Salicylic acid and picolinic acid derivatives as inhibitors of energy coupling factor (ECF) transporters for the treatment of bacterial infections

Abstract

The present invention relates to novel inhibitors of the Energy Coupling Factor (ECF) Transporters. These compounds of general formula (I) are useful in the treatment of bacterial infections, especially caused by Streptococcus pneumoniae, Enterococcus faecium, Enterococcus faecalis.

Description

[0001] SALICYLIC ACID AND PICOLINIC ACID DERIVATIVES AS INHIBITORS OF ENERGY COUPLING FACTOR (ECF) TRANSPORTERS FOR THE TREATMENT OF BACTERIAL INFECTIONS

[0002] The present invention relates to novel inhibitors of the Energy Coupling Factor (ECF) Transporters. These compounds are useful in the treatment of bacterial infections, especially caused by Streptococcus pneumoniae, Enterococcus faecium, Enterococcus faecalis.

[0003] The energy-coupling factor (ECF) transporters are a family of transmembrane proteins involved in the uptake of vitamins into a wide range of bacteria. The term ECF transporter was coined in the 1970s to describe transporters that are used in Lactobacillus casei for the uptake of vitamins.1Later on, ECF transporters have been found to be particulary abundant in the Firmicutes phylum of Gram-positive bacteria, including human pathogenic species.2Importantly, they are not present in eukaryotes and are specific importers of essential micronutrients such as water-soluble vitamins (folate3, riboflavin4, cobalamin5, biotin6, niacin7, thiamine8, pantothenate9) and metal cations (Ni2+and Co2+)10into bacteria and archaea. Clinically relevant bacteria where the ECF tranporters genes are essential are: S. pneumoniae, Staphylococcus aureus, E. faecium, E. faecalis, Clostridium tetani, C. novyi and C. difficile.''’' Therefore, ECF transporters can be considered as novel potential antimicrobial targets to tackle infection due to their central role in the metabolism of bacteria.

[0004] They belong to the adenosine 5’-triphosphate (ATP)-binding cassette (ABC) transporters and consist of two ATP-hydrolyzing, nucleotide-binding domain named ECF-A and, two transmembrane proteins, termed ECF-T and the S-component.12'13The ECF-A and ECF-T together form the tricomponent ECF module.13Main scaffold of the entire complex is the integral membrane ECF-T having a coupling domain on the cytoplasmatic side and two long a-helices that are arranged in X shape. These a- helices interact tightly with the ATPases and moved jointly when, upon nucleotide binding and release, the ATPase switch between the open and closed conformation. The S-components are integral membrane proteins (20-25 KDa) and bind the substrate to be transported. This organization is typical and a unique feature for the ECF transporters, as other ABC utilize a soluble substrate-binding protein to capture ligands.14

[0005] ECF transporters are classified into two groups, group-l and -II. The ECF module in group-l interacts exclusively with a single “dedicated” S-component, whereas the module in group-ll interacts with different ones. The present invention describes novel inhibitors of the ECF-type II, meaning that multiple S-components (specific for different substrate) can interact with the same ECF module,15opening up the possibility to simultaneously block the uptake of several vitamins at the same time with only one inhibitor.

[0006] Despite the important role played by the ECF transporters, so far, substrate mimicking the thiamine for the S-component ThiT from Lactococcus lactis™ and small molecules with limitations for drug-discovery hit-to-lead optimization have been reported.17’18

[0007] The present invention provides compounds of formula (I): wherein

[0008] A is N or CR2;

[0009] X is a group of formula -Ar1-Ar2-; a group of formula -Ar1a(-Ar2a)-Ar2-; a group of formula -Ar1a(-Ar2a)-; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 1Q ring atoms selected from C, N, O and S; Ar1is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;

[0010] Ar1ais a phenyl group;

[0011] Ar2is an optionally substituted phenylene group; an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S; or an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O;

[0012] Ar2ais an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S;

[0013] L1is selected from the following groups: -O-; -NH-; -O-CH2-; -CO-NH-; -NH-CO-; -SO2- NH-; -NH-CH2-; -NH-SO2-; -NH-CO-NH-; or a triazole group;

[0014] L2is a bond or selected from the following groups: -O-; -NH-; -CH2-; -O-CH2-;

[0015] -SO2-O-; -SO2-; -NH-SO2-; -SO2-NH-; -CO-; -CO-O-; -CO-NH-; -NH-CO-; -NH-SO2- (CH2)n, wherein n is 1, 2, 3 or 4; -NH-CO-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO- (CH2)O-O-, wherein o is 1 , 2, 3 or 4;

[0016] R1is a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; or a group of formula -X1- Ar3;

[0017] X1is a C1-10 alkylene group; a C1-10 heteroalkylene group; an optionally substituted C3- 7 cycloalkylene group; an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;

[0018] Ar3is an optionally substituted phenyl group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;

[0019] R2is a hydroxy group; or a group of formula -NH-R3;

[0020] R3is a group of formula -CO-O-R3a; -CO-NH-R3b; or -CO-R3c;

[0021] R3ais an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted;

[0022] R3bis an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted; and

[0023] R3cis an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyi; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted; or a salt thereof.

[0024] The present invention further provides compounds of formula (I): wherein

[0025] A is N or CR2;

[0026] X is a group of formula -Ar1-Ar2-; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;

[0027] Ar1is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;

[0028] Ar2is an optionally substituted phenylene group; an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S; or an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O;

[0029] L1is selected from the following groups: -O-; -NH-; -O-CH2-; -CO-NH-; -NH-CO-; -SO2- NH-; or a triazole group;

[0030] L2is a bond or selected from the following groups: -O-; -NH-; -CH2-; -O-CH2-;

[0031] -SO2-O-; -SO2-; -NH-SO2-; -SO2-NH-; -CO-; -CO-O-; -CO-NH-; -NH-CO-; -NH-SO2- (CH2)n, wherein n is 1 , 2, 3 or 4; -NH-CO-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO- (CH2)O-O-, wherein o is 1 , 2, 3 or 4;

[0032] R1is a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycioalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; or a group of formula -X1- Ar3;

[0033] X1is a C1-10 alkylene group; a C1-10 heteroalkylene group; an optionally substituted C3- 7 cycloalkylene group; an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;

[0034] Ar3is an optionally substituted phenyl group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;

[0035] R2is a hydroxy group; or a group of formula -NH-R3;

[0036] R3is a group of formula -CO-O-R3a; -CO-NH-R3b; or -CO-R3c;

[0037] R3ais an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted;

[0038] R3bis an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted; and

[0039] R3cis an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted; or a salt thereof.

[0040] Preferably, A is a group of formula C-OH.

[0041] Further preferably, A is N.

[0042] Moreover preferably, L1is selected from the following groups: -NH-; -O-CH2-; -CO-NH- ; -NH-CO-; -SO2-NH-; -NH-CH2-; -NH-SO2-; -NH-CO-NH-; or a triazole group. Further preferably, L1is a group of formula -O-CH2-.

[0043] The present invention further provides compounds of formula (II): wherein X, L2and R1are as defined above or below; or a salt thereof.

[0044] Moreover preferably, X is a group of formula -Ar1-Ar2-.

[0045] Further preferably, Ar1is an optionally substituted phenylene group; an optionally substituted pyridylene group; an optionally substituted pyrimidinylene group; or an optionally substituted thiazolylene group.

[0046] Moreover preferably, Ar1is selected from the following groups:

[0047] Further preferably, Ar2is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S. Further preferably, Ar2is an optionally substituted phenylene group; an optionally substituted pyridylene group; an optionally substituted piperazinylene group; or an optionally substituted indolylene group. wherein R5is halogen, a C1-4 alky group or a C1-4 heteroalkyl group; p is 1 or 2; R5is halogen, a C1-4 alky group or a C1-4 heteroalkyl group; and q is 0, 1 or 2.

[0048] Further preferably, Ar2is selected from the following groups:

[0049] wherein R5is halogen, a Ci-4 alky group or a C1-4 heteroalkyl group; p is 1 or 2; R6is halogen, a C1-4 alky group or a C1-4 heteroalkyl group; and q is 0, 1 or 2.

[0050] Further preferably, X is an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S.

[0051] Moreover preferably, X is selected from the following groups:

[0052] Further preferably, X is an optionally substituted phenylene group.

[0053] Further preferably, X is a group of formula -Ar1a(-Ar2a)-Ar2- (i.e., a group of the following formula group of formula -Ar1a(-Ar2a)- (i.e., a group of the following formula:

[0054] Moreover preferably, Ar1ais a 1 ,3,5-phenyl group. Further preferably, Ar2ais an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S.

[0055] Moreover preferably, Ar2ais an optionally substituted pyridyl group; or an optionally substituted thiophenyl group; or an optionally substituted triazole group.

[0056] Further preferably, L2is -O-; -CH2-; -O-CH2-; -SO2-; -SO2-NH-; -NH-SO2-; -SO2-O-; - CO-; -CO-O-; -NH-SO2-(CH2)n, wherein n is 1 , 2, 3 or 4; -NH-CO-; -NH-CO-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO-(CH2)o-O-, wherein o is 1 , 2, 3 or 4.

[0057] Moreover preferably, L2is a bond or selected from the following groups: -O-; -NH-; - CH2-; -O-CH2-; and -CO-.

[0058] Moreover preferably, L2is -O-; -CH2-; or -O-CH2-.

[0059] Further preferably, R1is a C1-10 alkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S.

[0060] Moreover preferably, R1is an optionally substituted phenyl group.

[0061] Further preferably, the present invention provides compounds of formula (II): wherein X is a group of formula -Ar1-Ar2-;

[0062] Ar1is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;

[0063] Ar2is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;

[0064] L2is a bond or selected from the following groups: -O-; -NH-; -CH2-; -O-CH2-;

[0065] -SO2-O-; -SO2-; -NH-SO2-; -SO2-NH-; -CO-; -CO-O-; -CO-NH-; -NH-CO-; -NH-SO2- (CH2)n, wherein n is 1, 2, 3 or 4; -NH-CO-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO- (CH2)O-O-, wherein o is 1 , 2, 3 or 4;

[0066] R1is a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, 0 and S; or a group of formula -X1- Ar3;

[0067] XIis a C1-10 alkylene group; a C1-10 heteroalkylene group; an optionally substituted C3- 7 cycloalkylene group; an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;

[0068] Ar3is an optionally substituted phenyl group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S; and wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O-; or a salt thereof.

[0069] Moreover preferably, Ar1is selected from the following groups: Further preferably, Ar2is selected from the following groups:

[0070] Moreover preferably, L2is selected from the following groups: -O-; -O-CH2-; -NH-SO2- ; and -CO-O-.

[0071] Further preferably, R1is a C1-6 alkyl group; or an optionally substituted phenyl group; wherein the optional substituents are preferably selected from F; Cl; -CH3; -O-CH3; - O-CF3; and -CF3.

[0072] Further preferably, the present invention provides compounds of formula (III): wherein

[0073] X is a phenylene group (especially a 1 ,4 phenylene group; or a 1 ,3 phenylene group); and

[0074] R1is an optionally substituted phenyl group; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O- (especially from F; Cl; -CH3; -O- CH3; -O-CF3; and -CF3); or a salt thereof.

[0075] Further preferably, the present invention provides compounds of formula (IV):

[0076] wherein

[0077] X is a phenylene group (especially a 1 ,4 phenylene group; or a 1 ,3 phenylene group); and

[0078] R1is an optionally substituted phenyl group; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O- (especially from F; Cl; -CH3; -O- CH3; -O-CF3; and -CF3); or a salt thereof.

[0079] Further preferably, the present invention provides compounds of formula (V): wherein

[0080] Ar2ais an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; or a group of formula -Ar2-L2-R1;

[0081] Ar2is an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;

[0082] L2is a bond or selected from the following groups: -0-; and -CH2-; and

[0083] R1is a C1-10 alkyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O- (especially from F; Cl; -CH3; - CH2CH3; -CH(CH3)2; -O-CH3; -O-CF3; and -CF3); or a salt thereof.

[0084] Further preferably, the present invention provides compounds of formula (VI): wherein

[0085] X is a group of formula -Ar1-Ar2-;

[0086] Ar1is the following group:

[0087] Ar2is selected from the following groups:

[0088] L2is a group of formula -O-CH2-;

[0089] R1is an optionally substituted phenyl group;

[0090] R3is a group of formula -CO-O-R3a; -CO-NH-R3b; or -CO-R3c; and

[0091] R3a;R3b; and R3care selected from a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; or a group of formula -CH2-cyclopropyl; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O-; or a salt thereof.

[0092] The most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.

[0093] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment for R1may be combined with any embodiment of X).

[0094] The term "optionally substituted" refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two) substituents.

[0095] If a group comprises more than one substituent, these substituents are independently selected, i.e. , they may be the same or different.

[0096] If a group is substituted by a cyclic group, such as e.g., a cycloalkyl group or a heterocycloalkyl group, this cyclic group may be bonded to this group via a single or double bond or this cyclic group may be annulated or fused to said group.

[0097] Examples for substituents are fluorine, chlorine, bromine and iodine and OH, =0, SH, NH2, -SO3H, -SO2NH2, -COOH, -COOMe, -COMe (Ac), -NHSO2Me, -SO2NMe2, - CH2NH2, -NHAc, -S02Me, -CONH2, -CN, -NHCONH2, -NHC(NH)NH2, -NOHCH3, -N3 and -NO2 groups. Further examples of substituents are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C1-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C1-C19 heteroalkylcycloalkyl, C6-C18 aryl, C1-C17 heteroaryl, C7-C20 aralkyl and C1-C19 heteroaralkyl groups; especially Ci-Ce alkyl, C2-C6 alkenyl, C2-C0 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl and C1-C11 heteroaralkyl groups, further preferably Ci-Ce alkyl and Ci-Ce heteroalkyl groups.

[0098] Preferably, the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl (e.g.: CH3, CH2CH3, CF3); C1-8 heteroalkyl (e.g., -O-C1-8 alkyl, such as e.g., OCH3, OCF3, OCH(CH3)2; CH2OH; CH2NH2; -CO-O-C(CH3)3, CH2-NH-CO-O- C(CH3)3); -O-CH2-CH2-; and -O-CH2-O-.

[0099] The suffix "-ene" like e.g., in "phenylene" refers to the corresponding divalent group.

[0100] The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 15 carbon atoms, especially from 1 to 10 (e.g., 1 , 2, 3 or 4) carbon atoms, for example a methyl (Me, CH3), ethyl (Et), n-propyl (nPr), / so-propyl ( / Pr), n-butyl (nBu), / so-butyl ( / Bu), sec-butyl (sBu), tert-butyl (fBu), n-pentyl, / so-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

[0101] Especially preferred alkyl groups are C1-6 alkyl groups; moreover preferred alkyl groups are C1-4 alkyl groups.

[0102] The expression C1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms. The expression C1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl or tert-butyl group.

[0103] The expressions alkenyl and alkynyl refer to at least partially unsaturated, straightchain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g., 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl (acetylenyl), propynyl (e.g., propargyl), butynyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).

[0104] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2,2,2-trichloroethyl or a trifluoromethyl group.

[0105] The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group as defined above, in which one or more (preferably 1 to 8; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO2 group. A heteroalkyl group contains at least one carbon atom.

[0106] Accordingly, the expression heteroalkyl also refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.

[0107] Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0108] Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g., 1, 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). The term C1-C10 heteroalkyl refers to a heteroalkyl group containing from 1 to 10 carbon atoms and 1 , 2, 3, 4, 5 or 6 heteroatoms selected from O, S and / or N (especially O and / or N). The term C1-C6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from 0, S and / or N (especially O and / or N). The term C1-C4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and / or N (especially O and / or N).

[0109] Further preferably, the expression heteroalkyl refers to an alkyl group as defined above (straight-chain or branched) in which one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, sulfur or nitrogen atom or a CO group or a SO group or a SO2 group; this group preferably contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen); this group may preferably be substituted by one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or OH, =0, SH, =S, NH2, =NH, N3ICN or NO2 groups.

[0110] Examples of heteroalkyl groups are groups of formulae: Ra-0-Ya-, Ra-S-Ya-, Ra-SO-Ya-, Ra-SO2-Ya-, Ra-N(Rb)-SO2-Ya-, Ra-SO2-N(Rb)-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-,

[0111] Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-,

[0112] Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-, wherein Rabeing a hydrogen atom, a C1-C6 alkyl, a

[0113] C2-C6 alkenyl or a C2-C6 alkynyl group; Rbbeing a hydrogen atom, a C1-C6 alkyl, a

[0114] C2-C6 alkenyl or a C2-C6 alkynyl group; Rcbeing a hydrogen atom, a C1-C6 alkyl, a

[0115] C2-C6 alkenyl or a C2-C6 alkynyl group; Rdbeing a hydrogen atom, a C-i-Ce alkyl, a

[0116] C2-C6 alkenyl or a C2-C6 alkynyl group and Yabeing a bond, a Ci-Ce alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, / so-propyloxy, n-butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, -SCteMe, -NHAc, methoxyethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, A / -ethyl- / V-methyl- carbamoyl or / V-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile (- CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0117] The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. Preferably, the expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2- cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, propellane (e.g., [1.1.1]propellane) tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group. Preferably, the expression cycloalkyl refers to a saturated cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.

[0118] The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heterocycloalkyl group has preferably 1 or 2 ring(s) and 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Preferably, the expression heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g., -N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides. A heterocycloalkyl group contains at least one carbon atom.

[0119] The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings and from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.

[0120] The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heteroaikylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroaikylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or triunsaturated.

[0121] The expression aryl refers to an aromatic group that contains one or more rings and from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Preferably, the expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH.2, N3 or NO2 groups. Examples are the phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

[0122] The expression heteroaryl refers to an aromatic group that contains one or more rings and from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Preferably, the expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridyl (4-pyridonyl), 3,4- hydroxypyridyl (3, 4-pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g., 3-pyrazolyl) and isoquinolinyl groups. A heteroaryl group contains at least one carbon atom.

[0123] The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are phenylcyclopentyl, cyclohexylphenyl as well as groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 / - / -indene, tetraline, dihydronaphthalene, indanone, cumene, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 3, 4, 5, 6 or 7 ring carbon atoms. The expression heteroaralkyl refers to groups containing both aryl and / or heteroaryl groups and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, O and S) and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and N and / or one or two cycloalkyl groups each containing 3, 4, 5, 6 or 7 ring carbon atoms and / or one or two heterocycloalkyl groups, each containing 3, 4, 5, 6 or 7 ring atoms comprising 1 , 2, 3 or 4 oxygen, sulfur or nitrogen atoms. A heteroaralkyl group preferably contains at least one oxygen, nitrogen or sulfur atom.

[0124] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsatu rated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.

[0125] As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, NS or NO2 groups.

[0126] The term halogen refers to F, Cl, Br or I. When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated or fused or bridged.

[0127] Owing to their substitution, the compounds of the present invention may contain one or more centers of chirality. The present invention therefore includes both all pure enantiomers and all pure diastereomers and also mixtures thereof in any mixing ratio. The present invention moreover also includes all c / s / trans-isomers of the compounds of the present invention and also mixtures thereof. The present invention moreover includes all tautomeric forms of the compounds of the present invention.

[0128] The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a salt, solvate or hydrate thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants. The pharmaceutical composition of the present invention may contain a further antibacterial compound.

[0129] The present invention furthermore provides compounds or pharmaceutical compositions as described herein for use in the treatment of bacterial infections, especially caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis; especially by inhibiting the Energy Coupling Factor (ECF) Transporters.

[0130] The present invention further provides a compound as described herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of bacterial infections, especially caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis; especially by inhibiting the Energy Coupling Factor (ECF) Transporters.

[0131] According to a further preferred embodiment, the present invention provides a method for the treatment of bacterial infections, especially caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis in a subject by inhibiting the Energy Coupling Factor (ECF) Transporters which comprises administering to the subject an effective amount of a compound as described herein or of a pharmaceutical composition as defined herein.

[0132] According to a moreover preferred embodiment, the present invention provides a method for treating a bacterial infection, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein or of a pharmaceutical composition as defined herein.

[0133] According to a moreover preferred embodiment, the present invention provides a method for treating a bacterial infection caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein or of a pharmaceutical composition as defined herein.

[0134] Examples of salts (especially of pharmacologically acceptable salts) of sufficiently basic compounds are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein.

[0135] The compounds described herein may be solvated, especially hydrated. The solvation / hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water-free compounds. The solvates and / or hydrates may e.g. be present in solid or liquid form. The therapeutic use of the compounds described herein, their salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

[0136] In general, the compounds and pharmaceutical compositions described herein will be administered by using the established and acceptable modes known in the art.

[0137] For oral administration, such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g., liquid aerosol), transdermal, for example via an transdermal drug delivery system (TDDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules, one may use excipients as are e.g., vegetable, petroleum, animal or synthetic oils, wax, fat, and polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g., water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations, one may use compressed gases suitable for this purpose, e.g., oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g., UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.

[0138] In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 1 mg to about 10,000 mg, preferably from about 5 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

[0139] EXAMPLES

[0140] 1. Chemistry

[0141] 1.1 General information

[0142] Solvents for synthesis, analysis and purification were purchased as analytical-grade from commercial suppliers and used directly without further purification. Chemical reagents were purchased as reagent-grade and used without further purification.

[0143] NMR spectra were recorded on a Bruker UltraShield Plus 500 MHz device. LC-MS analysis were measured on a LC-MS system, consisting of a Thermo Scientific Dionex UltiMate 3000 pump, autosampier, column compartment, and detector (Thermo Fisher Scientific, Dreieich, Germany) and ESI quadrupole MS (MSQ Plus or ISQ EC, Thermo Fisher Scientific, Dreieich, Germany). High-resolution mass was determined by LC- MS / MS using Thermo Scientific Q Exactive Focus Orbitrap LC-MS / MS system. Flash chromatography was performed using either a Teledyne ISCO CombiFlash Rf+ 150 or a Teledyne ISCO CombiFlash NEXTGEN 300+ equipped with RediSepRf silica columns. Preparative HPLC was performed on a Thermo Scientific Dionex Ultimate 3000 system. General methods for preparative HPLC:

[0144] General Method acid:

[0145] MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular Preparative HPLC System; column: Waters XSelect (C18, 100x30mm, 10pm); flow: 55 ml / min prep pump; column temp: RT; eluent A: 0.1% formic acid in water; eluent B: 100% acetonitrile; gradient based on the retention time on LC-MS; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100 - 800; fraction collection based on MS and DAD.

[0146] OR

[0147] HPLC instrument type: UltiMate 3000 Semi-Preparative System (Thermo Fisher Scientific); column: nucleodur® C18 Gravity (250 mm x 10 mm, 5 pm); flow: 10 ml / min pump; column temp: RT; eluent A: 0.05% formic acid in water; eluent B: 100% acetonitrile; gradient based on the retention time on LC-MS; detection: DAD (220-320 nm); fraction collection based on DAD.

[0148] General Method base:

[0149] MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular Preparative HPLC System; column: Waters XSelect (C 18, 100x30mm, 10pm); flow: 55 ml / min prep pump; column temp: RT; eluent A: 10mM ammonium bicarbonate in water pH=9.5, eluent B: 100% acetonitrile; gradient based on the retention time on LC-MS; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100 - 800; fraction collection based on MS and DAD.

[0150] 1.2 General synthesis schemes

[0151] The compounds of the present invention can be prepared according to the synthesis schemes shown in Schemes 1 to 13. Scheme 1. Synthesis of 1—30.

[0152] 27) X = N; W=CH, Y 58% 30) Y = 63%

[0153] 28)X = CH; W=N, Y= 28%

[0154] Scheme 2. Synthesis of 31—39.

[0155] 39, Y= 95%

[0156] Scheme 3. Synthesis of compounds 40—51.

[0157] Scheme 4. Synthesis of compounds 52—57.

[0158] Scheme 5. Synthesis of compounds 58—68.

[0159] Scheme 6. Synthesis of compounds 69—82.

[0160] 77, Y = 22%

[0161] 81, Y = 15%

[0162] 82, Y = 33%

[0163] Scheme 7. Synthesis of compounds 83—85.

[0164] Scheme 8. Synthesis of compounds 86—90.

[0165] Scheme 9. Synthesis of 92 and 93,

[0166] Scheme 10. Synthesis of compounds 95—98.

[0167] Scheme 11. Synthesis of compounds 99—103.

[0168] Scheme 12. Synthesis of compounds 104—112.

[0169] 105, Y = 4% 109, Y = 44%

[0170] 106, Y = 38%

[0171] 110, Y = 45%

[0172] 107, Y = 6% 111, Y= 18% 108, Y= 10% 112, Y = 6%

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] Scheme 1 shows the synthesis of compounds 1 to 30. Reagents and conditions: a) Acetone, TFA, TFAA, 90 °C, overnight; b) BrBnBr, K2CO3, DMF, 65 °C, overnight; c) Substituted phenyl boronic acid, [Pd(PPh3)4], K2CO3, 1 ,4-dioxane / H2O, MW @ 100°C for 2h (3) or 45 min (4); d) Alk-OH, CMBP, toluene, 50 °C, overnight (5—16); e) Ar- B(OH)2, CU(II)AC2, pyridine, ACN at 65 °C or DCM (19-26); f) Amines, DMAc, rt for 1 h, then STAB, 40 °C, overnight; g) HCI cone., ACN / H2O, 9:1, overnight.

[0179] Scheme 2 shows the synthesis of compounds 31 to 39. Reagents and conditions: a), K2CO3, aromatic bromide, acetone, rt, 2h); b) NaOH (in aq. 10%, 10 eq.), MeOH, 65 °C, overnight, c) (3-((3-chlorobenzyl)oxy)phenyl)boronic acid, K2CO3, palladium catalyst (0.05 eq.) ([Pd(PPh3)4] or [Pd(dppf)Cl2], 1 ,4-dioxane / H2O (0.2 M) , MW @ 60 or 80 °C for 40 min d) Substituted phenyl boronic acid, K2CO3, [Pd(dppf)Cl2], 1 ,4- dioxane / FhO (0.2 M) , MW @ 60°C for 40 min, e) propane-2-sulfonyl chloride, pyridine, CH2CI2, 0° to rt, 30 min.

[0180] Scheme 3 shows the synthesis of compounds 40 to 51. Reagents and conditions: a) substituted phenyl boronic acid, K2CO3, [Pd(PPh3)4], 1 ,4-dioxane / H2O (0.2 M) , MW @ 80 °C for 40 min.

[0181] Scheme 4 shows the synthesis of compounds 52 to 57. Reagents and conditions: a) K2CO3, 2-bromo-5-(bromomethyl)pyrimidine, acetone, rt, 2 h (for 52a); b) substituted aromatic boronic acid, K2CO3, palladium catalyst (0.05 eq.) ([Pd(PPh3)4] or [Pd(dppf)Cl2], 1,4-dioxane / H2O (0.2 M) , MW @ 60 or 80 °C for 40 min (for 53a— 57a); c) NaOH (in aq. 10%, 10 eq.), MeOH, 65°C, overnight. (55-57) d) (CH3)3SnOH, dichloroethane, 80°C, on (for 52 and 53).

[0182] Scheme 5 shows the sulfonamide formation (compounds 58 to 68). Reagents and conditions: a) substituted sulfonyl chloride, pyridine, CH2CI2 from 0 °C to room temperature for 2 hours (for 58a— 60a); a1) substituted sulfonyl chloride (1.3 eq.), DMAP (0.25 eq.), DIPEA (1.5 eq.) in pyridine, room temperature, overnight (for 61a— 67a); a2) THF, 2,4-dimethyl-1 ,3-thiazole-5-sulfonyl chloride, TEA, 60 °C, 18 h for 68; b) NaOH (in aq. 10%, 10 eq.), MeOH, 65°C, overnight (for 58-60); b1) THF, 1 M NaOH, room temperature for 18 hours (for 61—67).

[0183] Scheme 6 shows the amide formation (compounds 69 to 82). Reagent and conditions: a) Substituted carboxylic acids, HATU, DIPEA in DMAc, rt for 18 h; b) NaOH 1 M, THF, room temperature for 18 hours.

[0184] Scheme 7 shows the formation of compounds 83—85. Reagent and conditions: a) alcohol, KOtBu, THF; b) [Pd(PPh3)4], KOAc, dioxane.

[0185] Scheme 8 shows the formation of compounds 86—90. Reagent and conditions: a) corresponding sulfonyl chloride, DMAP, DIPEA, THF, rt for 18h, followed by treatment with HCI in MeCN / HzO (Y = 60, 20%) ; b) corresponding carboxylic acid, HATU, DIPEA, DMAc, 18h, 80 °C followed by treatment with HCI in MeCN / H2O (Y = 38, 31%).

[0186] Scheme 9 shows the formation of compounds 92 and 93. Reagent and conditions: a) corresponding sulfonyl chloride, DMAP, DIPEA, DCE, rt for 18h, followed by treatment with HCI in MeCN / HsO (Y = 17%) ; b) corresponding carboxylic acid, HATU, DIPEA, DCE, 18 h, 80 °C followed by treatment with HCI in MeCN / HzO (Y = 10%).

[0187] Scheme 10 shows the formation of compounds 95—98. Reagent and conditions: a) corresponding sulfonyl chloride, DMAP, DIPEA, DCE, rt for 18h, followed by treatment with HCI in MeCN / HsO (Y = 28 and 15%) ; b) corresponding carboxylic acid, HATU, DIPEA, DCE, 18h, 80 °C followed by treatment with HCI in MeCN / H2O (Y = 18 and 6%).

[0188] Scheme 11 shows the formation of compounds 99—103. Reagent and conditions: a) corresponding sulfonyl chloride, NaOH, tetrabutylammonium hydrogen sulfate, DCM, rt for 18h, followed by treatment with HCI in MeCN / H2O (Y = 8-59%) ; b) corresponding carboxylic acid, HATU, DIPEA, DMAc, 18h, 100 °C followed by treatment with HCI in MeCN / H2O (Y = 40%). Scheme 12 shows the formation of compounds 104—112. Reagent and conditions: a) methyl 5-hydroxy-2-nitrobenzoate, K2CO3, acetone, 18 h, rt (Y = 60%); b) (4-((3- chlorobenzyl)oxy)phenyl)boronic acid, [Pd(PPhs)4], K2CO3, dioxane / H2O, 90 °C for 2 h (Y = 71 %); c) Fe, NH4CI, H2O, THF:MeOH 75 °C, 4h (Y = 79%); d) corresponding chloroformate / alcohol, TEA, DMAP; e) LiOH, THF:H2O (Y = 4—45%, over steps d and e).

[0189] Scheme 13 shows the formation of compounds 113—123. Reagent and conditions: a) NaOH, H2O / THF, b) corresponding isocyanate, TEA, DCM, rt, 18 h (for 114—116, 13—28%) c) corresponding amine, triphosgene, TEA, DCM (for 117 and 118, 9.5%, 53%); d) HATU, DIPEA, DMF (for 119-123, 19-46%).

[0190] Scheme 14 shows the formation of compounds 124—127. Reagent and conditions: a) benzyl bromide derivative, K2CO3, acetone, rt, 3 h (124b, Y = 65%); b) 10% aq. NaOH, MeOH, reflux, on; c) Ar-B(OH)2, K2CO3, Pd(PPh3)4, 1 ,4-Dioxane / H2O (6:1), 85 °C, 1 h, microwave.

[0191] Scheme 15 shows the formation of compounds 128—131. Reagent and conditions: a) PBr3, pyridine, DCM, 0 °C to rt, on; b) 128f, K2CO3, acetone, rt, on; c) Boronic acid, [Pd(PPh3)l, K2CO3, dioxane / H2O (6:1), 80 °C (MW), 30 min, (128d, Y = 68 %); d) Fe, NH4CI, EtOH / H2O 3:1 , 80 °C, 1 h; e) NaNO2, NaN3, dioxane / HCI (6M) 1 :1 , 0 °C to rt, 1 h (128b, Y = 85%); f) NaOH (10% in aq.), MeOH, 60 °C, 48 h; g) CuSO4x(H2O)5, sodium ascorbate, THF / H2O (2:1), rt, 60 min.

[0192] Scheme 16 shows the formation of compounds 132—144. Reagent and conditions: a) EtOAc, pyridine, T3P, 40 °C, 12 h; b) ester, THF, LiOH, r.t, 15 min.

[0193] Scheme 17 shows the formation of compounds 145—148. Reagent and conditions: a) DMF, corresponding isocyanate, rt, 1 h (for 145, 38%); b) EtOAc, pyridine, T3P, 40 °C, 12 h (for 146, 57%); c) methyl 4-bromopicolinate, 4-phenoxyaniline, Xantphos, palladium (II) acetate, CS2CO3, 1 -butanol, 95 °C, 16h (for 147); d) Azide derivative, corresponding alkyne, (THF / H2O, 2:1) sodium ascorbate, CuSO4-5H2O, 2d, 65 °C (for 148, 58%); e) ester, THF, LiOH, r.t., 15 min (for 145-146); f) ester, MeOH, NaOH, 65 °C (for 148).

[0194] 1.3 Abbreviations

[0195] DMAc (A / ,A / -Dimethylacetamide); Cu(0Ac)2 (Copper II Acetate); TFA (trifluoro acetic acid); TFAA (trifluoroacetic anhydride); fBu3PH BF4 (tri-tert-butylphosphonium tetrafluoroborate); CMBP (tributylphosphoranylidene)acetonitrile solution; DMAP (4- (dimethylamino)pyridine); KOAc (potassium acetate); STAB (sodium triacetoxyborohydride); PBrs (Phosphorus tribromide); DIAD (Diisopropyl azodicarboxylate); PPhs (Triphenylphosphine); (CHsJsSnOH (Trimethyltin hydroxide)

[0196] 1.4 General procedures

[0197] General procedure A (GP-A): Chan-Lam coupling

[0198] To a mixture of phenol 3 (56 mg, 0.15 mmol, 1 equiv), aryl boronic acid (2 equiv) and CU(OAC)2 (60 mg, 0.33 mmol, 2.2 equiv) in CH2CI2 or MeCN (1.5 mL) was added pyridine (49 μL, 0.60 mmol, 4 equiv) and mol. sieves (3A), and the reaction was stirred in an open vial at room temperature or 65 °C overnight. When the solvent had evaporated, additional solvent was added, the solids were resuspended and stirring continued. To the reactions that showed partial conversion, additional boronic acid (2 equiv), pyridine (49 μL, 0.60 mmol, 4 equiv) and Cu(OAc)2 (1 equiv) were added and stirring was continued overnight.

[0199] The reaction was diluted with solvent, the suspension was filtered over celite, the residue was washed with additional CH2CI2. Aq. NH4OH (32%) was added to the filtrate and the mixture was shaken vigorously, the layers were separated using a phase separator and the organic layer was concentrated in vacuo. The crude was dissolved in a mixture of MeCN and DMSO, filtered (0.45 pm) and purified by basic preparative HPLC-MS to yield the desired compounds.

[0200] General procedure B (GP-B): Reductive amination To aldehyde 4 (1 eq.) in DMAc (1 mL) was added amine (1 .5 or 2.5 eq. as stated) and the reaction was stirred for at room temperature for 1 hour. STAB (2.5 eq.) was added and stirring was continued at 40 °C overnight. The reaction mixture was filtered and purified by basic preparative HPLC-MS to yield final compounds.

[0201] General procedure C (GP-C): Mitsunobu coupling

[0202] To a mixture of phenol 3 (38 mg, 0.10 mmol, 1 equiv) and alkyl alcohol (2 - 4 equiv, as stated) in toluene (0.5 mL) was added CMBP (52 μL, 0.20 mmol, 2 equiv) and the reaction was stirred at 50 °C overnight. To reactions that showed partial conversion, additional alcohol (2 equiv) and CMBP (52 μL, 0.20 mmol, 2 equiv) were added and stirring was continued at 50 °C overnight. The reaction mixture was concentrated in vacuo, redissolved in MeCN, filtered (0.45 pm) and purified by basic preparative HPLC- MS to yield the desired compounds

[0203] General procedure D (GP-D): Acetal deprotection

[0204] The crude was redissolved in a mixture of MeCN and water (9:1 , 1 mL), cone. HCI (0.2 mL, 2.4 mmol) was added and the reaction was stirred at room temperature overnight.

[0205] General procedure E (GP-E): Etherification of salicylic acid

[0206] To a solution of methyl-2,5-dihydroxybenzoate (1.1 eq.) and K2CO3 (2 eq.) dissolved in acetone (0.15 M), the desired benzyl bromide (1 eq.), was added and the suspension was stirred at room temperature or 60 °C (as stated) for 3 h. After LC-MS and TLC showed complete consumption of the starting materials, the solution was concentrated under vacuum and the residue was suspended in H2O. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 * 10 mL) and dried over Mg2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography.

[0207] General procedure F (GP-F): Ester saponification

[0208] To a stirred solution of ester (1 eq.) in MeOH or THF as stated (0.1 M), NaOH (in aq. 10%, 10 eq.) was added. The solution was stirred at 65 °C or room temperature (as stated) overnight, then the solvent was concentrated under vacuum and the residue was dissolved in EtOAc. HCI (1 M) was added, and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over Mg2SO4, filtered, concentrated in vacuo and purified by flash chromatography.

[0209] General procedure G (GP-G): Suzuki cross-coupling

[0210] An oven-dried microwave tube was charged with aryl halide (1.0 eq.), phenylboronic acid (1.0 or 2.5 eq., as stated), K2CO3 (3.0 eq.) and palladium catalyst (0.05 eq.) ([Pd(PPh3)4] or [Pd(dppf)Cl2], as stated), and flushed with N2. Then, a mixture of 1 ,4- dioxane / H2O (0.2 M) was added via a syringe, and the test tube was stirred under microwave irradiation at 60 or 80 °C for 40 min, as stated. After the starting materials were consumed as indicated by UPLC-MS analysis, 1,4-dioxane was removed under vacuum, and the aqueous phase was diluted with HCI (1 M) and extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried over Mg2SO4, filtered, concentrated in vacuo and purified by flash chromatography.

[0211] General procedure H (GP-H): Sulfonylchlorides formation

[0212] To solution of aniline (1 eq.) and pyridine (2 eq., when stated) in CH2CI2 (0.15 M, when stated) was added dropwise at 0 °C the desired chloride (1.1 equiv or 1.3 eq., as stated); DIPEA (1.5 eq., when stated) and DMAP (0.25 eq., when stated) were added when stated. The reaction mixture was allowed to warm to room temperature and was stirred for 2 h or overnight as stated. After the starting materials were consumed as indicated by UPLC-MS analysis, the mixture was diluted with aq. sat. Na2COs and extracted with CH2CI2 (2 x 10 mL). The organic layers were combined, dried over Mg2SO4, filtered, concentrated in vacuo and purified by flash chromatography.

[0213] General procedure I (GP-I): Amide coupling

[0214] To a solution of the corresponding carboxylic acids (0.11 mmol, 1.3 equiv) in DMAc (0.5 mL), DIPEA was added (0.40 mmol, 3 equiv), and the reaction mixture was stirred for 10 min. Then, HATU (0.11 mmol, 1.3 equiv) was added, and the reaction mixture stirred for another 10 min. Afterwards, a solution of amine (30 mg, 0.085 mmol, 1.0 eq.) in DMAc (0.5 mL) was added and let to stir at room temperature for 18 h. The reaction mixtures were then concentrated in the Genevac and purified by acidic or basic (as stated) preparative HPLC-MS to yield the desired final compounds. General procedure J (GP-J): Carbamate formation

[0215] To a stirring solution of 104 (1.0 equiv) in DCE (2.0 mL) TEA (3.0 equiv) was added. At 0 °C is added dropwise the corresponding chloroformate (1.5 equiv) and the reaction mixture was stirred at 80 °C for 18 h.

[0216] In the case where the desired chloroformate is not available (GP-J2), to a solution of 104 is added phenyl chloroformate (3.0 equiv) and DMAP (0.1 equiv) and the reaction is stirred overnight at room temperature. After evaporating the solvent, the desired alcohol (0.5 equiv), and TEA (1 equiv) are added, and the reaction mixture was heated to 80 °C and stirred for 18 h. The mixtures were then concentrated in the Genevac, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield the desired compounds.

[0217] General procedure K (GP-K): Urea formation

[0218] To a stirring suspension of 113 (40 mg, 1 equiv, 87 pmol) in CH2CI2 (2 mL) was added EtsN (36 μL, 3 equiv, 0.26 mmol) and isocyanate (0.11 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 18 h. The reaction mixtures were then concentrated in the Genevac, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield the desired isocyanates.

[0219] In the case the desired isocyanate was not available (GP-K2). In separate vials, triphosgene (7.1 mg, 0.3 equiv, 24 pmol) was dissolved in CH2CI2 (1.0 mL) and cooled to 0 °C. Then, a solution of amine (1.2 equiv, 96 pmol) and TEA (28 μL, 2.5 equiv, 0.20 mmol) in CH2CI2 (1.0 mL) was added dropwise. After complete addition the reaction mixture was stirred at 0 °C for 1 h. Then, compound 113 (37 mg, 1 equiv, 80 pmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixtures were then concentrated in the Genevac, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC-MS.

[0220] General procedure L (GP-L): Bromination of benzylic alcohol

[0221] Under argon atmosphere, the corresponding alcohol (1 .0 equiv.) was dissolved in DCM (0.3 M) and, PBr3 (5.0 equiv.) was added at 0 °C. After 10 min, pyridine was added, and the reaction mixture was stirred at rt overnight. Once the reaction was completed, the mixture was cooled to 0 °C and quenched with H2O. The aqueous phase was extracted with DCM (3 x 10 ml_). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and purified by flash chromatography.

[0222] General procedure M (GP-M): Nitro reduction

[0223] To a suspension of the corresponding nitro compound (1.0 eq.) in ethanol / H2O (3:1 , 0.2 M) iron powder (6.0 eq.) was added at refluxing temperature. After 20 min, NH4CI (6.0 eq.) was added and the mixture was stirred for 1 h at reflux. Once the reaction was completed, the mixture was filtered over celite to remove iron residue and washed several times with EtOAc. The filtrate was partitioned with saturated Na2CO3 and the basic layer was further extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and purified by flash chromatography.

[0224] General procedure N (GP-N): Amine-to-Azide Conversion

[0225] To a solution of the amine (1.0 eq.) in 1 ,4-dioxane / HCI 6 M (0.15 M), NaNO2 (3 eq.) was added at 0 °C, and the mixture was stirred for 20 min. Then, NaN3 (4 eq.) was added slowly at 0 °C and the reaction was stirred at room temperature for 30 min. After removal of 1 ,4-dioxane under vacuum, the aqueous phase was neutralised with saturated (sat.) Na2CO3 solution and then extracted with ethyl acetate (3 x). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and used in the next step without further purification.

[0226] General procedure O (GP-O): Copper-catalyzed azide-alkyne cycloaddition (CuAAC) The azide (1.0 eq.) and alkyne (1.0 eq.) derivatives were dissolved in (THF / H2O: 2:1 , 0.4 M). Sodium ascorbate (0.4 eq.) was added, followed by the addition of copper (II) sulfate pentahydrate (0.2 eq.). The resulting reaction was vigorously stirred for 20 min -3 h at room temperature. Then, THF was removed under vacuum, and the mixture diluted with EtOAc. The aqueous phase was acidified with HCI (2 M) until pH 2-3, and extracted with EtOAC (3 x 10 mL). The organic solvent was dried over MgSO4 and evaporated under reduced pressure. Purification was done by semi-preparative HPLC. General Procedure P (GP-P): Amide Coupling (Picolinic acid analogues)

[0227] To a solution of the respective carboxylic acid (1 equiv.) and methyl 4-aminopicolinate (5a) (1.1 equiv.) in EtOAc (0.15 M) and pyridine (70 equiv.), T3P (11 equiv.) was added. The reaction mixture was stirred at 40 °C overnight. After cooling to rt, the reaction mixture was poured into concentrated aq. Na2CO3 solution and extracted with EtOAc (3 x). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by preparative HPLC to afford the respective methyl esters.

[0228] General procedure Q (GP-Q): Ester hydrolysis (Picolinic acid analogues)

[0229] To a suspension of the corresponding ester (1 equiv.) in THF (0.3 M), an aq. solution of LiOH (4M) was added and the reaction mixture was stirred at rt for 15-30 min. After completion of the reaction, THF was removed under vacuum and the reaction mixture was treated with 2M HCI (3-4) and the aq. phase was extracted with a mixture of CHCI3 / i-PrOH (3:1). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by preparative HPLC to afford the respective acid.

[0230] 2. Synthesis of compounds

[0231] 6-Hydroxy-2,2-dimethyl-4H-benzo[oQ[1 ,3]dioxin-4-one (1 )

[0232] To a suspension of 2,5-dihydroxybenzoic acid (7.0 g, 45 mmol) in TFA (45 mL) was added acetone (20 mL, 0.27 mol) and TFAA (35 mL) and the reaction was stirred at 90 °C overnight. The reaction mixture was concentrated, coevaporated with toluene (3 x 10 mL) and the residue was partitioned between EtOAc and aq. sat. NaHCOs. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was dissolved in CH2CI2 and MeOH, coated on hydromatrix and purified by flash chromatography (0 - 50% EtOAc in heptane) to obtain 1 (3.8 g, 20 mmol, 43%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1 H), 7.17 (d, J = 3.0 Hz, 1 H), 7.09 (dd, J = 8.8, 3.0 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 1.65 (s, 6H).

[0233] 6-((3-Bromobenzyl)oxy)-2,2-dimethyl-4H-benzo[dj[1,3]dioxin-4-one (2)

[0234] A mixture of 1 (3.2 g, 17 mmol), 1-bromo-3-(bromomethyl)benzene (5.0 g, 20 mmol) and K2CO3 (4.6 g, 33 mmol) was suspended in DMF (35 mL) and stirred at 65 °C overnight. The reaction mixture was diluted with aq. sat. NH4CI, extracted with EtOAc (2 x 10 mL), and the combined organic layers were dried over NazSCU, filtered and concentrated in vacuo. The crude was dissolved in CH2CI2 and purified with flash chromatography (0 - 20% EtOAc in heptane) to obtain 2 (5.7 g, 16 mmol, 93%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 7.67 (t, J = 1.9 Hz, 1 H), 7.55 (dt, J = 7.9, 1.5 Hz, 1 H), 7.47 (dt, J = 7.9, 1.4 Hz, 1 H), 7.43 - 7.33 (m, 3H), 7.10 (d, J = 8.8 Hz, 1 H), 5.15 (s, 2H), 1.67 (s, 6H).

[0235] 6-((3‘-Hydroxy-[1 ,1 ’-biphenyl]-3-yl)methoxy)-2,2-dimethyl-4H- benzo[cQ[1,3]dioxin-4-one (3)

[0236] A mixture of 2 (4.4 g, 12 mmol), (3-hydroxyphenyl)boronic acid (2.5 g, 18 mmol) and K2CO3 (3.0 g, 22 mmol) in 1 ,4-dioxane (45 mL) and water (15 mL) was purged with argon. Then, [Pd(PPhs)4] (0.90 g, 0.78 mmol) was added and the reaction was stirred at 100°C for 2 h and then allowed to cool to room temperature over the weekend. The reaction mixture was diluted with water, extracted with EtOAc (2 x 10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was dissolved in CH2CI2 and purified by flash chromatography (0 - 40% EtOAc in heptane) to give 3 (3.7 g, 9.7 mmol, 80%) as a slightly yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1 H), 7.68 (t, J = 1 .8 Hz, 1 H), 7.57 (dt, J = 7.4, 1.8 Hz, 1 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.46 - 7.42 (m, 2H), 7.40 (dd, J = 8.9, 3.1 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1 H), 7.10 (d, J = 9.0 Hz, 1 H), 7.09 - 7.04 (m, 1 H), 7.03 (t, J = 2.1 Hz, 1 H), 6.78 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H), 5.21 (s, 2H), 1.67 (s, 6H).

[0237] 3'-(((2,2-Dimethy l-4-oxo-4H-benzo[d][1 ,3]dioxin-6-y l)oxy)methyl)-[1 ,T-bipheny I]- 3-carbaldehyde (4)

[0238] In a microwave vial, bromide 2 (0.19 g, 0.52 mmol), (3-formylphenyl)boronic acid (0.13 g, 0.83 mmol) and K2CO3 (0.11 g, 0.78 mmol) were mixed with 1 ,4-dioxane (4 ml_) and water (1 mL). The suspension was purged with argon, [Pd(PPh3)4] (63 mg, 55 pmol) was added, the vial was capped and the reaction was stirred under microwave irradiation at 100 °C for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was dissolved in CH2CI2 and purified by flash chromatography (0 - 50% EtOAc in heptane) to obtain aldehyde 4 (0.18 g, 0.47 mmol, 89%) as a yellowish solid.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1 H), 8.23 (t, J = 1.9 Hz, 1 H), 8.08 - 8.01 (m, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.87 (s, 1 H), 7.77 - 7.68 (m, 2H), 7.59 - 7.50 (m, 2H), 7.46 (d, J = 3.1 Hz, 1 H), 7.41 (dd, J = 9.1 , 2.9 Hz, 1 H), 7.10 (d, J = 8.9 Hz, 1 H), 5.24 (s, 2H), 1.68 (s, 6H).

[0239] 5-((3'-(4-Fluorophenoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (5)

[0240] According to GP-A, 3 (56 mg, 0.15 mmol), 4-fluorophenyl boronic acid (42 mg, 0.3 mmol), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 (1.5 mL) were stirred at room temperature overnight to afford 5 as white powder after acetonide deprotection using GP-D (19 mg, 40 μmol, 53%, over twp steps).1H NMR (500 MHz, DMSO-d6) δ 7.71 (s, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.46 (m, 4H), 7.37 (d, J = 3.1 Hz, 1 H), 7.28 (s, 1 H), 7.24 (m, 3H), 7.13 (dd, J = 8.9, 4.5 Hz, 2H), 6.97 (d, J = 7.9 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1H) 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.6, 159.2, 157.7, 157.3, 155.6, 152.5, 150.5, 142.0, 139.5, 137.8, 130.6, 129.1, 127.1 , 126.2, 126.1 , 124.2, 121.8, 120.8, 120.7, 118.1, 117.1 , 116.7, 116.5, 116.4, 113.9, 112.7, 69.7.19F NMR (470 MHz, DMSO-d6) δ -119.67. HRMS (ESI) m / z calcd for C26HI8FO5[M-H]-: 429.11438, found: 429.11252.

[0241] 2-Hydroxy-5-((3'-(pyrimidin-5-yloxy)-[1,r-biphenyl]-3-yl)methoxy)benzoic acid (6)

[0242] According to GP-A, 3 (56 mg, 0.15 mmol), pyrimidin-5-boronic acid (37 mg, 2.0 equiv), CU(OAC)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in MeCN at 65 °C overnight were used to give 6 as white powder after acetonide deprotection using GP- D (10 mg, 24μmol, 68%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1 H), 8.68 (s, 2H), 7.77 (s, 1 H), 7.65 (d, J = 7.0 Hz, 1 H), 7.55 (d, J = 7.7 Hz, 2H), 7.49 - 7.46 (m, 3H), 7.37 (d, J = 3.2 Hz, 1 H), 7.22 (dd, J = 9.0, 3.2 Hz, 1 H), 7.17 - 7.13 (m, 1 H), 6.89 (d, J = 9.0 Hz, 1H), 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 156.0, 155.6, 153.3, 151.7, 150.4, 147.5, 147.5, 142.3, 139.1, 137.9, 130.9, 129.1, 127.2, 126.3, 126.2, 123.9, 123.1 , 118.0, 117.7, 117.0, 113.9, 69.7. HRMS (ESI) calcd for C24H17N2O5 [M-H]-r 413.11430, found: 413.11261.

[0243] 2-Hydroxy-5-((3'-(py ridin-3-y loxy)-[1 , 1 '-bipheny l]-3-y l)methoxy)benzoic acid (7)

[0244] According to GP-A, 3 (56 mg, 0.15 mmol), pyridin-3-boronic acid (37 mg, 2.0 equiv), CU(OAC)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in MeCN at 65 °C overnight were used to give 7 as white powder after acetonide deprotection using GP- D (9.5 mg, 23 μmol, 34%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J = 2.7 Hz, 1 H), 8.38 (dd, J = 4.5, 1.1 Hz, 1 H), 7.74 (s, 1 H), 7.62 (d, J = 7.0 Hz, 1 H), 7.51 (dd, J = 7.0, 3.7 Hz, 2H), 7.50 - 7.45 (m, 2H), 7.44 (dd, J = 8.4, 4.5 Hz, 2H), 7.37 (d, J = 3.1 Hz, 2H), 7.23 (dd, J = 9.0, 3.2 Hz, 1 H), 7.09 - 7.03 (m, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 156.6, 155.6, 153.3, 150.5, 144.6, 142.2, 141.0, 139.3, 137.9, 130.8, 129.1 , 127.2, 126.2, 126.1 , 125.7, 124.7, 124.1 , 122.5, 118.1 , 117.7, 117.0, 113.9, 112.9, 69.7. HRMS (ESI) calcd for C25H20NO5 [M+H]+: 414.13360, found: 414.13202.

[0245] 2-Hydroxy-5-((3'-(4-(trifluoromethyl)phenoxy)-[1,T-biphenyl]-3- yl)methoxy)benzoic acid (8)

[0246] According to GP-A, 3 (56 mg, 0.15 mmol), 4-(trifluoromethyl)-phenyl boronic acid (57 mg, 2.0 equiv), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 were stirred at room temperature overnight to give 8 as white powder after acetonide deprotection using GP-D (19 mg, 40μmol, 53%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.76 (dd, J = 15.6, 7.7 Hz, 3H), 7.65 (d, J = 7.0 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.50 - 7.44 (m, 3H), 7.37 (d, J = 3.2 Hz, 1 H), 7.23 (dd, J = 9.0, 3.2 Hz, 1 H), 7.20 (d, J = 8.7 Hz, 2H), 7.14 (dt, J = 7.2, 1.9 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 160.4, 155.58, 155.52, 150.5, 142.3, 139.1, 137.8, 130.9, 129.1 , 127.5 (q, J = 3.7 Hz), 127.2, 126.3, 126.1 , 125.4, 124.1 , 123.71 - 122.86 (m), 123.2, 119.1 , 118.3, 118.1 , 117.9, 113.9, 112.8, 69.7.19F NMR (470 MHz, DMSO-d6) δ -60.12. HR-MS (ESI) calcd for C27H18F3O5 [ / W-Hp: 479.11118, found: 479.10916.

[0247] 2-Hydroxy-5-((3’-(4-methoxyphenoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)benzoic acid

[0248] (9)

[0249] According to GP-A, 3 (56 mg, 0.15 mmol), 4-methoxyphenyl-boronic acid (45 mg, 2.0 equiv), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 were stirred at room temperature overnight to give 9 as white powder after acetonide deprotection using GP-D (11 mg, 25 μmol, 77%, over two steps).1H NMR (500 MHz, DMSO-c / e) δ 7.69 (s, 1 H), 7.57 (d, J = 7.2 Hz, 1 H), 7.49 - 7.41 (m, 3H), 7.37 (d, J = 3.3 Hz, 2H), 7.25 - 7.18 (m, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 5.12 (s, 2H), 3.75 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 158.6, 155.7, 155.6, 150.5, 149.3, 141.8, 139.6, 137.8, 130.5, 129.1 , 127.0, 126.2, 126.0, 124.1 , 121.0, 120.8, 118.1, 116.3, 115.6, 115.1 , 113.9, 112.8, 69.7, 55.4. HR- MS (ESI) calcd for C27H21O6 [M-H]-. 441.13436, found: 441.13267.

[0250] 5-((3'-(4-Chlorophenoxy)-[1,T-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (10)

[0251] According to GP-A, 3 (56 mg, 0.15 mmol), 4-chlorophenyl boronic acid (47 mg, 2.0 equiv), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 were stirred at room temperature overnight to give 10 as white powder after acetonide deprotection using GP-D (14 mg, 31 μmol, 41%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.74 (d, J = 6.7 Hz, 1 H), 7.61 (dt, J = 7.2, 1.7 Hz, 1 H), 7.50 (dd, J = 9.0, 5.3 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.37 (d, J = 3.2 Hz, 1 H), 7.35 - 7.33 (m, 1 H), 7.24 (dd, J = 9.0, 3.2 Hz, 1H), 7.12 - 7.06 (m, 2H), 7.05 - 7.00 (m, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 156.7, 155.6, 155.5, 150.5,

[0252] 142.1 , 139.3, 137.8, 130.7, 129.9, 129.1 , 127.2, 127.1 , 126.2, 126.1 , 124.1 , 122.3,

[0253] 120.2, 118.1 , 117.9, 117.1 , 113.9, 112.7, 69.7. HR-MS (ESI) calcd for C26H18CIO5 [M- H]-: 445.08482, found: 445.08282. 5-((3'-(4-Cyanophenoxy)-[1 ,1 ’-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (11)

[0254] According to GP-A, 3 (56 mg, 0.15 mmol), 4-cyanophenyl boronic acid (44 mg, 2.0 equiv), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 were stirred at room temperature overnight to give 11 as white powder after acetonide deprotection using GP-D (28 mg, 65 μm 7o4l%, , over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.88 - 7.82 (m, 2H), 7.77 (s, 1 H), 7.65 (d, J = 7.0 Hz, 1 H), 7.58 (dt, J = 15.5, 7.8 Hz, 2H), 7.51 - 7.43 (m, 3H), 7.37 (d, J = 3.2 Hz, 1H), 7.24 (dd, J = 9.0, 3.2 Hz, 1 H), 7.18 - 7.13 (m, 3H), 6.90 (d, J = 9.0 Hz, 1 H), 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 161.1 , 155.5, 155.0, 150.5, 142.3, 139.1 , 137.8, 134.7, 131.0, 129.1 , 127.2, 126.3, 126.2, 124.2, 123.5, 119.3, 118.7, 118.5, 118.1 , 118.1 , 113.9, 112.7, 105.1, 69.7. HR-MS (ESI) calcd for C27H18NO5 [M-H]-; 436.11905, found; 436.11700.

[0255] 5-((3'-(4-Aminophenoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (12)

[0256] According to GP-A, 3 (56 mg, 0.15 mmol), 4-(N-Boc-amino)phenylboronic acid (71 mg, 2.0 equiv), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 were stirred at room temperature overnight to give 12 as white powder after acetonide deprotection using GP-D (31 mg, 72 μm 6o7l,%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.66 (s, 1 H), 7.54 (d, J = 7.3 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.43 (m, 2H), 7.39 (m, 2H), 7.38 - 7.35 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1 H), 7.13 (s, 1 H), 6.89 (d, J = 9.0 Hz, 1H), 6.84 (t, J = 7.1 Hz, 3H), 6.64 (d, J = 8.6 Hz, 2H), 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) 5171.5, 159.4, 155.6, 150.4, 145.8, 144.7, 141.7, 139.8, 137.8, 130.3, 129.1 , 126.9, 126.1 , 125.9, 123.9, 120.9, 120.3, 118.0, 115.6, 115.3, 114.7, 113.9, 113.1 , 69.6. HR-MS (ESI) calcd for C26H22NO5 [M+H]+: 428.14925, found: 428.14755.

[0257] 2-Hydroxy-5-((3’-(p-tolyloxy)-[1 ,r-biphenyl]-3-yl)methoxy)benzoic acid (13)

[0258] According to GP-A, 3 (56 mg, 0.15 mmol), p-tolylboronic acid (47 mg, 0.34 mmol, 2.3 equiv), Cu(OAc)2 (60 mg, 0.33 mmol) and pyridine (49 μL, 0.60 mmol) in CH2CI2 were stirred at room temperature overnight to give 13 as white powder after acetonide deprotection using GP-D (33 mg, 77 μm 6o9l,%, over two steps).1H NMR (500 MHz, DMSO-d6) 57.70 (s, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.49 - 7.43 (m, 3H), 7.41 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 3.1 Hz, 1 H), 7.28 - 7.17 (m, 4H), 6.98 (d, J = 8.4 Hz, 2H), 6.96 - 6.92 (m, 1H), 6.90 (d, J = 9.0 Hz, 1H), 5.12 (s, 2H), 2.29 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 157.8, 155.5, 154.1 , 150.5, 141.9, 139.6, 137.8, 132.8, 130.5, 130.5, 129.1 , 127.0, 126.2, 126.0, 124.2, 121.5, 119.0, 118.1 , 117.1 , 116.3, 113.9, 112.7, 69.7, 20.3. HR-MS (ESI) calcd for C27H21O5 425.13945, found:

[0259] 425.13794.

[0260] 5-((3'-(Cyclohexyloxy)-[1,r-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (14)

[0261] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), cyclohexano! (24 mg, 0.24 mmol, 2.4 equiv), CMBP (52 μL, 0.2 mmol, 2.0 eq.) in toluene (0.5 ml_) were used to afford 14 as white powder after acetonide deprotection using GP-D (18 mg, 43 pmol, 62%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.71 (s, 1 H), 7.60 (d, J = 7.4 Hz, 1 H), 7.48 - 7.42 (m, 2H), 7.38 (d, J = 3.2 Hz, 1 H), 7.35 (dd, J = 13.9, 5.8 Hz, 1 H), 7.22 - 7.18 (m, 2H), 7.16 - 7.14 (m, 1 H), 6.94 (dd, J = 8.1 , 2.0 Hz, 1 H), 6.86 (d, J = 9.0 Hz, 1H), 5.12 (s, 2H), 4.49 - 4.38 (m, 1 H), 1.99 - 1.89 (m, 2H), 1.72 (dd, J = 9.1 , 3.4 Hz, 2H), 1.53 (dd, J = 9.2, 3.3 Hz, 1H), 1.49 - 1.36 (m, 4H), 1.31 - 1.22 (m, 1H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 157.7, 155.7, 150.3, 141.5, 140.2, 137.8, 130.0, 129.0, 126.7, 126.2, 126.1 , 123.5, 118.9, 118.9, 117.8, 114.8, 114.2, 114.0, 74.2, 69.7, 31.3, 25.1 , 23.1. HRMS (ESI) m / z calcd for C26H25O5 [ / W-Hp: 417.17075, found: 417.16934.

[0262] 5-((3'-(Cyclopentyloxy)-[1 ,1 '-bipheny l]-3-yl)methoxy)-2-hydroxybenzoic acid (15)

[0263] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), cyclopentanol (19 mg, 2.2 equiv) and CMBP (52 μL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 15 as white powder after acetonide deprotection using GP-D (19 mg, 46 62μ%m,ol, over two steps).1H NMR (500 MHz, DMSO-d6) δ7.71 (s, 1 H), 7.60 (d, J = 7.4 Hz, 1 H), 7.48 - 7.41 (m, 2H), 7.36 (dt, J = 12.1 , 3.6 Hz, 2H), 7.25 (dd, J = 9.0, 3.2 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1 H), 7.12 (s, 1 H), 6.93 - 6.88 (m, 2H), 5.14 (s, 2H), 4.93 - 4.88 (m, 1 H), 1.99 - 1.87 (m, 2H), 1.77 - 1.68 (m, 4H), 1.63 - 1.53 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 158.1, 155.5, 150.5, 141.4, 140.2, 137.7, 130.0, 129.0, 126.8, 126.2, 126.1 , 124.2, 118.7, 118.1 , 114.5, 113.9, 113.7, 112.7, 78.6, 69.7, 32.3, 23.6. HRMS (ESI) m / z calcd for C25H23O5 [M-Hp: 403.15510, found: 403.15329.

[0264] 2-Hydroxy-5-((3,-isopropoxy-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (16)

[0265] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1 .0 eq.), propan-2-ol (20 mg, 0.33 mmol, 3.3 eq.) and CMBP (52 μL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 16 (32 mg, 76 μmol 7, 6%).1H NMR (500 MHz, DMSO-d6) δ 7.72 (s, 1 H), 7.61 (m, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 7.43 (m, 1 H), 7.38 (d, J = 3.2 Hz, 1 H), 7.36 (t, J = 7.9 Hz, 1 H), 7.25 (dd, J = 9.0, 3.2 Hz, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 7.14 (t, J = 1.9 Hz, 1 H), 6.94 - 6.92 (m, 1 H), 6.92 - 6.89 (m, 1 H), 5.13 (s, 2H), 4.70 (hept, J = 5.9 Hz, 1 H), 1 .29 (s, 3H), 1 .28 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171 .5, 157.9, 155.5, 150.5, 141.5, 140.2, 137.7, 130.1 , 129.0, 126.8, 126.2, 126.1 , 124.2, 118.8, 118.1 , 114.7, 113.9, 113.9, 112.7, 69.8, 69.1, 21.9. HRMS (ESI) m / z calcd for C23H22O5 [M-Hp: 377.13945, found 377.13776.

[0266] 2-Hydroxy-5-((3'-(morpholinomethyl)-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (17)

[0267] According to GP-B, 4 (65 mg, 0.17 mmol), morpholine (37 μL, 0.42 mmol) and STAB (89 mg, 0.42 mmol) in DMAc (1 ml_) were stirred to yield 17 after acetonide deprotection using GP-D (23 mg, 54 μm 7o0l,%, over two steps).1H NMR (500 MHz, DMSO-d6) 5 7.90 (s, 1 H), 7.80 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 6.9 Hz, 1 H), 7.52 (d, J = 3.2 Hz, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.00 (dd, J = 8.9, 3.2 Hz, 1 H), 6.73 (d, J = 8.9 Hz, 1 H), 5.09 (s, 2H), 4.05 (s, 2H), 3.84 - 3.75 (m, 4H), 2.88 (s, 4H).13C NMR (126 MHz, DMSO-d6) δ 172.3, 155.9, 149.5, 140.3, 139.6, 137.8, 133.8, 129.5, 129.2, 129.2, 128.7, 127.4, 127.3, 126.6, 126.2, 122.3, 117.2, 116.6, 114.7, 69.7, 64.3, 60.4, 51 .8. HRMS (ESI) m / z calcd for C25H26NO5 [A4+H]+: 420.18055, found: 420.17865.

[0268] 2-Hydroxy-5-((3'-(pyrrolidin-1-ylmethyl)-[1,r-biphenyl]-3-yl)methoxy)benzoic acid (18)

[0269] According to GP-B, 4 (39 mg, 0.10 mmol, 1.0 eq.), pyrrolidine (21 μL, 0.15 mmol, 1.5 eq.) and STAB (53 mg, 0.25 mmol, 2.5 equiv) in DMAc (1 ml_) were stirred to give 18 as white powder after acetonide deprotection using GP-D (7.1 mg, 18 18%μ, omvoelr, two steps).1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1 H), 7.91 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.69 (s, 1 H), 7.57 (d, J = 3.7 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1H), 7.43 (m, 3H), 6.82 (dd, J = 8.8, 3.2 Hz, 1 H), 6.58 (d, J = 8.8 Hz, 1 H), 5.11 (s, 2H), 4.32 (s, 2H), 3.17 (s, 4H), 2.01 (s, 4H).13C NMR (126 MHz, DMSO-d6) δ 172.6, 155.9, 148.7, 140.4, 139.3, 139.1 , 137.6, 129.3, 129.2, 129.0, 128.6, 128.1 , 126.5, 126.4, 126.2, 121.2, 118.8, 116.5, 115.1 , 69.5, 57.1 , 52.8, 22.8. HRMS (ESI) m / z calcd for C25H25NO4 [M+H]+: 404.18563, found 404.18412.

[0270] 2-Hydroxy-5-((3'-((4-(trifluoromethyl)benzyl)oxy)-[1,1'-biphenyl]-3- yl)methoxy)benzoic acid (19)

[0271] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), (4-(trifluormethyl)- benzylalcohol (35 mg, 0.2 mmol, 2.0 equiv) and CMBP (52 ml_, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 19 as white powder after acetonide deprotection using GP-D (27 mg, 55 μmo 6l,9%).1H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J = 8.1 Hz, 2H), 7.74 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.32 (s, 1 H), 7.26 (dd, J = 12.3, 5.3 Hz, 2H), 7.04 (d, J = 6.9 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 5.32 (s, 2H), 5.14 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 158.5, 155.5, 150.5, 142.1 , 141.5, 140.0, 137.7, 130.1 , 129.0, 128.0, 126.9, 126.2, 126.1, 125.3 (ArCCF3, q, J = 3.8 Hz), 124.2, 119.5, 118.1 , 114.1 , 113.9, 113.1 , 112.7, 69.8, 68.3.19F NMR (470 MHz, DMSO-d6) 5 -60.92. HRMS (ESI) m / z calcd for C28H20F3O5 [M-H]’: 493.12683, found 493.12488.

[0272] 5-((3,-((4-Chlorobenzyl)oxy)-[1,T-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (20)

[0273] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), (4- chlorophenyl)methanol (0.028 g, 0.2 mmol, 2.0 eq) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 20 as white powder after acetonide deprotection using GP-D (22 mg, 47 μm 6o2l,%, over twp steps).1H NMR (500 MHz, DMSO-d6) δ 7.74 (s, 1 H), 7.62 (d, J = 7.4 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 2H), 7.49 - 7.43 (m, 4H), 7.41 - 7.35 (m, 2H), 7.29 (s, 1 H), 7.27 - 7.23 (m, 2H), 7.02 (dd, J = 8.1 , 2.0 Hz, 1H), 6.91 (d, J= 9.0 Hz, 1 H), 5.19 (s, 2H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO- cfe) 6 171.5, 158.6, 155.5, 150.5, 141.4, 140.0, 137.7, 136.2, 132.4, 130.1, 129.5, 129.0, 128.4, 126.9, 126.2, 126.1 , 124.2, 119.4, 118.1 , 114.1 , 113.9, 113.1 , 112.7, 69.8, 68.4. HRMS (ESI) m / z calcd for C2zH21CIO5[M-H]-: 459.10048, found 459.10048.

[0274] 5-((3'-((4-Cyanobenzy l)oxy)-[1 , 1 '-bipheny l]-3-y l)methoxy)-2-by droxy benzoic acid (21)

[0275] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), 4- (hydroxymethyl)benzonitrile (26 mg, 0.2 mmol, 2.0 equiv) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 21 as white powder after acetonide deprotection using GP-D (27 mg, 60 μm 75o%l, , over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J = 7.2 Hz, 2H), 7.74 (s, 1 H), 7.68 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 6.5 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.39 (dd, J = 10.1 , 5.5 Hz, 2H), 7.31 (s, 1 H), 7.26 (dd, J = 13.8, 5.0 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 5.31 (s, 2H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 158.5, 155.6, 150.5, 142.9, 141.5, 139.9, 137.7, 132.4, 130.1 , 129.0, 128.1 , 126.9, 126.2, 126.1 , 124.2, 119.5, 118.7, 118.1, 114.1, 113.9, 113.1 , 112.7, 110.5, 69.8, 68.3. HRMS (ESI) m / z calcd for C28H21NO5 [M-H]-; 450.13470, found 450.13297.

[0276] 2-Hydroxy-5-((3,-((4-(trifluoromethoxy)benzyl)oxy)-[1,1'-biphenyl]-3- yl)methoxy)benzoic acid (22)

[0277] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), (4- (trifluoromethoxy)phenyl)methanol (38 mg, 0.2 mmol, 2.0 equiv) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 22 as white powder after acetonide deprotection using GP-D (30 mg, 58 μm 74o%l, , over two steps).1H NMR (500 MHz, DMSO-d6) δ7.74 (s, 1 H), 7.62 (d, J= 8.6 Hz, 3H), 7.50 - 7.43 (m, 2H), 7.39 (dd, J = 9.7, 5.6 Hz, 4H), 7.30 (s, 1 H), 7.28 - 7.23 (m, 2H), 7.03 (dd, J = 8.2, 2.3 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 5.23 (s, 2H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO- d6) 5 171.5, 158.7, 155.5, 150.5, 147.8, 141.5, 140.0, 137.7, 136.6, 130.1 , 129.6, 129.0, 126.9, 126.2, 126.1, 124.2, 121.1 , 119.4, 119.1 , 118.1 , 114.1 , 113.9, 113.1 , 112.7, 69.8, 68.3.19F NMR (470 MHz, DMSO-d6) δ -56.78. HRMS (ESI) m / z calcd for C28H20F3O6 [M-Hp: 509.12175, found 509.11938.

[0278] 2-Hydroxy-5-((3'-((4-methylbenzyl)oxy)-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (23)

[0279] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), p-tolylmethanol (24 mg, 0.2 mmol, 2.0 equiv) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 23 as white powder after acetonide deprotection using GP-D (30 mg, 58 pmol, 74%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 7.73 (s, 1 H), 7.62 (d, J = 7.4 Hz, 1 H), 7.50-7.42 (m, 2H), 7.39 (d, J = 3.0 Hz, 1 H), 7.36 (dd, J = 8.0, 1 .7 Hz, 3H), 7.30 - 7.22 (m, 3H), 7.20 (d, J = 7.8 Hz, 1 H), 7.00 (dd, J = 8.1 , 2.0 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 5.13 (s, 4H), 2.30 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 158.8, 155.5, 150.6, 141.4, 140.1 , 137.7, 137.0, 134.0, 130.0, 129.0, 129.0, 127.8, 126.8, 126.2, 126.1 , 124.2, 119.1 , 118.1 , 114.1 , 113.9, 113.0, 112.7, 69.8, 69.1 , 20.7. HRMS (ESI) m / z calcd for C28H24O5 [M-Hp: 439.15510, found 439.1550.

[0280] 2-Hydroxy-5-((3'-(pyrimidin-2-ylmethoxy)-[1,r-biphenyl]-3-yl)methoxy)benzoic acid (24) According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), pyrimidin-2-ylmethanol (22 mg, 0.2 mmol, 2.0 equiv) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 24 as white powder after acetonide deprotection using GP-D (3.3 mg, 7.7 μmol, 10%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J = 4.9 Hz, 1 H), 7.71 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.49 - 7.41 (m, 4H), 7.39 - 7.36 (m, 2H), 7.28 - 7.21 (m, 3H), 6.98 (dd, J = 8.1 , 2.1 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 5.36 (s, 2H), 5.12 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 165.4, 158.7, 157.6, 155.6, 150.5, 141.4, 140.1, 137.7, 130.0, 129.0, 127.0, 126.1, 126.0, 124.0, 120.5, 119.35, 119.34, 118.1 , 113.9, 113.9, 112.9, 70.3, 69.8. HR-MS (ESI) m / z calcd for C25H21 N2O5 [M+H]+: 429.14450, found: 429.14240.

[0281] 2-Hydroxy-5-((3'-(pyridin-4-ylmethoxy)-[1,r-biphenyl]-3-yl)methoxy)benzoic acid (25)

[0282] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1.0 eq.), pyridin-4-ylmethanol (43 mg, 0.4 mmol, 4.0 equiv) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 25 as white powder after acetonide deprotection using GP-D (14 mg, 32 μmol, 73%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 8.59 (d, J = 5.6 Hz, 2H), 7.74 (s, 1 H), 7.62 (d, J = 7.5 Hz, 1 H), 7.48 (t, J = 6.2 Hz, 3H), 7.46 - 7.36 (m, 3H), 7.31 (s, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.24 (dd, J = 9.0, 3.2 Hz, 1 H), 7.03 (dd, J = 8.2, 2.2 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.28 (s, 2H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ171.5, 158.4, 155.5, 150.4, 149.6, 146.3, 141.5, 139.9, 137.8, 130.2, 129.0, 126.9, 126.2, 126.1 , 124.0, 121.8, 119.6, 118.1 , 114.0, 113.9, 113.1 , 113.0, 69.8, 67.5. HR-MS (ESI) m / z calcd for C26H20NO5 [M-Hp: 426.13470, found: 426.13318.

[0283] 2-Hydroxy-5-((3’-(pyridin-3-yimethoxy)-[1,r-biphenyl]-3-yl)methoxy)benzoic acid (26)

[0284] According to GP-C, compound 3 (38 mg, 0.10 mmol, 1 .0 eq.), pyridin-3-ylmethanol (43 mg, 0.4 mmol, 4.0 equiv) and CMBP (52 mL, 0.2 mmol, 2.0 eq.) in toluene (0.5 mL) were used to afford 26 as white powder after acetonide deprotection using GP-D (4.7 mg, 11 μmol, 80%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.55 (d, J = 4.5 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.76 (s, 1 H), 7.63 (d, J = 7.4 Hz, 1 H), 7.54 - 7.46 (m, 2H), 7.46 - 7.42 (m, 2H), 7.42 - 7.37 (m, 2H), 7.33 (dd, J = 9.0, 2.6 Hz, 1 H), 7.28 (t, J = 6.4 Hz, 1 H), 7.22 (dd, J = 9.0, 3.1 Hz, 1 H), 7.05 (d, J = 8.1 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 5.25 (d, J = 3.8 Hz, 1H), 5.14 (d, J = 6.0 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ171.5, 158.6, 156.6, 150.4, 149.1 , 149.0, 141.5, 140.0, 137.6, 135.7, 132.6, 130.1 , 129.0, 128.5, 127.8, 126.9, 126.2, 123.8, 123.6, 119.5, 117.9, 114.1 , 114.0, 113.1 , 69.8, 66.9. HRMS (ESI) m / z calcd for C26H20NO5 [M-Hp: 426.13470, found: 426.13315.

[0285] 2-(Benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (27a)

[0286] A mixture of 2-(benzyloxy)-6-bromopyridine (27b) (0.10 g, 0.38 mmol), bis(pinacolato)diboron (0.11 g, 0.41 mmol, 1.1 eq.) and KOAc (0.11 g, 1.1 mmol, 2.9 eq) in 1 ,4-dioxane (1 mL) was purged with argon. Then, [PdCl2(dppf)] (17 mg, 23 pmol) was added and the reaction was stirred at 115 °C for 1.5 hours. The reaction mixture was filtered over celite, the residue was washed with EtOAc and the combined filtrates were concentrated in vacuo to afford 27a (0.110 g) that was used as such in the next step due to its instability. GC El+: 311.1 (and 310.1 for boron isotope), calculated: 311.169.

[0287] 5-((3-(6-(benzyloxy)pyridin-2-yl)benzyl)oxy)-2-hydroxybenzoic acid (27)

[0288] According to GP-G, compound 2 (60 mg, 0.17 mmol), 27a (94 mg, 0.19 mmol, ca. 63 wt%), [Pd(PPh3)4] (16 mg, 14 pmol) and K2CO3 (39 mg, 0.28 mmol) in 1 ,4-dioxane / H2O (1 mL, 4:1) were stirred under microwave irradiation at 120 °C for 30 min. The reaction mixture was purified by basic preparative HPLC-MS to afford 27 as white powder after acetonide deprotection using GP-D (9.6 mg, 22 μ 5m8o%l,, over two steps).1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1 H), 8.03 (s, 1H), 7.81 (t, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.4 Hz, 1 H), 7.50 (m, 4H), 7.39 (m, 1 H), 7.37 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1 H), 7.25 (dd, J = 8.9, 3.0 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 6.85 (d, J = 8.3 Hz, 1 H), 5.47 (s, 2H), 5.16 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 162.6, 155.6, 153.4, 150.5, 140.3, 138.4, 137.6, 137.5, 128.8, 128.3, 128.0, 127.7, 125.9, 125.7, 124.0, 118.1 , 113.9, 113.3, 109.7, 69.8, 66.8. HRMS (ESI) m / z calcd for C26H20NO5 [M-Hf: 426.13470, found: 426.13300.

[0289] 3-(Benzyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-y l)py ridine (28 a)

[0290] Commercially available and purchased from Ambeed.

[0291] 5-((3-(5-(Benzyloxy)pyridin-3-yl)benzyl)oxy)-2-hydroxybenzoic acid (28)

[0292] According to GP-G, compound 2 (39 mg, 0.11 mmol), 28a (46 mg, 0.15 mmol), Pd(PPhs)4 (7.4 mg, 6.4 pmol) and K2CO3 (25 mg, 0.18 mmol) in 1 ,4-dioxane / H2O (1 mL, 6:1) was stirred under microwave irradiation at 110°C for 20 min. The reaction mixture was purified by flash chromatography (0 - 80% EtOAc in heptane) to yield 28 as white powder after acetonide deprotection using GP-D (11 mg, 25 28%μ,m oovel,r two steps).1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J = 1.7 Hz, 1 H), 8.36 (d, J = 2.7 Hz, 1 H), 7.82 (s, 1 H), 7.75 - 7.73 (m, 1H), 7.71 (dt, J = 6.8, 2.0 Hz, 1H), (t, J = 7.1 Hz, 3H), 7.42 (d, J = 7.2 Hz, 1 H), 7.41 - 7.38 (m, 3H), 7.37 - 7.33 (m, 1 H), 7.24 (dd, J = 9.0, 3.2 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.29 (s, 2H), 5.14 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ171.5, 155.6, 154.7, 150.4, 139.9, 138.0, 137.2, 136.9, 136.5, 136.1 , 129.2, 128.5, 128.1 , 127.9, 127.5, 126.5, 126.4, 124.0, 119.3, 118.0, 113.9, 69.7, 69.6. HRMS (ESI) m / z calcd for C26H22NO5 [A4+H]+: 428.14925, found: 428.14764.

[0293] 7-(Benzyloxyjquinoline-2-carboxylic acid (29d)

[0294] A suspension of 7-bromoquinoline-2-carboxylic acid (29e) (0.25 g, 0.99 mmol), BnOH (0.51 ml_, 5.0 mmol), CS2CO3 (0.80 g, 2.5 mmol), 3,4,7,8-tetramethyl-1 ,10- phenanthroline (0.23 g, 0.99 mmol) and Cui (0.15 g, 0.77 mmol) in toluene (5 mL) was purged with argon and stirred at 130 °C for 48 h. The reaction mixture was filtered over celite, the residue was washed with CH2CI2, and to the combined filtrates were added aq. HCI (1 M). The layers were separated, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (0 - 6% MeOH in CH2CI2) to yield 29d as a yellowish solid (0.10 g, 0.36 mmol, 36%). LC- MS retention time: 0.79 min. ESI+: [ / W+H]+280.0 (279.090 calculated).

[0295] Methyl 7-(benzyloxy)quinoline-2-carboxyiate (29c)

[0296] To a solution of 29d (0.10 g, 0.36 mmol) in dry MeOH (4 mL, 0.09 M), cat. H2SO4 was added and the reaction was stirred at 65 °C for 48 hours. Then, the reaction mixture was concentrated in vacuo and the crude purified by flash chromatography (0 - 10% MeOH in CH2CI2) to yield 29c (60 mg, 57%) as yellow solid.1H NMR (400 MHz, CDCI3) 58.24 (d, J = 8.4 Hz, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 2.6 Hz, 1 H), 7.49 (d, J = 7.3 Hz, 2H), 7.45 - 7.35 (m, 4H), 5.22 (s, 2H), 4.08 (s, 3H). (7-(Benzyloxy)quinolin-2-yl)methanol (29b)

[0297] To a solution of 29c (50 mg, 0.17 mmol) in MeOH (2 mL) was added NaBFU (0.13 g, 3.4 mmol) and the reaction was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo, aq. NaOH (1 M, 20 mL) was added, the mixture was stirred for 1 hour and then extracted with CH2CI2 (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield alcohol 29b as white solid (43 mg, 95%) which was used in the next step without any purification. LC-MS retention time: 1.13 min. ESI+: [ / W+H]+266.1 , calculated: 265.110.

[0298] (7-(Benzyloxy)quinolin-2-yl)methyl 4-methylbenzenesulfonate (29a)

[0299] To a solution of 29b (43 mg, 0.16 mmol) in CH2CI2 (1.5 mL) was added EtsN (35 μL, 0.25 mmol, 1.5 eq.), DMAP (2.0 mg, 16 pmol) and TsCI (45 mg, 0.22 mmol, 1.4 eq.) and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with aq. sat. NH4CI and extracted with CH2CI2 (2 x 10 mL). The combined organic layers were concentrated in vacuo to yield 29a (48 mg) as brownish solid that was directly in the next step.

[0300] 5-((7-(Benzyloxy)quinolin-2-yl)methoxy)-2-hydroxybenzoic acid (29)

[0301] A mixture of phenol 1 (26 mg, 0.13 mmol), 29a (48 mg, 0.12 mmol) and K2CO3 (39 mg, 0.28 mmol) were suspended in DMF (0.7 mL) and stirred at 65 °C overnight. The reaction mixture was filtered (0.45 pm) and purified by basic preparative HPLC-MS to yield 29 as white powder after acetonide deprotection using GP-D (15 mg, 37 pmol, 69%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 9.0 Hz, 1 H), 7.45 - 7.54 (m, 4H), 7.42 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 3.2 Hz, 1 H), 7.28 - 7.32 (m, 2H), 7.18 (m, 1 H), 6.81 (dd, J = 28.7, 8.8 Hz, 1H), 5.30 (s, 2H), 5.27 (d, J = 8.2 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 159.5, 136.7, 129.2, 128.6, 128.0, 127.8, 127.8, 122.5, 119.6, 117.5, 117.2, 108.3, 71.4, 69.6. HRMS m / z calcd for C24H20NO5 [ / W+H]+: 402.13360, found 402.13194.

[0302] 4-(Benzyloxy)-2-bromopyridine (30a)19

[0303] To a solution of 2-bromopyridin-4-ol (30b) (71 mg, 0.41 mmol) and BnBr (49 μL, 0.41 mmol) in THF (2 mL) was added Ag2COs (0.14 g, 0.49 mmol). The reaction mixture was wrapped in aluminum foil and stirred at 70 °C overnight. The reaction mixture was filtered and purified by flash chromatography (0 - 50% EtOAc in heptane) to afford 30a (76 mg, 0.29 mmol, 71%) as a white solid.

[0304] 5-((4-(3-(Benzyloxy)phenyl)pyridin-2-yl)methoxy)-2-hydroxybenzoic acid (30)

[0305] Into a mixture of bromide 2 (50 mg, 0.14 mmol), B2(pin)2 (38 mg, 0.15 mmol) and KOAc (40 mg, 0.41 mmol) in dry 1 ,4- dioxane (1 mL) purged with argon, [PdCl2(dppf)] (5 mg, 6.8 pmol) was added and the reaction was stirred at 100 °C for 2.5 h. Then, after the reaction was cooled to rt, 30a (36 mg, 0.14 mmol), K2CO3 (57 mg, 0.41 mmol) and water (0.2 mL) were added and the mixture was purged with argon. [Pd2(dba)s] (2.5 mg, 2.7 pmol) and fBusPH BF4 (4.0 mg, 14 pmol) were added and the reaction was stirred at 90 °C overnight. The reaction mixture was partitioned between CH2CI2 (5 mL) and water (2 mL) and mixed vigorously. The layers were separated using a phase separator and the organic layer was concentrated in vacuo. The crude was redissolved in MeCN, filtered (0.45 pm) and purified by basic preparative HPLC-MS to yield after acetonide deprotection using GP-D 30 (7.6 mg, 18 μm 6o3l,%, over two steps).1H NMR (500 MHz, DMSO-ofe) 58.62 (d, J = 5.0 Hz, 1 H), 7.81 (s, 1 H), 7.67 (d, J = 3.5 Hz, 1 H), 7.48 (d, J = 7.1 Hz, 2H), 7.46 - 7.42 (m, 1 H), 7.42 - 7.38 (m, J = 9.4, 5.3 Hz, 4H), 7.38 - 7.31 (m, 2H), 7.27 (dd, J = 9.1 , 3.1 Hz, 1H), 7.13 (d, J = 6.6 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1H), 5.21 (s, 2H), 5.18 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ171.4, 159.0,

[0306] 157.4, 155.7, 150.3, 149.7, 147.6, 138.6, 136.9, 130.3, 128.4, 127.8, 127.7, 123.7,

[0307] 120.5, 119.3, 119.2, 118.0, 115.9, 114.1 , 113.0, 70.9, 69.3.

[0308] Methyl 5-((2-bromothiazol-4-yl)methoxy)-2-hydroxybenzoate (31a)

[0309] According to GP-E, 2-bromo-4-(bromomethyl) thiazole (670 mg, 2.6 mmol, 1.1 eq.), methyl-2,5-dihydroxybenzoate (400 mg, 2.4 mmol, 1 eq.) and K2CO3 (655 mg, 4.7 mmol, 2 eq.) in acetone (17 ml_) were stirred at room temperature overnight. The crude mixture was purified via flash chromatography (8% EtOAc in cyclohexane) to afford 31a as a light brown solid (560 mg, 2.6mmol, 65%).1H NMR (500 MHz, CDCI3) δ 10.43 (s, 1 H), 7.54 (s, 1 H), 7.36 (d, J = 3.1 Hz, 1 H), 7.11 (dd, J = 9.1 , 3.1 Hz, 1 H), 6.94 (d, J = 9.1 Hz, 1 H), 5.15 (s, 2H), 3.96 (s, 3H).13C NMR (126 MHz, CDCh) δ 170.1 , 157.1 , 150.0, 141.6, 138.1 , 137.3, 125.2, 119.1 , 114.1, 112.1 , 63.5, 52.6. LC-MS for Ci2HioBrN04S [M+H]+: 344.0.

[0310] 5-((2-Bromothiazol-4-yl)methoxy)-2-hydroxybenzoic acid (31)

[0311] According to GP-F, 31a (610 mg, 1.78 mmol, 1 eq.) and NaOH (in aq. 10%, 0.5 mL) were refluxed at 65 °C for 2 hours, to give after flash chromatography (12% EtOAc in cyclohexane) 31 as an off-white solid (557 mg, 1.78 mmol, 95%)1H. NMR (500 MHz, DMSO-d6) δ 7.75 (s, 1 H), 7.35 (dd, J = 6.9, 2.7 Hz, 1H), 7.22 (dd, J = 8.2, 4.1 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1 H), 5.30 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.4, 155.9,

[0312] 149.5, 142.4, 138.6, 136.4, 124.3, 118.2, 114.5, 112.78, 62.4. HRMS (ESI) m / z calcd for CnH8BrNO4S [M-Hf: 327.92846, found, 327.92874. Methyl 5-((2-bromopyridin-4-yl)methoxy)-2-hydroxybenzoate (32a)

[0313] According to GP-E, 2-bromo-4-(bromomethyl)pyridine (656 mg, 2.6 mmol.), methyl- 2,5-dihydroxybenzoate (400 mg, 2.4 mmol) and K2CO3 (657 mg, 4.76 mmol) were mixed in acetone (17 mL) to give after purification via flash chromatography (20% EtOAc in cyclohexane) 32a as an off-white solid (876 mg, 2.6 mmol, 75%).1H NMR (500 MHz, DMSO-d6) 5 10.12 (s, 1H), 8.39 (d, J = 5.0 Hz, 1 H), 7.70 (s, 1 H), 7.50 (d, J = 5.0 Hz, 1 H), 7.35 (d, J = 3.2 Hz, 1 H), 7.27 (dd, J = 9.0, 3.2 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 5.16 (s, 2H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 168.8, 154.7, 150.6, 150.2, 150.1 , 141.6, 125.7, 124.1 , 121.5, 118.7, 113.8, 112.9, 67.4, 52.6. LC- MS for Ci4Hi2BrNO4[M+H]+: 338.1.

[0314] 5-((2-Bromopyridin-4-yl)methoxy)-2-hydroxybenzoic acid (32)

[0315] According to GP-F, 32a (605 mg, 1.8 mmol, 1 eq.) and NaOH (in aq. 10%, 0.3 mL) in MeOH (34 mL) were mixed to afford after purification via prep HPLC (product at 60% MeCN + 0.1% FA) 32 as a off-white solid (550 mg, 1.8 mmol, 95%).1H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 5.0 Hz, 1 H), 7.70 (s, 1H), 7.50 (d, J = 4.9 Hz, 1 H), 7.34 (d, J = 3.2 Hz, 1 H), 7.25 (dd, J = 9.0, 3.2 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.16 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.4, 155.8, 150.5, 150.2, 149.8, 141.5, 125.6, 123.9, 121.4, 118.2, 114.0, 113.0, 67.4. HRMS (ESI) m / z calcd for Ci3HioBrN04[M-Hp: 321 .97204, found 321 .97201.

[0316] 2-Bromo-5-(bromomethyl)pyrimidine (33b)

[0317] A solution of PBrs (3.3 ml, 35 mmol) in DCM was added dropwise at 0 °C to a suspension of (2-chloropyrimidin-5-yl)methanol (1 g, 7 mmol, 1 eq) in DCM (23 mL) The resulting mixture was stirred at room temperature overnight. After reaction completion, the PBrs was quenched with the addition of H2O (10 mL) and the reaction mixture was extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as an oil which was used in the next step without purification due to its instability.

[0318] Methyl 5-((2-bromopyrimidin-5-yl)methoxy)-2-hydroxybenzoate (33a)

[0319] According to GP-E, freshly prepared 33b (574 mg, 2.28 mmol, 1.1 eq.), methyl-2,5- dihydroxybenzoate (700 mg, 2.07 mmol, 1.0 eq.) and K2CO3 (715 mg, 5.1 mmol, 2.5 eq.) were stirred for 2h in acetone at room temperature to give after purification via flash chromatography (40% EtOAc in cyclohexane) 33a as an off-white solid (920 mg, 3.14 mmol, 70%).1H NMR (500 MHz, DMSO-d6) δ 15.67 (d, J = 46.8 Hz, 1 H), 8.64 (s, 2H), 7.33 (d, J = 2.9 Hz, 1H), 6.78 (d, J = 34.1 Hz, 1H), 6.53 (s, 1H), 4.94 (s, 2H), 3.91 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171.1 , 170.9, 164.8, 159.5, 157.1 , 156.4, 148.7, 148.5, 124.6, 120.9, 120.7, 119.5, 119.3, 116.1 , 115.9, 115.3, 115.2, 65.0, 54.6. LC-MS for Ci3HiiBrN2O4 [M+H]+: 339.1.

[0320] 5-((2-Bromopyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (33)

[0321] According to GP-F, 33a (500 mg, 1.8 mmol, 1 eq.) and NaOH (in aq. 10%, 0.3 mL) in MeOH (34 mL) were mixed to afford after purification via flash chromatography (10% MeOH in CH2CI2) 33 as an off-white solid (550 mg, 1.8 mmol, 95%).1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 2H), 7.39 (d, J = 3.2 Hz, 1 H), 7.25 (dd, J = 9.0, 3.2 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.14 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 159.7, 155.9, 151.6, 149.9, 130.4, 124.2, 118.3, 114.3, 113.0, 64.8. HRMS (ESI) m / z calcd for Ci2H8BrN2O4 [M-Hp: 322.96729, found, 322.9660.

[0322] Methyl 5-((3-bromobenzyl)oxy)-2-hydroxybenzoate (34a)

[0323] According to GP-E, 3-bromobenzyl bromide (1.14 g, 4.6 mmol, 1.1 eq.), methyl-2,5- dihydroxybenzoate (70 mg, 4.1 mmol, 1 eq.) and K2CO3 (1.15 g, 8.3 mmol, 3 eq.) in acetone (31 ml_) were stirred at 60 °C for 2 h. The crude mixture was purified via flash chromatography (0 - 5% MeOH in CH2CI2) to afford 34a as a white solid (0.9 g, 4.1 mmol, 75%).1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1 H), 7.65 (s, 1 H), 7.53 (d, J = 7.9 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.35 (dd, J = 13.5, 5.5 Hz, 2H), 7.25 (dd, J = 9.0, 3.1 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 5.08 (s, 2H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 168.8, 154.5, 150.5, 139.8, 130.6, 130.2, 126.5, 124.1 , 121.7, 118.6, 113.7, 112.8, 68.8, 52.5. LC-MS for Ci5Hi3BrO4[ / W+H]+: 335.9, found 336.1.

[0324] 5-((3-Bromobenzyl)oxy)-2-hydroxybenzoic acid (34)

[0325] According to GP-F, 34a (150 mg, 0.445 mmol, 1.0 eq.) and NaOH (in aq. 10%, 0.16 mL) in MeOH (4.45 mL) were heated to 65 °C overnight, to afford after purification via flash chromatography (8% MeOH in CH2CI2) 34 as a white solid (137 mg, 0.445 mmol, 95%).1H NMR (500 MHz, DMSO-c / 6) 57.65 (s, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 7.7 Hz, 1H), 7.35 (dd, J = 9.9, 5.5 Hz, 2H), 7.24 - 7.18 (m, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.07 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.6, 155.8, 150.4, 140.1 , 130.8, 130.8, 130.3, 126.7, 124.2, 121.8, 118.3, 114.2, 69.1. LC-MS for CuHnBrCU [ / W+H]+: found: 323.1.

[0326] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)thiazol-4-yl)methoxy)-2-hydroxybenzoic acid (35)

[0327] According to GP-G, 31 (100 mg, 0.3 mmol), (3-((3-chlorobenzyl)oxy)phenyl)boronic acid (200 mg, 0.78 mmol), [Pd(dppf)Cl2] (11 mg, 0.015 mmol) and K2CO3 (125 mg, 0.9 mmol) in 1 ,4-dioxane / H2O (4 / 1 mL) were stirred at 80 °C for 2 days to give after flash chromatography (product at 12% EtOAc in cyclohexane) 35 as an off-white solid (21 mg, 0.03 mmol, 15%).1H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1 H), 7.55 (d, J = 1.9 Hz, 1 H), 7.55 - 7.49 (m, 2H), 7.46 (d, J = 5.8 Hz, 1 H), 7.43 (m, 2H), 7.39 (m, 2H), 7.23 (dd, J = 9.0, 3.2 Hz, 1H), 7.15 (dd, J = 8.2, 2.4 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.37 (s, 2H), 5.22 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.4, 167.6, 158.5, 155.9, 149.6, 143.2, 139.4, 134.7, 134.3, 133.1 , 130.5, 130.4, 127.8, 127.3, 126.2, 124.1 , 119.0, 118.1 , 117.1 , 114.6, 111.7, 68.4, 62.7. HRMS (ESI) m / z calcd for C24Hi8CINO5S [M-H]-: 466.05214, found, 466.05212.

[0328] 5-((2-(3-((3-Chlorobenzyi)oxy)phenyl)pyridin-4-yl)methoxy)-2-hydroxybenzoic acid (36)

[0329] According to GP-G, 32 (150 mg, 0.46 mmol), (3-((3-chlorobenzyl)oxy)phenyl)boronic acid (145 mg, 0.55 mmol), [Pd(PPhs)4] (33 mg, 0.032 mmol) and K2CO3 (190 mg, 1.38 mmol) in 1 ,4-dioxane / H2O (4 / 1 mL) were stirred at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 75% MeCN + 0.1% FA) to afford 36 as an off-white solid (40 mg, 0.46 mmol, 25%).1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J = 5.0 Hz, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.47 (m, 1 H), 7.44 (dd, J = 6.9, 3.9 Hz, 1 H), 7.42 (m, 3H), 7.39 (d, J = 3.1 Hz, 1 H), 7.29 (dd, J = 9.0, 3.2 Hz, 1 H), 7.11 (dd, J = 8.1 , 2.4 Hz, 1 H), 6.93 (d, J = 9.0 Hz, 1 H), 5.22 (s, 2H), 5.21 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ171.4, 158.6, 155.8, 155.7, 150.2, 149.6,

[0330] 147.3, 140.0, 139.7, 133.1, 130.3, 129.9, 127.7, 127.3, 126.2, 124.1 , 120.8, 119.2,

[0331] 118.4, 118.2, 115.7, 113.9, 112.8, 112.7, 68.4, 68.3. HRMS (ESI) m / z calcd for C26H21CINO5 [ / W+H]+: 462.11028, found, 462.11002.

[0332] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (37)

[0333] According to GP-G, 33 (90 mg, 0.28 mmol), (3-((3-chlorobenzyl)oxy)phenyl)boronic acid (180 mg, 0.69 mmol), [Pd(PPh3)4] (15 mg, 0.014 mmol) and K2CO3 (73 mg, 0.69 mmol) in 1 ,4-dioxane / H2O (1.28 / 0.32 ml_) were stirred at 80 °C for 30 min. The crude mixture was purified via flash chromatography (30% EtOAc in cyclohexane) to give 37 as an off-white solid (30 mg, 0.28 mmol, 23%).1H NMR (500 MHz, DMSO-d6) 5 8.99 (s, 2H), 8.04 - 8.01 (m, 2H), 7.57 (s, 1 H), 7.48 (s, 1 H), 7.50 - 7.47 (m, 1 H), 7.46 - 7.43 (m, 1 H), 7.43 - 7.41 (m, 1 H), 7.41 - 7.39 (m, 1 H), 7.29 (dd, J = 9.0, 3.2 Hz, 1 H), 7.23 - 7.18 (m, 1 H), 6.94 (d, J = 9.0 Hz, 1H), 5.23 (s, 2H), 5.18 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 158.6, 157.3, 155.9, 150.2, 139.6, 133.1 , 130.4, 130.0, 128.7, 127.8, 127.4, 127.3, 126.2, 124.3, 120.6, 120.3, 118.3, 114.1 , 113.5, 113.4, 112.8, 68.3, 65.4. HRMS (ESI) m / z calcd for C25H18CIN2O5 [M-Hp: 322.96729, found, 461.08926.

[0334] 5-((3'-((3-Chlorobenzyi)oxy)-[1,r-biphenyi]-3-yl)methoxy)-2-hydroxybenzoic acid (38) According to GP-G, 34 (90 mg, 0.28 mmol), (3-((3-chlorobenzyl)oxy)phenyl)boronic acid (73 mg, 0.28 mmol), [Pd(PPh3)4] (23 mg, 0.02 mmol) and K2CO3 (102 mg, 0.74 mmol) in 1 ,4-dioxane / H2O (0.88 / 0.32 mL) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via flash prep (product at 78% MeCN + 0.1% FA) to afford 38 as a yellowish solid (28 mg, 0.28 mmol, 20%).1H NMR (500 MHz, DMSO-d6) δ 7.74 (s, 1 H), 7.63 (d, J = 7.5 Hz, 1 H), 7.56 (s, 1 H), 7.48 (t, J = 7.5 Hz, 1H), 7.44 (m, 3H), 7.40 (dd, J = 7.7, 5.2 Hz, 2H), 7.38 (d, J = 3.0 Hz, 1 H), 7.32 - 7.28 (m, 1H), 7.26 (m, 1H), 7.25 (m, 1 H), 7.03 (dd, J = 8.1, 2.1 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1H), 5.21 (s, 2H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.6, 158.6, 155.6, 150.6, 141.5, 140.0, 139.7, 137.7, 133.1 , 130.4, 130.2, 129.1 , 127.8, 127.4, 127.0, 126.3, 126.3, 126.2, 124.3, 119.4, 118.2, 114.1 , 113.8, 113.1 , 112.7, 69.8, 68.3. HRMS (ESI) m / z calcd for C27H21CIO5 [A4-H]": 459.10048, found, 459.10059.

[0335] Methyl 5-((3'-amino-[1 ,1 '-biphenyl]-3-yl)methoxy)-2-hydroxy benzoate (39b)

[0336] According to GP-G, bromide 34a (200 mg, 0.59 mmol), (3-amino-phenyl)boronic acid (81 mg, 0.59 mmol), [Pd(PPhs)4] (34mg, 0.03 mmol) and K2CO3 (228 mg, 1.6 mmol) in 1 ,4-dioxane / H2O (1.93 / 0.65 mL) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via flash chromatography (product at 25% EtOAc in cyclohexane) to afford 39b as a light brown solid (94 mg, 0.59 mmol, 45%).1H NMR (500 MHz, CDCI3) δ 10.39 (s, 1 H), 7.62 (s, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.47 - 7.37 (m, 3H), 7.23 (dd, J = 9.9, 5.7 Hz, 1 H), 7.17 (dd, J = 9.0, 3.1 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1 H), 6.92 (dd, J = 8.6, 5.4 Hz, 2H), 6.69 (dd, J = 7.9, 1.7 Hz, 1 H), 5.07 (s, 2H), 3.95 (d, J = 4.2 Hz, 3H), 3.89 - 3.59 (m, 2H).13C NMR (126 MHz, CDCI3) δ 156.4, 151.3, 146.9, 142.2, 141.9, 137.3, 129.8, 129.0, 127.0, 126.6, 126.5, 125.0, 118.7, 117.8, 114.4, 114.0, 113.6, 112.1 , 71.1 , 52.5. LC-MS for C21H19NO4 [M+H]+: 352.1.

[0337] Methyl 2-hydroxy-5-((3*-((1 >methy!ethyl)sulfonamido)-2,3-dihydro-[1 ,1 biphenyl]-3-yl)methoxy)benzoate (39a)

[0338] According to GP-H, propane-2-sulfonyl chloride (0.015 ml, 0.111 mmol), 39b (40 mg, 0.111 mmol) and pyridine (0.018 ml, 0.17 mmol) in CH2CI2 (0. 76 ml) were used to afford after flash chromatography (product at 20% EtOAc in cyclohexane) 39a as a white solid (46 mg, 0.085 mmol, 88%).1H NMR (500 MHz, CDCI3) δ 10.32 (s, 1H), 7.55 (s, 1 H), 7.47 (d, J = 7.5 Hz, 1H), 7.43 - 7.28 (m, 6H), 7.14 (dt, J = 7.2, 2.0 Hz, 1 H), 7.14 (dt, J = 7.2, 2.0 Hz, 1 H), 7.10 (dd, J = 9.1 , 3.1 Hz, 1H), 7.10 (dd, J = 9.1 , 3.1 Hz, 1 H), 6.87 (d, J = 9.0 Hz, 1 H), 6.34 (s, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.27 (hept, J = 6.8 Hz, 1H), 1.35 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, CDCh) δ 170.4, 156.5,

[0339] 151.2, 142.7, 140.7, 137.7, 137.6, 130.2, 129.3, 127.1 , 127.1 , 126.5, 124.9, 123.9,

[0340] 119.3, 119.1 , 118.8, 113.6, 112.1 , 70.9, 52.8, 52.5, 16.7. LC-MS for C24H27NO6S [M- H]-: 456.2.

[0341] 2-Hydroxy-5-((3'-(W-isopropylsulfamoyl)-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (39)

[0342] According to GP-F, 39a (46 mg, 0.1 mmol) and NaOH (in aq. 10%, 10 eq., 0.014 ml) in MeOH (1 mL) were heated to 65 °C overnight, to afford after flash chromatography (product at 8% MeOH in CH2CI2) 39 as a white solid (42 mg, 0.1 mmol, 95%).1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1 H), 7.66 (s, 1H), 7.62 - 7.30 (m, 7H), 7.25 (dd, J =

[0343] 9.1 , 3.1 Hz, 2H), 6.91 (d, J = 9.0 Hz, 1 H), 5.14 (s, 2H), 1.25 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 155.6, 150.5, 141.1 , 140.0, 139.3, 137.9, 129.96, 129.2, 127.0, 126.2, 125.9, 124.0, 122.0, 118.3, 118.1 , 117.4, 113.9, 112.8, 69.7, 51.4,

[0344] 16.1. HRMS (ESI) m / z calcd for C23H22NO6S [M-HF: 440.11733, found, 440.11737.

[0345] 2-Hydroxy-5-((3’-((tetrahydro-2W-pyran-2-yl)methoxy)-[1,T-biphenyl]-3- yl)methoxy)benzoic acid (40)

[0346] According to GP-G, bromide 34 (80 mg, 0.25 mmol), (3-((tetrahydro-2 / - / -pyran-2- yl)methoxy)phenyl)boronic acid (58 mg, 0.25 mmol), [Pd(PPhs)4] (14 mg, 0.012 mmol) and K2CO3 (103 mg, 0.74 mmol) in 1 ,4-dioxane / H2O (0.87 / 0.31 mL) were stirred under microwave irradiation at 80 °C for 30 min to give after flash chromatography (product at 8% MeOH in CH2CI2) 40 as a yellowish solid (27 mg, 0.25mmol, 30%).1H NMR (500 MHz, MeOD) δ 7.66 (s, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.48 - 7.40 (m, 3H), 7.34 (t, J = 7.9 Hz, 1 H), 7.19 (dd, J = 9.0, 3.2 Hz, 2H), 7.15 (t, 1H), 6.92 (dd, J = 8.2, 2.4 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 5.10 (s, 2H), 4.03 - 3.97 (m, 3H), 3.76 - 3.71 (m, 1 H), 3.53 (td, J = 11 .2, 3.0 Hz, 1 H), 1.94 - 1.87 (m, J = 10.6, 7.3 Hz, 1 H), 1 .72 (d, J = 12.7 Hz, 1 H), 1.64 - 1.54 (m, J = 15.7, 10.0, 3.8 Hz, 3H), 1.48 (qd, J = 12.5, 3.9 Hz, 1 H).13C NMR (126 MHz, MeOD) δ 173.3, 160.8, 157.7, 152.43, 143.7, 142.6, 139.2, 130.9, 130.0, 127.7, 127.6, 127.3, 125.4, 120.7, 119.1, 115.5, 114.5, 114.4, 113.8, 77.6, 72.4, 71.8, 69.4, 29.1 , 27.0, 24.1. HR-MS (ESI) m / z calcd for C26H25O6 [M-H]’: 433.16566, found: 433.1651.

[0347] 2-Hydroxy-5-((3'-methoxy-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (41)

[0348] According to GP-G, 34 (80 mg, 0.25 mmol), (3-methoxyphenyl)boronic acid (35 mg, 0.25 mmol), [Pd(PPh3)4] (20 mg, 0.02 mmol) and K2CO3 (10 mg, 0.74 mmol) in 1,4- dioxane / H2O (0.88 / 0.32 mL) were stirred at 80 °C for 30 min. The crude mixture was purified via flash chromatography (0 - 10% EtOAc) to afford 41 as a yellowish oil (25 mg, 0.25 mmol, 29%).1H NMR (500 MHz, DMSO-d6) δ 7.74 (s, 1 H), 7.62 (d, J = 7.4 Hz, 1 H), 7.49 - 7.43 (m, 2H), 7.40 - 7.36 (m, 2H), 7.24 (dd, J = 11.3, 5.4 Hz, 2H), 7.18 (t, 1 H), 6.95 (dd, J = 8.2, 2.4 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1 H), 5.13 (s, 2H), 3.82 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 159.8, 155.6, 141.5, 140.2, 137.8, 130.1 , 129.1 , 126.9, 126.3, 126.2, 119.1, 118.1 , 113.9, 113.3, 112.1 , 69.7, 55.2. HRMS (ESI) calcd for C21H17O5 [M-Hp: 349.10815, found: 349.10803.

[0349] 2-Hydroxy-5-((3'-phenoxy-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (42)

[0350] According to GP-G, 34 (40 mg, 0.12 mmol), (3-phenoxyphenyl)boronic acid (26 mg, 0.12 mmol), [Pd(PPhs)4] (14 mg, 0.006 mmol) and K2CO3 (50 mg, 0.37 mmol) in 1 ,4- dioxane / H2O (0.44 / 0.16 mL) were stirred at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 60% MeCN + 0.1 % FA) to afford 42 as yellowish solid (10 mg, 0.12 mmol, 20%).1H NMR (500 MHz, MeOD) 57.63 (s, 1 H), 7.52 (dt, J = 6.8, 1.9 Hz, 1 H), 7.46 (d, J = 3.2 Hz, 1 H), 7.44 - 7.39 (m, 3H), 7.36 (dt, J = 9.8, 1 .9 Hz, 3H), 7.24 - 7.20 (m, 1 H), 7.16 (dd, J = 9.0, 3.2 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1 H), 7.06 - 7.01 (m, 2H), 6.95 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1 H), 5.09 (s, 2H).13C NMR (126 MHz, MeOD) 5 173.3, 159.3, 158.6, 157.6, 152.3, 144.2, 142.0,

[0351] 139.4, 131.3, 130.9, 130.1, 127.9, 127.5, 127.1 , 125.2, 124.5, 122.9, 120.0, 119.0,

[0352] 118.5, 118.2, 115.5, 114.0, 71.6. HRMS (ESI) calcd for C26H19O5 [M-Hp: 411.12380, found: 411.12326.

[0353] 5-((3'-(Benzyloxy)-[1 ,1 ‘-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (43)

[0354] According to GP-G, 34 (35 mg, 0.11 mmol), (3-(benzyloxy)phenyl)boronic acid (25 mg, 0.11 mmol), [Pd(PPhs)4] (6 mg, 0.005 mol) and K2CO3 (45 mg, 0.32 mmol) in 1 ,4- dioxane / H2O (0.4 / 0.14 mL) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 78% MeCN + 0.1% FA) to afford 43 as a white solid (25 mg, 0.11 mmol, 50%).1H NMR (500 MHz, DMSO-d6) 6 7.74 (s, 1 H), 7.62 (d, J = 7.4 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 5.5 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.37 - 7.40 (m, 4H), 7.33 (t, J = 7.3 Hz, 1 H), 7.29 (s, 1 H), 7.24 (dd, J = 9.0, 3.1 Hz, 2H), 7.02 (dd, J = 8.1, 2.0 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1H), 5.19 (s, 2H), 5.13 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ171.5, 158.8, 155.6, 150.5, 141.4, 140.1 , 137.7, 137.1, 130.0, 129.0, 128.4, 127.8, 127.7, 126.8, 126.2, 126.1 , 124.0, 119.2, 118.1 , 114.1 , 113.9, 113.0, 112.9, 69.8, 69.2. HRMS (ESI) m / z calcd for C27H21O5 [M-Hp: 425.13945, found 425.13904.

[0355] 5-((5-Chloro-3'-((3-chlorobenzyl)oxy)-[1,T-biphenyl]-3-yl)methoxy)-2- hydroxybenzoic acid (44)

[0356] According to GP-G, 34 (55 mg, 0.14 mmol), (3-chloro-5-((3- chlorobenzyl)oxy)phenyl)boronic acid (37 mg, 0.14 mmol), [Pd(PPh3)4] (8 mg, 7 pmol) and K2CO3 (58 mg, 0.42 mmol) in 1 ,4-dioxane / H2O (0.5 / 0.18 mL) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 80% MeCN + 0.1 % FA) to afford 44 as a yellowish solid (15 mg, 0.14 mmol, 20%).1H NMR (500 MHz, CDCI3) <5 10.21 (s, 1 H), 7.52 (d, J = 1.6 Hz, 1 H), 7.49 (d, J = 13.8 Hz, 2H), 7.44 (d, J = 3.1 Hz, 1 H), 7.42 (s, 1 H), 7.37 (t, J = 7.9 Hz, 1 H), 7.35 - 7.29 (m, 3H), 7.22 (dd, J = 9.1 , 3.1 Hz, 1H), 7.19 (s, 1 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.00 - 6.93 (m, 2H), 5.09 (s, 2H), 5.05 (s, 2H).13C NMR (126 MHz, CDCI3) δ 173.2, 159.0, 157.2, 151.0, 143.1 , 141.2, 139.2, 139.0, 135.0, 134.7, 130.2, 130.0, 128.3, 127.6, 127.1 , 126.5, 126.1 , 125.5, 124.5, 120.2, 119.1 , 114.2, 114.1 , 114.0, 111.1 , 70.1 , 69.4. HRMS (ESI) m / z calcd for C27H20C12O5 [M-Hp: 493.06150, found, 493.06177.

[0357] 2-Hydroxy-5-((3'-((4-methoxybenzyl)oxy)-5-(trifluoromethyl)-[1,r-biphenyl]-3- yi)methoxy)benzoic acid (45) According to GP-G, 34 (50 mg, 0.14 mmol), (3-((3-methoxybenzyl)oxy)-5- (trifluoromethyl)phenyl)boronic acid (45 mg, 0.14 mmol), [Pd(PPh3)4] (8 mg, 7 pmol) and K2CO3 (58 mg, 0.42 mmol) in 1 ,4-dioxane / H2O (0.5 / 0.18 mL) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 75% MeCN + 0.1% FA) to afford 45 as yellowish solid (20 mg, 0.14 mmol, 28%).1H NMR (500 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.76 - 7.69 (m, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.51 (d, J = 5.5 Hz, 2H), 7.43 (m, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.33 (s, 1H), 7.25 (dd, J = 9.0, 3.2 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 9.0 Hz, 1H), 5.20 (s, 2H), 5.14 (s, 2H), 3.75 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171.6, 159.3, 159.2, 155.6, 150.6, 142.6, 138.5, 138.0, 131.5 - 130.1 (ArCCFs), 129.8, 129.3, 128.3, 127.7, 126.6, 126.5, 124.3 (CF3), 122.1 , 118.2, 117.1, 115.4, 113.9 (ArCCFs), 113.8, 110.7 ArCCF3, 69.7, 69.6, 55.1.19F NMR (470 MHz, DMSO-d6) δ - 61.05. HRMS (ESI) m / z calcd for C29H22F3O6 [ / W-Hp: 523.13727, found, 523.13740.

[0358] 2-Hydroxy-5-((3'-((neopentyloxy)sulfonyl)-[1,r-biphenyl]-3-yl)methoxy)benzoic acid (46)

[0359] According to GP-G, 34 (80 mg, 0.25 mmol), (3-((neopentyloxy)sulfonyl)phenyl)boronic acid (67 mg, 0.25 mmol), [Pd(PPh3)4] (17 mg, 0.014 mmol) and K2CO3 (86 mg, 0.62 mmol) in 1 ,4-dioxane / H2O (0.87 / 0.31 mL) were stirred at 80 °C for 30 min. The crude mixture was purified via HPLC (product at 70% MeCN + 0.1 % FA) to afford 46 as white solid (57 mg, 0.25 mmol, 50%).1H NMR (500 MHz, MeOD) 58.10 (t, J = 1.7 Hz, 1H), 8.02 - 7.98 (m, 1 H), 7.92 - 7.86 (m, 1 H), 7.73 (s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.64 - 7.59 (m, 1 H), 7.51 (m, 2H), 7.47 (d, J = 3.2 Hz, 1H), 7.19 (dd, J = 9.0, 3.2 Hz, 1H), 6.86 (d, J= 9.0 Hz, 1H), 5.13 (s, 2H), 3.75 (s, 2H), 0.90 (s, 9H).13C NMR (126 MHz, MeOD) 5 173.2, 157.8, 152.3, 143.7, 140.5, 139.8, 138.1, 133.5, 131.2, 130.4, 128.7, 127.7, 127.6, 127.2, 127.0, 125.3, 119.1, 115.6, 113.8, 81.1, 71.5, 32.5, 26.2. HRMS (ESI) m / z calcd for C25H25O7S [M-H]-; 469.13265, found, 469.13205.

[0360] 2-Hydroxy-5-((4,-((neopentyloxy)suifonyl)-[1,r-biphenyi]-3-yl)methoxy)benzoic acid (47)

[0361]

[0362] According to GP-G, 34 (80 mg, 0.25 mmol), (3-((neopentyloxy)sulfonyl)phenyl)boronic acid (67 mg, 0.25 mmol), [Pd(PPh3)4] (17 mg, 0.014 mmol) and K2CO3 (86 mg, 0.62 mmol) in 1,4-dioxane / H2O (0.87 / 0.31 mL) were mixed at 80 °C for 30 min. The crude mixture was purified via HPLC (product at 70% MeCN + 0.1% FA) to give 47 as a white solid (90 mg, 0.25 mmol, 75%).1H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 4H), 7.86 (s, 1 H), 7.75 - 7.71 (m, 1 H), 7.57 - 7.53 (m, J = 6.6, 3.7 Hz, 2H), 7.40 (d, J = 3.2 Hz, 1 H), 7.26 (dd, J = 9.0, 3.2 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 5.16 (s, 2H), 3.76 (s, 2H), 0.86 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 155.6, 150.5, 150.0, 145.3, 138.2, 138.2, 134.1, 129.4, 128.3, 128.1 , 127.8, 126.7, 126.5, 124.2, 118.2, 114.0, 112.7, 79.5, 69.5, 31.4, 25.7. HRMS (ESI) m / z calcd for C25H25O7S [M-H]': 469.13265, found, 469.13290.

[0363] 2-Hydroxy-5-((3'-(piperidin-1-ylsulfonyl)-[1,T-biphenyl]-3-yl)methoxy)benzoic acid (48)

[0364] According to GP-G, 34 (85 mg, 0.26 mmol), (3-(piperidin-1-ylsulfonyl)phenyl)boronic acid (71 mg, 0.26 mmol), [Pd(PPhs)4] (15 mg, 0.013 mmol) and K2CO3 (109 mg, 0.78 mmol) in 1 ,4-dioxane / H2O (0.9 / 0.3 mL) were stirred at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 75% MeCN + 0.1% FA) to give 48 as a white solid (50 mg, 0.26 mmol, 40%).1H NMR (500 MHz, MeOD) δ 7.87 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.77 (s, 1 H), 7.63 -7.67 (m, 1 H), 7.52 (d, J = 4.8 Hz, 2H), 7.48 (d, J = 2.6 Hz, 1H), 7.16 - 7.22 (m, 1 H), 6.87 (d, J = 9.0 Hz, 1H), 5.14 (s, 2H), 3.07 - 2.97 (m, 4H), 1.65 (dt, J = 11.3, 5.8 Hz, 4H), 1 .49 - 1.41 (m, 2H).13C NMR (126 MHz, MeOD) 5 157.7, 152.3, 146.7, 140.8, 139.7, 136.2, 130.3, 129.4, 128.8, 128.7, 127.8, 127.5, 125.2, 120.4, 119.1 , 114.0, 115.6, 71.6, 48.2, 26.4, 24.5. HRMS (ESI) m / z calcd for C25H24NO6S [M-Hp: 466.13298, found, 466.13287.

[0365] 5-((3'-(N-Cyclopropylsulfamoyl)-[1,T-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (49)

[0366] According to GP-G, 34 (120 mg, 0.37 mmol), (3-( / V- cyclopropylsulfamoyl)phenyl)boronic acid (90 mg, 0.37 mmol), [Pd(PPh3)4] (21 mg, 0.018 mmol) and K2CO3 (153 mg, 1.1 mmol) in 1 ,4-dioxane / H2O (1.2 / 0.4 ml_) were stirred at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 60% MeCN + 0.1% FA) to afford 49 as an off-white solid (9 mg, 0.37 mmol, 20%).1H NMR (500 MHz, MeOD) 5 8.17 - 8.08 (m, 1 H), 7.88 (dt, J = 22.1 , 10.9 Hz, 2H), 7.76 (d, J = 9.1 Hz, 1 H), 7.70 - 7.60 (m, 2H), 7.56 - 7.44 (m, 3H), 7.18 (td, J = 8.6, 3.0 Hz, 1 H), 6.90 - 6.80 (m, 1 H), 5.15 (s, 2H), 2.24 - 2.15 (m, 1H), 1.30 (t, J = 6.4 Hz, 1 H), 0.59 - 0.48 (m, 4H).13C NMR (126 MHz, MeOD) δ 173.8, 157.5, 152.2, 143.3, 142.1 , 140.9, 139.8, 132.2, 130.8, 130.4, 128.5, 127.6, 127.3, 127.1 , 126.5, 124.7, 118.8, 115.8, 115.3, 71.6, 25.1 , 9.2, 6.1. HRMS (ESI) m / z calcd for C23H20NO6S [M-Hp: 438.10168, found, 438.10172.

[0367] 5-((3'-(A / -(tert-butyl)sulfamoyl)-[1,r-biphenyl]-3-yl)methoxy)-2-hydroxybenzoic acid (50)

[0368] According to GP-G, 34 (90 mg, 0.28 mmol), (3-( / V-(tert-butyl)sulfamoyl)phenyl)boronic acid (72 mg, 0.28 mmol), [Pd(PPhs)4] (16 mg, 0.014 mmol) and K2CO3 (115 mg, 0.83 mmol) in 1 ,4-dioxane / H2O (0.98 / 0.35 mL) were stirred at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 50% MeCN + 0.1 % FA) to afford 50 as an off white-solid (50 mg, 0.28 mmol, 42%).1H NMR (500 MHz, MeOD) 58.04 (t, J = 1.7 Hz, 1 H), 7.76 (tt, J = 5.3, 3.7 Hz, 2H), 7.64 (s, 1 H), 7.55 - 7.50 (m, 2H), 7.43 - 7.37 (m, 3H), 7.08 (dd, J = 9.0, 3.2 Hz, 1 H), 6.75 (d, J = 9.0, 4.2 Hz, 1 H), 5.04 (s, J = 12.9 Hz, 2H), 1.11 (d, J = 4.8 Hz, 9H).13C NMR (126 MHz, MeOD) δ157.6, 152.3, 146.3, 143.2, 141.1 , 139.8, 131.6, 130.6, 130.4, 128.4, 127.6, 127.2, 126.6, 126.2, 124.9, 118.9, 115.6, 71.6, 54.9, 30.4. HRMS (ESI) m / z calcd for C24H24NO6S [7V7-H]-: 454.13298, found, 454.13266.

[0369] 5-((5'-( / V-(tert-butyl)sulfamoyl)-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-2- hydroxybenzoic acid (51)

[0370] According to GP-G, bromide 34 (130 mg, 0.4 mmol), (5-(A / -(tert-butyl)sulfamoyl)-2- methylphenyl)boronic acid (109 mg, 0.4 mmol), [Pd(PPhs)4] (23 mg, 0.02 mmol) and K2CO3 (154 mg, 1.12 mmol) in 1 ,4-dioxane / H2O (1.3 / 0.44 ml_) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via prep HPLC (product at 70% MeCN + 0.1 % FA) to afford 51 as a pink solid (62 mg, 0.4 mmol, 35%).1H NMR (500 MHz, DMSO-d6) 57.71 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.54 - 7.46 (m, 4H), 7.43 (s, 1 H), 7.37 (d, J = 3.2 Hz, 1 H), 7.32 (dt, J = 6.8, 1.8 Hz, 1H), 7.24 (dd, J = 9.0, 3.2 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 5.15 (s, 2H), 2.28 (s, 3H), 1.10 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 155.6, 150.5, 141.9, 141.5, 139.9, 139.3, 137.4, 131.0, 128.6, 128.3, 128.0, 127.2, 126.8, 125.1 , 124.2, 118.1 , 114.0, 112.7, 69.6, 53.2, 29.7, 20.1. HRMS (ESI) m / z calcd for C25H26NO6S [M- H]-: 468.14863, found, 468.14880. fert-Butyl 4-(5-((4-hydroxy-3-(methoxycarbonyl)phenoxy)methyl)pyrimidin-2- yl)piperazine-1 -carboxylate (52a) To a solution of 33a (67 mg, 0.2 mmol, 1 .0 eq) and K2CO3 (66 mg, 0.48 mmol, 3 eq) in acetonitrile (0.5 mL), tert-butyl piperazine-1 -carboxylate (37mg, 0.2 mmol, 1 eq) was added and the mixture was stirred at 80 °C overnight. The crude mixture was purified via prep HPLC (product at 25% MeCN + 0.1 % FA) to obtain 52a as an off-white solid (38 mg, 0.2 mmol, 45%). LC-MS for C22H28N4O6 [M+H]+: 444.2, found 445.2.

[0371] 5-((2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (52)

[0372] To a solution of compound 52a (30 mg, 0.063 mmol, 1 eq) in dichloroethane (0.63 mL) (CH3)3SnOH (56 mg, 0.32 mmol, 5 eq) was added and the mixture was stirred at 80 °C overnight. After completion of the reaction, the solvent was removed under vacuum, and the aqueous phase was diluted with Na2COs and extracted with CH2CI2 (3 * 10 mL). The combined organic layers were combined and dried over Mg2SO4.20The solvent of the organic phase was removed under vacuum and the crude mixture was purified via prep HPLC (70% ACN) to obtain 52 as a light brown solid (26 mg, 0.063 mmol, 90%).1H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 2H), 7.34 (d, J = 3.1 Hz, 1 H), 7.20 (dd, J = 9.0, 3.1 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 4.90 (s, 2H), 3.73 (t, 4H), 3.39 (t, 4H), 1.42 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 160.9, 158.5, 155.6, 153.9, 150.2, 124.3, 118.4, 118.1 , 114.1 , 112.7, 79.0, 65.5, 43.2, 28.0. HRMS (ESI) m / z calcd for C21H25N4O6 [M-Hp: 429.17796, found, 429.17627. tert-Butyl 3-(5-((4-hydroxy-3-(methoxycarbonyl)phenoxy)methyl)pyrimidin-2-yl)- 1H-indole-1 -carboxylate (53a)

[0373]

[0374] According to GP-G, bromide 33a (40 mg, 0.12 mmol, 1 eq), tert-butyl 3-(4,4,5,5- tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1H-indole-1 -carboxylate (77 mg, 0.3 mmol, 1 eq), [Pd(PPh3)4] (7 mg, 0.06 mmol, 0.05 eq) and K2CO3 (40 mg, 0.29 mmol, 3 eq) in 1,4- dioxane / H2O (0.55 / 0.11 mL) were stirred under microwave irradiation at 80 °C for 30 min. The crude mixture was purified via flash chromatography (product at 25% EtOAc in cyclohexanre) to obtain 53a as a light brown solid (37 mg, 0.12 mmol, 65%).1H NMR (500 MHz, CDCI3) δ 10.44 (s, 1H), 8.85 (s, 2H), 8.71 - 8.67 (m, 1H), 8.55 (s, 1 H), 8.26 (d, J = 7.4 Hz, 1 H), 7.43 - 7.36 (m, 3H), 7.18 (dd, J = 9.0, 3.1 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1 H), 5.06 (s, 2H), 3.97 (s, 3H), 1.70 (s, 9H).13C NMR (126 MHz, CDCI3) δ 170.2, 162.9, 156.9, 156.6, 150.6, 149.5, 136.5, 129.3, 128.2, 126.5, 125.1 , 125.1 , 123.7, 122.8, 119.7, 119.1 , 115.3, 113.7, 112.1 , 84.6, 66.7, 52.6, 28.3. LC-MS forC26H25N3O6 [M+H]+: 476.2.

[0375] 5-((2-(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (53)

[0376] Boc

[0377] To a solution of compound 53a (30 mg, 0.063 mmol, 1 eq) in dichloroethane (0.63 mL) (CHsJsSnOH (56 mg, 0.32 mmol, 5 eq) was added and the mixture was stirred at 80 °C overnight. After completion of the reaction, the solvent was removed under vacuum, and the aqueous phase was diluted with Na2CO3 and extracted with CH2CI2 (3 x 10 mL). The combined organic layers were combined and dried over Mg2SO4.20The solvent of the organic phase was removed under vacuum and the crude mixture was purified via prep HPLC (70% ACN) to obtain 53 as a light brown solid (26 mg, 0.063 mmol, 90%).1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 2H), 8.65 (d, J = 7.6 Hz, 1 H), 8.45 (s, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), 7.48 - 7.34 (m, 3H), 7.21 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 5.14 (s, 2H), 1.67 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 161.3, 157.0, 155.9, 149.8, 148.7, 146.4, 135.9, 135.6, 128.6, 127.6, 127.4, 125.0, 123.6, 122.65, 119.0, 117.8, 114.8, 114.5, 84.8, 65.6, 27.6. HRMS (ESI) m / z calcd for C25H22N306 [M- H]-: 460.15141 , found: 460.14978.

[0378] 5-((2-(1 H-lndol-3-y l)py rimidin-5-yl)methoxy)-2-hydroxy benzoic acid (54)

[0379] Compound 53 (20 mg, 0.042 mmol) was dissolved in DCM / TFA (9 / 1) to afford after purification via prep HPLC (product at 55% MeCN + 0.1 % FA) 54 as a yellowish solid (12 mg, 0.042 mmol, 80%).1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.84 (s, 2H), 8.52 (d, J = 7.3 Hz, 1 H), 8.25 (d, J = 2.8 Hz, 1 H), 7.44 (dd, J = 28.8, 5.2 Hz, 2H), 7.25 (dd, J = 9.0, 3.1 Hz, 1H), 7.22 - 7.13 (m, 2H), 6.91 (d, J = 9.0 Hz, 1 H), 5.10 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 163.4, 156.9, 155.8, 150.1 , 137.1 , 129.6, 125.5, 125.3, 124.1 , 122.0, 121.8, 120.5, 118.1 , 114.5, 114.2, 112.0, 65.8. LC-MS for C20H15N3O4 [M+H]+: 362.2.

[0380] Methyl 5-((2-(3-amino-4-fluoropheny!)pyrimidin-5-yl)methoxy)-2- hydroxybenzoate (55a)

[0381] According to GP-G, 33a (100 mg, 0.3 mmol), (3-amino-4-fluorophenyl)boronic acid (123,2 mg, 0.92 mmol), [Pd(dppf)Cl2] (11 mg, 0.015 mmol) and K2CO3 (125 mg, 0.9 mmol) in 1 ,4-dioxane / H20 (4 / 1 mL) were stirred under microwave irradiation at 60 °C for 40 min to give after flash chromatography (product at 30% EtOAc in cyclohexane) 55a as an yellow solid (24 mg, 0.024 mmol, 28%).1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.93 (s, 2H), 7.90 (dd, J = 9.1, 2.1 Hz, 1H), 7.64 - 7.55 (m, 1H), 7.39 (d, J = 6.6 Hz, 1 H), 7.29 (dd, J = 9.0, 3.2 Hz, 1 H), 7.11 (q, J = 11.2, 8.5 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1 H), 5.35 (s, 2H), 5.15 (s, 2H), 3.90 (s, 3H).13C NMR (126 MHz, DMSO- d6) 5 168.8, 162.8, 157.0, 154.7, 153.4, 151.5, 150.3, 136.6, 136.5, 133.3, 127.9, 124.3, 118.6, 115.9, 115.7, 115.2, 115.0, 113.9, 112.8, 65.6, 52.5. LC-MS for C19H16FN3O4: 369.1 , found 370.2.

[0382] 5-((2-(3-Amino-4-fluorophenyl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (55)

[0383] According to GP-F, ester 55a (20 mg, 0.05 mmol) and NaOH (in aq. 10%, 10 eq., 0.003 mL) in MeOH (0.5 ml) were heated to 65 °C overnight, to afford after purification via prep HPLC (product at 50% MeCN + 0.1% FA) 55 as a yellow solid (8 mg, 0.05 mmol, 50%).1H NMR (500 MHz, DMSO-d6) δ 8.91 (s, 4H), 8.15 (s, 1 H), 7.92 (dd, J = 9.1, 2.2 Hz, 2H), 7.63 - 7.55 (m, J = 8.4, 4.6, 2.2 Hz, 2H), 7.37 (d, J = 3.3 Hz, 2H), 7.11 (dd, J = 11.2, 8.5 Hz, 2H), 6.87 (tt, 2H), 6.57 (d, J = 8.7 Hz, 2H), 5.34 (s, 4H), 5.07 (s, 4H).13C NMR (126 MHz, DMSO-d6) δ 170.7, 163.1 , 162.6, 157.3, 156.9, 153.41 , 151.5, 148.5, 136.6, 136.5, 133.4, 128.6, 120.8, 119.5, 116.2, 116.0, 115.9, 115.8, 115.8, 115.2, 115.0, 115.0, 65.5.19F NMR (470 MHz, DMSO-cfe) -132.05. LC / MS for C18H14FN3O4 [M+H]+: 356.2, found 356.1.

[0384] Methyl 5-((2-(3-amino-4-methylphenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoate (56a) According to GP-G, 33a (50 mg, 0.14 mmol), (3-amino-4-methylphenyl)boronic acid (56 mg, 0.37 mmol), [Pd(dppf)CI2] (5 mg, 0.0.007 mmol) and K2CO3 (58 mg, 0.42 mmol) in 1 ,4-dioxane / H2O (4 / 1 mL) were stirred under microwave irradiation at 60 °C for 40 mins to give after flash chromatography (product at 30% EtOAc in cyclohexane) 56a as a light brown solid (10 mg, 0.014 mmol, 20%).1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1 H), 8.90 (s, 2H), 7.73 (d, J = 1.4 Hz, 1H), 7.54 (dd, J = 7.7, 1.5 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1 H), 7.29 (dd, J = 9.0, 3.1 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1H), 5.15 (s, 2H), 5.03 (s, 2H), 3.90 (s, 3H), 2.12 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 168.8, 163.7, 156.9, 154.7, 150.4, 146.8, 135.2, 130.2, 127.6, 124.4, 124.3, 118.6, 115.8, 113.9, 113.2, 112.8, 65.6, 52.5, 17.5. LC-MS for C20H19N3O4 [M+H]+: 366.1 found, 366.2.

[0385] 5-((2-(3-Amino-4-methylphenyl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (56)

[0386] According to GP-F, ester 56a (50 mg, 0.09 mmol) and NaOH (in aq. 10%, 10 eq., 0.005 mL) in MeOH (0.9 mL) were heated to 65 °C overnight, to afford after purification via prep HPLC (product at 50% MeCN + 0.1% FA) 56 a white solid (12 mg, 0.09 mmol, 25%).1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 2H), 7.73 (d, J = 1.5 Hz, 1H), 7.54 (dd, 1 H), 7.40 (d, J = 3.0 Hz, 1 H), 7.23 (dd, J = 9.0, 3.0 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 5.13 (s, 2H), 2.12 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 171.4, 163.7, 156.9, 155.9, 150.0, 146.8, 135.2, 130.2, 127.8, 124.45, 123.7, 118.0, 115.9, 114.3, 113.3, 65.6, 17.5. LC-MS for C19H17N3O4 [M+H]+: 352.1 , found, 352.2.

[0387] Methyl 5-((2-aminopyrimidin-5-yl)methoxy)-2-hydroxybenzoate (57a)

[0388] According to GP-G, 33a (100 mg, 0.3 mmol), (3-aminophenyl)boronic acid (123,2 mg, 0.92 mmol), [Pd(dppf)Ch] (11 mg, 0.015 mmol) and K2CO3 (125 mg, 0.9 mmol) in 1 ,4- dioxane / H2O (4 / 1 ml_) were stirred at 60 °C under microwave irradiation for 40 min to give after flash chromatography (product at 30% EtOAc in cyclohexane) 57a as an off-white solid (21 mg, 0.03 mmol, 15%).1H NMR (500 MHz, CDCI3) δ 10.43 (s, 1 H), 8.84 (s, 2H), 7.86 (t, J = 9.5 Hz, 1 H), 7.83 - 7.77 (m, 1 H), 7.42 (t, J = 11.2 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1 H), 7.17 (dd, J = 9.0, 3.1 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 6.83 (dd, J = 7.9, 2.3 Hz, 1H), 5.06 (s, 2H), 3.96 (s, 3H).13C NMR (126 MHz, CDCh) δ

[0389] 170.2, 164.8, 156.9, 156.8, 150.6, 146.9, 138.4, 129.8, 127.6, 125.1 , 119.08, 118.8, 117.8, 114.8, 113.6, 112.1, 66.5, 52.6. LC-MS for Ci9Hi7N3O4 / W+H]+: 352.2, found,

[0390] 352.3.

[0391] 5-((2-(3-Aminophenyl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (57)

[0392] According to GP-F, ester 57a (21 mg, 0.09 mmol) and NaOH (in aq. 10%, 10 eq., 0.005 ml) in MeOH (0.9 m!_) were heated to 65 °C overnight to afford 57.

[0393] Methyl 5-((2-(3-((3-(1H“tetrazol-1-yl)propyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxy benzoate (58a) According to GP-H, 3-(1 / - / -tetrazol-1-yl)propane-1 -sulfonyl chloride (66 mg, 0.31 mmol), 57a (100 mg, 0.29 mmol, 1 eq) and pyridine (0.046 ml, 0.57 mmol, 2 eq) in CH2CI2 (0.6 mL) were mixed to afford after flash chromatography (product at 65% EtOAc in cyclohexane) 58a as an off-white solid (114 mg, 0.28 mmol, 77%).1H NMR (500 MHz, DMSO-d6) δ 10.11 (d, J = 24.2 Hz, 2H), 9.35 (s, 1H), 9.00 (s, 2H), 8.30 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.65 - 7.52 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 7.8, 1.7 Hz, 1H), 7.30 (dd, J = 9.0, 3.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 5.19 (s, 2H), 4.57 (t, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.24 - 3.17 (m, 1H), 2.32 - 2.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 168.8, 162.4, 157.2, 154.7, 150.3, 144.0, 138.5, 138.0, 129.8, 128.7, 124.2, 123.3, 122.0, 118.8, 118.6, 113.9, 112.9, 65.5, 52.5, 47.7, 45.6, 23.8. LC-MS for C23H23N7O6S [ / W+H]+: 526.3.

[0394] 5-((2-(3-((3-(1H-Tetrazol-1-yl)propyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (58)

[0395] According to GP-F, 58a (114 mg, 0.22 mmol) and NaOH (in aq. 10%, 10 eq., 0.013 mL) in MeOH (2.2 mL) were heated to 65 °C overnight to afford after prep HPLC (product at 65% MeCN + 0.1 %FA) 58 as an off-white solid (60 mg, 0.22 mmol, 54%).1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.35 (s, 1H), 9.00 (s, 2H), 8.30 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.61 - 7.18 (m, 4H), 6.92 (d, J = 9.0 Hz, 1H), 5.19 (s, 2H), 4.57 (t, J = 7.1 Hz, 2H), 3.22 - 3.18 (m, 2H), 2.38 - 2.12 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.2, 162.4, 157.2, 155.9, 150.0, 144.0, 138.6, 138.1 , 129.8, 128.8, 124.0, 123.3, 122.0, 118.8, 118.1, 114.2, 65.5, 47.7, 45.6, 23.8. HRMS (ESI) m / z calcd for C22H20N7O6 [M-Hp: 510.12013, found, 510.1182.

[0396] Methyl 2-hydroxy-5-((2-(3-(octylsulfonamido)pheny!)pyrimidin-5- yl)methoxy)benzoate (59a)

[0397]

[0398] According to GP-H, octane-1 -sulfonyl chloride (0.03 ml, 0.17 mmol), 57a (50 mg, 0.14 mmol) and pyridine (0.02 ml_, 0.28 mmol) in CH2CI2 (0.6 mL) were mixed to afford after flash chromatography (product at 45% EtOAc in cyclohexane) 59a as an off-white solid (25 mg, 0.14 mmol, 30%).1H NMR (500 MHz, CDCI3) δ 10.43 (s, 1 H), 8.89 (s, 2H), 8.26 (dt, J = 13.0, 4.6 Hz, 2H), 7.52 - 7.45 (m, 2H), 7.41 (d, J = 3.1 Hz, 1H), 7.16 (dd, J = 12.7, 6.3 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.69 (s, 1 H), 5.08 (s, 2H), 3.97 (s, 3H), 3.18 - 3.09 (m, 2H), 1.87 - 1.80 (m, 2H), 1.42 - 1.16 (m, 8H), 0.83 (t, 3H).13C NMR (126 MHz, CDCh) 6 170.2, 163.3, 156.9, 156.8, 150.4, 138.4, 137.6, 130.3, 128.4, 125.1 , 124.9, 123.0, 120.2, 119.1 , 113.6, 112.2, 66.3, 52.6, 52.01 , 31.8, 29.1, 29.0, 28.3, 23.6, 22.7, 14.18. LC-MS for C27H33N3O6S [M+H]+: 528.2.

[0399] 2-Hydroxy-5-((2-(3-(octylsulfonamido)phenyl)pyrimidin-5-yl)methoxy)benzoic acid (59)

[0400] According to GP-F, 59a (20 mg, 0.038 mmol) and NaOH (in aq. 10%, 10 eq., 0. 002 mL) in MeOH (0.38 mL) were heated to 65 °C overnight to afford after prep HPLC (product at 75% MeCN + 0.1 %FA) 59 as an off-white solid (15 mg, 0.038 mmol, 75%).1H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1 H), 8.99 (s, 2H), 8.32 (s, 1 H), 8.13 (d, J =

[0401] 7.8 Hz, 1 H), 7.48 (t, J = 7.9 Hz, 1 H), 7.39 (dd, J = 11.6, 5.6 Hz, 2H), 7.16 (dd, J = 8.9,

[0402] 2.9 Hz, 1 H), 6.83 (d, J = 8.9 Hz, 1H), 5.16 (s, 2H), 3.09 (d, J = 8.0 Hz, 2H), 1.74 - 1.62 (m, 2H), 1.34 - 1.08 (m, 12H), 0.78 (t, J = 6.9 Hz, 3H).13C NMR (126 MHz, DMSO-cfe) 5 171.3, 162.4, 157.1 , 156.2, 149.6, 139.0, 138.0, 129.7, 128.9, 123.0, 121.7, 118.5, 117.6, 114.4, 65.4, 50.4, 31.0, 28.3, 28.2, 27.2, 22.9, 21.9, 13.8. HRMS (ESI) m / z calcd for C26H30N3O6 [M-H]-: 512.18608, found, 512.18402. Methyl 5-((2-(3-(benzo[cQthiazole-6-sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoatee (60a)

[0403] According to GP-H, benzo[d]thiazole-7-sulfonyl chloride (68.5 mg, 0.16 mmol, 1.1 eq), aniline 57a (50 mg, 0.14 mmol) and pyridine (0.02 ml, 0.28 mmol) in CH2CI2 (0.6 mL) were mixed to afford after flash chromatography (product at 58% EtOAc in cyclohexane) 60a as a white solid (42 mg, 0.14 mmol, 53%).1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.13 (s, 1H), 9.58 (s, 1H), 8.95 (s, 2H), 8.72 (d, J = 1.7 Hz, 1H), 8.22 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 8.7, 1.9 Hz, 1H), 7.38 (dd, J = 12.5, 5.5 Hz, 2H), 7.29 (dd, J = 9.0, 3.3 Hz, 2H), 6.97 (d, J = 9.0 Hz, 1H), 5.16 (s, 2H), 3.90 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 168.8, 162.3, 161.0, 157.1 , 155.2, 154.7, 150.3, 137.8, 134.1 , 129.6, 128.6, 124.3, 124.2, 123.7, 122.6, 122.5, 119.5, 118.6, 113.9, 112.9, 65.5, 52.5. LC-MS for C26H20N4O6S2: 547.1.

[0404] 5-((2-(3-(Benzo[cQthiazole-6-sulfonamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (60)

[0405] According to GP-F, ester 60a (50 mg, 0.09 mmol) and NaOH (in aq. 10%, 10 eq., 0.005 ml) in MeOH (0.9 mL) were heated to 65° C overnight to afford after purification via prep HPLC (product at 50% MeCN + 0.1% FA) 60 as a white solid (12 mg, 0.09 mmol, 25%).1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.58 (s, 1H), 8.96 (s, 2H), 8.73 (d, J = 1.8 Hz, 1 H), 8.23 (t, J = 8.6 Hz, 2H), 8.06 (dd, J = 7.8 Hz, 1 H), 7.91 (dd, J = 8.7, 1.9 Hz, 1H), 7.39 (q, J = 14.8, 5.6 Hz, 2H), 7.32 - 7.23 (m, J = 12.2, 8.5, 2.2 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 5.16 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 162.2,

[0406] 161.1 , 157.2, 155.8, 155.2, 150.1 , 138.1 , 137.8, 136.2, 134.1 , 129.7, 128.7, 124.3,

[0407] 124.2, 123.8, 123.6, 122.7, 122.5, 119.5, 118.2, 114.1 , 112.8, 65.44. HRMS (ESI) m / z calcd for C25H17N4O6S2 [M-Hf: 533.05950, found, 533.05768.

[0408] Methyl 5-((2-(3-(((4-chlorophenyl)methyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxy benzoate (61a)

[0409] According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq.), 4- chlorophenyl)methanesulfonyl chloride (0.025 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002g, 0.021 mmol, 0.25 eq.) in pyridine (1 ml_) were mixed to give after basic preparative HPLC-MS 61a as (8.8 mg, 16 19μ%m)o. l, LC-MS: [M+H]+: 540.99, found: 541.

[0410] 5-((2-(3-(((4-Chlorophenyl)methyl)sulfonamido)phenyl)pyrimidin-5-yl)methoxy)- 2-hydroxy benzoic acid (61)

[0411] According to GP-F, 61a and 1M aqueous NaOH (0.5 mL) in THF (0.5 ml_) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 61 as white solid (5.1 mg, 9.7 μmol, 11%). HRMS (ESI) m / z calcd for C26H22CIN3O6S [M+H]+: 526.08341 , found, 526.08121.

[0412] Methyl 2-hydroxy-5-((2-(3-((phenylmethyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)benzoate (62a)

[0413] According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq.), phenylmethanesulfonyl chloride (0.021 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002 g, 0.021 mmol, 0.25 eq.) in pyridine (1 mL) were mixed to give after basic preparative HPLC-MS 62a (21 mg, 41 μmo 4l,8%).1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1 H), 10.05 (s, 1 H), 9.01 (s, 2H), 8.31 (t, J = 1.9 Hz, 1 H), 8.12 (dt, J = 7.8, 1.3 Hz, 1 H), 7.48 (t, J = 7.9 Hz, 1 H), 7.42 (d, J = 3.1 Hz, 1 H), 7.37 - 7.29 (m, 5H), 7.29 - 7.22 (m, 2H), 6.98 (d, J = 9.0 Hz, 1 H), 5.20 (s, 2H), 4.48 (s, 2H), 3.91 (s, 3H). LC-MS: [M+H]+: 506.55, found: 506.1.

[0414] 2-Hydroxy-5-((2-(3-((phenylmethyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)benzoic acid (62)

[0415] According to GP-F, 62a and 1M aqueous NaOH (0.5 mL) in THF (0.5 mL) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 62 as beige solid (7.9 mg, 16 μmol, 19%). HRMS (ESI) m / z calcd for C25H22N3O6S [M+H]+: 492.12238, found, 492.11996.

[0416] Methyl 2-hydroxy-5-((2-(3-((2-phenylethyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)benzoate (63a) According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq.), 2-phenylethane-1 -sulfonyl chloride (0.022 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002 g, 0.021 mmol, 0.25 eq.) in pyridine (1 ml_) were mixed to give after basic preparative HPLC-MS 63a (3.1 mg, 6.1 μmol, 7%). LC-MS [M+H]+: 520.58, found: 520.2.

[0417] 2-Hydroxy-5-((2-(3-((2-phenylethyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)benzoic acid (63)

[0418] According to GP-F, 63a and 1M aqueous NaOH (0.5 mL) in THF (0.5 mL) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 63 as beige solid (3.6 mg, 7.1 μmol, 8.4%). HRMS (ESI) m / z calcd for C26H24N3O6S [A4+H]+: 506.13803, found, 506.13570.

[0419] Methyl 5-((2-(3-((2,3-dihydrobenzofuran)-6-sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoate (64a)

[0420] According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq.), 2,3-dihydrobenzofuran-6- sulfonyl chloride (0.018 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002 g, 0.021 mmol, 0.25 eq.) in pyridine (1 mL) were mixed to give after basic preparative HPLC-MS 64a (6.3 mg, 12 μmo 1l,4%). LC-MS [M+H]+: 534.56, found: 534.2. 5-((2-(3-((2,3-diHydrobenzofuran)-6-sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (64)

[0421] According to GP-F, 64a and 1M aqueous NaOH (0.5 mL) in THF (0.5 ml_) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 64 (2.4 mg, 4.6μmol, 5.4%). HRMS (ESI) m / z calcd for C26H22N3O7S [M+H]+: 520.11730, found, 520.11491.

[0422] Methyl 2-hydroxy-5-((2-(3-((3,3,3-trifluoropropyl)sulfonamido)phenyl)pyrimidin- 5-yl)methoxy)benzoate (65a)

[0423] According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq.), 3,3,3-trifluoropropane-1- sulfonyl chloride (0.017 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002 g, 0.021 mmoi, 0.25 eq.) in pyridine (1 mL) were mixed to give after basic preparative HPLC-MS 65a (14 mg, 24 μmol 2, 9%). LC-MS [A4+H]+: 512.48, found: 512.1.

[0424] 2-Hydroxy-5-((2-(3-((3,3,3-trifluoropropyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)benzoic acid (65) According to GP-F, 65a and 1M aqueous NaOH (0.5 mL) in THF (0.5 ml_) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 65 (2.2 mg, 4.4 μmol, 5.2%). HRMS (ESI) m / z calcd for C21H19F3 N3O6S [M+H]+‘ 498.09412, found, 498.09140.

[0425] Methyl 2-hydroxy-5-((2-(3-((3-methylthiophene)-2- sulfonamido)phenyl)pyrimidin-5-yl)methoxy)benzoate (66a)

[0426] According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq), 3-methylthiophene-2-sulfonyl chloride (0.016 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002 g, 0.021 mmol, 0.25 eq.) in pyridine (1 mL) were mixed to give after basic preparative HPLC-MS 66a (3.3 mg, 6.5 μmo 7l,.6%). LC-MS: [M+H]+:512.5, found: 512.1.

[0427] 2-Hydroxy-5-((2-(3-((3-methylthiophene)-2-sulfonamido)phenyl)pyrimidin-5- yl)methoxy)benzoic acid (66)

[0428] According to GP-F, 66a and 1M aqueous NaOH (0.5 mL) in THF (0.5 mL) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 66 (2.2 mg, 4.4μmol, 5.2 %). HRMS (ESI) m / z calcd for C23H20N3O6S2 [M+H]+: 498.07880, found, 498.09140.

[0429] Methyl 5-«2-(3-((1 -ethyl-5-methy 1-1 H-py razole)-4-sulfonamido)pheny l)py rimidin- 5-yl)methoxy)-2-hydroxybenzoate (67a)

[0430]

[0431] According to GP-H, 57a (0.030 g, 0.085 mmol, 1.0 eq), 1-ethyl-5-methyl-1 / 7-pyrazole- 4-sulfonyl chloride (0.017 g, 0.11 mmol, 1.3 eq.), DIPEA (0.016 g, 0.127 mmol, 1.5 eq.) and DMAP (0.002 g, 0.021 mmol, 0.25 eq.) in pyridine (1 ml_) were mixed to give after basic preparative HPLC-MS 67a (16 mg, 31 μmol, 36%). LC-MS [A4+H]+: 523.56, found: 524.2.

[0432] 54(2434(1 -Ethyl-5-methyl-1H-pyrazole)-4-sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (67)

[0433] According to GP-F, 67a and 1M aqueous NaOH (0.5 ml_) in THF (0.5 mL) were stirred at room temperature for 18 hours to give after acidic preparative HPLC-MS 67 as yellow solid (9.5 mg, 19 μmo 2l,2%).1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1 H), 8.98 (s, 2H), 8.19 (t, J = 2.1 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.67 (s, 1 H), 7.45 - 7.38 (m, 2H), 7.31 - 7.23 (m, 2H), 6.93 (d, J = 9.0 Hz, 1 H), 5.18 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). HRMS (ESI) m / z calcd for C24H24N5O6S [ / W+H]+: 510.14418, found, 510.14206.

[0434] 54(2434(2, 4-dfNiethylthiazole)-5-sulfonamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (68)

[0435]

[0436] To a stirring solution of 57a (30 mg, 0.085 mmol) in THF (1.0 mL) was added 2,4- dimethyl-1 ,3-thiazole- 5-sulfonyl chloride (23 mg, 0.11 mmol, 1.3 equiv) and EtsN (22 μL, 0.25 mmol, 3 equiv). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was concentrated in the Genevac. The compound was dissolved in THF (0.5 mL) and 1M aqueous NaOH (0.5 mL) solution was added. The reaction mixture was stirred at room temperature for 18 h and after solvent removal, it was purified by acidic preparative HPLC to obtain 68 as white solid (3.4 mg, 0.0066 mmol, 7.7%). HRMS (ESI) m / z calcd for C23H21N4O6S2 [M+H]+: 513.08970, found, 513.08745.

[0437] 5-((2-(3-(3-(4-(4-Chlorophenyl)oxazol-2-yl)propanamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (69)

[0438] According to GP-I, 57a (0.030 g, 0.085 mmol), 3-(4-(4-chlorophenyl)oxazol-2- yl)propanoic acid (0.027 g, 0.11 mmol, 1.3 eq), DIPEA (45 μL, 0.40 mmol, 3 equiv) and HATU (0.042 g, 0.11 mmol, 1.3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1 M aqueous NaOH) yielded 69 as white solid after acidic preparative HPLC-MS (7.5 mg, 14 μ 1m7%ol,, over two steps).1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.99 (s, 2H), 8.70 (s, 1H), 8.08 (d, J = 7.8 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.60 (s, 1 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1 H), 7.25 (dd, J = 9.0, 3.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 5.17 (s, 2H), 3.15 (t, J = 7.1 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.4, 169.7, 163.5, 162.8, 157.2, 155.9, 150.0, 149.2, 139.6, 137.4, 132.5, 129.2, 129.1 , 128.6, 126.5, 125.4, 123.8, 123.2, 122.5, 121.4, 118.5, 118.1 , 114.2, 65.5, 32.6, 23.1. HRMS (ESI) m / z calcd for C30H24CIN4O6 [M+H]+: 571.13789, found, 571.13527.

[0439] 5-((2-(3-(4,4-diFluorocyclohexane-1-carboxamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (70)

[0440] According to GP-I, 57a (0.030 g, 0.085 mmol), 4,4-difluorocyclohexane-1-carboxylic acid (0.018 g, 0.11 mmol, 1.3 eq), DIPEA (45 μL, 0.40 mmol, 3 equiv) and HATU (0.042 g, 0.11 mmol, 1 .3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 70 as white solid after acidic preparative (19 mg, 33 39μ%mo, ol,ver two steps).1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1 H), 8.99 (s, 2H), 8.70 (s, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.42 (d, J = 3.1 Hz, 1 H), 7.25 (dd, J = 3.1 , 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1 H), 5.17 (s, 2H), 2.16 - 2.08 (m, 2H), 1.99 - 1.80 (m, 5H), 1.77 - 1.67 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 173.5, 171.9, 163.2, 157.6, 156.4, 150.5, 140.2, 137.8, 129.6, 129.1 , 126.1 , 124.3, 123.0, 122.0, 119.1 , 118.5, 114.7, 66.0, 42.5, 32.9, 32.7, 32.5, 26.1 , 26.0. HRMS (ESI) m / z calcd for C25H24F2N3O5 [M+H]+: 484.16785, found, 484.16560.

[0441] 5-((2-(3-(2-(Cyclohexyloxy)acetamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (71)

[0442] According to GP-I, 57a (0.030 g, 0.085 mmol), 2-(cyclohexyloxy)acetic acid (0.017 g, 0.11 mmol, 1 .3 eq), DIPEA (45 μL, 0.40 mmol, 3 equiv) and HATU (0.042 g, 0.11 mmol, 1.3 equiv), in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 ml_ of 1 M aqueous NaOH) yielded 71 as white solid (16 mg, 33 μmo 3l,9%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1 H), 9.00 (s, 2H), 8.73 (s, 1H), 8.12 (d, J = 7.8 Hz, 1 H), 7.83 (d, J = 9.0 Hz, 1 H), 7.47 (t, J = 7.9 Hz, 1 H), 7.42 (d, J = 3.2 Hz, 1 H), 7.24 (dd, J = 9.0, 3.1 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1 H), 5.18 (s, 2H), 4.08 (s, 1H), 3.43 - 3.36 (m, 1 H), 1.92 (d, 1 H), 1.70 (dd, J =

[0443] 8.9, 3.8 Hz, 1H), 1.53 - 1.46 (m, 1H), 1.38 - 1.14 (m, 3H).13C NMR (126 MHz, DMSO- d6) δ 171.4, 168.9, 162.7, 157.1 , 156.0, 149.9, 138.9, 137.3, 129.0, 128.7, 123.7,

[0444] 122.9, 122.1 , 119.1 , 118.0, 114.2, 77.5, 67.5, 65.5, 31.5, 25.3, 23.4. HRMS (ESI) m / z calcd for C26H28N3O6 [M+H]+: 478.19726, found, 478.1950.

[0445] 5-((2-(3-(Hex-5-ynamido)phenyl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (72)

[0446] According to GP-I, 57a (0.030 g, 0.085 mmol), hex-5-ynoic acid (0.012 g, 0.11 mmol, 1 .3 eq), DIPEA (45 μL, 0.40 mmol, 3 equiv) and HATU (0.042 g, 0.11 mmol, 1.3 equiv), in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 72 as white solid (13 mg, 29μmol, 34%, over two steps). HRMS (ESI) m / z calcd for C24H22N3O5 [M+H]+: 432.15540, found, 432.15320.

[0447] 2-Hydroxy-5-((2-(3-(3-(2-oxoazepan-1-yl)propanamido)phenyl)pyrimidin-5" yl)methoxy)benzoic acid (73)

[0448] According to GP-I, 57a (0.030 g, 0.085 mmol), 3-(2-oxoazepan-1-yl)propanoic acid (0.020 g, 0.11 mmol, 1.3 eq), DIPEA (45 μL, 0.40 mmol, 3 equiv) and HATU (0.042 g, 0.11 mmol, 1.3 equiv), in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1 M aqueous NaOH) yielded 73 as white solid (12 mg, 25 μmo 2l9, %, over two steps).1H NMR (500 MHz, DMSO-d6) 6 9.91 (s, 1 H), 8.99 (d, J = 7.7 Hz, 2H), 8.68 (s, 1 H), 8.07 (t, J = 6.5 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.43 (dd, J = 15.0, 5.6 Hz, 2H), 7.26 (dd, J = 9.0, 3.1 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 5.18 (s, 2H), 3-24 (dd, J = 16.8, 8.4 Hz, 5H), 2.34 - 2.17 (m, 2H), 2.17 - 2.04 (m, 3H), 2.04 - 1.89 (m, 1 H), 1.88 - 1.78 (m, 1 H).13C NMR (126 MHz, DMSO- d6) 5 173.0, 171.4, 162.8, 157.1 , 155.9, 150.0, 139.8, 137.3, 129.1, 128.6, 123.9, 122.3, 121.5, 118.5, 118.1 , 114.2, 65.5, 24.6, 17.7. HRMS (ESI) m / z calcd for C27H29N4O6 [M+H]+: 505.20816, found, 505.20551.

[0449] 5-((2-(3-(Cyclobutanecarboxamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid

[0450] According to GP-I, 57a (0.030 g, 0.085 mmol), cyclobutanecarboxylic acid (0.011 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1 M aqueous NaOH) yielded 74 as white solid (15 mg, 35 μmol, 41%, over two steps).1H NMR (400 MHz, MeOD) δ 8.92 (s, 2H), 8.58 (t, J = 2.0 Hz, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 7.83 - 7.73 (m, 1 H), 7.52 (d, J = 3.2 Hz, 1 H), 7.44 (t, J = 7.9 Hz, 1 H), 7.19 (dd, J = 9.0, 3.1 Hz, 1 H), 6.87 (d, J = 8.9 Hz, 1 H), 5.15 (s, 2H), 3.38 - 3.32 (m, 1 H), 2.47 - 2.30 (m, 2H), 2.30 - 2.18 (m, 2H), 2.13 - 1.98 (m, 2H), 1.98 - 1.87 (m, 1 H). HRMS (ESI) m / z calcd for C23H22N3O5 [M+H]+: 420.15540, found, 420.15325.

[0451] 5-((2-(3-(Benzo[d][1,3]dioxole-5-carboxamido)phenyi)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (75)

[0452] According to GP-I, 57a (0.030 g, 0.085 mmol), benzo[d][1 ,3]dioxole-5-carboxylic acid (0.018 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 ml_) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 75 as white solid (10 mg, 21 μm 2o4l,%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1 H), 9.00 (s, 2H), 8.85 (s, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.64 (dd, J = 1.5, 8.1 Hz, 1 H), 7.58 (s, 1 H), 7.50 (t, J = 7.9 Hz, 1 H), 7.42 (d, J = 3.1 Hz, 1H), 7.24 (dd, J = 3.0, 8.9 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1H), 6.14 (s, 2H), 5.18 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.9, 165.1,

[0453] 163.3, 157.6, 156.4, 150.6, 150.4, 147.9, 140.2, 137.7, 129.5, 129.1 , 128.8, 124.2,

[0454] 123.4, 123.2, 120.3, 118.5, 114.8, 114.3, 108.4, 108.2, 102.3, 66.0. HRMS (ESI) m / z calcd for C26H20N3O7 [M+H]+: 486.12958, found, 486.12715.

[0455] 2-Hydroxy-5-((2-(3-nonanamidophenyl)pyrimidin-5-yl)methoxy)benzoic acid (76)

[0456] According to GP-I, 57a (0.030 g, 0.085 mmol), nonanoic acid (0.017 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1 M aqueous NaOH) yielded 76 as white solid (9.9 mg, 21 pmol, 24%, over two steps).1H NMR (400 MHz, MeOD) δ 8.92 (s, 2H), 8.57 (t, J = 2.0 Hz, 1 H), 8.15 (dt, J = 7.9, 1.4 Hz, 1 H), 7.84 - 7.76 (m, 1 H), 7.52 (d, J = 3.1 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.20 (dd, J = 9.0, 3.0 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 5.15 (s, 2H), 2.40 (t, J = 7.5 Hz, 2H), 1.72 (m, 2H), 1.44 - 1.26 (m, 11 H), 0.94 - 0.82 (m, 3H). HRMS (ESI) m / z calcd for C27H32N3O5 [M+H]+: 478.23365, found, 478.23132. 5-((2-(3-(2-Cyclohexylacetamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (77)

[0457] According to GP-I, 57a (0.030 g, 0.085 mmol), 2-cyclohexylacetic acid (0.015 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 ml_) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 77 as white solid (8.5 mg, 18 μmol, 22%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1 H), 8.99 (s, 2H), 8.67 (s, 1 H), 8.07 (d, J = 7.7 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.46 - 7.40 (m, J = 13.4, 5.5 Hz, 2H), 7.27 (dd, J = 9.0, 3.1 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.18 (s, 2H), 2.21 (d, J = 7.1 Hz, 2H), 1.85 - 1.75 (m, 1 H), 1.74 - 1.57 (m, 5H), 1.26 - 1.19 (m, , 2H), 1.19 - 1.10 (m, 1 H), 1.04 - 0.94 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ

[0458] 171.4, 170.6, 162.8, 157.1, 155.8, 150.1, 139.7, 137.3, 129.0, 128.6, 124.1 , 122.3,

[0459] 121.4, 118.4, 118.1 , 114.21 , 113.11. HRMS (ESI) m / z calcd for C26H28N3O5 [M+H]+: 462.20235, found, 462.20019.

[0460] 5-((2-(3-(4-(4-Chlorophenoxy)butanamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (78)

[0461] According to GP-I, 57a (0.030 g, 0.085 mmol), 2-cyclohexylacetic acid (0.015 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1 M aqueous NaOH) yielded 78 as white solid (7.1 mg, 15 μmol, 18%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1 H), 8.99 (s, 2H), 8.68 (s, 1H), 8.08 (d, J = 7.8 Hz, 1 H), 7.80 (br d, J = 8.2 Hz, 1 H), 7.47 - 7.41 (m, 2H), 7.32 - 7.30 (m, 2H), 7.26 (dd, J = 3.1 , 8.9 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.92 (d, J = 9.0 Hz, 1H), 5.18 (s, 2H), 4.06 - 4.00 (m, 2H), 2.55 - 2.51 (m, 2H), 2.05 (dd, J = 6.3, 13.1 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.9, 171.3, 163.3, 157.9,

[0462] 157.6, 156.4, 150.5, 140.2, 137.8, 129.7, 129.6, 129.1 , 124.6, 122.9, 121.9, 119.0,

[0463] 118.6, 116.7, 114.7, 67.8, 66.0, 33.2, 25.0. HRMS (ESI) m / z calcd for C28H25CIN3O6 [A4-H]~: 532.12809, found 532.12714.

[0464] 2-Hydroxy-5-((2-(3-(2-propylpentanamido)phenyl)pyrimidin-5- yl)methoxy)benzoic acid (79)

[0465] According to GP-I, 57a (0.030 g, 0.085 mmol), 2-propylhexanoic acid (0.017 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 79 as white solid (15 mg, 30 μmol, 36%, over two steps). HRMS (ESI) m / z calcd for C27H32N3O5 [A4+H]+: 47464.21800, found, 464.21654.

[0466] 5-((2-(3-(1-(2-Fluorophenyl)cyclopentane-1-carboxamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (80)

[0467] According to GP-I, 57a (0.030 g, 0.085 mmol), 1-(2-fluorophenyl)cyclopentane-1- carboxylic acid (0.022 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 80 as white solid (6.4 mg, 12 μm 14o%l, , over two steps).1H NMR (500 MHz, DMSO-d6) δ 9.22 (br s, 1H), 8.97 - 8.90 (m, 2H), 8.56 - 8.53 (m, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.35 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 7.16 - 7.10 (m, 2H), 6.81 (d, J= 8.9 Hz, 1H), 5.14 (s, 2H), 2.54 (d, J = 5.2 Hz, 2H), 2.02 - 1.96 (m, 2H), 1.69 (br d, J = 5.2 Hz, 4H).19F NMR (470 MHz, DMSO-d6) δ-111.58 (s, 1F).13C NMR (126 MHz, DMSO-d6) δ 173.7, 171.8, 163.2, 161.9, 160.0, 157.5, 156.7, 150.1, 140.3, 137.5, 129.3, 129.2, 124.6, 123.1, 123.0, 120.2, 118.0, 116.1 , 116.0, 115.0, 66.0, 57.1 , 35.8, 24.1. HRMS (ESI) m / z calcd for C30H27FN3O5 [M-H]-: 528.19293, found, 526.17837.

[0468] 5-((2-(3-(3-(Furan-2-yl)propanamido)phenyl)pyrimidin-5-yl)methoxy)-2- hydroxybenzoic acid (81)

[0469] According to GP-I, 57a (0.030 g, 0.085 mmol), 3-(furan-2-yl)propanoic acid (0.015 g, 0.11 mmol, 1.3 eq), HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight. Then, GP-F (0.5 mL of THF and 0.5 mL of 1M aqueous NaOH) yielded 81 as white solid (5.9 mg, 13 μmol, 15%, over two steps).1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.98 (s, 2H), 8.66 (s, 1H), 8.12 - 8.05 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 3.2 Hz, 1H), 7.16 - 6.96 (m, J = 2.5, 8.6 Hz, 2H), 6.75 (d, J = 8.9 Hz, 1H), 6.35 (t, J = 1.0 Hz, 1H), 6.13 (d, J = 2.9 Hz, 1H), 5.14 (s, 2H), 2.95 (t, J = 7.4 Hz, 3H), 2.68 (t, J = 7.5 Hz, 3H).13C NMR (126 MHz, DMSO-cfe) 5 171.6, 170.5, 163.2, 157.6, 157.0, 155.0, 150.9, 149.8, 141.9, 140.1, 137.9, 129.6, 129.4, 124.0, 122.9, 122.3, 121.8, 118.9, 115.1 , 113.2, 110.9, 105.6, 66.0, 35.0, 23.7. HRMS (ESI) m / z calcd for C25H22N3O6 [M+HF: 460.15031 , found, 460.14804.

[0470] 5-((2-(3-(1 -Aminocyclopropane-1 -carboxamido)phenyl)pyrimidin-5-yl)methoxy)- 2-hydroxybenzoic acid (82)

[0471]

[0472] According to GP-I, 57a (0.030 g, 0.085 mmol), tert-butyl (1- carbamoylcyclopropyl)carbamate (0.022 g, 0.11 mmol, 1.3 eq) HATU (0.042 g, 0.11 mmol, 1.3 equiv), DIPEA (45 μL, 0.40 mmol, 3 equiv) in DMAc (1 mL) were mixed and stirred at room temperature overnight to afford 82a (20 mg, 0.038 mmol) that was treated with CH2CI2 (0.5 mL) and 4 M HCI in 1 ,4-dioxane (0.5 mL, 2.0 mmol, 52 equiv). The reaction mixture was stirred for 2 h. The solid was filtered off and washed with CH2CI2. The solid was dissolved in DMSO filtered using a nylon syringe filter and purified by acidic preparative HPLC-MS to yield 82 as an off white solid (5.3 mg, 0.013 mmol, 33%).1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1 H), 8.96 (s, 2H), 8.68 (s, 1 H), 8.13 (d, J = 7.8 Hz, 1 H), 7.85 (d, J = 8.1 Hz, 1 H), 7.51 - 7.45 (m, 1 H), 7.41 (d, J = 3.2 Hz, 1H), 7.03 (dd, J = 3.1 , 8.7 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 5.11 (s, 2H), 1.55 - 1.46 (m, 2H), 1.19 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.9, 171.2, 163.0, 157.6, 157.1 , 149.6, 139.3, 137.9, 129.6, 129.5, 123.6, 122.9, 121.7, 120.0, 118.3, 117.4, 115.3, 65.9, 36.4, 15.5. HRMS (ESI) m / z calcd for C22H19N4O5 [M-H]" 419.13609, found, 519.18852.

[0473] 6-((2-Chloropyrimidin-5-yl)methoxy)-2,2-dimethyl-4H-benzo[c(][1 ,3]dioxin-4-one (83)

[0474] To a solution of (2-chloropyrimidin-5-yl)methanol (1.43 g, 1.1 equiv, 9.91 mmol), 1 (1.75 g, 1 equiv, 9.01 mmol) PPha (2.84 g, 1.2 equiv, 10.8 mmol) in dry THF (200 mL) and DIAD (2.63 mL, 1.5 equiv, 13.5 mmol) were slowly added at 0°C. Then, the reaction mixture was allowed to warm-up to room temperature and stirred for 1.5 h. Once the reaction is finished, heptane (100 mL) was added to the reaction mixture and the volume was reduced to form a suspension. The solids were filtered off, washed with some heptane and dried to afford 83 as a white solid (2.0 g, 6.2 mmol, 69%).1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.47 (d, J = 3.1 Hz, 1 H), 7.41 (dd, J = 8.9,

[0475] 3.1 Hz, 1 H), 7.12 (d, J = 8.9 Hz, 1 H), 5.24 (s, 2H), 1.68 (s, 6H).

[0476] 2-Bromo-6-((4-(trifluoromethyl)benzyl)oxy)pyridine (84b)

[0477] To a stirring solution of 2-bromo-6-fluoro-pyridine (300 mg, 1 equiv, 1.70 mmol) and (4-(trifluoromethyl)phenyl)methanol (1.2 equiv, 2.05 mmol) was added KOtBu (230 mg,

[0478] 1.2 equiv, 2.05 mmol) and the mixture was stirred at room temperature for 18 h to afford 84b as a colourless oil (410 mg, 1.23 mmol, 72%).1H NMR (400 MHz, DMSO- d6) δ 7.81 - 7.74 (m, 2H), 7.74 - 7.65 (m, 3H), 7.28 (d, J = 7.5 Hz, 1 H), 6.98 (d, J = 8.1 Hz, 1 H), 5.43 (s, 2H).

[0479] 2-(4,4,5,5-Tetramethyl-1,3>2-dioxaborolan-2-yl)-6-((4 trifluoromethyl)benzyl)oxy)pyridine (84a)

[0480] According to GP-G, 84b (54 mg, 1 equiv, 0.16 mmol), bis(pinacolato)diborane (50 mg,

[0481] 1.2 equiv, 0.20 mmol) KOAc (48 mg, 3 equiv, 0.49 mmol) and [PdCl2(dppf)] (12 mg, 0.1 equiv, 16 pmol) were suspended in 1 ,4-dioxane (2.0 mL) and the reaction was heated to 100 °C for 2 h. The reaction mixture was cooled down, diluted with EtOAc, filtered over a silica plug and concentrated to afford compound 84a as a brown oil (70 mg, 0.18 mmol).

[0482] 2-Hydroxy-5-((2-(6-((4-(tnfluoromethyl)benzyl)oxy)pyridin-2-yi)pyrimidin-5 yl)methoxy)benzoic acid (84)

[0483] A stirring solution of 83 (36 mg, 1.2 equiv, 0.11 mmol), 84a (70 mg, 1 equiv, 92 pmol) and K2CO3 (38 mg, 3 equiv, 0.28 mmol) in 1 ,4-dioxane (3.0 ml_) was purged with N2. Then, [Pd(PPh3)4] (11 mg, 0.1 equiv, 9.2 pmol) was added and the reaction mixture was heated to 90 °C for 3 h. The reaction mixture was then concentrated, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield 84 as an off white solid after acetonide deprotection using GP-D (3 mg, 6 pmol, 32%, over two steps)1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1 H), 9.08 (d, J = 5.8 Hz, 2H), 8.08 (d, J = 7.5 Hz, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.87 - 7.70 (m, 4H), 7.41 (dd, J = 16.3, 3.1 Hz, 1H), 7.30 (dd, J = 9.0, 3.1 Hz, 1 H), 7.19 (d, J = 6.3 Hz, 1 H), 7.08 (t, J = 4.3 Hz, 1 H), 7.00 - 6.91 (m, 1H), 6.82 (d, J = 8.8 Hz, 1 H), 5.60 (d, J = 3.8 Hz, 2H), 5.23 (s, 2H). HRMS (ESI) m / z calcd for C25H18F3N3O5 [M-Hf: 496.11258, found, 496.11087.

[0484] 2-Bromo-6-(cyclohexyloxy)pyridine (85b)

[0485] To a stirring solution of 2-bromo-6-fluoro-pyridine (300 mg, 1 equiv, 1.70 mmol) and cyclohexanol (1.2 equiv, 2.05 mmol) was added KOtBu (230 mg, 1 .2 equiv, 2.05 mmol) and the mixture was stirred at room temperature for 18 h to afford 85b as a colourless oil (298 mg, 1.16 mmol, 68%).1H NMR (400 MHz, DMSO-d6) δ 7.63 (t, J = 7.8 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 1 H), 6.80 (d, J = 8.2 Hz, 1 H), 4.95 - 4.84 (m, 1 H), 2.01 - 1.85 (m, 2H), 1.80 - 1.65 (m,2H), 1.61 - 1.19 (m, 6H).

[0486] 2-(Cyclohexyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yi)pyr!dine (85a) According to GP-G, 85b (54 mg, 1 equiv, 0.16 mmol), bis(pinacolato)diborane (50 mg, 1.2 equiv, 0.20 mmol), KOAc (48 mg, 3 equiv, 0.49 mmol) and [PdCl2(dppf)] (12 mg, 0.1 equiv, 16 pmol) were suspended in 1 ,4-dioxane (2.0 mL) and the mixture was heated to 100 °C for 2 h. The reaction mixture was cooled down, diluted with EtOAc, filtered over a silica plug and concentrated to afford 85a as a brown oil that is used directly in the next step due to instability issue (70 mg, 0.18 mmol).

[0487] 5-((2-(6-(Cyclohexyloxy)pyridin-2-yl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (85)

[0488] To a stirring solution of 83 (36 mg, 1.2 equiv, 0.11 mmol) in 1,4-dioxane (3.0 mL), 85a (70 mg, 1 equiv, 92 μmol), H2O (0.6 mL), K2CO3 (62 mg, 3 equiv, 0.59 mmol) and [Pd(PPh3)4] (23 mg, 0.1 equiv, 20 pmol) were added and the reaction mixture was heated to 90 °C for 2 h. Then, the reaction mixture was concentrated, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield 85 as an off white solid after acetonide deprodection using GP-D (3 mg, 7.1 pmol, 36%, over two steps).1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.04 (s, 1H), 7.96 (dd, J = 7.3, 3.8 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.41 (dd, J= 16.0, 3.2 Hz, 1H), 7.30 (dd, J= 9.0, 3.1 Hz, 1H), 6.93 (dd, J = 13.7, 8.6 Hz, 2H), 5.25 - 5.17 (m, 3H), 1.98 (s, 2H), 1.75 (t, J = 7.5 Hz, 2H), 1.60 - 1.27 (m, 7H). HRMS (ESI) m / z calcd for C23H23N3O5 [M+H]+: 422.17105, found, 422.16882.

[0489] 6-((2-(5-Amino-2-methy!phenyl)pyrimidin-5-yl)methoxy)-2,2-dimethyl-4H- benzo[d][1,3]dioxin-4-one (86) According to GP-G, 4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (150 mg, 1 equiv, 643 μmol), 83 (206 mg, 1 equiv, 643 μmol), K2CO3 (267 mg, 3 equiv, 1.93 mmol), [Pd(PPhs)4] (74.4 mg, 0.1 equiv, 64.3 pmol) in 1 ,4-dioxane / H2O (5.0 / 1.7 mL): were heated to 90 °C for 1 h. The reaction mixture was cooled down and purified by column chromatography (0-100% EtOAc in heptane) to afford 86 as a yellow solid (203 mg, 519 pM, 81%).1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 2H), 7.66 - 7.52 (m, 1H), 7.50 (d, J = 3.1 Hz, 1 H), 7.43 (dd, J = 9.0, 3.2 Hz, 1 H), 7.13 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 2.6 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1H), 6.60 (dd, J = 8.1 , 2.5 Hz, 1 H), 5.25 (s, 2H), 5.01 (s, 2H), 2.32 (s, 3H), 1.69 (s, 6H).

[0490] 5-((2-(5-((2,4-d / Methylthiazole)-5-sulfonamido)-2-methylphenyl)pyrimidin-5- yl)methoxy)-2-hydroxy benzoic acid (87)

[0491] According to GP-H, 86 (50 mg, 1.0 equiv, 129 μmol), 2,4-dimethylthiazole-5-sulfonyl chloride (27 mg, 1.0 eq), DMAP (4.73 mg, 0.3 equiv, 39 pmol) and DIPEA (67.4 μL, 3 equiv, 387 pmol) were mixed in THF (2.0 mL) and the mixture was stirred at room temperature for 18 h to afford after basic preparative HPLC-MS 87as a yellow powder after acetonide deprotection following GP-D (40 mg, 76 μ 6m0%ol,, over two steps).1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1 H), 10.64 (s, 1 H), 9.02 (s, 2H), 7.66 (d, J = 2.3 Hz, 1 H), 7.43 (d, J = 3.1 Hz, 1 H), 7.34 - 7.23 (m, 2H), 7.16 (d, J = 8.3 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 5.19 (s, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H).HRMS (ESI) m / z calcd for C24H22N4O6S2 [M-Hj-; 525.09080, found, 525.08868.

[0492] 2-Hydroxy-5-((2-(2-methyl-5-((4- trifluoromethyl)phenyl)sulfonamido)phenyl)pyrimidin-5-yl)methoxy)benzoic acid (88)

[0493]

[0494] According to GP-H, 86 (50 mg, 1.0 equiv, 129 μmol), 4-

[0495] (trifluoromethyl)benzenesulfonyl chloride (31 mg, 1.0 eq), DMAP (4.73 mg, 0.3 equiv, 39 pmol) and DIPEA (67.4 μL, 3 equiv, 39 pmol) were mixed in THF (2.0 mL) and the mixture was stirred at room temperature for 18 h to afford after basic preparative HPLC-MS 88 as a white powder after acetonide deprotection following GP-D (14 mg, 25μmol, 20% over two steps). HRMS (ESI) m / z calcd for C26H20F3N3O6S [M-H]-: 543.09555, found, 543.09326.

[0496] 2-Hydroxy-5-((2-(2-methyl-5-(2-methyl-4-(trifluoromethyl)thiazole-5- carboxamido)phenyl)pyrimidin-5-yl)methoxy)benzoic acid (89)

[0497] According to GP-I, 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid (35 mg, 1.3 equiv, 168 μmol), 86 (50 mg, 1 equiv, 129 μmol), HATU (63.8 mg, 1 .3 equiv, 168 pmol), DIPEA (67 μL, 3 equiv, 387 pmol) in DMAc (2.0 mL) were stirred for 18 h at 80 °C. The compounds were filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield 89 after acetonide deprotection following GP-D as off white (27 mg, 50μmol, 38%).1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1 H), 10.89 (s, 1H), 9.03 (s, 2H), 8.18 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 3.0 Hz, 1H), 7.37 - 7.27 (m, 2H), 6.95 (d, J = 9.0 Hz, 1 H), 5.20 (s, 2H), 2.77 (s, 3H). HRMS (ESI) m / z calcd for C25H19F3N4O6S2 [M-Hp: 598.09555, found, 598.09308.

[0498] 2-Hydroxy-5-((2-(2-methyi-5-(4-(trifiuoromethyl)benzamido)phenyl)pyrimidin-5- yl)methoxy)benzoic acid (90)

[0499]

[0500] According to GP-1, 4-(trifluoromethyl)benzoic acid (32mg, 1.3 equiv, 168 μmol), 86 (50 mg, 1.0 equiv, 129 μmol), HATU (63.8 mg, 1.3 equiv, 168 μmol), DIPEA (67 μL, 3 equiv, 387 pmol) in DMAc (2.0 mL) were stirred for 18 h at 80 °C. The compound was filtered using a nylon syringe and purified by basic preparative HPLC-MS to yield 90 after acetonide deprotection following GP-D as off white powder (21 mg, 41 pmol, 31%). HRMS (ESI) m / z calcd for C27H20F3N3O5 [ / W-Hp: 522.12823, found 522.12677.

[0501] 6-((2-(3-Amino-4-chlorophenyl)pyrimidin-5-yl)methoxy)-2,2-dimethyl-4H- benzo[cfl[1,3]dioxin-4-one (91)

[0502] According to GP-G, 3-amino-4-chlorophenylboronic acid (150 mg, 1 equiv, 875 pmol), 83 (281 mg, 1 equiv, 875 pmol) K2CO3 (363 mg, 3 equiv, 2.63 mmol), [Pd(PPhs)4] (101 mg, 0.1 equiv, 87.5 pmol) in 1 ,4-dioxane (5.0 mL): water (1.7 mL) was heated to 90 °C for 1 h. The reaction mixture was cooled down and washed with some heptane to afford 91 as an off white solid (180 mg, 437 μ 5m0o%l, yield).1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 2H), 7.93 (d, J = 2.1 Hz, 1 H), 7.59 (dd, J = 8.4, 2.1 Hz, 1 H), 7.49 (d, J = 3.1 Hz, 1 H), 7.42 (dd, J = 9.0, 3.1 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 8.9 Hz, 1H), 5.57 (s, 2H), 5.24 (s, 2H), 1.68 (s, 6H).

[0503] 5-((2-(4-Chloro-3-((4-(trifluoromethyl)phenyl)suIfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (92) 117

[0504] CF3

[0505] Cl rf

[0506] N V o N %

[0507] H

[0508] 0 N0

[0509] HO'

[0510] HO

[0511] According to GP-H, 91 (50 mg, 1.0 equiv, 130 pmol), 4-

[0512] (trifluoromethyl)benzenesulfonyl chloride (32 mg, 1.0 eq), DMAP (4.73 mg, 0.3 equiv, 39 pmol) and DIPEA (66 pL, 3.0 equiv, 37 pmol) were mixed in DOE (2.0 ml) and the mixture was stirred at 80 °C for 18 h to afford after basic preparative HPLC-MS 92 as a light brown after acetonide deprotection following GP-D (13 mg, 20 pmol, 17%, over two steps). HRMS (ESI) m / z calcd for C25H17CIF3N3O6S [M-Hp: 578.04059, found, 578.03884,

[0513] 5-((2-(4-Chloro-3-(4-(trifluoromethyl)benzamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (93)

[0514] According to GP-I, 4-(trifluoromethyl)benzoic acid (32mg, 1.3 equiv, 168 μmol), 91 (50 mg, 1.0 equiv, 129 pmol), HATU (63 mg, 1.3 equiv, 16 pmol), DIPEA (67 μl, 3.0 equiv, 37 pmol) in DCE (2.0 ml) were stirred for 18 h at 80 °C. The mixture was filtered using a nylon syringe and purified by basic preparative HPLC-MS to yield 93 as light brown after acetonide deprotection following GP-D (7 mg, 12 μmol, 10%). HRMS (ESI) m / z calcd for C26H17CIF3N3O5 [M-Hp: 542.07361, found 542.0728.

[0515] 6-((2-(3-Amino-5-fluorophenyl)pyrimid!n-5-yl)methoxy)-2,2-dimethyl-4H- benzo[d][1,3]dioxin-4-one (94)

[0516]

[0517] According to GP-G, 3-amino-5-fluorophenylboronic acid (150 mg, 1 equiv, 968 pmol) (150 mg, 1 equiv, 875 μmol), 83 (311 mg, 1 equiv, 968 pmol) K2CO3 (401 mg, 3 equiv, 2.90 mmol), [Pd(PPh3)4] (112 mg, 0.1 equiv, 96.8 pmol) in 1 ,4-dioxane / water (5.0 mL / 1.7 mL) was heated to 90 °C for 1 h. The reaction mixture was cooled down and and washed with some heptane to afford 94 as an off-white solid (200 mg, 506 pmol, 52% yield).1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 2H), 7.54 (t, J = 1.7 Hz, 1 H), 7.48 (d, 1 H), 7.45 - 7.39 (m, 1 H), 7.26 - 7.19 (m, 1 H), 7.12 (d, J = 9.0 Hz, 1 H), 6.47 (dt, J = 11.3, 2.3 Hz, 1 H), 5.66 (s, 2H), 5.24 (s, 2H), 1.68 (s, 6H).

[0518] 5-((2-(3-Fluoro-5-((4-(trifluoromethyl)phenyl)sulfonamido)phenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (95)

[0519] According to GP-H, 94 (50 mg, 1.0 equiv, 130 μmol), 4-

[0520] (trifluoromethyl)benzenesulfonyl chloride (32 mg, 1.0 eq), DMAP (4.73 mg, 0.3 equiv, 39 pmol) and DIPEA (66 μL, 3.0 equiv, 37 pmol) were mixed in DCE (2.0 mL) and the mixture was stirred at 80 °C for 18 h to afford after basic preparative HPLC-MS 95 as a white solid after acetonide deprotection following GP-D (20 mg, 35 28%μm oovel,r two steps). HRMS (ESI) m / z calcd for C27H20F3N3O5 [M-Hp: 562.07014, found 562.06818.

[0521] 5-((2-(3-((2,4-d / W!ethylthiazole)-5-sulfonamido)-5-fluorophenyl)pyrimidin-5- yl)methoxy)-2-hydroxybenzoic acid (96)

[0522]

[0523] According to GP-H, 94 (50 mg, 1.0 equiv, 129 μmol), 2,4-dimethylthiazole-5-sulfonyl chloride (27 mg, 1.0 eq), DMAP (4.73 mg, 0.3 equiv, 39 pmol) and DIPEA (67.4 μL, 3 equiv, 387 pmol) were mixed in THF (2.0 ml_) and the mixture was stirred at room temperature for 18 h to afford after basic preparative HPLC-MS 96 as a orange powder after acetonide deprotection following GP-D (10 mg, 19 1μ5m%o)l., HRMS (ESI) m / z calcd for C23H19FN4O5S [A4-H]-; 529.06573, found 529.0634.

[0524] 5-((2-(3-Fluoro-5-(2-methyl-4-(tnfluoromethyl)thiazole-5- carboxamido)phenyl)pyrimidin-5-yl)methoxy)-2-hydroxybenzoic acid (97)

[0525] According to GP-I, 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid (35 mg, 1.3 equiv, 168 μmol), 94 (50 mg, 1 equiv, 129 μmol), HATU (63 mg, 1.3 equiv, 168 pmol), DIPEA (67 μL, 3 equiv, 387 pmol) in DMAc (2.0 mL) were stirred for 18 h at 60 °C. The compound was filtered using a nylon syringe and purified by basic preparative HPLC- MS to yield 97 after acetonide deprotection following GP-D as light brown solid (13 mg, 24μmol, 18%). HRMS (ESI) m / z calcd for C24H19FN4O5S [M-H]" 547.07048, found 547.06884.

[0526] 5-((2-(3-Fluoro-5-(4-(trifluoromethyl)benzamido)phenyl)pyrimidin-5-yl)methoxy)- 2-hydroxybenzoic acid (98)

[0527]

[0528] According to GP-I, 4-(trifluoromethyl)benzoic acid (32mg, 1 .3 equiv, 168 μmol), 94 (50 mg, 1.0 equiv, 129 μmol), HATU (63 mg, 1.3 equiv, 16 μmol), DIPEA (67 μL, 3.0 equiv, 37 pmol) in DCE (2.0 mL) were stirred for 18 h at 60 °C. The compounds were filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield 98 after acetonide deprotection following GP-D as off white (4 mg, 7.4 6%μ)m. HolR, MS (ESI) m / z calcd for C26H17F4N3O5 [M-H]" 526.10316, found 526.10144. tert-Butyl-3-(5-(((2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-6- y l)oxy)methyl)py rimidin-2-y l)-1 H-indole-1 -carboxylate (99a)

[0529] According to GP-G, 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 / 7-indole-1- carboxylate (598 mg, 1.1 equiv, 1.74 mmol), 83 (508 mg, 1 equiv, 1.58 mmol), K2CO3 (657 mg, 3 equiv, 4.75 mmol), [Pd(PPhs)4] (91.5 mg, 0.05 equiv, 79.2 pmol) in 1 ,4- dioxane / FhO (10.0 / 3.3 mL) was heated to 90 °C for 2 h. The reaction mixture was cooled down and and washed with heptane to afford 99a as an off white solid (656 mg, 1.31 mmol, 83%).1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.66 (dd, J = 7.6, 1.7 Hz, 1 H), 8.47 (s, 1H), 8.19 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 3.1 Hz, 1 H), 7.47 - 7.37 (m, 3H), 7.14 (d, J = 8.9 Hz, 1 H), 5.26 (s, 2H), 1.69 (s, 7H), 1.68 (s, 9H).

[0530] 6-((2-(1H-lndol-3-yl)pyrimidin-5-yl)methoxyj-2,2-d!methyl-4H- benzo[d][1,3]dioxin-4-one (99)

[0531]

[0532] To a stirring suspension of 99a (650 mg, 1 equiv, 1.30 mmol) in CH2CI2 (10 ml_) was added TFA (7.4 g, 5.0 mL, 50 equiv, 65 mmol) and was stirred at room temperature for 1.5 h. Then, the reaction mixture was concentrated and co-evaporated with EtOAc to yield a yellow solid. The solid was suspended in EtOAc and aqueous sat. NaHCOa solution was added. The layers were separated and the organic phase was washed with sat. NaHCOa solution. The organic phase was washed with brine, dried over Na2SO4 and concentrated to afford 99 as an off-white solid (448 mg, 1.12 mmol, 86%).1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1 H), 8.87 (s, 2H), 8.56 - 8.50 (m, 1H), 8.26 (d, J = 2.9 Hz, 1 H), 7.52 - 7.46 (m, 2H), 7.43 (dd, J = 8.9, 3.1 Hz, 1 H), 7.23 - 7.14 (m, 2H), 7.12 (d, J = 8.9 Hz, 1 H), 5.19 (s, 2H), 1.69 (s, 6H).

[0533] 2-Hydroxy-5-((2-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-indol-3-yl)pyrimidin- 5-yl)methoxy)benzoic acid (100)

[0534] To a solution of 99 (10 mg, 0.025 mmol, 1.0 eq.) in DCM (0.5 ml_) was added NaOH (3 equiv), 3-(trifluoromethyl)benzenesulfonyl chloride (1.5 equiv) and tetrabutylammonium hydrogen sulfate (0.3 equiv) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated, dissolved in DMSO, filtered using a nylon syringe and purified by basic preparative HPLC-MS to yield after acetonide deprotection using GP-D 100 as a white solid (2 rng, 3.5 pmol, 37%). HRMS (ESI) m / z calcd forCzyHisCINaOeS [M+H]+: 570.09412, found 570.09241. 5-((2-(1-((2,4-d / Methylthiazol-5-yl)sulfonyl)-1 H-indol-3-yl)pyrimidin-5- yl)methoxy)-2-hydroxy benzoic acid (101)

[0535] To a solution of 99 (40 mg, 0.1 mmol, 1.0 eq.) in DCM (0.5 ml_) was added NaOH (3 equiv), 2,4-dimethylthiazole-5-sulfonyl chloride (1.5 equiv) and tetrabutylammonium hydrogen sulfate (0.3 equiv) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield after acetonide deprotection using GP-D 101 as a white solid (4.4 mg, 8.2 5μ9m%o).l,1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.01 (s, 2H), 8.66 (d, J = 7.5 Hz, 1 H), 8.46 (s, 1 H), 7.94 (d, J = 8.1 Hz, 1 H), 7.56 - 7.44 (m, 2H), 7.42 (d, J = 3.2 Hz, 1 H), 7.29 (dd, J = 9.0, 3.2 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1 H), 5.19 (s, 2H), 2.61 (d, J = 2.7 Hz, 6H). HRMS (ESI) m / z calcd for C25H20N4O6S2 [M-H]’: 537.08970, found, 537.08853.

[0536] 2-Hydroxy-5-((2-(1-((2-(tr<fluoromethoxy)phenyl)sulfonyl)-1H-indol-3- yl)pyrimidin-5-yl)methoxy)benzoic acid (102)

[0537] To a solution of 99 (10 mg, 0.025 mmol, 1.0 eq.) in DCM (0.5 mL) was added NaOH (3 equiv), 3-(trifluoromethoxy)benzenesulfonyl chloride (1.5 equiv) and tetrabutylammonium hydrogen sulfate (0.3 equiv) and the reaction mixture was stirred at room temperature for 18 h. Then, the reaction mixture was concentrated, dissolved in DMSO, filtered using a nylon syringe filter and purified by basic preparative HPLC- MS to yield after acetonide deprotection using GP-D 102 as a white solid (4.3 mg, 7.5μmol, 8.1%)1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.64 (d, J = 7.8 Hz, 1 H), 8.51 (s, 1 H), 8.44 (d, J = 8.0 Hz, 1 H), 7.91 (t, J = 8.0 Hz, 1 H), 7.82 - 7.68 (m, 2H), 7.59 (d, J = 8.3 Hz, 1 H), 7.51 - 7.35 (m, 3H), 7.33 - 7.19 (m, 1 H), 6.93 (d, J = 9.0 Hz, 1 H), 5.18 (s, 2H). HRMS (ESI) m / z calcd for C27H18F3N3O7S [M-H]’: 586.08903, found, 586.08746.

[0538] 2-Hydroxy-5-((2-(1-(octylsulfonyl)-1H-indol-3-yl)pyrimidin-5-yl)methoxy)benzoic acid (103)

[0539] According to GP-I, pelargonic acid (16 μL, 1.2 equiv, 90 μmol), 99 (30 mg, 1 equiv, 75 μmol), HATU (34 mg, 1.2 equiv, 90 μmol), DIPEA (39 μL, 3 equiv, 0.22 mmol) in DMAc (2.0 mL) were stirred for 18 h at 100 °C. The compound was filtered using a nylon syringe filter and purified by basic preparative HPLC-MS to yield 103 after acetonide deprotection following GP-D as yellow solid (5.9 mg, 12 4μ0m%o.l ), HRMS (ESI) m / z calcd for C29H31N3O5 [M-H]-; 500.21909, found 500.21744.

[0540] Methyl 5-((2 bromopyrirnidin-5-yl)methoxy)-2-nitrobenzoate (104b)

[0541] Freshly prepared 33b (960 mg, 3.05 mmol, 1.0 eq.), methyl 5-hydroxy-2-nitrobenzoate (601 mg, 3.05 mmol, 1.0 eq.) and K2CO3 (548 mg, 3.96 mmol, 1.3 eq.) in acetone (30 mL) were stirred for 18 h at room temperature. Afterward, the reaction was diluted with EtOAc and water is added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL), dried over Na2SO4 and concentrated under vacuum. The solids was suspended in EtOAc, filtered off and washed with heptane to afford a white solid. In the mother liquor precipitation was formed after the addition of heptane. The solids was filtered off and washed with heptane to afford 104b as white solid (672 mg, 1.83 mmol, 60%).1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 2H), 8.18 (d, J = 9.1 Hz, 1 H), 7.45 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 9.1, 2.8 Hz, 1H), 5.38 (s, 2H), 3.86 (s, 3H).

[0542] Methyl 5-((2-(3-((3-chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2- nitrobenzoate

[0543] According to GP-G, 104b (672 mg, 1.83 mmol), (3-((3- chlorobenzyl)oxy)phenyl)boronic acid (575 mg, 1.2 equiv, 2.19 mmol), K2CO3 (757 mg, 3 equiv, 5.48 mmol) and [Pd(PPh3)4] (105 mg, 0.05 equiv, 91.3 pmol) in 1 ,4-dioxane: H2O (3.0 mL) were heated to 90 °C for 2 h. The reaction mixture was cooled down and water: EtOAc (1 :1) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford 104a as a lightbrown solid (656 mg, 1.30 mmol, 71%).1H NMR (400 MHz, DMSO-d6) <59 05 (s, 2H), 8.20 (d, J = 9.1 Hz, 1 H), 8.08 - 8.00 (m, 2H), 7.58 (s, 1H), 7.54 - 7.37 (m, 7H), 7.22 (dd, J = 8.0, 2.6 Hz, 1 H), 5.41 (s, 2H), 5.24 (s, 2H), 3.87 (s, 3H).

[0544] Methyl 2-amino-5-((2-(3-((3-chlorobenzyl)oxy)phenyl)pyrimidin-5- yl)methoxy)benzoate (104) To a stirring suspension of Fe (331 mg, 5 equiv, 5.93 mmol) and NH4CI (317 mg, 5.0 equiv, 5.93 mmol) in H2O (5.0 mL), 104a (600 mg, 1 .0 equiv, 1 .19 mmol) in THF / MeOH (5.0, mL, 1 :1) was added and the reaction mixture was heated to 75 °C for 4 h. After cooling down, the reaction mixture was diluted with EtOAc and filtered over Kieselguhr and over a silica-plug (eluting with 10% MeOH in CH2CI2) to afford 104 as a yellow oil (448 mg, 0.94 mmol, 79%).1H NMR (400 MHz, CDCI3) δ 7.52 - 7.48 (m, 1 H), 7.47 (d, J = 3.1 Hz, 1 H), 7.42 (t, J = 7.9 Hz, 1 H), 8.86 (s, 2H), 8.13 - 8.05 (m, 2H), 7.37 - 7.29 (m, 4H), 7.26 (s, 2H), 7.11 (ddd, J = 8.1 , 2.5, 1.1 Hz, 1 H), 7.02 (dd, J = 8.9, 3.0 Hz, 1 H), 6.66 (d, J = 8.8 Hz, 1 H), 5.50 (s, 2H), 5.16 (s, 2H), 5.05 (s, 2H), 3.89 (s, 3H).

[0545] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2- (((cyclopentyloxy)carbonyl)amino)benzoic acid (105)

[0546] According to GP-J, 104 (40 mg, 1 equiv, 84 μmol), cyclopentyl carbonochloridate (19 mg, 1 .5 equiv, 0.13 mmol) and TEA (35 μL, 3 equiv, 0.25 mmol) in DCE (2.0 mL) were mixed to yield 105 as a white solid after saponification using GP-F (2 mg, 3.8 pmol, 4%, over two steps). HRMS (ESI) m / z calcd for C31H28CIN3O6 [A4+H]+: 574.17394, found, 574.17279.

[0547] 5-((2"(4-((3-Chiorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2- ((isobutoxycarbonyl)amino)benzoic acid (106)

[0548]

[0549] According to GP-J, 104 (40 mg, 1 equiv, 84 μmol), isobutyl carbonochloridate (18 mg, 1.5 equiv, 0.13 mmol) and TEA (35 μL, 3 equiv, 0.25 mmol) in DOE (2.0 mL) were mixed to yield 106 as white solid after saponification using GP-F (18 mg, 32 38% μmol, over two steps).1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.01 (s, 2H), 8.17 (d, J = 9.2 Hz, 1 H), 8.06 - 8.00 (m, 2H), 7.63 - 7.55 (m, 2H), 7.51 - 7.38 (m, 4H), 7.35 (dd, J = 9.3, 3.1 Hz, 1H), 7.25 - 7.17 (m, 1H), 5.23 (s, 4H), 3.88 (d, J = 6.7 Hz, 2H), 1.93 (dq, J = 13.4, 6.7 Hz, 1 H), 0.92 (d, J = 6.6 Hz, 6H). HRMS (ESI) m / z calcd for C30H28CIN3O6 [M+H]+: 562.17394, found, 562.17267.

[0550] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-

[0551] (((cyclopentyimethoxy)carbonyl)amino)benzoic acid (107)

[0552] According to GP-J2, 104 (40 mg, 1 equiv, 84 μmol), cyclopentylmethanol (4 mg, 0.042 mmol, 0.5 equiv.), DMAP (1.0 mg, 0.1 equiv, 8.4 pmol) and TEA ( 12 μL, 0.084 mmol, 1 equiv) in DOE (4.0 mL) were mixed to yield 107 as white solid after saponification using GP-F (3 mg, 4.9 μmol, 6%, over two steps). HRMS (ESI) m / z calcd for C32H3oCiN306 [M+H]+: 588.18959, found, 588.18806. 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(((3-(2- oxopyrrolidin-1-yl)propoxy)carbonyl)amino)benzoic acid (108)

[0553] According to GP-J2, 104 (40 mg, 1 equiv, 84 μmol), 1-(3-hydroxypropyl)pyrrolidin-2- one (6 mg, 0.042 mmol, 0.5 equiv.), DMAP (1.0 mg, 0.1 equiv, 8.4 pmol) and TEA ( 12 μL, 0.084 mmol, 1 equiv) in DCE (4.0 ml_) were mixed to yield 108 as white solid after saponification using GP-F (5 mg, 8.4 μmol, 10% over two steps). HRMS (ESI) m / z calcd for C33H31CIN4O7 [ / W+H]+: 631.19540, found 631.19392.

[0554] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(((3-

[0555] (dimethylamino)-2,2-dimethylpropoxy)carbonyl)amino)benzoic acid (109)

[0556] According to GP-J2, 104 (40 mg, 1 equiv, 84 μmol), 3-(dimethylamino)-2,2- dimethylpropan-1-ol (11 mg, 0.042 mmol, 0.5 equiv.), DMAP (1.0 mg, 0.1 equiv, 8.4 pmol) and TEA ( 12 μL, 0.084 mmol, 1 equiv) in DCE (4.0 mL) were mixed to yield 103 as white solid after saponification using GP-F (22 mg, 35 4μ4m%o,l, over two steps)1H NMR (400 MHz, DMSO-c / 6) 59.00 (s, 2H), 8.09 (d, J = 9.0 Hz, 1 H), 8.06 - 8.00 (m, 2H), 7.64 (d, J = 3.2 Hz, 1 H), 7.59 - 7.55 (m, 1 H), 7.51 - 7.38 (m, 4H), 7.23 - 7.13 (m, 2H), 5.23 (s, 2H), 5.20 (s, 2H), 3.90 (s, 2H), 0.98 (s, 6H). HRMS (ESI) m / z calcd for C33H35CIN4O6 [ / W+H]+: 619.23179, found, 619.23045.

[0557] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-((((1,5-dimethyl-

[0558] 1H-pyrazol-3-yl)methoxy)carbonyl)amino)benzoic acid (110)

[0559] According to GP-J2, 104 (40 mg, 1 equiv, 84 μmol), (1 ,5-dimethyl-1 / - / -pyrazol-3- yl)methanol (10 mg, 0.042 mmol, 0.5 equiv.), DMAP (1.0 mg, 0.1 equiv, 8.4 pmol) and TEA (12 μL, 0.084 mmol, 1 equiv) in DCE (4.0 mL) were mixed to yield 110 as white solid after saponification using GP-F (22 mg, 35 μ 4m5o%l,, over two steps).1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.20 (d, J = 9.2 Hz, 1 H), 8.08 - 7.99 (m, 2H), 7.61 (d, J = 3.2 Hz, 1 H), 7.58 (s, 1 H), 7.51 - 7.40 (m, 4H), 7.35 (d, J = 9.9 Hz, 1 H), 7.24 - 7.16 (m, 1 H), 6.08 (s, 1 H), 5.24 (s, 4H), 4.99 (s, 2H), 3.70 (s, 3H), 2.23 (s, 3H). HRMS (ESI) m / z calcd for C32H28CIN5O6 [M+H]+: 614.1809, found, 614.17877.

[0560] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(((2-(2- methoxyethoxy)ethoxy)carbonyi)amino)benzoic acid (111)

[0561]

[0562] According to GP-J2, 104 (40 mg, 1 equiv, 84 μmol), 2-(2-methoxyethoxy)ethan-1-ol (10 mg, 0.042 mmol, 0.5 equiv.), DMAP (1.0 mg, 0.1 equiv, 8.4 pmol) and TEA ( 12 μL, 0.084 mmol, 1 equiv) in DOE (4.0 mL) were mixed to yield 111 as white solid after saponification using GP-F (9 mg, 14 μmo 1l8, %, over two steps).1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1 H), 9.01 (s, 2H), 8.18 (d, J = 9.2 Hz, 1 H), 8.03 (dd, J = 5.1 , 3.2 Hz, 2H), 7.60 (d, J = 3.1 Hz, 1 H), 7.57 (s, 1 H), 7.50 - 7.45 (m, 1 H), 7.43 (d, J = 7.4 Hz, 1 H), 7.40 (dt, J = 7.7, 1.9 Hz, 1 H), 7.37 (dd, J = 9.2, 3.1 Hz, 1 H), 7.22 - 7.17 (m, 1 H),

[0563] 5.23 (d, J = 4.2 Hz, 4H), 4.23 - 4.17 (m, J = 5.4, 3.9 Hz, 2H), 3.67 - 3.61 (m, J = 5.4, 3.9 Hz, 2H), 3.58 - 3.53 (m, J = 5.7, 3.8 Hz, 2H), 3.47 - 3.43 (m, J = 5.6, 3.8 Hz, 2H),

[0564] 3.24 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ169.2, 162.7, 158.5, 157.2, 152.9, 152.3,

[0565] 139.6, 138.4, 134.9, 133.2, 133.1 , 130.4, 130.0, 128.6, 127.8, 127.3, 126.2, 121.6,

[0566] 120.6, 117.8, 116.1 , 113.5, 71.2, 69.6, 68.5, 68.4, 65.2, 64.0, 58.1. HRMS (ESI) m / z calcd for C31H30CIN3O8 [M+H]+: 608.17942, found 608.17810.

[0567] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yI)methoxy)-2-

[0568] (((cyciopropylmethoxy)carbonyl)amino)benzoic acid (112)

[0569]

[0570] According to GP-J2, 104 (40 mg, 1 equiv, 84 μmol), cyclopropylmethanol (6 mg, 0.042 mmol, 0.5 equiv.), DMAP (1.0 mg, 0.1 equiv, 8.4 pmol) and TEA (12 μL, 0.084 mmol, 1 equiv) in DOE (4.0 ml_) were mixed to yield 112 as white solid after saponification using GP-D (3 mg, 5.9 μmol, 6%, over two steps). HRMS (ESI) m / z calcd for C30H26CIN3O6 [M-H]-: 558.14538, found, 558.14197.

[0571] 2-Anriino-5-((2-(3-((3-chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)benzoic acid (113)

[0572] To a mixture of 104 (300 mg, 1 equiv, 630 pmol) in THF (6.0 mL), aqueous 1M NaOH (6.30 mL, 10 equiv, 6.30 mmol) was added and the reaction mixture was heated to 70 °C for 18 h. Then, aqueous 1M HCI solution was added until the pH was ~2. The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed brine, dried over Na2SO4 and concentrated to afford 113 as a yellow / brown solid (312 mg, 675 μm 1o0l,0%).1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 2H), 8.03 (d, J = 6.8 Hz, 2H), 7.57 (s, 1H), 7.51 - 7.37 (m, 5H), 7.18 (ddd, J = 18.0, 8.5, 2.8 Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H), 5.23 (s, 2H), 5.15 (s, 2H).

[0573] 5-((2“(4-((3-Chiorobenzyl)oxy)phenyl)pyrimidin-5-y!)methoxy)-2-(3- phenylureido)benzoic acid (114)

[0574]

[0575] According to GP-K, 113 (40 mg, 1 equiv, 87 μmol), phenyl isocyanate (13 mg, 0.11 mmol, 1.3 equiv), TEA (36 μL, 3 equiv, 0.26 mmol) in DCM (2 mL) were mixed to yield 114 as a beige solid (7 mg, 12 μmo 1l4, %). HRMS (ESI) m / z calcd for C32H25CIN4O5 [M-HJ-: 579.14407, found, 579.14252.

[0576] 5-((2-(4-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(3- cyclopentylureido)benzoic acid (115)

[0577] According to GP-K, 113 (40 mg, 1 equiv, 87 μmol), cyclopentyl isocyanate (12 mg, 0.11 mmol, 1.3 equiv) TEA (36 μL, 3 equiv, 0.26 mmol) in DCM (2 mL) were mixed to yield 115 as an off-white solid (11 mg, 18 μm 28o%l, ). ’H NMR (500 MHz, DMSO-cfe) 6 13.37 (s, 1H), 9.75 (s, 1H), 9.00 (s, 2H), 8.32 (d, J = 9.3 Hz, 1H), 8.07 - 7.99 (m, 2H), 7.57 (s, 1H), 7.52 (d, J = 3.1 Hz, 1H), 7.50 - 7.38 (m, 4H), 7.30 (d, J = 5.8 Hz, 1 H), 7.26 (dd, J = 9.3, 3.2 Hz, 1 H), 7.23 - 7.20 (m, 1 H), 7.19 (dd, J = 2.5, 0.7 Hz, 1 H), 5.21 (d, J = 14.6 Hz, 4H), 3.97 - 3.86 (m, 1H), 1.81 (dt, J = 12.0, 5.9 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H), 1.44 - 1.35 (m, 2H).13G NMR (126 MHz, DMSO- d6) 5 188.1 , 169.4, 163.1 , 159.0, 157.66, 155.0, 151.3, 140.1 , 138.9, 137.9, 133.6, 130.9, 130.5, 129.2, 128.2, 127.8, 126.6, 121.9, 121.5, 121.0, 118.3, 115.9, 113.9, 68.9, 65.6, 51.6, 33.00, 23.8. HRMS (ESI) m / z calcd for C31H29CIN4O5 [M+H]+: 573.18992, found, 573.18854.

[0578] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(3- (cyclopropylmethyl)ureido)benzoic acid (116)

[0579] According GP-K, 113 (40 mg, 1 equiv, 87 μmol), (isocyanatomethyl)cyclopropane (10.6 mg, 0.11 mmol, 1.3 equiv), TEA (36 μL, 3 equiv, 0.26 mmol) in DCM (2 mL) were mixed to yield 116 as a white solid (6 mg, 11 μm 13o%l, ). HRMS (ESI) m / z calcd for C30H27CIN4O5 [M-H]-: 557.15972, found, 557.15765.

[0580] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(3-(2- ethylbutyl)ureido)benzoic acid (117)

[0581] According to GP-K2, to a solution of triphosgene (7.1 mg, 0.3 equiv, 24 pmol) in CH2Cl2 (1.0 mL), 2-ethylbutan-1 -amine (10 mg, 1.2 equiv, 96 pmol) and EtsN (28 μL, 2.5 equiv, 0.20 mmol) in CH2CI2 (1.0 mL) was added dropwise. Then, 113 (37 mg, 1 equiv, 80 pmol) was added and the mixture yield 117 as an off white solid after purification (26 mg, 44 μmol 5,5%).1H NMR (500 MHz, DMSO-d6) δ 13.36 (s, 1 H), 9.80 (s, 1 H), 9.00 (s, 2H), 8.29 (d, J = 9.3 Hz, 1 H), 8.06 - 8.00 (m, 2H), 7.57 (s, 1 H), 7.53 (d, J = 3.1 Hz, 1 H), 7.50 - 7.38 (m, J = 22.8, 14.0, 7.7 Hz, 4H), 7.25 (dd, J = 9.2, 3.1 Hz, 1H), 7.22 - 7.18 (m, 1H), 5.23 (s, 1H), 5.20 (s, 1H), 3.00 (t, J = 5.6 Hz, 2H), 1.37 - 1.21 (m, 5H), 0.85 (t, J = 7.2 Hz, 6H).13C NMR (126 MHz, DMSO-d6) δ 168.9, 162.6, 158.5, 157.2, 155.0, 150.8, 139.6, 138.4, 137.4, 133.11, 130.4, 130.0, 128.7, 127.8, 127.3, 126.2, 121.4, 121.2, 120.6, 117.8, 115.5, 113.5, 68.3, 65.1, 41.7, 40.8, 23.1, 10.8.. HRMS (ESI) m / z calcd for C32H33CIN4O5 [M-Hp: 587.20667, found, 587.20477.

[0582] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(3-(3-(2- oxopyrrolidin-1-yl)propyl)ureido)benzoic acid (118)

[0583] According to GP-K2, to a solution of triphosgene (7.1 mg, 0.3 equiv, 24 pmol) in CH2Cl2 (1.0 ml_), 1-(3-aminopropyl)pyrrolidin-2-one (13 mg, 1.2 equiv, 96 pmol) and EtsN (28 μL, 2.5 equiv, 0.20 mmol) in CH2CI2 (1.0 ml_) was added dropwise. Then, 113 (37 mg, 1 equiv, 80 pmol) was added and the reaction mixture was stirred at room temperature for 18 n to afford 118 as an off white solid after purification (5 mg, 7.6 pmol, 9.5%). HRMS (ESI) m / z calcd for C33H32CIN5O6 [M-Hp: 628.19684, found, 628.19472.

[0584] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(2- cyclopropyiacetamido)benzoic acid (119)

[0585]

[0586] According to GP-I, 2-cyclopropylacetic acid (11 mg, 1.3 eq., 109 μmol), HATU (42 mg, 1.3 equiv, 0.11 mmol), DIPEA (44 μL, 3 equiv, 0.25 mmol) and 113 (40 mg, 1 equiv, 84 pmol) in DMF (2.0 ml_) were mixed to afford 119 as an off white solid after basic HPLC-MS preparative (21 mg, 38 μm 4o6l,%).1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1 H), 11 .09 (s, 1 H), 9.01 (s, 2H), 8.51 (d, J = 9.2 Hz, 1 H), 8.06 - 8.00 (m, 2H), 7.61 (d, J = 3.1 Hz, 1 H), 7.57 (s, 1H), 7.50 - 7.39 (m, J = 22.6, 14.3, 7.6 Hz, 2H), 7.35 (dd, J = 9.2, 3.1 Hz, 1 H), 7.24 - 7.17 (m, 1H), 5.24 (d, J = 7.9 Hz, 4H), 2.29 (d, J = 7.1 Hz, 2H), 1 .07 - 0.96 (m, 1 H), 0.63 - 0.53 (m, 2H), 0.25 (q, J = 4.9 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 170.5, 169.0, 162.7, 158.5, 157.2, 152.6, 139.7, 138.3, 133.1 , 130.4, 130.0, 128.5, 127.8, 127.3, 126.2, 121.7, 121.1 , 120.7, 120.6, 117.8, 116.1 , 113.5, 68.4, 65.1 , 42.5, 7.0, 4.6.. HRMS (ESI) m / z calcd for C30H26CIN3O5 [ / W-Hp: 542.14882, found, 542.14702.

[0587] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(1- methylcyclopropane-1-carboxamido)benzoic acid (120)

[0588] According to GP-I, 1-methylcyclopropane-1 -carboxylic acid (11 mg, 1.3 eq, 109 pmol), HATU (42 mg, 1.3 equiv, 0.11 mmol), DIPEA (44 μL, 3 equiv, 0.25 mmol) and 113 (40 mg, 1 equiv, 84 pmol) in DMF (2.0 mL) were mixed to afford 120 as an off white solid (15 mg, 26 μmol, 31%). HRMS (ESI) m / z calcd for C30H20CIN3O5 [M-Hp: 542.14882, found, 542.14697. 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(1-ethyl-5- methyl-1H-pyrazole-4-carboxamido)benzoic acid (121)

[0589] According to GP-1, 1-ethyl-5-methyl-1 / 7-pyrazole-4-carboxylicacid (17 mg, 1.3 eq, 109 μmol), HATU (42 mg, 1.3 equiv, 0.11 mmol), DIPEA (44 μL, 3 equiv, 0.25 mmol) and 113 (40 mg, 1 equiv, 84 pmol) in DMF (2.0 mL) were mixed to afford 121 as a white solid (10 mg, 16 μmol, 19%). HRMS (ESI) m / z calcd for C32H28CIN5O5 [M-Hp: 596.17062, found 596.16870.

[0590] 5-((2-(3-((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)-2-(3,3- difluorocyclobutane-1-carboxamido)benzoic acid (122)

[0591] According to GP-I, 3,3-difluorocyclobutane-1-carboxylic acid (15 mg, 1.3 eq, 109 μmol), HATU (42 mg, 1.3 equiv, 0.11 mmol), DIPEA (44 μL, 3 equiv, 0.25 mmol) and 113 (40 mg, 1 equiv, 84 pmol) in DMF (2.0 mL) were mixed to afford 122 as an off white solid (18 mg, 30 μmo 3l6, %). HRMS (ESI) m / z calcd for C30H24CIF2N3O5 [M+H]+: 580.14453, found.580.14257

[0592] 5-((2-(3“((3-Chlorobenzyl)oxy)phenyl)pyrimidin-5-yl)methoxy)"2-(pent-4- ynamido)benzoic acid (123)

[0593]

[0594] According to GP-I, pent-4-ynoic acid (10 mg, 1.3 eq, 109 μmol), HATU (42 mg, 1.3 equiv, 0.11 mmol), DIPEA (44 μL, 3 equiv, 0.25 mmol) and 113 (40 mg, 1 equiv, 84 pmol) in DMF (2.0 mL) were mixed to afford 123 as off white (14 mg, 24 29μ%m).ol, HRMS (ESI) m / z calcd for C30H29CIN3O5 [M-Hf: 540.13317, found 540.13123.

[0595] Methyl 5-((3,5-dibromobenzyl)oxy)-2-hydroxybenzoate (124b)

[0596] According to GP-E, 1 ,3-dibromo-5-(bromomethyl)benzene (670 mg, 2.60 mmol) was added to a solution of 38 (400 mg, 2.40 mmol) and K2CO3 (655 mg, 4.70 mmol) in acetone (17 mL to afford after flash chromatography (c-Hex / EtOAc 92:8) 124b as a light brown solid (560 mg, 2.6mmol, 65 %).1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1 H), 7.80 (t, J = 1.7 Hz, 1 H), 7.68 (d, J = 1.6 Hz, 2H), 7.34 (d, J = 3.2 Hz, 1 H), 7.26 (dd, J = 9.0, 3.2 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 5.08 (s, 2H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 168.9, 154.7, 150.3, 141.9, 132.7, 129.4, 124.2, 122.5, 118.6, 113.8, 112.9, 68.1 , 52.6. LC-MS calcd for Ci5Hi2Br2O4 [M-Hp: 414.9, found 414.9.

[0597] 5-((3,5-diBromobenzy!)oxy)-2-hydroxy benzoic acid (124a) According to GP-F, 124a was synthesised using 124b (600 mg, 0.96 mmol) and NaOH (in aq. 10%, 1.70 mL). The crude material was purified by flash chromatography (c- Hex / EtOAc 88:12) and 124a was isolated as an off-white solid (550 mg, 95%).1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1 H), 7.80 (t, J = 1.7 Hz, 1 H), 7.68 (d, J = 1.7 Hz, 2H), 7.34 (d, J = 3.2 Hz, 1 H), 7.24 (dd, J = 9.0, 3.2 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 1 H), 5.08 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.4, 155.7, 150.1 , 141.9, 132.6, 129.3, 124.2, 122.5, 118.2, 113.9, 112.7, 68.1. HR-MS (ESI) calcd for Ci4HioBr204 [M+H]+: 400.90186, found 400.88315.

[0598] 5-((3,5-di(Thiophen-3-yl)benzyl)oxy)-2-hydroxy benzoic acid (124)

[0599] According to GP-G, 124 was synthesised using 124a (80 mg, 0.19 mmol) thiophen-3- ylboronic acid (64 mg, 0.50 mmol), K2CO3 (61 mg, 0.48 mmol,) and [Pd(PPhs)4] (12 mg, 0.01 mmol). The crude material was purified by preparative HPLC (75% ACN) and 124 was isolated as a light brown solid (30 mg, 37 %).1H NMR (500 MHz, DMSO-cfe) 5 10.86 (br s, 1 H), 8.0-8.0 (m, 3H), 7.72 (s, 2H), 77-7.7 (m, 4H), 7.42 (d, 1 H, J=3.1 Hz), 7.28 (d, 1 H, J=8.8 Hz), 6.92 (d, 1H, J=9.0 Hz), 5.14 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 155.5, 150.6, 141.1 , 138.3, 135.9, 127.1 , 126.4, 124.2, 123.3, 121.6, 118.2, 114.0, 112.7, 69.9.

[0600] 5-((3,5-bis(5-(((tert-butoxycarbonyl)amino)methyl)thiophen-3-yl)benzyl)oxy)-2- hydroxy benzoic acid (125)

[0601]

[0602] According to GP-G, 125 was synthesised using 124a (80 mg, 0.19 mmol) (5-(((tert- butoxycarbonyl)amino)methyl)thiophen-3-yl)boronic acid (127 mg, 0.50 mmol), K2CO3 (61 mg, 0.47 mmol,) and [Pd(PPhs)4] (12 mg, 0.01 mmol). The crude material was purified by preparative HPLC (82% ACN) and 125 was isolated as a pink solid (39 mg, 30%).1H NMR (500 MHz, CHLOROFORM-cQ 610.43 (br s, 1H), 7.65 (s, 1H), 7.55 (br s, 3H), 7.36 (d, 2H, J=1.0 Hz), 7.16 (dd, 1 H, J=3.1 , 9.0 Hz), 6.90 (d, 1H, J=9.2 Hz), 5.08 (s, 2H), 5.0-5.1 (m, 1 H), 4.51 (br d, 3H, J=5.6 Hz), 4.4-4.6 (m, 1 H), 4.4-4.4 (m, 1H), 1.49 (br s, 18H).13C NMR (126 MHz, CHLOROFORM-d) 5 172.1, 156.8, 155.9, 150.8, 142.8, 141.6, 137.8, 136.6, 125.4, 125.1 , 124.0, 120.1 , 118.6, 114.0, 111.4, 80.3, 70.8, 39.6, 28.4. HR-MS (ESI) calcd for C34H38N2O8S2 [M-H]- : 667.21533, found 667.21307.

[0603] 5-((3,5-bis(6-fsopropoxy py ridin-3-y l)benzy i)oxy)-2-hydroxy benzoic acid (126)

[0604] According to GP-G, 126 was synthesised using 124a (80 mg. 0.190 mmol) (6- isopropoxypyridin-3-yl)boronic acid (109 mg, 0.569 mmol), K2CQ3 (69 mg, 0.497 mmol,) and [Pd(PPh3)4] (12 mg, 0.010 mmol). The crude material was purified by preparative HPLC (70% AON) and 126 was isolated as a white solid (30 mg, 30%).1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 2.6 Hz, 2H), 8.10 (dd, J = 8.6, 2.6 Hz, 2H), 7.86 (s, 1 H), 7.71 (s, 2H), 7.42 (d, J = 3.2 Hz, 1 H), 7.28 (dd, J = 9.0, 3.2 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 5.34 - 5.27 (m, 2H), 5.18 (s, 2H), 1.32 (d, J = 6.2 Hz, 12H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 162.6, 155.6, 150.5, 145.0,

[0605] 138.7, 138.0, 137.8, 128.5, 124.5, 124.20, 123.8, 118.2, 114.0, 112.8, 111.2, 69.7,

[0606] 67.7, 21.9. HR-MS (ESI) calcd for [M-Hp : 513.20311, found 513.20197.

[0607] 5-((3,5-bis(5-Chloro-6-fsopropoxypyridin-3-yl)benzyl)oxy)-2-hydroxybenzoic acid (127)

[0608] According to GP-G, 127 was synthesised using 124a (80 mg, 0.189 mmol) (5-chloro- 6-isopropoxypyridin-3-yl)boronic acid (108 mg, 0.497 mmol), K2CO3 (61 mg, 0.437 mmol,) and [Pd(PPh3)4] (12 mg, 0.010 mmol). The crude material was purified by preparative HPLC (90% ACN) and 127 was isolated as a white solid (46 mg, 40%).1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 2.2 Hz, 2H), 8.39 (d, J = 2.2 Hz, 2H), 7.98 (s, 1 H), 7.80 (d, J = 1.3 Hz, 2H), 7.42 (d, J = 3.2 Hz, 1 H), 7.28 (dd, J = 9.0, 3.2 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 5.36 (dq, J = 12.4, 6.2 Hz, 2H), 5.16 (s, 2H), 1.36 (d, J = 6.2 Hz, 12H).13C NMR (126 MHz, DMSO-d6) δ 171.5, 157.5, 155.6, 150.5, 143.1 , 138.8, 137.2, 136.7, 129.6, 125.1 , 124.2, 118.1 , 117.5, 114.0, 112.9, 69.7, 69.4, 21.8. HR-MS (ESI) calcd for [M-Hp ; 581.12517, found 581.12463.

[0609] 1 -Bromo-3-(bromomethy l)-5-nitrobenzene (128f)

[0610] According to GP-L, 128f was synthesized using 128g (2.00 g, 8.62 mmol), pyridine (0.7 mL, 8.62 mmol) and phosphorus tribromide (4.1 mL, 43.10 mmol). The crude material was purified by flash chromatography (c-Hex / EtOAc 13:1) and 128f was isolated as a light yellow solid (3.30 g, 65%).1H NMR (500 MHz, CHLOROFORM-d) δ 8.32 (s, 1H), 8.21 (s, 1 H), 7.88 (s, 1 H), 4.49 (s, 2H).13C NMR (126 MHz, CHLOROFORM-d) δ 148.8, 141.3, 137.8, 126.5, 123.1 , 122.6, 29.9. LC-MS calcd for C7H5Br2NO2[M-H]" 291.9, found: 293.9.

[0611] Methyl 5-((3-bromo-5-nitrobenzyl)oxy)-2-hydroxybenzoate (128e)

[0612] According to GP-E, 128e was synthesized using 128f (3.30 g, 11.19 mmol), methyl-2,5-dihydroxybenzoate (1.71 g, 10.17 mmol) and K2CO3 (1.69 g, 12.21 mmol). The crude material was purified by flash chromatography (c-Hex / EtOAc 6:1) and 128e was isolated as a yellow solid (3.00 g, 77%).1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1 H), 8.35 (t, 1 H, J=1.8 Hz), 8.31 (s, 1 H), 8.14 (s, 1H), 7.38 (s, 1H), 7.29 (dd, 1H, J=3.2, 9.0 Hz), 6.97 (d, 1 H, J=9.0 Hz), 5.22 (s, 2H), 3.90 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 168.8, 154.7, 150.2, 148.6, 141.5, 136.4, 125.4, 124.1 , 122.0, 121.2, 118.7, 113.9, 112.9, 68.0, 52.5. LC-MS calcd for Ci5Hi2BrNO6[M-H]-; 380.0, found: 380.0.

[0613] Methyl 5-((3-(5-chloro-6-isopropoxypyridin-3-yl)-5-nitrobenzy!)oxy)-2- hydroxybenzoate (128d)

[0614] According to GP-G, 128d was synthesized using 128e (1.20 g, 3.14 mmol), (4-chloro- 6-isopropoxypyridin-3-yl)boronic acid (0.81 g, 4.41 mmol), K2CO3 (1.48 g, 10.68 mmol) and [Pd(dppf)Cl2] (0.11 g, 0.16 mmol). The crude material was purified by flash chromatography (c-Hex / EtOAc 6:1) and 128d was isolated as a yellow solid (1.00 g, 68%).1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1 H), 8.58 (d, 1 H, J=2.1 Hz), 8.49 (s, 1 H), 8.40 (d, 1 H, J=2.3 Hz), 8.29 (d, 2H, J=6.0 Hz), 7.42 (d, 1 H, J=3.2 Hz), 7.32 (dd, 1 H, J=3.1 , 9.0 Hz), 6.97 (d, 1 H, J=9.0 Hz), 5.38 (spt, 1 H, J=12.4 Hz), 5.27 (s, 2H), 3.90 (s, 3H), 1.37 (d, 6H, J=6.1 Hz)13C NMR (126 MHz, DMSO-d6) δ 168.8, 158.0, 154.6, 150.4, 148.6, 143.5, 140.1, 137.6, 137.4, 132.0, 127.8, 124.2, 121.1 , 120.6, 118.7, 117.7, 113.9, 112.9, 69.7, 68.6, 52.5, 21.8. LC-MS calcd for C23H21CIN2O7 [M-H]-: 471.1 , found: 471.1.

[0615] Methyl 5-((3-amino-5-(5-chloro-6-isopropoxypyridin-3-yl)benzyl)oxy)-2- hydroxy benzoate (128c)

[0616] According to GP-M, 128c was synthesized using 128d (0.73 g, 1.54 mmol), NH4CI (0.50 g, 9.26 mmol) and iron powder (0.52 g, 9.26 mmol). The crude material was purified by flash chromatography (c-Hex / EtOAc 3:1) and 128c was isolated as a brown oil (0.57 g, 83%).1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1 H), 8.30 (d, 1 H, J=2.1 Hz), 8.02 (d, 1 H, J=2.1 Hz), 7.34 (d, 1H, J=3.1 Hz), 7.23 (dd, 1 H, J=1.0 Hz), 6.93 (d, 1 H, J=9.0 Hz), 6.87 (s, 1 H), 6.77 (s, 1 H), 6.66 (s, 1H), 5.33 (spt, 1 H, J=1.0 Hz), 4.97 (s, 2H), 3.88 (s, 3H), 1.34 (d, 6H, J=6.1 Hz).13C NMR (126 MHz, DMSO-de) δ 168.9, 157.2, 154.4, 150.8, 149.4, 142.4, 138.5, 136.6, 136.3, 130.8, 124.1 , 118.5, 117.3, 113.7, 113.4, 112.7, 112.4, 111.2, 70.1 , 69.3, 52.5, 21.8. LC-MS calcd for C23H23CIN2O5 [M+H]+: 443.1 , found: 443.1. Methyl 5-((3-azido-5-(5-chloro-6-isopropoxypyridin-3-yl)benzyl)oxy)-2- hydroxy benzoate (128b)

[0617] According to GP-N, 128b was synthesized using 128c (0.55 g, 1.25 mmol), NaNCh (0.26 g, 3.75 mmol) and NaNa (0.32 g, 4.99 mmol). The crude material was used without further purification in the next step. (0.50 g, 85%)1H NMR (500 MHz, DMSO- d6) δ 10.11 (s, 1 H), 8.48 (d, 1 H, J=2.1 Hz), 8.27 (d, 1 H, J=2.1 Hz), 7.61 (s, 1 H), 7.40 (s, 1 H), 7.37 (d, 1 H, J=3.2 Hz), 7.28 (dd, 1 H, J=3.1, 9.0 Hz), 7.19 (s, 1H), 6.95 (d, 1 H, J=9.2 Hz), 5.36 (spt, 1 H, J=6.2 Hz), 5.12 (s, 2H), 3.89 (s, 3H), 1.35 (d, 6H, J=6.1 Hz).13C NMR (126 MHz, DMSO-d6) δ 168.9, 157.7, 154.5, 150.5, 143.1 , 140.5, 139.9, 137.6, 137.1 , 128.9, 124.2, 122.5, 118.6, 117.5, 117.3, 116.6, 113.8, 112.8, 69.5, 69.2, 52.5, 21.8. LC-MS calcd for C23H21CIN4O5 [M+H]+: 469.1 found: 469.1.

[0618] 5-((3-Azido-5-(5-chloro-6-isopropoxypyridin-3-yl)benzyl)oxy)-2-hydroxybenzoic acid (128a)

[0619] According to GP-F, 128a was synthesized using 128b (0.62 g, 1.33 mmol) and NaOH (in aq. 10%, 5.3 mL). The crude material was purified by flash chromatography (c- Hex / EtOAc 9:1) and 128b was isolated as a light brown solid (0.50 g, 84%).1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, 1 H, J=2.1 Hz), 8.26 (d, 1 H, J=2.1 Hz), 7.60 (s, 1 H), 7.40 (s, 1 H), 7.38 (d, 1H, J=3.2 Hz), 7.26 (dd, 1 H, J=3.1 , 8.9 Hz), 7.19 (s, 1H), 6.91 (d, 1 H, J=9.0 Hz), 5.35 (spt, 1 H, J=1.0 Hz), 5.12 (s, 2H), 1.35 (d, 6H, J=6.1 Hz).13C NMR (126 MHz, DMSO-d6) δ 171.5, 157.7, 155.7, 150.4, 143.1 , 140.5, 140.1 , 137.7, 137.1 , 129.0, 124.2, 122.5, 118.2, 117.6, 117.4, 116.7, 114.1 , 112.9, 69.6, 69.2, 21.9. LC-MS calcd for C22H19CIN4O5 [M-H]~: 453.1 found: 453.1.

[0620] 5-((3-(5-Chloro-6-isopropoxypyridin-3-yl)-5-(4-cyclopentyl-1 H-1 ,2,3-triazol-1 - yl)benzyl)oxy)-2-hydroxybenzoic acid (128)

[0621] According to GP-O, 128 was synthesized using 128a (80 mg, 0.18 mmol), ethynylcyclopentane (20 μL, 0.18 mmol), sodium ascorbate (14 mg, 0.07 mmol) and copper (II) sulfate pentahydrate (9 mg, 0.03 mmol). The crude material was purified by preparative HPLC (85% ACN) and 128 was isolated as a white solid (55 mg, 57%).1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1 H), 8.60 (d, 1H, J=2.1 Hz), 8.38 (d, 1 H, J=2.3 Hz), 8.13 (s, 1 H), 8.04 (s, 1 H), 7.90 (s, 1 H), 7.42 (d, 1 H, J=3.2 Hz), 7.30 (dd, 1 H, J=3.1 , 9.0 Hz), 6.93 (d, 1 H, J=9.0 Hz), 5.38 (spt, 1 H, J=1.0 Hz), 5.22 (s, 2H), 3.22 (quin, 1 H, J=1.0 Hz), 2.0-2.1 (m, 2H), 1.6-1.8 (m, 6H), 1.37 (d, 6H, J=6.1 Hz).13C NMR (126 MHz, DMSO-d6) δ 171.5, 157.8, 155.7, 152.6, 150.4, 143.2, 140.0, 137.6, 137.4, 137.1, 128.7, 125.1 , 124.2, 119.4, 118.2, 117.8, 117.6, 116.8, 114.1 , 112.8, 69.6, 69.2, 38.9, 36.1, 32.7, 24.7, 21.8. HR-MS (ESI) calcd for C29H29CIN4O5 [M-H]~ 547.17537, found: 547.17499.

[0622] 5-((3-(5-Chloro-6-isopropoxypyridin-3-yl)-5-(4-(thiophen-3-y!)-1 H-1 ,2,3-triazol-1 - yl)benzyl)oxy)-2-hydroxy benzoic acid (129)

[0623]

[0624] According to GP-O, 129 was synthesized using 128a (65 mg, 0.14 mmol), 3- ethynylthiophene (14 μL, 0.14 mmol), sodium ascorbate (11 mg, 0.05 mmol) and copper (II) sulfate pentahydrate (7 mg, 0.03 mmol). The reaction was stopped after 3 h. The crude material was purified by preparative HPLC (80% AON) and 129 was isolated as a white solid (20 mg, 25%).1H NMR (500 MHz, DMSO-de) δ 9.31 (s, 1 H), 8.61 (d, 1 H, J=2.3 Hz), 8.40 (d, 1 H, J=2.3 Hz), 8.19 (s, 1 H), 8.09 (s, 1H), 7.9-8.0 (m, 2H), 7.72 (dd, 1 H, J=3.0, 5.0 Hz), 7.59 (dd, 1H, J=1.2, 5.0 Hz), 7.44 (d, 1 H, J=3.2 Hz), 7.31 (dd, 1H, J=3.1, 9.0 Hz), 6.93 (d, 1H, J=9.0 Hz), 5.39 (spt, 1H, J=6.2 Hz), 5.25 (s, 2H), 1.37 (d, 6H, J=6.3 Hz).13C NMR (126 MHz, DMSO-d6) δ 171.5, 157.8, 155.7, 150.4, 143.9, 143.2, 140.1, 137.5, 137.4, 137.1 , 131.4, 128.6, 127.5, 125.7, 125.5, 124.2, 121.5, 119.5, 118.2, 118.0, 117.6, 117.1 , 114.1 , 112.8, 69.6, 69.2, 21.8. HR- MS (ESI) calcd for C28H23CIN4O5S [M-H]-: 561.10049, found: 561.10016.

[0625] 5-((3-(5-Chloro-6- / sopropoxy py ridin-3-yl)-5-(4-(thiophen-2-y !)-1 H-1 ,2,3-triazol-1 - yl)benzyl)oxy)-2-hydroxy benzoic acid (130)

[0626] According to GP-O, compound 130 was synthesized using 128a (65 mg, 0.14 mmol), 2-ethynylthiophene (14 μL, 0.14 mmol), sodium ascorbate (11 mg, 0.05 mmol) and copper (II) sulfate pentahydrate (7 mg, 0.03 mmol). The reaction was stopped after 3 h. The crude material was purified by preparative HPLC purification and 130 was isolated as a white solid (15 mg, 19%).1H NMR (DMSO-cfe, 500 MHz) δ 9.36 (s, 1 H),

[0627] 8.62 (d, 1H, J=2.1 Hz), 8.40 (d, 1H, J= 2.1 Hz), 8.21 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H),

[0628] 7.62 (d, 1H, J= 5.0 Hz), 7.54 (d, 1H, J= 3.5 Hz), 7.44 (d, 1H, J= 3.1 Hz), 7.31 (dd, 1H, J= 3.1, 9.0 Hz), 7.20 (dd, 1H, J= 3.8, 4.7 Hz), 6.93 (d, 1H, J= 9.0 Hz), 5.39 (spt, 1H, J= 12.4 Hz), 5.25 (s, 2H), 1.37 (d, 6H, J= 6.3 Hz).13C NMR (DMSO-cfe, 126 MHz) δ 171.5,

[0629] 157.8, 155.7, 150.3, 143.3, 142.7, 140.2, 137.5, 137.2, 137.1 , 132.3, 128.6, 128.1, 126.0, 125.6, 124.6, 124.1, 119.1, 118.2, 118.0, 117.6, 117.1, 114.1, 112.9, 69.6, 69.2,

[0630] 21.8. HR-MS (ESI) calcd for C28H23CIN4O5S [M-H]~: 561.10049, found: 561.09735.

[0631] 5-((3-(4-(Tert-butyl)-1H-1,2,3-triazol-1-yl)-5-(5-chloro-6- / sopropoxypyridin-3- yl)benzyl)oxy)-2-hydroxy benzoic acid (131)

[0632] According to GP-O, compound 131 was synthesized using 128a (80 mg, 0.18 mmol), 3,3-dimethylbut-1-yne (22 μL, 0.18 mmol), sodium ascorbate (14 mg, 0.07 mmol) and copper (II) sulfate pentahydrate (9 mg, 0.03 mmol). The reaction was stopped after 20 min. The crude material was purified by preparative HPLC purification and 131 was isolated as a white solid (61 mg, 65%).1H NMR (DMSO-d6, 500 MHz) 58.76 (s, 1H), 8.61 (d, 1H, J= 2.1 Hz), 8.38 (d, 1H, J= 2.1 Hz), 8.14 (s, 1H), 8.04 (s, 1 H), 7.90 (s, 1H), 7.42 (d, 1H, J= 3.2 Hz), 7.30 (dd, 1H, J= 3.1, 9.0 Hz), 6.93 (d, 1H, J= 9.0 Hz), 5.38 (spt, 1H, J= 1.0 Hz), 5.23 (s, 2H), 1.3-1.4 (m, 15H).13C NMR (DMSO-d6, 126 MHz) 5 171.5, 157.8, 157.5, 155.7, 150.4, 143.3, 140.0, 137.6, 137.4, 137.1 , 128.7, 125.1, 124.2, 118.5, 118.2, 117.9, 117.6, 116.8, 114.1, 112.8, 69.6, 69.2, 30.6, 30.2, 21.8. HR-MS (ESI) calcd for C28H29CIN4O5 [M-H]": 535.17537, found: 535.17487. Methyl 4-(4-phenoxybenzamido)picolinate (132a)

[0633] According to GP-P, T3P (2.27 ml_, 7.70 mmol) was added to a solution of 4- phenoxybenzoic acid (132b) (150 mg, 0.70 mmol) and 132c (117.2 mg, 0.77 mmol) in EtOAc (4 mL) and pyridine (4 mL, 49.0 mmol) to afford after preparative HPLC 132a (130 mg, 52 %) as a transparent oil.1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1 H), 8.60 (d, J = 5.5 H50 mgz, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.08 - 8.03 (m, 3H), 7.51 - 7.43 (m, 2H), 7.25 (t, J = 7.4 Hz, 1 H), 7.17 - 7.10 (m, 4H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.71 , 165.30, 160.47, 155.29, 150.56, 148.26, 147.13, 130.34, 128.26, 124.60, 119.75, 117.38, 116.62, 115.20, 52.91. LC-MS ca led for C20H16N2O4 [M+H]+: 349.10, found 349.10.

[0634] 4-(4-Phenoxybenzamido)picolinic acid (132)

[0635] According to GP-Q, to a suspension of 132a (50 mg, 0.14 mmol) in THF (0.5 mL), an aq. solution of LiOH (0.5 mL) was added to afford after preparative HPLC 132 (10 mg, 0.14 mmol, 35%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.57 (d, J = 5.5 Hz, 1 H), 8.48 (s, 1 H), 8.04 (d, J = 8.5 Hz, 3H), 7.47 (t, J = 7.9 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1 H), 7.12 (dd, J = 8.2, 6.3 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 166.33, 166.20, 160.94, 155.77, 150.16, 147.97, 130.81 , 128.98, 128.76, 128.29, 125.07, 120.22, 117.86, 116.76, 115.37. HR-MS ealed for C19H14N2O4 [M+H]+: 335.10263, found 335.10134.

[0636] Methyl 4-(4-(4-methoxyphenoxy)benzamido)picolinate (133a) According to GP-P, T3P (2.0 mL, 6.76 mmol) was added to a solution of 4-(4- methoxyphenoxy)benzoic acid (133b) (150 mg, 0.61 mmol) and 132c (102.8 mg, 0.67 mmol) in EtOAc (3.5 mL) and pyridine (3.5 mL, 42.99 mmol) to afford after preparative HPLC 133a (100 mg, 43 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 5.5, 2.1 Hz, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.14 - 7.07 (m, 2H), 7.05 - 7.00 (m, 4H), 3.89 (s, 3H), 3.78 (s, 3H).13C NMR (126 MHz, DMSO-d6) 5 165.73, 165.28, 156.30, 150.51, 148.21, 148.10, 147.20, 130.27, 127.56, 121.54, 116.61, 116.30, 115.30, 115.20, 55.45, 52.44. LC-MS calcd for C21H18N2O5 [M+H]+: 379.13, found 379.20.

[0637] 4-(4-(4-Methoxyphenoxy)benzamido)picolinic acid (133)

[0638] According to GP-Q, to a suspension of 133a (50 mg, 0.13 mmol) in THF (0.4 mL), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 133 (12 mg, 29%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.58 (d, J = 5.5 Hz, 1 H), 8.48 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 5.6, 1.9 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.12 - 7.08 (m, 2H), 7.06 - 7.01 (m, 4H), 3.79 (s, 3H).13C NMR (126 MHz, DMSO- d6) 6166.37, 166.20, 162.06, 156.76, 150.12, 148.57, 147.95, 130.75, 128.08, 122.00, 116.76, 116.66, 115.77, 115.33, 55.92. HR-MS calcd for C20H16N2O5 [M+H]+: 365.11320, found 365.11191.

[0639] Methyl 4-(4-(3-cyanophenoxy)benzamido)picolinate (134a)

[0640] According to GP-P, T3P (2.03 mL, 6.90 mmol) was added to a solution of 4-(4- cyanophenoxy)benzoic acid 134b (150 mg, 0.63 mmol) and 132c (104.9 mg, 0.69 mmol) in EtOAc (3.5 mL) and pyridine (3.5 mL, 43.90 mmol) to afford after preparative HPLC 134a (93 mg, 40 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1 H), 8.11 (d, J = 8.7 Hz, 2H), 8.06 (dd, J = 5.5, 2.1 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.77, 165.46, 160.08, 158.36, 150.77, 148.47, 147.21 , 135.02, 130.73, 130.18, 119.55, 119.39, 118.75, 116.83, 115.39, 106.37, 52.62. LC-MS calcd for C21H15N3O4 [M+H]+: 374.11 , found 374.09.

[0641] 4-(4-(3-Cyanophenoxy)benzamido)picolinic acid (134)

[0642] According to GP-Q, to a suspension of 134a (50 mg. 0.13 mmol) in THF (0.4 mL), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 134 (15 mg, 31%) as a transparent oil.1H NMR (500 MHz, DMSO-d6) δ 10.81 (br s, 1 H), 8.59 (br d, J = 5.3 Hz, 1 H), 8.48 (d, J = 1.8 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 2H), 8.05 (dd, J = 5.5, 2.0 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 166.09, 160.40, 158.62, 153.64, 153.25, 150.09, 147.82, 135.33, 131.08, 130.46, 119.87, 119.70, 119.08, 115.30, 106.65. HR-MS calcd for C2OHI3N304 [M+H]+: 360.7988, found 360.09648.

[0643] Methyl 4-(4-(4-chlorophenoxy)benzamido)pico!inate (135a)

[0644] According to GP-P, T3P (1.95 mL, 6.64 mmol) was added to a solution of 4-(4- chlorophenoxy)benzoic acid 135b (150 mg, 0.60 mmol) and 132c (101.0 mg, 0.66 mmol) in EtOAc (3.4 mL) and pyridine (3.4 mL, 42.2 mmol) to afford after preparative HPLC 135a (110 mg, 46 %) as a white powder.1H NMR (500 MHz, DMSO-d6) 5 10.77 (s, 1H), 8.61 (d, J = 5.5 Hz, 1 H), 8.53 (d, J = 2.1 Hz, 1 H), 8.10 - 8.03 (m, 3H), 7.54 - 7.49 (m, 2H), 7.20 - 7.14 (m, 4H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.65, 165.30, 160.02, 154.34, 150.58, 148.28, 147.09, 130.40, 130.19, 128.69, 128.36, 121.43, 117.69, 116.63, 115.21, 52.44. LC-MS calcd for C20H15CIN2O4 [M+H]+: 383.08, found 383.20.

[0645] 4-(4-(4-Chlorophenoxy)benzamido)picolinic acid (135)

[0646] According to GP-Q, to a suspension of 135a (50 mg, 0.13 mmol) in THF (0.4 ml), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 135 (31 mg, 32%) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.46 (d, J = 2.2 Hz, 1 H), 8.03 - 8.00 (m, 3H), 7.47 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 4H). HR-MS calcd for C19H13CIN2O5 [M+H]+: 369.06366, found 369.06264.

[0647] Methyl 4-(4-(4-fluorophenoxy)benzamido)picolinate (136a)

[0648] According to GP-P, T3P (2.09 mL, 7.11 mmol) was added to a solution of 4-(4- fluorophenoxy)benzoic acid 136b (150 mg, 0.65 mmol) and 132c (108.1 mg, 0.71 mmol) in EtOAc (3.6 mL) and pyridine (3.6 mL, 45.2 mmol) to afford after preparative HPLC 136a (140 mg, 59 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1 H), 8.60 (d, J = 5.5 Hz, 1 H), 8.52 (d, J = 2.1 Hz, 1 H), 8.06 - 8.01 (m, 3H), 7.31 (t, J = 8.7 Hz, 2H), 7.20 (dd, J = 9.0, 4.5 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.74, 165.35, 160.87, 158.92 (d, J = 240.4 Hz), 151.26 (d, J = 2.3 Hz), 150.64, 148.29, 147.17, 130.42, 128.21, 121.96 (d, J = 8.3 Hz), 117.00, 116.99 (d, J = 23.4 Hz), 116.67, 115.24, 52.51.19F NMR (470 MHz, DMSO-d6) δ -118.30. LC-MS calcd for C2OHI5FN204 [M+H]+: 367.11 , found 367.20.

[0649] 4-(4-(4-Fluorophenoxy)benzamido)picolinic acid (136)

[0650] According to GP-Q, to a suspension of 136a (50 mg, 0.14) in THF (0.5 mL), an aq. solution of LiOH (0.5 mL) was added to afford after preparative HPLC 136 (18 mg, 37%) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1 H), 8.58 (d, J = 5.6 Hz, 1 H), 8.49 (d, J = 2.2 Hz, 1 H), 8.04 (d, J = 8.3 Hz, 3H), 7.30 (t, J = 8.6 Hz, 2H), 7.19 (dd, J = 9.0, 4.5 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H).13C NMR (126 MHz, DMSO) δ 166.04, 165.85, 160.96, 159.98, 158.07, 151.41 (d, J = 2.3 Hz), 149.88, 147.63, 130.54, 128.41 , 122.07, 122.00, 117.18, 117.15, 116.99, 116.44, 115.07.19F NMR (470 MHz, DMSO-d6) δ -118.38. HR-MS calcd for C19H13FN2O4 [M+H]+: 353.09321 , found 353.09198.

[0651] Methyl 4-(4-(3-(trifluoromethy l)phenoxy)benzamido)picolinate (137a)

[0652] According to GP-P, T3P (1.72 mL, 5.85 mmol) was added to a solution of 4-(4- (trifluoromethyl)phenoxy)benzoic acid 137b (150 mg, 0.53 mmol) and 132c (89.0 mg, 0.58 mmol) in EtOAc (3 mL) and pyridine (3 mL, 37.2 mmol) to afford after preparative HPLC 137a (90 mg, 41 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1 H), 8.61 (d, J = 5.4 Hz, 1 H), 8.52 (s, 1 H), 8.09 (d, J = 8.7 Hz, 2H), 8.05 (dd, J = 3.6, 2.0 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 2H), 7.30 - 7.25 (m, 4H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) <5 165.64, 165.30, 159.17, 158.76, 150.60, 148.30, 147.07, 130.54, 129.65, 127.71 (q, J = 3.9 Hz), 124.34 (q, J = 32.1 Hz), 124.21 (q, J = 271.6 Hz), 119.18, 119.01 , 116.67, 115.23, 52.46.19F NMR (470 MHz, DMSO-d6) δ -60.29. LC-MS calcd for C21H15F3N2O4 [M+H]+: 417.11, found 417.10.

[0653] 4-(4-(4-(Trifluoromethyl)phenoxy)benzamido)picolinic acid (137)

[0654] According to GP-Q, to a suspension of 137a (50 mg, 0.12 mmol) in THF (0.4 mL), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 137 (13 mg, 27%) as an off-white powder.1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.60 (d, J = 5.5 Hz, 1 H), 8.50 (d, J = 1.8 Hz, 1 H), 8.11 (d, J = 8.7 Hz, 2H), 8.06 (dd, J = 5.3, 2.1 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.28 (dd, J = 8.8, 2.5 Hz, 4H).13C NMR (126 MHz, DMSO-d6) 5167.39, 165.51, 159.24, 158.61, 156.83, 148.59, 147.23, 130.55, 129.91, 127.71 (q, J = 3.9 Hz), 124.29 (q, J = 32.2 Hz), 124.22 (q, J = 271.2 Hz), 119.16, 118.98, 114.54, 114.03.19F NMR (470 MHz, DMSO-d6) δ -60.29. HR-MS calcd for C20H13F3N2O4 [M+H]+: 403.09002, found 403.08866.

[0655] Methyl 4-(4-(4-(trifluoromethoxy)phenoxy)benzamido)picolinate (138a)

[0656] According to GP-P, T3P (1.63 mL, 5.53 mmol) was added to a solution of 4-(4- (trifluoromethoxy)phenoxy)benzoicacid 138b (150 mg, 0.50 mmol) and 132c (84.2 mg, 0.55 mmol) in EtOAc (2.8 mL) and pyridine (2.8 mL, 35.20 mmol) to afford after preparative HPLC 138a (80.5 mg, 37 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.61 (d, J = 5.5 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.09 - 8.03 (m, 3H), 7.47 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO) 6 165.72, 165.35, 159.90, 154.45, 150.66, 148.30, 147.14, 130.51, 128.92, 123.30, 120.14 (q, J = 256.0 Hz) 117.99, 116.69, 115.25, 52.52.19F NMR (470 MHz, DMSO-d6) δ -57.10. LC-MS calcd for C21H15F3N2O5 [M+H]+: 433.10, found 433.20.

[0657] 4-(4-(4-(Triflucromethoxy)phenoxy)benzamido)picolinic acid (138)

[0658] According to GP-Q, to a suspension of 138a (50 mg, 0.12 mmol) in THF (0.4 ml_), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 138 (19 mg, 39%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1 H), 8.57 (d, J = 5.5 Hz, 1 H), 8.49 (s, 1 H), 8.06 (t, J = 6.8 Hz, 3H), 7.46 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 166.06, 165.76, 163.29, 159.91 , 154.47, 149.66, 147.57, 144.47 (q, J = 4.8 Hz), 130.58, 128.97, 123.32, 121.09, 120.17 (q, J = 256.0 Hz), 117.99, 116.24, 114.92.19F NMR (470 MHz, DMSO-cfe) 6 -57.12. HR-MS calcd for C20H13F3N2O5 [M+H]+: 419.08493, found 419.08347.

[0659] Methyl 4-(4-benzylbenzamido)picolinate (139a)

[0660] According to GP-P, T3P (2.3 mL, 7.77 mmol) was added to a solution of 4- benzylbenzoic acid 139b (150 mg, 0.70 mmol) and 132c (118.3 mg, 0.78 mmol) in EtOAc (4.0 mL) and pyridine (4.0 mL, 49.47 mmol) to afford after preparative HPLC 139a (125 mg, 51 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1 H), 8.60 (d, J = 5.4 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.03 (dd, J = 5.4, 2.1 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.34 - 7.25 (m, 4H), 7.20 (t, J = 7.2 Hz, 1 H), 4.04 (s, 2H), 3.88 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 166.92, 165.79, 151.07, 148.78, 147.58, 146.57, 141.14, 132.17, 129.35, 129.26, 129.04, 128.69, 126.68, 117.09, 115.67, 52.93, 41.39. LC-MS calcd for C21H18N2O3 [M+H]+: 347.14, found 347.11.

[0661] 4-(4-Benzylbenzamido)picolinic acid (139)

[0662] According to GP-Q, to a suspension of 139a (50 mg, 0.14 mmol) in THF (0.5 mL), an aq. solution of LiOH (0.5 mL) was added to afford after preparative HPLC 139 (21 mg, 43%) as a white solid.1H NMR (500 MHz, DMSO-ofe) 5 10.73 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 5.6, 2.2 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.32 - 7.24 (m, 4H), 7.22 - 7.17 (m, 1H), 4.04 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 166.45, 165.84, 149.74, 149.25, 147.46, 146.08, 140.65, 131.70, 128.86, 128.77, 128.55, 128.22, 126.19, 116.31, 114.91 , 40.90. HR- MS calcd for C20H16N2O3 [M+H]+: 333.12337, found 333.12242.

[0663] Methyl 4-(4-(benzyloxy)benzamido)picolinate (140a)

[0664] According to GP-P, T3P (2.1 mL, 7.23 mmol) was added to a solution of 4- (benzyloxy)benzoic acid 140b (150 mg, 0.66 mmol) and 132c (110 mg, 0.72 mmol) in EtOAc (3.7 mL) and pyridine (3.7 mL, 46.0 mmol) to afford after preparative HPLC 140a (142 mg, 60 %) as a beige solid.1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.62 (d, J = 15.4 Hz, 2H), 8.17 (dd, J = 5.8, 2.2 Hz, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 3.92 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.92, 164.42, 161.70, 149.37, 148.46, 146.82, 136.52, 130.12, 128.51, 128.03, 127.83, 125.79, 116.63, 115.30, 114.69, 69.50, 52.72. LC-MS calcd for C21H18N2O4 [M+H]+: 363.13, found 363.03.

[0665] 4-(4-(Benzyloxy)benzamido)picolinic acid (140)

[0666] According to GP-Q, to a suspension of 140a (50 mg, 0.14 mmol) in THF (0.5 ml_), an aq. solution of LiOH (0.5 ml_) was added to afford after preparative HPLC 140 (17 mg, 35%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.66 (br s, 1 H), 8.57 (d, J = 5.3 Hz, 1 H), 8.48 (br s, 1 H), 8.07 - 8.03 (m, 1 H), 8.00 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H) , 7.41 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 2H), 5.22 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 165.94, 165.83, 161.56, 149.53, 147.64, 147.61 , 136.56, 130.03, 128.51 , 128.02, 127.83, 126.06, 116.08, 114.80, 114.64, 69.49. HR-MS calcd for C20H16N2O4 [M+H]+: 349.1828, found 349.1170.1.

[0667] Methyl 4-(4-benzoylbenzamido)picolinate (141a)

[0668] According to GP-P, T3P (2.1 mL, 7.29 mmol) was added to a solution of 4- benzoylbenzoic acid 141b (150 mg, 0.66 mmol) and 132c (111.0 mg, 0.73 mmol) in EtOAc (3.7 mL) and pyridine (3.7 mL, 46.41 mmol) to afford after preparative HPLC 141a (105 mg, 44%) as a white powder.1H NMR (500 MHz, DMSO-c / e) 511.01 (s, 1 H), 8.64 (d, J = 5.4 Hz, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.16 (d, J = 8.2 Hz, 2H), 8.07 (dd, J = 5.5, 2.1 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2H), 7.79 (dd, J = 7.7, 1.4 Hz, 2H), 7.76 - 7.70 (m, 1 H), 7.61 (t, J = 7.7 Hz, 2H), 3.90 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 195.51 , 166.07, 165.42, 150.85, 148.53, 147.03, 140.27, 137.23, 136.68, 133.37, 129.95, 129.76, 128.92, 128.31 , 116.93, 115.46, 52.64. LC-MS calcd for C21H16N2O4 [M+H]+: 361.12, found 361.13.

[0669] 4-(4-Benzoylbenzamido)picolinic acid (141)

[0670] According to GP-Q, to a suspension of 141a (50 mg, 0.12 mmol) in THF (0.4 mL), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 141 (10 mg, 25%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 5 11.01 (s, 1H), 8.63 (d, J = 5.5 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.18 - 8.14 (m, J = 8.1 Hz, 2H), 8.08 (dd, J = 5.4, 1.9 Hz, 1H), 8.15 (d, J = 8.0 Hz, 2H), 8.07 (dd, J = 5.6, 2.2 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H).13C NMR (126 MHz, DMSO-cfe) 6 195.35, 165.91, 165.89, 150.00, 149.29, 147.12, 140.10, 137.10, 136.51, 133.20, 129.78, 129.59, 128.75, 128.16, 116.50, 115.04. HR-MS calcd for C20H14N2O4 [M+H]+: 347.10263, found 347.11708.

[0671] Methyl 4-(4-(phenylamino)benzamido)picolinate (142a)

[0672] According to GP-P, T3P (2.3 mL, 7.74 mmol) was added to a solution of 4- (phenylamino)benzoic acid 142b (150 mg, 0.70 mmol) and 132c (117.8 mg, 0.77 mmol) in EtOAc (4 mL) and pyridine (4 ml_, 49.24 mmol) to afford after preparative HPLC 142a (96 mg, 39%) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.77 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 5.5, 2.1 Hz, 1H), 7.94 - 7.90 (m, 2H), 7.36 - 7.31 (m, 2H), 7.23 - 7.17 (m, 2H), 7.15 - 7.09 (m, 2H), 6.99 (t, J = 7.3 Hz, 1H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.50, 165.06, 150.12, 147.87, 147.52, 147.14, 141.15, 129.51 , 129.03, 122.81, 121.38, 118.73, 116.14, 114.77, 113.74, 52.08. LC-MS calcd for C20H17N3O3 [M+H]+: 348.13, found 348.20.

[0673] 4-(4-(Phenyiamino)benzamido)picolinic acid (142)

[0674] According to GP-Q, to a suspension of 142a (50 mg, 0.14 mmol) in THF (0.5 mL), an aq. solution of LiOH (0.5 mL) was added to afford after preparative HPLC 142 (16 mg, 33%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.76 (s, 1H), 8.52 (d, J = 1.0 Hz, 1H), 8.45 (s, 1 H), 8.07 - 8.02 (m, 1 H), 7.92 (d, J = 1.0 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ 166.08, 165.80, 149.17, 147.84, 147.81, 141.51 , 129.85, 129.37, 123.22, 121.69, 119.04, 115.68, 114.57, 114.08. HR-MS calcd for C19H15N3O3 [M+H]+: 334,11862 found 334.11754.

[0675] Methyl 4-(2-phenoxybenzamido)picolinate (143a)

[0676] According to GP-P, T3P (2.27 mL, 7.70 mmol) was added to a solution of 2- phenoxybenzoic acid 143b (150 mg, 0.70 mmol) and 132c (117.2 mg, 0.77 mmol) in EtOAc (4 mL) and pyridine (4 mL, 49.0 mmol) to afford after preparative HPLC 143a (160 mg, 66 %) as a transparent oil.1H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1 H), 8.56 (d, J = 5.3 Hz, 1 H), 8.39 (s, 1 H), 7.84 (dd, J = 5.3, 1.7 Hz, 1 H), 7.68 (d, J = 6.7 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.4 Hz, 1 H), 7.04 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1 H), 3.87 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 166.21 , 165.66, 156.82, 154.16, 151.10, 148.87, 147.09, 132.84, 130.50, 130.09, 128.51, 124.28, 124.09, 119.42, 119.21, 116.68, 115.07, 52.90. LC-MS calcd for C20H16N2O4 [M+H]+: 349.12, found 349.10.

[0677] 4-(2-Phenoxybenzamido)picolinic acid (143)

[0678]

[0679] According to GP2, to a suspension of 143a (50 mg, 0.14 mmol) in THE (0.4 mL), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 143 (25 mg, 52%) as a beige solid.1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.68 (dd, J = 7.6, 1.7 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.3 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ 166.58, 165.66, 163.72, 156.34, 153.72, 149.27, 146.80, 132.28, 130.04, 129.65, 128.15, 123.84, 123.59, 118.86, 118.81, 114.97, 113.87.

[0680] Methyl 4-(3-phenoxybenzamido)picoiinate (144a)

[0681] According to GP-P, T3P (2.27 mL, 7.70 mmol) was added to a solution of 3- phenoxybenzoic acid 144b (150 mg, 0.70 mmol) and 132c (117.2 mg, 0.77 mmol) in EtOAc (4 mL) and pyridine (4 mL, 49.0 mmol) to afford after preparative HPLC 144a (152 mg, 62 %) as a yellowish oil.1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.61 (d, J = 5.5 Hz, 1H), 8.50 (s, 1H), 8.04 (dd, J = 5.6, 2.1 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.63 (s, 1H), 7.58 (t, J = 7.9 Hz, 1 H), 7.44 (t, J = 7.9 Hz, 2H), 7.27 (dd, J = 8.2, 2.5 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.9 Hz, 2H), 3.88 (s, 3H).13C NMR (126 MHz, DMSO-d6) 5 165.71 , 165.26, 156.88, 156.18, 150.62, 148.30, 146.91, 135.68, 130.41, 130.27, 124.00, 122.91 , 122.34, 119.33, 118.93, 116.75, 115.32, 52.46. LC-MS calcd for C20H16N2O4 [M+H]+: 349.12, found 349.10.

[0682] 4-(3-Phenoxybenzamido)picoiin!C acid (144)

[0683] According to GP2, to a suspension of 144a (50 mg, 0.12 mmol) in THF (0.4 mL), an aq. solution of LiOH (0.4 mL) was added to afford after preparative HPLC 144 (20 mg, 42%) as a brown solid.1H NMR (500 MHz, DMSO-d6) 5 10.83 (s, 1 H), 8.52 (s, 1H), 8.43 (s, 1 H), 8.02 (s, 1 H), 7.80 (d, J = 7.7 Hz, 1 H), 7.64 (s, 1H), 7.58 (t, J = 8.0 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 8.2 Hz, 1 H), 7.19 (t, J = 7.4 Hz, 1 H), 7.08 (d, J = 7.9 Hz, 2H).13C NMR (126 MHz, DMSO-d6) 5 166.58, 165.72, 156.90, 156.23, 152.02, 149.49, 147.17, 135.83, 130.45, 130.32, 124.04, 123.00, 122.34, 118.98, 117.83, 115.82, 114.78.

[0684] Methyl 4-(3-(4-phenoxyphenyl)ureido)picolinate (145a)

[0685] In a round bottom flask, to a solution of 132c (150 mg, 0.98 mmol) in DMF (2 mL) was added 1 -isocyanato-4-phenoxybenzene 145b (312.4 mg, 1.48 mmol). The mixture was left stirring at r.t. for 1 h to afford after preparative HPLC 145a (135 mg, 38 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1 H), 8.97 (s, 1 H), 8.47 (d, J = 5.5 Hz, 1 H), 8.24 (d, J = 2.2 Hz, 1 H), 7.58 (dd, J = 5.6, 2.2 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1 H), 6.99 (dd, J = 19.0, 8.4 Hz, 4H), 3.87 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 165.47, 157.51 , 152.16, 151.39, 150.35, 148.24, 147.79, 134.84, 130.04, 122.99, 120.69, 119.76, 117.83, 115.06, 113.43, 52.47. LC-MS calcd for C20H17N3O4 [M+H]+: 364.13, found 364.20.

[0686] 4-(3-(4-Phenoxyphenyl)ureido)picolinic acid (145) According to GP-Q, to a suspension of 145a (50 mg, 0.14 mmol) in THF (0.5 mL), an aq. solution of LiOH (0.5 mL) was added to afford after preparative HPLC 145 as (19 mg, 40 %) a white solid.1H NMR (500 MHz, DMSO-d6) δ8.45 (d, J = 6.0 Hz, 1H), 8.13 (s, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 6.99 (dd, J = 17.4, 8.4 Hz, 4H).13C NMR (126 MHz, DMSO-ofe) 5 165.81, 163.59, 157.56, 152.37, 151.23, 149.62, 146.19, 135.30, 129.96, 122.86, 120.73, 119.65, 117.72, 113.74, 112.82.

[0687] Methyl 4-((4-phenoxyphenyl)carbamoyl)picolinate (146a)

[0688] According to GP-P, T3P (2.7 mL, 9.11 mmol) was added to a solution of 2- (methoxycarbonyl)isonicotinic acid 146c (150 mg, 0.83 mmol) and 4-phenoxyaniline 146b (168.7 mg, 0.91 mmol) in EtOAc (4.7 mL) and pyridine (4.7 mL, 58.0 mmol) to afford after preparative HPLC 146a (160 mg, 57 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.17 (s, 1H), 8.80 (d, J = 15.3 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.15 - 7.10 (m, 4H), 3.91 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 165.64, 165.51, 160.61, 155.73, 145.74, 144.88, 136.39, 130.67, 130.50, 128.77, 127.47, 125.74, 124.88, 120.03, 117.79, 52.87. LC-MS calcd for C20H16N2O4 [M+H]+: 349.12, found 349.20.

[0689] 4-((4-Phenoxyphenyl)carbamoyl)picolinic acid (146)

[0690] According to GP-Q, to a suspension of 146a (50 mg, 0.14 mmol) in THF (0.5 mL), an aq. solution of LiOH (0.5 mL) was added to afford after preparative HPLC 146 (29 mg, 60%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.91 (d, J = 4.9 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1 H), 8.09 (dd, J = 5.0, 1.7 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.39 (t, J = 7.9 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1 H), 7.09 - 7.03 (m, 2H), 7.01 (d, J = 8.1 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 165.87, 162.99, 157.11, 152.74, 150.35, 149.27, 143.09, 134.24, 130.04, 124.80, 123.22, 122.34, 122.30, 119.23, 118.15. HR- MS calcd for C19H14N2O4 [M+H]+: 335.10263, found 335.10127.

[0691] 4-((4-Phenoxyphenyl)amino)picolinic acid (147)

[0692] A seal tube containing methyl 4-bromopicolinate 147c (200 mg, 0.93 mmol), 4- phenoxyaniline 146b (205.7 mg 1.11 mmol), Xantphos (53.6 mg, 0.09 mmol), palladium (II) acetate (41.6 mg, 0.18 mmol) and CS2CO3 (905 mg, 2.78 mmol) in 1- butanol (8 ml_) was degassed with N2 gas for 5 min. The tube was then sealed and placed on a heating block while stirring and heating at 95 °C for 16h. After completion, the mixture was passed through a bed of celite and purified using preparative HPLC to afford 147 (50 mg, 18 %) as a white powder.1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1 H), 8.05 (d, J = 6.7 Hz, 1 H), 7.45 - 7.39 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1 H), 7.09 (dd, J = 18.2, 8.2 Hz, 4H), 7.01 (dd, J = 6.8, 2.7 Hz, 1 H).13C NMR (126 MHz, DMSO-d6) δ 160.34, 156.74, 156.51 , 154.62, 148.81 , 140.72, 133.02, 130.23, 125.36, 123.80, 119.74, 118.87, 108.59, 107.33.

[0693] Methyl 4-azidopicolinate (148c)

[0694] To a solution of methyl 4-bromopicolinate (500 mg, 2.77 mmol, 1 equiv.) in DMF / H2O (20:1, 0.8 M) NaNa (215 mg, 3.30 mmol, 1.2 equiv.) was added portionwise and the reaction mixture was heated at 80°C overnight. Once the reaction was completed the mixture was diluted with EtOAc and washed with sat. aq. NaHCOs (x 3). The combined organic layers were dried over MgSO4 to obtain after evaporation methyl 148c (400 mg, 83%) as a yellow oil.1H NMR (500 MHz, DMSO-ds) 5 8.63 (d, J = 5.4 Hz, 1 H), 7.67 (d, J = 2.2 Hz, 1H), 7.41 (dd, J = 5.3, 2.3 Hz, 1 H), 3.89 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 164.69, 151.12, 149.62, 149.02, 117.54, 115.30, 52.63. LC-MS calcd for C7H6N4O2 [M+H]+: 179.06, found 179.1.

[0695] Methyl 4-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)picolinate (148a)

[0696] To a solution of 148c (200 mg, 1.12 mmol, 1.0 equiv.) and 1-ethynyl-4- phenoxybenzene 148b (218.05 mg, 1.12 mmol, 1.0 equiv.) in (THF / H2O, 2:1 , 0.4 M) sodium ascorbate (88.96 mg, 0.45 mmol, 0.4 equiv.) was added, followed by the addition of CUSO4 5H2O (56 mg, 0.22 mmol, 0.2 equiv.). The reaction mixture was vigorously stirred for 2 d at 65 °C. After completion of the reaction, THF was removed under vacuum, and the aqueous phase was extracted with EtOAc (3*). The combined organic layers were dried over MgSCU and concentrated in vacuo to afford after preparative HPLC 148a (250 mg, 60 %) as a white solid.1H NMR (500 MHz, ACETONITRILE-^) 58.87 (d, J = 5.3 Hz, 1 H), 8.80 (s, 1 H), 8.53 (d, J = 2.1 Hz, 1 H), 8.06 (dd, J = 5.3, 2.3 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1 H), 7.12 - 7.06 (m, 4H), 3.97 (s, 3H).13C NMR (ACETONITRILE-c / 3, 126 MHz) 5 165.9, 158.9, 157.8, 152.8, 151.3, 149.0, 145.2, 131.3, 131.1 , 128.4, 126.1 , 124.9, 120.2, 120.0, 119.5, 117.5, 115.8, 53.6. LC-MS calcd for C21H16N4O3 [M+H]+: 373.13, found 373.29.

[0697] 4-(4-(4-Phenoxyphenyl)-1H-1,2,3-triazol-1-yl)picolinic acid (148)

[0698] To a stirred suspension of 148a (160 mg, 0.43 mmol, 1 equiv.) in CH3OH (0.2 M), 10% aq. NaOH (43 μL, 2.15 mmol, 5 equiv.) was added and the solution was stirred at 65 °C. After completion of the reaction, CH3OH was removed under vacuum and the crude residue was dissolved in EtOAc. Aq. HCI (2 M) was added, and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were dried over MgSCM and concentrated in vacuo to afford after preparative HPLC 148 (90 mg, 58%) as a yellow solid.1H NMR (500 MHz DMSO-d6) δ 9.64 (s, 1H), 8.94 (d, 1H, J=5.3 Hz), 8.61 (d, 1 H, J=2.1 Hz), 8.26 (dd, 1H, J=2.2, 5.4 Hz), 7.99 (d, 2H, J=7.7 Hz), 7.44 (t, 2H, J=7.3 Hz), 7.1-7.2 (m, 3H), 7.10 (d, 2H, J=7.8 Hz).13C NMR (126 MHz, DMSO-d6) δ 165.46, 157.10, 156.24, 151.64, 150.67, 147.48, 143.66, 130.18, 127.26, 124.89, 123.85, 119.35, 119.01 , 118.98, 116.17, 114.12. HR-MS calcd for C20H14N4O3 [M-H]“: 357.09931 , found 357.09947.

[0699] 3. Biology

[0700] Two different and complementary assays were used to measure the inhibitory activity of compounds against the energy coupling factor (ECF) transporter: A whole-cellbased transport assay18using Lactobacillus casei and a transport activity assay21using Lactobacillus delbrueckii.

[0701] Whole-cell uptake assay: it is performed using L. casei cell that is a gram-positive, non- pathogenic strain with the ability to import several essential vitamins (e.g. folic acid, thiamine, biotin and riboflavin) from the environment. This assay is performed in 96- well format.

[0702] Radiolabelled folate transport assay: purified ECF-FolT2 is reconstituted into proteoliposomes. The transport assays is performed with radiolabeled folate in the presence of luminal MgATP as ECF-FolT mediates folate translocation only under ATP hydrolysing conditions.

[0703] Table 1: Activity on L. casei

[0704] Table 2: Activity on L. delbrueckii transport activity assay.

[0705] Antibacterial assay:

[0706] Al! microorganisms were obtained from the German Collection of Microorganisms and Cell Cultures (DSMZ) and were handled according to standard procedures. Bacteria were inoculated into tryptic soy broth (TSB) to obtain a final inoculum of 105 colonyforming units (CFU) / mL.

[0707] The tested compounds were prepared as DMSO stocks (20 mM). Serial dilutions of derivatives in the growth medium (0.06 to 128 pM) were prepared in sterile 96-well plates and the bacterial suspensions were added. Growth inhibition was assessed after static incubation at 37 °C for 24 h. S. pneumoniae was grown at 5% CO2. Minimum inhibitory concentrations (MIC) are defined as the lowest compound concentration where no visible growth is observed.

[0708] Cytotoxicity

[0709] Cytotoxicity assays is based on the human hepatocellular carcinoma (HepG2) cell.

[0710] The cells (2 * 105cells per well) were seeded in 24-well, flat-bottomed plates. Culturing of cells, incubations, and OD measurements were performed as described previously.22Twenty-four hours after seeding the cells, the incubation was started by the addition of test compound in a final DMSO concentration of 1%. The living cell mass was determined after 48 h. All samples were run in duplicate for each condition, and experiments were performed independently at least twice.

[0711] Table 3: MIC determination against a panel of Gram-positive bacteria and percentage of inhibition against HepG2 cell line.

[0712] [a]VRE: Vancomycin-resistant Enterococcus;1131PRSP: Penicillin resistant Streptococcus pneumonia; n.i. = no inhibition; tbd = to be done.

[0713] Kinetic Turbidimetric Solubility

[0714] The desired compounds were sequentially diluted in DMSO in a 96-well plate. 1.5 pL of each well were transferred into another 96-well plate and mixed with 148.5 pL of PBS. Plates were shaken for 5 min at 600 rpm at room temperature (r.t.), and the absorbance at 620 nm was measured. Absorbance values were normalized by blank subtraction and plotted using GraphPad Prism 8.4.2 (GraphPad Software, San Diego, CA, USA). Solubility (S) was determined based on the First X value of AUC function using a threshold of 0.005.

[0715] Metabolic Stability in Liver S9 Fractions

[0716] For the evaluation of combined phase I and phase II metabolic stability, the compound (1 pM) was incubated with 1 mg / mL pooled mouse liver S9 fraction (Xenotech, Kansas City, USA) or human liver S9 fraction (Corning, USA), 2 mM NADPH, 1 mM UDPGA, 10 mM MgCh, 5 mM GSH and 0.1 mM PAPS at 37 °C for 240 min. The metabolic stability of testosterone, verapamil and ketoconazole were determined in parallel to confirm the enzymatic activity of mouse S9 fractions, for human S9 testosterone, diclofenac and propranolol were used. The incubation was stopped after defined time points by precipitation of aliquots of S9 enzymes with 2 volumes of cold acetonitrile containing internal standard (150 nM diphenhydramine). Samples were stored on ice until the end of the incubation and precipitated protein was removed by centrifugation (15 min, 4 °C, 4,000 g). Concentration of the remaining test compound at the different time points was analyzed by HPLC-MS / MS (TSQ Quantum Access MAX, Thermo Fisher, Dreieich, Germany) and used to determine half-life (ti / 2).

[0717] Metabolic Stability in Liver Microsomes For the evaluation of phase I metabolic stability, the compound (1 pM) was incubated with 0.5 mg / mL pooled mouse liver microsomes (Xenotech, Kansas City, USA), 2 mM NADPH, 10 mM MgCh at 37 °C for 120 min on a microplate shaker (Eppendorf, Hamburg, Germany). The metabolic stability of testosterone, verapamil and ketoconazole were determined in parallel to confirm the enzymatic activity of mouse liver microsomes. The incubation was stopped after defined time points by precipitation of aliquots of S9 enzymes with 2 volumes of cold acetonitrile containing internal standard (150 nM diphenhydramine). Samples were stored on ice until the end of the incubation and precipitated protein was removed by centrifugation (15 min, 4 °C, and 4,000 g). Concentration of the remaining test compound at the different time points was analyzed by HPLC-MS / MS (TSQ Quantum Access MAX, Thermo Fisher, Dreieich, Germany) and used to determine half-life (t-1 / 2).

[0718] Stability in Mouse Plasma

[0719] To determine stability in mouse plasma, the compound (1 pM) was incubated with pooled CD-1 mouse plasma (Neo Biotech, Nanterre, France). Samples were taken at defined time points by mixing aliquots with 4 volumes of acetonitrile containing internal standard (125 nM diphenhydramine). Samples were stored on ice until the end of the incubation and precipitated protein was removed by centrifugation (15 min, 4 °C, 4,000 g, 2 centrifugation steps). Concentration of the remaining test compound at the different time points was analyzed by HPLC-MS / MS (TSQ Quantum Access MAX, Thermo Fisher, Dreieich, Germany). The plasma stability of procain, propantheline and diltiazem were determined in parallel to confirm the enzymatic activity.

[0720] Plasma Protein Binding

[0721] Plasma protein binding was determined using the Rapid Equilibrium Dialysis (RED) system (Thermo Fisher Scientific, Waltham MA, USA). Compounds were diluted in murine (CD-I) plasma (Neo Biotech, Nanterre, France) to 10 pM and added to the respective chamber according to the manufacturer’s protocol, followed by addition of PBS pH 7.4 to the opposite chamber. Samples were taken immediately after addition to the plate as well as after 2, 4 and 5 h by mixing 10 pL with 80 pL ice-cold acetonitrile containing 125 nM diphenhydramine as internal standard, followed by addition of 10 pL plasma to samples taken from PBS and vice versa. Samples were stored on ice until the end of the incubation and precipitated protein was removed by centrifugation (15 min, 4 °C, 4,000 g, 2 centrifugation steps). Concentration of the remaining test compound at the different time points was analyzed by HPLC-MS / MS (TSQ Quantum Access MAX, Thermo Fisher, Dreieich, Germany). The amount of compound bound to protein was calculated using the equation PPB [%] = 100 - 100 x (amount in buffer chamber / amount in plasma chamber).

[0722] LogD7.4 was analyzed using an HPLC-MS based method. The retention time of 12 compounds with known LogD7.4 was determined and plotted toward their LogD7.4. Linear regression was used to determine the LogD7.4 of unknown compounds. Analysis was performed using a Dionex Ultimate 3000 HPLC system coupled to a TSQ Quantum Access MAX (Thermo Fisher, Dreieich, Germany) with the following conditions: EC150 / 2 NUCLEODUR C18 Pyramid column, 5 pM (Macherey Nagel, Duren, Germany); eluent A: 50 mM NHAOAC pH 7.4, eluent B: acetonitrile, and flow: 0.6 mL / min. The gradient was set to 0-100% B from 0 to 2.5 min, 100% B from 2.5 to 3.0 min, 100-0% B from 3.0 to 3.2 min, and 0% B from 3.2-5.0.

[0723] Table 4: in vitro ADME-T profiling

[0724] Tbd = to be done

[0725] References

[0726] (1) Henderson, G. B.; Zevely, E. M. Binding and transport of thiamine by Lactobacillus casei. J Bacterial 1978, 733 (3), 1190-1196. DOI: 10.1128 / jb.133.3.1190-1196.1978. Henderson, G. B.; Zevely, E. M.; Huennekens, F. M. Coupling of energy to folate transport in Lactobacillus casei. J Bacterial 1979, 139 (2), 552-559. DOI: 10.1128 / jb.139.2.552-559.1979. Henderson, G. B.; Zevely, E. M.; Kadner, R. J.; Huennekens, F. M. The folate and thiamine transport proteins of Lactobacillus casei. J Supramol Struct 1977, 6 (2), 239-247. DOI: 10.1002 / iss.400060209.

[0727] (2) Slotboom, D. J. Structural and mechanistic insights into prokaryotic energycoupling factor transporters. Nat Rev Microbiol 2014, 72 (2), 79-87. DOI: 10.1038 / nrmicro3175 From NLM Medline.

[0728] (3) Eudes, A.; Erkens, G. B.; Slotboom, D. J.; Rodionov, D. A.; Naponeili, V.; Hanson, A. D. Identification of genes encoding the folate- and thiamine-binding membrane proteins in Firmicutes. J Bacteriol 2008, 790 (22), 7591-7594. DOI: 10.1128 / JB.01070- 08.

[0729] (4) Song, J.; Ji, C.; Zhang, J. Z. Unveiling the gating mechanism of ECF transporter RibU. Sci Rep 2013, 3, 3566. DOI: 10.1038 / srep03566.

[0730] (5) Santos, J. A.; Rempel, S.; Mous, S. T.; Pereira, C. T.; Ter Beek, J.; de Gier, J. W.; Guskov, A.; Slotboom, D. J. Functional and structural characterization of an ECF-type ABC transporter for vitamin B12. Elife 2018, 7. DOI: 10.7554 / eLife.35828.

[0731] (6) Finkenwirth, F.; Kirsch, F.; Eitinger, T. Solitary BioY proteins mediate biotin transport into recombinant Escherichia coli. J Bacteriol 2013, 795 (18), 4105-4111. DOI: 10.1128 / JB.00350-13.

[0732] (7) Majsnerowska, M.; Ter Beek, J.; Stanek, W. K.; Duurkens, R. H.; Slotboom, D. J. Competition between Different S-Components for the Shared Energy Coupling Factor Module in Energy Coupling Factor Transporters. Biochemistry 2015, 54 (31), 4763- 4766. DOI: 10.1021 / acs.biochem.5b00609.

[0733] (8) Erkens, G. B.; Berntsson, R. P.; Fulyani, F.; Majsnerowska, M.; Vujicic-Zagar, A.; Ter Beek, J.; Poolman, B.; Slotboom, D. J. The structural basis of modularity in ECF- type ABC transporters. Nat Struct Mol Biol 2011, 18 (7), 755-760. DOI: 10.1038 / nsmb.2073.

[0734] (9) Zhang, M.; Bao, Z.; Zhao, Q.; Guo, H.; Xu, K.; Wang, C.; Zhang, P. Structure of a pantothenate transporter and implications for ECF module sharing and energy coupling of group II ECF transporters. Proc Natl Acad Sci U SA 2014, 777 (52), 18560- 18565.

[0735] (10) Yu, Y.; Zhou, M.; Kirsch, F.; Xu, C.; Zhang, L; Wang, Y.; Jiang, Z.; Wang, N.; Li, J.; Eitinger, T.; et al. Planar substrate-binding site dictates the specificity of ECF-type nickel / cobalt transporters. Cell Res 2014, 24 (3), 267-277. DOI: 10.1038 / cr.2013.172. Bao, Z.; Qi, X.; Hong, S.; Xu, K.; He, F.; Zhang, M.; Chen, J.; Chao, D.; Zhao, W.; Li, D.; et al. Structure and mechanism of a group-l cobalt energy coupling factor transporter. Cell Res 2017, 27 (5), 675-687. DOI: 10.1038 / cr.2017.38.

[0736] (11) Bousis, S.; Setyawati, I.; Diamanti, E.; Slotboom, D. J.; Hirsch, A. K. H. Energy- Coupling Factor Transporters as Novel Antimicrobial Targets. Advanced Therapeutics 2019, 2 (2). (12) Davidson, A. L.; Dassa, E.; Orelle, C.; Chen, J. Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiol Mol Biol Rev 2008, 72 (2), 317- 364, table of contents. DOI: 10.1128 / MMBR.00031-07.

[0737] (13) Rodionov, D. A.; Hebbeln, P.; Eudes, A.; ter Beek, J.; Rodionova, I. A.; Erkens, G. B.; Slotboom, D. J.; Gelfand, M. S.; Osterman, A. L.; Hanson, A. D.; et al. A novel class of modular transporters for vitamins in prokaryotes. J Bacterial 2009, 191 (1), 42- 51.

[0738] (14) Berntsson, R. P.; Smits, S. H.; Schmitt, L.; Slotboom, D. J.; Poolman, B. A structural classification of substrate-binding proteins. FEBS Lett 2010, 584 (12), 2606- 2617. DOI: 10.1016 / j.febslet.2O10.04.043.

[0739] (15) ter Beek, J.; Duurkens, R. H.; Erkens, G. B.; Slotboom, D. J. Quaternary structure and functional unit of energy coupling factor (ECF)-type transporters. J Biol Chem 2011, 286 (7), 5471-5475. DOI: 10.1074 / jbc.M 110.199224.

[0740] (16) Swier, L. J.; Monjas, L; Guskov, A.; de Voogd, A. R.; Erkens, G. B.; Slotboom, D.

[0741] J.; Hirsch, A. K. Structure-based design of potent small-molecule binders to the S- component of the ECF transporter for thiamine. Chembiochem 2015, 16 (5), 819-826. DOI: 10.1002 / cbic.201402673. Monjas, L.; Swier, L. J. Y. M.; de Voogd, A. R.; Oudshoorn, R. C.; Hirsch, A. K. H.; Slotboom, D. J. Design and synthesis of thiamine analogues to study their binding to the ECF transporter for thiamine in bacteria. MedChemComm 2016, 7 (5), 966-971. DOI: 10.1039 / c6md00022c. Swier, L.; Monjas, L.; Reessing, F.; Oudshoorn, R. C.; Aisyah; Primke, T.; Bakker, M. M.; van Olst, E.; Ritschel, T.; Faustino, I.; et al. Insight into the complete substrate-binding pocket of ThiT by chemical and genetic mutations. Medchemcomm 2017, 8 (5), 1121-1130. DOI: 10.1039 / c7md00079k.

[0742] (17) Kiefer, A. F.; Bousis, S.; Hamed, M. M.; Diamanti, E.; Haupenthal, J.; Hirsch, A.

[0743] K. H. Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters. J Med Chem 2022, 65 (13), 8869- 8880. DOI: 10.1021 / acs.jmedchem.1c02114 From NLM Medline.

[0744] (18) Bousis, S.; Winkler, S.; Haupenthal, J.; Fulco, F.; Diamanti, E.; Hirsch, A. K. H. An Efficient Way to Screen Inhibitors of Energy-Coupling Factor (ECF) Transporters in a Bacterial Uptake Assay. I nt J Mol Sci 2022, 23 (5). DOI: 10.3390 / ijms23052637 From NLM Medline. (19) US 2017 / 0313700 A1.

[0745] (20) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. A mild and selective method for the hydrolysis of esters with trimethyltin hydroxide. Angew Chem Int Ed Engl 2005, 44 (9), 1378-1382. DOI: 10.1002 / anie.200462207 From NLM Medline.

[0746] (21) Swier, L. J.; Guskov, A.; Slotboom, D. J. Structural insight in the toppling mechanism of an energy-coupling factor transporter. Nat Commun 2016, 7, 11072. DOI: 10.1038 / ncommsl 1072 From NLM Medline.

[0747] (22) Haupenthal, J.; Baehr, C.; Zeuzem, S.; Piiper, A. RNAse A-like enzymes in serum inhibit the anti-neoplastic activity of siRNA targeting polo-like kinase 1 . Int J Cancer 2007, 121 (1), 206-210. DOI: 10.1002 / ijc.22665 From NLM Medline.

Claims

Claims1 . A compound of formula (I):whereinA is N or CR2;X is a group of formula -Ar1-Ar2-; a group of formula -Ar1a(-Ar2a)-Ar2-; a group of formula -Ar1a(-Ar2a)-; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;Ar1is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;Ar1ais a phenyl group;Ar2is an optionally substituted phenylene group; an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S; or an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O;Ar2ais an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S;L1is selected from the following groups: -O-; -NH-; -O-CH2-; -CO-NH-; -NH-CO- ; -SO2-NH-; -NH-CH2-; -NH-SO2-; -NH-CO-NH-; or a triazole group;L2is a bond or selected from the following groups: -O-; -NH-; -CH2-; -O-CH2-; -SO2-O-; -SO2-; -NH-SO2-; -SO2-NH-; -CO-; -CO-O-; -CO-NH-; -NH-CO-; -NH- SO2-(CH2)n, wherein n is 1 , 2, 3 or 4; -NH-C0-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO-(CH2)O-0-, wherein o is 1, 2, 3 or 4;R1is a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; or a group of formula -X1-Ar3;X1is a C1-10 alkylene group; a C1-10 heteroalkylene group; an optionally substituted C3-7 cycloalkylene group; an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;Ar3is an optionally substituted phenyl group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;R2is a hydroxy group; or a group of formula -NH-R3;R3is a group of formula -CO-O-R3a; -CO-NH-R3b; or -CO-R3c;R3ais an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted;R3bis an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted; andR3cis an alkyl; alkenyl; alkynyl; heteroalkyl; cycloalkyl; heterocycloalkyl; alkylcycloalkyl; heteroalkylcycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl group; all of which may optionally be substituted; or a salt thereof.

2. A compound according to claim 1 , wherein A is a group of formula C-OH.

3. A compound according to claim 1, wherein A is N.

4. A compound according to any one of the preceding claims, wherein L1is selected from the following groups: -NH-; -O-CH2-; -CO-NH-; -NH-CO-; -SO2- NH-; -NH-CH2-; -NH-SO2-; -NH-CO-NH-; or a triazole group.

5. A compound according to any one of the preceding claims 1 to 3, wherein L1is a group of formula -O-CH2-.

6. A compound according to claim 1 of formula (II):wherein X, L2and R1are as defined in claim 1 ; or a salt thereof.

7. A compound according to any one of the preceding claims, wherein X is a group of formula -Ar1-Ar2-.

8. A compound according to any one of the preceding claims, wherein X is a group of formula -Ar1-Ar2-; and L1is a group of formula -O-CH2-.

9. A compound according to any one of the preceding claims, wherein Ar1is an optionally substituted phenylene group; an optionally substituted pyridylene group; an optionally substituted pyrimidinylene group; or an optionally substituted thiazolylene group.

10. A compound according to any one of the preceding claims, wherein Ar1is selected from the following groups:

11. A compound according to any one of the preceding claims, wherein Ar2is an optionally substituted phenylene group; an optionally substituted pyridylene group; an optionally substituted piperazinylene group; or an optionally substituted indolylene group.

12. A compound according to any one of the preceding claims, wherein Ar2is selected from the following groups:wherein R5is halogen, a C1-4 alky group or a C1-4 heteroalkyl group; p is 1 or 2; R6is halogen, a Ci-4 alky group or a C1-4 heteroalkyl group; and q is 0, 1 or 2.

13. A compound according to any one of claims 1 to 6, wherein X is an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S.

14. A compound according to any one of claims 1 to 6, wherein X is selected from the following groups:

15. A compound according to any one of claims 1 to 6, wherein X is an optionally substituted phenylene group.

16. A compound according to any one of claims 1 to 6, wherein X is a group of formula -Ar1a(-Ar2a)-Ar2-; or a group of formula -Ar1a(-Ar2a)-.

17. A compound according to any one of claims 1 to 6 and 16, wherein Ar1ais a 1 ,3,5-phenyl group.

18. A compound according to any one of claims 1 to 6, 16 and 17, wherein Ar2ais an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S.

19. A compound according to any one of claims 1 to 6, 16 and 17, wherein Ar2ais an optionally substituted pyridyl group; or an optionally substituted thiophenyl group; or an optionally substituted triazole group.

20. A compound according to any one of the preceding claims 1 to 19, wherein L2is a bond or selected from the following groups: -O-; -CH2-; -O-CH2-; -SO2-; - SO2-NH-; -NH-SO2-; -SO2-O-: -CO-; -CO-O-; -NH-SO2-(CH2)n, wherein n is 1 , 2, 3 or 4; -NH-CO-; -NH-CO-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO- (CH2)O-0-, wherein o is 1 , 2, 3 or 4.21 . A compound according to any one of the preceding claims 1 to 19, wherein L2is a bond or selected from the following groups: -O-; -NH-; -CH2-; -O-CH2-; and -CO-.

22. A compound according to any one of the preceding claims, wherein L2is -O-; - CH2-; or -O-CH2-.

23. A compound according to any one of the preceding claims, wherein R1is a C1-10 alkyl group; an optionally substituted C3-7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S.

24. A compound according to any one of the preceding claims 1 to 22, wherein R1is an optionally substituted phenyl group.

25. A compound according to any one of the preceding claims, wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O-.

26. A compound of formula (II):whereinX is a group of formula -Ar1-Ar2-;Ar1is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;Ar2is an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;L2is a bond or selected from the following groups: -O-; -NH-; -CH2-; -O-CH2-;-SO2-O-: -SO2-: -NH-SO2-: -SO2-NH-; -CO-; -CO-O-; -CO-NH-; -NH-CO-; -NH- SO2-(CH2)n, wherein n is 1 , 2, 3 or 4; -NH-C0-(CH2)m, wherein m is 1 , 2, 3 or 4; or -NH-CO-(CH2)O-0-, wherein o is 1 , 2, 3 or 4;R1is a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloaikyl group; an optionallysubstituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; or a group of formula -X1-Ar3;X1is a C1-10 alkylene group; a C1-10 heteroalkylene group; an optionally substituted C3-7 cycloalkylene group; an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenylene group; or an optionally substituted heteroarylene group containing 5 to 10 ring atoms selected from C, N, O and S;Ar3is an optionally substituted phenyl group; or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S; and wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O-; or a salt thereof.

27. A compound according to claim 26, wherein Ar1is selected from the following groups:

28. A compound according to claim 26 or 27, wherein Ar2is selected from the following groups:

29. A compound according to claim 26, 27 or 28, wherein L2is selected from the following groups: -0-; -O-CH2-; -NH-SO2-; and -C0-0-.

30. A compound according to claim 26, 27, 28 or 29, wherein R1is a C1-6 alkyl group; or an optionally substituted phenyl group; wherein the optional substituents are preferably selected from F; Cl; -CH3; -O-CH3; -O-CF3; and -CF3.

31. A compound of formula (III):whereinX is a phenylene group (especially a 1 ,4 phenylene group; or a 1 ,3 phenylene group); andR1is an optionally substituted phenyl group; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O- (especially from F; Cl; -CH3; -O-CH3; -O-CFs; and -CF3); or a salt thereof.

32. A compound of formula (IV):whereinX is a phenylene group (especially a 1 ,4 phenylene group; or a 1 ,3 phenylene group); andR1is an optionally substituted phenyl group; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O- (especially from F; Cl; -CH3; -O-CH3; -O-CF3; and -CF3); or a salt thereof.

33. A compound of formula (V):whereinAr2ais an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; or a group of formula -Ar2-L2-R1;Ar2is an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S;L2is a bond or selected from the following groups: -O-; and -CH2-; andR1is a C1-10 alkyl group; a C1-10 heteroalkyl group; an optionally substituted C3- 7 cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; wherein the optional substituents are selected from halogen; -OH; -NH2; =0; CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O- (especially from F; Cl; -CH3; -CH2CH3; -CH(CH3)2; -O-CH3; -O-CF3; and -CF3); or a salt thereof.

34. A compound of formula (VI):whereinX is a group of formula -Ar1-Ar2-;Ar1is the following group:Ar2is selected from the following groups:L2is a group of formula -O-CH2-;R1is an optionally substituted phenyl group;R3is a group of formula -CO-O-R3a; -CO-NH-R3b; or -CO-R3c; andR3a;R3b; and R3care selected from a C1-10 alkyl group; a C2-10 alkenyl group; a C2-10 alkynyl group; a C1-10 heteroalkyl group; an optionally substituted C3-7 cycloaikyl group; an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms selected from C, N and O; an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; or a group of formula -CH2-cyclopropyl; wherein the optional substituents are selected from halogen; -OH; -NH2; =0;CN; C1-8 alkyl; C1-8 heteroalkyl; -O-CH2-CH2-; and -O-CH2-O-; or a salt thereof.

35. Pharmaceutical composition comprising a compound according to anyone of the preceding claims and optionally one or more carrier substances and / or one or more adjuvants.

36. Compound according to any one of claims 1 to 34 or pharmaceutical composition according to claim 35 for use in the treatment of a bacterial infection.

37. Compound according to any one of claims 1 to 34 or pharmaceutical composition according to claim 35 for use in the treatment of bacterial infections caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis.

38. Use of a compound according to any one of claims 1 to 34 or of a pharmaceutical composition according to claim 35 for the preparation of a medicament for the treatment of a bacterial infection.

39. Use of a compound according to any one of claims 1 to 34 or of a pharmaceutical composition according to claim 35 for the preparation of a medicament for the treatment of bacterial infections caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis.

40. A method for treating a bacterial infection, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 34 or of a pharmaceutical composition according to claim 35.

41. A method for treating a bacterial infection caused by Streptococcus pneumoniae, Enterococcus faecium, or Enterococcus faecalis, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 34 or of a pharmaceutical composition according to claim 35.

42. A method for treating a bacterial infection caused by Streptococcus pneumoniae, Enterococcus f aecium, or Enterococcus faecalis in a subject by inhibiting the Energy Coupling Factor (ECF) Transporters which comprises administering to the subject an effective amount of a compound according to any one of claims 1 to 34 or of a pharmaceutical composition according to claim 35.

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