NZ620935B2 - Novel estrogen receptor ligands - Google Patents

Abstract

Disclosed are biphenyl and terphenyl compounds of formula (I), wherein the substituents are as defined in the specification. Also disclosed is the use of compounds of formula (I) for treating as estrogen receptor ligands that are preferably selective for the estrogen receptor ? isoform. The compounds are useful for the treatment of diseases related to the estrogen receptor such as depressive disorders, anxiety disorders, Alzheimer's disease, cognitive disorders, osteoporosis, elevated blood triglyceride levels, atherosclerosis, endometriosis, urinary incontinence, autoimmune disease, and cancer of the lung, colon, breast, uterus and prostate. Examples of a compound of formula (I) are: 2-(3 ,5-dimethylisoxazol-4-yl)-N',4'-dihydroxy-5-methyl-[1,1'-biphenyl]-3 -carboximidamide 2"-ethyl-N',4-dihydroxy-5'-propyl-[1,1':2',1"-terphenyl]-3'-carboximidamide 2-(2,4-dimethylfuran-3-yl)-4'-hydroxy-5-propyl-[1,1'-biphenyl]-3-carbonitrile s are useful for the treatment of diseases related to the estrogen receptor such as depressive disorders, anxiety disorders, Alzheimer's disease, cognitive disorders, osteoporosis, elevated blood triglyceride levels, atherosclerosis, endometriosis, urinary incontinence, autoimmune disease, and cancer of the lung, colon, breast, uterus and prostate. Examples of a compound of formula (I) are: 2-(3 ,5-dimethylisoxazol-4-yl)-N',4'-dihydroxy-5-methyl-[1,1'-biphenyl]-3 -carboximidamide 2"-ethyl-N',4-dihydroxy-5'-propyl-[1,1':2',1"-terphenyl]-3'-carboximidamide 2-(2,4-dimethylfuran-3-yl)-4'-hydroxy-5-propyl-[1,1'-biphenyl]-3-carbonitrile

Description

Field of Invention This invention relates to compounds which are estrogen receptor ligands and are preferably selective for 5 the estrogen receptor β isoform, to methods of preparing such compounds and to methods for using such compounds in treatment of diseases related to the estrogen receptor such as depressive disorders, anxiety disorders, Alzheimer’s disease, cognitive disorders, osteoporosis, elevated blood triglyceride levels, atherosclerosis, endometriosis, urinary incontinence, autoimmune disease, and cancer of the lung, colon, breast, uterus and prostate. 10 Background of Invention The estrogen receptor (ER) is a ligand activated mammalian transcription factor involved in the up and down regulation of gene expression. The natural hormone for the estrogen receptor is βestradiol (E2) and closely related metabolites. Binding of estradiol to the estrogen receptor causes a dimerization of the 15 or and the dimer in turn binds to estrogen response elements (ERE’s) on DNA. The ER/DNA x recruits other transcription factors sible for the transcription of DNA downstream from the ERE into mRNA which is eventually translated into protein. Alternatively the interaction of ER with DNA may be indirect through the intermediacy of other transcription factors, most notably fos and jun.

Since the expression of a large number of genes is regulated by the estrogen receptor and since the 20 estrogen receptor is expressed in many cell types, modulation of the estrogen receptor through binding of either natural hormones or synthetic ER ligands can have profound effects on the physiology and hysiology of the organism.

Historically it has been believed there was only one estrogen receptor. However a second subtype (ER-β) 25 has been ered. While both the ical” ER-α and the more recently discovered ER-β are widely distributed in different tissues, they nevertheless display markedly different cell type and tissue butions. Therefore synthetic ligands which are either ER-α or ER-β ive may preserve the beneficial effects of estrogen while ng the risk of undesirable side effects. 30 Estrogens are critical for sexual development in females. In addition, estrogens play an important role in maintaining bone density, regulation of blood lipid , and appear to have rotective effects.

Consequently decreased estrogen tion in post-menopausal women is associated with a number of diseases such as osteoporosis, atherosclerosis, depression and cognitive disorders. Conversely certain types of proliferative diseases such as breast and uterine cancer and endometriosis are stimulated by 35 estrogens and therefore trogens (i.e., estrogen nists) have y in the prevention and treatment of these types of disorders.

KB 640 / 15887 WO The efficacy of the natural estrogen, 17β-estradiol, for the treatment of various forms of depressive illness has also been trated and it has been suggested that the anti-depressant activity of estrogen may be mediated via regulation of tryptophan hydroxylase activity and subsequent nin synthesis (See, e.g., Lu N Z, Shlaes T A, Cundlah C, Dziennis S E, Lyle R E, Bethea C L, an steroid action on 5 tryptophan hydroxylase protein and serotonin ed to localization of ovarian steroid receptors in midbrain of guinea pigs." Endocrine 11:257-267, 1999). The pleiotropic nature of natural estrogen precludes its widespread, more c use due to the increased risk of proliferative effects on breast, uterine and ovarian tissues. The identification of the estrogen receptor, ERβ, has provided a means by which to fy more selective estrogen agents which have the desired anti-depressant activity in the 10 absence of the proliferative effects which are mediated by ER. Thus, it has been shown that therapeutic agents having ERβ-selectivity are potentially effective in the ent of sion.

What is needed in the art are compounds that can produce the same positive responses as estrogen replacement therapy without the negative side effects. Also needed are estrogen-like compounds that 15 exert selective effects on different tissues of the body.

The synthesis of a series of polysubstituted biphenyl compounds and their g affinity towards the human recombinant estrogen receptor alpha is disclosed in D. Lesuisse et al, . Med. Chem.

Lett.,2001, 11, 1709-1712. A series of 4-hydroxy-biphenyl-carbaldehyde oxime derivatives and their 20 binding affinity towards the estrogen receptor (ER) subtypes ER and ER is disclosed in C. Yang et al, . Med. Chem. Lett., 2004, 12, 2553-2570 and also in WO 99122. Further aryl -carbaldehyde oxime derivatives and their use as estrogenic agents are described in WO 2004/103941. Certain other biphenyl compounds and their use in the treatment of multiple sclerosis are disclosed in WO 2006/105442. 25 The compounds of the present invention are ligands for estrogen ors and as such may be useful for treatment or prevention of a variety of conditions d to estrogen functioning.

Summary of the Invention 30 This present disclosure provides a compound of formula (I) or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such an ester, amide or carbamate KB 640 / 15887 WO 2 R 1 R H 9 R 8 R 3 R 4 R 7 5 R R 6 R (I) in which 5 R1 is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, ally substituted , ally substituted naphthyl, optionally substituted C3-8cycloalkyl, optionally substituted C5-6cycloalkenyl, optionally substituted phenylC2-4alkenyl, C2-8alkenyl, -8alkenyl, dihaloC2-8alkenyl, trihaloC2-8alkenyl, and C3-8cycloalkylC2-4alkenyl, wherein when said heterocyclyl, phenyl or yl group or part of group is substituted, it is substituted with from 1 to 5 substituents, 10 each substituent being independently selected from the group consisting of ORA, N(RB)2, n, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and oC1-6alkyl, and when said C3-8cycloalkyl or C5-6cycloalkenyl group is substituted, it is tuted with 1, 2 or 3 substituents selected from C1-5alkyl, C1-5alkenyl , C1-5alkynyl, C1-5alkyl substituted with up to 3 halogen atoms, -CO-C1-5alkyl, and halogen; 15 R2 is selected from the group consisting of -C(NH2)=N-OH, -C(O)N(RC)2, cyano, -CHO, -CH=N-OH, -C(O)NH-OH, -C(CO2H)=N-OH, -C(O-C1-4alkyl)=NH, -C(NH2)=N-NH2, -C(O)-C(O)-NH2, -C(O)CO2H, -CO2H, -CH2-CO2H, -CH(OH)CO2H, -CH2NH-CONH2, C1-6alkyl-NH2, C1-6alkyl-OH, - CH2SO3H, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), N(RB)2, N(OH)2, NHSO2RD, 20 -S-CN, -S-C(NH2)=NH, -S-C(NH2)=N-OH, SO2N(RE)2, SO3H, cyanoC1-6alkyl, and optionally substituted 5-10 membered heterocyclyl containing from one to three nitrogen atoms, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group ting of ORA, N(RB)2, n, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl; 25 R3 is selected from the group consisting of hydrogen, halogen, cyano, kyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl , cloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, oC1-6alkyl, optionally substituted phenyl, optionally substituted phenylC1-4alkyl, optionally substituted 5-10 membered heterocyclyl, and optionally substituted 5-10 membered heterocyclylC1-4alkyl, n when said phenyl 30 or heterocyclyl group or part of group is substituted, it is substituted with from 1 to 5 substituents, each KB 640 / 15887 WO substituent being independently selected from the group consisting of ORA, N(RB)2, halogen cyano, nitro, C1-6alkyl, kenyl, C2-6alkynyl, haloC1-6alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl; R4 is ed from the group consisting of hydrogen, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 5 and haloC1-6alkyl, dihaloC1-6alkyl, and trihaloC1-6alkyl; each of R5, R6, R8 and R9 is independently selected from the group consisting of hydrogen, ORA, N(RB)2, halogen, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl; 10 R7 is ORA; or R6 and R7 may, together with the atoms they are ed to, form a 5-, 6- or 7- membered cyclic group optionally containing one to three heteroatoms selected from O, N and S, said 5-, 6- or 7- membered 15 cyclic group being optionally substituted with one of more groups selected from ORA, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 l, halo C1-6 alkyl, dihalo C1-6 alkyl and o C1-6 alkyl; and each RA, each RB, each RC, each RD and each RE is ndently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and C3-8cycloalkylC1-6alkyl; each optionally 20 substituted by from 1 to 3 halogen atoms.

In one embodiment R2 is selected from the group ting of -C(NH2)=N-OH, -C(O)N(RC)2, cyano, -CHO, -CH=N-OH, -C(O)NH-OH, -C(CO2H)=N-OH, -C(O-C1-4alkyl)=NH, -C(NH2)=N-NH2, -C(O)-C(O)-NH2, O2H, -CO2H, -CH2-CO2H, -CH(OH)CO2H, -CONH2, -C1-6alkyl-NH2, - 25 CH2SO3H, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), NHSO2RD, -S-CN, -S-C(NH2)=NH, -S-C(NH2)=N-OH, SO2N(RE)2, SO3H, cyanoC1-6alkyl-, and optionally substituted 5-10 membered heterocyclyl containing from one to three nitrogen atoms, wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of ORA, , halogen, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2- 30 6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. nds of the invention have surprisingly been found to be ligands of the estrogen receptor. The compounds accordingly have use in the treatment or prophylaxis of conditions ated with estrogen receptor activity. 35 KB 640 / 15887 WO Detailed Description of Invention The compounds of the invention may contain chiral (asymmetric) s or the molecule as a whole may 5 be chiral. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.

Certain compounds of the invention contain an oxime group which may be present as the (E) or (Z) oxime isomer. The individual (E) and (Z) oxime s and mixtures of these are within the scope of 10 the t invention. Throughout the specification, where the oxime structure is shown with a wavy line bond, this indicates either that a single isomer is present but the stereochemistry is unknown, or that a mixture of both isomers is present. - 4A - KB 640 / 15887 WO The present invention provides compounds that are estrogen receptor ligands. The term "estrogen receptor ligand" as used herein is intended to cover any moiety which binds to an estrogen receptor. The ligand may act as an agonist, a partial agonist, an antagonist or a partial antagonist. The ligand may be 5 ERβ selective or display mixed ER and ERβ activity. For example, the ligand may act both as an agonist or a partial agonist of ERβ and as an antagonist or a partial antagonist of ER. Compounds of the present ion are ably estrogen receptor ligands that display ERβ ive agonism.

In one ment, hereinafter referred to as embodiment R1(A), R1 represents an optionally substituted 10 5-10 membered heterocyclyl, wherein when said cyclyl group is substituted, it is substituted with from 1 to 5 substituents, each substituent being ndently selected from the group consisting of ORA, N(RB)2, halogen, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1- 6alkyl and trihaloC1-6alkyl. 15 In r embodiment, hereinafter referred to as embodiment R1(B), R1 represents an optionally substituted phenyl or naphthyl group, wherein when said phenyl or naphthyl group is substituted, it is substituted with from 1 to 5 substituents, each tuent being independently selected from the group consisting of ORA, N(RB)2, halogen, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. Within embodiment R1(B), preferably R1 represents 20 an optionally substituted phenyl group.

In another embodiment, hereinafter referred to as embodiment R1(C), R1 represents an optionally substituted cloalkyl or optionally substituted C5-6cycloalkenyl group, wherein when said C3-8cycloalkyl or C5-6cycloalkenyl group is substituted, it is tuted with 1, 2 or 3 substituents selected 25 from C1-5alkyl, kenyl , C1-5alkynyl, C1-5alkyl tuted with up to 3 halogen atoms, -5alkyl, and halogen.

In r embodiment, hereinafter referred to as embodiment R1(D), R1 represents an optionally substituted phenylC2-4alkenyl, C2-8alkenyl, haloC2-8alkenyl, dihaloC2-8alkenyl, trihaloC2-8alkenyl, or 30 C3-8cycloalkylC2-4alkenyl, wherein when said phenyl part of group is substituted, it is substituted with from 1 to 5 substituents, each substituent being independently selected from the group consisting of ORA, N(RB)2, halogen, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, C1-6alkyl and trihaloC1-6alkyl.

KB 640 / 15887 WO When R1 represents a C2-8alkenyl, -8alkenyl, dihaloC2-8alkenyl, or trihaloC2-8alkenyl, group, this may for example be a C2-6alkenyl, haloC2-6alkenyl, dihaloC2-6alkenyl, or trihaloC2-6alkenyl group. When R1 represents a C3-8 cycloalkyl group, this may for example be a C3-6cycloalkyl group. When R1 represents a C3-8cycloalkylC1-4alkenyl group, this may for example be a C3-6cycloalkylC1-4alkenyl group. 5 When R1 represents a C5-6cycloalkenyl group, this may for e be a entenyl group.

When R1 represents a cyclyl group, the heterocyclyl group may be saturated or unsaturated and may contain one or more O, N and/or S atoms. Suitable heterocyclyl groups e furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, isoxazolyl, lyl, isothiazolyl, imidazolyl, imidazolinyl, 10 imidazolidine, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, morpholinyl, benzofuryl, quinolinyl, dioxazolyl, benzimidazolyl, and piperidyl. In one red embodiment, the heterocyclyl group is 6- ed or, especially, 5-membered; it may be unsaturated, especially aromatic, or saturated. Furyl, pyrrolyl, thienyl, isoxazolyl, isothiazolyl, pyrazolyl and pyridyl are preferred heterocyclyl groups, with isoxazolyl, isothiazolyl, pyridyl, and pyrrolidinyl being particularly preferred groups. In another 15 embodiment, the heterocyclyl group may be 9- or 10-membered, for e it may be a benzofuryl, dioxazolyl or benzimidazolyl group. A heterocyclyl group R1 may include 1 to 5, for e 1 to 3, particularly 1 or 2, substituents. Preferred substituents are selected from ORA, N(RB)2, halogen, cyano, nitro, 1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1- 6alkyl. More preferred substituents are selected from halogen, cyano, C1-4alkyl (especially methyl or 20 ethyl), trihaloC1-4alkyl (especially trifluoromethyl), -C(O)C1-4alkyl, and ORA in which RA ably represents a hydrogen atom or a C1-4alkyl group. Still more preferred substituents are selected from halogen, cyano, C1-4alkyl (especially methyl or ethyl), and trihaloC1-4alkyl (especially trifluoromethyl). ally preferred substituents are selected from halogen, cyano and C1-4alkyl (especially methyl or ethyl), especially halogen and C1-4alkyl (especially methyl or ethyl). In one preferred embodiment R1 is 25 isoxazolyl, isothiazolyl, pyridyl, or pyrrolidinyl ally tuted by up to 3, for example 1 or 2, tuents independently selected from halogen atoms and methyl and ethyl groups. In another embodiment, R1 is a 5-membered, aromatic heterocyclyl group substituted by two methyl groups. When said group contains only one ring heteroatom, an additional substituent, for example a halogen atom, may also be present. 30 A phenyl, naphthyl or phenylC2-4alkenyl group R1 may include 1 to 5, for example 1 to 3, particularly 1 or 2, substituents. Preferred substituents for a phenyl, yl or phenylC2-4alkenyl group R1 include those mentioned above for a heterocyclyl group R1.

KB 640 / 15887 WO Further preferred substituents for a phenyl, naphthyl or phenylC2-4alkenyl group R1 are selected from ORA, halogen, kyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl.

More preferred substituents are selected from halogen (especially fluorine or chlorine), C1-4alkyl (especially methyl or ethyl), C2-4alkenyl ially ethenyl), C2-4alkynyl (especially ethynyl), 5 trihaloC1-4alkyl (especially trifluoromethyl), and ORA in which RA preferably represents a hydrogen atom, a kyl group or a trihaloC1-4alkyl group. Still more preferred substituents are selected from halogen (especially fluorine or chlorine), kyl (especially methyl or ethyl), C2-4alkenyl ially ethenyl), C2-4alkynyl (especially ethynyl), trifluoromethyl, and ORA in which RA represents hydrogen, methyl, ethyl or trifluoromethyl. Especially preferred tuents are ed from halogen (especially fluorine 10 or chlorine), methyl, methoxy and trifluoromethyl.

Preferably, R1 is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally tuted phenyl, optionally substituted naphthyl, optionally substituted C5-6cycloalkenyl, optionally substituted phenylC2-4alkenyl, C2-8alkenyl, C2haloC2-8alkenyl, 15 dihaloC2-8alkenyl, trihaloC2-8alkenyl, and C3-8cycloalkylC2-4alkenyl, n when said heterocyclyl or phenyl or naphthyl group or part of group is substituted, it is substituted with from 1 to 5 substituents, each substituent being independently selected from the group ting of ORA, N(RB) 2, halogen, cyano, nitro, C1-6alkyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl, and wherein when said C5-6cycloalkenyl group is substituted, it is substituted with 1 or 2 substituents selected from n 20 atoms and methyl groups nafter referred to as embodiment R1(E). More preferably, R 1 is ed from the group consisting of optionally substituted 5-10 membered heterocyclyl, ally substituted phenyl, optionally substituted phenylC2-4alkenyl, cyclopentenyl, C2-8alkenyl, and C3-8cycloalkylC2- 4alkenyl, wherein when said heterocyclyl or phenyl group or part of group is substituted, it is tuted with from 1 to 5 substituents, each substituent being ndently selected from the group consisting of 25 ORA, halogen, C1-6alkyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. Still more preferably, R1 is selected from the group ting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally tuted phenylC2-4alkenyl, cyclopentenyl, and C2-6alkenyl, n when said heterocyclyl or phenyl group or part of group is substituted, it is substituted with from 1 to 5 substituents, each substituent being independently selected from the group consisting of ORA, halogen, 30 C1-4alkyl, and trihaloC1-4alkyl (hereinafter referred to as embodiment R1(F)).

In one preferred embodiment, hereinafter referred to as embodiment R1(G), R1 represents an optionally substituted 5-10 ed heterocyclyl (for example an optionally substituted 5- or 6-membered heterocyclyl, for example a pyridyl, pyrrolidinyl, isoxazolyl, isothiazolyl, yl, thienyl or furyl group, 35 especially an isoxazolyl, isothiazolyl, pyridyl, or pyrrolidinyl group, or an optionally substituted 9- or 10- KB 640 / 15887 WO membered cyclyl such as a benzolfuryl, dioxazolyl or benzimidazolyl group), and n when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently ed from the group consisting of ORA, halogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and trihaloC1-4alkyl, and each RA represents hydrogen or C1-4alkyl. In this embodiment, R1 5 may for example represent a 5-membered aromatic heterocyclyl group (for example an isoxazolyl, isothiazolyl, pyrrolyl, thienyl or furyl group) which is substituted by two methyl groups. In a ularly preferred embodiment, R1 represents isoxazolyl, isothiazolyl, yl, pyrazolyl, pyridyl, or pyrrolidinyl optionally substituted by up to 3, for example 1 or 2, substituents independently selected from halogen atoms and methyl and ethyl groups (hereinafter referred to as embodiment R1(H)). In an alternative 10 embodiment, R1 may include 3,5-dimethylisoxazolyl, 3,5-dimethylisothiazolyl, ro-3,5- dimethyl-furyl, 3,5-dimethyl-furyl, or 3,5-dimethyl-thiophenyl.

In an alternative preferred embodiment, R1 represents an optionally substituted phenyl group, wherein when said phenyl group is substituted, it is substituted with from 1 to 5 substituents, more preferably from 15 1 to 3 substituents, each substituent being ndently selected from the group consisting of ORA, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. In this embodiment, more preferably R1 represents an optionally substituted phenyl, group wherein when said phenyl group is substituted, it is substituted with from 1 to 5 substituents, more preferably from 1 to 3 substituents, each substituent being independently selected from the group ting of halogen 20 (especially fluorine or chlorine), C1-4alkyl ially methyl or ethyl), C2-4alkenyl (especially ethenyl), C2-4alkynyl (especially ethynyl), trihaloC1-4alkyl (especially trifluoromethyl), and ORA in which RA preferably represents a hydrogen atom, a kyl group or a trihaloC1-4alkyl group. Most ably, R1 represents an optionally substituted phenyl group, wherein when said phenyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group 25 consisting of n (especially fluorine or chlorine), kyl (especially methyl or ethyl), C2-4alkenyl (especially ethenyl), kynyl (especially ethynyl), trihaloC1-4alkyl (especially trifluoromethyl), and ORA in which RA preferably represents a hydrogen atom, a C1-4alkyl group or a trihaloC1-4alkyl group (hereinafter referred to as embodiment R1(I)). 30 In a particularly red embodiment, hereinafter ed to as embodiment R1(J), R1 ents a phenyl group, optionally substituted with 1 or 2 substituents, each substituent being independently selected from the group consisting of halogen (especially fluorine or chlorine), C1-4alkyl (especially methyl or ethyl), C2-4alkenyl (especially ethenyl), C2-4alkynyl (especially ethynyl), trifluoromethyl, and ORA in which RA ents hydrogen, methyl, ethyl or trifluoromethyl. 35 KB 640 / 15887 WO In one ment, R1 represents an ally substituted yl group, n the optional substituents and preferred substitutents are as given above for an optionally substituted phenyl group (hereinafter referred to as embodiment R1(K)). 5 In one embodiment, R1 represents an ally substituted phenylC2-4alkenyl group, wherein the optional substituents and preferred substituents on the phenyl portion are as given above for an optionally substituted phenyl group (hereinafter ed to as embodiment .

In one embodiment, R1 represents a C2-8alkenyl, haloC2-8alkenyl, dihaloC2-8alkenyl, trihaloC2-8alkenyl, or 10 C3-8cycloalkylC2-4alkenyl group (hereinafter referred to as embodiment R1(M)).

In one embodiment, R1 represents a cyclopentenyl group (hereinafter referred to as embodiment R1(N)).

In one embodiment, hereinafter referred to as embodiment R2(A), R2 is selected from the group consisting 15 of -C(NH2)=N-OH, -C(O)N(RC)2, cyano, -CHO, -CH=N-OH, -C(O)NH-OH, -C(CO2H)=N-OH, -C(O-C1- 4alkyl)=NH, -C(NH2)=N-NH2, -C(O)-C(O)-NH2, -CONH2, C1-6alkyl-NH2, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), N(OH)2, -S-CN, -S-C(NH2)=NH, -S-C(NH2)=N-OH, cyanoC1-6alkyl, and an optionally substituted 5-6 membered heterocyclyl containing from one to three en atoms; wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 20 substituents, each substituent being independently selected from the group consisting of OH, n, cyano, nitro, C1-4alkyl, haloC1-4 alkyl, dihaloC1-4alkyl and trihaloC1-4alkyl. Preferably, R2 represents - C(NH2)=N-OH, -C(O)NH2, cyano, -CHO, -CH=N-OH, C1-6alkyl-NH2, or an optionally substituted 5-6 membered heterocyclyl containing from one to three nitrogen atoms (hereinafter referred to as embodiment R2(B). M ore ably R2 represents C(NH2)=N-OH, -C(O)NH2, cyano, -CH=N-OH, or an 25 optionally substituted 5-membered heterocyclyl ning from one to two nitrogen atoms, such as an optionally substituted pyrrolyl or pyrazolyl group, especially unsubstituted lyl (hereinafter referred to as embodiment R2(C). Most preferably R2 represents -C(NH2)=N-OH, -C(O)NH2, -CH=N-OH, or cyano (hereinafter referred to as embodiment R2(D). 30 The above preferred embodiments for R2, particularly embodiments R2A, R2B, R2C and R2D, may be t together with any of the specific embodiments, for example any one of embodiments R1A to R1N, and especially any one of embodiments R1A, R1b, R1C and R1D, mentioned for R1 above.

In one embodiment, hereinafter referred to as embodiment R3(A), R3 is preferably selected from the group 35 consisting of hydrogen, halogen, cyano, C1-6alkyl, C2-6alkenyl, kynyl, C3-8cycloalkyl , C3- KB 640 / 15887 WO 8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, oC1-6alkyl, optionally substituted phenyl, and optionally substituted phenylC1-4alkyl, wherein when said phenyl group or part of group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of ORA, N(RB)2, halogen cyano, nitro, C1-4alkyl, and trihaloC1-4alkyl. In this embodiment, 5 more preferably, R3 is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, trihaloC1-6alkyl, phenyl, and C1-4alkyl (hereinafter referred to as ment R3(B),. In this embodiment, R3 most preferably ents en, halogen (especially chlorine or e), C1-6alkyl, C2-6alkenyl, trihaloC1-4alkyl (especially trifluoromethyl), phenyl, or C1-2alkyl (hereinafter referred to as 10 embodiment R3(C). For example, R3 may represent hydrogen, chlorine, bromine, C1-4alkyl, C2-4alkenyl, trifluoromethyl, phenyl, or phenylC1-2alkyl; especially hydrogen, chlorine, bromine, C1-4alkyl, C2-4alkenyl, or trifluoromethyl (hereinafter referred to as embodiment .

In an alternative embodiment, R3 is selected from the group consisting of halogen, cyano, C1-6alkyl, 15 kenyl, C2-6alkynyl, C3-8cycloalkyl , C3-8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, oC1-6alkyl, optionally substituted phenyl, optionally substituted phenylC1-4alkyl, optionally substituted 5-10 membered heterocyclyl, and optionally substituted 5-10 membered heterocyclylC1-4alkyl, wherein when said phenyl or heterocyclyl group or part of group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of ORA, 20 N(RB)2, halogen cyano, nitro, C1-6alkyl, kenyl, C2-6alkynyl, haloC1-6alkyl, C1-6alkyl and trihaloC1-6alkyl. In this embodiment, R3 is preferably selected from the group consisting of halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl , C3-8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1- 6alkyl, trihaloC1-6alkyl, optionally substituted phenyl, and optionally substituted phenylC1-4alkyl, wherein when said phenyl group or part of group is substituted, it is substituted with from 1 to 3 tuents, each 25 substituent being independently selected from the group consisting of ORA, N(RB)2, halogen cyano, nitro, C1-4alkyl, and trihaloC1-4alkyl. In this embodiment, R3 is more preferably selected from the group consisting of halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, trihaloC1-6alkyl, phenyl, and C1-4alkyl. Most preferably, R3 represents n (especially chlorine or bromine), cyano, C1-6alkyl, C2-6alkenyl, trihaloC1-4alkyl 30 (especially trifluoromethyl), phenyl, or phenylC1-2alkyl. For example, R3 may represent chlorine, e, cyano, kyl, C2-4alkenyl, trifluoromethyl, phenyl, or C1-2alkyl; especially chlorine, bromine, C1-4alkyl, C2-4alkenyl, or trifluoromethyl.

The above preferred embodiments for R3, particularly embodiments R3A, R3B, R3C and R3D, may be 35 present together with any of the specific embodiments mentioned for R1 and/or R2 above.

KB 640 / 15887 WO Preferably, R4 is selected from the group ting of en, halogen, cyano, C1-6alkyl, and trihaloC1-6alkyl (hereinafter referred to as embodiment R4(A). More preferably, R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, and trihaloC1-4alkyl (especially oromethyl) 5 (hereinafter referred to as embodiment R4(B). Most ably, R4 is selected from the group consisting of en, halogen, and C1-4alkyl (hereinafter referred to as embodiment R4(C).

The above preferred embodiments for R4, particularly embodiments R4A, R4B, and R4C, may be present together with any of the specific ments mentioned for R1 and/or R2 and/or R3 above. 10 In one embodiment, when R3 represents hydrogen, R4 is selected from the group consisting of halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, dihaloC1-6alkyl, and oC1-6alkyl.

Preferably, R7 represents ORA wherein RA represents hydrogen or C1-4alkyl, for example ethyl or methyl 15 nafter referred to as embodiment R7(A)). More preferabl y, R7 ents OH (hereinafter referred to as embodiment R7(B)). In embodiment s R7(A) and R7(B), each of R5, R6, R8 and R9 is preferably independently selected from the group ting of hydrogen, ORA, N(RB)2, halogen, cyano, nitro, C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. More preferably, each of R5, R6, R8 and R9 is independently selected from the group consisting of hydrogen, ORA, N(RB)2, 20 halogen, cyano, nitro, C1-6alkyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. Still more preferably each of R5, R6, R8 and R9 is independently selected from the group consisting of en, OH, NH2, halogen, cyano, nitro, C1-4alkyl, for example methyl, haloC1-4alkyl, for example - or fluoro-methyl, dihaloC1-4alkyl, for example dichloro- or difluoromethyl, and trihaloC1-4alkyl, for example trichloro- or trifluoromethyl. Yet more preferably, each of R5, R6, R8 and R9 is independently selected from the group 25 consisting of hydrogen, halogen, C1-4alkyl, for example methyl or ethyl, and trihaloC1-4alkyl, for example trichloro- or trifluoromethyl. In one embodiment, each of R5, R6, R8 and R9 independently represents methyl, trifluoromethyl or, especially, hydrogen or halogen, especially fluorine. Yet more preferably, each of R5, R6, R8 and R9 is independently selected from the group consisting of hydrogen and halogen.

In one preferred embodiment, each of R5, R6, R8 and R9 represents hydrogen. In an alternative preferred 30 embodiment, one of R5 and R6 ents fluorine and the remainder of R5, R6, R8 and R9 represents en. The above preferred embodiments for R6 and R5, R6, R8 and R9 may be present together with any of the ic embodiments mentioned for R1 and/or R2 R3 and/or R4 above.

In another aspect of the ion, (hereinafter referred to as ment R6/7(A)) R6 and R7, together 35 with the atoms they are attached to, preferably form a 5-, 6- or 7- membered cyclic group optionally KB 640 / 15887 WO containing one to three atoms selected from O, N and S, said 5-, 6- or 7- membered cyclic group being optionally tuted with one of more groups selected from ORA, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo C1-6 alkyl, dihalo C1-6 alkyl and trihalo C1-6 alkyl. More preferably, R6 and R7, er with the atoms they are attached to, form a 5-, 6- or 7- membered cyclic group, especially a 5- or 5 6- membered cyclic group, ally ning one to three heteroatoms selected from O and N, said 5-, 6- or 7- membered cyclic group being optionally substituted with one of more groups selected from OH, cyano, nitro, C1-4 alkyl, -4 alkyl, dihaloC1-4 alkyl and trihaloC1-4 alkyl (hereinafter referred to as embodiment R6/7(B)). Most preferably, R6 and R7, together with the atoms they are attached to, form a 5- membered cyclic group optionally containing one or two heteroatoms selected from O and N, said 5- 10 membered cyclic group being optionally tuted with one of more groups selected from OH, cyano, methyl and trifluoromethyl (hereinafter referred to as embodiment R6/7(C)). In this aspect, preferably each of R5, R8 and R9 is independently selected from the group consisting of hydrogen, ORA, N(RB)2, halogen, cyano, nitro, C1-6alkyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. Mor e preferably each of R5, R8 and R9 is independently selected from the group consisting of hydrogen, OH, NH2, halogen, 15 cyano, nitro, C1-4alkyl, for example methyl, haloC1-4alkyl, for example chloro- or fluoro-methyl, dihaloC1- , for example dichloro- or difluoromethyl, and trihaloC1-4alkyl, for example trichloro- or trifluoromethyl. Most preferably, each of R5, R8 and R9 is independently ed from the group consisting of en, halogen, methyl, and trifluoromethyl, especially hydrogen and halogen (hereinafter referred to as embodiment R6/7(D)). 20 The above preferred ments for R6/7 and R5, R8 and R9 may be present together with any of the specific embodiments mentioned for R1 and/or R2 R3 and/or R4 above.

Each RA is preferably independently selected from the group consisting of hydrogen, C1-6alkyl, C2- 25 6alkenyl, C2-6alkynyl and C3-6cycloalkyl. More preferably, each RA is independently selected from the group consisting of hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl and C3-6cycloalkyl. Most preferably, each RA ndently represents hydrogen or C1-4alkyl, still more preferably hydrogen, methyl or ethyl, especially hydrogen or methyl. 30 Each RB is preferably independently selected from the group consisting of hydrogen and C1-6alkyl. In on e preferred embodiment, each RB is kyl. In another embodiment, each RB is preferably selected from the group consisting of hydrogen or C1-4alkyl, more preferably hydrogen and C1-3 alkyl, especially methyl or ethyl. In one red embodiment, each RB is hydrogen.

KB 640 / 15887 WO Each RC is preferably independently selected from the group consisting of hydrogen and C1-4alkyl, especially methyl.

Each RD is preferably independently selected from the group consisting of hydrogen and C1-4alkyl, 5 ally methyl.

Each RE is preferably independently selected from the group consisting of hydrogen and C1-4alkyl, especially .

Especially preferred sub-groups of compounds are those in which R1 is one of R1A, R1B, R1C and R1D, 10 together with one of R2A, R2B, R2C and R2D, especially R2D, and one of R6A and R7B, especially R7B.

Thus, especially preferred sub-groups of compounds are those in which R1 is one of R1A, R1B, R1C and R1D, together with R2D, and R7B.

Compounds of the formula (I) include, but are not limited to, the nds specifically mentioned in 15 the Examples herein, including pharmaceutically acceptable esters, amides, carbamates or salts thereof, including salts of such , amides or ates.

In the compounds in the Examples, the compound names were generated in accordance with IUPAC by the ACD Labs 8.0/name program, version 8.05 and/or with ISIS DRAW Autonom 2000 and/or 20 ChemBioDraw Ultra version 12.02.

Depending upon the substituents present in compounds of the formula (I), the nds may form esters, amides, carbamates and/or salts. Salts of compounds of formula (I) which are le for use in medicine are those wherein a counterion is pharmaceutically acceptable. However, salts having non- 25 ceutically acceptable counterions are within the scope of the present ion, for example, for use as ediates in the preparation of the compounds of formula (I) and their pharmaceutically acceptable salts, and physiologically functional derivatives. By the term “physiologically functional derivative” is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I), for example, by being convertible in the body thereto. 30 Esters, amides and carbamates are examples of physiologically functional derivatives. le salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention e those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are 35 unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, KB 640 / 15887 WO such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C - 1 C )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. 4 Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, , tartaric, acetic, phosphoric, lactic, pyruvic, acetic, oroacetic, succinic, 5 perchloric, fumaric, maleic, ic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, ptoluenesulfonic , , benzoic, malonic, naphthalenesulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the nds of the invention and their pharmaceutical acceptable acid addition salts. 10 Pharmaceutically acceptable base salts include um salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example ohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, 15 tert-butyl-, diethyl-, ropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding al salts may furthermore be formed. nds of formula (I) may have an appropriate group converted to an ester, an amide or a carbamate. 20 Thus l ester and amide groups formed from an acid group in the compound of the formula I include –COORG, -CONRG2, -SO2ORG, or -SO2N(RG)2, while typical ester and amide and carbamate groups formed from an -OH or –NHRG group in the compound of the formula (I) include -OC(O)RG, -NRGC(O)RG, -NRGCO2RG, G, and –NRGSO2RG, where RG is selected from the group consisting of kyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl, -8alkyl, dihaloC1- 25 G is selected from the group 8alkyl, trihaloC1-8alkyl, phenyl and phenylC1-4alkyl; more ably R consisting of C1-6alkyl, kenyl, C2-6alkynyl, C3-8cycloalkyl and C3-8cycloalkylC1-6alkyl.

Those skilled in the art of c chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. 30 These complexes are known as "solvates". For example, a complex with water is known as a "hydrate".

Solvates, such as hydrates, exist when the drug substance incorporates solvent, such as water, in the crystal lattice in either stoichiometric or non-stoichiometric amounts. Drug substances are routinely screened for the existence of hydrates since these may be encountered at any stage of the drug manufacturing process or upon storage of the drug nce or dosage form. Solvates are described in S. 35 Byrn et al, Pharmaceutical Research 12(7), 1995, 954-954, and Water-Insoluble Drug Formulation, 2nd KB 640 / 15887 WO ed. R. Liu, CRC Press, page 553, which are incorporated herein by reference. Accordingly, it will be understood by the skilled person that the the compounds of formula (I), as well as esters, , carbamates and/or salts thereof may therefore be present in the form of solvates. Solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the associated solvent is 5 pharmaceutically acceptable. For example, a hydrate is an example of a ceutically acceptable solvate. r, solvates having non -pharmaceutically acceptable associated solvents may find use as intermediates in the preparation of the compounds of formula (I) and their pharmaceutically acceptable esters, amides, carbamates and/or salts thereof. 10 A compound which, upon administration to the recipient, is capable of being converted into a compound of formula (I) as described above, or an active metabolite or residue thereof, is known as a “prodrug”. A prodrug may, for example, be ted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutical acceptable prodrugs are described in T. Higuchi and V.

, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); n of 15 gs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

The following tions apply to the terms as used throughout this specification, unless otherwise 20 limited in ic instances.

As used herein, the term "alkyl" means both straight and branched chain saturated hydrocarbon .

Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, tyl, pentyl and hexyl groups. Among unbranched alkyl groups, there are preferred methyl, ethyl, n-propyl, 25 iso-propyl, n-butyl groups. Among branched alkyl groups, there may be mentioned t-butyl, i-butyl, 1- ethylpropyl and 1-ethylbutyl groups.

As used herein, the term “alkoxy” means the group O-alkyl, where “alkyl” is used as described above.

Examples of alkoxy groups e y and ethoxy groups. Other examples include propoxy and 30 butoxy.

As used herein, the term "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Examples of l groups include ethenyl, propenyl, butenyl, yl and hexenyl. Preferred alkenyl groups include ethenyl, 1-propenyl, 2- 35 propenyl and butenyl.

KB 640 / 15887 WO As used herein, the term "alkynyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Preferred alkynyl groups include ethynyl, 1-propynyl and 2- 5 propynyl.

As used herein, the term "cycloalkyl" means a saturated group in a ring system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group may, for example, be fused or bridged. Examples of monocyclic cycloalkyl groups include ropyl, cyclobutyl and entyl. Other examples of 10 monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and ctyl. Examples of bicyclic cycloalkyl groups include bicyclo [2. ptyl. Preferably, the cycloalkyl group is monocyclic.

As used herein, the term "halogen" means fluorine, chlorine, e or iodine. Fluorine, chlorine and bromine are particularly preferred. 15 As used , the term "haloalkyl" means an alkyl group having a halogen substituent, the terms "alkyl" and "halogen" being understood to have the meanings outlined above. Similarly, the term "dihaloalkyl" means an alkyl group having two n substituents and the term "trihaloalkyl" means an alkyl group having three halogen tuents. Examples of haloalkyl groups include fluoromethyl, methyl, 20 bromomethyl, fluoromethyl, fluoropropyl and fluorobutyl ; examples of dihaloalkyl groups include difluoromethyl and difluoroethyl groups; examples of triihaloalkyl groups include trifluoromethyl and trifluoroethyl groups.

As used herein, the term "heterocyclyl" means an aromatic or a non-aromatic cyclic group of carbon 25 atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. A heterocyclyl group may, for example, be monocyclic or bicyclic. In a bicyclic cyclyl group there may be one or more heteroatoms in each ring, or only in one of the rings. A atom may be S, O or N and is preferably O or N. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. 30 Examples of monocyclic non-aromatic heterocyclyl groups (also ed to as monocyclic heterocycloalkyl rings) include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, ydropyranyl, morpholinyl, thiomorpholinyl and azepanyl. 35 KB 640 / 15887 WO Examples of bicyclic heterocyclyl groups in which one of the rings is omatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl. 5 Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl ) include furanyl, thienyl, pyrrolyl, yl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, nyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl, with preferred monocyclic aromatic heterocyclyl groups being furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, azolyl, isoxazolyl, pyrazinyl, 10 pyrazolyl and pyrimidinyl.

Examples of bicyclic ic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, azolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, l, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, 15 pyridopyrimidinyl, isoquinolinyl and roxazole.

Examples of preferred heterocyclyl groups include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrimidinyl and indolyl. Preferred cyclyl groups also include thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, olyl and imidazolyl. 20 As used herein the term “cycloalkylalkyl” means a group cycloalkyl-alkyl- attached through the alkyl group, “cycloalkyl” and “alkyl” being understood to have the meanings ed above.

As mentioned above, the compounds of the invention have activity as en receptor ligands. The 25 compounds of the invention have activity as estrogen receptor modulators, and may be agonists, partial agonists, antagonists, or l antagonists of the estrogen or. Particularly preferred compounds of the invention have activity as an agonist or a partial agonist of ERβ. Preferred compounds of this type are selective agonists of the estrogen receptor-beta (ERβ). 30 The invention also provides a compound according to the ion, or a composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier, for use as a medicament.

A ccompound of the invention, or a composition comprising a compound of the invention, may thus be 35 used in the ent of diseases or disorders associated with estrogen receptor activity. In particular, the KB 640 / 15887 WO nds of the invention that are agonists or partial agonists of the estrogen receptor may be used in the treatment of diseases or disorders for which selective agonists or partial agonists of the estrogen receptor are indicated. The compounds of the ion that are antagonists or partial antagonists of the estrogen receptor may be used in the treatment of diseases or disorders for which selective nists or 5 partial antagonists of the estrogen receptor are indicated.

Clinical conditions for which an agonist or partial agonist is indicated include, but are not limited to, bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL terol, cardiovascular disease, impairment of cognitive functioning, 10 cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, y, inence, y, depression, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, and lung, colon, breast, uterus, and prostate cancer, lymphoma, and/or disorders related to estrogen functioning. 15 The compounds of the invention find particular application in the ent or prophylaxis of the ing: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flushes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, cerebral rative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, 20 perimenopausal sion, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention t disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, anger management, hearing disorders, le sclerosis, son’s disease, Alzheimer’s disease, Huntington’s e, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal 25 degeneration, lung cancer, colon cancer, breast cancer, uterus cancer, prostate cancer, and the bile duct cancer form named cholangiocarcinoma. The compounds of the invention also find particular application in the treatment or prophylaxis of the following: benign tic hyperplasia, lower urinary tract ms, overactive bladder, interstitial cystitis, painful bladder symptoms, vaginal atrophy, wound healing, chronic pain, sepsis, inflammatory and neuropathic pain, ovarian cancer, melanoma, lymphoma 30 (B-cell lymphoma, T-cell ma), atherosclerosis, left ventricular rophy, congestive heart failure, mesothelioma, gallbladder cancer and extra-hepatic cholangiocarcinoma.

Preferably, the compounds of the invention find application in the treatment or prophylaxis of the ing: bone loss, bone res, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid 35 disease, hot s, increased levels of LDL cholesterol, cardiovascular e, restenosis, KB 640 / 15887 WO gynecomastia, vascular smooth muscle cell proliferation, obesity, inence, anxiety, depression, perimenopausal depression, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, ivity, anger management, hearing disorders, spinal cord injury, stroke, 5 autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer, breast cancer, uterus cancer, prostate cancer, the bile duct cancer form named cholangiocarcinoma, benign tic hyperplasia, lower urinary tract symptoms, overactive r, interstitial cystitis, l r symptoms, vaginal atrophy, wound healing, chronic pain, sepsis, inflammatory and neuropathic pain, ovarian cancer, ma, lymphoma, sclerosis, left 10 ventricular hypertrophy, congestive heart failure, mesothelioma, gallbladder cancer and extra-hepatic cholangiocarcinoma.

In combination with drugs that are known to induce vasomotor symptoms, the compounds of the invention find utility as follows: in combination with SERMs such as tamoxifen, in its use for the 15 treatment of breast cancer, and raloxifene, used for the treatment and/or prevention of osteoporosis, to alleviate SERM-induced vasomotor symptoms; in combination with an aromatase inhibitor, used for the treatment of breast cancer or endometriosis, to alleviate aromatase inhibitor-induced tor symptoms; and in male prostate cancer patients that have one androgen deprivation therapy. 20 In one embodiment of the invention, the present compounds finds particular ation in the treatment or prophylaxis of depression, perimenopausal depression, post-partum depression, premenstrual syndrome and manic depression.

The treatment or prophylaxis of hot flashes (or hot flushes) in males, is preferable for patients that have 25 had an androgen ablation for ent of prostate cancer.

The phrase “depression” es but is not limited to, major depressive disorder, dysthymic disorder, bipolar disorder, hymic disorder, mood disorder due to a general medical condition, substanceinduced mood misorder, seasonal affective disorder (SAD), postpartum depression and premenstrual 30 dysphoric disorder.

The invention also provides a method for the treatment or prophylaxis of a condition associated with a e or er associated with estrogen or activity in a , which comprises administering to the mammal a therapeutically effective amount of a compound according to the 35 invention, or a composition comprising a compound according to the invention together with a KB 640 / 15887 WO pharmaceutically acceptable carrier. Clinical conditions ed by an estrogen receptor that may be treated by the method of the invention are ably those described above.

The invention also provides the use of a compound according to the invention, for the manufacture of a 5 medicament for the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen or activity. Clinical ions mediated by an estrogen or that may be treated by the method of the invention are preferably those described above.

The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary 10 with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the t and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. 15 Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day, for adult humans. For oral administration, the compositions are preferably ed in the form of tablets or other 20 forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be d. A ment typically contains from about 0.01 mg to about 500 mg of the active ient, preferably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most red doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. 25 Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery 30 system, the dosage administration will, of , be continuous rather than intermittent throughout the dosage regimen.

While it is possible for the active ingredient to be administered alone, it is preferable for it to be t in a pharmaceutical formulation or ition. Accordingly, the invention provides a pharmaceutical 35 formulation or composition comprising a compound according to the invention, and a pharmaceutically KB 640 / 15887 WO acceptable diluent, excipient or carrier (collectively referred to herein as “carrier” materials).

Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as bed below. 5 The pharmaceutical formulations according to the ion include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered does pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and l (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route 10 may depend upon, for example, the condition and disorder of the recipient.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the s well known in the art of pharmacy. All s include the step of bringing the active ingredient into association with the carrier which tutes one or more ory ingredients. In 15 general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid rs or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the t invention le for oral administration may be presented as discrete units 20 such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ient; as a powder or granules; as a on or a suspension in an aqueous liquid or a non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. 25 A tablet may be made by compression or moulding, ally with one or more ory ingredients.

Compressed tablets may be prepared by compressing in a suitable e the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may 30 optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ient therein. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the t compounds, or, particularly in the case of ed release, by the use of devices such as subcutaneous implants or osmotic pumps. The present 35 compounds can also be administered liposomally.

KB 640 / 15887 WO Exemplary compositions for oral administration include sions which can contain, for example, microcrystalline ose for imparting bulk, c acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the 5 art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, s, extenders, disintegrants, diluents and lubricants such as those known in the art.

Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, poly- 10 ethylene , waxes and the like. Disintegrators e without limitation starch, methylcellulose, agar, ite, xanthan gum and the like. The compounds of formula (I) can also be red through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or dried tablets are exemplary forms which may be used. ary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose 15 and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), y propyl methyl cellulose (HPMC), sodium carboxy methyl ose (SCMC), maleic ide copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring 20 agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium de and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, ceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. 25 The compounds of the present invention can also be administered in the form of liposome ry systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.

Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, atidyl ethanolamine (cephaline) , or phosphatidylcholine (lecithin). 30 Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may e suspending agents and thickening . The formulations may be presented in unit-dose or 35 multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried KB 640 / 15887 WO (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and s of the kind previously described. ary compositions for parenteral administration include able solutions or suspensions which can contain, 5 for e, suitable non-toxic, erally acceptable diluents or ts, such as mannitol, 1,3- butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor. 10 Exemplary compositions for nasal, l or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other lizing or dispersing agents such as those known in the art.

Formulations for rectal administration may be presented as a suppository with the usual carriers such as 15 cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but y and/or dissolve in the rectal cavity to release the drug. ations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, 20 and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and . Exemplary compositions for topical administration include a topical carrier such as Plastibase al oil gelled with hylene).

Preferred unit dosage formulations are those containing an effective dose, as hereinbefore d, or an 25 appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. 30 Whilst a compound of the invention may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further therapeutic agents. Thus, the invention also provides a compound according to the invention er with a further therapeutic agent, for simultaneous, sequential or separate administration. Such further therapeutic agents may be 35 further nds according to the invention, or they may be different therapeutic agents, for example an [Link] http://en.wikipedia.org/wiki/Lorazepam [Link] http://en.wikipedia.org/wiki/Alprazolam [Link] http://en.wikipedia.org/wiki/Diazepam KB 640 / 15887 WO antidepressant, an anxiolytic, an anti-psychotic, an agent useful in the prevention or treatment of osteoporosis, an agent useful in the prevention or treatment of cancer or other pharmaceutically active material. For example, the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an antidepressant, an anxiolytic, an anti- 5 psychotic, an organic bisphosphonate or a cathepsin K inhibitor. In one preferred embodiment, the compounds of the invention may be effectively administered in combination with an effective amount of an antidepressant. Nonlimiting examples of antidepressants include noradrenaline reuptake inhibitors (NRI), selective serotonin reuptake inhibitors, monoamine e inhibitors, lic antidepressants (TCA), dopamine reuptake tors (DRI), opioids, selective nic reuptake enhancers, tetracyclic 10 antidepressants, ible inhibitors of monoamine e, melatonin agonists, nin and noradrenaline ke inhibitors (SNRI), corticotropin ing factor antagonists, α-adrenoreceptor antagonists, 5HT1α receptor agonists and nists, lithium and atypical anti-psychotics. Examples of antidepressants of the SSRI class include Fluoxetine and Sertraline; examples of antidepressants of the SNRI class Venlafaxine, pram, Paroxetine, Escitalopram, Fluvoxamine; examples of 15 antidepressants of the SNRI class include Duloxetine; examples of antidepressants of the DRI and NRI classes include Bupropion; examples of pressants of the TCA class e Amitriptyline and Dothiepin (Dosulepin). Examples of atypical antipsychotics include: Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone and Dopamine l agonists. Nonlimiting examples of anxiolytics include benzodiazepines and nzodiazapines. Examples of benzodiazapines include 20 lorazepam, alprazolam, and diazepam. Examples of non-benzodiazapines include Buspirone (Buspar®), barbiturates and meprobamate. One or more of those further epressants may be used in combination.

Examples of ancer agents include tamoxifen or an aromatase inhibitor, used in treatment of breast 25 cancer.

In the event that hot flashes are d by a particular treatment, a compound of the ion may be used in combination therapy with the agent of such treatment. Nonlimiting examples of such combination treatment therapies e: a compound of the invention in combination with tamoxifene treatment of 30 breast cancer, a compound of the invention in combination with aromatase inhibitor treatment of breast cancer or a compound of the invention in combination with raloxifene treatment of osteoporosis.

Nonlimiting examples of above-mentioned organic bisphosphonates include adendronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, onate, piridronate, pamidronate, 35 tiludronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

KB 640 / 15887 WO Preferred organic biphosphonates include alendronate and ceutically acceptable salts and mixtures thereof. Most preferred is alendronate monosodium trihydrate.

The precise dosage of the bisphosphonate will vary with the dosing schedule, the oral potency of the 5 particular bisphosphonate chosen, the age, size, sex and condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount cannot be ied in advance and can be readily determined by the caregiver or clinician. An appropriate amount can be determined by routine experimentation from animal models and human clinical studies. Generally, an appropriate amount of bisphosphonate is chosen to 10 obtain a bone resorption inhibiting , i.e. a bone resorption inhibiting amount of the bisphonsphonate is stered. For humans, an ive oral dose of sphonate is typically from about 1.5 to about 6000 µg/kg of body weight and preferably about 10 to about 2000 µg/kg of body weight.

For human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof, or 15 pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises from about 8.75 mg to about 140 mg of the alendronate compound, on an alendronic acid active weight basis, i.e. on the basis of the corresponding acid.

The compounds of the present ion can be used in combination with other agents useful for treating 20 estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly. It will be tood that the scope of combinations of the compounds of this invention with other agents useful for 25 treating en-mediated ions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning.

The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for e, in those amounts indicated in the Physicians' Desk Reference (PDR) 30 or as otherwise determined by one of ordinary skill in the art.

Where the compounds of the invention are utilized in combination with one or more other therapeutic agent(s), either concurrently or sequentially, the following combination ratios and dosage ranges are preferred: 35 KB 640 / 15887 WO When combined with an antidepressant, an anxiolytic, an anti-psychotic, an organic bisphosphonate or a cathepsin K inhibitor, the nds of formula (I) may be employed in a weight ratio to the additional agent within the range from about 10:1 to about 1:10. 5 The compounds of the invention as described above also find use, optionally in labelled form, as a diagnostic agent for the diagnosis of conditions associated with a disease or disorder ated with estrogen receptor activity. For example, such a compound may be rad ioactively labelled.

The compounds of the invention as described above, optionally in labelled form, also find use as a 10 reference compound in methods of identifying s for the estrogen receptor (i.e. ering other agonists, partial agonists, antagonists or partial antagonists of the estrogen or). Thus, the invention provides a method of identifying an estrogen receptor ligand which comprises use of a compound of the invention or a compound of the invention in labelled form, as a reference compound. For example, such a method may involve a competitive binding experiment in which binding of a nd of the invention 15 to the estrogen receptor is d by the presence of a r compound which has estrogen receptorbinding characteristics, for example stronger estrogen receptor-binding characteristics than the compound of the invention in question.

Numerous synthetic routes to the compounds of the present invention can be devised by any person 20 skilled in the art and the le synthetic routes described below do not limit the invention. Many methods exist in the literature for the synthesis of biphenyls, for e: Metal- catalyzed Cross- coupling reactions, A. Meijere, F. Diederich, 2004; N. Miyaura et al.Chem. Rev., 1995, 7, 2457-2483; D.

Lesuisse et al, . Med. Chem. Lett.,2001, 11, 1709-1712; C. Yang et al, Bioorg. Med. Chem. Lett., 2004, 12, 2553-2570; WO 2009/130434 and WO 2006/105442. A number of possible synthetic routes 25 are shown tically below. Where appropriate, any initially produced compound according to the invention can be converted into another compound ing to the invention by known methods.

General method I KB 640 / 15887 WO General Method I as shown in the reaction scheme above was used for the synthesis of intermediates used in general methods II – VI. Full experimental details of the individual steps of the general method 5 applicable for the synthesis of the intermediates are described in Intermediates A and B.

General method II 10 General Method II as shown in the reaction scheme above was used for the sis of the following Examples: 1-14, 85 and 05, 297, 298, 300-303, 312-318, 320, 321, 328, 343, 344, 346 and 352- KB 640 / 15887 WO 360. Full experimental s of the individual steps of the general method applicable for the synthesis of the final compounds of those Examples are described in Examples 1 and 328.

KB 640 / 15887 WO General method III 5 General Method III as shown in the reaction scheme above was used for the synthesis of the following Examples: 15 - 49, 59-66, 72, 75-84, 86-91, 93-102, 106-116, 122-296, 304-309 and 322-327. Full experimental details of the dual steps of the general method applicable for the synthesis of the final nds of those Examples are described in Examples 15-18, 59, 61,72, 277, 284, 287-289, 322, 326 and 327. 10 KB 640 / 15887 WO General method IV General Method IV as shown in the reaction scheme above was used for the synthesis of the following 5 Examples: 50-58, 299, 310, 329-342, 345, 347, 348 and 350. Full experimental details of the individual steps of the general method applicable for the sis of the final compounds of those Examples are described in Examples 50 and 51.

General method V 10 KB 640 / 15887 WO General Method V as shown in the reaction scheme above was used for the synthesis of the following Examples: 67-71 and 119-121. Full experimental details of the individual steps of the general method applicable for the synthesis of the final compounds of those Examples are described in Example 67. 5 General method VI 10 General Method VI as shown in the reaction scheme above was used for the synthesis of the following Examples: 73 and 92. Full mental s of the individual steps of the general method applicable for the synthesis of the final nds of those Examples are described in Example 73.

KB 640 / 15887 WO General method VII 5 General Method VII as shown in the reaction scheme above was used for the synthesis of the following Examples: 74, 117 and 118. Full experimental s of the individual steps of the general method applicable for the synthesis of the final compounds of those Examples are described in Example 74.

Synthesis of Intermediate A 10 Scheme 1 KB 640 / 15887 WO Step (a): 2-aminobromobenzonitrile (25 mg, 0.13 mmol), propylboronic acid (78.08 mg, 0.89 mmol), Pd(OAc)2 (5.70 mg, 0.03 mmol), RuPhos (23.68 mg, 0.05 mmol) and K2CO3 (87.68 mg, 0.63 mmol) were mixed in toluene /water (2 mL, 10:1) under nitrogen. The reaction mixture was heated in microwave at 5 140 °C for 20 min, cooled to room temperature and filtered through celite. The solvent was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (10 - 20 % EtOAc) as mobile phase. 17.1 mg 2-aminopropylbenzonitrile was obtained as yellowish oil.

Step (b): 2-aminopropylbenzonitrile (71.4 mg, 0.45 mmol) was dissolved in EtOH (3 mL). Iodine 10 (113.11 mg, 0.45 mmol) and AgSO4 (138.95 mg, 0.45 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and was then filtered through celite. The solvent was evaporated under d pressure and the crude product was purified on silica using EtOAc/n-heptane (5:95) as mobile phase. 99.7 mg 2-aminoiodopropylbenzonitrile was obtained as a straw coloured solid. 15 Synthesis of Intermediate B Scheme 2 20 Step (a): 2-aminochlorobenzonitrile (765 mg, 5.01 mmol) was dissolved in DCM (10 mL) and NBS (1160 mg, 6.52 mmol) was added at 0 °C. The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 h. The t was evaporated under reduced re and the crude product was purified on silica using DCM as mobile phase. 750 mg obromo chlorobenzonitrile was obtained. 25 Step (b): obromochlorobenzonitrile (212 mg, 0.92 mmol), propylboronic acid (80.5 mg, 0.92 mmol), Pd(OAc)2 (10.3 mg, 0.05 mmol), RuPhos (42.7 mg, 0.09 mmol) and K2CO3 (633 mg, 4.6 mmol) were mixed in toluene /water (3 mL, 10:1) under nitrogen. The reaction mixture was heated in microwave at 120 °C for 20 min. H2O was added and the aqueous mixture was extracted with DCM and EtOAc. The 30 ed c phases were filtered h a phase separator and the solvent was evaporated under KB 640 / 15887 WO reduced pressure. The crude product was purified on preparative HPLC. 100 mg 2-aminochloro propylbenzonitrile was obtained.

Step (c): 2-aminochloropropylbenzonitrile (100 mg, 0.51 mmol) was dissolved in HOAc (3.6 mL) 5 and NBS (91.4 mg, 0.51mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was ated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (20 % EtOAc) as mobile phase. 117 mg 2-aminobromochloro propylbenzonitrile was obtained. 10 Synthesis of Intermediate C Scheme 3 15 Step (a): 2-bromoiodo(trifluoromethoxy)aniline (300 mg, 0.79 mmol), 4-methoxyphenylboronic acid (131 mg, 0.86 mmol), PdCl2(PPh3)2 (27.6 mg, 0.04 mmol) and K2CO3 (434 mg, 3.14 mmol) were mixed in DME/EtOH/H2O (10 mL, 4:1:1) under nitrogen. The on mixture was heated in microwave at 130 °C for 20 min. The solvent was concentrated, the residue was dissolved in EtOAc and filtered through a plug of silica. The crude t was purified on silica using EtOAc/n-heptane (2.5-5 % 20 EtOAc) as mobile phase. 199 mg o-4'-methoxy(trifluoromethoxy)-[1,1'-biphenyl]amine was ed as a white solid.

Step (b): 3-bromo-4'-methoxy(trifluoromethoxy)-[1,1'-biphenyl]amine (199 mg, 0.55 mmol) and CuCN (54.1 mg, 0.60 mmol were mixed in NMP (1 mL) under nitrogen. The on mixture was heated 25 in microwave at 175 °C for 30 min and then at 180 °C for 75 min. EtOAc (10 mL) was added and the mixture was washed with NH3OH (25 %, aq) and brine. The combined aqueous layers were extracted with EtOAc (3x) and the combined organic layers were dried with brine and over Na2SO4. The solvent was concentrated and the crude product was purified on silica using EtOAc/n-heptane (5-20 % EtOAc) as mobile phase. 138 mg 2-amino-4'-methoxy(trifluoromethoxy)-[1,1'-biphenyl]carbonitrile was 30 obtained as a yellow oil.

KB 640 / 15887 WO The following Examples illustrate the invention.

Example 1N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 5 (E1) Scheme 4 10 Step (a): 2-aminoiodopropylbenzonitrile (99.7 mg, 0.35 mmol), 4-methoxyphenylboronic acid (158.8 mg, 1.05 mmol), Pd(OAc)2 (7.82 mg, 0.03 mmol), RuPhos (32.5 mg, 0.0 mmol) and K2CO3 (240.8 mg, 1.74 mmol) were mixed in e /water (5 mL, 10:1) under nitrogen. The reaction mixture was heated in microwave at 140 °C for 20 min, cooled to room temperature and filtered through celite. The t was evaporated under reduced pressure and the crude product was purified on silica using 15 EtOAc/n-heptane (5 - 10 % EtOAc) as mobile phase. 17.1 mg 2-amino-4'-methoxypropylbiphenyl carbonitrile was obtained as straw coloured oil.

KB 640 / 15887 WO Step (b): 2-amino-4'-methoxypropylbiphenylcarbonitrile (91.0 mg, 0.34 mmol) and CuBr2 (152.6 mg, 0.68 mmol) were mixed in MeCN (3.5 mL). l nitrite (35.23 mg, 0.34 mmol) was added. The reaction mixture was d at room ature for 0.5 h. The solvent was evaporated under reduced 5 pressure and the crude product was filtered through silica using DCM as mobile phase. 113 mg 2-bromo- 4'-methoxypropylbiphenylcarbonitrile was obtained as yellowish oil.

Step (c): 2-Bromo-4'-methoxypropylbiphenylcarbonitrile (113 mg, 0.34 mmol) was dissolved in DCM (2 mL) under nitrogen and the solution was cooled to -78 °C. BBr3 (1.71 mL, 1M) was added. The 10 reaction mixture was added at 0 °C to quench the reaction. NaHCO3 (25 mL, sat.) and EtOAc (25 mL) were added, the phases were partitioned and the s phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified on silica using EtOAc/n-heptane (0 - 20 % EtOAc) as mobile phase. 102.1 mg 2-bromo-4'- 15 hydroxypropylbiphenylcarbonitrilewas obtained as a colourless solid.

Step (d): 2-Bromo-4'-hydroxypropylbiphenylcarbonitrile (25 mg, 0.08 mmol), 3-methylthiophene- 2-boronic acid (22.45 mg, 0.16 mmol), Pd(OAc)2 (3.55 mg, 0.02 mmol), RuPhos (14.76 mg, 0.03 mmol) and K2CO3 (54.63 mg, 0.40 mmol) were mixed in toluene /water (1 mL, 10:1) under nitrogen. The 20 reaction e was heated in microwave at 140 °C for 20 min, cooled to room temperature and filtered through celite. The solvent was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (10 - 20 % EtOAc) as mobile phase. 9.7 mg roxy(3- methylthiophenyl)propylbiphenylcarbonitrile was obtained. 25 Step (e): 4'-hydroxy(3-methylthiophenyl)propylbiphenylcarbonitrile (9.7 mg, 0.03 mmol) was treated with hydroxylamine (200 eq, 16 M, aq) in MeOH (1 mL). The reaction mixture was heated in microwave at 120 °C for 15 min under nitrogen. The solvent was evaporated under reduced pressure and the crude product was purified on preparative HPLC using MeCN/acidic H2O (5 – 50% MeCN) as mobile phase. N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide (E1) 30 ES/MS m/z: 367.4 (M+H), 365.2 (M-H); 1H NMR (MeOD 3, ): δ 7.33 (s, 1H), 7.29 (s, 1H), 7.22 (d, 1H, J=4.8Hz), 6.92 (m, 2H), 6.68 (d, 1H, J=4.8Hz), 6.59 (m, 2H), 2.69 (t, 2H, J=7.5Hz), 1.74 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.4Hz). was obtained as a solid. The title compound was identified by 1H-NMR which showed that the oxime t was a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 35 KB 640 / 15887 WO Examples 2-14 Examples 2-14 were prepared using a method analogous to that used to synthesise Example 1above. Full experimental details of the individual steps of the general s are described in e 1 above. For examples 2, 3 and 6-14 identification of the title compounds by 1H-NMR showed that the oxime product 5 was a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

E 2 2-(3,5-dimethylisoxazolyl)-N',4'-dihydroxymethyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= methyl R6=H R8=H ES/MS m/z: 338.18 (pos. M + H), 336.27 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.34 (s, 1H), 7.32 (s, 1H), 6.89 (m, 2H), 6.67 (m, 2H), 2.44 (s, 3H), 2.07 (s, 3H) and 1.84 (s, 3H).

E 3 2-(3,5-dimethylisoxazolyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= propyl R6=H R8=H ES/MS m/z: 366.27 (pos. M + H), 364.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.32 (d, 1H, J=1.7Hz), 7.28 (d, 1H, J=1.7Hz), 6.94 (m, 2H), 6.74 (m, 2H), 2.69, (t, 2H, J=7.7Hz), 2.01 (s, 3H), 1.82 (s, 3H), 1.72 (m, 2H) and 0.99 (t, 3H, J=7.2Hz). 10 E 4 2-(3,5-dimethylisoxazolyl)-4'-hydroxypropyl-[1,1'-biphenyl]carboxamide R1 = methylisoxazolyl R2 = carbamoyl R3= propyl R6=H R8=H ES/MS m/z: 351.3 (pos. M + H), 349.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): 7.36 (d, 1H, J=1.7Hz), 7.30 (d, 1H, J=1.7Hz), 6.96 (m, 2H), 6.75 (m, 2H), 2.70, (t, 2H, J=7.6Hz), 2.04 (s, 3H), 1.84 (s, 3H), 1.72 (m, 2H) and 0.99 (t, 3H, J=7.3Hz).

E 5 2-(3,5-dimethylisoxazolyl)-4'-hydroxypropyl-[1,1'-biphenyl]carbonitrile R1 = 3,5-dimethylisoxazolyl R2 = CN R3= propyl R6=H R8=H KB 640 / 15887 WO ES/MS m/z: 333.25 (pos. M + H), 331.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.71 (d, 1H, z), 7.61 (d, 1H, J=1.7Hz), 7.04 (m, 2H), 6.80 (m, 2H), 2.77, (t, 2H, J=7.5Hz), 2.15 (s, 3H), 1.84 (s, 3H), 1.75 (m, 2H) and 0.99 (t, 3H, J=7.6Hz).

E 6 N',4'-dihydroxymethyl(3-methylthiophenyl)-[1,1'-biphenyl]carboximidamide R1 = 3-methylthiophenyl R2 = N-hydroxy carbaimidoyl R3= methyl R6=H R8=H ES/MS m/z: 339.2 (pos. M + H), 337.17 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.33 (s, 1H), 7.27 (s, 1H), 7.21 (d, 1H, J=5.1Hz), 6.91 (m, 2H), 6.67 (d, 1H, J=5.1Hz), 6.58 (m, 2H), 2.43 (s, 3H) and 1.73 (s, 3H).

E 7 difluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R1 = 3-methylthiophenyl R2 = N-hydroxy carbaimidoyl R3= propyl R6=F R8=F ES/MS m/z: 403.14 (pos. M + H), 401.2 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.34 (br s, 1H), 7.33 (s, 1H), 7.27 (d, 1H, z), 6.74 (d, 1H, J=5.1Hz), 6.63 (m, 2H), 2.70 (t, 2H, J=7.6Hz), 1.80 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, z).

E 8 2-(3,5-dimethylisoxazolyl)-3',5'-difluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl] carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= propyl R6=F R8=F ES/MS m/z: 402.22 (pos. M + H), 400.22 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.38 (d, 1H, J=1.9Hz), 7.35 (d, 1H, J=1.9Hz), 6.63 (m, 2H), 2.71 (t, 2H, J=7.4Hz), 2.11 (s, 3H), 1.89 (s, 3H), 1.72 (m, 2H) and 1.01 (t, 3H, J=7.4Hz).

E 9 5-bromo-N',4'-dihydroxy(3-methylthiophenyl)-[1,1'-biphenyl]carboximidamide R1 = 3-methylthiophenyl R2 = N-hydroxy carbaimidoyl R3= Br R6=H R8=H ES/MS m/z: 405.03 (pos. M + H), 401.08 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.60 (d, 1H, J=2.2Hz), 7.58 (d, 1H, J=2.2Hz), 7.28 (d, 1H, J=5.1Hz), 6.97 (m, 2H), 6.71-6.68 (m, 3H) and 1.77 (s, 3H). 5 E 10 5-bromo-N',4'-dihydroxyiodo-[1,1'-biphenyl]carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= Br R6=H R8=H KB 640 / 15887 WO ES/MS m/z: 383.13 (pos. M + H), 383.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.56 (d, 1H, J=2.2Hz), 7.55 (d, 1H, J=2.2Hz), 7.18-7.15 (m, 3H), 7.12-7.10 (m, 2H), 6.87 (m, 2H) and 6.64 (m, 2H).

E 11 5''-fluoro-N',4-dihydroxy-2'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethylphenyl R2 = oxy carbaimidoyl R3= methyl R6=H R8=H ES/MS m/z: 349.34 (pos. M + H), 351.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.28 (d, 1H, J=1.1Hz), 7.23 (d, 1, J=1.1Hz), .89 (m, 4H), 6.82 (m, 1H), 6.63 (m, 2H), 2.42 (s, 3H) and 1.83 (s, 3H).

E 12 5''-fluorohydroxy-2'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 5-fluoromethylphenyl R2 = carbamoyl R3= methyl R6=H R8=H ES/MS m/z: 336.26 (pos. M + H), 334.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.34 (d, 1H, J=1.1Hz), 7.25 (d, 1, J=1.1Hz), 7.00 (dd, 1H, J=8.4, 6.2Hz), 6.93-6.89 (m, 3H), 6.84 (m, 1H), 6.64 (m, 2H), 2.43 (s, 3H) and 1.86 (s, 3H).

E 13 5-chloro(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= Cl R6=H R8=H ES/MS m/z: 358.23 (pos. M + H), 356.24 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.47 (d, 1H, J=2.2Hz), 7.45 (d, 1H, J=2.2Hz), 6.98 (m, 2H), 6.76 (m, 2H), 2.04 (s, 3H) and 1.83 (s, 3H).

E 14 5-chloro(3,5-dimethylisoxazolyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide R1 = 3,5-dimethylisoxazolyl R2 = carbamoyl R3= Cl R6=H R8=H ES/MS m/z: 343.19 (pos. M + H), 341.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.52 (d, 1H, J=2.3Hz), 7.48 (d, 1H, J=2.3Hz), 6.94 (m, 2H), 6.78 (m, 2H), 2.08 (s, 3H) and 1.88 (s, 3H). 5 e 15 2-(3,5-dimethylisoxazolyl)-3'-fluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl] carboximidamide (E15) KB 640 / 15887 WO Scheme 5 Step (a): 2-aminoiodopropylbenzonitrile (150 mg, 0.52 mmol), 3-fluorohydroxyphenylboronic 5 acid 1 mg, 0.79 mmol), PdCl2(PPh3)2 (36.8 mg, 0.05 mmol) and K2CO3 (144.9 mg, 1.05 mmol) were mixed in DME/EtOH/H2O (2 mL, 1) under nitrogen. The reaction e was heated in microwave at 130 °C for 20 min, cooled to room temperature, diluted with DCM and washed with NH4Cl aq, sat). The mixture was filtered through a phase separator, the solvent was evaporated under d pressure and the crude product was purified on silica using EtOAc/n-heptane (20 % EtOAc) as mobile 10 phase. 122 mg 2-amino-3'-fluoro-4'-hydroxypropylbiphenylcarbonitrile was obtained.

Step (b): 2-amino-3'-fluoro-4'-hydroxypropylbiphenylcarbonitrile (122.0 mg, 0.45 mmol) and CuBr2 (201.6 mg, 0.90 mmol) were mixed in dry MeCN (5 mL). t-Butyl nitrite (46.54 mg, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was evaporated 15 under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (20 % EtOAc) as mobile phase. 71.6 mg 2-bromo-3'-fluoro-4'-hydroxypropylbiphenylcarbonitrile was obtained.

Step (c): 2-bromo-3'-fluoro-4'-hydroxypropylbiphenylcarbonitrile (71.0 mg, 0.21 mmol), 3,5- 20 dimethylisoxazoleboronic acid (59.9 mg, 0.42 mmol), Pd(OAc)2 (9.54 mg, 0.04 mmol), RuPhos (39.7 mg, 0.08 mmol) and K2CO3 (146 mg, 1.06 mmol) were mixed in toluene /water (2 mL, 10:1) under nitrogen. The reaction mixture was heated in microwave at 140 °C for 20 min, cooled to room KB 640 / 15887 WO temperature and filtered through celite. The solvent was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (20 % EtOAc) as mobile phase. 25 mg 2-(3,5- dimethylisoxazolyl)-3'-fluoro-4'-hydroxypropylbiphenylcarbonitrile was obtained. 5 Step (d): -dimethylisoxazolyl)-3'-fluoro-4'-hydroxypropylbiphenylcarbonitrile (25 mg, 0.07 mmol) and hydroxylamine (0.5 mL, 16 M, aq) were mixed in DMSO (0.3 mL). The reaction mixture was heated in ave at 140 °C for 15 min under nitrogen. The crude mixture was purified on preparative HPLC using MeCN/acidic H2O (5 – 50% MeCN) as mobile phase. 4.0 mg - dimethylisoxazolyl)-3'-fluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide (E15) was 10 obtained. ES/MS m/z: 384.24 (M+H), 382.24 (M-H); 1H NMR (MeOD, 500MHz): δ 7.66 (t, 1H, J=1.5Hz), 7.48-7.43 (m, 3H), 7.25 (m, 1H), 2.68 (t, 2H, J=7.7Hz), 2.35 (s, 3H), 2.21 (s, 3H), 1.70 (m, 2H) and 0.97 (t, 3H, J=7.2Hz). The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 15 Examples 16, 17 and 18 -dimethylfuranyl)-4'-hydroxypropyl-[1,1'-biphenyl]carbonitrile (E16) 2-(2,4-dimethylfuranyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide (E17) 2-(2,4-dimethylfuranyl)-4'-hydroxypropyl-[1,1'-biphenyl]carboxamide (E18) 20 Scheme 6 KB 640 / 15887 WO Step (a): 2-amino-4'-hydroxypropylbiphenylcarbonitrile (144.0 mg, 0.57 mmol), obtained analogous to example 15 step (a), and CH2I2 (3057 mg, 11.4 mmol) were mixed in dry MeCN (1 mL) at 0 °C under nitrogen. t-Butyl e (64.74 mg, 0.63 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h and then at 50 °C for 1 h. After cooling to room temperature DCM was added, the mixture was 5 washed with NaHSO3 (aq) and filtered through a phase separator. The solvent was evaporated under reduced pressure and the crude t was purified on silica using DCM/isohexane (50-100 % DCM) as mobile phase. 101 mg 4'-hydroxyiodopropylbiphenylcarbonitrile was obtained.

Step (b): 4'-hydroxyiodopropylbiphenylcarbonitrile (17.0 mg, 0.05 mmol), methyl methyl- 10 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)furancarboxylate (19.7 mg, 0.07 mmol), Pd(OAc)2 (2.10 mg, 0.01 mmol), SPhos (4.37 mg, 0.01 mmol) and K2CO3 (19.4 mg, 0.14 mmol) were mixed in toluene /water (0.7 mL, 5:2) under en. The on mixture was heated in microwave at 140 °C for 20 min, cooled to room temperature and d with H2O. The aqueous mixture was extracted with DCM and the organic phase was filtered through a phase separator. The solvent was ated under 15 reduced pressure and the crude product was purified on silica using DCM/MeOH (0-2.5 % MeOH) as mobile phase. 6.0 mg methyl 4-(3-cyano-4'-hydroxypropylbiphenylyl)-3,5-dimethylfuran carboxylate was obtained.

Step (c): 4-(3-cyano-4'-hydroxypropylbiphenylyl)-3,5-dimethylfurancarboxylate (6.0 mg, 0.02 20 mmol) was dissolved in THF (0.5 ML) and NaOH (0.04 mL, 2M) was added. The reaction mixture was heated in microwave at 130 °C for 15 min, cooled to room temperature and acidified by adding HCl (2M, aq). The aqueous mixture was extracted with DCM, the organic phase was filtered through a phase separator and the solvent was evaporated under d pressure. The residue was mixed with Cu2O (2.20 mg, 0.02 mmol) in quinolone (0.5 mL). The mixture was heated in ave at 195 °C for 30 min. 25 After cooling to room temperature DCM was added, the mixture was washed with HCl (2 M, aq) and filtered through a phase separator. The solvent was evaporated under reduced pressure and the crude product was filtered through a plug of silica using DCM as mobile phase. 2-(2,4-dimethylfuranyl)-4'- hydroxypropyl-[1,1'-biphenyl]carbonitrile (E16) was obtained. ES/MS m/z: 332.23 (M+H), 330.2 (M-H); 1H NMR (Acetone-d6, 500MHz): δ 7.64 (d, 1H, J=1.8Hz), 7.57 (d, 1H, J=1.8Hz), 7.18 (q, 1H, 30 z), 7.04 (m, 2H), 6.77 (m, 2H), 2.74, (t, 2H, J=7.5Hz), 1.95 (s, 3H), 1.75 (m, 2H), 1.61 (d, 3H, J=1.1Hz) and 0.99 (t, 3H, J=7.3Hz).

Step (d): . 2-(2,4-dimethylfuranyl)-4'-hydroxypropyl-[1,1'-biphenyl]carbonitrile and hydroxylamine (0.11 mL, 16 M, aq) were mixed in MeOH (0.5 mL). The reaction mixture was heated in 35 microwave at 120 °C for 30 min under nitrogen. The crude mixture was purified on preparative HPLC KB 640 / 15887 WO using MeCN/acidic H2O (20-60 % MeCN) as mobile phase. 1.1 mg 2-(2,4-dimethylfuranyl)-N',4'- dihydroxypropyl-[1,1'-biphenyl]carboximidamide (E17) ES/MS m/z: 365.27 (M+H), 363.36 (MH ); 1H NMR (Acetone-d6, 500MHz): δ 7.30 (d, 1H, J=2.0Hz), 7.25 (d, 1H, J=2.0Hz), 7.05 (q, 1H, J=1.2Hz), 6.97 (m, 2H), 6.71 (m, 2H), 2.67, (t, 2H, J=7.7Hz), 1.86 (s, 3H), 1.71 (m, 2H), 1.60 (d, 3H, 5 J=1.2Hz) and 0.99 (t, 3H, z) and 2-(2,4-dimethylfuranyl)-4'-hydroxypropyl-[1,1'-biphenyl]- 3-carboxamide (E18) ES/MS m/z: 350.25 (M+H), 348.28 (M-H); 1H NMR (Acetone-d6, 500MHz): δ 7.41 (d, 1H, J=1.8Hz), 7.28 (d, 1H, J=1.8Hz), 7.07 (q, 1H, J=1.3Hz), 6.97 (m, 2H), 6.72 (m, 2H), 2.68, (t, 2H, J=7.6Hz), 1.87 (s, 3H), 1.72 (m, 2H), 1.63 (d, 3H, J=1.3Hz) and 0.99 (t, 3H, J=7.5Hz) were obtained.

For Example 17 the title compound was identified by 1H-NMR which showed that the oxime product was 10 a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples –19-49 Examples 19-49 were prepared using a method analogous to that used to synthesise es –15-18 above. Full experimental details of the individual steps of the general methods are described in Examples 15 –15-18 above. For examples 19-49 identification of the title nds by1H-NMR showed that the oxime product was a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

E19 N',4'-dihydroxy(4-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide R1 = 4-methylthiophenyl R3= propyl ES/MS m/z: 367.19 (pos. M + H), 365.21 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.29 (d, 1H, J=1.9Hz), 7.27 (d, 1H, J=1.9Hz), 7.09 (d, 1H, J=3.2Hz), 6.94 (m, 2H), 6.86 (m, 1H), 6.66 (m, 2H), 2.68 (t, 2H, J=7.3Hz), 1.73 (d, 3H, J=0.7Hz), 1.72 (m, 1H) and 0.99 (t, 3H, J=7.3Hz). 20 E 20 N',4-dihydroxy-5'-propyl-2''-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-(trifluoromethoxy)phenyl R3= propyl ES/MS m/z: 431.28 (pos. M + H), 429.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.36-7.34 (m, 2H), 7.29 (m, 1H), 7.25 (d, 1H, J=1.8Hz), 7.17 (m, 1H), 7.06 (m, 1H), 6.86 (m, 2H), 6.62 (m, 2H), KB 640 / 15887 WO 2.69 (m, 2H, J=7.5Hz), 1.72 (m, 2H) and 0.99 (t, 3H, J=7.3Hz).

E 21 2-(2,4-dimethylthiophenyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide R1 = 2,4-dimethylthiophenyl R3= propyl ES/MS m/z: 381.24 (pos. M + H), 379.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.36 (d, 1H, J=1.8Hz), 7.28 (d, 1H, J=1.8Hz), 6.90 (m, 2H), 6.68-6.65 (m, 3H), 2.68, (t, 2H, z), 2.01 (s, 3H), 1.80 (d, 3H, J=1.0Hz), 1.73 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

E 22 N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R3= propyl ES/MS m/z: 347.24 (pos. M + H), 345.36 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.26 (d, 1H, J=1.9Hz), 7.23 (d, 1H, z), .09 (m, 5H), 6.85 (m, 2H), 6.61 (m, 2H), 2.67 (t, 2H, J=7.5Hz), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

E 23 2-((E)cyclopropylvinyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide R1 = (E)cyclopropylvinyl R3= propyl ES/MS m/z: 337.24 (pos. M + H), 335.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.14 (m, 2H), 7.10 (d, 1H, J=1.7Hz), 7.05 (d, 1H, J=1.7Hz), 6.87 (m, 2H), 6.34 (d, 1H, Hz), 5.24 (dd, 1H, J=16.0, 8.8Hz), 2.58 (t, 2H, J=7.4Hz), 1.64 (m, 2H), 1.33 (m, 1H), 0.99 (t, 3H, J=7.4Hz), 0.62 (m, 2H) and 0.21 (m, 2H).

E 24 N',4'-dihydroxy(3-methylbutenyl)propyl-[1,1'-biphenyl]carboximidamide R1 = 3-methylbutenyl R3= propyl ES/MS m/z: 339.27 (pos. M + H), 337.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.21 (d, 1H, J=1.9Hz), 7.11 (d, 1H, J=1.9Hz), 7.09 (m, 2H), 6.81 (m, 2H), 2.60 (t, 2H, J=7.4Hz), 1.67 (m, 2H), 1.66 (s, 3H), 1.55 (s, 3H), 1.35 (s, 3H) and 0.96 (t, 3H, J=7.5Hz). 5 E 25 N',4-dihydroxy-3''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = o-tolyl R3= propyl ES/MS m/z: 361.24 (pos. M + H), 358.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.26 (d, 1H, J=1.9Hz), 7.22 (d, 1H, J=1.9Hz), 7.02 (m, 1H), 6.96-6.94 (m, 2H), 6.89 (m, 1H), 6.86 (m, 2H), 6.62 KB 640 / 15887 WO (m, 2H), 2.66 (t, 2H, J=7.3Hz), 2.17 (s, 3H), 1.72 (m, 2H) and 0.99 (t, 3H, J=7.3Hz).

E 26 5''-fluoro-N',4-dihydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethylphenyl R3= propyl ES/MS m/z: 379.22 (pos. M + H), 377.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.30 (d, 1H, J=1.8Hz), 7.25 (d, 1H, J=1.8Hz), 6.98-6.89 (m, 4H), 6.82 (m, 1H), 6.63 (m, 2H), 2.69 (m, 2H, J=7.8Hz), 1.82 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.3Hz).

E 27 2''-ethyl-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-ethylphenyl R3= propyl ES/MS m/z: 375.25 (pos. M + H), 373.28 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.32 (d, 1H, J=1.8Hz), 7.24 (d, 1H, J=1.8Hz), 7.16-7.13 (, 2H), 7.09-7.03 (m, 2H), 6.87 (m, 2H), 6.59 (m, 2H), 2.68, (t, 2H, J=7.4Hz), 2.31 (m, 1H), 2.12 (m, 1H), 1.72 (m, 2H), 1.00 (t, 3H, J=7.6Hz) and 0.90 (t, 3H, J=7.6Hz).

E 28 N',4'-dihydroxypropyl(thiophenyl)-[1,1'-biphenyl]carboximidamide R1 = thiophenyl R3= propyl ES/MS m/z: 353.19 (pos. M + H), 351.23 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.29 (dd, 1H, J=5.0, 1.0Hz), 7.26 (d, 1H, J=1.7Hz), 7.23 (d, 1H, J=1.7Hz), 6.95 (m, 2H), 6.86 (dd, 1H, J=5.0, 3.4Hz), 6.81 (dd, 1H, J=3.4, 1.0Hz), 6.68 (m, 2H), 2.66 (t, 2H, J=7.2Hz), 1.70 (m,2H) and 0.98 (t, 3H, 7.2Hz).

E 29 N',4'-dihydroxypropyl(quinolinyl)-[1,1'-biphenyl]carboximidamide R1 = quinolinyl R3= propyl ES/MS m/z: 398.24 (pos. M + H), 396.27 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.67 (dd, 1H, J=4.3, , 7.90-7.86 (m, 2H), 7.66 (m, 1H), 7.51 (dd, 1H, J=7.2, 1.0Hz), 7.41 (s, 2H), 7.28 (dd, 1H, J=8.5, 4.3Hz), 6.74 (m, 2H), 6.36 (m, 2H), 2.77 (t, 2H, z), 1.78 (m,2H) and 1.05 (t, 3H, 7.4Hz). 5 E 30 3''-chloro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-chlorophenyl R3= propyl KB 640 / 15887 WO ES/MS m/z: 381.17 (pos. M + H), 379.21 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.28 (d, 1H, z), 7.25 (d, 1H, J=1.4Hz), 7.17-7.12 (m, 3H), 7.04 (m, 1H), 6.86 (m, 2H), 6.65 (m, 2H), 2.68 (t, 2H, z), 1.71 (m, 2H) and 0.99 (t, 3H, J=7.3Hz).

E 31 N',4'-dihydroxypropyl(pyridinyl)-[1,1'-biphenyl]carboximidamide R1 = pyridinyl R3= propyl ES/MS m/z: 348.27 (pos. M + H), 346.34 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.31 (dd, 1H, J=4.9, 1.5Hz), 8.22 (d, 1H, J=1.5Hz), 7.61 (m, 1H), 7.37 (d, 1H, J=1.9Hz), 7.36 (d, 1H, J=1.9Hz), 7.28 (dd, 1H, J=4.9, 7.8Hz), 6.82 (m, 2H), 6.59 (m, 2H), 2.72 (t, 2H, J=7.5Hz), 1.73 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

E 32 2-(benzofuranyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide R1 = benzofuranyl R3= propyl ES/MS m/z: 387.25 (pos. M + H), 385.35 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.75 (d, 1H, J=2.2Hz), 7.38 (d, 1H, J=1.6Hz), 7.30 (d, 1H, J=8.6Hz), 7.28 (d, 1H, J=1.8Hz), 7.24 (d, 1H, J=1.8Hz), 7.05 (dd, 1H, J=8.6, 1.9Hz), 6.86 (m, 2H), 6.75 (dd, 1H, J=2.2, 0.8Hz), 6.58 (m, 2H), 2.68 (t, 2H, J=7.3Hz), 1.72 (m,2H) and 1.01 (t, 3H, 7.3Hz).

E 33 4''-chloro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-chlorophenyl R3= propyl ES/MS m/z: 381.23 (pos. M + H), 379.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.26 (d, 1H, J=1.8Hz), 7.23 (d, 1H, J=1.8Hz), 7.16 (m, 2H), 7.09 (m, 2H), 6.86 (m, 2H), 6.68 (m, 2H), 2.67 (t, 2H, J=7.7Hz), 1.71 (m,2H) and 0.99 (t, 3H, .

E 34 N',4'-dihydroxypropyl(pyridinyl)-[1,1'-biphenyl]carboximidamide R1 = pyridinyl R3= propyl ES/MS m/z: 348.29 (pos. M + H), 346.33 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.28 (m, 2H), 7.33 (d, 1H, J=1.8Hz), 7.31 (d, 1H, J=1.8Hz), 7.18 (m, 2H), 6.83 (m, 2H), 6.59 (m, 2H), 2.70 (t, 2H, J=7.4Hz), 1.72 (m,2H) and 1.00 (t, 3H, 7.3Hz). 5 E 35 N',4'-dihydroxy(1-phenylvinyl)propyl-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO R1 = 1-phenylvinyl R3= propyl ES/MS m/z: 373.27 (pos. M + H), 371.32 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.28 (d, 1H, J=1.6Hz), 7.13 (d, 1H, J=1.6Hz), 7.10-7.05 (m, 5H), 6.97 (m, 2H), 6.59 (m, 2H), 5.67 (d, 1H, J=1.3Hz), 5.23 (d, 1H, J=1.3Hz), 2.66 (t, 2H, J=7.5Hz), 1.70 (m,2H) and 0.98 (t, 3H, 7.4Hz).

E 36 2-(5-chlorothiophenyl)-N',4'-dihydroxypropylbiphenylcarboximidamide R1 = 5-chlorothiophenyl R3= propyl ES/MS m/z: 387.19 (pos. M + H), 385.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.25 (d, 1H, J=1.9Hz), 7.23 (d, 1H, J=1.9Hz), 7.00 (m, 2H), 6.77 (d, 1H, J=3.8Hz), 6.73 (m, 2H), 6.62 (d, 1H, J=3.8Hz), 2.66 (t, 2H, J=7.3Hz), 1.69 (m,2H) and 0.98 (t, 3H, 7.3Hz).

E 37 5''-fluoro-N',4-dihydroxy-2''-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R3= propyl ES/MS m/z: 395.24 (pos. M + H), 393.26 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.27 (d, 1H, J=1.5Hz), 7.20 (d, 1H, J=1.5Hz), 6.92-6.87 (m, 3H), 6.79-6.73 (m, 2H), 6.63 (m, 2H), 3.52 (s, 3H), 2.67 (t, 2H, J=7.6Hz), 1.72 (m,2H) and 1.00 (t, 3H, 7.6Hz).

E 38 N',4'-dihydroxy(isoquinolinyl)propyl-[1,1'-biphenyl]carboximidamide R1 = isoquinolinyl R3= propyl ES/MS m/z: 398.25 (pos. M + H), 396.29 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 9.12 (s, 1H), 8.35 (d, 1H, J=6.1Hz), 7.86 (d, 1H, J=8.8Hz), 7.73 (s, 1H), 7.66 (d, 1H, z), 7.40 (dd, 1H, J=8.5, 1.5Hz), 7.37 (d, 1H, J=1.7Hz), 7.36 (d, 1H, J=1.7Hz), 6.84 (m, 2H), 6.50 (m, 2H), 2.73 (t, 2H, J=7.8Hz), 1.75 (m,2H) and 1.02 (t, 3H, 7.4Hz).

E 39 2-(benzofuranyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide R1 = benzofuranyl R3= propyl ES/MS m/z: 387.2 (pos. M + H), 385.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.59 (s, 1H), 7.37 (m, 1H), 7.32 (d, 1H, J=1.8Hz), 7.31 (d, 1H, J=1.8Hz), 7.15 (m, 1H), 7.09 (d, 1H, J=7.7Hz), 7.02 (m, 2H), 6.98 (m, 1H), 6.57 (m, 2H), 2.71 (t, 2H, J=7.3Hz), 1.74 (m,2H) and 1.01 (t, 3H, 7.3Hz). 5 E 40 5''-fluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- KB 640 / 15887 WO carboximidamide R1 = 5-fluoromethoxyphenyl R3= CF3 ES/MS m/z: 421.2 (pos. M + H), 419.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.72 (d, 1H, z), 7.64 (d, 1H, J=1.3Hz), 6.98-6.94 (m, 3H), 6.84-6.81 (m, 2H), 6.68 (m, 2H) and 3.53 (s, 3H).

E 41 5''-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-fluoromethylphenyl R3= CF3 ES/MS m/z: 405.28 (pos. M + H), 403.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.75 (d, 1H, J=1.4Hz), 7.70 (d, 1H, J=1.4Hz), .96 (m, 4H), 6.89 (m, 1H), 6.68 (m, 2H) and 1.84 (s, 3H).

E 42 ihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = o-tolyl R3= CF3 ES/MS m/z: 387.26 (pos. M + H), 385.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.75 (d, 1H, J=1.5Hz), 7.68 (d, 1H, J=1.5Hz), 7.19 (dd, 1H, J=7.3, 1.5Hz), 7.15-7.07 (m, 2H), 7.02 (d, 1H, J=7.3Hz), 6.94 (m, 2H), 6.64 (m, 2H) and 1.88 (s, 3H).

E 43 N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R3= CF3 ES/MS m/z: 373.2 (pos. M + H), 371.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.71 (d, 1H, J=1.5Hz), 7.68 (d, 1H, J=1.5Hz), 7.21-7.14 (m, 5H), 6.91 (m, 2H) and 6.66 (m, 2H).

E 44 N',4'-dihydroxy(4-methylthiophenyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 4-methylthiophenyl R3= CF3 ES/MS m/z: 393.21 (pos. M + H), 391.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.73 (d, 1H, J=1.6Hz), 7.69 (d, 1H, J=1.6Hz), 7.21 (d, 1H, J=3.2Hz), 7.00 (m, 2H), 6.92 (m, 1H), 6.70 (m, 2H) and 1.75 (d, 3H, J=0.9Hz). 5 E 45 -dimethylthiophenyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 2,4-dimethylthiophenyl R3= CF3 KB 640 / 15887 WO ES/MS m/z: 407.2 (pos. M + H), 405.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.80 (d, 1H, J=1.9Hz), 7.72 (d, 1H, z), 6.96 (m, 2H), 6.74 (q, 1H, J=1.1Hz), 6.71 (m, 2H), and 1.82-1.81 (m, 6H).

E 46 2'',5''-difluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-difluorophenyl R3= propyl ES/MS m/z: 383.27 (pos. M + H), 381.32 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44 (s, 1H), 7.31 (s, 1H), 6.88 (m, 2H), 6.68 (m, 2H), 6.55 (d, 1H, J=2.5Hz), 5.74 (d, 1H, J=2.5Hz), 3.21 (s, 3H), 2.68 (t, 2H, J=7.6Hz), 1.72 (m,2H), 1.57 (s, 3H) and 1.00 (t, 3H, 7.3Hz).

E 47 2-(1,3-dimethyl-1H-pyrrolyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide R1 = 1,3-dimethyl-1H-pyrrolyl R3= propyl ES/MS m/z: 364.31 (pos. M + H), 362.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44 (s, 1H), 7.31 (s, 1H), 6.88 (m, 2H), 6.68 (m, 2H), 6.55 (d, 1H, J=2.5Hz), 5.74 (d, 1H, z), 3.21 (s, 3H), 2.68 (t, 2H, J=7.6Hz), 1.72 (m,2H), 1.57 (s, 3H) and 1.00 (t, 3H, 7.3Hz). 5 E 48 3'',5''-difluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R3= propyl ES/MS m/z: 383.27 (pos. M + H), 381.32 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.28 (d, 1H, J=1.8Hz), 7.25 (d, 1H, J=1.8Hz), 6.90 (m, 2H), 6.78 (m, 1H), 6.73-6.67 (m, 4H), 2.68 (t, 2H, J=7.3Hz), 1.72 (m,2H) and 0.99 (t, 3H, J=7.3Hz).

E 49 -dimethylfuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = methylfuranyl R3= CF3 ES/MS m/z: 383.27 (pos. M + H), 381.32 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.28 (d, 1H, J=1.8Hz), 7.25 (d, 1H, J=1.8Hz), 6.90 (m, 2H), 6.78 (m, 1H), 6.73-6.67 (m, 4H), 2.68 (t, 2H, J=7.3Hz), 1.72 (m,2H) and 0.99 (t, 3H, J=7.3Hz).

Example 50 KB 640 / 15887 WO 3'-chloro-5'-fluoro-N',4'-dihydroxy(3-methylthiophenyl)propylbiphenyl carboximidamide (E50) Scheme 7 5 Step (a): 2-aminobromopropylbenzonitrile (296.0 mg, 1.24 mmol) and CH2I2 (1657 mg, 6.19 mmol) were mixed in dry MeCN (3 mL) at 0 °C under en. t-Butyl nitrite (255.3 mg, 2.48 mmol) was added. The reaction mixture was stirred at 0 °C for 0.5 h and then at 50 °C for 1 h. After g to room temperature DCM was added, the mixture was washed with NaHSO3 (aq) and filtered through a 10 phase separator. The solvent was evaporated under reduced pressure and the crude product was purified on silica using ohexane (25 % DCM) as mobile phase. 320 mg 3-bromoiodo propylbenzonitrile was obtained.

Step (b): 2-aminoiodopropylbenzonitrile (63 mg, 0.18 mmol), 3-methylthiophenylboronic acid 15 (30.67 mg, 0.22 mmol), PdCl2(PPh3)2 (12.63 mg, 0.02 mmol) and K2CO3 (74.63 mg, 0.54 mmol) were mixed in OH/H2O (0.51 mL, 40:10:1) under nitrogen. The reaction mixture was heated in microwave at 125 °C for 20 min, cooled to room temperature, d with DCM and washed with H2O.

The mixture was filtered through a phase separator, the solvent was evaporated under reduced pressure and the crude product was purified on silica using DCM/isohexane (10- 50 % isohexane) as mobile phase. 20 32 mg 3-bromo(3-methylthiophenyl)propylbenzonitrile was obtained.

KB 640 / 15887 WO Step (c): 3-bromo(3-methylthiophenyl)propylbenzonitrile (20 mg, 0.06 mmol), hloro fluoromethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35.8 mg, 0.12 mmol), PdCl2(PPh3)2 (4.38 mg, 0.01 mmol) and K2CO3 (25.9 mg, 0.19 mmol) were mixed in DME/EtOH/H2O (1 mL, 40:10:1) 5 under nitrogen. The on e was heated in microwave at 140 °C for 20 min, cooled to room temperature, diluted with DCM and washed with NH4Cl (aq). The mixture was filtered through a phase separator, the t was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (15 % EtOAc) as mobile phase. 21 mg oro-5'-fluoro-4'-methoxy(3- methylthiophenyl)propylbiphenylcarbonitrile was obtained. 10 Step (d): 3'-chloro-5'-fluoro-4'-methoxy(3-methylthiophenyl)propylbiphenylcarbonitrile (17 mg, 0.04 mmol) was dissolved in DCM (5 mL) under nitrogen and the solution was cooled to 0 °C. BBr3 (0.26 mL, 1M) was added. The reaction mixture was stirred at 0 °C for 0.5 h, at room temperature for 2 h and then at 4 °C for 16 h. HCl (1M) and H2O were added to quench the reaction and the aqueous mixture 15 was extracted with DCM. The organic phase was filtered through a phase separator, the solvent was ated under reduced pressure and the crude product was ed on silica using EtOAc/n-heptane (20 % EtOAc) as mobile phase. 15.0 mg 3'-chloro-5'-fluoro-4'-hydroxy(3-methylthiophenyl) propylbiphenylcarbonitrile was obtained. 20 Step (e): 3'-chloro-5'-fluoro-4'-hydroxy(3-methylthiophenyl)propylbiphenylcarbonitrile (15 mg, 0.04 mmol) and hydroxylamine (0.5 mL, 16 M, aq) were mixed in DMSO (0.3 mL). The reaction mixture was heated in microwave at 140 °C for 15 min under nitrogen. The crude mixture was purified on preparative HPLC using MeCN/acidic H2O (5 – 60% MeCN) as mobile phase. 4.0 mg 3'-chloro-5'-fluoro- N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide (E50) was 25 obtained. ES/MS m/z: 419.1 (M+H), 417.14 (M-H); 1H NMR (MeOD, 500MHz): δ 7.34 (d, 1H, J=1.7Hz), 7.33 (d, 1H, z), 7.26 (d, 1H, J=5.2Hz), 6.88 (t, 1H, J=1.8Hz), 6.74-6.72 (m, 2H), 2.70 (t, 2H, J=7.4Hz), 1.80 (s, 3H), 1.73 (m, 2H) and 1.00 (t, 3H, J=7.3Hz). The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 30 35 KB 640 / 15887 WO 5 Example 51 roxy(1H-indazolyl)(3-methylthiophenyl)propylbenzimidamide (E51) 10 Scheme 8 Step (a): 3-bromo(3-methylthiophenyl)propylbenzonitrile (20 mg, 0.06 mmol), tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indazolecarboxylate (43.0 mg, 0.12 mmol), PPh3)2 (4.38 mg, 0.01 mmol) and K2CO3 (25.9 mg, 0.19 mmol) were mixed in DME/EtOH/H2O (1 15 mL, 40:10:1) under nitrogen. The reaction mixture was heated in microwave at 140 °C for 20 min, cooled to room temperature, diluted with DCM and washed with NH4Cl (aq). The mixture was filtered through a phase separator and the solvent was evaporated under reduced pressure. 12 mg crude product tert-butyl 5- (3-cyano(3-methylthiophenyl)propylphenyl)-1H-indazolecarboxylate was obtained.

KB 640 / 15887 WO Step (b): tert-butyl 5-(3-cyano(3-methylthiophenyl)propylphenyl)-1H-indazolecarboxylate was dissolved in DCM (2 mL) and TFA (2 mL). The e was stirred at room ature for 1 h.

NaHCO3 (aq, sat) was added and the aqueous mixture was extracted with DCM. The organic phase was evaporated under reduced pressure and 9.0 mg 3-(1H-indazolyl)(3-methylthiophenyl) 5 propylbenzonitrile was obtained as a crude mixture.

Step (c): 3-(1H-indazolyl)(3-methylthiophenyl)propylbenzonitrile and hydroxylamine (0.3 mL, 16 M, aq) were mixed in DMSO (0.3 mL). The reaction mixture was heated in microwave at 140 °C for 15 min under nitrogen. The crude e was purified on preparative HPLC using MeCN/acidic H2O 10 (5 – 60% MeCN) as mobile phase. 2.5 mg N'-hydroxy(1H-indazolyl)(3-methylthiophenyl) propylbenzimidamide (E51) was obtained. ES/MS m/z: 391.25 (M+H); The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 15 Examples 52-58 Examples 52-58 were prepared using a method analogous to that used to sise Example 50 above.

Full experimental details of the dual steps of the general methods are bed in Example 50 above. For examples 52-58 identification of the title compounds by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 20 E 52 3'-fluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R4 = H R5 = F R7= H R8 = H ES/MS m/z: 385.22 (pos. M + H), 383.2 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.35 (d, 1H, J=1.6Hz), 7.32 (d, 1H, J=1.6Hz), 7.25 (d, 1H, J=5.2Hz), 6.77-6.71 (m, 4H), 2.70 (t, 2H, J=7.5Hz), 1.77 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

KB 640 / 15887 WO E 53 3'-chloro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] imidamide R4 = H R5 = Cl R7= H R8 = H ES/MS m/z: 401.18 (pos. M + H), 399.19 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.31 (s, 2H), 7.24 (d, 1H, J=5.1Hz), 7.01 (d, 1H, J=2.2Hz), 6.86 (dd, 1H, J=8.4, 2.2Hz), 6.71 (d, 1H, J=8.4Hz), 6.70 (d, 1H, J=5.1Hz), 2.69 (t, 2H, J=7.5Hz), 1.77 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

E 54 3',5'-dichloro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R4 = H R5 = Cl R7= Cl R8 = H ES/MS m/z: 435.12 (pos. M + H), 433.18 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.34 (d, 1H, J=1.4Hz), 7.32 (d, 1H, J=1.4Hz), 7.26 (d, 1H, z), 6.99 (s, 2H), 6.74 (d, 1H, J=5.1Hz), 2.70 (t, 2H, J=7.6Hz), 1.80 (s, 3H), 1.73 (m, 2H) and 1.00 (t, 3H, J=7.3Hz).

E 55 N',4'-dihydroxy-3'-methyl(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R4 = H R5 = Methyl R7= H R8 = H ES/MS m/z: 381.24 (pos. M + H), 379.25 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.33 (d, 1H, J=1.9Hz), 7.28 (d, 1H, z), 7.22 (d, 1H, J=5.0Hz), 6.81 (d, 1H, J=2.1Hz), 6.73 (dd, 1H, J=8.2, 2.1Hz), 6.68 (d, 1H, J=5.0Hz), 6.54 (d, 1H, J=8.2Hz), 2.69 (t, 2H, J=7.4Hz), 2.04 (s, 3H), 1.74 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, z).

E 56 2'-fluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R4 = F R5 = H R7= H R8 = H ES/MS m/z: 385.17 (pos. M + H), 383.21 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.33 (d, 1H, J=1.9Hz), 7.25 (d, 1H, J=1.9Hz), 7.16 (d, 1H, J=5.0Hz), 6.77 (t, 1H, J=8.5Hz), 6.67 (d, 1H, J=5.0Hz), 6.40-6.37 (m, 2H), 2.68 (t, 2H, J=7.5Hz), 1.85 (s, 3H), 1.71 (m, 2H) and 0.99 (t, 3H, J=7.7Hz).

E 57 2',3'-difluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R4 = F R5 = F R7= H R8 = H ES/MS m/z: 403.14 (pos. M + H), 401.25 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.37 (d, 1H, KB 640 / 15887 WO z), 7.28 (br s, 1H), 7.18 (d, 1H, J=5.1Hz), 6.69 (d, 1H, J=5.1Hz), 6.58 (m, 1H), 6.50 (m, 1H), 2.69 (t, 2H, J=7.4Hz), 1.88 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.6Hz).

E 58 2',5'-difluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R4 = F R5 = H R7= F R8 = H ES/MS m/z: 403.21 (pos. M + H), 401.31 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.37 (s, 1H), 7.31 (s, 1H), 7.22 (d, 1H, J=5.1Hz), 6.71 (d, 1H, J=5.1Hz), 6.64 (dd, 1H, J=11.4, , 6.55 (dd, 1H, J=10.8, 7.5Hz), 2.70 (t, 2H, J=7.5Hz), 1.87 (s, 3H), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.2Hz).

Example 59 5 N',4'-dihydroxy(2-methylallyl)propyl-[1,1'-biphenyl]carboximidamide (E59) Scheme 9 10 Step (a): 2-amino-4'-hydroxypropylbiphenylcarbonitrile (30.0 mg, 0.12 mmol), ed analogous to example 15 step (a), was dissolved in dry MeCN under nitrogen. 3-Bromomethylpropene (80.3 mg, 0.59 mmol) and t-butyl nitrite (14.7 mg, 0.14 mmol) were added. The reaction mixture was stirred at 60 °C for 1 h. After cooling to room ature DCM was added, the mixture was washed with H2O and filtered through a phase separator. The solvent was evaporated under reduced pressure and the crude 15 product was purified on preparative HPLC using cidic H2O (20 – 100% MeCN) as mobile phase. 4.0 mg 4'-hydroxy(2-methylallyl)propylbiphenylcarbonitrile was obtained.

Step (b): 4'-hydroxy(2-methylallyl)propylbiphenylcarbonitrile (4.0 mg, 0.01 mmol) and hydroxylamine (0.1 mL, 16 M, aq) were mixed in DMSO (0.4 mL). The reaction mixture was heated in 20 microwave at 140 °C for 15 min under nitrogen. The crude mixture was purified on preparative HPLC using MeCN/acidic H2O (5 – 60% MeCN) as mobile phase. 1.05 mg N',4'-dihydroxy(2-methylallyl) KB 640 / 15887 WO propyl-[1,1'-biphenyl]carboximidamide (E59) was ed. ES/MS m/z: 325.28 (M+H), 323.36 (MH ); 1H NMR (Acetone-d6, 500MHz): δ 7.19 (d, 2H, j=2.1Hz), 7.13 (m, 2H), 7.03 (d, 1H, J=2.1Hz), 6.84 (m, 2H), 4.67 (m, 1H), 4.23 (m, 1H), 3.44 (s, 2H), 2.60 (t, 2H, J=7.5Hz), 1.66 (m, 2H), 1.56 (s, 3H) and 0.94 (t, 3H, J=7.3Hz). The title compound was identified by 1H-NMR which showed that the oxime 5 product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Example 60 2-allyl-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide (E60) 10 Example 60 was prepared using a method analogous to that used to synthesise Example 60 above. Full experimental details of the individual steps of the general methods are described in Example60 above.

ES/MS m/z: 311.28 (M+H), 309.29 (M-H); 1H NMR (Acetone-d6, 500MHz): δ 7.16 (d, 1H, z), 7.11 (m, 2H), 7.01 (d, 1H, J=1.9Hz), 6.87 (m, 2H), 5.83 (m, 1H), 4.76 (m, 1H), 4.64 (m, 1H), 3.51 (m, 2H), 2.58 (t, 2H, J=7.4Hz), 1.64 (m, 2H) and 0.94 (t, 3H, J=7.2Hz). The title compound was identified by 15 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been ed.

Example 61 N',4'-dihydroxypropylvinyl-[1,1'-biphenyl]carboximidamide (E 61) 20 Scheme 10 Step (a): 4'-hydroxyiodopropylbiphenylcarbonitrile (20 mg, 0.06 mmol), obtained analogous to e 16 step (a), tributylethenylstannane (34.9 mg, 0.11mmol), PdCl2(PPh3)2 (3.87 mg, 0.01 mmol) 25 were mixed in dioxane (1.5 mL) under nitrogen. The reaction mixture was heated in microwave at 130 °C KB 640 / 15887 WO for 20 min, cooled to room temperature, diluted with DCM and washed with H2O. The mixture was filtered through a phase separator and the solvent was evaporated under d pressure. The crude product was purified on preparative HPLC using MeCN/acidic H2O (20 – 100% MeCN) as mobile phase. 9.0 mg 4'-hydroxypropylvinylbiphenylcarbonitrile was obtained. 5 Step (b): 4'-hydroxypropylvinylbiphenylcarbonitrile (7.0 mg, 0.03 mmol)was treated with hydroxylamine (0.1 mL, 16 M, aq) in DMSO (0.4 mL). The reaction mixture was heated in microwave at 140 °C for 15 min under en. The crude mixture was ed on preparative HPLC using MeCN/acidic H2O (5 – 50% MeCN) as mobile phase. 1.05 mg N',4'-dihydroxypropylvinyl-[1,1'- 10 biphenyl]carboximidamide (E61) ES/MS m/z: 297.23 (M+H), 295.29 (M-H); 1H NMR (Acetone-d6, 500MHz): δ .13 (m, 3H), 7.08 (d, 1H, J=1.9Hz), 6.87 (m, 2H), 6.69 (dd, 1H, J=17.9, 11.6Hz), 5.31 (dd, 1H, J=17.9, 2.1Hz), 5.14 (dd, 1H, J=11.6, 2.1Hz), 2.60 (t, 2H, J=7.6Hz), 1.66 (m, 2H) and 0.95 (t, 3H, J=7.3Hz) wasobtained.The title compound was identified by 1H-NMR which showed that the oxime product was a single , but did not confirm r the (E) or (Z) oxime isomer had been obtained. 15 Examples 62-66 Examples 62-66 were prepared using a method analogous to that used to synthesise Example 61 above.

Full experimental details of the individual steps of the general methods are described in Example 61 above. For examples 62-66 fication of the title compounds by 1H-NMR showed that the oxime 20 product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

E 62 5-bromo-N',4'-dihydroxy(1-methyl-1H-imidazolyl)-[1,1'-biphenyl]carboximidamide R1 = 1-methyl-1H-imidazolyl R3 = Br ES/MS m/z: 390.12; 387.12 (pos. M + H), 388.26; 387.16 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.63 (d, 1H, J=2.2Hz), 7.62 (d, 1H, J=2.2Hz), 7.38 (s, 1H), 7.00 (m, 2H), 6.82 (s, 1H), 6.72 (m, 2H) and 2.52 (s, 3H).

KB 640 / 15887 WO E 63 N',4'-dihydroxypropyl(pyridinyl)-[1,1'-biphenyl]carboximidamide R1 = pyridinyl R3 = propyl ES/MS m/z: 348.25 (pos. M + H), 346.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.45 (m, 1H), 7.50 (m, 1H), 7.33 (d, 1H, J=1.8Hz), 7.25 (m, 1H, J=1.8Hz), 7.13 (m, 1H), 7.00 (m, 1H), 6.86 (m, 2H), 6.61 (m, 2H), 2.69 (t, 2H, J=7.6Hz), 1.72 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

E 64 N',4'-dihydroxy(2-methoxythiazolyl)propyl-[1,1'-biphenyl]carboximidamide R1 = 2-methoxythiazolyl R3 = propyl ES/MS m/z: 384.2 (pos. M + H), 382.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.24 (d, 1H, J=1.7Hz), 7.19 (d, 1H, J=1.7Hz), 6.96 (m, 2H), 6.69 (m, 2H), 6.43 (s, 1H), 3.86 (s, 3H), 2.63 (t, 2H, J=7.3Hz), 1.66 (m, 2H) and 0.94 (t, 3H, J=7.5Hz).

E 65 N',4'-dihydroxypropyl(thiazolyl)-[1,1'-biphenyl]carboximidamide R1 = thiazolyl R3 = propyl ES/MS m/z: 354.24 (pos. M + H), 352.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.77 (d, 1H, J=0.6Hz), 7.55 (d, 1H, J=0.6Hz), 7.28 (d, 1H, z), 7.25 (d, 1H, z), 6.94 (m, 2H), 6.71 (m, 2H), 2.68 (t, 2H, J=7.4Hz), 1.95 (s, 3H), 1.71 (m, 2H) and 0.99 (t, 3H, .

E 66 N',4'-dihydroxypropyl(thiazolyl)-[1,1'-biphenyl]carboximidamide R1 = thiazolyl R3 = propyl ES/MS m/z: 354.21 (pos. M + H), 352.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.69 (d, 1H, J=3.3Hz), 7.51 (d, 1H, J=3.3Hz), 7.36 (d, 1H, J=1.9Hz), 7.29 (d, 1H, J=1.9Hz), 6.96 (m, 2H), 6.68 (m, 2H), 2.71 (t, 2H, J=7.6Hz), 1.95 (s, 3H), 1.73 (m,2H) and 0.99 (t, 3H, 7.6Hz). 5 Example 67 5'-ethyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide (E67) KB 640 / 15887 WO Scheme 11 Step (a): 5'-bromohydroxy-[1,1':2',1''-terphenyl]-3'-carbonitrile (14.0 mg, 0.04 mmol), obtained 5 analogous to example 1 step (a-d), ethylboronic acid (11.8 mg, 0.16 mmol), Pd(OAc)2 (0.90 mg, 0.004 mmol), RuPhos (3.73 mg, 0.008 mmol) and K2CO3 (27.6 mg, 0.20 mmol) were mixed in toluene /water (0.55 mL, 10:1) under nitrogen. The on mixture was heated in microwave at 140 °C for 20 min, cooled to room temperature and diluted with NH4Cl. The aqueous mixture was extracted with DCM and the organic phase was filtered through a phase separator. The solvent was evaporated under reduced 10 pressure and the crude product was purified on preparative HPLC using MeCN/acidic H2O (20 – 100% MeCN) as mobile phase. 6.30 mg 5'-ethylhydroxy-[1,1':2',1''-terphenyl]-3'-carbonitrile was obtained.

Step (b): 5'-ethylhydroxy-[1,1':2',1''-terphenyl]-3'-carbonitrile (5.70 mg, 0.02 mmol) and ylamine (0.23 mL, 16 M, aq) were mixed in DMSO (0.7 mL). The reaction mixture was heated in 15 microwave at 130 °C for 30 min under nitrogen. The crude e was purified on preparative HPLC using MeCN/acidic H2O (5 – 50% MeCN) as mobile phase. 5.30 mg 5'-ethyl-N',4-dihydroxy-[1,1':2',1''- nyl]-3'-carboximidamide (E67) was obtained. ES/MS m/z: 333.28 (M+H); 1H NMR (Acetone-d6, 500MHz): δ 7.28 (d, 1H, J=2.0Hz), 7.24 (d, 1H, J=2.0Hz), 7.15-7.09 (m, 5H), 6.85 (m, 2H), 6.61 (m, 2H), 2.72 (q, 2H, J=7.6Hz) and 1.28 (t, 3H, z). The title compound was identified by 1H-NMR which 20 showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples 68-71 Examples 68-71 were prepared using a method analogous to that used to sise Example 67 above. 25 Full experimental details of the individual steps of the general methods are described in Example 67 above. For examples 68-71 identification of the title compounds by 1H-NMR showed that the oxime product was a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

KB 640 / 15887 WO E 68 N',4-dihydroxy-5'-isobutyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R3 = isobutyl ES/MS m/z: 361.31 (pos. M + H), 359.33 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.24 (d, 1H, J=1.8Hz), 7.20 (d, 1H, J=1.8Hz), 7.15-7.10 (m, 5H), 6.85 (m, 2H), 6.61 (m, 2H), 2.57 (d, 2H, z), 1.95 (m, 1H) and 0.97 (d, 6H, J=6.6Hz).

E 69 N',4-dihydroxy-5'-((E)-propenyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R3 = (E)-propenyl ES/MS m/z: 345.29 (pos. M + H), 343.36 (neg. M – H); 1H NMR (CDCl 3, 500MHz): δ 7.54 (d, 1H, J=1.9Hz), 7.50 (d, 1H, J=1.9Hz), 7.28-7.22 (m, 5H), 6.99 (m, 2H), 6.75 (m, 2H), 6.64 (m, 1H), 6.55 (m, 1H) and 2.03 (dd, 3H, J=6.4, 1.5Hz).

E 70 5'-allyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R3 = allyl ES/MS m/z: 345.29 (pos. M + H), 343.33 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.27 (d, 1H, J=1.6Hz), 7.24 (d, 1H, J=1.6Hz), 7.15-7.10 (m, 5H), 6.84 (m, 2H), 6.62 (m, 2H), 6.06 (m, 1H), 5.19 (m, 1H), 5.09 (m, 1H), and 3.48 (d, 2H, J=6.8Hz). 5 E 71 yl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R3 = butyl ES/MS m/z: 361.31 (pos. M + H), 359.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.26 (d, 1H, J=2.1Hz), 7.23 (d, 1H, J=2.1Hz), 7.15-7.09 (m, 5H), 6.85 (m, 2H), 6.61 (m, 2H), 2.70 (t, 2H, J=7.6Hz), 1.68 (m, 2H), 1.43 (m, 2H) and 0.96 (t, 3H, J=7.6Hz).

Example 72 KB 640 / 15887 WO 2-(2,5-dimethyl-1H-pyrrolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide (E72) 5 Scheme 12 Step (a): 2-amino-4'-hydroxy(trifluoromethyl)biphenylcarbonitrile (39 mg, 0.14 mmol) and - 2,5-dione (160 mg, 1.40 mmol) were mixed in AcOH (1 mL). The reaction mixture was heated in microwave at 200 °C for 60 min. The solvent was evaporated under reduced re and the crude 10 product was purified on silica using DCM/isohexane (25– 75% DCM) as mobile phase. 17 mg 2-(2,5- dimethyl-1H-pyrrolyl)-4'-hydroxy(trifluoromethyl)biphenylcarbonitrile was obtained.

Step (b): 2-(2,5-dimethyl-1H-pyrrolyl)-4'-hydroxy(trifluoromethyl)biphenylcarbonitrile (11 mg, 0.03 mmol) and hydroxylamine (0.38 mL, 16 M, aq) were mixed in DMSO/MeOH (0.4 mL 1:1). The 15 reaction mixture was heated in microwave at 120 °C for 45 min under en. The crude mixture was purified on preparative HPLC using MeCN/acidic H2O (25 – 55% MeCN) as mobile phase. 6.30 mg 2- (2,5-dimethyl-1H-pyrrolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide (E72) was obtained. ES/MS m/z: 390.27 (M+H), 388.34 (M-H); 1H NMR (Acetone-d6, 500 MHz): δ 7.98 (m, 1H), 7.86 (m, 1H), 6.96 (m, 2H), 6.76 (m, 2H), 5.77 (s, 2H) and 1.85 (s, 6H). 20 Example 73 4-hydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carbaldehyde oxime (E73) KB 640 / 15887 WO Scheme 13 Step (a): 4-hydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carbonitrile (20 mg, 0.06 mmol) was dissolved in 5 DCM (2 mL). Diisobutylaluminum e (90.7 mg, 0.64 mmol) was added dropwise at -78 °C. The reaction mixture was d at -78 °C for 2 h. HCl (2 M, aq) was added, the mixture was allowed to attain room temperature and was then filtered through a phase separator. The solvent was evaporated under d pressure. 18 mg 4-hydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide was obtained. 10 Step (b): 4-hydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide (18 mg, 0.06 mmol) and hydroxylamine (0.35 mL, 16 M, aq) were mixed in DMSO/i-PrOH (0.4 mL 1:1). The reaction mixture was heated in microwave at 130 °C for 20 min under nitrogen. The crude mixture was purified on ative HPLC using MeCN/acidic H2O (30 – 50% MeCN) as mobile phase. 15 mg 4-hydroxy-5'- propyl-[1,1':2',1''-terphenyl]-3'-carbaldehyde oxime (E73) was obtained. ES/MS m/z: 332.27 (M+H), 15 330.33 (M-H); 1H NMR (Acetone-d6, 500 MHz): δ 7.75 (d, 1H, J=1.8Hz), 7.31-7.23 (m, 4H), 7.06 (m, 2H), 6.89 (m, 2H), 6.63 (m, 2H), 2.69 (m, 2H), 1.73 (m, 2H) and 1.00 (t, 3H, J=7.3Hz).

Example 74 5'-propyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol (E74) KB 640 / 15887 WO Scheme 14 Step (a): A mixture 4-propylaniline (2200 mg, 16.3 mmol) and NaHCO3 (2050 mg, 24.4mmol) in H2O 5 (30 mL) was cooled in an ice bath. Iodine (4130 mg, 16.3 mmol) was added in portions over 20 min with slight cooling. The on mixture was stirred at room temperature for 16 h and was then ted with EtOAc (3 X). The combined organic extracts were dried over Na2SO4 and the solvent was concentrated under reduced pressure. 4100 mg 2-iodopropylaniline was obtained as a brownish solid. 10 Step (b): 2-Iodopropylaniline (2000 mg, 7.66 mmol), 4-methoxyphenylboronic acid (1164 mg, 7.66 mmol), Pd(PPh3)4 (443 mg, 0.38 mmol) and K2CO3 (4234 mg, 30.64 mmol) were mixed in DME/H2O (30 mL, 1:1). The reaction mixture was degassed with N2 for 5 min and then heated in microwave at 110 °C for 40 min. H2O was added and the aqueous mixture was extracted with EtOAc (3 X). The combined organic ts were washed with water and dried over Na2SO4. The solvent was evaporated under KB 640 / 15887 WO reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (0-10 % EtOAc) as mobile phase. 1.17 mg 4'-methoxypropylbiphenylamine was obtained as yellow oil.

Step (c): 4'-Methoxypropylbiphenylamine (1170 mg, 4.85 mmol) was dissolved in DMF (12 mL) 5 and NBS (863 mg, 4.85 mmol) was added in portions. The reaction mixture was stirred at room temperature for 3 h and was then partitioned between H2O and DCM. The s layer was extracted with DCM and the combined organic ts were concentrated under reduced pressure. The crude t was ed on silica using n-heptane (0-5 % EtOAc) as mobile phase. 840 mg 3-bromo- 4'-methoxypropylbiphenylamine was obtained as orange oil. 10 Step (d): 3-bromo-4'-methoxypropylbiphenylamine (261 mg, 0.82 mmol), 1-benzyl(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (301 mg, 1.06 mmol), Pd(PPh3)4 (94.2 mg, 0.08 mmol) and K2CO3 (451 mg, 3.26 mmol) were mixed in DME/H2O (12 mL, 1:1). The reaction mixture was flushed with N2 for 10 min and then heated in microwave at 110 °C for 2 h. H2O was added and the 15 aqueous mixture was extracted with DCM (3 X). The combined organic extracts were concentrated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (0-40 % EtOAc) as mobile phase. 294 mg3-(1-benzyl-1H-pyrazolyl)-4'-methoxypropylbiphenylamine was obtained as tan oil. 20 Step (e): 3-(1-Benzyl-1H-pyrazolyl)-4'-methoxypropylbiphenylamine(290 mg, 0.73 mmol) was dissolved in MeCN (4 mL). CH2I2 (821 mg, 3.06 mmol) was added ed by t-butyl nitrite (188 mg, 1.82 mmol). The reaction mixture was stirred at 50 °C for 48 h. The solvent was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (0-10 % EtOAc) as mobile phase. 178 mg 1-benzyl(2-iodo-4'-methoxypropylbiphenylyl)-1H-pyrazole was obtained 25 as a yellowish semi solid.

Step (f): 1-benzyl(2-iodo-4'-methoxypropylbiphenylyl)-1H-pyrazole (25 mg, 0.05 mmol), phenylboronic acid (7.79 mg, 0.06 mmol), Pd(PPh3)4 (5.68 mg, 0.005 mmol) and K2CO3 (27.2 mg, 0.20 mmol) were mixed in DME/H2O (2.5 mL, 1:1). The on mixture was flushed with N2 for 10 min and 30 then heated in microwave at 130 °C for 30 min. H2O was added and the aqueous mixture was extracted with DCM (3 X). The combined organic extracts were concentrated under reduced pressure. 1-benzyl (4-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-yl)-1H-pyrazole was obtained as a crude e.

Step (g): 1-benzyl(4-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-yl)-1H-pyrazole (22.6 mg, 0.05 35 mmol) was dissolved in DCM (4 mL) under en and the solution was cooled to 0 °C. BBr3 (0.25mL, KB 640 / 15887 WO 1M) was added. The reaction e was stirred at 0 °C for 16 h. Ice was added to quench the reaction ed by DCM. The layers were separated and the c layer was evaporated under reduced pressure. The crude product was purified on preparative HPLC using MeCN/acidic H2O (20 – 100% MeCN) as mobile phase. 13 mg 3'-(1-benzyl-1H-pyrazolyl)-5'-propyl-[1,1':2',1''-terphenyl]ol was 5 obtained as an off white solid.

Step (h): 3'-(1-benzyl-1H-pyrazolyl)-5'-propyl-[1,1':2',1''-terphenyl]ol (7.0 mg, 0.02 mmol) was ved in EtOH (2 mL). Cyclohexene (1 mL) was added followed by 2 (20% wt on carbon, 15 mg). The reaction mixture was heated at 80 °C for 27 h and then it was stirred at room temperature for 48 10 h. The catalyst was removed using PTFE filter and the solvent was evaporated under reduced pressure.

The crude product was purified on silica using EtOAc/n-heptane (0-60 % EtOAc) as mobile phase. 3.2 mg 5'-propyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol (E74) was obtained as a white solid. ES/MS m/z: 355.28 (M+H), 353.32 (M-H); 1H NMR (Acetone-d6, 500 MHz): δ 7.40 (d, 1H, J=1.9Hz), 7.17-7.14 (m, 3H), .08 (m, 3H), 6.99-6.96 (m, 2H), 6.90 (m, 2H), 6.61 (m, 2H), 2.68 (t, 2H, J=7.6Hz), 1.75 15 (m,2H) and 1.01 (t, 3H, J=7.4Hz).

Example 75 Example 75 was prepared using a method analogous to that used to synthesise Example 15 above. Full experimental s of the individual steps of the general methods are described in Example 15 20 above.Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

E 75 5-chloro(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-3'-nitro-[1,1'-biphenyl] carboximidamide R1 = 3,5-dimethylisoxazolyl ES/MS m/z: 403.14 (pos. M + H), 401.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.93 (d, 1H, J=2.3Hz), 7.61 (d, 1H, J=2.2Hz), 7.58 (d, 1H, J=2.2Hz), 7.46 (dd, 1H, J=8.8, 2.3Hz), 7.13 (d, 1H, J=8.8Hz), 2.09 (s, 3H) and 1.88 (s, 3H).

KB 640 / 15887 WO Examples 76 - 116 Examples 76 - 116 were prepared using methods analogous to that used to synthesise Examples 1 and 15 - 18 above. Full experimental details of the individual steps of the general methods are described in Examples 1and –15 - 18 above. For examples 76 – 90, 92, 93, 96, 97, 100 and 102 - 116 fication of 5 the title nds by 1H-NMR showed that the oxime product was a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

E 76 5'-chloro-5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R4 = H ES/MS m/z: 371.18 (pos. M + H), 369.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.46 (d, 1H, J=2.2Hz), 7.42 (d, 1, J=2.2Hz), 7.02-6.92 (m, 4H), 6.86 (m, 1H), 6.65 (m, 2H) and 1.83 (s, 3H). 10 E 77 5'-chloro-5''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R4 = H ES/MS m/z: 387.19 (pos. M + H), 385.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.43 (d, 1H, z), 7.37 (d, 1, J=2.2Hz), 6.95-6.90 (m, 3H), 6.81-6.77 (m, 2H), 6.65 (m, 2H) and 3.52 (s, 3H).

E 78 5-chloro-N',4'-dihydroxy(4-methylthiophenyl)-[1,1'-biphenyl]carboximidamide R1 = 4-methylthiophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R4 = H ES/MS m/z: 359.2 (pos. M + H), 357.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44 (d, 1H, z), 7.42 (d, 1, J=1.8Hz), 7.15 (t, 1H, J=2.5Hz), 6.96 (m, 2H), 6.88 (d, 1H, J=2.2Hz), 6.67 (m, 2H) and 1.73 (s, 3H).

E 79 5'-chloro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = o-tolyl R2 = N-hydroxy carbaimidoyl R3= Cl R4 = H KB 640 / 15887 WO ES/MS m/z: 353.19 (pos. M + H), 351.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.46 (d, 1H, z), 7.41 (d, 1, J=2.2Hz), 7.16 (dd, 1H, J=7.3, 1.4Hz), 7.10 (m, 1H), 7.06 (m, 1H), 6.99 (d, 1H, J=7.6Hz), 6.90 (m, 2H), 6.61 (m, 2H) and 1.87 (s, 3H).

E 80 2-(2,4-dimethylthiophenyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = 2,4-dimethylthiophenyl R2 = N-hydroxy carbaimidoyl R3= H R4 = H ES/MS m/z: 339.25 (pos. M + H), 337.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.51 (dd, 1H, J=6.0, 3.1Hz), 7.47-7.43 (m, 2H), 6.90 (m, 2H), 6.69-6.66 (m, 3H), 2.02 (s, 3H) and 1.81 (d, 3H, z).

E 81 5-chloro(2,4-dimethylthiophenyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = 2,4-dimethylthiophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R4 = H ES/MS m/z: 373.2 (pos. M + H), 371.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.51 (d, 1H, z), 7.45 (d, 1H, J=2.5Hz), 6.92 (m, 2H), 6.71-6.68 (m, 3H), 2.02 (s, 3H) and 1.81 (d, 3H, J=1.0Hz).

E 82 2''-chloro-5''-fluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = H ES/MS m/z: 399.22 (pos. M + H), 397.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.35 (d, 1H, J=1.8Hz), 7.24 (d, 1H, J=1.8Hz), 7.21 (dd, 1H, J=8.9, 5.2Hz), 7.01 (dd, 1H, J=9.3, 5.2Hz), 6.98- 6.93 (m, 3H), 6.65 (m, 2H), 2.70 (t, 2H, z), 1.73 (m, 2H) and 1.00 (t, 3H, J=7.3Hz).

E 83 6'-chloro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = Cl ES/MS m/z: 381.24 (pos. M + H), 379.33 (neg. M – H); 1H NMR (acetone-d6, 500MHz): δ 7.41 (s, 1H), 7.10-7.03 (m, 5H), 6.80 (m, 2H), 6.63 (m, 2H), 2.82 (t, 2H, J=7.7Hz), 1.73 (m, 2H) and 1.04 (t, 3H, J=7.3Hz). 5 E 84 N',4-dihydroxy-5',6'-dipropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = propyl ES/MS m/z: 389.35 (pos. M + H); 1H NMR (Acetone-d6, 500MHz): δ 7.30 (s, 1H), 7.05-6.99 (m, 5H), KB 640 / 15887 WO 6.79 (m, 2H), 6.62 (m, 2H), 2.70 (m, 2H), 2.43 (m, 2H), 1.71 (m, 2H), 1.35 (m, 2H), 1.06 (t, 3H, J=7.2Hz) and 0.73 (t, 3H, J=7.1Hz).

E 85 N',4'-dihydroxy(3-methylthiophenyl)-[1,1'-biphenyl]carboximidamide R1 = 3-methylthiophenyl R2 = N-hydroxy carbaimidoyl R3= H R4 = H ES/MS m/z: 325.25 (pos. M + H), 323.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.47-7.42 (m, 3H), 7.25 (d, 1H, J=5.0Hz), 6.96 (m, 2H) and .66 (m, 3H) and 1.77 (s, 3H).

E 86 5'-bromo-6'-chloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= Br R4 = Cl ES/MS m/z: 419.14 (pos. M + H), 417.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.78 (s, 1H), 7.12-7.05 (m, 5H), 6.83 (m, 2H) and 6.66 (m, 2H).

E 87 6'-chloro-N',4-dihydroxy-5'-phenyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= phenyl R4 = Cl ES/MS m/z: 415.25 (pos. M + H), 413.35 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.55-7.41 (m, 6H), 7.12-7.09 (m, 5H), 6.87 (m, 2H) and 6.65 (m, 2H).

E 88 6'-chloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= H R4 = Cl ES/MS m/z: 339.27 (pos. M + H), 337.29 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.71 (d, 1H, J=2.3Hz), 7.68 (d, 1H, J=2.3Hz), .46 (m, 4H), 7.41 (m, 1H), 7.40 (m, 2H) and 6.94 (m, 2H). 5 E89 N',4-dihydroxy-6'-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = methyl ES/MS m/z: 361.35 (pos. M + H), 359.37 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.27 (s, 1H), 7.07-7.00 (m, 5H), 6.74 (m, 2H), 6.62 (m, 2H), 2.69 (m, 2H), 2.04 (s, 3H), 1.67 (m, 2H) and 1.04 (t, 3H, J=7.3Hz).

E 90 5'',6'-difluoro-N',4-dihydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = 5-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = F ES/MS m/z: 397.34 (pos. M + H), 395.45 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.37 (d, 1H, J=7.6Hz), 6.96 (dd, 1H, J=8.6, 6.2Hz), 6.92-6.88 (m, 3H), 6.79 (m, 1H), 6.66 (m, 2H), 2.71 (m, 2H), 1.89 (s, 3H), 1.71 (m, 2H) and 1.01 (t, 3H, J=7.4Hz).

E 91 -difluorohydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 5-fluoromethylphenyl R2 = carbamoyl R3= propyl R4 = F ES/MS m/z: 382.29 (pos. M + H), 380.38 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.50 (d, 1H, J=7.4Hz), 7.00 (dd, 1H, J=8.4, 5.9Hz), 6.92 (m, 2H), 6.87 (dd, 1H, J=9.6, 2.7Hz), 6.82 (m, 1H), 6.67 (m, 2H), 2.72 (m, 2H), 1.92 (s, 3H), 1.72 (m, 2H) and 1.01 (t, 3H, J=7.2Hz).

E 92 4-hydroxy-6'-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carbaldehyde oxime R1 = phenyl R2 = hydroxyimino methyl R3= propyl R4 = methyl ES/MS m/z: 346.33 (pos. M + H), 344.37 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.64 (s, 1H), 7.19-7.10 (m, 3H), 6.97 (m, 2H), 6.78 (m, 2H), 6.64 (m, 2H), 2.70 (m, 2H), 2.05 (s, 3H), 1.68 (m, 2H) and 1.05 (t, 3H, J=7.4Hz).

E 93 5'',6'-difluoro-N',4-dihydroxy-2''-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = F ES/MS m/z: 413.29 (pos. M + H), 411.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.33 (d, 1H, z), 6.91-6.85 (m, 3H), 6.76-6.73 (m, 2H), 6.65 (m, 2H), 3.55 (s, 3H), 2.69 (m, 2H), 1.70 (m, 2H) and 1.01 (t, 3H, z).

E 94 5'',6'-difluorohydroxy-2''-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 5-fluoromethoxyphenyl R2 = carbamoyl R3= propyl R4 = F ES/MS m/z: 398.32 (pos. M + H), 396.4 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.47 (d, 1H, J=7.6Hz), 6.91-6.87 (m, 3H), 6.80-6.74 (m, 2H), 6.66 (m, 2H), 3.58 (s, 3H), 2.70 (m, 2H), 1.71 (m, 2H) and 1.02 (t, 3H, J=7.6Hz). 5 E 95 6'-fluorohydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = phenyl R2 = carbamoyl R3= propyl R4 = F KB 640 / 15887 WO ES/MS m/z: 350.36 (pos. M + H), 348.41 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44 (d, 1H, J=7.6Hz), 7.17-7.13 (m, 3H), 7.07 (m, 2H), 6.85 (m, 2H), 6.65 (m, 2H), 2.71 (m, 2H), 1.71 (m, 2H) and 1.01 (t, 3H, J=7.4Hz).

E 96 6'-fluoro-N',4-dihydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = o-tolyl R2 = oxy carbaimidoyl R3= propyl R4 = F ES/MS m/z: 379.29 (pos. M + H), 377.33 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.38 (d, 1H, J=7.7Hz), 7.10-6.95 (m, 4H), 6.88 (m, 2H), 6.62 (m, 2H), 2.71 (m, 2H), 1.93 (s, 3H), 1.71 (m, 2H) and 1.01 (t, 3H, J=7.2Hz).

E 97 6-fluoro-N',4'-dihydroxy(4-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide R1 = 4-methylthiophenyl R2 = oxy carbaimidoyl R3= propyl R4 = F ES/MS m/z: 385.25 (pos. M + H), 383.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.36 (d, 1H, J=7.7Hz), 7.06 (d, 1H, J=3.2Hz), 6.92 (m, 2H), 6.83 (m, 1H), 6.67 (m, 2H), 2.69 (m, 2H), 1.80 (s, 3H), 1.70 (m, 2H) and 1.00 (t, 3H, J=7.3Hz).

E 98 orohydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = o-tolyl R2 = carbamoyl R3= propyl R4 = F ES/MS m/z: 364.31 (pos. M + H), 362.35 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.55 (d, 1H, J=7.7Hz), 7.10-6.99 (m, 4H), 6.89 (m, 2H), 6.63 (m, 2H), 2.72 (m, 2H), 1.95 (s, 3H), 1.72 (m, 2H) and 1.01 (t, 3H, J=7.5Hz).

E 99 6-fluoro-4'-hydroxy(4-methylthiophenyl)propyl-[1,1'-biphenyl]carboxamide R1 = 4-methylthiophenyl R2 = carbamoyl R3= propyl R4 = F ES/MS m/z: 415.11 (pos. M + H), 413.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.54 (d, 1H, z), 7.08 (d, 1H, J=3.3Hz), 6.93 (m, 2H), 6.89 (m, 1H), 6.69 (m, 2H), 2.71 (m, 2H), 1.83 (s, 3H), 1.71 (m, 2H) and 1.01 (t, 3H, J=7.5Hz). 5 E 100 2-(2,4-dimethylthiophenyl)fluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl] KB 640 / 15887 WO carboximidamide R1 = 2,4-dimethylthiophenyl R2 = N-hydroxy carbaimidoyl R3= propyl R4 = F ES/MS m/z: 399.25 (pos. M + H), 397.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.42 (d, 1H, J=7.6Hz), 6.89 (m, 2H), 6.68 (m, 2H), 6.64 (s, 1H), 2.70 (m, 2H), 1.83 (s, 3H), 1.71 (m, 2H) and 1.00 (t, 3H, J=7.4Hz).

E 101 5'-chloro-5''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 5-fluoromethoxyphenyl R2 = carbamoyl R3= Cl R4 = H ES/MS m/z: 372.18 (pos. M + H), 370.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.49 (d, 1H, J=2.4Hz), 7.40 (d, 1H, J=2.4Hz), 6.96-6.92 (m, 3H), 6.83 (dd, 1H, J=8.9, 4.4Hz), 6.79 (dd, 1H, J=8.8, 3.2Hz), 6.66 (m, 2H) and 3.54 (s, 3H).

E 102 6'-fluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy midoyl R3= propyl R4 = F ES/MS m/z: 365.36 (pos. M + H), 363.43 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.33 (d, 1H, J=7.5Hz), 7.13-7.06 (m, 5H), 6.84 (m, 2H), 6.64 (m, 2H), 2.69 (m, 2H), 1.70 (m, 2H) and 1.01 (t, 3H, J=7.4Hz).

E 103 5''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= H R4 = H ES/MS m/z: 353.26 (pos. M + H), 351.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44-7.36 (m, 3H), 6.92-6.88 (m, 3H), 6.80-6.75 (m, 2H), 6.63 (m, 2H) and 3.52 (s, 3H).

E 104 N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = oxy carbaimidoyl R3= H R4 = H ES/MS m/z: 305.26 (pos. M + H), 303.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44-7.39 (m, 3H), .11 (m, 5H), 6.85 (m, 2H9 and 6.62 (m, 2H). 5 E 105 5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= H R4 = H KB 640 / 15887 WO ES/MS m/z: 337.25 (pos. M + H), 335.33 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.47-7.40 (m, 3H), .94 (m, 2H), 6.91 (m, 2H), 6.83 (m, 1H), 6.64 (m, 2H) and 1.83 (s, 3H).

E 106 N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-vinylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 399.24 (pos. M + H), 397.32 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.77 (d, 1H, J=1.6Hz), 7.67 (d, 1H, J=1.6Hz), 7.46 (d, 1H, J=7.8Hz), 7.23 (m, 1H), 7.18-7.16 (m, 2H), 6.89 (m, 2H), 6.61 (m, 2H), 6.40 (dd, 1H, J=17.4, 11.1Hz), 5.48 (dd, 1H, J=17.4, 1.3Hz) and 4.99 (dd, 1H, , 1.3Hz).

E 107 2''-ethyl-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-ethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 401.25 (pos. M + H), 399.33 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.76 (d, 1H, J=1.6Hz), 7.68 (d, 1H, J=1.6Hz), 7.22-7.19 (m, 2H), 7.13-7.08 (m, 2H), 6.92 (m, 2H), 6.64 (m, 2H), 2.29 (m, 1H), 2.09 (m, 1H) and 0.92 (t, 3H, z).

E 108 3''-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 405.24 (pos. M + H), 403.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.76 (d, 1H, J=1.5Hz), 7.70 (d, 1H, J=1.5Hz), 7.11 (m, 1H), 7.04 (dd, 1H, J=7.6, 1.1Hz), 6.96-6.92 (m, 3H), 6.68 (m, 2H) and 1.76 (d, 3H, J=2.2Hz).

E 109 3''-fluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-fluoromethylphenyl R2 = oxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 421.2 (pos. M + H), 419.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.75 (d, 1H, J=1.5Hz), 7.67 (d, 1H, J=1.5Hz), 7.04 (m, 1H), 6.98 (m, 2H), 6.93-6.89 (m, 2H), 6.68 (m, 2H) and 3.59, 3.58 (two s, 3H). 5 E 110 5',6'-dichloro-5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R4 = Cl KB 640 / 15887 WO ES/MS m/z: 405.17 (pos. M + H), 403.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.48 (s, 1H), 7.39 (m, 2H), 7.27 (dd, 1H, J=8.6, 6.1Hz), 7.05 (m, 1H), 6.99-6.96 (m, 3H) and 2.07 (s, 3H).

E 111 3'',5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 409.23 (pos. M + H), 407.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.73 (d, 1H, J=1.3Hz), 7.71 (d, 1H, J=1.3Hz), 6.97 (m, 2H), 6.87 (m, 1H), 6.81-6.77 (m, 2H) and 6.73 (m, 2H).

E 112 5''-chloro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 437.22 (pos. M + H), 435.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.73 (d, 1H, J=1.6Hz), 7.64 (d, 1H, J=1.6Hz), 7.20 (dd, 1H, J=8.8, 2.8Hz), 7.04 (d, 1H, J=2.8Hz), 6.95 (m, 2H), 6.85 (d, 1H, J=8.8Hz), 6.68 (m, 2H) and 3.56 (s, 3H).

E 113 2''-ethynyl-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = nylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 397.23 (pos. M + H), 395.3 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.77 (d, 1H, J=1.4Hz), 7.66 (d, 1H, J=1.4Hz), 7.35 (dd, 1H, J=7.9, 1.2Hz), 7.29-7.20 (m, 3H), 6.98 (m, 2H), 6.64 (m, 2H) and 3.47 (s, 1H).

E 114 loro-5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 425.18 (pos. M + H), 423.25 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.73 (d, 1H, J=1.4Hz), 7.71 (d, 1H, J=1.4Hz), 7.10 (m, 1H), 7.01 (m, 1H), 6.97 (m, 2H), 6.92 (m, 1H) and 6.74 (m, 2H). 5 E 115 5''-fluoro-N',4-dihydroxy-2'',5'-bis(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoro(trifluoromethyl)phenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 459.19 (pos. M + H), 457.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.84 (d, 1H, J=1.4Hz), 7.67 (d, 1H, J=1.4Hz), 7.59 (dd, 1H, J=8.7, 5.5Hz), 7.23-7.18 (m, 2H), 6.97 (m, 2H) and KB 640 / 15887 WO 6.69 (m, 2H).

E 116 3'',5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3,5-difluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R4 = H ES/MS m/z: 439.19 (pos. M + H), 437.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.86 (d, 1H, J=1.3Hz), 7.71 (d, 1H, J=1.3Hz), .96 (m, 3H), 6.77-6.70 (m, 3H) and 3.77 (s, 3H).

Examples 117 and 118 es 117 and 118 were prepared using a method analogous to that used to synthesise Example 74 5 above. Full mental s of the individual steps of the general methods are described in Example 74 above.

E 117 5'-methyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol R1 = phenyl R3= methyl ES/MS m/z: 327.33 (pos. M + H), 325.38 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.39 (m, 1H), 7.18-7.14 (m, 3H), 7.09-7.04 (m, 3H), 6.98-6.95 (m, 2H), 6.90 (m, 2H), 6.61 (m, 2H) and 2.42 (s, 3H). 10 E 118 3'',5''-difluoro-5'-propyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol R1 = 3,5-difluorophenyl R3= propyl ES/MS m/z: 391.28 (pos. M + H), 389.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.39 (d, 1H, J=1.6Hz), 7.24 (s, 2H), 7.13 (d, 1H, J=1.6Hz), 6.94 (m, 2H), 6.80 (m, 1H), 6.69 (m, 2H), 6.64-6.60 (m, 2H), 2.69 (m, 2H), 1.74 (m, 2H) and 1.01 (t, 3H, J=7.3Hz).

Examples 119-121 KB 640 / 15887 WO Examples 119 - 121 were prepared using a method analogous to that used to synthesise Example 67 above. Full experimental details of the individual steps of the general methods are described in Example 67 above. For examples 119-121 identification of the title compounds by 1H-NMR showed that the oxime t was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 5 E 119 N',4-dihydroxy-5'-phenyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R3= phenyl ES/MS m/z: 381.31 (pos. M + H), 379.41 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.78 (m, 2H), 7.70 (d, 1H, J=1.8Hz), 7.67 (d, 1H, J=1.8Hz), 7.50 (m, 2H), 7.40 (m, 1H), 7.17 (s, 5H), 6.94 (m, 2H) and 6.65 (m, 2H).

E 120 5'-benzyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R3= benzyl ES/MS m/z: 395.31 (pos. M + H); 1H NMR (Acetone-d6, 500MHz): δ 7.38-7.30 (m, 6H), 7.21 (m, 1H), 7.14-7.08 (m, 5H), 6.82 (m, 2H), 6.60 (m, 2H) and 4.06 (s, 2H).

E 121 ihydroxy-5'-phenethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R3= 2-phenethyl ES/MS m/z: 409.3 (pos. M + H); 1H NMR (Acetone-d6, ): δ 7.35-7.26 (m, 6H), 7.20 (m, 1H), 7.15-7.10 (m, 5H), 6.83 (m, 2H), 6.61 (m, 2H) and 3.00 (s, 4H). 10 Examples 122 - 276 Examples 122 - 276 were prepared using methods analogous to that used to synthesise Examples 1 and 15 above. Full experimental details of the individual steps of the general methods are described in Examples 1 and 15 above. For examples 122 – 129, 132, 134-138, 140 – 159, 162 – 172, 174- 178, 182-184, 186, 15 188, 190-198, 200- 224, 226, 228-257, 259, 261, 263-267, 269-273 and 275 identification of the title KB 640 / 15887 WO compounds by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

E 122 2,5''-difluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- imidamide R1 = 5-fluoromethylphenyl) R2 = N-hydroxy midoyl R3= CF3 R5 = F ES/MS m/z: 423.2 (pos. M + H), 421.4 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.79 (d, 1H, J=1.1Hz), 7.67 (d, 1H, J=1.1Hz), 6.99 (dd, 1H, J=8.5, 5.9Hz), 6.94 (dd, 1H, J=9.6, 2.4Hz), 6.85-6.81 (m, 2H), 6.42-6.37 (m, 2H) and 1.89 (s, 3H).

E 123 2,5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 439.4 (pos. M + H), 437.3 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.75 (d, 1H, J=1.5Hz), 7.63 (d, 1H, J=1.5Hz), 6.91 (m, 1H), 6.86 (dd, 1H, J=8.9, 3.2Hz), 6.80 (m, 1H), 6.74 (dd, 1H, J=9.0, 4.3Hz), 6.41-6.37 (m, 2H) and 3.54 (s, 3H). 5 E 124 2-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = o-tolyl R2 = oxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 405.2 (pos. M + H), 403.7 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.79 (s, 1H), 7.67 (s, 1H), 7.15-7.09 (m, 2H), 7.05-7.01 (m, 2H), 6.78 (m, 1H), 6.38-6.34 (m, 2H) and 1.94 (s, 3H).

E 125 2-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 391.4 (pos. M + H), 389.5 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.77 (d, 1H, J=1.5Hz), 7.68 (d, 1H, z), 7.19-7.13 (m, 5H), 6.82 (t, 1H, J=8.6Hz), 6.43 (dd, 1H, J=8.5, 2.3Hz) and 6.34 (dd, 1H, J=11.6, 2.3Hz).

KB 640 / 15887 WO E 126 5''-chlorofluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- imidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 455.21 (pos. M + H), 453.24 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.79 (d, 1H, J=1.4Hz), 7.68 (d, 1H, J=1.4Hz), 7.18 (dd, 1H, J=8.7, 2.7Hz), 7.08 (d, 1H, J=2.7Hz), 6.89 (t, 1H, J=8.6Hz), 6.80 (d, 1H, J=8.7Hz), 6.52-6.46 (m, 2H) and 3.56 (s, 3H).

E 127 2,3''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 439.25 (pos. M + H), 437.32 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.82 (d, 1H, J=1.3Hz), 7.67 (s, 1H), 7.01 (m, 1H), 6.92-6.86 (m, 3H), 6.50-6.47 (m, 2H) and 3.68, 3.67 (two s, 3H).

E 128 2,3'',5''-trifluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 427.22 (pos. M + H), 425.27 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.80 (d, 1H), J=1.6Hz), 7.72 (d, 1H, J=1.6Hz), 7.01 (t, 1H, J=8.6Hz), 6.86 (m, 1H), 6.81-6.76 (m, 2H), 6.61 (m, 1H) and 6.50 (dd, 1H, J=11.6, 2.5Hz).

E 129 2-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 2-vinylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 417.28 (pos. M + H), 415.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.84 (s, 1H), 7.68 (s, 1H), 7.45 (d, 1H, J=7.7Hz), 7.21-7.12 (m, 3H), 6.78 (t, 1H, z), 6.44-6.37 (m, 3H), 5.50 (d, 1H, J=17.6Hz) and 5.02 (d, 1H, J=10.6Hz).

E 130 5''-chlorofluorohydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboxamide R1 = 5-chloromethoxyphenyl R2 = carbamoyl R3= CF3 R5 = F ES/MS m/z: 440.23 (pos. M + H), 438.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.86 (d, 1H, J=1.6Hz), 7.69 (d, 1H, z), 7.20 (dd, 1H, J=8.9, 2.5Hz), 7.09 (d, 1H, J=2.5Hz), 6.91 (t, 1H, J=8.6Hz), 6.83 (d, 1H, J=8.9Hz), 6.53 (dd, 1H, J=8.4, 2.4Hz), 6.49 (dd, 1H, J=11.6, 2.4Hz) and 3.57 (s, KB 640 / 15887 WO 3H).

E 131 2-fluorohydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 2-vinylphenyl R2 = carbamoyl R3= CF3 R5 = F ES/MS m/z: 402.27 (pos. M + H), 400.35 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.91 (s, 1H), 7.71 (s, 1H), 7.47 (d, 1H, J=7.9Hz), 7.23-7.14 (m, 3H), 6.81 (m, 1H), 6.45-6.38 (m, 3H), 5.52 (dd, 1H, J=1.3, 17.5Hz) and 5.04 (dd, 1H, J=1.3, 11.0Hz).

E 132 3''-chloro-2,5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- imidamide R1 = 3-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 443.17 (pos. M + H), 441.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.80 (d, 1H, J=1.7Hz), 7.72 (d, 1H, J=1.7Hz), 7.09 (m, 1H), 7.03-7.00 (m, 2H), 6.91 (m, 1H), 6.62 (dd, 1H, J=8.4, 2.4Hz) and 6.49 (dd, 1H, J=11.6, 2.4Hz).

E 133 3''-chloro-2,5''-difluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3-chlorofluorophenyl R2 = carbamoyl R3= CF3 R5 = F ES/MS m/z: 428.18 (pos. M + H), 426.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.86 (d, 1H, J=1.7Hz), 7.75 (d, 1H, J=1.7Hz), 7.13 (m, 1H), 7.07-7.03 (m, 2H), 6.91 (m, 1H), 6.64 (dd, 1H, J=8.4, 2.4Hz) and 6.50 (dd, 1H, J=11.6, 2.4Hz).

E 134 2''-ethynylfluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- imidamide R1 = nylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 415.23 (pos. M + H), 413.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.83 (d, 1H, J=1.3Hz), 7.68 (d, 1H, J=1.3Hz), 7.32 (d, 1H, J=8.0Hz), 7.29-7.20 (m, 3H), 6.94 (m, 1H), 6.48-6.43 (m, 2H) and 3.48 (s, 1H). 5 E 135 5'-chloro-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 375.19 (pos. M + H), 373.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44 (d, 1H, z), 7.43 (d, 1H, J=2.2Hz), 6.93 (m, 2H), 6.83 (m, 1H) and 6.76-6.70 (m, 4H).

KB 640 / 15887 WO E 136 5'-chloro-3''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 387.19 (pos. M + H), 385.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.46 (d, 1H, J=2.1Hz), 7.39 (d, 1H, J=2.1Hz), 7.01 (m, 1H), 6.94 (m, 2H), 6.90-6.88 (m, 2H), 6.66 (m, 2H) and 3.57 (d, 3H, J=2.8Hz).

E 137 5',5''-dichloro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 403.14 (pos. M + H), 401.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.43 (d, 1H, J=2.3Hz), 7.37 (d, 1H, J=2.3Hz), 7.16 (dd, 1H, J=8.9, 2.6Hz), 6.99 (d, 1H, z), 6.92 (m, 2H), 6.82 (d, 1H, J=8.9Hz), 6.66 (m, 2H) and 3.55 (s, 3H).

E 138 3''-chlorofluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 439.18 (pos. M + H), 437.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.83 (s, 1H), 7.70 (s, 1H), 7.23 (dd, 1H, J=7.8, 1.3Hz), 7.11 (m, 1H), 7.05 (m, 1H), 6.88 (t, 1H, J=8.5Hz), 6.51 (dd, 1H, J=8.3, 2.4Hz), 6.47 (dd, 1H, J=11.5, 2.4Hz) and 1.96 (s, 3H).

E 139 3''-chlorofluorohydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboxamide R1 = 3-chloromethylphenyl R2 = carbamoyl R3= CF3 R5 = F ES/MS m/z: 424.2 (pos. M + H), 422.25 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.89 (s, 1H), 7.73 (s, 1H), 7.25 (dd, 1H, J=7.8, , 7.11 (m, 1H), 7.08 (m, 1H), 6.92 (t, 1H, J=8.8Hz), 6.53 (dd, 1H, J=8.5, 2.4Hz), 6.48 (dd, 1H, J=11.7, 2.4Hz) and 2.00 (s, 3H). 5 E 140 N',4-dihydroxy-5'-methyl-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-vinylphenyl R2 = oxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 345.29 (pos. M + H), 343.34 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.42 (d, 1H, J=7.8Hz), 7.29 (s, 1H), 7.21 (s, 1H), 7.16 (m, 1H), 7.12-7.09 (m, 2H), 6.83 (m, 2H), 6.56 (m, 2H), 6.45 (dd, 1H, J=17.5, 10.6Hz), 5.45 (dd, 1H, J=17.5, 1.1Hz), 4.95 (dd, 1H, J=10.6, 1.1Hz) and 2.42 (s, KB 640 / 15887 WO 3H).

E 141 3'',5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 385.23 (pos. M + H), 383.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.36 (d, 1H, J=1.5Hz), 7.23 (d, 1H, J=1.5Hz), 6.95-6.88 (m, 3H), 6.70-6.64 (m, 3H), 3.74 (s, 3H) and 2.43 (s, 3H).

E 142 uoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 367.25 (pos. M + H), 356.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.28 (s, 1H), 7.21 (s, 1H), 6.97 (m, 1H), 6.92 (m, 2H), 6.88-6.84 (m, 2H), 6.63 (m, 2H), 3.55, 3.54 (two s, 3H) and 2.41 (s, 3H).

E 143 5''-fluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 367.25 (pos. M + H), 365.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.25 (s, 1H), 7.18 (s, 1H), .87 (m, 3H), 6.79-6.73 (m, 2H), 6.62 (m, 2H), 3.52 (s, 3H) and 2.40 (s, 3H).

E 144 3''-chloro-5''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.29 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.27 (s, 1H), 7.24 (s, 1H), 7.01 (m, 1H), 6.94 (t, 1H, J=1.5Hz), 6.89 (m, 2H), 6.83 (m, 1H), 6.69 (m, 2H) and 2.42 (s, 3H). 5 E 145 5''-chloro-N',4-dihydroxy-2'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-chloromethylphenyl R2 = N-hydroxy midoyl R3= Me R5 = H ES/MS m/z: 367.25 (pos. M + H), 365.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.28 (d, 1H, J=1.3Hz), 7.23 (d, 1H, J=1.3Hz), 7.18 (d, 1H, J=2.4Hz), 7.07 (dd, 1H, J=8.2, 2.4Hz), 6.96 (d, 1H, J=8.2Hz), 6.89 (m, 2H), 6.63 (m, 2H), 2.42 (s, 3H) and 1.84 (s, 3H).

KB 640 / 15887 WO E 146 5''-chloro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 421.1 (pos. M + H), 418.6 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.76 (d, 1H, J=1.4Hz), 7.69 (d, 1H, J=1.4Hz), 7.24 (d, 1H, J=2.2Hz), 7.14 (dd, 1H, J=8.2, 2.2Hz), 7.02 (d, 1H, J=8.2Hz), 6.96 (m, 2H), 6.68 (m, 2H) and 1.85 (s, 3H).

E 147 3''-chloro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 421.1 (pos. M + H), 418.6 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.76 (d, 1H, J=1.4Hz), 7.69 (d, 1H, J=1.4Hz), 7.26 (dd, 1H, J=8.0, 1.2Hz), 7.17 (dd, 1H, J=7.6, 1.4Hz), 7.10 (t, 1H, J=7.9Hz), 6.93 (m, 2H), 6.67 (m, 2H) and 1.88 (s, 3H).

E 148 loro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 383.27 (pos. M + H), 381.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.25 (d, 1H, z), 7.17 (d, 1H, J=1.3Hz), 7.13 (dd, 1H, J=8.4, 2.8Hz), 6.96 (d, 1H, J=2.8Hz), 6.89 (m, 2H), 6.80 (d, 1H, J=8.4Hz), 6.63 (m, 2H), 3.54 (s, 3H) and 2.40 (s, 3H).

E 149 2''-chloro-5''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy midoyl R3= Me R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.32 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.32 (s, 1H), 7.23-7.20 (m, 2H), 7.01-6.92 (m, 4H), 6.65 (m, 2H) and 2.43 (s, 3H).

E 150 N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = oxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 317.2 (pos. M + H), 319.1 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.24 (s, 1H), 7.22 (s, 1H), 7.14-7.08 (m, 5H), 6.84 (m, 2H), 6.61 (m, 2H) and 2.40 (s, 3H). 5 E 151 N',4-dihydroxy-3'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = m-tolyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 333.2 (pos. M + H), 331.3 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.24 (s, 1H), 7.21 (s, 1H), 7.02 (m, 1H), 6.95 (d, 1H, J=7.8Hz), 6.88 (m, 1H), 6.85 (m, 2H), 6.61 (m, 2H), 2.40 (s, 3H) and 2.17 (s, 3H).

E 152 3''-chloro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-chlorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 353.3 (pos. M + H), 351.4 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.25 (s, 1H), 7.23 (s, 1H), 7.16-7.11 (m, 3H), 7.04 (m, 1H), 6.85 (m, 2H), 6.65 (m, 2H) and 2.41 (s, 3H).

E 153 N',4-dihydroxy-3''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-methoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 349.4 (pos. M + H), 347.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.24 (s, 1H), 7.23 (s, 1H), 7.04 (t, 1H, J=7.9Hz), 6.87 (m, 2H), .64 (m, 3H), 6.63 (m, 2H), 3.62 (s, 3H) and 2.40 (s, 3H).

E 154 4''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = rophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 391.24 (pos. M + H), 389.27 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.70 (s, 1H), 7.68 (s, 1H), 7.17 (m, 2H), 6.97 (m, 2H), 6.91 (m, 2H) and 6.69 (m, 2H).

E 155 4''-chloro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4- chlorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 407.2 (pos. M + H), 405.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.70 (s, 1H), 7.68 (s, 1H), 7.23 (m, 2H), 7.15 (m, 2H), 6.92 (m, 2H) and 6.69 (m, 2H). 5 E 156 N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-methoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 403.21 (pos. M + H), 401.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.72 (d, 1H, J=1.3Hz), 7.63 (d, 1H, J=1.3Hz), 7.21 (m, 1H), 7.02 (dd, 1H, J=7.3, 1.6Hz), 6.92 (m, 2H), 6.85- 6.80 (m, 2H), 6.63 (m, 2H) and 3.55 (s, 3H).

KB 640 / 15887 WO E 157 4''-fluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 4-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 421.2 (pos. M + H), 419.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.71 (d, 1H, J=1.4Hz), 7.63 (d, 1H, J01.4Hz), 7.04 (dd, 1H, J=8.4, 6.7Hz), 6.93 (m, 2H), 6.68-6.64 (m, 3H), 6.59 (m, 1H) and 3.56 (s, 3H).

E 158 ihydroxy-2''-isopropyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-isopropylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 415.25 (pos. M + H), 413.32 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.77 (d, 1H, J=1.6Hz), 7.68 (d, 1H, J=1.6Hz), 7.29-7.23 (m, 2H), 7.17-7.11 (m, 2H), 6.95 (m, 2H), 6.65 (m, 2H), 2.45 (m, 1H), 1.00 (d, 3H, J=6.8Hz) and 0.58 (d, 3H, J=6.8Hz).

E 159 2-(3,5-dimethylisoxazolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = methylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 392.23 (pos. M + H), 390.31 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.75 (s, 1H), 7.73 (s, 1H), 6.95 (m, 2H), 6.72 (m, 2H), 2.09 (s, 3H) and 1.86 (s, 3H).

E 160 2-(3,5-dimethylisoxazolyl)-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carboxamide R1 = methylisoxazolyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 377.24 (pos. M + H), 375.3 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.79 (s, 1H), 7.75 (s, 1H), 6.95 (m, 2H), 6.73 (m, 2H), 2.11 (s, 3H) and 1.86 (s, 3H). 5 E 161 3''-chlorohydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3-chloromethylphenyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 406.21 (pos. M + H), 404.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.81 (d, 1H, J01.4Hz), 7.72 (d, 1H, J=1.4Hz), 7.29 (dd, 1H, J=7.9, 1.4Hz), 7.18 (dd, 1H, J=7.7, 1.4Hz), 7.13 (t, 1H, J=7.8Hz), 6.96 (m, 2H), 6.68 (m, 2H) and 1.92 (s, 3H).

KB 640 / 15887 WO E 162 N',4-dihydroxy-2'',5''-dimethyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dimethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 401.25 (pos. M + H), 399.46 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.75 (d, 1H, J=1.3Hz), 7.67 (d, 1H, J=1.3Hz), 7.03 (s, 1H), 6.96-6.93 (m, 3H), 6.90 (d, 1H, J=7.7Hz), 6.64 (m, 2H), 2.22 (s, 3H) and 1.82 (s, 3H).

E 163 N',4-dihydroxy-2''-methoxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 2-methoxymethylphenyl R2 = oxy midoyl R3= CF3 R5 = H ES/MS m/z: 417.28 (pos. M + H), 415.33 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.71 (d, 1H, J=1.7Hz), 7.62 (d, 1H, z), 7.01 (dd, 1H, J=8.4, 1.9Hz), 6.93 (m, 2H), 6.83 (d, 1H, z), 6.73 (d, 1H, J=8.4Hz), 6.64 (m, 2H), 3.53 (s, 3H) and 2.14 (s, 3H). 2.22 (s, 3H) and 1.82 (s, 3H).

E 164 2''-chloro-N',4-dihydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 2-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 421.25 (pos. M + H), 419.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.78 (d, 1H, J=1.6Hz), 7.67 (d, 1H, J=1.6Hz), 7.12-7.10 (m, 2H), 7.05 (dd, 1H, J=8.2, 1.8Hz), 6.98 (m, 2H), 6.66 (m, 2H) and 2.23 (s, 3H).

E 165 5'-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 323.25 (pos. M + H), 321.41 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.19-7.15 (m, 5H), 7.12-7.09 (m, 2H), 6.87 (m, 2H) and 6.63 (m, 2H).

E 166 5''-chloro-5'-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 387.21 (pos. M + H), 385.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.20-7.11 (m, 3H), 6.97 (d, 1H, J=2.7Hz), 6.92 (m, 2H), 6.82 (d, 1H, J=8.9Hz), 6.65 (m, 2H) and 3.55 (s, 3H). 5 E 167 3'',5'-difluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = 3-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 371.28 (pos. M + H), 369.32 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.21 (dd, 1H, J=9.3, 3.0Hz), 7.15 (dd, 1H, J=9.5, 3.0Hz), 7.00 (m, 1H), 6.94 (m, 2H), 6.90-6.85 (m, 2H), 6.65 (m, 2H) and 3.57, 3.56 (two s, 3H).

E 168 ,5''-trifluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 359.23 (pos. M + H), 357.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.20 (m, 2H), 6.93 (m, 2H), 6.82 (m, 1H) and .69 (m, 4H).

E 169 3''-chloro-5',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-chlorofluorophenyl R2 = N-hydroxy midoyl R3= F R5 = H ES/MS m/z: 375.2 (pos. M + H), 373.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.22-7.18 (m, 2H), 7.05 (m,1H), 6.95 (m, 1H), 6.93 (m, 2H), 6.85 (m, 1H) and 6.71 (m, 2H).

E 170 5'-fluoro-N',4-dihydroxy-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-vinylphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 349.27 (pos. M + H), 347.45 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.44 (d, 1H, J=7.7Hz), 7.23 (dd, 1H, J=9.2, 2.8Hz), 7.21-7.11 (m, 4H), 6.86 (m, 2H), 6.58 (m, 2H), 6.43 (dd, 1H, J=17.6, ), 5.46 (dd, 1H, J=17.6, 1.4Hz) and 4.98 (dd, 1H, J=11.1, 1.4Hz).

E 171 5'-chloro-N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dimethylphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 367.25 (pos. M + H), 365.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.46 (d, 1H, J=2.6Hz), 7.39 (d, 1H, J=2.6Hz), 6.99 (s, 1H), 6.93-6.87 (m, 4H), 6.62 (m, 2H), 2.20 (s, 3H) and 1.82 (s, 3H). 5 E 172 N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dimethylphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H ES/MS m/z: 333.28 (pos. M + H), 331.34 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.47-7.38 (m, 3H), 6.99 (s, 1H), 6.91-6.86 (m, 4H), 6.60 (m, 2H), 2.20 (s, 3H) and 1.82 (s, 3H).

KB 640 / 15887 WO E 173 2''-chlorohydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 2-chloromethylphenyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 406.19 (pos. M + H), 404.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.85 (d, 1H, J=1.6Hz), 7.72 (d, 1H, z), 7.16 (d, 1H, J=8.1Hz), 7.10 (d, 1H, J=1.9Hz), 7.06 (dd, 1H, J=8.1, , 7.00 (m, 2H), 6.68 (m, 2H) and 2.23 (s, 3H).

E 174 3''-chloro-N',4-dihydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 421.2 (pos. M + H), 419.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.71 (s, 1H), 7.68 (s, 1H), 7.05 (s, 1H), 6.97-6.92 (m, 4H), 6.70 (m, 2H) and 2.20 (s, 3H).

E 175 2'',5''-dichloro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dichlorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 441.14 (pos. M + H), 439.19 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.81 (d, 1H, J=1.2Hz), 7.70 (d, 1H, z), 7.32 (m, 1H), 7.27-7.24 (m, 2H), 7.00 (m, 2H) and 6.70 (m, 2H).

E 176 5''-chloro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H ES/MS m/z: 353.26 (pos. M + H), 351.25 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.50--7.43 (m, 3H), 7.25 (d, 1H, J=2.3Hz), 7.08 (dd, 1H, J=8.2, 2.3Hz), 6.95 (d, 1H, J=8.2Hz), 6.86 (m, 2H), 6.56 (m, 2H) and 1.81 (s, 3H). 5 E 177 5''-chloro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H ES/MS m/z: 369.22 (pos. M + H), 367.32 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.49-7.43 (m, 3H), 7.17 (dd, 1H, J=8.9, 2.8Hz), 6.99 (d, 1H, J=2.8Hz), 6.86 (m, 2H), 6.80 (d, 1H, J=8.9Hz), 6.57 (m, 2H) and 3.57 (s, 3H).

E 178 3'',5''-difluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamid R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 355.28 (pos. M + H), 353.32 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.26 (s, 1H), 7.24 (s, 1H), 6.89 (m, 2H), 6.78 (s, 1H), 6.73-6.67 (m, 4H) and 2.42 (s, 3H).

E 179 3'',5''-difluorohydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3,5-difluorophenyl R2 = carbamoyl R3= Me R5 = H ES/MS m/z: 340.25 (pos. M + H), 338.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.30 (s, 1H), 7.25 (s, 1H), 6.91 (m, 2H), 6.81 (s, 1H), 6.73-6.68 (m, 4H) and 2.43 (s, 3H).

E 180 3''-chlorohydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3-chloromethylphenyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 406.22 (pos. M + H), 404.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.76 (s, 1H), 7.70 (s, 1H), 7.09 (s, 1H), .94 (m, 4H), 6.72 (m, 2H) and 2.22 (s, 3H). 5 E 181 2'',5''-dichlorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 2,5-dichlorophenyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 428.12 (pos. M + H), 426.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.89 (d, 1H, J=1.4Hz), 7.75 (d, 1H, J=1.4Hz), 7.32-7.27 (m, 3H), 7.02 (m, 2H) and 6.72 (m, 2H).

E 182 3'',5''-dichloro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-dichlorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 441.14 (pos. M + H), 439.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.74 (d, 1H, z), 7.71 (d, 1H, J=1.6Hz), 7.31 (t, 1H, z), 7.14 (d, 2H, J=1.9Hz), 6.97 (m, 2H) and KB 640 / 15887 WO 6.74 (m, 2H).

E 183 3'',5''-dichloro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-dichlorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 387.19 (pos. M + H), 385.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.27 (m, 1H), 7.24 (m, 1H), 7.22 (t, 1H, J02.1Hz), 7.06 (d, 2H, J=2.1Hz), 6.89 (m, 2H), 6.70 (m, 2H) and 2.42 (s, 3H).

E 184 2-(3,5-dimethylisoxazolyl)-2'-fluoro-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F ES/MS m/z: 410.21 (pos. M + H), 408.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.83 (d, 1H, J=1.9Hz), 7.73 (d, 1H, J=1.9Hz), 7.08 (t, 1H, J=8.7Hz), 6.68 (dd, 1H, J=8.7, 2.3Hz), 6.54 (dd, 1H, J=11.8, 2.3Hz), 2.03 (s, 3H) and 1.90 (s, 3H).

E 185 2-(3,5-dimethylisoxazolyl)-2'-fluoro-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl] carboxamide R1 = 3,5-dimethylisoxazolyl R2 = oyl R3= CF3 R5 = F ES/MS m/z: 395.22 (pos. M + H), 393.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.88 (d, 1H, J=1.8Hz), 7.77 (d, 1H, J=1.8Hz), 7.10 (t, 1H, J=8.6Hz), 6.69 (dd, 1H, J=8.6, 2.4Hz), 6.55 (dd, 1H, J=11.8, 2.4Hz), 2.07 (s, 3H) and 1.92 (s, 3H).

E 186 3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy midoyl R3= H R5 = H ES/MS m/z: 341.23 (pos. M + H), 339.33 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.49-7.43 (m, 3H), 6.86 (m, 2H), 6.76-6.70 (m, 3H) and 6.62 (m, 2H). 5 E 187 3'',5''-difluorohydroxy-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = fluorophenyl R2 = carbamoyl R3= H R5 = H ES/MS m/z: 326.24 (pos. M + H), 324.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ .47 (m, 2H), 7.44 (m, 1H), 6.93 (m, 2H), 6.83 (m, 1H) and 6.76-6.69 (m, 4H).

KB 640 / 15887 WO E 188 3''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = romethoxyphenyl R2 = N-hydroxy midoyl R3= H R5 = H ES/MS m/z: 353.26 (pos. M + H), 351.32 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.52-7.45 (m, 3H), 7.01 (m, 1H), 6.93-6.86 (m, 4H), 6.60 (m, 2H) and 3.57, 3.56 (two s, 3H).

E 189 3''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3-fluoromethoxyphenyl R2 = carbamoyl R3= H R5 = H ES/MS m/z: 338.27 (pos. M + H), 336.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.53 (dd, 1H; J=7.6, 1.5Hz), 7.46 (t, 1H, z), 7.41 (dd, 1H, J=7.6, 1.5Hz), 7.00 (m, 1H), 6.94 (m, 2H), 6.91- 6.86 (m, 2H), 6.65 (m, 2H) and 3.60, 3.59 (two s, 3H).

E 190 2''-ethyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-ethylphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H ES/MS m/z: 333.32 (pos. M + H), 331.44 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.53-7.45 (m, 3H), 7.21-7.18 (m, 2H), 7.13-7.08 (m, 2H), 6.86 (m, 2H), 6.52 (m, 2H), 2.28 (m, 1H), 2.09 (m, 1H) and 0.89 (t, 3H, J=7.6Hz).

E 191 4''-chloro-2''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.31 (s, 1H), 7.22 (s, 1H), 7.18 (t, 1H, J08.1Hz), 7.05 (dd, 1H, J=8.4, 2.0Hz), 6.07 (dd, 1H, J=9.4, 2.0Hz), 6.89 (m, 2H), 6.66 (m, 2H) and 2.09 (s, 3H).

E 192 4''-chloro-3''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-chlorofluorophenyl R2 = N-hydroxy midoyl R3= Me R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.19 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.28-7.23 (m, 3H), 7.01 (dd, 1H, J=10.6, 1.9Hz), 6.91-6.86 (m, 3H), 6.67 (m, 2H) and 2.09 (s, 3H). 5 E 193 N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-methoxyphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H KB 640 / 15887 WO ES/MS m/z: 335.28 (pos. M + H), 333.35 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.53-7.45 (m, 3H), 7.21-7.18 (m, 2H), 7.13-7.08 (m, 2H), 6.86 (m, 2H), 6.52 (m, 2H), 2.28 (m, 1H), 2.09 (m, 1H) and 0.89 (t, 3H, J=7.6Hz).

E 194 5'-chloro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-methoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 369.21 (pos. M + H), 367.27 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.43 (d, 1H, J=2.2Hz), 7.35 (d, 1H, J=2.2Hz), 7.18 (m, 1H), 6.97 (dd, 1H, J=7.4, 1.7Hz), 6.89 (m, 2H), 6.82 (d, 1H, J=8.2Hz), 6.78 (m, 1H), 6.61 (m, 2H) and 3.55 (s, 3H).

E 195 4''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H ES/MS m/z: 353.26 (pos. M + H), 351.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.42 (dd, 1H, J=7.3, 1.9Hz), 7.40 (t, 1H, J=7.3Hz), 7.34 (dd, 1H, J=7.3, 1.9Hz), 6.98 (t, 1H, J=7.8Hz), 6.88 (m, 2H), 6.64-6.60 (m, 3H), 6.54 (m, 1H) and 3.55 (s, 3H).

E 196 5'-chloro-4''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 387.19 (pos. M + H), 385.27 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.42 (d, 1H, J=2.2Hz), 7.35 (d, 1H, J=2.2Hz), 6.99 (dd, 1H, J=8.5, 6.9Hz), 6.89 (, m, 2H), .61 (m, 3H), 6.56 (m, 1H) and 3.55 (s, 3H).

E 197 3''-chloro-N',4-dihydroxy-5',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = romethylphenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 367.25 (pos. M + H), 365.31 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.24 (s, 1H), 7.21 (s, 1H), 6.98 (s, 1H), 6.91 (s, 1H), 6.88-6.85 (m, 3H), 6.65 (m, 2H), 2.40 (s, 3H) and 2.17 (s, 3H). 5 E 198 2'',5''-dichloro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dichlorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 387.19 (pos. M + H), 385.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.33 (d, 1H, KB 640 / 15887 WO J=1.0Hz), 7.23-7.17 (m, 4H), 6.93 (m, 2H), 6.65 (m, 2H) and 2.43 (s, 3H).

E 199 3'',5''-difluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3,5-difluorophenyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 394.19 (pos. M + H), 392.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.78 (s, 1H), 7.73 (s, 1H), 7.00 (m, 2H), 6.91 (m, 1H), 6.81 (m, 2H) and 6.74 (m, 2H).

E 200 N',4-dihydroxy-4'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = p-tolyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 333.3 (pos. M + H), 331.23 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.23 (s, 1H), 7.19 (s, 1H), 6.99-6.94 (m, 4H), 6.85 (m, 2H), 6.62 (m, 2H), 2.39 (s, 3H) and 2.25 (s, 3H).

E 201 N',4-dihydroxy-2'',4'',5'-trimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,4-dimethylphenyl R2 = N-hydroxy midoyl R3= Me R5 = H ES/MS m/z: 347.31 (pos. M + H), 345.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.27 (d, 1H, J=1.¤Hz), 7.20 (d, 1H, J=1.4Hz), 7.01 (d, 1H, J=7.7Hz), 6.90-6.84 (m, 3H), 6.60 (m, 2H), 2.40 (s, 3H), 2.22 (s, 3H) and 1.83 (s, 3H).

E 202 4''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-fluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 337.24 (pos. M + H), 335.37 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.23 (s, 1H), 7.22 (s, 1H), 7.10 (m, 2H), 6.90 (m, 2H), 6.84 (m, 2H), 6.64 (m, 2H) and 2.40 (s, 3H). 5 E 203 2'',4''-difluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,4-difluorophenyl R2 = oxy carbaimidoyl R3= Me R5 = H ES/MS m/z: 355.28 (pos. M + H), 353.33 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.29 (s, 1H), 7.22 (s, 1H), 7.19 (m, 1H), 6.89 (m, 2H), 6.82 (m, 1H), 6.73 (m, 1H), 6.65 (m, 2H) and 2.42 (s, 3H).

E 204 5''-chloro-5'-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = 5-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.16 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.22 (dd, 1H, J=9.0,2.8Hz), 7.19-7.17 (m, 2H), 7.10 (dd, 1H, J=8.2, , 6.98 (d, 1H, J08.2Hz), 6.92 (m, 2H), 6.66 (m, 2H) and 1.84 (s, 3H).

E 205 5',5''-difluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 371.26 (pos. M + H), 369.19 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.18 (dd, 1H, J=9.0, 2.6Hz), 7.13 (dd, 1H, J=9.6, 2.9Hz), 6.94-6.89 (m, 3H), 6.81-6.75 (m, 2H), 6.65 (m, 2H) and 3.53 (s, 3H).

E 206 2''-chloro-5'-fluoro-N',4-dihydroxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = romethylphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.17 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.23 (dd, 1H, J=9.1, 2.8Hz), 7.16 (dd, 1H, J=9.4, 2.8Hz), 7.09-7.07 (m, 2H), 7.01 (dd, 1H, J=8.2, 2.4Hz), 6.94 (m, 2H), 6.63 (m, 2H) and 2.21 (s, 3H).

E 207 '-dichloro-5'-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dichlorophenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 391.18; 393.20 (pos. M + H), 389.07; 391.10 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.29-7.17 (m, 5H), 6.96 (m, 2H) and 6.67 (m, 2H).

E 208 5'-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-methoxyphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 353.26 (pos. M + H), 351.21 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.19-7.16 (m, 2H), 7.11 (dd, 1H, J=9.5, 2.6Hz), 6.96 (dd, 1H, J=7.5, 1.7Hz), 6.89 (m, 2H), 6.82 (d, 1H, z), 6.77 (t, 1H, J=7.5Hz), 6.61 (m, 2H) and 3.55 (s, 3H). 5 E 209 4'',5'-difluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-fluoromethoxyphenyl R2 = oxy carbaimidoyl R3= F R5 = H KB 640 / 15887 WO ES/MS m/z: 371.26 (pos. M + H), 369.17 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.17 (dd, 1H, J=9.3, 3.0Hz), 7.12 (dd, 1H, J=9.5, 2.7Hz), 6.97 (dd, 1H, J=8.4, 6.9Hz), 6.89 (m, 2H), 6.65-6.61 (m, 3H), 6.55 (m, 1H) and 3.55 (s, 3H).

E 210 5'-fluoro-N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = 2,5-dimethylphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 351.3 (pos. M + H), 349.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.21 (dd, 1H, J=9.3, 2.9Hz), 7.16 (dd, 1H, J=9.8, 2.9Hz), 6.98 (s, 1H), 6.93-6.87 (m, 4H), 6.62 (m, 2H), 2.20 (s, 3H) and 1.81 (s, 3H).

E 211 5'-fluoro-N',4-dihydroxy-2''-methoxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-methoxymethylphenyl R2 = N-hydroxy carbaimidoyl R3= F R5 = H ES/MS m/z: 367.32 (pos. M + H), 365.21 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.16 (dd, 1H, J=9.3, 2.7Hz), 7.10 (dd, 1H, J=9.6, 2.7Hz), 6.98 (dd, 1H, J=8.3, 2.1Hz), 6.91 (m, 2H), 6.78 (d, 1H, J=2.1Hz), 6.71 (d, 1H, J=8.3Hz), 6.61 (m, 2H), 3.53 (s, 3H) and 2.13 (s, 3H).

E 212 ihydroxy-2''-methoxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-methoxymethylphenyl R2 = N-hydroxy carbaimidoyl R3= H R5 = H ES/MS m/z: 349.4 (pos. M + H), 347.2 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.50-7.42 (m, 3H), 7.01 (dd, 1H, J=8.7, 2.3Hz), 6.86 (m, 2H), 6.78 (d, 1H, J=2.3Hz), 6.74 (d, 1H, J=8.7Hz), 6.54 (m, 2H), 3.56 (s, 3H) and 2.14 (s, 3H).

E 213 N',4-dihydroxy-2''-methoxy-5',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-methoxymethylphenyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 363.33 (pos. M + H), 361.36 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.23 (s, 1H), 7.15 (s, 1H), 6.94 (dd, 1H, J=8.1, 2.0Hz), 6.88 (m, 2H), 6.76 (d, 1H, J=2.0Hz), 6.69 (d, 1H, J=8.1Hz), 6.59 (m, 2H), 3.52 (s, 3H), 2.39 (s, 3H) and 2.12 (s, 3H). 5 E 214 4''-fluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 367.3 (pos. M + H), 365.26 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.23 (s, 1H), 7.16 (s, 1H), 6.95 (m, 1H), 6.87 (m, 2H), 6.63-6.59 (m, 3H), 6.53 (m, 1H), 3.55 (s, 3H) and 2.39 (s, 3H).

E 215 2''-chloro-N',4-dihydroxy-5',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = 2-chloromethylphenyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 367.25 (pos. M + H), 365.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.29 (s, 1H), 7.21 (s, 1H), 7.07-7.05 (m, 2H), 6.98 (dd, 1H, J=8.1, , 6.92 (m, 2H), 6.61 (m, 2H), 2.42 (s, 3H) and 2.20 (s, 3H).

E 216 N',4-dihydroxy-5'-methyl-2''-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-(trifluoromethoxy)phenyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 403.21 (pos. M + H), 401.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.34-7.26 (m, 3H), 7.23 (d, 1H, J=1.4Hz), 7.16 (m, 1H), 7.05 (m, 1H), 6.85 (m, 2H), 6.61 (m, 2H) and 2.42 (s, 3H).

E 217 N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-methoxyphenyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 349.27 (pos. M + H), 347.33 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.24 (s, 1H), 7.18-7.13 (m, 2H), 6.94 (dd, 1H, J=7.4, 1.7Hz), 6.87 (m, 2H), 6.80 (dd, 1H, J=8.1, , 6.76 (m, 1H), 6.59 (m, 2H), 3.54 (s, 3H) and 2.39 (s, 3H).

E 218 3'',5''-difluoro-N',4-dihydroxy-5'-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3=Methoxy R5 = H ES/MS m/z: 371.24 (pos. M + H), 369.27 (neg. M – H); 1H NMR (Acetone-d6, ): δ 7.00 (d, J = 2.7 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 6.91 (m, 2H), 6.76 (m, J = 2.9 Hz, 1H), 6.71-6.64 (m, 4H), 3.90 (s, 3H).

E 219 5''-fluoro-N',4-dihydroxy-2'',5'-dimethoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3=Methoxy R5 = H ES/MS m/z: 383.23 (pos. M + H), 381.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 6.99 (d, J = 2.8 Hz, 1H), .86 (m, 4H), 6.76 (dd, J = 4.6, 9.0 Hz, 1H), 6.73 (dd, J = 3.2, 9.1 Hz, 1H), 6.63 (m, 2H), 3.88 (s, 3H), 3.52 (s, 3H). 5 E 220 2-(5-fluoromethoxypyridinyl)-N',4'-dihydroxymethyl-[1,1'-biphenyl] carboximidamide KB 640 / 15887 WO R1 = 5-fluoromethoxypyridinyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 368.23 (pos. M + H), 366.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.83 (d, 1H, J=3.0Hz), 7.28 (d, 1H, z), 7.20-7.18 (m, 2H), 6.89 (m, 2H), 6.66 (m, 2H), 3.59 (s, 3H) and 2.42 (s, 3H).

E 221 N',4'-dihydroxymethyl(2-methylpyridinyl)-[1,1'-biphenyl]carboximidamide R1 = 2-methylpyridinyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 334.23 (pos. M + H), 332.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.23 (dd, 1H, J=4.8, 1.7Hz), 7.49 (dd, 1H, J=7.6, 1.7Hz), 7.30 (s, 1H), 7.25 (s, 1H), 7.03 (dd, 1H, J=7.6, , 6.86 (m, 2H), 6.62 (m, 2H), 2.43 (s, 3H) and 2.08 (s, 3H).

E 222 N',4'-dihydroxy(2-methoxypyridinyl)methyl-[1,1'-biphenyl]carboximidamide R1 = 2-methoxypyridinyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 350.25 (pos. M + H), 348.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.95 (dd, 1H, J=5.1, , 7.30 (dd, 1H, J=6.9, 1.9Hz), 7.26 (s, 1H), 7.18 (s, 1H), 6.86 (m, 2H), 6.76 (dd, 1H, J=7.3, 5.1Hz), 6.62 (m, 2H), 3.63 (s, 3H) and 2.41 (s, 3H).

E 223 2-(3,5-dimethylisothiazolyl)-N',4'-dihydroxymethyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-dimethylisothiazolyl R2 = N-hydroxy carbaimidoyl R3=Me R5 = H ES/MS m/z: 354.5 (pos. M + H), 352.6 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.14-7.11 (m, 3H), 7.09-7.07 (m, 2H), 6.99 (d, J = 2.8 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.86 (m, 2H), 6.61 (m, 2H), 3.88 (s, 3H). 5 E 224 N',4-dihydroxy-5'-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = phenyl R2 = oxy carbaimidoyl R3=Methoxy R5 = H ES/MS m/z: 335.28 (pos. M + H), 333.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.14-7.11 (m, 3H), 7.09-7.07 (m, 2H), 6.99 (d, J = 2.8 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.86 (m, 2H), 6.61 (m, 2H), 3.88 (s, 3H).

KB 640 / 15887 WO E 225 2-(3,5-dimethylisothiazolyl)-4'-hydroxymethyl-[1,1'-biphenyl]carboxamide R1 = 3,5-dimethylisothiazolyl R2 = carbamoyl R3=Me R5 = H ES/MS m/z: 339.2 (pos. M + H), 337.29 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.39 (d, J = 1.0 Hz, 1H), 7.31 (d, J = 0.9 Hz, 1H), 6.88 (m, 2H), 6.69 (m, 2H), 2.45 (s, 3H), 2.16 (s, 3H) and 2.02 (s, 3H).

E 226 5-chloro(5-fluoromethoxypyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl] carboximidamide R1 = 5-fluoromethoxypyridinyl R2 = N-hydroxy midoyl R3=Cl R5 = H ES/MS m/z: 388.17 (pos. M + H), 386.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.86 (d, J = 3.0 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 3.0, 8.5 Hz, 1H), 6.92 (m, 2H), 6.69 (m, 2H) and 3.60 (s, 3H).

E 227 luoromethoxypyridinyl)-4'-hydroxymethyl-[1,1'-biphenyl]carboxamide R1 = 5-fluoromethoxypyridinyl R2 = carbamoyl R3=Cl R5 = H ES/MS m/z: 368.23 (pos. M + H), 366.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.83 (d, J = 3.0 Hz, 1H), 7.28 (d, J = 1.0 Hz, 1H), 7.20-7.18 (m, 2H), 6.89 (m, 2H), 6.66 (m, 2H), 3.59 (s, 3H) and 2.42 (s, 3H).

E 228 2-(3,5-dimethylisothiazolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-dimethylisothiazolyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 408.18 (pos. M + H), 406.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.81 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 6.94 (m, 2H), 6.73 (m, 2H), 2.17 (s, 3H), 2.01 (s, 3H).

E 229 5-chloro(3,5-dimethylisothiazolyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = 3,5-dimethylisothiazolyl R2 = N-hydroxy midoyl R3=Cl R5 = H ES/MS m/z: 374.18 (pos. M + H), 372.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.52 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 6.90 (m, 2H), 6.71 (m, 2H), 2.15 (s, 3H), 2.00 (s, 3H). 5 E 230 4''-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide KB 640 / 15887 WO R1 = romethylphenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 405.24 (pos. M + H), 403.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.74 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.22 (dd, J = 6.0, 8.4 Hz, 1H), 6.95 (m, 2H), 6.86 (m, 1H), 6.80 (dd, J = 2.7, 10.1 Hz, 1H), 6.67 (m, 2H), 1.88 (s, 3H).

E 231 2'',4''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,4-difluorophenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 409.17 (pos. M + H), 407.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.78 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.28 (m, J = 4.7 Hz, 1H), 6.96 (m, 2H), 6.89 (m, 1H), 6.80 (m, 1H), 6.70 (m, 2H).

E 232 N',4'-dihydroxy(4-methylpyridinyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 4-methylpyridinyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 388.17 (pos. M + H), 386.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.33 (s, 1H), 8.25 (d, J = 5.0 Hz, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 6.99 (d, J = 5.1 Hz, 1H), 6.94 (m, 2H), 6.67 (m, 2H) and 1.89 (s, 3H).

E 233 -dimethylpyridinyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 2,5-dimethylpyridinyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 402.16 (pos. M + H), 400.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.14 (d, J = 1.9 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 6.94 (m, 2H), 6.67 (m, 2H), 2.22 (s, 3H) and 1.99 (s, 3H).

E 234 2''-chloro-4''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- imidamide R1 = 2-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 425.11 (pos. M + H), 423.16 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.75 (s, 1H), 7.69 (s, 1H), 7.27 (dd, J = 6.1, 8.6 Hz, 1H), 7.08 (dd, J = 2.5, 8.8 Hz, 1H), 6.97 (m, 1H), 6.92 (m, 2H), 6.61 (m, 2H). 5 KB 640 / 15887 WO E 235 4'',5''-difluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 423.15 (pos. M + H), 421.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.25 (d, J = 1.1 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.36 (dd, J = 8.2, 11.0 Hz, 1H), 7.22 (dd, J = 8.1, 11.6 Hz, 1H), 7.08 (m, 2H), 6.77 (m, 2H), 1.94 (s, 3H).

E 236 2'',5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-difluorophenyl R2 = oxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 409.16 (pos. M + H), 407.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.79 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.06-6.98 (m, 4H), 6.94 (m, 1H), 6.71 (m, 2H).

E 237 N',4'-dihydroxy(pyridinyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide R1 = pyridinyl R2 = oxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 374.18 (pos. M + H), 372.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.37 (dd, J = 1.6, 4.8 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.53 (m, 1H), 7.19 (m, 1H), 6.92 (m, 2H), 6.69 (m, 2H).

E 238 2-(2,3-dihydrobenzofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 2,3-dihydrobenzofuranyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 415.18 (pos. M + H), 413.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.72 (d, J = 1.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 0.8, 7.3 Hz, 1H), 6.96 (m, 2H), 6.85 (d, J = 7.5 Hz, 1H), 6.69 (t, J = 7.5 Hz, 2H), 6.65 (m, 2H), 4.41 (m, 1H), 4.11 (q, J = 8.9 Hz, 1H), 3.11 (m, 1H), 3.02 (m, 1H).

E 239 2-(benzofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide R1 = benzofuranyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 413.15 (pos. M + H), 411.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.81 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 1.2, 7.6 Hz, 1H), 7.17 (dd, J = 1.0, 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.88 (m, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.52 (m, 2H). 5 KB 640 / 15887 WO E 240 N',4'-dihydroxy(1-methyl-1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 1-methyl-1H-indolyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 426.16 (pos. M + H), 424.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.80 (d, J = 1.4 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 1.3, 7.7 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.94 (dd, J = 1.3, 7.2 Hz, 1H), 6.92-6.88 (m, 3H), 6.51 (m, 2H), 6.31 (d, J = 3.1 Hz, 1H), 3.34 (s, 3H).

E 241 2''-chloro-5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 2-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 425.11 (pos. M + H), 423.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.81 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.27 (dd, J = 5.1, 8.8 Hz, 1H), 7.10 (dd, J = 3.1, 9.1 Hz, 1H), 7.04 (dd, J = 3.1, 8.5 Hz, 2H), 7.01 (m, 2H), 6.70 (m, 2H).

E 242 loro-2''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 425.11 (pos. M + H), 423.15 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.80 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.29-7.26 (m, 2H), .96 (m, 3H), 6.72 (m, 2H).

E 243 2-(4-fluorobenzofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 4-fluorobenzofuranyl R2 = N-hydroxy midoyl R3=CF3 R5 = H ES/MS m/z: 431.13 (pos. M + H), 429.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.80 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.19 (dd, J = 5.2, 8.2 Hz, 1H), 6.93-6.88 (m, 4H), 6.83 (m, 2H).

E 244 3'',4''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,4-difluorophenyl R2 = N-hydroxy carbaimidoyl R3=CF3 R5 = H ES/MS m/z: 409.4 (pos. M + H), 407.2 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.70 (s, 1H), 7.69 (s, 1H), .03 (m, 2H), 6.93-6.87 (m, 3H), 6.65 (m, 2H). 5 KB 640 / 15887 WO E 245 5'-chloro-2'',4''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,4-difluorophenyl R2 = N-hydroxy midoyl R3=Cl R5 = H ES/MS m/z: 375.2 (pos. M + H), 373.3 (neg. M – H); 1H NMR (CD 3CN, 500MHz): δ 7.48 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.15 (m, 1H), 6.90 (m, 2H), 6.84 (m, 1H), 6.75 (m, 1H), 6.62 (m, 2H).

E 246 5'-chloro-2'',4''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3=Cl R5 = H ES/MS m/z: 375.2 (pos. M + H), 373.3 (neg. M – H); 1H NMR (CD 3CN, 500MHz): δ 7.49 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 6.99 (m, 1H), 6.95-6.87 (m, 4H), 6.62 (m, 2H).

E 247 2-(benzo[d][1,3]dioxolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = benzo[d][1,3]dioxolyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 417.14 (pos. M + H), 415.21 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.74 (d, J = 1.5 Hz, 1H), 7.67 (t, J = 0.9 Hz, 1H), 6.98 (m, 2H), 6.72-6.68 (m, 5H), 5.80 (d, J = 1.1 Hz, 1H), 5.38 (d, J = 1.0 Hz, 1H).

E 248 3'',4'',5''-trifluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3,4,5-trifluorophenyl R2 = N-hydroxy midoyl R3= CF3 R5 = H ES/MS m/z: 427.1 (pos. M + H), 425 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.71 (s, 1H), 7.70 (s, 1H), 6.92-6.85 (m, 4H), 6.69 (m, 2H).

E 249 5'-chloro-3'',4''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,4-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 375.2 (pos. M + H), 373 (neg. M – H); 1H NMR (MeOD, ): δ 7.45 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.05 (m, 1H), 6.99 (m, 1H), 6.89-6.84 (m, 3H), 6.62 (m, 2H). 5 E 250 5'-chloro-3'',4'',5''-trifluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,4,5-trifluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H KB 640 / 15887 WO ES/MS m/z: 393.2 (pos. M + H), 391.3 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.47 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 6.89-6.80 (m, 4H), 6.66 (m, 2H).

E 251 ro-N',4'-dihydroxy(4-methylpyridinyl)-[1,1'-biphenyl]carboximidamide R1 = 4-methylpyridinyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 354.2 (pos. M + H), 391.3; 1H NMR (MeOD, 500MHz): δ 8.28 (s, 1H), 8.19 (d, J = 5.0 Hz, 1H), 7.49 (m, 2H), 7.09 (d, J = 5.1 Hz, 1H), 6.85 (m, 2H), 6.57 (m, 2H), 1.92 (s, 3H).

E 252 5',5''-dichloro-2''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = rofluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 391.07 (pos. M + H), 389.07 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.48 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.21-7.19 (m, 2H), 6.89-6.87 (m, 3H), 6.60 (m, 2H).

E 253 2'',5'-dichloro-5''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-chlorofluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 391.07 (pos. M + H), 389.07 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.49 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 5.1, 8.8 Hz, 1H), 7.01 (dd, J = 3.0, 9.0 Hz, 1H), 6.96 (m, 1H), 6.91 (m, 2H), 6.59 (m, 2H).

E 254 5'-chloro-2''-fluoro-N',4-dihydroxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 371.11 (pos. M + H), 369.13 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.47 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.02 (m, 1H), 6.96 (dd, J = 1.9, 7.0 Hz, 1H), 6.87 (m, 2H), 6.78 (t, J = 8.9 Hz, 1H), 6.57 (m, 2H), 2.20 (s, 3H). 5 E 255 5'-chloro-2''-fluoro-N',4-dihydroxy-4''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 371.13 (pos. M + H), 369.14 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.47 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.88-6.83 (m, 3H), 6.75 (d, J = 10.5 Hz, 1H), 6.57 (m, 2H), 2.27 (s, 3H).

KB 640 / 15887 WO E 256 2-(5-fluoromethoxypyridinyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 5-fluoromethoxypyridinyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 422.14 (pos. M + H), 420.13 (neg. M – H); 1H NMR (CDCl 3, 500MHz): δ 7.89 (d, J = 3.0 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 3.0, 7.9 Hz, 1H), 6.89 (m, 2H), 6.66 (m, 2H), 4.62 (s, broad, 2H) and 3.68 (s, 3H).

E 257 5'-chloro-N',4-dihydroxy-2'',4''-dimethoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,4-dimethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 399.13 (pos. M + H), 397.12 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.42 (s, 2H), 6.87-6.85 (m, 3H), 6.56 (m, 2H), 6.39-6.37 (m, 2H), 3.74 (s, 3H), 3.54 (s, 3H).

E 258 orohydroxy-2'',4''-dimethoxy-[1,1':2',1''-terphenyl]-3'-carbonitrile R1 = 2,4-dimethoxyphenyl R2 = CN R3= Cl R5 = H ES/MS m/z: 366.13 (pos. M + H), 364.16 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.73 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.89 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.60 (m, 2H), 6.50 (d, J = 2.3 Hz, 1H), 6.46 (dd, J = 2.3, 8.4 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 3H).

E 259 5-chloro(5-chloromethoxypyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl] imidamide R1 = 5-chloromethoxypyridinyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 404.07 (pos. M + H), 402.12 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.94 (d, J = 2.6 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 6.86 (m, 2H), 6.61 (m, 2H), 3.65 (s, 3H).

E 260 5-chloro(5-chloromethoxypyridinyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide R1 = 5-chloromethoxypyridinyl R2 = carbamoyl R3= Cl R5 = H ES/MS m/z: 389.05 (pos. M + H), 387.1 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.95 (d, J = 2.6 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 6.86 (m, 2H), 6.63 (m, 2H), 3.69 (s, 3H). 5 KB 640 / 15887 WO E 261 5-chloro(2,5-dimethylpyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = 2,5-dimethylpyridinyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 368.13 (pos. M + H), 366.22 (neg. M – H); 1H NMR (MeOD, ): δ 8.10 (d, J = 1.7 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.49 (q, J = 2.3 Hz, 2H), 6.84 (m, 2H), 6.58 (m, 2H), 2.27 (s, 3H), 2.00 (s, 3H).

E 262 5-chloro(2,5-dimethylpyridinyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide R1 = 2,5-dimethylpyridinyl R2 = carbamoyl R3= Cl R5 = H ES/MS m/z: 353.12 (pos. M + H), 351.14 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.10 (d, J = 1.7 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 6.85 (m, 2H), 6.59 (m, 2H), 2.27 (s, 3H), 2.02 (s, 3H).

E 263 2-(benzo[d][1,3]dioxolyl)chloro-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = benzo[d][1,3]dioxolyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 383.07 (pos. M + H), 381.11 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.47 (s, 2H), 6.90 (m, 2H), 6.72-6.59 (m, 5H), 5.77 (d, J = 1.2 Hz, 1H), 5.40 (d, J = 1.1 Hz, 1H).

E 264 5-chloro-N',4'-dihydroxy(naphthalenyl)-[1,1'-biphenyl]carboximidamide R1 = naphthalenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 389.11 (pos. M + H), 387.17 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.75 (m, 1H), 7.69-7.67 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.46 (m, 2H), 7.40 (m, 2H), 7.17 (dd, J = 1.6, 8.4 Hz, 1H), 6.85 (m, 2H), 6.50 (m, 2H).

E 265 5-chloro-N',4'-dihydroxy(isoquinolinyl)-[1,1'-biphenyl]carboximidamide R1 = isoquinolinyl R2 = oxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 390.09 (pos. M + H), 388.17 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 9.13 (s, 1H), 8.35 (d, 1H), 8.18 (s, 1H), 7.88 (d, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.53 (m, 2H), 7.39 (dd, 1H), 6.85 (dd, 2H), 6.51 (dd, 2H). 5 E 266 5-chloro-N',4'-dihydroxy(quinolinyl)-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO R1 = inyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 390.09 (pos. M + H), 388.17 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.77 (dd, J = 1.6, 4.4 Hz, 1H), 8.21 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.52 (m, 2H), 7.48 (m, 2H), 6.86 (m, 2H), 6.52 (m, 2H).

E 267 5-chloro-N',4'-dihydroxy(1-methyl-1H-benzo[d]imidazolyl)-[1,1'-biphenyl] imidamide R1 = 1-methyl-1H-benzo[d]imidazolyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 393.16 (pos. M + H), 391.07 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.06 (s, 1H), 7.46 (m, 3H), 7.37 (d, J = 8.3 Hz, 1H), 7.10 (dd, J = 1.5, 8.4 Hz, 1H), 6.83 (m, 2H), 6.50 (m, 2H), 3.85 (s, 3H).

E 268 5-chloro-4'-hydroxy(1-methyl-1H-benzo[d]imidazolyl)-[1,1'-biphenyl]carboxamide R1 = 1-methyl-1H-benzo[d]imidazolyl R2 = carbamoyl R3= Cl R5 = H ES/MS m/z: 378.13 (pos. M + H), 376.09 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.07 (s, 1H), 7.45 (m, 3H), 7.38 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 1.5, 8.4 Hz, 1H), 6.83 (m, 2H), 6.50 (m, 2H), 3.85 (s, 3H).

E 269 2-(5-chloromethoxypyridinyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 5-chloromethoxypyridinyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 438.1 (pos. M + H), 436.07 (neg. M – H); 1H NMR (CDCl 3, 500MHz): δ 8.00 (t, J = 1.7 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.68 (d, J = 1.4 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 6.90 (m, 2H), 6.68 (m, 2H), 3.69 (s, 3H).

E 270 2''-fluoro-N',4-dihydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 2-fluoromethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H ES/MS m/z: 405.14 (pos. M + H), 403.12 (neg. M – H); 1H NMR (CDCl 3, 500MHz): δ 7.79 (d, J = 1.3 Hz, 1H), 7.71 (t, J = 0.9 Hz, 1H), 7.02 (m, 1H), 6.95 (m, 2H), 6.83-6.81 (m, 2H), 6.66 (m, 2H), 2.21 (s, 3H). 5 KB 640 / 15887 WO E 271 5-chloro(6-chloromethoxypyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl] carboximidamide R1 = 6-chloromethoxypyridinyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 404.06 (pos. M + H), 402.1 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.45 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 6.85 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 6.61 (m, 2H), 3.65 (s, 3H).

E 272 5-chloro-N',4'-dihydroxy(2-methoxymethylpyridinyl)-[1,1'-biphenyl] carboximidamide R1 = 2-methoxymethylpyridinyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 384.15 (pos. M + H), 382.24 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.77 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.84 (m, 2H), 6.58 (m, 2H), 3.62 (s, 3H), 2.14 (s, 3H).

E 273 5-chloro(cyclopentenyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = cyclopentenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H ES/MS m/z: 329.16 (pos. M + H), 327.23 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.34 (t, J = 1.6 Hz, 2H), 7.14 (m, 2H), 6.77 (m, 2H), 2.32 (m, 2H), 2.10 (m, 2H), 1.73 (m, 2H).

E 274 5-chloro(cyclopentenyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide R1 = cyclopentenyl R2 = carbamoyl R3= Cl R5 = H ES/MS m/z: 314.12 (pos. M + H), 312.22 (neg. M – H); 1H NMR (MeOD, ): δ 7.32 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.15 (m, 2H), 6.77 (m, 2H), 5.71 (t, J = 2.0 Hz, 1H), 2.32 (m, 2H), 2.08 (m, 2H), 1.72 (m, 2H).

E 275 2-(cyclopentenyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = cyclopentenyl R2 = N-hydroxy midoyl R3= CF3 R5 = H ES/MS m/z: 363.17 (pos. M + H), 361.25 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.60 (d, J = 1.2 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.17 (m, 2H), 6.79 (m, 2H), 5.75 (t, J = 2.0 Hz, 1H), 2.34 (m, 2H), 2.15 (m, 2H), 1.75 (m, 2H). 5 KB 640 / 15887 WO E 276 2-(cyclopentenyl)-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carboxamide R1 = entenyl R2 = carbamoyl R3= CF3 R5 = H ES/MS m/z: 348.18 (pos. M + H), 346.21 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.59 (d, J = 1.3 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.18 (m, 2H), 6.80 (m, 2H), 5.78 (m, 1H), 2.35 (m, 2H), 2.12 (m, 2H), 1.75 (m, 2H).

Example 277 mo-5''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide (E277) 5 Scheme 15 Step (a): 5'-chloro-5''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carbonitrile (15.0 mg, 0.04 10 mmol), obtained analogous to example 15 step (a) – (c), and NiBr2 (18.4 mg, 0.08 mmol) were mixed in dry DMF under nitrogen. The reaction e was heated at 170 °C for 25 min in microwave. After cooling to room temperature HCl (1M) was added, the mixture was extracted with EtOAc and DCM and filtered through a phase separator. The solvent was ated under reduced pressure and the crude product was purified on preparative HPLC using MeCN/acidic H2O (20 – 100 % MeCN) as mobile phase. 15 8.0 mg 5'-bromo-5''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carbonitrile was obtained.

Step (b): 5'-bromo-5''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carbonitrile (8.0 mg, 0.02 mmol) and hydroxylamine (0.25 mL, 16 M, aq) were mixed in MeOH (1 mL). The reaction mixture was heated in microwave at 130 °C for 15 min under nitrogen. The crude mixture was purified on preparative 20 HPLC using MeCN/acidic H2O (5 – 50 % MeCN) as mobile phase. 2.0 mg 5'-bromo-5''-fluoro-N',4- dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide (E277) was obtained. ES/MS m/z: 431.16 (M+H), 431.21 (M-H); 1H NMR (Acetone-d6, 500MHz): 7.57 (d, 1H, J=2.3Hz), 7.51 (d, 1H, J=2.3Hz), 6.95-6.90 (m, 3H), 6.81-6.77 (m, 2H), 6.65 (m, 2H) and 3.53 (s, 3H). The title compound was KB 640 / 15887 WO identified by 1H-NMR which showed that the oxime product was a single , but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples 278-283 5 Examples 278 - 283 were prepared using a method analogous to that used to sise Example 277 above. Full experimental details of the individual steps of the general methods are described in Examples 15 and 277 above. For es 278-283 identification of the title compounds by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 10 E 278 5'-bromo-5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-fluoromethylphenyl ES/MS m/z: 417.14 (pos. M + H), 415.17 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.60 (d, 1H, J=2.2Hz), 7.56 (d, 1H, J=2.2Hz), 7.01-6.92 (m, 4H), 6.85 (m, 1H), 6.65 (m, 2H) and 1.83 (s, 3H).

E 279 mo-3''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-fluoromethoxyphenyl ES/MS m/z: 431.18; ; 435.21 (pos. M + H); 1H NMR (Acetone-d6, 500MHz): δ 7.60 (d, 1H, J=2.2Hz), 7.54 (d, 1H, J=2.2Hz), 7.00 (m, 1H), 6.94 (m, 2H), 6.90-6.88 (m, 2H), 6.66 (m, 2H) and 3.58, 3.57 (two s, 3H).

E 280 5'-bromo-N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dimethylphenyl ES/MS m/z: 411.19; 413.17 (pos. M + H), 409.24; 411.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.60 (d, 1H, J=2.3Hz), 7.54 (d, 1H, J=2.3Hz), 6.99 (s, 1H), 6.93-6.87 (m, 4H), 6.62 (m, 2H), 2.20 (s, 3H) and 1.82 (s, 3H).

KB 640 / 15887 WO E 281 5'-bromo-N',4-dihydroxy-5''-methoxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-methoxymethylphenyl ES/MS m/z: ; 429.17 (pos. M + H), ; 427.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.56 (d, 1H, J=2.2Hz), 7.48 (d, 1H, J=2.2Hz), 6.98 (dd, 1H, J=8.5, 2.1Hz), 6.90 (m, 2H), 6.79 (d, 1H, J=2.1Hz), 6.71 (d, 1H, J=8.5Hz), 6.62 (m, 2H), 3.52 (s, 3H) and 2.13 (s, 3H).

E 282 5'-bromo-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-methoxyphenyl ES/MS m/z: 413.15; 415.18 (pos. M + H), ; 413.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.58 (d, 1H, J=2.2Hz), 7.50 (d, 1H, J=2.2Hz), 7.18 (m, 1H), 6.98 (dd, 1H, J=7.6, 1.5Hz), 6.89 (m, 2H), 6.81 (d, 1H, J=7.6Hz), 6.78 (m, 1H), 6.61 (m, 2H) and 3.55 (s, 3H).

E 283 5'-bromo-4''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-fluoromethoxyphenyl ES/MS m/z: 431.14; 433.15 (pos. M + H), 429.25; 431.39 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.57 (d, 1H, J=2.2Hz), 7.50 (d, 1H, J=2.2Hz), 6.99 (dd, 1H, J=8.4, 6.9Hz), 6.89 (m, 2H), 6.66-6.61 (m, 3H), 6.56 (m, 1H) and 3.55 (s, 3H). 5 Example 284 5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide (E284) 10 Scheme 16 KB 640 / 15887 WO Step (a): Methyltriphenylphosphonium bromide (125 mg, 0.35 mmol) and lithium 2-methylpropan olate (25.6 mg, 0.35 mmol) were mixed in THF (4 mL) under N2 at 0 °C.The mixture was stirred for 30 min. uoro-2''-formylhydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carbonitrile (15.0 mg, 0.04 mmol), obtained analogous to example 15 step (a) – (c), was added at 0 °C. The reaction mixture 5 was then heated at 50 °C for 16 h. After cooling to room temperature H2O and HCl (2 M) were added.

The e was extracted with EtOAc and filtered through a phase separator. The solvent was evaporated under reduced pressure and the crude product was purified on silica using MeOH/DCM (1-2 % MeOH) as mobile phase. 4.0 mg 5''-fluorohydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''- nyl]-3'-carbonitrile was obtained. 10 Step (b): uorohydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carbonitrile (4.0 mg, 0.01 mmol) and hydroxylamine (0.15 mL, 16 M, aq) were mixed in DMSO (0.4 mL). The reaction mixture was heated in microwave at 120 °C for 20 min under en. The crude mixture was purified on preparative HPLC using MeCN/acidic H2O (15 – 40% MeCN) as mobile phase. 2.3 mg 5''-fluoro-N',4- 15 dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide (E284) was obtained.

ES/MS m/z: 417.21 (M+H), 415.28 (M-H); 1H NMR (Acetone-d6, 500MHz): 7.56 (d, 1H, J=2.2Hz), 7.48 (d, 1H, J=2.2Hz), 6.98 (dd, 1H, J=8.5, 2.1Hz), 6.90 (m, 2H), 6.79 (d, 1H, J=2.1Hz), 6.71 (d, 1H, J=8.5Hz), 6.62 (m, 2H), 3.52 (s, 3H) and 2.13 (s, 3H). The title compound was identified by 1H-NMR which showed that the oxime t was a single isomer, but did not confirm whether the (E) or (Z) 20 oxime isomer had been obtained.

Examples 285 and 286 Examples 285 and 286 were prepared using a method analogous to that used to synthesise Example 284 25 above. Full experimental details of the individual steps of the general methods are described in Examples 15 and 284 above. For examples 285 and 286 identification of the title compounds by 1H-NMR showed that the oxime t was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained 30 KB 640 / 15887 WO E 285 2,5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-fluorovinylphenyl R5 = F ES/MS m/z: 435.2 (pos. M + H), 433.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.84 (d, 1H, J=1.8Hz), 7.69 (d, 1H, J=1.8Hz), 7.46 (dd, 1H, J=9.4, 5.8Hz), 6.99-6.94 (m, 2H), 6.85 (t, 1H, J=9.2Hz), 6.48-6.44 (m, 2H), 6.32 (dd, 1H, J=17.7, 11.2Hz), 5.44 (dd, 1H, J=17.7, 1.0Hz) and 4.99 (dd, 1H, , .

E 286 5''-chloro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'- imidamide R1 = 5-chlorovinylphenyl R5 = H ES/MS m/z: 433.23 (pos. M + H), 431.28 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.77 (d, 1H, J=1.6Hz), 7.68 (d, 1H, J=1.6Hz), 7.46 (d, 1H, J=8.2Hz), 7.24-7.21 (m, 2H), 6.91 (m, 2H), 6.65 (m, 2H), 6.35 (dd, 1H, J=17.5, 11.0Hz), 5.50 (dd, 1H, J=17.5, 0.8Hz) and 5.03 (dd, 1H, J=11.0, 0.8Hz).

Example 287 2''-ethynyl-5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- 5 imidamide (E287) Scheme 17 10 Step (a): 5''-fluoro-2''-formylhydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carbonitrile (8.0 mg, 0.02 mmol), obtained analogous to example 15 step (a) – (c), and dimethyl (1-diazo oxopropyl)phosphonate (99.7 mg, 0.52 mmol) were mixed in MeOH (1 mL). K2CO3 (66.0 mg, 0.48 mmol) was added and the resulting mixture was stirred for 16 h. NH4Cl (aq) was added, the mixture was 15 extracted with EtOAc and filtered through a phase separator. The solvent was evaporated under reduced KB 640 / 15887 WO pressure and the crude product was purified on preparative HPLC using MeCN/acidic H2O (20 – 80% MeCN) as mobile phase. 5.0 mg 2''-ethynyl-5''-fluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''- terphenyl]-3'-carbonitrile was obtained. 5 Step (b): 2''-ethynyl-5''-fluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carbonitrile (5.0 mg, 0.01 mmol) and hydroxylamine (0.15 mL, 16 M, aq) were mixed in DMSO (0.45 mL). The reaction mixture was heated at 70 °C for 2 h under nitrogen. The crude mixture was purified on ative HPLC using MeCN/acidic H2O (15 – 50% MeCN) as mobile phase. 5.21 mg 2''-ethynyl-5''-fluoro-N',4- dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide (E287) was obtained. ES/MS 10 m/z: 415.23 (M+H), 413.29 (M-H); 1H NMR (Acetone-d6, 500MHz): 7.78 (d, 1H, J=1.6Hz), 7.68 (d, 1H, z), 7.38 (m, 1H), 7.03-6.99 (m, 4H), 6.68 (m, 2H) and 3.44 (s, 1H). The title nd was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been ed. 15 Example 288 4-hydroxy-2''-methoxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide (E288) 20 Scheme 18 Step (a): 4'-hydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]carbonitrile (100 mg, 0.26 mmol), obtained analogous to example 15 step (a) and (b), NaOH (1 M, 5.14 mL) and hydrogen peroxide (12 M, 0.43 mL) were mixed in MeOH (3 mL ). The reaction mixture was stirred at room temperature for 1 h. 25 HCl (1 M) was added and the s mixture was extracted with DCM. The combined organic extracts were evaporated under reduced pressure. 407 mg 4'-hydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]- 3-carboxamide was obtained.

KB 640 / 15887 WO Step (b): 4'-hydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]carboxamide (20 mg, 0.05 mmol), (2- methoxymethylphenyl)boronic acid (16.3 mg, 0.10 mmol), PdCl2(PPh3)2 (3.45 mg, 0.005 mmol) and K2CO3 (20.3 mg, 0.15 mmol) were mixed in DME/EtOH/H2O (1 mL, 4:1:1) under nitrogen. The reaction mixture was heated in microwave at 130 °C for 30 min, cooled to room temperature, filtered through 5 celite and evaporated under reduced pressure. The crude e was purified on preparative HPLC using MeCN/acidic H2O (0 – 20 % MeCN) as mobile phase. 7.6 mg 4-hydroxy-2''-methoxy-5''-methyl-5'- uoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide (E288) was obtained. ES/MS m/z: 402.2 (M+H), 400.4 (M-H); 1H NMR (MeOD, 500MHz): 7.73 (d, 1H, J=1.6Hz), 7.64 (d, 1H, J=1.6Hz), 7.03 (m, 1H), 6.88 (m, 2H), 6.80 (d, 1H, J=2.0Hz), 6.74 (d, 1H, J=8.4Hz), 6.57 (m, 2H), 3.54 (s, 3H) and 2.15 (s, 3H). 10 Example 289 5'-bromo-5''-chloro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide (E289) 15 Scheme 19 Step (a): 5''-chloromethoxy-2''-methyl-5'-nitro-[1,1':2',1''-terphenyl]-3'-carbonitrile (50.0 mg, 0.13 mmol), obtained ous to example 1 step (a), (b), (d) and SnCl2* (H2O)2 (149 mg, 0.66 mmol) were mixed in EtOH (6.6 mL ). The reaction mixture was heated at reflux for 5 h. Silica was added and the 20 solvent was concentrated. The crude mixture was purified on silica using EtOAc/n-heptane (1:1) as mobile phase. 40 mg 5'-amino-5''-chloromethoxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carbonitrile was obtained.

KB 640 / 15887 WO Step (b): 5'-amino-5''-chloromethoxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carbonitrile (48.0 mg, 0.14 mmol) and CuBr2 (61.5 mg, 0.28 mmol) were mixed in MeCN (1.7 mL). t-Butyl nitrite (21.3 mg, 0.21 mmol) was added. The reaction e was stirred at room temperature for 18 h. The solvent was evaporated under reduced re and the crude product was filtered through silica using EtOAc/n- 5 heptane (1:1) as mobile phase 5'-bromo-5''-chloromethoxy-2''-methyl-[1,1':2',1''-terphenyl]-3'- carbonitrile was obtained in quantitative yield.

Step (c): mo-5''-chloromethoxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carbonitrile (56.8 mg, 0.14 mmol) was dissolved in DCM (1.7 mL) under nitrogen. BBr3 (0.69 mL, 1M) was added. The reaction 10 mixture was stirred at room temperature for 18 h. DCM and HCl (1M) were added and the phases were separated using a phase separator. The organic phase was evaporated under reduced pressure. 50 mg 5'- bromo-5''-chlorohydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carbonitrile was ed.

Step (d): 5'-bromo-5''-chlorohydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carbonitrile (50 mg, 0.12 15 mmol) and hydroxylamine (0.4 mL, 16 M, aq) were mixed in MeOH (0.8 mL). The reaction mixture was heated in microwave at 130 °C for 15 min under nitrogen. The crude e was ed on preparative HPLC using MeCN/acidic H2O (5 – 40% MeCN) as mobile phase. 15.8 mg 5'-bromo-5''-chloro-N',4- dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide (E289) was obtained. ES/MS m/z: 433.16; 435.19 (M+H), 431.06 (M-H); 1H NMR (Acetone-d6, 500MHz): 7.61 (d, 1H, J=2.2Hz), 7.56 (d, 20 1H, z), 7.20 (d, 1H, J=2.2Hz), 7.10 (dd, 1H, J=8.3, 2.2Hz), 6.99 (d, 1H, J=8.3Hz), 6.92 (m, 2H), 6.66 (m, 2H) and 1.85 (s, 3H). The title nd was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 25 Examples 290-296 Examples 290 - 296 were prepared using a method analogous to that used to synthesise Example 289 above. Full experimental details of the individual steps of the general methods are described in Examples 1 and 289 above. For examples 290- 296 identification of the title compounds by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been 30 obtained.

KB 640 / 15887 WO E 290 5'-bromo-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl ES/MS m/z: 419.19 (pos. M + H), 419.06 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.59 (d, 1H, J=2.2Hz), 7.57 (d, 1H, J=2.2Hz), 6.94 (m, 2H), 6.83 (m, 1H) and 6.76-6.70 (m, 4H).

E 291 5'-bromo-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3-chlorofluorophenyl ES/MS m/z: 437.15; 439.16 (pos. M + H), 435; 437.10 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.59 (d, 1H, J=2.2Hz), 7.58 (d, 1H, J=2.2Hz), 7.06 (m, 1H), 6.97 (br s, 1H), 6.93 (m, 2H), 6.87 (d, 1H, z) and 6.71 (m, 2H).

E 292 5'-bromo-2''-chloro-5''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-chlorofluorophenyl ES/MS m/z: 437.15; 439.15 (pos. M + H), 435.05; 437.00 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.66 (d, 1H, J=2.1Hz), 7.57 (d, 1H, J=2.1Hz), 7.24 (dd, 1H, J=8.8, 5.2Hz), 7.05 (dd, 1H, J=9.2, 2.9Hz), 7.02-6.95 (m, 3H) and 6.67 (m, 2H). 5 E 293 5'-bromo-4''-chloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 4-chlorophenyl ES/MS m/z: 419.17; 421.14 (pos. M + H), 417.06; 419.17 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.29 (m, 2H), 7.15 (m, 2H9, 7.07 (d, 1H, J=2.5Hz), .98 (m, 3H) and 6.77 (m, 2H).

E 294 5'-bromo-2'',5''-dichloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2,5-dichlorophenyl KB 640 / 15887 WO ES/MS m/z: 453.11 (pos. M + H), 451.04 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.67 (d, 1H, J=2.0Hz), 7.57 (d, 1H, J=2.0Hz), 7.27 (m, 1H), 7.24-7.20 (m, 2H), 6.96 (m, 2H) and 6.68 (m, 2H).

E 295 mo-2''-chloro-N',4-dihydroxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-chloromethylphenyl ES/MS m/z: 433.09 (pos. M + H), 431.17 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.63 (d, 1H, J=2.0Hz), 7.54 (d, 1H, J=2.0Hz), 7.09-7.07 (m, 2H), 7.01 (dd, 1H, J=8.1, , 6.94 (m, 2H), 6.64 (m, 2H) and 2.22 (s, 3H).

E 296 5-bromo(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide R1 = 3,5-dimethylisoxazolyl ES/MS m/z: 402.16; 404.19; 406.18 (pos. M + H), 400.19; 402.19; 404.36 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.61 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 6.97 (m, 2H), 6.76 (m, 2H), 2.04 (s, 1H) and 1.83 (s, 1H).

Examples 297-303 5 Examples 297 - 303 were prepared using a method analogous to that used to synthesise Examples 1 and 50 above. Full experimental details of the individual steps of the general methods are described in Examples 1 and 50 above. For examples 297 and 299-303 identification of the title compounds by 1H-NMR showed that the oxime product was a single isomer, but did not m whether the (E) or (Z) oxime isomer had been obtained. 10 E 297 3-chlorofluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = phenyl R2 = N-hydroxy midoyl R3 = CF3 ES/MS m/z: 425 (pos. M + H), 423.2 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.85 (m, 2H), 7.39-7.35 (m, 3H), 7.24 (m, 2H), 7.00 (t, 1H, J=1.8Hz) and 6.87 (dd, 1H, J=11.3, 2.1Hz).

KB 640 / 15887 WO E 298 3-chlorofluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = phenyl R2 = carbamoyl R3 = CF3 ES/MS m/z: 410.3 (pos. M + H), 408.5 (neg. M – H); 1H NMR (Acetone-d6 3, 500MHz): δ 7.93 (m, 1H), 7.86 (m, 1H), .39 (m, 3H), 7.26-7.24 (m, 2H), 7.01 (t, J = 1.9 Hz, 1H) and 6.87 (dd, J = 2.1, 11.4 Hz, 1H).

E 299 3,5'-dichloro-3'',5,5''-trifluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3 = Cl ES/MS m/z: 427.08 (pos. M + H), 425.17 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.65 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.99 (t, J = 1.8 Hz, 1H), 6.96-6.88 (m, 4H).

E 300 3'-chloro(3,5-dimethylisoxazolyl)-5'-fluoro-N',4'-dihydroxy(trifluoromethyl)-[1,1'- biphenyl]carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy midoyl R3 = CF3 ES/MS m/z: 444.15 (pos. M + H), 442.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.83 (s, 2H), 7.06 (t, J = 1.8 Hz, 1H), 6.95 (dd, J = 2.1, 11.1 Hz, 1H), 2.11 (s, 3H), 1.91 (s, 3H).

E 301 3-chloro-3'',5,5''-trifluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3 = CF3 ES/MS m/z: 461.15 (pos. M + H), 459.16 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.81 (s, 1H), 7.80 (d, J = 0.4 Hz, 1H), 7.03 (t, J = 1.9 Hz, 1H), 6.95-6.90 (m, 2H), 6.89-6.84 (m, 2H).

E 302 3-chloro-5,5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]- 3'-carboximidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3 = CF3 ES/MS m/z: 473.12 (pos. M + H), 471.23 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.79 (s, 1H), 7.74 (s, 1H), 7.03-6.99 (m, 2H), 6.91-6.88 (m, 3H), 3.61 (s, 3H). 5 E 303 3-chlorofluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = oxyphenyl R2 = N-hydroxy carbaimidoyl R3 = CF3 KB 640 / 15887 WO ES/MS m/z: 455.16 (pos. M + H), 453.18 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.79 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.26 (m, 1H), 7.05 (dd, J = 1.7, 7.4 Hz, 1H), 6.96 (t, J = 1.8 Hz, 1H), .83 (m, 3H), 3.63 (s, 3H).

Examples 304-310 Examples 304-310 were prepared using methods analogous to that used to synthesise Examples 1, 15 and 50 above. Full mental details of the individual steps of the general methods are described in 5 Examples 1, 15 and 50 above. For examples 304-308 and 310 fication of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 10 E 304 5'-chloro-3'',5''-difluoro-N'-hydroxymethoxymethyl-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl RA = Me R6 = Me ES/MS m/z: 403.25 (pos. M + H), 401.3 (neg. M – H); 1H NMR (CDCl 3, 500MHz): δ 7.50 (d, 1H, J=2.3Hz), 7.46 (d, 1H, J=2.3Hz), 6.81 (d, 1H, J=1.9Hz), 6.75 (dd, 1H, J=8.4, 2.4Hz), 6.70-6.62 (m, 4H), 3.79 (s, 3H) and 2.11 (s, 3H).

E 305 5'-chloro-3'',5''-difluoro-N',4-dihydroxymethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl RA = H R6 = Me ES/MS m/z: 389.22 (pos. M + H), 387.24 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.43 (s, 2H), 6.88 (d, 1H, J=1.7Hz), 6.83 (m, 1H), .66 (m, 4H) and 2.10 (s, 3H).

E 306 5-chloro(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-3'-methyl-[1,1'-biphenyl] carboximidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl RA = H R6 = Me ES/MS m/z: 372.22 (pos. M + H), 370.27 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.46 (d, KB 640 / 15887 WO 1H, J=2.2Hz), 7.44 (d, 1H, J=2.2Hz), 6.90 (d, 1H, J=1.7Hz), 6.77-6.72 (m, 2H), 2.13 (s, 3H), 2.05 (s, 3H) and 1.83 (s, 3H).

E 307 5'-chloro-N',4-dihydroxy-2'',3-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = o-tolyl R2 = N-hydroxy carbaimidoyl RA = H R6 = Me ES/MS m/z: 367.24 (pos. M + H), 365.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.45 (d, 1H, J=2.3Hz), 7.41 (d, 1H, J=2.3Hz), 7.16 (dd, 1H, J=7.1, 1.4Hz), 7.12-7.05 (m, 2H), 7.00 (m, 1H), 6.83 (d, 1H, z), 6.69 (dd, 1H, J=8.3, 2.3Hz), 6.58 (d, 1H, J=8.3Hz), 2.03 (s, 3H) and 1.87 (s, 3H).

E 308 5'-chloro-5''-fluoro-N',4-dihydroxy-2''-methoxymethyl-[1,1':2',1''-terphenyl]-3'- imidamide R1 = 5-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl RA = H R6 = Me ES/MS m/z: 401.18 (pos. M + H), 399.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.42 (d, 1H, J=2.3Hz), 7.36 (d, 1H, J=2.3Hz), 6.92 (m, 1H), 6.85 (d, 1H, J=1.8Hz), 6.81 (dd, 1H, J=9.0, 4.5Hz), 6.75 (dd, 1H, J=9.0, , 6.71 (dd, 1H, J=8.2, 2.2Hz), 6.61 (d, 1H, z), 3.55 (s, 3H) and 2.07 (s, 3H).

E 309 5'-chloro-5''-fluorohydroxy-2''-methoxymethyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 5-fluoromethoxyphenyl R2 = carbamoyl RA = H R6 = Me ES/MS m/z: 386.21 (pos. M + H), 384.25 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.48 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 6.94 (m, J = 4.1 Hz, 1H), 6.87 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 4.5, 9.1 Hz, 1H), 6.77 (dd, J = 3.2, 9.0 Hz, 1H), 6.72 (dd, J = 2.2, 8.3 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 3.56 (s, 3H), 2.07 (s, 3H).

E 310 5'-chloro-3'',5''-difluoro-N',4-dihydroxyisopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl RA = H R6 = isopropyl ES/MS m/z: 417.21 (pos. M + H), 415.28 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.45 (d, J = 2.3 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 2.3, 8.2 Hz, 1H), 6.83 (m, 1H), 6.78-6.71 (m, 4H), 3.19 (m, 1H), 1.00 (d, J = 7.0 Hz, 6H). 5 Example 311 KB 640 / 15887 WO 2'-(3,5-dimethylisoxazolyl)-3'-(1H-1,2,3-triazolyl)-5'-(trifluoromethyl)-[1,1'-biphenyl]ol (E311) Scheme 20 5 Step (a): 2-iodo(trifluoromethyl)aniline (2.0 g , 6.97 mmol), 4-methoxyphenylboronic acid (2.12 g, 13.9 mmol), PdCl2(PPh3)2 (244 mg, 0.35 mmol) and K2CO3 (3.85 g, 27.8 mmol) were mixed in DME/EtOH/H2O (24 mL, 4:1:1) under nitrogen. The reaction mixture was heated at 100 °C for 1 h and then d at room temperature for 66 h. The mixture was washed with brine (sat, 30 mL) and H2O (30 10 mL). The aqueous layers were extracted with DCM (30 ml) and the combined organinc layers were passed through a phase separator. The solvent was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (0 - 20 % EtOAc) as mobile phase. 1.38 g 4'- methoxy(trifluoromethyl)-[1,1'-biphenyl]amine was ed as red oil. 15 Step (b): 4'-methoxy(trifluoromethyl)-[1,1'-biphenyl]amine (1.38 g, 5.14 mmol) was dissolved in MeOH (40 mL). Iodine (1.37 g, 5.40 mmol) and AgSO4 (1.68 g, 5.40 mmol) were added. The reaction mixture was stirred at room temperature for 45 min and was then ed through celite. The solvent was KB 640 / 15887 WO concentrated under reduced pressure. DCM (50 mL), H2O (20 mL) and NaHCO3 (1.4 g) were added to the residue and the resulting mixture was stirred for 16 h. The e was filtered through a phase separator. The organic layer was evaporated under reduced pressure and the crude product was purified on silica using EtOAc/n-heptane (2.5-5 % EtOAc) as mobile phase. 1.63 g -4'-methoxy 5 (trifluoromethyl)-[1,1'-biphenyl]amine was obtained asyellowish oil.

Step (c): 3-iodo-4'-methoxy(trifluoromethyl)-[1,1'-biphenyl]amine (1.63 g, 4.14 mmol) and CuBr2 (1.85 g, 8.28 mmol) were mixed in MeCN (50 mL). t-Butyl e (0.64 g, 6.21 mmol) was added. The reaction mixture was stirred at room temperature for 40 min. The solvent was evaporated under reduced 10 pressure and the crude product was ed on silica using EtOAc/n-heptane (0-5 % EtOAc) as mobile phase. 1.66 g 2'-bromo-3'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]ol was obtained as a white solid.

Step (d): mo-3'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]ol was obtained (1.66 g, 3.65 mmol) was dissolved in DCM (30 mL) under nitrogen and the solution was cooled to 0 °C . BBr3 (18.2 mL, 1M) 15 was added drop wise at 0 °C. After 10 min the cooling bath was removed and the reaction mixture was stirred for 1h and 45 min. NaHCO3 (sat) was added and the e was stirred for 2 min. The mixture was filtered through a phase separator and the aqueous layer was extracted with DCM. The combined organic layers were evaporated and the crude product was purified on silica using DCMc/n-heptane (0-75 % DCM) as mobile phase. 1.48 g mo-3'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]ol was obtained 20 as white solid.

Step (e): 2'-bromo-3'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]ol (200 mg , 0.45 mmol), ethynyltrimethylsilane (66.5 mg, 0.68 mmol), CuI (8.60 mg, 0.045 mmol), PdCl2(PPh3)2 (15.84 mg, 0.02 mmol) and Et3N (0.188 mL, 1.35 mmol) were mixed in THF (1.5 mL). The reaction mixture was stirred 25 at room temperature for 5h. The solvent was ated and the crude mixture was purified on silica using DCMc/n-heptane (0-50 % DCM) as mobile phase. 136 mg 2'-bromo-5'-(trifluoromethyl)-3'- ((trimethylsilyl)ethynyl)-[1,1'-biphenyl]ol was obtained as ess oil.

Step (f): 2'-bromo-5'-(trifluoromethyl)-3'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]ol (136 mg, 0.33 30 mmol), 3,5-dimethylisoxazoleboronic acid (185 mg, 1.32 mmol), Pd(OAc)2 (7.39 mg, 0.03 mmol), RuPhos (30.71 mg, 0.07 mmol) and K2CO3 (273 mg, 1.97mmol) were mixed in e /water (0.8 mL, 1:1) under nitrogen. The reaction mixture was heated in microwave at 120 °C for 30 min and cooled to room temperature. NH4Cl (2 mL, sat) was added and the aqueous mixture was extracted with DCM. The combined extracts were evaporated under reduced pressure and the crude product was purified on silica KB 640 / 15887 WO using DCM/n-heptane (50-100 % DCM) as mobile phase. 82 mg 2'-(3,5-dimethylisoxazolyl)-5'- (trifluoromethyl)-3'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]ol was ed as yellow oil.

Step (g): 2'-(3,5-dimethylisoxazolyl)-5'-(trifluoromethyl)-3'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]- 5 4-ol (82 mg, 0.19 mmol) was dissolved in THF (1 mL) and Bu3NF (250 mg, 0.95 mmol) was added. The reaction e was stirred at room temperature. After 1 h additional Bu3NF (250 mg, 0.95 mmol) was added and the stirring continued for 1 h. The solvent was ated under reduced pressure and the crude product was purified on silica using heptane (0-100 % DCM) as mobile phase. 47 mg 2'- (3,5-dimethylisoxazolyl)-3'-ethynyl-5'-(trifluoromethyl)-[1,1'-biphenyl]ol was obtained as a red 10 semi solid.

Step (h): 2'-(3,5-dimethylisoxazolyl)-3'-ethynyl-5'-(trifluoromethyl)-[1,1'-biphenyl]ol (37 mg, 0.10 mmol), CuI (19.7 mg, 0.10 mmol) and N3SiMe3 (59.6 mg, 0.52 mmol) were mixed in DMF/MeOH (0.5 mL, 9:1). The reaction mixture was heated in microwave at 140 °C for 30 min under nitrogen. EtOAc was 15 added and the e was filtered through celite. The solvent was evaporated under reduced pressure and the crude mixture, ved in DMSO, was purified on preparative HPLC using MeCN/acidic H2O (20 – 100% MeCN) as mobile phase. 2.9 mg 2'-(3,5-dimethylisoxazolyl)-3'-(1H-1,2,3-triazolyl)-5'- uoromethyl)-[1,1'-biphenyl]ol (E311) was obtained. ES/MS m/z: 401.25 (M+H), 399.3 (M-H); 1H NMR (Acetone-d6, ): 7.73 (s, 1H), 7.28 (s, 1H), 7.06 (m, 2H), 6.82 (m, 2H), 1.91 (s, 3H), 1.72 20 (s, 3H).

Examples 312-321 Examples 312-321 were prepared using methods analogous to that used to synthesise Example 1 above.

Full experimental details of the individual steps of the general methods are described in Example 1. 25 Intermediate C was used to synthesise examples 312-316. The intermediate used to synthesise examples 318-321 was obtained by an analogous method. For examples 312-314, and 317-319, identification of the title compounds by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 30 E 312 N',4-dihydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = phenyl R2 = N-hydroxy carbaimidoyl R3 = romethoxy ES/MS m/z: 389.6 (pos. M + H), 387.4 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.36 (s, 1H), 7.20- 7.17 (m, 3H), 7.13-7.11 (m, 2H), 6.84 (m, 2H), 6.56 (m, 2H).

E 313 3'',5''-difluoro-N',4-dihydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3 = trifluromethoxy ES/MS m/z: 425.3 (pos. M + H), 423.5 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.35 (d, J = 1.7 Hz, 2H), 6.88 (m, 2H), .70 (m, 3H), 6.64 (m, 2H).

E 314 5''-chloro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'- carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3 = trifluromethoxy ES/MS m/z: 453.5 (pos. M + H), 451.4 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.36 (s, 1H), 7.33 (s, 1H), 7.19 (dd, J = 2.6, 8.8 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.9 Hz, 1H), 6.59 (d, J = 8.5 Hz, 2H), 3.56 (s, 3H).

E 315 4-hydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = phenyl R2 = carbamoyl R3 = trifluromethoxy ES/MS m/z: 374.3 (pos. M + H), 372.1 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.34 (m, 1H), 7.31 (m, 1H), 7.21-7.19 (m, 3H), 7.12-7.10 (m, 2H), 6.84 (m, 2H), 6.57 (m, 2H).

E 316 3'',5''-difluorohydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = 3,5-difluorophenyl R2 = carbamoyl R3 = trifluromethoxy ES/MS m/z: 410.6 (pos. M + H), 408.5 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.37 (t, J = 1.2 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 6.89 (m, 2H), 6.80 (m, 1H), 6.71 (m, 2H), 6.66 (m, 2H). 5 E 317 N',4-dihydroxy-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO R1 = phenyl R2 = N-hydroxy carbaimidoyl R3 = isopropyl ES/MS m/z: 347.3 (pos. M + H), 345.1 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.33-7.31 (m, 2H), 7.17-7.15 (m, 3H), 7.11-7.09 (m, 2H), 6.82 (m, 2H), 6.54 (m, 2H), 3.01 (m, 1H), 1.32 (d, J = 7.0 Hz, 6H).

E 318 3'',5''-difluoro-N',4-dihydroxy-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = oxy carbaimidoyl R3 = isopropyl ES/MS m/z: 383.3 (pos. M + H), 381.4 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.32 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 6.85 (m, 2H), 6.73-6.69 (m, 3H), 6.62 (m, 2H), 3.00 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H).

E 319 5''-chloro-N',4-dihydroxy-5'-isopropyl-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3 = isopropyl ES/MS m/z: 411.5 (pos. M + H), 409.7 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.32 (s, 2H), 7.16 (dd, J = 2.6, 8.8 Hz, 1H), 6.97 (d, J = 2.7 Hz, 1H), 6.85 (m, 2H), 6.80 (d, J = 8.9 Hz, 1H), 6.57 (m, 2H), 3.57 (s, 3H), 3.01 (m, J = 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H).

E 320 o-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboxamide R1 = phenyl R2 = carbamoyl R3 = isopropyl ES/MS m/z: 332.3 (pos. M + H), 330.4 (neg. M – H). 5 E 321 3'',5''-difluoro-N',4-dihydroxy-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 3,5-difluorophenyl R2 = oyl R3 = isopropyl ES/MS m/z: 368.3 (pos. M + H), 366.1 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.35 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 6.86 (m, 2H), 6.74 (m, 1H), 6.70-6.66 (m, 2H), 6.63 (m, 2H), 3.01 (m, 1H), 1.32 (d, J = 7.0 Hz, 6H).

Example 322 2-(3-cyanofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide (E322) KB 640 / 15887 WO Scheme 21 5 Step (a): 4'-hydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]carbonitrile (250 mg, 0.64 mmol), ed analogous to example 15 and hydroxylamine (1.0 mL, 16 M, aq) were mixed in MeOH (3.0 mL). The reaction mixture was heated in microwave at 120 °C for 20 min under nitrogen. HCl (1M) and DCM were added. The phases were separated and the organic phase was evaporated under reduced pressure. 140 mg N',4'-dihydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]carboximidamide was 10 obtained.

Step (b): N',4'-dihydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]carboximidamide (140 mg, 0.33 mmol) was dissolved in AcOH (5 mL) and acetone (1.18 mL, 16.06 mmol) was added. The reaction e was heated at 70 °C for 20 h and then concentrated to dryness. DCM and NaOH (0.5M) were 15 added. The phases were separated and the organic phase was evaporated under reduced pressure. The crude product was purified on silica using EtOAc/n-heptane (10-50 % EtOAc) as mobile phase. 117 mg 3'-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-2'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]ol was obtained as a white solid. 20 Step (c): 3'-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-2'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]- 4-ol (10.0 mg , 0.02 mmol), butylstannyl)furancarbonitrile (16.5 mg, 0.04 mmol), Pd(OAc)2 (0.49 KB 640 / 15887 WO mg, 0.002 mmol), tri(furanyl)phosphine (0.93 mg, 0.004mmol) and CuI (0.41 mg, 0.004 mmol) were mixed in THF (0.5 mL). The reaction mixture was heated in microwave at 100 °C for 30 min under nitrogen. The crude mixture was ed on preparative HPLC using MeCN/acidic H2O (35 – 45% MeCN) as mobile phase. 3.0 mg 2-(3-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-4'-hydroxy 5 (trifluoromethyl)-[1,1'-biphenyl]yl)furancarbonitrile was obtained as a white solid.

Step (d): 5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-4'-hydroxy(trifluoromethyl)-[1,1'- biphenyl]yl)furancarbonitrile (3.0 mg, 0.01 mmol) was ved in EtOH (0.5 mL) and HCl (conc, 0.05 mL) was added. The reaction mixture was stirred at room temperature for 4 h. DCM/EtOAc and 10 NH4Cl (sat) were added. The phases were separated and the organic phase was evaporated under reduced pressure. The crude product was purified on preparative HPLC using MeCN/acidic H2O (20 – 100% MeCN) as mobile phase. 2.0 mg 2-(3-cyanofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'- biphenyl]carboximidamide (E322) was obtained as a colorless oil. ES/MS m/z: 388.4 (M+H), 386.2 (M-H); 1H NMR (Acetone-d6, 500MHz): 7.92 (d, J = 1.3 Hz, 1H), 7.82 (d, J = 1.1 Hz, 1H), 7.69 (d, J = 15 2.0 Hz, 1H), 7.02 (m, 2H), 6.80 (m, 2H), 6.68 (d, J = 2.1 Hz, 1H). The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Examples 323-325 20 es 323 - 325 were prepared using a method analogous to that used to synthesise Examples 15 and 322 above. Full experimental details of the individual steps of the general methods are described in es 15 and 289 above. For es 323-325 fication of the title compounds by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 25 E 323 2-(3-cyanofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide R1 = 3-cyanofuranyl ES/MS m/z: 402.5 (pos. M + H), 400.3 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.00 (d, J = 1.2 Hz, 1H), 7.82 (m, 1H), 7.71 (s, 1H), 7.02 (m, 2H), 6.79 (m, 2H), 3.47 (s, 3H).

KB 640 / 15887 WO E 324 2''-cyano-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide R1 = 2-cyanophenyl ES/MS m/z: 398.3 (pos. M + H), 396.4 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.84 (d, J = 1.3 Hz, 1H), 7.73 (t, J = 0.9 Hz, 1H), 7.58 (m, 1H), 7.54 (dd, J = 0.8, 7.8 Hz, 1H), 7.49 (dd, J = 0.6, 7.9 Hz, 1H), 7.40 (m, 1H), 6.95 (m, 2H), 6.67 (m, 2H).

E 325 2-(3-cyanomethyl-1H-pyrrolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] imidamide R1 = 3-cyanomethyl-1H-pyrrolyl ES/MS m/z: 401.3 (pos. M + H), 399.1 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.35 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 6.86 (m, 2H), 6.74 (m, 1H), 6.70-6.66 (m, 2H), 6.63 (m, 2H), 3.01 (m, 1H), 1.32 (d, J = 7.0 Hz, 6H). 5 Example 326 2'-(3,5-dimethylisoxazolyl)-3'-(hydroxymethyl)-5'-(trifluoromethyl)-[1,1'-biphenyl]ol (E326) Scheme 22 10 KB 640 / 15887 WO Step (a): 2-(3,5-dimethylisoxazolyl)-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carbonitrile (250 mg, 0.64 mmol) obtained analogous to example 15, was dissolved in DCM (6 mL) and the solution was cooled to -78 °C. DIBAL-H (4.19 mL, 1 M) was added drop wise. The reaction mixture was stirred at -78 °C for 1.5 h. HCl (5 mL, 2 M) was added at -78 °C and the mixture was allowed to attain room 5 temperature. Water was added and the aqueous mixture was extracted with DCM. The combined organic extracts were dried with brine and over Na2SO4. The solvent was evaporated and the crude product was filtered through silica using EtOAc as mobile phase. 147 mg 2-(3,5-dimethylisoxazolyl)-4'-hydroxy (trifluoromethyl)-[1,1'-biphenyl]carbaldehyde was obtained as yellow glassy solid . 10 Step (b): 2-(3,5-dimethylisoxazolyl)-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carbaldehyde (147 mg, 0.41 mmol) and TBDMSCl (91.7 mg, 0.61 mmol) were mixed in DCM (2.5 mL). Et3N (0.17 mL, 1.22 mmol) was added and the reaction mixture was stirred at room temperature for 16 h.The solvent was concentrated and the crude product was purified on silica using EtOAc/n-heptane (5 - 20 % EtOAc) as mobile phase. 162 mg ert-butyldimethylsilyl)oxy)(3,5-dimethylisoxazolyl) 15 (trifluoromethyl)-[1,1'-biphenyl]carbaldehyde was obtained as yellow glassy solid.

Step (c): Anhydrous ZnCl2 (18.5 mg, 0.14 mmol), was dried at 100 °C for 16 h and was then cooled to room temperature. Dry THF (3.5 mL) ed by (trimethylsilyl)methyl magnesium chloride (40 mg, 0.27 mmol) were added. The resulting mixture was stirred for 15 min at room temperature. 20 Isopropylmagnesium chloride lithium chloride (123 mg, 0.85 mmol) was added. The mixture was stirred for 45 min at room ature and then cooled to 0 °C. ert-butyldimethylsilyl)oxy)(3,5- dimethylisoxazolyl)(trifluoromethyl)-[1,1'-biphenyl]carbaldehyde (162 mg, 0.34 mmol) dissolved in THF (2.5 mL) was added drop wise at 0 °C and the on mixture was stirred at 0 °C for 1.5 h. NH4Cl (sat) was added and the s mixture was extracted with EtOAc. The combined ts 25 were dried with brine and over Na2SO4. The solvent was evaporated and the crude product was purified on silica using EtOAc/n-heptane (10 - 30 % EtOAc) as mobile phase. 33 mg (4'-((tertbutyldimethylsilyl )oxy)(3,5-dimethylisoxazolyl)(trifluoromethyl)-[1,1'-biphenyl]yl)methanol was obtained. 30 Step (d): (4'-((tert-butyldimethylsilyl)oxy)(3,5-dimethylisoxazolyl)(trifluoromethyl)-[1,1'- yl]yl)methanol (33 mg, 0.07 mmol) was dissolved in THF (2 mL) and HCl (1 mL, 2 M) was added. The reaction mixture was d at room temperature for 20 h. NaHCO3 (1 M) was added and the solvent was evaporated. The remaining aqeuos e was extracted with EtOAc and the combined extracts were dried with brine and over Na2SO4. The solvent was concentrated under reduced pressure and 35 the crude product was purified on silica using EtOAc/n-heptane (30 - 50 % EtOAc) as mobile phase. 8.7 KB 640 / 15887 WO mg 5-dimethylisoxazolyl)-3'-(hydroxymethyl)-5'-(trifluoromethyl)-[1,1'-biphenyl]ol (E326) was obtained as a white solid. ES/MS m/z: 364.4 (M+H), 362.5 (M-H); 1H NMR (CDCl3, 500MHz): δ 7.89 (s, 1H), 7.62 (s, 1H), 6.90 (m, 2H), 6.73 (m, 2H), 4.51 (s, 2H), 2.04 (s, 3H), 1.92 (s, 3H).The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did 5 not confirm r the (E) or (Z) oxime isomer had been obtained.

Example 327 5'-cyano-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide (E327) 10 Scheme 23 Step (a): 5'-chloro-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide (57 mg, 0.15 mmol) obtained analogous to example 15, was dissolved in e (15 mL) and TFA (0.3 mL) was 15 added. The reaction mixture was heated at 80 °C for 110 min and then evaporated to dryness. The crude product was purified on silica using EtOAc/n-heptane (10-50 % EtOAc) as mobile phase. 63 mg 5'- chloro-3'-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-3'',5''-difluoro-[1,1':2',1''-terphenyl]ol was obtained as glassy solid. 20 Step (b): 5'-chloro-3'-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-3'',5''-difluoro-[1,1':2',1''- terphenyl]ol (15.0 mg, 0.04 mmol), SPhos (1.47 mg, 0.004 mmol), Pd2(dba)3 (1.65 mg, 0.002 mmol) and Zn(CN)2 (3.87 mg, 0.041 mmol) were mixed in DMF/H2O (1.5 mL, 99:1) under nitrogen. The reaction mixture was heated in microvawe at 150 °C for 60 min. EtOAc was added and the e was filtered through celite. The solvent was evaporated and the crude product was purified on silica using KB 640 / 15887 WO EtOAc/n-heptane (20 - 40 % EtOAc) as mobile phase. 12.6 mg 6'-(5,5-dimethyl-4,5-dihydro-1,2,4- oxadiazolyl)-3,5-difluoro-4''-hydroxy-[1,1':2',1''-terphenyl]-4'-carbonitrile was obtained as glassy solid.

Step (c): 6'-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazolyl)-3,5-difluoro-4''-hydroxy-[1,1':2',1''- 5 terphenyl]-4'-carbonitrile (12.6 mg, 0.03 mmol) was dissolved in EtOH (1 mL) and HCl (0.1 mL, conc) was added. The reaction mixture was stirred at room temperature for 4 h. NaHCO3 (sat) was added and the mixture was filtered. The solvent was evaporated under reduced pressure and the crude product was purified on preparative HPLC using MeCN/ H2O (10 – 50 % MeCN) as mobile phase. 8.9 mg 5'-cyano- '-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide (E327) was ed as a white 10 solid. ES/MS m/z: 366.2 (M+H), 364.3 (M-H); 1H NMR (MeOD, ): δ 7.79 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 6.89 (m, 2H), 6.79 (m, 1H), 6.72 (m, 2H), 6.65 (m, 2H). The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not m whether the (E) or (Z) oxime isomer had been obtained. 15 Example 328 N',4'-dihydroxy(pyrrolidinyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide (E328) Scheme 24 20 Step (a): 2-bromo-4'-methoxy(trifluoromethyl)-[1,1'-biphenyl]carbonitrile (40.0 mg, 0.11 mmol) obtained analogous to example 1, pyrrolidine (15.98 mg, 0.22 mmol), Pd(OAc)2 (2.52 mg, 0.01 mmol), BINAP (17.48 mg, 0.03 mmol) and KOtBu (12.6 mg, 0.11 mmol) were mixed in toluene (1 mL) under nitrogen. The reaction mixture was heated at 100 °C for 16.5 h. Water (15 mL) and DCM (20 mL) was 25 added. The layers were separated and the aqueous layer was ted with DCM (5 mL). The combined organic layers were evaporated and the crude product was purified on silica using EtOAc/n-heptane (0 - 10 % EtOAc) as mobile phase. 24 mg 4'-methoxy(pyrrolidinyl)(trifluoromethyl)-[1,1'-biphenyl]- 3-carbonitrile was obtained as brown oil.

KB 640 / 15887 WO Step (b): 4'-methoxy(pyrrolidinyl)(trifluoromethyl)-[1,1'-biphenyl]carbonitrile (20.0 mg, 0.06 mmol) was dissolved in DCM (1 mL) under nitrogen. BBr3 (0.12 mL, 1M) was added. The reaction mixture was stirred at room temperature for 3 h. A few drops MeOH, water and HCl (1M) were added and the phases were partitioned. The aqueous layer was extracted with DCM and the combined organic 5 layers were concentrated under reduced pressure. The crude product was purified on silica using EtOAc/n-heptane (10 - 20 % EtOAc) as mobile phase. roxy(pyrrolidinyl)(trifluoromethyl)- [1,1'-biphenyl]carbonitrile was obtained in quantitative yield.

Step (c): roxy(pyrrolidinyl)(trifluoromethyl)-[1,1'-biphenyl]carbonitrile (6.0 mg, 0.02 10 mmol) and hydroxylamine (0.06 mL, 16 M, aq) were mixed in DMF (0.5 mL). The reaction mixture was heated in microwave at 100 °C for 30 min under nitrogen. H2O was added, the mixture was extracted with DCM and the combined organic layers were evaporated. The crude product was purified on preparative HPLC using MeCN/acidic H2O (10 – 50% MeCN) as mobile phase. The cation was repeated using MeCN/ H2O (15 – 50% MeCN) as mobile phase. 0.5 mg N',4'-dihydroxy(pyrrolidin 15 yl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide (E328) was obtained. ES/MS m/z: 366.23 (M+H), 364.27 (M-H); 1H NMR (MeOD, 500MHz): δ 7.39 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.15 (m, 2H), 6.82 (m, 2H), 3.03 (m, 4H), 1.69 (m, 4H). The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. 20 Examples 329-360 es 329 - 360 were ed using methods analogous to that used to synthesise Examples 1, 50 and example 288 step a above. Full experimental details of the individual steps of the general methods are described in Examples 1, 50 and 288 above. For examples 329-331,335-343 and 345-360 identification of 25 the title compounds by 1H-NMR showed that the oxime product was a single , but did not confirm r the (E) or (Z) oxime isomer had been obtained.

E 329 4-chloro-3',5'-difluoro-N'-hydroxy(1H-indazolyl)-[1,1'-biphenyl]carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H KB 640 / 15887 WO R6 = C R7 = N X = N ES/MS m/z: 399.18 (pos. M + H), 397.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.00 (d, 1H, J=1.0Hz), 7.61 (m, 1H), 7.53 (d, 1H, J=2.2Hz), 7.50 (d, 1H, J=2.2Hz), 7.42 (m, 1H), 7.05 (dd, 1H, J=8.5, 1.5Hz) and .74 (m, 3H).

E 330 6-(1H-benzo[d]imidazolyl)chloro-3',5'-difluoro-N'-hydroxy-[1,1'-biphenyl] imidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Cl R5 = H R6 = N R7 = N X = C ES/MS m/z: 399.19 (pos. M + H), 397.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.13 (s, 1H), 7.52 (m, 1H), 7.49 (d, 1H, J=2.2Hz), 7.46 (br s, 1H), 7.39 (br s, 1H), 6.94 (dd, 1H, J=8.5, 1.6Hz) and 6.79-6.74 (m, 3H).

E 331 4-chloro-3',5'-difluoro(1H-indolyl)-[1,1'-biphenyl]carboxamide R1 = 3,5-difluorophenyl R2 = N-hydroxy midoyl R3= Cl R5 = H R6 = C R7 = N X = C ES/MS m/z: 398.18 (pos. M + H), 396.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.50 (d, 1H, J=2.4Hz), 7.46 (d, 1H, J=2.4Hz), 7.39 (s, 1H), 7.32 (t, 1H, z), 7.26 (d, 1H, J=8.2Hz), 6.80- 6.73 (m, 4H) and 6.41 (m, 1H).

E 332 4-chloro-3',5'-difluoro(1H-indolyl)-[1,1'-biphenyl]carboxamide R1 = 3,5-difluorophenyl R2 = carbamoyl R3= Cl R5 = H R6 = C R7 = N X = C ES/MS m/z: 383.21 (pos. M + H), 381.21 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.51 (d, 1H, J=2.1Hz), 7.50 (d, 1H, J=2.1Hz), 7.40 (m, 1H), 7.32 (m, 1H), 7.27 (d, 1H, J=8.5Hz), 6.82-6.76 (m, 4H) and 6.42 (m, 1H).

E 333 4-chloro-3',5'-difluoro(1H-indazolyl)-[1,1'-biphenyl]carboxamide R1 = 3,5-difluorophenyl R2 = carbamoyl R3= Cl R5 = H R6 = C R7 = N X = N ES/MS m/z: 384.22 (pos. M + H), 382.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.00 (d, 1H, J=0.8Hz), 7.63 (m, 1H), 7.55 (m, 2H), 7.43 (m, 1H), 7.07 (dd, 1H, J=8.6, 1.7Hz) and 6.83-6.76 (m, KB 640 / 15887 WO 3H).

E 334 6-(1H-benzo[d]imidazolyl)chloro-3',5'-difluoro-[1,1'-biphenyl]carboxamide R1 = fluorophenyl R2 = carbamoyl R3= Cl R5 = H R6 = N R7 = C X = N ES/MS m/z: 384.2 (pos. M + H), 382.2 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.15 (s, 1H), 7.56 (d, 1H, J=2.2hz), 7.54 (d, 1H, J=2.2Hz), 7.48 (br s, 1H), 7.34 (br s, 1H), 7.01 (dd, 1H, J=8.2, 1.4Hz) and 6.76-6.69 (m, 3H).

E 335 difluoro-N'-hydroxy(1H-indolyl)methyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H R6 = C R7 = N X = C ES/MS m/z: 378.24 (pos. M + H), 376.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.35 (s, 1H), 7.31 (s, 1H), 7.29 (t, J = 2.7 Hz, 2H), 7.27 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.75-6.71 (m, 4H), 6.39 (t, J = 2.0 Hz, 1H), 2.44 (s, 3H).

E 336 3',5'-difluoro-N'-hydroxy(1H-indolyl)methyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H R6 = N R7 = C X = C ES/MS m/z: 378.24 (pos. M + H), 376.24 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.39 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.28 (m, 2H), 7.15 (s, 1H), 6.74-6.69 (m, 4H), 6.39 (m, 1H), 2.43 (s, 3H).

E 337 3',5'-difluoro-N'-hydroxy(1H-indazolyl)methyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= Me R5 = H R6 = C R7 = N X = N ES/MS m/z: 379.23 (pos. M + H), 377.26 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.97 (s, 1H), 7.56 (t, J = 0.7 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 7.32 (s, 1H), 7.02 (dd, J = 1.6, 8.6 Hz, 1H), 6.75-6.70 (m, 3H), 2.45 (s, 3H). 5 E 338 3',5'-difluoro-N'-hydroxy(1H-indazolyl)propyl-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= propyl R5 = H R6 = C R7 = N X = N ES/MS m/z: 407.2 (pos. M + H), 405.27 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.97 (d, J = 0.9 Hz, 1H), 7.57 (d, J = 0.5 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 1.6, 8.6 Hz, 1H), 6.76-6.70 (m, 3H), 2.71 (t, J = 7.7 Hz, 2H), 1.74 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H).

E 339 3',5'-difluoro-N'-hydroxy(1H-indolyl)propyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= propyl R5 = H R6 = C R7 = N X = C ES/MS m/z: 406.22 (pos. M + H), 404.35 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.36 (t, J = 0.8 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.29 (q, J = 1.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 6.78-6.68 (m, 4H), 6.39 (m, 1H), 2.70 (t, J = 7.7 Hz, 2H), 1.74 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

E 340 3',5'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 433.15 (pos. M + H), 431.22 (neg. M – H); 1H NMR (Acetone-d6, ): δ 8.01 (d, J = 0.9 Hz, 1H), 7.82 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.66 (q, J = 0.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.08 (dd, J = 1.6, 8.7 Hz, 1H), 6.84-6.79 (m, 3H).

E 341 3',5'-difluoro-N'-hydroxy(1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = N R7 = C X = C ES/MS m/z: 432.17 (pos. M + H), 430.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.78 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 2.8 Hz, 1H), 7.25 (d, J = 0.6 Hz, 1H), 6.83-6.77 (m, 4H), 6.43 (m, 1H).

E 342 3',5'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-difluorophenyl R2 = oxy carbaimidoyl R3= CF3 R5 = H KB 640 / 15887 WO R6 = N R7 = C X = N ES/MS m/z: 433.16 (pos. M + H), 431.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.01 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.42 (s, 1H), 6.90 (dd, J = 1.4, 8.3 Hz, 1H), 6.85-6.79 (m, 3H).

E 343 3',5'-difluoro-N'-hydroxy(1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = C ES/MS m/z: 432.16 (pos. M + H), 430.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.78 (d, J = 1.3 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.43 (t, J = 0.8 Hz, 1H), 7.33 (t, J = 2.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.83-6.77 (m, 4H), 6.43 (m, 1H).

E 344 3',5'-difluoro(1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl]carboxamide R1 = 3,5-difluorophenyl R2 = carbamoyl R3= CF3 R5 = H R6 = C R7 = N X = C ES/MS m/z: 417.14 (pos. M + H), 415.23 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.79 (d, J = 0.4 Hz, 2H), 7.45 (t, J = 0.8 Hz, 1H), 7.34 (t, J = 2.8 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), .81 (m, 4H), 6.43 (m, 1H).

E 345 3',5'-difluoro-N'-hydroxy(1H-indazolyl)propyl-[1,1'-biphenyl]carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= propyl R5 = H R6 = N R7 = C X = N ES/MS m/z: 407.3 (pos. M + H), 405.4 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 7.70 (d, J = 0.9 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 7.1, 8.4 Hz, 1H), 6.76 (dd, J = 0.5, 7.2 Hz, 1H), 6.73 (m, 2H), 6.66 (m, 1H), 2.74 (t, J = 7.7 Hz, 2H), 1.75 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H).

E 346 N'-hydroxy(1H-indazolyl)-2'-methoxy-5'-methyl(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 2-methoxymethylphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N KB 640 / 15887 WO ES/MS m/z: 441.5 (pos. M + H), 439.4 (neg. M – H); 1H NMR (CD 3CN, 500MHz): δ 7.89 (d, J = 0.9 Hz, 1H), 7.50 (d, J = 0.8 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.10 (dd, J = 1.6, 8.6 Hz, 1H), 6.97 (m, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 3.53 (s, 3H), 2.09 (s, 3H).

E 347 5'-chloro-N'-hydroxy(1H-indolyl)-2'-methoxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy midoyl R3= CF3 R5 = H R6 = C R7 = N X = C ES/MS m/z: 460.17 (pos. M + H), 458.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 7.74 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 0.6 Hz, 1H), 7.30 (t, J = 2.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 2.7, 8.8 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.86 (dd, J = 1.6, 8.4 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 3.56 (s, 3H).

E 348 5'-chloro-N'-hydroxy(1H-indazolyl)-2'-methoxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 5-chloromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 461.15 (pos. M + H), 459.22 (neg. M – H); 1H NMR (Acetone-d6, 500MHz): δ 8.00 (d, J = 0.9 Hz, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.63 (s, 1H), 7.43 (m, 1H), 7.13 (dd, J = 1.6, 8.6 Hz, 1H), 7.08 (m, 1H), 6.97 (m, 1H), 6.87 (m, 1H).

E 349 2',5'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 2,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 433.1 (pos. M + H), 431.12 (neg. M – H); 1H NMR ne-d6, 500MHz): δ 8.00 (d, J = 0.9 Hz, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.63 (s, 1H), 7.43 (m, 1H), 7.13 (dd, J = 1.6, 8.6 Hz, 1H), 7.08 (m, 1H), 6.97 (m, 1H), 6.87 (m, 1H).

E 350 3',5'-difluoro(6-fluoro-1H-indolyl)-N'-hydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,5-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = F R6 = C R7 = N X = C KB 640 / 15887 WO ES/MS m/z: 450.2 (pos. M + H), 448.1 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.80 (s, 1H), 7.76 (s, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 3.3 Hz, 1H), 6.97 (d, J = 10.6 Hz, 1H), 6.77 (d, J = 6.8 Hz, 2H), 6.69 (m, 1H), 6.39 (d, J = 2.8 Hz, 1H).

E 351 N'-hydroxy(1H-indazolyl)(naphthalenyl)(trifluoromethyl)benzimidamide R1 = naphthalenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 447.2 (pos. M + H), 445.4 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.88 (s, 1H), 7.87 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 0.4 Hz, 1H), 7.72-7.70 (m, 2H), 7.47 (t, J = 0.7 Hz, 1H), 7.43 (dd, J = 1.0, 8.0 Hz, 1H), 7.38 (dd, J = 1.2, 7.0 Hz, 1H), 7.34-7.26 (m, 3H), 7.06 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 1.6, 8.7 Hz, 1H).

E 352 2-(benzo[d][1,3]dioxolyl)-N'-hydroxy(1H-indazolyl) (trifluoromethyl)benzimidamide R1 = benzo[d][1,3]dioxolyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 441.5 (pos. M + H), 439.7 (neg. M – H).

E 353 4'-fluoro-N'-hydroxy(1H-indazolyl)-2'-methoxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 4-fluoromethoxyphenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 445.1 (pos. M + H), 443.9 (neg. M – H); 1H NMR (CD 3CN, 500MHz): δ 7.91 (s, 1H), 7.75 (s, 2H), 7.49 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.06 (dd, J = 1.5, 8.6 Hz, 1H), 6.97 (dd, J = 7.0, 8.1 Hz, 1H), 6.55-6.53 (m, 2H), 3.51 (s, 3H).

E 354 N'-hydroxy(1H-indazolyl)-3'-methyl(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = m-tolyl R2 = oxy midoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 411.2 (pos. M + H), 409.4 (neg. M – H); 1H NMR (CD 3CN, 500MHz): δ 7.91 (s, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.01-6.99 (m, 4H), 6.90 (d, J = 7.4 Hz, 1H), KB 640 / 15887 WO 2.14 (s, 3H).

E 355 3',4',5'-trifluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,4,5-trifluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 451.1 (pos. M + H), 449.3 (neg. M – H); 1H NMR (CD 3CN, 500MHz): δ 7.97 (d, J = 0.9 Hz, 1H), 7.82 (t, J = 0.9 Hz, 1H), 7.77 (t, J = 0.9 Hz, 1H), 7.57 (m, 1H), 7.39 (m, 1H), 7.03 (dd, J = 1.7, 8.7 Hz, 1H), 6.88 (m, 2H).

E 356 3',4'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = 3,4-difluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 432.8 (pos. M + H), 431.6 (neg. M – H); 1H NMR (CD 3CN, ): δ 7.95 (d, J = 1.0 Hz, 1H), 7.81 (t, J = 0.9 Hz, 1H), 7.76 (d, J = 1.3 Hz, 1H), 7.56 (q, J = 0.8 Hz, 1H), 7.35 (m, J = 2.1 Hz, 1H), 7.08-7.00 (m, 3H), 6.88 (m, 1H).

E 357 N'-hydroxy(1H-indazolyl)(2-methoxypyridinyl)(trifluoromethyl)benzimidamide R1 = 2-methoxypyridinyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 427.7 (pos. M + H), 426.2 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.95 (d, J = 0.9 Hz, 1H), 7.93 (dd, J = 1.9, 5.1 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.51 (q, J = 0.8 Hz, 1H), 7.45 (dd, J = 1.9, 7.3 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.08 (dd, J = 1.6, 8.6 Hz, 1H), 6.79 (dd, J = 5.1, 7.3 Hz, 1H), 3.63 (s, 3H).

E 358 2-(cyclopentenyl)-N'-hydroxy(1H-indazolyl)(trifluoromethyl)benzimidamide R1 = cyclopentenyl R2 = N-hydroxy midoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 387.5 (pos. M + H), 385.3 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.08 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.37 (dd, J = 1.3, 8.6 Hz, 1H), 5.75 (s, 1H), 2.29 (m, 2H), 2.12 (m, 2H), 1.67 (m, 2H).

KB 640 / 15887 WO E 359 2-(3,5-dimethylisoxazolyl)-N'-hydroxy(1H-indazolyl) (trifluoromethyl)benzimidamide R1 = 3,5-dimethylisoxazolyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 416.6 (pos. M + H), 414.5 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 8.05 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.10 (dd, J = 1.5, 8.7 Hz, 1H), 2.09 (s, 3H), 1.87 (s, 3H).

E 360 difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl] carboximidamide R1 = fluorophenyl R2 = N-hydroxy carbaimidoyl R3= CF3 R5 = H R6 = C R7 = N X = N ES/MS m/z: 433.2 (pos. M + H), 431.27 (neg. M – H); 1H NMR (MeOD, 500MHz): δ 7.97 (s, 1H), 7.81 (s, 2H), 7.56 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.25 (q, J = 7.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.71 (t, J = 8.6 Hz, 1H).

Binding Assay 1: en Receptor Binding Assay 5 The estrogen receptor ligand binding assays are designed as scintillation proximity assays (SPA), employing the use of tritiated estradiol (3H-E2) and recombinant expressed biotinylated estrogen receptor binding domains. The binding domains of human ER (ER-LBD, pET-N-AT #1, aa 301-595) and ER (ER-LBD, pET-N-AT #1, aa 255-530) proteins are produced in E.coli ((BL21, (DE3), pBirA)) at 22 C in 2xLB medium supplemented with 50 uM biotin. After 3 h of IPTG induction (0.55 mM), cells are 10 harvested by centrifugation at 7300xg for 15 min and cell pellets stored frozen in -20C. Extraction of ERα and ERβ are med using 5 g of cells suspended in 50 mL of extraction buffer (50 mM Tris, pH 8.0, 100 mM KCl, 4 mM EDTA, 4 mM DDT and 0.1 mM PMSF). The cell suspension is run twice through a Microfluidizer M-110L (Microfluidics) and fuged at 15,000xg for 60 min. The supernatant is aliquoted and stored in -70C. 15 Dilute ER-LBD or ER-LBD extracts in assay buffer (18 mM K2HPO4, 2 mM KH2PO4, 20 mM NasMoO4, 1 mM EDTA, 1mM TCEP) 1:676 and 1:517 for alpha and beta respectively. The diluted receptor concentrations should be 900 fmol/L. ubate the extracts with streptavidin coated polyvinyltoluene SPA beads (RPNQ0007, GE care) at a concentration of 0.43 mg/mL for 1hr at 20 room temperature.

KB 640 / 15887 WO Test compounds may be evaluated over a range of concentrations from 157 µM to 37.5 pM. The test compound stock solutions should be made in 100% DMSO at 5x of the final concentration desired for testing in the assay. The amount of DMSO in the test wells of the 384 well plate will be 20%. Add 18µl 5 aliquots of test compounds to the assay plates followed by 35µl of the preincubated receptor/SPA bead mix and finally add 35µl of 3nM 3H-E2. Cover the plates with a plastic sealer, centrifuge for 1 minute at 1000 rpm and equilibrate over night on a shaker at room temperature. The ing morning, centrifuge the plates 5 minutes at 2000 rpm and measure on a plate scintillation counter e.g. a PerkinElmer Microbeta 1450 Trilux. 10 For compounds able to displace 2 from the or an IC50-value (the concentration required to inhibit 50% of the binding of 3[H]-E2) is determined by a non-linear four parameter logistic model; b = ((bmax-bmin)/(1+(I/IC50)S))+bmin I is added concentration of binding inhibitor, IC50 is the concentration of inhibitor at half maximal binding and S is a slope factor. The Microbeta-instrument tes the 15 mean cpm (counts per minute) value / minute and corrects for individual variations between the detectors thus generating corrected cpm values. g Assay 2: en Receptor Binding Assay LanthaScreen® TR-FRET ER alpha competitive binding assay and LanthaScreen® TR-FRET ER beta 20 competitive binding assay were purchased from Invitrogen™.

GST tagged ligand binding domain of human estrogen receptor alpha or human estrogen receptor beta is combined with a terbium chelate labeled anti-GST-anitbody and a fluorescent ligand for estrogen receptors.

The m chelate is d by pulses of light in a fluorescence reader. When the fluorescent ligand is 25 in close proximity, which it will be when bound to the receptor ligand binding domain, part of the energy emitted from the terbium chelate upon relaxation will transfer as light and excite the ligand. Upon successive relaxation of the fluorescent ligand energy is released as light of a second emission wavelength.

The signal ratio of light emitted from the terbium chelate and the scent ligand is calculated and used 30 as a measurement of labeled ligand and receptor interaction. Upon testing of unlabelled ligands this ratio will decrease in a test ligand tration dependent manner which can be interpreted as a ition binding curve upon analysis. All reagents except test nds are purchased from Invitrogen™.

KB 640 / 15887 WO t concentrations used in this assay are as ended from Invitrogen™. 200nl test compounds serially diluted in DMSO are added to empty low volume plates (Corning) with a Mosquito robot (TTP Labtech). The other reagents are prepared as described in the manual provided by Invitrogen™, gently swiveled in a flask and then added to the assay plate with a Multidrop 384 (Titertek). The assay plates are 5 covered and quickly mixed on a shaker. After 3 hours equilibration time at ambient room temperature are the plates measured on an EnVision® mulitlabel reader (Perkin Elmer). ctivation Assay 1: Transactivation assay in human embryonic kidney 293 cells stably transfected with pERE-ALP and human estrogen receptor alpha 10 The expression vector pMThERα contains an insert of wild type human estrogen or alpha with deleted leader. The pERE-ALP reporter construct contains the gene for the ed form of placental alkaline phosphatase (ALP) and the vitellogenin estrogen response element (ERE). The human embryonic kidney 293 cells are transfected in two steps. Firstly, a stable clone mix transfected with the pERE-ALP reporter gene construct and eo for selection is developed. Secondly, the stable clone mix is 15 ected with pMThERα and a pKSV-Hyg ance vector for selection. All transfections are performed using Lipofectamine (Invitrogen) according to supplier’s recommendations. A ed clone with both pERE-ALP and pMThERα is used for the transactivation assay.

The cells are seeded in 384-well plates at 12 500 cells per well in Ham’s F12 Coon’s modification 20 (without phenol red) with 10 % dextran-coated charcoal treated (DCC) fetal bovine serum (FBS), 2 mM L-glutamine and 50 μg/ml gentamicin. After 24 h incubation (37°C, 5 % CO2) the seeding medium is discarded and replaced with 20 μl Ham’s F12 Coon’s modification ut phenol red) with 1.5 % DCC- FCS, 2 mM L-glutamine and supplemented with 100 U/ml penicillin and 100 µg/ml streptomycin. The selected compounds are added to the wells in 12 concentrations ranging from 3.3 pM to 33 μM. The 25 compounds are dissolved in 100 % dimethylsulphoxide (DMSO) and the final concentration of DMSO in the assay is 0.1 %. After 72 h incubation (37°C, 5 % CO2) the medium is assayed for ALP activity by a chemiluminescence assay; a 10 μl aliquot of the cell culture medium is mixed with 100 μl assay buffer (0.1 M diethanolamine, 1 mM MgCl2) and 0.5 mM um 3-(4-methoxyspiro l,2-dioxetane-3,2′-(5′- chloro)-tricyclo[3.3.1.13,7]decanyl)phenyl phosphate (CSPD) (Tropix, Applied Biosystems) and 30 incubated for 20 min at 37°C and 15 min at room temperature before measurement chemiluminescent light signal (one second per well) in a Wallac Microbeta Trilux 1450-028 nElmer). The half maximal effective concentrations (EC50) are calculated from the curves fitted to the concentrationresponse data with a four parameter logistic model in XLfit software version 2.0 (IDBS) or later.

KB 640 / 15887 WO Transactivation Assay 2: Transactivation assay in human embryonic kidney 293 cells stably transfected with pERE2-ALP and human estrogen or beta Generation of stable HEK293 cell lines (CRL-1573; an Type Culture Collection) expressing the reporter vector pERE2-ALP and human en receptor beta (hERß 530) have been described (Mol 5 Pharmacol 1998, 54,105–112; Endocrinology 2002, 143, 1558-1561).

The cells were seeded in 384-well plates at 12 500 cells per well in Ham’s F12 Coon’s modification (without phenol red) with 10 % dextran-coated al treated (DCC) fetal bovine serum (FBS), 2 mM L-glutamine and 50 µg/ml gentamicin. After 24 h incubation (37°C, 5 % CO2) the seeding medium was 10 discarded and replaced with 20 µl Ham’s F12 Coon’s modification (without phenol red) with 1.5 % DCC- FCS, 2 mM amine and supplemented with 100 U/ml penicillin and 100 µg/ml streptomycin. The selected compounds were added to the wells in 12 concentrations ranging from 3.3 pM to 33 µM. The compounds were dissolved in 100 % dimethylsulfoxide (DMSO) and the final concentration of DMSO in the assay was 0.1 %. After 72 h incubation (37°C, 5 % CO2) the medium was assayed for ALP activity by 15 a chemiluminescence assay; a 10 µl aliquot of the ioned medium was mixed with 100 µl assay buffer (0.1 M diethanolamine, 1 mM MgCl2) and 0.5 mM disodium 3-(4-methoxyspiro l,2-dioxetane- 5'-chloro)-tricyclo[3.3.1.13,7]decanyl)phenyl ate (CSPD) x, d Biosystems) and incubated for 20 min at 37°C and 15 min at room temperature before measurement of the chemiluminescent signal (one second per well) in a Wallac Microbeta Trilux 1450-028 (PerkinElmer). 20 The ALP activity expressed in LCPS is directly proportional to the level of ALP expressed by the cells.

The half maximal effective concentrations of the test compounds (EC50) were calculated from the curves fitted to the concentration-response data with a four parameter logistic model in XLfit software version 2.0 (IDBS) or later. 25 The Example compounds were tested in transactivation assays 1 and 2.

The compounds of the Examples exhibit one or more of the following: (i) a potency in the range of EC50 1 to 10,000 nM at the estrogen receptor α-subtype in transactivation assay 1; 30 (ii) a potency in the range of EC50 0.1 to 10,000 nM at the estrogen receptor β-subtype in transactivation assay 2.

Preferred compounds of the invention are those which display a potency at the estrogen receptor βsubtype at lower concentrations within the EC50 range shown above. For example, the compounds of 35 Examples 1-3, 6, 7, 8-11, 13, 17, 19, 21, 22, 24, 25-28, 30, 32, 33, 36, 37, 39-50, 52, 55-58, 67, 70, 71, KB 640 / 15887 WO 73, 78, 79, 81, 82, 85, 106-109, 111-117, 122-140, 142-159, 162-172, 174-178, 182-184, 186-196, 198- 224, 226, 228-257, 259-261, 263-266, 5, 277-287, 289-299, 301-303, 305-308, 311-318, 322-329, 331, 335, 337, 339-341, 343, 346-358 and 360 t a potency in the range of EC50 0.1 to 100 nM at the estrogen receptor β-subtype in transactivation assay 2. 5 Preferred compounds of the invention are those which are selective for the estrogen receptor β-subtype over the estrogen receptor α-subtype in the transactivation assays 1 and 2. For example, the compounds of Examples 2, 3, 6, 7, 8-11, 13, 14, 17, 19, 21, 25-27, 30, 31, 33, 37, 39-49, 52, 56, 57, 62, 79, 81, 82, 106-109, 5, 122-128, 130-132, 134, 135-137, 139-157, 159, 162-178, 181-186, 188-196, 198, 199, 10 204-224, 226-239, 241-261, 263, 265, 2, 275, 276, 279, 281, 284, 285, 290, 292-296, 298, 300, 302, 303, 306, 308, 311-319, 322-325, 327, 328, 340, 346-349, 351-354, 357, 359 and 360 display selectivity for the estrogen receptor β-subtype of 20 or greater in the transactivation assays; with the compounds of Examples 2, 3, 8, 10, 11, 13, 14, 17, 37, 40-43, 45, 49, 106-109, 111-114, 123, 125, 126, 130, 132, 135-137, 142, 143, 145, 9, 151, 7, 159, 162-164, 166, 167, 169, 171, 172, 174, 15 175, 177, 178, 182, 184, 188, 189, 193-196, 198, 5, 217-220, 222, 223, 226-239, 241-248, 251- 254, 256, 259, 261, 263, 269-272, 279, 281, 284, 290, 292, 294-296, 302, 303, 306, 314, 318, 322, 323, 325, 346-348, 352, 353, 357, 359 and 360 ying selectivity of 50 or greater.

Some of the Example compounds were also tested in the binding assays 1 and 2. All of those tested 20 showed binding IC50 (nM) in the range of 0.1 to 5,000 nM at the estrogen receptor β-subtype. For e, the compounds of Examples 10, 11, 13, 40-43, 72, 76, 77, 79, 82, 90, 96, 97, 100, 9, 111- 115, 118, 2, 134, 135, 137, 156-159, 163, 175, 184, 228, 281, 286 and 296 show binding IC50 (nM) of 0.1 to 10. Preferred compounds of the invention are those which are ive for the estrogen receptor β-subtype over the estrogen receptor α-subtype in the binding assays 1 and 2. For example, the 25 compounds of Examples 10, 11, 13, 40-43, 72, 76, 77, 79, 82, 86, 90, 91, 93, 95-98, 100-103, 106-116, 123, 126, 128, 130-132, 134, 137, 150, 159, 163, 175, 177, 184, 281 and 286, displayed selectivity for the estrogen receptor β-subtype of 20 or greater.

Claims (24)

Claims

1. A compound of formula (I) or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, ing a salt of such an ester, amide or carbamate 2 R 1 R H 9 R 8 R 3 R 4 R 7 5 R R 6 5 R (I) in which 10 R1 is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C3-8cycloalkyl, optionally substituted C5-6cycloalkenyl, optionally tuted phenylC2-4alkenyl, C2-8alkenyl, haloC2-8alkenyl, dihaloC2-8alkenyl, trihaloC2-8alkenyl, and C3-8cycloalkylC2-4alkenyl, wherein when said cyclyl, phenyl or naphthyl group or part of group is substituted, it is substituted with from 1 to 5 tuents, 15 each substituent being independently selected from the group consisting of ORA, N(RB)2, n, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, kynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl, and when said C3-8cycloalkyl or C5-6cycloalkenyl group is substituted, it is substituted with 1, 2 or 3 tuents selected from C1-5alkyl, kenyl , C1-5alkynyl, C1-5alkyl substituted with up to 3 halogen atoms, -CO-C1-5alkyl, and halogen; 20 R2 is selected from the group consisting of -C(NH2)=N-OH, -C(O)N(RC)2, cyano, -CHO, -CH=N-OH, -C(O)NH-OH, -C(CO2H)=N-OH, -C(O-C1-4alkyl)=NH, -C(NH2)=N-NH2, -C(O)-C(O)-NH2, -C(O)CO2H, -CO2H, -CH2-CO2H, -CH(OH)CO2H, -CH2NH-CONH2, -C1-6alkyl-NH2, -CH2SO3H, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), NHSO2RD, -S-CN, H2)=NH, 25 -S-C(NH2)=N-OH, SO2N(RE)2, SO3H, cyanoC1-6alkyl-, and optionally tuted 5-10 membered heterocyclyl containing from one to three nitrogen atoms, wherein when said heterocyclyl group is tuted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of ORA, N(RB)2, halogen, cyano, nitro, -C(O)C1-4alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl; KB 640 / 15887 WO R3 is selected from the group consisting of hydrogen, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl , C3-8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, trihaloC1-6alkyl, optionally substituted , optionally substituted phenylC1-4alkyl, optionally substituted 5-10 membered 5 heterocyclyl, and optionally tuted 5-10 ed heterocyclylC1-4alkyl, wherein when said phenyl or heterocyclyl group or part of group is substituted, it is substituted with from 1 to 5 substituents, each substituent being independently selected from the group consisting of ORA, N(RB)2, halogen cyano, nitro, C1-6alkyl, kenyl, kynyl, haloC1-6alkyl, C1-6alkyl and trihaloC1-6alkyl; 10 R4 is selected from the group consisting of hydrogen, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and haloC1-6alkyl, dihaloC1-6alkyl, and trihaloC1-6alkyl; each of R5, R6, R8 and R9 is independently selected from the group consisting of hydrogen, ORA, N(RB)2, halogen, cyano, nitro, -C(O)C1-4alkyl, kyl, C2-6alkenyl, C2-6alkynyl, -6 alkyl, C1-6alkyl 15 and trihaloC1-6alkyl; R7 is ORA; or R6 and R7 may, together with the atoms they are attached to, form a 5-, 6- or 7- membered cyclic group 20 optionally containing one to three heteroatoms selected from O, N and S, said 5-, 6- or 7- membered cyclic group being ally substituted with one of more groups selected from ORA, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo C1-6 alkyl, dihalo C1-6 alkyl and trihalo C1-6 alkyl; and each RA, each RB, each RC, each RD and each RE is independently selected from the group consisting of 25 en, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl and C3-8cycloalkylC1-6alkyl; each optionally substituted by from 1 to 3 halogen atoms.

2. A compound as claimed in claim 1, in which R1 is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl, optionally tuted phenyl, optionally substituted naphthyl, 30 optionally substituted C5-6cycloalkenyl, optionally substituted phenylC2-4alkenyl, C2-8alkenyl, haloC2- 8alkenyl, dihaloC2-8alkenyl, trihaloC2-8alkenyl, and C3-8cycloalkylC2-4alkenyl, wherein when said heterocyclyl or phenyl or naphthyl group or part of group is substituted, it is substituted with from 1 to 5 substituents, each substituent being independently selected from the group consisting of ORA, N(RB)2, halogen, cyano, nitro, C1-6alkyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl, and wherein when KB 640 / 15887 WO said C5-6cycloalkenyl group is substituted, it is substituted with 1 or 2 substitutents selected from halogen atoms and methyl groups.

3. A compound as claimed in claim 2, in which R1 is ed from the group consisting of optionally 5 substituted 5-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C5-6cycloalkenyl, optionally substituted phenylC2-4alkenyl, C2-8alkenyl, C3-8cycloalkyl, and cloalkylC2-4alkenyl, wherein when said heterocyclyl or phenyl or naphthyl group or part of group is substituted, it is tuted with from 1 to 5 substituents, each substituent being independently selected from the group consisting of ORA, halogen, C1-6alkyl, haloC1-6 alkyl, dihaloC1- 10 6alkyl and oC1-6alkyl, and wherein where said optionally substituted C5-6cycloalkenyl group is substituted, it is tuted with 1 or two substituents selected from halogen atoms and methyl groups.

4. A compound as claimed in any one of the preceding , in which R1 ents an optionally substituted isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, l or pyrrolidinyl group. 15

5. A compound as d in any one of the ing claims, in which R 2 is selected from the group consisting of -C(NH2)=N-OH, -C(O)N(RC)2, cyano, -CHO, -CH=N-OH, -C(O)NH-OH, -C(CO2H)=N-OH, -C(O-C1-4alkyl)=NH, )=N-NH2, -C(O)-C(O)-NH2, -CH2NH-CONH2, C1-6alkyl-NH2, NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), -S-CN, -S-C(NH2)=NH, 20 -S-C(NH2)=N-OH, cyanoC1-6alkyl-, and an optionally substituted 5-6 membered heterocyclyl containing from one to three nitrogen atoms; wherein when said heterocyclyl group is substituted, it is substituted with from 1 to 3 substituents, each substituent being independently selected from the group consisting of OH, halogen, cyano, nitro, C1-4alkyl, haloC1-4 alkyl, dihaloC1-4alkyl and trihaloC1-4alkyl. 25

6. A compound as claimed in claim 5, in which R2 represents -C(NH2)=N-OH, -C(O)NH2, -CH=N-OH, cyano, or pyrazolyl.

7. A nd as claimed in any one of the preceding claims, in which R3 is selected from the group consisting of hydrogen, n, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, 30 C3-8cycloalkylC1-6alkyl, haloC1-6alkyl, dihaloC1-6alkyl, trihaloC1-6alkyl, phenyl, and phenylC1-4alkyl.

8. A compound as claimed in claim 7, in which R3 represents halogen, cyano, C1-6alkyl, C2-6alkenyl, trihaloC1-6alkyl, phenyl, or phenylC1-2alkyl. KB 640 / 15887 WO

9. A compound as claimed in any one of the preceding claims, in which each of R5, R6, R8 and R9 is ndently selected from the group consisting of hydrogen, ORA, N(RB)2, halogen, cyano, nitro, C1- , haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl. 5

10. A nd as d in claim 9, in which each of R5, R6, R8 and R9 is independently selected from the group consisting of hydrogen, halogen, methyl and trifluoromethyl.

11. A compound as claimed in any one of the preceding claims, in which R7 represents ORA. 10

12. A compound as claimed in claim 11, in which R7 represents OH.

13. A compound as claimed in any one of claims 1 to 8, in which each of R5, R8 and R9 is independently ed from the group consisting of hydrogen, ORA, N(RB)2, halogen, cyano, nitro, C1-6alkyl, haloC1-6 alkyl, dihaloC1-6alkyl and trihaloC1-6alkyl; and R6 and R7, together with the atoms they are attached to, 15 form a 5-, 6- or 7- membered cyclic group optionally containing one to three atoms ed from

O, N and S, said 5-, 6- or 7- membered cyclic group being optionally substituted with one of more groups selected from ORA, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo C1-6 alkyl, dihalo C1-6 alkyl and trihalo C1-6 alkyl. 20 14. A compound as d in claim 13, in which each of R5, R8 and R9 is independently selected from the group consisting of hydrogen and halogen.

15. A compound as claimed in claim 13 or claim 14, in which R6 and R7, together with the atoms they are attached to, form a 5-, 6- or 7- membered cyclic group optionally containing one to three heteroatoms 25 selected from O and N.

16. A compound as claimed in claim 1, which is any one of the following compounds: N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 30 2-(3,5-dimethylisoxazolyl)-N',4'-dihydroxymethyl-[1,1'-biphenyl]carboximidamide 2-(3,5-dimethylisoxazolyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 2-(3,5-dimethylisoxazolyl)-4'-hydroxypropyl-[1,1'-biphenyl]carboxamide 2-(3,5-dimethylisoxazolyl)-4'-hydroxypropyl-[1,1'-biphenyl]carbonitrile N',4'-dihydroxymethyl(3-methylthiophenyl)-[1,1'-biphenyl]carboximidamide 35 3',5'-difluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO 2-bromo-3',5'-difluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 2-(3,5-dimethylisoxazolyl)-3',5'-difluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 5-bromo-N',4'-dihydroxy(3-methylthiophenyl)-[1,1'-biphenyl]carboximidamide 5-bromo-N',4'-dihydroxyiodo-[1,1'-biphenyl]carboximidamide 5 5'-bromo-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluorohydroxy-2'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboxamide 5-chloro(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide ro(3,5-dimethylisoxazolyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide 10 2-(3,5-dimethylisoxazolyl)-3'-fluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 2-(2,4-dimethylfuranyl)-4'-hydroxypropyl-[1,1'-biphenyl]carbonitrile 2-(2,4-dimethylfuranyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 2-(2,4-dimethylfuranyl)-4'-hydroxypropyl-[1,1'-biphenyl]carboxamide N',4'-dihydroxyiodopropyl-[1,1'-biphenyl]carboximidamide 15 N',4'-dihydroxy(4-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide ihydroxy-5'-propyl-2''-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(2,4-dimethylthiophenyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-((E)cyclopropylvinyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 20 N',4'-dihydroxy(3-methylbutenyl)propyl-[1,1'-biphenyl]carboximidamide N',4-dihydroxy-3''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2''-ethyl-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide dihydroxypropyl(thiophenyl)-[1,1'-biphenyl]carboximidamide 25 N',4'-dihydroxypropyl(quinolinyl)-[1,1'-biphenyl]carboximidamide 3''-chloro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4'-dihydroxypropyl(pyridinyl)-[1,1'-biphenyl]carboximidamide 2-(benzofuranyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 4''-chloro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 30 N',4'-dihydroxypropyl(pyridinyl)-[1,1'-biphenyl]carboximidamide N',4'-dihydroxy(1-phenylvinyl)propyl-[1,1'-biphenyl]carboximidamide 2-(5-chlorothiophenyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 5''-fluoro-N',4-dihydroxy-2''-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4'-dihydroxy(isoquinolinyl)propyl-[1,1'-biphenyl]carboximidamide 35 2-(benzofuranyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO 5''-fluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 N',4'-dihydroxy(4-methylthiophenyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 2-(2,4-dimethylthiophenyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide N',4'-dihydroxyiodo(trifluoromethyl)-[1,1'-biphenyl]carboximidamide '-difluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(1,3-dimethyl-1H-pyrrolyl)-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 10 '-difluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(2,4-dimethylfuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 3'-chloro-5'-fluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl] carboximidamide roxy(1H-indazolyl)(3-methylthiophenyl)propylbenzimidamide 15 3'-fluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 3'-chloro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 3',5'-dichloro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide N',4'-dihydroxy-3'-methyl(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 2'-fluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 20 2',3'-difluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide 2',5'-difluoro-N',4'-dihydroxy(3-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide N',4'-dihydroxy(2-methylallyl)propyl-[1,1'-biphenyl]carboximidamide 2-allyl-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide N',4'-dihydroxypropylvinyl-[1,1'-biphenyl]carboximidamide 25 5-bromo-N',4'-dihydroxy(1-methyl-1H-imidazolyl)-[1,1'-biphenyl]carboximidamide N',4'-dihydroxypropyl(pyridinyl)-[1,1'-biphenyl]carboximidamide N',4'-dihydroxy(2-methoxythiazolyl)propyl-[1,1'-biphenyl]carboximidamide N',4'-dihydroxypropyl(thiazolyl)-[1,1'-biphenyl]carboximidamide N',4'-dihydroxypropyl(thiazolyl)-[1,1'-biphenyl]carboximidamide 30 5'-ethyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5'-isobutyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5'-((E)-propenyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-allyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-butyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 35 2-(2,5-dimethyl-1H-pyrrolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO 4-hydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carbaldehyde oxime 5'-propyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol 5-chloro(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-3'-nitro-[1,1'-biphenyl]carboximidamide 5'-chloro-5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 5'-chloro-5''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5-chloro-N',4'-dihydroxy(4-methylthiophenyl)-[1,1'-biphenyl]carboximidamide 5'-chloro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide -dimethylthiophenyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 5-chloro(2,4-dimethylthiophenyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 10 2''-chloro-5''-fluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 6'-chloro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5',6'-dipropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4'-dihydroxy(3-methylthiophenyl)-[1,1'-biphenyl]carboximidamide 5'-bromo-6'-chloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 15 6'-chloro-N',4-dihydroxy-5'-phenyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 6'-chloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-6'-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'',6'-difluoro-N',4-dihydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'',6'-difluorohydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide 20 4-hydroxy-6'-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carbaldehyde oxime 5'',6'-difluoro-N',4-dihydroxy-2''-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'',6'-difluorohydroxy-2''-methoxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide 6'-fluorohydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide oro-N',4-dihydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 25 6-fluoro-N',4'-dihydroxy(4-methylthiophenyl)propyl-[1,1'-biphenyl]carboximidamide orohydroxy-2''-methyl-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboxamide 6-fluoro-4'-hydroxy(4-methylthiophenyl)propyl-[1,1'-biphenyl]carboxamide 2-(2,4-dimethylthiophenyl)fluoro-N',4'-dihydroxypropyl-[1,1'-biphenyl]carboximidamide 5'-chloro-5''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboxamide 30 6'-fluoro-N',4-dihydroxy-5'-propyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 35 2''-ethyl-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO 3''-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-fluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5',6'-dichloro-5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 loro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2''-ethynyl-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-chloro-5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2'',5'-bis(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 10 5'-methyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol 3'',5''-difluoro-5'-propyl-3'-(1H-pyrazolyl)-[1,1':2',1''-terphenyl]ol N',4-dihydroxy-5'-phenyl-[1,1':2',1''-terphenyl]-3'-carboximidamide zyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5'-phenethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 15 2,5''-difluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2,5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-fluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chlorofluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- 20 carboximidamide 2,3''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2,3'',5''-trifluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chlorofluorohydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide 25 2-fluorohydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboxamide 3''-chloro-2,5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide loro-2,5''-difluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide 2''-ethynylfluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 30 5'-chloro-3''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5',5''-dichloro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-chlorofluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide 3''-chlorofluorohydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide 35 N',4-dihydroxy-5'-methyl-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO 3'',5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-fluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-chloro-5''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 5''-chloro-N',4-dihydroxy-2'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chloro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide loro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chloro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2''-chloro-5''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 10 N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-3'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-chloro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-3''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 4''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 15 4''-chloro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 4''-fluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide ihydroxy-2''-isopropyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(3,5-dimethylisoxazolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 20 2-(3,5-dimethylisoxazolyl)-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carboxamide 3''-chlorohydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide N',4-dihydroxy-2'',5''-dimethyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methoxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2''-chloro-N',4-dihydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 25 5'-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chloro-5'-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5'-difluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5',5''-trifluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-chloro-5',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 30 5'-fluoro-N',4-dihydroxy-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide lorohydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide 3''-chloro-N',4-dihydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 35 2'',5''-dichloro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO 5''-chloro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chloro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluorohydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboxamide 5 3''-chlorohydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide '-dichlorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide 3'',5''-dichloro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-dichloro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(3,5-dimethylisoxazolyl)-2'-fluoro-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] 10 carboximidamide 2-(3,5-dimethylisoxazolyl)-2'-fluoro-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carboxamide 3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluorohydroxy-[1,1':2',1''-terphenyl]-3'-carboxamide 3''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 15 3''-fluorohydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboxamide 2''-ethyl-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 4''-chloro-2''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 4''-chloro-3''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 20 5'-chloro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 4''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-4''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3''-chloro-N',4-dihydroxy-5',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2'',5''-dichloro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 25 3'',5''-difluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide N',4-dihydroxy-4'',5'-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2'',4'',5'-trimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 4''-fluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide '-difluoro-N',4-dihydroxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 30 loro-5'-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5',5''-difluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 2''-chloro-5'-fluoro-N',4-dihydroxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2'',5''-dichloro-5'-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 35 4'',5'-difluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO 5'-fluoro-N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-fluoro-N',4-dihydroxy-2''-methoxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methoxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methoxy-5',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 4''-fluoro-N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2''-chloro-N',4-dihydroxy-5',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-5'-methyl-2''-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4-dihydroxy-2''-methoxy-5'-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluoro-N',4-dihydroxy-5'-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 10 5''-fluoro-N',4-dihydroxy-2'',5'-dimethoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(5-fluoromethoxypyridinyl)-N',4'-dihydroxymethyl-[1,1'-biphenyl]carboximidamide N',4'-dihydroxymethyl(2-methylpyridinyl)-[1,1'-biphenyl]carboximidamide dihydroxy(2-methoxypyridinyl)methyl-[1,1'-biphenyl]carboximidamide 2-(3,5-dimethylisothiazolyl)-N',4'-dihydroxymethyl-[1,1'-biphenyl]carboximidamide 15 N',4-dihydroxy-5'-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(3,5-dimethylisothiazolyl)-4'-hydroxymethyl-[1,1'-biphenyl]carboxamide 5-chloro(5-fluoromethoxypyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide luoromethoxypyridinyl)-4'-hydroxymethyl-[1,1'-biphenyl]carboxamide 2-(3,5-dimethylisothiazolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 20 5-chloro(3,5-dimethylisothiazolyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide uoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2'',4''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4'-dihydroxy(4-methylpyridinyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 2-(2,5-dimethylpyridinyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 25 2''-chloro-4''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 4'',5''-difluoro-N',4-dihydroxy-2''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2'',5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide N',4'-dihydroxy(pyridinyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 2-(2,3-dihydrobenzofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 30 2-(benzofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide N',4'-dihydroxy(1-methyl-1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 2''-chloro-5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chloro-2''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(4-fluorobenzofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 35 3'',4''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO 5'-chloro-2'',4''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-2'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(benzo[d][1,3]dioxolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 3'',4'',5''-trifluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 5'-chloro-3'',4''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-3'',4'',5''-trifluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5-chloro-N',4'-dihydroxy(4-methylpyridinyl)-[1,1'-biphenyl]carboximidamide 5',5''-dichloro-2''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 2'',5'-dichloro-5''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 10 5'-chloro-2''-fluoro-N',4-dihydroxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-2''-fluoro-N',4-dihydroxy-4''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide luoromethoxypyridinyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 5'-chloro-N',4-dihydroxy-2'',4''-dimethoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 15 5'-chlorohydroxy-2'',4''-dimethoxy-[1,1':2',1''-terphenyl]-3'-carbonitrile 5-chloro(5-chloromethoxypyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 5-chloro(5-chloromethoxypyridinyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide 5-chloro(2,5-dimethylpyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 5-chloro(2,5-dimethylpyridinyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide 20 2-(benzo[d][1,3]dioxolyl)chloro-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 5-chloro-N',4'-dihydroxy(naphthalenyl)-[1,1'-biphenyl]carboximidamide ro-N',4'-dihydroxy(isoquinolinyl)-[1,1'-biphenyl]carboximidamide 5-chloro-N',4'-dihydroxy(quinolinyl)-[1,1'-biphenyl]carboximidamide 5-chloro-N',4'-dihydroxy(1-methyl-1H-benzo[d]imidazolyl)-[1,1'-biphenyl]carboximidamide 25 5-chloro-4'-hydroxy(1-methyl-1H-benzo[d]imidazolyl)-[1,1'-biphenyl]carboxamide 2-(5-chloromethoxypyridinyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 2''-fluoro-N',4-dihydroxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5-chloro(6-chloromethoxypyridinyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 30 5-chloro-N',4'-dihydroxy(2-methoxymethylpyridinyl)-[1,1'-biphenyl]carboximidamide 5-chloro(cyclopentenyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 5-chloro(cyclopentenyl)-4'-hydroxy-[1,1'-biphenyl]carboxamide 2-(cyclopentenyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide lopentenyl)-4'-hydroxy(trifluoromethyl)-[1,1'-biphenyl]carboxamide 35 5'-bromo-5''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide KB 640 / 15887 WO 5'-bromo-5''-fluoro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-3''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-N',4-dihydroxy-2'',5''-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-N',4-dihydroxy-5''-methoxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 5'-bromo-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-4''-fluoro-N',4-dihydroxy-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2,5''-difluoro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5''-chloro-N',4-dihydroxy-5'-(trifluoromethyl)-2''-vinyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 10 2''-ethynyl-5''-fluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 4-hydroxy-2''-methoxy-5''-methyl-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide mo-5''-chloro-N',4-dihydroxy-2''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-3''-chloro-5''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 15 5'-bromo-2''-chloro-5''-fluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide mo-4''-chloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-2'',5''-dichloro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-bromo-2''-chloro-N',4-dihydroxy-5''-methyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5-bromo(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-[1,1'-biphenyl]carboximidamide 20 3-chlorofluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3-chlorofluorohydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboxamide 3,5'-dichloro-3'',5,5''-trifluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'-chloro(3,5-dimethylisoxazolyl)-5'-fluoro-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 25 3-chloro-3'',5,5''-trifluoro-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3-chloro-5,5''-difluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide 3-chlorofluoro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'- carboximidamide 30 oro-3'',5''-difluoro-N'-hydroxymethoxymethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-3'',5''-difluoro-N',4-dihydroxymethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5-chloro(3,5-dimethylisoxazolyl)-N',4'-dihydroxy-3'-methyl-[1,1'-biphenyl]carboximidamide 5'-chloro-N',4-dihydroxy-2'',3-dimethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 5'-chloro-5''-fluoro-N',4-dihydroxy-2''-methoxymethyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 35 5'-chloro-5''-fluorohydroxy-2''-methoxymethyl-[1,1':2',1''-terphenyl]-3'-carboxamide KB 640 / 15887 WO oro-3'',5''-difluoro-N',4-dihydroxyisopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 2'-(3,5-dimethylisoxazolyl)-3'-(1H-1,2,3-triazolyl)-5'-(trifluoromethyl)-[1,1'-biphenyl]ol ihydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluoro-N',4-dihydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide 5 5''-chloro-N',4-dihydroxy-2''-methoxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboximidamide oxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboxamide 3'',5''-difluorohydroxy-5'-(trifluoromethoxy)-[1,1':2',1''-terphenyl]-3'-carboxamide N',4-dihydroxy-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 3'',5''-difluoro-N',4-dihydroxy-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboximidamide 10 5''-chloro-N',4-dihydroxy-5'-isopropyl-2''-methoxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 4-amino-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboxamide 3'',5''-difluorohydroxy-5'-isopropyl-[1,1':2',1''-terphenyl]-3'-carboxamide 2-(3-cyanofuranyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 2-(4-cyanomethyl-1H-pyrazolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] 15 carboximidamide 2''-cyano-N',4-dihydroxy-5'-(trifluoromethyl)-[1,1':2',1''-terphenyl]-3'-carboximidamide 2-(3-cyanomethyl-1H-pyrrolyl)-N',4'-dihydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 5'-cyano-3'',5''-difluoro-N',4-dihydroxy-[1,1':2',1''-terphenyl]-3'-carboximidamide 20 N',4'-dihydroxy(pyrrolidinyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 4-chloro-3',5'-difluoro-N'-hydroxy(1H-indazolyl)-[1,1'-biphenyl]carboximidamide 6-(1H-benzo[d]imidazolyl)chloro-3',5'-difluoro-N'-hydroxy-[1,1'-biphenyl]carboximidamide 4-chloro-3',5'-difluoro-N'-hydroxy(1H-indolyl)-[1,1'-biphenyl]carboximidamide 4-chloro-3',5'-difluoro(1H-indolyl)-[1,1'-biphenyl]carboxamide 25 4-chloro-3',5'-difluoro(1H-indazolyl)-[1,1'-biphenyl]carboxamide 6-(1H-benzo[d]imidazolyl)chloro-3',5'-difluoro-[1,1'-biphenyl]carboxamide 3',5'-difluoro-N'-hydroxy(1H-indolyl)methyl-[1,1'-biphenyl]carboximidamide 3',5'-difluoro-N'-hydroxy(1H-indolyl)methyl-[1,1'-biphenyl]carboximidamide 3',5'-difluoro-N'-hydroxy(1H-indazolyl)methyl-[1,1'-biphenyl]carboximidamide 30 3',5'-difluoro-N'-hydroxy(1H-indazolyl)propyl-[1,1'-biphenyl]carboximidamide 3',5'-difluoro-N'-hydroxy(1H-indolyl)propyl-[1,1'-biphenyl]carboximidamide 3',5'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 3',5'-difluoro-N'-hydroxy(1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 3',5'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 35 3',5'-difluoro-N'-hydroxy(1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide KB 640 / 15887 WO 3',5'-difluoro(1H-indolyl)(trifluoromethyl)-[1,1'-biphenyl]carboxamide difluoro-N'-hydroxy(1H-indazolyl)propyl-[1,1'-biphenyl]carboximidamide N'-hydroxy(1H-indazolyl)-2'-methoxy-5'-methyl(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 5 5'-chloro-N'-hydroxy(1H-indolyl)-2'-methoxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 5'-chloro-N'-hydroxy(1H-indazolyl)-2'-methoxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide 2',5'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 10 difluoro(6-fluoro-1H-indolyl)-N'-hydroxy(trifluoromethyl)-[1,1'-biphenyl] carboximidamide N'-hydroxy(1H-indazolyl)(naphthalenyl)(trifluoromethyl)benzimidamide 2-(benzo[d][1,3]dioxolyl)-N'-hydroxy(1H-indazolyl)(trifluoromethyl)benzimidamide 4'-fluoro-N'-hydroxy(1H-indazolyl)-2'-methoxy(trifluoromethyl)-[1,1'-biphenyl] 15 imidamide N'-hydroxy(1H-indazolyl)-3'-methyl(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 3',4',5'-trifluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide 3',4'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide N'-hydroxy(1H-indazolyl)(2-methoxypyridinyl)(trifluoromethyl)benzimidamide 20 2-(cyclopentenyl)-N'-hydroxy(1H-indazolyl)(trifluoromethyl)benzimidamide 2-(3,5-dimethylisoxazolyl)-N'-hydroxy(1H-indazolyl)(trifluoromethyl)benzimidamide 2',4'-difluoro-N'-hydroxy(1H-indazolyl)(trifluoromethyl)-[1,1'-biphenyl]carboximidamide or a ceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such an ester, 25 amide or carbamate.

17. The compound as claimed in any one of claims 1 to 16 together with a further therapeutic agent, for simultaneous, sequential or separate administration. 30

18. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 16, together with a pharmaceutically acceptable carrier.

19. The nd as claimed in any one of claims 1 to 17, or the composition as claimed in claim 18, for use as a medicament. 35 KB 640 / 15887 WO

20. The compound as claimed in any one of claims 1 to 17, or the composition as claimed in claim 18, for use in the treatment or prophylaxis of a condition ed from the group consisting of bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flushes, increased levels of LDL cholesterol, cardiovascular e, impairment of ive functioning, age- 5 related mild cognitive impairment, cerebral rative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, y, incontinence, anxiety, depression, perimenopausal depression, post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, anger management, hearing ers, multiple sclerosis, Parkinson’s disease, Alzheimer’s 10 disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, ension, retinal degeneration, lung cancer, colon cancer, breast cancer, uterus cancer, prostate cancer, the bile duct cancer form named giocarcinoma, benign prostatic hyperplasia, lower y tract symptoms, overactive bladder, interstitial cystitis, painful bladder symptoms, vaginal y, wound healing, chronic pain, sepsis, 15 inflammatory and neuropathic pain, ovarian cancer, melanoma, ma, atherosclerosis, left ventricular hypertrophy, congestive heart failure, mesothelioma, gallbladder cancer and extra-hepatic giocarcinoma.

21. The compound as claimed in any one of claims 1 to 17, or the composition as claimed in claim 18, for 20 use in the treatment or prophylaxis of a condition selected from the group consisting of bone loss, bone fractures, osteoporosis, age degeneration, endometriosis, uterine fibroid disease, hot flushes, increased levels of LDL cholesterol, cardiovascular disease, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, nopausal depression, rtum sion, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, 25 attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, anger management, hearing ers, spinal cord injury, stroke, autoimmune disease, mation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer, breast cancer, uterus cancer, prostate , the bile duct cancer form named cholangiocarcinoma, benign prostatic hyperplasia, lower urinary tract symptoms, overactive bladder, interstitial cystitis, l bladder 30 symptoms, vaginal atrophy, wound healing, chronic pain, sepsis, inflammatory and neuropathic pain, n cancer, melanoma, lymphoma, atherosclerosis, left ventricular hypertrophy, congestive heart e, mesothelioma, gallbladder cancer and extra-hepatic cholangiocarcinoma.

22. Use of a compound as claimed in any one of claims 1 to 17, for the manufacture of a medicament for 35 the treatment or prophylaxis of a condition ed from the group consisting of bone loss, bone KB 640 / 15887 WO fractures, osteoporosis, cartilage degeneration, endometriosis, uterine d disease, hot flushes, increased levels of LDL terol, cardiovascular disease, impairment of cognitive functioning, agerelated mild cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, perimenopausal depression, 5 post-partum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention t disorder, ion deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, anger management, hearing ers, multiple sclerosis, Parkinson’s e, mer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation, IBD, IBS, sexual dysfunction, hypertension, retinal degeneration, lung cancer, 10 colon cancer, breast cancer, uterus cancer, prostate cancer, the bile duct cancer form named cholangiocarcinoma, benign prostatic hyperplasia, lower urinary tract symptoms, overactive bladder, interstitial cystitis, painful bladder symptoms, vaginal atrophy, wound healing, chronic pain, sepsis, inflammatory and neuropathic pain, ovarian cancer, melanoma, lymphoma, atherosclerosis, left ventricular rophy, congestive heart failure, mesothelioma, gallbladder cancer and extra-hepatic 15 giocarcinoma.

23. Use of a compound as d in any one of claims 1 to 17, for the manufacture of a ment for the treatment or laxis of a condition selected from the group consisting of bone loss, bone fractures, osteoporosis, cartilage degeneration, triosis, uterine fibroid disease, hot flushes, 20 increased levels of LDL terol, cardiovascular disease, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, anxiety, depression, nopausal depression, postpartum depression, premenstrual syndrome, manic depression, ia, obsessive compulsive behavior, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, irritability, impulsivity, anger ment, hearing disorders, spinal cord injury, stroke, autoimmune disease, inflammation, IBD, 25 IBS, sexual dysfunction, hypertension, l degeneration, lung cancer, colon cancer, breast , uterus cancer, prostate cancer, the bile duct cancer form named cholangiocarcinoma, benign prostatic hyperplasia, lower urinary tract symptoms, overactive bladder, interstitial cystitis, painful bladder symptoms, vaginal atrophy, wound healing, chronic pain, sepsis, inflammatory and neuropathic pain, ovarian cancer, melanoma, lymphoma, atherosclerosis, left cular hypertrophy, congestive heart 30 failure, mesothelioma, gallbladder cancer and hepatic cholangiocarcinoma.

24. The compound of claim 1 according to formula (I) or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such an ester, amide or carbamate, substantially as hereinbefore described with reference to any one of the ing Examples.