared by analogous procedures, from appropriate starting materials.

104

Table A - Physical Data for Compounds of the Invention

Compound Number	Structure	¹H NMR
A1	I O Οχ // / 0	(400MHz, D₂O) 10.19 (d, 1H) 9.84 (d, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.27-5.18 (m, 2H) 3.71-3.63 (m, 2H)
A2	Cl ii₊ Il U JL / Br“	(400MHz, D₂O) 10.22 (d, 1H) 9.84 (d, 1H) 9.30 (dd, 1H) 9.01 (d, 2H) 7.66 (t, 1H) 5.84 (s, 2H) 3.79 (s, 3H)
A3	Z^ \-Z Z /) W // O i O	(400MHz, D2O) 10.26 (brs, 1H) 9.94 (br d, 1H) 9.27-9.39 (m, 1H) 8.96-9.14 (m, 2H) 7.56-7.73 (m, 1H) 5.97 (s, 2H)
A4	t A ° S. O* °	(400MHz, D2O) 10.09 (d, 1H) 9.87 (d, 1H) 9.35 (d, 1H) 9.12 (dd, 1H) 9.04 (d, 1H) 8.29 (dd, 1H) 5.24 (t, 2H) 3.67 (t, 2H)
A5	i O // ω_χ/—z / \^χ\ ^zv \ / \=z	(400MHz, D2O) 10.15 (d, 1H) 9.87 (d, 1H)9.33 (dd, 1H) 9.12 (dd, 1H)8.52(dd, 1H) 7.99 (dd,1H) 5.32-5.19 (m, 2H) 3.73-3.65 (m, 2H)
A6	€} Z^ 7 \ / Z=^/ω'' O i O	(400MHz, D2O) 10.18 (d, 1H) 9.80 (d, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.01 (t, 2H) 2.98 (t, 2H) 2.53 (quin, 2H)

105

Compound Number	Structure	¹H NMR
A7	x o // ,--Z \ ^Z __/ b U- LL	(400MHz, D₂O) 10.08 (d, 1H) 9.79 (d, 1 H) 9.39 (d, 1 H) 9.08 (dd, 1 H) 8.89-8.83 (m, 1H) 8.78 (d, 1H) 5.24-5.16 (t, 2H) 3.65 (t, 2H)
A8	tV. , ^N ï Ί / l ₊ o—' IL /x / // ^0 ⁰ L F. JL 0 K I F	(400MHz, CD3OD) 10.32 (d, 1H) 10.02 (d, 1H) 9.65 (d, 1H) 9.34 (dd, 1H) 8.988.94 (m, 1H) 8.92-8.89 (m, 1H) 5.225.12 (m, 2H) 4.22-4.11 (m, 4H) 2.872.76 (m, 2H) 1.38-1.31 (m, 6H)
A9	X O Γ /--Z # \^χ\ ^z/ *°	(400MHz, CD3OD) 10.28 (d, 1H) 10.00 (d, 1H) 9.62 (d, 1H) 9.28 (dd, 1H) 8.968.93 (m, 1H) 8.90 (d, 1H) 5.19-5.12 (t, 2H) 3.28 (t, 2H) (one CO₂H proton missing)
A10	^N Τι Ί o „ n 'L /,^Nx A OH Fy^⁰' ^F F	(400MHz, CD3OD) 10.27 (d, 1H) 9.93 (d, 1H) 9.63 (d, 1H) 9.28 (dd, 1H) 8.968.92 (m, 1H) 8.88 (d, 1H) 5.11 (t, 2H) 2.95 (t, 2H) 2.62 (quin, 2H)
A11	O O<. // ω / o -------/ I r=^z Z /Z z=z	(400MHz, D2O) 9.80-9.97 (m, 2H) 9.629.75 (m, 1H) 9.35-9.50 (m, 1H) 8.97 (dd, 1H) 8.19-8.42 (m, 1H) 5.20-5.29 (m, 2H) 3.59-3.73 (m, 2H)

106

Compound Number	Structure	¹H NMR
A12	X / y--Z Z^ V i \ / ο Z=^ \ /⁺ / ° O_x / -Tl Tl // ^xo O 1	(400MHz, D₂O) 9.86-9.95 (m, 2H) 8.909.00 (m, 3H) 8.35 (brd, 2H) 5.27 (t, 2H) 3.69 (t, 2H) (one NH proton missing)
A13	1 O °< / ___/ ''O z=z O—\ /^z	(400MHz, D2O) 10.28 (s, 1H) 9.88 (d, 1H) 9.27 (d, 1H) 8.71 (d, 1H) 7.10 (d, 1 H) 5.29 (t, 2H) 4.13 (s, 3H) 3.74 (t, 2H)
A14	z=z Cfl / ^xo o	(400MHz, D2O) 10.19 (s, 1H) 9.78 (d, 1H) 9.14 (d, 1H) 8.74 (s, 2H) 5.24 (t, 2H) 4.06 (s, 3H) 3.71 (t, 2H)
A15	1 O // / \ G Z y_/ CO	(400MHz, D2O) 10.39 (s, 1H) 10.01 (s, 1H) 9.57 (s, 2H) 9.44 (s, 1H) 5.23-5.50 (m, 2H) 3.70-3.85 (m, 2H) 3.45 (s, 3H)
A16	1) z^ 'S \ _/ O. / ^xo O'	(400 MHz, D2O) 10.17 (d, 1H) 10.03 (d, 1H) 9.20 (dd, 1H) 8.23 (d, 1H) 6.99 (d, 1H) 5.35 (m, 2H) 3.74 (m, 2H) 3.35 (s, 6H)

107

Compound Number	Structure	¹H NMR
A17	o // ''O o ।	(400MHz, D₂O) 10.24 (d,1H) 9.86 (d, 1H) 9.24 (dd, 1H) 9.05 (s, 2H) 5.26 (t, 2H) 3.70 (t, 2H)
A18	i o // / \ Λ z. —^Z\	(400MHz, D₂O) 9.98 (d, 1H) 9.45 (d, 1H) 8.81 (dd, 1H) 8.37 (s, 2H) 5.06 (t, 2H) 3.56 (t, 2H) 3.12 (s, 6H)
A19	Tl z^ \=z 7 \ _/ // O ।	(400MHz, D₂O) 10.22 (d, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 8.96 (s, 2H) 5.25 (t, 2H) 3.69 (t, 2H)
A20	NH, o ll₊ o F IJ >< O // OH F^l 0 F	(400 MHz, D₂O) 10.11 (d, 1H) 9.96 (d, 1H) 9.13 (dd, 1H) 8.29 (d, 1H) 6.83 (d, 1H) 5.31 (m, 2H) 3.73(m, 2H) (Two NH₂protons and one SO3H proton missing)
A21	I O °< / __/ Ό + / z=z ---\ ^z	(400 MHz, D₂O) 10.24 (s, 1H) 9.90 (d, 1H) 9.24 (d, 1H) 8.86 (d, 1H) 7.57 (d, 1H) 5.31 (t, 2H) 3.74 (t, 2H) 2.66 (s, 3H)

108

Compound Number	Structure	¹H NMR
A22	'Q IL ο L. '/ o	(400 MHz, D₂O) 10.22 (d, 1H) 9.86 (d, 1H) 9.21 (dd, 1H) 8.90 (s, 2H) 5.25-5.31 (m, 2H) 3.69-3.77 (m, 2H) 2.44 (s, 3H)
A23	O /--^Z Ή z=z ''en / ''O O I	(400 MHz, D2O) 10.30 (s, 1H) 9.90 (d, 1H) 9.32 (d, 1H) 9.29 (d, 1H) 8.04 (d, 1H)5.25(t, 2H) 3.68 (t, 2H)
A24	F ri ^F La IL L,. A* ο A o	(400 MHz, D₂O) 10.31 (d, 1H) 9.94 (d, 1H) 9.33-9.38 (m, 3H) 5.26-5.31 (m, 2H) 3.69-3.73 (m, 2H)
A25	hK La ^_νΑ\^^Ν IL o A ,N* // AA A/	(400 MHz, D2O) 10.35 (d, 1H) 9.97 (m, 1H) 9.45 (m, 2H) 9.36 (m, 1H) 5.30-5.36 (m, 2H) 3.73 (m, 2H)
A26	p_N ^cr L· _N* \^° OH	(400 MHz, D₂O) 10.16 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1 H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO2H proton missing)

109

Compound Number	Structure	¹H NMR
A27	I O // /=Z / \ G z Ά // \\ H ⁺z--/ T l_ O	(400 MHz, D₂O) 9.87-9.97 (m, 2H) 8.929.07 (m, 3H) 8.44-8.53 (m, 2H) 5.27 (t, 2H) 3.68 (dd, 2H) (one NH proton missing)
A28	^=z Z\ λ Z^ 7 \ / Z=^ O—Z Z V O o 1	(400MHz, CD3OD) 10.32 (d, 1 H) 10.13 (d, 1H) 9.56 (s, 1H) 9.42-9.35 (m, 1H) 9.23 (d, 1H) 8.61 (d, 1H) 5.21 (t, 2H) 3.32-3.27 (m, 2H) (one CO2H proton missing)
A29	^N II ΌΗ 0 CF	(400MHz, D2O) 10.03 (d, 1H) 9.80 (d, 1H) 9.35 (d, 1H) 9.05 (dd, 1H) 8.87-8.82 (m, 1H) 8.76 (d, 1H) 5.08 (t, 2H) 3.22 (t, 2H) (one CO₂H proton missing)
A30	CD² O —	(400MHz, CD3OD) 10.30-10.26 (m, 1H) 10.04-10.00 (m, 1H) 9.66-9.64 (m, 1H) 9.33-9.30 (m, 1H) 8.97-8.93 (m, 1H) 8.91-8.88 (m, 1H) 5.25-5.14 (m, 2H) 3.71-3.68 (m, 3H) 3.35-3.27 (m, 2H)
A31	1 O Οχ // /---Z / \^χ\ ^z V ^z	(400MHz, D2O) 10.07 (d, 1H) 9.87 (d, 1H) 9.10 (dd, 1H) 8.95 (d, 1H) 8.13 (d, 1H) 5.24 (t, 2H) 3.67 (t, 2H) 2.78 (s, 3H)
A32	1 O / ^wx ___/ 'o z=z O--	(400MHz, D₂O) 10.26 (s, 1H) 9.86 (d, 1H) 9.26 (dd, 1H) 6.42 (s, 1H) 5.28 (t, 2H) 4.06 (s, 6H) 3.74 (t, 2H)

110

Compound Number	Structure	¹H NMR
A33	^o ll₊ o	(400 MHz, D2O) 10.34 (d, 1H) 9.96 (d, 1H) 9.54 (s, 2H) 9.37 (m, 1H) 5.25 (m, 2H) 4.02 (s, 3H) 3.70 (m, 2H)
A34	lûl ll₊ o // X/ ''g o^/cr	(400 MHz, D2O) 10.20 (m, 1H) 9.80 (m, 1H) 9.10 (m, 1H) 8.76 (s, 2H) 5.30 (m, 2H) 3.70 (m, 2H) 2.10 (m, 1H) 1.20 (m, 2H) 0.95 (m, 2H)
A35	o Οχ // ! Z—Z V \ / Y=z	(400MHz, D2O) 10.12 (d, 1H) 9.83 (d, 1H) 9.08 (dd, 1H) 8.42 (d, 1H) 7.89 (d, 1H) 5.28-5.19 (m, 2H) 3.71-3.64 (m, 2H) 2.74 (s, 3H)
A36	o Γ 0 P o	(400MHz, D2O) 10.15 (s, 1H) 9.84 (d, 1H) 9.15 (dd, 1H) 8.86 (s, 2H) 5.13 (t, 2H) 3.27 (t, 2H) 2.40 (s, 3H) (one CO2H proton missing)
A37	jpz=z J o I	(400MHz, D2O) 10.20 (d, 1H) 9.91 (d, 1H) 9.22 (dd, 1H) 8.86 (d, 1H) 7.58 (d, 1H) 5.18 (t, 2H) 3.31 (t, 2H) 2.66 (s, 3H)
A38	O Ta IL o	(400MHz, D2O) 10.15 (d, 1H) 9.79 (d, 1H) 9.12 (dd, 1H) 8.73 (s, 2H) 5.12 (t, 2H) 4.06 (s, 3H) 3.29 (t, 2H)

Compound Number	Structure	¹H NMR
A39	F	\ // \ rT z=z J O 1	(400MHz, D₂O) 10.32 (d, 1H) 9.96 (d, 1H) 9.32-9.38 (m, 2H) 8.10 (d,1H) 5.19 (t, 2H) 3.30 (t, 2H)
A40	b O t	(400MHz, D2O) 10.22 (d, 1H) 9.92 (d, 1H) 9.18-9.26 (m, 1H) 8.99-9.05 (m, 2H) 7.68 (t, 1H) 5.49-5.60 (m, 1H) 3.39 (dd, 1 H) 3.10-3.21 (m, 1 H) 1.71 (d, 3H) (One CO2H proton missing)
A41	I O Γ Z—Z \___/ I /=⁷ o « ?—λ o=\ i // Λ \ Z—Ç z V-u.	(400 MHz, D2O) 10.06 (s, 1H) 10.00 (d, 1H) 9.13 (dd, 1H) 8.28 (d, 1H) 6.85 (d, 1H) 5.20 (t, 2H) 3.31 (t, 2H) (Two NH₂protons and one CO2H proton missing)
A42	r	k Γ ji \|O ₊'V 0	(400MHz, D2O) 9.93 (d, 1H) 9.53 (d, 1H) 8.80 (dd, 1H) 8.35 (s, 2H) 5.01 (t, 2H) 3.23 (t, 2H) 3.14 (s, 6H)
A43	CL Il ll₊ 0	(400MHz, D2O) 10.18 (s, 1H) 9.86 (brd, 1H) 9.21 (dd, 1H) 9.03 (s, 2H) 5.12 ( t, 2H) 3.25 ( t, 2H)

112

Compound Number	Structure	¹H NMR
A44	h₂n. Γ î l,o 0	(400MHz, D₂O) 9.98 (br s, 1H) 9.60 (br d, 1H) 8.88 (br d, 1H) 8.37 (s, 2H) 5.03 (br t, 2H) 3.20 (br t, 2H) (Two NH2 protons missing)
A45	Γχ ¹ ζ A rr > L^o 0“	(400 MHz, D2O) 10.07 (s, 1H) 9.83 (d, 1H) 9.07 (dd, 1H) 8.15 (d, 1H) 6.76 (d, 1H) 5.10 (t, 2H) 3.20 (t, 2H) 3.16 (s, 6H)
A46	1 O \=O J? ω // O	(400 MHz, D2O) 10.33 (d, 1H) 10.00 (d, 1H) 9.54 (s, 2H) 9.40 (dd, 1H) 5.20 (t, 2H) 3.43 (s, 3H) 3.32 (t, 2H)
A47	rS ll₊ 0	(400 MHz, D2O) 10.09 (d, 1H) 9.81 (d, 1H) 9.10 (m, 1H) 7.37 (s, 1H) 5.08 (t, 2H) 3.21 (t, 2H) 2.51 (s, 6H)
A48	/S ll ₊ o // o °~	(400 MHz, D2O) 10.13 (s, 1H) 9.80 (d, 1H)9.12(dd, 1H)7.27-7.42 (m, 1 H)5.21 (t, 2H) 3.66 (t, 2H) 2.52 (s, 6H)

113

Compound Number	Structure	¹H NMR
A49	(S ll₊ o L· /V // o °’	(400MHz, D₂O) 10.39 (d, 1H) 9.92 (d, 1H) 9.39-9.46 (m, 1H) 9.27 (d, 1H) 8.10 (d, 1H) 5.30 (t, 2H) 3.73 (t, 2H) 2.82 (s, 3H)
A50	1 O °< / / ''O + / z=z	(400 MHz, D2O) 10.18 (m, 1H) 9.8 (m, 1H) 9.18 (m, 1H) 8.7 (m, 1H) 7.46 (m, 1H)5.24 (m, 2H) 3.7 (m, 2H) 2.2 (m, 1H) 1.2 (m, 4H) (one OH proton missing)
A51	V^N 0	(400 MHz, D2O) 10.10 (m, 1H) 9.80 (m, 1H) 9.10 (m, 1H) 8.60 (m, 2H) 5.10 (m, 2H) 3.20 (m, 2H) 1.90 (m, 1H) 1.10 (m, 2H) 0.85 (m, 2H)
A52	Ο 1 W z° /^w°^X \ 0 r\ \ / y=z O I	(400 MHz, D2O) 9.91 (d, 1H) 9.67 (d, 1H) 8.83 (dd, 1H) 8.22 (d, 1H) 7.19 (d, 1H) 4.93 (t, 2H) 2.95 (t, 2H) 2.49 (quin, 2H)
A53	O w O z° Ui' O \	(400 MHz, D2O) 10.05 (d, 1H) 9.84 (d, 1H) 9.11 (dd, 1H) 8.93 (d, 1H) 8.23 (d, 1H) 5.01 (t, 2H) 2.96 (t, 2H) 2.51 (quin, 2H)
A54	—O t Z—Z O0	(400 MHz, D2O) 10.15 (d,1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.98 (d, 2H) 7.63 (t, 1H) 5.12 (t, 2H) 3.59 (s, 3H) 3.25 (t, 2H)

114

Compound Number	Structure	¹H NMR
A55	J O I	(400MHz, CD₃0D) 10.26 (d, 1H) 10.05 (d, 1H) 9.30 (dd, 1H) 9.03 (d, 1H) 8.24 (d, 1H) 5.17 (t, 2H) 3.26 (t, 2H) 2.85 (s, 3H)
A56	-O Γ ? o^	(400MHz, CD3OD) 10.21-10.34 (m, 1H) 9.97 (d, 1H) 9.25-9.35 (m, 1H) 9.10-9.15 (m, 2H) 7.60-7.76 (m, 1H) 7.16-7.34 (m, 5H) 5.16-5.24 (m, 2H) 5.05-5.15 (m, 2H) 3.31-3.39 (m, 2H)
A57	I /—^zz' \=O z Λ W / z--' O I	(400 MHz, D2O) 9.94 (d, 1H) 9.81 (d, 1H) 8.97 (dd, 1H) 8.43 (d, 1H) 7.36 (d, 1H) 5.22 (t, 2H) 3.66 (t, 2H) (one NH proton missing)
A58	O^_N^Ν^ίίί^γί^ίί^'Ν ιι₊N* 0	(400 MHz, D2O) 10.29 (m, 1H) 9.91 (m, 1H) 9.49 (s, 2H) 9.31 (m, 1H) 5.14 (m, 2H) 3.26(m, 2H) 2.74 (s, 3H)
A59	O । y— ° z=z o ^=⁷	(400 MHz, D2O) 10.26-10.42 (m, 1H) 9.94 (d, 1H) 9.33-9.49 (m, 1H) 9.23-9.31 (m, 1H) 8.06-8.27 (m, 1H) 8.19 (s, 1H) 5.17 (t, 2H) 3.28 (t, 2H) 3.01 (s, 3H)

115

Compound Number	Structure	¹H NMR
A60	i o °x // «X ,----Z. // W \ /“4 V Z M O--	(400MHz, CD3OD) 10.28-10.21 (m, 1H) 9.99 (d, 1H) 9.26 (dd, 1H) 8.93 (d, 1H) 8.04 (d, 1H) 5.27 (t, 2H) 4.16 (s, 3H) 3.59 (t, 2H)
A61	S. 0^°	(400MHz, CDsOD) 10.26-10.22 (m, 1H) 9.87 (d, 1H) 9.49-9.47 (m, 1H) 9.20 (dd, 1H) 8.85-8.82 (m, 1H) 5.24 (t, 2H) 3.58 (t, 2H) 2.71 (s, 3H)
A62	f=\/ Z λ—O ^zO ω=ο /W 0 0	(400MHz, CD3OD) 10.24-10.20 (m, 1H) 9.93 (d, 1H) 9.24 (dd, 1H) 9.02 (d, 1H) 7.89 (d, 1H) 5.11 (t, 2H) 4.11 (s, 3H) 2.93 (t, 2H) 2.61 (quin, 2H)
A63	Œ H ₊ 0	(400 MHz, D₂O) 9.89 (br s, 1H) 9.69 (br d, 1H) 8.82-8.98 (m, 1H) 7.83-8.03 (m, 2H) 7.49 (br d, 1H) 5.02 (br t, 2H) 3.19 (brt, 2H) 2.55 (s, 3H)
A64	I O Οχ // ^ωχ z=z ^z—	(400 MHz, D2O) 10.03 (d, 1H) 9.78 (d, 1H) 8.99 (dd, 1H) 8.82 (d, 1H) 8.29 (d, 1 H) 8.13 (t, 1H) 7.70 (dd, 1H) 5.24 (t, 2H) 3.71 (t, 2H)
A65	Ql ll₊ 0	(400 MHz, D2O) 9.82 (d, 1H) 9.68 (m, 1 H) 8.73-8.74 (m, 1 H) 8.56-8.57 (m, 1 H) 7.91-7.93 (m, 1H) 7.54-7.56 (m, 1H) 5.13 (t, 2H) 3.27 (t, 2H) 2.45 (s, 3H)

116

Compound Number	Structure	¹H NMR
A66	Z z=z / o I	(400 MHz, D₂0) 9.80 (d, 1H) 9.71 (d, 1H) 8.75 (dd, 1H) 8.52-8.58 (m, 1H) 7.85-7.94 (m, 1H) 7.53 (dd, 1H) 5.215.30 (m, 2H) 3.66-3.75 (m, 2H) 2.44 (s, 3H)
A67	I O z=z ^z—	(400 MHz, D2O) 9.91 (d, 1H) 9.72 (d, 1 H) 8.91 (dd, 1 H) 8.55 (dt, 1 H) 7.74-7.82 (m, 1H) 7.61-7.67 (m, 1H) 5.00-5.05 (m, 2H)3.18(t, 2H)
A68	2—z z=z / ''O o I	(400 MHz, D2O) 10.05-10.10 (d, 1H) 9.80 (d, 1H) 8.02 (m, 1H) 8.60-8.69 (m, 1 H) 7.83-7.93 (m, 1 H) 7.67-7.79 (m, 1 H) 5.15-5.35 (m, 2H) 3.69-3.73 (m, 2H)
A69	CL YY YYWY ll₊ o Y // o	(400 MHz, D₂O) 10.03 (d, 1H) 9.74 (d, 1H) 8.98 (dd, 1H) 8.80 (d, 1H) 8.25 (d, 1H) 8.11 (dd, 1H) 5.17-5.24 (m, 2H) 3.65-3.72 (m, 2H)
A70	F. YY >Υ>Υ^ν I IL o o °’	(400 MHz, D₂O) 10.03 (d,1H) 9.77 (d, 1H) 8.99 (dd, 1H) 8.63 (d, 1H) 7.77 (d dd, 1H) 5.19-5.29 (m, 2H) 3.66-3.72 (m, 2H)
A71	F. XX^ 11 .... 0 O	(400 MHz, D2O) 9.99 (d, 1H) 9.75 (d, 1H) 8.94 (dd, 1H) 8.70 (d, 1H) 8.34 (dd, 1H) 7.67-7.90 (m, 1H) 5.09 (t, 2H) 3.24 (t, 2H)
A72	\-Z z Λ W / z--' °	(400 MHz, D₂O) 10.01 (d,1H) 9.72 (d, 1H) 8.94 (dd, 1H) 8.69 (d, 1H) 8.34 (dd, 1H) 7.74-7.89 (m, 1H) 5.19 (t, 2H) 3.67 (t, 2H)

117

Compound Number	Structure	¹H NMR
A73	F F	I O Γ !--Z / \^X \ ^Z LL z—/ .. \ / Ά	(400 MHz, D₂O) 10.11 (d, 1H) 9.83 (d, 1H) 9.08 (dd, 1H) 8.46 (d, 1H) 8.29 (t, 1 H) 8.06 (d, 1 H) 5.11 (t, 2H) 3.25 (t, 2H)
A74	F	F >Ο* . Χ_Ν^ \X ^S. o °~	(400 MHz, D2O) 10.15 (d, 1H) 9.81 (d, 1H) 9.10 (dd, 1H) 8.48 (d, 1H) 8.28 (t, 1H) 8.06 (d, 1H) 5.24 (t, 2H) 3.7 (t, 2H)
A75	I O O W/ ω=θ r--Z / w \ ^z /Z--/	(400 MHz, D2O) 9.91 (d, 1H) 9.67 (d, 1H) 8.87 (dd, 1H) 7.95-8.03 (m, 1H) 7.85-7.94 (m, 1H) 7.48 (d, 1H) 5.14 (t, 2H) 3.61 (t, 2H) 2.54 (s, 3H)
A76	o Γ z=z o--	(400 MHz, D2O) 10.21 (s, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 6.41 (s, 1H) 5.14 (t, 2H) 4.04 (s, 6H) 3.28 (t, 2H)
A77	Cl 0 CCcC° f CL ^N _Fp °“ F	(400MHz, CD3OD) 10.35-10.47 (m, 1H) 10.05 (d, 1H) 9.37-9.44 (m, 1H) 9.089.15 (m, 2H) 7.65-7.78 (m, 1H) 7.327.43 (m, 2H) 7.18-7.27 (m, 1H) 7.037.15 (m, 2H) 5.30 (t, 2H) 3.58 (t, 2H)
A78	\d V o । o	(400 MHz, D₂O) 9.98-9.93 (m, 1H) 9.58 (d, 1H) 8.98 (d, 1H) 8.89 (dd, 1H) 8.42 (d, 1H) 4.91 (t, 2H) 4.01 (s, 3H) 2.95 (t, 2H) 2.48 (quin, 2H)

118

Compound Number	Structure	¹H NMR
A79	O v o I o	(400 MHz, D₂0) 10.06-10.04 (m, 1H) 9.76-9.72 (m, 1H) 9.21 (d, 1H) 9.05 (dd, 1H) 8.88 (d, 1H) 4.97 (t, 2H) 2.96 (t, 2H) 2.51 (quin, 2H)
A80	Cl ^N^Ci. T U .0 ^N oV F^ I ° >< O F I F	(400 MHz, D₂0) 10.28-10.42 (m, 1H) 9.93-10.10 (m, 1H) 9.37-9.45 (m, 1H) 9.12 (d, 2H) 7.70 (t, 1H) 5.06-5.20 (m, 2H) 3.21 (t, 2H) 1.40-1.46 (m, 9H)
A81	Cl ⁿ'O Y G X o X/ F	(400 MHz, CDsOD) 10.29-10.43 (m, 1H) 10.02 (d, 1H) 9.36-9.49 (m, 1H) 9.049.18 (m, 2H) 7.63-7.76 (m, 1H) 5.105.24 (m, 2H) 4.92-5.04 (m, 1H) 3.143.41 (m, 2H) 1.12-1.25 (m, 6H)
A82	Cl îtXX >Λ Ώί F	(400 MHz, D2O) 10.07-10.18 (m, 1H) 9.77-9.90 (m, 1H) 9.12-9.23 (m, 1H) 8.96 (d, 2H) 7.52-7.70 (m, 1H) 5.04-5.17 (m, 2H) 4.03 (q, 2 H) 3.14-3.30 (m, 2H) 1.01-1.13 (m, 3H)
A83	Cu - 0^°	(400 MHz, D₂O) 10.09-10.03 (m, 1H) 9.80-9.76 (m, 1H) 9.15 (s, 1H) 9.04 (dd, 1H) 8.66 (s, 1H) 5.20 (t, 2H) 3.65 (t, 2H) 2.62 (s, 3H)
A84	^Cxô··	(400 MHz, D₂O) 10.08-10.04 (m, 1H) 9.78 (d, 1H) 9.32 (s, 1H) 9.08 (dd, 1H) 8.82 (s, 1H) 4.99 (t, 2H) 2.96 (t, 2H) 2.57-2.46 (m, 2H)

119

Compound Number	Structure	¹H NMR
A85	o / z J W / O I	(400MHz, CD₃0D) 10.29-10.24 (m, 1H) 10.02-9.95 (m, 1H) 9.41 (s, 1H) 9.299.25 (m, 1H) 8.79 (s, 1H) 5.16 (t, 2H) 3.30-3.23 (m, 2H) 2.73 (s, 3H) (one CO2H proton missing)
A86	T O O ) ⁽ I __/ O A A⁷- O	(400MHz, CD3OD) 10.16-10.12 (m, 1H) 10.09 (d, 1H) 9.22 (dd, 1H) 8.36 (d, 1H) 7.44 (d, 1H) 5.18 (t, 2H) 3.27 (t, 2H) (one CO2H proton and one OH proton missing)
A87	I O / z=z	(400 MHz, D2O) 9.83-9.86 (m, 1H) 9.62- 9.75 (m, 1H) 9.01-9.04 (m, 2H) 7.40- 7.83 (m, 1H) 5.18-5.25 (m, 2H) 3.57- 3.80 (m, 2H) 2.64-2.87 (m, 3H)
A88	I O °< / __/ ^vo Z=Z Z /Z ^z	(400 MHz, D2O) 9.76 (d, 1H) 9.69-9.88 (m, 1 H) 9.02 (d, 1 H) 8.77 (d, 1 H) 7.69 (t, 1H) 5.21 (t, 2H) 3.71 (t, 2H) 2.94 (s, 3H)
A89	O Il i —ω—z O ^=° Z—Z rQ O I	(400 MHz, D2O) 10.22 (d, 1H) 9.93 (d, 1H) 9.25 (dd, 1H) 9.05 (d, 2H) 7.70 (t, 1H) 5.22 (t, 2H) 3.30-3.40 (m, 2H) 3.27 (s, 3H) (one NH proton missing)
A90	--O y_f 0 O I O	(400 MHz, D2O) 10.10-10.04 (m, 1H) 9.67 (d, 1H) 9.05 (dd, 1H) 8.91 (s, 1H) 8.34 (s, 1H) 4.94 (t, 2H) 4.01 (s, 3H) 2.97-2.90 (m, 2H) 2.54-2.44 (m, 2H)

120

Compound Number	Structure	¹H NMR
A91	I O -ΓΡ ? O	(400 MHz, D₂O) 9.98 (m, 1H) 9.78 (m, 1H) 8.98 (m, 1H) 8.76 (s, 1H) 8.24 (m, 1H) 8.10 (m, 1H) 7.68 (m, 1H) 5.12 (m, 2H) 4.10 (m, 2H) 3.26 (m, 2H) 1.14 (m, 3H)
A92	V/ O /—^z J O	(400 MHz, D2O) 10.23 (m, 1H) 9.89 (m, 1H) 9.25 (m, 1H) 9.12 (s, 2H) 5.16 (m, 2H) 3.26(m, 2H) 3.08 (s, 3H) 3.02 (s, 3H)
A93	O 'X I ^zO /—^z /Λ î	(400 MHz, D2O) 10.27 (m, 1H) 9.94 (m, 1H) 9.33 (s, 3H) 5.18 (m, 2H) 3.26 (m, 2H) 2.94 (m, 3H) (one NH proton missing)
A94	O o<. // ω / o Ç i ,---Z / \^χ/°—\ /^z	(400MHz, D2O) 10.22 (d, 1H) 9.84 (d, 1 H) 9.21 (d, 1 H) 6.91 (s, 1 H) 5.25 (t, 2H) 4.05 (s, 3H) 3.70 (t, 2H) 2.52 (s, 3H)
A95	^=O )—Z / I Z—Z // O I	(400MHz, D₂O) 9.89-9.98 (m, 1H) 9.83 (d, 1H) 8.97 (dd, 1H) 6.49 (s, 1 H) 5.18 (t, 2H) 3.60 (t, 2H) 2.33 (s, 3H) (one NH proton missing)
A96	O Γ /—Z \ ^z -^7	(400MHz, D₂O) 10.06 (d, 1H) 9.65-9.77 (m, 1H) 9.00-9.09 (m, 1H) 8.48-8.63 (m, 1H) 5.02 (t, 2H) 3.15 (t, 2H) 2.49 (s, 3H) 2.26 (s, 3H)

121

Compound Number	Structure	¹H NMR
A97	Cl·· Z /> W // Z.----' / ^xo o,	(400MHz, D₂O) 10.10 (d, 1H) 9.73 (d, 1H)9.07 (dd, 1H) 8.57 (s, 1H) 5.13-5.18 (m, 2H) 3.58-3.64 (m, 2H) 2.49 (s, 3H) 2.26 (s, 3H)
A98	O Z-x-O in' °. A	(400MHz, D2O) 10.06-10.03 (m, 1H) 9.75-9.71 (m, 1H) 9.12-9.09 (m, 1H) 9.04 (dd, 1H) 8.74 (dd, 1H) 4.97 (t, 2H) 3.00-2.94 (m, 2H) 2.56-2.47 (m, 2H)
A99	I O // ô A-/ ô	(400 MHz, D2O) 10.23 (d, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 8.89 (s, 1H) 5.25 (m, 2H)3.70 (m, 2H)2.70 (s, 3H)
A100	b Γ z—z / \^X \ ^z —C/ ô	(400 MHz, D2O) 10.53 (br s, 1 H) 9.58 (br s, 1H) 9.16 (brs, 1H) 8.85-8.92 (m, 1H) 5.15-5.22 (m, 2H) 3.23 (br s, 2H) 2.69 (s, 3H)
A101	CH z Λ w / J o I	(400 MHz, D2O) 10.20 (d, 1H) 9.85 (d, 1H) 9.21 (dd, 1H) 8.66 (d, 1H) 7.05 (d, 1H) 5.13 (t, 2H) 4.08 (s, 3H) 3.26 (t, 2H)
A102	I O I ,—ω=ο / ¹¹y z=z ô	(400 MHz, D2O) 9.65-9.81 (m, 2H) 8.67- 8.77 (m, 1H) 8.53-8.61 (m, 1H) 7.91- 8.00 (m, 1H) 4.95-5.10 (m, 2H) 2.98- 3.02 (m, 2H) 2.54-2.56 (m, 2H) 2.43- 2.45 (m, 3H)

122

Compound Number	Structure	¹H NMR
A103	CL	(400 MHz, D2O) 9.77 (d, 1 H) 9.68 (s, 1 H) 8.72 (d, 1H) 8.54 (s, 1H) 7.92 (s, 1H) 5.22 (t, 2H) 3.67 (t, 2H) 2.42 (s, 3H)
A104	। O // ^wx r--Z O ZLL.	(400 MHz, D2O) 9.77-9.85 (m, 1H) 9.72 (br s, 1H) 8.74 (br s, 1H) 8.52-8.59 (m, 1H) 7.73 (br s, 1H) 5.26 (br s, 2H) 3.71 (br s, 2H) 2.49 (br s, 3H)
A105	/—^H Z /> W / o I	(400 MHz, D2O) 10.19 (d, 1H) 9.83 (d, 1H) 9.19 (dd, 1H) 6.92 (s, 1H) 5.11 (s, 2H) 4.05 (s, 3H) 3.22 (t, 2H) 2.52 (s, 3H)
A106	O Γ Γ--Z / \^χ\ ^z	(400 MHz, D2O) 10.40-10.51 (m, 1H) 9.48-9.65 (m, 1H) 8.99-9.23 (m, 1H) 8.36-8.54 (m, 1H) 5.13-5.30 (m, 2H) 3.97-4.21 (m, 3H) 3.17-3.37 (m, 2H) 2.14-2.25 (m, 3H)
A107	/⁼⁼\ JW _m Z Λ ® / ¹ z--J O T	(400MHz, D2O) 10.16 (d, 1H) 9.86 (d, 1H) 9.21-9.15 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO2H proton missing)
A108	। O O_x // / -ο 0 0= z==^^	(400MHz, D2O) 10.21-10.16 (m, 1H) 9.92 (d, 1H) 9.25-9.20 (m, 2H) 8.51 (d, 1H) 5.26 (t, 2H) 3.68 (t, 2H)

123

Compound Number	Structure	¹H NMR
A109	i O // z--Z \ ^Z U- !-----( “•ΉΤ/ LL Z---'	(400MHz, D₂O) 10.20-10.14 (m, 1H) 9.93 (d, 1H) 9.56-9.53 (m, 1H) 9.21 (dd, 1H) 8.79-8.74 (m, 1H) 5.25 (t, 2H) 3.67 (t, 2H)
A110	O* Z-^xo O I	(400MHz, D2O) 10.19-10.16 (m, 1H) 9.87 (d, 1H) 9.65 (s, 1H) 9.22 (s, 1H) 9.19 (dd, 1H) 5.23 (t, 2H) 3.66 (t, 2H)
A111	/^z=\ / Z\ Λ—o z A W / Z--' /O ω'' O I O	(400MHz, D2O) 10.08-10.04 (m, 1H), 9.84-9.79 (m, 1H) 9.06 (dd, 1H) 9.01 (d, 1H) 7.95 (d, 1H) 5.01 (t, 2H) 4.01 (s, 3H) 3.01-2.95 (m, 2H) 2.58-2.49 (m, 2H)
A112	.· S. 0^°	(400MHz, D₂O) 10.18-10.15 (m, 1H) 9.90-9.85 (m, 1H) 9.56-9.53 (m, 1H) 9.30-9.27 (m, 1H) 9.19 (dd, 1H) 5.23 (t, 2H) 3.67 (t, 2H)
A113	o ff II I F. ^χ o rr n ll ₊ F ^x zK OH < / /x. o -o^x	(400 MHz, D2O) 10.22 (d, 1H) 9.86 (d, 1H) 9.23 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 5.06 (dt, 2H) 3.85 (quin, 2H) 2.442.53 (m, 2H) 1.13 (t, 3H) (one OH proton missing)
A114	I O Οχ // ^ωχ z=z <0	(400 MHz, D2O) 10.17-10.12 (m, 1H) 9.75-9.71 (m, 1H) 9.15 (dd, 1H) 8.97 (d, 2H) 7.61 (t, 1 H) 5.04 (s, 2H) 1.37 (s, 6H)

124

Compound Number	Structure	¹H NMR
A115	/ \ W V O \\ I O	(400MHz, D₂O) 10.00-10.13 (m, 1H) 9.67-9.78 (m, 1H) 8.93-9.06 (m, 1H) 8.30-8.44 (m, 1H) 7.40 (d, 1H) 4.98 (t, 2H) 4.11 (s, 3H) 2.97 (t, 2H) 2.52 (quin, 2H)
A116	X /—^z Z 2=0 Z /> w / z--' z° O i O	(400MHz, D₂O) 9.86-9.98 (m, 1H) 9.729.81 (m, 1H) 8.96 (dd, 1H) 8.34-8.48 (m, 1H) 7.35 (d, 1H) 4.86-5.10 (m, 2H) 2.843.05 (m, 2H) 2.43 (s, 2H) (one NH proton missing)
A117	I O °x // ^ωχ /--Z / \^X\ ^Z/r\ ---\ ^z Z=/	(400MHz, D2O) 9.98-10.10 (m, 1H) 9.85 (d, 1H) 9.13-9.22 (m, 1H) 9.06 (dd, 1H) 8.12-8.24 (m, 1H) 5.16-5.31 (m, 2H) 3.58-3.73 (m, 2H) 2.57-2.69 (m, 3H)
A118	v/^{1 m} vJ* °, /=( 4 O X	(400MHz, CD3OD) 10.28 (d, 1H) 10.14 (d, 1H) 9.40-9.32 (m, 2H) 8.67 (d, 1H) 5.21 (t, 2H) 3.34-3.26 (m, 2H) (one CO₂H proton missing)
A119	F F^TF H 1 ^N^ ₊ O < /x ^OH Λ N^ ^O’ ° ^f V	(400MHz, CD3OD) 10.39-10.33 (m, 1H) 10.14 (d, 1H) 9.71-9.68 (m, 1H) 9.44 (dd, 1H) 8.93 (d, 1H) 5.20 (t, 2H) 3.353.24 (m, 2H) (one CO₂H proton missing)
A120	X O 4 O \___/ 1 /-- °	(400MHz, CD3OD) 10.31-10.23 (m, 1H) 10.08 (d, 1H) 9.89 (s, 1H) 9.38-9.31 (m, 2H) 5.19 (t, 2H) 3.34-3.26 (m, 2H) (one CO2H proton missing)

125

Compound Number	Structure	¹H NMR
A121	F I >L N. ^F ( 1 M ο Ιί .N* .OH U x°‘ ° ^F 'f	(400MHz, CDsOD) 10.35-10.28 (m, 1H) 10.09 (d, 1H) 9.77 (d, 1H) 9.40-9.34 (m, 2H) 5.19 (t, 2H) 3.34-3.23 (m, 2H) (one CO2H proton missing)
A122	i O °s // »x ^^o r—z / W \ / /^=z	(400MHz, D2O) 10.24-10.20 (m, 1H) 9.91 (d, 1H) 9.20 (dd, 1H) 8.76 (d, 1H) 8.40 (d, 1H) 5.26 (t, 2H) 3.68 (t, 2H)
A123	^N v 0 L X OH Il JL ^F II ‘c'y 0 1 F F	(400MHz, D2O) 10.16 (d, 1H) 9.79 (d, 1H) 9.20 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1 H) 5.04 (s, 2H) 1.25 (s, 6H) (one CO2H proton missing)
A124	CV t rr \ IL o O Lx _N* X / F	(400MHz, D2O) 10.26 (d, 1H) 9.89 (d, 1 H) 9.27 (dd, 1 H) 9.00-9.06 (m, 2H) 7.69 (t, 1H) 5.11-5.23 (m, 2H) 4.03-4.15 (m, 4H) 2.84 (dt, 2H)1.21 (t, 6H)
A125	Γχ ^n/XO₊ O L· N* ^x OH N^x X R JL X CT o F 1 F	(400MHz, D2O) 10.18-10.13 (m, 1H) 9.87-9.82 (m, 1H) 9.20-9.14 (m, 1H) 8.98 (d, 2H) 7.63 (s, 1H) 5.10 (s, 2H) 3.24 (t, 2H) (one CO2H proton missing)
A126	F ργ ^F ιί^ N. A /x ^N II Ί O L ZK ^OH Χ⁰’ ° ^f f	(400MHz, CDsOD) 10.39 (d, 1H) 10.15 (d, 1H) 9.40 (dd, 1H) 8.89 (d, 1H) 8.45 (d, 1H) 5.22 (t, 2H) 3.34-3.25 (m, 2H) (one CO2H proton missing)

126

Compound Number	Structure	¹H NMR
A127	S fi iCt a f IL ^h0	(400MHz, D₂O) 9.99 (d, 1H) 9.91 (d, 1H) 9.04 (d, 1H) 8.34 (d, 1H) 6.74 (d, 1H) 5.13 (t, 2H) 3.24 (t, 2H) (One NH proton and one CO2H proton missing)
A128	Π y \ 1Q Z—Z ( τι Tl _/ Λ ° \ /⁼° ?	(400MHz, D2O) 9.99 (s, 1H) 9.62 (d, 1H) 8.88 (d, 1H) 8.71 (dd, 1H) 8.37 (d, 1H) 7.79 (dd, 1H) 5.14 (t, 2H) 3.25 (t, 2H) (one CO2H proton missing)
A129	F M ' U. A_nAAAA_n n IL ° a At ,oh A JL 11 F^^ ° F	(400MHz, D2O) 10.29 (d, 1H) 9.9510.00 (m, 1H) 9.32-9.41 (m, 3H) 5.18 (t, 2H) 3.25-3.35 (m, 2H) (one CO2H proton missing)
A130	Cl o ”♦ h a/ⁿ\Ca^^ohr JL ii F>T °’ O F	(400MHz, D2O) 10.16-10.25 (m, 1H) 9.81-9.89 (m, 1H) 9.19-9.27 (m, 1H) 8.97-9.09 (m, 2H) 7.63-7.74 (m, 1H) 5.08-5.20 (m, 1H) 4.92-5.01 (m, 1H) 3.35-3.47 (m, 1H) 1.31 (d, 3H) (one CO2H proton missing)
A131	Cl o IL Il As/^N1 AA /^OH F. JL 7\ (1 >A /\ Il F^J O F	(400 MHz, D2O) 10.18 (m, 1H) 9.97 (m, 1H) 9.21 (m, 1H) 8.98 (m, 2H) 7.61 (m, 1H) 3.36 (s, 2H) 1.94 (s, 6H) (one CO2H proton missing)
A132	I o 1 z=z / o / - °=c \ / x—	(400 MHz, D2O) 9.72 (d, 1H) 8.98 (d, 1H) 8.66-8.74 (m, 1H) 8.71 (d, 1H) 7.65 (t, 1H) 5.06 (t, 2H) 3.21 (t, 2H) 2.87 (s, 3H) (one CO2H proton missing)

127

Compound Number	Structure	¹H NMR
A133	Cl cr O	(400 MHz, D₂O) 9.72 (d, 1H) 8.98 (d, 1H) 8.66-8.74 (m, 1H) 8.71 (d, 1H) 7.65 (t, 1H) 5.06 (t, 2H) 3.21 (t, 2H) 2.87 (s, 3H) (one CO₂H proton missing)
A134	O // σκ 4 r--Z // \ ^Z	(400MHz, D2O) 10.20-10.18 (m, 1H) 9.81 (dd, 1H) 9.19 (dd, 1H) 9.00 (d, 2H), 7.65 (t, 1H) 5.10-5.07 (m, 2H) 3.84-3.74 (m, 1H) 1.39 (d, 3H)
A135	Z Z—Z ''ω // ^XO O ।	(400MHz, D₂O) 10.00 (d, 1H) 9.73 (d,1H) 8.96 (d, 1H) 8.50 (s, 1H) 7.69 (d, 1H) 5.18-5.23 (m, 2H) 3.66-3.71 (m, 2H) 2.45 (s, 3H)
A136	, O <=C // /=Z / \ ά /Z Z—Z C /—ü	(400MHz, D2O) 9.85 (s, 1H) 9.80 (d, 1H) 8.95 (dd, 1H) 8.52 (s, 1H) 7.95 (s, 1H) 5.24 (t, 2H) 3.67-3.72 (m, 2H) 2.40 (s, 3H)
A137	0 - JL .F T /1 ⁰lj^ï₊Cl 0	(400MHz, D2O) 9.78-9.89 (m, 1H) 8.96 (dd, 1H) 8.87-9.00 (m, 1H) 8.53 (d, 1H) 7.96 (d, 1 H) 5.14 (t, 2H) 3.28 (t, 2H) 2.41 (s, 3H) (one CO2H proton missing)
A138	N. n₊ 1¾. N* ^x^.0 ^Cl OH	(400 MHz, D2O) 10.11 (d, 1H) 9.87 (d, 1H) 9.32 (dd, 1 H) 9.12-9.08 (m, 1 H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.12 (t, 2H) 3.24 (t, 2H) (one CO₂H proton missing)

128

Compound Number	Structure	¹H NMR
A139	—o Γ / \ ά /Z __/ b ^o=( \ / \^LL ^=z Λ~	(400MHz, D₂O) 10.05-10.15 (m, 1H) 9.84-9.94 (m, 1H) 9.28-9.39 (m, 1H) 9.05-9.14 (m, 1H) 8.41-8.56 (m, 1H) 7.90-8.06 (m, 1H) 5.07-5.21 (m, 2H) 3.56-3.67 (m, 3H) 3.22-3.34 (m, 2H)
A140	oj° F--Z \ ^ZZ—/ LL ' ' LL	(400 MHz, D₂O) 9.86 (d, 1H) 9.62 (d, 1H) 8.85 (d, 1H) 8.70 (m, 1H) 8.35 (d, 1H) 7.77 (m, 1H) 5.24 (m, 2H) 3.65 (m, 2H)
A141	I O // z=z z-/	(400 MHz, D2O) 9.83-9.92 (m, 2H) 8.98 (d, 1H) 8.68 (d, 1H) 8.12 (d, 1H) 7.597.66 (m, 1H) 5.27 (t, 2H) 3.71 (t, 2H)
A142	I O Οχ // ω_χ ^Ό z=z z-/ —ô ô	(400 MHz, D₂O) 9.87 (d, 1H) 9.83 (d, 1H) 8.99 (dd, 1H) 8.71 (d, 1H) 8.23 (d, 1H) 5.25 (t, 2H) 3.70 (t, 2H)
A143	Ot OH η IL I * /°’ 0	(400 MHz, D₂O) 10.24 (d, 1H) 9.80 (d, 1H) 9.25 (dd, 1H) 9.04 (d, 2H) 7.68 (t, 1H) 5.21 (dd, 1H) 4.93 (dd, 1H) 4.644.71 (m, 1H) 3.19-3.36 (m, 2H) (one OH proton missing)
A144	O ^FY^i ^°- L f I IL ⁰	(400 MHz, D₂O) 9.95 (d, 1H) 9.74 (d, 1 H) 8.93 (dd, 1 H) 8.58 (d, 1 H) 7.67-7.83 (m, 1H) 5.06 (t, 2H) 3.26 (t, 2H) (one CO2H proton missing)

129

Compound Number	Structure	¹H NMR
A145	o ? z=z z—/ b / O LL· LL·	(400 MHz, D₂O) 9.68 (d, 1H) 8.73 (d, 1H) 8.49 (d, 1H) 8.09 (td, 1H) 7.80 (d, 1H) 7.65 (dd, 1H) 5.07 (t, 2H) 3.26 (t, 2H) 2.77 (s, 3H) (one CO2H proton missing)
A146	° ^OH ex n -₀ ll₊ ^x X N* X Xz \Z w 0	(400 MHz, D2O) 10.23-10.33 (d, 1H) 9.81 (d, 1H) 9.30 (dd, 1H) 9.15 (d, 1H) 8.06 (d, 1H) 5.01 (t, 2H) 2.97 (t, 2H) 2.52 (m, 2H) (one CO2H proton missing)
A147	N II ex ^^Ν^ιΧ^ι ⁰ _Λ- I. w ,o IL .n* s' ^N *₀	(400 MHz, D2O) 10.23 (d, 1H) 9.85 (d, 1H) 9.25 (m, 2H) 8.06 (d, 1H) 5.02 (t, 2H) 2.98 (t, 2H) 2.53 (t, 2H)
A148	Cl o n₊ Il X/^N\/\/^0H F. JL II f^°’ 0 F	(400 MHz, D2O) 9.99 (s, 1 H) 9.77 (d, 1 H) 8.96 (dd, 1H) 8.80 (d, 1H) 8.25 (d, 1H) 8.06-8.12 (m, 1H) 7.68 (t, 1H) 5.10 (t, 2H) 3.25 (t, 2H) (one CO2H proton missing)
A149	O rC^7 - y j >r ° F I n₊ ^Cl C>/ⁿ\x^\^/^oh0	(400 MHz, D2O) 9.78-9.88 (m, 2H) 8.95 (dd, 1H) 8.66 (d, 1H) 8.10 (d, 1H) 7.567.65 (m, 1H) 5.12 (t, 2H) 3.23 (t, 2H) (one CO2H proton missing)
A150	-Π -Π - ^o={ e y °' / ^zz=z 1 o	(400 MHz, D2O) 9.99 (d, 1H) 9.75 (d, 1H) 8.96 (dd, 1H) 8.80 (d, 1H) 8.24 (d, 1H) 8.10 (dd, 1H) 5.09 (t, 2H) 3.25 (t, 2H) (one CO₂H proton missing)

130

Compound Number	Structure	¹H NMR
A151	o ^FIL 0	(400 MHz, D₂0) 9.80 (d, 1 H) 9.68 (s, 1 H) 8.72 (d, 1H) 8.46-8.54 (m, 1H) 7.71 (d, 1H) 5.12 (t, 2H) 3.26 (t, 2H) 2.48 (s, 3H) (one CO2H proton missing)
A152	I O // Z—Z Z-/ // c__	(400 MHz, D2O) 9.75 (d, 1H) 9.69 (d, 1H) 8.70 (dd, 1H) 8.42 (s, 1H) 7.74 (s, 1H) 5.23 (t, 2H) 3.69 (t, 2H) 2.42 (s, 3H) 2.36 (s, 3H)
A153	F ,^{F F}^/A°~ o IL OH	(400 MHz, D2O) 9.84 (s, 1H) 9.64-9.69 (m, 1H) 8.99-9.05 (m, 1H) 9.02 (d, 1H) 7.67 (t, 1 H) 5.09 (t, 2H) 3.26 (t, 2H) 2.78 (s, 3H)
A154	4 A-χ n n IL * A⁵ A A S' xx XXxx \\ 0	(400 MHz, D2O) 10.25 (s, 1H) 9.84 (d, 1H) 9.26 (d, 1H) 8.97 (d, 1H) 7.72 (d, 1H) 5.05 (t, 2H) 4.86 (s, 2H) 3.02 (t, 2H) 2.59 (t, 2H) (one OH proton missing)
A155	Ta o X XX // X^ X_X o^Z/ °‘	(400 MHz, D2O) 9.96 (d, 1H) 9.69 (d, 1H) 8.90 (dd, 1H) 8.62 (s, 1H) 8.14 (d, 1H) 7.89 (dd, 1H) 5.19 (t, 2H) 3.67 (t, 2H) 2.40 (s, 3H)
A156	0 Χν -θ^ ιι ₊ । P/^N\X^OH 0	(400 MHz, D2O) 9.81 (d, 1H) 9.68 (d, 1H) 8.73 (dd, 1H) 8.57 (d, 1H) 7.95 (d, 1H) 5.12 (t, 2H) 3.26 (t, 2H) 2.44 (s, 3H) (one CO2H proton missing)

131

Compound Number	Structure	¹H NMR
A157	/=H /----\ H z=z \ “Π “Π 4 -ÿ. g ?	(400 MHz, D2O) 9.86 (d, 1H) 9.81 (d, 1H) 8.90 (dd, 1H) 8.73 (d, 1H) 8.63 (d, 1H) 7.89 (t, 1H) 5.16 (brt, 2H) 3.29 ppm (t, 2H) (one CO2H proton missing)
A158	I M Z z /> \\ / z λ W / z.----' ''ω // ''o o ।	(400 MHz, D2O) 10.04-9.99 (m, 1H) 9.87 (d, 1H) 9.07 (dd, 1H) 8.51 (d, 1H) 7.57 (d, 1H) 5.23 (t, 2H) 3.66 (t, 2H) (two NH protons missing)
A159	O II lX ’° I ₊ o IL // // ^XOH 0	(400 MHz, D2O) 9.90 (d, 1H) 9.85 (d, 1H) 8.93 (dd, 1H) 8.79 (d, 1H) 8.67 (d, 1H) 8.01 (t, 1H) 5.12-5.35 (m, 2H) 3.633.81 (m, 2H) (one SO3H proton missing)
A160	Z M Z w X/ 4 T O ¹ I	(400MHz, CD3OD) 10.16 (d, 1H) 10.00 (d, 1H) 9.18 (dd, 1H) 8.57 (d, 1H) 7.53 (d, 1H) 5.12 (t, 2H) 3.25 (t, 2H) (two NH2 protons and one CO2H proton missing)
A161	o z \=o - Ο -η -n I	(400 MHz, D2O) 9.95 (s, 1 H) 9.87 (d, 1 H) 9.00 (dd, 1H) 8.44 (s, 1H) 5.09 (t, 2H) 3.22 (t, 2H) (one CO2H proton missing)
A162	z—z // \\ 9 o r	(400 MHz, D2O) 10.21 (s, 1H) 9.87 (d, 1H) 9.23 (dd, 1H) 9.02 (s, 2H) 5.16 (t, 2H) 4.81 (s, 2H) 3.26 (t, 2H) (one OH proton and one CO2H proton missing)

132

Compound Number	Structure	¹H NMR
A163	/=^zz Λ—z J Z Λ W / Z-/ Tl Tl o=/ 2=0 o	(400MHz, CD₃OD) 10.12-10.06 (m, 1H) 10.01-9.93 (m, 1H) 9.10 (dd, 1H) 8.63 (d, 1H) 7.43 (d, 1H) 5.14 (t, 2H) 3.26 (t, 2H) (two NH2 protons and one CO2H proton missing)
A164	Î=-Z z Λ—z z Λ W / z--' ''O O I	(400 MHz, D2O) 9.92-9.86 (m, 1H) 9.829.76 (m, 1H) 8.90 (dd, 1H) 8.58-8.49 (m, 1H) 7.32 (d, 1H) 5.23-5.18 (m, 2H) 3.673.63 (m, 2H) (two NH2 protons missing)
A165	F	(400 MHz, D2O) 9.82-10.02 (m, 2H) 8.86-9.05 (m, 2H) 8.44 (s, 1H) 8.22 (dd, 1H) 5.24-5.34 (m, 2H) 3.66-3.77 ppm (m, 2H)
F	F
r₌Z^ Z—Z °x. ^χω. / ''O o ; I
A166	F I	F 0 A ^^ο~ >/_N ^f IL Α^^ΝΑ^\^^0Η 0	(400 MHz, D2O) 9.78-9.94 (m, 2H) 8.849.04 (m, 2H) 8.43 (s,1H) 8.21 (dd, 1H) 5.15 (t, 2H) 3.28 (t, 2H) (one CO2H proton missing)
A167	0 ^FAA fl l n₊ V A A A AA/^0H o	(400 MHz, D2O) 10.03-10.10 (m, 1H) 9.83-9.89 (m, 1H) 9.38 (s, 1H) 9.15 (dd, 1H) 9.07 (d, 1H) 8.31 (dd, 1H) 5.08 (s, 2H) 1.28 (s, 6H) (one CO2H proton missing)

133

Compound Number	Structure	¹H NMR
A168	O / \ w Z=< / \ w O O 1 O	(400 MHz, D₂0) 10.23 (d, 1H) 9.86 (d, 1H) 9.20 (dd, 1H) 8.82 (d, 1H) 8.70 (d, 2H) 8.03 (d, 1H) 5.04 (t, 2H) 3.00 (t, 2H) 2.56 (quin, 2H)
A169	oj° /=Z / \ y_7 /	(400 MHz, D2O) 10.1 (d, 1H) 9.85 (d, 1H) 9.14-9.13 (m, 1H) 9.09 (dd, 1H) 8.47-8.41 (m, 2H) 5.25 (t, 2H) 3.70 (t, 2H)
A170	1 O Οχ // 7=Z / \ A P O I	(400 MHz, D2O) 10.24 (d, 1H) 9.87 (d, 1H) 9.24 (m, 1H) 9.02 (s, 2H) 5.26 (m, 2H) 4.80 (s, 2H) 3.70 (m, 2H) (one OH proton missing)
A171	b 0=^ Z O ^=o z=z	(400 MHz, D2O) 10.07 (d, 1H) 9.88 (d, 1H) 9.37 (s, 1H) 9.13 (dd, 1H) 9.039.08 (m, 1H) 8.26-8.33 (m, 1H) 5.14 (dd, 1H) 4.98 (dd, 1H) 3.41-3.45 (m, 1H) 1.30 (d, 3H) (one CO₂H proton missing)
A172	z=z 5 O Z 5=o O	(400 MHz, D2O) 10.12 (d, 1H) 9.95 (d, 1H) 9.39 (d, 1H) 9.06-9.16 (m, 2H) 8.31 (dd, 1H) 5.50-5.60 (m, 1H) 3.37 (dd, 1H) 3.14 (dd, 1H) 1.72 (d, 3H) (one CO2H proton missing)
A173	O z 7=0 / ¹z=z o' \ o	(400 MHz, D2O) 10.24 (m, 1H) 9.80 (m, 1H) 9.04 (m, 1H) 8.44 (s, 1H) 5.03 (m, 2H) 3.04 (m, 2H) 2.50 (m, 2H) (one NH proton missing)
A174	4 y /—^z O Z-''ω // Ό O 1	(400 MHz, D₂O) 10.10 (d, 1H) 9.84 (d, 1H) 9.13 (s, 1H) 9.08 (dd, 1H) 8.458.39 (m, 2H) 5.25 (t, 2H) 3.71 (t, 2H)

134

Compound Number	Structure	¹H NMR
A175	! O Οχ // z--Z \ ^z	(400 MHz, D₂O) 9.91-9.89 (m, 2H) 9.04-9.02 (m, 2H) 8.51 (s, 1H) 5.27 (t, 2H) 3.71 (t, 2H)
A176	jp o 4 O 7^_o o	(400 MHz, D2O) 10.07 (d, 1H) 9.86 (d, 1H) 9.14-9.13 (m, 1H) 9.08 (dd, 1H) 8.47-8.40 (m, 2H) 5.13 (t, 2H) 3.25 (t, 2H) (one CO₂H proton missing)
A177	o=^~ p I o Γ Z—Z Z	(400 MHz, D2O) 9.77 (d, 1H) 9.65 (d, 1H) 8.69 (dd, 1H) 8.42 (s, 1H) 7.76 (s, 1H) 5.10 (t, 2H) 3.24 (t, 2H) 2.41 (s, 3H) 2.36 ppm (s, 3H) (one CO2H proton missing)
A178	PZ/ Z—Z .4' O I O¹ ^^=o	(400 MHz, D2O) 9.95 (s, 1H) 9.74 (d, 1H) 8.93 (dd, 1H) 8.48 (s, 1H) 7.70 (s, 1H) 5.07 (t, 2H) 3.22 (m, 2H) 2.44 (s, 3H) (one CO2H proton missing)
A179	o // ω i° /—z / \^X\ ^H O	(400MHz, D2O) 10.36 (d, 1H) 9.66 (d, 1H) 9.29 (d, 1H) 8.97 (dd, 1H) 8.92 (dd, 1H) 8.85 (m, 1H) 8.12 (m, 1 H) 5.36 (t, 2H) 3.76 (t, 2H)
A180	rf^N LÀ îî OH F. JL IL 1 >r 0' L· ^^Nx Jk ^^OH κ I F 0	(400 MHz, D2O) 10.25 (d, 1H) 9.83 (dd, 1H) 9.28 (dd, 1H) 9.06 (m, 2H) 7.73 (dd, 1H) 5.33 (dd, 1H) 5.23 (dd, 1H) 4.98 (m, 1H) (one OH proton and one CO2H proton missing)
A181	o // c/r r--Z O o	(400MHz, CD3OD) 10.43-10.37 (m, 1H) 9.93 (dd, 1H) 9.34 (dd, 1H) 9.11 (d, 2H) 7.68 (t, 1H) 5.66-5.53 (m, 1H) 3.66 (dd, 1 H) 3.43 (dd, 1H) 1.83 (d, 3H)

135

Compound Number	Structure	¹H NMR
A182	O î o o o	(400 MHz, D₂0) 10.11 (d, 1H) 9.88 (d, 1H) 9.32 (dd, 1H) 9.10 (dd, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.13 (t, 2H) 3.26 (t, 2H) (one CO2H proton missing)
A183	o^x Z—Z Z-Z cm y< ¹ o	(400 MHz, D2O) 9.83 (d, 1H) 9.54 (d, 1H) 8.92 (d, 1H) 8.81 (dd, 1H) 8.178.23 (m, 1H) 8.10-8.16 (m, 1H) 4.79- 4.81 (m, 2H) 2.78 (t, 2H) 2.33 (q, 2H) (two NH protons missing)
A184	1 O Οχ // ^ωχ z--Z \	(400MHz, CD3OD) 10.41-10.35 (m, 1H) 10.05-9.99 (m, 1H) 9.31 (dd, 1H) 9.12 (d, 2H) 7.67 (t, 1H) 3.67 (s, 2H) 2.10 (s, 6H)
A185	,ω o i o	(400 MHz, D2O) 10.22-10.14 (m, 1H) 9.85-9.77 (m, 1H) 9.24-9.16 (m, 1H) 9.04-8.95 (m, 2H) 7.70-7.60 (m, 1H) 5.13-4.96 (m, 2H) 3.05-2.91 (m, 1H) 2.66-2.51 (m, 1H) 2.42-2.25 (m, 1H) 1.36-1.26 (m, 3H)
A186	N II Il ï ⁰ ^N^Y^^N ’O^YY ll₊ Yf Y/Y/'-OH	(400MHz, D2O) 10.25 (s, 1H) 9.82 (d, 1H) 9.30 (dd, 1H) 9.27 (d, 1H) 8.08 (d, 1H) 4.98 (t, 2H) 4.15 (t, 2H) (one OH proton missing)
A187	T f? z )=^Z\ 4 \ z ,)—z ^zw //—^z // ¹ __/j Y—y ^m// z Λ \ / W / ^XZ=Z^Z /Y “Λ Y ( O» °x / ° Y “ ° // O ।	(400MHz, CD3OD) 10.01 (d, 1H) 9.94 (d, 1H) 9.00-8.95 (m, 1H) 6.87 (s, 1H) 5.39-5.25 (m, 2H) 3.30-3.22 (m, 2H) (Four NH protons missing) [isolated as a 1:1 mixture of isomers with 10.36 (s, 1H) 9.71 (d, 1H) 8.95-8.90 (m, 1H) 6.82 (s, 1H), 5.39-5.25 (m, 2H) 3.30-3.22 (m, 2H) (Four NH protons missing)]

136

Compound Number	Structure	¹H NMR
A188	Z ’z M J O Z ^= O O	(400MHz, CDsOD) 10.00-9.98 (m, 1H) 9.96 (d, 1H) 9.01 (dd, 1H) 6.78 (s, 1H) 5.13 (t, 2H) 3.29-3.23 (m, 2H) (Four NH protons and one CO2H proton missing)
A189	y o n₊ e .N* ΌΗ X 0 f i A Il F ' ^X 0	(400 MHz, D2O) 10.13 (d, 1H) 10.03 (d, 1H) 9.42 (d, 1H) 9.17 (dd, 1H) 9.10 (d, 1H) 8.35 (dd, 1H) 3.39 (s, 2H) 1.96 (s, 6H) (one CO₂H proton missing)
A190	N^N 0	(400 MHz, D2O) 10.12 (d, 1H) 9.83 (d, 1H) 9.41 (s, 1H) 9.19 (dd, 1H) 9.10 (br s, 1H) 8.34 (dd, 1H) 5.30 (dd, 1H) 5.18 (dd, 1H) 4.86 (dd, 1H) (one OH proton and one CO2H proton missing)
A191	O °o / /=Z / \ ZA r	(400 MHz, D₂O) 10.21 (d, 1H) 9.94 (d, 1H) 9.61 (d, 1H) 9.31 (d, 1H) 9.24 (dd, 1H) 5.30 (t, 2H) 3.73 (t, 2H)
A192	Pï	(400MHz, CD₃OD) 10.47-10.41 (m, 1H) 10.07-10.00 (m, 1H) 9.49 (dd, 1H) 9.13 (d, 2H) 7.71 (t, 1H) 6.14 (q, 1H) 3.84 (s, 3H) 2.07 (d, 3H)
A193	Zï H 1 o UyU A	(400MHz, CD3OD) 10.50-10.40 (m, 1H) 10.07-9.98 (m, 1H) 9.51 (dd, 1H) 9.15 (d, 2H) 7.70 (t, 1H) 6.02 (q, 1H) 2.02 (d, 3H) 1.48 (s, 9H)
A194	jp Z 7 \ / 2=⁷ O \ o I o	(400 MHz, D2O) 10.28 (d, 1H) 9.87 (d, 1H) 9.29 (dd, 1H) 9.07 (d, 2H) 7.72 (t, 1H) 5.18-5.28 (m, 2H) 4.62-4.72 (m, 2H)
A195	p ΓΧ z=z o ¥ O	(400 MHz, D2O) 10.25 (d, 1H) 9.81 (d, 1H) 9.26 (dd, 1H) 9.05 (d, 2H) 7.70 (t, 1H) 4.94-5.08 (m, 2H) 4.17-4.22 (m, 2H) (one OH proton missing)

137

Compound Number	Structure	¹H NMR
A196	c? z=z o I o	(400 MHz, D₂O) 9.75 (m, 1H) 9.70 (m, 1H) 8.75 (m, 1H) 8.49 (m, 1H) 7.72 (m, 1H) 5.04 (m, 2H) 3.03 (m, 2H) 2.57 (m, 2H) 2.48 (m, 3H)
A197	_FJ 0 ^F la a °' AAAAA F Cl O	(400 MHz, D2O) 9.92 (d, 1H) 9.89 (d, 1H) 9.04 (td, 2H) 8.54 (d, 1H) 5.16 (t, 2H) 3.24 (t, 2H) (one CO2H proton missing)
A198	X I ¹ O b o_K / A Ç z=z Cz	(400 MHz, D2O) 10.21 (d, 1H) 9.819.89 (m, 1H) 9.18-9.26 (m, 1H) 9.02 (d, 2H) 7.67 (t, 1H) 5.09 (dt, 2H) 2.46-2.60 (m, 2H) (two POH protons missing)
A199	AA A_y F A At /O AA Ai- OH	(400 MHz, D2O) 9.95 (d, 1H) 9.72 (d, 1H) 8.91 (dd, 1H) 8.65 (d, 1H) 8.16 (d, 1H) 7.98-7.87 (m, 1H) 5.08 (t, 2H) 3.26 (t, 2H) 2.42 (s, 3H) (one CO2H proton missing)
A200	F F A O F^\A^^N II _F 1 o^ y/ _p Α^ΑΑΆ^⁰OH	(400 MHz, D2O) 10.07 (d, 1H) 9.86 (d, 1H) 9.13 (s, 1H) 9.07 (dd, 1H) 8.448.38 (m, 2H) 5.14 (t, 2H) 3.28 (t, 2H) (one CO2H proton missing)
A201	0 o ’C”' N OH IL \| _n k .N* Ja fl A/ -AAA._o ji nh; _F>f ° F	(400 MHz, D2O) 10.26 (d, 1H) 9.90 (d, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 5.17 (t, 2H) 4.09 (dd, 1H) 2.76-2.79 (m, 2H) (Three NH protons and one CO2H proton missing)
A202	LL IL τ \/ o Γ Z—Z >=H X / Z-K O	(400 MHz, D₂O) 10.18 (d, 1H) 9.92 (d, 1H) 9.51 (d, 1H) 9.43 (d, 1H) 9.20 (dd, 1H) 5.18 (t, 2H) 3.31 (t, 2H) (two NH protons and one CO2H proton missing)

138

Compound Number	Structure	¹H NMR
A203	0 fl p>A°' X/X/X ^F \ ll₊ I X N* .0 xx y 0	(400 MHz, D₂O) 9.84-9.78 (m, 2H) 8.87 (dd, 1H) 8.80-8.75 (m, 2H) 8.02-7.96 (m, 2H) 5.10 (t, 2H) 3.61 (s, 3H) 3.26 (t, 2H)
A204	Cl z IL w .o lx P 0 ^xx xx' \ F	(400 MHz, D2O) 10.23 (d, 1H) 9.83 (d, 1H) 9.24 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 4.97 (t, 2H) 4.05-4.15 (m, 4H) 2.352.48 (m, 2H) 1.93-2.09 (m, 2H) 1.27 (t, 6H)
A205	X^N Γ if ΧΙ^χΧ^Ν 0 ll₊ Il .oh X NC X XX XX X_Q-	(400 MHz, D2O) 10.16-10.13 (m, 1H) 9.72-9.68 (m, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (d, 2H) (one OH proton missing)
A206	0 cv χ^°· ^N \|f^L ^F	(400 MHz, D₂O) 10.21 (d, 1H) 9.85 (d, 1H) 9.22 (dd, 1H) 9.04 (d, 2H) 7.69 (t, 1H) 5.00 (t, 2H) 3.70 (t, 2H) 2.31-2.39 (m, 2H) (one OH proton missing)
A207	0 n ^Ν^ίί^Χ^ί^Ν OH IL I ⁰ X ,-^NL X F	(400 MHz, D2O) 10.22 (s, 1H) 9.87 (d, 1H) 9.24 (d, 1H) 8.99-9.04 (m, 2H) 7.66 (t, 1H) 5.16 (t, 2H) 4.17 (dd, 1H) 2.692.85 (m, 2H) (Three NH protons and one CO2H proton missing)
A208	o 1 JL ^F H,⁺N IL ? 0 X .N* Z. OH X x F	(400 MHz, D₂O) 10.26 (s, 1H) 9.94 (d, 1H) 9.31-9.34 (m, 1H) 9.04 (dd, 2H) 7.69 (t, 1H) 5.48 (d, 2H) 4.75 (t, 1H) (Three NH protons and one CO2H proton missing)

139

Compound Number	Structure	¹H NMR
A209	O o.// w / i ) Z—Z 4 '4° 1 O /\	(400MHz, D₂0) 10.34 (s, 1H) 9.99 (d, 1H) 9.46 (s, 2H) 9.39 (m, 1H) 5.21 (t, 2H) 3.28 (t, 2H) 2.72 (s, 3H) (one NH proton and one CO2H proton missing)
A210	h₂n νΑχ ° y 1 a xL _Fx^°· 1 IL F ' V^ho	(400MHz, D₂0) 9.93 (d, 1H) 9.83 (d, 1H) 8.90 (dd, 1H) 8.03 (d, 1H) 7.53 (d, 1H) 7.30 (d, 1H) 5.23-5.15 (m, 2H) 3.29 (t, 2H) (two NH protons and one CO2H proton missing)
A211	L A /x ~ ^H°x ^A A Cl AA IL 1 ^cl A N* zx Jx _χ A/	(400MHz, D₂0) 10.24 (dd, 1H) 9.87 (dd, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 4.99 (t, 2H) 4.08 (t, 1H) 2.232.44 (m, 2H) 2.00-2.16 (m, 2H) (three NH protons and one CO2H proton missing)
A212	L X ^N A xL A o ‘a X <S	¹H NMR (400 MHz, D2O) 10.00 (d, 1H) 9.08 (d, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.16 (t, 2H) 3.68 (t, 2H) 3.12 (s, 3H)
A213	CF [l J A Αχ zx γΑ A IL o A _yN* zx // A/ Y o^Z/	(400 MHz, D2O) 10.13 (d, 1H) 9.86 (d, 1H) 9.35 (dd, 1H) 9.11 (dd, 1H) 8.57 (dd, 1H) 8.05 (dd, 1H) 5.27-5.21 (m, 2H) 3.71-3.64 (m, 2H) (one NH proton missing)
A214	O 1 W Z^z\ Ί	(400 MHz, de-DMSO) 10.36 (s, 1H) 10.06-10.10 (m, 1H) 9.56-9.62 (m, 1H) 9.18-9.22 (m, 2H) 7.82-7.86 (m, 1H) 5.88-5.94 (m, 2H) 2.80-2.86 (m, 6H)

140

Compound Number	Structure	¹H NMR
A215	i o Ck // / \ y/ V/	(400 MHz, D₂O) 10.18 (s, 1H) 9.78- 9.82 (m, 1H) 9.16-9.20 (m, 1H) 8.96- 9.02 (m, 2H) 7.62-7.66 (m, 1H) 4.86- 4.94 (m, 2H) 2.88-2.94 (m, 2H) 2.18- 2.28 (m, 2H) 1.72-1.82 (m, 2H)
A216	I O Os // W s / O / \ y/ O	(400 MHz, D2O) 10.16 (s, 1H) 9.80 (d, 1H) 9.14-9.20 (m, 1H) 8.96-9.00 (m, 2H) 7.60-7.66 (m, 1H) 4.96-5.04 (m, 2H) 4.06-4.12 (m, 2H) 2.44-2.52 (m, 2H)
A217	Γ if 9 0 „ k J< N“ \	(400 MHz, D2O) 10.16 (s, 1H) 9.789.82 (m, 1H) 9.16-9.20 (m, 1H) 8.969.00 (m, 2H) 7.62-7.66 (m, 1H) 4.884.94 (m, 2H) 3.16 (s, 3H) 2.52-2.58 (m, 2H) 2.36-2.42 (m, 2H)
A218	O z /¹ O\	(400 MHz, D2O) 10.18 (s, 1H) 9.82- 9.86 (m, 1H) 9.18-9.24 (m, 1H) 8.98- 9.02 (m, 2H) 7.64-7.68 (m, 1H) 5.12- 5.18 (m, 2H) 3.60 (s, 3H) 3.00-3.04 (m, 2H)
A219	Γ jï ⁰ L Jk JL .c> N^- \	(400 MHz, D2O) 10.22 (s, 1H) 9.84- 9.88 (m, 1H) 9.28-9.32 (m, 1H) 8.99- 9.04 (m, 2H) 7.64-7.68 (m, 1H) 5.64- 5.68 (m, 2H) 3.72 (s, 3H)
A220	\=z Ζ^Λ O 1	(400 MHz, D2O) 10.18 (s, 1H) 9.81 (d, 1H) 9.18-9.22 (m, 1H) 8.98-9.02 (m, 2H) 7.64-7.68 (m, 1H) 4.90-4.96 (m, 2H) 2.50-2.56 (m, 2H) 2.34-2.42 (m, 2H)
A221	\| 0 - Il ₊ w U ,n* JL s? H 0	(400 MHz, D2O) 10.18 (s, 1H) 9.68- 9.76 (m, 1H) 9.18-9.22 (m, 1H) 9.00- 9.06 (m, 2H) 7.64-7.70 (m, 1H) 4.96- 5.04 (d, 1H) 4.60-4.68 (m, 1H) 3.82- 3.92 (m, 1H) 1.36 (d, 3H) (one NH proton missing)

141

Compound Number	Structure	¹H NMR
A222	^N \|A. ΓΛ A .A >A / 0^S-°“ ° w o	(400 MHz, D₂0) 10.12 (s, 1H) 9.629.68 (m, 1H) 9.12-9.18 (m, 1H) 8.949.02 (m, 2H) 7.60-7.66 (m, 1H) 4.94 (d, 1 H) 4.58-4.66 (m, 1H) 4.04-4.14 (m, 1H) 3.16-3.28 (m, 2H) 2.04-2.18 (m, 1H) 1.72-1.98 (m, 3H)
A223	O I W A An o^x \ ZI :	(400 MHz, D2O) 10.18 (s, 1H) 9.689.74 (m, 1H) 9.14-9.18 (m, 1H) 8.969.02 (m, 2H) 7.62-7.66 (m, 1H) 5.145.24 (m, 1H) 3.38-3.54 (m, 2H) 1.68 (d, 3H) (one NH proton missing)
A224		(400 MHz, D2O) 10.16 (d, 1H) 9.85 (dd, 1H) 9.41-9.44 (m, 1H) 9.21 (dd, 1H) 9.11 (d, 1H) 8.36 (dd, 1H) 5.26 (dd, 1H) 4.97 (dd, 1H) 4.71-4.78 (m, 1H) 3.213.37 (m, 2H) (one OH proton missing)
A225	u. O LA W X U. θ'' Ί	(400 MHz, D2O) 10.14-10.18 (m, 1H) 9.64-9.68 (m, 1H) 9.16-9.22 (m, 1H) 8.96-9.00 (m, 2H) 7.60-7.64 (m, 1H) 4.82-4.88 (m, 2H) 3.58-3.64 (m, 2H)
A226	A^N Il ^N Αχ n A. N* _N“ ^A xx y o	(400 MHz, D2O) 10.16 (s, 1H) 9.86 (d, 1H) 9.16-9.20 (m, 1H) 8.96-9.02 (m, 2H) 7.60-7.66 (m, 1H) 5.08-5.14 (m, 2H) 3.20-3.28 (m, 2H)
A227	AA [ 1 ^N i^Pi r* L 'p 1 z^N^A \/A	(400 MHz, D₂O) 10.18 (s, 1H) 10.0010.04 (m, 1H) 9.26-9.30 (m, 1H) 8.969.02 (m, 2H) 7.62-7.66 (m, 1H) 6.426.48 (m, 2H)
A228	^f>4 An A o A<A	(400MHz, CD3OD) 10.44-10.30 (m, 1H) 10.12-10.05 (m, 1H) 9.42 (dd, 1H) 9.10 (d, 2H) 8.10 (d, 2H) 7.74-7.67 (m, 3H) 6.19 (s, 2H)

142

Compound Number	Structure	¹H NMR
A229	p ? rp 7=0 °\	(400MHz, CD₃OD) 10.40-10.35 (m, 1H) 10.10-10.05 (m, 1H) 9.43 (dd, 1H) 9.11 (d, 2H) 8.14-8.08 (m, 2H) 7.75-7.68 (m, 3H)6.18(s, 2H) 3.91 (s, 3H)
A230	o F. o Γ î ^F < ll₊ w .0 W W W/ \ Q-\	(400 MHz, de-DMSO) 10.39-10.35 (m, 1H) 10.01 (d, 1H) 9.47 (dd, 1H) 9.22 (d, 2H) 7.84 (t, 1H) 5.78 (d, 2H) 4.24-4.13 (m, 4H) 1.27 (t, 6H)
A231	I O θχ // Z-Z / \^χ--C ^z M	(400 MHz, D2O) 10.04-9.99 (m, 1H) 9.85 (d, 1H) 9.05 (dd, 1H) 8.03 (s, 1H) 5.23 (t, 2H) 3.66 (t, 2H) 2.71 (s, 3H) 2.59 (s, 3H)
A232	€} O Λ o / /^⁼° \ _xo ή ” ,-o^z o \ I O-\	(400 MHz, D2O) 10.24 (dd, 1H) 9.86 (dd, 1H) 9.26 (dd, 1H) 9.06 (d, 2H) 7.71 (t, 1H) 4.98 (t, 2H) 3.92 (quin, 2H) 2.37 (ddd, 2H) 1.69-1.80 (m, 2H) 1.23 (t, 3H) (one POH proton missing)
A233	o p_N '0°· L JL ^F^Ν^ί:^>/^ί^Ν _Q ll ₊ W/OH ΐχ nL p X/ \/ X/ \ OH	(400 MHz, D2O) 10.22 (d, 1H) 9.84 (d, 1H) 9.23 (dd, 1H) 9.03 (d, 2H) 7.68 (t, 1H) 4.97 (t, 2H) 2.33-2.46 (m, 2H) 1.771.89 (m, 2H) (two OH protons missing)
A234	H cr î χ ll₊ J./^N\/\/0 ^Cl OH	(400MHz, D2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.36 (brd, 1H) 9.10 (dd, 1H) 8.488.56 (m, 1H) 7.92-8.07 (m, 1H) 4.985.20 (m, 2H) 3.18-3.32 (m, 2H) (one CO2H proton missing)

143

Compound Number	Structure	¹H NMR
A235	o ‘f	(400 MHz, D₂O) 10.14 (d, 1H) 9.92 (d, 1H) 9.42 (d, 1H) 9.18 (dd, 1H) 9.10 (d, 1H) 8.35 (dd, 1H) 5.09-5.21 (m, 2H) 3.87 (dd, 1H) 2.72 (dd, 2H) (three NH protons and one CO2H proton missing) [Note: pentafluoropropionic acid was used in the HPLC eluent instead of trifluoroacetic acid]
A236	r=Z. y—z O ô o Œ	(400 MHz, D2O) 10.03 (d, 1H) 9.749.69 (m, 1H) 9.34 (s, 1H) 9.14-9.09 (m, 1H) 9.04-9.00 (m, 1H) 8.30-8.26 (m, 1H) 5.11 (d, 2H) (one POH proton missing)
A237	/=^zy—z C— Co \ z°k -π ω=ο ^z o \ ο Ο— I	(400 MHz, D₂O) 10.19-10.13 (m, 1H) 9.93-9.87 (m, 1H) 9.43-9.38 (m, 1H) 9.27-9.22 (m, 1H) 9.11-9.05 (m, 1H) 8.34 (dd, 1H) 5.72-5.65 (m, 2H) 3.903.84 (m, 6H)
A238	0 ο. Il F. /x ⁰ Cl / L \ /° LL t N^ \\ 0	(400 MHz, D2O) 10.37 (d, 1H) 10.00 (d, 1H) 9.48-9.42 (m, 1H) 9.23-9.20 (m, 2H) 7.83 (t, 1H) 5.82 (d, 2H) 3.83 (s, 3H) 3.82-3.78 (m, 3H)
A239	ç °x^ / o ।	(400 MHz, D2O) 10.09 (d, 1H) 9.86 (d, 1H) 9.40-9.35 (m, 1 H) 9.13 (dd, 1H) 9.06 (d, 1H) 8.31 (dd, 1H) 5.11-4.98 (m, 2H) 3.88-3.76 (m, 2H) 2.44 (td, 2H) 1.11 (t, 3H)

144

Compound Number	Structure	¹H NMR
A240	I O °x / Q-_x Z--Z / \^χ \ ^H z—/ Z	(400 MHz, D₂0) 10.10-10.06 (m, 1H) 9.89-9.85 (m, 1H) 9.39-9.36 (m, 1H) 9.15-9.10 (m, 1H) 9.07-9.04 (m, 1H) 8.33-8.28 (m, 1H) 5.11-5.02 (m, 2H) 2.51-2.40 (m, 2H) (one OH proton missing)
A241	—o \ A 0.^ o z—z / \^χ\ ^zz-/ z=A	(400 MHz, D2O) 10.11-10.08 (m, 1H) 9.80-9.75 (m, 1H) 9.41-9.38 (m, 1H) 9.20-9.15 (m, 1H) 9.10-9.06 (m, 1H) 8.36-8.31 (m, 1H) 5.26-5.20 (m, 2H) 3.67-3.61 (m, 3H)
A242	\—o \ A z—z / L \ ^zz-/ Z=/	(400 MHz, D2O) 10.02-9.98 (m, 1H) 9.71-9.64 (m, 1H) 9.33-9.28 (m, 1H) 9.11-9.06 (m, 1H) 9.01-8.96 (m, 1H) 8.26-8.21 (m, 1H) 5.15-5.08 (m, 2H) 3.94-3.84 (m, 2H) 1.12 (t, 3H)
A243	A? o \ T / / C) \ o )	(400 MHz, D2O) 10.14-10.11 (m, 1H) 9.92-9.88 (m, 1H) 9.37 (d, 1H) 9.199.14 (m, 1H) 9.05 (d, 1H) 8.32-8.28 (m, 1H) 5.20-5.10 (m, 2H) 4.12-4.02 (m, 4H) 2.88-2.76 (m, 2H) 1.18 (t, 6H)
A244	r=Z /--^Z ^Z\ / Tl n c A· O O \ I °—\	(400 MHz, D2O) 10.17-10.13 (m, 1H) 9.91-9.85 (m, 1H) 9.40-9.36 (m, 1H) 9.25-9.19 (m, 1H) 9.08-9.04 (m, 1H) 8.34-8.29 (m, 1H) 5.66-5.58 (m, 2H) 4.32-4.14 (m, 4H) 1.25 (br t,6H)
A245	—o \ CL z—z / w \ \	(400 MHz, D2O) 10.19-10.15 (m, 1H) 9.73-9.69 (m, 1H) 9.25-9.20 (m, 1H) 9.01 (d, 2H) 7.68-7.62 (m, 1 H) 5.19 (d, 2H) 3.61 (d, 3H)

145

Compound Number	Structure	¹H NMR
A246	^O=\ I >— ai + / /—z \ ^zz—/ Z——'	(400 MHz, D₂0) 10.20 (d, 1H) 10.00 (dd, 1H) 9.45 (d, 1H) 9.28 (dd, 1H) 9.13 (d, 1H) 8.39 (dd, 1H) 6.15 (d, 1H) 3.82 (s, 3H) 2.05 (d, 3H)
A247	y--Z z^z y o h.	(400 MHz, D₂O) 10.11-10.05 (m, 1H) 9.88-9.83 (m, 1H) 9.39-9.35 (m, 1H) 9.15-9.09 (m, 1H) 9.07-9.03 (m, 1H) 8.32-8.27 (m, 1H) 7.61-7.56 (m, 2H) 7.30-7.25 (m, 2H) 5.09-4.97 (m, 2H) 3.45 (d, 3H) 2.52-2.39 (m, 2H) 2.30 (s, 3H) (one POH proton missing)
A248	o /°x // a. O z=z «D	(400 MHz, D2O) 10.18 (d, 1H) 9.81 (d, 1H) 9.19 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.07-4.97 (m, 2H) 3.46 (d, 3H) 2.53-2.42 (m, 2H)
A249	I o \ o=( O \ o. / A—U- /\ / CT LL LL y-----' /=Z / \ ά /Z z---'	(400 MHz, D2O) 10.16-10.13 (m, 1H) 9.94-9.90 (m, 1H) 9.42-9.39 (m, 1H) 9.21-9.16 (m, 1H) 9.11-9.07 (m, 1H) 8.36-8.31 (m, 1H) 5.23-5.13 (m, 2H) 3.76-3.70 (m, 6H) 2.93-2.81 (m, 2H)
A250	o	(400 MHz, D₂O) 10.16-10.11 (m, 1H) 9.91-9.86 (m, 1H) 9.41-9.37 (m, 1H) 9.26-9.21 (m, 1H) 9.10-9.05 (m, 1H) 8.37-8.30 (m, 1H) 5.87 (s, 2H) 3.80 (s, 3H)
A251	o y—z z Λ w / 6 o^x \ o—\	(400 MHz, D2O) 10.16 (s, 1H) 9.70 (br d, 1H) 9.24-9.18 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.15 (br d, 2H) 3.99-3.89 (m, 2H) 1.17 (t, 3H)

146

BIOLOGICAL EXAMPLES

Post-emergence efficacy

Method A

Seeds of a variety of test species were sown in standard soil in pots. After cultivation for 14 days (postemergence) 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 dissolution of the technical active ingrédient formula (I) in a small amount of acetone and a spécial solvent and emulsifier 10 mixture referred to as IF50 (11.12% Emulsogen EL360 TM + 44.44% N-methylpyrrolidone + 44.44%

Dowanol DPM glycol ether), to create a 50g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC70 (Sodium lauryl ether sulphate) + 1% ammonium sulphate as diluent. The test plants were then grown in a glasshouse under controlled conditions (at 24/16 °C, day/night; 14 hours light; 65 % humidity) and watered twice daily. After 13 days the test was evaluated (100 = total 15 damage to plant; 0 = no damage to plant).

The results are shown in Table B (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

Test plants:

Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (ΑΜΑΡΑ), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)

Table B - Control of weed species by compounds of Formula (I) after post-emergence application

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	IPOHE	SETFA	ECHCG	z LU LU	DIGSA	LOLPE
A1	500	100	100	100	100	100	70	100	100	70
A2	500	60	20	90	10	80	50	30	40	0
A4	500	100	80	100	90	60	60	100	80	100
A5	500	100	100	100	40	90	100	100	100	100
A6	500	100	100	100	60	100	80	100	100	60
A7	500	100	100	100	60	90	80	100	100	60
A8	500	10	10	10	10	20	10	20	20	0
A9	500	100	100	70	30	60	100	100	100	80
A10	500	100	100	100	40	60	30	50	60	90
A11	500	100	100	100	100	30	60	100	80	80
A12	500	100	100	40	30	70	80	100	100	90

147

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	IPOHE	< LU ω	ECHCG	ELEIN	DIGSA	LOLPE
A13	500	100	50	70	50	60	50	100	70	50
A14	500	80	60	20	40	60	60	90	90	40
A15	500	n/a	90	20	10	50	40	80	60	10
A16	500	60	30	50	40	50	60	70	50	10
A17	500	100	30	30	30	40	40	60	60	10
A18	500	n/a	0	10	10	40	30	60	50	10
A19	500	100	60	60	40	60	40	60	50	20
A20	500	n/a	100	80	40	100	100	100	100	60
A21	500	100	80	80	40	90	60	100	90	80
A22	500	n/a	100	70	30	100	100	100	100	80
A23	500	n/a	80	90	60	100	70	100	80	70
A24	500	90	70	80	70	70	60	40	40	60
A25	500	100	60	40	50	60	70	50	50	40
A26	500	n/a	100	100	40	100	100	100	100	90
A28	500	100	100	100	100	100	90	100	90	70
A29	500	100	100	100	20	90	90	90	100	50
A30	500	100	90	100	80	100	80	100	100	70
A31	500	100	100	50	100	50	60	80	90	60
A32	500	n/a	70	70	40	80	70	100	90	30
A33	500	100	80	60	40	60	40	80	60	50
A34	500	100	70	70	70	70	30	90	60	60
A35	500	100	100	100	n/a	100	80	90	100	90
A36	500	100	90	90	30	100	90	100	90	80
A37	500	n/a	100	80	30	100	100	100	100	80
A38	500	100	50	30	20	70	30	70	100	40
A39	500	100	90	90	0	40	30	80	70	60
A40	500	90	70	90	100	100	90	90	90	90
A41	500	n/a	90	90	30	100	100	100	100	70
A42	500	50	0	30	20	50	30	20	50	0
A43	500	n/a	90	80	30	100	70	100	90	20
A44	500	40	10	20	20	60	30	20	40	20
A45	500	n/a	60	50	20	100	90	80	80	30
A46	500	70	10	60	10	50	30	50	50	20
A47	500	n/a	100	80	50	100	70	100	100	60
A48	500	n/a	100	90	20	100	70	100	90	70
A49	500	100	80	70	60	100	60	100	90	50
A50	500	100	20	90	50	60	40	90	50	60

148

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	IPOHE	SETFA	ECHCG	ELEIN	DIGSA	LOLPE
A51	500	n/a	70	30	20	70	60	90	90	60
A52	500	n/a	60	60	20	70	60	70	70	10
A53	500	n/a	100	80	70	80	70	70	80	40
A54	500	90	90	70	10	100	90	100	100	70
A55	500	n/a	80	70	70	100	90	100	100	60
A56	500	90	90	100	30	100	80	100	100	40
A57	500	n/a	⁶⁰	60	10	60	40	40	80	10
A58	500	100	80	60	10	90	60	80	90	50
A59	500	90	90	100	80	100	80	90	100	70
A60	500	n/a	100	70	60	90	90	100	100	70
A61	500	n/a	80	90	50	100	90	100	100	70
A62	500	n/a	100	100	60	100	70	90	100	30
A63	500	40	30	30	20	40	40	50	30	20
A64	500	90	90	100	20	90	60	100	80	80
A65	500	40	10	20	10	40	30	40	30	10
A66	500	40	20	50	40	60	50	40	30	50
A67	500	60	50	80	20	70	80	70	60	40
A68	500	60	70	100	50	60	70	70	40	60
A69	500	100	60	50	40	40	40	60	50	50
A70	500	90	70	50	20	30	30	20	30	20
A71	500	100	60	40	40	30	30	30	30	10
A72	500	60	40	70	40	40	40	30	30	20
A73	500	40	30	60	30	60	60	60	30	40
A74	500	60	30	60	50	80	60	80	50	60
A75	500	60	30	60	20	70	50	60	50	50
A76	500	30	20	30	20	40	30	30	20	30
A77	500	100	80	80	30	100	90	100	100	80
A78	500	0	10	20	20	40	30	30	40	20
A79	500	10	30	10	0	10	10	20	20	0
A81	500	100	90	100	40	90	90	80	100	40
A82	500	70	80	40	20	60	30	60	30	0
A83	500	90	80	90	40	90	50	100	100	70
A84	500	100	80	90	30	50	20	20	50	30
A85	500	90	90	100	30	90	70	90	90	70
A86	500	30	40	50	40	40	20	10	30	10
A87	500	50	30	50	40	70	70	60	70	70
A88	500	100	70	60	30	70	60	90	90	60

149

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	IPOHE	SETFA	ECHCG	ELEIN	DIGSA	LOLPE
A89	500	100	40	100	70	70	60	40	50	40
A90	500	40	20	60	30	30	20	20	30	20
A91	500	40	20	40	20	60	60	60	50	20
A92	500	90	90	70	100	90	80	90	60	50
A93	500	90	80	40	20	100	80	100	100	80
A94	500	70	90	40	30	40	30	20	30	20
A95	500	30	40	40	30	50	50	30	40	20
A96	500	70	20	90	40	70	70	40	40	60
A97	500	90	20	70	30	90	90	90	90	70
A98	500	40	20	40	30	20	20	20	10	0
A99	500	80	30	90	30	50	50	80	40	20
A100	500	60	60	90	20	20	70	60	40	10
A101	500	80	70	80	10	80	60	40	60	70
A102	500	20	50	20	0	10	10	10	10	10
A103	500	0	50	50	30	10	30	30	20	10
A104	500	10	0	20	30	30	30	50	30	10
A105	500	90	20	50	0	90	40	20	60	50
A106	500	80	20	20	10	60	50	80	60	60
A107	500	100	100	100	100	100	100	100	100	70
A108	500	40	80	80	70	60	40	60	50	40
A109	500	60	60	60	50	30	40	50	50	30
A110	500	100	100	80	80	50	50	90	40	50
A112	500	100	100	80	40	70	40	50	40	40
A113	500	40	90	100	60	50	60	40	60	10
A114	500	100	60	80	60	40	60	90	80	70
A115	500	100	100	30	40	60	50	30	30	30
A116	500	100	80	50	10	30	20	20	30	10
A117	500	90	90	100	80	100	90	90	70	50
A118	500	80	80	90	60	70	40	70	90	90
A119	500	100	100	70	50	40	30	30	40	30
A120	500	90	70	50	10	40	40	30	40	20
A121	500	100	80	80	20	30	40	20	40	30
A122	500	100	100	100	70	60	40	90	40	70
A123	500	100	80	100	100	100	90	100	100	60
A124	500	0	0	0	0	20	0	0	10	0
A125	500	100	80	100	30	100	100	100	100	90
A126	500	100	80	100	30	100	80	90	80	70

150

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	LU T o Q.	SETFA	ECHCG	ELEIN	DIGSA	LOLPE
A127	500	10	20	20	10	30	40	20	80	10
A128	500	30	10	0	0	30	30	50	30	40
A129	500	70	50	70	10	60	90	40	60	80
A130	500	100	90	100	40	100	100	100	90	80
A131	500	100	70	40	50	100	100	100	90	30
A132	500	90	30	30	10	100	70	90	90	50
A133	500	60	40	20	20	90	70	90	70	40
A134	500	100	80	90	70	100	80	100	100	80
A135	500	60	20	50	30	50	50	70	30	60
A136	500	60	30	30	30	70	40	50	60	20
A137	500	60	20	20	10	40	30	40	40	20
A138	500	100	100	100	30	100	100	80	100	100
A139	500	80	100	90	10	100	100	100	100	90
A140	500	60	50	50	20	30	20	10	10	0
A141	500	100	60	20	30	50	50	60	40	30
A142	500	10	20	60	20	30	40	60	40	10
A143	500	100	90	80	30	100	100	100	90	70
A144	500	20	10	20	10	20	20	20	30	10
A145	500	10	10	10	10	0	0	0	10	0
A146	500	90	40	50	30	100	90	80	80	50
A147	500	40	50	70	60	40	30	20	20	40
A148	500	100	40	60	20	50	50	40	50	20
A149	500	30	40	30	10	40	50	60	50	40
A151	500	20	20	40	10	20	20	20	20	10
A152	500	20	10	20	0	20	20	20	30	10
A153	500	90	60	40	20	20	40	20	20	0
A154	125	40	50	70	20	30	20	10	20	10
A155	500	20	10	30	20	40	40	30	50	50
A156	500	30	50	50	10	20	10	20	20	0
A157	500	100	100	80	60	80	80	90	70	30
A158	500	100	80	80	30	40	20	50	30	30
A159	500	100	100	80	50	60	70	50	30	40
A160	500	100	100	90	70	90	70	80	70	70
A161	500	30	70	50	20	10	20	20	20	10
A162	500	100	70	80	10	70	90	80	70	90
A163	500	100	60	50	30	n/a	40	90	50	70
A164	500	100	80	90	40	50	30	80	30	40

151

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	IPOHE	SETFA	ECHCG	ELEIN	DIGSA	LOLPE
A165	500	100	50	50	40	60	70	70	60	60
A166	500	30	50	60	60	40	50	60	70	70
A167	500	20	70	90	100	40	60	80	50	40
A168	500	0	40	30	20	10	20	20	10	10
A169	500	100	70	n/a	40	50	40	90	50	50
A170	500	100	100	70	40	80	80	40	40	50
A171	500	100	80	n/a	80	60	60	80	60	70
A172	500	30	60	50	40	50	50	70	80	20
A173	500	30	50	40	20	30	30	10	20	10
A174	500	100	40	60	50	60	50	60	50	60
A175	500	30	60	30	20	30	30	40	40	10
A176	500	40	30	n/a	40	40	30	70	30	40
A177	500	60	50	30	20	0	0	10	10	0
A178	500	90	70	40	20	10	10	0	10	0
A179	500	30	30	60	20	60	40	50	50	10
A180	500	100	90	80	20	70	70	90	60	30
A181	500	90	90	n/a	80	60	100	100	80	90
A183	500	10	0	n/a	20	10	20	10	30	10
A185	500	100	80	n/a	30	50	40	30	30	30
A186	500	70	70	30	30	60	30	50	60	10
A187	500	50	40	50	20	10	20	10	20	10
A188	500	90	50	30	20	30	50	20	40	20
A189	500	100	100	90	70	70	80	90	50	30
A190	500	100	80	80	70	40	60	70	60	40
A191	500	100	30	30	30	20	10	30	20	30
A192	500	90	60	40	30	20	30	30	30	10
A193	500	70	60	60	30	10	10	30	30	10
A194	500	100	70	70	60	50	70	90	50	50
A195	500	n/a	60	n/a	20	n/a	10	10	20	0
A196	500	30	40	30	20	0	0	10	0	0
A197	500	100	10	10	10	0	0	10	20	0
A198	500	100	100	100	50	90	80	80	80	50
A199	500	n/a	40	n/a	10	30	20	10	50	0
A200	500	100	70	70	10	50	40	30	40	40
A201	500	100	100	90	40	80	70	100	80	30
A202	500	100	90	100	60	70	80	20	60	70
A203	500	100	90	50	20	60	50	60	70	0

152

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	CHEAL	EPHHL	IPOHE	SETFA	ECHCG	ELEIN	DIGSA	LU Q. —1 g
A204	500	10	20	0	0	0	0	0	0	0
A205	500	80	60	n/a	80	80	60	60	80	40
A206	500	60	90	60	20	10	20	10	20	0
A207	500	100	100	90	90	100	60	100	90	20
A208	500	100	80	50	20	60	30	60	40	10
A209	125	30	10	0	0	20	10	0	30	10
A210	500	70	10	10	10	30	10	20	60	20
A211	500	100	100	100	60	100	100	90	100	60
A212	500	100	100	100	30	80	70	90	90	70
A213	500	100	90	100	70	100	100	100	100	90
A214	500	100	100	100	40	90	100	100	100	80
A215	500	100	60	90	60	20	30	30	60	20
A216	500	100	90	100	60	90	70	100	100	70
A218	500	100	80	80	70	60	60	60	70	70
A219	500	100	80	90	60	90	40	100	70	70
A220	500	100	100	90	80	60	40	20	90	60
A221	500	100	90	90	60	80	60	100	100	60
A222	500	80	60	n/a	70	80	70	60	90	20
A223	500	100	90	80	60	80	70	90	90	80
A224	500	100	90	n/a	80	40	40	80	80	40
A225	500	100	90	100	70	30	30	90	60	30
A226	500	100	100	100	50	90	90	100	100	90
A228	500	80	60	n/a	60	10	10	10	20	0
A229	500	10	0	n/a	10	10	0	0	20	0
A230	500	50	60	n/a	20	50	60	10	70	0
A231	500	100	90	n/a	60	60	50	60	80	60
A232	500	100	90	n/a	0	80	100	50	90	20
A233	500	100	100	n/a	70	70	60	50	60	20
A234	500	100	100	100	60	100	100	100	100	90
A235	500	10	40	20	20	30	30	10	40	0
A236	500	90	20	30	40	30	50	10	80	0
A237	500	60	10	0	50	20	10	70	50	10
A238	500	50	20	50	40	50	40	30	50	10

Method B

An “instant formulation”, known as the IF50, containing 50 g/L ofthe“technical” (i.e. unformulated) active ingrédient was prepared by dissolving the active ingrédient in a mixture of organic solvents and

153 emulsifier, details of which are provided in the table. This IF50 was then mixed with a small, variable amount of acetone to aid dissolution, before addition of an aqueous solution of 1% v/v ammonium sulphate + 1% v/v Empicol ESC70 (Sodium lauryl ether sulphate) adjuvant, as the aqueous diluent, to form an aqueous spray solution which contains a predetermined concentration of the active ingrédient 5 (which varies depending on the application rate of the active ingrédient to the plants).

Composition of the mixture of organic solvents and emulsifier used as a base for the instant formulation.

Component	Supplier	Chemical description	CAS Registry number	Amount / %w/w
Emulsogen EL360™	Clariant	Castor oil ethoxylate	61791-12-6	10.6
/V-methylpyrrolidone	Widely available	1 -Methyl-2-py rrolidone	872-50-4	42.2
Dowanol DPM glycol ether	Dow	Dipropylene glycol monomethyl ether	34590-94-8	42.2

This aqueous spray solution was then sprayed onto the plants, after about 12 days’ cultivation. The 10 plants were grown from seeds sown in standard soil, placed in a glasshouse under controlled conditions (at24/18°C or20/16°C, day/night; 16 hours light; 65% humidity). After spray application the plants were then grown on in a glasshouse under the same conditions and watered twice daily. After 15 days the test was evaluated (100 = total damage to plant; 0 = no damage to plant).

The results are shown in Table C (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

Test plants:

Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), 20 Amaranthus retroflexus (AMARE), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-gallî (ECHCG), Setaria faberi (SETFA)

Table C - Control of weed species by compounds of Formula (I) after post-emerqence application

Compound Number	Application Rate g/Ha	AMARE	CHEAL	EPHHL	LU T o Q.	SETFA	ECHCG	ELEIN	DIGSA	LOLPE
A4	500	100	80	100	100	40	70	80	100	90
A28	1000	100	90	100	100	40	100	100	100	70
A41	1000	100	90	100	20	100	100	50	100	60
A138	1000	100	100	100	40	100	100	100	100	100
A207	1000	100	90	70	100	100	100	100	90	20
A211	500	100	90	80	100	100	100	100	100	10

154

Compound Number	Application Rate g/Ha	AMARE	CHEAL	EPHHL	IPOHE	SETFA	ECHCG	ELEIN	DIGSA	LOLPE
A213	1000	100	80	100	80	100	100	100	100	90
A220	1000	100	90	100	30	30	90	100	100	90
A226	1000	100	100	n/a	100	70	100	n/a	100	70

Method C

An “instant formulation”, known as the IF50, containing 50 g/L of the “technical” (i.e. unformulated) active ingrédient was prepared by dissolving the active ingrédient in a mixture of organic solvents and 5 emulsifier, details of which are provided in the table. This IF50 was then mixed with a small, variable amount of acetone to aid dissolution, before addition of a 1% v/v aqueous solution of the adjuvant Empicol ESC70 3EO (Sodium lauryl ether sulphate) and 1% v/v Ammonium sulphate, as the aqueous diluent, to form an aqueous spray solution which contains a predetermined concentration of the active ingrédient (which varies depending on the application rate of the active ingrédient to the plants).

Component	Supplier	Chemical description	CAS Registry number	Amount / %w/w
Emulsogen EL360™	Clariant	Castor oil ethoxylate	61791-12-6	10.6
/V-methylpyrrolidone	Widely available	1 -Methy l-2-pyrrolidone	872-50-4	42.2
Dowanol DPM glycol ether	Dow	Dipropylene glycol monomethyl ether	34590-94-8	42.2

This aqueous spray solution was then sprayed onto the plants after about 21 days’ cultivation. The 15 plants were grown from seeds sown in standard soil, placed in a glasshouse under controlled conditions (at 24/18°C, day/night; 14 hours light; 65% humidity). After spray application the plants were then grown on in a glasshouse under the same conditions and watered twice daily. The test was evaluated at 21 days (100 = total damage to plant; 0 = no damage to plant).

The results are shown in Table D (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

Test plants:

Ipomoea hederacea (IPOHE), Amaranthuspalmeri(ΑΜΑΡΑ), Lolium perenne (LOLPE), Eleusine indica 25 (ELEIN), Echinochloa crus-galli (ECHCG), Conyza canadensis (ERICA)

155

Table D - Control of weed species by compounds of Formula (I) after post-emerqence application

Compound Number	Application Rate g/Ha	ΑΜΑΡΑ	IPOHE	ECHCG	ELEIN	LOLPE	ERICA
A3	400	65	83	13	15	25	100
A27	400	77	90	43	80	68	65

Claims

1. A compound of Formula (I) or an agronomically acceptable sait or zwitterionic species thereof:

wherein

R¹ is selected from the group consisting of hydrogen, halogen, Ci-Cealkyl, C2-Cealkenyl, C2Cealkynyl, C3-Cecycloalkyl, Ci-Cehaloalkyl, -OR⁷, -OR^15a, -N(R⁶)S(O)2R¹⁵, -N(R⁶)C(O)R¹⁵, N(R⁶)C(O)OR¹⁵, -N(R⁶)C(O)NR¹⁶R¹⁷, -N(R⁶)CHO, -N(R^7a)₂ and -S(O)rR¹⁵;

and wherein when R¹ is selected from the group consisting of-OR⁷, -OR^15a, -N(R⁶)S(O)2R¹⁵, N(R⁶)C(O)R¹⁵, -N(R⁶)C(O)OR¹⁵, -N(R⁶)C(O)NR¹⁶R¹⁷, -N(R⁶)CHO, -N(R^7a)2 and -S(O)_rR¹⁵, R² is selected from the group consisting of hydrogen and Ci-Cealkyl; or

R¹ and R² together with the carbon atom to which they are attached form a C₃-Cecycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O;

Q is (CR^1aR^2b)_m;

m is 0, 1, 2 or 3;

each R^1a and R^2b are independently selected from the group consisting of hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, -OH, -OR⁷, -OR^15a, -NH2, -NHR⁷, -NHR^15a, -N(R⁶)CHO, -NR^7bR^7cand -S(O)rR¹⁵; or each R^1a and R^2b together with the carbon atom to which they are attached form a C₃Cecycloalkyl ring or a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and

157

R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -S(O)_rR¹⁵, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, Ci-Cealkoxy, C3Cecycloalkyl and -N(R⁶)₂;

each R⁶ is independently selected from hydrogen and O-Cealkyl;

each R⁷ is independently selected from the group consisting of Ci-Cealkyt, -S(O)₂R¹⁵, -C(O)R¹⁵, -C(O)OR¹⁵ and -C(O)NR¹⁶R¹⁷;

each R^7a is independently selected from the group consisting of -S(O)₂R¹⁵, -C(O)R¹⁵, -C(O)OR¹⁵-C(O)NR¹⁶R¹⁷and -C(O)NR⁶R^15a;

R^7b and R^7c are independently selected from the group consisting of Ci-Cealkyl, -S(O)₂R¹⁵, C(O)R¹⁵, -C(O)OR¹⁵, -C(O)NR¹⁶R¹⁷ and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or different; or

A is a 6-membered heteroaryl, which comprises 1,2, 3 or 4 nitrogen atoms and wherein the heteroaryl may be optionally substituted by 1, 2, 3 or 4 R⁸ substituents, which may be the same or different, and wherein when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, S(O)rR¹⁵, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -S(O)2NR¹⁶R¹⁷, Ci-Cealkyl, C1Cehaloalkyl, Cs-Cecycloalkyl, Cs-Cehalocycloalkyl, Cs-Cecycloalkoxy, C2-Cealkenyl, C₂Cehaloalkenyl, C₂-Cealkynyl, Ci-C3alkoxyCi-C₃alkyl-, hydroxyCi-Cealkyl-, Ci-CsalkoxyCiCsalkoxy-, Ci-Cehaloalkoxy, Ci-CshaloalkoxyCi-Csalkyl-, Cs-Cealkenyloxy, Cs-Csalkynyloxy, NCs-Cecycloalkylamino, -C(R⁶)=NOR⁶, phenyl, a 3- to 6- membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6- membered heteroaryl, which comprises 1,2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R⁹substituents, which may be the same or different;

and wherein when A is substituted by 3 or 4 substituents, each R⁸ is independently selected from the group consisting of halogen, -NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -C(O)NR¹⁶R¹⁷, S(O)₂NR¹⁶R¹⁷, Ci-Cealkyl and Ci-Cehaloalkyl; and each R⁹ is independently selected from the group consisting of halogen, cyano, -OH, -N(R⁶)₂, Ci-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl and Ci-C4haloalkoxy;

158

X is selected from the group consisting of Cs-Cecycloalkyl, phenyl, a 5- or 6- membered heteroaryl, which comprises 1,2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6- membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R⁹ substituents, and wherein the aforementioned CR¹R², Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties;

n is 0 or 1;

Z is selected from the group consisting of -C(O)OR¹⁰, -CH2OH, -CHO, -C(O)NHOR¹¹, C(O)NHCN, -OC(O)NHOR¹¹, -OC(O)NHCN, -NR⁶C(O)NHOR¹¹, -NR⁶C(O)NHCN, C(O)NHS(O)2R¹², -OC(O)NHS(O)2R¹², -NR⁶C(O)NHS(O)2R¹², -S(O)2OR¹°, -OS(O)2OR^w, NR⁶S(O)2OR¹⁰, -NR⁸S(O)OR¹⁰, -NHS(O)2R¹⁴, -S(O)OR¹⁰, -OS(O)OR¹⁰, -S(O)2NHCN, S(O)₂NHC(O)R¹⁸, -S(O)2NHS(O)2R¹², -OS(O)2NHCN, -OS(O)₂NHS(O)₂R¹²,

OS(O)₂NHC(O)R¹⁸, -NR⁶S(O)2NHCN, -NR⁶S(O)2NHC(O)R¹⁸, -N(OH)C(O)R¹⁵, -ONHC(O)R¹⁵, -NR⁶S(O)₂NHS(O)₂R¹², -P(O)(R¹³)(OR¹⁰), -P(O)H(OR¹⁰), -OP(O)(R¹³)(OR¹⁰),

NR⁶P(O)(R¹³)(OR¹⁰) and tetrazole;

R¹² is selected from the group consisting of Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OH, N(R⁶)₂ and phenyl, and wherein said phenyl is optionally substituted by 1,2 or 3 R⁹ substituents, which may be the same or different;

R¹⁴ is Ci-Cehaloalkyl;

R¹⁵ is selected from the group consisting of Ci-Cealkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or different;

R^15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹ substituents, which may be the same or different;

159

R¹® and R¹⁷ are independently selected from the group consisting of hydrogen and Ci-Cealkyl; or

R¹⁶ and R¹⁷ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected 5 from N, O and S; and

R¹⁸ is selected from the group consisting of hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -N(R⁶)₂ and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R⁹substituents, which may be the same or different;

and ris 0, 1 or2.

15

2. A compound according to claim 1, wherein R¹ and R² are independently selected from the group consisting of hydrogen and Ci-Cealkyl.

3. A compound according to claim 1 or claim 2, wherein each R^1a and R^2b are independently selected from the group consisting of hydrogen, Ci-Cealkyl, -OH and -NH₂

4. A compound according to any one of daims 1 to 3, wherein m is 1 or 2.

5. A compound according to any one of daims 1 to 4, wherein R³, R⁴ and R⁵ are independently selected from the group consisting of hydrogen, Ci-Cealkyl and Ci-Cealkoxy.

6. A compound according to any one of daims 1 to 5, wherein R³, R⁴ and R⁵ are hydrogen.

7. A compound according to any one of daims 1 to 6, wherein A is selected from the group consisting of formula A-l to A-VII below

160 wherein the jagged line defines the point of attachment to the remaining part of a compound of Formula (I), p is 0, 1 or 2 and R⁸ is as defined in claim 1.

8. A compound according to any one of daims 1 to 7, wherein A is selected from the group consisting of formula A-l to A-V below

A-V

wherein the jagged line defines the point of attachment to the remaining part of a compound of

10 Formula (I), p is 0, 1, or 2 and R⁸ is as defined in claim 1.

9. A compound according to any one of daims 1 to 8, wherein when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of halogen, nitro, cyano, NH2, -NHR⁷, -N(R⁷)2, -OH, -OR⁷, -S(O)rR^{12 13 14 15}, -NR⁶S(O)2R¹⁵, -C(O)OR¹⁰, -C(O)R¹⁵, -C(O)NR¹⁶R¹⁷, -

15 S(O)₂NR¹⁶R¹⁷, Ci-C₆alkyl and Ci-C₆haloalkyl.

10. A compound according to any one of daims 1 to 9, wherein when A is substituted by 1 or 2 substituents, each R⁸ is independently selected from the group consisting of chloro, fluoro, cyano, -NH₂, -N(Me)₂, -OMe, -S(O)₂Me, -C(O)NHMe, -C(O)N(Me)₂, methyl and trifluoromethyl.

11. A compound according to any one of daims 1 to 10, wherein A is selected from the group consisting of formula A-l to A-V and p is 0.

12. A compound according to any one of daims 1 to 11, wherein Z is selected from the group 25 consisting of -C(O)OR¹°, -C(O)NHS(O)2R¹², -S(O)2OR¹⁰, and -P(O)(R¹³)(OR¹°).

13. A compound according to any one of daims 1 to 12, wherein Z is -C(O)OH or -S(O)₂OH.

14. A compound according to any one of daims 1 to 13, wherein n is 0.

161

15. An agrochemical composition comprising a herbicidally effective amount of a compound of

Formula (I) as defined in any one of daims 1 to 14 and an agrochemically-acceptable diluent or carrier.

16. A method of controlling unwanted plant growth, comprising applying a compound of Formula (I) as defined in any one of daims 1 to 14, or a herbicidal composition according to daim 15, to the unwanted plants or to the locus thereof.

17. A process for preparing a compound of formula (I) as defined in any one of daims 1 to 14, comprising (i) either (a) reacting a compound of formula (H)

A—Hal formula (H) wherein

A is as defined in any one of daims 1, 7 or 8 and Hal is a halogen or pseudo halogen, with a compound of formula (J)

formula (J) wherein

R³, R⁴ and R⁵ are as defined in any one of daims 1, 5 or 6 and M’ is an organostannane or an organoborane, in the presence of a palladium catalyst, to give a compound of formula (X)

formula (X) or (b) reacting a compound of formula (K)

162

formula (K) wherein R³, R⁴ and R⁵ are as defined in any one of daims 1, 5 or 6 and Hal is a halogen or pseudo halogen, with a compound of formula (L)

A—M' formula (L) wherein

A is as defined in any one of daims 1, 7 or 8 and M’is an organostannane or an organoborane, in the presence of a palladium catalyst, to give a compound of formula (X);

(ii) reacting a compound of formula (X) with an alkylating agent of formula (W)

LG Q ,Z

X

R¹' R² formula (W) wherein R¹, R², Q, X, Z and n are as defined in any one of daims 1, 2, 3, 4, 12, 13 or 14, and LG is a suitable leaving group, in an inert solvent or mixture of inert solvents, at a température of from -78 °C to 150 °C, to give a compound of formula (I);

(iii) optionally, partially or fully hydrolysing a compound of formula (I) in the presence of a suitable acid.

18. Use of a compound of formula (J) as defined in daim 17, in a process for the manufacture of a compound of formula (I) as defined in any one of daims 1 to 14.

19. Use according to claim 18, wherein for a compound of formula (J), M’is tributylstannane.

20. Use of a compound of formula (X) as defined in claim 17, in a process for the manufacture of a compound of formula (I) as defined in any one of daims 1 to 14.

21. Use according to claim 20, wherein the compound of formula (X) is selected from the group consisting of 2-pyridazin-4-ylpyrimidine, 4-pyridazin-4-ylpyrimidine, 3-pyridazin-4-ylpyridazine, 2pyridazin-4-ylpyrazine and 4-pyridazin-4-ylpyridazine.

163

22. A compound of formula (X) selected from the group consisting of 2-pyridazin-4-ylpyrimidine, 4- pyridazin-4-ylpyrimidine, 3-pyridazin-4-ylpyridazine and 2-pyridazin-4-ylpyrazine.