Synthesis of pyrrolic acid derivatives

Abstract

The present invention relates to the synthesis of compounds that can be used to treat bacterial infections in combination with other antibacterial agents, more particularly in combination with the class of antibacterial agents known as carbapenems. The compounds obtained from the novel methods of the present invention are enzyme inhibitors, more particularly metallo-beta-lactamase inhibitors.

Description

[Technical Field]

[0001] The present invention relates to the synthesis of compounds that can be used in combination with other antibacterial agents, more particularly in combination with the class of antibacterial agents known as carbapenems, to treat bacterial infections. The compounds obtained by the novel methods of the present invention are enzyme inhibitors, more particularly metallo-beta-lactamase inhibitors. [Background technology]

[0002] Each year across Europe, over 4 million people suffer from healthcare-associated bacterial infections, resulting in approximately 37,000 deaths (Public Health England). The prevalence of multidrug-resistant bacteria is worsening patient outcomes, lengthening hospital stays, and necessitating the use of potentially toxic antimicrobial drugs and "last resort" treatments, such as colistin and polymyxin B. Antibiotic-resistant bacteria kill more than 10 million people each year, representing an economic burden of US$100 trillion.

[0003] In clinical practice, antibiotic-resistant Gram-negative pathogens 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 organisms are limited, and empirical antibiotic therapy often fails in patients infected with Gram-negative bacteria of the ESKAPE pathogen group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).

[0004] In February 2017, the World Health Organization (WHO) issued a priority list of pathogenic bacteria to help member states focus research and development efforts on areas of greatest need. Among these bacteria, WHO classified the following Gram-negative bacteria as key priorities: carbapenem-resistant Acinetobacter baumannii; carbapenem-resistant Pseudomonas aeruginosa; and carbapenem-resistant and ESBL-producing Enterobacteriaceae (including K. pneumoniae and E. coli). Consequently, carbapenem-resistant Gram-negative bacteria have been defined as a significant unmet medical need. The mechanism of action of β-lactams, such as carbapenems, involves covalent binding to the active sites of transpeptidases that link the peptidoglycan chains of the bacterial cell wall. This inhibits cell wall synthesis and ultimately leads to cell death. The advantage of carbapenems is that they have a broader spectrum of activity compared with most other β-lactams, and until recently their use has not been significantly affected by the development of resistance.

[0005] The use of carbapenems as a last line of defense against multidrug-resistant Gram-negative bacteria has been compromised by the emergence of carbapenemases from the metallo-β-lactamase (MBL) class. These enzymes bind to carbapenems and cleave the β-lactam ring, inactivating the antibiotic. The Ambler classification system divides known β-lactamase enzymes into four classes according to their amino acid sequence. Class A, C, and D β-lactamases cleave β-lactams by transiently binding a serine group within the enzyme's active site to the carbonyl of the β-lactam ring. This forms an acyl-enzyme and cleaves the β-lactam ring. Subsequently, an activated water molecule deacylates the acyl-enzyme intermediate, hydrolyzing the bond between the serine and the carbonyl to release the inactivated β-lactam. MBLs are mechanistically and structurally distinct from class A, C, and D serine-β-lactamases. In this case, β-lactam cleavage occurs in a single step without the formation of a covalent intermediate. MBLs place water molecules and zinc ions at His, Cys, and Asp residues in their active site, where the water molecules facilitate nucleophilic attack and bond cleavage within the β-lactam ring. MBL subclasses are structurally distinct; B1 and B3 enzymes contain two zinc ions in the active site and exhibit a broad substrate profile. Group B2 enzymes rely on a single zinc ion and hydrolyze only carbapenems. Clinically, B1 class MBLs, including NDM, VIM, and IMP, are the most common and are frequently identified within mobile genetic elements.

[0006] Existing serine-β-lactamase inhibitors (effective against Ambler class A, C, and some class D β-lactamases) have been successful in restoring the activity of many β-lactams. The inhibitors bind transiently or permanently with high affinity to the enzyme's active site, effectively outcompeting β-lactam binding. Commercially available 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 clinically available, demonstrating the commercial potential of broad-spectrum MBLIs that restore the activity of carbapenems.

[0007] The first carbapenem used clinically was imipenem for the treatment of complicated microbial infections. A drawback of imipenem is its hydrolysis in mammalian kidneys by dehydropeptidase I (DHPI), necessitating co-formulation with the dehydropeptidase inhibitor cilastatin. Subsequent carbapenem iterations, including meropenem, are immune to DHPI hydrolysis due to the presence of a methyl group at the 1-β position of the carbapenem moiety. While less potent than imipenem against Gram-positive pathogens, meropenem has enhanced efficacy against Gram-negative bacteria and is widely used clinically. To combat resistance to carbapenems, we have discovered a series of compounds that inhibit metallo-β-lactamase enzymes. When co-administered with meropenem, these compounds significantly improve the efficacy of meropenem against drug-resistant bacteria. The present invention particularly relates to methods for preparing these compounds.

[0008] It is believed that other approved carbapenems may also benefit from co-formulation with the compounds of the invention. Other currently approved carbapenems include ertapenem, doripenem, panipenem, biapenem, and tebipenem.

[0009] Until relatively recently, bacterial infections were one of the most common causes of death, disfigurement, and disability. The development of a series of antibiotic classes in the 19th century 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 important challenges facing human health. In fact, multidrug resistance is already common in some bacterial pathogens.

[0010] The greatest unmet medical need is the lack of effective treatments for multidrug-resistant Gram-negative bacteria. Therefore, the discovery of new antibiotics effective against WHO-listed pathogens or agents that circumvent existing bacterial resistance mechanisms is essential.

[0011] WO2019 / 220125 and GB1916915.0 (unpublished) disclose a series of compounds that are inhibitors of metallo-β-lactamases used in combination with antibacterial agents to treat bacterial infections.

[0012] It is an object of certain embodiments of the present invention to provide an alternative method for synthesizing metallo-beta-lactamase inhibitors that is more scalable, provides a purer product, or is more resource-efficient than previously disclosed methods. Summary of the Invention

[0013] In each of the following aspects of the invention, the compounds of formula (I) through formula (XIX) may be the free acid or free base as depicted, or may be a pharmaceutically acceptable salt thereof.

[0014] In a first aspect of the present invention, there is provided a method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) reacting a compound of formula (I) with a compound of formula (II) in the presence of Pd / C to form a compound of formula (III): [ka] and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (III): [ka] [In the formula, X is independently Cl, Br, I, N2 + , or OSO2CF3; R 1 is H or C 1-4 alkyl; R 2 is a protecting group; R 3 is independently selected from -CH2-aryl, or tert-butyl; Each R 4 independently for each occurrence, C 1-4 is alkyl; R 8a is BF3K, or B(OR 9a )2, where R 9a For each occurrence, H or C 1-4 alkyl; or two R 9a The substituents, taken together, form (CR a R b ) n or two R 9a The substituents taken together form -C(O)-(CR a R b )-N(R c )-(CR a R b )-C(O)-; R a , R b and R c independently for each occurrence, H, and C 1-4 alkyl; n is 2 or 3; and A is H or a cation. A method is provided, comprising:

[0015] In certain embodiments, step (b) of the first aspect comprises: (i) reacting a compound of formula (III) with a compound of formula (V) to form a compound of formula (VI): [ka] and (ii) from a compound of formula (VI), R 2 , R 3 and R 5 to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 5 is a protecting group. may include:

[0016] In certain embodiments, a compound of formula (I) can be prepared by reacting a compound of formula (VII) with a compound of formula (VIII) to form a compound of formula (I): [ka] [In the formula, R 6 are independently F, Cl, Br, I, or [ka] Selected from.] is formed by

[0017] In a second aspect of the present invention, there is provided a method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) reacting a compound of formula (I) with a compound of formula (IX) to form a compound of formula (X): [ka] and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (X): [ka] [In the formula, X is independently selected from Cl, Br, I, or OS(O)2CF3; R 1 are independently H or C 1-4 alkyl; R 2 is a protecting group; R 3 is independently selected from -CH2-aryl, or tert-butyl; Each R 4 independently for each occurrence, C 1-6 is alkyl; R 5 is a protecting group; R 7 are independently -OR 7a , or -N(R 4 )CH2CH2NR 4 R 5 Selected from; R 7a -C 1-6 alkyl, and -CH2-aryl; R 8b independently, BF3K, or B(OR 9b )2, where each R 9b is H or C 1-4 alkyl; or two R 9b The substituents, taken together, form (CR a R b ) n or two R 9a The substituents taken together form -C(O)-(CR a R b )-N(R c )-(CR a R b )-C(O)-; R a , R b and R cindependently for each occurrence, H, and C 1-4 alkyl; n is 2 or 3; and A is independently selected from H or a cation. A method is provided, comprising:

[0018] In certain embodiments of the second aspect, R 7 -OR 7a and Step (b) is (i) from the compound of formula (Xa), R 7a cleaving the substituent to form a compound of formula (III): [ka] and (ii) reacting a compound of formula (III) with a compound of formula (V) to form a compound of formula (VI): [ka] and (iii) from the compound of formula (VI), R 2 , R 3 and R 5 to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] may include:

[0019] In another embodiment of the second aspect, R 7 is -N(R 4 )CH2CH2NR 4 R 5 (i.e., the compound of formula (X) is a compound of formula (VI)), Step (b) is the preparation of a compound of formula (VI) by the reaction of R 2 , R 3 and R 5 to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] may include:

[0020] The reaction may be as described above for the first aspect of the invention. Thus, in certain embodiments, R 2 , R 3 and R 5 The substituent is cleaved by catalytic hydrogenation, for example as described for the first aspect of the invention.

[0021] In a further embodiment, the method of preparation comprises the steps of reacting a compound of formula (XI) with a compound of formula (V) to form a compound of formula (XII) (an illustrative example of a compound of formula (IX)): [ka] may include:

[0022] The compound of formula (XII) can then be reacted with a compound of formula (I).

[0023] Compounds of formula (I) may be prepared as described above for the first aspect of the invention.

[0024] In a third aspect of the present invention, there is provided a method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) reacting a compound of formula (XIII) with a compound of formula (XIV) to form a compound of formula (XV): [ka] and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (XV): [ka] [In the formula, R 1are independently H or C 1-4 alkyl; R 3 is independently selected from -CH2-aryl, or tert-butyl; Each R 4 independently for each occurrence, C 1-6 is alkyl; R 7 are independently -OR 7a , and -N(R 4 )CH2CH2NR 4 R 5 selected from; and R 7a is C 1-6 alkyl, or CH2-aryl. A method is provided, comprising:

[0025] In certain embodiments of the third aspect, R 7 is -N(R 4 )CH2CH2NR 4 R 5 and Step (b) is (i) reacting a compound of formula (XV) with a compound of formula (VIII) to form a compound of formula (VI): [ka] and (ii) from a compound of formula (VI), R 2 , R 3 and R 5 to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 5 is a protecting group; and R 6 are independently F, Cl, Br, I, or [ka] Selected from.] may include:

[0026] In certain embodiments of the third aspect, R 7 is -N(R 4 )CH2CH2NR 4 R 5 and the compound of formula (XIIIa) can be prepared by reacting a compound of formula (XVI) with a compound of formula (V): [ka] [In the formula, R 5 is a protecting group. It can be formed by:

[0027] In certain embodiments of the third aspect, R 7 -OR 7a and step (b) is (i) from a compound of formula (XVb), R 7a cleaving the substituent to form a compound of formula (XVII): [ka] ; (ii) reacting a compound of formula (XVII) with a compound of formula (V) to form a compound of formula (XVa): [ka] ; (iii) reacting a compound of formula (XVa) with a compound of formula (VIII) to form a compound of formula (VI): [ka] and (iv) from the compound of formula (VI), R 2 , R 3 and R 5 to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R5 is a protecting group; and R 6 are independently F, Cl, Br, I, or [ka] Selected from.] may include:

[0028] In a fourth aspect of the present invention, there is provided a method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) reacting a compound of formula (XVIII) with a compound of formula (XIX) to form a compound of formula (XV): [ka] and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (XV): [ka] [In the formula, R 1 are independently H or C 1-4 alkyl; R 2 is a protecting group; R 3 is independently selected from -CH2-aryl, or tert-butyl; Each R 4 independently for each occurrence, C 1-6 is alkyl; R 7 are independently -OR 7a , and -N(R 4 )CH2CH2NR 4 R 5 is selected from R 7a is C 1-6 alkyl, or CH2-aryl; and R 8c is BF3K, or B(OR 9c )2, where R 9cFor each occurrence, H or C 1-4 alkyl; or two R 9c The substituents, taken together, form (CR a R b ) n or two R 9c The substituents taken together form -C(O)-(CR a R b )-N(R c )-(CR a R b )-C(O)-.] A method is provided, comprising:

[0029] In certain embodiments of the fourth aspect, step (b) may comprise converting the compound of formula (XV) to a compound of formula (IV) or a pharmaceutically acceptable salt thereof according to any of the procedures described above for the third aspect.

[0030] R 1 can be H. R 1 is C 1-4 It can be alkyl.

[0031] R 2 represents independently at each occurrence a tert-butyloxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a tert-butyl ( t Bu), para-methoxybenzyl (PMB), and phthalimide. 2 may be independently selected from tert-butyloxycarbonyl (Boc), or benzyloxycarbonyl (Cbz). 2 R may be a tert-butyloxycarbonyl group (Boc). 2 may be benzyloxycarbonyl (Cbz).

[0032] R 3 R can be -CH-aryl, for example, benzyl, or paramethoxybenzyl. 3 R may be benzyl. 3 can be tert-butyl.

[0033] R 4 R may be independently selected at each occurrence from methyl, ethyl, n-propyl, or isopropyl. 4 R may be methyl. 4 may be ethyl.

[0034] R 5 R may be independently selected from tert-butyloxycarbonyl (Boc), or benzyloxycarbonyl (Cbz). 5 R may be a tert-butyloxycarbonyl group (Boc). 5 may be benzyloxycarbonyl (Cbz).

[0035] R 2 is Cbz and R 5 is Cbz and R 3 can be benzyl. 2 is Boc and R 5 is Boc and R 3 can be tert-butyl.

[0036] R 2 , R 3 and R 5 is R 2 , R 3 and R 5 can be selected to be cleaved under the same conditions. For example, 2 , R 3 and R 5 Each of the groups can be cleaved by catalytic hydrogenation (e.g., R 2 , R 5 and R 3 is a benzyl and Cbz group). Alternatively, R 2 , R 3 and R 5 Each of the following can be cleaved using a Bronsted acid (e.g., R 2 , R 5 and R 3 is a tert-butyl and Boc group).

[0037] Alternatively, R 2 , R 3 and R 5 or R so that they are all cleaved under different conditions. 2 , R 3 and R 5 Any two of R 2 , R 3 and R 5 may be selected to be cleaved under conditions different from those of the remaining one of R 3 Under conditions that result in cleavage of R 2 and R 5 To prevent disconnection, R 2 , R 3 and R 5 You can select:

[0038] R 7 -OR 7a R may be, for example, -O-CH, -O-CHCH, -CHCHCH, or OC(CH). 7 can be OC(CH3)3. R 7 Alternatively, R 7 is N(R 4 )CH2CH2NR 4 R 5 For example, N(R 4 )CH2CH2NR 4 Cbz, or N(R 4 )CH2CH2NR 4 It can be Boc.

[0039] R 8a , R 8b or R 8c independently for each occurrence: BF3K, -B(OH)2, -B(OCH3)2, [ka] may be selected from:

[0040] In certain embodiments of any of the first, second or third aspects, the compound of formula (IV) has the formula (IVa): [ka] (IVa) It is a compound represented by the formula:

[0041] In certain embodiments of any of the first, second or third aspects, the compound of formula (V) has the formula (Va): [ka] (Va) It is a compound represented by

[0042] X can be independently selected from Cl, Br, and I. X can be Cl. X can be Br.

[0043] R 9a For each occurrence, R can be H. 8a can be B(OH)2.

[0044] The reaction of the compound of formula (I) with the compound of formula (II) can be carried out in the presence of an inorganic base (e.g., NaHCO3). The reaction of the compound of formula (I) with the compound of formula (II) can be carried out in a mixture of water and a C1-C4-alcohol (e.g., methanol). The reaction of the compound of formula (I) with the compound of formula (II) can be carried out in a mixture of water and an aromatic hydrocarbon (e.g., toluene).

[0045] The reaction of a compound of formula (III) with a compound of formula (V) can be carried out by first converting the compound of formula (III) to an acid chloride, and then reacting the acid chloride with an amine (V). The conversion of formula (III) to an acid chloride can be carried out using oxalyl chloride, for example, in the presence of DMAP or DMF. Alternatively, the conversion can be carried out using thionyl chloride, for example, in the presence of DMAP or DMF. The reaction of the acid chloride with an amine (V) can be carried out in the presence of a base, for example, an inorganic base (e.g., NaHCO).

[0046] The reaction of a compound of formula (III) with a compound of formula (V) may be carried out using a suitable amide coupling reagent (e.g., propanephosphonic anhydride). The reaction may be carried out in the presence of a suitable organic base (e.g., triethylamine). The reaction may be carried out in acetonitrile.

[0047] The conversion of a compound of formula (VI) to a compound of formula (IV) can be carried out using hydrogenation with a palladium catalyst (e.g., using H2 and Pd / C). The reaction can be carried out in the presence of NH3 and methanol. The reaction can be carried out in 1,4-dioxane. The reaction can also be carried out in a polyfluorinated C1-C4-alcohol (e.g., 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-2-propanol).

[0048] The reaction of the compound of formula (VII) with the compound of formula (VIII) is typically carried out in the presence of a base (e.g., NaH). The reaction can be carried out in THF.

[0049] A can be Na.

[0050] R 8b teeth, [ka] It could be.

[0051] The reaction of a compound of formula (I) with a compound of formula (IX) is typically carried out in the presence of palladium (e.g., Pd / C, XPhos Pd G2, Pd(PPh3)4, Pd(dppf)Cl2). The reaction may also be carried out in the presence of XPhos Pd G2, Pd(PPh3)4, or Pd(dppf)Cl2. The reaction can be carried out in the presence of an inorganic base (e.g., K3PO4). The reaction can be carried out in 1,4-dioxane.

[0052] R 7 -OC 1-6 -alkyl, or -O-CH2-aryl. R 7 R may be selected from -O-tert-butyl, and O-benzyl. 7 But, -OC 1-6 -alkyl, or -O-CH2-aryl, R 2 and R 3 is preferably R 7 It is selected so that it will not be cleaved under the same conditions as R 7 -OC 1-6 -alkyl, for example, -O-tert-butyl. 7 But, -OC 1-6 -alkyl, for example -O-tert-butyl, when R 2 is preferably Cbz, and R 3 is preferably benzyl. 7 R can be -O-CH-aryl, for example -O-benzyl. 7 is -O-CH2-aryl, e.g., -O-benzyl, then R 2 is preferably Boc, and R 3 is preferably t-Bu.

[0053] R 7 When is -O-tert-butyl, the conversion of the compound of formula (Xa) to the compound of formula (III) can be carried out in the presence of a Bronsted acid (e.g., TFA). The conversion can be carried out in DCM.

[0054] R7 When is -O-benzyl, the conversion of the compound of formula (Xa) to the compound of formula (III) can be carried out using palladium-catalyzed hydrogenation (e.g., using H2 and Pd / C). The reaction can be carried out in the presence of NH3 and methanol. The reaction can be carried out in 1,4-dioxane.

[0055] R 7 is N(R 4 )CH2CH2NR 4 R 5 , for example, N(R 4 )CH2CH2NR 4 Cbz, or N(R 4 )CH2CH2NR 4 Boc, can be. 7 is N(Me)CH2CH2NMeR 5 , for example, N(Me)CH2CH2NMeCbz, or N(Me)CH2CH2NMeBoc.

[0056] The reaction of a compound of formula (XI) with a compound of formula (V) can be carried out by first converting the compound of formula (XI) to an acid chloride, and then reacting the acid chloride with an amine (V). The conversion of formula (XI) to an acid chloride can be carried out using oxalyl chloride, for example, in the presence of DMAP or DMF. Alternatively, the conversion can be carried out using thionyl chloride, for example, in the presence of DMAP or DMF. The reaction of an acid chloride with an amine (V) can be carried out in the presence of a base, for example, an inorganic base (e.g., NaHCO).

[0057] The reaction of the compound of formula (XIII) with the compound of formula (XIV) can be carried out in the presence of a silver salt or a copper salt. The reaction can be carried out in the presence of a silver salt (e.g., AgCO). The reaction can be carried out in the presence of a copper salt. The copper salt can be a Cu(I) salt, such as CsCO / CuBr, CuO / 1,10-phenanthroline, or Cu(I) thiophene-2-carboxylate. The copper salt can be a copper(II) salt, such as Cu(OAc). The reaction can be carried out in 1,4-dioxane.

[0058] The reaction of a compound of formula (XVIII) with a compound of formula (XIX) can be carried out in the presence of palladium (e.g., Pd / C, XPhos Pd G2, Pd(PPh3)4, Pd(dppf)Cl2). The reaction can also be carried out in the presence of XPhos Pd G2, Pd(PPh3)4, or Pd(dppf)Cl2. The reaction can be carried out in the presence of an inorganic base (e.g., K3PO4). The reaction can be carried out in 1,4-dioxane / water.

[0059] The reaction of the compound of formula (XV) with the compound of formula (VIII) is typically carried out in the presence of a base (e.g., NaH). The reaction can be carried out in THF.

[0060] The reaction of the compound of formula (XVI) with the compound of formula (V) can be carried out in the presence of HBTU. The reaction can be carried out in DCM. DETAILED DESCRIPTION OF THE INVENTION

[0061] Chemical terms used herein have meanings generally accepted in the art.

[0062] The term "halo" means fluoro, chloro, bromo, and iodo.

[0063] The term "alkyl" refers to a saturated monovalent hydrocarbon chain, either linear or branched. For example, C1-C6-alkyl can refer to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. An alkyl group can be unsubstituted or substituted with one or more substituents.

[0064] The term "alkylene" means a linear saturated divalent hydrocarbon chain. An alkylene group can be unsubstituted or substituted with one or more substituents.

[0065] The term "haloalkyl" refers independently at each occurrence to a hydrocarbon group substituted with at least one halogen atom selected from fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C6-haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloroethyl and 2-chloroethyl, trichloroethyl, e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, e.g., 1-fluoroethyl and 2-fluoroethyl, trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl. A haloalkyl group can be a fluoroalkyl group, i.e., a hydrocarbon chain substituted with at least one fluorine atom. Thus, a haloalkyl group can have any number of halogen substituents. The group can contain a single halogen substituent, or it can have two or three halogen substituents, or it can be saturated with halogen substituents.

[0066] The term "alkenyl" refers to a branched or straight-chain hydrocarbon group containing at least one double bond. The double bond may exist as an E or Z isomer. The double bond may be at any possible position on the hydrocarbon chain. For example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. Alkenyl groups may be unsubstituted or substituted with one or more substituents.

[0067] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. The triple bond may be located at any possible position on the hydrocarbon chain. For example, "C2-C6-alkynyl" may refer to ethynyl, propynyl, butynyl, pentynyl, and hexynyl. An alkynyl group may be unsubstituted or substituted with one or more substituents.

[0068] The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing, for example, 3, 4, 5, or 6 carbon atoms. For example, "C3-C6-cycloalkyl" can refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl groups can be unsubstituted or substituted by one or more substituents.

[0069] The term "heterocycloalkyl" can refer to a monocyclic or bicyclic saturated or partially saturated group having the indicated number of atoms in the ring system and containing one or two heteroatoms independently selected from O, S, and N in the ring system (i.e., one or two of the atoms forming the ring system are selected from O, S, and N). Partially saturated means that the ring may contain one or two double bonds. This applies particularly to 5- to 6-membered monocyclic rings. The double bond is typically between two carbon atoms, but may also be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, and azepine. Heterocycloalkyl groups can be unsubstituted or substituted with one or more substituents.

[0070] The term "aryl" can refer to an aromatic carbocyclic ring system (i.e., a ring system containing 2(2n+1) pi electrons). An aryl group can have 6 to 12 carbon atoms in the ring system. An aryl group is typically a phenyl group. An aryl group can also be a naphthyl group or a biphenyl group.

[0071] The terms "heteroaryl" or "heteroaromatic" refer to a 5- to 10-membered ring system that is aromatic (i.e., a ring system containing 2(2n+1) pi-electrons) and contains 1 to 4 heteroatoms independently selected from O, S, and N (in other words, 1 to 4 of the atoms forming the ring system are selected from O, S, and N). Thus, a heteroaryl group can be independently selected from: a 5-membered heteroaryl group in which the heteroaromatic ring is substituted with 1 to 4 heteroatoms independently selected from O, S, and N; a 6-membered heteroaryl group in which the heteroaromatic ring is substituted with 1 to 3 (e.g., 1 to 2) nitrogen atoms; a 9-membered bicyclic heteroaryl group in which the heteroaromatic system is substituted with 1 to 4 heteroatoms independently selected from O, S, and N; and a 10-membered bicyclic heteroaryl group in which the heteroaromatic system is substituted with 1 to 4 nitrogen atoms. Specifically, heteroaryl groups may be independently selected from pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, thiazole, isothiazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzothiazole, benzisoxazole, benzofurazine, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine, carbazole, phenazine, benzoisoquinoline, pyridopyrazine, thiophenofuran, 2H-furopyrazine, 5H-pyridoxazine, 1H-pyrazolooxazole, 4H-imidazothiazole, pyrazinopyridazine, imidazothiazole, and imidazotriazine.

[0072] As used herein, the term "protecting group" is given its ordinary meaning, which is readily understandable to those skilled in the art. It is used herein to mean a group suitable for protecting nitrogen or oxygen. Examples of protecting groups suitable for protecting nitrogen include tert-butyloxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz), tert-butyl group ( tExamples of protecting groups suitable for protecting oxygen include benzyl (Bn) and tert-butyl ( t Bu).

[0073] When multiple protecting groups are present in the same compound, the protecting groups may or may not be orthogonal to one another (i.e., if the first protecting group can be removed without removing the second protecting group, the two groups are said to be orthogonal). In the methods of the present invention, the protecting groups are typically not orthogonal to one another.

[0074] Compounds disclosed herein containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When compounds contain double bonds, such as C=C or C=N groups, geometric cis / trans (or Z / E) isomers are possible. When structural isomers are interconvertible via a low energy barrier, tautomers ("tautomerism") can occur. This can take the form of, for example, proton tautomerism in compounds disclosed herein containing imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. Thus, a single compound may exhibit multiple types of isomers.

[0075] Included within the scope of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compounds produced by the methods of the present invention, including compounds representing more than one type of isomer, and mixtures of one or more thereof.

[0076] The compounds produced by the methods of the present invention can be prepared, stored, and / or used in the form of pharmaceutically acceptable salts. Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of agriculturally acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid. Suitable salts include salts of inorganic and organic bases, such as those with counterions of Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium, and the like. Compounds may also be prepared, stored, and / or used in the form of their N-oxides. Also included are acid addition or base salts in which the counterion is optically active, e.g., d-lactate or l-lysine, or racemic, e.g., dl-tartrate or dl-arginine.

[0077] Pharmaceutically acceptable salts of the compounds produced by the methods of the present invention can be prepared, for example, by one or more of the following methods: (i) reacting the compound with the desired acid or base; (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using a desired acid or base; or (iii) Converting one salt of the compound to another by reaction with an appropriate acid or base or by a suitable ion exchange column. These methods are typically carried out in solution. The resulting salt precipitates and can be recovered by filtration or collected by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.

[0078] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0079] Conventional techniques for preparing / isolating individual enantiomers, if desired, include chiral synthesis from suitable optically pure precursors or separation of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Thus, the chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography on an asymmetric resin, typically HPLC, using a mobile phase typically consisting of a hydrocarbon, heptane or hexane, containing 0-50% by volume of isopropanol, typically 2%-20%, and, in certain instances, 0-5% by volume of an alkylamine, e.g., 0.1% diethylamine. The eluate can be concentrated to provide the enriched mixture.

[0080] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound of the invention contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomer by means well known to those skilled in the art.

[0081] When a racemate crystallizes, two different types of crystals can result: the first type is the racemate (true racemate) described above, where one homogeneous form of crystals containing both enantiomers in equimolar amounts is produced; the second type is a racemic mixture or conglomerate, where two forms of crystals containing each single enantiomer are produced in equimolar amounts.

[0082] Both crystalline forms present in a racemic mixture have identical physical properties, but they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, 1994).

[0083] Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in "Advanced Organic Chemistry", 7th edition J. March, John Wiley and Sons, New York, 2013).

[0084] The present invention also encompasses compounds prepared by the methods of the invention as defined herein and which contain one or more isotopic substitutions, for example, H is 1 H, 2 H(D), and 3 H(T) may be in isotopic form; C may be in isotopic form, including 12 C. 13 C, and 14 C may be in isotopic form; 16 O and 18 It may be in an isotopic form, including O. Similarly, isotopic variants of N, S, and P may also be utilized.

[0085] The steps described above as individual steps may also be carried out in tandem. In other words, the reaction product from one step may not be isolated and purified before the next step. Reagents for one step may also be added to the reaction mixture from the previous step upon completion of the reaction of the first step. For example, if the reaction sequence involves a Suzuki reaction (e.g., step a) or the first aspect of the present invention followed by hydrogenolysis, H2 can simply be added to the reaction mixture of the Suzuki reaction upon completion of the reaction.

[0086] Throughout the description and claims of this specification, the terms "comprise" and "contain," and variations thereof, mean "including, but not limited to," and are not intended to (and do not) exclude other moieties, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context clearly dictates otherwise. In particular, when the indefinite article is used, the specification should be understood to contemplate the singular as well as the plural, unless the context clearly dictates otherwise.

[0087] It is to be understood that any feature, integer, property, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention is applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith.

[0088] The reader's attention is directed to all articles and documents related to this application that have been filed contemporaneously or previously hereto and that are open to public inspection herewith, and the contents of all such articles and documents are incorporated herein by reference. [Example]

[0089] The following examples represent specific methods for preparing compounds of formula (IV).

[0090] General Experiment The following abbreviations are used: Bn: Benzyl Cbz: carboxybenzyl DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMAP: N,N-dimethyl-4-aminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide HBTU: N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol T3P: Propanephosphonic anhydride TFA: Trifluoroacetic acid TFE: 2,2,2-trifluoroethanol THF: tetrahydrofuran XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0091] Analysis method 1 All H-NMR spectra were obtained on a Bruker AVI 500 with a 5 mm QNP. Chemical shifts (δ) are expressed in parts per million (ppm) and are referenced to the solvent. Coupling constants (J) are expressed in hertz (Hz).

[0092] LC-MS was obtained on a Waters Alliance ZQ (Methods A and B) or a Waters Acquity H-class UPLC (Method C) using the methods detailed below. Wavelengths were 254 nm and 210 nm. Method A Column: YMC-Triart C18, 2.0 × 50 mm, 5 μm. Flow rate: 0.8mL / min. Injection volume: 6 μL. Mobile phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% formic acid. [Table 1] Method B Column: YMC-Triart C18, 2.0 × 50 mm, 5 μm. Flow rate: 0.8mL / min. Injection volume: 6 μL. Mobile phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% formic acid. [Table 2] Method C Column: CSH C18, 2.1 x 50 mm, 1.7 μm. Flow rate: 1.0mL / min. Injection volume: 5 μL. Mobile phase: A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid. [Table 3]

[0093] Synthesis of intermediates Intermediate 1: Benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate [ka] To a cooled (0°C) solution of N,N'-dimethylethane-1,2-diamine (130 mL, 1.20 mol) in DCM (500 mL) was added dropwise a solution of N-(benzyloxycarbonyloxy)succinimide (60 g, 241 mmol) in DCM (500 mL) over approximately 90 minutes and stirred at room temperature for an additional 2.5 hours. Workup A: Isolation of the HCl salt The reaction mixture was concentrated to dryness, and the residue was redissolved in ethyl acetate (1500 mL) and washed with water (2 × 750 mL). The aqueous phase was extracted with ethyl acetate (500 mL), and the combined organics were washed with brine (500 mL), then dried over MgSO4, filtered, and concentrated to dryness to give a colorless oil. The oil was redissolved in ethyl acetate (500 mL), cooled to 0 °C, and 4 M HCl in 1,4-dioxane (78.2 mL, 313 mmol) was added dropwise to the stirred solution. The resulting precipitate was isolated by filtration and washed with ethyl acetate followed by petroleum ether to give the desired HCl salt as a white solid (49.1 g, 79%). 1 H NMR (500 MHz, DMSO-d6) δ 9.19-8.97 (m, 2H), 7.42-7.30 (m, 5H), 5.08 (s, 2H), 3.60-3.51 (m, 2H), 3.03 (br s, 2H), 2.94-2.85 (m, 3H), 2.57-2.48 (m, 3H). Workup B: Distillation of the free base The reaction mixture was concentrated under reduced pressure, followed by the addition of water (300 mL) and extraction with diethyl ether (2 x 300 mL). The combined organic phases were dried over MgSO, filtered, and concentrated to dryness. The resulting yellow oil was purified by short-path distillation (product distilled at 116 °C and 0.45 mbar) to give the desired free base as a colorless oil (36 g, 64%). 1 H NMR (500 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.13 (s, 2H), 3.41 (br s, 2H), 2.96 (s, 3H), 2.80-2.69 (m, 2H), 2.49-2.36 (m, 3H).

[0094] Intermediate 2: Benzyl N-chlorosulfonylcarbamate [ka] Chlorosulfonyl isocyanate (30 mL, 346 mmol) was added to DCM (500 mL) and cooled to 0°C under a nitrogen atmosphere. After cooling, a solution of benzyl alcohol (37.4 g, 35.7 mL, 346 mmol) in DCM (100 mL) was slowly added to the mixture, and the reaction was then warmed to room temperature and stirred for 1 h. The mixture was evaporated to approximately 50% of the solvent volume, and petroleum ether was added with vigorous stirring until a solid broke up. The resulting slurry was stirred for 20 min, then filtered and dried under a stream of nitrogen for 1 h to give the desired product as a white solid (79 g, 91%). 1 H NMR (500 MHz, CDCl3) δ 8.88 (br s, 1H), 7.40 (s, 5H), 5.31 (s, 2H).

[0095] Example 1 Synthesis of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid [ka] Process 1 Sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrol-1-yl)sulfonyl-azanilide 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, followed by the dropwise addition of a solution of benzyl 3-bromo-1H-pyrrole-2-carboxylate (55 g, 196 mmol) in anhydrous THF (200 mL) over 45 minutes, maintaining the temperature below −5° C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and then recooled to −10° C. Benzyl N-chlorosulfonylcarbamate (53.9 g, 216 mmol) was added in portions to the reaction mixture over 30 minutes, maintaining the temperature below −5° C. The reaction mixture was warmed to room temperature and stirred for 2 hours, before being recooled to −10° C. and quenched by the dropwise addition of 50:50 water:brine (250 mL). The mixture was extracted with 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, the residue was treated with diethyl ether (200 mL), filtered, sucked dry, then treated again with diethyl ether (250 mL), filtered, and sucked dry to give the desired product as a white solid (99.8 g, 98%). 1 H NMR (500 MHz, DMSO-d6) δ 7.56-7.52 (m, 2H), 7.36-7.26 (m, 9H), 6.17 (d, J=3.4 Hz, 1H), 5.23 (s, 2H), 4.85 (s, 2H).

[0096] Process 2 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid A solution of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromopyrrol-1-yl)sulfonyl azanide (20.0 g, 38.8 mmol) and 4-carboxyphenylboronic acid (7.08 g, 42.7 mmol) in methanol (100 mL) was degassed with nitrogen for 30 minutes. Subsequently, 10% palladium on activated carbon (type 58, normal, reduced, nominally 50% water-wet, 2.07 g, 0.97 mmol) was added, and the mixture was evacuated under vacuum and replaced with nitrogen three times. A degassed (30 min, nitrogen) solution of sodium bicarbonate (6.52 g, 77.6 mmol) in water (100 mL) was slowly added to the reaction mixture. After the addition was complete, the reaction mixture was evacuated under vacuum, replaced with nitrogen, and then heated at 80 °C overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® (pretreated with water), the pad was washed with water (2 × 100 mL), and the combined filtrates were extracted with diethyl ether (2 × 100 mL). The aqueous layer was added in a slow, steady stream to a stirred mixture of acetic acid (30 mL) and water (270 mL) at 50 °C over approximately 1 h. After the addition was complete, the resulting slurry was stirred at 50 °C for 10 min, then cooled to room temperature and stirred for an additional 1 h. The precipitated solid was isolated by filtration, washed with water (2 × 50 mL), and dried under vacuum at 60 °C to give the desired product as a white solid (17.0 g, 80%). 1 H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=8.2 Hz, 2H), 7.43-7.39 (m, 3H), 7.36-7.30 (m, 5H), 7.29-7.25 (m, 5H), 6.42 (d, J=2.6 Hz, 1H), 5.19 (s, 2H), 5.00 (s, 2H). LC-MS (Method A): R T = 3.42 min, m / z = 533.8 [M−H] - .

[0097] Process 3 Benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate To a suspension of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (15.0 g, 28.0 mmol) in ethyl acetate (150 mL) was added DMF (43 μL, 0.56 mmol), followed by the dropwise addition of oxalyl chloride (2.68 mL, 30.9 mmol). The resulting suspension was heated at 40° C. for 1 hour and then concentrated under reduced pressure to approximately half its volume. Solid sodium bicarbonate (5.19 g, 61.7 mmol) was then added, followed by the dropwise addition of a solution of benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate (7.49 g, 33.7 mmol) in ethyl acetate (75 mL). After stirring overnight at room temperature, the reaction mixture was acidified by the addition of 2 M aqueous HCl (100 mL). The layers were separated, and the organic phase was washed with 2 M aqueous HCl (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a volume of approximately 100 mL. This was heated to 60 °C, followed by the slow addition of cyclohexane (200 mL). After stirring at 60 °C for 15 minutes, the resulting suspension was cooled to room temperature and stirred overnight. The precipitated solid was isolated by filtration, washed with cyclohexane (2 × 50 mL), and sucked dry to give the desired product as a white solid (17.0 g, 82%). 1 H NMR (500 MHz, DMSO-d6) δ 7.52-7.09 (m, 20H), 6.51-6.34 (m, 1H), 5.20 (br s, 2H), 5.14-4.78 (m, 4H), 3.71-2.53 (m, 10H). LC-MS (Method A): R T = 3.70 min, m / z = 739.9 [M+H] + .

[0098] Process 4 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid (Compound IVa) 10% Palladium on activated carbon (type 58, standard, reduced, nominally 50% water-wet, 720 mg, 0.34 mmol) was added to a purged (evacuated under vacuum and replaced with nitrogen three times) solution of benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (5.00 g, 6.77 mmol) in a mixture of methanol (17.5 mL) and 1,4-dioxane (17.5 mL). The reaction mixture was purged with vacuum / nitrogen three times, and 7 M ammonia in methanol (7.73 mL, 54.1 mmol) was added. The reaction mixture was purged with vacuum once, the atmosphere replaced with hydrogen (1 atm), and stirred at room temperature overnight. The reaction mixture was filtered through a Celite® pad (pretreated with 7 M ammonia in methanol), and the pad was further washed with 7 M ammonia in methanol (50 mL). The combined filtrates were diluted with methanol (50 mL) and concentrated under reduced pressure to remove approximately 50 mL of solvent in three portions, then stirred at room temperature for 1 hour. The resulting precipitate was isolated by filtration and dried overnight under vacuum at 60° C. to afford the desired product as a white solid (2.20 g, 85%). 1 H NMR (500 MHz, D2O) δ 7.51 (br d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 1.5 H), 7.37 (br d, J=7.9 Hz, 0.5 H), 7.19 (d, J=3.1 Hz, 1H), 6.41 (d, J=3.0 Hz, 1H), 3.81 (t, J=5.7 Hz, 1.5H), 3.69-3.65 (m, 0.5H), 3.31 (t, J=5.7 Hz, 1.5H), 3.15 (t, J=6.3 Hz, 0.5H), 3.05 (s, 0.8H), 3.01 (s, 2.2H), 2.72 (s, 2.2H), 2.53 (s, 0.8H). Multiple rotamers observed. LC-MS (Method B): RT = 4.93 min, m / z = 379.7 [MH] - .

[0099] Example 2: Alternative conditions for step 3 of Example 1 Synthesis of benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate [ka] To a suspension of benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate hydrochloride (25.4 g, 98.2 mmol) and 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (50.0 g, 93.5 mmol) in acetonitrile (125 mL) was added triethylamine (78.2 mL, 561 mmol) and stirred at 20° C. for 20 minutes. Propanephosphonic anhydride (50% in ethyl acetate, 82.7 mL, 140 mmol) was added over 1 hour, maintaining the temperature below 25° C., and stirred at room temperature for an additional 1 hour. The reaction mixture was diluted with ethyl acetate (500 mL) and 5% aqueous citric acid (500 mL) and then stirred for 15 minutes. The layers were separated, and the organic phase was washed sequentially with 5% aqueous citric acid (500 mL) and 1 M aqueous sodium bicarbonate (500 mL). The organic phase was concentrated to a final volume of 100 mL and diluted with ethyl acetate (150 mL) to form a mobile slurry and stirred at 20° C. overnight. n-Heptane (100 mL) was added to the slurry over 4 hours, and the mixture was stirred overnight. The product was isolated by filtration, washed with 1:3 ethyl acetate:n-heptane (100 mL), n-heptane (100 mL), and dried under vacuum at 40° C. overnight to afford the desired product as a white solid (63.0 g, 91%). Analytical data were consistent with those reported in Example 1, step 3.

[0100] Example 3: Alternative conditions for step 4 of Example 1 Synthesis of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid [ka] A mixture of benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (100 g, 135 mmol) and 10% palladium on activated carbon (type 58, normal, reduced, nominally 50% water-wet, 4.50 g, 2.13 mmol) in HFIP (500 mL) was vacuum / nitrogen purged three times, then purged with hydrogen three times, and then pressurized to approximately 850 mbar of hydrogen. The reaction mixture was maintained at this pressure at 20 °C for 24 h, then purged with nitrogen, filtered through a pad of Solka-floc (60 g), and washed with HFIP (150 mL). The combined filtrate was stirred with SEM26 (60 g) at 20 °C for 68 h, then filtered through filter paper and washed with HFIP (150 mL). The combined filtrate was concentrated under reduced pressure to a final volume of 200 mL, followed by the addition of water (100 mL) and methanol (100 mL), ultimately yielding seed crystals of the product (200 mg). The mixture was stirred at 20° C. for 30 minutes, and methanol (300 mL) was added over 2 hours. The resulting slurry was stirred overnight. The slurry was filtered, and the cake was washed with 80:20 methanol:water (2×300 mL) and dried overnight under vacuum at 30° C. to afford the crude product as a white solid (44.5 g, 87% crude yield).

[0101] Recrystallization process A suspension of the crude product (40.6 g, 107 mmol) in DMSO (160 mL) was stirred at 20 °C until a solution formed. Water (200 mL) was added over 1 h, maintaining the temperature below 25 °C, and the resulting slurry was stirred for 1 h. Methanol (240 mL) was charged over 1 h, and the mixture was stirred overnight. The resulting slurry was filtered, and the cake was washed with 80:20 methanol:water (2 × 120 mL) and dried on the filter under vacuum. The wet cake was then slurried in a mixture of methanol (400 mL) and water (40 mL) at 20 °C for 20 h, isolated by filtration, washed with 80:20 methanol:water (240 mL), and dried under vacuum at 30 °C overnight to give the desired product as a white solid (37.1 g, 91% recrystallization yield, 79% overall yield). Analytical data were consistent with those reported in Example 1, step 4.

[0102] Example 4: Alternative conditions for step 4 of Example 1 Synthesis of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-sulfamoyl-pyrrole-2-carboxylic acid [ka] A mixture of benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (20 g, 27 mmol) and 10% palladium on activated carbon (nominally 50% water-wet, 2.0 g, 0.94 mmol) in TFE (1000 mL) was vacuum / purged twice with nitrogen, then purged three times with hydrogen, and then pressurized to 2-4 atm of hydrogen. The reaction mixture was maintained at this pressure for 16 h at room temperature, then purged with nitrogen, filtered, and washed with TFE (20 mL). The combined filtrate was concentrated under reduced pressure to a final volume of 160 mL and stirred for 6 h. The precipitated solid was isolated by filtration. The solid was resuspended in methanol (400 mL), stirred for 2 h, isolated by filtration, and washed with methanol (60 mL). The filtered solid was resuspended in a mixture of methanol (200 mL) and water (200 mL) and stirred for 2 h. The solid was isolated by filtration, washed with methanol (60 mL), and dried under vacuum at 40° C. for 8 h to give the desired product as a white solid (7.2 g, 70%). Analytical data were consistent with those reported in Example 1, step 4.

[0103] Example 5 An alternative synthetic route to 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (via the sodium salt) [ka] Process 1 Sodium [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-{4-[(tert-butoxy)carbonyl]phenyl}-1H-pyrrol-1-yl}sulfonyl)azanide A stirred suspension of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromopyrrol-1-yl)sulfonyl azanide (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, followed by the addition of 3 M aqueous KPO4 (67.9 mL, 204 mmol). After heating at 45 °C for 2 h, the reaction mixture was cooled, the phases were separated, and the organic phase was concentrated to dryness. 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 under reduced pressure to approximately 60 mL. It 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, 97%). 1 H NMR (500 MHz, CDCl3) δ 7.61 (br d, J=7.6 Hz, 2H), 7.56 (br s, 1H), 7.11-6.86 (m, 11H), 6.58 (br d, J=6.7 Hz, 2H), 5.87 (br s, 1H), 4.86 (br s, 2H), 4.78 (s, 2H), 1.61 (s, 9H). LC-MS (Method A): R T = 3.93 min, m / z = 589.6 [M - H] - .

[0104] Process 2 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid To a stirred solution of sodium [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-{4-[(tert-butoxy)carbonyl]phenyl}-1H-pyrrol-1-yl}sulfonyl)azanide (40.5 g, 65.8 mmol) in DCM (300 mL) was added TFA (73 mL, 0.99 mol). The reaction mixture was stirred at room temperature for 1 h and then concentrated to dryness. The residue was treated with isopropanol, filtered, and sucked dry to give the desired product as an off-white solid (25.0 g, 71%), which was used in the subsequent step without further removal of residual salts. 1 H NMR (500 MHz, DMSO-d6) δ 7.85 (br d, J=7.9 Hz, 2H), 7.49 (br s, 1H), 7.44-7.23 (m, 10H), 7.19 (br d, J=6.4 Hz, 2H), 6.51 (br s, 1H), 5.22 (s, 2H), 5.12 (s, 2H). LC-MS (Method A): R T = 3.20 min, m / z = 533.5 [MH] - .

[0105] Compound IVa is synthesized from 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid according to the methods of Steps 3 and 4 of Example 1.

[0106] Example 6 An alternative synthetic route to 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid (via the free sulfonamide) [ka] Process 1 Benzyl 1-(benzyloxycarbonylsulfamoyl)-3-(4-tert-butoxycarbonylphenyl)pyrrole-2-carboxylate Sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrol-1-yl)sulfonyl-azanide (51.9 g, 101 mmol) was converted to sodium [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-{4-[(tert-butoxy)carbonyl]phenyl}-1H-pyrrol-1-yl}sulfonyl)azanide in a similar manner as described above, which was redissolved in DCM (500 mL), washed with 2 M aqueous HCl (500 mL), dried over NaSO, filtered, and concentrated to dryness to give the desired product as an off-white solid (58.0 g, 96%). LC-MS (Method A): R T = 4.12 min, m / z = 589.6 [M - H] - .

[0107] Process 2 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid To a stirred solution of benzyl 1-(benzyloxycarbonylsulfamoyl)-3-(4-tert-butoxycarbonylphenyl)pyrrole-2-carboxylate (58.0 g, 98.2 mmol) in DCM (300 mL) was added TFA (109 mL, 1.47 mol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was treated with isopropanol, filtered, and sucked dry to give the desired product as an off-white solid (39.2 g, 75%). 1 H NMR (500 MHz, CDCl3) δ 8.68 (br s, 1H), 7.94 (br d, J=7.6 Hz, 2H), 7.65 (br s, 1H), 7.40-7.21 (m, 10H), 7.00 (br d, J=7.0 Hz, 2H), 6.29 (br s, 1H), 5.19 (s, 2H), 5.11 (s, 2H). LC-MS (Method A): R T = 3.17 min, m / z = 533.5 [MH] - .

[0108] Compound IVa is synthesized from 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylsulfamoyl)pyrrol-3-yl]benzoic acid according to the methods of Steps 3 and 4 of Example 1.

[0109] Example 7 An alternative synthetic route to benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate [ka] Process 1 Benzyl N-methyl-N-[2-[methyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino]ethyl]carbamate To a suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.0 g, 4.03 mmol) in ethyl acetate (10 mL) was added DMF (6 μL, 81 μmol). After cooling to 0 °C, thionyl chloride (0.32 mL, 4.43 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred overnight. The resulting solution was concentrated under reduced pressure to approximately half its volume, followed by the addition of solid sodium bicarbonate (745 mg, 8.87 mmol), followed by the dropwise addition of a solution of benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate (986 mg, 4.43 mmol) in ethyl acetate (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was filtered. The filtrate was concentrated to approximately 5 mL, followed by the addition of petroleum ether (40 mL) and stirring for 10 minutes. The precipitated solid was isolated by filtration and sucked dry to give the desired product as a white solid (1.44g, 79%). 1H NMR (500 MHz, CDCl3) δ 7.85-7.77 (m, 2H), 7.39-7.20 (m, 7H), 5.18-4.93 (m, 2H), 3.77-2.63 (m, 10H), 1.35 (s, 12H). LC-MS (Method A): R T = 3.65 min, m / z = 453.6 [M+H] + .

[0110] Process 2 Benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate XPhos (278 mg, 0.58 mmol) and palladium(II) acetate (44 mg, 0.19 mmol) were pre-stirred in 1,4-dioxane (5 mL) for 5 min, followed by the addition of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrol-1-yl)sulfonyl-azanide (2.00 g, 3.88 mmol) and benzyl N-methyl-N-[2-[methyl-[4-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoyl]amino]ethyl]carbamate (2.28 g, 5.05 mmol) along with 1,4-dioxane (10 mL). The mixture was degassed and placed under a nitrogen atmosphere, after which 3M aqueous KPO (3.88 mL, 11.6 mmol) was added and heated to 60°C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (approximately 100 mL) and washed with water (2 x approximately 60 mL) and brine (approximately 60 mL). The organic phase was dried over NaSO, filtered, and concentrated to dryness. The residue was then reconcentrated from IPA, treated with diethyl ether, and isolated by filtration. The isolated solid was redissolved in DCM with the aid of methanol and acidified by washing with 1M aqueous HCl. The organic phase was dried over NaSO, filtered, concentrated to dryness, and then reconcentrated from a mixture of DCM and petroleum ether to give the desired product as an off-white solid (2.55 g, 88%). 1H NMR (500 MHz, CDCl3) δ 8.64 (br s, 1H), 7.55 (d, J=3.1 Hz, 1H), 7.39-7.20 (m, 17H), 7.10-7.01 (br m, 2H), 6.25 (d, J=2.4 Hz, 1H), 5.20-4.95 (m, 6H), 3.76 (br t, J=5.5 Hz, 1H), 3.70-3.57 (br m, 2H), 3.45-3.28 (br m, 1H), 3.20-2.76 (m, 5H), 2.72-2.61 (br m, 1H). LC-MS (Method A): R T = 3.31 min, m / z = 739.5 [M+H] + .

[0111] Compound IVa is synthesized from benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate according to the method of Example 1, Step 4.

[0112] Example 8 An alternative synthetic route to benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate (via coupling with chloride) [ka] Process 1 Sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-chloro-pyrrol-1-yl)sulfonyl-azanilide A suspension of sodium hydride (60% in mineral oil, 25.2 g, 630 mmol) in anhydrous THF (200 mL) was cooled to −10° C. under a nitrogen atmosphere, followed by the dropwise addition of a solution of benzyl 3-chloro-1H-pyrrole-2-carboxylate (49.5 g, 210 mmol) in anhydrous THF (200 mL) over 60 minutes, maintaining the temperature below −5° C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and then recooled to −10° C. Benzyl N-chlorosulfonylcarbamate (57.7 g, 231 mmol) was added in portions over 45 minutes, maintaining the temperature below −5° C. The reaction mixture was warmed to room temperature and stirred for 2 hours, then recooled to −10° C. and quenched by the dropwise addition of 50:50 water:brine (250 mL). The mixture was extracted with 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, the residue was treated with diethyl ether (200 mL), filtered and sucked dry to give the desired product as a white solid (94.5 g, 96%). 1 H NMR (500 MHz, DMSO-d6) δ 7.54-7.50 (m, 2H), 7.36-7.25 (m, 9H), 6.13 (d, J=3.1 Hz, 1H), 5.23 (s, 2H), 4.85 (s, 2H). LC-MS (Method A): R T = 3.48 min, m / z = 447.2 / 449.2 [MH] - .

[0113] Process 2 Benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate A mixture of sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-chloropyrrol-1-yl)sulfonyl azanide (500 mg, 1.06 mmol) and benzyl N-methyl-N-[2-[methyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino]ethyl]carbamate (606 mg, 1.34 mmol) in 1,4-dioxane (4 mL) was degassed by bubbling nitrogen through for 5 min, followed by the addition of a solution of XPhos Pd G (88 mg, 0.11 mmol) and KPO (711 mg, 3.35 mmol) in water (1 mL). The reaction mixture was then heated at 50 °C under a nitrogen atmosphere for 2 h. The reaction mixture was then cooled to room temperature, diluted with 50:50 water:brine (3 mL), and extracted with ethyl acetate (3 × 3 mL). The combined organic phases were washed with 2 M aqueous HCl (5 mL) and brine (5 mL), dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether:ethyl acetate, 90:10 to 0:100 gradient elution) to afford the desired product as a pale yellow solid (280 mg, 36% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.45-7.17 (m, 20H), 6.46-6.32 (m, 1H), 5.19 (br s, 2H), 5.13-4.99 (m, 4H), 3.71-2.72 (m, 10H). LC-MS (Method A): R T = 3.73 min, m / z = 740.0 [M+H] + .

[0114] Compound IVa is synthesized from benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate according to the method of Example 1, Step 4.

[0115] Example 9 An alternative synthetic route to benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate [ka] Process 1 Benzyl N-{2-[1-(4-ethynylphenyl)-N-methylformamido]ethyl}-N-methylcarbamate To a mixture of 4-ethynylbenzoic acid (6.86 g, 46.9 mmol) and benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate hydrochloride (13.4 g, 51.6 mmol) in DCM (150 mL) was added HBTU (23.1 g, 61.0 mmol) followed by DIPEA (36.1 mL, 211 mmol) and stirred for 3 days at 20° C. The reaction mixture was concentrated to dryness, redissolved in ethyl acetate (400 mL), and washed with 2 M aqueous HCl (2×200 mL), water (200 mL), saturated aqueous sodium bicarbonate (2×200 mL), water (200 mL), and brine (100 mL). The organic phase was dried over MgSO4, filtered, concentrated to dryness, and purified by column chromatography (silica, petroleum ether:ethyl acetate, gradient elution from 100:0 to 0:100) to give the desired product as a straw-colored gum (16.0 g, 97%). 1 H NMR (500 MHz, CDCl3) δ 7.47 (br d, J=7.8 Hz, 2H), 7.40-7.25 (m, 7H), 5.20-4.90 (m, 2H), 3.74 (t, J=5.2 Hz, 1H), 3.68-3.27 (br m, 3H), 3.17-2.79 (m, 6H), 2.76-2.65 (br m, 1H). LC-MS (Method C): R T = 1.76 min, m / z = 351.2 [M+H] + .

[0116] Process 2 Benzyl 3-{4-[(2-{[(benzyloxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]phenyl}-1H-pyrrole-2-carboxylate A mixture of benzyl N-{2-[1-(4-ethynylphenyl)-N-methylformamido]ethyl}-N-methylcarbamate (3.50 g, 9.99 mmol) and silver carbonate (551 mg, 2.00 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 100 °C under an argon atmosphere. To the heated suspension, a solution of benzyl 2-isocyanoacetate (2.10 g, 12.0 mmol) in anhydrous 1,4-dioxane (10 mL) was added dropwise (via syringe pump over approximately 80 min) and then heated at 100 °C for an additional 2 h. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (200 mL), stirred for 10 min, and then filtered through Celite®. The filtrate was concentrated to dryness to give the desired product as a yellow gum (4.26 g, 81%). 1 H NMR (500 MHz, CDCl3) δ 9.28 (br s, 1H), 7.54 (br d, J=7.8 Hz, 2H), 7.40-7.25 (m, 12H), 6.95 (t, J=2.7 Hz, 1H), 6.34 (br s, 1H), 5.24 (s, LC-MS (Method C): R T = 1.98 min, m / z = 526.3 [M+H] + .

[0117] Process 3 Benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate A suspension of sodium hydride (60% in mineral oil, 228 mg, 5.71 mmol) in anhydrous THF (5 mL) was cooled to −10° C. under an argon atmosphere, followed by the dropwise addition of a solution of benzyl 3-{4-[(2-{[(benzyloxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]phenyl}-1H-pyrrole-2-carboxylate (1.00 g, 1.90 mmol) in anhydrous THF (5 mL) over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for an additional 60 minutes before being recooled to −10° C. To the reaction mixture was added benzyl N-chlorosulfonylcarbamate (523 mg, 2.09 mmol) in portions over 25 minutes, and the mixture was then allowed to warm to room temperature and stirred for an additional 2 hours. The reaction mixture was recooled to -10°C, carefully quenched with a 1:1 brine:water solution (20 mL), acidified with 2 M aqueous HCl (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO, filtered, and concentrated to dryness to give the crude product as a colorless gum (1.29 g, 92%). 1 H NMR (500 MHz, CDCl3) δ 8.67 (br s, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.40-7.20 (m, 17H), 7.05 (br s, 2H), 6.15 (br d, J=2.3 Hz, 1H), 5.20-5.00 (m, 6H), 3.79-3.72 (br m, 1H), 3.70-3.56 (br m, 2H), 3.45-3.29 (br m, 1H), 3.18-2.77 (br m, 5H), 2.71-2.62 (br m,1H). LC-MS (Method C): R T = 2.17 min, m / z = 739.3 [M+H] + .

[0118] Compound IVa is synthesized from benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylsulfamoyl)pyrrole-2-carboxylate according to the method of Example 1, Step 4.

Claims

1. A process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising: (a) reacting a compound of formula (I) with a compound of formula (II) in the presence of Pd / C to form a compound of formula (III): 【Chemistry 1】 and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (III): 【Chemistry 2】 [In the formula, X is independently Cl, Br, I, N ２ ＋ , or OSO ２ CF ３ Selected from: R １ are independently H, or C １－４ alkyl; R ２ is a protecting group; R ３ are independently —CH ２ -aryl, or tert-butyl; Each R ４ is independently expressed as C １－４ is alkyl; R ８ａ is BF ３ K, or B (OR ９ａ ) ２ where R ９ａ For each occurrence, H or C １－４ alkyl; or two R ９ａ The substituents taken together form (CR ａ R ｂ ) ｎ or two R ９ａ The substituents taken together form -C(O)-(CR ａ R ｂ )-N(R ｃ )-(CR ａ R ｂ )—C(O)—; R ａ , R ｂ and R ｃ independently for each occurrence, H, and C １－４ alkyl; n is 2 or 3; and A is independently selected from H or a cation. A method comprising:

2. Step (b) is the following step: (i) reacting a compound of formula (III) with a compound of formula (V) to form a compound of formula (VI): 【Transformation 3】 and (ii) from a compound of formula (VI), R ２ , R ３ and R ５ to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 [In the formula, R ５ is a protecting group. The method of claim 1 , comprising:

3. reacting a compound of formula (I) with a compound of formula (VII) to form a compound of formula (VIII): 【Transformation 5】 [In the formula, R ６ are independently F, Cl, Br, I, or 【Transformation 6】 is selected from.

3. The method of claim 1 or 2, wherein the compound is formed by

4. A process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising: (a) reacting a compound of formula (I) with a compound of formula (IX) to form a compound of formula (X): 【Transformation 7】 and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (X): 【Transformation 8】 [In the formula, X is independently Cl, Br, I, N ２ ＋ , or OS(O) ２ CF ３ Selected from: R １ are independently H, or C １－４ alkyl; R ２ is a protecting group; R ３ are independently —CH ２ -aryl, or tert-butyl; Each R ４ is independently expressed as C １－６ is alkyl; R ５ is a protecting group; R ７ are independently -OR ７ａ , and -N(R ４ ) CH ２ CH ２ NR ４ R ５ Selected from: R ７ａ is -C １－６ Alkyl, and —CH ２ - selected from aryl; R ８ｂ is independently, BF ３ K, or B (OR ９ｂ ) ２ where each R ９ｂ is H; or two R ９ｂ The substituents taken together form (CR ａ R ｂ ) ｎ forming a ring containing the oxygen and boron atoms; or two R ９ａ The substituents taken together form -C(O)-(CR ａ R ｂ )-N(R ｃ )-(CR ａ R ｂ )-C(O)-; R ａ , R ｂ and R ｃ independently for each occurrence, H, and C １－４ alkyl; n is 2 or 3; and A is independently selected from H or a cation. A method comprising:

5. R ７ But, -OR ７ａ and Step (b) (i) from the compound of formula (Xa), R ７ａ cleaving the substituent to form a compound of formula (III): 【Chemistry 9】 and (ii) reacting a compound of formula (III) with a compound of formula (V) to form a compound of formula (VI): 【Chemistry 10】 and (iii) from the compound of formula (VI), ２ , R ３ and R ５ to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 11】 The method of claim 4, comprising:

6. R ７ But -N(R ４ ) CH ２ CH ２ NR ４ R ５ and Step (b) is the step of converting a compound of formula (VI) into R ２ , R ３ and R ５ to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 12】 The method of claim 4, comprising:

7. R ２ , R ３ and R ５ The method of claim 6, wherein the substituent of is cleaved from the compound of formula (VI) by catalytic hydrogenation.

8. The compound of formula (VI) (i) reacting a compound of formula (XI) with a compound of formula (V) to form a compound of formula (XII): 【Chemistry 13】 8. The method of claim 6 or 7, wherein the compound is formed by

9. A process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising: (a) reacting a compound of formula (XIII) with a compound of formula (XIV) to form a compound of formula (XV): 【Chemistry 14】 and (b) forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (XV): 【Chemistry 15】 [In the formula, R １ are independently H, or C １－４ alkyl; R ３ are independently —CH ２ -aryl, or tert-butyl; Each R ４ is independently expressed as C １－６ is alkyl; R ７ are independently -OR ７ａ , and -N(R ４ ) CH ２ CH ２ NR ４ R ５ is selected from: R ７ａ is C １－６ Alkyl, or CH ２ -aryl.] A method comprising:

10. R ７ But -N(R ４ ) CH ２ CH ２ NR ４ R ５ and Step (b) (i) reacting a compound of formula (XV) with a compound of formula (VIII) to form a compound of formula (VI): 【Chemistry 16】 wherein R 2 is a protecting group. and (ii) from a compound of formula (VI), R ２ , R ３ and R ５ to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 17】 [In the formula, R ５ is a protecting group; and R ６ are independently F, Cl, Br, I, or [Chemistry 18] is selected from.

10. The method of claim 9, comprising:

11. R ７ But -N(R ４ ) CH ２ CH ２ NR ４ R ５ and the compound of formula (XIIIa) is reacted with a compound of formula (XVI) with a compound of formula (V): 【Chemistry 19】 [In the formula, R ５ is a protecting group.

11. The method of claim 9 or 10, wherein the compound is formed by

12. R ７ But, -OR ７ａ and Step (b) (i) from a compound of formula (XVb), R ７ａ Cleavage of the substituent to form a compound of formula (XVII): 【Chemistry 20】 ； (ii) reacting a compound of formula (XVII) with a compound of formula (V) to form a compound of formula (XVa): 【Chemistry 21】 ； (iii) reacting a compound of formula (XVa) with a compound of formula (VIII) to form a compound of formula (VI): 【Chemistry 22】 wherein R 2 is a protecting group. and (iv) from the compound of formula (VI), ２ , R ３ and R ５ to form a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 【Chemistry 23】 [In the formula, R ５ is a protecting group; and R ６ are independently F, Cl, Br, I, or 【Chemistry 24】 is selected from.

10. The method of claim 9, comprising:

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