INHIBITORS OF PSEUDOMONAS AERUGINOSA VIRULENCE FACTOR LasB

Abstract

The present invention relates to compounds of formula (Ia) and the use thereof as inhibitors of P. aeruginosa virulence factor LasB. Formula (Ia). These compounds are useful in the treatment of bacterial infections, especially caused by P. aeruginosa.

##STR00001##

Claims

1.-2. (canceled)

3. A method for treating a subject suffering from or susceptible to a bacterial infection comprising administering to the subject an effective amount of a compound of formula (Ia): ##STR00194## wherein X is a group of formula —PO(OH).sub.2, —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR.sup.3, —PO(OH)(OR.sup.4) or —PO(OR.sup.4)(OR.sup.5); R.sup.1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, or a group of formula —C(Me).sub.2—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—R.sup.8; R.sup.2 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted; R.sup.3 is a group of formula —COR.sup.3a or —CON(R.sup.3b).sub.2; wherein R.sup.3a is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group and R.sup.3b is independently selected from hydrogen or an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; R.sup.4 is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; R.sup.5 is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; R.sup.6 is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted; R.sup.7 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R.sup.8 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; and R.sup.1a is hydrogen, or, if R.sup.1 is a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, R.sup.1a and R.sup.6 together may be a group of formula —(CH.sub.2).sub.3— or —(CH.sub.2).sub.4—; or a pharmaceutically acceptable salt thereof.

4. The method according to claim 3, wherein the compound is a compound of formula (I) ##STR00195## wherein X is a group of formula —PO(OH).sub.2, —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR.sup.3, —PO(OH)(OR.sup.4) or —PO(OR.sup.4)(OR.sup.5); R.sup.1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group: or a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, or a group of formula —C(Me).sub.2—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—R.sup.8; and R.sup.2 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted, or a pharmaceutically acceptable salt thereof.

5. The method according to claim 3, wherein the compound is a compound of formula (II), (III), (IV), (V) or (VI): ##STR00196## wherein R.sup.1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, or a group of formula —C(Me).sub.2—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—R.sup.8; and R.sup.2 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted, or a pharmaceutically acceptable salt thereof.

6. The method according to claim 3, wherein R.sup.2 is a C.sub.1-6 alkyl group; a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; a C.sub.4-10 alkylcycloalkyl group; or a C.sub.7-12 aralkyl group; all of which may optionally be substituted.

7. The method according to claim 3, wherein R.sup.2 is an optionally substituted benzyl group; or wherein R.sup.2 is a group of formula —CH.sub.2CH(CH.sub.3).sub.2.

8-9. (canceled)

10. The method according to claim 3 wherein R.sup.1 is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heteroaryl group containing one or two rings and from 5 to 10 ring atoms selected from C, O, N and S.

11. (canceled)

12. The method according to claim 3 wherein R.sup.1 is a group of formula —Cy.sup.1-L-Cy.sup.2, wherein Cy.sup.1 is an optionally substituted cycloalkylene group containing 1 or 2 rings and from 3 to 7 carbon ring atoms, an optionally substituted heterocycloalkylene group containing 1 or 2 rings and from 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted phenylene group, or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S; Cy.sup.2 is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted; and L is a bond or —O—, —S—, —NH—, —CH.sub.2—, —CO—, —NHCO—, —CO—NH—, —CH.sub.2—CO—NH—, —NH—CO—CH.sub.2—, —CH.sub.2—O—CO—NH—, —NH—CO—O—CH.sub.2—, —O—CO—NH—, —NH—CO—O—, —NHSO.sub.2—, —SO.sub.2NH—, —CH.sub.2—SO.sub.2—NH—, —NH—SO.sub.2—CH.sub.2—, —S—CH.sub.2—, —CH.sub.2—S—, —NH—CH.sub.2—, —CH.sub.2—NH—, —O—CH.sub.2— or —CH.sub.2—O—.

13. The method according to claim 12, wherein Cy.sup.2 is an optionally substituted phenyl group, an optionally substituted biphenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, an optionally substituted cycloalkyl group containing from 3 to 7 ring atoms, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted heterocycloalkylaryl group containing 9 or 10 ring atoms selected from C, N, S and O, or a group of formula —CH(CH.sub.2Ph)Ph; L is a bond or —NHCO—, —CO—NH—, —CH.sub.2—CO—NH—, —NH—CO—CH.sub.2—, —NHSO.sub.2— or —SO.sub.2NH—; and Cy.sup.1 is a 1,4-phenylene group.

14-15. (canceled)

16. The method according to claim 3 wherein R.sup.1 is a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7 or a group of formula —CH(R.sup.6)—R.sup.8; wherein R.sup.6 is hydrogen or a C.sub.1-6 alkyl group, a C.sub.3-7 cycloalkyl group, a heterocycloalkyl group containing from 3 to 7 ring atoms selected from C, N, O and S, a phenyl group or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O, or a group of formula —CH.sub.2—R.sup.6awherein R.sup.6a is a C.sub.3-7 cycloalkyl group, a heterocycloalkyl group containing from 3 to 7 ring atoms selected from C, N, O and S, a phenyl group or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O; R.sup.7 is an optionally substituted phenyl group or an optionally substituted C.sub.3-7 cycloalkyl group; and R.sup.8 is an optionally substituted benzimidazole group or an optionally substituted triazole group or an optionally substituted imidazole group.

17.-20. (canceled)

21. The method according to claim 3 wherein the bacterial infection is caused by P. aeruginosa.

22. A compound of formula (Ia): ##STR00197## wherein X is a group of formula —PO(OH).sub.2, —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR.sup.3, —PO(OH)(OR.sup.4) or —PO(OR.sup.4)(OR.sup.5); R.sup.1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, or a group of formula —C(Me).sub.2—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—R.sup.8; R.sup.2 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted; R.sup.3 is a group of formula —COR.sup.3a or —CON(R.sup.3b).sub.2; wherein R.sup.3a is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group and R.sup.3b is independently selected from hydrogen or an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; R.sup.4 is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; R.sup.5 is an alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group; R.sup.6 is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted; R.sup.7 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R.sup.8 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; and R.sup.1a is hydrogen, or, if R.sup.1 is a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, R.sup.1a and R.sup.6 together may be a group of formula —(CH.sub.2).sub.3— or —(CH.sub.2).sub.4—; or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 22, wherein the compound is a compound of formula (I) ##STR00198## wherein X is a group of formula —PO(OH).sub.2, —SH, —C(═O)—NH—OH, an optionally substituted triazolyl group, —SR.sup.3, —PO(OH)(OR.sup.4) or —PO(OR.sup.4)(OR.sup.5); R.sup.1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, or a group of formula —C(Me).sub.2—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—R.sup.8; R.sup.2 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted, or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 22, wherein the compound is a compound of formula (II), (III), (IV), (V) or (VI): ##STR00199## wherein R.sup.1 is an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group or an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; or a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7, or a group of formula —C(Me).sub.2—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—CH.sub.2—C(═O)—NH—R.sup.7, or a group of formula —CH(R.sup.6)—R.sup.8; R.sup.2 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted, or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 22, wherein R.sup.2 is a C.sub.1-6 alkyl group; a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N; a C.sub.4-10 alkylcycloalkyl group; or a C.sub.7-12 aralkyl group; all of which may optionally be substituted.

26. The compound according to claim 22, wherein R.sup.2 is an optionally substituted benzyl group; or wherein R.sup.2 is a group of formula —CH.sub.2CH(CH.sub.3).sub.2.

27.-28. (canceled)

29. The compound according to claim 22, wherein R.sup.1 is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted heteroaryl group containing one or two rings and from 5 to 10 ring atoms selected from C, O, N and S.

30. (canceled)

31. The compound according to claim 22, wherein R.sup.1 is a group of formula —Cy.sup.1-L-Cy.sup.2, wherein Cy.sup.1 is an optionally substituted cycloalkylene group containing 1 or 2 rings and from 3 to 7 carbon ring atoms, an optionally substituted heterocycloalkylene group containing 1 or 2 rings and from 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted phenylene group, or an optionally substituted heteroarylene group containing 5 or 6 ring atoms selected from C, N, O and S; Cy.sup.2 is a cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which may optionally be substituted; and L is a bond or —O—, —S—, —NH—, —CH.sub.2—, —CO—, —NHCO—, —CO—NH—, —CH.sub.2—CO—NH—, —NH—CO—CH.sub.2—, —CH.sub.2—O—CO—NH—, —NH—CO—O—CH.sub.2—, —O—CO—NH—, —NH—CO—O—, —NHSO.sub.2—, —SO.sub.2NH—, —CH.sub.2—SO.sub.2—NH—, —NH—SO.sub.2—CH.sub.2—, —S—CH.sub.2—, —CH.sub.2—S—, —NH—CH.sub.2—, —CH.sub.2—NH—, —O—CH.sub.2— or —CH.sub.2—O—.

32. The compound according to claim 31, wherein Cy.sup.2 is an optionally substituted phenyl group, an optionally substituted biphenyl group, an optionally substituted naphthyl group, an optionally substituted heteroaryl group containing one or two rings and 5, 6, 9 or 10 ring atoms selected from C, O, N and S, an optionally substituted cycloalkyl group containing from 3 to 7 ring atoms, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms selected from C, N, O and S, an optionally substituted heterocycloalkylaryl group containing 9 or 10 ring atoms selected from C, N, S and O, or a group of formula —CH(CH.sub.2Ph)Ph; L is a bond or —NHCO—, —CO—NH—, —CH.sub.2—CO—NH—, —NH—CO—CH.sub.2—, —NHSO.sub.2— or —SO.sub.2NH—; and Cy.sup.1 is a 1,4-phenylene group.

33.-34. (canceled)

35. The compound according to claim 22, wherein R.sup.1 is a group of formula —CH(R.sup.6)—C(═O)—NH—R.sup.7 or a group of formula —CH(R.sup.6)—R.sup.8, wherein R.sup.6 is hydrogen or a C.sub.1-6 alkyl group, a C.sub.3-7 cycloalkyl group, a heterocycloalkyl group containing from 3 to 7 ring atoms selected from C, N, O and S, a phenyl group or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O, or a group of formula —CH.sub.2—R.sup.6awherein R.sup.6a is a C.sub.3-7 cycloalkyl group, a heterocycloalkyl group containing from 3 to 7 ring atoms selected from C, N, O and S, a phenyl group or a heteroaryl group containing 5 or 6 ring atoms selected from C, N, S and O; R.sup.7 is an optionally substituted phenyl group or an optionally substituted C.sub.3-7 cycloalkyl group; and R.sup.8 is an optionally substituted benzimidazole group or an optionally substituted triazole group or an optionally substituted imidazole group.

36.-39. (canceled)

40. Pharmaceutical composition comprising a compound according to claim 22 and optionally one or more carrier substances and/or one or more adjuvants and/or one or more further antibacterial compounds.

41.-42. (canceled)

Description

EXAMPLES

[0133] 1. General Procedures:

##STR00014##

General Procedure A: Synthesis of 2-chloroalkanoic acids (1)

[0134] Amino acid (1.0 equiv.) was dissolved in 6 M hydrochloric acid (2 mL/mmol or until mostly dissolved) under nitrogen atmosphere and cooled to −5° C. Sodium nitrite (3.5 equiv.) was dissolved in water (0.3 mL/mmol amino acid) and slowly added dropwise. The mixture was stirred overnight while warming to rt. The reaction mixture was extracted with EtOAc/THF (3:1, 3 x). The combined organic extracts were washed with saturated aqueous NaCl solution, dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was removed under reduced pressure to afford the crude product, which was used in the next step without further purification.

General Procedure B-1: Synthesis of N-aryl-2-halo-2-alkylacetamide Derivatives (3)

[0135] 2-Haloalkanoic acid (1.2 equiv.) (2-chloroalkanoic acid (1) as crude or commercially available 2-bromoalkanoic acid (2)) and EDC-HCl (1.2 equiv.) were added to a solution of the corresponding aniline (1.0 equiv.) in DCM. The resultant mixture was stirred at rt, until the starting aniline was consumed (monitored by TLC or LC-MS). The obtained solution was washed with 1 M HCl and saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the crude product. The crude product obtained was either used for the next step without further purification or purified using column chromatography.

General Procedure B-2: Synthesis of N-heteroaryl-2-halo-2-alkylacetamide Derivatives

[0136] 2-Haloalkanoic acid (1.0 equiv.) (2-chloroalkanoic acid (1) as crude or commercially available 2-bromoalkanoic acid (2)) was dissolved in THF. Et.sub.3N (1.0 equiv.) was added to this solution at rt, followed by dropwise addition of ethylchloroformate (1.1 equiv.). A solution of the corresponding heterocyclic amine (0.8 equiv.) was dissolved in THF and added dropwise to this mixture. The reaction was stirred at r.t overnight. THF was evaporated, the crude solid was dissolved in DCM, and the solution was washed with aqueous KHCO.sub.3 (10% wt) and water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the crude product. The resultant crude was purified via flash chromatography.

General Procedure C: Synthesis of N-aryl-2-thioacetyl-2-alkylacetamide Derivatives and N-heteroaryl-2-thioacetyl-2-alkylacetamide Derivatives (4)

[0137] N-Aryl-2-halo-2-alkylacetamide derivative or N-heteroaryl-2-halo-2-alkylacetamide derivative (1.0 equiv.) ((3) purified or as crude) was dissolved in acetone, and potassium thioacetate (2.0 equiv.) was added to the solution. The resultant mixture was stirred at rt until full conversion (monitored by TLC or LC-MS). After concentration under vacuum, the resultant residue was diluted with H.sub.2O and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue was purified using column chromatography.

General Procedure D: Synthesis of N-aryl-2-mercapto-2-alkylacetamide Derivatives and N-heteroaryl-2-mercapto-2-alkylacetamide Derivatives (II)

[0138] NaOH (3.0 equiv.) was added to a solution of compound 4 (1.0 equiv.) in MeOH under argon atmosphere. The reaction was stirred at rt. The reaction mixture was acidified with 2 M HCl and extracted with EtOAc. The obtained organic layer was washed with 0.5 M HCl solution and with saturated aqueous NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. In case of heterocyclic derivatives, instead of HCl, pH was adjusted to acidic values with Amberlite IR-120.

[0139] The product was obtained as pure or purified using column chromatography or preparative HPLC.

##STR00015##

General Procedure E: Synthesis of diethyl phosphonate Derivatives (5)

[0140] N-Aryl-2-bromo-2-alkylacetamide derivative (3) (1.0 equiv.) was suspended in triethyl phosphite (10 equiv.), equipped with a reflux condenser, heated to 150° C. and stirred for a total of 18 h. Most of unreacted triethyl phosphite was evaporated in vacuo and the resultant oil was purified by column chromatography.

General Procedure F: Synthesis of phosphonic acid Derivatives (III)

[0141] To a solution of diethyl phosphonate (5) (1.0 equiv.) in dry DCM, bromotrimethylsilane (5.0 equiv.) was added dropwise over a period of 15 min. The reaction mixture was stirred at r.t. overnight. Then, MeOH was added and stirred for 30 min at r.t. to cleave the previously formed TMS ester. Solvents were concentrated in vacuo and the resultant oil was purified by preparative HPLC.

##STR00016##

2-Bromo-4-methylpentanoic acid (2a)

[0142] 10.5 g racemic leucine 1 (80.0 mmol, 1.0 equiv.) was dissolved in 48% HBr (80 mL) and 72 mL dist. water. The mixture was cooled to 0° C. and a solution of NaNO.sub.2 (8.82 g, 128.0 mmol, 1.6 equiv.) in 20 mL dist. water was added dropwise over 2 h. The mixture was warmed up to rt and was stirred overnight. After that, the mixture was transferred into a separatory funnel and extracted with acetone (4×100 mL). The combined organic layers were washed with dist. water (400 mL) and saturated aqueous NaCl solution (400 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The compound 2a (15.06 g, 80.0 mmol, quantitative) was obtained as a pale yellow liquid and was used in the next step without further purification.

Ethyl 2-bromo-4-methylpentanoate (2b)

[0143] To α-bromo acid 2a (15.06 g, 80.0 mmol, 1.0 equiv.) a solution of concentrated sulphuric acid (30 μL/mmol) in ethanol (2 mL/mmol) was added and the mixture was refluxed for 2 h. After that, the solution was cooled to rt and concentrated under reduced pressure. Et.sub.2O (150 mL) was added and the organic layer was washed with aqueous saturated NaHCO.sub.3 solution (150 mL), followed by saturated aqueous NaCl solution (150 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The compound 2b (14.45 g, 64.7 mmol, 81% yield) as a pale yellow liquid and was used in the next step without further purification.

2-(Diethoxyphosphoryl)-4-methylpentanoate (2c)

[0144] The α-bromo ester 2b (14.45 g, 64.7 mmol, 1.0 equiv.) and P(OEt).sub.3 (22.41 mL, 129.4 mmol, 2.0 equiv.) were mixed and heated to 150° C. for 48 h. After that, the mixture was cooled down to rt, and Et.sub.2O (350 mL) was added. The mixture was transferred into a separatory funnel and washed with saturated aqueous NaCl solution (2×350 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The product was purified using flash chromatography (SiO.sub.2, hexanes/EtOAc 1:1), and compound 2c (7.93 g, 28.3 mmol, 44%) was obtained as pale yellow oil. .sup.1H NMR (CDCl.sub.3, 500 MHz) δ ppm: 4.18-4.24 (m, 2H), 4.11-4.17 (m, 4H), 3.00-3.07 (m, 1H), 1.95-2.07 (m, 1H), 1.55-1.66 (m, 2H), 1.33 (dt, 6H, J=2.3, 7.0 Hz), 1.28 (t, 3H, J=7.2 Hz), 0.92 (d, 3H, J=6.1 Hz), 0.89 (d, 3H, J=6.3 Hz). .sup.13C NMR (CDCl.sub.3, 126 MHz) δ ppm: 169.4 (d, J=5.5 Hz), 62.7 (d, J=6.4 Hz), 62.6 (d, J=6.4 Hz), 61.3, 44.5, 43.4, 35.5 (d, J=5.5 Hz), 26.9 (d, J=14.7 Hz), 22.9, 21.2, 16.4 (d, J=3.7 Hz), 16.3 (d, J=3.7 Hz), 14.1. .sup.31P NMR (CDCl.sub.3, 202 MHz) δ ppm: 23.4.

[0145] HRMS (ESI+) calculated for C.sub.12H.sub.26O.sub.5P [M+1].sup.+281.1518, found: 281.1503.

2-(Diethoxyphosphoryl)-4-methylpentanoic acid (2d)

[0146] The compound 2c (7.93 g, 28.3 mmol, 1.0 equiv.) was dissolved in EtOH (270 mL), and NaOH (2.15 g, 53.88 mmol, 2.0 equiv.) in dist. H.sub.2O (100 mL) was added. The mixture was stirred at rt overnight. The progress was monitored using LC-MS. After completion, the mixture was transferred into a separatory funnel, dist. water (300 mL) and Et.sub.2O (400 mL) were added, and the layers were separated. The aqueous layer was acidified to pH=1 using HCl (6 M), and extracted with EtOAc (3×300 mL). The combined EtOAc-layers were washed with saturated aqueous NaCl solution (2×500 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The compound 2d (6.63 g, 26.29 mmol, 98%) was obtained as a pale-yellow oil, which was used without further purification. .sup.1H NMR (CDCl.sub.3, 500 MHz) δ ppm: 8.33 (br s, 2H), 4.13-4.25 (m, 4H), 3.07 (ddd, 1H, J=3.1, 11.3, 23.0 Hz), 1.99 (dddd, 1H, J=4.8, 8.5, 11.4, 13.5 Hz), 1.58-1.70 (m, 1H), 1.49-1.57 (m, 1H), 1.33 (dt, 6H, J=2.7, 7.1 Hz), 0.92 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6 Hz). .sup.13C NMR (CDCl.sub.3, 126 MHz) 5 ppm: 171.9 (d, J=3.7 Hz), 63.7 (d, J=6.4 Hz), 62.9 (d, J=6.4 Hz), 44.4, 43.4, 35.6 (d, J=5.5 Hz), 26.8 (d, J=13.8 Hz), 23.0, 21.2, 16.3 (d, J=2.8 Hz), 16.2 (d, J=2.8 Hz)..sup.31P NMR (CDCl.sub.3, 202 MHz) δ ppm: 24.3. HRMS (ESI+) calculated for C.sub.10H.sub.22O.sub.5P [M+1].sup.+ 253.1205, found: 253.1191.

##STR00017##

General Procedure G: Synthesis of diethyl phosphonate Derivatives (5a)

[0147] Aniline (commercially available or synthesized according to conventional protocols that can be found in literature, examples given in general procedures G-1, G-2, G-3, G-4 below) (1.0 equiv.), 2-(diethoxyphosphoryl)-4-methylpentanoic acid (2d) (1.2 equiv.) and N-methylmorpholine (2.5 equiv.) were dissolved in DCM or DMF. The reaction mixture is cooled in an ice-bath and TBTU (1.5 equiv.) was added. The temperature was maintained for 30 minutes and then allowed to warm up to r.t. As another alternative route, instead of TBTU/NMM, EDC-HCl (2.0 equiv.), HOBt (2.0 equiv.) and DIPEA (2.5 equiv.) were used. In both cases, the reaction mixture was stirred overnight, then washed with water and saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude product was either used for the next step without further purification or purified using column chromatography.

General Procedure G-1: Synthesis of anilines with the amide linker (CONH and CH.SUB.2.CONH)

[0148] The corresponding carboxylic acid (1.2 equiv.) was dissolved in DCM and EDC-HCl (1.2 equiv.) was added, followed by tert-butyl (4-aminophenyl)carbamate (1.0 equiv.). The reaction mixture was stirred at rt. In case a precipitate was formed, it was filtered and washed with DCM. When no precipitate was formed, after the consumption of the starting material, the reaction mixture was washed with 1 M HCl (×2) and saturated aqueous NaCl solution (×1) and purified on column chromatography. Obtained product was suspended in DCM/TFA mixture (3:1) at 0° C. The mixture was then stirred at rt for 2 h. Solvents were evaporated. EtOAc was added, washed with 2.5 M NaOH (×2) and saturated aqueous NaCl solution (×2). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the desired aniline.

General Procedure G-2: Synthesis of anilines with the sulfonamide linker (SO.SUB.2.NH and CH.SUB.2.SO.SUB.2.NH)

[0149] Tert-butyl (4-aminophenyl)carbamate (1.0 equiv.) was dissolved in DCM and cooled to 0° C. Et.sub.3N (1.2 equiv.) was added, followed by the corresponding sulfonyl chloride (1.1 equiv.). The reaction mixture was stirred at rt for 8 h. Precipitate was filtered and filtrate purified on column chromatography. The product obtained was suspended in DCM/TFA mixture (3:1) at 0° C. The mixture was then stirred at rt for 2 h. Solvents were evaporated. EtOAc was added, washed with 2.5 M NaOH (×2) and saturated aqueous NaCl solution (×2). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the desired aniline.

General Procedure G-3: Synthesis of anilines with the ether linker (CH.SUB.2.O)

[0150] Tert-butyl (4-hydroxyphenyl)carbamate (1.0 equiv.) was dissolved in DMF. Potassium carbonate (2.0 equiv.) was added, and the reaction mixture stirred for 15 minutes. The corresponding benzyl bromide was then added drop-wise during 15 minutes and left to stir at rt overnight. Water was added, extracted with EtOAc (×3), and the organic layer was washed with saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Obtained product was suspended in DCM/TFA mixture (3:1) at 0° C. Mixture was then stirred at rt for 2 h. Solvents were evaporated. EtOAc was added, washed with 2.5 M NaOH (×2) and saturated aqueous NaCl solution (×2). Organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the desired aniline.

General Procedure G-4: Synthesis of anilines without linker

[0151] Aryl amine (1.0 equiv.) was placed in a sealed tube, followed by the corresponding boronic acid (1.5 equiv.), NaOH 2M, tetrakis(triphenylphosphine)palladium (0.02 equiv.) and a mixture of dioxane/H.sub.2O (4:1, v:v). The reaction mixture was flushed with N.sub.2 and submitted to microwave irradiation (150° C., 150 W) for 20 minutes. After cooling down to rt, a mixture of EtOAc/H.sub.2O (1:1, v:v) was added to stop the reaction. The aqueous layer was extracted with EtOAc (×3). The organic layer was washed with saturated aqueous NaCl solution (1×) and with water (1×), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified using column chromatography.

##STR00018##

General Procedure H: Synthesis of aniline substituted Derivatives (6)

[0152] The corresponding Boc-protected amino acid (1.0 equiv.) was dissolved in THF (0.1 M) and cooled down to −20° C. Then NMM (2.5 equiv.) and isobutyl chloroformate (1.0 equiv.) were added dropwise. The reaction mixture was stirred at this temperature for 30 minutes and then the aniline (1.0 equiv.), dissolved in THF (1 M), was added. After the reaction mixture had reached rt, it was diluted with EtOAc. The organic phase was washed with KHSO.sub.4 (1 N) solution, saturated NaHCO.sub.3 solution and saturated aqueous NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Column chromatographic purification afforded the corresponding peptide.

General Procedure I: Synthesis of phosphor containing dipeptides (5b)

[0153] The Boc-protected peptide (1.0 equiv.) was dissolved in DCM (0.1 M) and treated at 0° C. with HCl (10.0 equiv., 4 M in dioxane). The mixture was warmed up to rt and after complete conversion (TLC), the solvent was removed under reduced pressure with the result that the crystalline hydrochloride remained, which was subsequently dissolved in DMF (0.1 M). 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (1.1 equiv.) was added to this solution and the reaction mixture was cooled to 0° C. Coupling was achieved by TBTU (1.1 equiv.) and NMM (2.5 equiv.). The reaction mixture was warmed up to rt and after complete conversion (TLC) diluted with EtOAc and washed successively with 1 N KHSO.sub.4 solution, saturated NaHCO.sub.3 solution and saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and the residue was used without further purification for the next step.

##STR00019##

General Procedure J: Synthesis of alkinyl diethyl phosphonates (8)

[0154] Alkyne component 7 (1.0 equiv.), which was synthesized as previously reported (https://doi.org/10.1002/anie.201601564), was dissolved in DCM (10 mL/mmol), and HCl (10.0 equiv., 4 M in dioxane) was added at rt. The mixture was stirred for 18 h and then concentrated under reduced pressure. In the meantime, a mixture of compound 2d (1.1 equiv.) and TBTU (1.2 equiv.) in DMF (5 mL/mmol) was cooled to 0° C. and NMM (2.5 equiv.) was added. The reaction mixture was stirred for 30 minutes and then Boc-deprotected alkenyl amino acid was dissolved in DMF (5 mL/mmol) and added dropwise at 0° C. The mixture was stirred for 22 h and allowed to warm to rt. After addition of EtOAc, the organic layer was subsequently washed with saturated aqueous NaHCO.sub.3solution, 1 M HCl, water and saturated aqueous NaCl solution. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified via automated combiflash purification (Teledyne ISCO).

General Procedure K: Synthesis of 1H-1,2,3-triazole containing diethyl phosphonates (5c)

[0155] A solution of the corresponding alkenyl diethyl phosphonate (1.0 equiv.) and the azide (1.1 equiv.), which was synthesized according to (https://doi.org/10.1016/j.ejmech.2019.06.007) in tBuOH/H.sub.2O/MeOH (2:2:1, 10 mL/mmol) was purged with argon. Sodium ascorbate (20 mol %) and CuSO.sub.4.Math.5 H.sub.2O (10 mol %) were added, and the reaction mixture was stirred at rt for 14 h. Then, saturated EDTA solution was added, and the mixture extracted with EtOAc (×3), the combined organic layers were washed with saturated aqueous NH.sub.4Cl solution and saturated aqueous NaCl solution. After drying over anhydrous Na.sub.2SO.sub.4 and filtration, the solvent was removed under reduced pressure to yield the title compound, which was used in the next step without further purification.

##STR00020##

##STR00021##

General Procedure L: Synthesis of benzannulated heteropentacycles (11)

[0156] The corresponding Boc-protected amino acid (1.0 equiv.) was dissolved in DMF (10 mL/mmol). After cooling to 0° C., NMM (1.1 equiv.) and TBTU (1.1 equiv.) were added subsequently. The reaction mixture was stirred for 30 minutes, and the corresponding nucleophile (1.0) was added. After 3 days, saturated aqueous NH.sub.4Cl solution was added, and the mixture extracted with EtOAc (×3) and subsequently washed with saturated aqueous NaHCO.sub.3solution and saturated aqueous NaCl solution. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure, the crude product was redissolved in toluene (5 mL), and HOAc (5 mL) was added. The mixture was heated under reflux for 3 hours and quenched by the slow addition of saturated aqueous NaHCO.sub.3solution. After stirring for 20 minutes, the mixture was extracted with EtOAc (×3) and washed with 1 M HCl. Subsequent washing with saturated aqueous NaHCO.sub.3solution (×4) and saturated aqueous NaCl solution afforded the title compound after drying over anhydrous Na.sub.2SO.sub.4, filtration and concentration under reduced pressure, which was used in the next step without further purification.

##STR00022##

General Procedure M: Synthesis of ethyl ester Derivatives (12)

[0157] Diethyl 2-alkylmalonate (1.0 equiv.) was dissolved in EtOH/H.sub.2O (4:1), and NaOH (1.2 equiv.) was added. The reaction was stirred at rt overnight. EtOH was evaporated under reduced pressure, saturated aqueous NaHCO.sub.3solution was added and extracted with DCM. The organic layer was discarded. The aqueous layer was acidified with 6 M HCl and extracted with DCM. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The obtained mono-acid (1.2 equiv.) and EDC-HCl (1.2 equiv.) were added to a solution of the corresponding aniline (1.0 equiv.) in DCM. The resultant mixture was stirred at rt, until the starting aniline was consumed (monitored by TLC or LC-MS). The solution obtained was washed with 1 M HCl and saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude product was purified using column chromatography.

General Procedure N: Synthesis of hydroxamic acid Derivatives (IV)

[0158] Ethyl ester derivative 12 (1.0 equiv.) was dissolved in MeOH. NH.sub.2OH 50 wt % in H.sub.2O (same volume as methanol) was added, followed by KCN (0.2 equiv.). The mixture was stirred at rt overnight. Solvents were concentrated under reduced pressure, and the resultant oil was purified by preparative HPLC.

##STR00023##

General Procedure O: Synthesis of 1H-1,2,3-triazole (V) and 2H-1,2,3-triazole (VI) Derivatives

[0159] N-aryl-2-bromo-2-alkylacetamide derivative 3 (1.0 equiv.) was placed in a crimp vial and dissolved in acetone. 1H-1,2,3-triazole (1.1 equiv.) and K.sub.2CO.sub.3 (1.1. equiv.) were added and the mixture heated to 70° C. overnight. EtOAc was added, the organic layer washed with water and saturated aqueous NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by preparative HPLC.

II. Synthesis Examples

Example 1

2-Chloro-3-phenylpropanoic acid

[0160] ##STR00024##

2-Chloro-3-phenylpropanoic acid was prepared according to general procedure A, using D,L-phenylalanine (1.00 g, 6.0 mmol) and sodium nitrite (1.46 g, 21.2 mmol). The crude product was obtained as light-yellow oil (1.05 g, 94%) and used without further purification. .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 7.37-7.24 (m, 5H), 4.51 (dd, J=7.8, 6.9 Hz, 1H), 3.42 (dd, J=14.0, 6.7 Hz, 1H), 3.21 (dd, J=14.1, 7.9 Hz, 1H). MS (ESI.sup.−) m/z 183.25 (M−H).sup.−, 147.23 (M−H—HCl).sup.−.

2-Chloro-N,3-diphenylpropanamide

[0161] ##STR00025##

2-Chloro-N,3-diphenylpropanamide was prepared according to general procedure B-1 using 2-chloro-3-phenylpropanoic acid (934 mg, 5.06 mmol), EDC-HCl (786 mg, 5.06 mmol) and aniline (385 μL, 4.22 mmol). Purification was done via automated flash chromatography (hexane/EtOAc=100:0 to 0:100). The product was obtained as white solid (404 mg, 31%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 7.95 (s, 1H), 7.60-7.52 (m, 2H), 7.38-7.28 (m, 6H), 7.27-7.19 (m, 1H), 7.11-7.04 (m, 1H), 4.76 (t, J=7.5 Hz, 1H), 3.41 (dd, J=13.8, 7.2 Hz, 1H), 3.13 (dd, J=13.9, 7.8 Hz, 1H). MS (ESI.sup.+) m/z 260.08 (M+H).sup.+.

S-(1—Oxo-3-phenyl-1-(phenylamino)propan-2-yl) ethanethioate

[0162] ##STR00026##

S-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl) ethanethioate was prepared according to general procedure C using 2-chloro-N,3-diphenylpropanamide (242 mg, 0.93 mmol) and potassium thioacetate (196 mg, 1.86 mmol). Purification was done via automated flash chromatography (hexane/EtOAc=100:0 to 0:100). The product was obtained as colorless oil (127 mg, 46%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 7.96 (br s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.33-7.22 (m, 6H), 7.12-7.07 (m, 1H), 4.30 (t, J=7.7 Hz, 1H), 3.46 (dd, J=14.1, 8.5 Hz, 1H), 3.01 (dd, J=14.1, 7.1 Hz, 1H), 2.38 (s, 3H), 1.59 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ ppm: 197.3, 168.3, 137.6, 137.6, 129.2, 128.9, 128.6, 127.0, 124.4, 119.8, 48.5, 35.7, 30.4. MS (ESI.sup.+) m/z 300.17 (M+H).sup.+, 258.10 (M-Ac+2H).sup.+.

2-Mercapto-N,3-diphenylpropanamide (1)

[0163] ##STR00027##

[0164] 2-Mercapto-N,3-diphenylpropanamide was prepared according to general procedure D using S-(1-oxo-3-phenyl-1-(phenylamino) propan-2-yl)ethanethioate (127 mg, 0.42 mmol) and NaOH (50 mg, 1.3 mmol). Purification was done via automated flash chromatography (hexane/EtOAc=100:0 to 0:100). The product was obtained as white solid (46 mg, 43%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 8.02 (brs, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.36-7.29 (m, 4H), 7.29-7.23 (m, 4H), 7.14 (t, J=7.6 Hz, 1H), 3.72 (dd, J=14.8, 6.6 Hz, 1H), 3.38 (dd, J=13.8, 6.5 Hz, 1H), 3.24 (dd, J=13.8, 6.8 Hz, 1H), 2.11 (d, J=8.9 Hz, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ ppm: 169.5, 137.3, 137.2, 129.4, 129.0, 128.6, 127.1, 124.8, 120.0, 45.9, 41.5. HRMS (ESI.sup.+) calculated for C.sub.15H.sub.15NOS [M+H].sup.+ 258.0947, found 258.0943.

Example 2

S-(4-Methyl-1-oxo-1-(p-tolylamino)pentan-2-yl) ethanethioate

[0165] ##STR00028##

S-(4-Methyl-1-oxo-1-(p-tolylamino)pentan-2-yl) ethanethioate was synthesized in two steps. The first step was performed according to general procedure B-1, using p-toluidine (80 mg, 0.75 mmol), 2-bromo-4-methylpentanoic acid (175 mg, 0.90 mmol), EDC-HCl (172 mg, 0.90 mmol) and DCM (5 mL). The reaction was stirred at rt for 5 h. The crude product obtained was used in the next step without further purification. The second step was achieved according to general procedure C, using the crude product obtained from the first step, potassium thioacetate (171 mg, 1.49 mmol) and acetone (7 mL). The reaction was stirred at rt for 2.5 h. The crude product was purified using column chromatography (100% DCM). The product was obtained as beige solid (131 mg, 63% (over 2 steps)). 1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.23 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 4.27 (br t, J=7.5 Hz, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.88-1.75 (m, 1H), 1.62-1.40 (m, 2H), 0.95 (d, J=6.5 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 194.5, 168.6, 136.2, 132.6, 129.1, 119.4, 46.4, 41.7, 30.3, 25.9, 22.5, 22.1, 20.5. HRMS (ESI.sup.+) calculated for C.sub.15H.sub.22NO.sub.2S [M+H].sup.+280.1371, found 280.1358.

2-Mercapto-4-methyl-N-(p-tolyl)pentanamide (2)

[0166] ##STR00029##

2-Mercapto-4-methyl-N-(p-tolyl)pentanamide was synthesized according to general procedure D, using S-(4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl) ethanethioate (90 mg, 0.32 mmol), NaOH (39 mg, 0.97 mmol) and MeOH (5 mL). The reaction was stirred at rt for 2 h. The crude product was purified using preparative HPLC (H.sub.2O (HCOOH 0.05%)—CH.sub.3CN (HCOOH 0.05%): 9.0-1.0 to 0.0-10.0). The product was obtained as beige solid (38 mg, 50%, MP=90° C.).sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 9.99 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 3.51 (br t, J=7.8 Hz, 1H), 2.93 (s, 1H), 2.25 (s, 3H), 1.84-1.73 (in, 1H), 1.67-1.56 (m, 1H), 1.54-1.43 (in, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.86 (d, J=6.5 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 170.9, 136.5, 132.4, 129.2, 119.2, 44.4, 39.9, 25.8, 22.2, 22.1, 20.5. HRMS (ESI.sup.+) calculated for C.sub.13H.sub.20NOS [M+H].sup.+ 238.1266, found 238.1254.

TABLE-US-00001 TABLE 1 The following further compounds have been prepared according to the procedures described above: [00030] Example R.sup.1 R.sup.2  4 3,4-di—Cl—Ph Bn  5 4-OH—Ph Bn  6 2-Me—Ph Bn  7 3-Me—Ph Bn  8 4-Me—Ph Bn  9 4-NO.sub.2—Ph Bn 10 4-OMe—Ph Bn 11 Ph 4-OH—Bn 12 Ph 3-NO.sub.2—4-OH—Bn 13 Ph 4-Me—Bn 14 Ph Me 15 3,4-di—Cl—Ph Me 16 4-OMe—Ph Me 17 4-Ac—Ph Me 18 3,4-di—Cl—Ph Et 19 4-OMe—Ph Et 20 4-Ac—Ph Et 21 3,4-di—Cl—Ph iPr 22 4-OMe—Ph iPr 23 4-Ac—Ph iPr 24 Ph nPr 25 4-Me—Ph nPr 26 3,4-di—Cl—Ph nPr 27 4-OMe—Ph nPr 28 4-Ac—Ph nPr 29 3,4-di—Cl—Ph nBu 30 4-OMe—Ph nBu 31 3,4-di—Cl—Ph iBu 32 2-OMe—Ph iBu 33 3-OMe—Ph iBu 34 4-OMe—Ph iBu 35 2,4-di—OMe—Ph iBu 36 3,4-di—OMe—Ph iBu 38 4-Cl—Ph iBu 39 4-Ac—Ph iBu 40 2-OH—Ph iBu 41 4-OH—Ph iBu 42 2-OH—4-Cl—Ph iBu 43 3,4-di—Cl—Ph sBu 44 4-OMe—Ph sBu 45 3,4-di—Cl—Ph cyclopropylmethyl 46 4-OMe—Ph cyclopropylmethyl 47 3,4-di—Cl—Ph cyclohexylmethyl 48 4-OMe—Ph cyclohexylmethyl 49 3,4-di—Cl—Ph CH.sub.2OCH.sub.3 50 4-OMe—Ph CH.sub.2OCH.sub.3 51 3,4-di—Cl—Ph CH.sub.2COOMe 52 4-OMe—Ph CH.sub.2COOMe 53 4-Ac—Ph CH.sub.2COOH 54 3,4-di—Cl—Ph CH.sub.2COOH 55 2-benzothiazolyl Bn 56 6-methoxy-2-benzothiazolyl Bn 57 6-chloro-2-benzothiazolyl Bn 58 2-thiazolyl Bn 59 methyl 2-aminothiophenyl-3-carboxylate Bn 60 pyridin-3-yl Bn 61 2-benzoimidazolyl Bn 62 2-benzothiazolyl iBu

Example 63

Diethyl (4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)phosphonate

[0167] ##STR00031##

Diethyl (4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl) phosphonate was synthesized over two steps. The first step was performed according to general procedure B-1, using p-toluidine (92 mg, 0.85 mmol), 2-bromo-4-methylpentanoic acid (200 mg, 1.02 mmol), EDC-HCl (196 mg, 1.02 mmol) and DCM (15 mL). The reaction was stirred at rt for 5 h. The crude product obtained was used in the next step without further purification. The second step was achieved according to general procedure E, using the crude product obtained from the first step and triethyl phosphite (1.5 mL, 17.1 mmol). The crude product was purified using column chromatography (hexane/EtOAc=1:1). The product was obtained as white solid (114 mg, 39% (over 2 steps)). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 8.41 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 4.21-4.08 (m, 4H), 2.97 (ddd, J=22.6, 11.3, 3.5 Hz, 1H), 2.28 (s, 3H), 2.09-1.99 (m, 1H), 1.77-1.68 (m, 1H), 1.61-1.52 (m, 1H), 1.32 (q, J=7.1 Hz, 6H), 0.97-0.91 (m, 6H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ ppm: 165.6 (J=1.8 Hz), 135.3, 133.8, 129.4, 119.8, 63.0 (J=7.4 Hz), 62.8 (J=6.4 Hz), 45.2 (J=128.6 Hz), 35.8 (J=4.6 Hz), 26.6 (J=13.8 Hz), 23.2, 21.2, 20.8, 16.4 (J=1.8 Hz), 16.4 (J=2.8 Hz). MS (ESl+) m/z 342.2 [M+H].sup.+.

(4-Methyl-1-oxo-1-(p-tolylamino)pentan-2-vl)phosphonic acid (63)

[0168] ##STR00032##

(4-Methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)phosphonic acid was synthesized according to general procedure F, using diethyl (4-methyl-1-oxo-1-(p-tolylamino)pentan-2-yl)phosphonate (110 mg, 0.32 mmol), bromotrimethylsilane (213 μL, 1.61 mmol) and DCM (6 mL). The reaction was stirred at rt overnight. Then, MeOH (10 mL) was added, the reaction mixture was stirred for additional 30 minutes, and the solvent evaporated under the reduced pressure. The crude product was purified using preparative HPLC (CH.sub.3CN (HCOOH 0.05%)-H.sub.2O (HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was obtained as white solid (56 mg, 71%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 9.84 (s, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 2.95 (ddd, J=22.4, 11.4, 2.9 Hz, 1H), 2.22 (s, 3H), 1.99-1.89 (m, 1H), 1.51-1.34 (m, 2H), 0.87-0.82 (m, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 167.6 (J=4.6 Hz), 137.0, 131.8, 129.0, 119.0, 46.0 (J=126.8 Hz), 35.8 (J=3.7 Hz), 26.5 (J=14.7 Hz), 23.3, 21.4, 20.5. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 20.1. HRMS (ESI.sup.−) calculated for C.sub.13H.sub.19NO.sub.4P [M−H].sup.− 284.1057, found 284.1058.

Example 95

[0169] ##STR00033##

Diethyl (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate

[0170] ##STR00034##

Diethyl (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate was synthesized according to general procedure G, using 2-(4-isopropoxyphenyl)pyrimidin-5-amine synthesized according to the general procedure G-4 (60 mg, 0.26 mmol), 2d (100 mg, 0.40 mmol), EDC-HCl (100 mg, 0.52 mmol) in DCM (5 mL). The crude product was purified using column chromatography (DCM/MeOH from 0% to 3%). The product was obtained as white solid (84 mg, 69%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm:10.27 (s, 1H), 8.79 (s, 2H), 7.90 (d, J=8.8 Hz, 2H), 6.69 (d, J=8.8 Hz, 2H), 4.50 (hept, J=6.0 Hz, 1H), 4.32-4.17 (m, 2H), 4.10 (p, J=7.2 Hz, 2H), 3.34 (ddd, J=22.8, 11.3, 2.8 Hz, 1H), 2.17-2.06 (m, 1H), 1.60-1.52 (m, 1H), 1.43 (dtd, J=13.1, 10.2, 2.9 Hz, 1H), 1.31 (ddd, J=19.2, 12.6, 6.2 Hz, 12H), 0.86 (dd, J=13.1, 6.5 Hz, 6H). MS (ESI.sup.+) m/z 464 [M+H].sup.+.

(1-((2-(4-Isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (95)

[0171] ##STR00035##

(1-((2-(4-Isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (95) was synthesized according to general procedure F, using diethyl (1-((2-(4-isopropoxyphenyl)pyrimidin-5-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (65 mg, 0.14 mmol), bromotrimethylsilane (100 μL, 0.72 mmol) and DCM (4 mL). The reaction was stirred at rt overnight. Then, MeOH (4 mL) was added, the reaction mixture was stirred for additional 30 minutes, and the solvent evaporated under the reduced pressure. The crude product was purified using preparative HPLC (CH.sub.3CN (HCOOH 0.05%)-H.sub.2O (HCOOH 0.05%). The product was obtained as white solid (41 mg, 72%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.46 (s, 1H), 9.05 (s, 2H), 8.24 (d, J=8.9 Hz, 2H), 7.01 (d, J=8.9 Hz, 2H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 3.04 (ddd, J=22.4, 11.1, 2.3 Hz, 1H), 2.00 (ddd, J=15.4, 10.0, 3.7 Hz, 1H), 1.61-1.35 (m, 2H), 1.30 (d, J=6.0 Hz, 6H), 0.88 (d, J=6.3 Hz, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 169.24, 169.20, 159.76, 158.52, 147.75, 132.71, 129.72, 129.36, 115.87, 69.75, 47.05, 46.05, 36.10, 36.06, 26.98, 26.87, 23.59, 22.28, 21.82. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 18.93. MS (ESI.sup.+) m/z 408 [M+H].sup.+.

Example 108

[0172] ##STR00036##

N-(4-Aminophenyl)-3,4-dichlorobenzenesulfonamide

[0173] ##STR00037##

N-(4-Aminophenyl)-3,4-dichlorobenzenesulfonamide was synthesized according to general procedure G-2, using tert-butyl (4-aminophenyl)carbamate (300 mg, 1.44 mmol), Et.sub.3N (240 μL, 1.73 mmol) and 3,4-dichlorobenzenesulfonyl chloride (250 μL, 1.58 mmol) in DCM (10 mL). Reaction mixture was stirred at rt for 8 h. Precipitate was filtered and filtrate purified on column chromatography (hexanes/EtOAc=7/3) giving tert-butyl (4-((3,4-dichlorophenyl)sulfonamido)phenyl)carbamate (316 mg, 52%). Obtained tert-butyl (4-((3,4-dichlorophenyl)sulfonamido)phenyl)carbamate was suspended in 3.5 mL DCM/TFA (3:1) and stirred at rt for 2 h. After the workup, N-(4-aminophenyl)-3,4-dichlorobenzenesulfonamide (193 mg, 81%) was obtained as beige solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 9.65 (br s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.54 (dd, J=8.5, 2.1 Hz, 1H), 6.66 (d, J=8.7 Hz, 2H), 6.40 (d, J=8.7 Hz, 2H), 5.01 (br s, 2H). MS (ESI.sup.−) m/z 314.99 [M−H].sup.−.

Diethyl (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate

[0174] ##STR00038##

Diethyl (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate was synthesized according to general procedure G, using N-(4-aminophenyl)-3,4-dichlorobenzenesulfonamide (84 mg, 0.26 mmol), 2d (100 mg, 0.40 mmol), EDC-HCl (100 mg, 0.52 mmol), HOBt (80 mg, 0.52 mmol) and DIPEA (110 μL, 0.62 mmol) in DCM (5 mL). The crude product was purified using column chromatography (hexanes/EtOAc=3/7). The product was obtained as white foam (84 mg, 58%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.27 (br s, 1H), 10.11 (s, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 2.1 Hz, 1H), 7.49-7.44 (m, 2H), 7.05-7.00 (m, 2H), 4.06-3.95 (m, 4H), 3.15 (ddd, J=22.6, 11.3, 3.1 Hz, 1H), 1.98-1.88 (m, 1H), 1.49-1.29 (m, 2H), 1.18 (dt, J=9.1, 7.1 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H). MS (ESI.sup.+) m/z 551.12 [M+H].sup.+.

(1-((4-((3,4-Dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (108)

[0175] ##STR00039##

(1-((4-((3,4-Dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid was synthesized according to general procedure F, using diethyl (1-((4-((3,4-dichlorophenyl)sulfonamido)phenyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (80 mg, 0.14 mmol), bromotrimethylsilane (100 μL, 0.72 mmol) and DCM (4 mL). The reaction was stirred at rt overnight. Then, MeOH (4 mL) was added, the reaction mixture was stirred for additional 30 minutes and the solvent evaporated under the reduced pressure. The crude product was purified using preparative HPLC (CH.sub.3CN (HCOOH 0.05%)-H.sub.2O (HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was obtained as white solid (48 mg, 70%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.22 (s, 1H), 9.92 (s, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.60 (dd, J=8.4, 2.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.01-6.97 (m, 2H), 2.93 (ddd, J=22.5, 11.3, 2.8 Hz, 1H), 1.97-1.88 (m, 1H), 1.49-1.34 (m, 2H), 0.83 (d, J=6.4 Hz, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 167.8 (d, J=5.5 Hz), 139.66, 136.86, 135.99, 132.15, 131.73, 131.51, 128.40, 126.85, 122.33, 119.82, 46.0 (d, J=126.8 Hz), 35.7 (d, J=3.7 Hz), 26.4 (d, J=14.7 Hz), 23.2, 21.3. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 19.8. HRMS (ESI.sup.−) calculated for C.sub.18H.sub.20Cl.sub.2N.sub.2O.sub.6PS [M−H].sup.− 493.0162, found 493.0156.

Example 147

[0176] ##STR00040##

Tert-butyl-(S)-(1-(4-chlorobenzyl)piperidin-3-yl)carbamate

[0177] ##STR00041##

To a heat-dried 50 mL Schlenk tube was added (S)-3-(Boc-amino)piperidine (200.3 mg, 1 mmol, 1 equiv.) and 4-chlorobenzyl bromide (205.5 mg, 1 mmol, 1 equiv.) and dissolved in dry DCM (2.5 mL, 0.4 M) followed by addition of Et.sub.3N (303.6 mg, 418.1 μL, 3 mmol, 3 equiv.) under nitrogen atmosphere. The reaction mixture was stirred at r.t. and after completion of the reaction (LCMS, 16 h) water (5 mL) was added, and the reaction mixture was extracted with DCM (3×10 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered, and volatiles were removed under reduced pressure to obtain the titled compound as an off-white solid (322 mg), which was used in the next step without further purification.

(S)-1-(4-Chlorobenzyl)piperidin-3-amine

[0178] ##STR00042##

In a 50 mL Schlenk tube, crude tert-butyl-(S)-(1-(4-chlorobenzyl)piperidin-3-yl)carbamate (322 mg, approx. 0.99 mmol, 1 equiv.) was dissolved in DCM (3 mL, 0.4 M). To a resulting solution was added TFA (383 μL, 5 equiv.), and the reaction mixture was kept stirring at rt. After completion of the reaction (LCMS, 19 h) solvent was removed under reduced pressure to obtain an oily residue, which was treated with 2M NaOH solution and extracted with EtOAc (3×20 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered, and volatiles were removed under reduced pressure to obtain the title compound as an oil (207 mg), which was used in the next step without further purification.

Diethyl (1-(((S)-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate

[0179] ##STR00043##

To a 4 mL glass vial were added (S)-1-(4-chlorobenzyl)piperidin-3-amine (50 mg, approx. 0.22 mmol, 1 equiv.), 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (84.2 mg, 0.33 mmol, 1.5 equiv.), HOBt.Math.H.sub.2O (68.2 mg, 0.44 mmol, 2 equiv.) and dissolved in DMF (1.5 mL). To the resulting solution was added EDC-HCl (85.3 mg, 0.44 mmol, 2 equiv.) and DIPEA (93 μL, 0.53 mmol, 2.4 equiv.) and the reaction was kept stirring at rt. After complete conversion (LCMS, 18 h), water (5 mL) and EtOAc (5 mL) were added to the reaction. The organic phase was removed, and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were passed through a pad of anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain the title compound (55 mg), which was used in the next step without further purification.

(1-(((S)-1-(4-Chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (147)

[0180] ##STR00044##

To a heat-dried 25-mL Schlenk tube were added crude diethyl (1-(((S)-1-(4-chlorobenzyl)piperidin-3-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (53 mg, 0.115 mmol, 1 equiv.) and dry DCM (1 mL) under argon. To the resulting solution was added dropwise bromotrimethylsilane (107 μL, 0.81 mmol, 7 equiv.), and the reaction kept stirring at r.t. After completion of the reaction (LCMS, 23h), MeOH (2 mL) was added and stirred at r.t. for 30 min. The volatiles were removed under reduced pressure and the crude was purified on preparative HPLC to obtain the title compound as white amorphous solid (21 mg, 0.052 mmol, 45%).

Mixture of Diastereomers:

[0181] Major diastereomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.05 (s, 1H), 7.72-7.24 (m, 4H), 4.43-4.18 (m, 2H), 4.08-3.92 (m, 1H), 3.44-3.04 (m, 2H), 3.00-2.30 (m, 3H), 1.98-1.80 (m, 2H), 1.80-1.62 (m, 2H), 1.54-1.27 (m, 3H), 0.81 (dd, J=6.4, 5.8 Hz, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 169.4, 158.6 (dd, J=31.2, 30.6 Hz), 134.8, 133.8, 133.7, 129.3, 58.7, 54.3, 51.0, 45.9 (d, J=124.0 Hz), 43.9, 36.0, 26.9 (t, J=14.5 Hz), 23.6, 21.8. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 19.7.

[0182] Minor diastereomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.05 (s, 1H), 8.39-7.77 (m, 4H), 4.47-4.18 (m, 3H), 3.44-3.04 (m, 2H), 3.00-2.30 (m, 3H), 1.98-1.80 (m, 2H), 1.80-1.62 (m, 2H), 1.54-1.27 (m, 3H), 0.81 (dd, J=6.4, 5.8 Hz, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 169.7, 158.6 (dd, J=31.2, 30.6 Hz), 134.9, 133.8, 133.7, 129.2, 58.7, 54.3, 51.5, 45.6 (d, J=125.0 Hz), 43.9, 27.8 (dd, J=33.1, 15.6 Hz), 23.6, 21.8. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 19.6.

[0183] HRMS (ESI+) calculated for C.sub.18H.sub.29ClN.sub.2O.sub.4P [M+1].sup.+ 403.1553, found 403.1537.

Example 151

Tert-butyl (3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0184] ##STR00045##

3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (46.6 mg, 0.205 mmol, 1.0 equiv.) was prepared as previously described (https://doi.org/10.1002/ejoc.201701296) and dissolved in DMF (2 mL), cooled to 0° C. and TBTU (73.0 mg, 0.23 mmol, 1.1 equiv.) was added, followed by addition of NMM (24 μL, 0.23 mmol, 1.1 equiv.). The reaction mixture was stirred at the indicated temperature for 1 hour and then 3,4-dichloroaniline (33 mg, 0.205 mmol) was added. After stirring 16 hours and warming up to rt, EtOAc was added and subsequently washed with saturated NaHCO.sub.3solution, 1 M HCl, water and saturated aqueous NaCl solution. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a colorless solid (42 mg, 0.113 mmol, 55%), which was used in the next step without further purification. .sup.1H NMR (CDCl.sub.3, 500 MHz) δ ppm: 7.77-7.76 (m, 1H), 7.38-7.37 (m, 2H), 7.12 (bs, 1H), 5.00 (bs, 1H), 2.37 (s, 6H), 1.47 (s, 9H). .sup.13C NMR (CDCl.sub.3, 126 MHz) δ ppm: 167.4, 136.8, 132.9, 130.6, 121.4, 118.8, 53.8, 45.1, 28.4. MS (ESI+): m/z [M+H].sup.+=372

Diethyl (1-((3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate

[0185] ##STR00046##

The title compound was prepared according to general procedure I. Tert-butyl (3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (40 mg, 0.108 mmol) and HCl (0.27 mmol, 1.08 mmol, 4 M in dioxane) were used for the deprotection. 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (30 mg, 0.119 mmol), NMM (31 μL, 0.298 mmol) and TBTU (43 mg, 0.131 mmol) were used in the peptide coupling to afford the title compound as a yellow oil (36.7 mg, 0.073 mmol, 67%), which was used in the next step without further purification. MS (ESI+): m/z [M+H].sup.+=506.

(1-((3-((3,4-Dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (151)

[0186] ##STR00047##

The title compound was prepared according to general procedure F. Diethyl (1-((3-((3,4-dichlorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (36 mg, 0.071 mmol) and bromotrimethylsilane (47 μL, 0.356 mmol) were used to afford the title compound as a colorless solid (8.6 mg, 0.019 mmol, 27%) after purification via preperative HPLC.

[0187] Mixture of diastereomeres 1H NMR (500 MHz, acetone-d.sub.6) δ ppm: 8.05 (d, J=2.3 Hz, 1H), 7.62 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 3.02-2.94 (m, 1H), 2.40 (s, 6H), 2.01-1.98 (m, 1H), 1.65-1.61 (m, 1H), 1.59-1.53 (m, 1H), 0.92 (d, J=6.3 Hz, 6H). .sup.13C NMR (126 MHz, acetone-d.sub.6) δ ppm: 169.9, 167.8, 138.9, 131.6, 130.4, 125.6, 121.0, 119.3, 53.8, 45.8, 45.0, 44.8, 38.2, 35.7, 26.7, 22.6, 21.0. 31P NMR (202 MHz, acetone-d.sub.6) δ ppm: 24.7, 24.6. HRMS (ESI+) calculated for C.sub.18H.sub.24Cl.sub.2N.sub.2O.sub.5P [M+H].sup.+ 449.0794, found: 449.0798.

Example 152

Tert-Butyl (S)-(1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate

[0188] ##STR00048##

(Tert-butoxycarbonyl)-L-valine (434 mg, 2.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL, 0.1 M) and cooled down to −20° C. Then NMM (0.55 ml, 2.5 equiv.) and isobutyl chloroformate (0.259 mL, 1.0 equiv.) were added dropwise. The reaction mixture was stirred at this temperature for 30 minutes and then the aniline (324 mg, 2 mmol, 1.0 equiv.), dissolved in THF (1 M), was added. After the reaction mixture had reached rt, it was diluted with EtOAc. The organic phase was washed with KHSO.sub.4 (1 N) solution, saturated aqueous NaHCO.sub.3solution and saturated aqueous NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. Purification by column chromatography (SiO.sub.2, hexanes/EtOAc 9:1) afforded the corresponding tert-butyl (S)-(1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (523.8 mg, 1.44 mmol, 72% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 8.85 (br s, 1H), 7.70 (br s, 1H), 7.2-7.3 (m, 2H), 5.27 (br d, 1H, J=8.2 Hz), 4.06 (br t, 1H, J=7.6 Hz), 2.15 (br d, 1H, J=6.1 Hz), 1.47 (s, 9H), 1.03 (dd, 6H, J=2.7, 6.7 Hz). .sup.13C NMR (126 MHz, CDCl.sub.3,) δ ppm: 170.7, 137.2, 132.5, 130.2, 121.2, 118.6, 61.1, 30.5, 28.3, 19.3, 18.4. HRMS (ESI+) calculated for C.sub.16H.sub.23C.sub.12N.sub.2O.sub.3 [M+H].sup.+ 361.1080, found 361.1080.

(1-(((S)-1-((3,4-Dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (152)

[0189] ##STR00049##

Tert-butyl (S)-(1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (100.0 mg, 0.28 mmol, 1.0 equiv.) was dissolved in DCM (0.1 M) and treated at 0° C. with HCl (0.69 mL, 10.0 equiv., 4 M in dioxane). The mixture was warmed up to rt and after complete conversion (TLC), the solvent was removed under reduced pressure with the result that the crystalline hydrochloride remained, which was subsequently dissolved in DMF (2.8 mL, 0.1 M). 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (77.7 mg, 0.308 mmol, 1.1 equiv.) was added to this solution, and the reaction mixture was cooled to 0° C. Coupling was achieved by TBTU (98.9 mg, 0.308 mmol, 1.1 equiv.) and NMM (0.08 mL, 2.5 equiv.).

[0190] The reaction mixture was warmed up to rt and after complete reaction (TLC) diluted with EtOAc and washed successively with 1N KHSO.sub.4 solution, saturated NaHCO.sub.3 solution and saturated aqueous NaCl solution. After drying over Na.sub.2SO.sub.4 and removing the solvent under reduced pressure, residue diethyl (1-(((S)-1-((3,4-dichlorophenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (136.7 mg, 0.28 mmol, quant.) was used without further purification for the next step. To a solution of diethyl phosphonate dipeptides (136.7 mg, 0.28 mmol) in DCM (0.1 M), bromotrimethylsilane (0.26 mL, 1.93 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was stirred at rt overnight. Then MeOH was added and stirred for 30 minutes at rt to cleave the previously formed TMS ester. The solvents were removed under reduced pressure and the crude product was purified via a Waters Autopurifier System (APS) with a Phenomenex Gemini C18 column (250×4.6 mm, particle size 5 μm) using mass trigger detection to afford dipeptide 152 (51.7 mg, 0.12 mmol, 43%) as a white amorphous solid.

[0191] Mixture of Diastereomers:

[0192] Major diastereomer: .sup.1H NMR (500 MHz, MeOH-d.sub.4,) δ ppm: 8.04 (d, 1H, J=2.4 Hz), 7.62 (dd, 1H, J=2.4, 8.9 Hz), 7.42 (d, 1H, J=8.9 Hz), 4.45 (d, 1H, J=5.0 Hz), 3.24 (ddd, 1H, J=2.7, 11.6, 23.3 Hz), 2.42 (qd, 1H, J=6.9, 12.1 Hz), 1.47-1.61 (m, 3H), 0.9-1.1 (m, 19H), 0.99 (d, 3H, J=7.02 Hz), 0.98 (d, 3H, J=6.87 Hz), 0.95 (d, 6H, J=6.56 Hz). .sup.13C NMR (126 MHz, MeOH-d.sub.4) δ ppm: 172.7, 172.5 (d, J=4.6 Hz), 139.6, 133.2, 131.5, 128.2, 123.5, 121.6, 60.7, 47.1, 46.0, 36.3 (d, J=4.6 Hz), 31.2, 28.4 (d, J=15.6 Hz), 23.7, 21.8, 19.9, 17.8 .sup.31P NMR (202 MHz, MeOH-d.sub.4) δ ppm: 22.7.

[0193] Minor diastereomer: 1H NMR (500 MHz, MeOH-d.sub.4) δ ppm: 7.92 (dd, 1H, J=0.61, 1.83 Hz), 7.44-7.46 (m, 1H), 4.27 (d, 1H, J=7.48 Hz), 3.24 (ddd, 1H, J=2.7, 11.9, 22.4 Hz), 1.95-2.20 (m, 2H), 1.28-1.35 (m, 2H), 1.05 (d, 3H, J=6.71 Hz), 1.00 (d, 3H, J=6.71 Hz), 0.92 (d, 3H, J=6.10 Hz), 0.90 (d, 3H, J=6.26 Hz). .sup.13C NMR (126 MHz, MeOH-d.sub.4) δ ppm: 172.6, 172.0 (d, J=4.6 Hz), 139.7, 133.5, 131.7, 128.1, 122.8, 120.8, 61.5, 46.8, 45.8, 37.3 (d, J=4.6 Hz), 32.3, 28.1 (d, J=15.6 Hz), 23.8, 21.9, 19.1. .sup.31P NMR (202 MHz, MeOH-d.sub.4) δ ppm: 22.4. HRMS (ESI+) calculated for C.sub.17H.sub.26Cl.sub.2N.sub.2O.sub.5P [M+H].sup.+ 439.0956, 439.0935.

Example 170

[0194] ##STR00050##

Diethyl (4-methyl-1-(((S)-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate

[0195] ##STR00051##

Compound tert-butyl (S)-(4-methylpent-1-yn-3-yl)carbamate (282 mg, 1.43 mmol), which was synthesized as previously reported (https://doi.org/10.1002/anie.201601564), was dissolved in DCM (11 mL) and HCl (, 2.85 mL, 11.4 mmol, 4 M in dioxane) was added at rt to afford the corresponding Boc-deprotected alkinyl amine hydrochloride. The mixture was stirred for 18 h and then concentrated under reduced pressure. In the meantime, a mixture of compound 2d (396 mg, 1.57 mmol) and TBTU (562 mg, 1.75 mmol) in DMF (7.5 mL) was cooled to 0° C., and NMM (0.91 mL, 3.58 mmol) was added. The reaction mixture was stirred for 30 min and then previously prepared Boc-deprotected alkinyl amine hydrochloride was dissolved in DMF (7.5 mL) and added dropwise at 0° C. The mixture was stirred for 22 h and allowed to warm to rt. After addition of EtOAc, the organic layer was subsequently washed with saturated aqueous NaHCO.sub.3solution, 1 M HCl, water and saturated aqueous NaCl solution. The organic layer was dried over Na.sub.2SO.sub.4 and the solvent removed under reduced pressure. The crude product was purified via automated combiflash purification (Teledyne ISCO) and yielded 359 mg of diethyl (4-methyl-1-(((S)-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate (1.08 mmol, 76% over 2 steps). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 6.68-6.58 (m, 1H), 4.67-4.64 (m, 1H), 4.18-4.09 (m, 4H), 2.87-2.80 (m, 1H), 2.24-2.23 (m, 1H), 1.99-1.93 (m, 2H), 1.70-1.61 (m, 1H), 1.56-1.52 (m, 1H), 1.34-1.30 (m, 6H), 1.02-1.00 (m, 6H), 0.95-0.90 (m, 6H). MS (ESI+): m/z [M+H].sup.+=332.

Diethyl (1-(((S)-1-(1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate

[0196] ##STR00052##

A solution of (4-methyl-1-(((S)-4-methylpent-1-yn-3-yl)amino)-1-oxopentan-2-yl)phosphonate (293 mg, 0.89 mmol) and 4-azido-1,2-dichlorobenzene (170 mg, 0.904 mmol), which was synthesized according to literature (https://doi.org/10.1016/j.ejmech.2019.06.007) in 2 mL tBuOH/H.sub.2O/MeOH (2:2:1) was purged with argon. Na ascorbate (20 mol %) and CuSO.sub.4.Math.5 H.sub.2O (10 mol %) were added, and the reaction mixture was stirred for 14 h at rt. Then, saturated EDTA solution was added and the mixture extracted with EtOAc (×3), the combined organic layers were washed with saturated aqueous NH.sub.4Cl solution and saturated aqueous NaCl solution. After drying over Na.sub.2SO.sub.4 and filtration, the solvent was evaporated to yield the title compound (394 mg, 0.759 mmol, 84%, mixture of diastereomers) which was used in the next step without further purification. MS (ESI+): m/z [M+H].sup.+=520.

(1-(((S)-1-(1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (170)

[0197] ##STR00053##

The title compound was prepared according to general procedure F. 52 mg (0.100 mmol) of compound diethyl (1-(((S)-1-(1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate was used and yielded the title compound after purification via preparative HPLC (12 mg, 0.026 mmol, 26%, Mixture of diastereomers:

[0198] Major diastereomer: .sup.1H NMR (500 MHz, MeOH-d.sub.4) δ ppm: 8.44 (s, 1H), 8.10-8.09 (m, 1H), 7.83-7.80 (m, 1H), 7.75-7.73 (m, 1H), 4.99-4.97 (m, 1H), 3.03-2.96 (m, 1H), 2.35-2.30 (m, 1H), 2.13-2.06 (m, 1H), 1.49-1.43 (m, 2H), 1.06-0.98 (m, 6H), 0.87-0.84 (m, 6H). .sup.31P NMR (202 MHz, MeOH-d.sub.4) δ ppm: 22.3. Minor diastereomer: 1H NMR (500 MHz, MeOH-d.sub.4) δ ppm: 8.58 (s, 1H), 8.10-8.09 (m, 1H), 7.83-7.80 (m, 1H), 7.73-7.70 (m, 1H), 5.08-5.07 (m, 1H), 3.17-3.12 (m, 1H), 2.42-2.35 (m, 1H), 2.02-1.98 (m, 1H), 1.61-1.51 (m, 2H), 0.98-0.95 (m, 6H). .sup.31P NMR (202 MHz, MeOH-d.sub.4,) δ ppm: 22.3. HRMS (ESI+) calculated for C.sub.18H.sub.26Cl.sub.2N.sub.4O.sub.4P [M+H].sup.+ 463.1063, found: 463.1065.

Example 171

[0199] ##STR00054##

Diethyl (1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate

[0200] ##STR00055##

The corresponding imidazolyl amino acid derivative tert-butyl (S)-(1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamate was synthesized as previously reported in the literature (https://doi.org/10.1016/j.ejmech.2016.08.070). Tert-butyl (S)-(1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamate (77 mg, 0.200 mmol) was dissolved in DCM (2 mL) and HCl (0.25 mL, 1.00 mmol, 4 M in dioxane) was added. After full consumption of the starting material (LCMS) the solvent was evaporated to yield (S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropan-1-amine hydrochloride, which was used in the coupling step without further purification. The title compound was synthesized using general procedure I using aforementioned (S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropan-1-amine hydrochloride, compound 2d (51 mg, 0.200 mmol), TBTU (70.6 mg, 0.220 mmol), NMM (53 μL, 0.500 mmol) in DMF (2 mL). Automated combiflash purification (Teledyne ISCO) yielded the title compound (22 mg, 0.042 mmol, 21%) as a mixture of diastereomers. MS (ESI+): m/z [M+H].sup.+=519.

[0201] Mixture of Diastereomers:

[0202] Major diastereomer: .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 7.88 (bs, 1H), 7.54 (dd, J=8.2 Hz, J=1.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.25 (bs, 1H), 5.26-5.23 (m, 1H), 4.20-4.09 (m, 4H), 3.00-2.93 (m, 1H), 2.76-2.68 (m, 1H), 2.18-2.11 (1 H), 1.70-1.61 (m, 1H), 1.52-1.44 (m, 1H), 1.34 (dd, J=6.10 Hz, 3H), 1.30 (dd, J=7.1 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.94 (dd, J=7.1 Hz, 6H), 0.90 (d, J=6.7 Hz, 3H). .sup.31P NMR (202 MHz, CDCl.sub.3) δ ppm: 26.3.

[0203] Minor diastereomer (selected signals): .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 7.93 (d. J=1.8 Hz, 1H), 7.64 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.08-4.04 (m, 4H), 3.09-3.03 (m, 1H), 2.58-2.51 (m, 1H). .sup.31P NMR (202 MHz, CDCl.sub.3) δ ppm: 26.5.

(1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonic acid (171)

[0204] ##STR00056##

The title compound was prepared according to general procedure F. Diethyl (1-(((S)-1-(5-(3,4-dichlorophenyl)-1H-imidazol-2-yl)-2-methylpropyl)amino)-4-methyl-1-oxopentan-2-yl)phosphonate (22 mg, 0.042 mmol) and bromotrimethylsilane (28 μL, 0.212 mmol) in DCM (0.5 mL) were used. Purification via preperative HPLC afforded the title compound as a colorless solid_(5.2 mg, 0.011 mmol, 26%, mixture of diastereomeres).

[0205] Mixture of Diastereomers:

[0206] Major diastereomer: 1H NMR (500 MHz, MeOH-d.sub.4) δ ppm: 8.09 (d, J=1.8 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=8.4 Hz, J=1.7 Hz, 1H), 7.62 (d, J=8.64 Hz, 1H), 5.21 (d, J=5.0 Hz,), 3.33-3.25 (m, 1H), 2.52-2.46 (m, 1H), 2.10-2.04 (m, 1H), 1.62-1.53 (m, 2H), 1.09 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.95 (dd, J=5.7 Hz, 6H). .sup.13C NMR (126 Mhz, MeOH-d.sub.4) δ ppm: 174.3, 151.1, 134.5, 132.9, 132.5, 131.1, 128.9, 126.8, 117.6, 61.7, 54.1, 47.6, 36.0, 32.3, 28.8, 23.5, 22.1, 19.4, 17.5, 14.6. .sup.31P NMR (202 MHz, MeOH-d.sub.4) δ ppm: 19.7.

[0207] Minor diastereomer (selected signals): .sup.1H NMR (500 MHz, MeOH-d.sub.4) δ ppm: 8.04 (d, J=2.1 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.89 (bs, 1H), 7.63 (d, J=7.6 Hz, 1H), 3.18-3.16 (m, 1H), 2.42-2.38 (m, 1H), 1.54-1.53 (m, 2H), 1.13 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.4 Hz, 3H). .sup.13C NMR (126 MHz, MeOH-d.sub.4) δ ppm: 134.6, 132.7, 128.8, 126.9, 54.9, 32.7, 23.6, 22.0, 19.7.

Example 172

[0208] ##STR00057##

Tert-butyl (S)-(1-((2-amino-5-phenoxyphenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate

[0209] ##STR00058##

The title compound was synthesized using general procedure L. Boc-Val-OH (543 mg, 2.50 mmol) was dissolved in DMF (25 mL) and NMM (302 μL, 2.75 mmol) followed TBTU (894 mg, 2.75 mmol) were added at 0° C. The reaction mixture was stirred at this temperature for 30 min and 4-phenoxybenzene-1,2-diamine (500 mg, 2.5 mmol) was added. After warming up to r.t. overnight, the reaction was quenched with saturated aqueous NaHCO.sub.3solution and extracted with EtOAc (×3). The combined organic layers were subsequently washed with 1 M HCl, water and saturated aqueous NaCl solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was obtained as a brown foam (1.00 g, 2.50 mmol, quantitative) and used in the next step without further purification. .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 7.62 (bs, 1H), 7.34-7.31 (m, 2H), 7.11-7.08 (m, 2H), 7.02-7.00 (m, 2H), 6.42-6.39 (m, 2H), 5.11 (bs, 1H), 3.99-3.97 (m, 1H), 2.31-2.23 (m, 1H), 1.46 (s, 9H), 1.07 (dd, J=6.71 Hz, 3H), 1.04 (dd, J=6.71 Hz, 3H). MS (ESI+): m/z [M+H].sup.+=400.

Tert-butyl (S)-(2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)carbamate

[0210] ##STR00059##

The title compound was synthesized using general procedure L. Tert-butyl (S)-(1-((2-amino-5-phenoxyphenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (200 mg, 1.00 mmol) was dissolved in 5 mL toluene/HOAc (1:1) and heated under reflux (pre-heated oil bath) for 3 h. After cooling to r.t. saturated aqueous NaHCO.sub.3solution was added carefully until pH=9. The solution was then stirred for 20 min and extracted with EtOAc (×3), washed with saturated aqueous NaHCO.sub.3solution (×4), water (×2) and saturated aqueous NaCl solution. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as an orange solid (191 mg, 0.500 mmol, quantitative), which was used in the next step without further purification. MS (ESI+): m/z [M+H].sup.+=382.

Diethyl (4-methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1-oxopentan-2-yl)phosphonate

[0211] ##STR00060##

Tert-butyl (S)-(2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)carbamate (159 mg, 0.417 mmol) was dissolved in DCM (4 mL) and then HCl (4 M in 1,4-dioxane, 1.04 mL, 4.17 mmol) was added. The reaction mixture was stirred for 18 h at r.t. and then concentrated under reduced pressure. In the meantime, a mixture of 2-(diethoxyphosphoryl)-4-methylpentanoic acid 2d (116 mg, 0.459 mmol) and TBTU (181 mg, 0.505 mmol) in DMF (2.5 mL) was cooled to 0° C., and NMM (121 μL, 1.15 mmol) was added. The reaction mixture was stirred for 30 minutes and then the Boc-deprotected benzimidazole amino acid derivative, dissolved in DMF (2.5 mL) was added dropwise at 0° C. After stirring for 21 h EtOAc and 1 M HCl was added, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and saturated aqueous NaCl solution. After drying over Na.sub.2SO.sub.4 and filtration, the solvent was removed under reduced pressure, and the title compound was obtained as a brownish resin (208 mg, 0.405 mmol, 97%). The title compound was used in the next step without any further purification. MS (ESI+): m/z [M+H].sup.+=516.

(4-Methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1-oxopentan-2-yl)phosphonic acid (172)

[0212] ##STR00061##

The title compound was prepared according to general procedure F. 166 mg (0.322 mmol) of diethyl (4-methyl-1-(((S)-2-methyl-1-(5-phenoxy-1H-benzo[d]imidazol-2-yl)propyl)amino)-1-oxopentan-2-yl)phosphonate were used and yielded the title compound after purification via preparative HPLC (1.74 mg, 0.004 mmol, 1.2%).

[0213] Mixture of Diastereomers:

[0214] Major diastereomer: .sup.1H NMR (500 MHz, DMSO-d.sub.6,) δ ppm: 8.14-8.12 (m, 1H), 7.53-7.51 (m, 1H), 7.37-7.33 (m, 2H), 7.13-7.05 (m, 2H), 6.97-6.95 (m, 2H), 4.94-4.91 (m, 1H), 3.28-3.22 (m, 1H), 2.32-2.26 (m, 1H), 1.87-1.81 (m, 1H) 1.50-1.37 (m, 2 H), 0.98-0.96 (m, 3H), 0.93-0.92 (m, 3H), 0.87-0.86 (m, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 169.8, 158.6, 156.2, 151.9, 130.5, 123.1, 118.1, 60.2, 53.7, 36.5, 32.4, 27.3 (d, J=14.7 Hz), 23.5, 22.0, 19.8, 18.8. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 20.7. Minor diastereomer (selected signals): .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 8.45-8.43 (m, 1H), 7.49-7.48 (m, 1H), 6.92-6.89 (m, 2H), 5.13-5.11 (m, 1H), 1.96-1.92 (m, 1H), 0.78-0.76 (m, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 170.71, 158.5, 157.4, 152.1, 123.4, 118.2, 115.1, 53.2, 34.9, 30.6, 26.8 (d, J=14.7 Hz), 23.4, 21.9, 19.7, 17.4. .sup.31P NMR (202 MHz, DMSO-d.sub.6) δ ppm: 20.9.

[0215] HRMS (ESI+) calculated for [M+H].sup.+: 460.1996, found: 460.1982.

Example 173

Ethyl 4-methyl-2-(p-tolylcarbamoyl)pentanoate

[0216] ##STR00062##

Ethyl 4-methyl-2-(p-tolylcarbamoyl)pentanoate was synthesized according to general procedure M, using diethyl 2-alkylmalonate (645 mg, 2.98 mmol), EtOH/H.sub.2O (30 mL, 4:1) and NaOH (143 mg, 3.58 mmol). The reaction was stirred at rt overnight. The obtained mono-acid (505 mg, 2.68 mmol) and EDC-HCl (515 mg, 2.68 mmol) were added to a solution of p-toluidine (240 mg, 2.23 mmol) in DCM (20 mL). The resultant mixture was stirred at rt overnight. After the workup, the obtained crude product was purified using column chromatography (Hex/EtOAc=8/2). The product was obtained as orange crystals (441 mg, 71%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ ppm: 8.45 (br s, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 4.31-4.17 (m, 2H), 3.43 (t, J=7.7 Hz, 1H), 2.32 (s, 3H), 1.94-1.80 (m, 2H), 1.69-1.61 (m, 1H), 1.35-1.28 (m, 3H), 0.96 (d, J=6.6 Hz, 6H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ ppm: 173.2, 166.4, 135.0, 134.0, 129.4, 119.8, 61.7, 52.4, 40.8, 26.4, 22.5, 22.0, 20.9, 14.1. MS (ESI+): m/z [M+H].sup.+=278

N.SUP.1.-hydroxy-2-isobutyl-N.SUP.3.-(p-tolyl)malonamide (173)

[0217] ##STR00063##

N.sup.1-hydroxy-2-isobutyl-N.sup.3-(p-tolyl)malonamide was synthesized according to general procedure N, using ethyl 4-methyl-2-(p-tolylcarbamoyl)pentanoate (100 mg, 0.36 mmol), MeOH (2 mL), NH.sub.2OH 50 wt % in H.sub.2O (2 mL) and KCN (4.7 mg, 0.07 mmol). The mixture was stirred at rt overnight. Solvents were concentrated in vacuo and the resultant oil was purified by preparative HPLC (CH.sub.3CN (HCOOH 0.05%)-H.sub.2O (HCOOH 0.05%): 1.0:9.0 to 10.0:0.0). The product was obtained as white solid (49 mg, 52%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.54 (s, 1H), 9.66 (s, 1H), 9.00 (s, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 3.18 (t, J=7.6 Hz, 1H), 2.24 (s, 3H), 1.67 (t, J=7.2 Hz, 2H), 1.47 (dquin, J=13.4, 6.7, 6.7, 6.7, 6.7 Hz, 1H), 0.87 (br d, J=6.6 Hz, 3H), 0.87 (br d, J=6.6 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 167.6, 166.5, 136.3, 132.4, 129.2, 119.4, 49.9, 38.1, 25.8, 22.5, 22.3, 20.5. HRMS (ESI+) calculated for C.sub.14H.sub.21N.sub.2O.sub.3 [M+H].sup.+ 265.1547, found 265.1545.

Example 174 and Example 177

4-Methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174) and 4-methyl-N-(p-tolyl)-2-(2H-1,2,3-triazol-2-yl)pentanamide (177)

[0218] 4-Methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174) and 4-methyl-N-(p-tolyl)-2-(2H-1,2,3-triazol-2-yl)pentanamide (177) were synthesized according to general procedure 0, using 2-bromo-4-methyl-N-(p-tolyl)pentanamide (70 mg, 0.25 mmol) (synthesized according to general procedure B-1), acetone (7 mL), 1H-1,2,3-triazole (18.7 mg, 0.27 mmol) and K.sub.2CO.sub.3 (37.4 mg, 0.27 mmol). The crude product was purified by preparative HPLC (CH.sub.3CN (HCOOH 0.05%)-H.sub.2O (HCOOH 0.05%): 1.0:9.0 to 10.0:0.0), giving products 174 (20.3 mg, 30%) and 177 (30 mg, 45%) as white solids.

4-Methyl-N-(p-tolyl)-2-(1H-1,2,3-triazol-1-yl)pentanamide (174)

[0219] ##STR00064##

[0220] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.53 (s, 1H), 8.30 (d, J=0.8 Hz, 1H), 7.77 (d, J=0.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 5.61 (dd, J=9.8, 6.1 Hz, 1H), 2.25 (s, 3H), 2.16-2.06 (m, 1H), 2.01-1.93 (m, 1H), 1.31-1.20 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 166.6, 135.7, 133.3, 133.1, 129.3, 123.9, 119.5, 61.6, 40.4, 24.5, 22.4, 21.5, 20.5. HRMS (ESI.sup.+) calculated for C.sub.15H.sub.21N.sub.4O [M+H].sup.+ 273.1710, found 273.1708.

4-Methyl-N-(p-tolyl)-2-(2H-1,2,3-triazol-2-yl)pentanamide (177)

[0221] ##STR00065##

[0222] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm: 10.35 (s, 1H), 7.83 (s, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 5.46 (dd, J=9.3, 6.0 Hz, 1H), 2.34-2.28 (m, 1H), 2.24 (s, 3H), 1.99 (ddd, J=13.8, 7.8, 6.2 Hz, 1H), 1.47-1.36 (m, 1H), 0.91 (t, J=6.2 Hz, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ ppm: 166.2, 135.9, 134.5, 132.9, 129.2, 119.4, 65.8, 24.5, 22.5, 21.7, 20.5. HRMS (ESI.sup.+) calculated for C.sub.15H.sub.21N.sub.4O [M+H].sup.+ 273.1710, found 273.1708.

III. Biological Evaluation

Activity Against LasB:

[0223] The activities of the compounds of the present invention were determined according to the procedures described in Kany, A. M.; Sikandar, A.; Haupenthal, J.; Yahiaoui, S.; Maurer, C. K.; Proschak, E.; Kohnke, J.; Hartmann, R. W. ACS Infect. Dis. 2018, 4, 988-997.

α-Benzylated Derivatives:

[0224]

TABLE-US-00002 TABLE 2 Activities of α-benzylmercaptoacetamides against LasB. [00066] Example R.sup.1 R.sup.21 IC.sub.50 [μM]  1 Ph Ph 1.2 ± 0.1  4 3,4-di—Cl—Ph Ph 2.7 ± 0.3  5 4-OH—Ph Ph 0.59 ± 0.04  6 2-CH.sub.3—Ph Ph 2.4 ± 1.0  7 3-CH.sub.3—Ph Ph 0.98 ± 0.43  8 4-CH.sub.3—Ph Ph 0.48 ± 0.04  9 4-NO.sub.2—Ph Ph 0.97 ± 0.10 10 4-OCH.sub.3—Ph Ph 0.73 ± 0.03 11 Ph 4-OH—Ph 7.3 ± 0.5 12 Ph 3-NO.sub.2—4-OH—Ph 2.5 ± 0.1 13 Ph 4-CH.sub.3—Ph 2.8 ± 0.3

Activity of Enantiomers:

[0225] To elucidate whether the configuration of the stereocenter has an influence on activity, the enantiomers (E1 and E2, labeled according to their elution order from the chiral column) of the compounds of examples 1 and 4 were separated using a chiral column with a preparative HPLC and independently examined. Although both enantiomers were active, a difference in activity between the two configurations was observed (Table 3). For both compounds, the E2 enantiomer was more active.

TABLE-US-00003 TABLE 3 Activity of the racemic mixtures and pure enantiomers for examples 1 and 4. Example IC.sub.50 [μM] 1 E1 4.8 ± 0.7 E2 1.0 ± 0.1 Rac 1.2 ± 0.1 4 E1 5.2 ± 0.6 E2 2.0 ± 0.4 Rac 2.7 ± 0.3
In order to ensure that no racemization occurs during the assays, the configurational stability in methanol and aqueous buffer (50 mM Tris, pH 7.2, 2.5 mM CaCl.sub.2)) was examined. The CD spectra were unchanged over one hour indicating that racemization does not occur during this period.

Selectivity:

[0226] The inhibition of zinc-containing human enzymes is described frequently for LasB inhibitors and poses a serious difficulty in the development of selective compounds. Particularly, the inhibition of matrix metalloproteases (MMPs) should be avoided. To further investigate this issue, three derivatives (the compounds of examples 1, 5 and 8) have been tested for their selectivity against several human off-targets, including six MMPs, ADAM17 (TACE), HDAC-3 and HDAC-8 (Table 4). The selectivity of the compounds is particularly high for MMPs and HDACs, whereas the inhibition of ADAM17 was considerably stronger.

TABLE-US-00004 TABLE 4 Selectivity of examples 1, 5 and 8 against off-targets. (n.i. = <10% inhibition). conc. Inhibition [%] [μM] 1 5 8 MMP-1 100 n.i. n.i. n.i. MMP-2 100 n.i. n.i. n.i. MMP-3 100 n.i. n.i. n.i. MMP-7 100 n.i. n.i. n.i. MMP-8 100 34 ± 11 19 ± 4 n.i. MMP-14 100 n.i. n.i. n.i. IC.sub.50 [μM] ADAM17 2.2 ± 0.1 2.3 ± 1.4 4.8 ± 1.2 HDAC-3 >100 >250 >100 HDAC-8 >100 >250 >100

Cytotoxicity:

[0227] The compounds of examples 1 and 5 were not toxic against the cell lines HepG2, HEK293 and A549 (Table 5). Additionally, the inhibitory effect against P. aeruginosa PA14 was evaluated to exclude an antibacterial effect of the compounds of the present invention. This is important as it was the aim to target virulence and not viability of the bacteria. The results show that for both compounds MIC values on PA14 as well as cytotoxicities (IC.sub.50 values) in the cell lines were greater than 100 μM and therefore unproblematic.

TABLE-US-00005 TABLE 5 Cytotoxicity data and PA14 inhibition by examples 1 and 5. 1 [μM] 5 [μM] HepG2 IC.sub.50 >100 >100 μM HEK293 IC.sub.50 >100 >100 A549 IC.sub.50 >100 >100 MIC PA14 >100 >100

α-Alkylated Derivatives:

[0228] Compounds bearing alkyl substituents in Ca-position are highly favorable for activity, leading to submicromolar IC.sub.50 values (Tables 6 and 7). Among these, the compound of example 2 with a 4-Me substituent on the aromatic core and iso-butyl chain proved to be one of the most promising ones, and was therefore further explored regarding selectivity and cytotoxicity (Table 8).

TABLE-US-00006 TABLE 6 α-alkylated derivatives and their corresponding activities towards LasB. [00067] R.sup.11 (n = 1 or 2) R.sup.2 IC.sub.50 [μM] 3,4-diCl.sup.1 H 6.6 ± 0.3 3,4-diCl (15) methyl 4.5 ± 0.7 4-MeO (16) methyl 45 ± 1 4-Ac (17) methyl 89 ± 9 3,4-diCl (18) ethyl 2.4 ± 0.4 4-MeO (19) ethyl 4.2 ± 0.6 4-Ac (20) ethyl 10 ± 2 3,4-diCl (21) i-propyl 2.5 ± 0.3 4-MeO (22) i-propyl 16 ± 1 4-Ac (23) i-propyl 22 ± 0 H (24) n-propyl 4.8 ± 0.4 4-Me (25) n-propyl 2.0 ± 0.2 3,4-diCl (26) n-propyl 4.0 ± 0.6 4-MeO (27) n-propyl 2.4 ± 0.6 4-Ac (28) n-propyl 2.6 ± 0.5 3,4-diCl (29) n-butyl 6.8 ± 1.1 4-OMe (30) n-butyl 2.8 ± 0.3 3,4-diCl (43) sec-butyl 7.5 ± 0.2 4-MeO (44) sec-butyl 17 ± 2 3,4-diCl (45) cyclopropylmethyl 6.3 ± 1.2 4-MeO (46) cyclopropylmethyl 3.9 ± 0.6 3,4-diCl (47) cyclohexylmethyl 12 ± 3 4-MeO (48) cyclohexylmethyl 2.6 ± 1.2 3,4-diCl (49) —CH.sub.2OCH.sub.3 2.4 ± 0.6 4-MeO (50) —CH.sub.2OCH.sub.3 17 ± 1 .sup.1Compound disclosed in Kany et al.

TABLE-US-00007 TABLE 7 Compounds bearing an iso-butyl group in α-position and their corresponding activities against LasB. [00068] R11 (n = 1 or 2) IC.sub.50 [μM] 3,4-diCl (31) 2.6 ± 0.2 2-OMe (32) 0.70 ± 0.04 3-OMe (33) 0.56 ± 0.03 4-OMe (34) 0.36 ± 0.11 3,4-diOMe (36) 0.73 ± 0.10 4-Me (2) 0.40 ± 0.13 4-Cl (38) 0.84 ± 0.24 4-Ac (39) 0.69 ± 0.34 2-OH (40) 1.4 ± 0.2

TABLE-US-00008 TABLE 8 Selectivity and cytotoxicity data for the compound of example 2. n.i. = inhibition <10%. Selectivity % inhibition MMP-1 n.i. at 100 μM MMP-2 n.i. MMP-3 n.i. MMP-7 n.i. MMP-8 n.i. MMP-14 n.i. IC.sub.50 [μM] HDAC-3 >100 HDAC-8 >100 TACE 4.5 ± 1.8 Cytotoxicity HepG2 >100 IC.sub.50 [μM] HEK293 >50 A549 >100
As the compound of example 2 has shown an impressive activity in the in vitro LasB inhibition assay, high selectivity over a broad spectrum of human enzymes and no signs of cytotoxicity in vitro, it has been subjected to a more advanced safety screening (Table 9). The IC.sub.50 value regarding the inhibition of the hERG potassium channel was determined to be >10 μM. Furthermore, it was of particular importance to determine the effect of the compound of example 2 on five human CYP450 isoforms, demonstrating weak or no inhibition. In addition, the compound of example 2 was analyzed using the mini-Ames reverse mutation assay, where no genotoxicity was observed up to 125 μg/mL.

TABLE-US-00009 TABLE 9 Advanced safety profile of the compound of example 2: hERG/CYP inhibition and mini-Ames test. hERG CYP1A CYP2C9 CYP3A4 CYP2C19 CYP2D6 Mini-Ames IC.sub.50 >10 >25 >25 15 1.0 22.3 No [μM] genotoxicity
Moreover, the compound of example 2 was subjected to pharmacokinetic (PK) studies in mice (Table 10). Injected intravenously (i.v.) at a dose of 10 mg/kg, it is detectable in blood for 2 h. Preliminary results indicate high clearance and low overall exposure, but the volume of distribution would account for good tissue penetration.

TABLE-US-00010 TABLE 10 PK parameters for example 2. C.sub.max [ng/ml] 200 T.sub.max [min]  15* T.sub.1/2 [min]  50 CL/F [mL/min/kg] 505 ± 119 AUC.sub.0-t [ng/mL * h] 241 ± 22  V/F [L/kg] 45.5 ± 2.8  *First measuring point

α-Carboxymethyl Derivatives:

[0229] The compound of Example 54 (Table 1) showed the following activity against LasB: IC.sub.50=3.9±0.4 μM.

Heterocyclic Derivatives:

[0230]

TABLE-US-00011 TABLE 11 Heterocyclic derivatives and their corresponding activities against LasB. Ex- ample Structure IC.sub.50 [μM] 55 [00069] 0.75 ± 0.07 56 [00070] 0.95 ± 0.08 57 [00071] 2.4 ± 0.2 58 [00072] 1.6 ± 0.1 59 [00073] 8 ± 1 60 [00074] 1.2 ± 0.1 61 [00075] 7.7 ± 1.4 62 [00076] 0.65 ± 0.14

Phosphonic Acid Derivatives:

[0231]

TABLE-US-00012 TABLE 12 Phosphonic acid derivatives and their corresponding activities against LasB. Examples 63 to 89 were prepared according to procedures described above. Example Structure IC.sub.50 [nM] 63 [00077] 51 ± 7 64 [00078] 26 ± 4 65 [00079] 116 ± 16 66 [00080]  52 ± 10 67 [00081]  40 ± 12 68 [00082] 26 ± 8 69 [00083] 84 ± 3 70 [00084]  93 ± 22 71 [00085] 48 ± 4 72 [00086] 49 ± 2 73 [00087] 25 ± 1 74 [00088] 28 ± 6 75 [00089] 69 ± 8 76 [00090]  64 ± 10 77 [00091] 44 ± 4 78 [00092] 137 ± 33 79 [00093] 102 ± 1  80 [00094] 2030 ± 110 81 [00095] 1870 ± 30  82 [00096] 501 ± 39 83 [00097] 1130 ± 20  84 [00098] 223 ± 16 85 [00099] 194 ± 11 86 [00100] 498 ± 25 87 [00101] 384 ± 2  88 [00102] 18800 ± 740  89 [00103] 7910 ± 390

TABLE-US-00013 TABLE 13 Further phosphonic acid derivatives and their corresponding activities against LasB. Example 90 to 151 were prepared according to procedures described above. Example Structure IC.sub.50 [nM] 90 [00104] 31% inhibition @ 50 μm 91 [00105] 191 ± 5  92 [00106]  9.5 ± 0.4 93 [00107]  8.5 ± 0.4 94 [00108] 29 ± 2 95 [00109] 15 ± 1 96 [00110] 22 ± 1 97 [00111] 38 ± 1 98 [00112] 49 ± 2 99 [00113] 174 ± 10 100 [00114] 110 ± 8  101 [00115] 1450 ± 30  102 [00116] 35840 ± 1750 103 [00117] 1910 ± 110 104 [00118] 49 ± 2 105 [00119] 37 ± 2 106 [00120] 21 ± 1 107 [00121] 2723 ± 166 108 [00122] 13 ± 0 109 [00123] 52 ± 2 110 [00124] 31 ± 1 111 [00125] 38 ± 1 112 [00126] 31 ± 1 113 [00127] 26 ± 2 114 [00128] 66 ± 3 115 [00129] 57 ± 3 116 [00130] 21 ± 1 117 [00131] 16 ± 1 118 [00132] 25 ± 1 119 [00133] 265 ± 11 120 [00134] 30 ± 1 121 [00135] 24 ± 1 122 [00136] 107 ± 4  123 [00137] 38 ± 1 124 [00138] 112 ± 6  125 [00139] 64 ± 3 126 [00140] 40 ± 2 127 [00141] 46 ± 4 128 [00142] 50 ± 1 129 [00143] 49 ± 2 130 [00144] 40 ± 2 131 [00145] 30 ± 2 132 [00146] 23 ± 1 133 [00147] 31 ± 2 134 [00148] 68 ± 4 135 [00149] 29 ± 2 136 [00150] 29 ± 1 137 [00151] 41 ± 3 138 [00152] 17 ± 1 139 [00153] 16 ± 1 140 [00154] 21 ± 1 141 [00155] 16 ± 1 142 [00156] 13 ± 0 143 [00157] 16 ± 1 144 [00158] 24 ± 1 145 [00159] 46 ± 1 146 [00160] 2270 ± 70  147 [00161] 5180 ± 530 148 [00162] 8360 ± 260 149 [00163] 7280 ± 960 150 [00164]  8660 ± 1110 151 [00165] 347 ± 12

TABLE-US-00014 TABLE 14 α-Phosphonate dipeptides and their corresponding activities against LasB. Examples 152 to 169 were prepared according to procedures described above. Compound Structure IC.sub.50 [nM] 152 [00166]  5.1 ± 0.2 153 [00167] 62 ± 2 154 [00168] 13 ± 1 155 [00169] 60 ± 2 156 [00170] 12 ± 0 157 [00171] 427 ± 48 158 [00172] 242 ± 21 159 [00173] 1500 ± 60  160 [00174] 573 ± 16 161 [00175] 1360 ± 50  162 [00176] 416 ± 23 163 [00177] 1756 ± 3  164 [00178] 27 ± 1 165 [00179] 100 ± 3  166 [00180] 2539 ± 69  167 [00181] 11 ± 0 168 [00182] 1756 ± 30  169 [00183] 378 ± 8 
All phosphonates are showing excellent selectivity and cytotoxicity profile, as well as no inhibition of PA14 bacterial growth (Tables 15, 17 and 18).

TABLE-US-00015 TABLE 15 Selectivity, cytotoxicity and PA14 inhibition for the compounds of examples 63, 92, 108 and 152. Example Example Example Example 63 92 108 152 Selectivity % MMP-1  n.i. n.i. 12 ± 1 13 ± 1 inhibition MMP-2  n.i. 18 ± 0 n.i.  7 ± 9 at 100 μM MMP-3  n.i. n.i. n.i. n.i. MMP-7  n.i. n.d. n.d. n.d. MMP-8  10 ± 0 n.d. n.d. n.d. MMP-14 12 ± 7 n.d. n.d. n.d. IC.sub.50 (μM) HDAC-3 >100 n.d. n.d. n.d. HDAC-8 >100 n.d. n.d. n.d. TACE >100 >100 >100 >100 COX-1 >100 >100 >100 >100 Cytotoxicity HepG2 >100 >100 >100 >100 IC.sub.50 (μM) HEK293 >100 >100 >100 >100 A549 >100 >100 >100 >100 MIC PA14 (μM) >100 >100 >100 >100 n.i. = inhibition < 10%; n.d. = not determined

TABLE-US-00016 TABLE 16 Triazoles, imidazoles and benzimidazoles as examples for heteropentacycles and benzannulated heteropentacycles. Compounds 170 and 172 were prepared according to procedures described above. Example Structure IC.sub.50 [μM] 170 [00184] 60 ± 3 171 [00185]   6 ± 0.2 172 [00186] 12 ± 1

TABLE-US-00017 TABLE 17 Selectivity of examples 170 and 172 against off-targets. (n.i. = <10% inhibition; n.d. = not determined). conc. Inhibition [%] [μM] 170 172 MMP-1 100 11 ± 0 18 ± 4 MMP-2 100 n.i. 12 ± 2 MMP-3 100 n.i. 18 ± 5 MMP-7 100 n.d. n.d. MMP-8 100 n.d. n.d. MMP-14 100 n.d. n.d. ADAM17 100 n.i. n.i. (TACE) HDAC-3 100 n.d. n.d. HDAC-8 100 n.d. n.d. COX-1 100 n.i. n.d.

TABLE-US-00018 TABLE 18 Cytotoxicity data and PA14 inhibition by examples 170 and 172 170 [μM] 172 [μM] HepG2 IC.sub.50 >100 >100 HEK293 IC.sub.50 >100 >100 A549 IC.sub.50 >100 >100 MIC PA14 >100 >100
As compounds of examples 63 and 170 showed an impressive activity in the in vitro LasB assay, high selectivity over a broad spectrum of human enzymes and no signs of cytotoxicity in vitro, they were subjected to a more advanced safety screening (SafetyScreen44 panel, performed by Eurofins CEREP). This screening comprises 44 different targets including GPCRs, transporters, ion channels, nuclear receptors, kinases and other non-kinase enzymes. Compounds of examples 63 and 170 demonstrated no inhibition of control specific binding (<22% inhibition at a compound concentration of 1.0E-0.5 M) of all of the targets tested.

Hydroxamic Acid Derivatives:

[0232]

TABLE-US-00019 TABLE 19 Hydroxamic acid derivatives and their corresponding activities against LasB. Example 173 was prepared according to procedures described above. Example Structure IC.sub.50 [nM] 173 [00187] 14 ± 1

TABLE-US-00020 TABLE 20 Selectivity, cytotoxicity and PA14 inhibition for the compound of example 173. Selectivity % MMP-1 29 ± 3 inhibition MMP-2 26 ± 2 at 100 μM MMP-3 16 ± 7 IC.sub.50 (μM) HDAC-3 >100 HDAC-8 >100 TACE 16 ± 2 COX-1 >100 Cytotoxicity HepG2 >100 IC.sub.50 (μM) HEK293 >100 A549 >100 MIC PA14 (μM) >100

Triazole Derivatives:

[0233]

TABLE-US-00021 TABLE 21 Triazole derivatives and their corresponding activities against LasB. Examples 174 to 178 were prepared according to procedures described above. Example Structure IC.sub.50 [μM] 174 [00188] 2.8 ± 0.1 175 [00189] 4.3 ± 0.2 176 [00190] 45.6* 177 [00191] 5.3 ± 0.2 178 [00192] 5.5 ± 0.2 179 [00193] 30.0* *n = 1

TABLE-US-00022 TABLE 22 Selectivity, cytotoxicity and PA14 inhibition for the compounds of examples 174 and 177. n.i. = inhibition < 10%; n.d .= not determined 174 177 Selectivity % MMP-1 n.i. 7 ± 4 inhibition MMP-2 n.i. n.i. at 100 μM MMP-3 −3 ± 17 n.i. IC.sub.50 (μM) HDAC-3 >100 >100 HDAC-8 >100 >100 TACE >100 >100 COX-1 >100 >100 Cytotoxicity IC.sub.50 (μM) HepG2 >100 >100 HEK293 >100 >100 A549 >100 >100 MIC PA14 (μM) >100 >100