1-aminosulfonyl-2-carboxypyrrole derivatives as metallo-beta-lactamase inhibitors

Abstract

The invention relates to a 1-aminosulfonyl-2-carboxyl pyrrole derivative serving as a metallo-beta-lactamase inhibitor and application of the compound in preparation of a medicine. More specifically, the present invention relates to 3-[4-[methyl-[2-(methylamino) ethyl] carbamoyl] phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid and the use of the compound in the preparation of a medicament for inhibiting the activity of metallo-beta-lactamase. The compounds of the invention may be used in combination with antibacterial agents to treat bacterial infections. More specifically, the compounds of the invention may be used in combination with a class of antibacterial agents referred to as carbapenems.

Description

[0001] The present invention is a divisional application of Chinese invention patent application No. 202080080912.8, filed on November 19, 2020, entitled “1-Aminosulfonyl-2-carboxypyrrole derivatives as metallo-β-lactamase inhibitors”.

[0002] introduction

[0003] The present invention relates to compounds that can be used in combination with other antibacterial agents, more particularly with a class of antibacterial agents known as carbapenems, to treat bacterial infections.The novel compounds of the present invention are enzyme inhibitors, more particularly metallo-β-lactamase inhibitors.

[0004] Every year, across Europe, more than 4 million people contract healthcare-associated bacterial infections, resulting in approximately 37,000 deaths (Public Health England). The growing prevalence of multidrug-resistant bacteria has worsened patient outcomes, prolonged hospital stays, and necessitated the use of “last resort” and potentially toxic antimicrobials such as colistin and polymyxin B. It is estimated that by 2050, without intervention, drug-resistant bacteria will cause more than 10 million deaths per year, amounting to an economic burden of $100 trillion.

[0005] In the clinic, drug-resistant Gram-negative bacteria can cause a variety of infections, including pneumonia, bloodstream infections, surgical site infections, skin and soft tissue infections, and urinary tract infections. Effective treatment options for these microorganisms are limited, and empirical antibiotic therapy often fails in patients infected with Gram-negative organisms of the ESKAPE pathogen group (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.).

[0006] In February 2017, the World Health Organization (WHO) published a priority list of bacterial pathogens to assist member states in focusing research and development on areas of greatest need. Among these bacteria, WHO has ranked the following Gram-negative organisms as the highest priority: carbapenem-resistant Acinetobacter baumannii; carbapenem-resistant Pseudomonas aeruginosa; carbapenem-resistant and ESBL-producing Enterobacteriaceae (including Klebsiella pneumoniae and Escherichia coli). Therefore, carbapenem-resistant Gram-negative bacteria have been defined as a major unmet medical need. The mode of action of β-lactams such as carbapenems involves covalent binding to the active site of transpeptidases that link peptidoglycan chains in the bacterial cell wall. This results in inhibition of cell wall synthesis and ultimately cell death. Carbapenems have the advantage of having a broader spectrum of activity than most other β-lactams, and until recently their use has not been significantly affected by the development of resistance.

[0007] The role of carbapenems as the last line of defense against multidrug-resistant Gram-negative bacteria has been compromised by the emergence of carbapenemases of the metallo-β-lactamase (MBL) class. These enzymes bind to carbapenems and cleave the β-lactam ring, resulting in the inactivation of the antibiotic. The Ambler classification system divides the known β-lactamases into four classes based on the amino acid sequence. Class A, C, and D β-lactamases cleave β-lactams by transient binding of a serine group within the enzyme active site to the carbonyl group of the β-lactam ring. This results in the formation of an acyl-enzyme and cleavage of the β-lactam ring. Subsequently, an activated water molecule deacylates the acyl-enzyme intermediate, hydrolyzing the bond between the serine and the carbonyl group to release the inactive β-lactam. MBLs are mechanistically and structurally unrelated to class A, C, and D serine-β-lactamases. In this case, cleavage of the β-lactam occurs in a single step without the formation of a covalent intermediate. MBL coordinates water molecules and zinc ions to His, Cys, and Asp residues in its active site, where the water molecules promote nucleophilic attack and bond cleavage within the β-lactam ring. Subclasses of MBL differ structurally, with B1 and B3 enzymes containing two zinc ions in the active site and displaying a broader substrate spectrum. Group B2 enzymes rely on only one zinc ion and hydrolyze only carbapenems. Clinically, class B1 MBLs (including NDM, VIM, and IMP) are the most prevalent and are often identified in mobile genetic elements.

[0008] Existing serine-β-lactamase inhibitors (active against Ambler class A, C, and some class D β-lactamases) have successfully restored the activity of many β-lactams. The inhibitors bind transiently or permanently to the active site of the enzyme with high affinity, effectively outcompeting the binding of the β-lactam. Marketed β-lactam / β-lactamase inhibitor combinations include amoxicillin and clavulanic acid (Co-amoxiclav) and ceftazidime and avibactam (Avycaz). Currently, there are no metallo-β-lactamase inhibitors (MBLIs) in clinical development or in the clinic, suggesting the commercial potential of broad-spectrum MBLIs that could restore the activity of carbapenems.

[0009] The first carbapenem used clinically was imipenem, which is used to treat complicated microbial infections. One disadvantage of imipenem is that it is hydrolyzed by dehydropeptidase I (DHPI) in mammalian kidneys and must therefore be co-formulated with the dehydropeptidase inhibitor cilastatin. Subsequent carbapenem iterations (including meropenem) are not easily hydrolyzed by DHPI due to the presence of a methyl group at the 1-β position of the carbapenem moiety. Meropenem is less effective than imipenem against Gram-positive pathogens, but has an enhanced effect on Gram-negative bacteria and is widely used clinically. In order to combat resistance to carbapenems, we have discovered a series of compounds that inhibit metallo-β-lactamases. When co-administered with meropenem, these compounds significantly improve the efficacy of meropenem against resistant bacteria. The present invention specifically relates to these compounds and combinations of these compounds with carbapenems (e.g., meropenem). The present invention also relates to methods of using the compounds and pharmaceutical preparations comprising the compounds.

[0010] It is expected that other approved carbapenems may also benefit from co-formulation with the compounds of the present invention. Other currently approved carbapenems include: ertapenem, doripenem, panipenem, biapenem, and tebipenem. Background Art

[0011] Until recently, bacterial infections were among the most common causes of death, disfigurement and disability. In the 19th century, the development of a range of antibiotic drugs meant that successful treatment of bacterial infections became routine. However, microbial resistance to antibiotics has become a significant problem, and many believe it will become one of the most significant challenges to human health. In fact, multidrug resistance has become common in some bacterial pathogens.

[0012] The greatest unmet medical need is the lack of effective treatments for multidrug-resistant Gram-negative bacteria. Therefore, the discovery of new antibiotics active against WHO-listed pathogens or drugs that circumvent existing bacterial resistance mechanisms is critical.

[0013] WO2015 / 112441 discloses a series of novel metallo-β-lactamase inhibitors and their uses aimed at reducing bacterial β-lactam antibiotic resistance. These compounds are a series of substituted 1H and 2H-tetrazol-5-ylphenylsulfonamides.

[0014] US2016 / 0272601 also discloses a series of novel compounds and their use as metallo-β-lactamase inhibitors in combination with β-lactam antibiotics. The disclosed compounds are thiazole-4-carboxylic acid derivatives.

[0015] WO2017 / 093727 discloses another series of compounds which are inhibitors of metallo-β-lactamases and can be used to treat bacterial infections. The exemplary compounds disclosed in this disclosure are a series of substituted 1H-indoles.

[0016] It is an object of certain embodiments of the present invention to provide compounds that can prevent or slow down the unwanted metabolism of β-lactam antibiotics (e.g., carbapenems, particularly meropenem). Another object is to provide a formulation of carbapenems (e.g., meropenem) containing a compound of the present invention, which is active against Gram-negative bacteria (including antibiotic-resistant organisms). It is an object of certain embodiments of the present invention to provide a compound that can be included in a formulation that is active against bacterial strains that are resistant to one or more other antibiotics. Although it is known in the art that there are a variety of different antibiotics for a variety of different infections, there is still a need to develop antibiotics that can provide effective treatment in a reliable manner. In addition, there is still a need for drugs that can avoid or reduce the side effects associated with known antibiotics. Another object of certain embodiments is to provide effective treatment in a selective manner at a selected target site. Another object of certain embodiments is to develop drugs with suitable pharmacokinetic characteristics and duration of action after administration.

[0017] The present invention seeks to overcome the shortcomings of known carbapenems. The present invention also aims to improve the efficacy of existing carbapenems (e.g., meropenem). In certain embodiments, the present invention aims to provide compounds that can restore or prolong the activity of antibiotics (particularly carbapenems) against antibiotic-resistant bacterial strains. Certain embodiments of the present invention also aim to improve the antibiotic efficacy of antibiotics against bacterial strains with broad-spectrum metallo-β-lactamases (e.g., some or all of VIM, NDM, and IMP).

[0018] It is an object of certain embodiments of the present invention to provide novel antibiotic formulations that are active against resistant strains of Gram-negative bacteria. It is another object of certain embodiments of the present invention to provide antibiotic formulations in which one or more metabolic fragments of the drug after absorption are GRAS (generally recognized as safe). It is another object of the present invention to provide prodrugs that are species independent and / or reduce inter-patient variability due to metabolic differences. It is another object of the present invention to provide prodrugs that can overcome food effects, meaning that they can be administered to fed or fasted patients without the need to carefully control the dosing schedule relative to meal times.

[0019] The novel compounds of the present invention meet some or all of the above-mentioned objects. DETAILED DESCRIPTION

[0020] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0021]

[0022] in

[0023] One of X and Y is N, and the other is C;

[0024] L is selected from a bond or -(CH2) a -Q-(CH2) b - a linking group, wherein Q is selected from the group consisting of O, NH, SO2, C=C and C≡C, or Q is absent;

[0025] R 1 It was an R 3 A 6-membered monocyclic aromatic, carbocyclic, heteroaromatic or heterocyclic ring substituted with a radical, R 1 may be further substituted by 0 or 1 selected from halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0026] R 2 is -C(O)OH or -C(O)OM; wherein M is a Group 1 cation;

[0027] R 3 Selected from: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CR a R b ) n C(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 、-NR 4 CO(CR a R b ) n NR 7 R 8 、-NR 4 CO(CRa R b ) n OSO2OR 5 、-NR 4 CO(CR a R b ) n CN、-NR 4 CO(CR a R b ) n C(=O)OH、-NR 4 CO(CR a R b ) n C(=O)NR 7 R 8 、-SO2NR 4 (CR a R b ) n NR 5 R 6 、-SO2NR 4 (CR a R b ) n OSO2OR 5 、-SO2NR 4 (CR a R b ) n CN, -SO2NR 4 (CR a R b ) n C(=O)OH、-SO2NR 4 (CR a R b ) n C(=O)NR 7 R 8

[0028]

[0029] R 4 Each occurrence is selected from: H, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, -(CH2) f -Aryl, -(CH2) d -heteroaryl, -(CH2) g -heterocyclyl; wherein, where chemically possible, R 4may be optionally substituted by one, two or three groups independently selected at each occurrence from the group comprising halogen, -NH2, -N(C 1-4 Alkyl)2, -OH, -SO2N(C 1-4 Alkyl)2, -NHC(=O)OC 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0030] R 5 and R 6 Each independently selected from H or C 1-6 alkyl;

[0031] Among them, when R 4 , R 5 and R 6 When each exists, R 4 , R 5 or R 6 At least one of them is C 1-6 alkyl;

[0032] R 7 and R 8 Each occurrence is independently selected from H or C 1-4 alkyl;

[0033] R 9 Selected from the group consisting of: H, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0034] R a and R b is independently selected at each occurrence from: H, halogen, NH2 and C 1-4 alkyl.

[0035] a, b, d, f and g are independently selected as integers from 0 to 3;

[0036] m is an integer selected from 1, 2 or 3;

[0037] n is an integer selected from 1, 2, 3, 4 or 5; and

[0038] --- Indicates the single or double bonds required to satisfy the valence requirements.

[0039] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0040]

[0041] in

[0042] One of X and Y is N, and the other is C;

[0043] L is selected from a bond or -(CH2) a -Q-(CH2) b - a linking group, wherein Q is selected from the group consisting of O, NH, SO2, C=C and C≡C, or Q is absent;

[0044] R 1 is an R 3 A 6-membered monocyclic aromatic, heteroaromatic or heterocyclic ring substituted with a radical, R 1 may be further substituted by 0 or 1 selected from halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0045] R 2 is -C(O)OH or -C(O)OM; wherein M is a Group 1 cation;

[0046] R 3 Selected from the group consisting of: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CR a R b ) n C(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 、-NR 4 CO(CR a R b ) n NR 7 R 8 、-NR 4 CO(CR a R b ) n OSO2OR 5 、-NR 4 CO(CR a Rb ) n CN、-NR 4 CO(CR a R b ) n C(=O)OH、-NR 4 CO(CR a R b ) n C(=O)NR 7 R 8 、-SO2NR 4 (CR a R b ) n NR 5 R 6 、-SO2NR 4 (CR a R b ) n OSO2OR 5 、-SO2NR 4 (CR a R b ) n CN, -SO2NR 4 (CR a R b ) n C(=O)OH、-SO2NR 4 (CR a R b ) n C(=O)NR 7 R 8

[0047]

[0048] R 4 Each occurrence is selected from the group consisting of: H, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, -(CH2) f -Aryl, -(CH2) d -heteroaryl, -(CH2) g -heterocyclyl; wherein, where chemically possible, R 4 may be optionally substituted by one, two or three groups independently selected at each occurrence from the group comprising halogen, -NH2, -N(C 1-4 Alkyl)2, -OH, -SO2N(C1-4 Alkyl)2, -NHC(=O)OC 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0049] R 5 and R 6 Each independently selected from H or C 1-6 alkyl;

[0050] Among them, when R 4 , R 5 and R 6 When each exists, R 4 , R 5 or R 6 At least one of them is C 1-6 alkyl;

[0051] R 7 and R 8 Each occurrence is independently selected from H or C 1-4 alkyl;

[0052] R 9 Selected from the group consisting of: H, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0053] R a and R b is independently selected at each occurrence from: H, halogen, NH2 and C 1-4 alkyl.

[0054] a, b, d, f and g are independently selected as integers from 0 to 3;

[0055] m is an integer selected from 1, 2 or 3;

[0056] n is an integer selected from 1, 2, 3, 4 or 5; and

[0057] Indicates the single or double bonds required to satisfy the valence requirements.

[0058] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0059]

[0060] in

[0061] One of X and Y is N, and the other is C;

[0062] L is selected from a bond or -(CH2) a -Q-(CH2) b- a linking group, wherein Q is selected from the group consisting of O, NH, SO2, C=C and C≡C, or Q is absent;

[0063] R 1 is an R 3 A 6-membered monocyclic carbon ring substituted with a radical, R 1 may be further substituted by 0 or 1 selected from halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0064] R 2 is -C(O)OH or -C(O)OM; wherein M is a Group 1 cation;

[0065] R 3 Selected from the group consisting of: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CR a R b ) n C(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 、-NR 4 CO(CR a R b ) n NR 7 R 8 、-NR 4 CO(CR a R b ) n OSO2OR 5 、-NR 4 CO(CR a R b ) n CN、-NR 4 CO(CR a R b )n C(=O)OH、-NR 4 CO(CR a R b ) n C(=O)NR 7 R 8 、-SO2NR 4 (CR a R b ) n NR 5 R 6 、-SO2NR 4 (CR a R b ) n OSO2OR 5 、-SO2NR 4 (CR a R b ) n CN, -SO2NR 4 (CR a R b ) n C(=O)OH、-SO2NR 4 (CR a R b ) n C(=O)NR 7 R 8

[0066]

[0067] R 4 Each occurrence is selected from the group consisting of: H, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, -(CH2) f -Aryl, -(CH2) d -heteroaryl, -(CH2) g -heterocyclyl; wherein, where chemically possible, R 4 may be optionally substituted by one, two or three groups independently selected at each occurrence from the group comprising halogen, -NH2, -N(C 1-4 Alkyl)2, -OH, -SO2N(C 1-4 Alkyl)2, -NHC(=O)OC 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0068] R 5 and R 6 Each independently selected from H or C 1-6 alkyl;

[0069] Among them, when R 4 , R 5 and R 6 When each exists, R 4 , R 5 or R 6 At least one of them is C 1-6 alkyl;

[0070] R 7 and R 8 Each occurrence is independently selected from H or C 1-4 alkyl;

[0071] R 9 Selected from the group consisting of: H, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0072] R a and R b is independently selected at each occurrence from: H, halogen, NH2 and C 1-4 alkyl.

[0073] a, b, d, f and g are independently selected as integers from 0 to 3;

[0074] m is an integer selected from 1, 2 or 3;

[0075] n is an integer selected from 1, 2, 3, 4 or 5; and

[0076] --- Indicates the single or double bonds required to satisfy the valence requirements.

[0077] In one embodiment, the compound of formula (I) is a compound of formula (II):

[0078] Among them, X, Y, L, R 1 and R 2 As defined in formula (I).

[0079] In one embodiment, the compound of formula (I) may be a compound of formula (III):

[0080] Among them, L, R 1 , R 2 and R 9 As defined in formula (I).

[0081] In one embodiment, the compound of formula (III) may be a compound of formula (IV):

[0082] Among them, L, R 1 and R 2 As defined in formula (I).

[0083] In one embodiment, the compound of formula (I) may be a compound of formula (V):

[0084] Where R 1 , R 2 and R 9 As defined in formula (I).

[0085] In one embodiment, the compound of formula (I) may be a compound of formula (VI):

[0086] Where R 1 and R 2 As defined in formula (I).

[0087] In an embodiment, the compound of formula (I) is a compound of formula (VII):

[0088] Where X, Y, R 4 , R 5 , R 6 , R a , R b and n are defined according to formula (I), and Z represents H or M.

[0089] In an embodiment, the compound of formula (I) is a compound of formula (VIII):

[0090] Where R 4 , R 5 , R 6 , R a , R b and n are defined according to formula (I), and Z represents H or M.

[0091] Thus, in one embodiment, Y is N, and X is C.

[0092] Thus, in an alternative embodiment, Y is C, and X is N.

[0093] In an embodiment, the compound of formula (I) is a compound of formula (IX):

[0094] Where R 4 , R5, Ra , R b and n are defined according to formula (I), and Z represents H or M.

[0095] Thus, in one embodiment, Y is N, and X is C.

[0096] Thus, in an alternative embodiment, Y is C, and X is N.

[0097] In an embodiment, the compound of formula (I) is a compound of formula (X):

[0098] Where R 4 , R a , R b and n are defined according to formula (I), and Z represents H or M.

[0099] Thus, in one embodiment, Y is N, and X is C.

[0100] Thus, in an alternative embodiment, Y is C, and X is N.

[0101] In an embodiment, the compound of formula (I) is a compound of formula (XI):

[0102] Where R 4 , R a , R b and n are defined according to formula (I), and Z represents H or M.

[0103] Thus, in one embodiment, Y is N, and X is C.

[0104] Thus, in an alternative embodiment, Y is C, and X is N.

[0105] In an embodiment, the compound of formula (I) is a compound of formula (XII):

[0106] Where R 4 , R 7 , R 8 , R a , Rb and n are defined according to formula (I), and Z represents H or M.

[0107] Thus, in one embodiment, Y is N, and X is C.

[0108] Thus, in an alternative embodiment, Y is C, and X is N.

[0109] In an embodiment, the compound of formula (I) is a compound of formula (XIII):

[0110] Where R 5 , R 6 , R a , R b and n are defined according to formula (I), and Z represents H or M.

[0111] Thus, in one embodiment, Y is N, and X is C.

[0112] Thus, in an alternative embodiment, Y is C, and X is N.

[0113] The following embodiments are applicable to any one of the compounds of formula (I) to (XIII). These embodiments are independent and interchangeable. Where chemically permitted, any one embodiment can be combined with any other embodiment. In other words, any feature described in the following embodiments can be combined with the feature described in one or more other embodiments below (where chemically permitted). In particular, in the case of illustrating or illustrative compounds in this specification, any two or more of the embodiments listed below that are described with any generality level that include the compound can be combined to provide another embodiment that forms a part of the present disclosure.

[0114] In one embodiment, R 1 is an R 3 A 6-membered monocyclic aromatic ring, a cycloalkyl ring, a heteroaromatic ring or a heterocyclic ring substituted by a radical, R 1 may be further substituted by 0 or 1 selected from halogen, C 1-6 Alkyl or C 1-6 The radical of haloalkyl is substituted; R 3 Groups are substituted on ring atoms in monocyclic ring systems as valency considerations permit.

[0115] In one embodiment, R 1 is an R 3 A 6-membered monocyclic aromatic ring, heteroaromatic ring or heterocyclic ring substituted by a group, R 1 may be further substituted by 0 or 1 selected from halogen, C 1-6 Alkyl or C 1-6 The radical of haloalkyl is substituted; R 3 Groups are substituted on ring atoms in monocyclic ring systems as valency considerations permit.

[0116] In one embodiment, R 1 is an R 3 A 6-membered monocyclic cycloalkyl ring substituted with a radical, R 1 may be further substituted by 0 or 1 selected from halogen, C 1-6 Alkyl or C 1-6 The radical of haloalkyl is substituted; R3 Groups are substituted on ring atoms in monocyclic ring systems as valency considerations permit.

[0117] R 3 Substituents may be present on the 6-membered ring R 1 Relative to R 1 The meta or para position of the point of attachment to the rest of the molecule in the compound of formula (I) is substituted. 3 The substituent is preferably in the 6-membered ring R 1 Relative to R 1 The para position is substituted with respect to the point of attachment to the rest of the molecule in the compound of formula (I).

[0118] R 1 It can be a 6-membered heteroaryl group, a 6-membered cycloalkyl group, a 6-membered aryl group, a 6-membered heterocycloalkenyl group or a 6-membered heterocycloalkyl group. 1 It can be a 6-membered heteroaryl group, a 6-membered aryl group, a 6-membered heterocycloalkenyl group or a 6-membered heterocycloalkyl group. 1 It may be a 6-membered cycloalkyl group.

[0119] In some embodiments, R 1 Selected from:

[0120]

[0121] In some embodiments, R 1 Selected from:

[0122]

[0123] In some embodiments, R 1 Selected from:

[0124]

[0125] In some embodiments, R 1 Selected from:

[0126]

[0127] In some embodiments, R 1 is an aryl group, and is preferably replaced by R 3 Substituted phenyl. 1 It may be selected from the group consisting of phenyl, pyridine, tetrahydropyridine, piperidine and pyrimidine.

[0128] In some embodiments, R 1 is a cycloalkyl group, and is preferably replaced by R 3 Substituted cycloalkyl.

[0129] In some embodiments, R 1 Selected from:

[0130]

[0131]

[0132]

[0133]

[0134] In an alternative embodiment, R 1 is a saturated or partially saturated 6-membered carbocyclic ring system. Preferred rings include:

[0135]

[0136] In an alternative embodiment, R 1 It is a saturated or partially saturated 6-membered heterocyclic ring system. The ring can be connected to the carbon or nitrogen of the pyrrole core. In the case of a carbon-connected ring, preferred rings include:

[0137]

[0138] In the case of nitrogen-linked rings, preferred R 1 Groups include:

[0139]

[0140] In one embodiment, R 2 is -C(O)OH or -C(O)OM. In one embodiment, R 2 is -C(O)OH. In one embodiment, R 2 It is -C(O)OM.

[0141] In one embodiment, R 3 Selected from the group consisting of: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CR a R b ) nC(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 ,

[0142]

[0143] In one embodiment, R 3 Selected from the group consisting of: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CR a R b ) n C(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 ,

[0144]

[0145] R 4 Selected from the group consisting of: H, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, -(CH2) f -C 6-10 Aryl, -(CH2) d -5 to 10 membered heteroaryl, -(CH2) g -3 to 10 membered heterocyclic group; wherein, where chemically possible, R 4 may be optionally substituted by one, two or three groups independently selected at each occurrence from the group comprising halogen, -NH2, -N(C 1-4Alkyl)2, -OH, -SO2N(C 1-4 alkyl)2, -NHC(=O)Otert-butyl and -C(=O)Otert-butyl.

[0146] In an embodiment, R 4 Selected from the group consisting of: H, -OH, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 10 membered heterocyclic group, C 3-8 Cycloalkyl; wherein, where chemically possible, each R 5 itself may be optionally substituted by one or two groups independently selected at each occurrence from the group comprising: -NH2, -OH, -SO2N(C 1-4 alkyl)2, -NHC(=O)Otert-butyl and -C(=O)Otert-butyl.

[0147] In an embodiment, R 4 Each occurrence is selected from the group consisting of: H, -OH, methyl, propyl, methylamine, ethylamine, n-propylamine, isopropylamine, trifluoroethylamine, piperidine, cyclopropyl, cyclopropylamine, -CH2OH, -(CH2)2NHC(=O)tert-butyl, methylpyrazole, piperazine, piperazine substituted by -C(=O)tert-butyl.

[0148] In an embodiment, R 4 is selected from the group consisting of: H, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-8 Cycloalkyl.

[0149] Preferably, R 4 It is H or Me.

[0150] R 5 and R 6 Each independently selected from H or C 1-6 In one embodiment, R 5 and R 6 Each independently selected from the group consisting of: H, Me, Et, n Pr, i Pr and n Bu.

[0151] In one embodiment, R 5 is H. In one embodiment, R 5 It's Me or Et.

[0152] In one embodiment, R 6 is H. In one embodiment, R 6 It's Me or Et.

[0153] In one embodiment, R 7 is H. In one embodiment, R 7 It's Me or Et.

[0154] In one embodiment, R 8 is H. In one embodiment, R 8 is Me or Et. In one embodiment, R 9 is H, Me, ethyl or CF3. In one embodiment, R 9 is H, Me or CF3. In some embodiments, R 9 It's H.

[0155] L can be a bond, -CH2-, -CH2NH-, -O- or -OCH2-. L can be a bond or -CH2-. L can be a bond. L can be O or NH. L can be -CH2- or -CH2CH2-.

[0156] In one embodiment, L is a bond or -CH2-, X is C and Y is N. In one embodiment, L is a bond or -CH2-, X is C and Y is N.

[0157] In an embodiment, a is 0 or 1. In an embodiment, a is 0.

[0158] In an embodiment, b is 0 or 1. In an embodiment, b is 0.

[0159] In an embodiment, d is 0 or 1. In an embodiment, d is 0. In an embodiment, f is 0 or 1. In an embodiment, f is 0.

[0160] In an embodiment, g is 0 or 1. In an embodiment, g is 0. In an embodiment, M is Na or K, preferably Na.

[0161] In one embodiment, Y is N, X is C, R 9 is H, L is a bond, and R 3 Selected from: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CRa R b ) n C(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 ,

[0162]

[0163] In one embodiment, Y is N, X is C, R 9 is H, L is a bond, and R 3 Selected from: -CONR 4 (CR a R b ) n NR 5 R 6 、-CONR 4 (CR a R b ) n OSO2OR 5 、-CONR 4 (CR a R b ) n CN, -CONR 4 (CR a R b ) n C(=O)OH、-CONR 4 (CR a R b ) n C(=O)NR 7 R 8 ,

[0164]

[0165] In one embodiment, Y is N, X is C, R 9 is H, L is a bond, and R 3 Selected from: -SO2NR 4 (CR a R b ) n NR 5 R 6 、-SO2NR 4 (CR a R b ) n OSO2OR 5 、-SO2NR 4 (CRa R b ) n CN, -SO2NR 4 (CR a R b ) n C(=O)OH and -SO2NR 4 (CR a R b ) n C(=O)NR 7 R 8 .

[0166] In one embodiment, Y is N, X is C, R 9 is H, L is a bond, and R 3 Selected from:-NR 4 CO(CR a R b ) n NR 7 R 8 、-NR 4 CO(CR a R b ) n OSO2OR 5 、-NR 4 CO(CR a R b ) n CN、-NR 4 CO(CR a R b ) n C(=O)OH and -NR 4 CO(CR a R b ) n C(=O)NR 7 R 8 .

[0167] The various embodiments described above for the various substituents can be applied independently of each other. These embodiments apply similarly to all other aspects of the invention described below.

[0168] In one embodiment of the present invention, the compound of formula (I) may be a compound selected from the following:

[0169]

[0170]

[0171]

[0172]

[0173] In an embodiment, the compound of formula (I) may be a compound selected from the following:

[0174]

[0175] These compounds are particularly soluble compared to certain prior art compounds. They also have fewer off-target interactions than certain prior art compounds.

[0176] In an embodiment, the compound of formula (I) is:

[0177]

[0178] In an embodiment, the compound of formula (I) is:

[0179]

[0180] In another aspect, the present invention provides a compound selected from the group consisting of:

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188] In another aspect, the present invention provides a compound selected from the group consisting of:

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0196] Throughout this application, the compounds of the present invention have been described as compounds or salts of compounds. It will be appreciated by those skilled in the art that compounds can be converted into salts, and salts can be converted into compounds, in other words, corresponding to the free acid or free base of the salt. Therefore, where compounds are disclosed or salts are disclosed, the present invention also appropriately includes the corresponding salt form, free acid form or free base form. For example, the disclosure of the following salts also encompasses the disclosure of the corresponding free acid, also as shown below. This applies to all compounds or salts disclosed herein.

[0197]

[0198] The compounds of the present invention are inhibitors of metallo-β-lactamase (MBL). As mentioned above, many bacteria have developed resistance to β-lactam antibiotics (BLAs), and one of the main resistance mechanisms is the hydrolysis of BLAs by MBL. The compounds of the present invention solve this problem. In particular, when one or more BLA compounds are administered together with the compounds of the present invention, the inhibitory effect of the compounds of formula (I) on bacterial MBL can significantly enhance the activity of BLA.

[0199] Bacterial infections that can be treated using compounds of formula (I) and compositions comprising compounds of formula (I) include those caused by gram-negative or gram-positive bacteria. For example, bacterial infections may be caused by bacteria from one or more of the following families: Streptococcus, acinetobacter, staphylococcus, clostridium, pseudomonas, Escherichia coli, Salmonella, Klebsiella, Legionella, Neisseria, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Mycobacterium, Morganella, Yersinia, Pasteurella, Haemophilus, Citrobacter, Burkholderia, Brucella or Moraxella.

[0200] Specific examples of bacteria targeted by the present invention include bacterial strains in the following bacterial families: Escherichia coli, Acinetobacter, Pseudomonas, and Klebsiella.

[0201] The bacterial infection may be caused, for example, by one or more bacteria selected from Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa or Klebsiella pneumoniae.

[0202] In one aspect of the present invention, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting metallo-β-lactamase activity.

[0203] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating a disease or condition involving metallo-β-lactamase activity.

[0204] In one embodiment, the compounds of the invention are useful for treating a disease or condition caused by aerobic or anaerobic Gram-positive bacteria or aerobic or anaerobic Gram-negative bacteria. In one embodiment, the disease or condition is caused by a Gram-positive bacterium that produces a metallo-β-lactamase.

[0205] In one embodiment, the compounds of the invention may be used to treat a disease or condition selected from the group consisting of pneumonia, respiratory tract infections, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bloodstream infections, sepsis, intrapartum and postpartum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis, and febrile neutropenia.

[0206] In one embodiment, the compounds of the invention may be used to treat a disease or condition selected from the group consisting of community-acquired pneumonia, nosocomial pneumonia (hospital-acquired / ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bacteremia, sepsis, intrapartum and postpartum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis, and febrile neutropenia.

[0207] In one embodiment, the compounds of the invention may be used to treat a disease or condition selected from the group consisting of community-acquired pneumonia, nosocomial pneumonia (hospital-acquired / ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bacteremia, and sepsis.

[0208] In embodiments, compounds of the invention may be used in a method of treatment wherein the compound is administered in combination with one or more BLAs.

[0209] The administration of one or more compounds of formula (I) may be together with one or more BLAs, all of which are present in the same dosage form, or it may be the case that one or more BLAs are present in separate dosage forms and one or more compounds of formula (I) are present in separate dosage forms. In a preferred embodiment, the effective antibacterial treatment will consist of a compound of formula (I) and a BLA. The BLA will preferably be meropenem. In another preferred embodiment, the compound of formula (I) and the BLA (which may preferably be meropenem) are co-administered in a single formulation (i.e., a single dosage form).

[0210] The compounds of formula (I) may be present in dosage forms suitable for oral use (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), or they may be suitable for topical use (e.g. creams, ointments, gels or aqueous or oily solutions or suspensions). Other suitable dosage forms also include dosage forms intended to be administered by inhalation (e.g., as fine powders or liquid aerosols), dosage forms administered by insufflation (e.g., as fine powders) or dosage forms for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration). In a preferred embodiment, oral or intravenous administration is preferred, wherein intravenous administration is most preferred.

[0211] Oral dosage forms may contain, together with the active compound, one or more of the following excipients: diluents, lubricants, binders, desiccants, sweeteners, flavoring agents, colorants, wetting agents, and effervescent agents.

[0212] If the MBLI and BLA are in separate dosage forms, they can be administered simultaneously or sequentially. Generally, it is preferred to administer the MBLI (i.e., the compound of formula (I) of the present invention) and the BLA (i.e., the antibacterial compound) in a single dosage form. Preferably, it is an intravenous dosage form, and more preferably, it is a solid dosage form. Tablets, capsules, and caplets are particularly preferred.

[0213] The process of contacting cells or indeed other biological material or sample containing bacteria with a compound of the invention actually means exposing the bacteria to the compound of the invention.

[0214] The compound of formula (I) is an inhibitor of metallo-β-lactamase, so the present invention provides a method for inhibiting bacterial metallo-β-lactamase activity in vitro or in vivo. The method comprises contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or contacting a cell with a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0215] Therefore, in one aspect of the present invention, a method for inhibiting bacterial metallo-β-lactamase activity in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof; or contacting cells with a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0216] The present invention provides a method for preventing or treating a bacterial infection in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of an antibacterial agent in combination with a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof; or administering to the patient a therapeutically effective amount of an antibacterial agent and a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0217] The present invention also provides a method for preventing or treating a disease or condition, the method comprising: administering to a patient in need of such treatment a therapeutically effective amount of an antibacterial agent in combination with a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof; or administering to the patient a therapeutically effective amount of an antibacterial agent and a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0218] In one embodiment, the invention provides a method for preventing or treating a disease or condition caused by aerobic or anaerobic Gram-positive or aerobic or anaerobic Gram-negative bacteria. In one embodiment, the disease or condition is caused by a Gram-positive bacterium that produces a metallo-β-lactamase.

[0219] In one embodiment, the present invention provides a method for preventing or treating a disease or condition selected from the group consisting of pneumonia, respiratory tract infection, urinary tract infection, intra-abdominal infection, skin and soft tissue infection, bloodstream infection, sepsis, intrapartum and postpartum infection, prosthetic joint infection, endocarditis, acute bacterial meningitis and febrile neutropenia.

[0220] In one embodiment, the present invention provides a method for preventing or treating a disease or condition selected from the group consisting of community-acquired pneumonia, nosocomial pneumonia (hospital-acquired / ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bacteremia, sepsis, intrapartum and postpartum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis, and febrile neutropenia.

[0221] In one embodiment, the present invention provides a method for preventing or treating a disease or condition selected from the group consisting of community-acquired pneumonia, nosocomial pneumonia (hospital-acquired / ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bacteremia, and sepsis.

[0222] In one embodiment, the antibacterial agent is a carbapenem. Non-limiting examples of carbapenems include: meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem / betamipron and biapenem, as well as razupenem, tebipenem, lenopenem and tomopenem.

[0223] The present invention also provides a method for inhibiting bacterial infection, the method comprising contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof and a suitable antibacterial agent. The contact of cells can occur in vitro or in vivo, preferably in vivo.

[0224] Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treatment.

[0225] Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating bacterial infection. The treatment may be therapeutic or prophylactic, i.e., preventive. In a preferred embodiment, the treatment is curative; this means that the treatment can reduce the overall level of bacterial infection.

[0226] Another aspect of the present invention provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a BLA. The kit may be provided together with instructions for treating bacterial infections and / or packaging providing a combined dose of a compound of formula (I) and a BLA.

[0227] Chemical terms used in the specification have meanings generally accepted in the art.

[0228] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0229] The term "alkyl" includes straight and branched chain alkyl groups having 1 to 6 carbon atoms and the like. References to individual alkyl groups, such as "propyl", are specific only to the straight chain form, and references to individual branched chain alkyl groups, such as "isopropyl", are specific only to the branched form. Similarly, a C4 alkyl group may be a straight chain butyl group, a secondary butyl group (sec-butyl) or a tertiary butyl group (tert-butyl). At each occurrence, the term may have any meaning within the above definition, regardless of any other usage of the term. The same comments apply to other terms defined in this specification, which are used in multiple contexts, and therefore, they are independently selected from the meaning of the overall definition in each case.

[0230] For the avoidance of doubt, the term “C 3-8 "Cycloalkyl" refers to a hydrocarbon ring containing 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl; the term "C 3-8 "Cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl (for example 3-cyclohexen-1-yl) or cyclooctenyl.

[0231] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes monovalent and divalent species. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, etc. In a specific embodiment, aryl is phenyl.

[0232] The heterocyclic ring may be saturated, unsaturated or aromatic. Aromatic heterocyclic species are often referred to as heteroaryl rings.

[0233] The term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spirocyclic bicyclic heterocyclic ring system. The term heterocyclyl includes monovalent and divalent species. The monocyclic heterocyclic ring contains about 3 to 12 (suitably 3 to 7) ring atoms in the ring, with 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The bicyclic heterocyclic ring contains 7 to 17 member atoms in the ring, suitably, 7 to 12 atoms. The bicyclic heterocyclic ring contains about 7 to about 17 ring atoms, suitably 7 to 12 ring atoms. The bicyclic heterocyclic ring can be a fused ring, spiro ring or bridged ring system. Examples of heterocyclyl groups include cyclic ethers such as oxiranyl, oxetane, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiopyridine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dihydrodioxolyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclic groups having 1 or 2 oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclic radical group is the saturated monocyclic 3 to 7 membered heterocyclic radical containing 1,2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidyl, homopiperidyl, piperazinyl or homopiperazinyl.As will be appreciated by the technician, any heterocycle can be connected to another group by any suitable atom (for example, by carbon or nitrogen atom).However, " piperidyl (piperidino) " and " morpholinyl (morpholino) " mentioned herein refer to piperidin-1-yl or morpholine-4-yl ring connected by ring nitrogen.

[0234] "Bridged ring system" refers to a ring system in which two rings share more than two atoms, see, e.g., Advanced Organic Chemistry by Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

[0235] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes monovalent and divalent substances. Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more generally containing five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic, such as a bicyclic structure formed by a fused five-membered ring and a six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms generally selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more generally containing up to 2 heteroatoms, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring may be basic (as in the case of imidazole or pyridine) or substantially non-basic (as in the case of indole or pyrrole nitrogen). Generally, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituents of the ring) will be less than five.

[0236] Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl , cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also covers partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings are non-aromatic saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothiophenyl, 4,5,6,7-tetrahydrobenzofuranyl, indolyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0237] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0238] Examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0239] A 5-membered or 6-membered heterocyclic ring is preferred.

[0240] The various functional groups and substituents that make up the compounds of formula I are typically selected so that the molecular weight of the compounds of formula I does not exceed 1000. More typically, the molecular weight of the compound is less than 900, such as less than 800, or less than 700, or less than 650, or less than 600. More preferably, the molecular weight is less than 550, such as 500 or less.

[0241] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. Suitable pharmaceutically acceptable salts of the compounds of the present invention include those having a Group 1 cation (e.g., Na + ), Group II cations (e.g. K + ) or ammonium salts (such as NH4 + ). When there is basic nitrogen in the compound of the present invention, the compound of the present invention can also form a hydrochloride, a phosphate or a salt of other inorganic acids. These salts can include acid addition salts and basic salts of the compound.

[0242] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfonate, naphthoate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, toluenesulfonate, and trifluoroacetate.

[0243] Suitable alkaline salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemi-salts of acids and bases, such as hemisulphates and hemicalcium salts, can also be formed. For a review of suitable salts, see Stahl and Wermuth "H and book of Pharmaceutical Salts: Properties, Selection and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0244] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared, for example, by one or more of the following methods:

[0245] by reacting a compound of the present invention with a desired acid or base;

[0246] By removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam), using a desired acid or base; or

[0247] One salt of a compound of the invention is converted into another salt by reaction with a suitable acid or base or with the aid of a suitable ion exchange column.

[0248] These methods are all usually carried out in solution. The resulting salt may precipitate out and be collected by filtration, or it may be recovered by evaporating the solvent. The degree of ionization in the resulting salt may range from completely ionized to almost non-ionized.

[0249] The compounds of the present invention (ie compounds of formula (I)) may in certain cases exist in a number of different tautomeric forms and references to compounds of formula I include all such forms.

[0250] Compounds that have the same molecular formula but different arrangements of their atoms are called "isomers."

[0251] Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". - Stereoisomers that are not mirror images of each other are called "diastereomers", while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, it is called a chiral compound. A chiral compound can exist as one or both of its enantiomeric pairs (in the case of a single chiral center). - Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the Cahn-Ingold-Prelog rule of R and S order. If there is more than one chiral center in a molecule, then the number of conceivable stereoisomers is 2 n , where n is the number of chiral centers; the only exception is the presence of symmetry in the molecule, which causes the number of isomers to vary from a maximum of 2 n reduce.

[0252] -- The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds may be produced as individual (R)-stereoisomers or (S)-stereoisomers or mixtures thereof.

[0253] -- Certain compounds of the present invention may have geometric isomeric centers (E-isomers and Z-isomers).

[0254] It should be understood that the present invention encompasses all isomeric forms and mixtures thereof that possess metallo-β-lactamase inhibitory activity.

[0255] - Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in "Advanced Organic Chemistry", 7th edition J. March, John Wiley and Sons, New York, 2013).

[0256] Compounds of formula I containing amine functional groups can also form N-oxides. Compounds of formula I containing amine functional groups mentioned herein also include N-oxides. When the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid); this is described in common textbooks, such as the Advanced Organic Chemistry by J. March mentioned above. N-oxides can be prepared in a variety of ways known to those skilled in the art; for example, by reacting an amine compound with meta-chloroperbenzoic acid (mCPBA) in a solvent (e.g., dichloromethane).

[0257] The present invention also encompasses compounds of the present invention as defined herein, which contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; etc. Similarly, isotopic variations of N, S, and P may be utilized.

[0258] Synthesis and Examples

[0259] The following compounds represent examples of compounds that can be synthesized according to the present invention. Certain compounds have also been subjected to biological testing, the results of which are shown below. The compounds have shown activity as metallo-β-lactamase inhibitors and are therefore useful in treating infections, particularly antibiotic-resistant infections.

[0260] General Experiments

[0261] Using Biotage Initiator+ TM Microwave synthesizers Microwave-assisted reactions were performed in sealed vials.

[0262] Throughout this document, the following abbreviations are used:

[0263] Bn – benzyl

[0264] Boc – tert-Butyloxycarbonyl

[0265] Cbz – carboxybenzyl

[0266] DCM – dichloromethane

[0267] DIPEA uses diisopropylethylamine

[0268] DME – 1,2-dimethoxyethane

[0269] DMF – N,N-dimethylformamide

[0270] DMSO – Dimethyl Sulfoxide

[0271] HBTU – N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate

[0272] Hoveyda-Grubbs Second generation – dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)

[0273] NMP – 1-Methyl-2-pyrrolidone

[0274] Pd(dppf)Cl2–[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0275] SEM–2-(Trimethylsilyl)ethoxymethyl

[0276] TFA – trifluoroacetic acid

[0277] THF – Tetrahydrofuran

[0278] XPhos Pd G2 – Chloro(2-dicyclohexylphosphino-2-hexylphosphinoPd G triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0279] Analytical methods

[0280] all 1 H and 19 F NMR spectra were all acquired on a Bruker AVI 500 with 5 mm QNP. Chemical shifts are expressed in parts per million (δ) and are referenced to the solvent. Coupling constants, J, are expressed in Hertz (Hz).

[0281] LC-MS were obtained on a Waters Alliance ZQ (methods A, B, C and E) or a Waters Acquity H-class UPLC (method D) using the methods detailed below. Wavelengths were 254 and 210 nm.

[0282] Method A

[0283] Chromatographic column: YMC-Triart C18, 2.0×50mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 6μL

[0284] Mobile phase: A = water, B = acetonitrile, C = 1:1 water: acetonitrile + 1.0% formic acid

[0285]

[0286]

[0287] Method B

[0288] Chromatographic column: YMC-Triart C18, 2.0×50mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 6μL

[0289] Mobile phase: A = water, B = acetonitrile, C = 1:1 water: acetonitrile + 1.0% ammonia (aqueous solution)

[0290] time ％A ％B ％C initial 90 5 5 4.0 0 95 5 6.0 0 95 5

[0291] Method C

[0292] Chromatographic column: YMC-Triart C18, 2.0×50mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 6μL

[0293] Mobile phase: A = water, B = acetonitrile, C = 1:1 water: acetonitrile + 1.0% formic acid

[0294] time ％A ％B ％C initial 95 0 5 2.0 95 0 5 12.0 0 95 5 14.0 0 95 5

[0295] Method D

[0296] Chromatographic column: CSH C18, 2.1×100mm, 1.7μm. Flow rate: 0.6mL / min. Injection volume: 5μL

[0297] Mobile phase: A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid

[0298] time ％A ％B initial 98 2 0.5 98 2 6.5 2 98 7.5 2 98

[0299] Method E

[0300] Chromatographic column: YMC-Triart C18, 2.0×50mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 6μL

[0301] Mobile phase: A = water, B = acetonitrile, C = 1:1 water: acetonitrile + 1.0% ammonia (aqueous solution)

[0302] time ％A ％B ％C initial 97.5 0 2.5 3.0 0 95 5 5.0 0 95 5

[0303] Method F

[0304] Chromatographic column: YMC-Triart C18, 2.0×50mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 6μL Mobile phase: A = water, B = acetonitrile, C = 1:1 water: acetonitrile + 1.0% formic acid

[0305]

[0306]

[0307] Preparative HPLC chromatography was performed using a Waters Auto Lynx Mass Directed Fraction Collector as detailed below.

[0308] Method A

[0309] Column: CSH C18, 30×100 mm, 5 μm. Flow rate: 80 mL / min. Injection volume: 2500 μL. Run time: 6.5 min (gradient range as follows), then 1.25 min 95% (% B in A).

[0310] Mobile phase A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid

[0311] Method Name Gradient range (% B in A solution) 0.60-0.80min. 2-12％ 0.80-1.00min. 5-15％ 1.00-1.11min. 8-18％ 1.22-1.33min. 15-25％ 1.78-1.90min. 40-50％

[0312] Intermediate 1: Sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromopyrrol-1-yl)sulfonyl-amino (azanide)

[0313]

[0314] Step A: 3-Bromo-1H-pyrrole-2-carboxylic acid benzyl ester

[0315] 3-Bromo-1H-pyrrole-2-carboxylic acid methyl ester (63 g, 309 mmol) was added to benzyl alcohol (267 g, 2.47 mol), followed by di-n-butyltin oxide (3.84 g, 15.4 mmol), and the mixture was stirred at 125 ° C for 24 hours. Low boiling point substances were removed under reduced pressure. The reaction was heated to 125 ° C for another 4 days. Benzyl alcohol was removed by vacuum distillation, and the residue was purified by silica plug, eluting with 20-30% ether in petroleum ether. The residue was dissolved in 20% ether: petroleum ether, and the mixture was seeded with the product to obtain a solid, which was stirred for 10 minutes, then filtered and dried. The obtained solid was then slurried in petroleum ether for 10 minutes and then filtered to obtain the desired product as a white solid (72.5 g, 84%).

[0316] 1 H NMR (500MHz, CDCl3) δ9.14 (br s, 1H), 7.50-7.30 (m, 5H), 6.82 (d, J = 3.2Hz, 1H), 6.34 (d, J = 3.2Hz, 1H), 5.35 (s, 2H).

[0317] Step B: Sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromopyrrol-1-yl)sulfonyl-amide

[0318] A suspension of sodium hydride (60% in mineral oil, 23.6 g, 589 mmol) in anhydrous THF (200 mL) was cooled to -10 ° C under a nitrogen atmosphere, and then a solution of 3-bromobenzyl-1H-pyrrole-2-carboxylic acid benzyl ester (55 g, 196 mmol) in anhydrous THF (200 mL) was added dropwise over 45 minutes, ensuring that the temperature remained below -5 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour, then recooled to -10 ° C. N-chlorosulfonyl benzyl carbamate (53.9 g, 216 mmol) was added to the reaction mixture in portions over 30 minutes, ensuring that the temperature remained below -5 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, then recooled to -10 ° C and quenched by the addition of 50:50 water:brine (250 mL). The reaction mixture was extracted into ethyl acetate (3 x 100 mL), the combined organic phases were washed with brine (200 mL), dried over MgSO4, the solution was decanted and concentrated to dryness under reduced pressure. The residue was purified by slurrying in diethyl ether (200 mL), filtered and sucked dry. The solid was re-slurried in diethyl ether (250 mL), filtered and sucked dry to give the desired product as a white solid (99.8 g, 99%).

[0319] 1H NMR (500MHz, DMSO-d6) δ7.56-7.52 (m, 2H), 7.36-7.26 (m, 9H), 6.17 (d, J = 3.4Hz, 1H), 5.23 (s, 2H), 4.85 (s, 2H).

[0320] LC-MS (Method A): R T =3.38min,m / z=491.4 / 493.4[MH] - .

[0321] Intermediate 2: 4-[2-Benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid

[0322]

[0323] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-(4-tert-butyloxycarbonylphenyl)pyrrole-2-carboxylate

[0324] A stirred suspension of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromopyrrol-1-yl)sulfonylamide (35.0 g, 67.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (22.7 g, 74.7 mmol) and XPhos Pd G2 (2.67 g, 3.40 mmol) in 1,4-dioxane (350 mL) was degassed and purged with nitrogen, then an aqueous solution of potassium phosphate (3M, 67.92 mL) was added. The mixture was heated at 45 °C for 2 hours. The reaction mixture was allowed to cool, the phases were separated and the organic phase was concentrated to dryness under reduced pressure. The residue was redissolved in ethyl acetate (300 mL), washed with water (2×300 mL) and saturated sodium bicarbonate solution (2×300 mL), dried over MgSO4, filtered and concentrated to about 60 mL under reduced pressure. This was diluted with diethyl ether (150 mL) and the resulting solution was added dropwise to petroleum ether with vigorous stirring. The precipitated solid was isolated by filtration and sucked dry to give the desired product as an off-white solid (40.4 g, 100%).

[0325] 1 H NMR (500MHz, CDCl3) δ7.61(br d,J=7.6Hz,2H),7.56(br s,1H),7.11-6.86(m,11H),6.58(br d,J=6.7Hz,2H),5.87(br s,1H),4.86(br s,2H),4.78(s,2H),1.61(s,9H).

[0326] LC-MS (Method A): R T=3.93min,m / z=589.6[M–H] - .

[0327] Step B: 4-[2-Benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid

[0328] To a stirred solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-(4-tert-butoxycarbonylphenyl)pyrrole-2-carboxylate (40.5 g, 68.6 mmol) in DCM (300 mL) was added TFA (76 mL, 1.03 mol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure. The residue was triturated with isopropanol, filtered and sucked dry to give the desired product as an off-white solid (25.0 g, 68%).

[0329] 1 H NMR (500MHz, DMSO-d6) δ7.85(br d,J=7.9Hz,2H),7.49(br s,1H),7.44-7.23(m,10H),7.19(br d,J=6.4Hz,2H),6.51(br s,1H),5.22(s,2H),5.12(s,2H).

[0330] LC-MS (Method A): R T =3.20min,m / z=533.5[MH] - .

[0331] Other intermediates

[0332] The following intermediate was prepared in a similar manner to 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (Intermediate 2).

[0333]

[0334] Intermediate 4: (3R)-3-ethynylpyrrolidine-1-carboxylic acid tert-butyl ester

[0335]

[0336] 1-Diazo-1-dimethoxyphosphoryl-propane-2-one (85% in acetonitrile, 409 mg, 1.81 mmol) was added to a solution of (3S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (524 μL, 1.81 mmol) and potassium carbonate (501 mg, 3.62 mmol) in methanol (10 mL) at ambient temperature and stirred for 1 hour. The reaction mixture was partitioned between DCM (50 mL) and water (20 mL). The organics were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organics were dried over Na2SO4, filtered, evaporated under reduced pressure and purified by column chromatography (0-100% ethyl acetate in petroleum ether) to give the desired product as a colorless oil (315 mg, 89%).

[0337] 1 H NMR (500MHz, CDCl3) δ3.77-3.41(m,2H),3.39-3.17(m,2H),3.05-2.82(m,1H),2.24-2.08(m,2H),2.02-1.88(m,1H),1.46(s,9H).

[0338] Other intermediates

[0339] The following intermediate was prepared in a similar manner to (3R)-tert-butyl 3-ethynylpyrrolidine-1-carboxylate (Intermediate 4).

[0340]

[0341] Intermediate 6: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-(4-piperidinyl)pyrrole-2-carboxylate, hydrochloride

[0342]

[0343] Step A: tert-Butyl 4-(2-benzyloxycarbonyl-1H-pyrrol-3-yl)piperidine-1-carboxylate

[0344] Tert-butyl 4-ethynylpiperidine-1-carboxylate (29.0 g, 139 mmol) was dissolved in anhydrous 1,4-dioxane (400 mL). Silver carbonate (19.1 g, 69.3 mmol) was added thereto and the mixture was heated to 100 ° C. Once the temperature was reached, the flask was covered with aluminum foil and a solution of 2-isocyanatoacetic acid benzyl ester (30.3 g, 173 mmol) in anhydrous 1,4-dioxane (150 mL) was added dropwise over 2 hours. After the addition, the mixture was kept at 100 ° C for another 2 hours and then evaporated in vacuo, and the resulting black residue was diluted with 60% ether in petroleum ether. The mixture was rinsed through a plug of silica and eluted with 60% ether in petroleum ether. The obtained fractions were then concentrated in vacuo, triturated with petroleum ether, and any volatiles were removed in vacuo to give the desired product as a pale yellow solid (44 g, 83%).

[0345] 1 H NMR(500MHz,DMSO-d6)δ11.60(br s,1H),7.56-7.28(m,5H),6.90(s,1H),6.12(s,1H),5.27(s,2H),4.11-3.90(m,2 H),3.27-3.17(m,1H),2.60-2.50(m,2H),1.75-1.65(m,2H),1.45-1.32(m,11H).

[0346] LC-MS (Method A): R T =3.95min,m / z=383.4[MH] - .

[0347] Step B: tert-Butyl 4-[2-benzyloxycarbonyl-1(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]piperidine-1-carboxylate, sodium salt

[0348] A suspension of sodium hydride (60% in mineral oil, 5.62 g, 140 mmol) in anhydrous THF (100 mL) was cooled to -10 °C under a nitrogen atmosphere. A solution of tert-butyl 4-(2-benzyloxycarbonyl-1H-pyrrol-3-yl)piperidine-1-carboxylate (18.0 g, 46.8 mmol) in THF (100 mL) was then added dropwise over 30 minutes, ensuring that the temperature remained below -5 °C. The reaction mixture was then stirred at this temperature for 1 hour and then recooled to -10 °C. N-chlorosulfonyl benzyl carbamate (12.8 g, 51.5 mmol) was added in batches of 2 g every 5 minutes, ensuring that the temperature remained below -5 °C. The reaction mixture was then allowed to warm to room temperature and stirred for 90 minutes, then recooled to -10 °C and quenched by the addition of brine (250 mL). The reaction mixture was extracted into ethyl acetate (3 × 100 mL), the combined organic phases were washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo to dryness. The residue was dissolved in DCM (30 mL), then ether was added under stirring, followed by a 60% ether solution in petroleum ether to give a turbid solution. The mixture was stirred for 20 minutes, then filtered under a nitrogen atmosphere. The solid obtained was resuspended in ether, slurried for 30 minutes and filtered to give the desired product as a colorless solid (23.4 g, 77%).

[0349] LC-MS (Method A): R T =2.50min,m / z=596.5[MH] - .

[0350] Step C: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-(4-piperidinyl)pyrrole-2-carboxylate, hydrochloride

[0351] Tert-butyl 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]piperidine-1-carboxylate sodium salt (5.60 g, 9.37 mmol) was dissolved in 1,4-dioxane (25 mL) and then 4M HCl in 1,4-dioxane (46.9 mL, 187 mmol) was added. The reaction was then stirred at room temperature for 3 hours before being diluted with ether (100 mL). The product was isolated by trituration, washed with additional portions of ether (2×50 mL) and dried under vacuum to give the desired product as a colorless solid (4.40 g, 88%).

[0352] 1H NMR(500MHz,DMSO-d6)δ8.79-8.31(m,2H),7.49-7.28(m,11H),6.17(br s,1H),5.30(s,2H),5.04(s,2H),3.29-3.20(m,2H),3.13-3.02(m,1H),2.76-2.62(m,2H),1.82-1.61(m,4H).

[0353] LC-MS (Method A): R T =2.71min,m / z=496.5[MH] - .

[0354] Other intermediates

[0355] The following intermediate was prepared in a similar manner to benzyl 1-(benzyloxycarbonylsulfamoyl)-3-(4-piperidinyl)pyrrole-2-carboxylate, hydrochloride (Intermediate 6).

[0356]

[0357]

[0358]

[0359]

[0360] *Despite the use of enantiomerically pure starting materials, epimerization of chiral centers was observed during the synthesis of these intermediates.

[0361] Intermediate 14: Benzyl 3-[1-(2-aminoacetyl)-4-piperidinyl]-1-[benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0362]

[0363] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[1-[2-(tert-butyloxycarbonylamino)acetyl]-4-piperidinyl]pyrrole-2-carboxylate

[0364] Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-(4-piperidinyl)pyrrole-2-carboxylate, hydrochloride (250 mg, 0.47 mmol) was dissolved in DMF (5 mL) and DIPEA (408 μL, 2.34 mmol) was added. The reaction was stirred for 10 minutes and then N-(tert-butoxycarbonyl)glycine (17 μL, 0.47 mmol) and HBTU (213 mg, 0.56 mmol) were added. After stirring at room temperature for 2 hours, the reaction mixture was poured into 1M HCl aqueous solution (50 mL) and the resulting solid was isolated by filtration and dried in vacuo to give the desired product as a colorless solid (244 mg, 79%).

[0365] 1 H NMR(500MHz,DMSO-d6)δ7.50(br d,J=7.0Hz,2H),7.44-7.27(m,10H),6.72-6.64(m,1H),6.21(br d,J=2.7Hz,1H),5.29(s,2H),5.05(s,2H),4.44-4.26(m,1H),3.83-3.70(m,4H),3.10-2.98(m,2H),1.67-1.55(m,2H),1.39(s,9H).

[0366] LC-MS (Method A): R T =3.74min,m / z=653.5[MH] - .

[0367] Step B: Benzyl 3-[1-(2-aminoacetyl)-4-piperidinyl]-1-[benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0368] Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[1-[2-(tert-butoxycarbonylamino)acetyl]-4-piperidinyl]pyrrole-2-carboxylate (244 mg, 0.37 mmol) was dissolved in 4M HCl in 1,4-dioxane (1.86 mL) and the reaction was stirred at room temperature for 2 hours. Ether (20 mL) was added to form a colorless solid which was isolated by filtration and freed on an SCX-2 cartridge eluting with ammonia in methanol to give the desired product as a colorless solid (180 mg, 87%).

[0369] 1H NMR (500MHz, DMSO-d6) δ8.03(br s,3H),7.50(br d,J=6.9Hz,2H),7.44-7.28(m,10H),6.18(d,J=3.1Hz,1H),5.30(s,2H),5.06(s,2H),4.38(br d,J=13.1Hz,1H),3.95-3.76(m,2H),3.69(br d,J=13.5Hz,1H),3.09(tt,J=12.0,3.5Hz,1H),2.83(br t,J=12.1Hz,1H),2.41-2.39(m,1H),1.66(br d, J=13.0Hz, 2H), 1.51 (dq, J=12.6, 3.8Hz, 1H), 1.35-1.28 (m, 1H). 1 H NMR is of the hydrochloride salt after which the material was passed through an SCX-2 cartridge.

[0370] LC-MS (Method A): R T =2.84min,m / z=553.4[MH] - .

[0371] Intermediate 15: 4-[2-Benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]cyclohex-3-ene-1-carboxylic acid

[0372]

[0373] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-(4-ethoxycarbonylcyclohexen-1-yl)pyrrole-2-carboxylate

[0374] A solution of tripotassium phosphate (891 mg, 4.20 mmol) in water (2 mL) was added to XPhos Pd G2 (55.0 mg, 69.9 μmol), sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrol-1-yl)sulfonyl-amide (690 mg, 1.40 mmol) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (470 mg, 1.68 mmol) in 1,4-dioxane (10 ml). The reaction mixture was heated to 50 ° C and stirred for 6 hours under nitrogen. The mixture was cooled to room temperature and the resulting layers were separated. The organic layer was diluted with brine (30 mL) and the aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% ethyl acetate in petroleum ether) to give the desired product (170 mg, 21%). A second crop of product was obtained from repurification of mixed fractions (220 mg, 28%).

[0375] 1 H NMR (500MHz, DMSO-d6) δ7.49-7.47(m,2H),7.35-7.24(m,8H),7.12(d,J=3.1Hz,1H),5.99(d,J=3.1Hz,1H),5.65(br s,1H),5.14(d,J=3.7Hz,2H),4.84(s,2H),4.07(q,J=7.0Hz,2H),2.45-2.38(m,1H ),2.21-2.13(m,4H),1.93-1.84(m,1H),1.59-1.51(m,1H),1.19(t,J=7.0Hz,3H).

[0376] LC-MS (Method A): R T =4.11min,m / z=565.6[MH] - .

[0377] Step B: 4-[2-Benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]cyclohex-3-ene-1-carboxylic acid

[0378] Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-(4-ethoxycarbonylcyclohexen-1-yl)pyrrole-2-carboxylate (220 mg, 0.39 mmol) was dissolved in a mixture of ethanol (2 mL) and water (2 mL) and lithium hydroxide monohydrate (41 mg, 0.97 mmol) was then added. Stirring was continued overnight at room temperature and then additional lithium hydroxide monohydrate (41 mg, 0.97 mmol) was added. After stirring for an additional 24 hours, a third portion of lithium hydroxide monohydrate (41 mg, 0.97 mmol) was added. After an additional 6 hours, the reaction was diluted with water and ethyl acetate and then separated. The aqueous layer was acidified with 2M aqueous HCl (10 mL) and then extracted with ethyl acetate (3×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as an orange gum (210 mg, 100%).

[0379] 1 H NMR (500MHz, DMSO-d6) δ7.47-7.28(m,11H),6.20(br s,1H),5.66(br d,J=1.7Hz,1H),5.23(br s,2H),5.06(br s,2H),2.34-2.25(m,1H),2.21-2.05(m,4H),1.91-1.81(m,1H),1.53-1.42(m,1H).

[0380] LC-MS (Method A): R T =3.34min, m / z=537.5[M–H] - .

[0381] Intermediate 16: Benzyl 3-(4-aminocyclohexen-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, hydrochloride

[0382]

[0383] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[4-(tert-butyloxycarbonylamino)cyclohexen-1-yl]pyrrole-2-carboxylate

[0384] To a solution of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrol-1-yl)sulfonyl-amide (2.75 g, 5.57 mmol) and tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-yl]carbamate (2.16 g, 6.69 mmol) in 1,4-dioxane (30 mL) under argon was added XPhos Pd G2 (219 mg, 279 μmol), followed by tripotassium phosphate (3.55 g, 16.7 mmol) and water (6 ml). The reaction mixture was stirred at 50° C. for 90 minutes, then diluted with saturated aqueous ammonium chloride solution (50 mL) and water (50 mL), and extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography (0-100% ethyl acetate in petroleum ether) to give the desired product as a cream solid (2.49 g, 73%).

[0385] 1 H NMR (500MHz, CDCl3) δ7.42(d,J=3.1Hz,1H),7.21(br d,J=6.1Hz,3H),7.17-7.05(m,8H),5.76(br s,1H),5.23(br s,1H),5.03-4.90(m,2H),4.87(s,2H),4.41-4.27(m,1H),3.55(br s,1H),2.13-1.86(m,4H),1.77-1.54(m,1H),1.45(s,9H),1.20-1.10(m,1H).

[0386] LC-MS (Method A): R T =3.96min,m / z=608.6[MH] - .

[0387] Step B: Benzyl 3-(4-aminocyclohexen-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, hydrochloride

[0388] A solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[4-(tert-butoxycarbonylamino)cyclohexen-1-yl]pyrrole-2-carboxylate (2.49 g, 4.08 mmol) in 4M HCl in 1,4-dioxane (30.6 mL) was stirred for 1 hour at 20° C. The reaction mixture was concentrated to dryness and azeotroped with petroleum ether and then diethyl ether to give the desired product as a cream solid (2.33 g, quantitative yield).

[0389] 1H NMR(500MHz,DMSO-d6)δ8.20(br s,3H),7.46-7.28(m,11H),6.22(br d,J=2.7Hz,1H),5.60(br s,1H),5.32-5.18(m,2H),5.05(s,2H),3.07(br s,1H),2.45-2.29(m,1H),2.21(br s,2H),2.18-2.03(m,1H),1.91(br d,J=10.1Hz,1H),1.65-1.53(m,1H).

[0390] LC-MS (Method A): R T =2.83min,m / z=508.5[MH] - .

[0391] Intermediate 17: Benzyl N-[3-(3a,7a-dihydrobenzotriazol-1-yl)-3-oxopropyl]carbamate

[0392]

[0393] Thionyl chloride (0.98mL, 13.4mmol) was added dropwise to a solution of benzotriazole (6.00g, 50.4mmol) in anhydrous THF (50mL) and stirred at room temperature under nitrogen for 30 minutes. 3-(Benzyloxycarbonylamino)propionic acid (2.5g, 11.2mmol) was added to the reaction mixture in batches and stirred vigorously for 3 hours. The obtained solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was absorbed in ethyl acetate (40mL) and washed with 2M HCl aqueous solution (2×20mL), saturated sodium carbonate aqueous solution (2×20mL), and brine (10mL). The remaining organic layer was dried over NaSO4, filtered and concentrated under reduced pressure to obtain the desired product as a white solid (3.42g, 94%). The product can be used in subsequent steps without further purification.

[0394] Intermediate 18: tert-Butyl N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]amino]ethyl]carbamate

[0395]

[0396] A stirred solution of tert-butyl N-[2-[(5-bromo-2-pyridyl)amino]ethyl]carbamate (1.50 g, 4.74 mmol), bis(pinacolato)diboron (1.57 g, 6.17 mmol), Pd(dppf)Cl2 (174 mg, 237 μmol) and potassium acetate (931 mg, 9.49 mmol) in 1,4-dioxane (30 mL) was degassed and heated at 90 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was suspended in ether (40 mL) and filtered to remove the solid. The filtrate was collected, washed with saturated aqueous sodium bicarbonate solution (2×30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was taken up in a minimum volume of DCM and then an excess of petroleum ether was added. The resulting saturated solution was filtered and the collected filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (50-100% ethyl acetate in petroleum ether) to give the desired product as a yellow gum (630 mg, 37%).

[0397] 1 H NMR (500MHz, DMSO-d6) δ8.21(d,J=0.9Hz,1H),7.03(dd,J=8.3,1.5Hz,1H),6.91(br t,J=4.8Hz,1H),6.86(br t,J=5.3Hz,1H),6.41(d,J=8.3Hz,1H),3.30(td,J=6.9,4.8Hz,2H),3.08(td,J=6.6,5.3Hz,2H),1.38(s,9H),1.26(s,12H).

[0398] LC-MS (Method B): R T =3.30min, m / z=364.3[M+H] + .

[0399] Example 1 (free acid): 3-[3-(methylcarbamoyl)phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0400]

[0401] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[3-(methylsulfamoyl)phenyl]pyrrole-2-carboxylate

[0402] To a solution of 1-(benzyloxycarbonylsulfamoyl)-3-bromo-pyrrole-2-carboxylic acid benzyl ester (513 mg, 1.04 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2)-dioxaborolan-2-yl)benzamide (272 mg, 1.04 mmol) in 1,4-dioxane (20 mL) was added XPhos Pd G2 (82 mg, 104 μmol) followed by a solution of tripotassium phosphate (662 mg, 3.12 mmol) in water (6 mL) and the reaction mixture was heated to 45°C for 2 hours. The reaction mixture was diluted with water (100 mL), 2M aqueous HCl (20 mL) and brine (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by column chromatography (0-100% ethyl acetate in petroleum ether) gave the desired product as a light yellow solid (230 mg, 40%).

[0403] 1 H NMR (500MHz, DMSO-d6) δ8.46(m,1H),7.85(s,1H),7.74(d,J=8.0Hz,1H),7.46(d,J=3.0Hz,1H),7.43(d,J=8.0Hz,1H),7.37(d,J=8. 0Hz,1H),7.36-7.32(m,5H),7.28-7.23(m,3H),7.20(m,2H),6.45(d,J=3.0Hz,1H),5.17(s,2H),5.06(s,2H),2.79(d,J=4.5Hz,3H).

[0404] LC-MS (Method B): R T =2.29min,m / z=546.6[MH] - .

[0405] Step B: 3-[3-(Methylcarbamoyl)phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0406] 10% palladium on carbon (20 mg, 197 μmol) was added to a methanol (20 mL) solution of 1-(benzyloxycarbonylsulfamoyl)-3-[3-(methylcarbamoyl)phenyl]pyrrole-2-carboxylic acid benzyl ester (223 mg, 407 μmol) and stirred for 90 minutes under a hydrogen atmosphere. The reaction mixture was filtered through a celite pad and eluted with methanol (150 mL). The solvent was removed in vacuo and purified by column chromatography (0-100% methanol in ethyl acetate) and triturated with ether to obtain the desired product as a white solid (60 mg, 41%).

[0407] 1 H NMR(500MHz,DMSO-d6)δ8.62(br s,1H),8.42(br d,J=4.5Hz,1H),7.89(s,1H),7.69(d,J=7.5Hz,1H),7.63(d,J=7.5Hz,1H),7. 40(t,J=7.5Hz,1H),7.27(m,1H),6.33(d,J=3.0Hz,1H),2.78(d,J=4.5Hz,3H).

[0408] LC-MS (Method A): R T =2.24min,m / z=322.4[MH] - .

[0409] Example 2 (free acid): 3-[4-(dimethylcarbamoyl)phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0410]

[0411] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[4-(dimethylcarbamoyl)phenyl]pyrrole-2-carboxylate

[0412] HBTU (101 mg, 267 μmol) was added to a solution of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (119 mg, 223 μmol), 2M dimethylamine in THF (134 μL) and DIPEA (116 μL, 668 μmol) in DCM (20 mL) and the reaction was stirred at room temperature overnight. The reaction was quenched by adding water (100 mL) and extracted into DCM (2×100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent removed in vacuo. Purification by column chromatography (0-100% ethyl acetate in petroleum ether followed by 0-100% methanol in ethyl acetate) gave the desired product as a white solid (74 mg, 59%).

[0413] 1 H NMR (500MHz, CDCl3) δ7.39-7.36 (m, 4H), 7.33-7.27 (m, 11H), 6.28 (d, J = 3.0Hz, 1H), 5.15 (s, 2H), 4.86 (s, 2H), 2.89 (br s, 3H), 2.93 (br s, 3H).

[0414] LC-MS (Method B): R T =2.28min,m / z=560.5[MH] - .

[0415] Step B: 3-[4-(Dimethylcarbamoyl)phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0416] 10% palladium on carbon (7 mg, 64 μmol) was added to a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[4-(dimethylcarbamoyl)phenyl]pyrrole-2-carboxylate (74 mg, 132 μmol) in methanol (20 mL) and stirred at room temperature for 90 minutes under 1 atm of hydrogen. The reaction mixture was stirred by Filter through a pad of Celite® and elute with methanol (150 mL). Removal of the solvent in vacuo and purification by column chromatography (0-100% methanol in ethyl acetate) followed by trituration with diethyl ether gave the desired product as a white solid (20 mg, 45%).

[0417] 1 H NMR (500MHz, DMSO-d6) δ8.33(br s,2H),7.61(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),7.10(d,J=3.0Hz,1H),6.27(d,J=3.0Hz,1H),2.98(br s,6H).

[0418] LC-MS (Method A): R T =2.34min,m / z=336.4[MH] - .

[0419] Other embodiments

[0420] The following examples were prepared in a similar manner to 3-[4-(dimethylcarbamoyl)phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (Intermediate 2).

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433] *Amide coupling step was performed using DMF as solvent. **Amide coupling was performed using a benzyl protected carboxylic acid. ***The hydrochloride salt was formed prior to hydrogenation. The hydrogenation step was performed by adding a solution of ammonia in methanol to ensure solubility.

[0434] Example 25 (free acid): 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0435]

[0436] Step A: Benzyl 3-[4-[2-[Benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0437] To a stirred suspension of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (19.1 g, 35.7 mmol) in DCM (150 mL) was added DIPEA (31.1 mL, 179 mmol) followed by HBTU (14.9 g, 39.3 mmol) followed by benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate, hydrochloride (10.2 g, 39.3 mmol). After 1 hour, the reaction mixture was concentrated, redissolved in ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (3×200 mL), followed by 2M aqueous HCl (3×200 mL) and brine (200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The residue was re-concentrated from a mixture of DCM / petroleum ether to give the desired product as a creamy foamy solid (28.0 g, quantitative yield).

[0438] LC-MS (Method A): R T =3.49min,m / z=737.8[MH] - .

[0439] Step B: 3-[4-[Methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0440] To a stirred solution of 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester (26 g, 35.2 mmol) in methanol (250 mL) was added 7 M ammonia in methanol (10 mL) followed by 10% palladium on carbon (3.75 g, 1.76 mmol). The vessel was purged of air and placed under a hydrogen atmosphere. After 1 hour, the reaction mixture was stirred by Filtered and concentrated to a white solid. The crude material from two such experiments was combined and purified in 5 g portions by column chromatography (ethyl acetate:methanol, gradient elution from 50:50 to 0:100 and held at 0:100 until the product eluted), slurried in diethyl ether (100 mL), isolated by filtration and sucked dry under a stream of nitrogen to give the desired product as a white solid (14.0 g, 52% average yield for two reactions).

[0441] 1 H NMR (500MHz, DMSO-d6) δ8.82(br s,4H),7.52(br d,J=5.5Hz,2H),7.33(br d,J=7.9Hz,2H),7.10(d,J=3.1Hz,1H),6.26(d,J=3.4Hz,1H),3.69(br s,2H),3.21-2.54(m,8H).

[0442] LC-MS (Method C): R T =4.43min,m / z=379.4[MH] - .

[0443] Example 25 (Sodium Salt) 3-[4-[Methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, sodium salt

[0444] To a suspension of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (200 mg, 0.53 mmol) in a mixture of ethanol (1 mL) and water (0.5 mL) was added 25% w / w aqueous sodium hydroxide solution (84 μL, 0.53 mmol) and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure and azeotroped with ethanol (2×5 mL). The residue was slurried in ethanol (2 mL) for 30 minutes, the solid was isolated by filtration, washed with ether (5 mL) and sucked dry to give the desired sodium salt as an off-white solid (132 mg, 56%).

[0445] 1H NMR(500MHz,DMSO-d6)δ7.61(d,J=7.3Hz,2H),7.29(d,J=7.6Hz,2H),7.02(s, 1H),6.22(s,1H),3.65-3.40(m,2H),2.97(s,3H),2.80-2.58(m,2H),2.24(br d,J=78.4Hz,3H).

[0446] LC-MS (Method C): R T =4.64min,m / z=379.4[MH] - .

[0447] Other embodiments

[0448] The following example was prepared in a manner similar to 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (Example 25).

[0449]

[0450]

[0451]

[0452]

[0453] *The free carboxylic acid was introduced using benzyl protection. Since the starting materials have sufficient methanol solubility, the hydrogenation step is carried out in the absence of ammonia.

[0454] Example 32 (free acid): 3-[4-[2-(methylamino)ethylcarbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0455]

[0456] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[4-[2-[tert-butyloxycarbonyl(ethyl)amino]ethylcarbamoyl]phenyl]pyrrole-2-carboxylate

[0457] HBTU (228 mg, 0.60 mmol) was added to a solution of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (268 mg, 0.50 mmol), N-(2-aminoethyl)-N-ethyl-carbamic acid tert-butyl ester (104 mg, 0.55 mmol) and DIPEA (262 μL, 1.50 mmol) in DCM (20 mL) and the reaction was stirred at room temperature overnight. The reaction was quenched by the addition of water (100 mL) and extracted into DCM (2×100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent removed in vacuo. Purification by column chromatography (0-100% ethyl acetate in petroleum ether, then 0-100% methanol in ethyl acetate) followed by trituration in ether gave the desired product as a white solid (200 mg, 57%).

[0458] 1 H NMR (500 MHz, DMSO-d6) δ 8.50 (br d, J = 21.4 Hz, 1H), 7.76 (br s, 2H), 7.41-7.37 (m, 4H), 7.34-7.26 (m, 9H), 6.31 (d, J = 3.0 Hz, 1H), 5.16 (s, 2H), 4.88 (s, 2H), 3.43-3.26 (m, 4H), 3.26-3.17 (m, 2H), 1.42-1.32 (m, 9H), 1.08-1.01 (m, 3H). The peak corresponding to 2H is obscured by the water peak.

[0459] LC-MS (Method B): R T =2.64min,m / z=703.8[MH] - .

[0460] Step B: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[4-[2-(ethylamino)ethylcarbamoyl]phenyl]pyrrole-2-carboxylate

[0461] 4M HCl in 1,4-dioxane (10 mL) was added to a suspension of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[4-[2-[tert-butyloxycarbonyl(ethyl)amino]ethylcarbamoyl]phenyl]pyrrole-2-carboxylate (200 mg, 0.28 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and freed on an SCX-2 cartridge, eluting with ammonia in methanol to give the desired product as a white solid (60 mg, 35%).

[0462] LC-MS (Method A): R T =2.96min,m / z=603.6[MH]- .

[0463] Step C: 3-[4-[2-(Ethylamino)ethylcarbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0464] 10% palladium on carbon (5 mg) was added to a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[4-[2-(ethylamino)ethylcarbamoyl]phenyl]pyrrole-2-carboxylate (60 mg, 99 μmol) in a mixture of methanol (20 mL) and 1 M ammonia in methanol (20 mL), and the reaction mixture was stirred under a hydrogen atmosphere for 90 minutes. The reaction mixture was stirred by The solvent was removed in vacuo and the residue was purified by column chromatography (30-100% methanol in ethyl acetate) followed by trituration with diethyl ether to give the desired product as a white solid (23 mg, 58%).

[0465] 1 H NMR(500MHz,DMSO-d6)δ9.17(br s,1H),8.38(br s,2H),7.84(d,J=8.5Hz,2H),7.63(d,J=8.5Hz,2H),7.11(d,J=3.0Hz,1H),6.29(d,J=3.0Hz ,1H),3.57-3.48(m,2H),3.00(t,J=6.0Hz,2H),2.87(q,J=7.0Hz,2H),1.12(t,J=7.0Hz,3H).

[0466] LC-MS (Method A): R T =1.99min,m / z=379.4[MH] - .

[0467] Other embodiments

[0468] The following example was prepared in a manner similar to 3-[4-(2-ethylamino)ethylcarbamoyl)phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (Example 32).

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482] *Amide coupling step was performed using DMF as solvent. The hydrogenation step is carried out in the absence of ammonia. TFA was used instead of HCl in the Boc deprotection step. No conversion to free base was achieved by passage through the SCX-2 cartridge.

[0483] Example 54 (free acid): 1-sulfamoyl-3-[4-(3-sulfoxypropylcarbamoyl)phenyl]pyrrole-2-carboxylic acid

[0484]

[0485] Sulfur trioxide pyridine complex (48 mg, 299 μmol) was added to a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[4-(3-hydroxypropylcarbamoyl)phenyl]pyrrole-2-carboxylate (57 mg, 97 μmol) in pyridine (5 mL) and the reaction mixture was heated to 60°C for 3 hours. The solvent was concentrated in vacuo, DCM (50 mL) and water (50 mL) were added and the phases were separated. The organic phase was washed with water (50 mL) and tetrabutylammonium hydrogen sulfate (36 mg, 107 μmol) was added to the combined aqueous phases. The aqueous phase was extracted with DCM (2×75 mL), the organic phase was washed with brine (75 mL), dried over MgSO4, filtered and the solvent was removed in vacuo. The resulting residue was dissolved in methanol (25 mL) and 10% palladium on carbon (6 mg, 56 μmol) was added and then hydrogenated under a hydrogen atmosphere for 3 hours. The reaction mixture was passed through Filter through a pad of Celite® and elute with methanol (150 mL). Removal of the solvent in vacuo and purification by column chromatography (0-100% methanol in ethyl acetate) gave the desired product as a white solid (18 mg, 41%).

[0486] 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (br s, 2H), 8.40 (t, J = 6.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.12-7.07 (m, 1H), 6.30 (d, J = 3.0 Hz, 1H), 3.80 (t, J = 6.5 Hz, 2H), 3.44-3.23 (m, 2H), 1.77 (quin, J = 6.5 Hz, 2H). The peak at 3.44-3.23 ppm is blocked by the residual water peak.

[0487] LC-MS (Method A): R T =2.28min,m / z=446.3[MH] - .

[0488] Example 55 (Hydrochloride) 3-[3-Piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, hydrochloride

[0489]

[0490] To a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[3-piperidinyl]pyrrole-2-carboxylate, hydrochloride (186 mg, 375 μmol) in methanol (10 mL) was added 10% palladium on carbon (40 mg, 18.7 μmol) and the resulting suspension was stirred under 1 atm of hydrogen at room temperature for 5 hours. The reaction mixture was stirred by Filtration, concentration to dryness under reduced pressure, slurrying in ether and drying under reduced pressure gave the desired product as a white solid (87 mg, 85%).

[0491] 1 H NMR(500MHz,DMSO-d6)δ13.41(br s,1H),9.09(br s,1H),8.99(br s,1H),8.19(br s,2H),7.40(d,J=3.1Hz,1H),6.31(d,J=3.4Hz,1H),3.60(tt,J=12.2,3.4Hz,1H),3.28-3.21(m,2H),2.95(br t,J=10.2Hz,1H),2.85(br t,J=12.1Hz,1H),1.89-1.81(m,2H),1.79-1.68(m,1H),1.66-1.56(m,1H).

[0492] LC-MS (Method C): R T =0.97min,m / z=272.3[MH] - .

[0493] Other embodiments

[0494] The following examples were prepared in a manner analogous to 3-[3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, hydrochloride (Example 55).

[0495]

[0496] Example 58 (free acid): 3-[1-acetyl-3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0497]

[0498] Step A: Benzyl 3-(1-acetyl-3-piperidinyl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0499] A mixture of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[3-piperidinyl]pyrrole-2-carboxylate, hydrochloride (466 mg, 0.94 mmol) and triethylamine (300 μL, 2.15 mmol) in DCM (5 mL) was cooled to 0 °C and then acetyl chloride (68 μL, 1.12 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The residue was washed with water (2×5 mL), brine (5 mL), dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:methanol, gradient elution from 100:0 to 90:10), redissolved in ethyl acetate (10 mL), washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over NaSO4, filtered and concentrated to dryness under reduced pressure to give the desired product as an off-white solid (262 mg, 52%).

[0500] 1 H NMR (500 MHz, DMSO-d6) δ 7.53-7.45 (m, 3H), 7.44-7.34 (m, 8H), 6.34 (br s, 1H), 5.41-5.29 (m, 2H), 5.11 (d, J = 7.9 Hz, 2H), 4.40 (br d, J = 12.5 Hz, 1H), 3.86-3.68 (m, 1H), 3.09-2.89 (m, 2H), 2.65-2.45 (m, 1H), 2.06 (s, 1.4H), 1.89 (s, 1.6H), 1.86-1.75 (m, 1H), 1.72-1.51 (m, 2H), 1.35-1.17 (m, 2H). Complex spectra were observed due to rotational restraint.

[0501] LC-MS (Method A): R T=3.37min,m / z=540.3[M+H] + .

[0502] Step B: 3-[1-Acetyl-3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0503] 10% palladium on carbon (52 mg, 24 μmol) was added to a solution of benzyl 3-(1-acetyl-3-piperidinyl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (262 mg, 0.49 mmol) in methanol (10 mL) and the resulting suspension was stirred under 1 atmosphere of hydrogen at room temperature for 6 hours. The reaction mixture was stirred by Filtration, concentration to dryness under reduced pressure, slurrying in ether and drying under reduced pressure gave the desired product as a white solid (125 mg, 82%).

[0504] 1 H NMR(500MHz,DMSO-d6)δ8.34(br s,2H),7.37-7.29(m,1H),6.29-6.21(m,1H),4.48-4.31(m,1H),3.92-3.77(m,1H),3.29-3.19( m,1H),3.06-2.83(m,1H),2.60-2.44(m,1H),2.02(s,3H),1.91-1.82(m,1H),1.77-1.28(m,3H).

[0505] LC-MS (Method C): R T =5.78min,m / z=314.4[MH] - .

[0506] Other embodiments

[0507] The following example was prepared in a manner similar to 3-[1-acetyl-3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (Example 58).

[0508]

[0509]

[0510]

[0511] Example 63 (free acid): 3-[1-(2-aminoacetyl)-3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0512]

[0513] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[1-[2-(tert-butyloxycarbonylamino)acetyl]-3-piperidinyl]pyrrole-2-carboxylate

[0514] To a solution of N-(tert-butoxycarbonyl)glycine (194 mg, 1.11 mmol) in DCM (5 mL) was added DIPEA (875 μL, 5.02 mmol) followed by HBTU (419 mg, 1.11 mmol). After stirring at room temperature for 5 minutes, 1-(benzyloxycarbonylsulfamoyl)-3-[3-piperidinyl]pyrrole-2-carboxylic acid benzyl ester, hydrochloride (500 mg, 1.00 mmol) was added and then stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (2×10 mL), 2M HCl aqueous solution (2×10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate, gradient elution from 90:10 to 0:100) to give the desired product as an off-white solid (427 mg, 65%).

[0515] 1 H NMR (500MHz, CDCl3) δ7.50 (t, J = 3.6Hz, 1H), 7.42-7.27 (m, 10H), 6.13 (br s,1H),5.65-5.41(m,1H),5.40-5.21(m,2H),5.20-5.07(m,2H),4.65-4.51(m,1H),3.9 2(brd,J=3.7Hz,1H),3.84-3.56(m,2H),3.20-3.04(m,1H),2.98-2.82(m,1H),2.54(br t,J=12.4Hz,1H),1.98-1.85(m,1H),1.75-1.64(m,1H),1.48(s,4.5H),

[0516] 1.45 (s, 4.5H), 1.37-1.05 (m, 2H). Complex splitting was observed due to restrained rotation.

[0517] LC-MS (Method A): R T =3.80min,m / z=653.7[MH] - .

[0518] Step B: Benzyl 3-[1-(2-aminoacetyl)-3-piperidinyl]-1-[benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0519] A solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[1-[2-(tert-butoxycarbonylamino)acetyl]-3-piperidinyl]pyrrole-2-carboxylate (504 mg, 770 μmol) in 4M HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure and freed on an SCX-2 cartridge, eluting with ammonia in methanol to give the desired product as an off-white solid (320 mg, 75%).

[0520] 1 H NMR(500MHz,DMSO-d6)δ7.73(br s,3H),7.61-7.50(m,2H),7.36-7.23(m,9H),6.05(dd,J=8.9,3.1Hz,1H),5.29-5.14(m,2H),4.84(s,2H),4.38(br d,J=12.2Hz,1H),3.95-3.74(m,2H),3.67(br t,J=11.7Hz,1H),3.07-2.91(m,1H),

[0521] 2.89-2.79 (m, 1H), 2.71-2.61 (m, 1H), 1.90-1.77 (m, 1H), 1.76-1.51 (m, 2H), 1.48-1.21 (m, 1H). Complex splitting was observed due to restrained rotation.

[0522] LC-MS (Method A): R T =2.85min,m / z=555.4[M+H] + .

[0523] Step C: 3-[1-(2-aminoacetyl)-3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0524] To a solution of benzyl 3-[1-(2-aminoacetyl)-3-piperidinyl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (320 mg, 577 μmol) in a mixture of methanol (9 mL) and 7M methanol (1 mL) solution was added 10% palladium on carbon (61 mg, 29 μmol) and the resulting suspension was stirred under 1 atm of hydrogen at room temperature for 6 hours. The reaction mixture was stirred by Filtration, concentration to dryness under reduced pressure, slurrying in ether and drying under reduced pressure gave the desired product as a white solid (125 mg, 66%).

[0525] 1H NMR (500 MHz, DMSO-d6) δ 9.06 (br s, 2H), 8.29 (br s, 3H), 7.09-6.99 (m, 1H), 6.10-6.03 (m, 1H), 4.46-4.29 (m, 2H), 4.00-3.89 (m, 1H), 3.86-3.77 (m, 1H), 3.35-3.27 (m, 1H), 2.70 (dd, J = 12.7, 11.4 Hz, 1H), 2.66-2.58 (m, 1H), 1.89-1.69 (m, 3H), 1.45-1.33 (m, 1H). Complex splitting was observed due to rotational restraint. Peaks were resolved at 80 °C.

[0526] LC-MS (Method C): R T =4.52min,m / z=329.4[MH] - .

[0527] Other embodiments

[0528] The following example was prepared in a manner similar to 3-[1-(2-aminoacetyl)-3-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (Example 63).

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] *Amide coupling was performed with Cbz protected amino acids followed by hydrogenation using Pd(OH)2 / C catalyst.

[0542] Example 83 (free acid): 3-[1-(2-guanidinoacetyl)-4-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0543]

[0544] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl-3-yl)-3-[1-(2-guanidinoacetyl)-4-piperidinyl]pyrrole-2-carboxylate

[0545] 3-[1-(2-aminoacetyl)-4-piperidinyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester (180mg, 0.32mmol) was suspended in acetonitrile (5mL), and DIPEA (282μL, 1.62mmol) was then added. After stirring for 10 minutes, N,N'-di-Boc-1H-pyrazole-1-carboxamidine (101mg, 0.32mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with 1M HCl aqueous solution (20mL) and the precipitated solid was separated by filtration. It was dissolved in a solution of 4M HCl in 1,4-dioxane (972μL) and stirred at room temperature for 2 hours. Ether (20mL) was added to form a colorless solid, which was separated by filtration. Freed on an SCX-2 cartridge, eluted with methanolic ammonia and concentrated in vacuo to give the desired product as a colourless solid (60 mg, 31%).

[0546] 1 H NMR(500MHz,DMSO-d6)δ7.60(d,J=3Hz,1H),7.30-7.20(m,10H),7.17-6.99(m,2H),5.95(d,J=3.1Hz,1H),5.20(s ,2H),4.84(s,2H),4.45-4.37(m,1H),4.16-3.98(m,3H),3.71-3.64(m,1H),3.05-2.85(m,2H),1.72-1.31(m,4H).

[0547] LC-MS (Method A): R T =3.05min, m / z=595.4[M–H] - .

[0548] Step B: 3-[1-(2-guanidinoacetyl)-4-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0549] 10% palladium on carbon (11 mg, 5.0 μmol) was added to a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[1-(2-guanidinoacetyl)-4-piperidinyl]pyrrole-2-carboxylate (60 mg, 0.10 mmol) in 1,4-dioxane (5 mL) and stirred under 1 atmosphere of hydrogen for 5 hours. The reaction mixture was stirred by The pad was filtered and washed with methanol (20 mL). The combined filtrates were concentrated under reduced pressure and azeotroped with diethyl ether (2 x 5 mL) to give the desired product as a colorless solid (38 mg, 87%).

[0550] 1 H NMR (500MHz, DMSO-d6) δ9.64-9.01(br,1H),7.61-7.06(br,6H),6.99(d,J=3.1Hz,1H),5.97(d,J=3.1Hz,1H),4.47(br d,J=11.1Hz,1H),4.17-4.02(m,2H),3.78-3.61(m,2H),3.58-3.46(m,1H), 3.10-3.00(m,1H),1.82-1.70(m,2H),1.59-1.45(m,1H),1.42-1.30(m,1H).

[0551] LC-MS (Method A): R T =1.66min,m / z=371.3[MH] - .

[0552] Example 84 (free acid): 1-sulfamoyl-3-[1-[2-(2,2,2-trifluoroethylamino)acetyl]-4-piperidinyl]pyrrole-2-carboxylic acid

[0553]

[0554] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[1-[2-(2,2,2-trifluoroethylamino)acetyl]-4-piperidinyl]pyrrole-2-carboxylate

[0555] 2,2,2-Trifluoroethyl trifluoromethanesulfonate (20 μL, 0.14 mmol) was added to a solution of benzyl 3-[1-(2-aminoacetyl)-4-piperidinyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (85 mg, 144 μmol) in a mixture of THF (0.5 mL) and DMF (0.5 mL) and stirred at room temperature for 2 hours. Triethylamine (60 uL, 0.43 mmol) was added to the reaction mixture and stirred at room temperature for 48 hours. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (20 μL, 0.14 mmol) was added to the reaction mixture and stirred for another 90 minutes. The reaction mixture was quenched with water (10 mL) and extracted into ethyl acetate (3×10 mL). The combined extracts were washed with 50:50 water:brine (2 x 10 mL), dried over NaSO4, filtered, concentrated under reduced pressure and purified by column chromatography (40-100% ethyl acetate in petroleum ether) to give the desired product as a white solid (22 mg, 24%).

[0556] LC-MS (Method A): RT = 3.50 min, m / z = 635.7 [M–H] - .

[0557] Step B: 1-sulfamoyl-3-[1-[2-(2,2,2-trifluoroethylamino)acetyl]-4-piperidinyl]pyrrole-2-carboxylic acid

[0558] 10% palladium on carbon (7.4 mg, 3.5 μmol) was added to a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[1-(2,2,2-trifluoroethylamino)acetyl]-4-piperidinyl]pyrrole-2-carboxylate (22 mg, 0.35 mmol) in methanol (1 mL) and stirred under 1 atmosphere of hydrogen for 3 hours. The reaction mixture was stirred by Filter through a pad of Celite®, wash with methanol (20 mL), collect the filtrate, concentrate under reduced pressure and azeotropize with diethyl ether (2 x 5 mL) to give the desired product as a white solid (11 mg, 69%).

[0559] 1 H NMR(500MHz,DMSO-d6)δ9.48(br s,2H),6.96(br s,1H),5.96(br s,1H),4.49-4.44(m,1H),3.78-3.73(m,1H),3.65-3.58(m,1H),3.54-3.44(m,3H),3.00-2.93(m,1H),1.75-1.69(2H),1.47-1.24(m,5H).

[0560] 19F NMR(470MHz,DMSO-d6)δ-70.77(s,3F).

[0561] LC-MS (Method A): R T =2.16min,m / z=411.4[MH] - .

[0562] Example 85 (free acid): 3-[1-(2-aminoethyl)-4-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0563]

[0564] Step A: Benzyl 3-[1-[2-Benzyloxycarbonylamino)ethyl]-4-piperidinyl]-1-[benzyloxycarbonylsulfamoyl]pyrrole-2-carboxylate

[0565] Triethylamine (78 μL, 562 μmol) was added to a solution of 1-(benzyloxycarbonylsulfamoyl)-3-(4-piperidinyl)pyrrole-2-carboxylic acid benzyl ester, hydrochloride (100 mg, 187 μmol) and (2-bromoethyl) benzyl carbamate (48 mg, 187 μmol) in DMF (2 mL). The reaction was stirred overnight at 50 ° C, then quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted into ethyl acetate (3 × 5 mL). The combined organic layer was dried with Na2SO4, filtered, concentrated in vacuo and purified by column chromatography (0-100% ethyl acetate in petroleum ether) to obtain the desired product (30 mg, 24%).

[0566] 1 H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.59-7.51(m,2H),7.42-7.24(m,13H),5.76(s,1H),5.20(s,2H),5.06(s,2H),4.84(s,2H),3.61(br t,J=6.2Hz,1H),1.89-1.65(m,4H),1.24(s,8H).

[0567] LC-MS (Method A): R T =3.42min,m / z=673.8[MH] - .

[0568] Step B: 3-[1-(2-aminoethyl)-4-piperidinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0569] 10% palladium on carbon (2.2 mg, 2.1 μmol) was added to a solution of benzyl 3-[1-[2-(benzyloxycarbonylamino)ethyl]-4-piperidinyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (30 mg, 42 μmol) in methanol (2 mL) and stirred under 1 atm of hydrogen for 5 hours. The reaction mixture was stirred by The product was filtered through a pad of 4% paraformaldehyde, washed with 1 M ammonia in methanol (20 mL), and the filtrate was collected and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% 1 M Nh3 / methanol in ethyl acetate) to give the desired product as 3 / methanol in ethyl acetate) to give the desired product as an off-white solid (4 mg, 24%).

[0570] 1 H NMR(500MHz, Methanol-d4)δ7.02(d,J=3.4Hz,1H),5.97(d,J=3.2Hz,1H),2.89-2.81(m,4H),2 .49-2.43(m,1H),2.13-2.05(m,2H),1.86-1.77(m,2H),1.66-1.53(m,2H),0.84-0.73(m,2H).

[0571] LC-MS (Method A): R T =0.41min, m / z=315.4[MH] - .

[0572] Example 86 (free acid): 3-(4-carboxycyclohexyl)-1-sulfamoyl-pyrrole-2-carboxylic acid

[0573]

[0574] 10% palladium on carbon (24 mg, 11 μmol) was added to a solution of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]cyclohex-3-ene-1-carboxylic acid (30 mg, 56 μmol) in methanol (5 mL), and the mixture was stirred under 1 atm of hydrogen at room temperature overnight. The mixture was diluted with methanol and then The volatiles were removed in vacuo and the residue was triturated with ether and dried in vacuo to give the desired product as an off-white solid (17 mg, 82%).

[0575] 1H NMR(500MHz,DMSO-d6)δ13.66-12.76(br,1H),12.72-11.84(br,1H),8.25-7.90(m,2H),7.32(br s,1H),6.11(d,J=2.9Hz,1H),3.20-3.04(m,1H),2.17-2.04(m,2H),2.03-1.91(m,1H),1.69-1.60(m,2H),1.58-1.34(m,4H).

[0576] LC-MS (Method A): R T =2.39min,m / z=315.3[MH] - .

[0577] Example 87 (free acid): 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]cyclohexyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0578]

[0579] Step A: 3-[4-[2-[Benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]cyclohexyl-1-yl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester

[0580] To a stirred suspension of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]cyclohex-3-ene-1-carboxylic acid (90 mg, 167 μmol) in DCM (5 mL) was added DIPEA (146 μL, 0.84 mmol). HBTU (70 mg, 184 μmol) was added followed a few minutes later by the addition of benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate, hydrochloride (48 mg, 184 μmol). The reaction was stirred at room temperature for 2 hours and then concentrated, diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate solution (3×10 mL) and then with 2M aqueous HCl solution (10 mL). The organic phase was then dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as an off-white solid (121 mg, 97%).

[0581] 1H NMR (500 MHz, DMSO-d6) δ 7.45-7.21 (m, 16H), 6.23 (br s, 1H), 5.70 (br s, 1H), 5.24 (s, 2H), 5.10-4.98 (m, 4H), 3.70-3.30 (m, 6H), 3.00-2.74 (m, 6H), 2.25-2.04 (m, 3H), 2.03-1.89 (m, 1H), 1.69-1.55 (m, 1H), 1.54-1.32 (m, 1H). The peak at 3.70-3.30 ppm was obscured by residual water.

[0582] LC-MS (Method A): R T =3.72min, m / z=743.6[M+H] + .

[0583] Step B: 3-[4-[Methyl-[2-(methylamino)ethyl]carbamoyl]cyclohexyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0584] 10% palladium on carbon (69 mg, 33 μmol) was added to a solution of 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]cyclohexen-1-yl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester (121 mg, 163 μmol) in methanol (5 mL). The mixture was stirred at room temperature under 1 atmosphere of hydrogen for 3 hours. The reaction mixture was then diluted with methanol and passed through Filter and wash with 1M ammonia in methanol. The combined filtrates were concentrated in vacuo, redissolved in 0.2M ammonia in methanol, and an additional portion of 10% palladium on carbon (35 mg, 16 μmol) was added. The reaction was stirred at room temperature under 1 atmosphere of hydrogen overnight, then diluted with methanol and washed with Filter and wash with 1 M ammonia in methanol.Remove volatiles in vacuo to give the desired product as a colorless solid (45 mg, 68%).

[0585] 1 H NMR (500 MHz, DMSO-d6) δ 6.94 (t, J = 3.0 Hz, 1H), 5.98 (d, J = 3.1 Hz, 0.8H), 5.95 (s, 0.2H), 3.01 (br d, J = 13.1 Hz, 3H), 2.80 (br d, J = 6.0 Hz, 3H), 2.33-2.25 (m, 4H), 2.22-2.11 (m, 2H), 1.82-1.63 (m, 6H), 1.57-1.48 (m, 2H). A mixture of cis and trans isomers was observed.

[0586] LC-MS (Method A): RT =2.15min,m / z=385.5[MH] - &R T =2.03min,m / z=

[0587] 385.5[MH] - .

[0588] Example 88 (hydrochloride salt): 3-(4-aminocyclohexyl)-1-sulfamoyl-pyrrole-2-carboxylic acid, hydrochloride

[0589]

[0590] To a solution of benzyl 3-(4-aminocyclohexen-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, hydrochloride (150 mg, 275 μmol) in methanol (15 mL) was added 10% palladium on carbon (17 mg, 162 μmol) and stirred at room temperature under 1 atm of hydrogen for 24 hours. The reaction mixture was filtered, washed with methanol and the filtrate was concentrated to dryness. The solid was triturated with diethyl ether and the solvent was decanted twice to give the desired product as a light tan solid (82 mg, 87%).

[0591] 1 H NMR (500 MHz, DMSO-d6) δ 13.20 (br s, 1H), 8.32-8.05 (br m, 5H), 7.36 (m, 1H), 6.50 (d, J = 3.1 Hz, 0.5H), 6.23 (d, J = 3.1 Hz, 0.5H), 3.75-3.43 (m, 1H), 3.17-3.06 (br m, 1H), 2.04-1.40 (m, 8H). A mixture of cis and trans isomers was observed.

[0592] LC-MS (Method A): R T =0.42min,m / z=286.4[MH] - .

[0593] Example 89 (free acid): 3-(4-acetylaminocyclohexyl)-1-sulfamoyl-pyrrole-2-carboxylic acid

[0594]

[0595] Step A: Benzyl 3-(4-acetamidocyclohexen-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0596] A mixture of HBTU (153 mg, 403 μmol), DIPEA (320 μL, 1.83 mmol) and acetic acid (23 μL, 403 μmol) in DCM (10 mL) was stirred at 20° C. for 5 minutes, then 3-(4-aminocyclohexene-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester, hydrochloride (200 mg, 366 μmol) was added and stirred for another 3 hours. The reaction mixture was concentrated to dryness, redissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution (50 mL), 1M HCl aqueous solution (50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography (0-100% ethyl acetate in petroleum ether) to give the desired product as a white solid (132 mg, 65%).

[0597] 1 H NMR (500MHz, CDCl3) δ7.49-7.36(m,1H),7.30(m,8H),7.28-7.22(m,3H),6. 05-5.97(m,1H),5.55-5.47(m,2H),5.29-5.13(m,2H),5.08(s,2H),4.02(br s,1H),2.32-2.09(m,3H),2.00-1.93(m,3H),1.85-1.75(m,1H),1.71-1.55(m,1H),1.52-1.35(m,1H).

[0598] LC-MS (Method A): R T =3.24min,m / z=552.3[M+H] + .

[0599] Step B: 3-(4-Acetylaminocyclohexyl)-1-sulfamoyl-pyrrole-2-carboxylic acid

[0600] To a solution of benzyl 3-(4-acetylaminocyclohexen-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (132 mg, 239 μmol) in methanol (15 mL) was added 10% palladium on carbon (15 mg, 141 μmol) and stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered, washed with methanol and concentrated to dryness. The residue was triturated with diethyl ether and the solvent was decanted twice to give the desired product as a tan solid (43 mg, 52%).

[0601] 1H NMR (500 MHz, DMSO-d6) δ 8.47 (br s, 2H), 7.85-7.73 (m, 1H), 7.30-7.19 (m, 1H), 6.25-6.10 (m, 1H), 3.61-3.30 (m, 2H), 1.92-1.17 (m, 11H). A mixture of cis and trans isomers was observed.

[0602] LC-MS (Method A): R T =2.23min,m / z=328.4[MH] - .

[0603] Example 90 (free acid): 3-[4-[(2-aminoacetyl)amino]cyclohexyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (mixture of stereoisomers)

[0604]

[0605] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[4-[[2-(tert-butoxycarbonylamino)acetyl]amino]cyclohexen-1-yl]pyrrole-2-carboxylate

[0606] A mixture of N-(tert-butyloxycarbonyl)glycine (71 mg, 403 μmol), HBTU (71 mg, 403 μmol) and DIPEA (320 μL, 1.83 mmol) in DCM (10 mL) was stirred at room temperature for 5 minutes, then 3-(4-aminocyclohexene-1-yl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester, hydrochloride (200 mg, 366 μmol) was added and stirred for another 20 hours. The reaction mixture was concentrated to dryness, redissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution (50 mL), 1M HCl aqueous solution (50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and purified by column chromatography (0-100% ethyl acetate in petroleum ether) to give the desired product as a white solid (196 mg, 80%).

[0607] 1H NMR (500MHz, DMSO-d6) δ7.64(br d,J=7.5Hz,1H),7.46-7.29(m,11H),7.25(d,J=3.1Hz,1H),6.87(br t,J=5.3Hz,1H),6.18(d,J=3.1Hz,1H),5.61(br s,1H),5.25-5.19(m,2H),5.01(s,2H),3.75(br s,1H),3.52(br d,J=5.0Hz,2H),2.25-2.14(m,3H),1.96-1.85(m,1H),1.70(br d,J=9.3Hz,1H),1.45(m,1H),1.35(s,9H).

[0608] LC-MS (Method A): R T =3.52min,m / z=667.5[M+H] + .

[0609] Step B: Benzyl 3-[4-[(2-aminoacetyl)amino]cyclohexen-1-yl]-1-[benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate

[0610] A solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[4-[[2-(tert-butoxycarbonylamino)acetyl]amino]cyclohexen-1-yl]pyrrole-2-carboxylate (196 mg, 294 μmol) in 4M HCl in dioxane (10 mL) was stirred at room temperature for 90 minutes. The reaction mixture was concentrated to dryness and run on an SCX-2 cartridge, eluting with ammonia in methanol to give the desired product as a cream solid (127 mg, 76%).

[0611] 1 H NMR (500MHz, DMSO-d6) δ8.21(d,J=7.5Hz,1H),7.50(br d,J=6.9Hz,4H),7.46-7.26(m,9H),7.13(d,J=3.1Hz,1H),6.02(d,J=3.1Hz,1H),5.63(br s,1H),5.15(d,J=1.8Hz,2H),4.84(s,2H),3.87-3.77(m,1H),3.48(s,2H), 2.33-2.17(m,3H),2.03-1.86(m,1H),1.85-1.67(m,1H),1.56-1.38(m,1H).

[0612] LC-MS (Method A): R T =2.85min,m / z=567.4[M+H]+ .

[0613] Step C: 3-[4-[(2-aminoacetyl)amino]cyclohexyl]-1-sulfamoyl-pyrrole-2-carboxylic acid

[0614] To a solution of benzyl 3-[4-[(2-aminoacetyl)amino]cyclohexen-1-yl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (127 mg, 224 μmol) in methanol (15 mL) with a few drops of 7M ammonia in methanol was added 10% palladium on carbon (14 mg, 132 μmol) and stirred under hydrogen atmosphere at room temperature for 3 days. The reaction mixture was filtered, washed with methanol and concentrated to dryness. The residue was triturated with diethyl ether and the solvent was decanted twice to give the desired product as a tan solid (1.42 mg, 2%).

[0615] 1 H NMR (500 MHz, DMSO-d6) δ 8.81-8.02 (br m, 5H), 7.08-6.95 (m, 1H), 6.08-6.02 (m, 1H), 4.02-3.52 (m, 4H), 1.98-1.19 (m, 8H). A mixture of cis and trans isomers was observed.

[0616] LC-MS (Method A): R T =1.60min,m / z=343.4[MH] - &R T =1.77min,m / z=

[0617] 343.4[MH] - .

[0618] Example 91 (free acid) & Example 92 (free acid): 3-[4-[(2-aminoacetyl)amino]cyclohexyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (isolated stereoisomers)

[0619]

[0620] 3-[4-[(2-Aminoacetyl)amino]cyclohexyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (60 mg, 174 μmol) was separated using preparative HPLC (Method A, 0.60-0.80 min). Each product fraction was passed through an SCX-2 column eluting with ammonia in methanol to give Isomer 1 as a white solid (6.4 mg, 9%), and Isomer 2 as a white solid (8.9 mg, 14%).

[0621] Isomer 1: 1H NMR(500MHz,DMSO-d6)δ8.37-7.83(br m,5H),6.93-6.88(m,1H),6.05(d,J=3.4Hz,1H),4.07-3.99(m,1H),3.56(s,2H),3.49-3.40(m,1H),1.75-1.50(m,8H).

[0622] LC-MS (Method A): R T =1.68min,m / z=343.4[MH] - .

[0623] Isomer 2: 1 H NMR(500MHz,DMSO-d6)δ8.91-8.00(br m,5H),7.05-7.00(m,1H),6.05(d,J=3.1Hz,1H),3.65-3.58(m,3H),3.42-3.37(m,1H),1.92-1.81(m,2H),1.77(br d,J=11.6Hz,2H),1.44-1.27(m,4H).

[0624] LC-MS (Method A): R T =1.73min,m / z=343.4[MH] - .

[0625] Example 93 (Sodium Salt) 3-[6-[(2-aminoacetyl)amino]3-pyridinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, sodium salt

[0626]

[0627] Step A: Benzyl 3-(6-amino-3-pyridinyl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, sodium salt

[0628] A mixture of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromopyrrol-1-yl)sulfonyl-amide (2.00 g, 4.05 mmol), 6-aminopyridine-3-boronic acid (726 mg, 5.26 mmol) and sodium carbonate (1.29 g, 12.2 mmol) in a mixture of 1,4-dioxane (20 mL) and water (10 mL) was degassed by bubbling nitrogen for 15 minutes, then Pd(dppf)Cl2 (296 mg, 0.40 mmol) was added. The resulting mixture was heated to reflux under nitrogen for 1 hour, then cooled to room temperature, diluted with water (30 mL) and extracted into ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol, gradient elution from 100:0 to 80:20) followed by column chromatography (ethyl acetate:methanol:1M ammonia in methanol, gradient elution from 100:0:0 to 80:20:0 to 80:0:30) and then slurried in diethyl ether to give the desired product as a tan solid (685 mg, 33%).

[0629] 1 H NMR(500MHz,DMSO-d6)δ7.95(dd,J=2.7,0.6Hz,1H),7.40-7.45(m,3H),7.25-7.35(m,9H),6.44-6.48(m,1H),6.19(br d, J=2.7Hz, 2H), 6.15 (d, J=3.2Hz, 1H), 5.13 (s, 2H), 4.86 (s, 2H).

[0630] LC-MS (Method A): RT = 2.71 min, m / z = 506.9 [M+H] + .

[0631] Step B: Benzyl 3-[6-[[2-(Benzyloxycarbonylamino)acetyl]amino]-3-pyridinyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, sodium salt

[0632] A solution of 3-(6-amino-3-pyridyl)-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylic acid benzyl ester sodium salt (200 mg, 378 μmol) and N-[2-(benzotriazole-1-yl)-2-oxo-ethyl] benzyl carbamate (176 mg, 567 μmol) in THF (3 mL) was heated to 70 ° C for 2 hours under microwave irradiation. Additional N-[2-(benzotriazole-1-yl)-2-oxo-ethyl] benzyl carbamate (176 mg, 567 μmol) was added to the reaction mixture and irradiated for another 1 hour at 70 ° C. The reaction mixture was quenched with water (10 mL) and extracted into ethyl acetate (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether, gradient elution from 10:90 to 100:0) to give the desired product as a white solid (112 mg, 43%).

[0633] 1 H NMR (500MHz, DMSO-d6) δ10.49(s,1H),8.31(d,J=1.8Hz,1H),7.97(br d,J=8.3Hz,1H),7.70(dd,J=8.3,2.1Hz,1H),7.56(br t,J=6.1Hz,1H),7.40-7.37(m,5H),7.35-7.25(m,11H),6.28(d,J=3.1Hz,1H),5.15(s,2H),5.07(s,2H),4.87(s,2H),3.89(brd,J=6.1Hz,2H).

[0634] LC-MS (Method B): R T =2.45min,m / z=698.4[M+H] + .

[0635] Step C: 3-[6-[(2-aminoacetyl)amino]3-pyridinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, sodium salt

[0636] 10% palladium on carbon (24 mg, 11 μmol) was added to a solution of benzyl 3-[6-[[2-(benzyloxycarbonylamino)acetyl]amino]-3-pyridyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate sodium salt (77 mg, 110 μmol) in a mixture of 7M ammonia in methanol (0.3 mL) and methanol (2 mL), and stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was stirred by Filter through a pad of Celite®, washing with methanol (2 x 10 mL) and then with 7M ammonia in methanol (10 mL). The combined filtrates were concentrated under reduced pressure, slurried with ether (3 x 5 mL) and dried under reduced pressure to give the desired product as a white solid (20 mg, 45%).

[0637] 1 H NMR(500MHz,Methanol-d4)δ8.34(d,J=2.1Hz,1H),8.00(br s, 1H), 7.84 (dd, J = 8.5, 2.4Hz, 1H), 7.11 (d, J = 3.2Hz, 1H), 6.18 (d, J = 3.2Hz, 1H), 3.41-3.38 (m, 2H).

[0638] LC-MS (Method A): R T =1.01min,m / z=338.3[MH] - .

[0639] Other embodiments

[0640] The following example was prepared in a manner similar to 3-[6-[(2-aminoacetyl)amino]-3-pyridinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid sodium salt (Example 93).

[0641]

[0642]

[0643] Example 95 (hydrochloride salt): 3-[6-(2-aminoethylamino)-3-pyridinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, hydrochloride

[0644]

[0645] Step A: Benzyl 1-(Benzyloxycarbonylsulfamoyl)-3-[6-[2-(tert-butoxycarbonylamino)ethylamino]-3-pyridinyl]pyrrole-2-carboxylate

[0646] To a solution of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrol-1-yl)sulfonylamide (200 mg, 387 μmol) and tert-butyl N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2-pyridyl]amino]ethyl]carbamate (211 mg, 465 μmol) in 1,4-dioxane (3.2 mL) was added XPhos Pd G2 (31 mg, 39 μmol) followed by a solution of tripotassium phosphate (329 mg, 1.6 mmol) in water (1.0 mL). The vial was degassed and then heated to 45 ° C for 2 hours under microwave irradiation. The reaction mixture was diluted with water (10 mL) and extracted into ethyl acetate (3×10 mL). The organic extract was washed with 2M aqueous HCl (2×20 mL), brine (20 mL), dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: petroleum ether: methanol, gradient elution from 30:70:0 to 100:0:0 and then 80:0:20) to give the desired product as a white solid (146 mg, 58%).

[0647] 1 H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.44-7.42(m,3H),7.34-7.26(m,10H),6.88(br t,J=4.7Hz,1H),6.47(br s,1H),6.15(d,J=1.7Hz,1H),5.13(s,2H),4.85(s,2H),3.31-3.27(m,2H),3.13-3.08(m,2H),1.38(s,9H).

[0648] LC-MS (Method B): R T =2.41min,m / z=648.5[MH] - .

[0649] Step B: Benzyl 3-[6-(2-aminoethylamino)-3-pyridinyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, hydrochloride

[0650] A 4M solution of HCl in 1,4-dioxane (0.5 mL) was added to a solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-[6-[2-(tert-butoxycarbonylamino)ethylamino]-3-pyridinyl]pyrrole-2-carboxylate (146 mg, 225 μmol) in dichloromethane (0.5 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (5 mL), concentrated under reduced pressure and azeotroped with dichloromethane (3×5 mL) to give the desired product as an off-white solid (141 mg, quantitative yield).

[0651] 1 H NMR(500MHz,DMSO-d6)δ8.07-8.03(m,4H),7.83(br s,1H),7.44-7.40(m,3H),7.35-7.28(m,9H),6.94(br s,1H),6.33(d,J=3.1Hz,1H),5.19(s,2H),4.93(s,2H),3.64-3.60(m,2H),3.09-3.04(m,2H).

[0652] LC-MS (Method A): R T =2.50min,m / z=548.4[MH] - .

[0653] Step C: 3-[6-(2-aminoethylamino)-3-pyridinyl]-1-sulfamoyl-pyrrole-2-carboxylic acid, hydrochloride

[0654] 10% palladium on carbon (18 mg, 8.5 μmol) was added to a solution of benzyl 3-[6-(2-aminoethylamino)-3-pyridyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate, hydrochloride (50 mg, 85 μmol) in methanol (2 mL) and the reaction mixture was stirred under 1 atm of hydrogen for 1 hour. The reaction mixture was stirred by The pad was filtered and washed with methanol (2 x 10 mL) and then with 7M ammonia in methanol (10 mL). The combined washings were concentrated under reduced pressure, slurried with ether (3 x 5 mL) and dried under reduced pressure to give the desired product as a yellow solid (13 mg, 34%).

[0655] 1 H NMR (500MHz, DMSO-d6) δ13.24(br s,1H),8.18(br s,2H),8.06(s,1H),7.98(brs,2H),7.47(br d,J=2.1Hz,1H),6.37(br s,1H),3.60-3.56(m,2H),3.06-3.01(m,2H).

[0656] LC-MS (Method A): R T =0.53min,m / z=324.3[MH] - .

[0657] Biological Example 1

[0658] The compounds of the invention were tested in a metallo-β-lactamase inhibition assay to investigate the mechanism of action of the compounds. Results are reported as 50% inhibition of enzyme activity (IC 50 ) The desired test article concentration. IC of the compound 50 The values ​​are consistent with potent and specific inhibition of the metallo-β-lactamases tested.

[0659] Inhibition of metallo-β-lactamase function was performed at 37°C in pH 7.5 buffer (50 mM HEPES, 150 mM NaCl, 0.1 mM ZnSO4, 20 μg / mL PEG4000) containing 1.5 nM NDM-1, 100 μM nitrocellulose and a series of compound concentrations. The absorbance at 490 nm was measured every 30 minutes using a BMG LABTECH FLUOstar Omega microplate reader. IC was determined from the mean increase in OD per minute vs. Log10 concentration of compound using GraphPad Prism. 50 The data are provided in Table 1 below.

[0660] Table 1

[0661]

[0662]

[0663] MICs were determined by exposing bacteria to serial dilutions of the antimicrobial agent in MHB-II (cation-adjusted Mueller-Hinton Broth pH 7.4) according to the Clinical and Laboratory Standards Institute (CLSI) liquid-based microdilution guidelines (Cockerill et al., 2012).

[0664] Combined MICs were performed as described in the MIC assay, with 4 mg / L of the test article added to MHB-II.

[0665] At 2 × 10 per well 5 Cytotoxicity was assessed in human Hep G2 cells (ATCC HB-8065) ​​seeded at a density of 100 μg / mL and incubated at 37°C with 5% CO2 for 24 h. Cells were exposed to a two-fold dilution series of the test article. After 24 h of exposure, the cells were diluted with (Promega, WI, USA), and the viability of the cells was determined according to the manufacturer's instructions. The results were reported as a 50% reduction in cell viability (CC 50 ) desired test article concentration.

[0666] The following literature references provide additional information on assay methods for evaluating compounds of the invention, and the disclosure of these documents in relation to these methods is expressly incorporated herein. For the avoidance of doubt, it is intended that the disclosure of the methods in each of those documents specifically constitutes a part of the teaching and disclosure of the present invention. The last two references below provide methods for establishing and demonstrating the presence of synergy, and thus the procedures described therein can be used to demonstrate synergistic activity between compounds of the invention and carbapenems (e.g., meropenem).

[0667] COCKERILL,FR,WICKLER,MA,ALDER,J.,DUDLAY,MN,ELIOPOULOS,GM,FERRARO,MJ,HARDY,DJANDHECHT,DW,HINDLER,JA,P ATEL,JB,POWEL,M.,SWENSON,JM,THOMPRON,JB,TRACZEWSKI,MM,TURNIDGE,JA,WEINSTEIN,MP,&ZIMMER,BL2012.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically(M07-A9).Wayne:Clinical and LaboratoryStandards Institute.

[0668] PILLAI, SK, MOELLERING, RC, & ELIOPOULOS, GM 2005. Antimicrobial combinations. In: Antibiotics in Laboratory Medicine. Philadelphia: Lippincott Williams and Wilkins, pp. 365–440.

[0669] BURKHART, CG, BURKHART, CN, &ISHAM, N. 2006. Synergistic AntimicrobialActivity by Combining an Allylamine with Benzoyl Peroxide with ExpandedCoverage against Yeast and Bacterial Species. British Journal of Dermatology 154(2):341-344.

[0670] Biological Example 2

[0671] Compounds of the present invention were tested and shown to significantly improve the activity of meropenem, as shown in the table below. All compounds tested significantly improved the activity of meropenem against a variety of different bacterial strains relative to a baseline study using meropenem alone. Some of the compounds tested increased the MIC of meropenem by more than 10 or 20 times compared to meropenem alone. Even the least active compounds had activity that increased the MIC of meropenem by at least 4 times compared to meropenem alone. When used in combination with meropenem, the compound is effective against a variety of different bacteria.

[0672] The compounds of the invention were tested against the major bacterial strain group in column IV of Table 2. Where appropriate, compounds considered suitable for further study were tested against the minor bacterial strain groups in columns VI and VII of Table 2.

[0673] Table 2: Meropenem combination MIC (μg / mL)

[0674]

[0675]

[0676]

[0677]

[0678]

[0679] Table Notes. The following letters in Table 2 above represent MIC (minimum inhibitory concentration) values ​​in μg / ml: A≤0.1, B≤1, C≤5, D≤10, E≤40, and F≤80.

[0680] Biological Example 3

[0681] The compounds were also tested for cytotoxicity. The data in Table 3 below show that the compounds tested did not exhibit any significant cytotoxic activity.

[0682] Table 3: Cytotoxicity assay

[0683]

[0684]

[0685] Biological Example 4

[0686] The solubility study of the compound was also tested. Each sample (2 mg) was weighed into a transparent 1.75 mL vial and then saline (40 mL, to reach 50 mg / mL) was added. Unless otherwise indicated, the compound was tested as a free base. Each mixture obtained was vortexed (if necessary) and visually determined to determine the solubility of each mixture.

[0687]

[0688]

[0689] Biological Example 5

[0690] The compounds were also tested for off-target inhibition in the Cerep SafetyScreen44 Panel. The data in Table 4 below show that of the four compounds tested, two compounds did not have ≥50% inhibition on any of the 44 targets, while the other two compounds had ≥50% inhibition on two of the 44 targets.

[0691] Table 5: Off-target inhibition

[0692]

Claims

1. A compound, which is 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid: or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is a pharmaceutically acceptable salt.

3. The compound according to claim 2, wherein the pharmaceutically acceptable salt is a base salt.

4. The compound of claim 3, wherein the base salt is selected from the group consisting of aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

5. A compound according to any preceding claim, wherein the pharmaceutically acceptable salt is a sodium salt.

6. The compound according to claim 1, wherein the compound is 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid.

7. A pharmaceutical composition comprising a compound according to any preceding claim, together with one or more pharmaceutically acceptable excipients.

8. The composition according to claim 7, wherein the composition further comprises a β-lactam antibiotic, optionally wherein the β-lactam antibiotic is a carbapenem selected from the group comprising meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem / betamipron and biapenem, azupenem, tebipenem, lenapenem and tomopenem, further optionally wherein the β-lactam antibiotic is meropenem.

9. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for inhibiting the activity of metallo-β-lactamase.

10. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of a disease or condition involving metallo-β-lactamase activity.

11. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for treating a disease or condition caused by aerobic or anaerobic Gram-positive bacteria or aerobic or anaerobic Gram-negative bacteria.

12. The use according to claim 11, wherein the disease or condition is caused by a Gram-positive bacterium producing a metallo-β-lactamase.

13. The use according to claim 11, wherein the disease or condition is caused by a gram-negative bacterium producing a metallo-β-lactamase.

14. The use according to claim 11, wherein the disease or condition is selected from the group consisting of pneumonia, respiratory tract infection, urinary tract infection, intra-abdominal infection, skin and soft tissue infection, bloodstream infection, sepsis, intrapartum and postpartum infection, prosthetic joint infection, endocarditis, acute bacterial meningitis and febrile neutropenia.

15. The use according to claim 14, wherein the disease or condition is selected from the group consisting of community-acquired pneumonia, nosocomial pneumonia, respiratory tract infection associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infection, skin and soft tissue infection, bacteremia, sepsis, intrapartum and postpartum infection, prosthetic joint infection, endocarditis, acute bacterial meningitis and febrile neutropenia.

16. The use according to claim 15, wherein the disease or condition is selected from the group consisting of community acquired pneumonia, nosocomial pneumonia, respiratory tract infection associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infection, skin and soft tissue infection, bacteremia and sepsis.

17. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for the treatment of bacterial infections.

18. Use of a compound according to any one of claims 1 to 6 in combination with a β-lactam antibiotic in the preparation of a medicament for treating bacterial infection.

19. The use according to claim 18, wherein the compound and the β-lactam antibacterial agent are present in the same dosage form.

20. The use according to claim 18, wherein the β-lactam antibacterial agent is a carbapenem, preferably, the carbapenem is selected from the group consisting of meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem / betamipron and biapenem, azupenem, tebipenem, lenapenem and tomopenem.

21. The use according to claim 20, wherein the β-lactam antibacterial agent is meropenem.

22. The method of claim 18, wherein the bacterial infection is caused by a bacterium from one or more of the following families: Streptococcus, Acinetobacter, Staphylococcus, Clostridium, Pseudomonas, Escherichia coli, Salmonella, Klebsiella, Legionella, Neisseria, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Mycobacterium, Morganella, Yersinia, Pasteurella, Haemophilus, Citrobacter, Burkholderia, Brucella or Moraxella.

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