3-TETRAZOLYL-BENZENE-1,2-DISULFONAMIDE DERIVATIVES AS METALLO-BETA-LACTAMASE INHIBITORS

Abstract

The present invention relates to metallo-beta-lactamase inhibitor compounds represented by formula i, and their pharmaceutically acceptable salts. In said formula, z, ra, x1, x2, and r1 are as defined herein. The present invention also relates to compositions comprising a metallo-beta-lactamase inhibitor compound or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, optionally combined with a beta-lactam antibiotic and / or a beta-lactamase inhibitor. The invention further relates to methods for treating a bacterial infection, which consist of administering to a patient a therapeutically effective amount of a compound of the invention, combined with a therapeutically effective amount of one or more beta-lactam antibiotics and optionally combined with one or more beta-lactamase inhibitor compounds.The compounds of the invention are useful in the processes of the invention for overcoming antibiotic resistance.

Description

FIELD OF THE INVENTION

[0001] This invention relates to novel metallo-β-lactamase inhibitors and their uses. A preferred use of the metallo-β-lactamase inhibitors is for reducing bacterial beta-lactam antibiotic resistance.BACKGROUND OF THE INVENTION

[0002] Bacterial antibiotic resistance has become one of the most serious threats to modern health care. Infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. See, e.g., Cohen, Science 1992, 257:1051-1055. The need for new antibiotics will continue to escalate because bacteria have a remarkable ability to develop resistance to new agents, rendering them quickly ineffective. See, e.g., Neu, Science 1992, 257: 1064-1073. The spread of antibiotic resistance has been referred to as a pandemic. A solution to the growing public health threat will require an interdisciplinary approach. See, e.g., Anderson, Nature America 1999, 5: 147-149. See also Bush et al., Nature Reviews in Microbiology 2011, 9: 894-896; Levy and Marshall, Nature Medicine 2004, 10: S122-S129; Livermore, Clinical Infectious Diseases 2003, 36: S11-S23; and Roberts et al., Clinical Infectious Diseases 2009, 49: 1175-1184.

[0003] The present crisis has prompted various efforts to elucidate the mechanisms responsible for bacterial resistance. The widespread use of penicillins and cephalosporins has resulted in the emergence of β-lactamases, a family of bacterial enzymes that catalyze the hydrolysis of the β-lactam ring common to numerous presently used antibiotics. See, Coulton et al., Progress in Medicinal Chemistry 1994, 31: 297-349. This family of bacterial β-lactamases is further divided into four sub-families: A, C, and D families, which comprise β-lactamases that have a serine at the active site that catalyzes the hydrolysis of β-lactam antibiotics, and B family, which comprises β-lactamases that are zinc metalloenzymes. Resistance mediated by β-lactamases is a critical aspect at the core of the development of bacterial antibiotic resistance. See, Dudley, Pharmacotherapy 1995, 15: 9S-14S. Clavulanic acid, which is a metabolite of Streptomyces clavuligerus, and two semi-synthetic inhibitors, sulbactam and tazobactam, are currently available semi-synthetic or natural product β-lactamase inhibitors. Synthetic β-lactamase inhibitors have also been described. See, U.S. Patent Nos. 5,698,577; 5,510,343; 6,472,406; Hubschwerlen et al., J. Med. Chem. 1998, 41: 3961; and Livermore et al., J. Med. Chem. 1997, 40: 335-343. Poole (Cell. Mol. Life Sci. 2004, 61: 2200-2223) provides a review of the resistance of bacterial pathogens to β-lactam antibiotics and approaches for overcoming resistance. For a review of inhibitors of metallo β-lactamases, see Fast and Sutton, Biochimica et Biophysica Acta - Proteins and Proteomics 2013, 1834(8): 1648-1659.

[0004] U.S. Patent Application Publication No. US 2003 / 0199541 discloses certain azabicyclic compounds including certain 7-oxo-6-diazabicyclic[3.2.1]octane-2-carboxamides and their use as anti-bacterial agents. U.S. Patent Application Publication No. US 2004 / 0157826 discloses heterobicyclic compounds including certain diazepine carboxamide and diazepine carboxylate derivatives and their use as anti-bacterials and β-lactamase inhibitors. International Patent Application Publication No. WO 2008 / 039420 discloses 7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfooxy-2-carboxamides and their use as β-lactamase inhibitors.

[0005] Zheng et al. (PLOS One 2013, 8(5), e62955) disclose substituted 2,5-bis-tetrazolylmethyl-thiophenes and their use as β-lactamse inhibitors. Chinese Patent Application Publication No. CN103130686 A discloses N,N'-diaryl-ureas and their use as inhibitors of metallo β-lactamases. Chinese Patent Application Publication No. CN103191091 A discloses substituted arylsulfonamides and their use as inhibitors of metallo β-lactamases.

[0006] U.S. Patent Nos. 4,786,311; 4,746,353; 4,838,925; European Patent Application Publication Nos. EP204513; EP244166; and Chinese Patent Application Publication No. CN1095549A disclose substituted 2-(1H-tetrazol-5-yl)benzenesulfonamides and their use as herbicides.

[0007] International Patent Application Publication No. WO 2015 / 112441 discloses substituted 1H- and 2H-tetrazol-5-yl sulfonamide compounds as metallo β-lactamase inhibitors.SUMMARY OF THE INVENTION

[0008] The present invention is directed to substituted 1H- and 2H-tetrazol-5-yl sulfonamide compounds and related compounds which are metallo-β-lactamase inhibitors. The compounds, and their pharmaceutically acceptable salts, are useful, for example, in combination with β-lactam antibiotics, and optionally serine β-lactamase inhibitors, for the treatment of bacterial infections, particularly antibiotic-resistant bacterial infections. More particularly, the present invention includes compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X 1< is N or CH; X 2< is N or CH; Z is tetrazolyl, wherein Z is linked through a carbon to carbon bond to the six-membered core ring having X 1 and X 2 ; R A< is -(CH 2 ) n -AryA1, -(CH 2 ) n -HetA1, -(CH 2 ) n -C 4 -C 6 cycloalkyl, or -(CH 2 ) n -C 4 -C 6 cycloalkenyl, wherein said -(CH 2 ) n -C 4 -C 6 cycloalkyl and -(CH 2 ) n -C 4 -C 6 cycloalkenyl are optionally substituted with 1, 2, or 3 substituents independently selected from -NH 2 , -OH,-F, and -NR a< C(O)C 1- C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF 3 , -NR a< R b< , and -OR a< ; R 1< is 1) -NH 2 ; 2) -NR a< -C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from -F, -CF 3 , C 1 -C 6 alkyl,-CH(NH 2 )C(O)NH 2 , -C(O)NR a< R b< , -C(O)OH, -(CH 2 ) 1-2 NH 2 ,-NR a< (CH 2 ) 2-3 NH 2 , -NR a< R b< , -N +< R a< R b< CH 3 , -NHCH 2 CH 2 OCH 3 , -OR a< , and -O(CH 2 ) 2-3 NH 2 ; 3) -NR a< C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF 3 , -C(O)NR a< R b< , -C(O)OH,-NR a< R b< , -N +< R a< R b< CH 3 , -NHCH 2 CH 2 OCH 3 , -OR a< , and -O(CH 2 ) 2-3 NH 2 ; 4) -NR a< (CH 2 )n-C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with -CH 2 OH or -NH 2 ; 5) a nitrogen-linked 4-6 membered monocyclic heterocycloalkyl with 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S, or a nitrogen-linked 6- to 10-membered bicyclic heterocycloalkyl with 0, 1, 2, or 3 additional heteroatom ring atoms selected from N, O and S wherein the bicyclic ring may be bridged, fused or spirocyclic, wherein the 4-6 membered monocyclic heterocycloalkyl and the 6- to 10-membered bicyclic heterocycloalkyl are optionally substituted with one to three substituents, independently selected from: -F, -NR a< R b< , oxo, -(CH 2 ) 1-2 OH, -CH 2 NH 2 , -SO 2 CH 3 , and C 1 -C 6 alkyl and wherein a ring sulfur atom is optionally substituted with one or two oxo; 6) -NR a< -(C 1 -C 3 alkyl) n -AryB1, wherein the C 1 -C 3 alkyl is optionally substituted with -NH 2 ; and 7) -NR a< -(C 1 -C 3 alkyl) n -HetB1; AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from: a) halogen, b) -C 1 -C 6 alkyl, c) -CN, d) -CH 2 OH, e) -C(O)NR a< R b< , f) -C(O)NH(CH 2 ) 2-4 NH 2 optionally substituted with one or two substituents independently selected from -NR a< R b< and --(CH 2 ) n OR a< , g) -C(O)OR a< , h) -(CH 2 ) p NHR a< optionally substituted with one or two substituents independently selected from -NR a< R b< or --OR a< , i) -(CH 2 ) p NR a< C(=NH)NH 2 , j) -NR a< C(O)C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from -NR a< R b< or --OR a< , k) -NR a< SO 2 -C 1 -C 6 alkyl, l) -NR a< SO 2 -cyclopropyl, m) -OR a< , n) oxo, o) -C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from -NR a< R b< or --OR a< ; p) -SO 2 R a< , q) -SO 2 NR a< R b< , r) -SO 2 NH-cyclopropyl, s) -AryA2, t) -(CH2) n NR a< AryA2, u) -C(O)NR a< HetA2 and v) -HetA2, and 2) an 8- to 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom optionally has one or two oxo substituents and a N atom is optionally in the form of an N-oxide, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from a) halogen; b) C 1 -C 6 alkyl optionally substituted with one to three substituents independently selected from -NR a< R b< , -F and -OR a< ; c) -(CH 2 ) n CF 3 ; d) -C(=NH)NH 2 ; e) -CN; f) -C(O)CF 3 ; g) -C(O)NR a< R b< ; h) -C(O)NHCH 2 C(O)OR a< ; i) -C(O)NH-C 2 -C 4 alkyl-NH 2 , j) -C(O)OR a< ; k) -NR a< R b< ; l) -NHCH 2 SO 3 H; m) -(CH 2 ) n NHC(=NH)NH 2 ; n) -NHC(O)C 1 -C 6 alkyl; o) -NHC(O)NH 2 ; p) -NHC(O)OR a< ; q) -NHSO 2 CH 3 ; r) -OR a< ; s) oxo; t) -SO 2 R a< , u) -CH 2 -phenyl-OCH 3 ; and v) -HetA2; HetA1 is dihydrothiopyranyl or tetrahydropyranyl; AryA2 is a 5-6-membered aromatic monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, and S, or 4 N ring atoms, optionally substituted with -CH 2 OH,-COOH,-CONH 2 , -C(O)OC 1 -C 6 alkyl, and -(CH 2 ) p NHR a< optionally substituted with one or two substituents independently selected from -NR a< R b< and-OR a< ; HetA2 is a 4-6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein the S is optionally substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, -CN, -OH, and oxo; AryB1 is an aromatic ring selected from: 1) a 5-6 membered monocyclic aromatic ring with 0, 1, 2, or 3 N ring atoms, optionally substituted with 1 substituent selected from -CF 3 , C 1 -C 6 alkyl, -(CH 2 ) n NH 2 and -OCH 3 ; or 2) a 9-membered bicyclic ring with 2 N ring atoms; HetB1 is a saturated ring selected from: 1) a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein a N ring atom is optionally in the form of a quaternary amine, wherein the S is substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from -F, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, -C(O)OR a< ,-(CH 2 ) k NR a< R b< , -OR a< , and oxo; or 2) a 6-10-membered bicyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with -OH or -NH 2 , wherein the bicyclic ring is bridged or fused; R a< and R b< are independently H or C 1 -C 6 alkyl; k is 0, 1, 2, 3, or 4; each n is independently 0 or 1; and each p is independently 0, 1, 2, or 3.

[0009] Compounds of Formula I inhibit metallo-β lactamases and can synergize the antibacterial effects of β lactam antibiotics (e.g., imipenem, ceftazidime, ceftolozane, and piperacillin) against microorganisms normally resistant to β lactam antibiotics as a result of the presence of the metallo-β lactamases. Compounds of the present invention are effective against metallo-β lactamases and their combination with a β-lactam antibiotic, such as imipenem, ceftazidime, ceftolozane, or piperacillin, can provide effective treatment of bacterial infections caused by metallo-β lactamase-producing microorganisms. Accordingly, in certain embodiments, the present invention provides compositions comprising a compound of Formula I, IA, or IB with a β-lactam antibiotic, and optionally one or more additional β-lactamase inhibitors, suitable for use against metallo-β lactamase producing bacteria such as Pseudomonas spp. and Klebsiella spp. In some embodiments, the additional one or more β-lactamase inhibitor(s) is a serine (Class A, C and D) β-lactamase inhibitor. The invention also includes compositions comprising a compound of Formula I, IA, or IB or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further includes a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, IA, or IB or its salt and a pharmaceutically acceptable carrier, for use in methods for treating bacterial infections. Also disclosed are methods for inhibiting bacterial growth by administration of a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, or by administration of a pharmaceutical composition comprising a compound of Formula I, IA, or IB or its salt and a pharmaceutically acceptable carrier.

[0010] Embodiments, sub-embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.DETAILED DESCRIPTION OF THE INVENTION

[0011] As noted above, the present invention includes compounds of Formula I, IA, and IB, wherein the compounds are metallo-β-lactamase inhibitors suitable for use in combination with β-lactam antibiotics and optionally class A, C, and / or D β-lactamase inhibitors for the treatment of bacterial infections.

[0012] The invention is based, in part, on the presence of a sulfur linker at the 6-position of the core ring as a sulfonamide. The presence of a sulfur at this position results in improved enzyme potency compared to when the linker is carbon and also provides improved activity on difficult to penetrate Pseudomonas bacterial strains. The improved Pseudomonal activity is likely due to a decrease in efflux from the cells as a result of the sulfonamide linker.

[0013] In each of the various embodiments of the compounds of the invention described herein, each variable including those of Formulas I, IA and IB and the various embodiments thereof, is selected independently of the other variables unless otherwise indicated.

[0014] The present invention encompasses for each of the various embodiments of the compounds of the invention described herein, including those of Formulas I, IA and IB, and the various embodiments thereof and the compounds of the examples, all forms of the compounds such as, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof, unless otherwise indicated. Additionally, in the examples described herein, the compounds of the invention may be depicted in the salt form. In such cases, it is to be understood that the compounds of the invention include the free acid or free base forms of such salts, and any pharmaceutically acceptable salt of said free acid or free base forms. In addition, in instances where an acidic group such as tetrazole and a basic group such as an amine are present within the same compound, these compounds may be drawn herein for convenience as the free acid and base forms but it should be understood that these can also be alternatively depicted in their zwitterionic forms in which the tetrazole bears a negative charge and the amine bears a positive charge, which are also included as compounds of the invention.The Compounds of Formula (I):

[0015] In one aspect, the present invention includes compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , Z, R A< and R 1< are as defined herein for the Compounds of Formula (I) (i.e. as defined in the Summary of the Invention); wherein the compounds may be suitable for use for the treatment of bacterial infections.

[0016] A first embodiment of the invention (Embodiment E1) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , Z, R A< and R 1< are as defined in Formula (I) in the Summary of the Invention.

[0017] A second embodiment (Embodiment E2) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH, and all other variables are as defined in Embodiment E1.

[0018] A third embodiment (Embodiment E3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is N, and all other variables are as defined in Embodiment E1.

[0019] A fourth embodiment (Embodiment E4) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is CH, and all other variables are as defined in Embodiment E1.

[0020] A fifth embodiment (Embodiment E5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is N, and all other variables are as defined in Embodiment E1.

[0021] A sixth embodiment (Embodiment E6) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is -(CH 2 ) n -AryA1 and all other variables are as defined in Embodiment E1.

[0022] A seventh embodiment (Embodiment E7) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is -(CH 2 ) n -HetA1 and all other variables are as defined in Embodiment E1.

[0023] An eighth embodiment (Embodiment E8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is -(CH 2 ) n -C 4 -C 6 cycloalkyl, wherein said -(CH 2 ) n -C 4 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from - NH 2 , -OH, -F, and -NR a< C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF 3 ,-NR a< R b< , and -OR a< and all other variables are as defined in Embodiment E1.

[0024] In one sub-embodiment of Embodiment E8, -(CH 2 ) n -C 4 -C 6 cycloalkyl is unsubstituted. In another sub-embodiment of Embodiment E8, -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with 1 substituent. In another sub-embodiment of Embodiment E8, -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with 2 substituents. In another sub-embodiment of Embodiment E8, -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with 3 substituents.

[0025] In another sub-embodiment of Embodiment E8 -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with at least one occurrence of NH 2 .

[0026] In a further sub-embodiment of Embodiment E8 -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with at least one occurrence of -OH.

[0027] In yet another sub-embodiment of Embodiment E8 -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with at least one occurrence of -F.

[0028] In one sub-embodiment of Embodiment E8 -(CH 2 ) n -C 4 -C 6 cycloalkyl is substituted with at least one occurrence of -NR a< C(O)C 1- C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF 3 ,-NR a< R b< , and -OR a< .

[0029] A ninth embodiment (Embodiment E9) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is -(CH 2 ) n -C 4 -C 6 cycloalkenyl, wherein -(CH 2 ) n -C 4 -C 6 cycloalkenyl is optionally substituted with 1, 2, or 3 substituents independently selected from -NH 2 , -OH,-F, and -NR a< C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF 3 ,-NR a< R b< , and -OR a< and all other variables are as defined in Embodiment E1.

[0030] In one sub-embodiment of Embodiment E9, -(CH 2 ) n -C 4 -C 6 cycloalkenyl is unsubstituted. In another sub-embodiment of Embodiment E9, -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with 1 substituent. In another sub-embodiment of Embodiment E9, -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with 2 substituents. In another sub-embodiment of Embodiment E9, -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with 3 substituents.

[0031] In another sub-embodiment of Embodiment E9 -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with at least one occurrence of NH 2 .

[0032] In a further sub-embodiment of Embodiment E9 -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with at least one occurrence of -OH.

[0033] In yet another sub-embodiment of Embodiment E9 -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with at least one occurrence of -F.

[0034] In one sub-embodiment of Embodiment E9 -(CH 2 ) n -C 4 -C 6 cycloalkenyl is substituted with at least one occurrence of -NR a< C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF 3 ,-NR a< R b< , and -OR a< .

[0035] A tenth embodiment (Embodiment E10) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is AryA1 and all other variables are as defined in Embodiment E1.

[0036] An eleventh embodiment (Embodiment E11) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is C 4 -C 6 cycloalkyl optionally substituted with -NH 2 or NHC(O)(CH 2 ) 1-3 NH 2 , and all other variables are as defined in Embodiment E1.

[0037] A twelfth embodiment (Embodiment E12) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is C 4 -C 6 cycloalkenyl optionally substituted with -NH 2 or NHC(O)(CH 2 ) 1-3 NH 2 , and all other variables are as defined in Embodiment E1.

[0038] A thirteenth embodiment (Embodiment E13) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is HetA1 and all other variables are as defined in Embodiment E1.

[0039] A fourteenth embodiment (Embodiment E14) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: selected from the group consisting of: R D< is F,-C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< each x is independently 0, 1, or 2, n is 0 or 1, and all other variables are as defined in Embodiment E1.

[0040] A fifteenth embodiment (Embodiment E15) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5 R A< is: R D< is F,-C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< each x is independently 0, 1, or 2, and all other variables are as defined in Embodiment E1.

[0041] A sixteenth embodiment (Embodiment E16) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: R D< is F-C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< each x is independently 0, 1, or 2, and all other variables are as defined in Embodiment E1.

[0042] A seventeenth embodiment (Embodiment E17) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: R D< is -F,-C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< , x is 0, 1, or 2, n is 0 or 1, and all other variables are as defined in Embodiment E1.

[0043] An eighteenth embodiment (Embodiment E18) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: R D< is F, -C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< x is 0, 1, or 2, n is 0 or 1, and all other variables are as defined in Embodiment E1.

[0044] In sub-embodiments of Embodiments E17 and E18, n is 0.

[0045] In other sub-embodiments of Embodiments E17 and E18, at least one occurrence of R D< is NH 2 . In other sub-embodiments of Embodiment E17 and E18, at least one occurrence of R D< is -(CH 2 ) x NHR a< . In further sub-embodiments of Embodiments E17 and E18, at least one occurrence of R D< is methyl. In yet other sub-embodiments of Embodiments E17 and E18, at least one occurrence of R D< is -CH 2 NH 2 . In further sub-embodiments of Embodiments E17 and E18, at least one occurrence of R D< is -F. In yet further sub-embodiments of Embodiments E17 and E18, at least one occurrence of R D< is -CONH-C 2 -C 4 alkyl-NH 2 . In other sub-embodiments of Embodiments E17 and E18, at least one occurrence of R D< is -C 1 -C 6 alkyl.

[0046] A ninteenth embodiment (Embodiment E19) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: R D< is F-C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< each x is independently 0, 1, or 2, and all other variables are as defined in Embodiment E1.

[0047] A twentieth embodiment (Embodiment E20) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: R D< is F,-C 1 -C 6 alkyl, -CONH-C 2 -C 4 alkyl-NH 2 , -NHR a< or -(CH 2 ) x NHR a< each x is independently 0, 1, or 2, and all other variables are as defined in Embodiment E1.

[0048] A twenty-first embodiment (Embodiment E21) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is: or and all other variables are as defined in Embodiment E1.

[0049] A twenty-second embodiment (Embodiment E22) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is a 5-6 membered aromatic monocyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from: halogen, -C 1 -C 6 alkyl, -CN, -CH 2 OH, - C(O)NR a< R b< , -C(O)NH(CH 2 ) 2-4 NH 2 optionally substituted with one or two substituents independently selected from -NR a< R b< and -(CH 2 ) n OR a< , -C(O)OR a< , -(CH 2 ) p NHR a< optionally substituted with one or two substituents independently selected from -NR a< R b< or --OR a< , - (CH 2 ) p NR a< C(=NH)NH 2 , -NR a< C(O)C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from -NR a< R b< or --OR a< , -NR a< SO 2 -C 1 -C 6 alkyl, -NR a< SO 2 -cyclopropyl, -OR a< , oxo, -SC 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from -NR a< R b< or --OR a< ; -SO 2 R a< , -SO 2 NR a< R b< , -SO 2 NH-cyclopropyl, - AryA2, -(CH 2 ) n NR a< AryA2, -C(O)NR a< HetA2 and -HetA2, and all other variables are as defined in Embodiment E1.

[0050] A twenty-third embodiment (Embodiment E23) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is an 8- to 10-membered bicyclic aromatic ring system with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom optionally has one or two oxo substituents and a N atom is optionally in the form of an N-oxide, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from halogen; C 1 -C 6 alkyl optionally substituted with one to three substituents independently selected from -NR a< R b< , -F and -OR a< ; -(CH 2 ) n CF 3 ; -C(-NH)NH 2 ; -CN; C(O)CF 3 ; -C(O)NR a< R b< ; - C(O)NHCH 2 C(O)OR a< ; -C(O)NH-C 2 -C 4 alkyl-NH 2 , -C(O)OR a< ; -NR a< R b< ; -NHCH 2 SO 3 H; - (CH 2 ) n NHC(=NH)NH 2 ; -NHC(O)C 1 -C 6 alkyl; -NHC(O)NH 2 ; -NHC(O)OR a< ; -NHSO 2 CH 3 ; - OR a< ; oxo; -SO 2 R a< , -CH 2 -phenyl-OCH 3 ; and -HetA2; and all other variables are as defined in Embodiment E1.

[0051] A twenty-fourth embodiment (Embodiment E24) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is dihydrothiopyranyl, and all other variables are as defined in Embodiment E1.

[0052] A twenty-fifth embodiment (Embodiment E25) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is tetrahydropyranyl, and all other variables are as defined in Embodiment E1.

[0053] A twenty-sixth embodiment (Embodiment E26) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6-E25, R 1< is NH 2 and all other variables are as defined in Embodiment E1.

[0054] A twenty-seventh embodiment (Embodiment E27) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is -NR a< -C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from -F, - CF 3 , C 1 -C 6 alkyl, -CH(NH 2 )C(O)NH 2 , -C(O)NR a< R b< , -C(O)OH, -(CH 2 ) 1-2 NH 2 , -NR a< (CH 2 ) 2 - 3 NH 2 , -NR a< R b< , -N +< R a< R b< CH 3 , -NHCH 2 CH 2 OCH 3 , -OR a< , and -O(CH 2 ) 2-3 NH 2 and all other variables are as defined in Embodiment E1.

[0055] A twenty-eighth embodiment (Embodiment E28) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NR a< C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from - F, -CF 3 , -C(O)NR a< R b< , -C(O)OH, -NR a< R b< , -N +< R a< R b< CH 3 , -NHCH 2 CH 2 OCH 3 , -OR a< , and - O(CH 2 ) 2-3 NH 2 and all other variables are as defined in Embodiment E1.

[0056] A twenty-ninth embodiment (Embodiment E29) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NR a< (CH 2 ) n -C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with -CH 2 OH or -NH 2 and all other variables are as defined in Embodiment E1.

[0057] A thirtieth embodiment (Embodiment E30) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is a nitrogen-linked 4-6 membered monocyclic heterocycloalkyl with 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S, or a nitrogen-linked 6- to 10-membered bicyclic heterocycloalkyl with 0, 1, 2, or 3 additional heteroatom ring atoms selected from N, O and S wherein the bicyclic ring may be bridged, fused or spirocyclic, wherein the 4-6 membered monocyclic heterocycloalkyl and the 6- to 10-membered bicyclic heterocycloalkyl are optionally substituted with one to three substituents, independently selected from: -F, -NR a< R b< , oxo, -(CH 2 ) 1-2 OH, -CH 2 NH 2 , -SO 2 CH 3 , and C 1 -C 6 alkyl and wherein a ring sulfur atom is optionally substituted with one or two oxo and all other variables are as defined in Embodiment E1.

[0058] A thirty-first embodiment (Embodiment E31) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is -NR a< -(C 1 -C 3 alkyl) n -AryB1, wherein the C 1 -C 3 alkyl is optionally substituted with -NH 2 and all other variables are as defined in Embodiment E1.

[0059] In a sub-embodiment of Embodiment E31, R a< is H and AryB1 is a 5-6 membered monocyclic aromatic ring with 0, 1, 2, or 3 N ring atoms, optionally substituted with 1 substituent selected from -CF 3 , C 1 -C 6 alkyl, -(CH 2 ) n NH 2 and -OCH 3 .

[0060] In a further sub-embodiment of Embodiment E31, R a< is H and AryB1 is a 9-membered bicyclic aromatic ring system with 2 N ring atoms.

[0061] A thirty-second embodiment (Embodiment E32) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is -NR a< -(C 1 -C 3 alkyl) n -HetB 1 and all other variables are as defined in Embodiment E1.

[0062] In a sub-embodiment of Embodiment E32, R a< is H and HetB1 is a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein a N ring atom is optionally in the form of a quaternary amine, wherein the S is substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from -F, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, -C(O)OR a< ,-(CH 2 ) k NR a< R b< , -OR a< , and oxo.

[0063] In another sub-embodiment of Embodiment E32, R a< is H and HetB1 is a 6-10-membered saturated bicyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with -OH or -NH 2 , wherein the bicyclic ring is bridged or fused.

[0064] In another sub-embodiment of Embodiment E32, R a< is H and HetB1 is: and all other variables are as defined in Embodiment E1.

[0065] A thirty-third embodiment (Embodiment E33) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is -NH-HetB1 optionally substituted with NH 2 and all other variables are as defined in Embodiment E1.

[0066] A thirty-fourth embodiment (Embodiment E34) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is NH-C 1 -C 3 alkylNH 2 , optionally substituted with -CH 3 , -OH or -NH 2 and all other variables are as defined in Embodiment E1.

[0067] A thirty-fifth embodiment (Embodiment E35) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is NH-HetB1, wherein HetB1 is a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with -NH 2 , and all other variables are as defined in Embodiment E1.

[0068] A thirty-sixth embodiment (Embodiment E36) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NH(CH 2 ) 2 NH 2 , and all other variables are as defined in Embodiment E1.

[0069] A thirty-seventh embodiment (Embodiment E37) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NHCH(CH 2 NH 2 )CH 2 NH 2 , and all other variables are as defined in Embodiment E1.

[0070] A thirty-eighth embodiment (Embodiment E38) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NHCH 2 CH(OH)CH 2 NH 2 , and all other variables are as defined in Embodiment E1.

[0071] A thirty-ninth embodiment (Embodiment E39) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NHCH 2 CH(NH 2 )CH 2 NH 2 , and all other variables are as defined in Embodiment E1.

[0072] A fortieth embodiment (Embodiment E40) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NHCH(CH 2 OH)CH 2 NH 2 , and all other variables are as defined in Embodiment E1.

[0073] A forty-first embodiment (Embodiment E41) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is - NHCH(CH 3 )CH 2 NH 2 , and all other variables are as defined in Embodiment E1.

[0074] A forty-second embodiment (Embodiment E42) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 is defined in Embodiment E2 or E3, X 2 is defined in Embodiment E4 or E5, R A< is defined in any of Embodiments E6- E25, R 1< is -NH 2 , - NH-HetB1 saturated bicyclic ring optionally substituted with -NH 2 , or -NH-C 2 -C 3 alkylNH 2 , optionally substituted with -CH 3 , -OH or -NH 2 , and all other variables are as defined in Embodiment E1.

[0075] A forty-third embodiment (Embodiment E43) is a compound or a pharmaceutically acceptable salt thereof, having the Formula IA: wherein: R A< is AryA1, C 4 -C 6 cycloalkyl, or C 4 -C 6 cycloalkenyl, wherein said C 4 -C 6 cycloalkyl and C 4 -C 6 cycloalkenyl are optionally substituted with -NH 2 or NHC(O)(CH 2 ) 1-3 NH 2 ; AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents independently selected from: a) F, b) -C 1 -C 6 alkyl, c) -CN, d) -CH 2 OH, e) -C(O)NR a< R b< , f) -C(O)NH(CH 2 ) 2-4 NH 2 , g) -C(O)OR a< , h) -(CH 2 ) n NHR a< , i) -NHC(=NH)NH 2 ; j) -NHC(O)CH 3 ; k) -NR a< SO 2 -C 1 -C 6 alkyl, l) -NHSO 2 -cyclopropyl, m) -OR a< , n) -SO 2 NR a< R b< , o) -SC 1 -C 6 alkyl, p) -SO 2 NH-cyclopropyl, q) -AryA2, r) -(CH2) n NR a< AryA2, s) -C(O)NR a< HetA2 and t) -HetA2, and 2) a 8- to 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom is optionally substituted with one or two oxo substituents and a N atom is optionally in the form of an N-oxide, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C 1 -C 6 alkyl, -CH 2 CF 3 , - CF 2 CH 2 NH 2 , -CF 3 , -C(=NH)NH 2 , -CH(NH 2 )CH 3 , -CN, -C(O)CF 3 , - C(O)NR a< R b< , -C(O)NHCH 2 C(O)OR a< , -C(O)OR a< , -(CH 2 ) 0-2 NR a< R b< , - NHC(O)CH 3 , -NHC(O)NH 2 , -NHC(O)OR a< , -NHCH 2 SO 3 H, - NHSO 2 CH 3 , -OR a< , oxo, -CH 2 -phenyl-OCH 3 , and -HetA2; wherein all other variables are defined in Embodiment E1.

[0076] A forty-fourth embodiment (Embodiment E44) is a compound, or a pharmaceutically acceptable salt thereof, having the Formula IB: wherein: AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0 or 1 N ring atoms substituted with 1 or 2 substituents independently selected from F,-C 1 -C 6 alkyl, -CONH-C 2-4 alkyl-NH 2 , or -NHR a< ; or 2) a 9-membered bicyclic ring with 2 heteroatom ring atoms selected from N and S, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C 1 -C 6 alkyl, and -(CH 2 ) x NR a< R b< ; R 1< is 1) -NH 2 ; 2) -NR-C 1-6 alkyl optionally substituted with 1 or 2 F substituents and optionally substituted with 1 or 2 substituents independently selected from -CF 3 , -CH(NH 2 )C(O)NH 2 ; -C(O)NR a< R b< ; -C(O)OH; -NR a< (CH 2 ) 2-3 NHz, - NR a< R b< , -N +< R a< R b< CH 3 , -NHCH 2 CH 2 OCH 3 , -OR a< , and -O(CH 2 ) 2-3 NH 2 ; 3) -NR a< (CH 2 ) n -C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with -CH 2 OH or -NH 2 ; 4) -NR a< -(C 1 -C 3 alkyl) n -AryB1; and 5) NR a< -(C 1 -C 3 alkyl) n -HetB1; Ra and Rb are H or -CH3; x is 0, 1 or 2, and all other variables are defined in Embodiment E1.

[0077] A forty-fifth embodiment (Embodiment E45) is a compound, or a pharmaceutically acceptable salt thereof, having the Formula (IB): wherein: AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0 or 1 N ring atoms substituted with 1 or 2 substituents independently selected from F, -C 1 -C 6 alkyl, -CONH-C 2-4 alkyl-NH 2 , or -NHR a< ; or 2) a 9-membered bicyclic ring with 2 heteroatom ring atoms selected from N and S, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C 1 -C 6 alkyl, and -(CH 2 ) 0-2 NR a< R b< ; R 1< is 1) -NH 2 ; 2) -NR a< -C 1 -C 6 alkyl optionally substituted with 1 or 2 F substituents and optionally substituted with 1 or 2 substituents independently selected from -CF 3 , -CH(NH 2 )C(O)NH 2 ; -C(O)NR a< R b< ; -C(O)OH; -NR a< R b< , - N +< R a< R b< CH 3 , -OR a< , and -O(CH 2 ) 1-2 NH 2 ; 3) -NR a< (CH 2 ) 0-1 -C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is optionally substituted with -CH 2 OH or -NH 2 ; 4) -NR a< -C 0-3 alkyl-AryB1; and 5) -NR a< -C 0-3 alkyl-HetB 1; HetB1 is: 1) a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein the S is substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, -NR a< R b< , -OH, C 1 - 6 alkoxy, -C(O)OR a< , and oxo; or 2) a 6-8-membered bicyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with -OH or -NH 2 , wherein the bicyclic ring is bridged or fused; Ra and Rb are H or -CH3, and all other variables are as provided in Embodiment E1.

[0078] A forty-sixth embodiment of the invention (Embodiment E46) is: (1) a compound having a structure of any of the compounds numbered 1-500 in the Examples herein, (2) the free acid or free base base form (when a basic amine group is present) of any compound numbered 1-500 herein that is depicted as a salt, (3) the zwitterionic form of any of compounds 1-500 which contains a basic amine group, wherein the tetrazole bears a negative charge and the amine group bears a positive charge, or (4) a pharmaceutically acceptable salt of the compounds described in (1), (2), and / or (3).

[0079] A forty-seventh embodiment of the invention (Embodiment E47) is a compound having the structure: or a pharmaceutically acceptable salt thereof.

[0080] Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of Formula I, IA, or IB as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (b) The pharmaceutical composition of (a), further comprising an effective amount of a β-lactam antibiotic and optionally further comprising an effective amount of a compound which is a class A β-lactamase inhibitor, class C β-lactamase inhibitor, and / or class D β-lactamase inhibitor. (c) The pharmaceutical composition of (b), wherein the β-lactam antibiotic is selected from the group consisting of imipenem, ertapenem, meropenem, doripenem, biapenem, panipenem, ticarcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, ticarcillin, cefoperazone, cefotaxime, ceftriaxone, cefipime, ceftolozane, and ceftazidime, and the class A, C and D β-lactamase inhibitor is selected from the group consisting of relebactam, avibactam, vaborbactam, tazobactam, sulbactam, clavulanic acid, or CB-618. (d) The pharmaceutical composition of (b), wherein the β-lactam antibiotic is imipenem. (e) The pharmaceutical composition of (b), wherein the β-lactam antibiotic is ceftazidime. (f) The pharmaceutical composition of (b), wherein the β-lactam antibiotic is ceftolozane. (g) The pharmaceutical composition of (b), wherein the β-lactam antibiotic is piperacillin. (h) The pharmaceutical composition of (a), further comprising a compound which is a class A β-lactamase inhibitor, class C β-lactamase inhibitor, and / or class D β-lactamase inhibitor. (i) The pharmaceutical composition of any of (b) -(h), wherein the β-lactamase inhibitor compound is relebactam. (j) The pharmaceutical composition of any of (b) -(h), wherein the β-lactamase inhibitor compound is tazobactam. (k) The pharmaceutical composition of (a), further comprising effective amounts of a β-lactam antibiotic, a renal dehydropeptidase (DHP) inhibitor, and optionally, a class A, C and D β-lactamase inhibitor. (l) The pharmaceutical composition of (k), wherein the β-lactam antibiotic is imipenem, the DHP inhibitor is cilastatin or a pharmaceutically acceptable salt thereof, and the class A, C and D β-lactamase inhibitor is relebactam. (m) A combination of effective amounts of a compound of Formula I as defined above, or a pharmaceutically acceptable salt thereof, a β-lactam antibiotic, and optionally, a class A, C and / or D β-lactamase inhibitor. (n) The combination of (j), wherein the β-lactam antibiotic is selected from the group consisting of imipenem, ertapenem, meropenem, doripenem, biapenem, panipenem, ticarcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, ticarcillin, cefoperazone, cefotaxime, ceftriaxone, cefipime, ceftolozane, and ceftazidime. (o) The combination of (n), wherein the β-lactam antibiotic is imipenem, optionally in combination with cilistatin, and the class A, C, D β-lactamase inhibitor is relebactam. (p) The combination of (n), wherein the β-lactam antibiotic is ceftazidime and the class A, C, D β-lactamase inhibitor is avibactam. (q) The combination of (n), wherein the β-lactam antibiotic is ceftolozane and the class A, C, D β-lactamase inhibitor is avibactam or relebactam. (r) The combination of (n), wherein the β-lactam antibiotic is piperacillin. (s) A combination of effective amounts of a compound of Formula I, IA or IB as defined above, or a pharmaceutically acceptable salt thereof, and a class A, C and / or D β-lactamase inhibitor. (t) A combination of effective amounts of a compound of Formula I, IA, or IB as defined above, or a pharmaceutically acceptable salt thereof, a β-lactam antibiotic, a DHP inhibitor, and optionally a class A, C and / or D β-lactamase inhibitor. (u) The combination of (t), wherein the β-lactam antibiotic is imipenem, the DHP inhibitor is cilastatin or a pharmaceutically acceptable salt thereof, and the class A, C and D β-lactamase inhibitor is relebactam. (v) A compound of Formula I, IA, or IB as defined above, or a pharmaceutically acceptable salt thereof, in combination with a β-lactam antibiotic and optionally in combination with a class A, C and D β-lactamase inhibitor, for use in a method for treating a bacterial infection in a subject. (w) A compound of Formula I, IA, or IB as defined above, or a pharmaceutically acceptable salt thereof, in combination with a β-lactam antibiotic and a DHP inhibitor, and optionally in combination with a class A, C and D β-lactamase inhibitor, for use in a method for treating a bacterial infection in a subject. (x) A composition of (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), or (1) for use in a method for treating a bacterial infection in a subject. (y) A combination of (m), (n), (o), (p), (q), (r), (s), (t), or (u) for use in a method for treating a bacterial infection in a subject. (z) A compound for use as set forth in (v), (w), (x), (y) or (z) wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichi spp.a, Morganella spp., Citrobacter spp., Serratia, spp. or Acintetobacter spp.

[0081] The present invention also includes a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, (i) for use in, or (ii) for use as a medicament for, treating bacterial infection. Also disclosed is a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, (i) for use in inhibiting beta-lactamase activity, (ii) for use as a medicament for inhibiting beta-lactamase activity, or (iii) for use in the preparation (or manufacture) of a medicament for inhibiting beta-lactamase activity or treating bacterial infection.

[0082] The compounds of the present invention can optionally be employed in combination with one or more β-lactam antibiotics, and may further be employed in combination with a class A, C, and / or D serine β-lactamase inhibitor and / or one or more DHP inhibitors.

[0083] Additional embodiments of the invention include the pharmaceutical compositions, combinations and uses set forth in (a)-(z) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments, classes or sub-classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments. In addition, the compound may optionally be used in the form of a prodrug that releases the active parent compound after dosing by intravenous or oral administration.

[0084] In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and uses provided as (a) through (z) above are understood to include all embodiments of the compounds and / or salts, including such embodiments as result from combinations of embodiments.

[0085] Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula I, IA, or IB or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "substantially pure" is in reference to a compound of Formula I, IA, or IB or its salt per se; i.e., the purity of the active ingredient in the composition.Definitions and Abbreviations:

[0086] The term "β-lactamase inhibitor" refers to a compound which is capable of inhibiting enzyme activity from β-lactamases. As used herein, inhibiting β-lactamase activity means inhibiting the activity of a class A, B, C, and / or D β-lactamase. For antimicrobial applications inhibition at a 50% inhibitory concentration is preferably achieved at or below about 100 micrograms / mL, or at or below about 50 micrograms / mL, or at or below about 25 micrograms / mL. The terms "class A", "class B", "class C", and "class D" β-lactamases are understood by those skilled in the art and are described in S. G. Waley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228.

[0087] The term "metallo-β-lactamase inhibitor" refers to a compound which is capable of inhibiting metallo-β-lactamase activity. As used herein, inhibiting metallo-β-lactamase activity means inhibiting the activity of a class B metallo-β-lactamase. For antimicrobial applications inhibition at a 50% inhibitory concentration is preferably achieved at or below about 100 µg / mL, or at or below about 50 µg / mL, or at or below about 25 µg / mL.

[0088] The term "metallo-β-lactamase" denotes a metalloprotein capable of inactivating a β-lactam antibiotic. The β-lactamase can be an enzyme which catalyzes the hydrolysis of the β-lactam ring of a β-lactam antibiotic. Of particular interest herein are microbial metallo-β-lactamases. The metallo-β-lactamase can be, for example, a zinc metallo-β-lactamase. β-Lactamases of interest include those disclosed in, e.g., S. G. Waley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228. β-Lactamases of particular interest herein include a metallo-β-lactamases of Escherichia coli (such as New Delhi Metallo-b-lactamase, NDM), Serratia marcescens(such as IMP), Klebsiella spp. (such as Verona integron-encoded metallo-β-lactamase, VIM)) and Pseudomonas spp (such as Verona integron-encoded metallo-β-lactamase, VIM)). Additional metallo-β-lactamases of interest herein include SPM-, GIM-, SIM-, KHM-, AIM-, DIM-, SMB-, TMB-, and FIM-type enzymes.

[0089] The term "antibiotic" refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism. The phrase "inhibits the growth or proliferation" means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold. Preferred antibiotics are those which can increase the generation time by at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, as in total cell death). As used in this disclosure, an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Examples of antibiotics suitable for use with respect to the present invention include penicillins, cephalosporins and carbapenems.

[0090] The term "β-lactam antibiotic" refers to a compound with antibiotic properties that contains a β-lactam functionality. Non-limiting examples of β-lactam antibiotics useful with respect to the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams.

[0091] The term "about", when modifying the quantity (e.g., kg, L, or equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and / or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like. In certain embodiments, "about" can mean a variation of ± 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 of the appropriate unit. In certain embodiments, "about" can mean a variation of ± 1%, 2%, 3%, 4%, 5%, 10%, or 20%.

[0092] Another embodiment of the present invention is a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, sub-embodiments, aspects, classes or sub-classes, wherein the compound or its salt is in a substantially pure form. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound of Formula I, IA or IB, or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and / or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method providing the highest level of purity governs. A compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis.

[0093] With respect to a compound of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer unless expressly depicted otherwise. The present invention encompasses all stereoisomeric forms of the compounds of Formula I, IA and IB. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds. Centers of asymmetry that are present in the compounds of Formula I, IA and IB can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers, diastereomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention.

[0094] The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I, IA and IB or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Unless a particular isomer, salt, solvate (including hydrates) or solvated salt of such racemate, enantiomer, or diastereomer is indicated, the present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and mixtures thereof.

[0095] "Alkyl" means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the prefix "alk", such as alkoxy and alkanoyl, also may be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0096] "Aminoalkyl" means saturated carbon chains which may be linear or branched or combinations thereof which are substituted with one amino group which may be terminal (-NH 2 ) or internal (-NH-).

[0097] "Hydroxyalkyl" means saturated carbon chains which may be linear or branched or combinations thereof which are substituted with one hydroxyl (-OH) group.

[0098] "Diaminoalkyl" means saturated carbon chains which may be linear or branched or combinations thereof which are substituted with two amino (-NH 2 ) groups.

[0099] "Dihydroxyalkyl" means saturated carbon chains which may be linear or branched or combinations thereof which are substituted with two hydroxyl (-OH) groups.

[0100] "Hydroxyaminoalkyl" means saturated carbon chains which may be linear or branched or combinations thereof which are substituted with one hydroxyl (-OH) group and one amino (-NH 2 ) group .

[0101] "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

[0102] "Aromatic ring system" means monocyclic, bicyclic or tricyclic aromatic ring or ring system containing 5-14 ring atoms, wherein at least one of the rings is aromatic. The term may be used to describe a carbocyclic ring fused to an aryl group. For example, a 5-7-membered cycloalkyl can be fused through two adjacent ring atoms to a 5-6-membered heteroaryl containing 1, 2, or 3 heteroatom ring atoms selected from N, O, and S. In other example, a heteromonocyclic ring is fused through two ring atoms to a phenyl or 5-6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In the case of a heteromonocyclic ring containing one or more N atoms, the N can be in the form of quarternary amine. In certain embodiments, a N ring atom can be in the form of an N-oxide.

[0103] "Aryl" means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[0104] "Cycloalkyl" means a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, 1,2,3,4-tetrahydronaphthyl and the like. In one embodiment of the present invention, cycloalkyl is selected from: cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0105] "Cycloalkenyl" means a nonaromatic monocyclic or bicyclic carbocylic ring containing at least one double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl and the like.

[0106] "Cycloheteroalkyl" or "heterocycloalkyl" means a saturated or partly unsaturated non-aromatic monocyclic, bicyclic (including spirocyclic) or bridged carbocyclic ring or ring system comprising 3 to about 11 ring atoms, containing at least one ring heteroatom selected from N, S and O and the remainder of the ring atoms are carbon atoms. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide. A heterocycloalkyl group can be joined via a ring carbon, or ring nitrogen atom, unless specified otherwise. The cycloheteroalkyl ring may be substituted on the ring carbons and / or the ring nitrogen(s). In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms (a "3 to 7-membered monocyclic heterocycloalkyl" group). In another embodiment, a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms (a "4 to 7-membered monocyclic heterocycloalkyl" group). In other embodiments, the heterocycloalkyl group is bicyclic and has 7-10 ring atoms, 8-10 ring atoms, or 9 or 10 ring atoms (a "9 or 10-membered bicyclic heterocycloalkyl" group). In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Examples of cycloheteroalkyl include tetrahydrofuran, piperazine, piperidine, morpholine, oxetane, tetrahydropyran, indolinyl, isoindolinyl, azabicyclooctane, hexahydrofuro[3,2-b]furan, and 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan. Where the ring or ring system contains one or more N atoms, the N can be in the form of quarternary amine.

[0107] As used herein, a "nitrogen-linked heterocycloalkyl" refers to a nitrogen-containing heterocycloalkyl that is linked to the rest of the compound through a sulfur-nitrogen bond to an SO 2 linker, which is connected to the 6-membered core ring containing X 1 and X 2 . For example, the following compounds of the invention contain a nitrogen-linked heterocycloalkyl:

[0108] A nitrogen-linked heterocycloalkyl may be a 4-6 membered monocyclic ring, which may contain 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S or a 7- to 10-membered bicyclic ring with 0, 1, 2, or 3 additional heteroatom ring atoms selected from N, O and S. A bicyclic nitrogen-linked heterocycloalkyl may be bridged, fused or spirocyclic. A nitrogen-linked heterocycloalkyl may optionally be substituted with one to three substituents as defined herein.

[0109] "Heteroaryl" means monocyclic, bicyclic or tricyclic ring or ring system containing 5-14 carbon atoms and containing at least one ring heteroatom selected from N, S (including SO and SO 2 ) and O, wherein at least one of the heteroatom containing rings is aromatic. In the case of a heteroaryl ring system where one or more of the rings are saturated and contain one or more N atoms, the N can be in the form of quarternary amine. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), benzotriazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. Examples of bicyclic heteroaryl rings include:

[0110] "Halogen" includes fluorine, chlorine, bromine and iodine.

[0111] "Oxo" means an oxygen atom connected to another atom by a double bond and is can be represented "=O".

[0112] Where any amine is present in the compound, the N atom may be optionally in the form of a quaternary amine having one or more appropriate additional substitutions, as further described herein.

[0113] When any ring atom is specified as being optionally substituted with, or in a specified form, for example, S substituted with oxo groups, or N in the form of a N-oxide, this does not preclude the substitution of any ring atom with the other listed optional substituents when not substituted with oxo groups or in the form of a N-oxide.

[0114] When any variable (e.g., n, Ra, Rb, etc.) occurs more than one time in any constituent or in Formula I, IA, or IB, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0115] A wavy line , as used herein indicates a point of attachment to the rest of the compound. Lines drawn into a ring system, for example: indicate that the bond may be attached to any of the substitutable ring atoms.

[0116] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described last, preceded by the adjacent functionality toward the point of attachment.

[0117] In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R 1< , R A< , etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

[0118] The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0119] In the compounds of Formula I, IA, or IB, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of Formula I, IA, or IB. For example, different isotopic forms of hydrogen (H) include protium ( 1< H) and deuterium ( 2< H or D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within Formula I, IA, or IB, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0120] Unless expressly stated to the contrary in a particular context, any of the various cyclic ring and ring system variables or substituents described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.

[0121] Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing from " 1 to 4 heteroatoms" means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from " 1 to 4 heteroatoms" is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. Similarly, C 1 -C 6 when used with a chain, for example an alkyl chain, means that the chain can contain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all ranges contained therein including C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 5 -C 6 , and all other possible combinations.

[0122] A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds embraced by Formulas I, IA and IB.

[0123] The term "compound" refers to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the compound complexed with an organic solvent.

[0124] As indicated above, the compounds of the present invention can be employed in the form of pharmaceutically acceptable salts. Those skilled in the art will recognize those instances in which the compounds of the invention may form salts. The term "pharmaceutically acceptable salt" refers to a salt (including an inner salt such as a zwitterion) which possesses effectiveness similar to the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Thus, an embodiment of the invention provides pharmaceutically acceptable salts of the compounds of the invention. The term "salt(s)", as employed herein, denotes any of the following: acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Salts of compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0125] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates ("mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0126] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartenized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0127] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0128] In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole, and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions ("inner salts") may be formed and are included within the terms "salt(s)" as used herein. It is undertood that certain compounds of the invention may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the invention.

[0129] The compounds of Formula I, IA, and IB may exist as rapidly interconverting tautomers with different points of attachment of hydrogen accompanied by one or more double bond shifts. The individual tautomers as well as mixtures thereof are encompassed by the present invention. The ratio between the tautomeric forms will vary depending on the conditions. As is well known to one of ordinary skill in the art, such compounds may be drawn and named in different ways. For example, the following structures depicted below show different ways that an illustrative compound of the invention may be drawn: and

[0130] It is understood that all possible tautomeric forms of the compounds of Formula I, IA, and IB are contemplated as being within the scope of the instant invention, as well as mixtures thereof. It is further understood that while only one said tautomeric form of each example compound and embodiment of the invention may be depicted in the specification and appended claims, such depiction includes reference to all tautomeric forms of said compounds, which are included within the scope of the invention.

[0131] As set forth above, the present invention includes pharmaceutical compositions comprising a compound of Formula I, IA, or IB of the present invention, optionally one or more other active components (e.g., a β-lactam antibiotic), and a pharmaceutically acceptable carrier. The characteristics of the carrier will depend on the route of administration. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other, do not interfere with the effectiveness of the active ingredient(s), and are not deleterious (e.g., toxic) to the recipient thereof. Thus, compositions according to the invention may, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.

[0132] Also as set forth above, the present invention includes a compound of Formula I, IA, or IB, or a pharmaceutically acceptable salt thereof, in combination with a β-lactam antibiotic and optionally a DHP inhibitor, for use in a method for treating a bacterial infection in a subject. The term "subject" (or, alternatively, "patient") as used herein refers to an animal, preferably a mammal, and in particular a human or a non-human animal including livestock animals and domestic animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals in need of treatment. In select embodiment, the subject is a human. In select embodiments, the subject has been the object of treatment, observation or experiment. The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula I, IA, or IB mean providing the compound, or a pharmaceutically acceptable salt thereof, to the individual in need of treatment. When a compound or a salt thereof is provided in combination with one or more other active agents (e.g., a carbapenem antibiotic or a DHP inhibitor or both), "administration" and its variants are each understood to include provision of the compound or its salt and the other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately. It is understood that a "combination" of active agents can be a single composition containing all of the active agents or multiple compositions each containing one or more of the active agents. In the case of two active agents a combination can be either a single composition comprising both agents or two separate compositions each comprising one of the agents; in the case of three active agents a combination can be either a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two compositions one of which comprises two of the agents and the other comprises the third agent; and so forth.

[0133] The compositions and combinations of the present invention are suitably administered in effective amounts. The term "effective amount," when used with a β-lactamase inhibitor (including a DHP inhibitor), means the amount of active compound sufficient to inhibit β-lactamase and thereby elicit the response being sought (i.e., an "inhibition effective amount") in a cell, tissue, system, animal or human. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated (e.g., the healing of conditions associated with bacterial infection, and / or bacterial drug resistance) in combination with a β-lactam antibiotic. In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound. An "effective amount" of a β-lactam antibiotic is an amount sufficient to alleviate the symptoms of the disease or condition being treated (e.g., the healing of conditions associated with bacterial infection, and / or bacterial drug resistance).

[0134] The administration of a composition of the present invention is suitably parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular, or intrarectal, wherein the composition is suitably formulated for administration by the selected route using formulation methods well known in the art, including, for example, the methods for preparing and administering formulations described in chapters 39, 41, 42, 44 and 45 in Remington - The Science and Practice of Pharmacy, 21st edition, 2006. In one embodiment, compounds of the invention are administered intravenously in a hospital setting. In another embodiment, administration is oral in the form of a tablet or capsule or the like. When administered systemically, a therapeutic composition is for example, suitably administered at a sufficient dosage to attain a blood level of inhibitor of at least about 1 µg / mL, and in additional embodiment at least about 10 µg / mL, and at least about 25 µg / mL. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated.

[0135] Intravenous administration of a compound of the invention can be conducted by reconstituting a powdered form of the compound with an acceptable solvent. Suitable solvents include, for example, saline solutions (e.g., 0.9% Sodium Chloride Injection) and sterile water (e.g., Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol). The powdered form of the compound can be obtained by gamma-irradiation of the compound or by lyophilization of a solution of the compound, after which the powder can be stored (e.g., in a sealed vial) at or below room temperature until it is reconstituted. The concentration of the compound in the reconstituted IV solution can be, for example, in a range of from about 0.1 mg / mL to about 20 mg / mL.

[0136] Also disclosed is a method for inhibiting bacterial growth which comprises administering to a bacterial cell culture, or to a bacterially infected cell culture, tissue, or organism, an inhibition effective amount of a compound of Formula I. Also disclosed is the bacterial growth inhibiting method just described, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments or classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt. The method can involve administration of a compound of Formula I, IA or IB to an experimental cell culture in vitro to prevent the growth of β-lactam resistant bacteria. The method can alternatively involve administration of a compound of Formula I, IA, or IB to an animal, including a human, to prevent the growth of β-lactam resistant bacteria in vivo. In these cases, the compound of Formula I, IA or IB is typically co-administered with a β-lactam antibiotic.

[0137] Compounds of the invention can be employed for the treatment, prophylaxis or inhibition of bacterial growth or infections due to bacteria that are resistant to β-lactam antibiotics in combination with a β-lactam antibiotic. More particularly, the bacteria can be metallo-β-lactamase positive strains that are highly resistant to β-lactam antibiotics. The terms "slightly resistant" and "highly resistant" are well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:11.20-11.26 (1995)). For the purposes of this invention, bacterial strains which are highly resistant to imipenem are those against which the MIC of imipenem is >16 µg / mL, and bacterial strains which are slightly resistant to imipenem 9are those against which the MIC of imipenem is >4 µg / mL.

[0138] Compounds of the invention can be used in combination with antibiotic agents for the treatment of infections caused by Class B-β-lactamase producing strains, in addition to those infections which are subsumed within the antibacterial spectrum of the antibiotic agent. Examples of class B-metallo-β-lactamase producing bacteria are Pseudomonas aeruginosa, Pseudomonas putida, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Serratia marcescens, Enterobacter aerogenes, Enterobacter asburiae, Citrobacter freundii, Proteus mirabilis, Morganella morganii, Providencia rettgeri, and Acinetobacter baumannii.

[0139] It is generally advantageous to use a compound of Formula I, IA, or IB in admixture or conjunction with a carbapenem, penicillin, cephalosporin, or other β-lactam antibiotic, or a prodrug thereof. It is advantageous to use a compound of Formula I, IA, or IB in combination with one or more β-lactam antibiotics because of the class B β-lactamase inhibitory properties of the compounds. It is also advantageous to use a compound of Formula I, IA, or IB in combination with one or more Class A, C, and D β-lactamase inhibitors to further limit β-lactam susceptability. As already noted, the compound of Formula I, IA, or IB and the β-lactam antibiotic can be administered separately (at the same time or as different times) or in the form of a single composition containing both active ingredients.

[0140] Carbapenems, penicillins, cephalosporins and other β-lactam antibiotics suitable for use in the present invention include both those known to show instability to or to be otherwise susceptible to class B-β-lactamases.

[0141] When the compounds of Formula I, IA, or IB are combined with a carbapenem antibiotic, a dehydropeptidase (DHP) inhibitor can also be combined. Many carbapenems are susceptible to attack by a renal enzyme known as DHP. This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. Inhibitors of DHP and their use with carbapenems are disclosed in, e.g., U.S. Patent Nos. 4,539,208; 4,616,038; 4,880,793; and 5,071,843. A preferred DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a pharmaceutically acceptable salt thereof.

[0142] Carbapenems suitable for co-administration with compounds of the present invention include imipenem, ertapenem, meropenem, biapenem, (4R, 5S, 6S)-3-[3S, 5S)-5-(3-carboxyphenyl-carbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (1S, 5R, 6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)-ethyl(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride, BMS181139 ([4R-[4α,5β,6β(R*)]]-4-[2-[(aminoiminomethyl)amino]ethyl]-3-[(2-cyanoethyl)thio]-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), BO2727 ([4R-3[3S*,5S*(R*)], 4α,5β,6β(R*)]]-6-(1-hydroxyethyl)-3-[[5-[1-hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrochloride), E1010 ((1R, 5S, 6S)-6-[1(R)-hydroxymethyl]-2-[2(S)-[1(R)-hydroxy-1-[pyrrolidin-3(R)-yl] methyl]pyrrolidin-4(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid hydrochloride) and S4661 ((1R,5S,6S)-2-[(3S,5S)-5-(sulfamoylaminomethyl) pyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid), (1S,5R,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1yl]-methyl-fluoren-9-on-3-yl}-6-(1R-hydroxyethyl)-carbapen-2-em-3 carboxylate chloride.

[0143] Penicillins suitable for co-administration with compounds of the present invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxicillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azlocillin, mezlocillin, sulbenicillin, piperacillin, and other known penicillins. The penicillins may be used in the form of pro-drugs thereof; for example as in vivo hydrolysable esters, for example the acetoxymethyl, pivaloyloxymethyl, α-ethoxycarbonyloxy-ethyl and phthalidyl esters of ampicillin, benzylpenicillin and amoxicillin; as aldehyde or ketone adducts of penicillins containing a 6-α-aminoacetamido side chain (for example hetacillin, metampicillin and analogous derivatives of amoxicillin); and as esters of carbenicillin and ticarcillin, for example the phenyl and indanyl α-esters.

[0144] Cephalosporins suitable for co-administration with compound of the present invention include cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin, cephaloglycin, cefoperazone, cefsulodin, ceftolozane, ceftazidime, cefuroxime, cefmetazole, cefotaxime, ceftriaxone, cefipime, and other known cephalosporins, all of which may be used in the form of pro-drugs thereof.

[0145] β-Lactam antibiotics other than penicillins and cephalosporins that may be co-administered with compounds of the present invention include aztreonam, latamoxef (MOXALACTAM), and other known β-lactam antibiotics such as carbapenems like imipenem, ertapenem, meropenem or (4R, 5S, 6S)-3-[(3S,5S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, all of which may be used in the form of pro-drugs thereof.

[0146] In one embodiment, the antibiotic co-administered with a compound of the present invention is selected from the group consisting of imipenem, ertapenem, meropenem and (4R, 5S, 6S)-3-[(3S,5S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.

[0147] In another embodiment, the antibiotic co-administered with a compound of the present invention is selected from the group of penicillins consisting of ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, and ticarcillin. Such penicillins can optionally be used in the form of their pharmaceutically acceptable salts, for example their sodium salts. Ampicillin or amoxicillin can alternatively be employed in the form of fine particles of the zwitterionic form (generally as ampicillin trihydrate or amoxicillin trihydrate) for use in an injectable or infusable suspension. In an aspect of this embodiment, the penicillin co-administered with a compound of the present invention is amoxicillin, optionally in the form of its sodium salt or the trihydrate.

[0148] In another embodiment, the antibiotic co-administered with a compound of the present invention is selected from the group of cephalosporins consisting of cefotaxime, ceftriaxone, cefipime, and ceftazidime, which are optionally used in the form of their pharmaceutically acceptable salts, for example their sodium salts.

[0149] In certain embodiments of the invention, the compounds of the invention in combination with serine β-lactamase inhibitors (which can inhibit class A, C, D beta lactamases) in addition to β-lactam antiobiotics. Serine β-lactamase inhibitors include but are not limited to avibactam, vaborbactam, relebactam, tazobactam, and clavulanic acid.

[0150] When co-administered with a β-lactam antibiotic, and optionally a β-lactamase inhibitor, the combination of the compound of the invention and the antibiotic can provide a synergistic effect. The terms "synergistic effect" and "synergy" indicate that the effect produced when two or more drugs are co-administered is greater than would be predicted based on the effect produced when the compounds are administered individually. While not wishing to be bound by theory, it is believed that the compounds of the present invention are β-lactamase inhibitors that act to prevent degradation of β-lactam antibiotics, thereby enhancing their efficacy and producing a synergistic effect.

[0151] Abbreviations employed herein include the following: Ac = acetyl = CH 3 C(=O); AcOH = acetic acid; ACN = MeCN = acetonitrile; aq = aqueous; BH3 DMS = borane dimethyl sulfide; BINAP = (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); BLI = β-lactamase inhibitor; Bn = benzyl; BOC (or Boc) = tert-butyloxycarbonyl; Boc anhydride = Boc 2 O = di-tert-butyl dicarbonate; BrettPhos precatalyst generation 3 = [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; BPBD = N,N'-{bis(pyridin-2-yl)benzylidene}butane-1,4-diamine; CBZ (or Cbz) = carbobenzoxy (alternatively, benzyloxycarbonyl); CH 3 CN = acetonitrile; CELITE = diatomaceous earth; conc. = concentrated; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate ; DIAD = diisopropyl azodicarboxylate; DIBAL-H = diisobutylaluminum hydride; DIEA = N,N-Diisopropylethylamine; DIPEA = diisopropylethylamine (or Hunig's base); DMA = dimethylacetamide; DMAP = 4-dimethylaminopyridine or N,N-dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EA = AcOEt = EtOAc = ethyl acetate; EDC = 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; Et = ethyl; EtOH = ethanol; HATU = (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate); hex = hexane; HOAt = 1-Hydroxy-7-azabenzotriazole; HPLC = high-performance liquid chromatography; h or hr or hrs = hours; i-Pr = isopropyl alcohol; KOAc = potassium acetate; LCMS = LC-MS = liquid chromatography / mass spectrometry; LDA = lithium di-isopropyl amide; mCPBA = meta-chloroperoxybenzoic acid; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MIC = minimum inhibitory concentration; min or mins = minutes; MPLC = medium pressure liquid chromatography; Ms = methanesulfonyl; MsCl = methane sulfonyl chloride; n-BuLi = n-butyllithium; NCS = N-Chlorosuccinimide; NIS = N-Iodosuccinimide; NMP = N-Methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; PCy3 Pd G2 = 2nd Generation PCy 3 precatalyst = Chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II); Pd(dppf)Cl 2 = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE = Pet. ether = petroleum ether; Ph = phenyl; PMB = p-Methoxybenzyl; PPh 3 precatalyst generation 2 = 2 nd< PPh3 precatalyst = Chloro(triphenylphosphine) [2-(2'-amino-1,1'-biphenyl)]palladium(II); prep-HPLC = preparative HPLC; RBF = round bottom flask; RPLC = reverse phase liquid chromatography; RT = room temp. = room temperature; SFC = supercritical fluid chromatography; SM = starting material; TBAF = tetrabutylammonium fluoride; tBuXPhos precatalyst generation 3= [(2-Di-tert-butylphosphino-2',4',6'-tiiisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TMS = trimethylsilane; TMSN 3 = azidotrimethylsilane; XPhos-Pd-2G or XPHOS Pd G2 precatalyst or Xphos precatalyst generation 2 = Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride precatalyst.

[0152] The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of known variants. Other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples.

[0153] Sulfonamide compounds of the current invention, ID , may be prepared according to general Scheme I. According to the Scheme, bromide intermediates 1a and 1b may be selectively reacted at the bromo position with 2(trimethylsilyl)enthanethiol in the presence of a base (such as cesium carbonate) to afford sulfides 2a and 2b. Oxidation, for example by using meta-chloroperoxybenzoic acid gives sulfones 3a and 3b. Treatment with tetrabutylammonium fluoride (TBAF) gives the coreesponding sulfinic acids 4a and 4b. The sulfinic acids may be converted to the corresponding sulfonyl chlorides in a variety of ways, for example by treatment with N-chlorosuccinimide. Treatment of the resulting sulfonyl chlorides 5a and 5b with an amine in the presence of a base such as triethyl amine affords the sulfonamides 6a and 6b. Alternatively, sulfinic acids 4a and 4b may be directly converted in one pot to the sulfonamides 6a and 6b by reaction with N-chlorosuccinimide in the presence of the amine reactant. Metal mediated coupling, for example using palladium catalysts, with alkyl, aryl, heteroaryl or vinyl boronic acids, boronic esters, organostannanes, organocopper or organo zinc reagents affords intermediates 7a and 7b. Final PMB protective group removal can be achieved under acidic conditions such as by using TFA in the optional presence of a carbocation scavenger, such as anisole or triethylsilane, providing target compounds ID.

[0154] Alternatively, sulfonamide compounds ID may be prepared according to Scheme II. According to the Scheme, iodo intermediates 3a and 3b are subjected to metal mediated coupling, for example using palladium catalysts, with alkyl, aryl, heteroaryl or vinyl boronic acids, boronic esters, organostannanes, organocopper or organo zinc reagents to give intermediates 8a and 8b. When R' contains active NH groups, these may optionally be protected as tert-butoxycarbamates using Boc anhydride and a base such as 4-dimethylaminopyridine, affording 9a and 9b. Conversion of the trimethylsilylethane sulfones to the corresponding sulfonyl chlorides can be accomplished in two steps (as described in Scheme I) to give 11a and 11b. Coupling of the sulfonyl chlorides with amines can then be accomplished in the presence of a base (such as trimethylamine), giving 12a and 12b. Final PMB protective group removal under acidic conditions such as by using TFA in the optional presence of a carbocation scavenger, such as anisole or triethylsilane, provides target compounds ID. Again, when intermediates 12a and 12b contain an acid labile protecting group (like tert-butoxycarbonyl), concurrent removal of this protecting group occurs in the final acidic removal of the PMB groups. This can be done in one step, or in stepwise fashion by treatment with TFA at room temperature to remove a group such as tert-butoxycarbonyl, then heating with TFA and anisole or thioanisole to remove the PMB group.

[0155] Intermediates 1a and 1b can be prepared according to Scheme III. According to the Scheme, commercially available aryl fluoride 13 can be converted to the carboxylic acid 14 by treatment with LDA, followed by dry ice. The carboxylic acid functionality can be transformed to the corresponding nitrile 15 in numerous ways known in the art. One approach involves conversion to the acid chloride, for example using oxalyl chloride, followed by treatment with ammonium hydroxide to afford the carboxamide, and finally, dehydration, for example using trichloro-1,3,5-triazine, to give the nitrile 15. Nucleophilic aromatic substitution of the fluoride using benzyl mercaptan and a base such as sodium hydride provides the sulfide 16. The nitrile present in 16 can be converted to the tetrazole 17 using one of several methods, for example by treatment with trimethylsilyl azide and dibutyltin oxide. Conversion of the benzyl sulfide to the sulfonyl chloride can be accomplished in several ways, for example, by treatment with N-chloro succinimide in acetic acid. Treatment with ammonium hydroxide then affords the sulfonamide 18. Concommittant protection of the tetrazole and sulfonamide to afford positional isomer mixture 1a and 1b can be achieved by treatment with excess of para-methoxybenzyl chloride in the presence of a base, such as potassium carbonate, and NaI and tetrabutyl ammonium chloride as catalysts. Typically 1a and 1b are used as a mixture of regioisomers, but the isomers can optionally be separated and used individually in the same way. In the examples below, it should be understood that the mixture of regioisomers or the individual regioisomers may be used interchangeably (occasionally only one isomer is shown for the sake of simplicity).REFERENCE EXAMPLE 16-bromo-3-iodo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 6-bromo-3-iodo-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide

[0156] Step A: 3-bromo-2-fluoro-6-iodobenzoic acid

[0157] Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (i-Pr) 2 NH (40.4 g, 400.00 mmol, 1.20 equiv) in THF (400 mL). This was followed by the addition of n-butyl lithium (146 mL, 1.10 equiv) dropwise with stirring at -20°C over 30 minutes. To this was added a solution of 1-bromo-2-fluoro-4-iodobenzene (100 g, 332.34 mmol, 1.00 equiv) in THF (600 mL) dropwise with stirring at -78°C. The resulting solution was stirred for 90 minutes at -78°C. The reaction mixture was then poured into 1.5 L of dry ice. The resulting mixture was concentrated under vacuum. The residue was diluted with 2000 mL of aq. sodium hydroxide (4 M), then washed with 2 x 800 mL of ether. The aq. solution was adjusted to pH 2 with HCl (2 M), then extracted with 3 x 800 mL of ethyl acetate. The organic layers were combined, washed with 3 x 500 mL of water, dried, and concentrated under vacuum to afford the title compound.Step B: 3-bromo-2-fluoro-6-iodobenzoyl chloride

[0158] Into a 3000-mL round-bottom flask was placed 3-bromo-2-fluoro-6-iodobenzoic acid (235 g, 681.35 mmol, 1.00 equiv) and thionyl chloride (1175 mL). The resulting solution was stirred for 2 hours at 80°C in an oil bath. The resulting mixture was cooled and concentrated under vacuum to afford the title compound.Step C: 3-bromo-2-fluoro-6-iodobenzamide

[0159] Into a 10000-mL 4-necked round-bottom flask was placed a solution of NH 4 OH (840 g) in THF (2000 mL), followed by the addition of a solution of 3-bromo-2-fluoro-6-iodobenzoyl chloride (223 g, 614 mmol, 1.00 equiv) in THF (2460 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 60 minutes at room temperature. The resulting mixture was concentrated under vacuum. The solids were collected by filtration to afford the title compound.Step D: 3-bromo-2-fluoro-6-iodobenzonitrile

[0160] Into a 10000-mL 4-necked round-bottom flask was placed a solution of 3-bromo-2-fluoro-6-iodobenzamide (223 g, 648 mmol, 1.00 equiv) in N,N-dimethylformamide (4460 mL), trichloro-1,3,5-triazine (840 g, 4.56 mol, 7.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into 10 L of aq. sodium bicarbonate. The solids were collected by filtration to afford the title compound.Step E: 2-(benzylsulfanyl)-3-bromo-6-iodobenzonitrile

[0161] Into a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of sodium hydride (14.8 g, 617 mmol, 1.20 equiv) in 1,4-dioxane (1000 mL). A solution of phenylmethanethiol (38.1 g, 306.76 mmol, 1.00 equiv) in 1,4-dioxane (100 mL) was added dropwise with stirring at 0°C over 20 minutes. To this was added a solution of 3-bromo-2-fluoro-6-iodobenzonitrile (100 g, 306.84 mmol, 1.00 equiv) in 1,4-dioxane (400 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 60 minutes at room temperature and for an additional 60 minutes at 60°C. The reaction was then quenched by the addition of 750 mL of HCl (1 M). The resulting solution was diluted with 3 L of water, then extracted with 3x1 L of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether (1:4) to afford the title compound.Step F: 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-1H-1,2,3,4-tetrazole

[0162] Into a 3000-mL 4-necked round-bottom flask was placed a solution of 2-(benzylsulfanyl)-3-bromo-6-iodobenzonitrile (54.0 g, 126 mmol, 1.00 equiv) in toluene (750 mL), TMSN 3 (43.4 g, 3.00 equiv) and dibutyltin oxide (6.3 g, 0.20 equiv). The resulting solution was stirred for 48 hour at 105°C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 3 L of aq. sodium hydroxide, then extracted with ethyl acetate. The aqueous layer was adjusted to pH 3 with HCl (2 M), then extracted with 2x1 L of ethyl acetate. The organic layers were combined, washed with 2x1 L of water, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the title compound.Step G: 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-1-[(4-methoxyphenyl)methyl]-1H-1,2,3,4-tetrazole and 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazole

[0163] Into a 3000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-1H-1,2,3,4-tetrazole (84.4 g, 178 mmol, 1.00 equiv) in chloroform (700 mL), a solution of potassium carbonate (49.0 g, 355 mmol, 2.00 equiv) in water (520 mL), and tetrabutylammonium chloride (10.2 g, 0.20 equiv). This was followed by the addition of para-methoxybenzyl chloride (42.2 g, 1.50 equiv) dropwise with stirring at 15°C. The resulting solution was stirred for 180 min at 50°C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 200 mL of water, then extracted with 2x200 mL of DCM. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether (1:2), resulting in the title compound as a mixture of two isomers.Step H: 6-bromo-3-iodo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzene-1-sulfonyl chloride and 6-bromo-3-iodo-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1-sulfonyl chloride

[0164] Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed mixture of 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-1-[(4-methoxyphenyl)methyl]-1H-1,2,3,4-tetrazole and 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazole (50.0 g, 84.3 mmol, 1.00 equiv, 60%), DCM (750 mL), AcOH (12.7 g, 211 mmol, 2.50 equivalents), and water (3.8 g, 2.5 equiv). SO 2 Cl 2 (28.3 g, 2.50 equivalents) was then added dropwise with stirring at 0°C. The resulting solution was stirred for 60 minutes at room temperature. The resulting mixture was concentrated under vacuum to afford the title compound isomer mixture.Step I: 6-bromo-3-iodo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 6-bromo-3-iodo-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide

[0165] Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 6-bromo-3-iodo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzene-1-sulfonyl chloride and 6-bromo-3-iodo-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1-sulfonyl chloride (isomer mixture, 50.0 g, 52.7 mmol, 1.00 equiv, 60%) in THF (300 mL) and a solution of NH 4 OH (200 mL) in THF (200 mL). The resulting solution was stirred for 60 minutes at room temperature. The resulting solution was extracted with 3x150 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified with Flash-Prep-HPLC under the following conditions: Column, C18 silica gel; mobile phase, H 2 O: MeCN = 25 increasing to H 2 O: MeCN = 55 within 30 min; Detector, UV 210 nm, to afford the title compound. H-NMR (DMSO-d6, 300MHz, ppm): δ 3.727-3.748 (3H, d), 5.001-5.068 (0.78H, m), 5.428-5.477 (0.75H, m), 5.941 (0.5H, m), 6.823-6.958 (2H, m), 7.148-7.363 (2H, m), 7.732-7.864 (1.6H, m), 7.993-8.117 (3H, m).REFERENCE EXAMPLE 26-bromo-3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 6-bromo-3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide

[0166] Step A: 3-bromo-2-fluoro-6-iodobenzoic acid

[0167] Into a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed bis(propan-2-yl)amine (121.2 g, 1.20 mol, 1.20 equiv) and THF (1000 mL). This was followed by the addition of n-butyllithium (440 mL, 2.5 M in hexanes, 1.10 mol, 1.10 equiv) dropwise with stirring at -78 °C for 20 minutes. After 60 minutes, a solution of 1-bromo-2-fluoro-4-iodobenzene (300 g, 997 mmol, 1.00 equiv) in THF (2000 mL) was added dropwise with stirring at -78 °C for 30 minutes. The resulting solution was stirred for 2 hours at -78 °C in a liquid nitrogen bath. The reaction progress was monitored by LCMS. The reaction was then quenched by pouring into 5000 g of dry ice. After stirring for 2 hours, the resulting mixture was concentrated under vacuum. The residue was dissolved in 3000 mL of 4 M sodium hydroxide aqueous solution. The resulting solution was extracted with 2x1000 mL of ether. The pH value of the aqueous solution was adjusted to 2-3 with hydrogen chloride aqueous solution (1 M). The resulting solution was extracted with 4x1000 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from hexanes to afford the title compound.Step B: 3-bromo-2-fluoro-6-iodobenzoyl chloride

[0168] Into a 5000-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-2-fluoro-6-iodobenzoic acid (273 g, 791.5 mmol, 1.00 equiv), THF (2730 mL), and N,N-dimethylformamide (27.3 mL). This was followed by the addition of oxalyl chloride (110.9 g, 873.7 mmol, 1.10 equiv) dropwise with stirring at 20°C for 20 minutes. The resulting solution was stirred for 1 hour at room temp. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum to afford the title compound.Step C: 3-bromo-2-fluoro-6-iodobenzamide

[0169] Into a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed NH 4 OH (1200 g). This was followed by the addition of a solution of 3-bromo-2-fluoro-6-iodobenzoyl chloride (280 g, 771 mmol, 1.00 equiv) in THF (2800 mL) dropwise with stirring at 0 °C for 30 minutes. The resulting solution was stirred for 1 hour at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solids were collected by filtration, and washed with H 2 O to afford the title compound.Step D: 3-bromo-2-fluoro-6-iodobenzonitrile

[0170] Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-2-fluoro-6-iodobenzamide (270 g, 785.1 mmol, 1.00 equiv), N,N-dimethylformamide (5400 mL). This was followed by the addition of trichloro-1,3,5-triazine (1014 g, 5.50 mol, 7.00 equiv) in portions at 0 °C. The resulting solution was stirred for 2 hours at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 15000 mL of saturated sodium bicarbonate aqeous solution. The solids were collected by filtration to afford the title compound.Step E: 2-(benzylsulfanyl)-3-bromo-6-iodobenzonitrile

[0171] Into a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (34 g, 60% dispersion in mineral oil, 850 mmol, 1.20 equiv) and 1,4-dioxane (700 mL). This was followed by the addition of a solution of phenylmethanethiol (88.7 g, 714.2 mmol, 1.00 equiv) in 1,4-dioxane (950 mL) dropwise with stirring at 10 °C for 15 minutes. After 30 minutes, to this reaction mixture was added a solution of 3-bromo-2-fluoro-6-iodobenzonitrile (230 g, 705.7 mmol, 1.00 equiv) in 1,4-dioxane (1800 mL) dropwise with stirring at 10 °C. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by pouring into 5000 mL of water / ice. The resulting solution was extracted with 5x1000 mL of ethyl acetate, and the organic layers were combined. The organic layers were washed with 2x1000 mL of water and 2x1000 mL of saturated sodium bicarbonate solution and 2x1000 mL of brine. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ether to afford the title compound.Step F: 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-1H-1,2,3,4-tetrazole

[0172] Into a 2000-mL 4-necked round-bottom flask, was placed 2-(benzylsulfanyl)-3-bromo-6-iodobenzonitrile (66 g, 153.5 mmol, 1.00 equiv), toluene (660 mL), azidotrimethylsilane (44.2 g, 383.6 mmol, 2.50 equiv), and dibutylstannanone (7.7 g, 30.93 mmol, 0.20 equiv). The resulting solution was stirred for 48 hours at 105 °C in an oil bath. The reaction progress was monitored by LCMS. The reaction mixture was cooled to room temperature, and concentrated under vacuum. The residue was purified by silica gel column chromatography with tetrahydrofuran:PE (100:1) as eluent to afford the title compound.Step G: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonyl chloride

[0173] Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 5-[2-(benzylsulfanyl)-3-bromo-6-iodophenyl]-1H-1,2,3,4-tetrazole (100 g, 211.4 mmol, 1.00 equiv), acetic acid (1000 mL) and water (100 mL). This was followed by the addition of NCS (70.7 g, 529.5 mmol, 2.50 equiv), in portions using an ice / water bath to contain exotherms occurring on addition of NCS, and maintaining the internal temperature approximately between 20-30 °C. The resulting solution was stirred for 2 hours at room temperature using an ice / water bath as needed to maintain the temperature following addition of NCS which is exothermic. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum and then was diluted with 2000 mL of EtOAc. The resulting mixture was washed with 2x1000 mL of water and 2x1000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound.Step H: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide

[0174] Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed NH 4 OH (1180 mL) and THF (290 mL). This was followed by the addition of a solution of 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonyl chloride (118 g, 262.5 mmol, 1.00 equiv) in THF (300 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 hours at 0-25 °C in an ice / salt bath (slowly warming to room temperature). The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum, and diluted with 500 mL ether. After stirring for 30 minutes, the solids were collected by filtration to afford the title compound.Step I: 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4-methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide and 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide

[0175] Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide (105 g, 244.2 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 73.4 mmol, 0.30 equiv), tetrabutylammonium chloride (20.4 g, 73.4 mmol, 0.30 equiv), and 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50 °C in an oil bath. The reaction progress was monitored by LCMS. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 2x1000 mL DCM. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. 1< H-NMR: (300 MHz, CDCl 3 , ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323-7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H).

[0176] In the experimental procedures below, the compound of REFERENCE EXAMPLE 2 can be used as a mixture of 4-methoxylbenzyl tetrazole regioisomers. Alternatively, the two regioisomers may be separated and each can be used as described below in the same fashion. In some REFERENCE EXAMPLES and EXAMPLES below, both regioisomers are explicitly used; however, in other cases, for the sake of simplicity, only one regioisomer is shown. It should be understood that in these cases the mixture of regioisomers was typically used.REFERENCE EXAMPLE 33-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0177] Step A: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2-(trimethylsilyl)ethylthio)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide

[0178] Commercially available (for example, from Sigma-Aldrich order # 364681), known (Canadian Journal of Chemistry, 1994, 72(2), 325; Journal of Organic Chemistry, 2005, 70(14), 5611) 2-(trimethylsilyl)ethanethiol (21.24 g, 158 mmol) was added to a mixture of NaH (7.59 g, 60% dispersion in mineral oil, 190 mmol) in DMF (350 mL). The resulting mixture was stirred at 0 °C for 30 minutes. After that, 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4-methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide and 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide (50 g, 63.4 mmol) was added in portions.The resulting mixture was stirred at room temperature for 2 hours under an atmosphere of nitrogen. The reaction was monitored by LCMS, and was quenched with water (500 mL). The resulting mixture was extracted with EtOAc(2x300 mL). The organic layers were combined and concentrated under vacuum to afford the title compound: LCMS [M + H] +< : 844.Step B: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2-(trimethylsilyl)ethylsulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0179] m-CPBA (654 g, 379 mmol) was added to a solution of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2-(trimethylsilyl)ethylthio)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (160 g, 190 mmol) in DCM (2000 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight under an atmosphere of nitrogen. The reaction was monitored by LCMS. The resulting mixture was quenched with saturated Na 2 S 2 O3 solution (150 mL), and washed with saturated Na 2 CO 3 solution (1 L) and water (1 L). The organic layer was collected and concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc / PE (1 / 2) as eluent to afford the title compound: : LCMS (ESI) calc'd for C 36 H 42 IN 5 O 7 S 2 Si [M + H] +< : 876, found 876; 1< H NMR (300 MHz, CDCl 3 ): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H).REFERENCE EXAMPLE 42-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)- 1H-tetrazol-5-yl)benzenesulfinic acid

[0180]

[0181] To a solution of 3-iodo-N,N-bi s(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (2.0 g, 2.28 mmol) in THF (23 mL) was added tetrabutylammonium fluoride (5.02 mL, 1.0 M in THF, 5.02 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature under N 2 for 30 minutes. The resulting mixture was diluted with ethyl acetate, washed with saturated KHSO 4 aqueous solution, dried over MgSO 4 , and concentrated under vacuum to afford the crude product as a solid. The crude material was used directly for to make compounds of the invention: LCMS [M + H] +< : 776.REFERENCE EXAMPLE 52-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonyl chloride and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonyl chloride

[0182]

[0183] 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid (800 mg, 1.031 mmol) in THF (10 mL) was cooled to 0°C. 1-chloropyrrolidine-2,5-dione (275 mg, 2.063 mmol) in THF (2 mL) was added over 5 minutes. The mixture was stirred at the same temperature for 30 minutes, then diluted with ethyl acetate, washed with saturated NaHCO 3 and brine, dried over MgSO 4 , and concentrated to afford the crude product: LCMS (ESI) [M + H] +< : 810.REFERENCE EXAMPLE 6tert-Butyl (4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(chlorosulfonyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)benzo[d]thiazol-2-yl)(tert-butoxycarbonyl)carbamate

[0184] Step A: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide

[0185] A suspension of 6-bromo-3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (10 g, 12.65 mmol), cesium carbonate (8.24 g, 25.3 mmol) and 2-(trimethylsilyl)ethanethiol (6.08 ml, 38.0 mmol) in DMF (100 ml) was stirred at room temperature overnight. The mixture was diluted with ether and washed with brine. The organic layer was dried (MgSO 4 ), and concentrated to give crude 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide, which was used directly in the next step. LCMS [M+1]: 844.63.Step B: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0186] The crude 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (10.5 g, 12.5 mmol) was dissolved in DCM (100 ml), and cooled to 0°C. m-CPBA (10.92 g, 63.3 mmol) was added in portions. The mixture was stirred overnight. Precipitate was filtered off through a CELITE pad, and the filtrate was diluted with DCM (100 ml), washed with IN NaOH and brine. The organic layer was dried and concentrated. The residue was purified by ISCO (120 g, 0-50% EtOAc in hexane, the 50% hexane). LCMS [M+1]: 876.49.Step C: 3-(2-aminobenzo[d]thiazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0187] A suspension of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (9 g, 10.28 mmol), (2-aminobenzo[d]thiazol-4-yl)boronic acid (3.99 g, 20.55 mmol), TETRAKIS(triphenylphosphine)Palladium(0) (1.187 g, 1.028 mmol) and sodium carbonate (3.27 g, 30.8 mmol) in dioxane (75 ml) and Water (25 ml) was degassed and heated at 80 °C for 3 hr. The mixture was diluted with AcOEt, washed with brine. The organic layer was dried (MgSO 4 ) and concentrated. The crude material was purified by ISCO (220 g, 0-50% then 50% EtOAc in heaxane. LCMS: 898.74.Step D: tert-butyl (4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)benzo[d]thiazol-2-yl)(tert-butoxycarbonyl)carbamate

[0188] To a mixture of 3-(2-aminobenzo[d]thiazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (7 g, 7.79 mmol), di-tert-butyl dicarbonate (5.95 g, 27.3 mmol) and TEA (3.80 ml, 27.3 mmol) in DCM (80 ml) was added DMAP (0.952 g, 7.79 mmol). The mixture was stirred at room temperature for 1 hour, diluted with ether, washed with KHSO 4 , saturated aqueous and brine. The organic layer was dried over MgSO 4 and concentrated. The crude material was purified by ISCO (120 g, 0-30% then 30% EtOAc in hexane). LCMS [M+1]: 1098.56.Step E: 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-(N,N-bis(tert-butoxycarbonyl)amido)benzo[d]thiazol-4-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0189] A solution of tert-butyl (4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)benzo[d]thiazol-2-yl)(tert-butoxycarbonyl)carbamate (6.9 g, 6.28 mmol) in THF (100 mL) was stirred with tetrabutylammonium fluoride (25.1 mL, 25.1 mmol) at room temperature under N 2 for 0.5 hour. The mixture was diluted with AcOEt, washed with KHSO 4 , saturated aqueous, then dried over MgSO 4 , and concentrated. The crude material was purified by ISCO (0-50% then 50% EtOH-EtOAc(1:3) in hexane. LCMS [M+1]: 998.51.Step F: tert-butyl (4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(chlorosulfonyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)benzo[d]thiazol-2-yl)(tert-butoxycarbonyl)carbamate

[0190] A mixture of sodium acetate (0.789 g, 9.62 mmol), acetic acid (0.551 ml, 9.62 mmol) and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-(N,N-bis(tert-butoxycarbonyl)amido)benzo[d]thiazol-4-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid (3.2 g, 3.21 mmol) in THF (75 ml) was cooled to 0°C. NCS solid (0.856 g, 6.41 mmol) was added. The mixture was stirred at the same temperature for 30 minutes, diluted with Et 2 O, washed with KHSO 4 and brine, then dried over MgSO 4 , and concentrated. The crude material was purified by ISCO 0-30% EtOAc then 30% EtOAc in hexane). LCMS [M+1]: 1032.67. The isolated material contained a small amount of mono-Boc compound. LCMS [M+1]: 932.57.REFERENCE EXAMPLE 72-amino-7-methylbenzo[d]thiazol-4-ylboronic acid

[0191] Step A: N-((2-bromo-5-methylphenyl)carbamothioyl)benzamide

[0192] 2-bromo-5-methylbenzenamine (10 g, 54 mmol) was added into the solution of benzoic cyanic thioanhydride (8.8 g, 54 mmol) in acetone (100 ml) at ambient temperature and stirred at 80°C for 1 hour. The reaction solution was cooled and filtered. The filtrate was washed with EA and dried to give the title compound as a solid. LCMS (ESI) [M + 1] +< 349; 1< H NMR (DMSO-d6, 400 MHZ): δ 12.54 (s, 1H), 9.16 (s, 1H), 8.06 (s, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.73-7.65 (m, 1H), 7.60-7.54 (m, 3H), 7.20 (dd, J = 8.0 Hz, 1H), 2.42 (s, 3H).Step B: 1-(2-bromo-5-methylphenyl)thiourea

[0193] A solution of N-((2-bromo-5-methylphenyl)carbamothioyl)benzamide (5 g, 14 mmol) and NaOH (5.6 g, 140 mmol) in water (100 ml) and MeOH (100 ml) was stirred at 80°C for 3 hour. The reaction mixture was diluted with water (80 mL) and extracted with DCM (3 x 80 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (3 x 10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound as a solid. LCMS (ESI): [M + 1] +< 245; 1< H NMR (DMSO-d6, 400 MHZ): δ 9.20 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H), 6.99 (dd, J = 1.2 Hz, 1H), 2.26 (s, 3H).Step C: 4-bromo-7-methylbenzo[d]thiazol-2-amine

[0194] Br 2 (4.20 ml, 82 mmol) in chloroform (50 mL) was added in drops to a stirred solution of 1-(2-bromo-5-methylphenyl)thiourea (3.1 g, 13 mmol) in chloroform (200 mL) in an ice bath and then stirred at 80°C for 4 hours. The reaction mixture was concentrated under vacuum and washed with EA (3 x 30 ml). The mixture was filtered and the filter cake was dried to give the title compound as a solid. LCMS (ESI): [M + 1] +< 243; 1< H NMR (DMSO-d6, 300 MHZ): δ 7.81 (s, 2H), 7.34 (d, J = 10.8 Hz, 1H), 6.77 (d, J = 10.8 Hz, 1H), 2.30 (s, 3H).Step D: (2-amino-7-methylbenzo[d]thiazol-4-yl)boronic acid

[0195] A solution of 4-bromo-7-methylbenzo[d]thiazol-2-amine (2.0 g, 8.3 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.79 g, 12.3 mmol), PCy3 Pd G2 (0.972 g, 1.645 mmol) and potassium acetate (2.422 g, 24.7 mmol) in 1,4-dioxane (40 ml) was stirred at 80°C for 16 hours. The reaction mixture was concentrated under vacuum and the solid was dissolved with EA (300 ml). The solution was washed with water (15 % NaOH) and the aqueous phase was adjusted to pH 3 with 2 M HCl, and then extracted with EA (3 x 100 ml). The organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound as a solid. LCMS (ESI): [M + 1] +< 209; 1< H NMR (DMSO-d6, 300 MHZ): δ 7.84 (s, 2H), 7.33 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 2.31 (s, 3H).REFERENCE EXAMPLE 82-aminobenzo[d]oxazol-4-ylboronic acid

[0196] Step A: 4-bromobenzo[d]oxazol-2-amine

[0197] A mixture of 2-amino-3-bromophenol (5 g, 26.6 mmol) and cyanic bromide (1.673 ml, 31.9 mmol) in DCM (25 ml) and MeOH (50 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was quenched with aq. sodium hydrogen carbonate (500 mL), diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (3 x 10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a solid. LCMS (ESI): [M + 1] +< 213; 1< H NMR (DMSO-d6, 400 MHZ): 7.70 (s, 2H), 7.35 (s, J = 7.6 Hz, 1H), 7.30 (s, J = 8.4 Hz, 1H), 6.93-6.89 (m, 1H).Step B: 2-aminobenzo[d]oxazol-4-ylboronic acid

[0198] A solution of 4-bromobenzo[d]oxazol-2-amine (1.00 g, 4.69 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (0.686 g, 0.939 mmol), bis(nneopentylglycolato)diboron (1.060 g, 4.69 mmol) and potassium acetate (0.921 g, 9.39 mmol) in 1,4-dioxane (30 ml) was stirred at 80°C for 24 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: Column, Sunfire C 18, 19 x 150mm; mobile phase: water (0.05% TFA) and acetonitrile (Gradient time: 7 min. B%: 10% - 2 0%); Detector, UV 220 and 254 nm. The collected fractions were combined and concentrated under reduced pressure to give the title compound as a solid. LCMS (ESI): [M + 1] +< 179.REFERENCE EXAMPLE 9(2-aminoquinolin-8-yl)boronic acid

[0199]

[0200] A solution of 8-bromoquinolin-2-amine (500 mg, 2.241 mmol), Pd(dppf)Cl 2 (328 mg, 0.448 mmol), bis(pinacolato)diboron (1138 mg, 4.48 mmol) and potassium acetate (440 mg, 4.48 mmol) in 1,4-Dioxane (20 ml) was stirred at 80°C for 2 hours under nitrogen. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give crude product. The crude product was purified by column C18 eluting with acetonitrile / water with 0.05% TFA (15 / 85). The collected fractions were combined and concentrated under vacuum to give the title compound as a solid. LCMS (ESI) [M + H] +< : 189; 1< H NMR (300 MHz, CD 3 OD): δ 8.32 (d, J = 9.6 Hz, 1H), 8.20-8.10 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H).REFERENCE EXAMPLE 102-aminobenzo[d]thiazol-7-ylboronic acid

[0201]

[0202] A mixture of 4-bromobenzo[d]thiazol-2-amine (commercially available, 2000 mg, 8.73 mmol) and bispinacolatodiboron (6651 mg, 26.2 mmol), potassium acetate (2570 mg, 26.2 mmol) and PCy3 Pd G2 (516 mg, 0.873 mmol) in dry dioxane (80 ml) was degassed, and heated at 80°C for 48 hours. The mixture was concentrated, and the residue was dissolved in hydrochloric acid (2N, 100 mL). The aqueous was washed with ethyl acetate (60 mL), and concentrated. The residue was dissolved in methanol (50 ml). The solid was filtered off and the filtrate was concentrated to give a solid which was directly used. LCMS (M+1): 195.12.

[0203] REFERENCE EXAMPLES 11-12 in the Table immediately below were prepared in an analagous fashion as described for 2-aminobenzo[d]thiazol-7-ylboronic acid (REFERENCE EXAMPLE 10) from the aryl bromide starting materials (SM) indicated. REF EX. NO.SMStructureNameLC / MS m / e [M+H] +< 11 (2-amino-3-cyanophenyl) boronic acid162.9912 (1H-benzo[d]imidazol -4-yl)boronic acid163.08 REFERENCE EXAMPLE 13(2-amino-1H-benzo[d]imidazol-4-yl)boronic acid

[0204]

[0205] A mixture of 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (5.59 g, 24.7 mmol), KOAc (4.86 g, 49.5 mmol), and commercially available (for example, from Sigma-Aldrich order # ARK379288552), known (PCT Int. Appl. WO 2015177367) 4-bromo-1H-benzo[d]imidazol-2-amine (3.50 g, 16.5 mmol) in 1,4-dioxane (82 mL) was degassed with N 2 before addition of chloro(triphenylphosphine) [2-(2'-amino-1,1'-biphenyl)]palladium(II) (945 mg, 1.65 mmol). The resulting mixture was heated at 80 °C overnight under N 2 . After cooling to room temperature the reaction mixture was filtered through CELITE, and rinsed with MeOH. The filtrate was concentrated under vacuum, and the residue was purified by reverse phase column chromatography (ISCO RediSep Rf Gold 150 g HP C18 column) eluting with 0-100% MeCN / water (no acid additive) to afford the title compound. LC / MS [M+1] +< : 178.38.REFERENCE EXAMPLE 142-amino-1-methyl-1H-benzo[d]imidazol-4-ylboronic acid

[0206] Step A: 3-bromo-N-methyl-2-nitrobenzenamine

[0207] A solution of 1-bromo-3-fluoro-2-nitrobenzene (10 g, 45.6 mmol) in NH 2 CH 3 in THF (2 M, 100 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under vacuum to give 3-bromo-N-methyl-2-nitrobenzenamine. LCMS (ESI) [M + 1] +< : 231, 1< H NMR (CDCl 3 , 400 MHZ): 7.21-7.16 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 2.94 (s, 3H).Step B: 3-bromo-N1-methylbenzene-1,2-diamine

[0208] HCl (12 M) was added in drops into a stirred solution of 3-bromo-N-methyl-2-nitrobenzenamine (10.1 g, 44 mmol) and Zn dust (14 g, 0.2 mmol) in methanol (200 ml) at room temperature and stirred at ambient temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 3-bromo-N1-methylbenzene-1,2-diamine. LCMS (ESI) [M + 1] +< : 201, 1< HNMR (DMSO, 400 MHZ): 6.70 (d, J= 8.0 Hz, 1H), 6.47 (t, J= 8.0 Hz, 1H), 6.37 (d, J= 8.0 Hz, 1H), 4.99 (s, 1H), 4.62 (s, 2H), 2.70 (s, 3H).Step C: 4-bromo-1-methyl-1H-benzor[d]imidazol-2-amine

[0209] A solution of 3-bromo-N1-methylbenzene-1,2-diamine (3.2 g, 16 mmol) and BrCN (1.68 g, 16 mmol) in methanol (100 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a saturated NaHCO 3 solution and filtered. The filter cake was dried to give 4-bromo-1-methyl-1H-benzo[d]imidazol-2-amine. LCMS (ESI) [M + 1] +< : 226, 1< H NMR (DMSO, 400 MHZ): 7.14-7.11 (m, 2H), 6.83-6.79 (m, 1H), 6.71 (s, 1H), 4.99 (s, 2H), 3.49 (s, 3H).Step D: 2-amino-1-methyl-1H-benzo[d]imidazol-4-ylboronic acid

[0210] A mixture of 4-bromo-1-methyl-1H-benzo[d]imidazol-2-amine (3.5 g, 15.5 mmol), bis(pinacolato)diboron (4.7 g, 18.6 mmol) and potassium acetate (4.5 g, 46.5 mmol) in 1,4-Dioxane (100 ml) was stirred at 80°C for 4 hours under nitrogen. The reaction mixture was concentrated under vacuum to give the crude product. The product was purified by Prep-HPLC with the following conditions: Column, Sunfire C 18, 19 x 150mm; mobile phase: water (0.05% TFA) and acetonitrile (Gradient time: 7 min. B%: 10%-20%); Detector, UV 220 and 254 nm. The collected fractions were combined and concentrated under vacuum to give 2-amino-1-methyl-1H-benzo[d]imidazol-4-ylboronic acid. LCMS (ESI) [M + 1] +< : 192.REFERENCE EXAMPLE 15(2-amino-6-fluoro-1H-benzo[d]imidazol-4-yl)boronic acid.

[0211]

[0212] To a 200 mL RBF was charged a solution of 3-bromo-5-fluorobenzene-1,2-diamine (5 g, 24.39 mmol) in ethanol (100ml), followed by addition of cyanic bromide (5.17 g, 48.8 mmol). The reaction mixture was heated at 80°C for overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo, then was purified by column chromatography (ISCO, 80g, 0-20% MeOH in DCM) to give 4-bromo-6-fluoro-1H-benzo[d]imidazol-2-amine (4.2g, 18.26 mmol), LC-MS [M+H] +< : 230.08. The intermediate was dissolved in 50 mL of anhydrous ethanol, followed by addition of 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (7.86 g, 34.8 mmol), potassium acetate (3.41 g, 34.8 mmol), PCy3 Pd G2 (2.054 g, 3.48 mmol) and anhydrous ethanol (50 ml). The mixture was degassed for 20 minutes, and then was heated at 80°C for 18 hours. The reaction mixture was acidified with 1.0 M HCl to ∼ pH 4, then was washed with EtOAc. The crude product was chromatographed over C18 column to give the desired product (2-amino-6-fluoro-1H-benzo[d]imidazol-4-yl)boronic acid. LC / MS (M+H) +< : 196.07.REFERENCE EXAMPLES 16A and 16B

[0213]

[0214] Racemic tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate was separated into individual enantiomers A and B via SFC (Column: AD-H 50x250 mm, UV detection: 210 nm, Solvent: 25% EtOH (with 0.2 % DIPA) in CO 2 , Flow 230 g CO 2 / min 120 bar). Absolute stereochemistry was not confirmed for the two pure enantiomers. Both enantiomers were useful for preparing metallo-β-lactamase inhibitors.REFERENCE EXAMPLES 17A and 17B

[0215]

[0216] Commercially available racemic tert-butyl 6-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate was separated into individual enantiomers A and B via SFC (Column: AD-H 50x250 mm, UV detection: 210 nm, Solvent: 15% EtOH (with 0.2 % DIPA) in CO 2 , Flow 230 g CO 2 / min 120 bar). Absolute stereochemistry was not confirmed for the two pure enantiomers. Both enantiomers were useful for preparing metallo-β-lactamase inhibitors.REFERENCE EXAMPLE 182-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-((tert-butoxycarbonyl)amino)-1H-benzo[d]imidazol-4-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0217] Step A: 3-(2-amino-1H-benzo[d]imidazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0218] The mixture of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (5.0 g, 5.71 mmol), (2-amino-1H-benzo[d]imidazol-4-yl)boronic acid (2.02 g, 11.42 mmol), Na 2 CO 3 (1.82 g, 17.13 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.699 g, 0.856 mmol) in dioxane (60 mL) and water (15 mL) was degassed with N 2 for 5 minutes. The resulting mixture was heated at 90°C for 6 hours. The reaction mixture was filtered and extracted with EtOAc (2 × 100 mL). The organic phases were dried (MgSO 4 ) and concentrated. The residue was purified by column chromatography on silica gel 220 g, eluting with EtOAc / isohexane (0 - 100% in 45 min) to give a solid. LC / MS [M+H] +< : 881.Step B: tert-butyl (4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-1H-benzo[d]imidazol-2-yl)carbamate

[0219] To 3-(2-amino-1H-benzo[d]imidazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (6.22 g, 7.06 mmol) in DCM (60 mL) at room temperature, was added BOC-Anhydride (1.69 g, 7.77 mmol), TEA (2.46 mL, 17.65 mmol) and DMAP (0.86 g, 7.1 mmol). The mixture was stirred at room temperature for 2 hours, diluted with ether, washed with aqueous KHSO 4 and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica gel 220 g, eluting with 0-80% EtOAc in hexane to afford pure product. LC / MS [M+H]: 981.Step C: 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-((tert-butoxycarbonyl)amino)-1H-benzo[d]imidazol-4-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0220] TBAF (10.1 mL, 10.1 mmol) was added to a stirred solution of tert-butyl (4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-1H-benzo[d]imidazol-2-yl)carbamate (4.5 g, 4. 6 mmol) in THF (50 mL) at room temperature. The mixture was stirred at room temperature for 45 minutes. The mixture was diluted with AcOEt, washed with saturated KHSO 4 aqueous (3 × 60 mL), dried over MgSO 4 , and concentrated to get the crude product as a solid after concentration. The crude material was used directly for the next step. LC / MS [M+H] +< : 881.REFERENCE EXAMPLE 192-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0221] Step A: 3-(2-aminopyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0222] 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (REFERENCE EXAMPLE 3; 2.69 g, 3.07 mmol), N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (1.610 g, 6.14 mmol), Na 2 CO 3 (0.977 g, 9.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.376 g, 0.461 mmol) were added to a 100 mL round bottle flask in dioxane (12 mL) and water (3 mL) at room temperature and the mixture was stirred at 80°C overnight. The mixture was filtered, washed with EtOAc, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO 4 ) and filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 40 g, eluting with EtOAc / isohexane to give the product as foam after concentration. LC / MS [M+H] +< : 842Step B: tert-butyl (3-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)pyridin-2-yl)carbamate

[0223] Boc-anhydride (0.31 mL, 1.33 mmol) and DMAP (0.148 g, 1.211 mmol) were added to a stirred solution of starting material 3-(2-aminopyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (1.02g, 1.211 mmol) in DCM (10 mL) at room temperature and the mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL), and extracted with DCM (2 x 50 mL). The residue was purified by column chromatography on silica gel 24 g, eluting with EtOAc / isohexane to give a foam after concentration. LC / MS [M+H] +< : 942Step C: 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0224] A solution of tert-butyl (3-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)pyridin-2-yl)carbamate (0.92 g, 0.97 mmol) in THF (9 mL) was stirred with TBAF (2.153 mL, 2.153 mmol) at room temperature under N 2 for 30 minutes. The mixture was diluted with AcOEt, washed with saturated KHSO 4 aqueous (3 × 50 mL), dried over MgSO 4 , and concentrated to give the crude product as a solid. The crude material was used directly for the next step.REFERENCE EXAMPLE 20Step A: (S)-methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate

[0225] To a solution of (S)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoic acid (6 g, 25.2 mmol) in MeOH (60 mL) was added SOCl 2 (9.19 mL, 126 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water (300 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford crude product (S)-methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate as a solid, which was directly used in the next step without further purification: LC / MS [M + 1] +< : 253.Step B: (S)-methyl-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino) propanoate

[0226] To a solution of (S)-methyl-3-amino-2-(((benzyloxy)carbonyl)amino)propanoate (4.0 g, 13.85 mmol) in MeOH (50 mL) were added (Boc) 2 O (6.4 mL, 27.70 mmol) and TEA (7.7 mL, 55.40 mmol) at 0°C. The mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched with water (200 mL), and then extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrate under vacuum. The residue was purified by silica gel column chromatography and eluted with 70% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-methyl-2-(((benzyloxy)carbonyl)amino)-3- ((tert-butoxycarbonyl) amino)propanoate as an oil: LC / MS [M + 1] +< : 353.Step C: (S)-benzyl-tert-butyl (3-hydroxypropane-12-diyl)dicarbamate

[0227] To a solution of (S)-methyl-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl) amino)propanoate (4.3 g, 12.2 mmol) in THF (45 mL) was added LiBH4 (0.8 g, 36.6 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aqueous NH 4 Cl (200 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 60% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-benzyl-tert-butyl(3-hydroxypropane -1,2-diyl)dicarbamate as an oil. LC / MS [M + 1] +< : 325.Step D: (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propyl methane sulfonate

[0228] To a solution of (S)-benzyl-tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (4.0 g, 12.33 mmol) in DCM (40 mL) were added MsCl (1.9 mL, 24.66 mmol), TEA (5.2 mL, 37.0 mmol) and DMAP (0.301 g, 2.47 mmol) at 0°C. The mixture was stirred at 50 °C for 1 hour. The resulting mixture was quenched with water (200 mL), and then extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 60% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-2-(((benzyloxy)carbonyl)amino)-3- ((tert-butoxycarbonyl)amino)propyl methanesulfonate as a solid: LCMS [M + 1] +< : 403.Step E: (S)-benzyl-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl) dicarbamate

[0229] To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl) amino)propyl methanesulfonate (3.8 g, 9.44 mmol) in DMF (60 mL) was added potassium 1,3-dioxoisoindolin-2-ide (3.5 g, 18.88 mmol) at room temp. The mixture was stirred at 60°C for 3 hours. The resulting mixture was quenched with water (200 mL), and then extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 60% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-benzyl tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl)dicarbamate as a solid: LCMS [M + 1] +< : 454.Step F: (R)-benzyl-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0230] To a solution of (S)-benzyl-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl) dicarbamate (3.0 g, 6.62 mmol) in EtOH (50 mL) was added N 2 H 4 H 2 O (80%, 0.99 g, 19.85 mmol) at room temperature. The mixture was stirred at 70 °C for 2 h. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (200 mL), and then extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (R)-benzyl tert-butyl (3-aminopropane-1,2-diyl)dicarbamate as a solid: LC / MS [M + 1] +< : 324.REFERENCE EXAMPLE 21(R)-benzyl (1-amino-3-hydroxypropan-2-yl)carbamate hydrochloride

[0231]

[0232] HCl (4 mL, 1.25 M in dioxane, 5.00 mmol) was added to a stirred solution of starting material (R)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (1.0 g, 3.08 mmol) in DCM (10 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The product was used as is. LC / MS [M+H] +< : 225.REFERENCE EXAMPLE 22tert-butyl (R)-(2-amino-3-hydroxypropyl)carbamate

[0233]

[0234] To a solution of (R)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (1.05 g, 3.24 mmol) in MeOH (20 mL) in a RBF at room temperature under N 2 , was added Pd-C (10% wt / wt, 0.689 g, 0.65 mmol) and hydrogenated at 1 atm. (balloon pressure) overnight. The reaction mixture was filtered through a CELITE pad, and washed with EtOAc (3×50 mL). The filtrate was concentrated under reduced pressure. The crude product was used as is. LC / MS [M+H] +: 191.REFERENCE EXAMPLE 23tert-butyl (R)-(3-amino-2-hydroxypropyl)carbamate

[0235]

[0236] To a solution of the epoxide (S)-tert-butyl (oxiran-2-ylmethyl)carbamate (2.0 g, 11.55 mmol) in ethanol (20 mL) was added ammonium hydroxide (20 mL, 114 mmol) at room temperature. The reaction mixture was stirred for 2 hours, and concentrated in vacuo. The residue was dissolved in DCM (40 mL), dried (MgSO 4 ) and concentrated in vacuo. The crude product was chromatographed over silica gel (40 g), eluting with 0-10% MeOH in DCM to give the desired product. LC / MS [M+H] +< : 191.REFERENCE EXAMPLE 24(3-(5-amino-1H-1,2,4-triazol-3-yl)phenyl)boronic acid

[0237]

[0238] Potassium acetate (1.232 g, 12.55 mmol) and PCy3 Pd G2 (0.371 g, 0.627 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.124 g, 8.37 mmol), were added to a stirred solution of 3-(3-bromophenyl)-1H-1,2,4-triazol-5-amine (1.0 g, 4.18 mmol) in dimethylsulfoxide (15 mL) at room temperature and the mixture was stirred at 90°C overnight. The reaction mixture was filtered through a pad of CELITE, diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The residue was purified by reverse phase column chromatography on silica gel 240 g C18, eluting with acetonitrile / water, 0 - 100% in 45 minutes to give the desired product as a solid after concentration. LC / MS [M+H] +< : 205.REFERENCE EXAMPLE 25tert-butyl (3R,4S)-3-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate

[0239] Step A : tert-butyl (3S,4S)-3-(((benzyloxy)carbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate

[0240] To a solution of (3S,4S)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (1000 mg, 4.94 mmol) in dioxane (12.4 mL) and water (12.4 mL) was added sodium carbonate (629 mg, 5.93 mmol) and Cbz-Cl (0.847 mL, 5.93 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. EtOAc (20 mL) was added. The organic layer was separated, washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH / DCM as eluent) to give the title compound. LC / MS [M+H] +< : 337.38.Step B : tert-butyl (3S,4S)-3-(((benzyloxy)carbonyl)amino)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

[0241] To the solution of (3S,4S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate (1200 mg, 3.57 mmol) in DCM (17.8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and MsCl (0.445 mL, 5.71 mmol) at 0°C. The reaction was stirred at room temperature for 2 hours. After evaporation, the residue was purified by flash chromatography on silica gel (40 g gold column, 0-10% MeOH / DCM as eluent) to give the title compound. LC / MS [M+H] +< : 415.38.Step C : tert-butyl (3R,4S)-3-azido-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate

[0242] To the solution of (3S,4S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (1470 mg, 3.55 mmol) in DMF (17.7 mL) was added sodium azide (922 mg, 14.19 mmol) at room temperature. The reaction was stirred at 100°C for 4 hours. EtOAc (20 mL) and water (20 mL) were added. The organic layer was separated, washed with water and brine, dried, filtered, and concentrated under reduced pressure to give the title compound. LC / MS [M+H] +< : 362.44.Step D : tert-butyl (3R,4S)-3-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate

[0243] To the solution of (3R,4S)-tert-butyl 3-azido-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate (1200 mg, 3.32 mmol) in THF (15.1 mL) and Water (1.51 mL) was added triphenylphosphine (1045 mg, 3.98 mmol) at room temperature. The reaction was stirred at 60°C overnight. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel (0-10% MeOH / DCM as eluent) to give the title compound. LC / MS [M+H] +< : 336.36.REFERENCE EXAMPLE 26tert-butyl (3S,4R)-3-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate

[0244]

[0245] The title compound was prepared in an analogous fashion to the above intermediate (REFERENCE EXAMPLE 25) using (3R,4R)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate. LC / MS [M+H] +< : 336.42.REFERENCE EXAMPLE 27(1H-benzo[d][1,2,3]triazol-4-yl)boronic acid

[0246]

[0247] A mixture of 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1027 mg, 4.54 mmol), potassium acetate (446 mg, 4.54 mmol), and 4-bromo-1H-benzo[d][1,2,3]triazole (300 mg, 1.515 mmol) in dioxane (7.6 mL) was degassed with nitrogen before addition of chloro(triphenylphosphine) [2-(2'-amino-1,1'biphenyl)] palladium (II) (130 mg, 0.227 mmol). The resulting mixture was further degassed by nitrogen and heated at 80°C overnight. After cooling to room temperature the reaction mixture was filtered through CELITE, and rinsed with EtOAc. The filtrate was concentrated and the residue was purified by reverse phase C18 column chromatography eluting with 0-100% MeCN / water (no acid additive) to afford the title compound. LC / MS [M+H] +< : 164.05.REFERENCE EXAMPLE 28benzo[c][1,2,5]oxadiazol-4-ylboronic acid

[0248]

[0249] The title compound was prepared in an analogous fashion to REFERENCE EXAMPLE 27 using 4-chlorobenzo[c][1,2,5]oxadiazole. LC / MS [M+H] +< : 165.20.REFERENCE EXAMPLE 29(R)-benzyl-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0250] Step A: (S)-3 -(((benzyl)oxy)carbonyl))amino)-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride

[0251] To a stirred solution of (S)-3-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl) amino) propanoic acid (20 g, 59 mmol) in THF (200 mL) was added isobutyl carbonochloridate (9.60 g, 71 mmol) and 4-methylmorpholine (7.20 g, 71 mmol) at 0°C. The reaction mixture was stirred for 6 hours at 0°C. The reaction mixture was filtered. The filtrate was concentrated under vacuum to afford (S)-3-(((benzyloxy)carbonyl) amino)-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride as an oil. The crude product was used directly in the next step without further purification.Step B: (S)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate

[0252] To a stirred solution of (S)-3-(((benzyloxy)carbonyl)amino) -2-((tert-butoxycarbonyl) amino)propanoic (isobutyl carbonic) anhydride (15 g, 34 mmol) in THF (100 mL) was added NaBH 4 (5.0 g, 136 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water (500 mL) and then extracted with EA (3 x 800 mL). The combined organic layers were washed with water (3 x 500 mL) and brine (3 x 500 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 5% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate as an oil: LCMS (ESI) calc'd for C 16 H 24 N 2 O 5 [M + 1] +< : 325, found 325.Step C: (S)-3-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)propyl methane sulfonate

[0253] To a stirred solution of (S)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (8.20 g, 25 mmol) in DCM (100 mL) was added TEA (10.4 mL, 75 mmol) and MsCl (2.38 mL, 30 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water (500 mL), and then extracted with EA (3 x 800 mL). The combined organic layers were washed with water (3 x 500 mL) and brine (3 x 500 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 5% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-3-(((benzyloxy)carbonyl)amino)-2((tert-butoxycarbonyl)amino)propyl methanesulfonate as an oil: LCMS [M + 1] +< : 403.Step D: (S)-benzyl-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl) dicarbamate

[0254] To a solution of (S)-3-(((benzyloxy)carbonyl)amino) -2-((tert-butoxycarbonyl) amino)propyl methanesulfonate (2.00 g, 4.97 mmol) in DMF (20 mL) was added potassium 1,3-dioxoisoindolin-2-ide (1.38 g, 7.45 mmol). The mixture was stirred at 60°C for 2 hours. The resulting mixture was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford (S)-benzyl-tert-butyl (3-(1,3-dioxoisoindolin-2-yl) propane-1,2-diyl)dicarbamate as a solid: LC / MS [M + 1] +< : 454.Step E: (R)-benzyl tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0255] To a solution of (S)-benzyl tert-butyl (3-(1,3-dioxoisoindolin-2-yl) propane-1,2-diyl) dicarbamate (1.80 g, 3.97 mmol) in EtOH (2 mL) was added N 2 H 4 H 2 O (80%, 5 mL, 3.97 mmol). The mixture was stirred at 80 °C for 1 hour. The resulting mixture was quenched with water (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 10% MeOH and 1% aqueous NH 3 in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford (R)-benzyl-tert-butyl (3-aminopropane -1,2-diyl)dicarbamate as a solid: LC / MS [M + 1] +< : 323.REFERENCE EXAMPLE 30Di-tert-butyl (2-aminopropane-1,3-diyl)dicarbamate

[0256] Step A: Di-tert-butyl (2-hydroxypropane-1,3-diyl)dicarbamate

[0257] To a solution of 1,3-diaminopropan-2-ol (10.0 g, 11 mmol) and KOH (16.0 g, 28 mmol) in THF (50 mL) and water (50 mL) was added (Boc) 2 O (64 mL, 28 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL), extracted with EA (2 x 300 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford di-tert-butyl (2-hydroxypropane-1,3-diyl)dicarbamate as an oil: LC / MS [M + 1] +< : 291.Step B: 2,2,12,12-Tetramethyl-4,10-dioxo-3,11-dioxa-5,9-diazatridecan-7-ylmethanesulfonate

[0258] To a solution of di-tert-butyl (2-hydroxypropane-1,3-diyl)dicarbamate (20.0 g, 68.9 mmol) in DCM (200 mL) was added MsCl (8.1 mL, 103 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 5 hours under nitrogen. The resulting mixture was diluted with EA (400 mL), and then washed with water (3 x 200 mL) and brine (3 x 150 mL). The collected organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford 2,2,12,12-tetramethyl -4,10-dioxo-3, 11-dioxa-5,9-diazatridecan-7-yl methanesulfonate as an oil, which was used in the next step directly without further purification: LC / MS [M + 1] +< : 369.Step C: Di-tert-butyl (2-(1,3-dioxoisoindolin-2-yl)propane-1,3-diyl)dicarbamate

[0259] To a solution of 2,2,12,12-tetramethyl-4,10-dioxo-3,11-dioxa-5,9-diazatridecan-7-yl methanesulfonate (20.0 g, 54.3 mmol) in DMF (200 mL) was added potassium 1,3-dioxoisoindolin-2-ide (10.0 g, 54.3 mmol) at room temperature. The reaction mixture was stirred for 16 hours at 80 °C under nitrogen. The resulting mixture was quenched with water (300 mL). The aqueous layer was extracted with EA (3 x 100 mL), and then the combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford di-tert-butyl(2-(1,3-dioxoisoindolin-2-yl)propane-1,3-diyl) dicarbamate as a solid, which was used in the next step directly without further purification: LC / MS [M + 1] +< : 420.Step D: Di-tert-bulyl (2-aminopropane-1,3-diyl)dicarbamate

[0260] To a solution of di-tert-butyl (2-(1,3-dioxoisoindolin-2-yl) propane-1,3-diyl) dicarbamate (14.0 g, 33.4 mmol) in EtOH (100 mL) was added N 2 H 4 H 2 O (80%, 6.7 g, 167 mmol) at room temperature. The reaction was allowed to warm to 80 °C. The reaction mixture was stirred for 4 hours at 80 °C under nitrogen. The resulting mixture was cooled to room temperature. The mixture was filtered. The filter cake was washed with EtOH (2 x 50 mL). The filtrate was concentrated under vacuum. The residue was re-crystallized with EA / PE (1 : 2) to afford di-tert-butyl(2-aminopropane-1,3-diyl) dicarbamate as a solid: LC / MS [M + 1] +< : 290.REFERENCE EXAMPLE 31(R)-di-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0261] Step A: (S)-di-tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate

[0262] To a solution of (S)-methyl 2,3-bis((tert-butoxycarbonyl)amino)propanoate (commercially available or prepared as described in WO 2006076706, 1.5 g, 4.71 mmol) in THF (15 mL) was added LiAlH 4 (0.27 g, 7.07 mmol) in several portions at 5°C under nitrogen. The mixture was stirred for 2 hours at 5 °C under nitrogen. The resulting mixture was quenched with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-di-tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate as a liquid: LC / MS / [M + 1] +< : 291.Step B: (S)-2,3-bis((tert-butoxycarbonyl)amino)propyl methanesulfonate

[0263] To a solution of (S)-di-tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (0.8 g, 2.76 mmol) and TEA (0.84 g, 8.27 mmol) in DCM (8 mL) was added MsCl (0.47 g, 4.13 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford (S)-2,3-bis((tert-butoxycarbonyl)amino)propyl methanesulfonate as a solid, which was directly used in the next step without further purification: LC / MS [M + 1 ] +< : 369.Step C: (S)-di-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl)dicarbamate

[0264] To a solution of (S)-2,3-bis((tert-butoxycarbonyl)amino)propyl methanesulfonate (1.1 g, 2.99 mmol) in DMF (10 mL) was added potassium 1,3-dioxoisoindolin-2-ide (0.83 g, 4.48 mmol) at room temperature. Then the mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature. The resulting mixture was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as a solid: LC / MS [M + 1] +< : 420.Step D: (R)-di-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0265] To a solution of (S)-di-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl) dicarbamate (0.5 g, 1.19 mmol) in EtOH (5 mL) was added N 2 H 4 H 2 O (80%, 0.12 g, 3.58 mmol) at room temperature. The reaction was allowed to warm to 80°C. The reaction mixture was stirred for 4 hours at 80°C under nitrogen. The resulting mixture was cooled to room temperature. The mixture was filtered. The filter cake was washed with EtOH (2 x 50 mL). The filtrate was concentrated under vacuum to afford (R)-di-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate as a solid, which was directly used for next step without further purification: LC / MS [M + 1] +< : 290.REFERENCE EXAMPLE 32(S)-benzyl-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0266] Step A: (R)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propyl methane sulfonate

[0267] To a solution of (R)-benzyl-tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (2 g, 6.17 mmol) in DCM (20 mL) was added TEA (2.6 mL, 18.50 mmol), MsCl (0.96 mL, 12.33 mmol) and DMAP (0.15 g, 1.23 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford crude product as an oil, which was directly used in the next step without further purification: LC / MS [M + 1] +< : 403.Step B: (R)-benzyl tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl) dicarbamate

[0268] To a solution of (R)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl) amino)propyl methanesulfonate (3.0 g, 7.45 mmol) in DMF (50 mL) was added potassium 1,3-dioxoisoindolin-2-ide (2.76 g, 14.90 mmol) at room temperature. The mixture was stirred at 60°C for 12 hours. The resulting mixture was allowed to cool down to room temperature, diluted with water (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 60% EA in PE to afford the desired compound as a solid: LC / MS [M + 1] +< : 454.Step C: (S)-benzyl tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0269] To a solution of (R)-benzyl-tert-butyl(3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl) dicarbamate (3.0 g, 6.62 mmol) in EtOH (50 mL), was added N 2 H 4 ·H 2 O (80%, 0.99 g, 19.85 mmol) at room temperature. The mixture was stirred at 70 °C for 2 hours. The resulting mixture was allowed to cool down to room temperature. The resulting reaction was quenched with water (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE to afford (S)-benzyl-tert-butyl(3-aminopropane-1,2-diyl)dicarbamate as a solid: LC / MS [M + 1] +< : 324.REFERENCE EXAMPLE 33(S)-di-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylate

[0270] Step A: (R)-1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate

[0271] To a solution of (R)-1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (2.00 g, 8.19 mmol) and TEA (3.42 mL, 24.57 mmol) in DCM (20 mL) was added (Boc) 2 O (2.28 mL, 9.83 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with water (100 mL), and then extracted with EA (3 x 70 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as an oil: LC / MS [M + 1] +< : 345.Step B: (R)-di-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate

[0272] To a solution of (R)-1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (2.00 g, 5.81 mmol) in THF (30 mL) was added LiAlH 4 (0.44 g, 11.61 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The resulting mixture was quenched with NaOH (1 M, 50 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 70 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 40% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as an oil: LC / MS [M + 1] +< : 317.Step C: (S)-di-tert-butyl2-((1,3-dioxoisoindolin-2-yl)methyl)piperazine-1,4-dicarboxylate

[0273] To a solution of (R)-di-tert-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.00 g, 3.16 mmol), triphenylphosphine (0.83 g, 3.16 mmol) and isoindoline-1,3-dione (0.47 g, 3.16 mmol) in THF (20 mL) was added DIAD (0.62 mL, 3.16 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 h under nitrogen. The resulting mixture was quenched with water (50 mL), and then extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 70 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 40% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound as a solid: LC / MS [M + 1] +< : 446.Step D: (S)-di-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylate

[0274] To a solution of (S)-di-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)methyl)piperazine-1,4- dicarboxylate (1.30 g, 2.92 mmol) in EtOH (30 mL) was added N 2 H 4 ·H 2 O (80%, 0.58 g, 14.59 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. The resulting mixture was filtered. The filtrate was concentrated under vacuum. The residue was diluted with EA (100 mL), washed with brine (3 x 80 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the title compound as an oil, which was used directly in the next step without further purification: LC / MS [M + 1] +< : 316.REFERENCE EXAMPLE 34(R)-di-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylate

[0275] Step A: (S)-1,4-di-tert-butyl-2-methyl-piperazine-1,2,4-tricarboxylate

[0276] To a solution of (S)-1-tert-butyl-2-methyl-piperazine-1,2-dicarboxylate (2.0 g, 8.19 mmol) and TEA (2.28 mL, 16.37 mmol) in DCM (20 mL) was added (Boc) 2 O (2.85 mL, 12.28 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was quenched with water (100 mL) and extracted with EA (3 x 70 mL). The combined organic layers was washed with brine (3 x 150 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as an oil: LC / MS [M + 1] +< : 345.Step B: (S)-di-tert-butyl-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

[0277] To a solution of (S)-1,4-di-tert-butyl-2-methyl -piperazine-1,2,4-tricarboxylate (1.50 g, 4.36 mmol) in THF (20 mL) was added LiAlH 4 (0.33 g, 8.71 mmol) at 0 °C. The reaction mixture was stirred at 0°C for 1 hour. The resulting mixture was quenched with NaOH (1 M, 40 mL), and then extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 70 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 40% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (S)-di-tert-butyl -2-(hydroxymethyl)piperazine-1,4-dicarboxylate as an oil: LC / MS [M + 1] +< : 317.Step C: (R)-di-tert-bulyl-2-((1,3-dioxoisoindolin-2-yl)methyl)piperazine-1,4- dicarboxylate

[0278] To a solution of (S)-di-tert-butyl-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.10 g, 3.48 mmol), triphenylphosphine (1.82 g, 6.95 mmol) and isoindoline-1,3-dione (1.02 g, 6.95 mmol) in THF (15 mL) was added DIAD (1.35 mL, 6.95 mmol) at 0 °C. The mixture was degassed with nitrogen for three times. The reaction mixture was stirred at room temperature for 16 h under nitrogen. The resulting mixture was quenched with water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 70 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 40% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound as an oil: LC / MS / [M + 1] +< : 446.Step D: (R)-di-tert-butyl-2-(aminomethyl)piperazine-1,4-dicarboxylate

[0279] To a solution of (R)-di-tert-butyl-2-((1,3-dioxoisoindolin-2-yl)methyl)piperazine-1,4- dicarboxylate (1.20 g, 2.69 mmol) in EtOH (10 mL) was added N 2 H 4 ·H 2 O (0.26 g, 8.08 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. The mixture was cooled to room temperature. The resulting mixture was filtered and the filtration was evaporated under vacuum. The residue was diluted with EA (100 mL), washed with brine (3 x 80 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired product as an oil, which was used directly in the next step without further purification: LC / MS [M + 1] +< : 316.REFERENCE EXAMPLE 35(S)-benzyl (3-aminobutyl)carbamate 2,2,2-trifluoroacetate

[0280] Step A: (S)-tert-butyl (4-hydroxybutan-2-yl)carbamate

[0281] To a solution of (S)-3-((tert-butoxycarbonyl)amino)butanoic acid (5.0 g, 24.60 mmol) in THF (30 mL) was added BF 3 ·THF (49 mL, 49 mmol, 1 M) dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (50 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 25% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as an oil: LC / MS [M + 1] +< : 190.Step B: (S)-3-((tert-butoxycarbonyl)amino)butyl methanesulfonate

[0282] To a solution of (S)-tert-butyl(4-hydroxybutan-2-yl)carbamate (2.5 g, 13.21 mmol) and TEA (5.5 mL, 39.60 mmol) in DCM (50 mL) was added MsCl (1.5 mL, 19.81 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EA (100 mL), washed with brine (3 x 30 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired product as an oil, which was used directly in the next step without further purification: LC / MS [M + 1] +< : 268.Step C: (S)-tert-bulyl (4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate

[0283] To a solution of (S)-3-((tert-butoxycarbonyl)amino)butylmethanesulfonate (3.0 g, 11.22 mmol) in DMF (40 mL) was added potassium 1,3-dioxoisoindolin-2-ide (3.0 g, 16.83 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 3 hours. The resulting mixture was quenched with water (100 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 20% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound as a solid: LC / MS [M + 1] +< : 319.Step D: (S)-tert-butyl (4-aminobutan-2-yl)carbamate

[0284] To a solution of (S)-tert-butyl (4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate (2.7 g , 8.48 mmol) in EtOH (50 mL) was added N 2 H 4 ·H 2 O (80%, 0.85 g, 16.96 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum to afford (S)-tert-butyl (4-aminobutan-2-yl)carbamate as an oil, which was used directly in the next step without further purification: LC / MS [M + 1] +< : 189.Step E : (S)-benzyl tert-butyl butane-1,3-diyldicarbamate

[0285] To a solution of (S)-tert-butyl(4-aminobutan-2-yl)carbamate (1.4 g, 7.44 mmol) in DCM (15 mL) was added TEA (1.5 g, 14.87 mmol) and CbzCl (1.5 g, 8.55 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hour. The resulting mixture was concentrated under vacuum. The residue was diluted with EA (100 mL), washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired product as an oil, which was used directly in the next step without further purification: LC / MS [M + 1] +< : 323.Step F: (S)-benzyl (3-aminobutyl)carbamate 2,2,2-trifluoroacetate

[0286] A solution of (S)-benzyl tert-butyl butane-1,3-diyldicarbamate (1 g, 3.1 mmol) in TFA (8 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to afford (S)-benzyl(3-aminobutyl)carbamate 2,2,2-trifluoroacetate as an oil, which was used directly in the next step without further purification: LC / MS [M + 1-TFA] +< : 223REFERENCE EXAMPLE 36(S)-di-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0287] Step A: (R)-23-bis((tert-butoxycarbonyl)amino)propyl methanesulfonate

[0288] MsCl (0.59 g, 5.16) was added to di-tert-butyl (3-hydroxypropane-1,2-diyl)(R)-dicarbamate (J. Med. Chem. 2010, 53(8), 3198-3213; 1.0 g, 3.44 mmol) and TEA (1.0 g, 10.34 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The resulting mixture was quenched with water (50 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired compound, which was directly used in the next step without further purification: LC / MS [M + 1] +< : 369.Step B: (R)-di-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl)dicarbamate

[0289] To a solution of (R)-2,3-bis((tert-butoxycarbonyl)amino)propyl methanesulfonate (1.4 g, 0.38 mmol) in DMF (15 mL) was added potassium 1,3-dioxoisoindolin-2-ide (1.41 g, 7.60 mmol) at room temperature. Then the mixture was stirred at 60 °C for 16 h. The resulting mixture was quenched with water (50 mL), and then extracted with EA (3 x 50 mL). The combined organic layers was washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound as a solid: LC / MS [M + 1] +< : 420.Step C: (S)-di-tert-butyl (3-aminopropane-1,2-diyl)dicarbamate

[0290] To a solution of (R)-di-tert-butyl (3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl)dicarbamate (1.0 g, 2.38 mmol) in EtOH (10 mL) was added N 2 H 4 H 2 O (80%, 0.36 g, 7.15 mmol). The mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered. The filtrate was concentrated under vacuum to the desired compound as a solid, which was used to make compounds of the invention without further purification: LC / MS [M + 1] +< : 290.REFERENCE EXAMPLE 37(R)-benzyl (2-aminobutyl)carbamate hydrochloride

[0291] Step A: (R)-tert-butyl (1-amino-1-oxobutan-2-yl)carbamate

[0292] TEA (13.7 mL, 98 mmol) and BoC 2 O (15.8 g, 72.2 mmol) were added to a solution of (R)-2-aminobutanamide hydrochloride (5.0 g, 36.1 mmol) in MeOH (100 mL). The mixture was stirred at room temp. for 3 hours. The resulting mixture was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with aqueous HCl (1 M, 2 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired compound as a solid, which was used in the next step without further purification: LC / MS [M + 1] +< : 203.Step B: (R)-tert-butyl (1-aminobutan-2-yl)carbamate

[0293] BH 3 ·DMS (9.39 g, 124 mmol) was added dropwise to a stirred solution of (R)-tert-butyl (1-amino-1-oxobutan-2-yl)carbamate (5.0 g, 24.72 mmol) in THF (50 mL) at 0 °C. The mixture was degassed with nitrogen three times. The reaction mixture was stirred for 12 hours at room temperature under nitrogen. The resulting mixture was quenched with aqueous NaOH (1 M, 150 mL), and then extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under vacuum to afford the title compound, which was directly used in the next step without further purification: LC / MS [M + 1] +< : 189.Step C: (R)-benzyl tert-butyl butane-1,2-diyldicarbamate

[0294] Benzyl carbonochloridate (8.16 g, 47.8 mmol) and TEA (10 mL, 71.7 mmol) were added to a solution of (R)-tert-butyl (1-aminobutan-2-yl)carbamate (4.50 g, 23.90 mmol) in DCM (50 mL). The mixture was stirred at room temperature for 1 hour under nitrogen. The resulting mixture was quenched with water (200 mL), and then extracted with EA (3 x 200 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 20% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LC / MS [M + 1] +< : 323.Step D: (R)-benzyl (2-aminobutyl)carbamate hydrochloride

[0295] A solution of (R)-benzyl tert-butyl butane-1,2-diyldicarbamate (1.0 g, 3.10 mmol) in HCl (1M in dioxane) (10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to afford crude (R)-benzyl (2-aminobutyl)carbamate hydrochloride as a solid, which was directly used in the next step without further purification: LC / MS [M + 1 - HCl] +< : 223.REFERENCE EXAMPLE 38(S)-tert-butyl(2-(3-aminopyrrolidin-1-yl)ethyl)carbamate

[0296] Step A: benzyl (S)-(1-(2-((tert-butoxycarbonyl)amino)ethyl)pyrrolidin-3-yl)carbamate

[0297] Tert-butyl (2-bromoethyl)carbamate (4.5 g, 20 mmol) and Na 2 CO 3 (2.9 g, 27 mmol) were added to a solution of (S)-benzylpyrrolidin-3-ylcarbamate (3 g, 13.5 mmol) in DMF (15 mL). The mixture was stirred for 10 hours at room temp. Then the mixture was poured into water (60 mL). The aqueous phase was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the title compound, which was used in the next step directly without further purification: LC / MS [M + 1] +< : 364.Step B: (S)-tert-bulyl(2-(3-aminopyrrolidin-1-yl)ethyl)carbamate

[0298] To a solution of benzyl (S)-(1-(2-((tert-butoxycarbonyl)amino)ethyl)pyrrolidin-3-yl)carbamate (4.8 g, 13 mmol) in MeOH (15 mL) was added Pd(OH) 2 / C (20% Pd, 2 g). The mixture was degassed with hydrogen for three times. Then the mixture was stirred at room temperature under hydrogen for 16 hours. The resulting mixture was filtered through CELITE. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 10% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LC / MS [M + 1 - 100] +< : 130.REFERENCE EXAMPLE 39(R)-tert-butyl(2-(3-aminopyrrolidin-1-yl)ethyl)carbamate

[0299] Step A: tert-butyl (R)-(2-(3-(((benzyloxy)carbonyl)amino)pyrrolidin-1-yl)ethyl)carbamate

[0300] Tert-butyl (2-bromoethyl)carbamate (4.48 g, 19.98 mmol) was added to a mixture of (R)-benzylpyrrolidin-3-ylcarbamate (2.2 g, 9.99 mmol) and K 2 CO 3 (4.14 g, 30.0 mmol) in DMF (40 mL). The reaction mixture was stirred for 4 hours at room temperature under nitrogen. The reaction mixture was diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 10% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound: LC / MS [M + 1] +< : 364.Step B : (R)-tert-butyl (2-(3-aminopyrrolidin-1-yl)ethyl)carbamate

[0301] Pd(OH)2 / C (20% Pd, 0.30 g, 2.14 mmol) was added to a solution of tert-butyl (R)-(2-(3-(((benzyloxy)carbonyl)amino)pyrrolidin-1-yl)ethyl)carbamate (2.96 g, 8.14 mmol) in MeOH (30 mL). The reaction mixture was degassed with hydrogen three times and stirred for 6 hours at room temperature under hydrogen (about 1.5 atm.). The resulting solution was filtered and the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under vacuum to afford the desired compound as an oil, which was used directly in next step without further purification: LC / MS [M + 1] +< : 230.REFERENCE EXAMPLE 40(R)-benzyl(3-aminobutyl)carbamate hydrochloride

[0302] Step A: (R)-tert-butyl (4-hydroxybutan-2-yl)carbamate

[0303] BF 3 ·THF (84 mL, 84.0 mmol, 1 M) was added dropwise at 0 °C to a solution of (R)-3-((tert-butoxycarbonyl)amino)butanoic acid (8.5 g, 41.8 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (50 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound as an oil: LC / MS [M + 1 - 56] +< : 134.Step B: (R)-3-((tert-butoxycarbonyl)amino)butyl methanesulfonate

[0304] TEA (7.0 g, 69.7 mmol) and MsCl (2.7 mL, 34.9 mmol) were added to a solution of (R)-tert-butyl (4-hydroxybutan-2-yl)carbamate (4.4 g, 23.3 mmol) in DCM (100 mL) at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with EA (300 mL), washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 10% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (R)-3-((tert-butoxycarbonyl) amino)butyl methanesulfonate as a solid: LCMS [M + 1] +< : 268.Step C: (R)-tert-butyl (4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate

[0305] Potassium 1,3-dioxoisoindolin-2-ide (5.7 g, 30.0 mmol) was added to a solution of (R)-3-((tert-butoxycarbonyl)amino)butyl methanesulfonate (5.5 g, 20.0 mmol) in DMF (20 mL). The mixture was stirred at 60 °C for 2 hours, diluted with water (100 mL), and then extracted with EA (3 x 200 mL). The combined organic fractions were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired compound as a solid, which was directly used in the next step without further purification: LC / MS [M + 1] +< : 319.Step D: (R)-tert-butyl (4-aminobutan-2-yl)carbamate

[0306] N 2 H 4 H 2 O (1.44 g, 28.30 mmol) was added to a solution of (R)-tert-butyl (4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate (4.5 g, 14.10 mmol) in EtOH (2 mL). The mixture was stirred at 80 °C for 1 hour, then allowed to cool to room temperature. The resulting mixture was filtered and the filtrate was concentrated under vacuum to afford (R)-tert-butyl (4-aminobutan-2-yl)carbamate as an oil, which was directly used in the next step without further purification: LCMS [M + 1] +< : 189.Step E: (R)-benzyl tert-butyl butane-1,3-diyldicarbamate

[0307] TEA (4.4 mL, 31.90 mmol) and CbzCl (1.7 mL, 12.20 mmol) were added to a solution of (R)-tert-butyl (4-aminobutan-2-yl)carbamate (2.0 g, 10.60 mmol) in THF (10 mL) and water (10 mL) at 0 °C over 5 minutes. The reaction was stirred for 30 minutes at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL), saturated aqueous NaHCO 3 (3 x 30 mL) and brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford (R)-benzyl tert-butyl butane-1,3-diyldicarbamate as a solid, which was used in the next step directly without further purification: LCMS [M + 1] +< : 323.Step F: (R)-benzyl (3-aminobutyl)carbamate hydrochloride

[0308] To a solution of (R)-benzyl tert-butyl butane-1,3-diyldicarbamate (1.0 g, 3.10 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (1 mL, 12 M). The mixture was stirring at room temperature for 1.5 hours. The resulting mixture was concentrated under vacuum to afford (R)-benzyl (3-aminobutyl)carbamate hydrochloride as an oil, which was used in the preparation of final compounds without further purification: LCMS [M + 1 - HCl] +< : 223.REFERENCE EXAMPLES 41 and 42

[0309] (R)-and (S)-tert-butyl-3-amino-3-(aminomethyl)pyrrolidine-1-carboxylate

[0310] Tert-butyl 3-amino-3-(aminomethyl)pyrrolidine-1-carboxylate (2.0 g, 9.29 mmol), prepared by following details described in Bioorganic and Medicinal Chemistry Letters, 2007, 17, 1181-1184), was separated by Chiral Prep-HPLC with the following conditions: Column: Chiralpak AD-H, 2 x 25 cm; Mobile Phase A: CO 2 (70%), Mobile Phase B: MeOH (2 mmol / L NH 3 / MeOH): 30%; Flow rate: 40 mL / min; Detector: 210 nm; Retention time: RT 1 : 2.27 min; RT 2 : 3.30 min; Temperature: 25 °C. The faster-eluting enantiomer 41 was obtained (R)-tert-butyl 3-amino-3-(aminomethyl) pyrrolidin e-1-carboxylate at 2.27 min as an oil: LCMS (ESI) calc'd for C 10 H 21 N 3 O 2 [M + 1] +< : 216, found 216. The slower-eluting enantiomer 42 was obtained (S)-tert-butyl 3-amino-3-(aminomethyl)pyrrolidine-1-carboxylate at 3.30 min as an oil: LCMS (ESI) calc'd for C 10 H 21 N 3 O 2 [M + 1] +< : 216, found 216.REFERENCE EXAMPLE 43(S)-tert-butyl-(3-amino-2-hydroxypropyl)carbamate

[0311]

[0312] 25% NH 3 ·H 2 O (20 mL) was added to a stirred solution of (R)-tert-butyl-(oxiran-2-ylmethyl)carbamate (1.50 g, 8.70 mmol) in EtOH (5 mL) at 0 °C. The reaction solution was stirred for 2 hours at room temp, then concentrated under vacuum to afford (S)-tert-butyl-(3-amino-2-hydroxypropyl) carbamate as a solid, which was used to make final compounds of the invention without further purification: LCMS [M + 1] +< : 191.REFERENCE EXAMPLE 44(3S,4R)-tert-butyl-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate

[0313] Step A: tert-butyl (3R,4R)-3-(((benzyloxy)carbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate

[0314] Cbz-Cl (10.12 g, 59.3 mmol) was added dropwise to a mixture of (3R,4R)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (10.0 g, 49.40 mmol) and Na 2 CO 3 (6.29 g, 59.30 mmol) in 1,4-dioxane (100 mL) and water (100 mL) at 0 °C. The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. The resulting solution was extracted with EA (3 x 100 mL). The combined organic layer was washed with aqueous NaOH (1 M, 2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by a silica gel column chromatography, eluted with 10% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford the desired compound: LCMS [M + 23] +< : 359.Step B: (3R,4R)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-4-((methylsulfonyl)oxy) pyrrolidine -1-carboxylate

[0315] MsCl (10.9 g, 95 mmol) was added dropwise to a solution of tert-butyl (3R,4R)-3-(((benzyloxy)carbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate (16.0 g, 47.6 mmol) and TEA (13.2 mL, 95 mmol) in DCM (200 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h under nitrogen. The resulting solution was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 32% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (3R,4R)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-4-((methylsulfonyl)oxy) pyrrolidine-1-carboxylate as a solid: LCMS [M + 23] +< : 437.Step C: (3S,4R)-tert-butyl 3-azido-4-(((benzyloxy)carbonyl)amino)pyrrolidine -1- carboxylate

[0316] NaN 3 (12.8 g, 198 mmol) was added to a solution of (3R,4R)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-4- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (20.5 g, 49.5 mmol) in DMF (200 mL) at room temperature. The reaction mixture was stirred at 100 °C for 3 hours under nitrogen. The resulting solution was quenched with water (200 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford (3S,4R)-tert-butyl-3-azido -4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate as an oil, which was used in the next step directly without further purification: LCMS [M + 23] +< : 384.Step D: (3S,4R)-tert-butyl 3-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate

[0317] To a solution of (3S,4R)-tert-butyl-3-azido-4-(((benzyloxy)carbonyl)amino) pyrrolidine-1-carboxylate (17.8 g, 49.30 mmol) in THF (200 mL) and water (20 mL) was added triphenylphosphine (15.5 g, 59.10 mmol) at room temperature. The mixture was stirred at 60 °C for 16 hours under nitrogen. The resulting solution was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 5% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound as an oil: LCMS [M + 23] +< : 358.REFERENCE EXAMPLE 45(S)-tert-butyl(1-amino-3-hydroxypropan-2-yl)carbamate

[0318]

[0319] Pd(OH) 2 / C (20% Pd, 0.46 g) was added to a solution of (S)-benzyl-tert-butyl(3-hydroxypropane-1,2-diyl)dicarbamate (2.10 g, 6.47 mmol) in MeOH (20 mL) at room temperature. The reaction mixture was degassed with hydrogen three times. The reaction mixture was stirred for 12 hours at room temperature under hydrogen (1.5 atm). The resulting mixture was filtered. The filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 45% MeOH and 5% NH 3 ·H 2 O in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford methyl-2-amino-3'-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4'-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-2'-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-carboxylate as a solid: LCMS [M + 1] +< : 191.REFERENCE EXAMPLE 46S)-benzyl (2-amino-3-hydroxypropyl)carbamate 2,2,2-trifluoroacetate

[0320]

[0321] TFA (3.3 mL) was added to a stirred solution of (S)-benzyl-tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (1.20 g, 3.70 mmol) in DCM (10 mL) at 0 °C. The reaction solution was stirred for 2 hours at 0 °C. The solution was concentrated under vacuum to afford (S)-benzyl (2-amino-3-hydroxypropyl)carbamate 2,2,2-trifluoroacetate as a solid, which was used to make final compounds of the invention directly without further purification: LCMS [M + 1 - TFA] +< : 225.REFERENCE EXAMPLE 47(R)-benzyl (2-aminopropyl)carbamate 2,2,2-trifluoroacetate

[0322] Step A: (R)-tert-butyl (1-amino-1-oxopropan-2-yl)carbamate

[0323] To a suspension of (R)-2-aminopropanamide hydrochloride (100 g, 0.80 mmol) in MeOH (1000 mL) were added TEA (244 g, 2.41 mol) and (Boc) 2 O (263 g, 1.20 mol) at 0 °C. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (1 L) and extracted with EA (3 x 1.5 L). The combined organic layers were washed with brine (3 x 2 L), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired product as a solid: LCMS [M + 1] +< : 189.Step B: (R)-tert-butyl (1-aminopropan-2-yl)carbamate

[0324] BH 3 -DMS (128 mL, 1.28 mol, 10 M) was added to a suspension of (R)-tert-butyl(1-amino-1-oxopropan-2-yl)carbamate (120 g, 0.64 mol) in THF (200 mL) at 0 °C. The reaction mixture was stirred for 4 hours at 45 °C. The resulting mixture was quenched with aqueous NaOH (1.0 M, 1.0 L) and extracted with EA (3 x 1 L). The combined organic layers were washed with brine (3 x 1.5 L), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford (R)-tert-butyl (1-aminopropan-2-yl)carbamate as an oil, which was used in the next step directly without further purification: LCMS [M + 1] +< : 175.Step C: (R)-benzyl-tert-butylpropane-1,2-diyldicarbamate

[0325] TEA (7.20 mL, 51.70 mmol) and Cbz-Cl (5.87 g, 34.4 mmol) were added to a solution of (R)-tert-butyl (1-aminopropan-2-yl)carbamate (3 g, 17.2 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with 20% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (R)-benzyl -tert-butyl propane-1,2-diyldicarbamate as a solid; LCMS [M + 1] +< : 309.Step D: (R)-benzyl (2-aminopropyl)carbamate 222-trifluoroacetate

[0326] A solution of (R)-benzyl-tert-butyl-propane-1,2-diyldicarbamate (1.10 g, 3.57 mmol) in TFA (15.0 ml, 214 mmol) and DCM (15.0 ml) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to afford the title compound as an oil, which was used to make final compounds of the invention without further purification: LCMS [M - TFA + 1] +< : 209.REFERENCE EXAMPLE 48(R)-benzyl (2-aminobutyl)carbamate hydrochloride

[0327] Step A: (R)-tert-butyl (1-amino-1-oxobutan-2-yl)carbamate

[0328] (Boc) 2 O (15.8 g, 72.20 mmol) and TEA (13.7 mL, 98.00 mmol) were added to a solution of (R)-2-aminobutanamide hydrochloride (5.0 g, 36.10 mmol) in MeOH (50 mL). The mixture was stirred at room temp. for 3 h. The resulting mixture was quenched with H 2 O (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with HCl (1 M, 2 x 50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired product as a solid, which was used in the next step directly without further purification: LCMS [M + 1] +< : 203.Step B: (R)-tert-butyl (1-aminobutan-2-yl)carbamate

[0329] BH 3 ·Me 2 S (9.39 g, 124.0 mmol, 10 M) was added dropwise to a solution of (R)-tert-butyl(1-amino-1-oxobutan-2-yl)carbamate (5.0 g, 24.7 mmol) in THF (50 mL) at 0 °C. The reaction mixture was stirred for 12 hours at room temperature. The resulting reaction mixture was quenched with aqueous NaOH (1 M, 150 mL), and then extracted with EA (3 x 100 mL). The combined organic layers was washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford (R)-tert-butyl(1-aminobutan-2-yl)carbamate as a solid, which was used in the next step directly without further purification: LCMS [M + 1] +< : 189.Step C: (R)-benzyl tert-butyl butane-1,2-diyldicarbamate

[0330] CbzCl (8.16 g, 47.80 mmol) and TEA (7.26 g, 71.70 mmol) were added to a solution of (R)-tert-butyl (1-aminobutan-2-yl)carbamate (4.5 g, 23.90 mmol) in DCM (50 mL). The mixture was stirred at room temperature for 3 h. The resulting mixture was quenched with water (50 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 20% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford (R)-benzyl tert-butyl butane-1,2-diyldicarbamate as a solid: LCMS [M + 1] +< : 323.Step D: (R)-benzyl(2-aminobutyl)carbamate hydrochloride

[0331] A solution of (R)-benzyl-tert-butylbutane-1,2-diyldicarbamate (1.0 g, 3.10 mmol) in HCl (1 M in dioxane) (10 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to afford the title compound as a solid: LCMS [M + 1 - HCl] +< : 223.REFERENCE EXAMPLE 49(S)-benzyl(2-aminobutl)carbamate hydrochloride

[0332] Step A: (S)-tert-butyl(1-amino-1-oxobutan-2-yl)carbamate

[0333] The title compound was prepared as described in REFERENCE EXAMPLE 48 step A using (S)-2-aminobutanamide hydrochloride (10 g, 65.50 mmol): LCMS [M + 1] +< : 203.Step B: (S)-tert-butyl (1-aminobutan-2-yl)carbamate

[0334] The title compound was prepared as described in REFERENCE EXAMPLE 48 step B using (S)-tert-butyl(1-amino-1-oxobutan-2-yl)carbamate (3 g, 14.83 mmol): LCMS [M + 1] +< : 189.Step C: (S)-benzyl tert-buiylbutane-1,2-diyldicarbamate

[0335] The title compound was prepared as described in REFERENCE EXAMPLE 48 step C using (S)-tert-butyl(1-aminobutan-2-yl)carbamate (1.0 g, 5.31 mmol): LCMS [M + 1] +< : 323.Step D: (S)-benzyl (2-aminobutyl)carbamate hydrochloride

[0336] The title compound was prepared as described in REFERENCE EXAMPLE 48 step D using (S)-benzyl tert-butyl butane-1,2-diyldicarbamate (1 g, 3.10 mmol): LCMS [M + 1 - HCl] +< : 223.REFERENCE EXAMPLE 50(3R, 4S)-tert-butyl 3 -amino-4-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate

[0337] Step A: (3R, 4S)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl) amino)pyrrolidine-1-carboxylate

[0338] TEA (1.02 g, 10.10 mmol) and (BOC) 2 O (1.76 g, 8.07 mmol) were added to a stirred solution of (3S, 4R)-tert-butyl-3-amino-4-(((benzyloxy)carbonyl) amino)pyrrolidine-1-carboxylate (REFERENCE EXAMPLE 44, 2.3 g, 6.72 mmol) in 1,4-dioxane (15 mL) and water (15 mL) in an ice bath. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with Et 2 O (3 x 200 mL). The combined organic layers were washed with saturated aqueous Na 2 CO 3 (2 x 100 mL), brine (2 x 100 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum to afford the title compound, which was used in the next step directly without further purification: LCMS [M + 1] +< : 436.Step B: (3R, 4S)-tert-butyl 3-amino-4-((tert-butoxycarb onyl)amino)pyrrolidine-1-carboxylate

[0339] Pd(OH) 2 / C (20% Pd, 0.35 g, 0.50 mmol) was added to a solution of (3R, 4S)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate (2.20 g, 4.95 mmol) in MeOH (20 mL) at room temperature. The reaction mixture was degassed with hydrogen for three times. The reaction mixture was stirred for 16 hours at room temperature under hydrogen (1.5 atm). The resulting mixture was filtered. The filtrate was concentrated under vacuum to afford (3R, 4S)-tert-butyl-3-amino-4-((tert-butoxycarbonyl)amino) pyrrolidine-1-carboxylate as a solid, which was used to make compounds of the invention without further purification: LCMS [M + 1] +< : 302.REFERENCE EXAMPLE 51(2-Carbamoyl-1H-benzo[d]imidazol-4-yl)boronic acid

[0340] Step A: 4-Bromo-2-(trichloromethyl)-1H-benzo[d]imidazole

[0341] Benzyl 2,2,2-trichloroacetimidate (13.50 g, 53.50 mmol) was added to a stirred solution of 3-bromobenzene-1,2-diamine (10.0 g, 53.50 mmol) in AcOH (50 mL) at room temperature. The reaction solution was stirred at room temp. for 4 hours. The resulting mixture was poured into water (300 mL) and the solid was precipitated. The resulting mixture was filtered. The filter cake was washed with water (3 x 50 mL) and dried under vacuum to afford the desired product as a solid, which was used in the next step directly without further purification: LCMS [M + 1] +< : 315.Step B: 4-Bromo-1H-benzo[d]imidazole-2-carbonitrile

[0342] 4-bromo-2-(trichloromethyl) -1H-benzo[d]imidazole (10.00 g, 31.80 mmol) was added to a solution of liquid NH 3 (20 mL) at -78 °C . The mixture was stirred at -78 °C for 20 min. The reaction mixture was allowed to warm to room temperature. After the ammonia was evaporated, the residue was dissolved in EA (300 mL). The organic layer was washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 4-bromo-1H-benzo[d]imidazole-2-carbonitrile as a solid: LCMS [M + 1] +< : 222, 224.Step C: 4-Bromo-1H-benzo[d]imidazole-2-carboxamide

[0343] 30% H 2 O 2 (0.3 mL, 2.25 mmol) and KOH (0.63 g, 11.26 mmol) were added to a solution of 4-bromo-1H-benzo[d]imidazole-2-carbonitrile (0.50 g, 2.25 mmol) in MeOH (10 mL) and water (5 mL). The reaction mixture was stirred at 25 °C for 4 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 10% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as a solid: LCMS [M + 1] +< : 240, 242.Step D: (2-Carbamoyl-1H-benzo[d]imidazol-4-yl)boronic acid

[0344] KOAc (1.23 g, 12.50 mmol), Pd(dppf)Cl 2 (0.51 g, 0.63 mmol) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.12 g, 9.37 mmol) were added to a solution of 4-bromo-1H-benzo[d]imidazole-2-carboxamide (0.75 g, 3.12 mmol) in 1,4-dioxane (6 mL). The mixture was degassed with nitrogen three times and stirred for 16 h at 80 °C under nitrogen. The resulting mixture was concentrated under vacuum. The residue was purified by RPLC with the following conditions: Column: C18; mobile phase: ACN / water (0.5% TFA); Flow rate: 60 mL / min; Gradiate: 5%-30% ACN in water in 30 min; Retention time: 20 min; Detector: UV 254 nm. The fractions containing desired product were combined and concentrated under vacuum to afford (2-carbamoyl-1H-benzo[d]imidazol-4-yl)boronic acid as a solid: LCMS [M + 1] +< : 206.REFERENCE EXAMPLE 52Tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1 ,2,3]triazol-2-yl)ethyl)carbamate

[0345] Step A: 4-Bromo-1H-benzo[d][1,2,3]triazole

[0346] Sodium nitrite (1.7 g, 25.0 mmol) was added in several portions to a solution of 3-bromobenzene-1,2-diamine (2.3 g, 12.5 mmol) in AcOH (10 mL) and water (4 mL) at 0 °C. The reaction mixture was stirred at room temp. for 4 h. The resulting mixtuire was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum to afford 4-bromo-1H-benzo[d][1,2,3]triazole as a solid, which was used in the next step directly without further purification: LCMS [M + 1] +< : 198, 200.Step B: Tert-butyl (2-(4-bromo-2H-benzo[d][1,2,3]triazol-2-yl)ethyl)carbamate

[0347] Na 2 CO 3 (2.6 g, 25 mmol) was added to a solution of 4-bromo-1H-benzo[d][1,2,3]triazole (2 g, 10 mmol) and tert-butyl (2-bromoethyl) carbamate (3.4 g, 15 mmol) in DMF (15 mL) at 0 °C. The reaction mixture was stirred at room temp. for 5 hours. The resulting mixture diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 15% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the desired product as a solid: LCMS [M + 1] +< : 341, 343.Step C: Tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1 ,2,3]triazol-2-yl)ethyl)carbamate

[0348] 4,4,4',4',5,5,5',5' -octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.47 g, 17.58 mmol), KOAc (0.86 g, 8.79 mmol) and Pd(dppf)Cl 2 adduct CH 2 Cl 2 (0.48 g, 0.59 mmol) were added to a solution of tert-butyl(2-(4-bromo-2H-benzo[d][1,2,3]triazol-2-yl)ethyl) carbamate (1.0 g, 2.93 mmol) in 1,4-dioxane (10 mL) at room temperature. The mixture was degassed with nitrogen three times and stirred for 16 hours at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 20% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1,2,3]triazol-2-yl) ethyl)carbamate as an oil: LCMS [M + 1] +< : 389.REFERENCE EXAMPLE 532-Amino-7-methyl-1H-benzo[d]imidazol-4-ylboronic acid

[0349] Step A: 4-Methylbenzo[c][1,2,5]thiadiazole

[0350] SOCl 2 (18 mL, 246 mmol) was added dropwise very slowly to a solution of 3-methylbenzene-1,2-diamine (10.0 g, 82 mmol) and TEA (45.6 mL, 327 mmol) in DCM (200 mL). The reaction mixture was refluxed for 4 hours. The resulting mixture was concentrated under vacuum. The residue was diluted with water (700 mL), and then extracted with DCM (3 x 200 mL). The combined organic layers were washed with water (2 x 200 mL), brine (2 x 200 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with 1% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 4-methylbenzo[c] [1,2,5]thiadiazole as an oil: LCMS [M +1] +< : 151.Step B: 4-Bromo-7-methylbenzo[c][1,2,5]thiadiazole

[0351] Br 2 (7.6 mL, 146 mmol) was added to a solution of 4-methylbenzo[c][1,2,5]thiadiazole (11 g, 73.2 mmol) in 48% aqueous HBr (120 mL, 1.06 mol). The reaction mixture was stirred for 16 hours at 80 °C. The resulting mixture was diluted with water (100 mL), and then extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 200 mL) and brine (2 x 200 mL), dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under vacuum to afford the desired product as a solid, which was used in the next step without further purification: LCMS [M +1] +< : 229, 231.Step C: 3-Bromo-6-methylbenzene-1,2-diamine

[0352] NaBH 4 (1.3 g, 34.90 mmol) and cobalt (II) chloride hexahydrate (0.4 g, 1.75 mmol) were added to a solution of 4-bromo-7-methylbenzo[c][1,2,5]thiadiazole (4.0 g, 17.46 mmol) in MeOH (80 mL) were added at 0°C. The reaction mixture was stirred at 70 °C for 3 hours. The resulting mixture was cooled to room temperature, and then filtered to remove the solid. The filtrate was concentrated under vacuum. The residue was dissolved in water (100 mL). The aqueous phase was extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 20% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 3-bromo-6-methylbenzene-1,2-diamine as an oil: LCMS [M +1] +< : 201, 203.Step D: 4-Bromo-7-methyl-1H-benzo[d]imidazol-2-amine

[0353] BrCN (1.05 g, 9.95 mmol) was added to a solution of 3-bromo-6-methylbenzene-1,2-diamine (2.00 g, 9.95 mmol) in MeOH (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 90 min. The reaction mixture was poured into saturated aqueous NaHCO 3 (50 mL). The solid was precipitated and filtered. The filter cake was dried under vacuum to afford the desired product, which was used in the next step without further purification: LCMS [M + 1] +< : 226, 228.Step E: 2-Amino-7-methyl-1H-benzo[d]imidazol-4-ylboronic acid

[0354] 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (4.50 g, 19.91 mmol), 2nd Generation PPh 3 precatalyst (0.69 g, 1.19 mmol) and KOAc (2.3 g, 23.90 mmol) were added to a solution of 4-bromo-7-methyl-1H-benzo[d]imidazol-2-amine (1.80 g, 7.96 mmol) in 1,4-dioxane (18 mL) at room temperature. The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen. The resulting mixture was concentrated under vacuum. The residue was purified by RPLC with the following conditions: Column: C18; mobile phase: ACN / water (0.5% TFA); Flow rate: 60 mL / min; Gradiate: 5%-30% ACN in water in 30 min; Retention time: 20 min; Detector: 254 nm. The fractions containing the desired product were concentrated under vacuum to afford the title compound acid as a solid: LCMS [M + 1 192.REFERENCE EXAMPLE 54Tert-butyl(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)carbamate

[0355] Step A: Tert-butyl (4-(3-bromophenyl)-1H-imidazol-2-yl)carbamate

[0356] To a solution of 2-bromo-1-(3-bromophenyl)ethanone (3 g, 10.79 mmol) in DMF (30 mL) was added tert-butyl-N-carbamimidoylcarbamate (3.5 g, 21.59 mmol). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (60 mL), and then extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 15% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl (4-(3-bromophenyl)-1H-imidazol-2-yl)carbamate as a solid: LCMS [M + 1] +< : 338, 340.Step B: Tert-butyl( 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole -2-yl)carbamate

[0357] To a solution of tert-butyl (4-(3-bromophenyl)-1H-imidazol-2-yl)carbamate (1.5 g, 4.44 mmol) in 1,4-dioxane (20 mL) were added 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane) (2.3 g, 8.87 mmol), Pd(dppf)Cl 2 adduct CH 2 Cl 2 (0.6 g, 0.68 mmol) and KOAc (1.3 g, 13.31 mmol). The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred for 16 hours under nitrogen at 80 °C. The resulting mixture was concentrated under vacuum to afford the title compound as a solid: LCMS [M + 1] +< : 386.REFERENCE EXAMPLE 55(1H-pyrrolo[3,2-b)]pyridin-6-yl)boronic acid

[0358]

[0359] KOAc (1.5 g, 15.20 mmol), 2nd Generation XPhosprecatalyst (1.2 g, 1.52 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.6 g, 10.15 mmol) were added to a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (1.0 g, 5.08 mmol) in 1,4-dioxane (4 mL). The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen. The resulting mixture was diluted with EA(30 mL), and then extracted with aqueous NaOH (2N, 2 x 100 mL). The combined aqueous layers were concentrated under vacuum. The residue was stirred in MeOH / DCM (1 / 10, 100 mL) for 20 min. The resulting mixture was filtered and the filtrate was concentrated under vacuum to afford the title compound as a solid: [M + 1] +< : 163.REFERENCE EXAMPLE 565-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

[0360] Step A: N-((3-bromophenyl)carbamothioyl)benzamide

[0361] 3-bromoaniline (3.50 mL, 32.1 mmol) was added dropwise to a solution of benzoyl isothiocyanate (5.81 g, 35.7 mmol) in acetone (50 mL) at 70 °C. The reaction mixture was stirred at 70 °C for 1 hour. The resulting solution was poured into ice-water (100 mL), stirred for 10 minutes, and filtered. The filter cake was washed with water (10 mL) and dried under vacuum to afford the desired product as a solid, which was used in the next step without further purification: LCMS [M + 1] +< : 335, 337.Step B: 1-(3-Bromophenyl)thiourea

[0362] N-((3-bromophenyl)carbamothioyl)benzamide (10.0 g, 29.8 mmol) was added to a solution of NaOH (10.0 g, 250 mmol) in water (100 mL) at 80 °C. The reaction mixture was stirred at 80 °C for 1 hour under nitrogen. The resulting mixture was poured into ice aqueous HCl (6M, 30 mL) and stirred for 10 minutes. The pH value was adjusted to 10 with 25% NH 3 ·H 2 O. The solid was precipitated and filtered. The filter cake was washed with water (10 mL) and dried under vacuum. The crude solid was purified by silica gel column chromatography, eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 1-(3-bromophenyl)thiourea as a solid: LCMS [M + 1] +< : 231, 233.Step C: 5-Bromobenzo[d]thiazol-2-amine

[0363] A solution of bromine (0.86 mL, 16.79 mmol) in AcOH (17.5 mL) was added dropwise at 0 °C to a solution of 1-(3-bromophenyl)thiourea (4.00 g, 17.31 mmol) in ACN (350 mL). The reaction mixture was stirred at room temperature for 18 hours under nitrogen. The resulting mixture was filtered. The filter cake was washed with EA (10 mL) and dried under vacuum to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: X Select CSH Prep C18 OBD Column 19 x 150 mm, 5 µm, 13 nm, Phase A: water with 0.05% TFA, Phase B: MeOH; Flow rate: 20; Injection volumn: 200 µL; Gradient: 30-100% of B; Rentation time: 28 min (faster peak). The fractions containing the desired product were combined and concentrated under vacuum to afford 5-bromobenzo[d]thiazol-2-amine as a solid: LCMS [M + 1] +< : 229, 231.Step D: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

[0364] KOAc (5.27 g, 53.70 mmol) and 2nd Generation PCy 3 precatalyst (2.11 g, 3.58 mmol) were added to a solution of 5-bromobenzo[d]thiazol-2-amine (4.10 g, 17.90 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.09 g, 35.80 mmol) in 1,4-dioxane (100 mL) at room temperature. The reaction mixture was stirred for 4 hours at 80 °C under nitrogen. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound as a solid: LCMS [M + 1] +< : 277.REFERENCE EXAMPLE 572-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1,2,3]triazole

[0365] Step A: 4-Bromo-2-methyl-2H-benzo[d][1,2,3]triazole

[0366] Iodomethane (2.87 g, 20.20 mmol) was added to a mixture of 4-bromo-2H-benzo[d][1,2,3]triazole (4.0 g, 20.20 mmol) and potassium carbonate (5.58 g, 40.40 mmol) in DMF (40 mL) at room temperature for 2 min. The reaction mixture was stirred at room temperature for 16 h under nitrogen, then concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 7% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 4-bromo-2-methyl-2H-benzo[d][1,2,3]triazole as a solid: LCMS [M + 1] +< : 212, 214.Step B: 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1,2,3] triazole

[0367] 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (1.72 g, 6.79 mmol), KOAc (1.67 g, 16.98 mmol) and Pd(dppf)Cl 2 adduct CH 2 Cl 2 (0.46 g, 0.57 mmol) were added to a solution of 4-bromo-2-methyl-2H-benzo[d][1,2,3]triazole (1.20 g, 5.66 mmol) in 1,4-dioxane (16 mL) at room temperature. The mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 10% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound as an oil: LCMS [M + 1] +< : 260.REFERENCE EXAMPLE 583-Oxocyclohex-1-enylboronic acid

[0368] Step A: 3-Oxocyclohex-1-enyl-trifluoromethanesulfonate

[0369] TEA (9.03 g, 89.4mmol) and Tf 2 O (15.1 g, 53.6 mmol) were added to a solution of cyclohexane-1,3-dione (5.00 g, 44.6 mmol) in DCM (50 mL) at -78°C for 10 minutes under nitrogen. The reaction mixture was stirred at -78 °C for 1 hour. The resulting mixture was quenched with saturated aqueous NaHCO 3 (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with 10% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 3-oxocyclohex-1-enyl- trifluoromethanesulfonate as an oil: LCMS [M + 1] +< : 245.Step B: 3-Oxocyclohex-1-enylboronic acid

[0370] 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (15.2 g, 60 mmol), KOAc (8.80 g, 90 mmol), Pd(dppf)Cl 2 adduct CH 2 Cl 2 (2.50 g, 3.0 mmol) were added to a solution of 3-oxocyclohex-1-enyl-trifluoromethanesulfonate (7.30 g, 30 mmol) in 1,4-dioxane (100 mL) at room temperature. The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 2 hours under nitrogen. The resulting mixture was diluted with EA (100 mL) and extracted with aqueous NaOH (2 M, 3 x 50 mL). The combined aqueous layers were concentrated under vacuum. The residue was purified by RPLC with the following conditions: Column: C18; mobile phase: ACN / water (1‰ TFA); Flow rate: 60 mL / min; Gradiate: 10%-40% ACN in water in 30 min; Retention time: 23 min; Detector: 254 nm. The fractions containing desired product were combined and concentrated under vacuum to afford 3-oxocyclohex-1-enylboronic acid as an oil: LCMS [M + 1] +< : 141.REFERENCE EXAMPLE 592-((2-((3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)thiazol-4-yl)methyl)isoindoline-1,3-dione

[0371] Step A: 2-((2-((3 -B romophenyl)amino)thiazol-4-yl)methyl)isoindoline-1,3-dione

[0372] 1,3-dibromopropan-2-one (2.2 g, 10 mmol) was added to a stirred solution of 1-(3-bromophenyl)thiourea (2.3 g, 10 mmol) in NMP (20 mL) at room temperature. The reaction mixture was stirred at 50 °C for 2 hours. The resulting mixture was allowed to cool to room temperature. Isoindoline-1,3-dione (2.2 g, 14.9 mmol) and K 2 CO 3 (2.8 g, 19.9 mmol) were added at room temperature to the reaction solution. The reaction mixture was stirred at room temperature for 3 days. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 70% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford 2-((2-((3-bromophenyl)amino)thiazol-4-yl) methyl)isoindoline-1,3-dione as a solid: LCMS [M + 1] +< : 414, 416.Step B: 2-((2-((3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)thiazol-4-yl) methyl)isoindoline-1,3 -dione

[0373] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.5 g, 9.66 mmol), KOAc (1.4 g, 14.5 mmol) and 2nd Generation PPh 3 precatalyst (0.57 g, 0.97 mmol) were added to a stirred solution of 2-((2-((3-bromophenyl)amino)thiazol-4-yl)methyl) isoindoline-1,3-dione (2.0 g, 4.83 mmol) in 1,4-dioxane (15 mL) at room temperature. The mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford ((2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) amino)thiazol-4-yl)methyl)isoindoline-1,3-dione as a solid: LCMS [M + 1] +< : 462.REFERENCE EXAMPLE 60Imidazo[1,2-a]pyridin-8-ylboronic acid

[0374] Step A: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0375] Pd 2 (dba) 3 (2.10 g, 2.30 mmol), 3-bromopyridin-2-amine (2.00 g, 11.56 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.87 g, 23.12 mmol) and KOAc (3.40 g, 34.7 mmol) were added to a solution of tricyclohexylphosphine (1.10 g, 4.10 mmol) in 1,4-dioxane (15 mL) at room temp. The mixture was degassed with nitrogen three times and stirred at 95 °C for 16 h. The resulting mixture was filtered. The filtrate was concentrated under vacuum to afford the title compound, which was used in the next step without further purification: LCMS [M + 1] +< : 139.Step B: Imidazo[1,2-a]pyridin-8-ylboronic acid

[0376] 2-chloroacetaldehyde (13.7 g, 68.20 mmol) was added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.00 g, 4.54 mmol) in EtOH (15 mL) at room temperature. The reaction mixture was stirred at 70 °C for 16 hours. The resulting mixture was concentrated under vacuum. The residue was diluted with EA (100 mL) and extracted with aqueous HCl (1 N, 3 x 30 mL). The combined aquous layers were concentrated under vacuum to afford the title compound as a solid, which was used in the next step without further purification: LCMS [M + 1] +< : 163.REFERENCE EXAMPLE 61Tert-butyl ((4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazol -2-yl)methyl)carbamate

[0377] Step A: Tert-butyl (2-((2-amino-3-bromophenyl)amino)-2-oxoethyl)carbamate

[0378] 2-((tert-butoxycarbonyl)amino)acetic acid (94 g, 535 mmol), HATU (610 g, 1.6 mol) and TEA (223 mL, 1.6 mol) were added to a solution of 3-bromobenzene-1,2-diamine (100 g, 535 mmol) in THF (1 L) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred for overnight at room temperature. The resulting mixture was diluted with water (500 mL) and extracted with EA (3 x 600 mL). The combined organic layers was washed with water (3 x 500 mL) and brine (3 x 500 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 60% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl(2-((2-amino-3-bromophenyl) amino)-2-oxoethyl)carbamate as a solid, which was used in the next step directly without further purification: LCMS [M + 1] +< : 344, 346.Step B: Tert-butyl ((4-bromo-1H-benzo[d]imidazol-2-yl)methyl(carbamate

[0379] A solution of tert-butyl (2-((2-amino-3-bromophenyl)amino)-2-oxoethyl)carbamate (180 g, 523 mmol) in AcOH (250 mL) was stirred for 0.5 h at 60 °C. The resulting mixture was concentrated under vacuum. The residue was crystallized from EA / PE (50 : 1, 200 mL). The solid was collected by filtration and dried under vacuum to afford tert-butyl ((4-bromo-1H-benzo[d]imidazol-2-yl)methyl)carbamate as a soild: LCMS [M + 1] +< : 326, 328.Step C: Tert-butyl((4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazol-2-yl) methyl)carbamate

[0380] To a solution of tert-butyl((4-bromo-1H-benzo[d]imidazol-2-yl)methyl)carbamate (70.0 g, 215 mmol) in 1,4-dioxane (350 mL) was added Chloro(triphenylphosphine)[2-(2'-amino-1,1-biphenyl)]Palladium (II) (24.6 g, 42.9 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (72.7 g, 322 mmol) and KOAc (63.2 g, 644 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 80 °C for 16 h. The resulting mixture was diluted with water (500 mL) and extracted with EA (3 x 400 mL). The combined organic layers was washed with water (3 x 800 mL) and brine (3 x 500 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 60% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl((4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo [d]imidazol-2-yl)methyl)carbamate: LCMS [M + 1] +< : 360.REFERENCE EXAMPLE 62Tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo[d][1,2,3]triazol-1-yl)ethyl)carbamate

[0381] Step A: Tert-butyl (2-((3-bromo-2-nitrophenyl)amino)ethyl)carbamate

[0382] Tert-butyl (2-aminoethyl)carbamate (3.3 g, 21 mmol) and Na 2 CO 3 (2.9 g, 27 mmol) were added to a solution of 1-bromo-3-fluoro-2-nitrobenzene (3.0 g, 14 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 5 hours. The resulting mixture was diluted with water (200 mL), and then extracted with EA (3 x 150 mL). The combined organic layers was washed with water (3 x 150 mL), brine (3 x 150 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum to afford tert-butyl (2-((3-bromo-2-nitrophenyl)amino)ethyl)carbamate as an oil, which was used in the next step without further purification: LCMS [M + 1] +< : 360, 362 (1: 1).Step B: Tert-butyl (2-((2-amino-3-bromophenyl)amino)ethyl)carbamate

[0383] Zn dust (5.9 g, 84.0 mmol) was slowly added in several portions to a solution of tert-butyl(2-((3-bromo-2-nitrophenyl)amino)ethyl)carbamate (5.5 g, 14.0 mmol) in concentrated HCl and MeOH (1 : 4, 30 mL). The reaction mixture was stirred for 2 hours at 50 °C. The resulting mixture was filtered. The filtrate was concentrated under vacuum to afford crude N1-(2-aminoethyl)-3-bromobenzene-1,2-diamine as an oil, which was used in the next step directly without further purification. To the solution of the crude N1-(2-aminoethyl)-3-bromobenzene-1,2-diamine in DCM (50 mL) was added (Boc) 2 O (4.5 g, 21 mmol) and TEA (2.8 g, 28 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL), and then extracted with DCM (3 x 250 mL). The combined organic layers were washed with water (3 x 250 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum to afford tert-butyl (2-((2-amino-3-bromophenyl)amino)ethyl)carbamate as a solid, which was used in the next step without further purification: LCMS [M + 1 - 100] +< : 230, 232.Step C: Tert-butyl (2-(4-bromo-1H-benzo[d][1,2,3]triazol-1-yl)ethyl)carbamate

[0384] NaNO 2 (1.9 g, 28.0 mmol) was added to a solution of tert-butyl(2-((2-amino-3-bromophenyl)amino)ethyl)carbamate (5.0 g, 14.0 mmol) in AcOH and H 2 O (1 : 3, 15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (100 mL), and then extracted with EA(3 x 200 mL). The combined organic fractions were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 10% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl(2-(4-bromo-1H-benzo[d][1,2,3]triazol-1-yl)ethyl) carbamate as a solid: LCMS [M + 1] +< : 341, 343.Step D: Tert-butyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo [d] [1,2,3] triazol-1-yl)ethyl)carbamate

[0385] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.5 g, 17.70 mmol), Pd(dppf)Cl 2 adduct CH 2 Cl 2 (0.5 g, 0.60 mmol) and KOAc (0.8 g, 8.70 mmol) were added to a solution of tert-butyl(2-(4-bromo-1H-benzo[d][1,2,3]triazol-1-yl)ethyl) carbamate (1.0 g, 2.90 mmol) in 1,4-dioxane (15 mL). The mixture was degassed with nitrogen three times and stirred at 80 °C for 16 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazol-1-yl) ethyl)carbamate as an oil: LCMS [M + 1] +< : 389.REFERENCE EXAMPLE 63(2-((2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl) carbamate

[0386] Step A: Tert-butyl (2-((5-bromo-2-nitrophenyl)amino)ethyl)carbamate

[0387] Cs 2 CO 3 (22.2 g, 68.2 mmol) and tert-butyl(2-aminoethyl) carbamate (8.74 g, 54.5 mmol) were added to a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.5 mmol) in NMP (35 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was diluted with water (200 mL), and then extracted with EA (3 x 200 mL). The combined organic layers were washed with water (3 x 200 mL) and brine (3 x 200 mL), dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl (2-((5-bromo-2-nitrophenyl)amino)ethyl)carbamate as a solid: LCMS [M + 1] +< : 360, 362.Step B: Tert-bulyl(2-((2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino) ethyl)carbamate

[0388] Pd(dppf)Cl 2 (1.22 g, 1.67 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.23 g, 16.70 mmol) and KOAc (2.45 g, 25.00 mmol) were added to a stirred solution of tert-butyl(2-((5-bromo-2-nitrophenyl)amino)ethyl)carbamate (3.0 g, 8.33 mmol) in 1,4-dioxane (30 mL) at room temperature. The mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 h under nitrogen. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers was washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl (2-((2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)carbamate as an oil: LCMS [M + 1] +< : 408.Step C: Tert-bulyl(2-((2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino) ethyl)carbamate

[0389] Pd / C (10% wt, 0.3 g, 0.28 mmol) was added to a solution of tert-butyl(2-((2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)amino)ethyl)carbamate (3 g, 7.37 mmol) in MeOH (30 mL) at room temperature under nitrogen. The mixture was degassed with hydrogen three times. The reaction mixture was stirred at room temperature for 16 hours under hydrogen (1.5 atm). The solid was removed by filtration. The filtrate was concentrated under vacuum to afford the title compound as an oil, which was used to make compounds of the invention without further purification: LCMS [M + 1] +< : 378.REFERENCE EXAMPLE 64(2-Aminobenzo[d]thiazol-4-yl)boronic acid

[0390]

[0391] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.43 g, 17.46 mmol), KOAc (2.84 g, 28.90 mmol) and 2nd Generation PCy 3 precatalyst (1.03 g, 1.75 mmol) were added to a solution of commercially available 4-bromobenzo[d]thiazol-2-amine (2.0 g, 8.8 mmol) in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 90 °C for 24 h under nitrogen. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers was washed with water (3 x 300 mL) and brine (3 x 300 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by RPLC with the following conditions: Column: C18 column chromatography; Flow rate: 60 mL / min; Gradiate: 25%-30% ACN in water with 0.5% TFA in 20 min; Detector: 254 nm. The fractions containing desired product were combined and concentrated under vacuum to afford (2-aminobenzo[d]thiazol-4-yl)boronic acid as a solid: LCMS [M + 1] +< : 195.REFERENCE EXAMPLE 65Tert-butyl ((5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)methyl)carbamate

[0392] Step A: 2-(3-bromophenyl)-2-oxoethyl (tert-butoxycarbonyl)glycinate

[0393] To a solution of 2-((tert-butoxycarbonyl)amino)acetic acid (1.26 g, 7.20 mmol) in EtOH (20 mL) was added Cs 2 CO 3 (1.17 g, 3.60 mmol) at room temperature. The reaction mixture was stirred at room temperature. The resulting solution was concentrated under vacuum to afford a cesium salt. To a solution of 2-bromo-1-(3-bromophenyl)ethanone (1.98 g, 7.20 mmol) in DMF (20 mL) was added the caesium salt. The reaction mixture was stirred for 2 hours at room temp. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 26% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + 1] +< : 372, 374.Step B: Tert-butyl ((4-(3-bromophenyl)-1H-imidazol-2-yl)methyl)carbamate

[0394] To a solution of the 2-(3-bromophenyl)-2-oxoethyl (tert-butoxycarbonyl)glycinate (2 g, 5.37 mmol) in toluene (20 mL) was added ammonium acetate (4.14 g, 53.70 mmol). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was then cooled to room temp., and then diluted with EA (50 mL). The resulting solution was washed with aqueous NaHCO 3 (5% W / V) (3 x 30 mL) and brine (3 x 30 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 40% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + 1] +< : 352, 354.Step C: Tert-butyl((5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole-2-yl)methyl)carbamate

[0395] To a solution of tert-butyl((4-(3-bromophenyl)-1H-imidazol-2-yl)methyl)carbamate (1 g, 2.84 mmol) in 1,4-dioxane (30 mL) were added 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane) (1.44 g, 5.68 mmol), 2nd Generation PCy 3 precatalyst (0.50 g, 0.85 mmol) and KOAc (0.84 g, 8.52 mmol) at room temp. The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 40% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford tert-butyl ((5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)methyl)carbamate as a solid: LCMS [M + 1] +< : 400.REFERENCE EXAMPLE 66(2-(Methylamino)-1H-benzo[d]imidazol-4-yl)boronic acid

[0396] Step A: 7-Bromo-N-methyl-1H-benzo[d]imidazol-2-amine

[0397] To a solution of commercially available 7-bromo-2-chloro-1H-benzo[d]imidazole (0.50 g, 2.16 mmol) in THF (10 mL) was added methanamine (2 M in THF, 5.40 mL, 10.80 mmol). The reaction solution was stirred for 24 hours at 80 °C. The resulting solution was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 2% MeOH in EA. The fractions containing desired product were combined and concentrated under vacuum to afford 7-bromo-N-methyl-1H-benzo[d]imidazole-2-amine as a solid: LCMS [M + H] +< : 226, 228.Step B: (2-(Methylamino)-1H-benzo[d]imidazol-4-yl)boronic acid

[0398] To a solution of 7-bromo-N-methyl-1H-benzo[d]imidazole-2-amine (0.30 g, 1.33 mmol) in dioxane (4 mL) were added 2nd PPh 3 precatalyst (76 mg, 0.13 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (0.45 g, 1.99 mmol) and KOAc (0.39 g, 3.98 mmol). The reaction mixture was degassed with nitrogen three times. The reaction mixture was stirred for 16 hours at 80 °C under nitrogen. The resulting mixture was filtered. The filtrate was purified by RPLC with the following conditions: Column: C18; Mobile phase: water (0.5% TFA) / ACN; Gradiate: 5%-30% ACN in water in 25 min; Retention time: 18 min; Flow rate: 60 mL / min; Detector: 254 nm and 220 nm. The fractions containing desired product were combined and concentrated under vacuum to afford (2-(methylamino)-1H-benzo[d]imidazol-4-yl) boronic acid as a solid: LCMS [M + 1] +< : 192.REFERENCE EXAMPLE 67tert-butyl (2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)ethyl)carbamate and tert-butyl (2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)ethyl)carbamate

[0399]

[0400] To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfinic acid (3 g, 3.87 mmol) in THF (38.7 ml) was added tert-butyl (2-aminoethyl)carbamate (1.239 g, 7.74 mmol), triethylamine (1.078 ml, 7.74 mmol), and NCS (1.033 g, 7.74 mmol) in sequence at 0°C under nitrogen. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with EtOAc, washed with NaHCO 3 solution and brine. The organic layer was dried over MgSO 4 , evaporated, and the crude product was purified by silica gel column eluting with 0-100% EtOAc / hex to give the title compound. LC / MS [M+H] +< : 934.53.REFERENCE EXAMPLE 68tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate and tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate

[0401]

[0402] To a solution of a mixture of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1-sulfonyl chloride and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzene-1-sulfonyl chloride (0.46 g, 0.48 mmol) in THF (10 mL) was added (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (90 mg, 0.48 mmol) at ambient temperature. The reaction was kept at 25°C for 30 minutes. The mixture was concentrated under vacuum. The residue was diluted with EA (3 x 20 mL), washed with brine (3 x 20 mL), dried and filtered. The filtrate was concentrated under vacuum. The residue was applied onto silica gel column chromatography with ethyl acetate / petroleum ether (1 : 50 to 1 : 1) to give the title compound: LCMS [M + 1] +< 960; 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (d, J= 8.4 Hz, 1H), 8.29 (d, J= 8.4 Hz, 1H), 7.29-7.25 (m, 2H), 6.83-6.69 (m, 10H), 5.95 (brs, 1H), 5.55-5.50 (m, 0.5H), 5.24-5.19 (m, 0.5H), 4.58-4.53 (m, 1H), 4.05-3.81 (m, 5H), 3.85 (s, 9H), 3.48-3.35 (m, 4H), 2.02-1.82 (m, 2H), 1.44 (s, 9H).REFERENCE EXAMPLE 69tert-butyl (R)-(2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propyl)carbamate and tert-butyl (R)-(2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)propyl)carbamate

[0403]

[0404] To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfinic acid (1.0 g, 1.289 mmol) in DCM (20 ml) was added (R)-tert-butyl (2-aminopropyl)carbamate (0.337 g, 1.934 mmol), triethylamine (0.261 g, 2.58 mmol), and NCS (0.344 g, 2.58 mmol) in sequence at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed with 10 ml of sat. aq. NaHCO 3 . The organic phase was dried over MgSO 4 , concentrated, and the crude product was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give the title compound. LC / MS [M+H] +< : 948.48.REFERENCE EXAMPLE 70tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate and tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate

[0405]

[0406] The title compound was prepared in an analogous fashion to REFERENCE EXAMPLE 67 using tert-butyl (3R,4S)-3-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate. LC / MS [M+H] +< : 1109.80.REFERENCE EXAMPLE 71tert-butyl (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate and tert-butyl (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate

[0407]

[0408] The title compound was prepared in an analogous fashion to REFERENCE EXAMPLE 67 using tert-butyl (3S,4R)-3-amino-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1-carboxylate. LC / MS [M+H] +< : 1109.8.

[0409] REFERENCE EXAMPLES 68 (alternative preparation) and 72-84 in the Table below were similarly prepared in an analogous fashion to that described for REFERENCE EXAMPLE 67 using 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid (as a mixture of two tetrazole-PMB regioisomers) and the corresponding amines, which were prepared as described herein, or which were available from commercial sources. While a single regioisomer of the PMB-protected tetrazole is shown for simplicity, it should be understood that the intermediates prepared here are in fact mixtures of both possible regioisomeric PMB substituted tetrazoles. Ex# Structure Chemical Name LC / MS [M+H] +< 68 (R)-tert-butyl3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo -3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)pyrrolidine-1-carboxylate96072 (S)-tert-butyl3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo -3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)pyrrolidine-1-carboxylate96073 (S)-tert-butyl(1-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-3-hydroxypropan-2-yl)carbamate96474 (R)-tert-butyl(3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-2-hydroxypropyl)carbamate96475 (S)-tert-butyl(3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-2-hydroxypropyl)carbamate96476 (S)-di-tert-butyl2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)methyl)piperazine-1,4-dicarboxylate108977 (R)-di-tert-butyl2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)methyl)piperazine-1,4-dicarboxylate108978 (S)-benzyltert-butyl(3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propane-1,2-diyl)dicarbamate109779 (R)-tert-butyl(2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-3-hydroxypropyl)carbamate96480 (R)-benzyl(1-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-3-hydroxypropan-2-yl)carbamate99881 (R) form (R)-di-tert-butyl(3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propane-1,2-diyl)dicarbamate106381 (S) form (S)-di-tert-butyl (3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxy benzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propane-1,2-diyl)dicarbamate82 (3R,4S)-tert-butyl 3-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-4-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate107583 (S)-benzyl (2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)-3-hydroxypropyl)carbamate99884 di-tert-butyl (2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)propane-1,3-diyl)dicarbamate106385 benzyl tert-butyl (3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)propane-1,2-diyl)(S)-dicarbamate REFERENCE EXAMPLE 86tert-butyl (S)-(2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propyl)carbamate and tert-butyl (S)-(2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)propyl)carbamate

[0410]

[0411] The title compounds were prepared in the same way as REFERENCE EXAMPLE 69 using tert-butyl (S)-(2-aminopropyl)carbamate. LC / MS [M+H] +< : 948.45.REFERENCE EXAMPLE 87tert-butyl (S)-(2-amino-3-hydroxypropyl)carbamate

[0412]

[0413] To a solution of (S)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate (1.5 g, 4.62 mmol) in 20 ml of ethanol was added Pd / C (0.325 g, 0.231 mmol). The mixture was stirred at 45 psi of H 2 for 4 hours. The volatile was removed in vacuo and the residue was dissolved in 10 mL of EtOAc, then concentrated again to give the desired product as a a powder. LC / MS [M+H] +< : 191.22.REFERENCE EXAMPLE 88tert-butyl (S)-(2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)-3-hydroxypropyl)carbamate and tert-butyl (S)-(2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)-3-hydroxypropyl)carbamate

[0414]

[0415] The title compounds were prepared in the same way as REFERENCE EXAMPLE 69 using tert-butyl (S)-(2-amino-3-hydroxypropyl)carbamate. LC / MS [M+H] +< : 964.58.REFERENCE EXAMPLE 89tert-butyl (2S,4R)-4-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)-2-(hydroxymethyl)pyrrolidine-1-carboxylate and tert-butyl (2S,4R)-4-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0416]

[0417] The title compounds were prepared in the same way as REFERENCE EXAMPLE 69 using commercially available tert-butyl (2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate. LC / MS [M+H] +< : 990.31.REFERENCE EXAMPLE 902-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0418] Step A. tert-butyl (5-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)pyridin-2-yl)carbamate

[0419] (6-((tert-butoxycarbonyl)amino)pyridin-3-yl)boronic acid (0.707 g, 2.97 mmol) and sodium carbonate (0.726 g, 6.85 mmol) and Pd(dppf)Cl 2 (0.373 g, 0.457 mmol) were added to a stirred solution of starting material 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (2.0 g, 2.283 mmol) in dioxane (16 mL) and water (4 ml) at room temp. and the mixture was degased for 5 minutes and then stirred at 90 °C overnight. The mixture was diluted with water (50 mL), extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel 120 g, eluting with EtOAc / isohexane, 0 - 40% in 30 minutes to give the product as a foam. LC / MS [M+H]+: 942.Step B. 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(6-((tert-butoxvcarbonyl)amino)pyridin-3-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0420] A solution of tert-butyl (5-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)pyridin-2-yl)carbamate (1.76 g, 1.87 mmol) in THF (16 mL) was stirred with TBAF (4.11 mL, 4.11 mmol) at RT under N 2 for 30 minutes. The mixture was diluted with EtOAc, washed with KHSO 4 aqueous (3×), dried over MgSO 4 , and concentrated to give the product. LC / MS [M+H]+: 842.REFERENCE EXAMPLE 913'-(5-amino-1H-1,2,4-triazol-3-yl)-3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-sulfinic acid

[0421] Step A. (3-(5-amino-1H-1,2,4-triazol-3-yl)phenyl)boronic acid

[0422] Potassium acetate (1.232 g, 12.55 mmol) and PCy3 Pd G2 (0.371 g, 0.627 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.124 g, 8.37 mmol), were added to a stirred solution of starting material 3-(3-bromophenyl)-1H-1,2,4-triazol-5-amine (1.0 g, 4.18 mmol) in dimethyl sulfoxide (15 mL) at room temp. and the mixture was stirred at 90 °C overnight. The reaction mixture was filtered through a pad of CELITE, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The residue was purified by reverse phase LC column chromatography on silica gel 240 g C18, eluting with Acetonitrile / Water, 0 - 100% in 45 minutes to give desired product. LC / MS [M+H]+: 205.Step B. 3'-(5-amino-1H-1,2,4-triazol-3-yl)-N,N-bis(4-methoxvbenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)-[1,1'-biphenyl]-3-sulfonamide

[0423] The mixture of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (1.0 g, 1.142 mmol), (3-(5-amino-1H-1,2,4-triazol-3-yl)phenyl)boronic acid (0.419 g, 2.055 mmol), Na 2 CO 3 (0.363 g, 3.43 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.140 g, 0.171 mmol) in dioxane (10 mL) and water (2 mL) was degassed with N 2 for 5 minutes. The resulting mixture was stirred at 95 °C for 16 hours. This reaction was filtered and extracted with EtOAc (2 × 100 mL), organic phase was dried (MgSO 4 ), and concentrated. The residue was purified by column chromatography on silica gel 40 g, eluting with EtOAc / isohexane, B = 0 - 100% in 45 min to give the title compound. LC / MS [M+H]+: 909. Step C. 3'-(5-amino-1H-1,2,4-triazol-3-yl)-3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-sulfinic acid

[0424] TBAF (2.0 mL, 2.0 mmol) was added to a stirred solution of starting material 3'-(5-amino-1H-1,2,4-triazol-3-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)-[1,1'-biphenyl]-3-sulfonamide (855 mg, 0.941 mmol) in THF at 0 °C and the mixture was stirred at 0 °C for 45 minutes. The mixture was diluted with KHSO 4 (saturated, 3 × 40 mL) and was extracted with EtOAc (3 x 40 mL). The organic phase was concentrated to give the title compound. LC / MS [M+H]+: 809.REFERENCE EXAMPLE 92benzyl tert-butyl (3-aminopropane-1,2-diyl)(S)-dicarbamate

[0425]

[0426] This intermediate was prepared in an analogous fashion to (R)-benzyl tert-butyl (3-aminopropane-1,2-diyl)dicarbamate (REFERENCE EXAMPLE 20) using (R)-benzyl tert-butyl (3-hydroxypropane-1,2-diyl)dicarbamate. LC / MS [M+H] +< : 324.42.REFERENCE EXAMPLE 93benzyl tert-butyl (3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propane-1,2-diyl)(R)-dicarbamate and benzyl tert-butyl (3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)propane-1,2-diyl)(R)-dicarbamate

[0427]

[0428] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using benzyl tert-butyl (3-aminopropane-1,2-diyl)(S)-dicarbamate. LC / MS [M+H] +< : 1097.98.REFERENCE EXAMPLE 94tert-butyl (3S,4R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)-4-hydroxypyrrolidine-1-carboxylate and tert-butyl (3S,4R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)-4-hydroxypyrrolidine-1-carboxylate

[0429]

[0430] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using commercially available tert-butyl (3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate. LC / MS [M+H] +< : 976.30.REFERENCE EXAMPLE 95tert-butyl (3R,4S)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)-4-hydroxypyrrolidine-1-carboxylateand tert-butyl (3R,4S)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)-4-hydroxypyrrolidine-1-carboxylate

[0431]

[0432] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using commercially available tert-butyl (3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate. LC / MS [M+H] +< : 976.44.REFERENCE EXAMPLE 96tert-butyl (3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propyl)carbamate and tert-butyl (3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propyl)carbamate

[0433]

[0434] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using tert- butyl (3-aminopropyl)carbamate. LC / MS [M+H] +< : 948.45.REFERENCE EXAMPLE 97tert- butyl (R)-(1-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propan-2-yl)carbamate and tert-butyl (R)-(1-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propan-2-yl)carbamate

[0435]

[0436] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using tert-butyl (R)-(1-aminopropan-2-yl)carbamate. LC / MS [M+H] +< : 948.49.REFERENCE EXAMPLE 98tert- butyl (S)-(1-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propan-2-yl)carbamate and tert-butyl (S)-(1-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)propan-2-yl)carbamate

[0437]

[0438] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using tert-butyl (S)-(1-aminopropan-2-yl)carbamate. LC / MS [M+H] +< : 948.37.REFERENCE EXAMPLE 99tert-butyl (3R,4R)-3-(((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfinyl)amino)-4-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate and tert-butyl (3R,4R)-3-(((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfinyl)amino)-4-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate

[0439]

[0440] The title compounds were prepared in an analogous fashion to REFERENCE EXAMPLE 69 using commercially available tert-butyl ((3R,4R)-4-amino-1-benzylpyrrolidin-3-yl)carbamate. LC / MS [M+H] +< : 1065.77.REFERENCE EXAMPLE 100tert-butyl (2S,4R)-4-amino-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate

[0441] Step A: tert-butyl (2S,4R)-4-(((benzyloxy)carbonyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0442] To a solution of (2S,4R)-tert-butyl 4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0g, 9.25 mmol) in dioxane (20 ml) and water (20 ml) was added sodium carbonate (1.176 g, 11.10 mmol) and Cbz-Cl (1.584 ml, 11.10 mmol) at 0 °C. The reaction was stirred at room temp. for 2 hours. EtOAc (20 mL) was added. The organic layer was separated, washed with brine, dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / hexanes to give the title compound. LC-MS: [M+H-56] +< : 295.28.Step B: tert-butyl (2S,4R)-4-(((benzyloxy)carbonyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate

[0443] To a solution of (2S,4R)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.67 g, 7.62 mmol), PPh 3 (2.60 g, 9.91 mmol) and isoindoline-1,3-dione (1.345 g, 9.14 mmol) in THF (40 ml) was added DEAD (2.062 ml, 9.91 mmol) at 0 °C dropwise. The reaction completed in 30 min. The reaction mixture was concentrated in vacuo and the residue was chromatographed over silic gel eluting with 0-60% EtOAc in hexanes to give the desired product (2S,4R)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate. LC-MS: [M+H] +< : 480.29.Step C: tert-butyl (2S,4R)-4-amino-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate

[0444] To a solution of (2S,4R)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate (3.0 g, 6.26 mmol) in 20 ml of ethanol was added Pd / C (0.44g, 0.313 mmol), the mixture was stirred at 45psi of H 2 for 8 hours. The catalyst was removed by filting through a CELITE pad. The filtrate was concentrated and chromatographed over silica gel eluting with 0-20% MeOH in DCM to give the desired product. LC-MS [M+H] +< : 346.41.REFERENCE EXAMPLE 101tert-butyl (2S,4R)-4-(((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfinyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate and tert-butyl (2S,4R)-4-(((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfinyl)amino)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate

[0445]

[0446] This intermediate was prepared in an analogous fashion to REFERENCE EXAMPLE 69 using tert-butyl (2S,4R)-4-amino-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate. LC / MS [M+H] +< : 1120.07.REFERENCE EXAMPLE 102(3-(2-Amino-1H-imidazol-4-yl)phenyl)boronic acid

[0447] Step A: N-(4-(3-Bromophenyl)-1H-imidazol-2-yl)acetamide

[0448] 2-Bromo-1-(3-bromophenyl)ethanone (3000 mg, 10.79 mmol) was stirred with N-carbamimidoylacetamide (3274 mg, 32.4 mmol) in DMF (8995 µl) at room temperature for 48 h. The reaction mixture was diluted with EtOAc and washed with saturated NH 4 Cl aqueous solution and brine. The organic layer was separated and concentrated and the resulting residue was purified by column chromatography (eluting with 0- 100% EtOAc / hexane) to give the title compound. LC / MS [M+H]+: 280.1, 282.1.Step B: 4-(3-Bromophenyl)-1H-imidazol-2-amine

[0449] N-(4-(3-Bromophenyl)-1H-imidazol-2-yl)acetamide (1.2 g, 4.28 mmol) was dissolved in MeOH (8 mL), and HCl in dioxane (4 N, 8 mL) and water (8 mL) were added. The mixture was heated at 100°C in a sealed bottle for 1 hour. LC-MS showed that the acyl group was removed. The reaction was cooled and concentrated to remove the solvents. The resulting residue was dissolved in MeOH, and purified by column chromatography (eluting with 100% hexane to 100% EtOAc / EtOH (3 / 1) to hexane) to give the title compound. LC / MS [M+H]+: 238.1, 240.1Step C: (3-(2-Amino-1H-imidazol-4-yl)phenyl)boronic acid

[0450] 4-(3-Bromophenyl)-1H-imidazol-2-amine (561 mg, 2.356 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1331 mg, 5.89 mmol), Ph 3 PPdG2 (202 mg, 0.353 mmol), and potassium acetate (925 mg, 9.43 mmol) were placed in a vial, Dioxane (3927 µl) was added. The reaction was degassed for 20 min, then heated at 90°C for 1 h. The reaction was then cooled to room temperature, and filtered. The filtrates were concentrated and the residue was purified with reverse C18 column eluting with 0-60% CH3CN / water. The correct fractions were combined and lypholized. LC / MS [M+H]+: 204.2.REFERENCE EXAMPLE 103(3-(2-Amino-5-(ethoxycarbonyl)thiazol-4-yl)phenyl)boronic acid

[0451] Step A: Ethyl 2-bromo-3-(3-bromophenyl)-3-oxopropanoat

[0452] Ethyl 3-(3-bromophenyl)-3-oxopropanoate (3.72 g, 13.72 mmol) was dissolved in DCM (35.4 ml), and 1-bromopyrrolidine-2,5-dione (2.93 g, 16.47 mmol) was added. The reaction mixture was stirred at room temperature under N 2 for 6 hours. The reaction mixture was partitioned between DCM and saturated NaHCO 3 aqueous solution. The organic layer was separated, concentrated and purified by column chromatography (eluting with 0-20%EtOAc / hexane) to give the title compound. LC / MS [M+H]+: 351.2.Step B: Ethyl 2-amino-4-(3-bromophenyl)thiazole-5-carboxylate

[0453] Ethyl 2-bromo-3-(3-bromophenyl)-3-oxopropanoate (3.26 g, 9.31 mmol) and thiourea (0.723 g, 9.50 mmol) were heated in ethanol (74.5 ml) at 75°C for 1 h. LC-MS showed the formation of the desired product. The reaction mixture was concentrated and partitioned between DCM and water. The organic layer was separated, washed with brine, and concentrated to afford the title compound. LC / MS [M+H]+: 327.2, 329.2.Step C: (3-(2-amino-5-(ethoxycarbonyl)thiazol-4-yl)phenyl)boronic acid

[0454] Ethyl 2-amino-4-(3-bromophenyl)thiazole-5-carboxylate (250 mg, 0.764 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (431 mg, 1.910 mmol), Ph 3 PPdG2 (65.6 mg, 0.115 mmol), and potassium acetate (300 mg, 3.06 mmol) were placed in a reaction vial. Dioxane (5458 µl) was added. The reaction mixture was degassed and heated at 90° for 1 hour 45 minutes. The reaction mixture was cooled to room temperature, and the product was used as crude for the next step. LC / MS [M+H]+: 293.2.REFERENCE EXAMPLE 104(3-(2-((tert-Butoxycarbonyl)amino)-5-(((tert-butoxycarbonyl)amino)methyl)thiazol-4-yl)phenyl)boronic acid

[0455] Step A: Ethyl 4-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate

[0456] Ethyl 2-amino-4-(3-bromophenyl)thiazole-5-carboxylate (Step B, Intermediate 103) (2 g, 6.11 mmol) was suspended in THF (30.6 ml). DMAP (0.075 g, 0.611 mmol) was added followed by BOC-Anhydride (3.12 ml, 13.45 mmol). The mixture was stirred at room temperature under N 2 for 1 h. LC-MS showed the reaction was completed. The reaction was partitioned between EtOAc and water. The organic layer was separated and concentrated and the residue was purified by column chromatography (100% hexane to 25% EtOAc / Hexane) to give the title compound. LC / MS [M+H]+: 427.3, 429.3.Step B: tert-Butyl (4-(3-bromophenyl)-5-(hydroxymethyl)thiazol-2-yl)carbamate

[0457] Ethyl 4-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (1.17 g, 2.74 mmol) was suspended in DCM (21.06 ml) and cooled to -78°C. DIBAL-H (8.21 ml, 8.21 mmol) (1.0 M in toluene) was added dropwise under N 2 . The mixture was allowed to warm up to room temperature for 12 hours. LC-MS showed about 1 / 3 of starting material remained. The reaction was cooled to -78°C, another 1.5 eq of DIBAL (4 mL, 1.0M in toluene) was added. The reaction mixture was stirred at -78°C for 1 hour and then the cold bath was removed and the reaction mixture was warmed to room temperature. The reaction was quenched with EtOAc and MeOH. The resulting mixture was stirred with CELITE and filtered. The filter cake was washed with MeOH. The filtrates were concentrated and the rsidue was purified by column chromatography (100% hexane to 40% EtOAc / Hexane) to give the product. LC / MS [M+H] +< : 385.3, 387.3.Step C: tert-Butyl (5-(azidomethyl)-4-(3-bromophenyl)thiazol-2-yl)carbamate

[0458] tert-Butyl (4-(3-bromophenyl)-5-(hydroxymethyl)thiazol-2-yl)carbamate (450 mg, 1.168 mmol) in DCM (1.17E+04 µl) was treated with DIEA (306 µl, 1.752 mmol) and cooled to -78°C. Ms-Cl (109 µl, 1.402 mmol) was added under N 2 . After stirred at -78°C for 5 minutes, the reaction mixture was allowed to warm up to room temperature and stirred at room temp. for 1 hour. The reaction mixture was concentrated and redissolved in DMF (4 mL). Sodium azide (228 mg, 3.50 mmol) was added. The mixture was heated at 80°C for 20 minutes and continued to stir at room temperature for 12 hours. LC-MS showed that majority of starting material was converted to the product. The reaction was partitioned between EtOAc and water. The organic layer was seaparated and concentrated. The resulting residue was purified by column chromatography (100% hexane to 45% then to 80% EtOAc / Hexane) to give the title compound. LC / MS [M+H]+: 410.2, 412.2.Step D: tert-Butyl ((4-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)thiazol-5-yl)methyl)carbamate

[0459] tert-Butyl (5-(azidomethyl)-4-(3-bromophenyl)thiazol-2-yl)carbamate (195 mg, 0.475 mmol) was dissolved in THF (1584 µl). Triphenylphosphine (249 mg, 0.951 mmol) and water (1 ml) were added. The mixture was stirred at 60°C for 12 hours under N 2 . LC-MS showed the desired mass. BOC-Anhydride (221 µl, 0.951 mmol) and 1mL of saturtaed NaHCO 3 aqueous solution were added. The reaction was stirred at room temperature under N 2 for 1 hour. LC-MS showed the formation of the desired product. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated and concentrated and the resulting residue was purified by column chromatography (100% hexane to 100% EtOAc / EtOH (3 / 1)) to give the title compound. LC / MS [M+H]+: 484.4, 486.4Step E: (3-(2-((tert-Butoxycarbonyl)amino)-5-(((tert-butoxycarbonyl)amino)methyl)thiazol-4-yl)phenyl)boronic acid.

[0460] tert-Butyl ((4-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)thiazol-5-yl)methyl)carbamate (148 mg, 0.306 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (173 mg, 0.764 mmol), Ph 3 PPdG2 (26.2 mg, 0.046 mmol), and potassium acetate (120 mg, 1.222 mmol)were placed in a reaction vial. Dioxane (2182 µl) was added. The reaction was degassed and heated at 90° for 45 minutes. The reaction mixture was cooled to room temp., and used directly in the next reaction. LC / MS [M+H]+: 450.5.REFERENCE EXAMPLE 105(3-(2-((tert-Butoxycarbonyl)amino)-5-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)thiazol-4-yl)phenyl)boronic acid

[0461] Step A: tert-Butyl (4-(3-bromophenyl)-5-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl) thiazol-2-yl)carbamate

[0462] tert-Butyl (4-(3-bromophenyl)-5-(hydroxymethyl)thiazol-2-yl)carbamate (Step B REFERENCE EXAMPLE 104) (320 mg, 0.831 mmol) in DCM (8306 µl) was cooled to -78°C and treated with triethylamine (109 mg, 1.080 mmol), and Ms-Cl (78 µl, 0.997 mmol) was added under N 2 . After stirring at -78°C for 20 minutes, the reation mixture was allowed to warm to room temperature. tert-Butyl (2-aminoethyl)carbamate (266 mg, 1.661 mmol) was then added. After the reaction was stirred at room temperature for 15 min, LC-MS showed the desired mass, and the major product was the reactive intermediate. Excess amount of tert-butyl (2-aminoethyl)carbamate was added. The reaction mixture was stirred at room temperature under N 2 for 40 min. The reaction mixture was concentrated and the residue was purified by column chromatography twice (100% hexane to 50% EtOAc / Hexane) to give the title compound. LC / MS [M+H]+: 527.4, 529.4.Step B: (3-(2-((tert-Butoxycarbonyl)amino)-5-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)thiazol-4-yl)phenyl)boronic acid

[0463] tert-Butyl (4-(3-bromophenyl)-5-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)thiazol-2-yl)carbamate (135 mg, 0.256 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (145 mg, 0.640 mmol), Ph 3 PPdG2 (21.97 mg, 0.038 mmol), and potassium acetate (100 mg, 1.024 mmol) were placed in a reaction vial. Dioxane (1828 µl) was added. The reaction mixture was degassed and heated at 90° for 45 minutes. The reaction mixture was cooled to room temperature, and used directly in the next reaction. LC / MS [M+H]+: 493.5.REFERENCE EXAMPLE 106tert-butyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate

[0464] Step A: 3-(2-amino-1H-benzo[d]imidazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-(2-amino-1H-benzo[d]imidazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide

[0465] A suspension of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (2.0 g, 2.283 mmol), (2-amino-1H-benzo[d]imidazol-4-yl)boronic acid (0.808 g, 4.57 mmol), PdCl 2 (dppf) (0.251 g, 0.343 mmol) and sodium carbonate (0.726 g, 6.85 mmol) in dioxane (30 mL) and water (6 ml) was degassed and heated at 100 °C for 2 hours. The mixture was diluted with 20 ml of EtOAc, then filtered through a CELITE pad. The organic layer was dried (MgSO 4 ) and concentrated. The crude material was purified by silica gel column chromatography eluting with 0-20% methanol in DCM to give the desired product. LC / MS [M+H] +< : 881.53.Step B: tert-butyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-2-(bis(tert-butoxycarbonynamino)-1H-benzo[d]imidazole-1-carboxylate

[0466] To a solution of 3-(2-amino-1H-benzo[d]imidazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-(2-amino-1H-benzo[d]imidazol-4-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (1.4 g, 1.589 mmol) in DCM (20 ml) was added N,N-dimethylpyridin-4-amine (0.582 g, 4.77 mmol) and di-tert-butyl dicarbonate (1.040 g, 4.77 mmol) at 0 °C. The reaction mixture was stirred at room temp. for 30 minutes. NMR shown conversion to the desired product. The volatile was removed and the residue was chromatographed over silica gel eluting with 0-100% EtOAc in hexanes to give the desired products. [M+H] +< : 1181.87.REFERENCE EXAMPLE 1072-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino) thiazole-4-carboxylate

[0467] Step A: Methyl 2-((3-bromophenyl)amino)thiazole-4-carboxylate

[0468] To a solution of methyl 3-bromo-2-oxopropanoate (3.96 g, 21.89 mmol) in MeOH (200 mL) was added 1-(3-bromophenyl)thiourea (4.6 g, 19.90 mmol) at room temperature. The reaction solution was stirred at 70 °C for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in EA (200 mL). The organic layer was washed with saturated aqueous NaHCO 3 (3 x 200 mL), brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + H] +< : 313, 315 .Step B: Methyl 2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino) thiazole-4-carboxylate

[0469] To a solution of methyl 2-((3-bromophenyl)amino)thiazole-4-carboxylate (2 g, 6.38 mmol) in 1,4-dioxane (20 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (3.24 g, 12.8 mmol), potassium acetate (1.88 g, 19.2 mmol) and 2nd Generation PCy 3 precatalyst (0.75 g, 1.278 mmol) at room temperature. The mixture was degassed with nitrogen three times and stirred at 80 °C for 16 hours under nitrogen. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 75% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + H] +< : 361.REFERENCE EXAMPLE 108(2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)thiazol -4-yl)methanol

[0470] Step A: 2-((3-Bromophenyl)amino)thiazole-4-carboxylic acid

[0471] To the solution of methyl 2-((3-bromophenyl)amino)thiazole-4-carboxylate (4.5 g, 14.37 mmol) in MeOH (50 mL) and THF (50 mL) was added aqueous NaOH (2 N, 28.7 mL) at room temperature. The reaction mixture was stirred at room temp. for 16 hours. The organic solvent was evaporated under vacuum. The remained aqueous phase was adjusted to pH 5 with IN HCl and a solid was precipitated. The solid was filtered. The filter cake was washed with water (2 x 10 mL), dried under an oven to afford the title compound: LCMS [M + 1] +< : 299, 301 (1 : 1); 1< H NMR (400 MHz, DMSO-d 6 ): δ 12.80 (s, 1H), 10.64 (brs, 1H), 8.04-8.01 (m, 1H), 7.75 (s, 1H), 7.59-7.51 (m, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.16-7.11 (m, 1H).Step B: (2-((3-Bromophenyl)amino)thiazol-4-yl)methanol

[0472] A stirred solution of 2-((3-bromophenyl)amino)thiazole-4-carboxylic acid (1.2 g, 4.01 mmol) in THF (10 mL) was degassed with nitrogen three times. Then BH 3 .THF (20.06 mL, 1 M in THF) was added dropwise to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for 16 hours under nitrogen. The resulting mixture was quenched by ice water (100 mL). The aqueous solution NaOH (8 mL, IN) was added to the mixture and stirred for 2 h. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum to afford the title compound: LCMS [M + 1]+: 285, 287 (1 : 1).Step C: (2-((3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino) thiazol -4-yl)methanol

[0473] To a solution of (2-((3-bromophenyl)amino)thiazol-4-yl)methanol (0.9 g, 3.16 mmol) in 1,4-dioxane (9 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (1.6 g, 6.31 mmol), potassium acetate (0.93 g, 9.47 mmol) and 2nd Generation PPh 3 precatalyst (0.34 mg, 0.63 mmol) at room temp. The resulting mixture was degassed with nitrogen three times and stirred at 80 °C for 16 hours. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers was washed with water (3 x 50 mL) and brine (3 x 50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 75% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + 1] +< : 333.REFERENCE EXAMPLE 109N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-amine

[0474] Step A: 2,2-Diethoxy-N-(iminomethylene)ethanamine

[0475] To a stirred solution of the 2,2-diethoxyethanamine (2.5 g, 18.8 mmol) in Et 2 O (20 mL) and hexane (20 mL) was added cyanic bromide (2.0 g, 18.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 5% MeOH in DCM. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + 1] +< : 159; 1< H NNM (400 MHz, CDCl 3 ): δ4.59 (t, J = 5.2 Hz, 1H), 3.77-3.70 (m, 2H), 3.66-3.53 (m, 2H), 3.18-3.15 (m, 2H), 1.23 (t, J = 7.0 Hz, 6H).Step B: 1-(3-Bromophenyl)-3-(22-diethoxyethyl)guanidine

[0476] To a solution of 3-bromoaniline (1 g, 5.81 mmol) in EtOH (16 mL) were added the solution of 2,2-diethoxy-N-(iminomethylene)ethanamine (1.8 g, 11.63 mmol) in Et 2 O (1.6 mL) and methanesulfonic acid (1.1 g, 11.63 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The resulting mixture was concentrated under vacuum to afford the title compound. The crude product was used in the next step without further purification: LCMS [M + 1] +< : 330, 332.Step C: N-(3-bromophenyl)-1H-imidazol-2-amine

[0477] 1-(3-Bromophenyl)-3-(2,2-diethoxyethyl)guanidine (0.8 g, 2.42 mmol) was dissolved in conc. HCl (2 mL, 12.00 mmol). The reaction solution was stirred at room temperature for 2 hours. Then aqueous solution NaOH (25%) was added until a precipitate formed (pH = 14). The mixture was stirred for 30 minutes. The resulting mixture was poured into aqueous solution NaOH (30 mL, 0.5 M), extracted with DCM (3 x 20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep C18 OBD Column; Mobile Phase A: water (10 mmoL / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 30% B in 30 min; Detector: UC 254 and 220 nm. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + 1] +< : 238, 240.Step D: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol -2- amine

[0478] To a solution of N-(3-bromophenyl)-1H-imidazol-2-amine (0.6 g, 2.52 mmol) in 1,4-dioxane (12 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (1.3 g, 5.04 mmol), PCy3 palladium(II) biphenyl-2-amine chloride (0.3 g, 0.50 mmol) and potassium acetate (0.05 g, 0.50 mmol). The reaction mixture was degassed with nitrogen three times and stirred for 16 hours at 80 °C under nitrogen. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 50% EA in PE. The fractions containing desired product were combined and concentrated under vacuum to afford the title compound: LCMS [M + 1] +< : 286REFERENCE EXAMPLE 1102-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(2-(((tert-butoxycarbonyl)amino)methyl)-1H-benzo[d]imidazol-4-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid

[0479]

[0480] The title compound was prepared in an analogous fashion as described for 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid (REFERENCE EXAMPLE 90) starting from 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and tert-butyl ((4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-benzo[d]imidazol -2-yl)methyl)carbamate (REFERENCE EXAMPLE 61). LCMS [M + 1] +< : 895.EXAMPLE 14-(2-amino-3H-benzo[d]imidazol-4-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide

[0481] Step A: 5-iodo-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1,2-disulfonamide and 5-iodo-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzene-1,2-disulfonamide

[0482] To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonyl chloride and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonyl chloride (synthesis described above, 400 mg, 0.741 mmol) in THF (10 mL) was added ammonium hydroxide (78 mg, 2.222 mmol) at ambient temperature. The reaction was kept for 30 minutes at room temp. The mixture was concentrated under reduced pressure. The residue was then applied onto silica gel column with DCM / methanol (10:1) to get the product as a mixture of regioisomers on the p-methoxybenzyl tetrazole: LCMS [M + hr - 15] +< : 791.Step B: 5-(2-amino-1H-benzo[d]imidazol-4-yl)-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1,2-disulfonamide and 5-(2-amino-1H-benzo[d]imidazol-4-yl)-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzene-1,2-disulfonamide

[0483] To a solution of 5-iodo-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1,2-disulfonamide and 5-iodo-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzene-1,2-disulfonamide (200 mg, 0.253 mmol) in 1,4-Dioxane (2 mL) / water (0.2 mL) (5:1) was added (2-amino-1H-benzo[d]imidazol-4-yl)boronic acid (90 mg, 0.506 mmol), sodium carbonate (80 mg, 0.759 mmol) and 2nd generation Xphos precatalyst (39.8 mg, 0.051 mmol) at ambient temperature. The flask was degassed with nitrogen three times. Then the mixture was stirred for 16 hours at 80°C under an atmosphere of nitrogen. The solid was filtered out and the filtrate was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was then applied onto silica gel column with DCM / methanol (10:1) to obtain the product as a mixture of PMB protected tetrazole regioisomers: LCMS [M + H] +< : 796.Step C: 4-(2-amino-3H-benzo[d]imidazol-4-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide

[0484] 5-(2-amino-1H-benzo[d]imidazol-4-yl)-N1,N1-bis(4-methoxybenzyl)-6-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1,2-disulfonamide (100 mg, 0.126 mmol) was dissolved in trifluoroacetic acid (3 ml) at ambient temperature. The reaction was kept at 80°C for 1 hour. The resulting mixture was concentrated under reduced pressure to get the crude product. The crude product was then applied onto Prep-HPLC with the condition (Column: X Bridge RP C18, 19*150 mm, 5 µM; Mobile Phase A:water / 10 mM NH 4 HCO 3 , Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 10-35% B in 10 min; 254 nm; Retention time: 5.89 min) to get the final product: LCMS [M + H] +< : 436; 1< H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.62-7.33 (m, 4H), 7.11-6.94 (m, 2H), 6.78 (t, J = 8.0 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H)

[0485] EXAMPLES 2-7 in the table below were prepared in an analogous fashion as described for EXAMPLE 1, starting with 5-iodo-N 1< ,N 1< -bis(4-methoxybenzyl)-6-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzene-1,2-disulfonamide (Step A, or the corresponding N-methyl sulfonamide, 4-iodo-N 2< ,N 2< -bis(4-methoxybenzyl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-N 1< -methylbenzene-1,2-disulfonamide, prepared in an analogous fashion) and coupling with boronic acids or boronic esters that are prepared as described herein or that are commercially available. EX. No. Structure Name LC / MS [M+H] +< 2 4-(2-aminoquinolin-8-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide4473 4-(1H-indazol-7-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide4214 4-(2-aminobenzo[d]oxazol-4-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide4375 4-(2-amino-1-methyl-1H-benzo[d]imidazol-4-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide4506 4-(2-amino-7-methylbenzo[d]thiazol-4-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide4677 4-(1H-indazol-7-yl)-N1-methyl-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide435 EXAMPLE 84-(3,4-disulfamoyl-2-(2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazole-2-carboxylic acid

[0486] Step A: 2',3'-diamino-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)-[1,1'-biphenyl]-3-sulfonamide

[0487] Into a 50 mL RBF was placed 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (0.802 g, 3.43 mmol), 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (Synthesis described above, 2.0 g, 2.3 mmol), Pd(PPh 3 ) 4 (0.528 g, 0.457 mmol) and sodium carbonate (0.726 g, 6.85 mmol) in 1,4-dioxane (6 ml) and water (1.500 ml). The reaction mixture was degassed with nitrogen for 3 times and stirred at 80°C for 16 hr. The resulting mixture was extracted with ethyl acetate (300 mL) and washed with water (250 mL). Then the organic layer was concentrated under vacuum. The residue was applied on a silica gel column with ethyl acetate / petrol ether (1 / 1) to give the title compound: LCMS [M + H] +< : 856; 1< H NMR (300 MHz, d-DMSO): δ 8.57-8.54 (d, J = 8.4 Hz, 1H), 7.92-7.89 (d, J = 8.4 Hz, 1H), 7.06-6.73 (m, 13H), 6.52-6.39 (m, 1H), 6.23-6.10 (m, 1H),4.79-4.45 (m, 2H), 4.30-4.11(m, 2H), 4.08-3.88 (m, 4H), 3.724 (s, 12H), 1.09-0.80 (m, 2H), 0.029 (s, 9H).Step B: N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3-(2-(trichloromethyl)-1H-benzo[d]imidazol-4-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl) benzenesulfonamide

[0488] Into a RBF was placed 2',3'-diamino-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)-[1,1'-biphenyl]-3-sulfonamide (1.1 g, 1.285 mmol) and benzyl 2,2,2-trichloroacetimidate (0.324 g, 1.285 mmol) in acetic acid (6 ml). Then the mixture was stirred at RT for 6 hours. Then the mixture was concentrated under vacuum to give the title compound: LCMS [M + H] +< : 982, 984,985(3: 4: 2).Step C: methyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-1H-benzo[d]imidazole-2-carboxylate

[0489] Into a 50 mL RBF was placed N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3-(2-(trichloromethyl)-1H-benzo[d]imidazol-4-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (500 mg, 0.508 mmol) and sodium carbonate (162 mg, 1.525 mmol) in methanol (0.5 ml). The mixture was stirred at 80°C overnight, then the solvent was removed under vacuum. The residue was extracted with ethyl acetate (200 mL) and washed with hydrogen chloride (1 mol) in water (5*100 mL). The organic layer was concentrated under vacuum. The residue was applied on a silica gel column with ethyl acetate / petrol ether(2 / 1) to give the title compound: LCMS [M + H] +< : 924; 1< H NMR (300 MHz, d-DMSO): δ 8.70-8.58 (d, J = 8.1 Hz, 1H), 8.14-8.11 (d, J = 8.7 Hz, 1H), 7.74-7.40 (m, 3H), 7.10-6.79 (m, 12H), 5.66 (s, 1H), 5.07-4.51 (m, 2H), 4.09-3.87 (m, 7H), 3.73 (s, 9H), 3.21-2.90 (m, 2H), 1.09-0.81 (m, 2H), 0.03 (s, 9H).Step D: 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-(2-(methoxycarbonyl)-1H-benzo[d]imidazol-4-yl)benzenesulfinic acid

[0490] To a solution of methyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-1H-benzo[d]imidazole-2-carboxylate (300 mg, 0.325 mmol) in THF (2 ml) was added tetrabutylammonium fluoride (1.623 ml, 1.623 mmol). The mixture was stirred at room temperature for 2 hours, then extracted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate for 2 hours and concentrated under vacuum to give the title compound: LCMS [M + H] +< : 824.Step E: methyl 4-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-sulfamoylphenyl)-1H-benzo[d]imidazole-2-carboxylate

[0491] Into a 50 mL RBF was placed 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-(2-(methoxycarbonyl)-1H-benzo[d]imidazol-4-yl)benzenesulfinic acid (300 mg, 0.364 mmol) and 1-chloropyrrolidine-2,5-dione (72.9 mg, 0.546 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 hours, and ammonia (0.350 ml, 0.699 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, extracted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was concentrated under vacuum. The residue was applied on a silica gel column with ethyl acetate / petrol ether (1 / 1) to give the title compound: LCMS [M + H] +< : 479; 1< H NMR (300 MHz, d-DMSO): δ 8.70-8.51 (d, J = 8.4 Hz, 1H), 8.12-8.03 (d, J = 8.4 Hz, 1H), 7.74-7.40 (m, 3H), 7.10-6.65 (m, 12H), 5.66 (s, 2H), 4.12-3.98 (m, 2H), 3.97-3.80 (m, 5H), 3.80-3.59 (m, 9H).Step F: methyl 4-(3,4-disulfamoyl-2-(2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazole-2-carboxylate

[0492] Into a 50 mL RBF was placed methyl 4-(3-(N,N-bi s(4-methoxybenzyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4-sulfamoylphenyl)-1H-benzo[d]imidazole-2-carboxylate (90 mg, 0.107 mmol) and trifluoroacetic acid (2 ml). The mixture was stirred at 60°C for 2 hours, then concentrated under vacuum. The residue was pH-adjusted with sodium carbonate (50 mg). Then it was purified by flash chromatography on silica with methanol / DCM (percent of methanol: 5-60% in 25 min) to give the title compound: LCMS [M + H] +< : 465.Step G: 4-(3,4-disulfamoyl-2-(2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazole-2-carboxylic acid

[0493] To a solution of methyl 4-(3,4-disulfamoyl-2-(2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazole-2-carboxylate (40 mg, 0.084 mmol) in methanol (1 ml) was added sodium hydroxide (13.38 mg, 0.334 mmol) in water (0.500 ml). The mixture was stirred at room temp. for 1 hour and concentrated under vacuum. The residue was pH-adjusted with hydrogen chloride (3 mol in methanol, 0.15 mL). The mixture was dissolved in N,N-dimethylfonnamide and purified by Pre-HPLC (condition: Column: XSelect CSH Prep C18 OBD Column, 5µM, 19* 150mm; Mobile Phase A:water with 10mmolNH 4 HCO 3 , Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 8% B to 35% B in 8 min; 254 / 220 nm) to give the title compound. LCMS [M + H] +< : 346; 1< H NMR (300 MHz, d-DMSO): δ 8.59-8.50 (d, J = 8.4 Hz, 1H), 8.07-8.04 (d, J = 8.4 Hz, 1H), 7.56 (s, 2H), 7.51-7.49 (d, J = 8.4 Hz, 1H), 7.30 (s, 2H), 7.20-7.15 (t, J = 8.1 Hz, 1H), 6.75-6.72 (d, J = 7.8 Hz, 1H).EXAMPLE 9N 1< -(2-aminoethyl)-4-(1H-indazol-7-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide

[0494] Step A: tert-butyl 2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yDphenylsulfonamido)ethylcarbamate

[0495] To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonyl chloride and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonyl chloride (synthesis described above, 1.4 g, 1.73 mmol) in THF (20 ml) was added tert-butyl (2-aminoethyl)carbamate (0.554 g, 3.46 mmol) and tr...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: X1 is N or CH; X2 is N or CH; Z is tetrazolyl, wherein Z is linked through a carbon to carbon bond to the six-membered core ring having X1 and X2; RA is -(CH2)n-AryA1, -(CH2)n-HetA1, -(CH2)n-C4-C6cycloalkyl, or -(CH2)n-C4-C6cycloalkenyl, wherein said -(CH2)n-C4-C6cycloalkyl and -(CH2)n-C4-C6cycloalkenyl are optionally substituted with 1, 2, or 3 substituents independently selected from -NH2, -OH,-F, and -NRaC(O)C1-C6alkyl optionally substituted with 1 or 2 substituents independently selected from -F, -CF3,-NRaRb, and -ORa; R1 is 1) -NH2; 2) -NRa-C1-C6alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from: -F, -CF3, C1-C6alkyl, -CH(NH2)C(O)NH2, - C(O)NRaRb, -C(O)OH, -(CH2)1-2NH2, -NRa(CH2)2-3NH2, -NRaRb, -N+RaRbCH3, -NHCH2CH2OCH3, -ORa, and -O(CH2)2-3NH2; 3) -NRaC(O)C1-C6alkyl optionally substituted with 1 or 2 substituents independently selected from: -F, -CF3, -C(O)NRaRb, -C(O)OH, -NRaRb, -N+RaRbCH3, - NHCH2CH2OCH3, -ORa, and -O(CH2)2-3NH2; 4) -NRa(CH2)n-C3-C6cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with -CH2OH or -NH2; 5) a nitrogen-linked 4-6 membered monocyclic heterocycloalkyl with 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S, or a nitrogen-linked 6- to 10-membered bicyclic heterocycloalkyl with 0, 1, 2, or 3 additional heteroatom ring atoms selected from N, O and S wherein the bicyclic ring may be bridged, fused or spirocyclic, wherein the 4-6 membered monocyclic heterocycloalkyl and the 6- to 10-membered bicyclic heterocycloalkyl are optionally substituted with one to three substituents, independently selected from: -F, -NRaRb, oxo, -(CH2)1-2OH, -CH2NH2, -SO2CH3, and C1-C6 alkyl and wherein a ring sulfur atom is optionally substituted with one or two oxo; 6) -NRa-(C1-C3alkyl)n-AryB1, wherein the C1-C3alkyl is optionally substituted with -NH2; and 7) -NRa-(C1-C3alkyl)n-HetB1; AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from: a) halogen, b) -C1-C6alkyl, c) -CN, d) -CH2OH, e) -C(O)NRaRb, f) -C(O)NH(CH2)2-4NH2 optionally substituted with one or two substituents independently selected from -NRaRb and -(CH2)nORa, g) -C(O)ORa, h) -(CH2)pNHRa optionally substituted with one or two substituents independently selected from -NRaRb or -ORa, i) -(CH2)pNRaC(=NH)NH2, j) -NRaC(O)C1-C6 alkyl optionally substituted with one or two substituents independently selected from -NRaRb or -ORa, k) -NRaSO2-C1-C6alkyl, l) -NRaSO2-cyclopropyl, m) -ORa, n) oxo, o) -SC1-C6 alkyl optionally substituted with one or two substituents independently selected from -NRaRb or -ORa; p) -SO2Ra, q) -SO2NRaRb, r) -SO2NH-cyclopropyl, s) -AryA2, t) -(CH2)nNRaAryA2, u) -C(O)NRaHetA2 and v) -HetA2, and 2) an 8- to 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom optionally has one or two oxo substituents and a N atom is optionally in the form of an N-oxide, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from a) halogen; b) C1-C6alkyl optionally substituted with one to three substituents independently selected from -NRaRb, -F and -ORa; c) -(CH2)nCF3; d) -C(=NH)NH2; e) -CN; f) -C(O)CF3; g) -C(O)NRaRb; h) -C(O)NHCH2C(O)ORa; i) -C(O)NH-C2-C4alkyl-NH2, j) -C(O)ORa; k) -NRaRb; l) -NHCH2SO3H; m) -(CH2)nNHC(=NH)NH2; n) -NHC(O)C1-C6alkyl; o) -NHC(O)NH2; p) -NHC(O)ORa; q) -NHSO2CH3; r) -ORa; s) oxo; t) -SO2Ra, u) -CH2-phenyl-OCH3; and v) -HetA2; HetA1 is dihydrothiopyranyl or tetrahydropyranyl; AryA2 is a 5-6-membered aromatic monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, and S, or 4 N ring atoms, optionally substituted with -CH2OH, -COOH, -CONH2, -C(O)OC1-C6alkyl, and -(CH2)pNHRa optionally substituted with one or two substituents independently selected from -NRaRb and -ORa; HetA2 is a 4-6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein the S is optionally substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from C1-C6alkyl, -CN, -OH, and oxo; AryB1 is an aromatic ring selected from: 1) a 5-6 membered monocyclic aromatic ring with 0, 1, 2, or 3 N ring atoms, optionally substituted with 1 substituent selected from -CF3, C1-C6 alkyl, - (CH2)nNH2 and -OCH3; or 2) a 9-membered bicyclic ring with 2 N ring atoms; HetB1 is a saturated ring selected from: 1) a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein a N ring atom is optionally in the form of a quaternary amine, wherein the S is substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from -F, C1-C6 alkyl, C1-C6 hydroxyalkyl, -C(O)ORa,-(CH2)kNRaRb, -ORa, and oxo; or 2) a 6-10-membered bicyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with -OH or -NH2, wherein the bicyclic ring is bridged or fused; Ra and Rb are independently H or C1-C6 alkyl; k is 0, 1, 2, 3, or 4; each n is independently 0 or 1; and each p is independently 0, 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are CH.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the Formula IA wherein: RA is AryA1, C4-C6cycloalkyl, or C4-C6cycloalkenyl, wherein said C4-C6cycloalkyl and C4-C6cycloalkenyl are optionally substituted with -NH2 or NHC(O)(CH2)1-3NH2; AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents independently selected from: a) F, b) -C1-C6 alkyl, c) -CN, d) -CH2OH, e) -C(O)NRaRb, f) -C(O)NH(CH2)2-4NH2, g) -C(O)ORa, h) -(CH2)nNHRa, i) -NHC(=NH)NH2; j) -NHC(O)CH3; k) -NRaSO2-C1-C6alkyl, l) -NHSO2-Cyclopropyl, m) -ORa, n) -SO2NRaRb, o) -SC1-C6alkyl, p) -SO2NH-cyclopropyl, q) -AryA2, r) -(CH2)nNRaAryA2, s) -C(O)NRaHetA2 and t) -HetA2, and 2) a 8- to 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom is optionally substituted with one or two oxo substituents and a N atom is optionally in the form of an N-oxide, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C1-C6 alkyl, -CH2CF3, -CF2CH2NH2, -CF3, -C(=NH)NH2, -CH(NH2)CH3, - CN, -C(O)CF3, -C(O)NRaRb, -C(O)NHCH2C(O)ORa, -C(O)ORa, -(CH2)0-2NRaRb, -NHC(O)CH3, -NHC(O)NH2, -NHC(O)ORa, -NHCH2SO3H, - NHSO2CH3, -ORa, oxo, -CH2-phenyl-OCH3, and -HetA2; and all other variables are defined in claim 1.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein RA is AryAl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein AryA1 is 1) pyridyl optionally substituted with -NH2, 2) benzoimidazolyl substituted with 1 or 2 substituents independently selected from F, -CH3 and - (CH2)nNH2; or 3) benzothiazolyl substituted with 1 or 2 substituents independently selected from -CH3 and -(CH2)nNH2.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is: 1) -NH2; 2) -NRa-C1-C6alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from -F, -CF3, C1-C6alkyl, -CH(NH2)C(O)NH2, -C(O)NRaRb, -C(O)OH, - (CH2)1-2NH2, -NRaRb, -N+RaRbCH3, -NHCH2CH2OCH3, -ORa, -NRa(CH2)2-3NH2, and - O(CH2)2-3NH2; 3) -NRa(CH2)n-C3-C6cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with -CH2OH or -NH2; 4) -NRa-(C1-C3alkyl)n-AryB1, wherein the C1-C3alkyl is optionally substituted with -NH2; and 5) -NRa-(C1-C3alkyl)n-HetB1.

7. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is: -NH2, -NH-HetB1 optionally substituted with -NH2, or -NH-C2-C3alkylNH2, optionally substituted with -CH3, -OH or -NH2.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the Formula IB: wherein: AryA1 is an aromatic ring system selected from: 1) a 5-6 membered monocyclic ring with 0 or 1 N ring atoms substituted with 1 or 2 substituents independently selected from F,-C1-C6 alkyl, -CONH-C2-4alkyl-NH2, or - NHRa; or 2) a 9-membered bicyclic ring with 2 heteroatom ring atoms selected from N and S, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C1-C6 alkyl, and -(CH2)xNRaRb; R1 is 1) -NH2; 2) -NRa-C1-6alkyl optionally substituted with 1 or 2 F substituents and optionally substituted with 1 or 2 substituents independently selected from -CF3, - CH(NH2)C(O)NH2; -C(O)NRaRb; -C(O)OH; -NRa(CH2)2-3NH2, -NRaRb, - N+RaRbCH3, -NHCH2CH2OCH3, -ORa, and -O(CH2)2-3NH2; 3) -NRa(CH2)n-C3-C6cycloalkyl, wherein the C3-C6cycloalkyl is optionally substituted with -CH2OH or -NH2; 4) -NRa-(C1-C3alkyl)n-AryB1; and 5) -NRa-(C1-C3alkyl)n-HetB1; Ra and Rb are H or -CH3; and x is 0, 1 or 2.

9. A compound of claim 1 having the structure or a pharmaceutically acceptable salt thereof.

10. A zwitterion of the compound of claim 9, in which the tetrazole bears a negative charge and the amine bears a positive charge.

11. The compound of claim 1, having the structure or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, having the structure or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, having the structure or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, having the structure or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, having the structure or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, having the structure or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition which comprises a compound acccording to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition according to claim 17, which further comprises an effective amount of a beta-lactam antibiotic.

19. The pharmaceutical composition according to claim 17 or 18, which further comprises an effective amount of one or more beta-lactamase inhibitor compounds.

20. The pharmaceutical composition according to claim 19, wherein the composition comprises a beta-lactamase inhibitor compound selected from the group consisting of: relebactam, avibactam, vaborbactam, tazobactam, sulbactam, and clavulanic acid.

21. The pharmaceutical composition according to claim 20, wherein the beta-lactamase inhibitor compound is tazobactam and the beta-lactam antibiotic is ceftolozane.

22. The pharmaceutical composition according to claim 20, wherein the beta-lactamase inhibitor compound is relebactam.

23. The pharmaceutical composition according to any of claims 18 -20, wherein the beta-lactam antibiotic is selected from the group consisting of imipenem, ertapenem, meropenem, doripenem, biapenem, panipenem, ticarcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, cefoperazone, cefotaxime, ceftriaxone, cefipime, ceftolozane, and ceftazidime.

24. The pharmaceutical composition according to any of claims 18-20 and 22-23, wherein the beta-lactam antibiotic is imipenem.

25. The pharmaceutical composition according to claim 24, further comprising cilastatin or a pharmaceutically acceptable salt thereof.

26. A compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof for use in the treatment of the human body by therapy.

27. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic or a pharmaceutical composition according to any one of claims 17 to 25 for use in treating a bacterial infection.

28. A compound for use according to claim 27, wherein the beta-lactam antibiotic is selected from the group consisting of imipenem, ertapenem, meropenem, doripenem, biapenem, panipenem, ticarcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, cefoperazone, cefotaxime, ceftriaxone, cefipime, ceftolozane, and ceftazidime.

29. A compound for use according to claim 27, wherein the beta-lactam antibiotic is imipenem.

30. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of imipenem, cilastatin, and relebactam for use in treating a bacterial infection.

31. A compound for use according to claim 27-30, wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichi spp., Morganella spp., Citrobacter spp., Serratia, spp. or Acintetobacter spp.