Antibacterial biphenyl compounds and uses thereof

Abstract

Antibiotic resistance leads to deadly hospital-acquired infections globally. The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have identified priority bacteria, including Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and particularly those carbapenem- resistant strains, also found in Enterobacterales (CRE) such as Escherichia coli and Klebsiella, as requiring new antibiotics. The present disclosure provides a chemical class of drugs less susceptible to existing mechanisms of antibiotic resistance and targeting difficult-to-treat bacterial infections. It more particularly provides compounds of formula (I), and compositions and uses thereof.

Description

[0001] TITLE

[0002] ANTIBACTERIAL BIPHENYL COMPOUNDS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application is a PCT application Serial No PCT / CA2025 / * tiled on October 28, 2025 and published in English under PCT Article 21(2), which itself claims benefit of U S provisional application Serial No 63 / 713,183, tiled on October 29, 2024 All documents above are incorporated herein in their entirety by reference

[0004] FIELD OF THE DISCLOSURE

[0005] The present disclosure relates to antibacterial biphenyl compounds and to their uses More specifically, the present disclosure is concerned with biphenyl compounds for treating bacterial infections caused by e g, antibiotic resistant bacteria

[0006] BACKGROUND OF THE DISCLOSURE

[0007] Bacterial infections remain a major health threat Antibiotic resistance is a leading cause of deadly hospital-acquired infections worldwide The World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) published lists of priority bacteria forwhich new antibiotics are immediately needed Among them, Staphylococcus aureus (SA) and its antibiotic-resistant forms, Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and even more so, carbapenem-resistant Enterobacterales (CRE), including Escherichia coli and Klebsiella, and Acinetobacter baumannii (CRAB) The so-called Gram-negative bacteria (e g, E. coli, P aeruginosa, A baumannii) are notoriously more difficult to penetrate with antibiotics due to their additional membrane barrier Furthermore, honzontal spread of antibiotic resistance genes among bactena has considerably reduced the activity of all existing classes of antibiotics and newly derived antibiotics from these classes rapidly become obsolete because of these underlying resistance mechanisms New chemical classes of drugs not susceptible to existing mechanisms of resistance are thus urgently needed

[0008] There is a need for new antibiotics for difficult-to-treat infections caused by Gram-positive and Gram-negative pathogens. The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety

[0009] SUMMARY OF THE DISCLOSURE

[0010] The present disclosure provides antibiotic compounds against difficult-to-treat bacterial infections caused by Gram-positive and Gram-negative pathogens

[0011] More specifically, in accordance with the present disclosure, there are provided the following items:

[0012] Item l A compound of formula:

[0013]

[0014] wherein

[0015] i is 0 or 1, wherein when i is 1:

[0016]

[0017] is an aryl(C3-C6), heteroaryl(C3-C7), cycloalkyl(C3-C7), or heterocycloalkyl; or is an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalky l(C3-C 7); or an heterocydoalkyl fused with an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalkyl(C3-C7) or an heterocydoalkyl, and W is absent;

[0018] Z is absent or is

[0019]

[0020] wherein W is absent; or

[0021] W is ORB orN(

[0022]

[0023] Rg)(Rio) and is absent;

[0024] wherein Ra is H, or alkyl(C 1-C6); and

[0025] R9 and R10 are each independently H or alkyl(C1-C6);

[0026] j is 0 or 1; wherein when j is 1: a is 0, 1 or 2;

[0027] each of X and Y are independently N or CH;

[0028] R2 is H or N(R11)(R12) wherein R11 and R12 are each independently H or alkyl(C1-C4),

[0029] n is O or 1;

[0030] R3 is H, alkyl(C1-C6)-O-alkyl(C1-C6) or -alkyl(C1-C6)aryl(C5-C6); or R4 and R3 form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;

[0031] m is O, 1, 2 or 3;

[0032] p is 1 or 2;

[0033] R4is H, alkyl(C1-C6), -alkyl(C1-C4)aryl(C

[0034]

[0035] 3-C7), or, wherein R13 is alkyl(C1-C7) or aryl(C5-C6), provided that when R13 is alkyl(C1-C7), W is not OH; or R4 and R3 form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;

[0036]

[0037] is an aryl(C3-C6), an heteroaryl(C3-C7), cycloalkyl(C3-C7) orheterocycloalkyl(C3-C7) provided that when it is an heteroaryl(C6), j is 1; or is an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalkyl(C3-C7) or an heterocycloalkyl(C3- C7) fused with an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalkyl(C3-C7) or an heterocydoalkyl(C3-C7);

[0038] Rs is H or CH3,

[0039]

[0040] wherein Ri and Rii form

[0041]

[0042] which is an heterocycloalkyl(C3-C8) ring formed with the nitrogen ( “nitrogen- comprising heterocycloalkyl(C3-C8) ring”) or a spirocyde comprising the nitrogen -comprising heterocycloalkyl(C3-C8) ring and another heterocycloalkyl(C3-C8) orcycloalkyl(C3-C8); or

[0043] each of Ri and Rii are independently an alkyl(C1-C6),

[0044] wherein each heteroaryl and heterocydoalkyl contains from 1 to 4 heteroatoms independently selected from N, 0 and S, and

[0045] wherein each alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents that are each independently halogen, N, 0, S, alkyl(C1-C8), aryl(C3-C7), cycloalkyl(C3-C7), -sulfonyl-

[0046]

[0047] aryl(C3-C7), OH, or 0-alkyl(C1-C6), provided that when i is 0, ii is 1, and is a single ring, is substituted with at least one alkyl(C3-C7) or cydoalkyl(C3-C7),

[0048]

[0049] or a salt, solvate, ester or stereoisomer thereof

[0050] Item 2 The compound of item 1, wherein:

[0051]

[0052] is an aryl(C4 -C6), heteroaryl(C4-C6), or cycloalkyl(C4-C6); or is an aryl(C4-C6), an heteroaryl(C4- C6), or a cydoalkyl(C4-C6) fused with an aryl(C4-C6), an heteroaryl(C4-C6), or a cydoalkyl(C4-C6) and W is absent; or

[0053] W is ORB, or N(Rg)(Rio), wherein Rs is H, or alkyl(C1-C3); and Rg and R are each independently H or

[0054] a

[0055]

[0056] lkyl(C1-C3), and is absent;

[0057] (ii) R2 is H or N(R11)(R12) wherein R11 and R12 are each independently H or alkyl(C1-C2);

[0058] (iii) p is 1;

[0059] (iv) R3 is H, alkyl(C1-C3)-O-alkyl(C1-C3) or -alkyl(C1-C3)aryl(C5-C6); or R4 and R3 form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;

[0060] (v) R4 is H, alkyl(C1-C3), or -S(=O)2aryl(C3-C7); or R4 and R3 form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;

[0061]

[0062] (vi) is an aryl(C3-C6), or an heteroaryl(C3-C7); or is an aryl(C3-C7) or an heteroaryl(C3-C7), fused with an aryl(C3-C7), or an heteroaryl(C3-C7); (vii) Rs is H;

[0063] (viii) R and Rs form —cwhich is an heterocydoalkyl(C4-C7) ring formed with the nitrogen (“nitrogen¬ comprising heterocydoalkyl(C4-C7) ring”) or a spirocycle comprising the nitrogen-composing heterocydoalkyl(C4-C7) nng and another heterocydoalkyl(C4-C7): or each of R„ and Rii are independently an alkyl(C1-C5);

[0064] (ix) R13 is alkyl(C4-C5) or aryl(C6), or

[0065] (x) any combination of at least two of (i) to (ix),

[0066] wherein each alkyl, aryl, heteroaryl, cydoalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in item 1, and wherein each heteroaryl and heterocycloalkyl contains from 1 to 4 heteroatoms as defined in item 1,

[0067] or a salt, solvate, ester or stereoisomer thereof

[0068] Item 3 The compound of item 1 or 2, wherein:

[0069] (i) is an aryl(C5-C6), heteroaryl(C5-C6), or cycloalkyl(C5-C6); or is an aryl(C5-C6), an heteroaryl(C5-C6), or a cycloalkyl(C5-C6) fused with an aryl(C5-C6), an heteroaryl(C5-C6), or a cycloalkyl(C5-C6) and W is absent; or

[0070]

[0071] (ii) R2 is H or N(R11)(R12) wherein R11 and R12 are each independently H or alkyl(C1);

[0072]

[0073] (iii) is an aryl(C4-C6), or an heteroaryl(C4-C7); or is an aryl(C4-C7) or an heteroaryl(C4-C7), fused with an aryl(C4-C7), or an heteroaryl(C4-C7);

[0074] (iv) Ri and Rii form

[0075]

[0076] which is an heterocycloal kyl(C5-C 7) ring formed with the nitrogen (“nifrogen- comprising heterocydoalkyl(C5-C7) ring”) or a spirocycle comprising the nitrogen-comprising heterocycloalkyl(C5-C7) ring and another heterocycloalkyl(C5-C7); or each of Ri and Rii are independently an alkyl(C1-C4), or

[0077] (v) any combination of at least two of (i) to (iv),

[0078] wherein each alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in item 1, and wherein each heteroaryl and heterocycloalkyl contains from 1 to 3 heteroatoms as defined in item 1,

[0079] or a salt, solvate, ester or stereoisomer thereof Item 4 The compound of any one of items 1 to 3, wherein:

[0080]

[0081] -7'1is an aryl(C5-C6), orheteroaryl(C5-C6); oris an aryl(C5-C6), oran heteroaryl(C5-C6) fused with an aryl(C5-C6), or an heteroaryl(C5-C6) and W is absent; or

[0082]

[0083] W is OH, or NH? and is absent;

[0084] (i) R2is H or NH2;

[0085]

[0086] (ii) is an aryl(C5-C6), or an heteroaryl(C5-C7); or is an aryl(C5-C7) or an heteroaryl(C5-C7), fused with an aryl(C5-C7), or an heteroaryl(C5-C7);

[0087] (iii) Rj and Rs formcwhich is an heterocydoalkyl(C5-C7) ring formed with the nitrogen (“nitrogen¬ comprising heterocydoalkyl(C5-C7) ring”) or a spirocycle comprising the nitrogen-compnsing heterocydoalkyl(C5-C7) nng and another heterocydoalkyl(C5-C6); or each of R„ and Rii are independently an alkyl(C1-C3); or

[0088] (iv) any combination of at least two of (i) to (iii),

[0089] wherein each alkyl, aryl, heteroaryl, cydoalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in item 1, and wherein each heteroaryl and heterocycloalkyl contains from 1 to 3 heteroatoms as defined in item 1,

[0090] or a salt, solvate, ester or stereoisomer thereof

[0091] Item 5 The compound of any one of items 1 to 4, wherein:

[0092] (a1),

[0093]

[0094] wherein

[0095] in (a1) 0, 1 or 2 of Q1, Q2, and Q3 are each independently N, O or S and the remainder is CR14 in (a2) 0, 1 or 2 of Q1a, Q2a, and Q3a are each independently N, O or S and the remainder is CR14; in (a3) 1 or 2 of Q5, Q6, Q7, and Q8 are each independently NR15, O or S and the remainder is CR14; in (a4) 1 or 2 of Q5a, Q6a, Q7a, and Q8a are each independently NR15, O or S and the remainder is CR14; in (a5) 1, 2 or 3 of Q9, Q10, Q11, Q12, Q13, and Q14 are each independently NR15, O or S and the remainder is CR14;

[0096] in (a6) 1, 2 or 3 of Q10a, Q11a, Q12a, Q13a, Q14a, and Q15, are each independently NR15, O or S and the remainder is CR14;

[0097] in (a7) 1, 2 or 3 of Q16, Q17, Q18, Q19, Q20, and Q21, are each independently NR15, O or S and the remainder is CR14; and

[0098] in (a8) 1, 2 or 3 of Q17a, Q18a, Q19a, Q20a, Q21a and Q22, are each independently NR15, O or S and the remainder is CR14;

[0099] wherein each R14 is independently H or a substituent as defined in item 1, provided that in each of (a1) to (a8), at most 3 of the R14 are not H; and

[0100] wherein each R15 is independently absent, H or a substituent as defined in item 1, provided that in each of (a3) to (a8), at most 2 of the R15 are not H;

[0101] or

[0102] W is OH, or NH2 and is absent;

[0103]

[0104] in (b1) 0, 1 or 2 of U1, U2, U3, U4, and U5 are each independently N, 0 or S and the remainder is CRu; in (b2) 0, 1 or 2 of U1a, U2a, U3a, U4a, and U5a are each independently N, O or S and the remainder is CR16; in (b3) 1 or 2 of U5, U6, U7, and U8 are each independently NR17 or O and the remainder is CR16; in (b4) 1 or 2 of U5a, U6a, U7a, and U8a are each independently NR17 or O and the remainder is CR16; in (b5) 1, 2 or 3 of U9, U10, U11, U12, U13, and U14 are each independently NR17, O or S and the remainder is CR16;

[0105] wherein each R16 is independently H or a substituent as defined in item 1, provided that in each of (b1) to (b5), at most 4, preferably at most 3 of the R16 are not H; and

[0106] wherein each R17 is independently absent, H or a substituent as defined in item 1, provided that in each of (b3) to (b5), at most 2 of the R17 is not H;

[0107] 0 i / v~R,sI L _ X I

[0108]

[0109] is (c ) r V, _ V:

[0110] 1 o (c2), wherein each of q, q’ and q” is independently 1, 2 or 3; Vi is N, 0, S or C, each ofV2, Vg,and 4, is independently NR20, 0, S or C(R2i)R22, wherein each ofRjo, R21 and R22 is independently H or asubstituentas defined in item 1, and one of R1 s and R19 is asubstituentas defined in item 1 and the other is H;

[0111] (iv) a combination of at least two of (i) to (iii),

[0112] or a salt, solvate, ester or stereoisomer thereof

[0113] Item 6 The compound of item 5, wherein:

[0114] (i) in (a1) 0, 1 or 2 of Q1, Q2, and Q3 are each independently N and the remainder is CR14

[0115] in (a2) 0, 1 or 2 of Q1a, Q2a, and Q3a are each independently N and the remainder is CR14,

[0116] in (a3) Q5 is NR15 or CR14; Q6 is O or CR14; Q7 is O or CR14, and Q8 is NR15, S or CR14

[0117] in (a4) Q5a is NR15 or CR14, Q6a is O or CR14; Q7a is O or CR14, and Q8a is NR15, S or CR14;

[0118] in (a5) Q9, Q10, and Q14 are each CR14; and 1 or 2 of Q11, Q12, and Q13 is independently NR15, O or S and the remainder is CR14;

[0119] in (a6) Q10a, Q11a, and Q15, are each CR14; and 1 or 2 of Q12a, Q13a, and Q14a is independently NR15, O or S and the remainder is CR14;

[0120] in (a7) Q18, Q19, Q20, and Q21, are each CR14; and each of Q16, and Q17 is independently NR15, O, S or CR14; and

[0121] in (a8) Q18a, Q19a, Q20a and Q21a are each CR14; and each of Q17a, and Q22, is independently NR15, O, S or CR14;

[0122] wherein each R14 is independently H or a substituent as defined in item 1, preferably wherein each R14 is independently H, halogen (e.g., I, F), -NO2, -OH, -fluoroalkyl(C1-C3), or alkyl(C1-C6), provided that in each of (a1) to (a8), at most 3 of the R14 are not H; and

[0123] wherein each R15 is independently absent, H or a substituent as defined in item 1, preferably wherein each R15 is independently absent, H or -sulfonyl- aryl(C3-C7), provided that in each of (a3) to (a8), at most 2 of the R15 are not H, or W

[0124]

[0125] is OH, or NH2 andy-— -J' is absent;

[0126] (ii) in (b 1) 0, 1 or 2 of U1, U2, U3, U4, and U5 are each independently 0 or S and the remainder is CRu or U2 or U4 is N and the remainder is CRu, wherein the CR16 at position U3 is CF3;

[0127] in (b2) 0, 1 or 2 of U1a, U2a, U3a, U4a, and U5a are each independently O or S and the remainder is CR16; or U2a or U4a is N and the remainder is CR16, wherein the CR16 at position U3a is CF3;

[0128] in (b3) 1 or 2 of U5, U6, U7, and U8 are each independently NR17 or O and the remainder is CR16; in (b4) 1 or 2 of U5a, U6a, U7a, and U8a are each independently NR17 or O and the remainder is CR16; in (b5) U11, U12, U13, and U14 are each CR16; and U9 and U10 are each independently NR17, O or S and the remainder is CR16;

[0129] wherein each R is independently H or a substituent as defined in item 1, provided that in each of (b1) to (b5), at most 3 of the Ru are not H; and

[0130] wherein each R17 is independently absent, H or a substituent as defined in item 1, provided that in each of (b3) to (b5), at most 2 of the Ru are not H;

[0131] (iii) i

[0132]

[0133] n V__Veach of q, q’ and q” is independently 1, 2 or 3; Vi is N, 0, or C, each of V2, V3, and V4, is independently NR20, 0 or C(R2i R22, wherein each of R20, R21 and R22 is independently H or a substituent as defined in item 1, and one of R and Ru is a substituent as defined in item 1 and the other is H;(iv) a combination of at least two of (i) to (iii),

[0134] or a salt, solvate, ester or stereoisomer thereof

[0135] Item 7 The compound of item 5 or 6, wherein:

[0136] (i) in (a1) 0 or 1 of Q1, Q2, and Q3 is independently N and the remainder is CR14;

[0137] in (a2) 0 or 1 of Q1a, Q2a, and Q3a are each independently N and the remainder is CR14;

[0138] in (a3) Q5 is NR15 or CR14; Q6 is O or CR14; Q7 is O or CR14, and Q8 is NR15, S or CR14;

[0139] in (a4) Q5a is NR15 or CR14, Q6a is O or CR14; Q7a is O or CR14, and Q8a is NR15, S or CR14;

[0140] in (a5) Q9, Q10, and Q14 are each CR14; and 1 or 2 of Q11, Q12, and Q13 is independently NR15, and the remainder is CR14;

[0141] in (a6) Q10a, Q11a, and Q15, are each CR14; and 1 or 2 of Q12a, Q13a, and Q14a is independently NR15, and the remainder is CR14;

[0142] in (a7) Q18, Q19, Q20, and Q21, are each CR14; and each of Q16, and Q17 is independently NR15, O or CR14, preferably 1 or 2 of Q16, and Q17 is independently NR15 or O; and the remainder is CR14;

[0143] in (a8) Q18a, Q19a, Q20a and Q21a are each CR14, and each of Q17a, and Q22, is independently NR15, O or CR14, preferably 1 or 2 of Q17a, and Q22, is independently NR15 or O and the remainder is CR14;

[0144] wherein each R14 is independently H, halogen (e.g., I, F), -NO2, -OH, -fluoroalkyl(C1-C3), or alkyl(C1-C6), provided that in each of (a1) to (a8), at most 3 of the R14 are not H; and wherein each Ri 5 is independently absent, H or -sulfonyl- aryl(C3-C7), provided that in each of (a3) to (a8), at most 2 of the R15 are not H; or

[0145] W is OH, or NH2 and K — is absent;

[0146] (ii) in (b 1) 0, 1 or 2 of U1, U2, U3, U4, and U5 are each independently 0 or S and the remainder is CRie or U2 or U4 is N and the remainder is CR, wherein the CR16 at position U3 is CF3;

[0147] in (b2) 0, 1 or 2 of U1a, U2a, U3a, U4a, and U5a are each independently O or S and the remainder is CR16; or U2a or U4a is N and the remainder is CR16, wherein the CR16 at position U3a is CF3;

[0148] in (b3) U5 or U8 is O and the remainder is CR16;

[0149] in (b4) U5a or U8a is O and the remainder is CR16; or U6a is S and U8a is N and the remainder is CR16; or U7a is S and U5a is N and the remainder is CR16

[0150] in (b5) U11, U12, U13, and U14 are each CR16; one or both of, preferably one of U9 and U10, preferably U10 are(is) O and the other is CR16;

[0151] wherein each R is independently H or a substituent as defined in item 1, provided that in each of (b1) to (b5), at most 3 of the R are not H; and

[0152] wherein each R17 is independently absent, H or a substituent as defined in item 1, provided that in each of (b3) to (b5), at most 2 of the R are not H;

[0153] (iii) in (c1), q is 1, 2 or 3; Vi is N, O, or C and one of R1 sand R19 is H or an alkyl(C1 C6) and the other is H; and in (c2) each ofq’ and q” is independently 1 or 2; V2 is 0, V3 is CH2 or NH; an d'K is 0, orCTh; or (iv) a combination of at least two of (i) to (iii),

[0154] or a salt, solvate, ester or stereoisomer thereof

[0155] Item 8 The compound of any one of items 1 to 7, wherein:

[0156] A )

[0157] (i)

[0158]

[0159] — K is phenyl, pyridyl, indolyl, benzooxazyl, oxazolyl, pyrrolyl, or thiazolyl, which is unsubstituted or substituted with 1, 2 or 3 substituents as defined in item 1;

[0160] ( B

[0161] (ii)

[0162]

[0163] K > K is phenyl, triflu oromethyl-pyndy I, furyl, or benzofuryl, which is unsubstituted or substituted with 1, 2 or 3 substituents as defined in item 1;

[0164] A

[0165] (iii) is azepyl, dioxaazaspiro

[0045] decanyl (e g, 1,4-dioxa-8-azaspiro

[0045] decane), morpholinyl, diazinanyl, pyrrolidinyl or oxa diazaspiro

[0045] decane (e g, 9 oxa 1,6 diaza-spiro

[0045] decane), which is unsubstituted or substituted with 1, 2 or 3 substituents as defined in item 1; or

[0166] (iv) a combination of at least two of (i) to (iii),

[0167] or a salt, solvate, ester or stereoisomer thereof

[0168] Item 9 The compound of any one of items 1 to 8, wherein

[0169]

[0170] unsubstituted or substituted with 1, 2 or 3 substituents, the 1, 2 or 3 substituents being independently halogen e g, I, F), -NO₂, -OH, -fluoroalkyl(C1-C3), O-alkyl(C1-C6) or alkyl(C1-C6), preferably halogen (e g, I, F), -NO₂, -OH, -CF₃, or alkyl(C1-C3), most preferably halogen (e g, I, F), -NO₂, -OH, -CF₃, or CH₃;

[0171]

[0172] unsubstituted or substituted with 1, 2 or 3 substituents, the 1, 2 or 3 substituents being independently halogen (e g, Cl, F), -fluoroalkyl(C1-C3), alkyl(C1-C6), or cycloalkyl(C3-C7), preferably halogen (e g, Cl, F), - CF₃, alkyl(C1-C5), or cycloalkyl(C4-C6), more preferably halogen (e g, Cl, F), -CF₃, alkyl(C1-C5), or cycloalkyl(C5);

[0173] (iii) in

[0174]

[0175] unsubstituted or substituted with 1, 2 or 3 substituents, the 1, 2 or 3 substituents being independently alkyl(C1-C8), preferably alkyl(C1-C3), more preferably CH3; or

[0176] (iv) a combination of at least two of (i) to (iii),

[0177] or a salt, solvate, ester or stereoisomer thereof

[0178] Item 10 The compound, salt, solvate, ester or stereoisomer thereof of any one of items 1 to 9, wherein at least two of

[0179]

[0180] and are present, or wherein all three are present

[0181] Item 11 The compound of item 1, which is of formula (la), formula (lb), formula (Ic), formula (Id), formula (le), formula (If), formula (Ig) or formula (th):

[0182]

[0183] O rH 1 Rii

[0184] (la): (lb), preferably wherein at least one of i and ii is 1,

[0185] Rb

[0186]

[0187] (Id),

[0188]

[0189]

[0190] wherein one of Ra, Rb, and Rc, is, and the others are H;

[0191] (

[0192]

[0193] ' J (B}

[0194] each of is as defined in any one of items 1-9;

[0195] each of i, ii, R4, Rs, Ri, Rn, m, and p is as defined in any one of items 1 to 4;

[0196] each of j, X, Y, R2, R3, a, n, Z and Rs are as defined in item 1;

[0197] R₇ and R₈ form together an aryl(C3-C6), a cycloalkyl(C3-C8), an heteroaryl(C3-C6) or an heterocycloalkyl(C3-C6), or each of R₇ and R₈ is independently H or an alkyl(C1-C6);

[0198] r is any integer between 1 and 6, preferably between 2 and 6, or 3 and 5;

[0199] r' is 0 or 1, preferably 1;

[0200] cycle B’ is attached to carbon at position b or c, preferably b;

[0201] at least one of R₂₃, R₂₄ and R₂₅ is an alkyl(C1-C6), a cycloalkyl(C3-C6), a fluoroakyl(C1-C3) or an halogen, preferably an alkyl(C3-C5), a cycloalkyl(C4-C5), a CF₃ or an halogen; and the remainders are each independently H or an alkyl(C1-C6); and

[0202] R₂₆ and R₂₇ form together an heterocycloalkyl(C4-C6), preferably an heterocyclopentyl, preferably a dioxalane; wherein each aryl, cydoalkyl, heteroaryl and heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in item 1 or 9, and wherein each heteroaryl and heterocycloalkyl contains from 1 to 3 heteroatoms as defined in item 1,

[0203] or a salt, solvate, ester or stereoisomer thereof

[0204] (

[0205]

[0206] Item 12 The compound, salt, solvate, ester or stereoisomer thereof of item 11, wherein Raor Rc, is, and f

[0207] preferably Rb is

[0208] Item 13 The compound, salt, solvate, ester or stereoisomer thereof of any one ofitems 1 to 12, wherein j is 1

[0209] Item 14 The compound of item 1, which is:

[0210] Compound Structure

[0211]

[0212] 0

[0213] TM-462

[0214] / \ ZX

[0215] OH / 1 1 J TM 462

[0216] zr 0

[0217] TM-456

[0218] H z— fl1]

[0219] "-"yvNvAA)^

[0220] V s

[0221] h[fY TM-456 Y7

[0222] 0

[0223] 0 o TM-396 HjN H [|

[0224] Y ’SzHN \Z JL -X JJL >;< XZ VN’V.x'X -Z OH I ) TM396

[0225] TM-336

[0226] F3C\ / X

[0227] XX Q TM-377 1 H I

[0228] N JL

[0229] H?V JOL

[0230] TM-377

[0231] Xji V

[0232] 1 H T

[0233] TM-378 -A. N

[0234] H'Nk 1 M - - - M-3 8 AH I ) T 7

[0235]

[0236]

[0237] TM-380

[0238] Q TM-387 M [f j

[0239] HphL -N. JL

[0240] 0

[0241] )HkV TM-387

[0242] o

[0243] 1 /

[0244] / \ / \ / \ 2——

[0245] z — 0

[0246] TM-397

[0247] z

[0248] 0

[0249] TM-398

[0250] 0

[0251] TM-418 o< X

[0252] 1 A

[0253] l l ) TM 4180,1

[0254] HTM-407H)N._,fl 1 A _ _.

[0255] '•y^\'' '%X'sX''o'^ N X X^tr^t, Hk- /

[0256] [1 T TM-407

[0257]

[0258] TM-373

[0259] H2N JL

[0260] OH TM-373

[0261] 0

[0262] TM-413

[0263] <!> H

[0264] TM-413

[0265] TM-372F]C'v<^1

[0266] XX, X

[0267] ^ZA1,hN J lIi xjiJL

[0268] OH TM-372

[0269] XX XX TH1

[0270] TM-376

[0271] TM-376

[0272] TM-411

[0273] OXUX-y^N'^XOHI J TM-411

[0274]

[0275] TM-414 H 01

[0276] JCL _ _

[0277] r^\ OH I_

[0278] ) TM-414

[0279] 0

[0280] TM-457

[0281] I^Y^“JSXY'N^°A

[0282] vH L-JX-NH

[0283] , TM-457

[0284] TM-381 I H T

[0285] JU JL

[0286] — — ^crnY OH I ) TM-381X

[0287] TM-382 H2N J-S.

[0288] VX-CL ^. O^ Y^N- TXL

[0289] OH I /

[0290] TM-382

[0291] F C\XX XX

[0292] TM-389 1 H 1

[0293] -X A

[0294] H3V JUl

[0295] OHI ) TM-389

[0296]

[0297] TM-361

[0298]

[0299] o

[0300] TM-392 S f

[0301] X1 X

[0302] H

[0303] J z - TM-392

[0304] o <H

[0305] C 1Hu

[0306] TM-424

[0307] XX [ 1 f j

[0308] L /

[0309] OHO'v^XS'sr

[0310] TM-427 XI A

[0311] JUSJJL

[0312] °HI )

[0313] TM-427

[0314] XX JQk

[0315] TM-434 f

[0316] TM-443

[0317]

[0318]

[0319]

[0320] uk Q

[0321] T H TM-421 T

[0322] JI JL

[0323] > | rj^|

[0324] I, N

[0325] '^ >RL ^OH

[0326] TM-421

[0327] TM-463

[0328] OH T^O

[0329] Q J TM 463

[0330] Q TM-464

[0331] H; NH HH I -'" S| [T^]^ 1 M 464

[0332] TM-365

[0333] HCL X<>. V Jd -xx- ^

[0334] OH I ) TM-339 / TM-365

[0335] TM-425 Av^HN AAJH O TM-425

[0336]

[0337] TM-337

[0338] H2N

[0339] JLxsL

[0340] OH I )

[0341] TM-337

[0342] CFj

[0343] FjC X- XX Q TM-445 J 1 H

[0344] L T JL

[0345] > S 1 rj^S

[0346] - TM-445

[0347] F3Cxvi^X, _ /

[0348] XX Q

[0349] 1 H N. J T- TM-452

[0350] H'N1 fl 4

[0351] '-SX- ^C> Y^ N A □H( ) TM-452

[0352] F1Cy^ X

[0353] TM-402 XUk X

[0354] NN^-x.

[0355] OH X / TM-402

[0356] TM-364

[0357] H° > L

[0358] OH I )

[0359] TM-342 / TM-364

[0360]

[0361] TM-386

[0362]

[0363] TM-406

[0364]

[0365]

[0366] TM-340

[0367] TM-450

[0368] ho ft i

[0369] f| \ZXZ\)H HCT ''^ / _ \ / \ / s——

[0370] TM-450

[0371] 2 -

[0372] i o

[0373] TM-408 H ft j

[0374] H, N x^ N x^ -Z^ x^

[0375] O N^^- x<^Y / 01 1

[0376] ft T TM-408

[0377] V

[0378] TM-231

[0379] o=s=o

[0380] 1

[0381] OH / TM-231

[0382] TM-393

[0383] H2N ^X'N

[0384] TM-393

[0385]

[0386] TM-339

[0387] H XO o X-frs

[0388] — V y _ N \.

[0389] Z - V > OH I J TM-339 / TM-365

[0390] / =\ / ^X 2

[0391] ) & —\ / \ / \ \ / y v y y cn _ _

[0392] z\ o —

[0393] TM-351

[0394] o

[0395] Cl

[0396] TM-438

[0397] H fi i

[0398] VI AH L? TM-438

[0399] F

[0400] 0

[0401] TM-429

[0402] / V H A

[0403] "< / / N^\ HN-JjlX OH L__ /

[0404] OH

[0405]

[0406]

[0407] TM-267

[0408] OH I ) TM-267

[0409] TM-311

[0410] □

[0411] g / \= / \= /

[0412] z —

[0413] o

[0414] TM-348 z HO xY,

[0415] XJJCXX^

[0416] OH I ) TM-348

[0417] TM-400 H ff j

[0418] H2N. 's / Jt v Y — ^fl A - OH

[0419] 0 J TM-400

[0420] TM-435 zXHf l

[0421] O N^\ IY>1 OH 1 - / 1 TM-435

[0422] OH

[0423]

[0424] CH

[0425] TM-446

[0426] CH H [fS

[0427] OH k^y

[0428] TM-446

[0429] o

[0430] TM-360 HO. \z x / ^lL Jl o y^ N \

[0431] q j OH I )

[0432] T z —M-359

[0433] 0 IZ

[0434] TM-214 0

[0435] O=S=0

[0436] HO.1

[0437] 0HX y

[0438] TM-214

[0439] TM-215

[0440] CF3

[0441] 0

[0442] TM-343 HO

[0443] OH I )

[0444] TM-343.or

[0445] " iQ

[0446] no JL

[0447] TM-346

[0448] OH I J

[0449]

[0450] TM 346

[0451]

[0452] or a salt, solvate, ester or stereoisomer thereof

[0453] Item 15 The compound of item 14, which is TM-292, TM-336, TM-337, TM-338, TM-340, TM-342, TM-350, TM-355, TM-364, TM-365, TM-372, TM-373, TM-375, TM-376, TM-377, TM-378, TM-379, TIM-463, TM-464, TM-380, TM-381, TM-382, TM-386, TIM-387, TM-389, TM-392, TM-394, TM-395, TM-396, TIM-397, TM-398, TM-399, TM-401, TM-402, TM-406, TM-407, TM-408, TM-410, TM-411, TM-412, TIM-413, TM-414, TM-416, TM-418, TM-420, TIM-421, TM-423, TM-424, TM-425, TM-426, TIM-427, TIM-431, TIM-432, TIM-433, TIM-434, TIM-439, TIM-440, TIM-441, TIM-442, TIM-443, TIM-445, TIM-450, TIM-452, TM-456, TM-457, TIM-462, TM-463, TM-464, or a salt, solvate, ester or stereoisomer thereof, as defined in item 14, preferably TIM-336, TM-355, TIM-372, TIM-373, TM-375, TIM-376, TIM-377, TM-378, TIM-379, TIM-463, TM-464, TIM-380, TM-381, TIM-382, TIM-387, TM-389, TIM-392, TM-394, TM-395, TIM-396, TM-397, TIM-398, TIM-401, TM-407, TIM-410, TM-411, TM-413, TM-414, TIM-416, TM-418, TIM-421, TM-423, TIM-424, TM-426, TIM-427, TIM-431, TM-434, TIM-442, TM-443, TM-456, TM-457, TM-462, TM-463, TM-464, or a salt, solvate, ester or stereoisomer thereof, and more preferably TM-462, TM-456, TM-457, TIM -336, TM-372, TIM-373, TM-376, TIM-377, TM-378, TIM-380, TIM-387, TM-396, TIM -397, TM-398, TM-407, TM-411, TM-413, TIM-414, TIM-418, TIM-456, TIM-457, TIM-462, TIM-463, TIM-464, or a salt, solvate, ester or stereoisomer thereof

[0454] Item 16 A pharmaceutical composition comprising (a) the compound, salt, solvate, ester or stereoisomer thereof defined in any one of items 1 to 15, and (b) (i) an antibiotic; (ii) an antiseptic;(iii) a disinfectant; (iv) a pharmaceutically acceptable carrier; or (v) any combination of (i)-(iv)

[0455] Item 17 The compound, salt, solvate, ester or stereoisomer thereof of any one of items 1 to 15 or the composition ofitem 16, for use in the treatment of a bacterial infection in a subject in need thereof

[0456] Item 18 The compound, salt, solvate, ester or stereoisomer thereof for use of item 17, wherein the bacterial infection is caused by an Enterobacterales (e g, Escherichia, Klebsiella), Bacilotta (e g, Staphylococcus Enterococcus, Streptococcus, Bacillus, Listeria), Pseudomonas, or Actinobacter, preferably Escherichia, Klebsiella, Pseudomonas, Acinetobacter or Staphylococcus, or preferably by an Escherichia coll, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus haemolyticus, Staphylococcus hominis, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus agalactiae, Bacillus cereus, Bacillus subtilis, or Listeria monocytogenes

[0457] Item 19 The compound, salt, solvate, ester or stereoisomer thereof for use of any one of items 17 to 19, wherein the bacterial infection is caused by an antibiotic-resistant (e.g., multi-resistant) bacterium

[0458] Item 20 The compound, salt, solvate, ester or stereoisomer thereof for use of any one of items 17 to 19, wherein the subject is a mammal, preferably a human

[0459] Other objects, advantages and features of the present disclosure will become more apparent upon reading of the following non -restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings BRIEF DESCRIPTION OF THE DRAWINGS

[0460] In the appended drawings:

[0461] FIGs 1A-C Synthesis of reference compound TM-01 (FIG 1A), reference compound TM-01 (FIG 1B), and reference compound TM-292 (FIG 1C)

[0462] FIG 2 Correlation between the inhibition of E colt ATP synthase activity (IC50) and potency (MIC) against the hyperpermeable £ coli strain imp4213 IptD for 74 compounds of the disclosure. MIC and IC50 data are from Table I but are expressed here in μM Table I also shows MIC against the parental strain MC4100 and strain AcrAB (pump deficient) and certain compounds exhibit reduced activity against those strains Hence, solid symbols represent compounds that were not influenced by efflux or a permeability barrier in E coli whereas, open triangles correspond to those influenced by efflux, and the X symbols represent those influenced by both efflux and permeability For the purpose of this graph, MIC >128 μg / ml were considered as 256 μg / ml

[0463] FIGs 3A-C Bactericidal activity of compounds TM-292 (FIG 3A), and TM-336 (FIG 3B) against Escherichia coli ATCC 25922, and of and TM-387 (FIG 3C) against the MDR E coli strain BAA-2471 Each log CFU / ml value represents the mean of three independent experiments and 100 CFU / ml was the detection limit

[0464] FIGs 4A-B Relative inhibition (IC50) of bacterial ATP synthases by compounds TM-387 (FIG 4A) and TM-397 (FIG 4B) Membrane vesicles from S aureus ATCC 29213 (triangles) or E coli ATCC 25922 (circles) were used as the source of bacterial ATP synthases A luciferin / luciferase assay system was used to generate the luminescent signal proportional to the ATP produced by the membrane vesicles in absence or presence of inhibitors at the indicated concentrations The I C50 expressed in piM was determined using the GraphPrism™ software

[0465] FIG 5 Enzyme kinetics and constants of inhibition ofE coli ATP synthase for compounds of the disclosure TM-381, TM-389, TM-415 and TM-425 and 4-Chloro-7-nitrobenzofrirazan (NBD-CI)

[0466] FIG 6 Relative inhibition (IC50) of mitochondrial ATP synthases by compounds TM-292, TM-387 and TM-397 compared to that of oligomycin Mitochondria isolated from Hep2 cells were used as the source of ATP synthase A luciferin / luciferase assay system was used to generate the luminescent signal proportional to the ATP produced by the membrane vesicles in absence or presence of inhibitors at the indicated concentrations The IC50 expressed in μM was determined using the GraphPrism™ software. The calculated IC50 values are reported in Table IX

[0467] FIGs 7A-B In vivo efficacy of TM-397 and TM-416 in the neutropenic mouse thigh infection model In FIGs 7A and 7B, mice were infected by E coli ATCC 25922 and compounds of the present disclosure (TM-397 and TM-416) were administered IV at the indicated dose (mg / kg of body weight) at 2h after infection Cefotaxime (CTX) was used as a comparator antibiotic and a dose response for that drug is shown in FIG 7B Bacterial loads in the thigh muscles were evaluated at 2h (2h growth control [CTRL]) and at 8h (end point) All compounds showed in vivo efficacy, causing a statistically significant reduction of the bacterial loads in the thigh muscles compared to the non-treated CTRL ANOVA and Kruskal-Wallis’ post-test (ns, not statistically significant; *, p <005; **, p <001; p <0001; ****, p <00001) FIG 8 In vivo efficacy of TM-381 (compared to cefotaxime, CTX) in the munne thigh infection model, administered intraperitoneally with two doses of 15 mg / kg (at 2h and 6h, respectively) ANOVA and Kruskal-Wallis’ post-test (ns, not statistically significant; **, p <001)

[0468] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0469] Definitions

[0470] Compounds of the present disclosure

[0471] Compounds of the present disclosure are antibiotic compounds as described herein including compounds of formulas (I), (II), (la), (lb), (Ic), (Id), (le), (If), (Ig) and (Ih), specific embodiments thereof identified in Table I and examples herein In formulas of the present disclosure and in specifically disclosed compounds, certain hydrogens are not explicitly shown for simplicity and clarity’s sake Compounds of the disclosure include diastereomer mixtures and diastereomers Without being so limited, illustrative compounds of the present disclosure are shown in e g Examples 2 to 148 Compounds of the present disclosure have antibacterial activities as shown in e g, any one of Table I to IX and FIGs 2, 3A-C, 7A-7B, and 8 In specific embodiments, compounds of formulas (I), (II), (la), (lb), (Ic), (Id), (le), (If), (Ig) and (Ih) do not include compounds 167, 168, 199, 200, 203, 204, 205, 206, 225, 225, 227, 228, 229, 254, 265, 266, 279, 280, 281, 298, 312, 313, 314, 316, 317, 318, 319, 324, 328, 341, 344, 345, 347, 349, 359 / 360, 437, and 447 In the event of any discrepancies between the compound names and the structures presented herein, the structures shall take precedence In compounds of formulas (I), (II), (la), (lb) and (le), the position of cycle B may be in position Ra, Rb and Rcas defined in formulas (Ic), (Id), (If) or (1g), and preferably in position Rb or Rcand more preferably in position Rb in specific embodiments, provisos of formula (I) apply to formula (la), (lb), (Ic), (Id), (le), (If), (Ig) and / or (Ih)

[0472] Chemical groups

[0473] As used herein, the term “alkyl" refers to a monovalent straight or branched chain, aliphatic hydrocarbon radical having a number of carbon atoms in the specified range Thus, for example, “C1-C8 alkyl” refers to any alkyl of up to 8 carbon atoms, including pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl, and methyl As another example, “alkyl(C1-C4)” refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl, and methyl As another example, “alkyl(C 1 -C3) ” refers to n -propyl, isopropyl, ethyl, and methyl

[0474] The term "halogen" (or “halo”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo, or F, Cl, Br and I, respectively) The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atomshave been replaced with a halogen (i e, F, Cl, Br and / or I) Thus, for example, “haloalkyl (C1-C6)” refers to a C1 to C10 linear or branched alkyl group as defined above with one or more halogen substituents The term “fluoroalkyl” has an analogous meaning except that the halogen substituents are restricted to fluoro Suitable fluoroalkyls include the series (CH2)0-4CF3 (i e, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc) The term "heteroalkyl" is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms is replaced with a heteroatom (e g, oxygen, nitrogen, sulfur, or derivatives thereof, and the tike) Examples of heteroalkyl groups include, but are not limited to, alkoxy, alkyl-substituted ammo, thiol such as methionine side group Up to two heteroatoms may be consecutive When a suffix such as C2-C6 is used to refer to a heteroalkyl group, the number of carbons (2-6, in this example) is meant to include the heteroatoms as well The term "aminoalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen or carbon atoms has been replaced with a nitrogen or an amino derivative such as but not limited to guanidine Thus, for example, “C1-C6 aminoalkyl” (or “aminoalkyl(C1-C6)’) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more amino derivatives (e g, NH, amide, diazirine, azide, etc )

[0475] The term "thioalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen or carbon atoms has been replaced with a sulfur atom or thiol derivative Thus, for example, “C1-C6 thioalkyl” (or“thioalkyl(C1-C6)’) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more sulfur atoms or thiol derivatives (e g, S, SH, etc)

[0476] Aminoalkyl and thioalkyls are specific embodiments of and encompassed by the term “heteroalkyl” or substituted alkyl depending on the heteroatom replaces a carbon atom or an hydrogen atom

[0477] The term "cycloalkyl (C3-C8)" refers to saturated alicyclic hydrocarbon consisting of saturated 3-8 membered rings optionally fused with additional (1-3) aliphatic (cycloalkyl) or aromatic ring systems, each additional ring consisting of a 3-8 membered or 3-7 membered ring It includes without being so limited cyclopropyl, cyclobutyl, cyclopentyl (cyp), cyclohexyl, cycloheptane, and cyclooctyl

[0478] The term "heterocycloalkyl(C3-C8)" refers to (i) a 3- to 8-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S, or(ii) is a heterobicyclic ring (e g, dioxa-azaspiro

[0045] decane (such as in TM-416 or TM-456 1,4-dioxa-8-azaspiro

[0045] decane), oxa diaza-spiro

[0045] decane (such as in TM-457, 9 oxa 1,6 diaza-spiro

[0045] decane, benzocyclopentyl, octahydromdol) Examples of 3- to 8-membered, saturated heterocyclic rings within the scope of this disclosure include, for example, azepanyl (such as in TM-336, etc ), oxane, azetidinyl, piperidinyl, morpholinyl (such as in TM-463), diazinanyl (such as in TM-464, a piperazine), thiomorpholinyl, thiazolidinyl, isothiazolidmyl, oxazolidmyl, isoxazolidmyl, pyrrolidmyl (such as in TM-422, TM-423, TM-434, TM-404 and TM-400), pyridine, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxa-azaspiro-decane (such as in TM-416, TM-456, dioxa-8-azaspiro

[0045] decane), oxa diaza-spiro

[0045] decane (such as in TM-457) and dioxanyl Examples of 3- to 8-membered, unsaturated heterocyclic rings within the scope of this disclosure include mono-unsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e g, a carbon-carbon single bond is replaced with a carbon-carbon double bond)

[0479] The term "aryl(C3-C8)" refers to aromatic (unsaturated) compounds consisting of 3-8 membered rings (e g, phenyl), optionally fused with additional (1-3) aliphatic (cycloalkyl) or aromatic ring systems, each additional ring consisting of 3-8 membered ring (such as anthracene, indane, Tic, 3-benzothienylalanine, dihydroindol or tetralinyl (such as in TM-348)) In a specific embodiment, aryl(C3-C8) refers to phenyl (such as in TM-336, etc), benzocyclopentyl, or naphthyl, preferably phenyl

[0480] The term "heteroaryl (C3-C8)" refers to (i) a 3-, 4-, 5-, 6-, 7- or 8-membered heteroaromatic ring (more specifically 3-7 or 3-6 membered ring) containing from 1 to 4 heteroatoms independently selected from N, 0 and S, such as oxazolyl (such as in TM-412), pyridinyl (such as in TM-386, TM-406, TM-444, TM-445), pyrrolyl (such as in TM-414), imidazolyl, thiazolyl (such as in TM-438), furyl (such as in TM-415, TM-435, TM-436, TM-451, TM-452), thiophenyl, and thienyl; or (ii) is a heterobicyclic ring selected from indolyl (such as in TM-431, TM-436), benzoxazolyl (such as in TM-413, TM-425, TM-446), benzofuryl (such as in TM-441, TM-442, TM-443, TM-446), isobenzofuryl, quinolinyl, isoquinolinyl, Tic, dihydroindolylglydne and quinoxalinyl Suitable 3-, 4-, 5- and 6-membered heteroaromatic rings include, for example, diazirine, pyridyl (also referred to as pyridinyl), pyrrolyl, diazine (e g, pyrazinyl, pyrimidinyl, pyridazinyl), triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl (e g, 1, 2, 3 triazolyl), tefrazolyl (e g, 1, 2, 3, 4 tetrazolyl), oxazolyl, iso-oxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl Heteroaryls of particular interest include oxazolyl, pyridinyl, pyrrolyl, and furyl Heterobicydic rings of particular interest include indolyl, benzoxazolyl, and benzofuryl

[0481] The term " C(0)" refers to carbonyl The terms " S(0)2" and " SO2" each refer to sulfonyl The term " S(0)" refers to sulfinyl The term “aralkyl” and more specifically “(C4-C 14)aralkyl” or “C4-14 aralkyl” refers herein to compounds comprising a 3-8 ring-member aryl substituted by a 1 to 7 alkyl In specific embodiments, it refers to a benzyl ora phenetyl

[0482] As used herein, and unless otherwise specified, the terms “alkyl”, "haloalkyl", "aminoalkyl", "cycloalkyl", "heterocyclyl", “aryl”, “heteroalkyl” and “heteroaryl” and the terms designating their specific embodiments (e g, butyl, fluoropropyl, aminobutyl, cydopropane, morpholine, phenyl, pyrazole, etc) encompass the substituted (i e, in the case of haloalkyl and aminoalkyl, in addition to their halogen and nitrogen substituents, respectively) and unsubstituted embodiments of these groups Hence for example, the term “phenyl” encompasses unsubstituted phenyl as well as fluorophenyl, hydroxyphenyl, methylsulfonyl phenyl (or biphenyl), diphenyl, frifluoromethyl-diazirin-phenyl, isopropyl-phenyl, trifluorohydroxy-phenyl Similarly, the term pyrazole encompasses unsubstituted pyrazole as well as methylpyrazole The one or more substituents may be an amine, halogen, hydroxyl, C1-6 aminoalkyl, C 1-6 heteroalkyl, C1-6 alkyl, C3-8 cycloalkyl, C 1-6 haloalkyl, aryl, heteroaryl and heterocyclyl groups (etc)

[0483] It is understood that the specific rings listed above are not a limitation on the rings which can be used in the present disclosure These nngs are merely representative

[0484] Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i e, any carbon atom or any heteroatom) provided that a stable compound results therefrom

[0485] Isomers, tautomers and polymorphs

[0486] As used herein, the term “isomers" refers to stereoisomers including optical isomers (enantiomers) and diastereomers, as well as the other known types of isomers

[0487] The compounds of the disclosure have asymmetric carbon atoms and can therefore exist in the form of optically pure enantiomers (optical isomers), and as mixtures thereof (racemates) It is to be understood, that, unless otherwise spedfied, the present disclosure embraces the racemates, the enantiomers and / or the diastereomers of the compounds of the disclosure as well as mixtures thereof

[0488] In addition, the present disclosure embraces all geometric isomers For example, when a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure

[0489] Within the present disclosure, it is to be understood that a compound of the disclosure may exhibit the phenomenon of tautomerism and that the formula drawings within this specification can represent only one of the possible tautomeric forms It is to be understood that the disclosure encompasses any tautomeric form and is not to be limited merely to any one tautomeric form utilized within the formula drawings

[0490] It is also to be understood that certain compounds of the disclosure may exhibit polymorphism, and that the present disclosure encompasses all such forms

[0491] Salts

[0492] The present disclosure relates to the compounds of the disclosure as hereinbefore defined as well as to salts thereof The term “salt(s)", as employed herein, denotes basic salts formed with inorganic and / or organic bases Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of the disclosure The term "pharmaceutically acceptable salts" refers to salts of compounds of the present disclosure that are pharmacologically acceptable and substantially non-toxicto the subject to which they are administered More specifically, these salts retain the biological effectiveness and properties of the antibacterial compounds of the disclosure and are formed from suitable non-toxic organic or inorganic acids or bases

[0493] For example, where the compounds of the disclosure are sufficiently basic, the salts of the disclosure include acidic salts formed with an inorganic or organic acid, such as a carboxylic acid Preferred salts include formate, hydrochloride, mesylate, sulfate, tartrate, triflu oroacetate, citrate, phosphate and lactate

[0494] Where the compounds of the disclosure are sufficiently acidic, the salts of the disclosure include base salts formed with an inorganic or organic base Such salts include alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts, metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and a cobalt salts; inorganic amine salts such as ammonium or substituted ammonium salts, such as e g, trimethylammonium salts; and salts with organic bases (for example, organic amines) such as chloroprocaine salts, dibenzylamine salts, dicydohexylamine salts, dicyclohexylamines, diethanolamine salts, ethylamine salts (including diethylamine salts and triethylamine salts), ethylenediamine salts, glucosamine salts, guanidine salts, methylamine salts (including dimethylamine salts and trimethylamine salts), morpholine salts, morpholine salts, N, N'-dibenzylethylen ediamine salts, N-benzyl-phenethylamine salts, N-methylglucamine salts, phenylglycine alkyl ester salts, piperazine salts, pipendine salts, procaine salts, t-butyl amines salts, tetramethylammonium salts, t-octylamine salts, tris-(2-hydroxyethyl)amine salts, and tns(hydroxymethyl)ammomethane salts Preferred salts include those formed with sodium, lithium, potassium, calcium and magnesium

[0495] Such salts can be formed routinely by those skilled in the art using standard techniques Indeed, the chemical modification of a pharmaceutical compound (i e, drug) into a salt is a technique well known to pharmaceutical chemists Salts of the compounds of the disclosure may be formed, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization

[0496] Esters

[0497] The present disclosure relates to the compounds of the disclosure as hereinbefore defined as well as to the esters thereof The term “ester(s)”, as employed herein, refers to compounds ofthe disclosure or salts thereof in which a carboxylic acid has been hydroxy groups have been converted to the corresponding esters using an alcohol and a coupling reagent Esters for use in pharmaceutical compositions will be pharmaceutically acceptable esters, but other esters may be useful in the production ofthe compounds of the disclosure

[0498] The term "pharmaceutically acceptable esters" or “esters” refers to esters of the compounds ofthe present disclosure that are pharmacologically acceptable and substantially non-toxic to the subject to which they are administered More specifically, these esters retain the biological effectiveness and properties ofthe antibacterial compounds ofthe disclosure and act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to produce the parent alcohol compounds

[0499] The compounds of this disclosure may be esterified by avariety of conventional procedures including the esters are formed from the acid ofthe molecule by reacting with a coupling agent such as DIC (diisopropyl carbodiimide) and a base, such as NN-dimethylaminopyridine (DMAP), and an alcohol, such as methanol (methyl ester), ethanol, longer chain alcohols or benzyl alcohol (benzyl ester) One skilled in the art would readily know how to successfully carry out these as well as other known methods of esterification of acid

[0500] Further information concerning examples of and the use of esters for the delivery of pharmaceutical compounds is available in Design ofProdrugs Bundgaard H ed (Elsevier, 1985) incorporated herein by reference See also, H Ansel et al, 1995 at pp. 108–109; Krogsgaard-Larsen, 1996 at pp. 152–191; Jarkko Rautio, 2008; and Pen-Wei Hsieh, 2009, all incorporated herein by reference

[0501] Esters of the compounds of the disclosure may form salts Where this is the case, this is achieved by conventional techniques as described above

[0502] Solvates

[0503] The compounds of the disclosure may exist in unsolvated as well as solvated forms with solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms

[0504] “Solvate” means a physical association of a compounds of this disclosure with one or more solvent molecules This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice ofthe crystalline solid “Solvate” encompasses both solution-phase and isolatable solvates Solvates for use in pharmaceutical compositions will be pharmaceutically acceptable solvates, but other solvates may be useful in the production of the compounds ofthe disclosure

[0505] As used herein, the term “pharmaceutically acceptable solvates” means solvates of compounds of the present disclosure that are pharmacologically acceptable and substantially non-toxic to the subject to which they are administered More specifically, these solvates retain the biological effectiveness and properties of the antibacterial compounds of the disclosure and are formed from suitable non-toxic solvents

[0506] Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like, as well as hydrates, which are solvates wherein the solvent molecules are H2O

[0507] Preparation of solvates is generally known Thus, for example, Caira, 2004, incorporated herein by reference, describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water Similar preparations of solvates, hemisolvate, hydrates and the like are descnbed by van Tonder, 2004; Bingham, 2001, both incorporated herein by reference

[0508] A typical, non-limiting, process for preparing a solvate involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods Analytical techniques such as, for example IR spectroscopy, can be used to show the presence of the solvent (or water) in the crystals as a solvate (or hydrate) Compositions, Combination and kits

[0509] Compositions

[0510] The present disclosure also relates to pharmaceutical compositions comprising at least one of the compounds of the disclosure or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt, hydrate, solvate, prodrug (e g, ester) or polymorph, and optionally a pharmaceutically acceptable carrier

[0511] As used herein, the terms “pharmaceutically acceptable” refer to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the tike, when administered to subjects (e g, humans) Preferably, as used herein, the term “pharmaceutically acceptable” means approved by regulatory agency of the federal or state government or listed in the U S Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle (e g, nanoparticles) with which the compounds of the present disclosure may be administered Sterile water or aqueous saline solutions and aqueous dextrose and glycerol solutions or nanoparticles may be employed as carriers, particularly for injectable solutions Suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E W Martin The pharmaceutical compositions of the present disclosure may also contain excipients / carriers such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the vanation of osmotic pressure, buffers, coating agents or antioxidants In certain embodiments, the compound or compounds of the disclosure are formulated into nanoparticles, such as chiton nanoparticles e g, thiolated chiton nanoparticles

[0512] In certain embodiments, compositions provided herein are administered by one or more routes of administration using one or more of a variety of suitable methods As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results Routes of administration for compounds of the present disclosure for uses disclosed herein include enteral and topical routes (e g, oral, topical, epidermal, mucosal such as intranasally, orally, vaginally, rectally, sublingually) and parenteral routes such as intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion or other parenteral routes of administration, for example by injection or infusion The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection Intravenous or oral administrations are preferred forms of use

[0513] Without being so limited, when the compound / pharmaceutical compositions of the disclosure is administered orally, it may take the form of nanoparticles, tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions for example; rectally using for example of suppositories; locally, topically, or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e g, intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions Furthermore, administration can be carried out sublingually, nasally, or as ophthalmological preparations or an aerosol, for example in the form of a spray, such as a nasal spray

[0514] The compounds of the disclosure may be incorporated into dosage forms in conjunction with any of the vehicles which are commonly employed in pharmaceutical preparations Methods for preparing appropriate formulations are well known in the art (see e g, Remington's Pharmaceutical Sciences, 16th Ed, 1980, A Oslo Ed, Easton, Pa incorporated herein by reference) Common pharmaceutically acceptable carriers include, without limitation, sterile aqueous or non-aqueous solutions, suspensions, and emulsions Examples of non-aqueous solvents include, without limitation, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters Aqueous carriers include, without limitation, water, alcohol, saline, and buffered solutions

[0515] For the preparation of tablets, coated tablets, dragees or hard gelatin capsules, the compounds of the present disclosure may be admixed with any known pharmaceutically inert, inorganic or organic excipient and / or earner Examples of suitable excipients / carriers include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof Suitable excipients for use with soft gelatin capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc According to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatin capsules For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose

[0516] For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols

[0517] In cases where parenteral administration is elected as the route of administration, preparations containing the compounds of the disclosure may be provided to patients in combination with pharmaceutically acceptable sterile aqueous or nonaqueous solvents, suspensions or emulsions Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters Aqueous carriers include water, water-alcohol solutions, emulsions or suspensions, including saline and buffered medical parenteral vehicles including sodium chloride solution, Ringer's dextrose solution, dextrose plus sodium chloride solution, Ringer's solution containing lactose, or fixed oils Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers, such as those based upon Ringer's dextrose, and the like

[0518] The medicaments / pharmaceutical compositions may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants They may also contain other therapeutically active agents

[0519] The active compounds, in certain embodiments, are prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems Biodegradable, biocompatible polymers are used in certain embodiments, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poly lactic acid Many methods for the preparation of such formulations are patented or generally known to those skilled in the art See, e g, Sustained and Controlled Release Drug Delivery Systems, J R Robinson, ed, Marcel Dekker, Inc, New York, 1978 In certain embodiments, therapeutic compositions are administered with medical devices known in the art For example, in one embodiment, therapeutic compositions provided herein are administered with a needleless hypodermic injection device

[0520] Any amount of a pharmaceutical composition can be administered to a subject The dosages will depend on many factors including the age, the animal (e g, bovine, human) and the requirements of the patient and the mode of application Typically, the amount of the compound of the disclosure contained within a single dose will be an amount that effectively prevents, delays or treats the disease or condition to be treated, delayed or prevented without inducing significant toxicity Hence a "therapeutically effective amount" or “effective amount” or "therapeutically effective dosage" of a specific compound of the disclosure or composition thereof can result in a reduction of pain and / or body temperature in a subject The effective amount of the compounds of the disclosure may also be measured directly The effective amount may be given daily or weekly or fractions thereof Typically, a pharmaceutical composition of the disclosure can be administered in an amount from about 0001 mg up to about 500 mg per kg of body weight per day (e g, 10 mg, 50 mg, 100 mg, or 250 mg) Dosages may be provided in either a single or multiple dosage regimen For example, in certain embodiments the effective amount may range from about 1 mg to about 25 grams of the composition per day, about 50 mg to about 10 grams of the composition per day, from about 100 mg to about 5 grams of the composition per day, about 1 gram of the composition per day, about 1 mg to about 25 grams of the composition per week, about 50 mg to about 10 grams of the composition per week, about 100 mg to about 5 grams of the composition every other day, and about 1 gram of the composition once a week

[0521] These are simply guidelines since the actual dose must be carefully selected and titrated by the attending physician based upon clinical factors unique to each patient The optimal daily dose will be determined by methods known in the art and will be influenced by factors such as the age of the patient and other clinically relevant factors In addition, patients may be taking medications for other diseases or conditions The other medications may be continued during the time that the pharmaceutical composition of the disclosure is given to the patient, but it is particularly advisable in such cases to begin with low doses to determine if adverse side effects are experienced

[0522] Combinations In accordance with another aspect, there is provided a combination of at least one of the compounds described herein with another of the compounds described herein and / or with another drug

[0523] Kits

[0524] In accordance with another aspect of the present disclosure, there is provided a kit comprising the compound or composition defined herein, and instructions to use the kit in the prevention or treatment of a bacterial infection In a specific embodiment of the kit, the kit comprises: (i) at least one of the compounds described herein; (ii) another drug for the prevention or treatment of a bacterial infection; (iii) instructions to use same in the prevention or treatment of a bacterial infection; or (iv) a combination of at least two of (i) to (iii)

[0525] Compound and composition for use. Uses and Methods

[0526] The present disclosure also relates to a method of preventing or treating (preferably treating) a bacterial infection or a symptom thereof in a subject in need thereof comprising administering an effective amount a compound or composition of the present disclosure (e g, compound of formula (I), (II), (la), (lb), (Ic), (Id), (le), (It), (Ig) and (lh), Table I or any Examples herein or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, solvate, prodrug or polymorph thereof) or composition of the present disclosure of to the subject

[0527] As used herein the term “bacterial infection” refers, without being so limited, to a difficult to treat infection caused by a Gram-positive or a Gram-negative pathogen In specific embodiments, it refers to an infection caused by a bacterium, such as but not limited to Enterobacterales such as Escherichia spp (such as Escherichia coll), Klebsiella spp (such as Klebsiella pneumoniae, Klebsiella oxytoca, and Klebsiella aerogenes), Enterobacter spp (such as Enterobactercloaceae), Citrobacter spp, and Shigella spp or caused by Pseudomonas spp such as Pseudomonas aeruginosa; or caused by Staphylococcus spp such as Staphylococcus aureus, Staphylococcus epidermidls, Staphylococcus saprophyticus, Staphylococcus agalactiae and Staphylococcus haemolyticus; or caused by Enterococcus spp such as Enterococcus faecalis and Enterococcus faecium; or caused by Streptococcus spp such as Streptococcus pyogenes, and Streptococcus agalactiae; or caused by Bacillus spp such as Bacillus cereus, and Bacillus subtilis; or caused by Listeria spp such as Listeria monocytogenes; or caused by Acinetobacter spp such as A baumannii It also refers to an infection caused by a strain of a bacterium such as a strain from a bacterium listed above, that is resistant to at least one antibiotic agent or is resistant to multiple antibiotic agents (multi-resistant) Without being so limited, it refers to an infection caused by e g bacteria having antibiotic susceptibility profiles similar to one of the following E coli strains ATCC 25922, BAA-2471, 70122, 95882, MC4100, MC4100 AcrAB, MC4100 imp4213 IptD; one of the following Staphylococcus aureus strains 29213, ATCC 29213 hemB, Newbould, Newbould hemB, Newbould EhemB SaR1 -1, Newbould hemB SaR1-2, Staphylococcus epidermidls ATCC 12228, Staphylococcus saprophyticus ATCC 15305; Staphylococcus haemolyticus CDC HIP-5979; Staphylococcus homlnls CDC M270; Pseudomonas aeruginosa ATCC 27853; one of the following Klebsiella pneumoniae strains ATCC 13883, ATCC BAA 2473, ATCC BAA 1705, ATCC 700603; Klebsiella oxytoca ATCC 43165, or ATCC 13182; Klebsiella aerogenes ATCC 35029; one of the following Actinobacter baumannii strains ATCC 19606, ATCC BAA-1800, or ATCC BAA-1700, Enterococcus faecalis ATCC 29212; Enterococcus faecium ATCC 35667 orVanA; Streptococcus pyogenes ATCC 19615; Streptococcus agalactiae 60440; Bacillus cereus ATCC 11778; Bacillus subti / is ATCC 6633; Bacillus subtilis ATCC 23857; or Listeria monocytogenes ATCC 13932

[0528] In specific embodiments, there is provided a compound or composition of the present disclosure for preventing or treating a bacterial infection caused by E. coli and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM 463, TM-372, TM-373, TM-374, TM-375, TM-379, TM 392, TM-394, TM-407, TM-410, TM-413, TM-414, TM 422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452 and preferably TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by E coli such as strain MC4100 and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, and preferably by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373 or any compound of any formula of the present disclosure covenng these compounds In specific embodiments, it is caused by E coli such as strain MC4100 AcrAB and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452, TM-214, TM-215, TM-231, TM-253, TM-350, TM-361, TM-365 / TM-339, TM-376, TM-386, TM-393, TM-399, TM-402, TM-406, TM-412, TM-421, TM-429, and preferably by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM- 414, TM-422, TM-424 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by E coli such as strain MC4100 imp4213 IptD and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM- 456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452, TM-214, TM-215, TM-231, TM-253, TM-350, TM-361, TM-365 / TM-339, TM-376, TM-386, TM-393, TM-399, TM-402, TM-406, TM-412, TM-421, TM-429, TM-433, TM-441, TM-167, TM-168, TM-169, TM-199, TM-200, TM-201, TM-203, TM-204, TM-205, TM-206, TM-207, TM-225, TM-226, TM-227, TM-228, TM-229, TM-232, TM-249, TM-250, TM-251, TM-254, TM-267, TM-279, and preferably by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452, TM-214, TM-215, TM-231, TM-253, TM-350, TM-361, TM- 365 / TM-339 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by an Staphylococcus (such as Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus haemolyticus, Staphylococcus hominis) and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452, TM-214, TM-215, TM-231, TM-253, TM-350, TM-361, TM-365 / TM-339, TM-376, TM-386, TM-393, TM-399, TM-402, TM-406, TM-412, TM-421, TM-429, TM-433, TM-441, TM-167, TM-168, TM-169, TM-199, TM-200, TM-201, TM-203, TM-204, TM-205, TM-206, and preferably by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, IM -425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by S aureus (such as ATCC 29213, ATCC 29213 hemB, ATCC BAA-41 and ATCC 700699) and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452, TM- 214, TM-215, TM-231, TM-253, TM-350, TM-361, TM-365 / TM-339, TM-376, TM-386, TM-393, TM-399, TM-402, TM-406, TM-412, TM-421, TM-429, TM-433, TM-441, TM-167, TM-168, TM-169, TM-199, TM-200, TM-201, and preferably by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, TM-463, TM-372, TM-373, TM-374, TM-375, TM-379, TM-392, TM-394, TM-407, TM-410, TM-413, TM-414, TM-422, TM-424, TM-425, TM-427, TM-434, TM-443, TM-457, TM-464, TM-337, TM-354, TM-355, TM-395, TM-401, TM-423, TM-426, TM-431, TM-432, TM-439, TM-440, TM-442, TM-445, TM-452, TM-214, TM-215, TM-231, TM-253, TM-350, TM-361, TM-365 / TM-339 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus haemolyticus, Staphylococcus hommts and is preferably treated by TM-336, TM-381, TM-387 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by P aeruginosa and is preferably treated by TM-462, TM-336, TM-381, TM-396, TM-397, TM-411, TM-377, TM-378, TM-380, TM-382, TM-387, TM-389, TM-398, TM-416, TM-418, TM-456, or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by Klebsiella and is preferably treated by TM- 336, TM-381, TM-387, TM-397, TM-416 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by Acinetobacter and is preferably treated by TM-336, TM-381, TM-387, TM-397, TM-416 or any compound of any formula of the present disclosure covering these compounds In specific embodiments, it is caused by Enterococcus (such as E faecalis, E faecium), Streptococcus (such as S pyogenes, S agalactiae), Bacillus (such as B cereus, B subfilis), Listeria (such as L monocytogenes) and is preferably treated by TM-336, TM-381, TM-387 or any compound of any formula of the present disclosure covering these compounds As used herein the terms “subject’ refers to an animal such as, but not limited to a human, mammal such as cattle (e g, bovine), mouse, rat or other animal (e g, pets such as cats, dogs, horses, etc; and fishes, swine, poultry, etc) As used herein the terms “subject in need thereof’ refer to a subject who would benefit from receiving an effective amount of the compound or composition of the present disclosure In the context of the method of preventing or treating (preferably treating) a bacterial infection, it refers to a subject (e g, a human) experiencing or at nsk of expenencing a bacterial infection

[0529] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context

[0530] The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i e, meaning "including, but not limited to") unless otherwise noted

[0531] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein

[0532] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context

[0533] The use of any and all examples, or exemplary language (e g, "such as") provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure

[0534] Herein, the term "about" has its ordinary meaning In embodiments, it may mean plus or minus 10% of the numerical value qualified

[0535] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs

[0536] Other objects, advantages and features of the present disclosure will become more apparent upon reading of the following non -restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings

[0537] The present disclosure is illustrated in further detail by the following non-limiting examples

[0538] EXAMPLE 1: Matenal and Method

[0539] General Experimental Method Unless otherwise noted, reactions were carried out in oven-dried glassware under an argon atmosphere Anhydride solvents and all reagents were purchased from commercial sources (Sigma-Aldrich, Combi-Blocs, TCI) and used as received Reactions were monitored by thin layer chromatography (Canadian Life Science, TLC, GLASS plates SIL 60 G-25 UV 254) The plates were visualized first with UV illumination followed by heating with ninhydrin [1.5% (w / v) ninhydrin, 97 / 03 n-butanol / acetic acid] Flash chromatography was performed on siliaFlash® P60 silica High-pressure liquid chromatography (HPLC) was performed on an Agilent™ 1100 apparatus using an ACE C18 column, 250 * 21 2 mm with 5 pm silica and 155% carbon load NMR spectra were recorded at room temperature on Bruker AVANCE 400 spectrometers (BBFO probes), using the residual peak of chloroform (7.26 ppm for 1H NMR and 77.0 ppm for 13C NMR) or methanol (3.31 ppm for 1H NMR and 49.0 ppm for 13C NMR) as internal standards. Chemicals shifts (5) are reported in parts per million (ppm) and coupling constant (J) are given in Hertz (Hz) 1H and 13C NMR assignments were based on COSY, HSQC, HMBC experiments Abbreviations used for peak multiplicities are: s (singlet) d (doublet) t (triplet); q (quartet); quint (quintet); m (multiplet or overlap of non-equivalent resonances); High-resolution mass spectrometry was performed by Philippe Venne at Universite de Sherbrooke on a Maxis (Bruker) Q-TOF (ESI) spectrometer General Synthetic Schemes

[0540] E.1)

[0541] OH A O_NH2E-1) { L-Tryptophanol Tri C.1), C.3|

[0542] Boc-Phe-OH J). E.1) V NHR RZV^ C.1), C.3)rRj: H, Aik Ar, Het,... D ) ( R Boe ai < Ri:Hal < R: H Rsz H. Me... n Aty: Aik, Cy, Het,..

[0543]

[0544] General Procedure A): Suzuki Coupling - Synthesis of biphenyl moiety

[0545]

[0546] To a mixture of 2 -bromo-phenyl derivative 1 (1.0 equiv), boromc acid derivative 2 (1.10 equiv.), potassium carbonate (20 equiv ), and tetrakis(triphenylphosphine)palladium (0.03 equiv.), was added 1,4-dioxane (165 mM) under Ar(g). The reaction was stirred at 80 °C for 12h After the reaction was cooled to rt, H₂O was added, and the mixture was extracted with ethyl acetate (3 times), dned over anhydrous MgSO₄. After evaporation of solvent, further purification was performed by chromatography on silica gel (Hexane / AcOEt) to yield the desired compound as a solid

[0547] General Procedure B 1): Alkylation

[0548]

[0549] To a solution of phenol derivative 4 (1 0 equiv) in dry DMF (150 mM) under Ar(g) at 0°C was slowly added NaH (1.5 equiv. 60% in mineral oil) After stirring for 0.5h with ice bath, epibromohydrin 5 (3.0 equiv.) was added dropwise and the reaction was stirred for 05h at 0“C and for 1h at rt Water was added and the reaction was extracted with AcOEt (3 times), washed with brine, dried over MgSO₄ and concentrated under reduced pressure The crude (1 0 equiv ) was dissolved in EtOH (85 mM) under Ar(g) and secondary amine (1.25 equiv.) was added The reaction was heated up at reflux for 16h The volatiles were removed under reduced pressure The crude was either engaged in the next step without further purification or purified by chromatography on silica gel (DCM: MeOH (10%NH4OH)) to yield the tittle compound 6

[0550] General Procedure B 2): Alkylation

[0551]

[0552] Epichlorohydrin 8 (1.0 equiv.) was added dropwise to an ice-cooled solution of secondary amine 7 (8.3 equiv.) and triethylamine (1 25 equiv ) dissolved in dry methanol (100 mM) under Ar(g). The reaction mixture was stirred 0°C until the reaction was completed ~3h Methanol was evaporated under reduced pressure and the residue was taken into AcOEt and filtered The filtrate was concentrated under reduced pressure to yield the tittle compound 9 that was engaged to the next reaction without further purification

[0553]

[0554] Phenol derivative 4 (1 0 equiv ) and epoxide 9 (3 0 equiv ) were dissolved in DMF (100 mM), potassium carbonate (3 0 equiv ) was added, and the mixture was stirred ~16h at 90°C The crude was diluted with DCM and NaHCO₃sat. The aqueous phase was extracted with DCM (twice) and the combined organic phase was washed with NaHCO₃sat (twice), dried over MgSO₄ and concentrated under reduced pressure The crude was either engaged in the next step without further purification or purified by chromatography on silica gel (DCM: MeOH(10%NH4OH)) to yield the tittle compound 6

[0555]

[0556]

[0557] Aldehyde derivative 10 (1 0 equiv) and Amine building block 11 (L -tryptophanol was used in the synthesis of TM-429) (1 5-4 0 equiv ) were dissolved in DCM (45 mM) under Ar(gj and stirred for 1h at r.t. Then, NaBH(OAc)₃ was added at rt and the mixture was stirred for ~16h The reaction was diluted with DCM and NaHCQjsat was added The aqueous phase was extracted with DCM (3 times) and the combined organic phase was washed with brine, dried over MgSO₄ and concentrated under reduced pressure The product 12 was engaged in the next step without purification

[0558] General Procedure C 2): Reductive amination

[0559]

[0560] 3-aminopropyl pivalate 13 (1 0 equiv ) and Aldehyde derivative 10 (1 0 equiv ) were dissolved in MeOH (250 mM) under Ar(gj and stirred for 1h at r.t. Then, the reaction was cooled down at 0°C and sodium borohydride (1.4 equiv.) was added in 4 portions The mixture was stirred an additional 1h while slowly warming back to rt Water was carefully added to the mixture at 0°C and MeOH was evaporated in vacuo The mixture was extracted with AcOEt (twice) Combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure The product 14 was used directly in the next reaction without purification

[0561] General Procedure C 3): Reductive amination

[0562]

[0563] To amine Derivative 15(1 0 equiv ) dissolved in dry DCM (440 mM) was added 37% formaldehyde (40 equiv ) and sodium triacetoxyborohydride (3 0 equiv ) portionwise (CAUTION: hydrogen generation) Mixture was stirred at rt for 1h The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 until no more gas evolved The aqueous phase was extracted with DCM and combined organic layer was dried over MgSO₄ and concentrated under reduced pressure The product 16 was used directly in the next reaction without purification

[0564] General Procedure C 4): Reductive amination

[0565]

[0566] Amine derivative 17 (1.0 equiv ) and aldehyde building block 18 (09 equiv) were dissolved in DCM (50 mM) under Ar(g) and stirred for 1h at r.t Then, NaBH(OAc)3 (1.5 equiv.) was added at rt and the mixture was stirred for- 1h The conversion was evaluated by UPLC-MS every 05h to control side product formation (double reductive amination) After 1 5 to 2h, the reaction was diluted with DCM and NaHCO3sat was added. NaOH (1M) was added to reach pH ~11 The aqueous phase was extracted with DCM (3 times) and the combined organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure Product 19 was engaged in the next step without purification

[0567] General Procedure D): Boc deprotection

[0568]

[0569] The residue 20 was dissolved in dry 1,4-dioxane under Ar(g)and HCl (4M in dioxane, 10 equiv.) was added dropwise at r t The mixture was stirred for -16h and the volatiles were removed under vacuum The following procedure was followed for final compounds: the crude 21 was dissolved in a mixture of DMSO, CH3CN and H2O, filtered and purified by MS preparative HPLC (Acidic conditions) to yield the corresponding product as a formate salt The following procedure was followed for intermediates: NaHCO3sat and NaOH (1M) were added to reach pH ~11 and the residue was dissolved in DCM. The aqueous phase was extracted with DCM (3 times) and the combined organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure The crude 21 was engaged in the next step without further purification

[0570] To a solution of residue 20 (1.0 equiv.) in DCM at 0° C was added TFA (4.0 equiv.) The ice bath was removed, and the reaction mixture was stirred at rt for 1h The solvents were removed in vacuo and the desired free amine was diluted with EtOAc. The mixture was cooled to 0° C and neutralized with a NaHCOs saturated solution until pH= 12 and then extracted with EtOAc 3 times The combined organic layers were dned over Na2SO4 and concentrated under reduced pressure to afford compound 21 as a dark brown gummy compound Next step was proceeded without further purification General Procedure E 1): Pivaloyl-deprotection

[0571]

[0572] To a solution of pivaloyl-protected alcohol derivative 22 / 23 (1 0 equiv ) in MeOH (60mM) was added NaOH (40 equiv ) at rt The mixture was stirred for 1 4h at TO and then cooled down to rt The solvent was removed under reduced pressure and H2O and AcOEt were added to the residue The organic layer was successively washed with water and brine (twice), dried over MgSO4 and concentrated under reduced pressure. The product 24 / 25 was either purified by chromatography on silica gel or engaged in the next step without further purification

[0573] General Procedure E 2): Pivaloyl-deprotection after Suzuki coupling

[0574]

[0575] Solvent from Suzuki reaction was removed under reduced pressure Water (1 0 mL) was added to the mixture, followed by 37% HCI (100 equiv ) The reaction vial was capped and the mixture was stirred at 100°C for 2 The mixture was concentrated in vacuo until it was dry, before it was dissolved in a mix of ACN / H2O and purified by preparative reversephase HPLC

[0576] General Procedure F): Sulfonamide synthesis

[0577]

[0578] To a solution of amine derivative 15 (1 0 equiv) in dry DCM (120mM) cooled atO°C was added EfeN (1 5 equiv ) After 10 mins, sulfonyl chlonde derivative (1 0 equiv ) was added dropwise, and the mixture was stirred for 1h from 0°C to rt The media was diluted with DCM and the organic layer was successively washed with water, NH4Clsat and brine, dried over MgSO4 and concentrated under reduced pressure. The product 26 was engaged in the next step without further purification

[0579] General Procedure G): Synthesis of Amine derivatives from N-Boc Amino Acids

[0580] 1. ClCOOEt, Et3N, THF

[0581] 2. NH4Cl(aq)

[0582] BocHN

[0583] 3 BH3 Me2S. THF "

[0584]

[0585] Commercial N-boc protected amino-acids 27 (1.0 equiv) were solubilized in dry THF (80 mM) under Ar(g) and cool down at 0°C (ice bath) Ethyl chloroformate (1.4 equiv ) and Triethylamine (3 0 equiv ) were simultaneously added dropwise at 0°C After 30 mins of slurring at 0°C, ammonium chloride solution (1 0 M in water, 1 5 equiv ) was added, and the mixture was stirred for another 30mins Then, the reaction was diluted with water and saturated ammonium chloride solution The mixture was extracted with ethyl acetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure to yield the corresponding N-boc protected amide The product was engaged in the next step without further purification

[0586] N-protected amides (1.0 equiv ) were solubilized in dry THF (200 mM) under Ar(g) and cooled down at 0°C (ice bath) Borane dimethyl sulfide complex (4-10 equiv) was added dropwise at r t and the reaction was stirred for > 24h The mixture was cooled at 0°C and methanol was added dropwise (gas formation) The volatiles were removed under reduced pressure The crude was dissolved in MeOH and concentrated under reduced pressure (4cycles) and dried under vacuum for >24h The resulting N-boc protected (bis)amine 11 was engaged in the next step without further purification General Procedure H): Synthesis of Aldehyde derivatives from N-Boc Amino Acids

[0587] 1. CDI, DCM, 0°C

[0588] 0 2 Dibal-H. DCM, -78°C

[0589] BocHN BocHN

[0590] 27 CDI: I J'-carbonyldiimidazole 18

[0591]

[0592] Commercial N-boc protected amino-acids 27 (1 0 equiv ) were solubilized in dry DCM (150 mM) under Ar(g) and the mixture was cool down at 0°C (ice bath) 1,1’-carbonyldiimidazole (1 2 equiv ) was added and the reaction was stirred for 1h Then, the mixture was cool down at -78°C (CO2(s): acetone bath) and Dibal-H (1.0M in DCM, 2.1 equiv.) was added dropwise (>05h ) The reaction was stirred for 1h at -78°C and then quenched by addition of tartaric acid saturated solution under vigorous stirring The mixture was warmed up to rt and diluted with AcOEt The aqueous phase was washed with AcOEt and the combined organic extracts were washed with HCl (1M), NaHCO3sat, brine, dried over MgSO4 and concentrated under reduced pressure Purification by flash chromatography on silica gel afforded desired aldehyde 18

[0593] General Procedure I): Pivaloyl-protection after alkylation B 2)

[0594]

[0595] Synthetized alcohol 28 (1 0 equiv ) was dissolved in dry DCM under Argon atm Triethylamine (10 equiv.) was added and the solution was cooled to 0°. After 10 min of stirring, trimethylacetyl chloride (2 equiv.) was added slowly and the reaction was then stirred for 3h at rt Water was added and the aqueous phase was extracted with DCM The combined organic extracts were dried and concentrated under reduced pressure Purification by flash chromatography on silica gel afforded desired protected alcohol 29 as a dark brown liquid

[0596] General Procedure J): Coupling of amine with carboxylic acid

[0597]

[0598] Secondary amine 15 / 17 (1 eq) and Boc-Phe-oh (1 5 eq) were dissolved in Dry DMF (160 mM) under inert atmosphere in 0° C. N, N-Diisopro py lethylamin e; DIPEA; Hunig's base (2 eq), HATU (1.5 eq) were added to it and stirred the reaction for 30 min in 0° C. The reaction was allowed to warm upto rt and stirred for 16h. After completion of the reaction, the reaction was diluted with ethyl acetate and washed with NaHCOs sat water solution and brine Organic Part was concentrated under reduced pressure The pivalate 30 / 31 was used for the next step without further purification

[0599] Minimal inhibitory concentration (MIC) The minimum inhibitory concentrations (MICs) of antibiotics were determined by a broth microdilution method according to the recommendations from the Clinical Laboratory Standards Institute (CLSI) for antimicrobial susceptibility testing The antibacterial agents, prepared in cation-adjusted Mueller-Hinton broth (CAMHB, Becton Dickinson, Mississauga, Canada) were added and further diluted by two-fold serial dilutions in 96-well plates An equal volume of a bacterial suspension ('10c5-10c6 colony-forming units (CFU) / mL) was added to each well containing the antibacterial agents and incubated at 35-37° C for 18-24 h In all assays, sterility and bacterial growth controls were included Vancomycin, ceftazidime, tetracycline and tobramycin (Sigma-Aldrich Inc) were included as reference drugs and for quality controls The MIC was defined as the lowest concentration of drug yielding no visible growth

[0600] Kill kinetics

[0601] Bacteria were inoculated at ~ 10e5-10e6 CFU / ml in cation-adjusted Mueller-Hinton broth (CAMHB) in the absence or presence of antibiotics at the specified concentrations At several time points during growth at 37°C (225 RPM), bacteria were sampled, serially diluted, and plated on TS agar (TSA) for colony-forming unit (CFU) determinations (i e, viable bacterial counts) Plates were incubated for 18-24h at 37°C

[0602] Bacterial ATP synthase inhibition assay

[0603] Quantification of ATP produced by bacterial ATP synthase was determined to look at the inhibitory effects of different compounds and to measure their relative affinity for this enzymatic target The expenment was performed on membrane vesicles (MV) isolated from various bacterial species

[0604] Preparation of bacterial membrane vesicles Membrane vesicles (MV) were prepared as previously described (Delbrouck et al, 2023) Briefly, several bacterial precultures were seeded consecutively to end up with a 1 2-L culture The culture was incubated at35-37°Cwith shaking until the optical density at 600 nm (QD600) was 08 to 09 After centrifugation, the bacterial pellet was washed twice in 50 mM MOPS buffer containing 10 mM MgCL, centrifuged again and the pellet was stored at -80° C The following day, the pellet was thawed softly on ice in MOPS MgCI? containing 10 % glycerol and the bacteria were lysed by chemical treatment with lysozyme in presence of phenylmethylsulfonyl fluoride (PMSF) and deoxyribonuclease (DNase) for 30 minutes at 4°C, followed by a mechanical lysis with a French press Mechanical lysis was done under a pressure of 18,000 psi and three passes were made with the lysate The lysate was kept on ice between runs, as was the French press cylinder The lysate was then centrifuged to remove large cell debris at 10,000 x g for 20 min The supernatant was then retained and centrifuged by ultracentrifugation at 150,000 x g for 40 min This step was repeated twice The MV were then suspended in a MOPS / MgCI2 buffer containing a cryoprotectant, glycerol, to ensure their preservation The protein content of MV were quantitated by the Micro BOA protein assay kit (Thermo Fisher Scientific, Rockford, IL) to know the exact amount of protein in the sample and stored frozen in aliquots (-80°C) Bacterial MV ATP production and inhibition (IC50 determination) Also as previously described (Delbrouck et al, 2023), MV were diluted to a pre-determined protein concentration (typically 20-50 |jg / ml) based on ATP synthetase activity in the sample Different concentrations of inhibitors were added to the MV and were incubated for 30 min To start the ATP synthesis reaction, 25 mM of NADH, 1 mM of ADP and 10 mM of potassium phosphate buffer (final concentrations) were added The reaction was stopped after 60 min by adding 2 mM ethylenediaminetetraacetic acid (ED TA) and 1% trichloroacetic acid (TCA) A small volume of the reaction was transferred to a white 96-well plate The plate was then read on a lumino meter by adding 50 pL of the luciferin / luciferase reagent from the ATP lite™ 1 step Luminescence Assay System kit (PerkinElmer, Waltham, MA) Luciferase, in the presence of oxygen, ATP and Mg2+ ions, oxidizes luciferin to oxyluciferin and emits light This light was quantified by a luminometer and is proportional to the quantity of ATP synthesized by the ATP synthase The concentration of inhibitor preventing 50% of the production of ATP by the ATP synthase in MV (IC50 in pM) was determined using the GraphPrism™ software (version 920), using the tool log(inhibitor) vs response-variable slope (four parameters)

[0605] Determination of the inhibitor constant Ki The determination of the Ki was done as described in Langlois et al (2024) Enzyme kinetics assays were also performed to obtain more precise information about the Ki, which is the concentration of inhibitor required to produce half maximum inhibition ATP production by the MV was performed as mentioned above to measure the activity of the bacterial ATP synthetase except for a few modifications No pre-exposure time was allowed for the inhibitors when added to the MV during the kinetics tests Several reaction times were tested to determine the rate of the enzyme Several substrate concentrations were tested to determine the affinity of the enzyme for its substrate The enzyme kinetics tests made it possible to determine a maximum rate of ATP production (Vmax) by the enzyme and affinity constant for the substrate (Km) The inhibition constants (Ki) for the inhibitory compounds were determined using the method of Burlingham et al, 2003 Briefly, the inverse of the luminescence production rate (s / RLU) was plotted against the inhibitor concentration The y intercept value was then divided by the slope To obtain the Ki, the value previously calculated is corrected with the Km

[0606] Mitochondrial ATP synthase assay

[0607] Preparation of mitochondria as the source of mammalian ATP synthase As described before (Delbrouck et al, 2023), HEp-2 (CCL-23™) cells were used to isolate mitochondria and determine IC50 of compounds for the mammalian ATP synthase HEp-2 cells were inoculated in a cell culture flask in Dulbecco's modified Eagle's medium (DMEM) containing 45 g / L glucose, 1x sodium pyruvate, 1x glutaMAX™, 10% bovine serum and a 1% antibiotic antimycotic solution They were incubated at 37°C with 5% CO2 until -95% confluence The cells were detached by the conventional trypsin dissociation method and centrifuged for 10 min at 375 x g to obtain a cell pellet The supernatant was aspirated, and the pellet was suspended in NKM buffer (containing NaCI, KOI, MgCh as well as Tris HCI) The suspension was centrifuged again, and the pellet was suspended in 10 volumes of NKM buffer for a second wash After another centrifugation, the pellet was suspended in 6 volumes of homogenization buffer and transferred to a glass Potter-Elvehjem™ homogenizer The cells were homogenized until the cells were mostly broken The homogenate was then transferred to a highly concentrated sucrose solution Centrifugation was carried out for 5 min at 1200x g to obtain a sucrose gradient where the mitochondna are found on the upper layer This layer was recovered, and this step was repeated The mitochondria are then recovered, transferred to a tube, and centrifuged for 10 min at 7000 x g A pellet of mitochondria is then obtained The pellet was suspended in a mitochondrial suspension buffer for fresh use If the pellet is not used the same day, then it is suspended in freezing buffer, quickly frozen in liquid nitrogen and stored at -80°C The protein content of the mitochondria samples was assayed by the Pierce Rapid Gold BCA Protein Assay Kit (Thermo Fisher Scientific, Rockford, IL)

[0608] For IC50 determination, mitochondria were diluted in assay buffer (Tris-HCI, KH2PO4, Sorbitol; MgSO4, Bovine Serum Albumin) to a final protein concentration of 150 pg-'mL (mitochondrial protein concentration) Different concentrations of inhibitors were added to the mitochondria suspension and incubated for 30 min To start the ATP synthesis reaction, 5 mM of succinate and 67 pM of ADP (final concentrations) were added The reaction was stopped after 60 min by adding 1 75 pF of 60% perchloric acid and by placing the reaction mixture on ice for 10 min This was followed by a centrifugation for 10 min at 15,300 x g, and the supernatant was transferred to another tube containing 11 5 pL of 1 M KOH to neutralize the acid The mixture was then incubated for 3 min on ice and centrifuged for 10 min at 15,300 x g A small volume of the reaction was transferred to a white 96-well plate. The plate was then read on a luminometer by adding 50 pL of the luciferin / luciferase reagent from the ATPlite™ 1 step Luminescence Assay System kit (PerkinElmer, Waltham, MA) Luciferase, in the presence of oxygen, ATP and Mg2+ions, oxidizes luciferin to oxyluciferin and emits light This light was quantified by a luminometer and is proportional to the quantity of ATP synthesized by the ATP synthase The concentration of inhibitor preventing 50% of the production of ATP by the ATP synthase in mitochondna (IC50 in pM) was determined using the GraphPrism™ software (version 920), using the tool log(inhibitor) vs. response-variable slope (four parameters)

[0609] EXAMPLE 2: TM-01

[0610]

[0611] TM-01

[0612] TM-01 [3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propan-1-ol] was synthetized following General Procedure B, C.2, C.3, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH(NH4OH))

[0613] 1H NMR (400 MHz, Methanol-d4) 5 7.42 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.18- 7.08 (m, 2H), 4.54 - 4.37 (m, 2H), 4.27 (d, J = 128 Hz, 1H), 4 10 (d, J = 48 Hz, 2H), 3 76 - 3 47 (m, 5H), 3 43 - 3 14 (m, 5H), 283 (s, 3H), 2 11 - 1 86 (m, 6H), 1 76 (t, J = 57 Hz, 4H)

[0614] 13C NMR (101 MHz, MeOD) 6 160.48, 132.48, 131.59, 124.73, 117.83, 117.77, 71.42, 65.49, 60.75, 60.25, 60.10, 57.85, 5552, 5487, 4047, 2796, 2792, 2774, 24 16 EXAMPLE 3: TM-167

[0615] TM-167 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-4-methylbenzenesulfonamide] (435 mg, 80 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH)) EXAMPLE 4: TM-168

[0616]

[0617] TM-168 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)methanesulfonamide] (37 mg, 52 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: HPLC prep / MS (H; O: ACN: MeOH, 0.1% Formic Acid).

[0618]

[0619] TM-169 [N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-4-methylbenzenesulfonamide] (27 mg, 63 %) was synthetized following General Procedure B, C.1, C.3, D, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH)) TM-199 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-4-methoxybenzenesulfonamide] (26 mg, 62 %) was synthetized following General Procedure B, C.2, F, E.1, Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0620] EXAMPLE 7: TM-200

[0621]

[0622] TM-200 [4-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)thiomorpholine 1,1-dioxide] (33 5 mg, 70 %) was synthetized following General Procedure B, C.1, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0623] EXAMPLE S: TM-201

[0624]

[0625] TM-201 [N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-4-methoxybenzenesulfonamide] (25 mg, 58 %) was synthetized following General Procedure B, C.1, C.3, D, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH)) EXAMPLE 9: TM-203

[0626]

[0627] TM-203 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)naphthalene-2-sulfonamide] (26.8 mg, 82 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0628] EXAMPLE 10: TM-204

[0629]

[0630] TM-204 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)quinoline-8-sulfonamide] (28 mg, 74 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH)) EXAMPLE 11: TM-205

[0631]

[0632] TM-205 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-4-cyano-N-(3-hydroxypropyl)benzenesulfonamide] (20 mg, 93 %) was synthetized following General Procedure B, C.2, F, El; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% NH4OH)

[0633] EXAMPLE 12: TM-206

[0634]

[0635] TM-206 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-4-butyl-N-(3-hydroxypropyl)benzenesulfonamide] (23 mg, 63 %) was synthetized following General Procedure B, C.2, F, E1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% formic acid)

[0636] 1H NMR (400 MHz, MeOD) 57.77 (d, J = 8.37 Hz, 2H), 7.41 (d, J = 8.37 Hz, 2H), 7.22 (t, J = 7.86 Hz, 1H), 6.99 (s, 1H), 690-686 (m, 2H), 431 (s, 2H), 425-422 (m, 1H), 398 (d, J = 461 Hz, 2H), 3 37 (t, J = 6.15 Hz, 2H), 3.23-1.19 (m, 7H), 3 06-3 01 (m, 1H), 272 (t, J = 769 Hz, 2H), 1 84-1 83 (m, 4H), 1 70-1 68 (m, 4H), 1 66-1 60 (m, 2H), 1 56-1 49 (m, 2H), 1 43-1 33 (m, 2H), 096 (t, J = 734 Hz, 3H)

[0637] 13C NMR (101 MHz, MeOD) 6 160.49, 150.0, 140.39, 138.47, 130.84, 130.54, 128.50, 122.22, 115.50, 115.27, 71.57, 6688, 6080, 6037, 5678, 5350, 4723, 3659, 3469, 3256, 28 19, 2595, 23 49, 1437 EXAMPLE 13: TM-207

[0638] TM-207 [N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)naphthalene-1-sulfonamide] (24 mg, 55 %) was synthetized following General Procedures, C.1, C.3, D, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% formic acid)

[0639] EXAMPLE 14: TM-214

[0640] TM-214 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-[1,r biphenyl]-4-sulfonamide] (21 0 mg, 20%) was synthetized following General Procedure B, C.2, F, E.1, Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Add)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.56 (s, 0.5H, HCO2H), 7.94-7.90 (m, 2H, Harom), 7.85-7.81 (m, 2H, Harom), 7.71-7.67

[0641]

[0642] (m, 752-746 (m, 744-739 (m, 723 (t, 1H, J = 8.1 694-686 (m, 437 (bs, 2H), 4.18 (td, 1H, J = 4.7 Hz, J = 8.9 Hz), 3.97-3.89 (m, 2H), 3.41 (t, 2H, J = 6.2 Hz), 3.30-3.25 (m, 2H), 3.13-3.05 (m, 5H), 2.94 (dd, 1H, J = 9.3 Hz, J = 13.1 Hz), 1.84-1.75 (m, 4H), 1.72-1.64 (m, 4H), 1.62-1.54 (m, 2H)

[0643] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.4 (HCO2H), 160.4 (Cq), 146.8 (Cq), 140.5 (Cq), 140.0 (Cq), 139.8 (Cq), 130.7 (CHarom), 130.2 (CHarom), 129.6 (CHarom), 128.9 (CHarom), 128.8 (CHarom), 128.3 (CHarom), 122.1 (CHarom), 115.3 (CHarom), 115.2 (CHarom), 71.4 (CH2), 66.9 (CH), 60.7 (CH2), 60.2 (CH2), 56.6 (CH2), 53.2 (CH2), 47.0 (CH2), 32.4 (CH2), 28.0 (CH2), 26.0 (CH2).

[0644] HRMS (ESI+): m / z calculated for C31H41N2O5S [M+H]+: calc. 553.2731; found: 553.2740 EXAMPLE 15: TM-215

[0645]

[0646] TM-215 [N-(3-((3-(3-(azepan- 1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-[1, T-biphenyl]-4-sulfonamide] (17 0 mg, 1 1%) was synthetized following General Procedure B, C.1, C.3, D, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Add)

[0647] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 1.7H, HCO2H), 7.93-7.89 (m, 2H, Harom), 7.84-7.80 (m, 2H, Harom), 7.69-7.65

[0648]

[0649] (m, 7 51-7 46 (m, 7 44-7 39 (m, 7 34 (t, 1H, J = 7 9 7 12-7 10 (m, 7 04-7 00 (m, 2H, Harem), 4 38 (dtd, 1H, J = 2 9 Hz, J = 4.9 Hz, J= 7 7 Hz), 4 07 (dd, 1H, J = 3 9 Hz, J= 8 8 Hz), 4 04 (dd, 1H, J = 4 1 Hz, J = 8 8 Hz), 3 99 (bs, 2H), 3 45 (dd, 1H, J = 2 8 Hz, J = 13.3 Hz), 3 41 (t, 4H, J= 5.3 Hz), 3 27 (dd, 1H, J = 10.5 Hz, J = 13 2 Hz), 3 00-2 90 (m, 4H), 2 55 (s, 3H), 1 95-1 83 (m, 6H), 1 76-1 67 (m, 4H)

[0650] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.9 (HCO2H), 160.3 (Cq), 146.8 (Cq), 140.5 (Cq), 140.2 (Cq), 135.8 (Cq), 131.2 (CHarom), 130.2 (CHarom), 129.6 (CHarom), 128.8 (CHarom), 128.6 (CHarom), 128.3 (CHarom), 124.4 (CHarom), 117.4 (CHarom), 116.6 (CHarom), 71.3 (CH2), 65.6 (CH), 61.4 (CH2), 60.2 (CH2), 56.3 (CH2), 54.8 (CH2), 41.7 (CH2), 40.9 (CH3), 28.0 (CH2), 26.2 (CH2), 24.1 (CH2)

[0651] HRMS (ESI+): m / z calculated for C32H44N3O4S [M+H]+: calc. 566.3047; found: 566.3063

[0652] EXAMPLE 16: TM-225

[0653]

[0654] TM-225 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)- 1-phenylmethanesulfonamide] (24.7 mg, 63 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Add) EXAMPLE 17: TM-226

[0655]

[0656] TM-226 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-2-(methylsulfonyl)benzenesulfonamide] (21 mg, 57 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0657] EXAMPLE 18: TM-227

[0658]

[0659] TM-227 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)benzo[d][1,3]dioxole-5-sulfonamide] (24 mg, 62 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid) EXAMPLE 19: TM-228

[0660]

[0661] TM-228 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-4-(1H-pyrazol-1-yl)benzenesulfonamide] (26 mg, 65 %) was synthetized following General Procedure B, C.2, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0662] EXAMPLE 20: TM-229

[0663]

[0664] TM-229 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-4-(1H-pyrazol-1-yl)benzenesulfonamide] (19 mg, 50%) was synthetized following General Procedures, C.2, F, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid) EXAMPLE 21: TM-231

[0665]

[0666] TM-231 [N-(3-aminopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-4-butylbenzenesulfonamide] (220 mg, 19%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0667] 1H NMR (400 MHz, CD3OD) 6 (ppm) 7.80-7.76 (m, 2H, Harm), 7.43 (d, 2H, J = 8.1 Hz, Harom), 7.22 (t, 1H, J = 8.0 Hz, Harom), 6.94-6.91 (m, 1H, Harom), 6.91-6.86 (m, 2H, Harom), 4.29 (bs, 2H), 4.10-4.02 (m, 1H), 3.98 (dd, 1H, J = 4.0 Hz, J = 9.8 Hz), 3.90 (dd, 1H, J = 5.8 Hz, J = 9.8 Hz), 3.22 (t, 2H, J = 6.9 Hz), 2.88-2.77 (m, 5H), 2.76-2.69 (m, 3H), 2.66 (t, 2H, J = 7.2 Hz), 1.75-1.68 (m, 4H), 1.68-1.62 (m, 6H), 1.62-1.53 (m, 2H), 1.39 (dq, 2H, J = 7.3 Hz, J = 14.6 Hz), 0.97 (t, 3H, J = 7.3 Hz)

[0668] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.7 (Cq), 150.0 (Cq), 139.8 (Cq), 137.8 (Cq), 130.8 (CHarom), 130.5 (CHarom), 128.4 (CHarom), 122.0 (CHarom), 115.6 (CHarom), 115.3 (CHarom), 71.8 (CH2), 68.5 (CH), 61.3 (CH2), 57.1 (CH2), 53.9 (CH2), 47.2 (CH2), 38.7 (CH2), 36.5 (CH2), 34.5 (CH2), 30.0 (CH2), 28.2 (CH2), 28.1 (CH2), 23.4 (CH2), 14.2 (CH3)

[0669] HRMS (ESI+): m / z calculated for C29H46N3O4S [M+H]+: calc. 532.3204; found: 532.3223

[0670] EXAMPLE 22: TM-232

[0671]

[0672] TM-232 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-4-butyl-N-(3-((4 butylphenyl) sulfonamido) propyl) benzene sulfonamide] (18 mg, 40%) was synthetized following General Procedures, C.1, F, D, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH)) EXAMPLE 23: TM-249

[0673]

[0674] TM-249 [N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-[1,1'-biphenyl]-2-sulfonamide] (190 mg, 44%) was synthetized following General Procedure B.2, C.3, D, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0675] 1H NMR (400 MHz, CDCI3) 6 (ppm) 8.12 (dd, J = 7.9, 1.4 Hz, 1H), 7.57 (td, J = 7.5, 1.4 Hz, 1H), 7.53 – 7.43 (m, 3H), 7.42 – 7.35 (m, 3H), 7.32 (dd, J = 7.5, 1.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.87 – 6.71 (m, 3H), 4.05 – 3.97 (m, 1H), 3.95 (dd, J = 4.9, 1.8 Hz, 1H), 3.32 (s, 2H), 2.86 – 2.64 (m, 6H), 2.59 (dd, J = 12.5, 9.8 Hz, 1H), 2.27 (t, J = 6.4 Hz, 2H), 2.02 (s, 3H), 1.75 – 1.52 (m, 10H), 1.51 – 1.40 (m, 2H)

[0676] 13C NMR (101 MHz, CDCI3) b (ppm) 159.0, 140.6, 140.1, 139.3, 138.3, 132.5, 132.2, 129.6, 129.3, 129.3, 128.4, 128.1, 127.9, 121.6, 115.0, 113.4, 70.3, 66.0, 62.3, 60.5, 56.1, 55.9, 55.8, 42.4, 42.2, 28.8, 28.1, 27.8, 27.1, 27.0, 26.8, 26.3.

[0677] EXAMPLE 24: TM-250

[0678]

[0679] TM-250 [N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-[1,1'-biphenyl]-3-sulfonamide] (230 mg, 53%) was synthetized following General Procedure B.2. C.3, D, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0680] 1H NMR (400 MHz, CDCI3) 6 (ppm) 8.07 (t, J = 1.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.61 - 7.52 (m, 3H), 7.48 - 7.35 (m, 3H), 7.17 (dd, J = 8.3, 7.4 Hz, 1H), 6.88 (t, J = 2.0 Hz, 1H), 6.83 (dd, J = 7.9, 2.1 Hz, 2H), 4.04 - 3.95 (m, 3H), 3.40 (s, 2H), 3.14 - 3.05 (m, 2H), 2.83 - 2.72 (m, 3H), 2.71 - 2.61 (m, 2H), 2.61 - 2.50 (m, 1H), 2.43 (t, J = 5.7 Hz, 2H), 1.75 - 1.50 (m, 13H).

[0681] 13C NMR (101 MHz, CDCI3) 5 (ppm) 159.3, 142.3, 141.0, 139.7, 139.5, 131.0, 129.6, 129.1, 128.3, 127.3, 125.7, 125.6, 121.5, 114.9, 113.9, 70.5, 66.1, 62.9, 60.4, 57.3, 55.9, 53.6, 44.3, 42.0, 28.5, 27.0, 24.8. EXAMPLE 25: TM-251

[0682]

[0683] TM-251 [N-(3-aminopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-[1,1'-biphenyl]-4-sulfonamide] (200 mg, 19%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0684] 1H NMR (400 MHz, CD3OD) 6 (ppm) 7.95-7.91 (m, 2H, Harom), 7.86-7.82 (m, 2H, Harom), 7.72-7.67 (m, 2H, Harom), 7.52-7.46 (m, 2H, Harom), 7.45-7.40 (m, 1H, Harom), 7.22 (dd, 1H, J = 7.7 Hz, J = 8.2 Hz, Harom), 6.92-6.84 (m, 3H, Harom), 4.36 (bs, 2H), 4.01-3.94 (m, 1H), 3.92 (dd, 1H, J = 3.9 Hz, J = 9.7 Hz), 3.84 (dd, 1H, J = 5.8 Hz, J = 9.7 Hz), 3.26 (t, 2H, J = 7.0 Hz), 2.75-2.65 (m, 5H), 2.59 (dd, 2H, J = 7.4 Hz, J = 13.2 Hz), 1.68-1.52 (m, 11H)

[0685] 13C NMR (101 MHz, CDaOD) 6 (ppm) 160.7 (Cq), 146.9 (Cq), 140.5 (Cq), 139.7 (Cq), 139.6 (Cq), 130.7 (CHarom), 130.2 (CHarom), 129.7 (CHarom), 128.9 (CHarom), 128.8 (CHarom), 128.3 (CHarom), 122.0 (CHarom), 115.4 (CHarom), 71.8 (CH2), 68.7 (CH), 61.4 (CH2), 57.1 (CH2), 53.4 (CH2), 47.2 (CH2), 39.1 (CH2), 31.3 (CH2), 28.6 (CH2), 28.1 (CH2)

[0686] HRMS (ESI+): m / z calculated for C31H42N3O4S [M+H]+: calc. 552.2891; found: 552.2879

[0687] EXAMPLE 26: TM-252

[0688]

[0689] TM-252 [N-(3-aminopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-[1,1'-biphenyl]-2-sulfonamide] (240 mg, 20%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0690] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.14 (dd, 1H, J = 1.2 Hz, J = 8.0 Hz, Harom), 7.67 (td, 1H, J = 1.3 Hz, J = 7.5 Hz, Harom), 7.58 (td, 1H, J = 1.4 Hz, J = 7.8 Hz, Harom), 7.42-7.36 (m, 3H, Harom), 7.35-7.30 (m, 3H, Harom), 7.16 (t, 1H, J = 7.9 Hz, Harom), 6.85 (dd, 1H, J = 1.9 Hz, J = 8.2 Hz, Harom), 6.90-6.64 (m, 2H, Harom), 4.06-3.99 (m, 1H), 3.93 (dd, 1H, J = 4.0 Hz, J = 9.8 Hz), 3 86 (dd, 1 H, J = 5 8 Hz, J = 9 8 Hz), 3 83 (bs, 2H), 2 85-2 77 (m, 4H), 2 76-2 63 (m, 4H), 2 44 (t, 2H, J = 7 2 Hz), 1 72- 1 61 (m, 8H), 1 42-1 34 (m, 2H)

[0691] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.6 (Cq), 142.8 (Cq), 140 8 (Cq), 140 3 (Cq), 139 7 (Cq), 134 4 (CHarom), 133.7 (CH arom ), 131 2 (CH arom ), 130 9 (CH arom ), 130 6 (CH arom ), 129 1 (CH arom ), 129 0 (CH arom ), 128 7 (CH arom ), 122 0 (CH arom), 1 15 6 (CHarom), 115.1 (CHarom), 71.8 (CH2), 68 7 (CH), 61 4 (CH2), 57 1 (CH2), 52 1 (CH2), 45 9 (CH2), 38 9 (CH2), 30 4 (CH2), 28 5 (CH2), 28 1 (CH2)

[0692] HRMS (ESI+): m / z calculated for C31H42N3O4S [M+H]+: calc. 552.2891; found: 552.2905

[0693] EXAMPLE 27: TM-253

[0694]

[0695] TM-253 [N-(3-aminopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-[1, T-biphenyl]-3-sulfonamide] (29 0 mg, 21%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0696] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.02 (t, 1H, J = 1.7 Hz, Harom), 7.91 (ddd, 1H, J = 1.1 Hz, J = 1.7 Hz, J = 7.8 Hz, Harom), 7

[0697]

[0698] 85 (ddd, 1H, J = 1 1 Hz, J = 1 8 Hz, J = 7 8 Hz, Harem), 7 69 (d, 1H, J = 7 8 Hz, Harom), 7 66-7 62 (m, 2H, Harem), 7 52-7 46 (m, 2H, Harcm), 7 43-7 38 (m, 1H, Harem), 7 20 (dd, 1 H, J = 7 6 Hz, J = 8 9 Hz, Ha™), 6 90-6 83 (m, 3H, Harem), 4 38 (bs, 2H), 4 02-3 95 (m, 1 H), 3 90 (dd, 1H, J = 3 9 Hz, J = 9 8 Hz), 3 82 (dd, 1H, J = 5.8 Hz, J = 9 8 Hz), 3 31-3 25 (m, 3H), 2 79-2 66 (m, 5H), 2 64-2 56 (m, 2H), 1 71-1 53 (m, 10H)

[0699] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.7 (Cq), 143.9 (Cq), 141.8 (Cq), 140.5 (Cq), 139.6 (Cq), 132.4 (CHarom), 131.1 (CHarom), 130.7 (CHarom), 130.2 (CHarom), 129.4 (CHarom), 128.2 (CHarom), 127.0 (CHarom), 126.3 (CHarom), 122.0 (CHarom), 115.5 (CHarom), 115.3 (CHarom), 71.8 (CH2), 68.7 (CH), 61.4 (CH2), 57.1 (CH2), 53.3 (CH2), 47.2 (CH2), 39.1 (CH2), 31.2 (CH2), 28.6 (CH2), 28.1 (CH2)

[0700] HRMS (ESH-): m / z calculated for C31H42N3O4S [M+H]+: calc 552 2891; found: 552 2878 EXAMPLE 28: TM-254

[0701]

[0702] TM-254 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-[1, 1'-biphenyl]-3-sulfonamide] (21 0 mg, 55%) was synthetized following General Procedure B.2, C.2, F, E.1; Purification: chromatography on silica gel (DCM: MeOH(NH4OH))

[0703] 1H NMR 1H NMR (400 MHz, CDCI3) 6 (ppm) 8.02 (t, J = 1.6 Hz, 1 Harem), 7.85 – 7.77 (m, 2Harom), 7.64 – 7.56 (m, 3Harom), 7

[0704]

[0705] 7.51 – 7.44 (m, 2Harom), 7.43 – 7.37 (m, 1Harom), 6.82 (t, J = 9.1 Hz, 3Harom), 4.33 (s, 2H), 4.14 – 4.06 (m, 1H), 3.92 (dd, J = 9.7, 5.2 Hz, 1H), 3.86 (dd, J = 9.7, 5.2 Hz, 1H), 3.57 (t, J = 5.7 Hz, 2H), 3.30 (t, J = 6.7 Hz, 2H), 2.99 – 2.80 (m, 5H), 2.68 (dd, J = 12.5, 10.0 Hz, 1H), 1.81 – 1.70 (m, 4H), 1.68 – 1.61 (m, J = 5.8, 2.9 Hz, 4H), 1.54 – 1.46 (m, 2H)

[0706] 13C NMR 13C NMR (101 MHz, CDCI3) 6 (ppm) 158.99 (Cq), 142.66 (Cq), 140.25 (Cq), 139.33 (Cq), 137.96 (Cq), 131.43 (CHarom), 129.85 (CHarom), 129.84 (CHarom), 129.22 (CHarom), 128.44 (CHarom), 127.35 (CHarom), 125.80 (CHarom), 125.6 (CHarom), 121.22 (CHarom), 114.53 (CHarom), 114.48 (CHarom), 70.07 (CH2), 65.62 (CH), 60.90 (CH2), 58.88 (CH2), 56.07 (CH2), 52.88 (CH2), 45.43 (CH2), 31.07 (CH2), 27.08 (CH2), 26.98 (CH2)

[0707] EXAMPLE 29: TM-265

[0708]

[0709] TM-265 [N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-N-(3-hydroxypropyl)-[1, T-biphenyl]-3-sulfonamide] (16 mg, 45%) was synthesized following General Procedure B.2, C.1, J, E.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH(NH4OH))

[0710] 1H NMR (400 MHz, MeOD) 6 7.33 - 7.16 (m, 5H), 7.16 - 7.11 (m, 1 H), 6.90 - 6.73 (m, 2H), 6.71 - 6.58 (m, 1 H), 4.65 -4 36 (m, 1H), 4 35 - 4 17 (m, 1 H), 4 15 - 3 86 (m, 4H), 3 20 - 2 94 (m, 2H), 2 93 - 2 79 (m, 6H), 2 79 - 2 51 (m, 4H), 1 78 - 1 59 (m, 10H)

[0711] 13C NMR (101 MHz, MeOD) 5 177.30, 160.95, 139.65, 138.66, 131.22, 130.64, 130.60, 130.53, 129.70, 129.66, 127.99, 127 89, 119 93, 114 69, 1 14 18, 71 90, 68 65, 61 34, 57 09, 53 93, 51 77, 49 00, 44 93, 43 37, 38 73, 28 67, 28 40, 28 33, 28 11 EXAMPLE 30: TM-266

[0712]

[0713] TM-266 [(2R)-2-amino-N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-3-phenylpropanamide| (19 mg, 46%) was synthefized following General Procedure B.2, C.1, C.3, J, E.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH (NH4OH))

[0714] 1H NMR (400 MHz, MeOD) 6 7.31 - 7.16 (m, 6H), 6.98 - 6.92 (m, 1H), 6.91 - 6.82 (m, J = 8.2, 7.5,.7 Hz, 2H), 4.11 - 404 (m, J = 84, 46 Hz, 1H), 403 - 389 (m, J = 156, 98, 49 Hz, 2H), 3 47 (d, J = 70 Hz, 1H), 3 44 (s, 2H), 3 23 - 3 06 (m, 2H), 297 - 268 (m, J = 287, 13 2, 73 Hz, 8H), 230 (t, J = 67 Hz, 2H), 2 15 (s, 3H), 1 75 - 1 55 (m, 10H)

[0715] 13C NMR (101 MHz, MeOD) 6 176.46, 160.46, 141.05, 138.90, 130.44, 130.35, 129.56, 127.77, 123.05, 116.61, 114.50, 71 80, 6855, 63 13, 61 35, 5788, 5707, 5573, 4900, 4261, 4235, 3860, 28 19, 28 12, 2756

[0716] EXAMPLE 31: TM-267

[0717]

[0718] TM-267 [3-(((4-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-propyl-[1, T-biphenyl]-2-yl)melhyl)(melhyl)amino)propan-1-ol] (303 mg, 43%) was synttietized following General Procedure A. C.2, C.3, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0719] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 0.7H, HCO2H), 724-720 (m, 2H, Harom), 7 19-7 13 (m, 4H, Harom), 694 (dd, 1H, J = 27 Hz, J = 8.5 Hz, Harcni), 432 (dtd, 1H, J = 3.5 Hz, J = 4.9 Hz, J = 8.4 Hz), 406 (d, 2H, J = 50 Hz), 3.59 (bs, 2H), 3 54 (t, 2H, J = 6 1 Hz), 3 32-3 25 (m, 5H), 3 14 (dd, 1H, J = 97 Hz, J = 13 1 Hz), 263 (t, 2H, J - 75 Hz), 246 (t, 2H, J= 72 Hz), 2 14 (s, 3H), 1.94-1.86 (m, 4H), 1 78-1 55 (m, 8H), 098 (t, 3H, J= 73 Hz)

[0720] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.3 (HCOjH), 159.3 (Cq), 1426 (Cq), 139.5 (Cq), 137.5 (Cq), 1373 (Cq), 1324 (CHarom), 130.7 (CHarom), 129.3 (CHarom), 116.4 (CHarom), 114.8 (CH.rom), 71.4 (CH2), 664 (CH), 61 9 (CH2), 605 (CH2), 599 (CH2), 565 (CH2), 56 1 (CH2), 422 (CH3), 387 (CH2), 30 1 (CH2), 280 (CH2), 258 (CH2), 253 (CH2), 142 (CH3) HRMS (ESI+): m / z calculated for C29H45N2O3[M +H]+: calc 469 3425; found: 469 3430

[0721] EXAMPLE 32: TM-279

[0722]

[0723] TM-279 [N-(3-ammopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-4-bromobenzenesulfonamide] (12 0 mg, 1 1%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0724] 1H NMR (400 MHz, CDjOD) 6 (ppm) 8.50 (s, 1.0H, HCO2H), 7 79 (bs, 4H, Harom), 7 29-7 24 (m, 1H, Haram), 6 95-6 90 (m, 3H, Harom), 4 40-4 34 (m, 1H), 4 34 (bs, 2H), 3 98 (d, 2H, J = 5 0 Hz), 3 46-3 40 (m, 5H), 3 31-3 27 (m, 2H), 3 25 (dd, 1H, J = 7 7 Hz, J = 10 4 Hz), 2 85-2 77 (m, 2H), 1 99-1 89 (m, 4H), 1 80-1 72 (m, 4H), 1 70 (dt, 2H, J = 7 0 Hz, J = 14 4 Hz)13C NMR ( 101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 3 (Cq), 139 8 (Cq), 139 5 (Cq), 133 8 (CH,rom). 131 0 (CH,™), 130 1 (CHarom), 128 8 (Cq), 122 4 (CHarom), 115.6 (CHarom), 1 15 4 (CHarom), 71 2 (CH2), 65 7 (CH), 60 2 (CH2), 56 4 (CH2), 53 8 (CH2), 47 1 (CH2), 38 1 (CH2), 28 0 (CH2), 27 9 (CH2), 24 3 (CH2)

[0725] HRMS (ESH-): m / z calculated for C25H37BrN3O4S [M+Hp: calc 554 1683, found: 554 1673

[0726] EXAMPLE 33: TM-280

[0727]

[0728] TM-280

[0729] TM-280 [N-(3-aminopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-3-bromobenzenesulfonamide] (18 0 mg, 13%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0730] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 1.4H, HCO2H), 7 98 (t, 1H, J = 1 7 Hz, Harcm), 7 88-7 82 (m, 2H, Harom), 7 54 (

[0731]

[0732] t, 1H, J = 8 0 Hz, Harcm), 7 26 (t, 1 H, J = 8 0 Hz, Harcm), 6 95-6 90 (m, 3H, Harcm), 4 41-4 34 (m, 1 H), 4 37 (bs, 2H), 4 00 (dd, 1 H, J = 5 0 Hz, J = 9 9 Hz), 3 97 (dd, 1H, J = 5 0 Hz, J = 9 9 Hz), 3 47-3 40 (m, 5H), 3 34-3 29 (m, 2H), 3 26 (dd, 1H, J = 10 4 Hz, J = 13 2 Hz), 2 86-2 80 (m, 2H), 1 98-1 90 (m, 4H), 1 79- 1 68 (m, 6H)13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 1603 (Cq), 1427 (Cq), 139 4 (Cq), 1372 (Cq), 132.4 (CHaroai), 131 0 (CH arom ), 1329 (CH arom ), 127 1 (CH arom ), 124 1 (CH arom ), 1224 (CH arom ), 1157 (CH arom ), 1155 (CH arom ), 71 2 (CH2), 667 (CH), 602 (CH2), 564 (CH2), 53 8 (CH2), 472 (CH2), 380 (CH2), 280 (CH2), 279 (CH2), 243 (CH2)

[0733] HRMS (ESH-): m / z calculated for C25H37BrN3O4S [M+H]+; calc 554 1683; found: 554 1688

[0734] EXAMPLE 34: TM-281

[0735]

[0736] TM-281 [N-(3-aminopropyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-2-bromobenzenesulfonamide] (160 mg, 10%) was synthetized following General Procedure B, C.1, F, E.1, D; Purification: HPLC prep / MS (HjO: ACN: MeOH, 0.1% Formic Acid)

[0737] 1H NMR (400 MHz, CD3OD) 6 (ppm) B.42 (s, 1.3H, HCO2H), 8.15-8 10 (m, 1H, Harom), 789-785 (m, 1H, Haram), 759-750 (m, 2H, Harom), 727-720 (m, 1H, Harom), 692 687 (m, 3H, Harem), 453 (bs, 2H), 439 (dtd, 1H, J = 28 Hz, J = 5.0 Hz, J = 78 Hz), 399 (dd, 1H, J = 4 0 Hz, J = 8.8 Hz), 3 96 (dd, 1H, J = 40 Hz, J = 88 Hz), 3 52-3 39 (m, 7H), 3 28 (dd, 1H, J = 9.5 Hz, J= 123 Hz), 284-277 (m, 2H), 2.00-191 (m, 4H), 1.86-1 72 (m, 6H)

[0738] 13C NMR (101 MHz, CD3OD) 6 (ppm) 168.9 (HCO2H), 1602 (Cq), 1403 (Cq), 139 2 (Cq), 137.1 (CHaroia), 1354 (Cq), 133 3 (CH arom ), 1309 (CH arom ), 129.2 (CH arom ), 1224 (CH arom ), 121 2 (CH arom ), 1156 (CH arom ), 1153 (CH arom ), 71 2 (CH2), 655 (CH), 602 (CH2), 564 (CH2), 524 (CH2), 460 (CH2), 38.1 (CH2), 280 (CH2), 270 (CH2), 242 (CH2)

[0739] HRMS (ESH-): m / z calculated for C25H37BrN3O4S [M+H]+: calc 554 1683; found: 554 1673

[0740] EXAMPLE 35: TM-292

[0741]

[0742] TM-292 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-propyl-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (264 mg, 59%) was synthetized following General Procedure C.2, C.3, A, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 7.52 (d, 2H, J = 8 2 Hz, Harom), 724 (d, 2H, J = 8 2 Hz, Harom), 7 15 (bs, 1H, Harom), 7 09 (t, 1H, J = 2 0 Hz, Harom), 6 91-6 90 (m, 1H, Harom), 4 12-3 96 (m, 3H), 3 63 (t, 2H, J = 6 2 Hz), 3 56 (bs, 2H), 2 82- 2 72 (m, 5H), 2 71-2 65 (m, 1H), 2 62 (t, 2H, J = 7 5 Hz), 2 56 (t, 2H, J = 7 3 Hz), 2 25 (s, 3H), 1 82-1 74 (m, 2H), 1 71- 1 58 (m, 10H), 0 96 (t, 3H, J = 7 3 Hz)

[0743] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.9 (Cq), 143 9 (Cq), 143 2 (Cq), 141 2 (Cq), 1396 (Cq), 129 9 (CHarom), 127.9 (CHarom), 121 6 (CHarom), 115 2 (CHarom), 113 2 (CHarom), 72 0 (CH2), 69 0 (CH), 63 3 (CH2), 62.1 (CH2), 61 5 (CH2), 57 2 (CH2), 56 0 (CH2), 42 4 (CH3), 38 7 (CH2), 30 5 (CH2), 28 7 (CH2), 282 (CH2), 25 8 (CH2), 14 1 (CH3)

[0744] HRMS (ESH-): m / z calculated for C29H45N2O3 [M+H]+: calc 469 3425; found: 429 3416

[0745] EXAMPLE 36: TM-298

[0746] H OH

[0747] 0.8equiv

[0748] •H I

[0749]

[0750] TM-298

[0751] TM-298 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (3 0 mg, 7%) was syn thetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: AON: MeOH, 0 1% Formic Acid)

[0752] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.47 (s, 0.8H, HCO2H), 7 68-7 63 (m, 2H, Harom), 7 49-743 (m, 2H, Harem), 7 41-7 35 (m, 2H, Harom), 7 32-7 29 (m, 1H, Harom), 7 19-7 16 (m, 1H, Harom), 4 43 (dtd, 1H, J = 2 9 Hz, J = 4 8 Hz, J = 7 6 Hz), 4 30 (bs, 2H), 4 15 (d, 2H, J = 4 9 Hz), 3 69 (t, 2H, J = 5 8 Hz), 3 50 (dd, 1H, J = 28 Hz, J = 13 2 Hz), 3 48-3 42 (m, 4H), 3 34- 3 27 (m, 1H), 3 22 (t, 2H, J = 7 5 Hz), 278 (s, 3H), 204-1 90 (m, 6H), 1 81-1 71 (m, 4H)

[0753] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.4 (HCO2H), 160 9 (Cq), 145 1 (Cq), 141 2 (Cq), 134 4 (Cq), 130 0 (CHarom), 129.1 (CHarom), 128 1 (CHarom), 123.3 (CHarom), 1 16.3 (CHarom), 115.8 (CHarom), 71.5 (CH2), 65 6 (CH), 61 2 (CH2), 606 (CH2), 60 1 (CH2), 56 4 (CH2), 55 7 (CH2), 408 (CH3), 28 1 (CH2), 28 0 (CH2), 24 2 (CH2)

[0754] HRMS (ESH-): m / z calculated for C26H39N2O3 [M+H]+: calc 427 2955; found: 427 2962 EXAMPLE 37: TM-311

[0755]

[0756] TM-311 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-isopropyl-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (3 0 mg, 7%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0757] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.56 (s, 1.45H, HCO2H), 758 (d, 2H, J = 8.3 Hz, Harcm), 735 (d, 2H, J = 82 Hz, Harom), 730 (S, 1H, Harom), 722 (bs, 1H, Harom), 703 (bs, 1H, Harem), 444-437 (m, 1H), 4 13 (d, 2H, J = 49 Hz), 392 (bs, 2H), 3 69 (t, 2H, J = 5.9 Hz), 3 46 - 3 39 (m, 5H), 3 28 (dd, 1H, J = 103 Hz, J = 13 1 Hz), 298 (dt, 1H, J = 6.9 Hz, J = 138 Hz), 289 (t, 2H, J = 7 2 Hz), 252 (s, 3H), 1 99-1 86 (m, 6H), 1 83-1 73 (m, 4H), 1 32 (s, 3H), 1 30 (s, 3H)

[0758] 13C NMR (101 MHz, CD.-OD) d (ppm) 160.7 (Cq), 1499 (Cq), 144 5(Cq), 1392 (Cq), 1280 (CHarOm), 1279 (CHa™n), 122.5 (CHarom), 1154 (CH 1142 (CHarom), 71 4 (CH2), 658 (CH), 61 5 (CH2), 602 (CH2), 564 (CH2), 559 (CH2), 41 7 (CH3), 35 1 (CH), 294 (CH2), 280 (CH2), 245 (CH3), 244 (CH3).

[0759] HRMS (ESH-): m / z calculated forCagH^Oa [M+H]+: calc 4693425; found: 4693431

[0760] EXAMPLE 38: TM-312

[0761]

[0762] TM-312 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-methoxy-[1,r-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (65 mg, 15%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0763] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.47 (s, 0.8H, HCO2H), 762-757 (m, 2H, Harcm), 735 (bs, 1H, Harcm), 728-724 (m, 1H, Harcm), 7 13-7 10 (m, 1H, Harcm), 704-699 (m, 2H, Harom), 442 (dtd, 1H, J = 28 Hz, J = 48 Hz, J = 76 Hz), 428 (bs, 2H), 4 13 (d, 2H, J = 49 Hz), 3 84 (s, 3H), 3 69 (t, 2H, J = 57 Hz), 3 50 (dd, 1H, J = 28 Hz, J = 13 2 Hz), 3 48-3 42 (m, 4H), 3 34-3 26 (m, 1H), 325-3 19 (m, 2H), 278 (s, 3H), 203-1 90 (m, 6H), 1 81-1 71 (m, 4H)13C NMR (101 MHz, CD3OD) 6 (ppm) 161.3 (Cq), 1608 (Cq), 1441 (Cq), 1342 (Cq), 1335 (Cq), 1292 (CHarom), 1228 (CHarom), 115.6 (CHarom), 115.4 (CHarom), 115.2 (CHarom), 71.5 (CH2), 656 (CH), 61 2 (CHj), 606 (CH3), 60.1 (CH2) 558 (CH2), 557 (CH2), 40 8 (CH3), 28.1 (CH2), 280 (CH2), 242 (CH2)

[0764] HRMS (ESH-): m / z calculated forC27H4iN2O4[M+H]t: calc 4573061; found: 4573072

[0765] EXAMPLE 39: TM-313

[0766] . N

[0767]

[0768] TM-313

[0769] TM-313 [3 (((5 (3 (azepan 1 yl) 2 hydroxypropoxy) 4' fluoro [ 1, T biphenyl] 3 yl)mettiyl)(mettiyl)amino)propan 1 ol] (60 mg, 14%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0770] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.43 (s, 0.6H, HCO2H), 771 - 765 (m, 2H, HarCm), 737 (bs, 1H, Harcm), 730-727 (m, 1H, Harcm), 723-7 17 (m, 3H, Harcm), 443 (dtd, 1H, J = 28 Hz, J = 49 Hz, J = 7.7 Hz), 430 (s, 2H), 4 15 (d, 2H, J = 49 Hz), 3 69 (t, 2H, J = 57 Hz), 350 (dd, 1H, J = 28 Hz, J = 132 Hz), 3 48-342 (m, 4H), 3 34-327 (m, 1H), 3 26-3 29 (m, 2H), 278 (s, 3H), 203-1 90 (m, 6H), 1 81-1 72 (m, 4H)

[0771] 13C NMR (101 MHz, CD3OD) 6 (ppm) 163.1 (Cq), 160.9 (Cq), 1440 (Cq), 137.5 (Cq), 130 1 (d, J = 82 Hz, CHarom), 123 2 (CHarom), 1167 (d, J = 21 8 Hz, CHarom), 1164 (CHarom), 1157 (CHarom), 71 5 (CH2), 655 (CH), 61 1 (CH2), 606 (CH2), 60 1 (CH2), 557 (CH2), 408 (CH3), 28 1 (CH?) 280 (CH2), 242 (CH2)

[0772] HRMS (ESIr): m / z calculated for CzM / FI [M+H]+: calc 4552861; found: 4552870 EXAMPLE 40: TM-314

[0773]

[0774] TM-314 [3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)-5-(pyridin-3-yl)benzyl)(methyl)amino)propan-1-ol] (1 7 mg, 4 1%) was synthetized following General Procedure A, B, C.2, C.3, E.1; Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0775] EXAMPLE 41: TM-316

[0776]

[0777] TM-316 [3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)-5-(thiazol-4-yl)benzyl)(methyl)amino)propan-1-ol] (20 mg, 5%) was synthetized following General Procedure C.2, C.3, B, A E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid).

[0778] 1H NMR (400 MHz, CD3OD) 6 (ppm) 9.10 (d, 1 H, J = 1.9 Hz, HarCm), 835 (s, 07H, HCO2H), 801 (d, 1H, J = 1 9 Hz, Harom), 770 (bs, 1H, Harem), 768-765 (m, 1H, HarCm), 7.20-7.16 (m, 1H, Harom), 446-439 (m, 1H), 429 (bs, 2H), 4 15 (d, 2H, J = 49 Hz), 3 69 (t, 2H, J = 58 Hz), 351 (dd, 1H, J = 28 Hz, J = 13 2 Hz), 349-3 40 (m, 4H), 334-327 (m, 1H), 3 25-3 20 (m, 2H), 279 (s, 3H), 202-1 91 (m, 6H), 1 81-1 72 (m, 4H)

[0779] HRMS (ESH-): m / z calculated for C23H36N3O3S [Mi-H]+: calc 4342472, found: 4342482 EXAMPLE 42: TM-317

[0780]

[0781] TM-317 [3'-(3-(azepan-1-yl)-2-hydroxypropoxy)-5'-(((3-hydroxypropyl)(methyl)amino)methyl)-[1,r-biphenyl]-4-carboxylic acid] (49 mg, 11%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0782] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.45 (s, 0.2H, HCO2H), 800 (d, 2H, J = 83 Hz, Harom), 764 (d, 2H, J = 83 Hz, Harom), 747 (bs, 1H, Harem), 735-731 (m, 1H, Harom), 7 19-7 14 (m, 1H, Harom), 446-439 (m, 1H), 429 (bs, 2H), 4 15 (d, 2H, J = 49 Hz), 369 (t, 2H, J = 57 Hz), 3 52-3 42 (m, 5H), 3 35-3 27 (m, 1H), 326-320 (m, 2H), 278 (s, 3H), 206-1 90 (m, 6H), 1 80-1 71 (m, 4H)

[0783] HRMS (ESH-): m / z calculated for C27H39N2O5[M+H]t: calc 471 2853; found: 471 2864

[0784] EXAMPLE 43: TM-318

[0785]

[0786] TM-318

[0787] TM-318 [3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)-5-(pyridin-4-yl)benzyl)(methyl)amino)propan-1-ol] (74 mg, 18%) was synthetized following General Procedure C.2, C.3, B, A E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0788] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.58 (dd, 2H, J = 1.5 Hz, J = 4.7 Hz, Harom), 772 (dd, 2H, J = 1.6 Hz, J = 47 Hz, Harom), 732 (bs, 1H, Harom), 727-723 (m, 1H, Harom), 709-706 (m, 1H, Harem), 4 15-401 (m, 3H), 3 66-3 59 (m, 4H), 287- 279 (m, 5H), 2 72 (dd, 1H, J = 73 Hz, J = 13 0 Hz), 257 (t, 2H, J = 75 Hz), 226 (s, 3H), 1 83-1 75 (m, 2H), 1 74-1.67 (m, 4H), 1.68-1.61 (m, 4H)

[0789] 13C NMR (101 MHz, CD3OD) 6 (ppm) 161.2 (Cq), 150.6 (CHarom), 1423 (Cq), 1402 (Cq), 123 3 (CHaram), 121.6 (Cq), 1175 (CHarom), 113 4 (CHar()in), 115.2 (CHarom), 72 1 (CH2), 687 (CH), 63 1 (CH2), 620 (CH2), 61 3 (CH2), 57 1 (CH2), 559 (CH2), 424 (CH3), 305 (CH2), 284 (CH2), 28 1 (CH2)

[0790] HRMS (ESH-): m / z calculated for C25H38N3O3 [M+H]+: calc 4282908; found: 4282917 EXAMPLE 44: TM-319

[0791]

[0792] TM-319 [3‘ (3 (azepan 1 yl) 2 hydroxypropoxy) 5' (((3 hydrox’ / propylilmettiyliamino) met) i vl) [1. T biphenyl] 4 ol] (7 4 mg, 18%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid)

[0793] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.45 (s, 1.4H, HCO2H), 7 51-7 47 (m, 2H, Harom), 7 32-729 (m, 1H, Haram), 7 24-7 21 (m, 1H, Harem), 7 06-7 03 (m, 1H, Harom), 689-6 85 (m, 2H, HarOm), 4 44-4 37 (m, 1H), 422 (bs, 2H), 4 12 (d, 2H, J = 4 9 Hz), 3 68 (t, 2H, J = 5 7 Hz), 3 51-3 40 (m, 5H), 3 31-3 25 (m, 1H), 3 17 (t, 2H, J = 7 5 Hz), 2 73 (s, 3H), 2 01-1 89 (m, 6H), 1 83-1 69 (m, 4H)

[0794] HRMS (ESH-): m / z calculated for C26H39N2O4[M+H]L calc 443 2904, found: 443 2911

[0795] EXAMPLE 45: TM-320

[0796] O

[0797]

[0798] TM-320 [3-(((3'-(3-(azepan-1-yl)-2-hydroxypropoxy)-[1, 1'-biphenyl]-2-yl)methyl)(methyl)amino)propan-1-ol] (16 0 mg, 13%) was synthetized following General Procedure C.2, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0799] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 0.9H, HCO2H), 754 (dd, 1H, J = 1 3 Hz, J = 7 5 Hz, Harom), 7 40-7 31 (m, 3H, Harom), 7 23 (dd, 1H, J - 1 6 Hz, J - 7 3 Hz, Harom), 7 01-6 96 (m, 1H, Haram), 6 95-6 89 (m, 2H, Haran), 4 36-4 28 (m, 1H), 4 05 (d, 2H, J = 5 0 Hz), 3 64 (s, 2H), 3 52 (t, 2H, J = 6 2 Hz), 3 35-3 27 (m, 5H), 3 20-3 11 (m, 1H), 2 49 (t, 2H, 7 1 Hz), 2 16 (s, 3H), 1 92-1 84 (m, 4H), 1 77-1 68 (m, 4H), 1 67-1 59 (m, 2H)

[0800] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.3 (HCO2H), 159 8 (Cq), 144 1 (Cq), 144 0 (Cq), 131 4 (CH,rom), 131 1 (CH,™), 130 4 (CH arom ), 128 7 (CH arom ), 128 6 (Cq), 123 6 (CH arom ), 117 1 (CH arom ), 114 3 (CH arom ), 71 4 (CH2), 66 3 (CH), 61 8 (CH2), 60 5 (CH2), 59 8 (CH2), 56 5 (CH2), 56 1 (CH2), 42 0 (CH3), 300 (CH2), 28 0 (CH2), 25 1 (CH2) HRMS (ESI+): m / z calculated forC26H39N2O3[M+H]+: calc 4272955; found: 4272954

[0801] EXAMPLE 46: TM-321

[0802]

[0803] TM-321

[0804] TM-321 [3-(((6-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-propyl-[1, T-biphenyl]-2-yl)methyl)(methyl)amino)propan-1-ol] (160 mg, 3%) was synthetized following General Procedure A, C.2, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0805] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 0.7H, HCO2H), 732 (t, 1H, J= 80 Hz, Harem), 7.25 (d, 2H, J = 78 Hz, Ha, 7 17 (d, 1H, J - 78 Hz, HarCm), 7 11 (t, 2H, 78 Hz, Harom), 698 (d, 1H. J 82 Hz, HarCm), 3 95 (dd, 2H, J- 1 6 Hz, J= 80 Hz), 382 (dd, 1H, J = 77 Hz, J = 10 7 Hz), 3 51 (t, 2H, J = 62 Hz), 3 36-3 33 (bs, 2H), 298-285 (m, 4H), 277-269 (m, 1H), 265 (t, 2H, J = 7.5 Hz), 265-256 (m, 1H), 237 (t, 2H, J = 68 Hz), 2 08 (s, 3H), 1 76-1 62 (m, 10H), 1 61-1 53 (m, 2H), 1 00265 (t, 3H, J= 73 Hz)

[0806] 13C NMR (101 MHz, CD3OD) 6 (ppm) 157.3 (Cq), 142.5 (Cq), 1389 (Cq), 135.5 (Cq), 1335 (Cq), 131 7 (CHarom), 131.6 (CHarom), 129.3 (CHarom), 129 1 (CHarom), 123.8 (CHarom), 112.6 (CHarom), 71.7 (CH2), 667 (CH), 62 1 (CH2), 607 (CH2), 599 (CH2), 566 (CH2), 563 (CH2), 424 (CH3), 389 (CH2), 303 (CH2), 280 (CH2), 259 (CH2), 143 (CHj).

[0807] HRMS (ESI-*-): m / z calculated for C29H45N2O3[M+H]+: calc 4693425; found: 4293416

[0808] EXAMPLE 47: TM-324

[0809] o

[0810] H OH

[0811] 026 equiv

[0812]

[0813] TM-324 [3 (((4' (3 (azepan 1 y I) -2-hydroxy propoxy) [1, 1' biphenyl] 2 yl)methyl) (meth yl)amino)propan 1 ol] (522 mg, 9%) was synthetized following General Procedure C.2, B, E; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 5 (ppm) 8.45 (s, 0.25H, HCO2H), 767 (dd, 1H, J = 1 6 Hz, J = 72 Hz, Harom), 7.54-7.46 (m, 2H, Harom), 736 (dd, 1H, J = 1 8 Hz, J = 72 Hz, Harem), 730 (d, 2H, J = 86 Hz, Harom), 7 12 (d, 2H, J = 86 Hz, Harem), 444 (did, 1H, J = 28 Hz, J = 48 Hz, J = 76 Hz), 436 (bs, 2H), 4 10 (d, 2H, J= 49 Hz), 358-3 42 (m, 7H), 336-3 28 (m, 1H), 3 01 (t, 2H, J = 75 Hz), 257 (s, 3H), 2.02-1.91 (m, 4H), 1 82-1 70 (m, 6H)

[0814] 13C NMR (101 MHz, CD3OD) 6 (ppm) 159.8 (Cq), 144.9 (Cq), 133 9 (Cq), 1323 (CHarom), 132.1 (CHarom), 132.0 (CHarom), 1309 (CHarom), 129.4 (Cq), 1293 (CHaram), 116.1 (CH,™), 71.4 (CH2), 656 (CH), 605 (CH2), 602 (CH2), 582 (CH2), 56 1 (CH2), 409 (CHj), 28 0 (CH2), 276 (CH2), 242 (CH2)

[0815] HRMS (E SH-): m / z calculated for C39H56F3N4O2 [M +HJ+calc 4683585; found: 4683574

[0816] EXAMPLE 48: TM-328

[0817]

[0818] TM-328 [3-(((4-(3-(azepan-1-yl)-2-hydroxypropoxy)-[1, r-biphenyl]-2-yl)methyl)(methyl)amino)propan-1-ol] (52 mg, 28%) was synthetized following General Procedure C.2, C.3, A, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0819] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 1,3H, HCO2H), 739 (d, 2H, J = 75 Hz, HarOm), 735-733 (m, 1H, Harom), 727-723 (m, 2H, Harom), 7 19-7 18 (m, 1H, Harom), 7 16 (d, 1H, J= 85 Hz, Harem), 695 (dd, 1H, J = 2.1 Hz, J= 84 Hz, Harom), 437-428 (m, 1H), 406 (d, 2H, J = 49 Hz), 3 59-3 50 (m, 5H), 3 30-3 28 (m, 2H), 3 15 (dd, 1H, J = 100 Hz, J= 127 Hz), 244 (t, 2H, J = 7.1 Hz), 2 13 (s, 3H), 1 95-1 84 (m, 5H), 1 75-1 73 (m, 5H), 1 67-1 61 (m, 2H)

[0820] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.3 (HCO2H), 1594 (Cq), 1422 (Cq), 137 3 (Cq), 1324 (Cq), 1308 (CH,™), 1292 (CH,™), 1280 (CHarOm), 1164 (CHa™), 1147 (CHarom), 71.4 (CH2), 664 (CH), 620 (CH2), 605 (CH2), 600 (CH2), 565 (CH2), 56 1 (CH2), 42 2 (CH3), 302 (CH2), 280 (CH2), 252 (CH2).

[0821] HRMS (ESH-): m / z calculated for C26H39N2O3 [M+H]+: calc 4272955; found: 4272955 EXAMPLE 49: TM-329

[0822]

[0823] TM-329

[0824] ID-243

[0825] TM-329 [5-(((3-hydroxypropyl)(methyl)amino)methyl)-4'-propyl-[1,1'-biphenyl]-3-ol] (74 mg, <1%) was synthetized following General Procedure A, C.1, C.3, Purification: Chromatography on silica gel (DCM: MeOH) TM-329 was obtained as a side product during synthesis of TM-292

[0826] 1H NMR (400 MHz, CD3OD) 6 (ppm) 7.53 (d, 2H, J = 80 Hz, HarQm), 725 (d, 2H, J = 8 1 Hz, Harom), 723 (bs, 1H, Harom), 7 13 (bs, 1H, Harom), 690 (bs, 1H, Harari). 428 (bs, 2H), 3 69 (t, 2H. J- 54 Hz), 3 26 (t, 2H, J = 73 Hz), 280 (s, 3H), 262 (t, 2H, J = 75 Hz), 204-1 94 (m, 2H), 1 72-1 61 (m 2H), 095 (t, 3H, J = 73 Hz)

[0827] 13C NMR (101 MHz, CD3OD) 6 (ppm) 159.8 (Cq), 1450 (Cq), 143 7 (Cq), 1388 (Cq), 1332 (Cq), 1300 (CHarom), 1279 (CHarom), 121.2 (CHarom), 1172 (CHarom), 116.0 (CHarom), 61 2 (CH2), 605 (CH2), 557 (CH2), 406 (CH3), 386 (CH2), 279 (CH2), 25.7 (CH2), 14 1 (CH3)

[0828] HRMS (ESI+): m / z calculated for C2oH27N02[M+H]t: calc 3142115; found: 3142110

[0829] EXAMPLE 50: TM-336

[0830]

[0831] TM-336 [ 1-((5-(((3-(((S)-2-amino-3-(4-(tnfluoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-propyl-[1, T-biphenyl] -3 -yl)oxy) -3 (azepan -1 -yl)propan -2 -ol] (260 mg, 20%) was synthetized following General Procedure A, C.1, C.3, B, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0832] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.42 (s, 2.4H, HCO2H), 765 (d, 2H, J = 8 1 Hz, Harm), 756 (d, 2H, J = 82 Hz, Harom), 748 (d, 2H, J = 8 1 Hz, Harm), 7.41-7 38 (m, 1H, Haram), 730-725 (m, 3H, Harom), 7 18-7 15 (m, 1H, Harom), 443 (dtd, 1H, J = 3 0 Hz, J= 48 Hz, J = 76 Hz), 427 (bs, 2H), 4 13 (d, 2H, J = 49 Hz), 3 53-3 42 (m, 6H), 335-3 27 (m, 1H), 3 24-3 18 (m, 2H), 2 99 (d, 2H, J = 7 2 Hz), 2 87 (dd, 1H, J = 3.9 Hz, J = 13 0 Hz), 2 84-2 69 (m, 3H), 2 73 (s, 3H), 2 65-2 61 (m, 2H), 2 04-1 90 (m, 6H), 1 81-1 72 (m, 4H) 1 67 (dq, 2H, J = 7 4 Hz, J= 14 7 Hz), 0 96 (t, 3H, J = 7 4 Hz)13C NMR (101 MHz, CD3OD) 6 (ppm) 168.8 (HCO2H), 160 8 (Cq), 144 9 (Cq), 144 0 (Cq), 142 1 (Cq), 138 6 (Cq), 134 2 (

[0833]

[0834] Cq), 131 1 (CHarom), 1305 (q, J = 32 4 Hz, Cq), 130 1 (CH,™), 128 0 (CHarom), 126 8 (q, J = 3 7 Hz, CHarom), 125 7 (q, J = 271 3 Hz, Cq), 123 2 (CHarom), 1 16 2 (CHarom), 115.5 (CHarom), 71 5 (CH2), 65 6 (CH), 61 2 (CH2), 60.1 (CH2), 56 4 (CH2), 55 6 (CH2), 53 1 (CH), 51 4 (CH2), 47 5 (CH2), 40 2 (CH3), 38 6 (CH2), 38 5 (CH2), 28 0 (CH2), 25 7 (CH2), 25 0 (CH2), 24 1 (CH2), 14 1 (CH3)

[0835] 19F NMR (377 MHz, CDCb) 6 (ppm) -64.0 (s, 3F).

[0836] HRMS (ESH-): m / z calculated for C39H56F3N4O2 [M +H]+: calc 669 4350; found: 669 4334

[0837] EXAMPLE 51: TM-337

[0838] H OH

[0839] 0 15 equiv

[0840] z N

[0841]

[0842] •H I

[0843] TM-337

[0844] TM-337 [ 1-((5-(((3-aminopropyl)(metiiyl)amino)methyl)-4,-propyl-[1,1,-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (13 3 mg, 13%) was synthetized following General Procedure A, C.1, C.3, B, D; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid)

[0845] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.23 (s, 0.15H, HCO2H), 7 61 -7.57 (m, 2H, Harcni), 7 45 (t, 1H, J= 1 3 Hz, Harcni), 7 32- 7

[0846]

[0847] 26 (m, 4H, Haram), 4 45 (dtd, 1H, J = 2 9 Hz, J = 4 9 Hz, J = 7.6 Hz), 4 37 (bs, 2H), 4 17 (d, 2H, J = 4.9 Hz), 3 54 (dd, 1H, J = 2 8 Hz, J = 13 2 Hz), 3 51-3 40 (m, 4H), 3 36-3 31 (m, 1H), 3 30-3 24 (m, 2H), 3 05 (t, 2H, J = 7 5 Hz), 2 80 (s, 3H), 2 63 (t, 2H, J = 7 5 Hz), 2 26-2 17 (m, 2H), 2 00-1 89 (m, 4H), 1 81- 1 73 (m, 4H), 1 67 (dq, 2H, J = 7 4 Hz, J = 14.7 Hz), 0 96 (t, 3H, J = 74 Hz).

[0848] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.8 (Cq), 145.0 (Cq), 144.0 (Cq), 138 5 (Cq), 133 5 (Cq), 130 1 (CHarom), 128.0 (CHarom), 123 4 (CHarom), 116.1 (CHarom), 1 15 9 (CHarom), 71.6 (CH2), 65 6 (CH), 61 4 (CH2), 60 1 (CH2), 54 3 (CH2) 40 2 (CH3), 38 6 (CH2), 38 2 (CH2), 28 0 (CH2), 25 7 (CH2), 25 0 (CH2), 24 2 (CH2), 23 8 (CH2), 14 1 (CH3)

[0849] HRMS (ESH-): m / z calculated for C39H56F3N4O2 [M +H]+calc 468 3585; found: 468 3574 EXAMPLE 52: TM-338

[0850]

[0851] TM-338 [ 3 -(( (5- (3 (azepa n - 1 -yl) -2-hy droxypropoxy) -4'-b u ty I -[ 1, 1 '-biph enyl]-3-yl)methy I) (m ethyl) amino)propan - 1 - ol ] (76 mg, 16%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid)

[0852] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.52 (s, 1,6H, HCO2H), 755 (d, 2H, J = 8 1 Hz, Harom), 734-731 (m, 1H, Harom), 729- 724 (m, 3H, Harm), 709-706 (m, 1H, Harc(tl), 444-437 (m, 1H), 4 17-408 (m, 4H), 3 67 (t, 2H, J = 5.8 Hz), 3 48-340 (m, 5H), 3 28 (dd, 1H, J = 105 Hz, J = 132 Hz), 3 07 (t, 2H, J = 7.5 Hz), 270-262 (m, 2H), 266 (s, 3H), 1 98-1 90 (m, 6H), 1 79-1 72 (m, 4H), 1.67-1.59 (m, 2H), 1 38 (dq, 2H, J = 7.5 Hz, J = 13 0 Hz), 096 (t, 3H, J = 7.5 Hz)

[0853] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 8 (Cq), 1498 (Cq), 144 1 (Cq), 1387 (Cq), 1358 (Cq), 1300 (CHarom), 128.0 (CHarom), 122.9 (CHarom), 115.8 (CHlrom), 115.0 (CHarom), 71.5 (CH2), 657 (CH), 61 6 (CH2), 609 (CH2), 602 (CH2), 564 (CH2), 557 (CH2), 41 1 (CH3), 362 (CH2), 349 (CH2), 286 (CH2), 280 (CH2), 243 (CH2), 23 3 (CH2), 143 (CH3).

[0854] HRMS (ESH-): m / z calculated for C30H47N2O3 [M +H]+: calc 483 3581; found: 483 3578

[0855] EXAMPLE 53: TM-340

[0856]

[0857] TM-340 [3-(((5-(3-(a epan-1-yl)-2-hydroxypropoxy)-4'-isobutyl-[1, 1,-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (83 mg, 18%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0858] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 1,4H, HCO2H), 756 (d, 2H, J = 8 1 Hz, Harom), 736-733 (m, 1H, Harom), 728- 722 (m, 3H, Harom), 7 11-708 (m, 1H, Harom), 445-438 (m, 1H), 4 18 (bs, 2H), 4 12 (d, 2H, J = 49 Hz), 3 67 (t, 2H, J = 58 Hz), 3 50 - 3 40 (m, 5H), 3 29 (dd, 1H, J = 105 Hz, J = 13 2 Hz), 3 12 (t, 2H, J = 7.5 Hz), 270 (s, 3H), 253 (d, 2H, J = 7.2 Hz), 2.00-1.85 (m, 7H), 1 81-1 71 (m, 4H), 094 (s, 3H), 092 (s, 3H)

[0859] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 8 (Cq), 1448 (Cq), 1429 (Cq), 1388 (Cq), 1352 (Cq), 1308 (CHarom), 127.8 (CHarom), 123.0 (CHarom), 115.9 (CHarom), 115.2 (CHarom), 71.5 (CH2), 657 (CH), 61.4 (CH2), 607 (CH2), 602 (CH2), 564 (CH2), 556 (CH2), 460 (CH2), 409 (CH3), 31 5(CH), 284 (CH2), 280 (CH2), 243 (CH3), 227 (CH3) HRMS (ESH-): m / z calculated for C30H47N2O3 [M +H]+: calc 483 3581; found: 483 3578

[0860] EXAMPLE 54: TM-341

[0861]

[0862] TM-341 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-cyclopropyl-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (1 7 mg, 4%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid)

[0863] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.52 (s, 2.0H, HCO2H), 757 (d, 1H, J = 83 Hz, Harm), 751 (d, 1H, J = 83 Hz, Harom), 743 (d, 1H, J = 8.3 Hz, Harmi), 730-726 (m, 1H, Harem), 7.22-7.18 (m, 1H, Harm), 7.15 (d, 1H, J = 83 Hz, Harom), 704-700 (m, 1H, Harem), 442-434 (m, 1H), 4.14-4.08 (m, 2H), 3 95 (bs, 2H), 3 66 (t, 2H, J = 59 Hz), 3 47-337 (m, 6H), 3 26 (dd, 1H, J = 104 Hz, J = 13 1 Hz), 292 (t, 2H, J = 73 Hz), 254 (s, 3H), 1.98-1.85 (m, 8H), 1.80-1.70 (m, 4H), 1 03-096 (m, 1H), 074-068 (m, 1H)

[0864] HRMS (ESH-): m / z calculated for C29H43N2O3 [M +H]+: calc 4673268; found: 4673262

[0865] EXAMPLE 55: TM-342 / TM-364

[0866]

[0867] TM-342 / TM-364 TM-342 / TM-364 [3-(((5-(3-(azepan- 1-yl)-2-hydroxypropoxy)-4'-cyclopentyl-[ 1,1'-biphenyl]-3-yl) methyl) (methyl)amino) propan-1-ol] (98 mg, 20%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0868] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.49 (s, 1.2H, HCO2H), 758-754 (m, 2H, HarOm), 736-732 (m, 3H, Harom), 728-725 (m, 1H, Harom), 7 11-708 (m, 1H, Harem), 4.41 (dtd, 1H, J = 28 Hz, J = 48 Hz, J = 77 Hz), 4 19 (bs, 2H), 4 13 (d, 2H, J = 49 Hz), 3 68 (t, 2H, J = 5.7 Hz), 350-3 41 (m, 5H), 3 31-3 25 (m, 1H), 3 13 (t, 2H, J = 74 Hz), 3 10-300 (m, 1H), 271 (s, 3H), 2 14-205 (m, 2H), 200-1 90 (m, 6H), 1 89-1 81 (m, 2H), 1 80-1 71 (m, 6H), 1 69-1 58 (m, 2H)

[0869] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.8 (Cq), 147.8 (Cq), 144 9(Cq), 1387 (Cq), 1287 (CHarom), 1279 (CHarom), 122.9 (CHarom), 1158 (CH a™), 1152 (CHarom), 71 5 (CH2), 656 (CH), 61 5 (CH2), 608 (CH2), 60 1 (CH2), 563 (CH2), 557 (CH2), 470 (CH), 41 0 (CH3), 357 (CH2), 284 (CH2), 280 (CH2), 265 (CH2), 242 (CH2)

[0870] HRMS (ESH-): m / z calculated for C31H47N2O3 [M+H]+: calc 4953581, found: 4953578

[0871] EXAMPLE 56: TM-343

[0872] H uH

[0873] 0.8 equiv

[0874]

[0875] TM-343

[0876] TM-343 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-(trifluoromethyl)-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1 -ol] (142 mg, 29%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H20: ACN: MeOH, 0 1% Formic Acid)

[0877] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.47 (s, 0.7H, HCO2H), 787 (d, 2H, J - 82 Hz, Haram), 777 (d, 2H, J - 84 Hz, Harom), 748 (t, 1H, 1 3 Hz, Harom), 740-737 (m, 1H, HarCm), 730-728 (m, 1H, Harom), 445 (dtd, 1H, J = 28 Hz, J = 48 Hz, J = 7.6 Hz), 435 (bs, 2H), 4 17 (d, 2H, J = 4.9 Hz), 3 69 (t. 2H, J = 5.7 Hz), 3 52 (dd, 1H, J = 2.7 Hz, J = 13 2 Hz), 3 51-3 42 (m, 4H), 337-3 29 (m, 1H), 3 25 (t, 2H, J = 74 Hz), 281 (s, 3H), 205-1 91 (m, 6H), 1 82-1 72 (m, 4H)

[0878] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.4 (HCO2H), 161.0 (Cq), 1450 (Cq), 1433 (Cq), 1344 (Cq), 131 0 (g, J = 324 Hz, Cq), 128 8 (CHarom), 126.9 (g, J = 3 7 Hz, CHarom), 1257 (q, J = 271 1 Hz, Cq), 123 5 (CHarom), 1174 (CH,™), 116.2 (CHarom), 71 6 (CH2), 656 (CH), 609 (CH2), 604 (CH2), 60.1 (CH2), 564 (CH2), 556 (CH2), 407 (CH3), 280 (CH2), 279 (CH2), 242 (CH2)

[0879] HRMS (ESH-): m / z calculated forC27H38F3N2O3 [M+H]+: calc 4952829; found: 4952825 EXAMPLE 57: TM-344

[0880]

[0881] TM-344

[0882] TM-344 [2-(3,-(3-(azepan-1-yl)-2-hydroxypropoxy)-5,-(((3-hydroxypropyl)(methyl)amino)methyl)-[1, 1'-biphenyl]-4-yl) Acetonitrile] (11 5 mg, 25%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0883] 1H NMR (400 MHz, CD3OD) 5 (ppm) 7.74-7.70 (m, 2H, Harm), 7 50-7 45 (m, 3H, Harom), 7 37-7 35 (m, 1H, Haram), 7 30-7 27 (m, 1H, Harom), 4 53 (d, 1H, J = 13 0 Hz), 4 49-4 42 (m, 1H), 4 33 (d, 1H, J = 13 0 Hz), 4 12 (d, 2H, J = 4 3 Hz), 3 97 (bs, 2H), 3 75-3 51 (m, 5H), 3 46-3 31 (m, 4H), 3 30-3 22 (m, 1H), 2 87 (s, 3H), 2 09-1 90 (m, 6H), 1 83-1 70 (m, 4H)13C NMR (101 MHz, CD3OD) 6 (ppm) 161.0 (Cq), 144 3 (Cq), 140 6 (Cq), 133 1 (Cq), 1324 (Cq), 129 8 (CHarom), 1288 (CHarom), 123 4 (CHarom), 1 19 5 (Cq), 116 8 (CHarom), 116 2 (CHarom), 71 6 (CH2), 65 5 (CH), 60 8 (CH2), 603 (CH2), 60 1 (CH2), 57 9 (CH2), 55 6 (CH2), 54 9 (CH2), 40 6 (CH3), 28 0 (CH2), 279 (CH2), 27 7 (CH2), 24 2 (CH2), 23 2 (CH2) HRMS (ESI+): m / z calculated for Caob ^Oa [M+H]+: calc 466 3064, found: 466 3060

[0884] EXAMPLE 58: TM-345

[0885]

[0886] TM-345 [ 3 -(( (5- (3 (azepa n - 1 -yl) -2-hy droxypropoxy) -3 '-e thy I -[ 1, 1 '-biph enyl]-3-yl)methy I) (m ethyl) ammo)propan - 1 -ol] (3 3 mg, 8%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0887] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.51 (s, 1,7H, HCO2H), 7 48-7 42 (m, 2H, HarCm), 736 (t, 1H, J = 76 Hz, Harom), 7 34- 7 31 (m, 1H, Harem), 7 26-7 21 (m, 2H, Harem), 7 09-706 (m, 1H, Harem), 440 (dtd, 1H, J = 2.6 Hz, J = 4.9 Hz, J = 7 8 Hz), 4 12 (d, 2H, J = 50 Hz), 4 10 (bs, 2H), 3 67 (t, 2H, J = 5 9 Hz), 3 49 - 3 39 (m, 5H), 3 27 (dd, 1H, J = 10 5 Hz, J = 13 2 Hz), 3 04 (t, 2H, J = 7 5 Hz), 2 72 (q, 2H, J = 7 6 Hz), 2 64 (s, 3H), 1 99-1 89 (m, 6H), 1 80-1 72 (m, 4H), 1 28 (t, 3H, J = 7 6 Hz)13C NMR (101 MHz, CD3OD) 6 (ppm) 160.7 (Cq), 146 3 (Cq), 145 1 (Cq), 141 5 (Cq), 135 4 (Cq), 130 0 (CHarom), 128 6 (CHarom), 127 6 (CHarom), 125 5 (CHarom), 123 0 (CHarom), 1 15.9 (CHarom), 115 1 (CHarom), 71 5 (CH2), 65 7 (CH), 61 8 (CH2), 61 0 (CH2), 60 2 (CH2), 56 4 (CH2), 55 8 (CH2), 41 2 (CH?), 30 0 (CH2), 28 7 (CH2), 28 0 (CH2), 24 3 (CH2), 16 3 (CH?) HRMS (ESH-): m / z calculated for CjgH^Og [M+H]+: calc 455 3268; found: 455 3261

[0888] EXAMPLE 59: TM-346

[0889] H v> H

[0890] 1,45equiv

[0891]

[0892] TM-346

[0893] TM-346 [3 (((5 (3 (azepan 1 yl) 2 hydroxypropoxy 3' isopropyl [1 T biphenyl] 3 yl)mettiyl)(mettiyl)amino)propan 1 ol] (8 2 mg, 18%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0894] 1H NMR (400 MHz, CD3OD) 3 (ppm) 8.52 (s, 1.2H, HCO2H), 7 48 (t, 1H, J = 1 7 Hz, Harcm), 7 46-7 42 (m, 1H, Harom), 7 38 (d, 1H, J = 7 6 Hz, Harom), 7 36-7 34 (m, 1 H, Harcni), 7 28-7 24 (m, 2H, Harcfn), 7 13-7 10 (m, 1H, Haram), 4 42 (dtd, 1H, J = 2 9 Hz, J = 4 8 Hz, J = 7 7 Hz), 4 18 (bs, 2H), 4 13 (d, 2H, J = 4.9 Hz), 3 68 (t, 2H, J = 5.8 Hz), 3 51-3 39 (m, 5H), 3 34- 3 25 (m, 1H), 3 12 (t, 2H, J = 7 5 Hz), 3 03-2 92 (m, 1H), 2 70 (s, 3H), 2 00- 1 90 (m, 6H), 1 80- 1 71 (m, 4H), 1 31 (s, 3H), 1 29 (s, 3H)

[0895] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 8 (Cq), 150.9 (Cq), 145.2 (Cq), 141 4 (Cq), 135 7 (Cq), 130.0 (CH arom ), 127 1 (CH arom ), 126 3 (CH arom ), 125 7 (CH arom ), 123 1 (CH arom ), 1 15 9 (CH arom ), 115 4 (CH arom ), 71 5 (CH2), 65 7 (CH), 61 6 (CH2), 60 8 (CH2), 60 2 (CH2), 56 4 (CH2), 55 7 (CH2), 41 1 (CH?), 35 5 (CH), 28 6 (CH2), 28 0 (CH2), 24 5 (CH?), 24 3 (CH?)

[0896] HRMS (ESH-): m / z calculated for CjgH^NgOa [M+H]+: calc 469 3425; found: 469 3422

[0897] EXAMPLE 60: TM-347

[0898] H OH

[0899] 1,1 equiv

[0900] ' N

[0901] 'H I

[0902]

[0903] TM-347 TM-347 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-3',4'-dimethyl-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (13 0 mg, 29%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 1.1 H, HCO2H), 7 43 (bs, 1H, HarOm), 7 39-7 34 (m, 2H, Haran), 7 29-7 26 (m, 1H, Harom), 7 21 (d, 1 H, J = 7 8 Hz, Harom), 7 15-7 12 (m, 1H, Harom), 4 43 (dtd, 1H, J = 2 7 Hz, J = 4 8 Hz, J = 7 6 Hz), 4 28 (

[0904]

[0905] bs, 2H), 4 13 (d, 2H, J = 4 9 Hz), 3 68 (t, 2H, J = 5.7 Hz), 3 49 (dd, 1H, J = 2 7 Hz, J = 13 3 Hz), 3 48 - 3 42 (m, 4H), 3 34-3 26 (m, 1H), 3 22 (t, 2H, J = 7.5 Hz), 2 77 (s, 3H), 2 33 (s, 3H), 2 30 (s, 3H), 2 03- 1 91 (m, 6H), 1 80-1 72 (m, 4H)13C NMR (101 MHz, CD3OD) 6 (ppm) 169.8 (HCO2H), 160 8 (Cq), 145 1 (Cq), 138 7 (Cq), 138 2 (Cq), 137.7 (Cq), 134 1 (Cq), 131 2 (CH arom ), 129 2 (CH arom ), 125 5 (CH arom ), 123 1 (CH arom ), 115.9 (CH arom ), 115.5 (CH aro ), 71 5 (CH2), 65 6 (CH), 61.2 (CH2), 60 5 (CH2), 60 2 (CH2), 56 4 (CH2), 55 6 (CH2), 40 7 (CH3), 28 1 (CH2), 28 0 (CH2), 24 2 (CH2),, 20 0 (CH3), 19 5 (CH3).

[0906] HRMS (ESH-): m / z calculated for C28H43N2O3 [M +H]+: calc 455 3268; found: 455 3270

[0907] EXAMPLE 61: TM-348

[0908] O

[0909] 11

[0910] H OH

[0911] 1 5 equiv

[0912] ■H I

[0913]

[0914] TM-348

[0915] TM-348 [3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)benzyl)(methyl)amino)propan- 1-ol] (2 3 mg, 5%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0916] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.50 (s, 1.5H, HCO2H), 7.35-729 (m, 3H, Harom), 7 23-7 21 (m, 1 H, Harcm), 7 12 (d, 1H, J = 7 8 Hz, Harom), 7 06-7 03 (m, 1 H, HarOm), 4 43-4 36 (m, 1H), 4 11 (d, 2H, J = 5.0 Hz), 4 08 (bs, 2H), 3 67 (t, 2H, J = 5.9 Hz), 3 49-3 40 (m, 5H), 3 26 (dd, 1 H, J = 10.5 Hz, J = 13 2 Hz), 3 04 (t, 2H, J = 7.5 Hz), 2 86-2 77 (m, 4H), 2 63 (s, 3H), 1 97-1 89 (m, 6H), 1 86-1 81 (m, 4H), 1.80-1.73 (m, 4H)

[0917] HRMS (ESH-): m / z calculated for CatTkNaOa [M+H]+: calc 481 3425, found: 481 3422 EXAMPLE 62: TM-349

[0918]

[0919] TM-349 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-3',5'-dimethyl-[1, T-biphenyl]-3-yl)methyl)(methyl)amino)propan-1-ol] (8 9 mg, 20%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0920] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 1,4H, HCO2H), 7 34 (t, 1 H, J = 1 3 Hz, HarOm), 7 26-7 23 (m, 3H, Harom), 7.12- 7

[0921]

[0922] 10 (m, 1H, Harem), 7 04-7 02 (bs, 1H, HarOm), 4 42 (dtd, 1H, J = 2 8 Hz, J = 4 8 Hz, J = 7 7 Hz), 4 22 (bs, 2H), 4 12 (d, 2H, J = 5.0 Hz), 3 68 (t, 2H, J = 5 8 Hz), 3.51 - 3 41 (m, 5H), 3 33-3 26 (m, 1H), 3.16 (t, 2H, J = 7 5 Hz), 2 73 (s, 3H), 2 37 (s, 6H), 2.01-1.90 (m, 6H), 1 80-1 71 (m, 4H)

[0923] 13C NMR ( 101 MHz, CD3OD) 6 (ppm) 169.9 (HCO2H), 160 8 (Cq), 145.2 (Cq), 141 2 (Cq), 139 6 (2 Cq), 134 8 (Cq), 130 5 (CHarom), 125.9 (2 CHarom), 123 2 (CHarom), 116.0 (CHarom), 1 15.5 (CHarom), 71.5 (CH2), 65 6 (CH), 61 4 (CH2), 60 7 (CH2), 60 2 (CH2), 56 3 (CH2), 55 6 (CH2), 40 9 (CH3), 28 3 (CH2), 28 0 (CH2), 24 2 (CH2),, 21 4 (2 CH3)

[0924] HRMS (ESH-): m / z calculated for C2BH«N2O3[M +H]+: calc 455 3268; found: 455 3273

[0925] EXAMPLE 63: TM-350

[0926] TM-350 [3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-3'-(tert-butyl)-5'-methyl-[1, 1,-biphenyl]-3-yl)methyl) (methyl) amino) propan-1-ol] (3 8 mg, 8%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 5 (ppm) 8.51 (s, 1.8H, HCO2H), 7 42-7 40 (m, 1 H, Harom), 7 33-7 30 (m, 1H, Harem), 7 27-7 23 (m, 2H, Harom), 7 22-7 21 (m, 1H, Harom), 7 09-7 06 (m, 1H, Harom), 4 40 (dtd, 1H, J = 2 8 Hz, J = 4 7 Hz, J = 7 7 Hz), 4 15- 4 09 (m, 4H), 3 67 (t, 2H, J = 5.8 Hz), 3 50-3 39 (m, 5H), 3 32-3 24 (m, 1H), 3 07 (t, 2H, J = 7.5 Hz), 2 66 (s, 3H), 2 40 (s,

[0927]

[0928] 3H), 1 98-1 90 (m, 6H), 1 79-1 72 (m, 4H), 1 36 (s, 9H)13C NMR (101 MHz, CD3OD) 6 (ppm) 169.9 (HCO2H), 160.7 (Cq), 153.0 (Cq), 145.6 (Cq), 141.2 (Cq), 139.3 (Cq), 135.8 (Cq), 126.8 (CHarom), 126.1 (CHarom), 123.2 (CHarom), 122.3 (CHarom), 115.7 (CHarom), 115.4 (CHarom), 71.4 (CH2), 65.7 (CH), 61.7 (CH2), 60.9 (CH2), 60.2 (CH2), 56.4 (CH2), 55.7 (CH2), 41.1 (CH3), 35.6 (Cq), 31.9 (CH3), 28.6 (CH2), 28.0 (CH2), 24.3 (CH2), 21.7 (CH3).

[0929] HRMS (ESI+): m / z calculated for C31H48N2O3[M+H]+: calc 497.3738; found: 497.3739

[0930] EXAMPLE 64: TM-351

[0931]

[0932] TM-351 [3-(((5-(3-(azepan- 1-yl)-2-hydroxypropoxy)-3',5'-di-tert-butyl-[ 1,1'-biphenyl]-3-yl)methyl)(methyl)amino)propan-1- ol] (1 8 mg, 4%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0933] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 2. OH, HCO2H), 748 (t, 1H, J = 1 7 Hz, HarCm), 741 (d, 2H, J = 1 8 Hz, Harom), 729-726 (m, 1H, Harom), 7.18-7.16 (m, 1H, Harom), 707-705 (m, 1H, Harom), 439 (dtd, 1H, J = 28 Hz, J = 48 Hz, J = 78 Hz), 4 12 (d, 2H, J = 50 Hz), 400 (bs, 2H), 366 (t, 2H, J = 59 Hz), 3 46 (dd, 1H, J = 3 1 Hz, J = 133 Hz), 3 45 - 3 41 (m, 4H), 3 26 (dd, 1H, J = 103 Hz, J = 13 2 Hz), 295 (t, 2H, J = 75 Hz), 257 (s, 3H), 1.98-1.87 (m, 6H), 1.80-1.70 (m, 4H), 1 38 (s, 18H)

[0934] HRMS (ESI+): m / z calculated for C34H55N2O3[M+H]+: calc 539.4207; found: 539.4205

[0935] EXAMPLE 65: TM-354

[0936]

[0937] TM-354

[0938] TM-354 [N-(3-aminopropyl)-N-((5-hydroxy-4'-propyl-[1, T-biphenyl]-3-yl)methyl)-4-methylbenzenesulfonamide] (170 mg, 21%) was synthetized following General Procedure A, C.1, F, D; Purification: HPLC prep / MS (H; O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.45 (s, 0.3H, HCO2H), 780 (t, 1H, J= 1 4 Hz, Harem), 776 (d, 2H, J = 83 Hz, Harom), 743 (d, 2H, J = 80 Hz, Harm), 739 (d, 2H, J = 82 Hz, Harem), 732 (t, 1H, J = 1 7 Hz, HarCm), 723 (d, 2H, J = 82 Hz, Harom), 707 (t, 1H, J= 1 7 Hz, HarCm), 425 (bs, 2H), 3 17 (t, 2H, J= 76 Hz), 3 09 (t, 2H, J = 76 Hz), 260 (t, 2H, J = 75 Hz), 244 (s, 3H), 2 19-209 (m, 2H), 1 70 (dt, 2H, J= 73 Hz, J = 147 Hz), 094 (t, 3H, J = 73 Hz)

[0939] 13C NMR (101 MHz, CD3OD) 5 (ppm) 151.6 (Cq), 1475 (Cq), 144.9 (Cq), 1444 (Cq), 1372 (Cq), 1356 (Cq), 133 4 (Cq), 131 2 (CH arom ), 1302 (CH arom ), 1298 (CH arom ), 1282 (CH arom ), 1278 (CH arom ), 1234 (CH arom ), 123 1 (CH arom ), 51 9 (CH2), 459 (CH2), 386 (CH2), 380 (CH2), 256 (CH2), 254 (CH2), 21 7 (CHj), 14.1 (CH3)

[0940] HRMS (ESI+): m / z calculated for C25H37BrN3O4S [M+H]+: calc 554.1683; found: 554.1673

[0941] EXAMPLE 66: TM-355

[0942]

[0943] TM-355

[0944] TM-355 [5-(((3-aminopropyl)(methyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-3-ol] (140 mg, 19%) was synthetized following General Procedure A, C.1, C.3, D, Purification: HPLC prep / MS (H2O: AON: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.24 (s, 0.15H, HCO2H), 757-753 (m, 2H, Harem), 728 (t, 1H, J= 1 5 Hz, Harem), 726 (d, 2H, J= 83 Hz, Harom), 7 13 (dd, 1H, J = 1 7 Hz, J = 22 Hz, Harem), 695-693 (m, 1H, Harem), 428 (bs, 2H), 3 27-3 19 (m, 2H), 304 (t, 2H, J= 75 Hz), 280 (s, 3H), 263 (t, 2H, J = 75 Hz), 221-2 13 (m, 2H), 1 72-1 61 (m, 2H), 096 (t, 3H, J = 74 Hz)

[0945] 13C NMR (101 MHz, CD3OD) 6 (ppm) 159.8 (Cq), 1450 (Cq), 143 7 (Cq), 1388 (Cq), 1333 (Cq), 130 1 (CHarom), 127.9 (CHarom), 121.4 (CHarom), 1173 (CHarom), 116.0 (CHarom), 61 6 (CH2), 54 1 (CH2), 40.4 (CH3), 38.6 (CH2), 38.2 (CH2), 25.7 (CH2), 23.8 (CH2), 14.1 (CH3)

[0946] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 468.3585; found: 468.3574: TM-359

[0947]

[0948] TM-359 [3-(((2-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-propyl-[1, T-biphenyl]-4-yl)methyl)(methyl)amino)propan-1-ol] (145 mg, 74%) was synthetized following General Procedure A, C.2, C.3, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0949] 1H NMR (400 MHz, CDgOD) 6 (ppm) 8.54 (s, 1,6H, HCO2H), 743 (d, 2H, J = 8 1 Hz, Haram), 728 (d, 1H, J = 77 Hz, Harom), 724 (d, 2H, J = 8 1 Hz, Harcni), 7 11 b(s, 1H, Harcni), 703 (d, 1H, J = 77 Hz, Harcfn), 422-4 14 (m, 1H), 409 (dd, 1H, J= 43 Hz, J = 9.7 Hz), 3 98 (dd, 1H, J = 59 Hz, J = 9.7 Hz), 3 72-3 68 (m, 2H), 3 65 (t, 2H, J = 6.1 Hz), 3 18-3 06 (m, 5H), 297 (dd, 1H, J = 9.7 Hz, J = 13 2 Hz), 272-265 (m, 2H), 265-257 (m, 2H), 237 (bs, 3H), 1.90-1.72 (m, 6H), 1.71-1.64 (m, 6H), 098 (t, 3H, J = 73 Hz)

[0950] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 156 8 (Cq), 1428 (Cq), 1370 (Cq), 1320 (Cq), 131 7 (Cq), 1306 (CHarom), 1292 (CHarom), 1240 (CHarom), 115.3 (CHarom), 71.8 (CH2), 66 1 (CH), 627 (CH2), 61 8 (CH2), 604 (CH2), 564 (CH2), 559 (CH2), 42 1 (CH3), 388 (CH2), 300 (CH2), 280 (CH2), 259 (CH2), 249 (CH2), 142 (CH3)

[0951] HRMS (ESI+): m / z calculated for C29H45N2O3[M+H]+: calc 469.3425; found: 469.3428

[0952] EXAMPLE 68: TM-361

[0953]

[0954] TM-361 [4-(((3-hydroxypropyl)(methyl)amino)methyl)-4'-propyl-[1,r-biphenyl]-2-ol] (69 mg, 3 4%) was syntbetized following General Procedure A, C.1, C.3, B, E.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid) TM-361 was obtained as a side product from synthesis of TM-359 / 1M- 60

[0955] 1H NMR (400 MHz, CDjOD) 6 (ppm) 8.51 (s, 0.8H, HCO2H), 747 (d, 2H, J = 8 1 Hz, Harm), 734 (d, 1H, J = 82 Hz, Harom), 722 (d, 2H, J = 8 1 Hz, Harom), 704-694 (m, 2H, Harom), 4 17 (bs, 2H), 3 69 (t, 2H, J = 57 Hz), 323-3 12 (m, 2H), 275 (s, 3H), 268-255 (m, 2H), 1 97 (dt, 2H, J= 59 Hz, J = 12 1 Hz), 1 75-1 60 (m, 2H), 097 (t, 3H, J = 73 Hz)13C NMR ( 101 MHz, CD3OD) 6 (ppm) 169.8 (HCO2H), 156 0 (Cq), 142 8 (Cq), 136 6 (Cq), 132 4 (CHarom), 132 0 (Cq), 131 5 (Cq), 130.2 (CHarom), 129.2 (CHarom), 123 0 (CHarom), 1 19.2 (CHarom), 61.0 (CH2), 60 6 (CH2), 55 6 (CH2), 407 (CH3), 38 8 (CH2), 28 2 (CH2), 25 8 (CH2), 14. 1 (CH3).

[0956] HRMS (ESI+): m / z calculated for C20H27NO2[M+H]+: calc 468.3585; found: 314.2112

[0957] EXAMPLE 69: TM-365

[0958] O

[0959] 11

[0960] H T)H

[0961] O 5 equiv

[0962] N

[0963] ■H I

[0964]

[0965] TM-339 / TM-365

[0966] TM-365 [3-(((5-(3-(azepan- 1-yl)-2-hydroxypropoxy)-4'-pentyl-[ 1, r-biphenyl]-3-yl)metfiyl)(methyl)amino)propan-1-ol] (5 0 mg, 10%) was synthetized following General Procedure C.2, C.3, B, A, E.2; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[0967] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.50 (s, 0.5H, HCO2H), 7 57 (d, 2H, J = 8 2 Hz, Harom), 7 38-7 36 (m, 1 H, Harom), 7 30- 7

[0968]

[0969] 26 (m, 3H, Harom), 7 16-7 14 (m, 1 H, HarOm), 4 46-4 39 (m, 1H), 4 25 (bs, 2H), 4 14 (d, 2H, J = 4.9 Hz), 3 68 (t, 2H, J = 5 8 Hz), 3 50 (dd, 1 H, J = 2 8 Hz, J = 13 2 Hz ), 3 47-3 41 (m, 4H), 3 34-3 26 (m, 1H), 3 19 (t, 2H, J = 7 4 Hz), 2 75 (s, 3H), 2 65 (t, 2H, J = 7 5 Hz), 2 02-1 89 (m, 6H), 1 80-1 72 (m, 4H), 1 70-1 61 (m, 2H), 1 41- 1 29 (m, 4H), 0 91 (t, 3H, J = 6.9 Hz)

[0970] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.8 (HCO2H), 160 8 (Cq), 145 0 (Cq), 144.2 (Cq), 138.6 (Cq), 134 6 (Cq), 130 1 (CHarom), 128.0 (CHarom), 123 1 (CHarom), 1 16.0 (CHarom), 115.5 (CHarom), 71.5 (CH2), 65 6 (CH), 61 3 (CH2), 60 6 (CH2), 60 1 (CH2), 56 4 (CH2), 55 7 (CH2), 40 9 (CH3), 36 5 (CH2), 32 6 (CH2), 32 4 (CH2), 28 2 (CH2), 28 0 (CH2), 24 2 (CH2), 23 6 (CH2), 14 4 (CH3)

[0971] HRMS (ESI+): m / z calculated for C31H48N2O3[M+H]+: calc 497.3738; found: 497.3752 EXAMPLE 70: TM-372

[0972]

[0973] TM-372

[0974] TM-372 [(S)-5-(((2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-3-ol] (183 mg, 95%) was synthetized following General Procedure A, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[0975] 1H NMR (400 MHz, CDCh) 6 (ppm) 7.46 (d, 2H, J = 80 Hz, Harem), 740 (d, 2H, J = 8 1 Hz, Harom), 721 (d, 2H, J = 80 Hz, Harom), 7 18 (d, 2H, J = 8 1 Hz, Harom), 698-696 (m, 1H, Harom), 693 (bs, 2H, Harom), 409 (bs, 3H, NHz, NH), 3 78 (d, 1H, J = 13 0 Hz), 3 69 (d, 1H, J = 13 0 Hz), 327-3 15 (m, 1H), 2.84-2.71 (m, 2H), 2.69-2.53 (m, 4H), 1 70-1 60 (m, 2H), 095 (t, J = 7.3 Hz, 3H)

[0976] 13C NMR (101 MHz, CDCh) 5 (ppm) 157.9 (Cq), 143 1 (Cq), 142 3 (Cq), 1422 (Cq), 1398 (Cq), 1380 (Cq), 129.7 (CH,™), 129 1 (m, Cq), 1290 (CHarom), 1269 (CHarom), 1257 (q, J= 36 Hz, CH™.), 1243 (m, Cq), 118.9 (CHarom), 114.2 (CHarom), 540 (CH2), 536 (CH2), 51 7 (CH), 41 5 (CH2), 378 (CH2), 247 (CH2), 140 (CH3).

[0977] 19F NMR (377 MHz, CDCl3) 5 (ppm) -62.42 (s, 3F).

[0978] HRMS (ESH-): m / z calculated for C39H56F3N4O2 [M +H]+: calc 4683585; found: 4683574

[0979] EXAMPLE 71: TM-373

[0980]

[0981] TM-373

[0982] TM-373 [5-(((3-aminopropyl)(methyl)amino)methyl)-4'-pentyl-[1, 1'-biphenyl]-3-ol] (140 mg, 21%) was synthetized following General Procedure A, C.1, C.3, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.41 (s, 0.5H, HCO2H), 755-750 (m, 2H, Harom), 725 (d, 2H, J= 82 Hz, Harom), 7.21-7 18 (m, 1H, Harom), 708-706 (m, 1H, Harom), 688-686 (m, 1H, Harem), 405 (bs, 2H), 3 02 (t, 4H, J = 73 Hz), 264 (t, 2H, J = 75 Hz), 263 (s, 3H), 2 11-203 (m, 2H), 1 69-1 60 (m, 2H), 1 41-1 30 (m, 4H), 091 (t, 3H, J = 69 Hz)13C NMR (101 MHz, CD3OD) 6 (ppm) 168.9 (HCO2H), 159 5 (Cq), 144 7 (Cq), 143 8 (Cq), 139 0 (Cq), 135 7 (Cq), 129 9 (CHarom), 127.9 (CHarom), 121.0 (CHarom), 116.9 (CHarom), 1153 (CHarom), 62 1 (CH2), 54 6 (CH2), 40 9 (CH3), 38 8 (CH2), 36.5 (CH2), 32.6 (CH2), 32.4 (CH2), 24.3 (CH2), 23.6 (CH2), 14.4 (CH3).

[0983] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 468.3585; found: 468.3574

[0984] EXAMPLE 72: TM-374

[0985]

[0986] TM-374

[0987] TM-374 [5-(((3-aminopropyl)(methyl)amino)methyl)-3',5'-di-tert-butyl-[ 1, 1 '-biphenyl]-3-ol] (17 0 mg, 23%) was synthetized following General Procedure A, C.1, C.3, D; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid)

[0988] 1H NMR (400 MHz, CD3OD) 6 (ppm) 7.45 (t, 1 H, J = 1 8 Hz, Harcm), 7 42 (d, 2H, J = 1 8 Hz, Harm), 7 20-7 17 (bs, 1H, H

[0989]

[0990] arOm), 7 06-7 04 (m, 1H, Harcm), 6 90-6 87 (m, 1H, HarCrn), 4 03 (bs, 2H), 3 01 (dd, 4H, J = 7 2 Hz, J = 14 7 Hz), 2 62 (s, 3H), 2 1 1-2 01 (m, 2H), 1 37 (s, 18H)

[0991] 13C NMR ( 101 MHz, CD3OD) 6 (ppm) 159.5 (Cq), 152 4 (Cq), 146 0 (Cq), 141 1 (Cq), 134 6 (Cq), 122 8 (CHarom), 122 5 (2 CHarom), 121 5 (CHarom), 117 1 (CHarom), 116 0 (CHarom), 61.9 (CH2), 54 4 (CH2), 40 6 (CHs), 38 5 (CH2), 35 8 (Cq), 32 0 (CH3), 24.1 (CH2)

[0992] HRMS (ESH-): m / z calculated for C39H56F3N4O2 [M +H]+: calc 468 3585; found: 468 3574

[0993] EXAMPLE 73: TM-375

[0994] 0.01 eqniv

[0995]

[0996] TM-375

[0997] TM-375 [5 (((3 aminopropyl)(methyl)amino)methyl) 4' cyclopentyl [ 1, T biphenyl] 3 ol] (15 0 mg, 16%) was synthetized following General Procedure A, C.1, C.3, D, Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1 % Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) B.41 (s, 0.2H, HCO2H), 7.57-7.52 (m, 2H, Harom), 732-727 (m, 3H, Harem), 7 13-7 12 (m, 1H, Harom), 696-693 (m, 1H, Harom), 425 (bs, 2H), 3.26-3.18 (m, 2H), 304 (t, 2H, J = 75 Hz), 3 03-296 (m, 1H), 277 (s, 3H), 222-2 13 (m, 2H), 2 11-201 (m, 2H), 1 87-1 78 (m, 2H), 1 76-1 66 (m, 2H), 1 66-1 54 (m, 2H)

[0998] 13C NMR (101 MHz, CD3OD) 6 (ppm) 159.7 (Cq), 1475 (Cq), 1448 (Cq), 1388 (Cq), 1336 (Cq), 1286 (CHarom), 127.9 (CHarom), 121.4 (CHarom), 1172 (CHarom), 1158 (CHarom), 61.5 (CH2), 54.2 (CH2), 46.9 (CH), 40.4 (CH3), 38.3 (CH2), 35.7 (CH2), 26.5 (CH2), 23.8 (CH2)

[0999] HRMS (ESH-): m / z calculated for C39H56F3N4O2 [M +H]+: calc 4683585; found: 4683574

[1000] EXAMPLE 74: TM-376

[1001] O H OH

[1002] 1.0 equiv

[1003]

[1004] TM-376

[1005] TM-376 [(S)-5-(((3-((2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-3',5'-di-tert-bulyl-[1, T-biphenyl]-3-ol] (240 mg, 40%) was synthetized following General Procedure A, C.1, C.3, D, C.4, D; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid).

[1006] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.46 (s, 1.1H, HCO2H), 764 (d, 2H, J = 8 1 Hz, Harom), 748-745 (m, 3H, Harom), 742 (d, 2H, J = 1 8 Hz, Harem), 722 (t, 1H, J - 1 4 Hz, Harom), 709 (dd, 1H, J = 1 8 Hz, J = 2 1 Hz, Harem), 693-691 (m, 1H, Harom), 4 19 (bs, 2H), 3 49-3 41 (m, 1H), 3 15 (dd, 2H, J = 6.7 Hz, J = 87 Hz), 296 (d, 2H, J = 72 Hz), 285 (dd, 1H, J = 40 Hz, J - 130 Hz), 2.81-2.65 (m, 3H), 272 (s, 3H), 200-1 91 (m, 2H), 1 37 (s, 18H)

[1007] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.2 (HCO2H), 159 6 (Cq), 1525 (Cq), 146.1 (Cq), 142.2 (Cq), 141 1 (Cq), 1343 (Cq), 131 1 (CHarom), 130.6 (ill, Cq), 1268 (q, J = 3 8 Hz, CHarom), 125.6 (m, Cq), 1229 (CHarom), 122.4 (CHarom), 121.5 (CHarom), 1172 (CHa™), 116.1 (CHarom), 61.5 (CH2), 55.6 (CH2), 53.1 (CH), 51.6 (CH2), 47.7 (CH2), 40.5 (CH3), 38.9 (CH2), 35.8 (Cq), 31.9 (CH3), 25.1 (CH2)

[1008] 19F NMR (377 MHz, CDCl3) 5 (ppm) -64.0 (s, 3F).

[1009] HRMS (ESI+): m / z calculated for C38H56IN4O2[M+H]+: calc 600.2445; found: 600.2451 EXAMPLE 75: TM-377

[1010]

[1011] TM-377

[1012] TM-377 [(S)-5-(((3-((2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-cyclopentyl-[1, T- brphenyl]-3-ol] (160 mg, 28%) was synthetized following General Procedure A, C.1, C.3, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1013] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.38 (s, 1.0H, HCO2H), 765 (d, 2H, J = 8 1 Hz, Harom), 756-752 (m, 2H, Harom), 748 (d, 2H, J = 80 Hz, Harom), 7.31 (d, 2H, J = 8 1 Hz, Harom), 727 (t, 1H, J = 1 4 Hz, Harom), 7 13-7 11 (m, 1H, Harom), 694-692 (m, 1H, Harom), 428 (bs, 2H), 356-3 46 (m, 1H), 3 28-3 21 (m, 2H), 3 04-3 00 (m, 1H), 299 (d, 2H, J = 7.2 Hz), 285 (dd, 1H, J = 40 Hz, J= 13 1 Hz), 281-267 (m, 3H), 280 (s, 3H), 2.12-2.03 (m, 2H), 202-1 95 (m, 2H), 1 88-1 79 (m, 2H), 1 77-1 69 (m, 2H), 1 66-1 55 (m, 2H)

[1014] 13C NMR (101 MHz, CD3OD) 6 (ppm) 168.2 (HCO2H), 159 8 (Cq), 1476 (Cq), 1449 (Cq), 1420 (Cq), 1387 (Cq), 133 2 (Cq), 131 1 (CHarom), 130.5 (m, Cq), 1286 (CH,™,), 127.8 (CHarom), 126.8 (q, J = 3 9 Hz, CH,™.), 125.7 (m, Cq), 121 4 (CHarom), 117 3 (CHarom), 1160 (CHarom), 61 2(CH2), 554 (CH2), 53 2 (CH), 51 3 (CH2), 475 (CH2), 470 (CH), 404(CH3), 383 (CH2), 357 (CH2), 265 (CH2), 250 (CH2)

[1015] 19F NMR (377 MHz, CDCh) 5 (ppm) -64.0 (s, 3F).

[1016] HRMS (ESI+): m / z calculated for C38H56IN4O2[M+H]+: calc 600.2445; found: 600.2451

[1017] EXAMPLE 76: TM-378

[1018]

[1019] TM-378 [1-((5-(((3-(((S)-2-amino-3-(4-(tritluoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-3',5'-di-tert- butyl [ 1, T -biphenyl] -3 -yl)oxy) -3 (azepan -1 -yl)propan 2 ol] (220 mg, 12%) was synthetized following General Procedure A, C.1, C.3, B, D, C.4, D, Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.31 (s, 0.3H, HCO2H), 7 66 (d, 2H, J = 8 1 Hz, HarCm), 751 (d, 2H, J = 8 1 Hz, Harom), 7 49 (t, 1H, J = 1 7 Hz, Harom), 7 47-744 (m, 3H, Harem), 730-7 29 (m, 1H, HarOm), 7 27-7 26 (m, 1H, Harm), 4 49-4 42 (m, 1H), 4 41 (bs, 2H), 4 18 (d, 2H, J = 4 9 Hz), 3 58-3 43 (m, 6H), 3 38-3 32 (m, 3H), 3 03 (d, 2H, J = 7 2 Hz), 289 (dd, 1H, J = 4 0 Hz, J = 13 1 Hz), 2 84-271 (m, 3H), 2 81 (s, 3H), 2 10-2 01 (m, 2H), 200-1 92 (m, 4H), 1 81-1 72 (m, 4H), 1 38 (s, 18H)

[1020] 13C NMR (101 MHz, CD3OD) 5 (ppm) 160.8(Cq), 152 6 (Cq), 146 3 (Cq), 1420 (Cq), 140 7 (Cq), 133 3 (Cq), 131 2 (CH,™), 130 5 (q, J - 32 3 Hz, Cq), 1268 (q, 3 7 Hz, CH, ), 1257 (q, J - 271 2 Hz„ Cq), 123.8 (CH,™), 123 2 (CH,™), 122 6 (CH,™), 116 6 (CH, rom), 115 9 (CH,™), 71 6 (CH2), 65 6 (CH), 61 1 (CH2), 60 1 (CH2), 557 (CH2), 53 3 (CH), 51 2 (CH2), 47 3 (CH2), 40.1 (CH3), 38.2 (CH2), 35.9 (Cq), 31.9 (CH3), 28.0 (CH2), 25.1 (CH2), 24.2 (CH2)

[1021] 19F NMR (377 MHz, CDCl3) δ (ppm) -64.0 (s, 3F).

[1022] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 669.4350; found: 669.4334

[1023] EXAMPLE 77: TM-379

[1024] H OH

[1025] 037 equiv

[1026]

[1027] TM-379

[1028] TM-379 [1-((5-(((3-aminopropyl)(mettiyl)amino)mettiyl)-4'-cyclopentyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2- ol] (14 0 mg, 19%) was synthetized following General Procedure A, C.1, C.3, B, D; Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1029] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.33 (s, 0.4H, HCO2H), 7 60-757 (m, 2H, Harom), 743-7 41 (m, 1H, Harem), 734 (d, 2H, J = 8 2 Hz, Harom), 7 29-7 27 (m, 1H, HarCm), 7 23-7 21 (m, 1H, Harem), 4 45 (dtd, 1H, J = 2 8 Hz, J= 49 Hz, J = 7 6 Hz), 4 27 (bs, 2H), 4 16 (d, 2H, J = 5 0 Hz), 3 53 (dd, 1H, J = 2 7 Hz, J = 13 2 Hz), 3 51-3 41 (m, 4H), 3 37-3 28 (m, 1H), 3 22- 3 16 (m, 2H), 3 05 (t, 3H, J = 7 5 Hz), 274 (s, 3H), 2 22-2 14 (m, 2H), 2 13-2 05 (m, 2H), 2 01-1 90 (m, 4H), 1 88-1 81 (m, 2H), 1 80-1 70 (m, 6H), 1 68-1 57 (m, 2H)

[1030] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.8 (Cq), 147 8 (Cq), 144 8 (Cq), 1386 (Cq), 1345 (Cq), 128 7 (CH,™), 1280 (CH,™), 123 2 (CH,rom), 116 0 (CH,™), 115 6 (CH,™), 71 5 (CH2), 65 6 (CH), 61 6 (CH2), 60 1 (CH2), 54 5 (CH2), 47 0 (CH), 40 4 (CH3), 38 4 (CH2), 35 7 (CH2), 280 (CH2), 26 5 (CH2), 24 2 (CH2), 240 (CH2)

[1031] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 468.3585; found: 468.3574 EXAMPLE 78: TM-380

[1032] JL o

[1033] Q H^OH

[1034] | 078 equiv

[1035]

[1036] TM-380

[1037] TM-380 [1-((5-(((3-aminopropyl)(methyl)amino)methyl)-4'-pentyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (21 0 mg, 22%) was synthetized following General Procedure A, C.1, C.3, B, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1038] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.40 (s, 0.9H, HCO2H), 756 (d, 2H, J = 82 Hz, Harom), 735-733 (m, 1H, Harom), 727 (d, 2H, J= 82 Hz, Harem), 724-722 (m, 1H, HarOm), 7 13-7 11 (m, 1H, HarCm), 443 (dtd, 1H, J = 2.8 Hz, J = 48 Hz, J = 75 Hz), 4 14 (d, 2H, J = 4 9 Hz), 405 (bs, 2H), 3 52 (dd, 1H, J = 27 Hz, J = 13 2 Hz), 3 50-3 43 (m, 4H), 3 36-3 28 (m, 1H), 3 06 296 (m, 4H), 265 (t, 2H, J = 75 Hz), 259 (s, 3H), 2 11-2.03 (m, 2H), 2.00-1.91 (m, 4H), 1.81-1.72 (m, 4H), 1.69- 1 61 (m, 2H), 1 41-1 31 (m, 4H), 091 (t, 3H, J = 69 Hz)

[1039] 13C NMR (101 MHz, CD3OD) 6 (ppm) 160.7 (Cq), 1447 (Cq), 1440 (Cq), 1388 (Cq), 1367 (Cq), 1300 (CHarom), 128.0 (CHarom), 1228 (CHarom), 1157 (CHarom), 1148 (CHarom), 71.4 (CH2), 656 (CH), 622 (CH2), 60 1 (CH2), 549 (CH2), 409 (CH3), 390 (CH2), 36 5 (CH2), 326 (CH2), 324 (CH2), 280 (CH2), 244 (CH2), 242 (CH2), 236 (CH2), 144 (CH3).

[1040] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 468.3585; found: 468.3574

[1041] EXAMPLE 79: TM-381

[1042]

[1043] TM-381 [1 -((5-(((3-(((S)-2-ammo-3-(4-(trit1uoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-4,-cydopentyl- [1, 1'-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (100 mg, 17%) was synthetized following General Procedure A, C.1, C.3, B, D, C.4, D; Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1044] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.31 (s, 1.3H, HCO2H), 765 (d, 2H, J = 8 1 Hz, Harom), 760-756 (m, 2H, Harom), 748 (d, 2H, J = 8 1 Hz, Harem), 743-741 (m, 1H, Harom), 734 (d, 2H, J = 82 Hz, Harom), 730-728 (m, 1H, HarCm), 723-721 (m, 1H, Harcni), 4 43 (dtd, 1H, J = 3 0 Hz, J = 4.9 Hz, J = 7 6 Hz), 4 32 (bs, 2H), 4 15 (d, 2H, J = 50 Hz), 3 54-3 43 (m, 6H), 3 29-3 23 (m, 2H), 3 09-3 02 (m, 1H), 2 99 (d, 2H, J = 7 2 Hz), 286 (dd, 1H, J = 4 0 Hz, J = 13 0 Hz), 2 83-268 (m, 3H), 2 77 (s, 3H), 2.13-2.1 91 (m, 9H), 1 88-1 81 (m, 2H), 1 80-1 70 (m, 6H), 1 67-1 57 (m, 2H)

[1045] 13C NMR (101 MHz, CD3OD) 6 (ppm) 167.8 (HCO2H), 160 8 (Cq), 147 9 (Cq), 144 9 (Cq), 142 1 (Cq), 138 5 (Cq), 134 1 (Cq), 131 1 (CHarom), 1305 (q, J = 32 1 Hz, Cq), 128.7 (CHarom), 128 0 (CHarom), 126.8 (q, J = 3.7 Hz, CHarom), 125 7 (q, J = 271 0 Hz, Cq), 123 2 (CHarom), 116 2 (CHarom), 115 6 (CHarom), 71 5 (CH2), 655 (CH), 61 3 (CH2), 60 1 (CH2), 56 4 (CH2), 55 8 (CH2), 53 2 (CH), 51 4 (CH2), 475 (CH2), 470 (CH), 40 3 (CH3), 38 5 (CH2), 35 7 (CH2), 28 0 (CH2), 26 5 (CH2), 25 2 (CH2), 24 2 (CH2)

[1046] 19F NMR (377 MHz, CDCl3) δ (ppm) -64.0 (s, 3F).

[1047] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc. 669.4350; found: 669.4334

[1048] EXAMPLE 80: TM-382

[1049]

[1050] TM-382 [1 -((5-(((3-aminopropyl)(methyl)amino)methyl)-3',5'-di-tert-butyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan- 1-yl)propan- 2 ol] (16 0 mg, 23%) was syntfietized following General Procedure A, C.1, C.3, B, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid).

[1051] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.44 (s, 0.5H, HCO2H), 7 48 (t, 1H, J = 1 8 Hz, Harcm), 7 43 (d, 2H, J = 1 8 Hz, Har™), 7 35-7 32 (m, 1H, HarOm), 7.21-7.19 (m, 1H, Harcm), 7 18-7 15 (m, 1H, HarOm), 4 45 (dtd, 1H, J = 2 8 Hz, J = 4 8 Hz, J = 7 5 Hz), 4 16 (d, 2H, J = 4 9 Hz), 4 12 (bs, 2H), 3 54 (dd, 1H, J = 2 7 Hz, J = 13 2 Hz), 3 51-3 41 (m, 4H), 3 34 (dd, 1H, J = 10 5 Hz, J = 13 2 Hz), 3 04 (t, 4H, J = 7 4 Hz), 2 63 (s, 3H), 2 15-2 06 (m, 2H), 2 00-1 91 (m, 4H), 1 81-1 71 (m, 4H), 1 38 (s, 18H)

[1052] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.0 (HCO2H), 160 6 (Cq), 152 6 (Cq), 146 0 (Cq), 141 0 (Cq), 136 3 (Cq), 123 3 (CHarom), 123 0 (CHarom), 122 5 (CHarom), 115.7 (CHarom). 115 5 (CHarom), 71 5 (CH2), 65 6 (CH), 62 1 (CH2), 602 (CH2), 54 8 (CH2), 40.8 (CH3), 38 8 (CH2), 358 (Cq), 31 9 (CH3), 280 (CH2), 24 3 (CH2), 24 2 (CH2)

[1053] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 468.3585; found: 468.3574 EXAMPLE 81: TM-386

[1054]

[1055] TM-386 [1-((5-((((S)-2-amino-3-(pyridin-4-yl)propyl)amino)methyl)-4'-propyl-[1,1 '-biphenyl]-3-yl)oxy)-3-(azepan-1- yl)propan-2-ol] (25 3 mg, 21%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid)

[1056] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.46-8.43 (m, 2H, Harcni), 8 28 (s, 1.6H, HCO2H), 7 53 (d, 2H, J= 8 2 Hz, HarQm), 7.37- 7

[1057]

[1058] 34 (m, 2H, Harom), 7.29-7.24 (m, 3H, Harom), 7 14 (m, 1H, Harcm), 7 01 (m, 1H, Haram), 4 43 (dtd, 1H, J= 2 7 Hz, J= 4 9 Hz, J = 7 6 Hz), 4 12 (d, 1 H, J = 10 4 Hz), 4.08 (d, 1H, J = 10 4 Hz), 4 01 (d, 1H, J= 13 4 Hz), 3 95 (d, 1H, J = 13 4 Hz), 3 64- 3 57 (m, 1H), 3 51 (dd, 1H, J = 2 8 Hz, J = 13.3 Hz), 3 49-3 43 (m, 4H), 3 35-3 28 (m, 1 H), 2 99 (d, 2H, J = 7 3 Hz), 2 95 (dd, 1 H, J = 3 9 Hz, J = 13 3 Hz), 2 84 (dd, 1H, J = 8 8 Hz, J= 13.3 Hz), 2 63 (t, 2H, J = 7 5 Hz), 2 00- 1 89 (m, 4H), 1 81 - 1 72 (m, 4H), 1 67 (dq, 2H, J = 7 4 Hz, J = 14 7 Hz), 0 96 (t, 3H, J = 7 4 Hz)

[1059] 13C NMR ( 101 MHz, CD3OD) 6 (ppm) 167.1 (HCO2H), 160 6 (Cq), 150.4 (CHarom), 148 1 (Cq), 144 4 (Cq), 143 6 (Cq), 140.3 (Cq), 139 1 (Cq), 130 0 (CH arom ), 127 9 (CH arom ), 126 4 (CH arom ), 121 4 (CH arom ), 114 5 (CH arom ), 113.9 (CHarom), 71 4 (CH2), 65 6 (CH), 60 2 (CH2), 56 4 (CH2), 53 6 (CH2), 52 1 (CH), 50 5 (CH2), 38 6 (CH2), 38 1 (CH2), 28 0 (CH2), 25 7 (CH2), 24 2 (CH2), 14 1 (CH 3)

[1060] HRMS (ESI+): m / z calculated for C33H48N4O2[M+2H]2+: calc 266.1883; found: 266.1893

[1061] EXAMPLE 82: TM-387

[1062]

[1063] TM-387 [1-((5-((((S)-3-amino-4-phenylbutyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (25 0 mg, 19%) was synthetized following General ProcedureA, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.45 (s, 0.8H, HCO2H), 7 57 (d, 2H, J = 8 2 Hz, Harom), 7 38-7 25 (m, 9H, Harom), 7 19-7.16 (m, 1H, Harom), 4 44 (dtd, 1H, J = 2 8 Hz, J = 4 8 Hz, J = 7 5 Hz), 4 20 (bs, 2H), 4 15 (d, 2H, J = 4 8 Hz), 3 69-3 62 (m, 1H), 3 52 (dd, 1H, J = 2 8 Hz, J = 13 2 Hz), 3 50-3 43 (m,4H), 3 35-3 27 (m, 1H), 3 26-3 17 (m, 1H), 3 16-3 07 (m, 1H), 3 05-2 92 (m, 2H), 2 63 (t, 2H, J = 7 5 Hz), 2 11 (dd, 2H, J = 7 5 Hz, J = 14.6 Hz), 1 99-1 91 (m, 4H), 1 81 -1 73 (m, 4H), 1 67 (dq, 2H, J = 7 4 Hz, J = 14 6 Hz), 0 96 (t, 3H, J = 7 4 Hz)

[1064] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.4 (HCO2H), 160 7 (Cq), 144 8 (Cq), 143 8 (Cq), 138 6 (Cq), 136 7 (Cq), 134 9 (Cq), 130 5 (CH arom ), 130 2 (CH arom ), 130 1 (CH arom ), 128 6 (CH arom ), 128 0 (CH arom ), 122 3 (CH arom ), 1 15 5 (CH arom ), 115 2 (CHarom), 71 5 (CHj), 65 6 (CH), 60 1 (CHj), 56 4 (CH2), 52 5 (CH2), 52 0 (CH), 45 2 (CH2), 40 1 (CH2), 38 6 (CH2), 30 3 (CH2), 27 9 (CH2), 25 7 (CH2), 24 2 (CH2), 14 1 (CH3).

[1065] HRMS (ESI+): m / z calculated for C35H51N3O2[M+2H]2+: calc 272.6985; found: 272.6990

[1066] EXAMPLE 83: TM-389

[1067]

[1068] TM-389 [1-((5-(((3-(((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-pentyl-[1,1'-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (19 1 mg, 7%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1 % Fomiic Acid)

[1069] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 2.4H, HCO2H), 7 63 (d, 2H, J = 8 1 Hz, HarCm), 7 54 (d, 2H, J = 8 1 Hz, Harom), 7

[1070]

[1071] 41 (d, 2H, J = 8 0 Hz, Harcni), 7 31 -7 29 (m, 1H, Harem), 7 26 (d, 2H, J = 8 1 Hz, Harom), 7 21 -7 18 (m, 1H, Harem), 7 03-6 99 (m, 1H, Harem), 4 40 (dtd, 1H, J = 2 8 Hz, J = 4 8 Hz, J = 7 8 Hz), 4 12 (d, 1H, J = 11 1 Hz), 4 01 (d, 1 H, J= 1 1 1 Hz), 3 93 (d, 1H, J = 13 9 Hz), 3 89 (d, 1 H, J= 13 9 Hz), 3 48-3 39 (m, 5H), 3 36-3 31 (m, 1H), 3.21-3.24 (m, 1H), 2 92-2 84 (m, 5H), 2 84-2 74 (m, 2H), 2 71-2 61 (m, 3H), 2 49 (s, 3H), 1 98- 1 87 (m, 6H), 1 80-1 71 (m, 4H), 1 68-1 59 (m, 2H), 1 40-1 29 (m, 4H), 0 90 (t, 3H, J = 7 0 Hz)

[1072] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 160 7 (Cq), 144 5 (Cq), 144 0 (Cq), 142 7 (Cq), 138 9 (Cq), 137 9 (Cq), 131 1 (CHarom), 130.3 (q, J = 32.1 Hz, Cq), 130 1 (CHarom), 128 0 (CHarom), 126 7 (q, J = 3 8 Hz, CHarom), 125 7 (q, J = 271 3 Hz, Cq), 122 6 (CHarom), 1 15 9 (CHarom), 114.2 (CHarom), 71 4 (CH2), 65 7 (CH), 62 3 (CH2), 60 3 (CH2), 56 4 (CH2), 56 0 (CH2), 52 4 (CH), 52 2 (CH2), 48 2 (CH2), 41 3 (CH3), 40 2 (CH2), 36 5 (CH2), 32 6 (CH2), 32 4 (CH2), 28 0 (CH2), 25 2 (CH2), 24 3 (CH2), 23 6 (CH2), 14 4 (CH3)

[1073] 19F NMR (377 MHz, CDCh) 5 (ppm) -64.0 (s, 3F). HRMS (ESI+): m / z calculated for C41H60F3N4O2[M+H]+: calc 697.4663; found: 697.4677

[1074] EXAMPLE 84: TM-390

[1075]

[1076] TM-390 [3-(3-hydroxypropyl)-8-(4-pentylphenyl)chroman-6-ol] (40 mg, 56%) was syn thetized following this procedure:

[1077]

[1078] Procedure 1) Halogenation

[1079]

[1080] To a solution of 1 (1 eq) in glacial acetic acid was added sodium acetate (1 6) and bromine (1.3). The resulting yellow mixture was stirred at room temperature for 1 hour and concentrated The residue was then dissolved in CH2CI2 (50 mL), washed twice with 20 mL of water, dried over MgSO4, filtered and concentrated under vacuum The crude solid was next recrystallized from ethanol to yield 2 as a yellow solid

[1081] Procedure 2) Cyclisation

[1082]

[1083] To a solution of 2 (1 eq) in dioxane was added K2CO3 (5 eq) and acrolein (2 eq) The reaction mixture was refluxed for 2 h The progress of the reaction was monitored by TLC checking After 2h, the reaction was completed, and the mixture was then poured into water The solution was extracted with ethyl acetate The combined organic layers were washed with brine (30 mL), dned over anhydrous NajSCU and evaporated under vacuum The residue was crystallized from CHCh / n-Hexanes to give 3

[1084] Procedure 3) Olefination

[1085]

[1086] Compound 3 was dissolved in anhydrous DCM under inert atm (Carbethoxymethylene) friphenylphosphorane (1 2 eq) was added to the solution and it was stirred for 3h at room temperature After completion of the reaction, DCM was evaporated, and the product was directly purified by flash chromatography on silica gel using 85:15 (Hexanes / AcOEt) Compound 4 was obtained as a yellow solid

[1087] Procedure 4) Pd / Hz reduction

[1088]

[1089] A stream of hydrogen was passed through a solution of 4 in THF (10 ml) in the presence of 10% Pd / C with stirring at room temperature After 18 h, the catalyst was removed by filtration and the solvent was removed in vacuum The residue 5 obtained was then used without purification in the next step

[1090] Procedure 5) Acidic cleavage

[1091]

[1092] Compound 5 (1 eq) and Tetrabutylammonium iodide (2.5 eq) were stirred in dry CH2CI2 at -78 °C under N2 A solution of BCI3 (1 M in CH2CI2, 25 eq) was added over 2 min After 8 min, the solution was warmed up to 0 °C and was stirred for 2 h The reaction solution was quenched with ice and H2O, stirred for 30 min, and partially concentrated to remove CH2CI2 After H₂O was added, the mixture was extracted with Et20 The combined organic layers were washed with saturated aqueous NaCI solution, dried over Na2SO4, concentrated, and purified by flash chromatography on silica gel 96:4 (Hexanes / AcOEt) to give 6 as a colorless oil

[1093]

[1094]

[1095] To a solution of 6 (1 eq) and boronic acid (1.5 eq) in degassed dioxane / H2O (5 / 1) were added, at room temperature under Argon, Pd(PPh3)4(0.1 eq) and K2CO3(2 M, 3 eq), and the mixture was heated at 100 °C for 3h The reaction mixture was then cooled to room temperature, quenched with water (5 mL) and extracted with CH2CI2 (10 mL x 3) The combined organic extracts were washed with bnne, dned (MgSCU), filtered and concentrated under reduced pressure The residue was then purified by flash chromatography on silica gel 97:3 (Hexanes / AcOEt) to give the title compound 7 as a pale- yellow oil

[1096] Procedure 7) Reduction

[1097]

[1098] To a stirred solution of 7 in DCM was added DIBAL -H (2 eq) at -78 °C The reaction mixture was stirred atO °C for2h and was quenched with Rochelle’s salt, diluted with H; O and DCM The organic layer was dried (Na; SOT) and then concentrated The final product was punfied by flash chromatography on SiOz 99:1 (Hexanes / AcOEt) to give the title compound 8 (TM-390) as a colorless oil

[1099] Purification: HPLC prep / MS (H2O: ACN: MeOH(NH4OH))

[1100] 1H NMR (400 MHz, Methanol-^) 67.38 - 7.32 (m, 2H), 7.16 - 7.10 (m, 2H), 6.56 (d, J = 3 0 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 4.16 - 4.07 (m, 1H), 3.69 - 3.54 (m, 3H), 2.91 - 2.80 (m, 1H), 2.60 (dd, J = 8.6, 6.8 Hz, 2H), 2.45 (dd, J = 16.3, 9.2 Hz, 1H), 201 - 1.90 (m, 1H), 1 71 - 1 56 (m, 4H), 1 49 - 1 24 (m, 6H), 0.98 - 0.86 (m, 3H)

[1101] 13C NMR (101 MHz, MeOD) δ 151.32, 146.09, 142.41, 137.40, 131.55, 130.34, 128.82, 124.19, 116.26, 115.98, 71.35, 62.98, 36.62, 33.44, 33.12, 32.65, 32.49, 30.82, 29.14, 23.62, 14.42

[1102]

[1103] TM-391 [3-(6-(3-(azepan-1-yl)-2-hydroxypropoxy)-8-(4-pentylphenyl)chroman-3-yl)propan-1-ol] (3 mg, 33%) was synthesized with the following Procedure:

[1104]

[1105] Procedure 8) Alkylation

[1106]

[1107] To a solution of compound 7 in dry DMF (70 mM) was slowly added NaH (1 5 eq) under Argon at 0 °C After stirnng for 30 min, epibromohydrin (2 eq) was added and the reaction continued to stir for 30 min at 0 °C and for 1h at room temperature Water was added and the reaction was extracted with AcOEt 3 limes, washed with brine, dned (MgSCk) and concentrated The product 9 obtained was then used directly in the next step

[1108]

[1109]

[1110] To a solution of compound 9 in EtOH (50 mM) was added at room temperature azepan (2 eq) and the reaction mixture was heated at 90 °C for 2h The solvent was evaporated, and the result crude product was then purified by flash chromatography on silica gel 95:5 (CH2CI2 / MeOH) producing compound 10 which was submitted to procedure 7) to afford the title compound TM-391 as a pale-yellow oil

[1111] Purification: HPLC prep / MS (H2O: ACN: MeOH(NH4OH))

[1112] 1H NMR (400 MHz, CDCI3) 67.41 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 3.1 Hz, 1H), 6.57 (d, J = 3.0 Hz, 1H), 4.58 - 4.38 (m, 1H), 4.24 - 4.17 (m, 1H), 4 11 (dd, J = 94, 4.6 Hz, 1H), 3.92- 3.80 (m, 1H), 3.76- 362 (m, 3H), 3 43 - 3 00 (m, 4H), 2.90 (dd, J = 16.1, 5.2 Hz, 1H), 2.67 - 2.58 (m, 2H), 2.52 (dd, J = 16.6, 9.6 Hz, 1H), 2 13 - 1 89 (m, 4H), 1.81 - 1 59 (m, J = 257, 21 8, 142, 73 Hz, 8H), 1 51 - 1 40 (m, J = 222, 127, 80 Hz, 2H), 1 39 - 1 23 (m, 7H), 0.90 (t, J = 7.0 Hz, 3H) EXAMPLE 86: TM-392

[1113] H OH

[1114] O equiv

[1115]

[1116] TM-392

[1117] TM-392 [1-((5-((((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)methyl)-4'-propyl-[1,1'-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (25.7 mg, 19%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1118] 1H NMR (400 MHz, CD3OD) 5 (ppm) 7.55 (s, 1H, Harom), 7.53 (d, 2H, J = 2.0 Hz, Harom), 7.50 (s, 1H, Harom), 7.37 (d, 2H, J = 7.9 Hz, Harom), 7.24 (d, 2H, J = 8.5 Hz, Harom), 7 17 (d, 1H, J = 1 5 Hz, HarCm), 707 (dd, 1H, J = 25, 1 6 Hz, HarCm), 692 (dd, 1H, J = 2.2, 1.3 Hz, Harom), 4.13-4.04 (m, 2H), 4.00 (q, 1H, J = 4.7 Hz), 3.82 (d, 1H, J = 13.3 Hz), 3.75 (d, 1H, J = 13.3 Hz), 3 19-3 09 (m, 1H), 2.89-2.74 (m, 6H), 2.72-2.58 (m, 5H), 2.50 (dd, 1H, J = 12.1, 8.2 Hz), 1 73-1 66 (m, 6H), 1 66- 1 60 (m, 4H), 0.96 (t, 3H, J = 7.3 Hz)

[1119] 13C NMR (101 MHz, CD3OD) δ (ppm) 161.0 (Cq), 144.9 (Cq), 144.0 (Cq), 143.3 (Cq), 143.0 (Cq), 139.6 (Cq), 131.0 (CHarom), 130.0 (m, Cq), 129.9 (CHarom), 127.9 (CHarom), 126.4 (CHarom), 126.3 (q, J = 4.1 Hz, CHarom), 125.6 (m, Cq), 120.7 (CHarom), 114.3 (CHarom), 113.0 (CHarom), 72.0 (CH2), 68.9 (CH), 61.5 (CH2), 57.2 (CH2), 55.2 (CH2), 54.7 (CH2), 53.2 (CH), 42.5 (CH2), 38.7 (CH2), 28.6 (CH2), 28.1 (CH2), 25.8 (CH2), 14.1 (CH3)

[1120] 19F NMR (377 MHz, CDCb) 5 (ppm) -63.8 (s, 3F).

[1121] HRMS (ESI+): m / z calculated for C35H47F3N3O2[M+H]+: calc 598.3615; found: 598.3640

[1122] EXAMPLE 87: TM-393

[1123] H2N

[1124]

[1125] TM-393

[1126] TM-393 [1-((4-((((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)methyl)-4'-propyl-[1,1'-biphenyl]-2-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (200 mg, 11%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 5 (ppm) 8.55 (s, 1.5H, HCO2H), 7 62 (d, 2H, J = 8 1 Hz, HarCm), 7 45 - 7 38 (m, 4H, Harom), 7 28-7 21 (m, 3H, Harcm), 7 10 (s, 1H, Harom), 7 00 (d, 1H, J = 7.5 Hz, Harom), 4 20-4 1 1 (m, 1H), 4 1 1-4 01 (m, 1H), 4 01 - 3 92 (m, 1H), 3 88 (d, 1H, J = 13 4 Hz), 3 81 (d, 1H, J = 13 3 Hz), 3 1 1-2 99 (m, 5H), 2 96-2 85 (m, 3H), 2 83-2 74 (m, 2H), 2 67- 2 58 (m, 3H), 1 78- 1 72 (m, 4H), 1 71- 1 65 (m, 6H), 0 98 (t, 3H, J = 7 3 Hz)

[1127] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.6 (HCO2H), 156 8 (Cq), 142 8 (Cq), 142 2 (Cq), 140 3 (Cq), 137.5 (Cq), 137 0 (Cq), 131 8 (CHarom), 131.1 (CHarom), 130.6 (CHarom), 130.5 (m, Cq), 129 2 (CHarom), 126.8 (q, J = 3 7 Hz, CHarom), 125.7 (q, J = 271 1 Hz, Cq), 123 0 (CHarom), 1 14 5 (CHarom), 71.8 (CH2), 65 5 (CH), 60 3 (CH2), 56 3 (CH2), 53 7 (CH2), 53 1 (CH), 50 7 (CH2), 38 8 (CH2), 38 6 (CH2), 27 9 (CH2), 25 9 (CH2), 24 0 (CH2), 14.2 (CH3).

[1128] 19F NMR (377 MHz, CDCl3) 5 (ppm) -63.95 (s, 3F).

[1129] HRMS (ESH-): m / z calculated for C35H47F3N3O2 [M+H]+: calc 598 3615; found: 546 3696

[1130] EXAMPLE 88: TM-394

[1131] H OH

[1132] 1 6 equiv

[1133] H

[1134] , N

[1135]

[1136] TM-394

[1137] TM-394 [1-((5-((((S)-2-amino-4-phenylbutyl)amino)methyl)-4,-propyl-[1,1,-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (38 0 mg, 28%) was synthetized following General ProcedureA, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1138] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.47 (s, 1.68H, HCO2H), 7 54 (d, 2H, J = 8 2 Hz, Harom), 7 28-7 23 (m, 5H, Harm), 7 21-7 13 (m, 4H, Harcm), 7 03-7 01 (m, 1H, Harm), 4 42 (dtd, 1H, J = 2 8 Hz, J = 4 9 Hz, J = 7.7 Hz), 4 13 (dd, 1H, J = 4 4 Hz, J = 9.3 Hz), 4 09 (dd, 1H, J = 4.6 Hz, J = 9 3 Hz), 3 95 (d, 1H, J = 13 5 Hz), 3 90 (d, 1 H, J = 13 5 Hz), 3 51-3 41 (m, 5H), 3 33-3 29 (m, 1H), 3 28-3 22 (m, 1 H), 3 02 (dd, 1H, J = 3 8 Hz, J = 13 2 Hz), 2 78 (dd, 1H, J = 8 8 Hz, J = 13 2 Hz), 2.71 (t, 2H, J = 7 9 Hz), 2 63 (t, 2H, J = 7 8 Hz), 1 99- 1 89 (m, 6H), 1.79-1.72 (m, 4H), 1.67 (dq, 2H, J = 7.4 Hz, J = 14.7 Hz), 0 96 (t, 3H, J = 7 4 Hz)

[1139] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.4 (HCO2H), 160.6 (Cq), 144 3 (Cq), 143 5 (Cq), 141 8 (Cq), 141.7 (Cq), 139 3 (Cq), 130 0 (CH arom ), 129.6 (CH arom ), 129.4 (CH arom ), 127 9 (CH arom ), 127.4 (CH arom ), 121 2 (CH arom ), 1 14 2 (CH arom ), 113.6 (CHarom), 71 3 (CH2), 65 7 (CH), 60 3 (CH2), 56 4 (CH2), 54 0 (CH2), 51 8 (CH), 50 8 (CH2), 38 6 (CH2), 34 3 (CH2), 32 5 (CH2), 27 9 (CH2), 25 7 (CH2), 24 2 (CH2), 14 1 (CH3).

[1140] HRMS (E SH-): m / z calculated for C35H50N3O2 [M +H]+: calc 544 3898; found: 544 3902 EXAMPLE 89: TM-395

[1141] TM-395 [ 1 -(( 5-(( ((S)-3 -ami n o-4 - phe ny Ibu ty I) am in o) m ethy I) -4 '-cycl op en ty I- [ 1, T-biph eny I ]- 3 -y l)oxy)-3-(azepan- 1 -y l)propan -2-ol] (42 4 mg, 26%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.49 (s, 1,2H, HCO2H), 7 57 (d, 2H, J = 8 3 Hz, Harom), 7 37-7 23 (m, 9H, Harom), 7 16-

[1142]

[1143] 7 13 (m, 1H, Harom), 4 44 (dtd, 1H, J = 2 5 Hz, J = 4.8 Hz, J = 7 5 Hz), 4 17 (bs, 2H), 4 13 (d, 2H, J = 5 0 Hz), 3 67-3 59 (m, 1H), 3 50 (dd, 1H, J = 2 7 Hz, J = 13 3 Hz), 3 48-3 46 (m,4H), 3 35-3 28 (m, 1H), 3 23-3 15 (m, 1H), 3 15-3 07 (m, 1H), 3 07-2 98 (m, 2H), 2 94 (dd, 1 H, J = 7 7 Hz, J = 13 9 Hz), 2 13-2 04 (m, 4H), 1 99-1 91 (m, 4H), 1 88-1 80 (m, 2H), 1 79- 1 70 (m, 6H), 1.67-1 58 (m, 2H)

[1144] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.9 (HCO2H), 160 7 (Cq), 147 7 (Cq), 144 8 (Cq), 138 6 (Cq), 136 8 (Cq), 135 3 (Cq), 130 5 (CH arom ), 130 1 (CH arom ), 128 7 (CH arom ), 128 6 (CH arom ), 127 9 (CH arom ), 122 2 (CH arom ), 1 15 3 (CH arom ), 115 1 (CHarom), 71 5 (CH2), 65 6 (CH), 60 2 (CH2), 56 4 (CH2), 52 5 (CH2), 52 1 (CH), 46 9 (CH), 45 2 (CH2), 40 2 (CH2), 35 7 (CH2), 30 4 (CH2), 27 9 (CH2), 26 5 (CH2), 24 2 (CH2)

[1145] HRMS (ESI+): m / z calculated for C37H52N3O2[M+H]+: calc 570.4054; found: 570.4063

[1146] EXAMPLE 90: TM-396

[1147]

[1148] TM-396 [1-((5-((((S)-3-amino-4-(4-iodophenyl)butyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl) pro pan-2-ol] (38 1 mg, 16%) was synthetized following General Procedure A, B, C.1, D: Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0 1 % Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.50 (s, 2.2H, HCO2H), 7.68 (d, 2H, J = 8.3 Hz, Harom), 7.55 (d, 2H, J = 8.3 Hz, Harom), 7.33 (bs, 1H, Harom), 7.27 (d, 2H, J = 8.3 Hz, Harom), 7.23 (m, 1H, Harom), 7.06 (m, 3H, Harom), 442 (dtd, 1H, J = 27 Hz, J = 49 Hz, J = 76 Hz), 4 16-4 08 (m, 4H), 3 59-3 51 (m, 1H), 351-3 40 (m,5H), 334-3 25 (m, 1H), 3 19-303 (m, 2H), 295-283 (m, 2H), 263 (t, 2H, J = 75 Hz), 203-1 89 (m, 6H), 1 81-1 73 (m, 4H), 1 68 (dq, 2H, J = 74 Hz, J = 147 Hz), 096 (t, 3H, J = 74 Hz)

[1149] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 1607 (Cq), 1448 (Cq), 1438 (Cq), 139.2 (CHarom), 1387 (Cq), 1369 (Cq), 1362 (Cq), 1326 (CH arom ), 130 1 (CH arom ), 1279 (CH arom ), 1220 (CH arom ), 1150 (CH arom ), 1149 (CH arom ), 93 5 (Cq), 71 4 (CH2), 656 (CH), 602 (CH2), 563 (CH2), 526 (CH2), 52 1 (CH), 454 (CH2), 400 (CH2), 386 (CH2), 306 (CH2), 280 (CH2), 257 (CH2), 24 2 (CH2), 14 1 (CH3)

[1150] HRMS (ESI+): m / z calculated for C35H48IN3O2[M+H]+: calc 670.2864; found: 670.2875

[1151] EXAMPLE 91: TM-397

[1152]

[1153] TM-397 [1-((5-((((S)-3-amino-4-(4-fluorophenyl)butyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan- 1-yl) pro pan-2-ol] (699 mg, 27%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1154] 1H NMR (400 MHz, CD3OD) δ (ppm) 8.49 (s, 1.2H, HCO2H), 7.57 (d, 2H, J = 8.2 Hz, Harom), 7.38 (bs, 1H, Harom), 7.34-7.30 (m, 2H, Harom), 7.29-7.24 (m, 3H, Harom), 7.15 (bs, 1H, Harom), 7.07 (t, 2H, J = 8.7 Hz, Harom), 444 (dtd, 1H, J = 24 Hz, J = 45 Hz, J= 73 Hz), 420 (bs, 2H), 4 14 (d, 2H, J= 49 Hz), 366-3 58 (m, 1H), 351 (dd, 1H, J = 26 Hz, J = 13 3 Hz), 3 48-3 44 (m,4H), 3 35-328 (m, 1H), 3 26-3 17 (m, 1H), 3 17-3 09 (m, 1H), 302-291 (m, 2H), 263 (t, 2H, J = 75 Hz), 208 (dd, 2H, J = 70 Hz, J = 143 Hz), 1 99-1 90 (m, 4H), 1 81-1 72 (m, 4H), 1 67 (dq, 2H, J = 73 Hz, J = 147 Hz), 0.96 (t, 3H, J = 7.3 Hz)

[1155] 13C NMR (101 MHz, CD3OD) δ (ppm) 169.9 (HCO2H), 163.6 (d, J = 244.6 Hz, Cq), 1607 (Cq), 1448 (Cq), 1438 (Cq), 1386 (Cq), 1352 (Cq), 132 8 (d, J = 3 2 Hz, Cq), 132.4 (d, J = 8.1 Hz, CHarom), 130.1 (CHarom), 127.9 (CHarom), 122.2 (CHarom), 116.8 (d, J = 21.6 Hz, CHarom), 115.3 (CHarom), 115.2 (CHarom), 71 5 (CH2), 656 (CH), 602 (CH2), 564 (CH2), 525 (CH2), 52 1 (CH), 452 (CH2), 393 (CH2), 386 (CH2), 303 (CH2), 279 (CH2), 257 (CH2), 24.2 (CH2), 14.1 (CH3).

[1156] 19F NMR (377 MHz, CDCl3) 5 (ppm) -117.1 (s, 1 F).

[1157] HRMS (ESI+): m / z calculated for C35H49FN3O2[M+H]+: calc 562.3803; found: 562.3811 EXAMPLE 92: TM-398

[1158]

[1159] TM-398 [1 ( (5^((((S) 3 ami n o 4 ( 4 n i tro ph en y l)b u ty l)amino)methy I) 4' propy l-[ 1, 1 '-biph enyl]-3-yl)oxy)-3-(azepan - 1 - yl)propan-2-ol] (68 3 mg, 27%) was synthetized following General Procedure A, B, C.1, D, Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid).

[1160] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.49 (s, 1.35H, HCO2H), 8 19 (d, 2H, J = 8 2 Hz, Harcni), 7 56 (d, 4H, J = 8 2 Hz, Harom), 7 38 (bS, 1H, Harem), 7 26 (d, 2H, J = 8 2 Hz, Harem), 7 23 (m, 1 H, Harom), 7 14 (Hl, 1H, Harom), 4 44 (dtd, 1H, J = 2 6 Hz, J = 4 8 Hz, J = 7 5 Hz), 4 20 (bs, 2H), 4 13 (d, 2H, J = 5 0 Hz), 3 75-3 67 (m, 1H), 3 51 (dd, 1 H, J = 2 7 Hz, J = 13 3 Hz), 3 48-3 45 (m,4H), 3 35-3 27 (m, 1H), 3 27-3 23 (m, 1H), 3 19-3 12 (m, 1H), 3 11 (d, 2H, J = 7 1 Hz), 2 62 (t, 2H, J = 7 5 Hz), 2 09 (dd, 2H, J = 7 3 Hz, J = 14 3 Hz), 1 99-1 89 (m, 4H), 1 80-1 72 (m, 4H), 1.67 (dq, 2H, J = 7 4 Hz, J = 14 7 Hz), 0 95 (t, 3H. J - 7 4 Hz)

[1161] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.9 (HCO2H), 160.7 (Cq), 148.7 (Cq), 144.9 (Cq), 144.7 (Cq), 143.8 (Cq), 138.6 (Cq), 135.2 (Cq), 131.7 (CHarom), 130.1 (CHarom), 127.9 (CHarom), 125.0 (CHarom), 122.2 (CHarom), 115.3 (CHarom), 115.1 (CHarom), 71.5 (CH2), 65.6 (CH), 60.2 (CH2), 56.4 (CH2), 52.5 (CH2), 51.7 (CH), 45.1 (CH2), 40.0 (CH2), 38.6 (CH2), 30.6 (CH2), 27.9 (CH2), 25.7 (CH2), 24.2 (CH2), 14.1 (CH3).

[1162] HRMS (ESI+): m / z calculated for C35H48N4O4[M+H]+: calc 589.3748; found: 589.3755

[1163] EXAMPLE 93: TM-399

[1164]

[1165] TM-399 [1 -((5-((((S)-3-amino-4-phenylbutyl)amino)methyl)-4'-methyl-[1.r-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (62 3 mg, 7%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.47 (s, 1.05H, HCO2H), 7 55 (d, 2H, J = 8.2 Hz, Harom), 7 37-7 24 (m, 9H, Harm), 7 17-7 15 (m, 1H, Harmi), 4 44 (dtd, 1H, J = 2 7 Hz, J = 4 8 Hz, J = 7 5 Hz), 4 19 (bs, 2H), 4 14 (d, 2H, J = 5 0 Hz), 3 69-3 61 (m, 1H), 3 51 (dd, 1H, J = 2 7 Hz, J = 13 2 Hz), 3 49-3 44 (m,4H), 3 35-3 28 (m, 1H), 3 26-3 17 (m, 1H), 3 15-3 07 (m, 1H), 3 02 (dd, 1H, J = 6 7 Hz, J = 13.9 Hz), 2 96 (dd, 1H, J = 7 6 Hz, J = 13.9 Hz), 2 37 (s, 3H), 2 15-2 07 (m, 2H), 2 00- 1 89 (m, 4H), 1 81-1 70 (m, 4H)

[1166] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.8 (HCO2H), 160 7 (Cq), 144 7 (Cq), 139 0 (Cq), 138 3 (Cq), 136 7 (Cq), 134.9 (Cq), 130 6 (CH arom ), 130 5 (CH arom ), 130 1 (CH arom ), 128.6 (CH arom ), 127 9 (CH arom ), 122.2 (CH arom ), 1 15 4 (CH arom ), 115 2 (CHarom), 71.5 (CH2), 65.6 (CH), 60.2 (CH2), 56.4 (CH2), 52 5 (CH2), 52 0 (CH), 45 1 (CH2), 40 1 (CH2), 30 3 (CH2), 27 9 (CH2), 24 2 (CH2), 21 1 (CH3).

[1167] HRMS (ESI+): m / z calculated for C33H46N3O2[M+H]+: calc 516.3585; found: 516.3589

[1168] EXAMPLE 94: TM-400

[1169] H T)H

[1170] 0 GO equiv.

[1171] HjN

[1172] TM-400

[1173]

[1174] TM-400 [1-((5-((((S)-3-amino-4-phenylbutyl)amino)methyl)-4'-mettiyl-[ 1, 1 '-biphenyl]-3-yl)oxy)-3-(pyrrolidin- 1-yl)propan-2-ol] (57 2 mg, 13%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1175] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.29 (s, 0.6H, HCO2H), 7 55 (d, 2H, J = 8 2 Hz, Harom), 7 40-7 24 (m, 9H, Harom), 7 19-7 16 (m, 1H, Harom), 4 42 -4.35 (m, 1H), 4 21 (bs, 2H), 4 17 (d, 1 H, J = 10.6 Hz), 4 13 (d, 1 H, J 10 6 Hz), 3 71-3.62 (m, 1H), 3 53-3 41 (m, 6H), 3 28-3 19 (m, 1H), 3.17-3.08 (m, 1H), 3 03 (dd, 1H, J = 6 7 Hz, J = 14 0 Hz), 2 97 (dd, 1 H, J = 7 6 Hz, J = 14 0 Hz), 2 37 (s, 3H), 2 18-2 08 (m, 6H)

[1176] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.5 (HCO2H), 160 7 (Cq), 144 7 (Cq), 139 0 (Cq), 138 3 (Cq), 136 6 (Cq), 134 6 (Cq), 130 6 (CH arom ), 130 5 (CH arom ), 130 1 (CH arom ), 128 6 (CH arom ), 127 9 (CH arom ), 122.3 (CH arom ), 1 15 4 (CH arom ), 115 2 (CHarom), 71 4 (CH2), 66 5 (CH), 58 5 (CH2), 55 7 (CH2), 52 5 (CH2), 52 0 (CH), 45 1 (CH2), 40 4 (CH2), 40 0 (CH2), 30 2 (CH2), 23 9 (CH2), 21 2 (CH3).

[1177] HRMS (ESI+): m / z calculated for C31H42N3O2[M+H]+: calc 488.3272; found: 488.3280 EXAMPLE 95: TM-401

[1178]

[1179] TM-401 [1 ((5 (((3 (((S) 2 amino 3 (4 (trifluoromettiyl)phenyl)propyl)amino)propyl)(methyl)amino)mettiyl) 4' methyl [1, 1' biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (180 mg, 3 0%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1180] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.42 (s, 2.2H, HCO2H), 765 (d, 2H, J = 8.2 Hz, Harm), 754 (d, 2H, J = 8.2 Hz, Harom), 747 (d, 2H, J = 8.0 Hz, Harm), 740-7 37 (m, 1H, Harm), 729-724 (m, 3H, Harom), 7 18-7 15 (m, 1H, Harom), 443 (dtd, 1H, J = 3 1 Hz, J = 49 Hz, J = 76 Hz), 426 (bs, 2H), 4 13 (d, 2H, J = 49 Hz), 3 53-3 43 (m, 6H), 3353 27 (m, 1H), 3 23-3 17 (m, 2H), 298 (d, 2H, J = 72 Hz), 287 (dd, 1H, J = 40 Hz, J = 13 0 Hz), 284-268 (m, 3H), 272 (s, 3H), 237 (s, 3H), 203 - 1 91 (m, 6H), 1 81-1 71 (m, 4H)

[1181] 13C NMR (101 MHz, CD3OD) 6 (ppm) 168.8 (HCO2H), 160 8 (Cq), 1449 (Cq), 142 1 (Cq), 1392 (Cq), 1383 (Cq), 1344 (Cq), 131 1 (CHarom), 1307 (CHarom), 1305 (q, J = 324 Hz, Cq), 1280 (CHarom), 1268 (q, J = 38 Hz, CH,™n). 125.7 (q, J = 271 1 Hz, Cq), 123 2 (CHarom), 1162 (CHarom), 115.4 (CHarom), 71 5 (CH2), 656 (CH), 61 3 (CH2), 60 1 (CH2), 564 (CH2), 557 (CH2), 53 1 (CH), 51 4 (CH2), 475 (CH2), 403 (CH3), 386 (CH2), 280 (CH2), 25 1 (CH2), 242 (CH2), 21 1 (CH3)19F NMR (377 MHz, CDCl3) 5 (ppm) -64.0 (s, 3F).

[1182] HRMS (ESI+): m / z calculated for C33H48N3O2[M+H]+: calc 516.3585; found: 516.3589

[1183] EXAMPLE 96: TM-402

[1184]

[1185] TM-402 [1-((5-(((3-(((S)-2-amino-3-(4-(trifluoromettiyl)phenyl)propyl)amino)propyl)(mettiyl)amino)mettiyl)-4'-methyl-[1, T- biphenyl] 3 yl)oxy) 3 (pyrrolidin 1 yl)propan 2 ol] (190 mg, 55%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid).1H NMR (400 MHz, CD3OD) 6 (ppm) 8.16 (s, 0.75H, HCO2H), 7 66 (d, 2H, J = 8 1 Hz, Harom), 7 59-7 50 (m, 4H, HarCm), 7 47-7 44 (m, 1H, Harom), 7 31-7 25 (m, 4H, HarCm), 4 42 (bs, 2H), 4 41-4 34 (m, 1 H), 4 17 (d, 2H, J = 5 0 Hz), 3 71-3 59 (m, 2H), 3 56-3 44 (m, 4H), 3 42-3 33 (m, 3H), 3 07 (d, 2H, J = 7 2 Hz), 2 97 (dd, 1H, J = 4 1 Hz, J = 13 2 Hz), 2 92-2 78 (m, 3H), 2 83 (s, 3H), 2 37 (s, 3H), 2 17-2 07 (m, 6H)

[1186] 13C NMR (101 MHz, CD3OD) δ (ppm) 165.5 (HCO2H), 160 9 (Cq), 145 0 (Cq), 141 6 (Cq), 139 2 (Cq), 138 1 (Cq), 133 0 (Cq), 131 2 (CHarom), 130 7 (CHarom), 130.7 (q, J = 32 3 Hz, Cq), 128 0 (CHarom), 126 9 (q, J = 3 7 Hz, CHarom), 125.7 (q, J = 271.1 Hz, Cq), 123 4 (CHarom), 116.3 (CHarom), 116.0 (CHarom), 71.4 (CH2), 66.5 (CH), 61 0 (CH2), 58 5 (CH2), 55 4 (CH2), 53 0 (CH), 51 0 (CH2), 47 2 (CH2), 40 1 (CH3), 38 0 (CH2), 24 6 (CH2), 23 9 (CH2), 21 1 (CH3)

[1187] 19F NMR (377 MHz, CDCl3) 5 (ppm) -64.0 (s, 3F).

[1188] HRMS (ESI+): m / z calculated for C35H48F3N4O2[M+H]+: calc 613.3724; found: 613.3730

[1189] EXAMPLE 97: TM-404

[1190]

[1191] TM-404 [1-(3-((((S)-3-amino-4-phenylbutyl)amino)methyl)phenoxy)-3-(azepan-1-yl)propan-2-ol] (40 2 mg, 10%) was synthetized following General Procedure B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% ammoniac) HOI salt was prepared by addition of 0 2 ml of HCI (4M in dioxane), water (2ml) and acetonitrile (2ml) followed by lyophilization cycles

[1192] 1H NMR (400 MHz, CD3OD) 6 (ppm) 7.39-7.27 (m, 7H, Harmi), 7.11 (d, 1H, J= 7 7 Hz, HarCm), 7 05 (dd, 1H, J = 2 0 Hz, J = 8 3 Hz, Harom), 4 44 (dtd, 1 H, J = 2 8 Hz, J = 4 9 Hz, J = 7 5 Hz), 4 20 (bs, 2H), 4 10 (d, 2H, J = 5 0 Hz), 3 72-3 56 (m, 3H), 3 51 (dd, 1H, J= 2 6 Hz, J= 13 2 Hz), 3 39-3 30 (m,3H), 3 28-3 21 (m, 1H), 3 18-3 09 (m, 1H), 3 06 (dd, 1H, J = 6 8 Hz, J = 14 0 Hz), 3 00 (dd, 1H, J = 7 6 Hz, J = 14 0 Hz), 2 16 (dd, 2H, J = 7 9 Hz, J = 14 8 Hz), 2.01-1.91 (m, 4H), 1 80 -1.70 (m, 4H)

[1193] 13C NMR (101 MHz, CD3OD) 5 (ppm) 160.3 (Cq), 136 5 (Cq), 133 7 (Cq), 131 4 (CHarom), 130 6 (2 CHarom), 130.2 (2 CHarom),

[1194]

[1195] 128 7 (CHarom), 123 8 (CHarom), 117 4 (CHarom), 1 16 9 (CHarom), 71 4 (CH2), 65 5 (CH), 60 2 (CH2), 57 8 (CH2), 55 0 (CH2), 52 3 (CH2), 51 8 (CH), 45 0 (CH2), 39 8 (CH2), 30 1 (CH2), 27 9 (2 CH2), 24 2 (2 CH2)

[1196] HRMS (ESI+): m / z calculated for C26H40N3O2[M+H]+: calc 426.3115; found: 426.3121

[1197]

[1198] TM-405 [N-((S)-3-amino-4-phenylbutyl)-N-(3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)-4-(trifluoromethyl) benzene sulfonamide] (499 mg, 39%) was synthetized following this Procedure:

[1199]

[1200] Following General Procedure B, C.1; compound 31 was synthetized and engaged in the next step without further purification

[1201] To a solution ofcompound31 (I O equiv ) in dry DCM (50 mM) under Aqg), was added EbN (1 5 equiv) atr t The mixture was cooled at 0°C and 4-(Trifluoromethy I) benzenesulfonyl chloride (095 equiv ) was added The mixture was stirred from 0°C to r t for 2h Theorganicphase was washed with NH4Clsatand diluted with DCM, washed with brine, dried over MgSCu, filtered and concentrated under reduced pressure The crude was engaged in the next step without further purification Following General Procedure D, TM-405(499 mg, 10%) was obtained as a white solid Purification: HPLC prep / MS (H2O: AON: MeOH, 0 1% Formic Acid)

[1202] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 1.1 H, HCO2H), 805 (d, 2H, J = 8.3 Hz, Harm), 791 (d, 2H, J = 83 Hz, Harom), 737-726 (m, 3H, Harom), 723-7 13 (m, 3H, Harom), 694-687 (m, 2H, Harom), 684 (d, 1H, J= 76 Hz, Harom), 441-434 (m, 1H), 435 (d, 1H, J = 15 0 Hz), 424 (d, 1H, J = 15 0 Hz), 400 (dd, 1H, J= 33 Hz, J = 82 Hz), 3 97 (dd, 1H, J = 3 3 Hz, J = 82 Hz), 346-3 32 (m, 8H), 3 24 (dd, 1H = 10 4 Hz, J = 13 2 Hz), 280 (dd, 1H, J= 6.9 Hz, J = 13 9 Hz), 273 (dd, 1H, J = 73 Hz, J= 139 Hz), 1 99-1 89 (m, 4H), 1 80-1 59 (m, 6H)

[1203] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 1602 (Cq), 144.5 (CHarom), 139.3 (Cq), 136.9 (Cq), 135.3 (q, J = 32.8 Hz, Cq), 131.0 (Cq), 130.4 (CHarom), 130.1 (CHarom), 129.1 (CHarom), 1285 (CHarom), 127.7 (q, J = 3.7 Hz, CHarom), 124.9 (q, J = 271.9 Hz, Cq), 122 3 (CHarom), 1157 (CHarom), 1153 (CHarom), 71 2 (CH2), 657 (CH), 603 (CH2), 564 (CH2), 53 6 (CH2), 51 6 (CH), 467 (CH2), 400 (CH2), 329 (CH2), 279 (CH2), 243 (CH2)

[1204] 19F NMR (377 MHz, CDCl3) 5 (ppm) -64.5 (s, 3F). HRMS (ESI+): m / z calculated for C33H43F3N3O4S [M+H]+: calc 634.2921; found: 634.2935

[1205] EXAMPLE 99: TM-406

[1206]

[1207] TM-406 [1-(azepan-1-yl)-3-((4'-propyl-5-(((2-(pyridin-2-yl)ethyl)amino)methyl)-[1, 1'-biphenyl]-3-yl)oxy) propan-2-ol] (22.8 mg, 14%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1208] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 0.33H, HCO2H), 8.47-8.41 (m, 1H, Harom), 774 (td, 1H, J = 1 8 Hz, J = 77 Hz, Harom), 751 (d, 2H, J = 82 Hz, Harem), 732 (d, 1H, J = 78 Hz, Harem), 727-722 (m, 3H, Hare ), 7 18 (bs, 1H, Harom), 7 10-706 (m, 1H, Harem), 693-690 (m, 1H, Harom), 4 16-406 (m, 2H), 401 (dd, 1H, J = 5.6 Hz, J = 9.6 Hz), 3 86 (s, 2H), 3 02 (bs, 4H), 292-288 (m, 5H), 278 (dd, 1H, J = 78 Hz, J = 13.0 Hz), 262 (t, 2H, J = 75 Hz), 1 75-1 70 (m, 4H), 1 69- 1 63 (m, 6H), 096 (t, 3H, J = 74 Hz)

[1209] 13C NMR (101 MHz, CD3OD) 3 (ppm) 160.9(Cq), 160.8(Cq), 1498 (CHarom), 1442 (Cq), 143 3 (Cq), 141 8 (Cq), 1395 (Cq), 1388 (CH arom ), 1299 (CH arom ), 1279 (CH arom ), 1250 (CH arom ), 123 1 (CH arom ), 1208 (CH arom ), 1143 (CH arom), 113 3 (CHarom), 71 9 (CH2), 683 (CH), 61 2 (CH2), 570 (CH2), 54 1 (CH2), 38.7 (CH2), 379 (CH2), 28 1 (CH2), 278 (CH2), 258 (CH2), 14 1 (CH3)

[1210] HRMS (ESI+): m / z calculated for C32H44N3O2[M+H]+: calc 502.3428; found: 502.3429

[1211] EXAMPLE 100: TM-407

[1212]

[1213] TM-407 [1-((4-((((S)-3-amino-4-phenylbutyl)amino)methyl)-4'-propyl-[1,1'-biphenyl]-2-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (21 2 mg, 12%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.45 (s, 0.9H, HCO2H), 7.43 (d, 2H, J = 8.2 Hz, Harom), 7 39-7 28 (m, 7H, Harom), 7 26 (d, 2H, J = 8.2 Hz, Harem), 7 13 (dd, 1H, J = 7 8, 1 2 Hz, HarOm), 4 36-4 28 (m, 1 H), 4 18 (d, 1H, J = 4 4 Hz), 4 16 (bs, 2H), 4 06 (dd, 1H, J = 9 8, 5 9 Hz), 3 67-3 60 (m, 1 H), 3 27-3 29 (m, 4H), 3 26-3 05 (m, 4H), 3 01 (dd, 1H J = 6 5 Hz, J = 13 6 Hz), 2 96 (dd, 1 H J = 7 4 Hz, J = 13 6 Hz), 2 68- 2 59 (m, 2H), 2 02-2 12 (m, 2H), 1 87-1 82 (m, 4H), 1 75-1 65 (m, 6H), 0 98 (t, 3H, J = 7 3 Hz)

[1214] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.3 (HCO2H), 156 9 (Cq), 143 2 (Cq), 136 8 (Cq), 136 5 (Cq), 134 0 (Cq), 133 3 (Cq), 132.3 (CH arom ), 130 6 (CH arom ), 130 5 (CH arom ), 130 2 (CH arom ), 129.3 (CH arom ), 128.6 (CH arom ), 124 0 (CH arom ), 115.6 (CHarom), 71.9 (CH2), 65.4 (CH), 60.2 (CH2), 56 3 (CH2), 52 4 (CH2), 52 3 (CH), 45 3 (CH2), 40 3 (CH2), 38 8 (CH2), 30 5 (CH2), 27 9 (CH2), 25 8 (CH2), 24 0 (CH2), 14 2 (CH3).

[1215] HRMS (ESI+): m / z calculated for C35H51N3O2[M+2H]2+: calc 272.6985; found: 272.6990

[1216] EXAMPLE 101: TM-408

[1217] H C’H

[1218] 050 equiv

[1219] H2N

[1220] OH I*

[1221] TM-408

[1222]

[1223] TM-408 [1-((5-((((S)-3-amino-4-phenylbutyl)amino)methyl)-4'-mettiyl-[ 1, T-biphenyl]-3-yl)oxy)-3-(diethylamino)propan-2-ol] (15 9 mg, 4 1%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1224] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.42 (s, 0.5H, HCO2H), 7 55 (d, 2H, J = 8 2 Hz, Harom), 7 38-7 24 (m, 9H, Harom), 7 19 (bs, 1H, Harom), 4 42 (dtd, 1 H, J 2 9 Hz, J = 4 9 Hz, J = 8 0 Hz), 4 21 (bs, 2H), 4 16 (dd, 2H, J - 2 0 Hz, J = 5 0 Hz), 3.70-3 62 (m, 1H), 3 43 (dd, 1H, J = 3 0 Hz, J = 13 5 Hz), 3 40-3 32 (m, 5H), 3 27-3 17 (m, 1 H), 3 17-3 07 (m, 1 H), 3 02 (dd, 1H, J = 6 5 Hz, J = 13.6 Hz), 2 97 (dd, 1H, J = 7 3 Hz, J = 13 6 Hz), 2 38 (s, 3H), 2 12 (q, 2H, J = 7 3 Hz), 1.37 (t, 6H, J = 7 3 Hz)

[1225] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.0 (HCO2H), 160 7 (Cq), 144 8 (Cq), 139 1 (Cq), 138 3 (Cq), 136 6 (Cq), 134 8 (Cq), 130 6 (CH arom ), 130 5 (CH arom ), 130 2 (CH arom ), 128 6 (CH arom ), 127 9 (CH arom ), 122 3 (CH arom ), 1 15 4 (CH arom ), 115.2 (CHarom), 71.4 (CH2), 65 5 (CH), 55 4 (CH2), 52 5 (CH2), 52 1 (CH), 45 2 (CH2), 40 1 (CH2), 30 3 (CH2), 21 1 (CH3), 9 1 (CH3).

[1226] HRMS (ESI+): m / z calculated for C31H44N3O2[M+H]+: calc 490.3428; found: 490.3445 EXAMPLE 102: TM-409

[1227]

[1228] TM-409 [3-((5-(((3-hydroxypropyl)amino)methyl)-4'-propyl-[1, 1'-biphenyl]-3-yl)oxy) propane- 1,2-diol] was synthetized following this Procedure

[1229]

[1230] Purification: HPLC prep / MS (H2O: ACN: MeOH(NH4OH))

[1231] 1H NMR (400 MHz, MeOD) 67.55 - 7.49 (m, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.21 (s, 1 H), 7.12 - 7.06 (m, 1 H), 6.95 (s, 1H), 464 (s, 2H), 424 (td, J = 87, 4.9 Hz, 1H), 409 (qd, J = 98, 52 Hz, 2H), 3 72 (t, J = 58 Hz, 2H), 3 27 - 3 14 (m, 2H), 3 14 - 3 05 (m, 2H), 265 - 259 (m, 2H), 1 95 - 1 86 (m, 2H), 1 73 - 1 62 (m, 2H), 096 (t, J = 74 Hz, 3H)

[1232] 13C NMR (101 MHz, MeOD) 6 159.12, 143.57, 142.67, 141.94, 138.16, 128.56, 126.47, 117.93, 111.69, 111.06, 69.90, 6584, 63 67, 5954, 5040, 4662, 3726, 2858, 2435, 1268

[1233] EXAMPLE 103: TM-410

[1234]

[1235] TM-410 [1-((5-(((3-(((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)amino)propyl)amino)methyl)-4,-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (70 mg, 3 8%) was synthetized following General Procedure A, B, C.1, D, C.4, D;

[1236] Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.46 (bs, 2.5H, HCO2H), 764 (d, 2H, J = 8.3 Hz, Harem), 754 (d, 2H, J = 8.3 Hz, Harom), 745 (d, 2H, J = 80 Hz, Harom), 736 (bs, 1H, Harem), 727 (d, 2H, J = 83 Hz, Harem), 724 (bs, 1H, Harom), 7 11 (bs, 1H, Harom), 444-435 (m, 1H), 4 19 (bs, 2H), 4 11 (d, 2H, J = 5 1 Hz), 349-339 (m, 6H), 3 30-324 (m, 1H), 3 14 (t, 2H, J = 7 1 Hz), 296 (d, 2H, J= 65 Hz), 287-267 (m, 4H), 263 (t, 2H, J = 76 Hz), 201-1 87 (m, 6H), 1 81-1 72 (m, 4H), 1 68 (dq, 2H, J= 73 Hz, J = 149Hz), 096 (t, 3H, J= 73 Hz)

[1237] 19F NMR (377 MHz, CDCh) 5 (ppm) -64.01 (s, 3F).

[1238] HRMS (ESH-): m / z calculated for C38H54F3N4O2 [M +H]+: calc 655.3724; found: 655.3730

[1239] EXAMPLE 104: TM-411

[1240] o

[1241] 11

[1242] i-r X> H

[1243] H2N 3.5 equiv.

[1244]

[1245] TM-411

[1246] TM-411 [1-((5-((3-((S)-2-amino-3-(4-(trif1uoromettiyl)phenyl)propyl)tetrahydropynmidin-1(2H)-yl)mettiyl)-4,-propyl-[1,1,-bi phenyl]-3-yl)oxy)-3-(azepan-1-yl) propan-2 -ol] (12 1 mg, 54%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1247] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.25 (s, 3.5H, HCO2H), 764 (d, 2H, J = 8 1 Hz, Harom), 759-755 (m, 2H, Harom), 748 (d, 2H, J= 80 Hz, Harom), 741-738 (m, 1H, Harcni), 730-725 (m, 3H, Harcfn), 721-7 18 (m, 1H, Haram), 443 (dtd, 1H, J = 27 Hz, J = 48 Hz, J = 75 Hz), 428-408 (m, 4H), 400-389 (m, 1H), 3 71-362 (m, 1H), 3 54-3 40 (m, 5H), 3 36-3 27 (m, 2H), 322-3 08 (m, 2H), 3 06-296 (m, 2H), 294-285 (m, 2H), 283-266 (m, 2H), 263 (dd, 2H, J = 73 Hz, J = 78 Hz), 201-1 87 (m, 6H), 1 81-1 73 (m, 4H), 1 67 (dq, 2H, J = 7.4 Hz, J = 147 Hz), 096 (t, 3H, J = 7.4 Hz)

[1248] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.1 (HCO2H), 160 6 (Cq), 1444 (Cq), 1437 (Cq), 141 6 (Cq), 1390 (Cq), 138 1 (Cq), 131 1 (CHarom), 1306 (q, J = 323 Hz, Cq), 130 1 (CH,™), 1279 (CHarom), 126.9 (q, J = 3 7 Hz, CH,™n). 125.6 (q, J = 271 1 Hz, Cq), 122.4 (CH,™), 1156 (CHaram), 114.1 (CH,™), 758 (CH2), 71 4 (CH2), 656 (CH), 602 (CH2), 600 (CH2), 567 (CH2), 564(CH2), 53 1 (CH2), 52 1 (CH2), 51 6 (CH), 386 (CH2), 377(CH2), 280 (CH2), 257 (CH2), 242 (CH2), 23 8 (CH2), 14 1 (CH 3)

[1249] 19F NMR (377 MHz, CDCl3) 5 (ppm) -64.0 (s, 3F).

[1250] HRMS (ESH-): m / z calculated for C39H54F3N4O2 [M +H]+calc 667.3585; found: 667.3589 EXAMPLE 105: TM-412

[1251] TM-412 [ 1-(azepan-1-yl)-3-((4'-cyclopentyl-5-((melhyl(3-((oxazol-4-ylmethyl)amino)propyl)amino)methyl)-[ 1, 1 '-biphenyl]-3 -yl)oxy) propan -2-ol] (6 1 mg, 67%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.52 (s, 2.2H, HCO2H), 8 12 (s, 1H, Harom), 7 94 (bs, 1H, Harcm), 7 51 (d, 2H, J = 7 8 Hz, HarOm), 7 31 (d, 2H, J = 8.1 Hz, Harcm), 7 26 (s, 1H, Harcm), 7 17 (s, 1 H, HarOm), 6 98 (bs, 1H, Harcm), 4 46-4 35 (m, 1H), 4

[1252]

[1253] 09 (d, 2H, J - 4 1 Hz), 4 01 (bs, 2H), 3 81 (bs, 2H), 3 49-3 41 (m, 5H), 3 31-3 21 (m, 1H), 3 1 1-3 00 (m, 3H), 2 86-2 75 (m, 2H), 2 44 (s, 3H), 2 14-2 03 (m, 2H), 2 02-1 89 (m, 6H), 1 89-1 80 (m, 2H), 1 80-1 69 (m, 6H), 1 69-1 53 (m, 2H)13C NMR ( 101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 160 6 (Cq), 154 1 (CH,™.), 147.6 (Cq), 144 4 (Cq), 139 4 (Cq), 139 1 (Cq), 134 6 (Cq), 128 6 (CHarom), 127 9 (CH,™), 122 3 (CHarom), 1 15 6 (CHarom), 1 13 8 (CHarom), 71 4 (CH2), 65 7 (CH), 62 6 (CH2), 60 2 (CH2), 56 7 (CH2), 56 4 (CH2), 47 0 (CH), 43 5 (CH2), 41 6 (CH3), 35 8 (CH2), 28 0(CH2), 26 5 (CH2), 24 3 (CH2), 24 0 (CH2)

[1254] HRMS (ESI+): m / z calculated for C35H51N4O3[M+H]+: calc 575.3956; found: 575.3978

[1255] EXAMPLE 106: TM-413

[1256]

[1257] TM-413 [1-(azepan- 1-yl)-3-((5-(((2-(5-methylbenzo[d]oxazol-2-yl)ethyl)amino)methyl)-4'-propyl-[1,1'-biphenyl]-3-yl)oxy) propan-2-ol] (8 7 mg, 4 7%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1 % Formic Acid)

[1258] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 1.2H, HCO2H), 7 53 (d, 2H, J = 8 2 Hz, Harom), 7 43-7 39 (m, 2H, Harom), 7 32 (

[1259]

[1260] bs, 1H, HarOm), 7 25 (d, 2H, J = 8.2 Hz, HarCm), 7 20-7 15 (m, 2H, Harcni), 7 04 (bs, 1H, Harom), 4 44-4 34 (m, 1H), 4 10 (bs, 4H), 3 46-3 35 (m, 7H), 3 33-3 21 (m, 3H), 2 62 (t, 2H, J= 1 5 Hz), 2 44 (s, 3H), 1 96-1 89 (m, 4H), 1 78-1 70 (m, 4H), 1 67 (dq, 2H, J = 7.4 Hz, J = 14.9 Hz), 0 96 (t, 3H, J = 7 4 Hz)

[1261] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.3 (HCO2H), 166 1 (Cq), 160 7 (Cq), 150 4 (Cq), 144 6 (Cq), 143 6 (Cq), 142 0 (Cq), 139 0 (Cq), 138 7 (Cq), 135.8 (Cq), 130 0 (CHarOm), 127.9 (CHarom), 127 3 (CHarom), 121 6 (CHarom), 120 1 (CHa™>), 1 14 7 (CHarom), 114.2 (CHarOm), 1 11 0 (CHarom), 71.4 (CH2), 65 8 (CH), 60 3 (CH2), 56 4 (CH2), 53 2 (CH2), 45 6 (CH2), 38 6 (CH2), 28 0 (CH2), 27 8 (CH2), 25 7 (CH2), 24 4 (CH2), 21 4 (CH3), 14 1 (CH3)

[1262] HRMS (ESI+): m / z calculated for C30H46N3O3[M+H]+: calc 495.2409; found: 495.2415

[1263] EXAMPLE 107: TM-414

[1264] H A' " OH

[1265] 2.2 equiv

[1266]

[1267] TM-414

[1268] TM-414 [1-(azepan-1-yl)-3-((4,-cyclopentyl-5-((methyl(3-(((1 (phenylsulfonyl)-1H-pyrrol-2-yl)methyl)amino) propyl) ammo) methyl)-[1, T-biphenyl]-3-yl)oxy)propan-2-ol] (5 9 mg, 5 2%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1269] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 2.2H, HCO2H), 7 83 (d, 2H, J = 7.5 Hz, Harm), 7 67 (d, 1H, J = 7 4 Hz, Harom), 7

[1270]

[1271] 56 (t, 2H, J = 7 8 Hz, Harcm), 7 52 (d, 2H, J = 8.2 Hz, Haram), 7 38 (dd, 1 H, J = 1 4 Hz, J = 3.2 Hz Harom), 7 30 (d, 2H, J = 8 2 Hz, Harom), 7 20 (bs, 1H, Harem), 7 13 (bs, 1H, Harem), 6 93 (bs, 1H, Harom), 6 32 (bs, 1 H, Harom), 6 27 (t, 1H, J = 3 2 Hz, Harom), 4 35-4 23 (m, 1H), 4 08 (bs, 2H), 3 94 (bs, 2H), 3 66 (bs, 2H), 3 30-3 18 (m, 4H), 3.16-2.95 (m,3H), 2 83-2 74 (m, 2H), 2 64-2 55 (m, 2H), 2 33 (s, 3H), 2 12-2.01 (m, 2H), 1 91-1 76 (m, 8H), 1.77-1 66 (m, 6H), 1.66-1.52 (m, 2H).

[1272] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 160 6 (Cq), 147 4 (Cq), 144 2 (Cq), 140 1 (Cq), 139 3 (Cq), 135.6 (Cq), 130 9 (CH arom ), 128.6 (CH arom ), 127 9 (CH arom ), 127 7 (CH arom ), 125 4 (CH arom ), 122 0 (Cq), 117 9 (CH arom), 1 15 3 (CHarOm), 1 13.5 (CH,™.), 113 4 (CHarom), 71.5 (CH2), 66 6 (CH), 62 9 (CH2), 60 6 (CH2), 56 7 (CH2), 56 5 (CH2), 48 0 (CH2), 47 0 (CH), 45 6 (CH2), 42.3 (CH3), 35 7 (CH2), 28 0 (CH2), 26 5 (CH2), 25 9 (CH2), 25 5 (CH2)

[1273] HRMS (ESI+): m / z calculated for C39H56F3N4O2[M+H]+: calc 669.4350; found: 669.4334 EXAMPLE 108: TM-415

[1274]

[1275] TM-415 [1-(3-((((S)-3-amino-4-phenylbutyl)amino)methyl)-5-(furan-2-yl)phenoxy)-3-(azepan-1-yl)propan-2-ol] (68.9 mg, 29%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1276] 1H NMR (400 MHz, CDjOD) 6 (ppm) 8.48 (s, 1 6H, HCO2H), 758 (dd, 1H, J = 05 Hz, J = 1 7 Hz, Harom), 745-743 (m, 1H, Hamm), 737-725 (m, 6H, Harem), 709-706 (m, 1H, Harom), 686 (dd, 1H, J = 05 Hz, J = 34 Hz, Harom), 654 (dd, 1H, J= 1 7 Hz, J = 3 4 Hz, Harem), 443 (dtd, 1H, J = 28 Hz, J = 49 Hz, J = 76 Hz), 4 16-408 (m, 4H), 3 66-3 58 (m, 1H), 3 52-3 43 (m, 5H), 3 34-327 (m, 1H), 3 21-3 13 (m, 1H), 3 12-3 04 (m, 1H), 300 (dd, 1H, J = 67 Hz, J= 139 Hz), 294 (dd, 1H, J = 77 Hz, J= 139 Hz), 2 10-203 (m, 2H), 200-1 89 (m, 4H), 1 80-1 71 (m, 4H)

[1277] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.8 (HCO2H), 160 7 (Cq), 154 1 (Cq), 1440 (Cq), 1368 (Cq), 1356 (Cq), 1343 (Cq), 1305 (CH arom ), 130 1 (CH arom ), 1286 (CH arom ), 1190 (CH arom ), 1155 (CH arom ), 113 0(CH arom ), 111 8 (CH arom ), 1075 (CHarom), 71 5 (CH2), 656 (CH), 60 1 (CH2), 564 (CH2), 524 (CH2), 52 1 (CH), 452 (CH2), 402 (CH2), 304 (CH2), 279 (CH2), 242 (CH2)

[1278] HRMS (ESI+): m / z calculated for C30H42N3O3[M+H]+: calc 492.3221; found: 492.3226

[1279] EXAMPLE 109: TM-416

[1280]

[1281] TM-416 [1-((5-((((S)-3-amino-4-phenylbutyl)amino)metfiyl)-4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(1,4-dioxa-8-azaspiro

[0045] decan-8-yl)propan-2-ol] (23 1 mg, 10%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1282] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.50 (s, 1.75H, HCO2H), 755 (d, 2H, J= 82 Hz, HarOm), 736-722 (m, 9H, Harem), 707 (s, 1H, Harom), 445-437 (m, 1H), 4 14 (bs, 2H), 4 10 (d, 2H, J = 47 Hz), 400 (bs, 4H) 364-3 56 (m, 1H), 3 44-3 32 (m, 5H), 3.28-3 19(m, 1H), 3.19-3 11 (m, 1H), 3 11-3 03 (m, 1H), 299 (dd, 1H, J = 6.5 Hz, J = 13 9 Hz), 292 (dd, 1H, J = 7 Hz, J = 13 9 Hz), 263 (t, 2H, J = 75 Hz), 209-1 94 (m, 6H), 1 72-1 62 (m,2H), 096 (t, 3H J = 73 Hz)

[1283] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 8 (Cq), 1448 (Cq), 1438 (Cq), 1387 (Cq), 1369 (Cq), 1355 (Cq), 1304 (CH arom ), 130 1 (CH arom ), 1300 (CH arom ), 1285 (CH arom ), 1279 (CH arom ), 122 1 (CH arom ), 115 1 (CH arom ), 1055 (Cq), 71 5 (CH2), 66 0 (CH), 658 (CH2), 599 (CH2), 529 (CH), 525 (CH2), 522 (CH2), 452 (CH2), 403 (CH2), 386 (CH2), 33 4 (CH2), 304 (CH2), 257 (CH2), 14 1 (CH3)

[1284] HRMS (ESI+): m / z calculated for C36H48N3O4[M+H]+: calc 272.6985; found: 272.6990

[1285] EXAMPLE 110: TM-417

[1286]

[1287] TM-417 [1 -(azepan-1-yl)-3-((5-(((3-(bis((S)-2-amino-3-(4-(tiifiuoromethyl)phenyl) propyl)amino)propyl)(metiyl) ammo) methyl)-4'-cyclopentyl-[ 1, 1'-biphenyl]-3-yl)oxy)propan-2-ol] (224 mg, 1 6%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid) Excess of aldehyde reagent in step C.4 resulted in double reductive amination product

[1288] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 2.2H, HCO2H), 764 (d, 4H, J= 8 1 Hz, Harom), 756 (d, 2H, J = 83 Hz), 748 (d, 4H, J= 8 1 Hz, Haram), 7.36-7.33 (m, 3H, Harcni), 722 (bs, 1H, Harcm), 707 (bs, 1H, Haram), 441 (dtd, 1H, J = 28 Hz, J = 47 Hz, J = 76 Hz), 4 12 (d, 2H, J = 50 Hz), 401 (bs, 2H), 359 (q, 2H, J = 78 Hz), 351-3 40 (m, 5H), 331-3 23 (m, 1H), 3 08-288 (m, 6H), 284-275 (m, 1H), 267-255 (m, 3H), 254 (s, 3H), 248 (dd, 2H, J = 2.6 Hz, J = 13.9 Hz), 242 (dd, 1H, J = 68 Hz, J = 13 5 Hz), 2 13-202 (m, 2H), 1 98-1 90 (m, 4H), 1 88-1 79 (m, 4H), 1 79-1 68 (m, 6H), 1 66-1 54 (m, 2H)13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 160 7 (Cq), 1477 (Cq), 1445 (Cq), 142 1 (Cq), 1388 (Cq), 1366 (Cq), 131 1 (CHarom), 1305 (q, J = 323 Hz, Cq), 1287 (CHarom), 1279 (CHarom), 1268 (q, J = 3 4 Hz, CHarom), 1256 (q, J = 271 1 Hz, Cq), 1228(CHar™), 116.0 (CHaram), 114.6 (CHar™), 71.5 (CH2), 65.7 (CH), 61.8 (CH2), 60.2 (CH2), 575 (CH2), 564 (CH2), 554 (CH2), 527 (CH2), 51.6 (CH), 469 (CH), 41 0 (CH3), 386 (CH2), 357 (CH2), 280 (CH2), 265 (CH2), 243 (CH2), 23 0 (CH2).

[1289] 19F NMR (377 MHz, CD3OD) 6 (ppm) -63.95 (s, 3F).

[1290] HRMS (ESI+): m / z calculated for C51H68F6N5O2[M+H]+: calc 986.3300; found: 986.3327 EXAMPLE 111: TM-418

[1291]

[1292] TM-418 [1-((5-(2-(((S)-3-amino-4-phenylbutyl)amino)ethyl)-4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (46 mg, 43%) was synthetized following this Procedure:

[1293]

[1294] Aldehyde 27 was prepared following General Procedure A, B

[1295] To a suspension ofmethoxymethyl triphenylphosphonium chlonde (1 2 equiv ) in THF (65mM) atO°Cwas added dropwise potassium tert-butoxide 1M in THF (25 equiv) The resulting mixture was stirred for 1h at 0“C and a solution of aldehyde 27 (1 0 equiv ) in dry THF (170 mM) was added dropwise at 0°C The mixture was allowed to warm at r t and stirred for ~ 16h The reaction was quenched by addition of water and THF was removed under reduced pressure The mixture was acidified with HCI 1M to pH ~6 and extracted with AcOEt (3 times) The combined organic phase was washed with brine, dried over MgSCu and concentrated under reduced pressure The crude was purified by flash chromatography on silica (Hex: AcOEt from 10% to 40%) to yield enol ether 28 (820 mg, 77%)

[1296] Methyl enol ether 28 in THF (80 mM) and HCI 3M (37 equiv) were stirred at rt for ~16h The reaction was quenched with NaHCQssat Volatiles were evaporated and saturated solution of aqueous NaHCQs was added and the mixture extracted with AcOEt Combined organic phase was washed with brine, dned over anhydrous MgSO4 then evaporated under vacuum to obtain compound 29 as pale-yellow oil which was used in the next step without further purification

[1297] The synthesis ofTM-418 continued following General Procedure C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1298] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.52 (s, 2.75H, HCO2H), 751 (d, 2H, J = 8 1 Hz, HarOm), 736-731 (m, 2H, Harm), 729-723 (m, 5H, Harom), 7 12 (m, 1H, Harm), 708 (m, 1H, Harom), 685 (m, 1H, Harom), 437 (m, 1H), 4 12-404 (m, 2H), 3 46-3 38 (m, 6H), 3 26 (dd, 1H, J = 105 Hz, J = 13 1 Hz), 3 17-3 09 (m, 2H), 305 (t, 2H, J = 69 Hz), 295 (t, 2H, J = 74 Hz), 287 (d, 2H, J = 70 Hz), 263 (t, 2H, J = 75 Hz), 1 98-1 82 (m, 6H), 1 80-1 73 (m, 4H), 1 67 (dq, 2H, J = 74 Hz, J = 148 Hz), 096 (t, 3H, J = 74 Hz)13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 160 7 (Cq), 144 6 (Cq), 143 6 (Cq), 140 9 (Cq), 139 3 (Cq), 137 6 (Cq), 130.4 (CH arom ), 130 0 (CH arom ), 128 3 (CH arom ), 127 9 (CH arom ), 121 4 (CH arom ), 1 14 7 (CH arom ), 1 12 8 (CH arom), 71.3 (CH2), 65.8 (CH), 60 3 (CH2), 56 4 (CH2), 53 1 (CH), 50 3 (CH2), 46 7 (CH2), 41 7 (CH2), 38 6 (CH2), 34 6 (CH2), 31 1 (CH2), 28 0 (CH2), 25 7 (CH2), 24 4 (CH2), 14.1 (CH3).

[1299] HRMS (ESI+): m / z calculated for C36H52N3O2[M+H]+: calc 558.4054; found: 558.4056

[1300] EXAMPLE 1 12: TM-419

[1301]

[1302] TM-419

[1303] TM-419 [(2S)-2-amino-N-(3-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)benzyl)(methyl)amino)propyl)-3-(4-(trifluoromethyl) phenyl) propenamide] (19 0 mg, 5 5%) was synthetized following this Procedure:

[1304]

[1305] Following General Procedure B, C.1, D, Boc-L-Phe(4-CF3)-OH (2 1 equiv ) was dissolved in dry DMF (75mM) under Arjg). HATU (2 5 equiv) was added and the mixture was stirred for 5 mins at rt This mixture was added dropwise to a solution of primary amine derivative 33 (1 0 equiv ) in dry DM F (210 mM) and cooled at 0°C Then, N, N -Diisopropylethylamine (3 0 equiv ) was added dropwise and the reaction was allowed to warm at r t and stirred for -16h The reaction was quenched by addition of water and diluted with AcOEt The organic phase was washed subsequently with NaHCXXsat, bnne, HCI ( 1M), brine, dried over MgSCM and concentrated under reduced pressure The crude was engaged in the next step without further purification Then, following General Procedure D; TM-419 was obtained as a white solid Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Fonnic Acid)

[1306] 1H NMR (400 MHz, CD3OD) 6 (ppm) 7.39-7.27 (m, 7H, Harcni), 7 11 (d, 1H, J= 1 7 Hz, HarCm), 7 05 (dd, 1H, J = 2.0 Hz, J = 8 3 Hz, Harom), 4 44 (dtd, 1 H, J = 2 8 Hz, J = 4 9 Hz, J = 7 5 Hz), 4 20 (bs, 2H), 4 10 (d, 2H, J = 5 0 Hz), 3 72-3 56 (m, 3H), 3 51 (dd, 1H, J= 2 6 Hz, J= 13 2 Hz), 3 39-3 30 (m,3H), 3.28-3.21 (m, 1H), 3.18-3.09 (m, 1H), 3 06 (dd, 1H, J = 6 8 Hz, J = 14.0 Hz), 3.00 (dd, 1H, J = 7 6 Hz, J = 14.0 Hz), 2 16 (dd, 2H, J = 7.9 Hz, J = 14 8 Hz), 2 01-1 91 (m, 4H), 1.80-1 70 (m, 4H)13C NMR ( 101 MHz, CD3OD) 6 (ppm) 171.2 (Cq), 168.9 (HCO2H), 160 4 (Cq), 141 1 (Cq), 133 9 (Cq), 131 4 (CHa™n), 131 3 (

[1307]

[1308] CHarom), 130.8 (q, J = 32 2 Hz, Cq), 126 8 (q, J = 3 8 Hz, CH,™), 125.7 (q, J = 271 2 Hz, Cq), 124 6 (CHar™), 117.7 (CHarom), 1 17 2 (CHaram), 71 3 (CH2), 65 5 (CH), 61.3 (CH2), 60 1 (CH2), 56 4 (CH2), 55 9 (CH2), 55 0 (CH), 40 2 (CH3), 39 1 (CH2), 37 6 (CH2), 28 0 (CH2), 25 8 (CH2), 24 2 (CH2)

[1309] 19F NMR (377 MHz, CDCh) 5 (ppm) -64.0 (s, 3F).

[1310] HRMS (ESI+): m / z calculated for C30H45F3N4O3[M+2H]2+: calc 283.1716; found: 283.1727

[1311] EXAMPLE 1 13: TM-420

[1312] TM-420 [ 1 -((5-(( (3 -(bi s(( S) - 2-a mi no-3-(4-iodophenyl)propyl)amin 0) propy I) ( me til y I) ami n 0) me th y I) - 4' -p en tyl-[ 1, 1 '-bipheny I]-3-yl)oxy)-3-(pyrrolidin-1-yl)propan-2-ol] (12 2 mg, 3 5%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid) Excess of aldehyde reagent in step C.4 resulted in double reductive amination product1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 1.9H, HCO2H), 7 67-7 62 (m, 4H, HarQm), 7 55-7 51 (m, 2H, Harcfn), 7 26 (d, 2H, 7 = 8 3 Hz, Harom), 7 23-7 21 (m, 1H, HarCm), 7 16-7 13 (m, 1 H, Harcm), 7 04-6 94 (m, 5H, Harom), 4 36-4 28 (m, 1H), 4 13-4 05 (m, 2H), 3 73 (s, 1H), 3 66 (s, 1H), 3.39-3.32 (m, 7H), 3 29-3 25 (m, 1H), 2 77 (dd, 2H, J = 7 1 Hz, J = 14 1 Hz), 2 72 (dd, 2H, J= 7 7 Hz, 7 = 14 1 Hz), 2 68-2 57 (m, 4H), 2 57-2 41 (m, 6H), 2 36 (s, 1H), 2 30 (bs, 2H), 2 13-2 03 (m, 4H), 1 71- 1 60 (m, 3H), 1 59-1 50 (m, 1H), 1 40-1 29 (m, 4H), 0 91 (dt, 3H, 7 = 3 5 Hz, 7 = 7 2 Hz)13C NMR ( 101 MHz, CD3OD) 6 (ppm) 170.3 (HCO2H), 160 6 (Cq), 144 2 (d, Cq), 143 9 (d, Cq), 139 7 (Cq), 139 21 (CHarom), 137 8 (Cq), 137 7 (Cq), 132 5 (d, CHarom), 130 1 (CHarom), 127 9 (CHarom), 122 4 (CHarom), 122 3 (CHarom), 1 15 7 (CHarom),

[1313]

[1314] 1 13 7 (CHarom), 113 6 (CHarom), 93.1 (Cq), 71 4 (CH2), 67 0 (CH), 62 7 (CH2), 62 5 (CH2), 59 2 (CH2), 58 9 (CH2), 57 8 (CH2), 55 6 (CH2), 52 6 (CH), 51 8 (CH), 42 1 (CH3), 42 0 (CH3), 39.1 (CH2), 39 0 (CH2), 36 5 (CH2), 32 6 (CH2), 32 4 (CH2), 24 0 (CH2), 23 6 (CH2), 14 4 (CH3)

[1315] HRMS (ESI+): m / z calculated for C47H66I2N5O2[M+H]+: calc 986.3300; found: 986.3327 EXAMPLE 114: TM-421

[1316]

[1317] TM-421

[1318] TM-421 [(S)-5-(((3-((2-amino-3-(4-iodophenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-pentyl-[1, T-biphenyl]-3-ol] (26 4 mg, 15%) was synthetized following General Procedure A, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1319] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.52 (s, 1.85H, HCO2H), 766 (m, 2H, Harom), 750 (d, 2H, J = 82 Hz, Harom), 724 (d, 2H, J = 82 Hz, Harom), 7 15 (t, 1H, J = 1 3 Hz, Harem), 705 (dd, 1H, J = 1 7 Hz, J = 2 1 Hz, Harom), 700 (d, 2H, J= 8.2 Hz, Harom), 686-682 (m, 1H, Harem), 3 96 (d, 1H, J = 13 5 Hz), 393 (d, 1H, J = 13 5 Hz), 3 30-3 23 (m, 1H), 298-290 (m, 2H), 286-278 (m, 2H), 277-269 (m, 3H), 267-259 (m, 3H), 257 (s, 3H), 1 93-1 83 (m, 2H), 1 68-1 59 (m, 2H), 1 40-1 29 (m, 4H), 091 (t, 3H, J= 69 Hz)

[1320] 13C NMR (101 MHz, CD3OD) 5 (ppm) 169.9 (HCO2H), 1595 (Cq), 1445 (Cq), 143 8 (Cq), 139 1 (2 CHarom, Cq), 1376 (Cq), 1364 (Cq), 1325(2 CHarom), 1300 (2 CHarom), 1279(2CHarom), 120.9 (CHaroai), 116 9 (CHarom), 115 1 (CH™), 93 1 (Cq), 62 1 (CH3), 558 (CH3), 527 (CH), 520 (CH3), 482 (CH3), 41 1 (CH3), 395 (CH3), 365 (CH3) 326 (CH3), 324 (CH3), 250 (CH3), 23 6 (CH3), 14 4 (CH3).

[1321] HRMS (ESI+): m / z calculated for C38H56IN4O2[M+H]+: calc 600.2445; found: 600.2451

[1322] EXAMPLE 115: TM-422

[1323]

[1324] TM-422 [ 1-((5-(((3-(((S)-2-amino-3-(4-iodophenyl)propyl)amino)propyl)(metbyl)amino)metbyl)-4'-pentyl-[ 1, T-biphenyl]-3-yl)oxy) 3 (pyrrolidin 1 yl)propan 2 ol] (242 mg, 2.1%) was synthetized following General Procedure A, B, C.1, D, C.4, D;

[1325] Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.38 (s, 2. OH, HCO2H), 7 69 (d, 2H, J = 8 2 Hz, Harm), 7 56 (d, 2H, J = 8 2 Hz, Harom), 7 39 (bs, 1H, Harom), 7 29-7 25 (m, 3H, Harem), 7 19-7 17 (m, 1H, Harem), 7 05 (d, 2H, J = 8 2 Hz, Harom), 4 41 -4 33 (m, 1H), 4 26 (bs, 2H), 4 14 (d, 2H, J = 4.9 Hz), 3 51-3 37 (m, 7H), 3 24-3 17 (m, 2H), 2 87-2 63 (m, 8H), 2 73 (s, 3H), 2 16-2 09 (m, 4H), 2 02-1 94 (m, 2H), 1 69- 1 60 (m, 2H), 1 40-1 31 (m, 4H), 0 91 (t, 3H, J = 6 9 Hz)13C NMR (101 MHz, CD3OD) 6 (ppm) 168.3 (HCO2H), 160 8 (Cq), 144 9 (Cq), 144 2 (Cq), 139 2 (2 CHarom), 138.5 (Cq), 137 2 (Cq), 134 3 (Cq), 132 5 (2 CHarOm), 130 1 (2 CHaram), 128 0 (2 CHarom), 123 2 (CHarom), 116.1 (CH,™), 1 15.5 (CH,™>), 93 3 (Cq), 71 4 (CH2), 66 5 (CH), 61 3 (CH2), 58 6 (CH2), 55 7 (2 CH2), 53 2 (CH), 51 3 (CH2), 47 6 (CH2), 40 4 (CH3), 38 3 (CH2), 36 5 (CH2), 32 6 (CH2), 32 4 (CH2), 25 1 (CH2), 23 9 (CH2), 23 6 (CH2) HRMS (ESI+): m / z calculated for C38H56IN4O2[M+H]+: calc 727.3443; found: 727.3450

[1326] EXAMPLE 1 16: TM-423

[1327] 1.9 equiv HjN

[1328]

[1329] TM-423

[1330] TM-423 [1-((5-(((3-(((S)-2-amino-3-(4-iodophenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-fluoro-[ 1, 1'-biphenyl]-3- yl)oxy)-3-(pyrrolidin-1-yl)propan-2-ol] (30 3 mg, 3.2%) was synttietized following General Procedure A, B, C.1, D, C.4, D;

[1331] Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1332] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.39 (s, 1,9H, HCO2H), 7 69 (m, 4H, Harm), 7 44-7 40 (m, 1H, Harm), 7 29-7 26 (m, 1H, Harcni), 7.25-7.22 (m, 1H, Haram), 7 22-7 16 (m, 2H, Haram), 7 09 (d, 2H, J = 8 2 Hz, Harom), 4.42-4 32 (m, 1H), 4 35 (bs, 2H), 4 16 (d, 2H, J - 5 0 Hz), 3 54-3 43 (m, 7H), 3 30-3 3 24 (m, 2H), 2 95-2 85 (m, 3H), 2 85-2 71 (m, 3H), 2 78 (s, 3H), 2 16-2 09 (m, 4H), 2 07-1 99 (m, 2H)

[1333] 13C NMR (101 MHz, CD3OD) 6 (ppm) 168.3 (HCO2H), 160 8 (Cq), 144 9 (Cq), 144 2 (Cq), 139 2 (2 CHarom), 138.5 (Cq), 137 2 (Cq), 134 3 (Cq), 132 5 (2 CHarom), 130 1 (2 CHaram), 128 0 (2 CHarom), 123 2 (CHarom), 1 16 1 (CHarom), 1 15 5 (CHar™), 93 3 (Cq), 71 4 (CH2), 66 5 (CH), 61 3 (CH2), 58 6 (CH2) 55 7 (2 CH2), 53 2 (CH), 51 3 (CH2), 47 6 (CH2), 40 4 (CH3), 38 3 (CH2), 36 5 (CH2), 32 6 (CH2), 32 4 (CH2), 25 1 (CH2), 23 9 (CH2), 23 6 (CH2)

[1334] 19F NMR (377 MHz, CDCb) 6 (ppm) -116.6 (s, 1 F).

[1335] HRMS (ESI+): m / z calculated for C33H45FIN4O2[M+H]+: calc 675.2566; found: 675.2574 EXAMPLE 1 17: TM-424

[1336]

[1337] TM-424 [ 1-((5-(((3-(((S)-2-amino-3-(4-iodophenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-pentyl-[1,1'-biphenyl]-3-yl)oxy)-3-(azepan-1-yl)propan-2-ol] (19.1 mg, 7%) was synthetized following General Procedure A, B, C.1, D, C.4, D;

[1338] Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1339] EXAMPLE 1 18: TM-425

[1340]

[1341] TM-425 [1-(azepan- 1-yl)-3-((4-(((2-(5-methylbenzo[d]oxazol-2-yl)ethyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-2-yl)oxy) propan-2-ol] (10 6 mg, 5 2%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1342] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.54 (s, 1.3H, HCO2H), 7 46-7 40 (m, 4H, Harom), 7 28 (d, 1H, J = 7 7 Hz, Harom), 7 24 (

[1343]

[1344] d, 2H, J = 8 2 Hz, Harom), 7.19 (dd, 1H, J = 1.3 Hz, J = 8.2 Hz, Harom), 7.15-7.13 (bs, 1H, Harom), 7 09-7 05 (m, 1H, Harom), 4 27-4 17 (m, 1H), 4 10 (dd, 1 H, J = 4.2 Hz, J = 9.7 Hz,), 4 00-3 94 (m, 1H), 3 97 (bs, 2H), 3 24 (t, 4H, J = 3.7 Hz), 3 19 (t, 4H, J = 5 3 Hz), 3 14 (dd, 1H, J = 2 5 Hz, J = 13 1 Hz), 3 01 (dd, 1H, J = 10 0 Hz, J = 13 1 Hz), 2 63 (t, 2H, J = 7 5 Hz), 2 45 (s, 3H), 1 81- 1 76 (m, 4H), 1 71-1 63 (m, 6H), 0 98 (t, 3H, J = 7 3 Hz)

[1345] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 166 9 (Cq), 156 9 (Cq), 150 4 (Cq), 142 8 (Cq), 142 1 (Cq), 139 4 (Cq), 137 0 (Cq), 135 8 (Cq), 132 0 (Cq), 131 9 (CHarom), 130 6 (CHarom), 129 2 (CHarom), 127 3 (CHarom), 123 1 (CHarom), 120 1 (CHarom), 114.6 (CHarom), 111.0 (CHarom), 71.8 (CH2), 65 8 (CH), 60 4 (CH2), 56 3 (CH2), 53 5 (CH2), 46 0 (CH2), 38 8 (CH2), 28 7 (CH2), 28 0 (CH2), 25 8 (CH2), 24 4 (CH2), 21 4 (CH3), 14 2 (CH3).

[1346] HRMS (ESI+): m / z calculated for C35H46N3O3[M+H]+: calc. 495.2409; found: 495.2415 EXAMPLE 1 19: TM-426

[1347]

[1348] TM-426 [3-(2-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-propyl-[1, T-biph enyl]-3-y l)methyl) amino)ethy l)phenol] (26 7 mg, 15%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1349] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.54 (s, 2H, HCO2H), 7.55 (d, 2H, J = 8.2 Hz, Harom), 7 34 (bs, 1H, Harom), 7 30-7 24 (m, 3H, Harom), 7.14 (td, 1H, J = 7.5, 1.1 Hz, Harom), 7.07 (bs, 1H, Harom), 6.75-6.66 (m, 3H, Harom), 4 40 (dtd, 1H, J = 2 9 Hz, J = 4 7 Hz, J = 7 6 Hz), 4 20 (s, 2H), 4 1 1 (d, 2H, J = 4.9 Hz), 3 48-3 36 (m, 5H), 3.28-3.18 (m, 3H), 2 99-2 88 (m, 2H), 2 64 (t, 2H, J = 7 5 Hz), 1 99-1 88 (m, 4H), 1.80-1.72 (m, 4H), 1 68 (dq, 2H, J = 7 4 Hz, J = 14 7 Hz), 0 96 (t, 3H, J = 7 4 Hz)

[1350] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 160 8 (Cq), 159 0 (Cq), 144 9 (Cq), 143 9 (Cq), 139 6 (Cq), 138 7 (Cq), 135 4 (Cq), 131 0 (CH arom ), 130 1 (CH arom ), 127 9 (CH arom ), 122.1 (CHarom), 120.7 (CHarom), 116.6 (CHarom), 1 15 2 (CHarom), 115.1 (CHarom), 71.5 (CH2), 65 8 (CH), 60 2 (CH2), 56 4 (CH2), 52 4 (CH2), 49 8 (CH2), 38 6 (CH2), 33 6 (CH2), 28 0 (CH2), 25 7 (CH2), 24.4 (CH2), 14 1 (CH3)

[1351] HRMS (ESI+): m / z calculated for C33H45N2O3[M+2H]2+: calc. 517.3425; found: 517.3421

[1352] EXAMPLE 120: TM-427

[1353]

[1354] TM-427

[1355] TM-427 [4-((2S)-2-amino-3-(((5-(3-(azepan-1-yl)-2-hydroxypropoxy)-4'-propyl-[ 1, 1 '-biphenyl]-3-yl)methyl)amino) propyl) phenol] (6 1 mg, 2 5%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid) (twice)

[1356] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.51 (s, 2.9H, HCO2H), 7.51 (d, 2H, J = 8.2 Hz, Harom), 7 26 (d, 2H, J = 8 2 Hz, Harom), 7 21 (bs, 1H, Harom), 7.10 (bs, 1H, Harom), 7 03 (d, 2H, J = 8 5 Hz, Harom), 6 90 (bs, 1H, Harom), 6 73 (d, 2H, J = 8 5 Hz, Harom), 4.44-4.35 (m, 1H), 4 12-4 01 (m, 2H), 3 87 (d, 1 H, J = 13 5 Hz), 3 81 (d, 1H, J = 13 5 Hz), 3.50-3.39 (m, 5H), 3 38-3 24 (m, 2H), 2.90-2.71 (m, 3H), 2 69-2 59 (m, 3H), 2 00-1 87 (m, 4H), 1 81 -1 72 (m, 4H), 1.68 (dq. 2H, J = 7 4 Hz, J = 14 7 Hz), 0 96 (t, 3H, J = 7 4 Hz)

[1357] 13C NMR (101 MHz, CD3OD) 5 (ppm) 169.8 (HCO2H), 160 6 (Cq), 157 8 (Cq), 144 3 (Cq), 143 5 (Cq), 142 4 (Cq), 139 4 (Cq), 131 5 (CH arom ), 131 3(CH arom ), 130 0 (CH arom ), 127 9 (CH arom ), 127 7 (Cq), 122 9 (CH arom ), 121 1 (CH arom), 1 16 7 (CHarom), 114.1 (CHarom), 113 3 (CHarom), 71 3 (CH2), 65 7 (CH), 60 3 (CH2), 56 4 (CH2), 54 1 (CH2), 53 9 (CH), 50 6 (CH2), 38 7 (CH2), 37 8 (CH2), 28 0 (CH2), 25 7 (CH2), 24 3 (CH2), 14 1 (CH3).

[1358] HRMS (ESI+): m / z calculated for C34H48N3O3[M+H]+: calc. 546.3690; found: 546.3696

[1359] EXAMPLE 121: TM-429

[1360]

[1361] TM-429 [(2S)-2-(((4'-fluoro-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-[1,1'-biphenyl]-3-yl)methyl)amino)-3-(1H-indol-3-yl) propan-1-ol] (21.3 mg, 11%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH(NH DH))

[1362] 1H NMR (400 MHz, MeOD) 6 7.65 - 7.58 (m, 2H), 7.44 (d, J = 7 9 Hz, 1H), 7 36 (d, J = 8 2 Hz, 1H), 7 27 (s, 1H), 7 23 (s, 1H), 7 21 - 7 15 (m, J = 10 1, 7 4 Hz, 3H), 7 13 - 7 07 (m, 2H), 6 95 (t, J = 7 4 Hz, 1H), 4 40 - 4 34 (m, J = 10 5, 6 0 Hz, 1H), 4 32 (d, J = 2 1 Hz, 2H), 4 14 - 4 04 (m, 2H), 3 83 (dd, J = 12 0, 3 4 Hz, 1H), 3 70 (dd, J = 12 0, 5 2 Hz, 1H), 3 55 -3 48 (m, J = 9.0, 5 1 Hz, 1H), 3 48 - 3 35 (m, 6H), 3 28 - 3 12 (m, J = 23 6, 14 4, 7 4 Hz, 2H), 2 14 - 2 06 (m, J = 6 3 Hz, 4H)

[1363] 13C NMR (101 MHz, MeOD) 6 168.71, 164.06, 161.61, 159.44, 142.42, 136.84, 136.18, 136.15, 133.85, 128.67, 128.59, 126 85, 123 71, 121.41, 120 97, 118 76, 1 17 72, 1 15 39, 115 17, 114.02, 1 11 23, 108 41, 69 98, 65 17, 58 73, 57.21, 54 23, 48 44, 24 06, 22 54 EXAMPLE 122: TM-430

[1364]

[1365] TM-430 [(2S)-2-(((4'-fluoro-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-[1,1'-biphenyl]-3-yl)methyl)amino)-3-(1H-imidazol-5-yl) propan-1-ol] (22.9 mg, 3.4%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1366] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 1.0H, HCO2H), 7.64-7.58 (m, 3H, Harom), 7.20-7.13 (m, 3H, Harom), 7.09 (dd, 1H, J = 1.7 Hz, J = 2.2 Hz, Harom), 6.95-6.92 (m, 1H, Harom), 6.88 (d, 1H, J = 0.9 Hz, Harom), 430-422 (m, 1H), 406 (d, 2H, J = 5 1 Hz), 396 (d, 1H, J = 144 Hz), 3 93 (d, 1H, J= 144 Hz), 3 66 (dd, 1H, J = 46 Hz, J= 11 4 Hz), 3 53 (dd, 1H, J = 59 Hz, J= 11 4 Hz), 3 24-3 12 (m, 6H), 3 11-303 (m, 1H), 281 (dd, 2H, J = 68 Hz), 205-1 97 (m, 4H)

[1367] 13C NMR (101 MHz, CD3OD) 5 (ppm) 170.4 (HCO2H), 164.1 (d, J = 245.4 Hz, Cq), 1608 (Cq), 143 2 (Cq), 141 6 (Cq), 1383 (d, J = 3.2 Hz, Cq), 1363 (CHarom), 135 5 (Cq), 130.0 (CHarom), 129.9 (CHarom), 121.2 (CHarom), 118.3 (CHarom), 116.6 (CHarom), 116.4 (CHarom), 114.5 (CHarom), 113.7 (CHarom), 71.5 (CH2), 677 (CH), 633 (CH2), 599 (CH), 592 (CH2), 557 (CH2), 51 6 (CH2), 29 0 (CH2), 240 (CH2)

[1368] 19F NMR (377 MHz, CDCl3) 5 (ppm) -117.3 (s, 1 F).

[1369] HRMS (ESI+): m / z calculated for C26H34FN4O2[M+H]+: calc. 469.2609; found: 469.2618

[1370] EXAMPLE 123: TM-431

[1371]

[1372] TM-431 [(2S)-2-(((3'-chloro-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)amino)-3-(1H-indol-3-yl)propan-1-ol] (4.3 mg, 5.9%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1373] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.52 (s, 2.3H, HCO2H), 7.43-7.41 (m, 1H, Harom), 7.41-7.39 (m, 1H, Harom), 7.35 (d, 1H, J = 8.2 Hz, Harom), 7.22 (t, 1H, J = 7.6 Hz, Harom), 7.16 (s, 1H, Harom), 7.11 (bs, 1H, Harom), 7.10-7.06 (m, 2H, Harom), 6 97-6 90 (m, 3H, Harom), 4 35-4 28 (m, 1H), 4 24 (bs, 2H), 4 06 (dd, 1H, J = 5 1 Hz, J = 11.6 Hz), 4 02 (dd, 1H, J = 4 9 Hz, J = 11 6 Hz), 3 78 (dd, 1 H, J = 3 7 Hz, J = 1 1 8 Hz), 3 66 (dd, 1 H, J = 5 4 Hz, J = 11 8 Hz), 3 48-3 33 (m, 7H), 3 18 (dd, 1H, J = 5 8 Hz, J = 14 4 Hz), 3 11 (dd, 1 H, J = 8 9 Hz, J = 14 4 Hz), 2 23 (s, 3H), 2 12-2 05 (m, 4H)

[1374] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 2 (Cq), 145 0 (Cq), 144 5 (Cq), 138 3 (Cq), 136 3 (Cq), 135 9 (Cq), 134 6 (Cq), 129 6 (CH arom ), 129 3 (CH arom ), 128 3 (Cq), 127 9 (CH arom ), 124 9 (CH arom ), 124 3 (CH arom ), 122 8 (CH arom), 120 1 (CHarom), 1 19 1 (CHarom), 117 4 (CHarom), 115 4 (CHarom), 1 12 6 (CHarom), 110 2 (Cq), 71 4 (CH2), 66 7 (CH), 60 8 (CH2), 60 0 (CH), 58 7 (CH2), 55 6 (CH2), 50 0 (CH2), 25 8 (CH2), 23 9 (CH2), 18 1 (CH3).

[1375] HRMS (ESI+): m / z calculated for C32H39ClN3O3[M+H]+: calc. 548.2674; found: 548.2679

[1376] EXAMPLE 124: TM-432

[1377]

[1378] TM-432 [3-(2-(((3'-chloro-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)amino)ethyl)phenol] (8.7 mg, 13%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1379] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.54 (s, 2.3H, HCO2H), 7 40 (dd, 1H, J = 1 1 Hz, J = 8 0 Hz, Harom), 7 22 (t, 1H, J = 7

[1380]

[1381] .8 Hz, Harom), 7 16-7 08 (m, 3H, Harom), 6 97 (bs, 1H, Harom), 6.94-6.91 (m, 1H, Harom), 6 72-6 65 (m, 3H, Harom), 4 35-4 27 (m, 1H), 4 12 (bs, 2H), 4 10-4 04 (m, 2H), 3 42-3 32 (m, 6H), 3 19-3 10 (m, 2H), 2 97-2 85 (m, 2H), 2 26 (s, 3H), 2 1 1-2 05 (m, 4H)

[1382] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 160 3 (Cq), 159 0 (Cq), 145 0 (Cq), 144 6 (Cq), 140 1 (Cq), 136 3 (Cq), 134 6 (Cq), 130 9 (CHarom), 129 6 (CH,™), 129.3 (CH,™), 127.9 (CHarom), 124.1 (CHarom), 120 7 (CHarom), 1 17 2 (CHarom), 1 16 6 (CHarom), 115 4 (CHarom), 1 14 9 (CHarom), 71.4 (CH2), 66 9 (CH), 58 8 (CH2), 55 6 (CH2), 52 5 (CH2), 50 1 (CH2), 34 1 (CH2), 24 0 (CH2), 18 0 (CH3)

[1383] HRMS (ESI+): m / z calculated for C29H36ClN2O2[M+H]+: calc. 495.2409; found: 495.2415 EXAMPLE 125: TM-433

[1384]

[1385] TM-433 [1-((5-((((S)-3-amino-4-phenylbutyl)amino)methyl)-3'-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)oxy)-3-(pyrrolidin-1-yl)propan-2-ol] (1.9 mg, 2.7%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1386] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 3.0H, HCO2H), 739 (dd, 1H, J = 1 1 Hz, J = 80 Hz, Harom), 736-722 (m, 5H, Harom), 720 (d, 1H, J = 80 Hz, Harom), 7 12 (dd, 1H, J = 09 Hz, J = 76 Hz, Harom), 705-700 (m, 1H, Harom), 690 (bs, 1H, Harom), 685 (bs, 1H, Harom), 434-427 (m, 1H), 4 10-402 (m, 2H), 3 96-3 86 (m, 2H), 3.51-344 (m, 1H), 3 42-3 32 (m, 6H), 3 00-283 (m, 4H), 225 (s, 3H), 2 13-205 (m, 4H), 1 91-1 74 (m, 2H)

[1387] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.0 (HCO2H), 160 2 (Cq), 1449 (Cq), 1447 (Cq), 1397 (Cq), 1375 (Cq), 1363 (Cq), 1345 (Cq), 1304 (CHarom), 1300 (CHarom), 129.5 (CHarom), 129.3 (CHarom), 128.4 (CHarom), 127.8 (CHarom), 123 5 (CHarom), 116 3 (CHarom), 1149 (CHarom), 71 4(CH2), 668 (CH), 587 (CH2), 556 (CH2), 539 (CH), 53 2 (CH2), 466(CH2), 41 4 (CH2), 31 6 (CH2), 23 9 (CH2), 18 1 (CH3)

[1388] HRMS (ESI+): m / z calculated for C31H41ClN3O2[M+H]+: calc. 522.2882; found: 522.2889

[1389] EXAMPLE 126: TM-434

[1390]

[1391] TM-434 [1-((5-(((3-(((S)-2-amino-3-(4-iodophenyl)propyl)amino)propyl)(methyl)amino)methyl)-4'-chloro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)-3-(pyrrolidin-1-yl)propan-2-ol] (13.3 mg, 4.1%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1392] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.25 (s, 0.3H, HCO2H), 7.74-7.69 (m, 2H, Harom), 734-730 (m, 1H, Harom), 7 14 (s, 2H, Harom), 7.10 (d, 2H, J = 8.3 Hz, Harom), 692 (t, 1H, J= 1 0 Hz, Harom), 685 (dd, 1H, J= 1 3 Hz, J = 23 Hz, Harom), 439-430 (m, 1H), 433 (bs, 2H), 4 13 (d, 2H, J = 50 Hz), 3 53-3 40 (m, 7H), 3 30-3 24 (m, 3H), 292-287 (m, 2H), 286-276 (m, 3H), 274 (s, 3H), 274-268 (m, 2H), 2 16-208 (m, 4H), 201 (s, 6H)13C NMR (101 MHz, CD3OD) 6 (ppm) 160.8 (Cq), 143 8 (Cq), 140.5 (Cq), 139.2 (CHarom), 139.0 (2 Cq), 137 1 (Cq), 134.0 (Cq), 133 8 (Cq), 132.5 (CHarom), 1282 (CHarom), 125.5 (CHarom), 1184 (CHarom), 116.5 (CHarom), 93 4 (Cq), 71 4 (CH2), 665 (CH), 608 (CH2), 585 (CH2), 560 (CH2), 534 (CH), 51.2 (CH2), 475 (CH2), 40 1 (CH3), 380 (CH2), 252 (CH2), 23 9 (CH2), 20.8 (2 CH3)

[1393] HRMS (ESI+): m / z calculated for C33H45FIN4O2[M+H]+: calc. 675.2566; found: 675.2574

[1394] EXAMPLE 127: TM-435

[1395] H T)H

[1396] 1 9 equiv.

[1397] TM-435

[1398]

[1399] TM-435 [3-(2-((3-(furan-2-yl)-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)benzyl)amino)ethyl)phenol] (25.0 mg, 26%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 1.9H, HCO2H), 758 (d, 1H, J = 1 3 Hz, Harem), 7.45 (bs, 1H, Harem), 734 (bs, 1H, Harem), 7 14 (t, 1H, J= 79 HZ, Harem), 7.05-7.01 (m, 1H, Harom), 685 (d, 1H, J = 32 Hz, Harem), 675-667 (m, 3H, Harem), 654 (dd, 1H, J = 1 8 Hz, J = 32 Hz, Harem), 4.40-4.31 (m, 1H), 4.19 (bs, 2H), 4 14-405 (m, 2H), 3 51-3 37 (m, 6H), 323 (dd, 2H, J = 70 Hz, J = 8 1 Hz), 295 (dd, 2H, J = 68 Hz, J = 9 1 Hz), 2 15-207 (m, 4H)

[1400] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 1608 (Cq), 1590 (Cq), 154 1 (Cq), 144.1 (CHarom), 1395 (Cq), 135.2 (Cq), 1344 (Cq), 131 0 (CHarom), 1207 (CHarom), 119.0 (CHarom), 116.6 (CHarom), 115.6 (CHarom), 115 1 (CHarom), 113.0 (CHarom), 111 7 (CHarom), 107.5 (CHarom), 71 4 (CH2), 666 (CH), 586 (CH2), 556 (CH2), 52 1 (CH2), 497 (CH2), 334 (CH2), 23 9 (CH2)

[1401] HRMS (ESI+): m / z calculated for C26H33N2O4[M+H]+: calc. 437.2435; found: 437.2442

[1402] EXAMPLE 128: TM-436

[1403]

[1404] TM-436

[1405] TM-436 [1-(3-((((1H-indol-6-yl)methyl)amino)methyl)-5-(furan-2-yl)phenoxy)-3-(pyrrolidin-1-yl)propan-2-ol] (28.5 mg, 30%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.54 (s, 1.8H, HCO2H), 7 62 (d, 1H, J = 8 1 Hz, Harem), 7 57 (dd, 1 H, J = 0 6 Hz, J = 1 8 Hz, Harom), 7 53 (bs, 1H, Harem), 7 42 (bs, 1H, Harem), 7 33-7 30 (m, 2H, Harem), 7 1 1 (dd, 1H, J = 1 4 Hz, J = 8 1 Hz, Harem), 6 99 (bs, 1 H, Harom), 6 82 (dd, 1H, J = 0 6 Hz, J = 3 4 Hz, Harem), 6 53 (dd, 1H, J = 1 8 Hz, J = 3 4 Hz, Harom), 6 48 (dd, 1H, J = 0 7 Hz, J = 3 1 Hz, Harom), 4 35-4 29 (m, 1 H), 4 27 (bs, 2H), 4 15 (bs, 2H), 4 09 (dd, 1H, J = 3 7 Hz, J = 8 6 Hz), 4 05 (dd, 1H, J = 3 8 Hz, J = 8 6 Hz), 3 43-3 32 (m, 6H), 2 1 1-2 04 (m, 4H)

[1406] 13C NMR ( 101 MHz, CD3OD) 5 (ppm) 170.4 (HCO2H), 160 8 (Cq), 154 2 (Cq), 144 0 (CHarom), 137 6 (Cq), 135 8 (Cq), 134 3 (Cq), 130.2 (Cq), 127 3 (CHarom), 125 6 (Cq), 121 9 (CHarom), 121 6 (CHarom), 1 18 9 (CHarom), 115 5 (CHarom), 1 14 1 (CHarom), 1 12 9 (CHarom), 11 1 5 (CHarom), 107 4 (CHarom), 102 5 (CHarom), 71 4 (CH2), 66 8 (CH), 58 7 (CH2), 55 6 (CH2), 53 0 (CH2), 51 5 (CH2), 23 9 (CH2)

[1407] HRMS (ESI+): m / z calculated for C27H32N3O3[M+H]+: calc. 446.2438; found: 446.2449

[1408] EXAMPLE 129: TM-437

[1409]

[1410] TM-437 [3-(2-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)-5-(6-methylpyridin-3-yl)benzyl)amino)ethyl)phenol] (8.2 mg, 10.3%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid).

[1411] EXAMPLE 130: TM-438

[1412]

[1413] TM-438 TM-438 [1-((4'-chloro-2',6'-dimethyl-5-(((2-(thiazol-2-yl)ethyl)amino)methyl)-[1,1'-biphenyl]-3-yl)oxy)-3-(pyrrolidin-1-yl)propan-2-ol] (7.7 mg, 5%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1414] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.52 (s, 1.75H, HCO2H), 770 (d, 1H, J = 3.4 Hz, Harcm), 750 (d, 1H, J = 3.4 Hz, H arom), 7.12 (s, 2H, Harom), 7.10-7.07 (m, 1H, Harom), 682 (bs, 1H, Harom), 676-672 (m, 1H, Harom), 436-429 (m, 1H), 4.11 (s, 2H), 409-403 (m, 2H), 3.41-3.36 (m, 8H), 3 28 (t, 2H, J = 6.8 Hz), 2.07-2.12 (m, 4H), 200 (s, 6H)

[1415] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 168.8 (Cq), 160.7 (Cq), 143.5 (Cq), 143.2 (CHarora), 141.0 (Cq), 139.1 (2 Cq), 138.3 (Cq), 133.8 (Cq), 128 1 (CHarom), 123.7 (CHarom), 120.8 (CHarom), 116.7 (CHarom), 114.9 (CHarom), 71 3 (CH2), 667 (CH), 587 (CH2), 556 (CH2), 528 (CH2), 480 (CH2), 31.3 (CH2), 239 (CH2), 208 (CH3).

[1416] HRMS (ESI+): m / z calculated for C27H35ClN3O2S [M+H]+: calc. 495.2409; found: 495.2415

[1417] EXAMPLE 131: TM-439

[1418] H OH

[1419] 1 75 equiv

[1420] H N N TM-439

[1421]

[1422] TM-439 [3-(2-(((4'-chloro-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methyl)amino)ethyl)phenol] (11.1 mg, 7%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1423] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 1 5H, HCO2H), 7.13 (s, 2H, Harom), 7 11 (bs, 1H, Harom), 705 (d, 2H, J = 8.5 Hz, Harom), 684-682 (m, 1H, HarOm), 6.81-678 (m, 1H, Harom), 676-672 (m, 2H, Harom), 435-429 (m, 1H, J = 63 Hz), 4 18 (bs, 2H), 406 (d, 2H, J = 5.0 Hz), 3.43-334(m, 6H), 3 18-3 08 (m, 2H), 294-284 (m, 2H), 2 14-206 (m, 4H), 200 (s, 6H)13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 160 8 (Cq), 157.7 (Cq), 143.7 (Cq), 140.7 (Cq), 139.0 (Cq), 135.9 (Cq), 133 9(Cq), 130.7 (CHarom), 128.8 (Cq), 128.2 (CHarom), 124.1 (CHarom), 117.4 (CHarom), 116.7 (CHarom), 115.3 (CHarom), 71.4 (CH2), 667 (CH), 587 (CH2), 556 (CH2), 522 (CH2), 50.1 (CH2), 329 (CH2), 23 9 (CH2), 20.7 (CH3).

[1424] HRMS (ESI+): m / z calculated for C30H38ClN2O3[M+H]+: calc. 495.2409; found: 509.2571 EXAMPLE 132: TM-440

[1425]

[1426] TM-440

[1427] TM-440 [4-(2-(((3'-chloro-5-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-2'-methyl-[1,1'-biphenyl]-3-yl)methyl)amino)ethyl)phenol] (9.2 mg, 15%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1428] 1H NMR (400 MHz, CD3OD) 5 (ppm) 8.52 (s, 1.25H, HCO2H), 7.40 (dd, 1H, J = 1.1 Hz, J = 8.0 Hz, Harom), 722 (t, 1H, J = 7.6 Hz, Harom), 720- 7 18 (m, 1H, Harom), 7 14 (dd, 1H, J = 1 2 Hz, J = 76 Hz, Harem), 7.010-7.06 (m, 2H, Harom), 7.04-7.02 (m, 1H, Harom), 6.96 (dd, 1H, J = 1.4 Hz, J = 2.3 Hz, Harom), 6.77-6.73 (m, 2H, Harom), 4.40-4.31 (m, 1H), 423 (bs, 2H), 4 10 (d, 2H, J = 50 Hz), 349-3 37 (m, 6H), 3 25-3 18 (m, 2H), 296-289 (m, 2H), 226 (s, 3H), 2 15-206 (m, 4H)

[1429] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 160.3 (Cq), 157.7 (Cq), 145.1 (Cq), 144.4 (Cq), 136.3 (Cq), 134.7 (Cq), 134.5 (Cq), 130.8 (CH arom ), 1297 (CH arom ), 1293 (CH arom ), 128.5 (Cq), 1279 (CH arom ), 1244 (CH arom ), 117.8 (CH arom), 1167 (CHarom), 115 7 (CHarom), 71 5 (CH2), 666 (CH), 586 (CH2), 556 (CH2), 52 1 (CH2), 50 1 (CH2), 326 (CH2), 23 9 (CH2), 18.1 (CH3)

[1430] HRMS (ESI+): m / z calculated for C29H36ClN2O3[M+H]+: calc. 495.2409; found: 495.2413

[1431] EXAMPLE 133: TM-441

[1432]

[1433] TM-441 [3-(2-((3-(3-(azepan-1-yl)-2-hydroxypropoxy)-5-(benzofuran-3-yl)benzyl)amino)ethyl)phenol] (38.3 mg, 22%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.54 (s, 1,4H, HCO2H), 808 (s, 1H, Harom), 7.91 (dd, 1H, J = 1 3 Hz, J= 1 1 Hz, Harom), 756 (dd, 1H, J = 09 Hz, J = 7 1 Hz, HarOm), 7.47-7.45 (m, 1H, Harom), 7.40-7.31 (m, 3H, Harom), 7 19-7 16 (m, 1H, Harom), 7 14 (t 1H, J = 79 Hz, Harem), 676-667 (m, 3H, Harem), 448-439 (m, 1H), 425 (bs, 2H), 4 14 (d, 2H, J = 47 Hz), 3 53- 3 38 (m, 5H), 334-3 23 (m,3H), 298 (dd, 2H, J = 7.5 Hz, J = 8.6 Hz), 1.99-1.87 (m, 4H), 1 80-169 (m, 4H)13C NMR ( 101 MHz, CD3OD) 6 (ppm) 170.2 (HCO2H), 160 9 (Cq), 159 0 (Cq), 157.3 (Cq), 143 7 (CHarom), 139 5 (Cq), 135 8 (Cq), 135 4 (Cq), 131 0 (CHarom), 127.1 (Cq), 126 0 (CHarom), 124.4 (CHarom), 122.6 (CHarom), 122.5 (Cq), 121 4 (CHarom), 120 7 (CH arom ), 116 6 (CH arom ), 115 7 (CH arom ), 115 6 (CH arom ), 115 1 (CH arom ), 112 7 (CH arom ), 71 5 (CH2), 65 7 (CH), 60 2 (CH2), 56 4 (CH2), 52 2 (CH2), 49 8 (CH2), 33 4 (CH2), 28 0 (CH2), 24 2 (CH2) HRMS (ESI+): m / z calculated for C32H39N2O4[M+H]+: calc 515.2904; found: 515.2906

[1434] EXAMPLE 134: TM-442

[1435]

[1436] TM-442 [1-(3-((((S)-3-amino-4-phenylbutyl)amino)methyl)-5-(benzofuran-3-yl)phenoxy)-3-(azepan-1 -yl)propan-2-ol] (38 9 mg, 22%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1437] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.47 (s, 1.4H, HCO2H), 8.09 (s, 1H, HarOm), 7.95-7.91 (m, 1H, Harem), 7 57 (dd, 1H, J = 1 1 Hz, J = 7.4 Hz, Harm), 7 45-7 43 (m, 1H, Harom), 7 41-7 23 (m, 8H, Harom), 7 21-7 18 (m, 1H, Harom), 4 45 (dtd, 1H, J = 2 6 Hz, J = 4 8 Hz, J = 7.5 Hz), 4 20 (bs, 2H), 4 16 (d, 2H, J = 4.9 Hz), 3 68-3 60 (m, 1H), 3 52 (dd, 1H, J = 2 7 Hz, J = 13 2 Hz), 3 49-3 45 (m, 4H), 3 36-3 28 (m, 1H), 3.25-3.16 (m, 1H), 3 16-3 08 (m, 1H), 3 00 (dd, 1H, J = 7 1 Hz, J = 14 3 Hz), 2 95 (dd, 1H, J = 7 9 Hz, J = 14 3 Hz), 2 13-2 05 (m, 2H), 2 00-1 89 (m, 4H), 1 81- 1 70 (m, 4H)

[1438] 13C NMR ( 101 MHz, CD3OD) 8 (ppm) 169.6 (HCO2H), 160 8 (Cq), 157 3 (Cq), 143 7 (CHarom), 136 7 (Cq), 135.8 (Cq), 135.7 (Cq), 130 5 (CH arom ), 130 1 (CH arom ), 128 6 (CH arom ), 127.1 (Cq), 126 0 (CH arom ), 124 4 (CH arom ), 122 5 (2 CH arom ), 121 4 (CHarom), 1 15 7 (CHarom), 115 6 (CHarom), 1 12 7 (CHarom), 71 5 (CH2), 65 6 (CH), 60.1 (CH2), 56 4 (CH2), 52 5 (CH2), 52 2 (CH), 45 3 (CH2), 40 2 (CH2), 30 4 (CH2), 28 0 (CH2), 24 2 (CH2)

[1439] HRMS (ESI+): m / z calculated for C34H44N3O3[M+H]+: calc 542.3377; found: 542.3380

[1440] EXAMPLE 135: TM-443

[1441]

[1442] TM-443 TM-443 [1-(3-(((3-(((S)-2-amino-3-(4-(trifluorometiyl)phenyl)propyl)amino)propyl)(methyl)amino)metiyl)-5-(benzoturan- 3 -yl)phenoxy)-3-(azepan-1-yl) propan-2 -ol] (87 mg, 8 2%) was synttictizcd following General Procedure A, B, C.1, D, C.4, D; Purification: HPLC prep / MS (H2O: AON: MeOH, 0 1% Formic Acid)

[1443] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.45 (s, 3.1 H, HCO2H), 8 08 (s, 1H, Harom), 7 91 -7 88 (m, 1H, Harem), 7 63 (d, 2H, J = 8 1 Hz, Harom), 7 57 (dd, 1H, J = 0 8 Hz, J = 7 5 Hz, Harem), 7 46-7 31 (m, 6H, Harem), 7 15-7 12 (m, 1 H, HarOm), 4 43 (dtd, 1H, J = 2 9 Hz, 7 = 4 9 Hz, J = 7 7 Hz), 4 17 (bs, 2H), 4 13 (d, 2H, J = 5 0 Hz), 3 51-3 40 (m, 6H), 3 35-3 28 (m, 1H), 3 13- 3 07 (m, 2H), 2 94 (d, 2H, J = 7 1 Hz), 2 87 (dd, 1H, J = 3 9 Hz, J = 13 0 Hz), 2 84-2 65 (m, 3H), 2 66 (s, 3H), 2.00-1.91 (m, 6H), 1 80-1 71 (m, 4H)

[1444] 13C NMR ( 101 MHz, CD3OD) 6 (ppm) 169.3 (HCO2H), 160 9 (Cq), 157 4 (Cq), 143 8 (CHarom), 142 2 (Cq), 135 9 (Cq), 135 7 (

[1445]

[1446] Cq), 131 1 (CHarom), 130.5 (q, J = 32 3 Hz, Cq), 127 1 (Cq), 126 8 (q, J = 3 7 Hz, CHarom), 126 0 (CHarom), 125 7 (q, J = 271 4 Hz, Cq), 124 4 (CH arom ), 123 3 (CH arom ), 122 6 (Cq), 121 3 (CH arom ), 116 6 (CH arom ), 1 15 4 (CH arom ), 1 12 8 (CH arom), 71.5 (CH2), 65.6 (CH), 61.4 (CH2), 60 2 (CH2), 56 3 (CH2), 55 6 (CH2), 52 8 (CH), 51 6 (CH2), 47 7 (CH2), 40 5 (CH3), 39 0 (CH2), 28 0 (CH2), 25 1 (CH2), 24 2 (CH2)

[1447] 19F NMR (377 MHz, CDCl3) 5 (ppm) -64.0 (s, 3F).

[1448] HRMS (ESI+): m / z calculated for C38H50F3N4O3[M+H]+: calc 667.3830; found: 667.3832

[1449] EXAMPLE 136: TM-444

[1450]

[1451] TM-444 [1 (3 ((((S) 3 amino 4 phenylbutyl)amino)methyl) 5 (6 (trifluoromethyl)pyridin 3 yl)phenoxy) 3 (azepan 1 yl) prop an-2-ol] (34 6 mg, 13%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1 % Formic Acid).

[1452] 1H NMR (400 MHz, CD3OD) 6 (ppm) 9.00 (d, 1 H, J = 2.0 Hz, HarOm), 8 46 (s, 1 8H, HCO2H), 8,32 (dd, 1 H, J = 2 0 Hz, J = 8 2 Hz, Harom), 7 92 (d, 1H, J = 8 2 Hz, Harem), 7 48-7 45 (m, 1H, Harom), 7 39-7 25 (m, 7H, Harom), 4 48-4 41 (m, 1H), 4 20- 4 14 (m, 4H), 3 67-3 59 (m, 1 H), 3 53-3 43 (m, 5H), 3 35-3 28 (m, 1 H), 3 20-3 06 (m, 2H), 3 00 (dd, 1 H, J = 6 8 Hz, J = 14 0 Hz), 2 94 (dd, 1 H, J = 7 7 Hz, J = 14 0 Hz), 2 09-2 02 (m, 2H), 1.99-1.91 (m, 4H), 1 81 -1 71 (m, 4H)

[1453] 13C NMR ( 101 MHz, CD3OD) 6 (ppm) 169.6 (HCO2H), 161 0 (Cq), 149 5 (CHarom), 148.0 (q, J = 34 8 Hz, Cq), 140 2 (d, J = 0

[1454]

[1455] .6 Hz, Cq), 139 6 (Cq), 137.6 (CHarom), 136 9 (Cq), 136 8 (Cq), 130 5 (CHarom), 130 1 (CHarom), 128.6 (CHarom), 123 1 (q, J = 272 9 Hz, Cq), 122 6 (CHarom), 122 0 (q, J = 2 5 Hz, CHarom), 117 3 (CHarom), 1 15 6 (CHarom), 71 6 (CH2), 65 6 (CH), 60.1 (CH2), 56 4 (CH2), 52 4 (CH2), 52 3 (CH), 45 5 (CH2), 40 3 (CH2), 30 6 (CH2), 28 0 (CH2), 24 2 (CH2)19F NMR (377 MHz, CDCl3) 5 (ppm) -69.2 (s, 3F).

[1456] HRMS (ESI+): m / z calculated for C32H42F3N4O2[M+H]+: calc 571.3254; found: 571.3257

[1457] EXAMPLE 137: TM-445

[1458] TM-445 [ 1 (3 (((3 (((S) 2 amino 3 (4 (trifluoromettiyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl) 5 (6 (trifluoro methyl)pyridin-3-yl)phenoxy)-3-(azepan-1-yl)propan-2-ol] (98 mg, 19%) was synthetized following General Procedure A, B, C.1, D, C.4, D; Punficalion: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 9.00 (d, 1H, J = 2.0 Hz, Harom), 844 (s, 3 1H, HCO2H), 831 (dd, 1H, J = 1 9 Hz, J = 8

[1459]

[1460] 2 Hz, 891 (d, 1H, J = 8 1 Hz, 765 (d, 2H, J= 8 1 Hz, 750-745 (m, 3H, 740-737 (m, 1H, Harom), 728-725 (m, 1H, Harom), 444 (dtd, 1H, J = 28 Hz, J = 48 Hz, J = 75 Hz), 4 17 (bs, 2H), 4 15 (d, 2H, J = 49 Hz), 3 52-3 42 (m, 6H), 3 35-327 (m, 1H), 3 12-3 06 (m, 2H), 299 (d, 2H, J = 7 1 Hz), 291 (dd, 1H, J = 3 9 Hz, J = 13 0 Hz), 288-272 (m, 3H), 264 (s, 3H), 201-1 92 (m, 6H), 1 80-1 72 (m, 4H)

[1461] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.0 (HCO2H), 161 1 (Cq), 149 5 (CHarom), 1480 (q, J = 348 Hz, Cq), 1422 (Cq), 1402 (Cq), 1396 (Cq), 137 6 (CHarom), 1365 (Cq), 131.1 (CHarom), 1305 (q, J = 323 Hz, Cq), 1268 (q, J = 3 7 Hz, CH,™), 1257 (q, J = 271 2 Hz, Cq), 123 4 (CH,™.), 123 1 (q, J = 273 0 Hz, Cq), 1220 (q, J = 27 Hz, CHarom), 118.2 (CHarom), 1155 (CHarom), 71 6 (CH2), 656 (CH), 61 3 (CH2), 60 1 (CH2), 563 (CH2), 557 (CH2), 528 (CH), 51 5 (CH2), 476 (CH2), 405 (CH3), 390 (CH2), 280 (CH2), 25 1 (CH2), 242 (CH2)

[1462] 19F NMR (377 MHz, CDCb) 5 (ppm) -64.0 (s, 3F), -69.2 (s, 3F).

[1463] HRMS (ESI+): m / z calculated for C36H48F6N5O2[M+H]+: calc 696.3707; found: 696.3709

[1464] EXAMPLE 138: TM-446

[1465]

[1466] TM-446 TM-446 [1-(azepan-1-yl)-3-(3-(((benzo[d]oxazol-2-ylmethyl)amino)methyl)-5-(benzofuran-3-yl)phenoxy)propan-2-ol] (7.1 mg, 4.1%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1467] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.53 (s, 1,4H, HCO2H), 7 99 (s, 1H, HarOm), 7 88 (dd, 1H, J = 0 9 Hz, J= 7 7 Hz, HarOm), 7 68-7 63 (m, 1H, Harcm), 7 59-7 56 (m, 1H, Harom), 7 56-7 52 (m, 1H, Harcni), 7 40-7 28 (m, 5H, Harcni), 7 15 (dd, 1H, J= 1 6 Hz, J = 2 1 Hz, HarCm), 7 03-7 01 (m, 1H, Harom), 4 41-434 (m, 1H), 4 11 (bs, 2H), 4 09 (dd, 2H, J = 2 1 Hz, J = 5 1 Hz), 3 95 (bs, 2H), 3 47-3 36 (m, 5H), 3 26 (dd, 1H, J - 103 Hz, J - 13 1 Hz), 1 97-1 88 (m, 4H), 1 79-1 70 (m, 4H)

[1468] 13C NMR (101 MHz, CD3OD) 6 (ppm) 170.1 (HCO2H), 166 7 (Cq), 160 6 (Cq), 157 3 (Cq), 152 2 (Cq), 143 3 (CHarom), 142.7 (Cq), 141 8 (Cq), 134 9 (Cq), 127 4 (Cq), 1265 (CHarom), 125.8 (CHarom), 125 7 (CHarom), 124 2 (CHarom), 123 0 (Cq), 121 6 (CH arom ), 121 5 (CH arom ), 120 5 (CH arom ), 114 6 (CH arom ), 113 6 (CH arom ), 112 6 (CH arom ), 111 8 (CH arom ), 71 3 (CH2), 65 8 (CH), 60 3 (CH2), 56 4 (CH2), 53 7 (CH2), 46 1 (CH2), 28 0 (CH2), 24 4 (CH2)

[1469] HRMS (ESI+): m / z calculated for C32H35N3O4[M+H]+: calc 526.2700; found: 526.2702

[1470] EXAMPLE 139: TM-447

[1471]

[1472] TM-447 [1-(azepan-1-yl)-3-(3-(((benzo[d]oxazol-2-ylmethyl)amino)methyl)-5-(6-(trifluoromethyl)pyridin-3-yl)phenoxy) propan-2-ol] (5 2 mg, 2.1%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1473] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.93 (d, 1H, J = 1 8 Hz, Harom), 8 54 (s, 1 6H, HCO2H), 8 23 (dd, 1H, J = 1 8 Hz, J = 8 2 Hz, Harem), 7 88 (d, 1H, J = 8 2 Hz, Harmi), 7 67-7 62 (m, 1H, HarCm), 758-7 54 (m, 1H, HarOm), 7 41-7 32 (m, 3H, HarOm), 7 18-7 15 (m, 1H, Harom), 7 14-7 12 (m, 1H, Harcm), 4 41-4 32 (m, 1H), 4 14-406 (m, 4H), 3 97 (bs, 2H), 3 45-3 34 (m, 5H), 3 23 (dd, 1H, J= 10 4 Hz, J = 13 0 Hz), 1 97-1 86 (m, 4H), 1 79-1 70 (m, 4H)

[1474] 13C NMR (101 MHz, CD3OD) 5 (ppm) 170.1 (HCO2H), 166 7 (Cq), 160 8 (Cq), 152 2 (Cq), 149 4 (CHarom), 147 7 (q, J = 34 7 Hz, Cq), 143 4 (Cq), 141 8 (Cq), 140 8 (Cq), 138.9 (Cq), 137 4 (CHarom), 1265 (CH™), 1258 (CHarara), 125 4 (m, Cq), 121 9 (q, J = 2 8 Hz, CH™), 121 6 (CHaram), 120 5 (CH™), 116 3 (CH™), 113 6 (CHarom), 111 8 (CH arom ), 71 5 (CH2), 65 9 (CH), 60 2 (CH2), 56 4 (CH2), 53 7 (CH2), 463 (CH2), 28 0 (CH2), 246 (CH2)

[1475] 19F NMR (377 MHz, CDCl3) 5 (ppm) -64.1 (s, 3F).

[1476] HRMS (ESI+): m / z calculated for C30H34F3N4O3[M+H]+: calc 555.2578; found: 555.2577 EXAMPLE 140: TM-448

[1477]

[1478] TM-448 [1 (3 ((((S) 3 amino 4 phenylbutyl)amino)methyl 5 (2 chloropyridin 4 yl)phenoxy) 3 (pyrrolidin 1 yl propan 2 ol] (2 8 mg, 57%) was synthetized following General ProcedureA, B, C.1, D; Purification: HPLC prep / MS (HjO: ACN: MeOH, 0.1% Formic Acid)

[1479] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 2.1 H, HCO2H), 8 42 (d, 1H, J = 5 6 Hz, HarCm), 7 76 (d, 1 H J = 1 0 Hz, Harom), 7

[1480]

[1481] 66 (dd, 1H J = 5 3, 1 6 Hz, Harom), 7 40 (s, 1H, Harom), 7 37-7 30 (m, 3H, Harm), 7 29-7 24 (m, 3H, Harem), 7 18 (s, 1H, Harom), 4 40-4 31 (m, 1H), 4 13 (d, 2H, J = 5 0 Hz), 4 00 (bs, 2H), 3 59-3 51 (m, 1H), 3 46-3 38 (m, 6H), 3 02-2 80 (m, 4H), 2 17-2 06 (m, 4H), 2 82-1 97 (m, 2H)

[1482] 13C NMR ( 101 MHz, CDjOD) 8 (ppm) 170.1 (HCO2H), 161 0 (Cq), 153 1 (Cq), 152 8 (Cq), 151 1 (CHarom), 139.9 (Cq), 139 7 (Cq), 137 2 (Cq), 130 4 (CH arom ), 130 1 (CH arom ), 128 4 (CH arom ), 123 2 (CH arom ), 122 1 (CH arom ), 121 8 (CH arom), 1 17 7 (CHarom), 1 14 4 (CHarom), 71.5 (CH2), 66.7 (CH), 58.6 (CH2), 55.6 (CH2), 53.4 (CH), 52.9 (CH2), 46.2 (CH2), 40.9 (CH2), 31.3 (CH2), 23.9 (CH2)

[1483] HRMS (ESI+): m / z calculated for C29H38ClN4O2[M+H]+: calc 509.2678; found: 509.2690

[1484] EXAMPLE 141: TM-450

[1485]

[1486] TM-450 [3'-chloro-5-(((4-hydroxyphenethyl)amino)methyl)-2'-metiyl-[1, T-biphenyl]-3-ol] (9 2 mg, 29%) was synthetized following General Procedure A, B, C.1; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1487] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.55 (s, 1,1H, HCO2H), 7 37 (dd, 1H, J = 1 1 Hz, J = 7 9 Hz, Harom), 7 20 (t, 1H, J - 7 8 Hz, Harem), 7.1 1 (dd, 1H, J = 1 1 Hz, J = 7 6 Hz, Haram), 7 06-7 00 (m, 2H, Haram), 6 86-6 83 (m, 1H, Harem), 6 78-6 76 (m, 1H, Harom), 6 75-6 71 (m, 2H, Harem), 6 70 (dd, 1H, J = 1 5 Hz, J = 2 2 Hz, HarOm), 3 97 (bs, 2H), 3 02 (dd, 2H, J = 6 9 Hz, J = 8 6 Hz), 2 82 (dd, 2H, J = 6 9 Hz, J = 8.6 Hz), 2 25 (s, 3H)13C NMR ( 101 MHz, CD3OD) 5 (ppm) 159.0 (Cq), 157 4 (Cq), 145.1 (Cq), 144 7 (Cq), 136 2 (Cq), 134.5 (Cq), 130 7 (CHar™), 129 3 (CH arom ), 129 2 (CH arom ), 127 7 (CH atom ), 121 9 (CH arom ), 1 17 2 (CH atom ), 116.5 (CH arom ), 116 1 (CH arom ), 53.1 (CH2), 50 7 (CH2), 33 9 (CH2), 18 0 (CH3).

[1488] HRMS (ESI+): m / z calculated for C22H23ClNO2[M+H]+: calc 368.1412; found: 368.1409

[1489] EXAMPLE 142: TM-451

[1490]

[1491] TM-451 [1 -(3-((((S)-3-amino-4-phenylbutyl)ammo)methyl)-5-(5 -metiylfuran-2-yl)phenoxy)-3-(azepan-1-yl)propan-2-ol] (7 3 mg, 6.5%) was synthetized following General ProcedureA, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1492] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.48 (s, 1.6H, HCO2H), 7 38-7 32 (m, 3H, Harcfn), 7 31-7 22 (m, 4H, Harom), 7 00 (bs,

[1493]

[1494] 1H, Harom), 6 72 (d, 1H, J = 3 2 Hz, Harom), 6 13 (dd, 1 H, J = 1 2 Hz, J = 3 3 Hz, Harm), 4 46-4 38 (m, 1H), 4 13-4 05 (m, 4H), 3 64-3 57 (m, 1H), 3 51-3 42 (m, 5H), 3 30-3 26 (m, 1H), 3 19-3 10 (m, 1H), 3 10-3 02 (m, 1H), 2 99 (dd, 1H, J = 6 7 Hz, J = 13.9 Hz), 2 93 (dd, 1H, J = 7 7 Hz, J = 13 9 Hz), 2 35 (s, 3H), 2 10-2 01 (m, 2H), 2 00-1 90 (m, 4H), 1 81-1 71 (s, 4H)

[1495] 13C NMR ( 101 MHz, CD3OD) 5 (ppm) 160.7 (Cq), 153 8 (Cq), 152.5 (Cq), 136.8 (Cq), 135.7 (Cq), 134 6 (Cq), 130.5 (CHaro„), 130 1 (CH arom ), 128 6 (CH arom ), 118 4 (CH arom ), 114.9 (CH arom ), 1 11 1 (CH arom ), 109.1 (CH arom ), 108.5 (CH arom ), 71 5 (CH2), 65 6 (CH), 60 2 (CH2), 56 4 (CH2), 52 5 (CH), 52 3 (CH2), 45 3 (CH2), 40 3 (CH2), 30 5 (CH2), 27 8 (CH2), 24 2 (CH2), 13.5 (CH3)

[1496] HRMS (ESI+): m / z calculated for C31H44N3O3[M+H]+: calc 272.6985; found: 272.6990

[1497] EXAMPLE 143: TM-452

[1498]

[1499] TM-452 TM-452 [1-(3-(((3-(((S)-2-amino-3-(4-(tnfluoromethyl)phenyl)propyl)amino)propyl)(methyl)amino)methyl)-5-(5-methylfuran -2-yl)phenoxy)-3-(azepan-1-yl)propan-2-ol] (12 3 mg, 8 9%) was synthetized following General Procedure A, B, C.1, D, C.4, D, Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1 % Formic Acid)

[1500] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.51 (s, 1 9H, HCO2H), 7 64 (d, 2H, J = 8 0 Hz, Harm), 7 44 (d, 2H, J = 8 0 Hz, Harom), 7 33 (s, 1 H, Harom), 7 22 (bs, 1H, Harom), 6 92 (bs, 1H, Harom), 6 69 (d, 1H, J = 3 2 Hz, Harom), 6 12 (dd, 1 H, J = 1 0 Hz, 7 = 3 2 Hz, Harem), 4 43-4 36 (m, 1H), 4 08 (d, 2H, 7 = 4 6 Hz), 3 88 (bs, 2H), 3 48-3 38 (m, 5H), 3 40-3 33 (m, 1H), 3 30-3 22 (m, 1H), 3 08-2 96 (m, 1H), 2 95-2 84 (m, 5H), 2 84-2 65 (m, 2H), 2 49 (s, 3H), 2 34 (s, 3H), 2 01 -1 85 (m, 6H), 1 81-1 70 (m, 4H)

[1501] 13C NMR (101 MHz, CD3OD) 6 (ppm) 169.8 (HCO2H), 160 6 (Cq), 153 7 (Cq), 152 7 (Cq), 142 7 (Cq), 137 8 (Cq), 134 4 (Cq), 131 1 (CHarom), 130 4 (q, J = 32 2 Hz, Cq), 126 7 (q, 7 = 3 8 Hz, CHarom), 125 7 (q, 7 = 271 0 Hz, Cq), 118 9 (CHarom), 1 15 7 (CHarom), 110 3 (CHarom), 109 1 (CHarom), 108 3 (CHarOm), 71 4 (CH2), 65 7 (CH), 62 2 (CH2), 60 2 (CH2), 56 4 (CH2), 56 0 (CH2), 52 5 (CH), 52 1 (CH2), 48 1 (CH2), 41 2 (CH3), 40 0 (CH2), 28 0 (CH2), 25 2 (CH2), 24 2 (CH2), 13 6 (CH3).

[1502] 19F NMR (377 MHz, CDCl3) 6 (ppm) -64.0 (s, 3F).

[1503] HRMS (ESI+): m / z calculated for C33H46N3O2[M+H]+: calc 516.3585; found: 516.3589

[1504] EXAMPLE 144: TM-456

[1505] ' N

[1506] •H

[1507] TM-456

[1508]

[1509] TM-456 [1 ((5 ((((S) 3 amino 4 (4 fluorophenyl)butyl)amino)methyl) 4' propyl [1,1' biphenyl] 3 yl)oxy) 3 (1,4 dioxa 8 aza spiro

[0045] decan-8-yl)propan-2-ol] (18 4 mg, 7 4%) was synthetized following General Procedure A, B, C.1, D, Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)

[1510] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.20 (s, 0.9H, HCO2H), 7 58 (d, 2H, J = 8 3 Hz, HarCm), 7 43- 7 40 (m, 1H, Harom), 7

[1511]

[1512] 37-7 32 (m, 2H, Harem), 7 29-7 26 (m, 3H, Harom), 7 24-7 21 (m, 1H, Harem), 7 11-7 05 (m, 2H, Harem), 4 48 (dtd, 1H J = 2 9 Hz, J = 4 9 Hz, J = 7 8 Hz), 4 26 (bs, 2H), 4 16 (d, 2H, J = 5 0 Hz), 4 02 (bs, 4H), 3 71-3.64 (m, 1H), 3 57-3 48 (m, 4H), 3 48 (dd, 1H, J = 2 9 Hz, 7 = 13 3 Hz), 3 37 (dd, 1H, 7 - 10 4 Hz, 7 = 13 3 Hz), 3 30-3 24 (m, 1 H), 3.22-3.13 (m, 1H), 2 99 (d, 2H, J = 7.2 Hz), 2 63 (t, 2H, J = 7.5 Hz), 2 15 (dd, 2H, J = 7.8 Hz, J = 14 3 Hz), 2 1 1- 1 98 (m, 4H), 1.73-1 62 (m, 2H), 0 96 (t, 3H 7 = 7.4 Hz)

[1513] 13C NMR ( 101 MHz, CD3OD) 6 (ppm) 166.1 (HCOjH), 163 7 (d, Cq, J = 244 7 Hz. CF), 160 7 (Cq), 144 9 (Cq), 143 9 (Cq), 138 5 (Cq), 134 3 (Cq), 132 5 (d, J = 3 2 Hz, Cq), 132 4 (d, J = 8 2 Hz, CHarom), 130.1 (CHaram), 127.9 (CHarara), 122.4 (CHarom), 1170 (CHarom), 1167 (CHarom), 1157 (CHarom), 1153 (CHarom), 1050 (Cq), 71 5 (CH2), 659 (CH2), 655 (CH), 595 (CH2), 525 (CH2), 51 8 (CH), 450 (CH2), 390 (CH2), 386 (CH2), 33 1 (CH2), 302 (CH2), 257 (CH2), 14 1 (CH3)19F NMR (377 MHz, CDCh) 5 (ppm) -116.96 (s, 3F).

[1514] HRMS (ESI+): m / z calculated for C35H51N3O2[M+2H]2+: calc 272.6985; found: 272.6990

[1515] EXAMPLE 145: TM-457

[1516] O

[1517] 11

[1518] H^^Oh

[1519] 005 equiv

[1520] H

[1521] HrN. N

[1522]

[1523] TM-457

[1524] TM-457 [1-((5-((((S)-3-amino-4-(4-f1uorophenyl)butyl)amino)methyl -4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(6-oxa-2,9-diaza spiro

[0045] decan-2-yl)propan-2-ol] (147 mg, 8%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: AON: MeOH, 0.1% Formic Acid).

[1525] 1H NMR (400 MHz, CD3OD) 5 (ppm) 7.58 (d, 2H, J = 82 Hz, Harcni), 742-739 (m, 1H, Harom), 736-731 (m, 2H, Harom), 730-726 (m, 3H, Harcni), 724-7.22 (m, 1H, Harom), 7.11-7.06 (m, 2H, Haram), 446-437 (m, 1H), 427 (bs, 2H), 4.21-4 14 (m, 2H), 406-401 (m, 2H), 3 96-3 81 (m, 1H), 3 71-3 58 (m, 3H), 3 58-3 44 (m, 4H), 3 31-3 23 (m, 3H), 322-3 12(m, 1H), 3 00 (bs, 1H), 298 (bs, 1H), 264 (m, 2H), 248 (bs, 1H), 2 15 (dd, 2H, J= 73 Hz, J = 147 Hz), 1 68 (m, 2H), 096 (t, 3H, J = 74 Hz)

[1526] 13C NMR (101 MHz, CD3OD) 6 (ppm) 163.7 (d, J = 2448 Hz, Cq), 1607 (Cq), 1450 (Cq), 1440 (Cq), 1385 (Cq), 1342 (Cq), 1324 (d, J = 3.2 Hz, Cq), 1324 (d, J = 8 1 Hz, CHaron), 130 1 (CHarom), 1280 (CHarom), 1225 (CHarom), 116.9 (d, J = 21.7 Hz, CHarom), 115.7 (d, J = 1 6 Hz, CHarom), 1153 (d, J = 3 3 Hz, CHarom), 798 (Cq), 71 4 (CH2), 665 (d, J = 297 Hz, CH), 600 (d, J = 66 Hz, CH2), 525 (CH2), 51 8 (CH), 450 (CH2), 43 5 (CH2), 389 (CH2), 386 (CH2), 302 (CH2), 257 (CH2), 14 1 (CH3)

[1527] 1BF NMR (377 MHz, CDCl3) 5 (ppm) -116.9 (s, 3F).

[1528] HRMS (ESI+): m / z calculated for C36H50FN4O3[M+H]+: calc 605.3861; found: 605.3868 EXAMPLE 146: TM-462

[1529]

[1530] TM-462 [1-((5-((((R)-3-amino-4-(4-fluorophenyl)butyl)amino)methyl)-4'-propyl-[1, T-biphenyl]-3-yl)oxy)-3-(azepan-1-yl) pro pan-2-ol] (11 5 mg, 12%) was synthetized following General Procedure A, B, C.1, D; Punfication: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)

[1531] 1H NMR (400 MHz, CD3OD) 6 (ppm) 8.29 (s, 1.8H, HCO2H), 757 (d, 2H, J = 82 Hz, Harom), 738 (t, 1H, J = 1.4 Hz, Harom), 735-726 (m, 5H, Harom), 7 19-7 17 (m, 1H, Harc(tl), 7 11-708 (m, 2H, Harom), 444 (dtd, 1H, J= 29 Hz, J = 49 Hz, J = 76 Hz), 423 (bs, 2H), 4 14 (d, 2H, J = 50 Hz), 3 68-359 (m, 1H), 3 52 (dd, 1H, J = 28 Hz, J = 132 Hz), 350-342 (m,4H), 3 35-3 29 (m, 1H), 328-3 21 (m, 1H), 3 19-3 10 (m, 1H), 297 (d, 2H, J= 72 Hz), 264 (t, 2H, J= 75 Hz), 2 15-208 (m, 2H), 2 / 00-1 90 (m, 4H), 1 81-1 73 (m, 4H), 1 67 (dq, 2H, J = 74 Hz, J = 147 Hz), 096 (t, 3H, J = 74 Hz)

[1532] 13C NMR (101 MHz, CD3OD) 3 (ppm) 169.3 (HCO2H), 163 7 (d, J- 2447 Hz, Cq), 1608 (Cq), 1449 (Cq), 1439 (Cq), 1386 (Cq), 1346 (Cq), 132 5 (d, J= 3 3 Hz, Cq), 1324 (d, J= 8 1 Hz, CHarom), 130 1 (CHarom), 1279 (CHarom), 1223 (CHar™), 1168 (d, J = 21 6 Hz, CHar01n), 1156 (CHarOm), 1152 (CHarom), 71 5 (CH2), 656 (CH), 60 1 (CH2), 564 (CH2), 525 (CH2), 51 9 (CH), 450 (CH2), 39.1 (CH2), 386 (CH2), 302 (CH2), 280 (CH2), 257 (CH2), 24 1 (CH2), 14.1 (CH3).

[1533] 19F NMR (377 MHz, CDCh) 3 (ppm) -117.0 (s, 1 F).

[1534] HRMS (ESI+): m / z calculated for C35H49FN3O2[M+H]+: calc 562.3803; found: 562.3811

[1535] EXAMPLE 147: TM-463

[1536]

[1537] TM-463 [1-((5-((((S)-3-amino-4-phenylbutyl)amino)methyl)-4'-propyl-[1,1'-biphenyl]-3-yl)oxy)-3-morpholinopropan-2-ol] (64 mg, 8%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0.1% Formic Acid)1H NMR (400 MHz, CD3OD) 6 (ppm) 8.49 (s, 1 5H, HCO2H), 7 54 (dd, 2H, J = 2 0 Hz, J = 8.2 Hz, 7 36-7 21 (m, 8

[1538]

[1539] H, 7 21-7 16 (m, 1H, 7 00-6 93 (m, 1H, 4 23-4 15 (m, 1 H), 4 15-3 94 (m, 4H), 3 72 (t, 4H, J = 4 3 Hz), 3 07 (dd, 1 H, J = 5 4 Hz, J = 13 5 Hz), 3 02-2 87 (m, 2H), 2 80-2 57 (m, 10H), 1 95-1 76 (m, 2H), 1 73-1 63 (m, 2H), 0 96 (t, 3H, J = 7 3 Hz)

[1540] 13C NMR (101 MHz, CD3OD) 5 (ppm) 169.7 (HCO2H), 161 2 (Cq), 144 7 (Cq), 143 7 (Cq), 139.1 (Cq), 137 6 (Cq), 137 3 (Cq), 130 4 (CH arom ), 130 3 (CH arom ), 130 1 (CH arom ), 128 4 (CH arom ), 128.3 (CH arom ), 127 9 (CH arom ), 121 3 (CH arom ), 114 9 (CHarom), 1 14.2 (CHaram), 72 0 (CH2), 67 8 (CH), 67 5 (CH2), 62 4 (CH2), 61 7 (CH), 55 3 (CH2), 41 2 (CH2), 38 6 (CH2), 38 5 (CH2), 28 7 (CH2), 25 7 (CH2), 14 1 (CH3)

[1541] HRMS (ESI+): m / z calculated for C35H51N3O2[M+2H]2+: calc 272.6985; found: 272.6990

[1542] EXAMPLE 148: TM-464

[1543] H 'OH 0.1 equiv.

[1544] H

[1545] , N ‘o' Y i OH TM-464

[1546] TM-464 [1-((5-((((S)-3 -amino-4-pheny Ibutyl) amino)methy I) - 4' -propyl -[ 1, 1 '- bip h e ny I] -3-yl) oxy)-3 -(4-methylpiperazin - 1 -yl)pro pan 2 ol] (15 2 mg, 6%) was synthetized following General Procedure A, B, C.1, D; Purification: HPLC prep / MS (H2O: ACN: MeOH, 0 1% Formic Acid)1H NMR (400 MHz, CD3OD) 5 (ppm) 8.09 (s, 0.1 H, HCO2H), 7 58-7 53 (m, 7 38-7 24 (m, 9H, 7 10-7 06 (m, 1H, Harem), 4 23-4 16 (m, 3H), 4 14 (dd, 1H, J = 4 1 Hz, J = 9 7 Hz), 4 07 (dd, 1 H, J = 5 7 Hz, J = 9 7 Hz), 3 69-3 59 (m, 1H), 3 33-3 17 (m, 4H), 3 15-3 12 (m, 1H), 3 12-3 04 (m, 1H), 3 00 (dd, 2H, J = 6 7 Hz, J = 14 2 Hz), 2 95 (dd, 2H, J = 7 8 Hz, J= 14 2 Hz), 2 84 (s, 3H), 2 84-2 72 (m, 3H), 2 69-2 60 (m, 3H), 2 10 (q, 2H, J = 7 6 Hz), 1 68 (dq, 2H, J= 7 4 Hz, J = 14 8 Hz), 0 96 (t, 3H, J = 7 4 Hz)13C NMR ( 101 MHz, CD3OD) 5 (ppm) 161.2 (Cq), 145 0 (Cq), 144 0 (Cq), 138 7 (Cq), 136 4 (Cq), 134 0 (Cq), 130 4 (CH a™),

[1547]

[1548] 130 3 (CH arom ), 130 1 (CH arom ), 128 8 (CH arom ), 128 0 (CH arom ), 122 0 (CH arom ), 115 4 (CH arom ), 115 3 (CH arom ), 71 8 (CH2), 68 1 (CH), 60 7 (CH2), 54 5 (CH2), 52 5 (CH2), 51 8 (CH), 45 0 (CH2), 43 7 (CH3), 39 9 (CH2), 38 6 (CH2), 30 2 (CH2), 25 7 (CH2), 14.1 (CH3).

[1549] HRMS (ESI+): m / z calculated for C35H51N3O2[M+2H]2+: calc 272.6985; found: 272.6990

[1550] EXAMPLE 149: Chemistry, breath of antibacterial activity, in vivo efficacy and inhibition of various bacteria and mitochondrial ATP synthases

[1551] Tables l-IX summarize the antibacterial spectrum of compounds of the disclosure against Gram-negative and Gram- positive bacterial species including Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and other Klebsiella species, as well as Acinetobacter baumannii and Pseudomonas aeruginosa, all of which representing important bacterial pathogens identified by the World Health Organization (WHO, 2017) and the Center for Disease Control and Prevention (CDC, 2019), and for which new treatments are critically needed

[1552] These tables present the following characteristics of compounds of the present disclosure: molecular weight (MW); hydrophilicity in terms of logP value (ClogP), i e, logarithm of the compound’s partition coefficient between n-octanol and water log(c_octand / c_water); Minimum inhibitory concentrations (MICs) (i e, lowest concentration of compound that will inhibit the visible growth of a microorganism after overnight incubation) against Gram-negative and Gram-positive bacterial strains including antibiotic-resistant, and multiple resistant strains thereof Gram-negative bacterial strains: E. coli strains, including wild type reference strains ATCC25922 and MC4100; the efflux pump mutant strain MC4100 AcrAB; and outer membrane-compromised hyperpenneable mutant strain MC4100 imp4213 IptD, (see e g, Tables l-ll, VII), Pseudomonas aeruginosa strains (see e g, Tables I, VII), Klebsiella spp (see e g, Table IV), Acinetobacter baumannii (see e g, Table V) Gram-positive bacterial strains: Staphylococcus strains (see e g, Tables I, VI-VI II), Enterococcus (see e g, Table VI), Streptococcus (see e g., Table VI), Bacillus strains (see e g, Table VI), and Listeria strains (see e g, Table VI) Affinity for E. coli ATP synthase (A TPs) in terms of e g, half-maximal inhibitory concentration (IC50), was also determined (see e g, Table I, Table VII, FIGs 2, 4A-B, 6)

[1553] The strain of E co / iMC4100 imp4213 is used to test compounds’ biological activity because it has a mutation in the / ptD gene (LPS assembly precursor), resulting in an outer membrane permeability defect and thus hyper-susceptibility to a variety of antibiotics, including large molecules such as vancomycin, which would otherwise be inactive against Gramnegative bacteria due to the lack of outer membrane penetration The use of this mutant strain allows a better understanding of both penetration and target affinity in the whole cell context MC4100 AcrAB, a strain ofE. coli in which the AcrAB efflux pump was deleted was also used This facilitated the identification of compounds that may be susceptible to efflux Compounds that are susceptible to efflux or influenced by membrane permeability may not perform as effectively against clinical isolates of Gram-negative bactena Few compounds disclosed herein were found to be affected by either efflux or membrane permeability or both by looking at the MIC ratio for efflux (MIC strain MC4100 / MIC strain AcrAB) or the MIC ratio for permeability (MIC strain MC4100 / MIC strain imp4213 IptD) In specific embodiments, compounds with MIC ratios of < 4 were considered not susceptible to these undesirable effects. See e g, TM-336, TM-381, TM-387 and TM-397 EXAMPLE 150: Antibacterial activities of compounds of the disclosure

[1554] Table I: Antibacterial activities (MIC) of compounds of the disclosure against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa strains, and relative affinity for the bactenal ATP synthase from E coir

[1555] p.

[1556] E. coli S. aureus

[1557] E. coli MC4100 E. coli MC4100 S. aureus aeruginosa

[1558] ATCC E, co / i MC4100 ATCC 29213 E. coliATPs IC50 (pM)

[1559] AcrAB imp4213 iptO ATCC 29213 ATCC

[1560] 25922 hemB

[1561] 27853

[1562] MW

[1563] com pound CLogP Broth Microdilution MIC (pjg / mL)

[1564] (g / mol)

[1565] TM-01 3505 273 >128 >128 >128 >128 >128 64a* >128 >60

[1566] TM-167 4907 434 >128 >128 >128 128 128 >128 nd

[1567] TM-168 4146 1 85 >128 >128 >128 >128 >128 >128 nd

[1568] TM-169 5037 495 >128 >128 >128 128 128 >128 nd

[1569] TM-199 5067 400 >128 >128 >128 >128 >128 >128 nd

[1570] TM-200 3965 1 88 >128 >128 >128 >128 >128 >128 nd

[1571] TM-201 5197 470 >128 >128 >128 >128 >128 >128 nd

[1572] TM-203 5267 501 >128 >128 >128 >128 128 >128 nd

[1573]

[1574] TM-204 5277 384 >128 >128 >128 >128 >128 >128 nd

[1575] TM-205 501.6 327 >128 >128 >128 >128 >128 >128 nd

[1576] TM-206 5327 592 >128 >128 32 >128 64 >128 3 7

[1577] TM-207 5397 561 >128 >128 128 128 >64 >128 nd

[1578] TM-214 5527 572 >64 >64 32 64 64 >64 2 8

[1579] TM-215 5658 632 >64 >64 64 32 64 >64 1 6

[1580] TM-225 4907 373 >128 >128 >128 >128 >128 >128 nd

[1581] TM-226 5547 242 >128 >128 >128 >128 >128 >128 nd

[1582] TM-227 5206 402 >128 >128 >128 >128 >128 >128 nd

[1583] TM-228 5427 405 >128 >128 >128 >128 >128 >128 nd

[1584] TM-229 5336 285 >128 >128 >128 >128 >128 >128 nd

[1585]

[1586] TM-231 531.8 600 64 64 64 16 64 >128 175 P.

[1587] E. coli S. aureus

[1588] E. coli MC4100 E. coli MC4100 S. aureus aeruginosa

[1589] ATCC E. coJiMC4100 ATCC 29213 E. coliATPs ICso (pM)

[1590] AcrAB imp4213 IptO ATCC 29213 ATCC

[1591] 25922 hemB

[1592] 27853

[1593] TM-232 7280 972 >128 >128 >128 >128 16 >128 1 0

[1594] TM-249 5858 632 >128 >128 64 32 >128 >128 nd

[1595] TM-250 5658 632 >128 >128 64 32 64 >128 nd

[1596] TM-251 551.7 580 128 128 64 32 64 >128 nd

[1597] TM-252 551.7 580 256 256 128 64 128 >128 nd

[1598] TM-253 551.8 581 64 128 32 32 64 256 nd

[1599] TM-254 5527 570 >128 >128 64 128 64 >128 nd

[1600] TM-265 482.66 329 >512 >512 >512 >512 >512 >512 >60

[1601] TM-266 496.68 383 >512 >512 >512 >512 >512 >512 >60

[1602] TM-267 4687 587 >128 >128 128 32 128 >512 2 7

[1603] TM-279 5545 478 >128 >128 128 >128 >128 >128 nd

[1604] TM-280 5545 478 >128 >128 128 64 >128 >128 nd

[1605] TM-281 5545 428 >128 >128 >128 >128 >128 >128 nd

[1606] TM-292 468.7 6.17 128 128 32 8 64 >512 0 6

[1607]

[1608] TM-298 4263 461 >128 >128 >128 >128 >128 >512 nd

[1609] TM-311 4687 604 >128 >128 128 32 128 >128 nd

[1610] TM-312 4566 457 >128 >128 >128 >128 >128 >128 nd

[1611] TM-313 4446 479 >128 >128 >128 >128 >128 >128 nd

[1612] TM-314 4276 322 >128 >128 >128 >128 >128 >128 nd

[1613] TM-316 4332 327 >128 >128 >128 >128 >128 >128 nd

[1614] TM-317 4706 2 13 >128 >128 >128 >128 >128 >128 nd

[1615] TM-318 4276 322 >128 >128 >128 >128 >128 >128 nd

[1616] TM-319 4426 398 >128 >128 >128 >128 >128 >128 nd

[1617] TM-320 4266 431 >128 >128 >128 >128 >128 >128 nd

[1618] TM-321 4687 531 >128 >128 >128 >128 >128 >128 nd

[1619]

[1620] TM-324 4266 431 >128 >128 >128 >128 >128 >128 nd P.

[1621] E. coli S. aureus

[1622] E. coli MC4100 E. coli MC4100 S. aureus aeruginosa

[1623] ATCC E. coJiMC4100 ATCC 29213 E. coliATPs ICso (pM)

[1624] AcrAB imp4213 IptO ATCC 29213 ATCC

[1625] 25922 hemB

[1626] 27853

[1627] TM-328 4266 431 >128 >128 >128 >128 >128 >128 nd

[1628] TM-329 313.2 454 >256 >256 64 64 32 >256 nd

[1629] TM-336 668.87 980 4 4 4 4 4 2 64 1.6

[1630] TM-337 4677 625 32 32 32 8 16 8 128 8 9

[1631] TM-338 4827 670 128 128 32 8 32 16 >128 nd

[1632] TM-340 4827 657 128 >128 32 8 32 32 >128 nd

[1633] TM-341 4667 556 >128 >128 128 32 128 128 >128 nd

[1634] TM-342 / TM-364 4947 668 128 256 16 8 16 16 >128 0 6

[1635] TM-343 4946 555 >256 >256 128 32 256 64 >256 nd

[1636] TM-344 4656 404 >128 >128 >128 >128 >128 >128 >128 nd

[1637] TM-345 4547 564 >128 >128 >128 64 >128 64 >128 nd

[1638] TM-346 4687 604 >128 >128 128 32 >128 128 >128 nd

[1639] TM-347 4547 556 >128 >128 >128 64 >128 >128 >128 nd

[1640] TM-348 4807 6 19 >128 >128 64 32 128 64 >128 nd

[1641]

[1642] TM-349 4547 561 >128 >128 >128 64 >128 >128 >128 nd

[1643] TM-350 4967 694 64 64 16 8 8 8 >128 0 7

[1644] TM-351 5388 827 128 128 32 16 16 16 >128 1 2

[1645] TM-354 452.61 623 32 16 16 16 16 4 32 nd

[1646] TM-355 312.5 460 32 32 32 16 16 4 64 nd

[1647] TM-359 / TM-360 4687 505 >128 >128 64 32 64 32 >128 nd

[1648] TM-361 3134 417 64 128 32 32 32 16 >256 nd

[1649] TM-365 / TM-339 4964 723 64 16 nd 8 16 8 >128 nd

[1650] TM-372 4425 538 16 >128 16 4 8 2 >128 nd

[1651] TM-373 3405 569 16 32 16 16 16 2 64 nd

[1652] TM-374 3826 672 16 16 8 8 16 8 32 nd

[1653] TM-375 3385 5 13 16 32 16 16 16 4 32 9 1

[1654]

[1655] TM-376 5838 797 64 >128 >128 32 16 2 >128 1 9 P.

[1656] E. coli S. aureus

[1657] E. coli MC4100 E. coli MC4100 S. aureus aeruginosa

[1658] ATCC E. co / i MC4100 ATCC 29213 E. coliATPs ICso (pM)

[1659] AcrAB imp4213 IptO ATCC 29213 ATCC

[1660] 25922 hemB

[1661] 27853

[1662] TM-377 5397 637 8 8 8 4 8 2 >128 2.3

[1663] TM-378 7390 987 8 8 8 4 4 2 64 1.9

[1664] TM-379 4937 676 16 16 16 8 8 4 64 3.3

[1665] TM-380 4957 731 8 8 8 4 4 2 32 3.6

[1666] TM-381 6949 828 4 8 8 4 8 4 128 1.6

[1667] TM-382 5378 835 8 8 8 4 8 8 32 1.9

[1668] TM-386 5308 577 64 64 32 8 16 16 >128 2.2

[1669] TM-387 5438 760 8 8 8 4 4 2 64 1.7

[1670] TM-389 6969 883 8 8 16 8 8 4 64 1.5

[1671] TM-390 354.5 620 >128 >128 >128 >128 8 8 >128 13 1

[1672] TM-391 5097 780 >128 >128 >128 64 8 8 >128 5 3

[1673] TM-392 5977 700 16 16 16 8 4 4 128 4.5

[1674] TM-393 5977 760 64 64 64 32 32 16 >128 8.8

[1675] TM-394 5438 765 16 32 8 8 4 4 128 1.2

[1676]

[1677] TM-395 569.8 8.11 32 16 8 4 4 4 32 2.1

[1678] TM-396 6697 872 4 4 4 2 4 2 >16 1.9

[1679] TM-397 561.8 774 4 8 4 2 2 1 32 1.9

[1680] TM-398 5888 735 8 8 8 2 2 2 32 1.9

[1681] TM-399 5157 655 64 64 64 16 16 8 >128 1.9

[1682] TM-400 4877 543 >128 >128 64 32 32 32 >128 3 9

[1683] TM-401 6408 671 32 16 8 4 8 4 >128 1 1

[1684] TM-402 6128 560 64 32 16 8 16 8 >128 3 1

[1685] TM-404 425.6 416 >128 >128 >128 >128 >128 >32 >128 269

[1686] TM-405 6338 668 >128 >128 16 16 32 16 >128 1 0

[1687] TM-406 501.7 650 64 128 16 8 16 8 >128 1 3

[1688]

[1689] TM-407 5438 704 16 16 8 4 4 2 64 1 5 32

[1690]

[1691]

[1692] P.

[1693] E. coli S. aureus

[1694] E. coli MC4100 E. coli MC4100 S. aureus aeruginosa

[1695] ATCC E. COHMC4100 ATCC 29213 E. coliATPs ICso (pM)

[1696] AcrAB imp4213 IptO ATCC 29213 ATCC

[1697] 25922 hemB

[1698] 27853

[1699] TM-435 4366 405 >128 >128 128 32 >128 >128 >128 209

[1700] TM-436 4456 377 128 128 64 32 128 64 >128 5 3

[1701] TM-437 4897 488 >128 >128 >128 >128 >128 >128 >128 309

[1702] TM-438 500.1 482 128 >128 32 16 64 32 >128 0 7

[1703] TM-439 509.1 580 32 64 16 8 16 16 >128 0 7

[1704] TM-440 495.1 560 32 64 16 8 16 16 >128 0 6

[1705] TM-441 5147 634 64 64 16 8 8 8 >128 nd

[1706] TM-442 541.7 660 32 16 16 4 8 8 128 nd

[1707] TM-443 6668 678 16 16 8 4 8 8 128 3 3

[1708] TM-444 5707 568 128 >128 64 16 64 64 >128 48

[1709] TM-445 6958 585 32 32 16 8 16 16 >128 nd

[1710] TM-446 5257 534 >128 >128 nd 64 32 nd >128 nd

[1711] TM-447 5546 442 >128 >128 nd 128 >128 nd >128 nd

[1712] TM-448 509.1 433 >128 >128 nd 128 >128 nd >128 >600

[1713]

[1714] TM-450 3679 5 13 128 >128 nd 8 16 nd >128 nd

[1715] TM-451 5057 593 128 128 nd 16 32 nd >128 176

[1716] TM-452 630.8 6.10 32 32 nd 8 16 nd >128 Nd

[1717] TM-456 6058 576 8 4 4 2 4 1 32

[1718] TM-457 6048 545 16 8 4 4 4 2 32

[1719] TM-462 561.8 775 2 4 4 1 2 0 5 16

[1720] TM-463 531.7 583 8 8 8 4 8 4 64

[1721]

[1722] TM-464 5448 490 16 32 16 8 8 4 128

[1723] 3MIC forS aureus ATCC 29740 tiemB EXAMPLE 151: Effect of efflux and permeability on the susceptibility of Escherichia coli

[1724] The antibiotic discovery process for Gram-negative bacteria needs to consider activity (MIC) but also the bacterial outer membrane permeability barrier and presence of defensive efflux pump systems Although certain compounds demonstrated a strong affinity for the ATP synthase enzyme target (indicated by a low IC50 value, as shown in Table I), their activity appeared to be diminished due to the permeability barrier, efflux, or a combination of both factors Indeed, the inventors considered that a decrease of >8-fold in the observed MIC for the AcrAB pump mutant or forthe imp4213 IptD hyperpermeable mutant, respectively, was indicative of compounds that were effluxed or that had difficulties to cross the outer membrane in the wildtype parental E colt strain MC4100 FIG 2 shows that there is a correlation between inhibition of ATP synthase activity and antibiotic potency against the hyperpermeable E. coli imp4213 IptD mutant (Pearson r2 0.5090, p = 0.0001) The more a compound inhibits ATP synthase (denoted by lower IC50 in FIG 2), the more it is active against the hyperpermeable strain imp4213 IptD (denoted by lower MIC in FIG 2) That correlation was not as good when IC50 values were plotted against the MIC forthe wildtype parental strain (Pearson r2 0.4819, p = 0.0001, data not shown) because several compounds had their MIC impacted by permeability or efflux. A decrease of >8-fold in the observed MIC for the AcrAB pump mutant or for the IptD hyperpermeable mutant, respectively, was indicative of these compounds that were effluxed or that had difficulties to cross the outer membrane in the wildtype parental E. coli strain MC4100 In FIG 2 open triangles correspond to those influenced by efflux, and the X symbols represent those influenced by both efflux and permeability

[1725] Table II below shows more specifically the permeability and efflux effects on the MIC of selected compounds For example, compound TM-292 sees its MIC drop by 4 folds in the pump-deficient mutant AcrAB, and by 16 folds against the hyperpermeable mutant IptD, compared to the MIC recorded for the parental strain MC4100 Since MIC susceptibility tests usually allow a plus or minus two-fold dilution for variability, it was considered that a >8-fold change in the MIC was significant The other TM-compounds presented in Table II below did not see their activity significantly modulated by permeability or efflux (<4-fold change). Besides, examples of antibiotics that are known to have permeability and efflux issues in Gram-negative bacteria are also shown in Table II below, for instance vancomycin, is only active against the hyperpermeable E. coli mutant with a permeability ratio of >512 Table II: Effect of efflux and permeability on the susceptibility of Escherichia coft’ to compounds of the disclosure

[1726] Antibiotic MIC (|jg / ml)

[1727] Bacterial strain Characteristic

[1728] TM-292 TM-336 TM-381 TM-389 TM-387 TM-397 TM-416 ERY VAN

[1729] E coli

[1730] MC4100 Parentstrain 128 4 8 8 8 8 8 128 >128

[1731] MC4100 AcrAB Pump deficient 32 4 8 16 8 4 8 4 >128

[1732] MC4100 IptD Hyperpermeable 8 4 4 8 4 2 4 0.5 025

[1733] Ratio efflux (MIC parent / AcrAB) 4 1 1 0.5 1 2 1 32 1

[1734] Ratio permeability (MIC parent / IptD) 16 1 2 1 2 4 2 256 >512

[1735]

[1736] Table III: Activity of certain compounds of the disclosure against multi-resistant E coli strains

[1737] Antibiotic MIC ( pi g / ml)

[1738] Bacterial strain Characteristic TM TM TM TM TM

[1739] CIP TOB MEM CAZ CST

[1740] 336 381 387 397 416

[1741] E COli

[1742] ATCC 25922 CLSI QC 4 4 8 4 8 003 (S) 025 (S) 006 (S) 0 12 (S) 1 (S)

[1743] ATCC BAA-2471 CRE, NDM-1 4 4 8 4 8 >32 (R) 64 (R) >32 (R) >128 (R) 1 (S)

[1744] 70122 CANWARD ESBL, CTX-M-15 4 4 8 4 8 >32 (R) 64 (R) 006 (S) 64 (R) 1 (S)

[1745] 95882 CANWARD ESBL, KPC 4 8 8 4 8 32 (R) 05 (S) 8 (R) 128 (R) 05 (S)

[1746] 94474 CANWARD mcr-1 4 8 8 4 16 32 (R) 32 (R) 006 (S) 025 (S) 32 (R)

[1747]

[1748] Abbreviations: ATCC, American type culture collection; CLSI, Clinical and laboratory standard institute; CANWARD strains are from Zhanel et al 2010; QC, quality control / reference bactenal strain; NDM-1, carbapenemase; ESBL, extended spectrum beta-lactamase (CTX or KPC); mcr-1, colistin resistance genetic element; reference antibiotic CIP, ciprofloxacin; TOB, tobramycin; MEM, meropenem; CAZ, ceftazidime; CST, colistin; antibiotic susceptibility R, resistant; S, susceptible; I, intermediately resistant The > sign represents the highest concentration tested E coh CLSI MIC breakpoints for resistance: CIP, >4; TOB, >16; MEM, >4; CAZ, >16; CST, £4 pg / ml. EXAMPLE 152: In vitro antibacterial activity against multi-resistant E. coil strains

[1749] Table III above shows that compounds TM-336, 381, 387, 397 and 416 remain active (MIC 4-16 pg / ml) against E. coli strains able to resist multiple classes of traditional antibiotics

[1750] EXAMPLE 153: In vitro antibacterial activity against Klebsiella strains

[1751] The in vitro inhibitory activity of TM-336, -381, -387, -397 and -416 against a variety of resistant and MDR Klebsiella species and strains is also reported in Table IV below

[1752] Table IV Activity of compounds of the disclosure against Klebsiella pneumoniae and other Klebsiella species Klebsiella Characteristic Broth microdilution MIC (pg / mL)

[1753] pneumoniae TM- TM- TM- TM- TM- CAZ MEM CIP CST 336 381 387 397 416

[1754] ATCC 13883 CLSI, QC 16 16 16 8 32 S S S S BAA 2473 CRE, NDM-1 16 8 16 8 32 R R R S BAA 1705 ESBL, KPC-2, SHV 32 16 32 16 32 R R R S ATCC 700603 ESBL, SHV-18, OXA-2 16 16 32 8 32 R R S S Klebsiella spp

[1755] K oxytoca QC 8 8 8 S S S S ATCC 43165

[1756] K oxytoca QC 8 8 16 S S s S ATCC 13182

[1757] K aerogenes QC 16 16 32 S S s s ATCC 35029

[1758]

[1759] Abbreviations: ATCC, American type culture collection; CLSI, Clinical and laboratory standard institute; QC, quality control / reference bacterial strain; NDM-1, carbapenemase; ESBL, extended spectrum beta-lactamase (KPC, SHV or OXA); reference antibiotic CIP, ciprofloxacin; MEM, meropenem; CAZ, ceftazidime; CST, colistin; antibiotic susceptibility R, resistant; S, susceptible; I, intermediately resistant, based on CLSI MIC breakpoints The > sign represents the highest concentration tested

[1760] MIC of 8-32 pg / ml were recorded against those strains

[1761] EXAMPLE 154: In vitro antibacterial activity against Acinetobacter baumannii

[1762] Table V: Activity of certain compounds of the disclosure against Acinetobacter baumannii

[1763] Acinetobacter Characteristic Broth microdilution MIC (µg / mL)

[1764] baumannii

[1765] TM- TM- TM- TM- TM- CAZ CIP GEN MEM TET 336 381 387 397 416

[1766] ATCC 19606 CLSI, QC 8 8 8 4 16 S S R S S ATCC BAA- 1800™ XDR 8 8 16 4 16 R R R R R

[1767]

[1768] ATCC BAA- 1710™ MDR 8 8 8 4 16 R R R S R

[1769]

[1770] CAZ (Ceftazidime), CIP (Ciprofloxacin), GEN (Gentamicin), MEM (Meropenem), TET (Tetracycline), QC (quality control / reference strain); MDR, multi-drug resistant; XDR (Extreme drug resistance); antibiotic susceptibility R, resistant; S, susceptible; I, intermediately resistant, based on CLSI MIC breakpoints

[1771] MIC of 4-16 pg / ml were demonstrated for these compounds against two MDR and extremely resistant (XDR) strains of Acinetobacter baumannii, including the carbapenem-resistant strain BAA- 1800 (Table V)

[1772] EXAMPLE 155: Efficacy of compounds against Gram-positive bacteria

[1773] Table VI: Efficacy of compounds of the disclosure against Staphylococcus aureus, Enterococcus strains, Streptococcus, Bacillus and Listeria strains

[1774] Bacteria Characteristic Broth microdilution MIC (µg / mL)

[1775] TM-336 TM-381 TM-387 CIP MEM VAN Staphylococcus aureus ATCC 29213 CLSI, QC 2 4 4 S S S Staphylococcus aureus ATCC BAA-41 MRSA 4 4 4 R R s Staphylococcus aureus ATCC 700699 Mu50 2 8 8 R R I

[1776] Staphylococcus epidermidis ATCC 12228 QC 2 8 8 S S s Staphylococcus saprophyticus ATCC QC 2 4 4 S S s 15305

[1777] Staphylococcus haemolyticus CDC HIP- MRCoNS 2 4 4 R R I 5979

[1778] Staphylococcus hominis CDC M270 4 4 4 S S s

[1779] Enterococcus faecahs ATCC 29212 CLSI, QC 4 8 8 S - s Enterococcus faecium ATCC 35667 QC 4 4 4 S - s Enterococcus faecium VanA VanA 2 4 4 S - R

[1780] Streptococcus pyogenes ATCC 19615 Group A, QC - 4 8 S - - Streptococcus agalactiae 60440 Group B 2 4 4 S - -

[1781] Bacillus cereus ATCC 11778 QC 8 8 16 - - s Bacillus subtilis ATCC 6633 QC 4 4 4 - - s Bacillus subtilis ATCC 23857 QC 4 4 4 - - s

[1782] Listeria monocytogenes ATCC 13932 QC 4 8 8 s - s

[1783]

[1784] CIP (Ciprofloxacin); MEM (Meropenem); VAN (Vancomycin); Ref (Reference); S (Susceptible); I (intermediate); R (Resistant); QC (quality control / reference strain); MRSA (Methicillin-resistant Staphylococcus aureus), MRCoNS (Methicillin-resistant coagulase-negative Staphylococcus), antibiotic susceptibility R, resistant; S, susceptible; I, intermediately resistant, based on CLSI MIC breakpoints

[1785] Compounds of the disclosure show antibacterial activity (MIC 2-16 ug / ml) against a variety of Gram-positive species and strains (Table VI), including multi-resistant MRSA EXAMPLE 156: Efficacy of compounds against Gram-positive and -negative bacteria

[1786] Table VII: Efficacy of compounds of the disclosure against Staphylococcus aureus, E. coli, and Pseudomonas aeruginosa strains

[1787] Broth microdilution MIC (pg / mL)

[1788] Bacteria Characteristic TM-397 TM-462 TM-456 TM-457 TM-463 TM-464 Staphylococcus aureus ATCC 29213 CLSI QC 2 2 4 4 8 8 Staphylococcus aureus ATCC 29213 A / iemfi SCV, A / iemB 1 0.5 1 2 4 4 Escherichia coli ATCC 25922 CLSI. QC 4 2 8 16 8 16 Escherichia coli MC4100 QC 4 4 4 8 8 32 Escherichia coli MC4100AcrAB AcrAB pump mutant 4 4 4 4 8 16 Escherichia coli MC4100 imp4213 lptD hyperpermeable 2 1 2 4 4 8 Pseudomonas aeruginosa ATCC 27853 CLSI. QC 16 16 32 32 64 128

[1789] Relative affinity for the E coli ATP synthase 1 1.10 0.74 0.74 0.52 0.31

[1790]

[1791] All compounds in a specific SAR around compound TM-397 (Table VII) showed antibacterial activity as measured by MIC The relative affinity for the E coli ATP synthase was calculated by normalizing the IC50 of TM-397 to 1 Certain compounds exhibited noticeable antibacterial activity againstP aeruginosa (MIC 16-32 µg / ml)

[1792] TM-292, TM-336 and TM-387 were capable of rapidly killing 99.9% of the initial inoculum of E coli including the wildtype strain ATCC 25922 and the XDR isolate ATCC BAA-2471. As shown in FIGs. 3B and 3C, TM-336 and TM-387 were rapidly bactericidal at concentrations equal to the broth microdilution MIC against E. coli ATCC 25922 and ATCC BAA-2471, respectively. TM-292 is also bactericidal at a concentration 4 times that of the MIC against E coli ATCC 25922, but it has less activity at lower concentrations (FIG. 3A). This could be due, in part, to the fact that TM-292 is susceptible to bacterial efflux as previously demonstrated in Table II. TM-336, TM-381 and TM-387 are less susceptible to efflux, an intrinsic mechanism of resistance that exists in several bacterial species (Table II).

[1793] An ATP synthase inhibition assay for S. aureus ATCC 29213, E. coli ATCC 25922 and P. aeruginosa ATCC 27853 using bacterial membrane vesicles from each species as the source of enzyme was also used The IC50 determination curves are shown in FIGs 4A B for TM-387 (FIG 4A) and TM-397 (FIG 4B) against the S aureus and E coli ATP synthases The IC50 of TM-387 and TM-397 for S aureus were of 1.01 and 0.93 µM, resulting in MIC of 4 and 2 pig / ml, respectively, whereas the IC50 for E coli were 1.79 and 1.85 µM, resulting in MIC of 8 and 4 pig / ml, respectively The IC50 of TM-387 for the P aeruginosa enzyme was approximately 3-fold higher (3.1 µM), resulting in a MIC of 64 pig / mL

[1794] As shown in FIG 5, enzyme kinetics and constant of inhibition (Ki) were also determined for further assessment of the compounds’ affinity for the E coli bacterial ATP synthase Compounds TM-381, TM-389, TM-415, TM-425 showed Ki between 0.11 and 0.86 µM and were all superior to 4-Chloro-7-nifrobenzofurazan (NBD-CI) in their inhibitory ability, a known ATP synthase inhibitor (Raheem etal, 2019), showing a Ki 1.76 µM in this assay

[1795] EXAMPLE 157: Small colony variants of Staphylococcus aureus

[1796] Table VIII: Efficacy of compounds of the disclosure against small colony variants of Staphylococcus aureus Staphylococcus Characteristic Broth microdilution MIC (pig / mL)

[1797] aureus

[1798] Tomatidine TM-336 TM-381 TM-387 TOB VAN Newbould ATCC Wild type

[1799] >128 4 4 4 0.25-0.5 0.5-1 29740

[1800] Newbould hemB SCV <0.25 4 4 4 >16 2 ATCC 29213 Wild type >128 4 8 4 0.25-0.5 05-1 ATCC 29213 hemB SCV <0.25 2 4 2 16->16 1-2

[1801]

[1802] TOB (Tobramycin), VAN (Vancomycin); QC (quality control / reference strain), SCV (S aureus Small Colony Variant); SaR1-1 and SaR5-1 are SCV tomatidine-resistant mutants selected by serial passage on tomatidine (Lamontagne Boulet etal, 2018) Strain Newbould hemB and ATCC29213 hemB are laboratory-derived SCVs from Brouillette etal (2004) and Cote-Gravel et al (2016), respectively Table VIII shows that compounds of the disclosure exert antibiotic action against wild type as well as S aureus SCV strains (MIC 2-4 pg / ml) whereas tomatidine (another inhibitor of ATP synthase) has no antibiotic activity against wild type strains (Lamontagne Boulet et al, 2018)

[1803] EXAMPLE 158: Compound selectivity compared to that of oligomycin

[1804] The inhibition of the Hep2 mitochondrial ATP synthase was measured The disclosed compounds are designed to specifically target bacterial ATP synthase while minimizing their effect on the human mitochondrial enzyme The IC50 values for these compounds, when tested on bacterial ATP synthases, differ from those for the Hep2 mitochondrial ATP synthase due to significantly different assay conditions (such as ATP synthase concentration, buffers, substrates, and exposure time) Therefore, a direct comparison of these values is not feasible Instead, this example provides the ratio of the IC50 value to that of oligomycin, a widely recognized inhibitor of mitochondrial ATP synthase, as referenced by Symersky et al, 2012 This ratio is determined under identical assay conditions In this assay, TM-292 inhibited this eukaryotic enzyme with an IC50 of 28.7 µM, whereas Oligomycin A, the reference inhibitor of the eukaryotic ATP synthase, showed an IC50 of 0.014 µM (FIG 6)

[1805] Table IX shows the Inhibition of Hep2 mitochondria ATP synthase by compounds of the present disclosure and relative selectivity index vs oligomycin Compounds of the disclosure are at least 300-fold less inhibitory than oligomycin for the Hep2 mitochondrial ATP synthase

[1806] Table IX: Inhibition of Hep2 mitochondria ATP Synthase by compounds and relative selectivity index vs oligomycin TM # Mitochondria ATP synthase IC50 (pM) Ratio ATP synthase IC50 TM compound / IC50 oligomycin

[1807] TM-292 28 7 2050

[1808] TM-336 5.8 414

[1809] TM-387 5.3 379

[1810] TM-389 8.8 629

[1811] TM-397 4.8 343

[1812] TM-416 6.0 429

[1813]

[1814] EXAMPLE 159: In vivo antibacterial activity of compounds in murine soft tissue infection model

[1815] TM-397 and TM-416 were able to significantly reduce the level of E coli ATCC 25922 (MIC 8 µg / ml) infection using a single dose IV of 45 mg / kg of body weight This in vivo activity was equivalent or superior to that of cefotaxime (CTX) for which the MIC was 0.06-0.12 µg / ml against that strain (FIGs 7A-7B)

[1816] EXAMPLE 160: In vivo antibacterial activity of compounds in murine thigh infection model

[1817] TM-381 was able to significantly reduce the infection level of the MDR E coli strain ATCC BAA-2471 in the murine thigh infection model using two intraperitoneal doses of 15 mg / kg of body weight at 2h and 6h postinfection This in vivo activity was equivalent or superior to that of cefotaxime (CTX) for which the bacterial load in the thigh muscles were not statistically reduced (FIG 8) 5 The scope of the claims should not be limited by the embodiments set forth in the examples but should be given the broadest interpretation consistent with the description as a whole REFERENCES

[1818] Burlingham, B T, and Widlanski, T S An Intuitive look at the relationship of Ki and IC50: A more general use for the Dixon plot J Chem Educ 2003, 80, 214, doi:10.1021 / ed080p214

[1819] Brouillette, E; Martinez, A, Boyll, B J, Allen, N E, Malouin, F Persistence of a Staphylococcus aureus small-colony variant under antibiotic pressure in vivo FEMS Immunol Med Microbiol 2004, 41, 35-41 https: / / doi.org / 10.1016 / j.femsim.2003.12.007

[1820] Cote-Gravel, J; Brouillette, E; Obradovi'c, N; Ster, C; Talbot, B G; Malouin, F Characterization of a VraG mutant in a genetically stable Staphylococcus aureus small-colony variant and preliminary assessment for use as a live- attenuated vaccine against intramammary infections PLoS ONE 2016, 11, e0166621

[1821] CDC The Biggest Antibiotic-Resistant Threats in the U S Available online: https: / / www.cdc.gov / drugresistance / biggest-threats.html (accessed on 21 July 2023)

[1822] CLSI, Clinical and Laboratory Standards Institute Methods for dilution antimicrobial susceptibility tests for bactena that grow aerobically 11th Ed CLSI standard M07 2018 (ISBN 1-56238-836-3 [Print]; ISBN 1-56238-837-1 [Electronic]) CLSI, 950 West Valley Road, suite 2500, PA 19087, USA

[1823] Delbrouck JA, A Murza, I Diachenko, A Ben Jamaa, R Devi, A Larose, S Chamberland, F Malouin, Pierre-Luc Boudreault 2024 From Garden to Lab: C-3 Chemical Modifications of Tomatidine Unveil Broad-Spectrum ATP Synthase Inhibitors to Combat Bacterial Resistance Eur J Med Chem 262: 115886

[1824] Lamontagne Boulet M, Charles Isabelle, Isabelle Guay, Eric Brouillette, Jean-Philippe Langlois, Pierre-Etienne Jacques, Sebastien Rodrigue, Ryszard Brzezinski, Kamal Bouarab, Kumaraswamy Boyapelly, Pierre-Luc Boudreault, Eric Marsault, and Francois Malouin 2018 Tomatidine, a lead antibiotic molecule that targets Staphylococcus aureus ATP synthase subunitC Antimicrob Agents Chemother 62: e02197-17

[1825] Langlois J-P, Larose A, Brouillette E, Delbrouck JA, Boudreault P-L, Malouin F 2024 Mode of antibacterial action of tomatidine C3-diastereoisomers Molecules, 29: 343 https: / / doi.org / 10.3390 / molecules29020343

[1826] Raheem S., A Steiner, Z Ahmad. 2019. Functional importance of αAsp-350 in the catalytic sites of Escherichia coli ATP synthase Archives of Biochemistry and Biophysics 672: 108050

[1827] Symersky J, Osowski D, Walters DE, Mueller DM Oligomycin frames a common drug-binding site in the ATP synthase Proc Natl Acad Sci 2012; 109:13961-13965

[1828] WHO Publishes List of Bacteria for Which New Antibiotics Are Urgently Needed Available online:

[1829] https: / / www.who.int / news / item / 27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed (accessed on 21 July 2023)

[1830] Zhanel, G ...

Claims

CLAIMS:1 A compound of formula:wherein:i is 0 or 1, wherein when i is 1:is an aryl(C3-C6), heteroaryl(C3-C7), cycloalkyl(C3-C7), or heterocycloalkyl; or is an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalky l(C3-C 7); or an heterocycloalkyl fused with an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalkyl(C3-C7) or an heterocycloalkyl, and W is absent;Z is absentor iswherein W is absent; orW is ORs orN(Rg)(Rio) and is absent;wherein Rg is H, or alkyl(C 1-C6); andR9 and R10 are each independently H or alkyl(C1-C6);j is 0 or 1, wherein when j is 1:a is 0, 1 or 2;each of X and Y are independently N or CH;R2 is H or N(R11)(R12) wherein R11 and R12 are each independently H or alkyl(C1-C4);n is 0 or 1;R3 is H, alkyl(C1-C6)-O-alkyl(C1-C6) or -alkyl(C1-C6)aryl(C5-C6); or R4 and R3 form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;m is O, 1, 2 or 3;p is 1 or 2;R4 is H, alkyl(C 1-C6), -alkyl(C 1-C4)aryl(C3-C7), or I, wherein R13 is alkyl(C1-C7) or aryl(C5-C6), provided that when R13 is alkyl(C1-C7), W is not OH; or R4and Rj form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4is attached;ii is 0 or 1, preferably ii is 1, wherein when ii is 0, R4 is I, R13 being as defined above, and wherein when ii is 1:f B )is an aryl(C3-C6), an heteroaryl(C3-C7), cycloalkyl(C3-C7) orheterocycloalkyl(C3-C7) provided that when it is an heteroaryl(C6), j is 1; or is an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalkyl(C3-C7) or an heterocycloalkyl(C3- C7) fused with an aryl(C3-C7), an heteroaryl(C3-C7), a cycloalkyl(C3 C7) or an heterocydoalkyl(C3-C7);Rs is H or CH3;Rs is H orwherein Ri and Rii formwhich is an heterocycloalkyl(C3-C8) ring formed with the nitrogen (“mtrogen- comprising heterocycloalkyl(C3-C8) ring”) or a spirocyde comprising the nitrogen -comprising heterocycloalkyl(C3-C8) ring and another heterocycloalkyl(C3-C8) orcycloalkyl(C3-C8); oreach of Ri and Rii are independently an alkyl(C1-C6),wherein each heteroaryl and heterocydoalkyl contains from 1 to 4 heteroatoms independently selected from N, 0 and S, andwherein each alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents that are each independently halogen, N, 0, S, alkyl(C1-C8), aryl(C3-C7), cycloalkyl(C3-C7), -sulfonyl-aryl(C3-C7), OH, or 0-alkyl(C1-C6), provided that when i is 0, ii is 1, and is a single ring, is substituted with at least one alkyl(C3-C7) or cydoalkyl(C3-C7),or a salt, solvate, ester or stereoisomer thereofThe compound of claim 1, whereinis an aryl(C4 -C6), heteroaryl(C4-C6), or cycloalkyl(C4-C6); or is an aryl(C4-C6), an heteroaryl(C4- C6), or a cydoalkyl(C4-C6) fused with an aryl(C4-C6), an heteroaryl(C4-C6), or a cydoalkyl(C4-C6) and W is absent; orW is ORB, or N(Rg)(Rio), wherein Rs is H, or alkyl(C1-C3); and Rg and R are each independently H oralkyl(C1-C3), and is absent;(ii) R2 is H or N(R11)(R12) wherein R11 and R12 are each independently H or alkyl(C1-C2);(iii) p is 1;(iv) R3 is H, alkyl(C1-C3)-O-alkyl(C1-C3) or -alkyl(C1-C3)aryl(C5-C6); or R4 and R3 form together an heterocycloalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;(v) R4 is H, alkyl(C1-C3), or -S(=O)2aryl(C3-C7); or R4and Rg form together an heterocydoalkyl(C5-C7) with Y and the nitrogen to which R4 is attached;(vi) is an aryl(C3-C6), or an heteroaryl(C3-C7); or is an aryl(C3-C7) or an heteroaryl(C3-C7), fused with an aryl(C3-C7), or an heteroaryl(C3-C7);(vii) Rs is H;(viii) R and Rs form —cwhich is an heterocydoalkyl(C4-C7) ring formed with the nitrogen (“nitrogen¬ comprising heterocydoalkyl(C4-C7) ring”) or a spirocycle comprising the nitrogen-composing heterocydoalkyl(C4-C7) nng and another heterocydoalkyl(C4-C7): or each of R„ and Rii are independently an alkyl(C1-C5);(ix) R13 is alkyl(C4-C5) or aryl(C6), or(x) any combination of at least two of (i) to (ix),wherein each alkyl, aryl, heteroaryl, cydoalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in claim 1, and wherein each heteroaryl and heterocydoalkyl contains from 1 to 4 heteroatoms as defined in claim 1,or a salt, solvate, ester or stereoisomer thereofThe compound of claim 1 or 2, wherein:(i) is an aryl(C5-C6), heteroaryl(C5-C6), or cycloalkyl(C5-C6); or is an aryl(C5-C6), an heteroaryl(C5-C6), or a cycloalkyl(C5-C6) fused with an aryl(C5-C6), an heteroaryl(C5-C6), or a cycloalkyl(C5-C6) and W is absent; or(ii) R2 is H or N(R11)(R12) wherein R11 and R12 are each independently H or alkyl(C1);(iii) is an aryl(C4-C6), or an heteroaryl(C4-C7); or is an aryl(C4-C7) or an heteroaryl(C4-C7), fused with an aryl(C4-C7), or an heteroaryl(C4-C7);(iv) Ri and Rii formwhich is an heterocycloal kyl(C5-C 7) ring formed with the nitrogen (“nifrogen- comprising heterocydoalkyl(C5-C7) ring”) or a spirocycle comprising the nitrogen-comprising heterocycloalkyl(C5-C7) ring and another heterocycloalkyl(C5-C7); or each of Ri and Rii are independently an alkyl(C1-C4), or(v) any combination of at least two of (i) to (iv),wherein each alkyl, aryl, heteroaryl, cycloalkyl, heterocydoalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in daim 1, and wherein each heteroaryl and heterocydoalkyl contains from 1 to 3 heteroatoms as defined in claim 1,or a salt, solvate, ester or stereoisomer thereof4 Th e compoun d of any on e of claims 1 to 3, wherein:-7'1is an aryl(C5-C6), orheteroaryl(C5-C6); oris an aryl(C5-C6), oran heteroaryl(C5-C6) fused with an aryl(C5-C6), or an heteroaryl(C5-C6) and W is absent; orW is OH, or NH? and is absent;(ii) R2is H or NH2;(iii) is an aryl(C5-C6), or an heteroaryl(C5-C7); or is an aryl(C5-C7) or an heteroaryl(C5-C7), fused with an aryl(C5-C7), or an heteroaryl(C5-C7);(iv) Rj and Rs formcwhich is an heterocydoalkyl(C5-C7) ring formed with the nitrogen (“nitrogen¬ comprising heterocydoalkyl(C5-C7) ring”) or a spirocycle comprising the nitrogen-compnsing heterocydoalkyl(C5-C7) nng and another heterocydoalkyl(C5-C6); or each of R„ and Rii are independently an alkyl(C1-C3); or(v) any combination of at least two of (i) to (iv),wherein each alkyl, aryl, heteroaryl, cydoalkyl, heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in claim 1, and wherein each heteroaryl and heterocydoalkyl contains from 1 to 3 heteroatoms as defined in claim 1,or a salt, solvate, ester or stereoisomer thereofTh e compoun d of any on e of claims 1 to 4, wherein:whereinin (a1) 0, 1 or 2 of Qi, Q2, and Q3 are each independently N, 0 or S and the remainder is CR14; in (a2) 0, 1 or 2 of Qia, Qsa, and Qsaare each independently N, 0 or S and the remainder is CRu in (a3) 1 or 2 of Q5, Qe, Qz, and Qs are each independently NR15, 0 or S and the remainder is CRu in (a4) 1 or 2 of Qb,a, Qaa, Qza, and Qtaare each independently NR15, 0 or S and the remainder is CR1, in (a5) 1, 2 or 3 of Qg, Qi 0, Qu, Q12, Q13, and Qnare each independently NR15, 0 orS and the remainder is CR14;in (a6) 1, 2 or 3 of Qioa, Qua, Qi2a, Qi3a, Qi4a, and Q15, are each independently NR15, 0 or S and the remainder is CR14;in (a?) 1, 2 or 3 of Qia, Q17, Q, Q, Q20, and Q21, are each independently NR15, 0 or S and the remainder is CR14; andin (aS) 1, 2 or 3 of Qa, Qisa, Q a, Q20a, Q2iaand Q22, are each independently NR15, 0 or S and the remainder is CRuwherein each Rwis independently H ora substituent as defined in claim 1, provided that in each of (a1) to (a8), at most 3 of the R^ are notH; andwherein each Risis independently absent, H or a substituent as defined in claim 1, provided that in each of (a3) to (aS), atmost 2 of the R15 are not H;Wis OH, or NH2 and is absent;in (b1) 0, 1 or 2 of Ui, U2, U3, LU, and U5 are each independently N, 0 or S and the remainder is CRis; in (b2) 0, 1 or 2 of IK, IK, IK, IK, and L are each independently N, 0 or S and the remainder is CRIB;in (b3) 1 or 2 of U5, Us, U7, and Ug are each independently NR17 or 0 and the remainder is CRis; in (b4) 1 or 2 of IK, IK, IK, and IK are each independently NRu or 0 and the remainder is CRie: in (b5) 1, 2 or 3 of Ug, U10, Un, U12, U13, and I are each independently NR17, 0 or S and the remainder is CRis;wherein each R is independently H ora substituent as defined in claim 1, provided that in each of (b1) to (b5), at most 4, preferably at most 3 of the R are not H; andwherein each R is independently absent, H or a substituent as defined in claim 1, provided that in each of (b3) to (b5), at most 2 of the R17 is not H;independently 1, 2 or 3; Vi is N, 0, S or C, each ofV2, V3,andV4, is independently NR20, 0, S or C(R2i)R22, wherein each of R20, R21 and R22 is independently H or a substituent as defined in claim 1, and one of RIB and R is a substituentas defined in claim 1 and the other is H;(iv) a combination of at least two of (i) to (iii),or a salt, solvate, ester or stereoisomer thereofThe compound of claim 5, wherein:(i) in (a1) 0, 1 or2 of Qi, Q2, and Qs are each independently N and the remainder is CRin (a2) 0, 1 or2 of Qia, CK. and CK are each independently N and the remainder is CR14;in (a3) Qs is NRigor CR14; Qt is 0 or CR14; Q? is 0 or CR14, and Qg is NR15, S orCRuin (a4) Qsa is NR15 orCR, CK is 0 or CR14; Q?ais 0 or CR14, and C is NR15, S or CR14;in (a5) Qg, Qu, and Qu are each CR; and 1 or 2 ofQn, Q12, and Q13 is independently NRu 0 or S and the remainder is CRu;in (a6) Q-ioa, Qua, and Qu, are each CRu and 1 or 2 of Qua, Qua, and Qua is independently NR15, 0 or S and the remainder is CRu;in (aZ) Qu, Q19, Q20, and Q;i, are each CRu; and each of Qu, and Qv is independently NRu, 0, S or CRu; andin (a8) Qisa, Qi9a, Qsoa and Qsu are each CRu; and each of Qua, and Q22, is independently NR, 0, S or CRu;wherein each R14 is independently H or a substituent as defined in claim 1, preferably wherein each R14 is independently H, halogen (e, I, F), -NO2, -OH, -fluoroalkyl(C 1-C3), or alkyl(C 1-C6), provided that in each of (a1) to (a8), at most 3 of the R14 are not H; andwherein each R15 is independently absent, H or a substituent as defined in claim 1, preferably wherein each R15 is independently absent, H or -sulfonyl- aryl(C3-C7), provided that in each of(a3) to (a8), at most 2 of the R15 are not H; or(ii) in (b1) 0, 1 or 2 of U1, U2, U3, LU, and Us are each independently 0 or S and the remainder is CRu;or U2 or U4 is N and the remainder is CR, wherein the CRu at position U3 is CF3;in (b2) 0, 1 or 2 of Uia, I, Ik, L, and lk are each independently 0 or S and the remainder is CRu; or l or U a is N and the remainder is CRu, wherein the CRu at position l is CF3;in (b3) 1 or 2 oflk Ue, lk and Us are each independently NR17 or 0 and the remainder is CR;in (b4) 1 or 2 of Ik, l, Ik, and Ik are each independently NR- 7 or 0 and the remainder is CRu; in (b5) U11, U12, U13, and Uu are each CR; andUg and U are each independently NRu, 0 or S and the remainder is CRu;wherein each Ruis independently H or a substituent as defined in claim 1, provided that in each of (b1) to (b5), at most 3 of the Ru are not H; andwherein each R17 is independently absent, H or a substituent as defined in claim 1, provided that in each of (b3) to (b5), at most 2 of the R17 are not H;f c(iii) inV_Veach of q, q’ and q” is independently 1, 2 or 3; Vi is N, 0, or C, each of V2. V3, and V4, is independently NR20, 0 or C(R2i)R22, wherein each of R20, R21 and R22 is independently H or a substituent as defined in claim 1, and one ofR and Ru is a substituent as defined in claim 1 and lhe other is H;(iv) a combination of at least two of (i) to (iii),or a salt, solvate, ester or stereoisomer thereofThe compound of claim 5 or 6, wherein:in (a 1) 0 or 1 of Qi, Qj, and Qj is independently N and me remainder is CRu;in (a2) 0 or 1 of Qu, Q2a, and Qsa are each independently N and the remainder is CR;in (a3) Qs is NR or CRu; Qs is 0 or CR; Q? is 0 or CRu, and Qa is NRu, S or CR;in (a4) Qsa is NR15 or CRu, Qea is 0 or CR, Q?ais 0 or CRu, and Qs,;is NR15, S or CRu;in (a5) Qg, Qu, and Qu are each CRu; and 1 or 2 of Qu, Qu, and Q13 is independently NR, and the remainder is CRu;in (a6) Qwa, Qua, and Qu, are each CRu; and 1 or 2 of Q-i2a, Qua, and Qua is independently NR15, and the remainder is CR;in (a7) Qu, Qu, Q20, and Q21, are each CR; and each of Qu, and Qu is independently NRu, 0 or CRu, preferably 1 or 2 of Qu, and Qv is independently NR or 0; and the reminder is CRu;in (aS) Qa, Qua, Qgoaand Qguare each CRu; and each ofQva, and Q22, is independently NR, 0 or CRu, preferably 1 or 2 of Qva, and Q22. is independently NRu or 0 and the remainder is CR;wherein each Ru is independently H, halogen (e g, I, F), -NO2, -OH, -fluoroalkyl(C1-C3), or alkyl(C 1-C6), provided that in each of (a1) to (aS), at most 3 of the Ru are not H, andwherein each Ru is independently absent, H or -sulfonyl- aryl(C3-C7), provided that in each of (a3) to (a8), at most 2 of the R are not H; or(ii) in (b1) 0, 1 or 2 of U1, U2, U3, I and U5 are each independently 0 or S and the remainder is CR or U2 or U4 is N and the remainder is CR, wherein the CRu at position U3 is CF3;in (b2) 0, 1 or 2 of Uia, Ik, Ik, Ik, and Ik are each independently 0 or S and the remainder is CRu; or tk or U 4a is N and the remainder is CR, wherein the CRu at position Ik is CF3in (b3) U5 or U a is 0 and the remainder is CR,in (b4) tk or Ik is 0 and the remainder is CR; or Ik is S and Lk is N and the remainder is CRu; or Ik is S and U 5ais N and the remainder is CR;in (b5) U11, U12, U13, and Un are each CRu; one or both of, preferably one ofll 9 and U, preferably Uu are(is) 0 and the other is CRu;wherein each Ruis independently H or a substituent as defined in claim 1, provided that in each of (b1) to (b5), at most 3 of the Ru are not H; andwherein each R17 is independently absent, H or a substituent as defined in claim 1, provided that in each of (b3) to (b5), at most 2 of the Ru are not H;(iii) in (c1), q is 1, 2 or 3; Vi is N, 0, or C and one of R and Ru is H or an alkyl(C1-C6) and the other is H; and in (c2) each ofq’ and q” is independently 1 or 2; V2 is 0, V3 is CH2 or NH; andKQis 0, orCk; or(iv) a combination of at least two of (i) to (iii),or a salt, solvate, ester or stereoisomer thereofTh e compoun d of any on e of claims 1 to 7, wherein:is phenyl, pyridyl, indolyl, benzooxazyl, oxazolyl, pyrrolyl, or thiazolyl, which is unsubstituted or substituted with 1, 2 or 3 substituents as defined in claim 1,is phenyl, triflu oromethyl-pyridy I, furyl, or benzofuryl, which is unsubstituted or substituted with 1, 2 or 3 substituents as defined in claim 1;is azepyl, dioxaazaspiro[45]decanyl (e g, 1,4-dioxa-8-azaspiro[45]decane), morpholinyl, diazmanyl, pyrrolidmyl or oxa diazaspiro [45]decane (e g, 9 oxa 1,6 diaza-spiro[45]decane), which is unsubstituted or substituted with 1, 2 or 3 substituents as defined in claim 1; ora combination of at least two of (i) to (iii),or a salt, solvate, ester or stereoisomer thereofThe compound of any one of claims 1 to 8, whereinunsubstituted or substituted with 1, 2 or 3 substituents, the 1, 2 or 3 substituents being independently halogen (e g, I, F), -NO2, -OH, -fluoroalkyl(C1-C3), O-alkyl(C1-C6) or alkyl(C1-C6), preferably halogen (e g, I, F), -NO;, -OH, -CF3, or alkyl(C1-C3), most preferably halogen (e g, I, F), -NO2, -OH, -CF3, or CH3;in unsubstituted or substituted with 1, 2 or 3 substituents, the 1, 2 or 3 substituents being independently halogen (e g, Cl, F), -fluoroalkyl(C1-C3), alkyl(C1-C6), or cydoalkyl(C3-C7), preferably halogen (e g, Cl, F), - CF3, alkyl(C1-C5), or cycloalkyl(C4-C6), more preferably halogen (e g, Cl, F), -CF3, alkyl(C1-C5), or cycloalkyl(Cb);cin --_ unsubstituted or substituted with 1, 2 or 3 substituents, the 1, 2 or 3 substituents being independently alkyl(C1-C8), preferably alkyl(C1-C3), more preferably CH3; or(iv) a combination of at least two of (i) to (iii),or a salt, solvate, ester or stereoisomer thereof10 The compound, salt, solvate, ester or stereoisomer thereof of any one of claims 1 to 9, wherein at least two ofand are present, or wherein all three are present11 The compound of claim 1, which is of formula (la), formula (lb), formula (Ic), formula (Id), formula (le), formula (It), formula (Ig) or formula (Ih):R’ Rs(lb), preferably wherein at least one of i and ii is 1;Rb(1h)wherein one of Ra, Rb, and Rc, is, and the others are H;Aeach of A is as defined in any one of claims 1-9;each of i, ii, R4, R5, Ri, Rii, m, and p is as defined in any one of claims 1 to 4;each of j, X, Y, R2, R3, a, n, Z and R6are as defined in claim 1;R7and R8form together an aryl(C3-C6), a cydoalkyl(C3-C8), an heteroaryl(C3-C6) or an heterocycloalkyl(C3-C6), or each of R7and R8is independently H or an alkyl(C1-C6);r is any integer between 1 and 6, preferably between 2 and 6, or 3 and 5;r” is 0 or 1, preferably 1;cycle B’ is attached to carbon at position b or c, preferably b;at least one of R23, R24 and R25 is an alkyl(C1-C6), a cydoalkyl(C3-C6), a fluoroakyl(C 1-C3) or a halogen, preferably an alkyl(C3-C5), a cycloalkyl(C4-C5), a CF3 or an halogen; and the remainders are each independently H or an alkyl(C1-C6); andR₂₆ and R₂₇ form together an heterocycloalkyl(C4-C6), preferably an heterocyclopentyl, preferably a dioxalane;wherein each aryl, cycloalkyl, heteroaryl and heterocycloalkyl is independently unsubstituted or substituted by 1, 2 or 3 substituents as defined in claim 1 or 9, and wherein each heteroaryl and heterocycloalkyl contains from 1 to 3 heteroatoms as defined in claim 1,or a salt, solvate, ester or stereoisomer thereof(B) 12 The compound, salt, solvate, ester or stereoisomer thereof of claim 11, wherein Raor Rc, is, and ( B jpreferably Rb is “13 The compound, salt, solvate, ester or stereoisomer thereof of any one of claims 1 to 12, wherein j is 1 14 The compound of claim 1, which is:Compound Structure0TM-462OH JU TM-462TM-456H fl lrv HrJTM-456TM-372TM-376TM-376TM-411TM-411TM-414110TM-361 V 'XJX'J \ZC -C TOHTM-361oTM-392 )OL JLHfl 1OH I ) TM-392XX Q TM-424^ A A -,™4-JOH I )HO'»X^xTM-427 Xjl JLAhA fLi x> ik. _ _OH I )TM-427Cl’x / XXK JCkA I^ ^nN. A 1.TM-434HiN^ 1 [plk -N^ AZ JkX xZik _ _ ^N-"'XLyTM-434TM-365HO / k— X / ''o'' Y N X.OH I J TM-339 / TM-365TM-425hrT^r“O'0AH OTM-425TM-337H2N 1X I IMx*N'^X5^XO'^X|^^ NOH I )TM-337CF3F*CXX Q1 H TTM-445 J.TM-445F3CX^> XUL Q1 H TTM-452 H?N*^ XX 'S | < XSL - X^ X'LX^''0''\X'''Nx" — 'S,OH I )TM-452F, CY^ fATM-402H? N^^ i fi jL J!,< Ly NA OH Lv TM-402TM-364HO JLVuCX -^ ^OH I )TM-342 / TM-364TM-432H fl Xrj^YX- / CT Y^ b|- \.OH L__ / TH TM-432ClTM-439XHX 11 1|Y O N' \)OH ’-— / T TM-439OHCI VYX5:>1TM-440-X Hv. n. f| o 1^N^ > HO"'^''^ °HTM-440TM-350 HO JLOH I ) TM-350TM-386 " Ok XOH I ) TM-386TM-399H M- O N(>*1\ f li'Sfi) TM-399TM-412 H IN JL X V-i^CkO-t OH I J TM-412Clx¥x'k>sJMTM-433Hif j^ / || J TM-433TM-450TM-351h° JLN X OH X _JTM-351ClTM-438H JMV_-S OH ’ - / TM-438F0TM-429 / ' \hfi i-O H0H U / TM-429Cf5CNTM-444H?hLhffXx^ XX i\. x - ^xx^'-Q^ X-X. Y X^^x. N Y x^Xj x^OH[I xJ TM-444TM-415 H;hLHfl J•XjX^ X\x / X. Xx^ JJXX x>^L0_-^ _x^x X^X.xNX-^^^"\C)Mk- / |l xj TM-415CHTM-446CH H [fSOH k^y TM-446TM-360 HO 'x / ^fL Jl V xJL '-Q'' NOH I / TM-3590TM-214 0o=s=oHO.1.XZ ''O N Aon I )TM-214o H i [i^ "iTM-215 ff '<> OH _ / |f JJ TM-215CF3TM-343 HO JLVJCkncoTM-343,0|.15 The compound of claim 14, which is TM-292, TM-336, TM-337, TM-338, TM-340, TM-342, TM-350, TM-355, TM-364, TM-365, TM-372, TM-373, TM-375, TM-376, TM-377, TM-378, TM-379, TM-463, TM-464, TM-380, TM-381, TM-382, TM-386, TM-387, TM 389, TM-392, TM 394, TM-395, TM-396, TM 397, TM-398, TM 399, T 401, TM-402, TM-406, TM- 407, TM-408, TM-410, TM-411. TM-412, TM-413, TM-414, TM-416, TM-418, TM-420, TM-421, TM-423, TM-424, TM-425, TM-426, TM-427, T -431, TM-432, TM-433, TM-434, TM-439, TM-440, TM-441, TM-442, TM-443, TM-445, TM-450, TM-452, TM-456, TM-457, TM-462, TM-463, TM-464, or a salt, solvate, ester or stereoisomer thereof as defined in claim 14, preferably TM-336, TM-355, TM-372, TM-373, TM-375, TM-376, TM-377, TM-378, TM-379, TM-463, TM-464, TM-380, TM-381, TM-382, TM-387, TM-389, TM-392, TM-394, TM-395, TM-396, TM-397, TM-398, TM-401, TM-407, TM-410, TM-411, TM-413, TM-414, TM-416, TM-418, TM-421, TM-423, TM-424, TM-426, TM-427, TM-431, TM-434, TM-442, TM-443, TM-456, TM-457, TM-462, TM-463, TM-464, or a salt, solvate, ester or stereoisomer thereof and more preferably TM-462, TM-456, TM-457, TM-336, TM-372, TM-373, TM-376, TM-377, TM-378, TM-380, TM-387, TM-396, TM-397, TM-398, TM-407, TM-411, TM-413, TM-414, TM-418, TM-456, TM-457, TM-462, TM-463, TM-464, or a salt, solvate, ester or stereoisomer thereof16 A pharmaceutical composition comprising (a) the compound, salt, solvate, ester or stereoisomer thereof defined in any one of claims 1 to 15, and (b) (i) an antibiotic; (ii) an antiseptic;(iii) a disinfectant; (iv) a pharmaceutically acceptable carrier; or (v) any combination of (i)-(iv)17 The compound, salt, solvate, ester or stereoisomer thereof of any one of claims 1 to 15 or of the composition of claim 16, for use in the treatment of a bacterial infection in a subject in need thereof18 The compound, salt, solvate, ester or stereoisomer thereof for use of claim 17, wherein the bacterial infection is caused by an Enterobacterales (e g, Escherichia, Klebsiella), Bacilotta (e g. Staphylococcus, Enterococcus, Streptococcus, Bacillus, Listeria), Pseudomonas, or Actinobacter, preferably Escherichia, Klebsiella, Pseudomonas, Acinetobacter or Staphylococcus, or preferably by an Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus haemolyticus, Staphylococcus hominis, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus agalactiae, Bacillus cereus, Bacillus subtilis, or Listeria monocytogenes19 The compound, salt, solvate, ester or stereoisomer thereof for use of any one of claims 17 to 19, wherein the bacterial infection is caused by an antibiotic-resistant (e.g., multi-resistant) bacterium20 The compound, salt, solvate, ester or stereoisomer thereof for use of any one of claims 17 to 19, wherein the subject is a mammal, preferably a human

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