Synthesis of pyrrolic acid derivatives

Abstract

This invention relates to the synthesis of compounds that can be used in combination with other antimicrobial agents, and more specifically, with a class of antimicrobial agents called carbapenems, to treat bacterial infections. The compounds obtained by the novel method of this invention are enzyme inhibitors, and more particularly, metallo-β-lactamase inhibitors.

Description

Technical Field

[0001] This invention relates to the synthesis of compounds that can be used in combination with other antimicrobial agents, and more specifically, with a class of antimicrobial agents called carbapenems, to treat bacterial infections. The compounds obtained by the novel method of this invention are enzyme inhibitors, and more particularly, metallo-β-lactamase inhibitors. Background Technology

[0002] Across Europe, more than 4 million people contract healthcare-associated bacterial infections each year, resulting in approximately 37,000 deaths (Public Health England). The increasing prevalence of multidrug-resistant bacteria has worsened patient outcomes, prolonged hospital stays, and necessitated the use of "last resort" and potentially toxic antimicrobial agents such as colistin and polymyxin B. It is estimated that by 2050, without intervention, antibiotic-resistant bacteria will cause more than 10 million deaths annually, amounting to a $100 trillion economic burden.

[0003] Clinically, 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 microorganisms are limited, and empirical antibiotic therapy frequently fails in patients infected with Gram-negative microorganisms of the ESKAPE pathogen group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae).

[0004] In February 2017, the World Health Organization (WHO) published a priority list of bacterial pathogens to help member states focus research and development on the areas of greatest need. Among these bacteria, the WHO designated the following Gram-negative bacteria as critical 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 critical unmet medical need. The mode of action of β-lactams (such as carbapenems) involves covalently binding to the transpeptidase active site that links the peptidoglycan chains of the bacterial cell wall. This leads to inhibition of cell wall synthesis and ultimately cell death. Compared to most other β-lactam antibiotics, carbapenems have the advantage of a broader spectrum of activity, and until recently, their application had 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 influenced by the emergence of metallo-β-lactamases (MBLs). These enzymes bind to carbapenems and cleave the β-lactam ring, leading to antibiotic inactivation. The Ambler classification system divides known β-lactamases into four classes based on their amino acid sequences. Class A, C, and D β-lactamases cleave β-lactams by briefly binding a serine group within the enzyme's active site to the carbonyl group of the β-lactam ring. This results in the formation of an acylase and the cleavage of the β-lactam ring. Subsequently, activated water molecules deacylate the acylase intermediate, hydrolyzing the bond between the serine and carbonyl groups, releasing the inactivated β-lactam. MBLs differ from Class A, C, and D serine-β-lactamases in both mechanism and structure. In this case, the cleavage of the β-lactam occurs in a single step, without the formation of a covalent intermediate. MBLs coordinate water molecules and zinc ions to the His, Cys, and Asp residues at their active sites, where the water molecules promote nucleophilic attack and bond breaking within the β-lactam ring. MBL subclasses are structurally distinct; B1 and B3 enzymes contain two zinc ions at their active sites and exhibit a broad substrate distribution. B2 enzymes rely on a single zinc ion and hydrolyze only carbapenems. Clinically, B1-class MBLs are the most prevalent, including NDM, VIM, and IMP, and are frequently identified in mobile genetic elements.

[0006] Pre-existing serine-β-lactamase inhibitors (effectively inhibiting class A, C, and some class D β-lactamases) have successfully restored the activity of various β-lactams. The inhibitors bind temporarily or permanently to the active site of the enzyme with high affinity, effectively replacing the binding of β-lactams. Marketed β-lactam / β-lactamase inhibitor combinations include amoxicillin and clavulanic acid (Co-amoxiclav) and ceftazidime and avibactam (Avycaz). Currently, no metallo-β-lactamase inhibitors (MBLIs) are in clinical development or available clinically, indicating the commercial potential of broad-spectrum MBLIs for restoring carbapenem activity.

[0007] The first carbapenem used clinically was imipenem for treating complex microbial infections. A drawback of imipenem is that it is hydrolyzed by dehydropeptidase I (DHPI) in mammalian kidneys and requires co-formulation with the DHPI inhibitor cilastatin. Subsequent carbapenem iterations, including meropenem, are less susceptible to DHPI hydrolysis due to the presence of a methyl group at the 1-β position of the carbapenem moiety. Meropenem is less potent against Gram-positive pathogens than imipenem but more potent 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-lactamases. When co-administered with meropenem, these compounds significantly enhance the efficacy of meropenem against resistant bacteria. This invention specifically relates to methods for forming these compounds.

[0008] Other approved carbapenems are also expected to benefit from co-formulation with the compounds of this invention. Other currently approved carbapenems include ertapenem, doribenem, panipenem, biapenem, and telbipenem.

[0009] Until recently, bacterial infections were one of the most common causes of death, disfigurement, and disability. In the 19th century, a range of antibiotics were developed, meaning that successfully treating bacterial infections became routine. However, antibiotic resistance in microorganisms is becoming a significant problem, considered by many to be one of the greatest challenges to human health. In fact, multidrug resistance has become widespread among 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 novel antibiotics active against pathogens of critical concern listed by the WHO, or drugs that circumvent existing bacterial resistance mechanisms, is crucial.

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

[0012] The object of certain embodiments of the present invention is to provide alternative methods for synthesizing metallo-β-lactamase inhibitors. One object is to provide a method for synthesizing metallo-β-lactamase inhibitors that is more scalable, yields purer products, 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 formulas (I) to (XIX) can be the free acid or free base shown, or can be their pharmaceutically acceptable salts.

[0014] In a first aspect of the invention, a method for forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof is provided, the method comprising:

[0015] (a) In the presence of Pd / C, the compound of formula (I) reacts with the compound of formula (II) to form the compound of formula (III):

[0016] and

[0017] (b) Formation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (III):

[0018]

[0019] in

[0020] x is independently selected from Cl, Br, I, N2 + Or OSO2CF3;

[0021] R 1 Is it H or C? 1-4 alkyl;

[0022] R 2 It is a protecting group;

[0023] R 3 Independently selected from -CH2-aryl or tert-butyl;

[0024] Each R 4 It is C independently each time it appears. 1-4 alkyl;

[0025] R 8a Is it BF3K or B(OR)? 9a )2; where R 9a It is either H or C each time it appears. 1-4 Alkyl; or two R 9a Substituents together form (CR) a R b ) n Or two Rs 9a Substituents together form -C(O)-(CR) a R b )-N(R c )-(CR a R b )-C(O)-;

[0026] R a R b and R c Each time it appears, it is independently selected from H and C. 1-4 alkyl;

[0027] n is 2 or 3;

[0028] and

[0029] A is independently selected from H or cations.

[0030] In some implementations, step (b) of the first aspect may include the following steps:

[0031] (i) Reacting compound (III) with compound (V) to form compound (VI):

[0032]

[0033] and

[0034] (ii) Cleavage of R from compound of formula (VI) 2 R 3 and R 5 Substituent-forming (IV) compounds or their pharmaceutically acceptable salts:

[0035]

[0036] in

[0037] R 5 It is a protecting group.

[0038] In some embodiments, compound (I) is formed by reacting compound (VII) with compound (VIII):

[0039]

[0040] Where R 6 Independently selected from F, Cl, Br, I or

[0041] In a second aspect of the invention, a method for forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof is provided, the method comprising:

[0042] (a) Reacting compound (I) with compound (IX) to form compound (X);

[0043]

[0044] (b) Formation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (X):

[0045]

[0046] in

[0047] x is independently selected from Cl, Br, I, N2+ Or OSO2CF3;

[0048] R 1 Independently selected from H or C 1-4 alkyl;

[0049] R 2 It is a protecting group;

[0050] R 3 Independently selected from -CH2-aryl or tert-butyl;

[0051] Each R 4 It is C independently each time it appears. 1-6 alkyl;

[0052] R 5 It is a protecting group

[0053] R 7 Independently selected from -OR 7a and -N(R) 4 )CH2CH2NR 4 R 5 ;

[0054] R 7a Selected from -C 1-6 Alkyl and -CH2-aryl; R 8a Independently selected from BF3K or B(OR) 9b )2, where each R 9b Is it H or C? 1-4 Alkyl; or two R 9b Substituents together form (CR) a R b ) n And a ring containing oxygen and boron atoms; or two Rs 9b Substituents together form -C(O)-(CR) a R b )-N(R c )-(CR a R b )-C(O)-;

[0055] R a R b and R c Each time it appears, it is independently selected from H and C. 1-4 alkyl;

[0056] n is 2 or 3;

[0057] and

[0058] A is independently selected from H or cations.

[0059] In some implementations of the second aspect, when R 7 For -OR 7a When, step (b) may include

[0060] (i) Cleavage of R from compound (Xa) 7a Substituents are used to form compounds of formula (III);

[0061] and

[0062] (ii) Reacting compound (III) with compound (V) to form compound (VI):

[0063]

[0064] and

[0065] (iii) Cleavage of R from compound (VI) 2 R 3 and R 5 Substituents are compounds of formula (IV) or pharmaceutically acceptable salts thereof:

[0066]

[0067] In another implementation of the second aspect, when R 7 It is -N(R) 4 )CH2CH2NR 4 R 5 When (i.e., the compound of formula (X) is a compound of formula (VI), step (b) may include cleaving R from the compound of formula (VI). 2 R 3 and R 5 Substituents, to form compounds of formula (IV) or their pharmaceutically acceptable salts:

[0068]

[0069] This reaction can be used in the first aspect of the invention as described above. Therefore, in some embodiments, R 2 R 3 and R 5 Substituents can be cleaved from compounds of formula (VI) by catalytic hydrogenation, for example as described in the first aspect of the invention.

[0070] In a further embodiment, the method may include reacting a compound of formula (XI) with a compound of formula (V) to form a compound of formula (XII) (a specific example of a compound of formula (IX)):

[0071]

[0072] Then the compound of formula (XII) can react with the compound of formula (I).

[0073] The compound of formula (I) can be produced as described above in the first aspect of the invention.

[0074] In a third aspect of the invention, a method for forming a formula (IV) compound or a pharmaceutically acceptable salt thereof is provided, the method comprising:

[0075] (a) Reacting compound (XIII) with compound (XIV) to form compound (XV):

[0076] and

[0077] (b) Formation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (XV):

[0078]

[0079] in

[0080] R 1 Independently selected from H or C 1-4 alkyl;

[0081] R 3 Independently selected from -CH2-aryl or tert-butyl;

[0082] Each R 4 It is C independently each time it appears. 1-6 alkyl;

[0083] R 7 Independently selected from -OR 7a and -N(R) 4 )CH2CH2NR 4 R 5 ;and

[0084] R 7a It is C 1-6 Alkyl or CH2-aryl. In some embodiments of the third aspect, when R... 7 It is -N(R) 4 )CH2CH2NR 4 R 5 When, step (b) may include

[0085] (i) Reacting compound (XV) with compound (VIII) to form compound (VI):

[0086] ;and

[0087] (ii) Cleavage of R from compound (VI)2 R 3 and R 5 Substituent-forming (IV) compounds or their pharmaceutically acceptable salts:

[0088]

[0089] Where R 5 It is a protecting group; and R 6 Independently selected from F, Cl, Br, I or

[0090] In some implementations of the third aspect, when R 7 It is -N(R) 4 )CH2CH2NR 4 R 5 At that time, compound (XIIIa) can be formed by the reaction of compound (XVI) with compound (V):

[0091]

[0092] Where R 5 It is a protecting group.

[0093] In some implementations of the third aspect, when R 7 For -OR 7a When this is the case, step (b) may include:

[0094] (i) Cleavage of R from compound of formula (XVb) 7a Substituents are used to form compounds of formula (XVII);

[0095]

[0096] (ii) Reacting a compound of formula (XVII) with a compound of formula (V) to form a compound of formula (XVa):

[0097]

[0098] (iii) Reacting compound (XVa) with compound (VIII) to form compound (VI):

[0099]

[0100] and

[0101] (iv) Cleavage of R from compound (VI) 2 R 3 and R 5 Substituents are compounds of formula (IV) or pharmaceutically acceptable salts thereof:

[0102]

[0103] Where R 5 It is a protecting group; and R 6 Independently selected from F, Cl, Br, I or

[0104] In a fourth aspect of the invention, a method for forming a compound of formula (IV) or a pharmaceutically acceptable salt thereof is provided, the method comprising:

[0105] (a) Reacting compound (XVIII) with compound (XIX) to form compound (XV):

[0106] and

[0107] (b) Formation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (XV):

[0108]

[0109] in

[0110] R 1 Independently selected from H and C 1-4 alkyl;

[0111] R 2 It is a protecting group;

[0112] R 3 Independently selected from -CH2-aryl or tert-butyl;

[0113] Each R 4 It is C independently each time it appears. 1-6 alkyl;

[0114] R 7 Independently selected from -OR 7a and -N(R) 4 )CH2CH2NR 4 R 5 ;

[0115] R 7a It is C 1-6 Alkyl or CH2-aryl; and

[0116] R 8c Is it BF3K or B(OR)? 9c )2; where R 9c It is either H or C each time it appears. 1-4 Alkyl; or two R 9c Substituents together form (CR) a R b ) n; or two Rs 9c Substituents form together

[0117] -C(O)-(CR a R b )-N(R c )-(CR a R b )-C(O)-.

[0118] In some embodiments of the fourth aspect, step (b) may include converting the compound of formula (XV) into the compound of formula (IV) or a pharmaceutically acceptable salt thereof by any of the methods described in the third aspect above.

[0119] R 1 It can be H. R 1 It can be C 1-4 alkyl.

[0120] R 2 Each time it appears, it is independently selected from: tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tert-butyl ( t Bu), p-methoxybenzyl (PMB), and phthalimide. R 2 It can be independently selected from tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz). R 2 It can be tert-butyloxycarbonyl (Boc). R 2 It can be benzyloxycarbonyl (Cbz).

[0121] R 3 It can be -CH2-aryl, such as benzyl or p-methoxybenzyl. R 3 It can be benzyl. R 3 It can be tert-butyl.

[0122] R 4 Each time it appears, it can be independently selected from methyl, ethyl, n-propyl, or isopropyl. R 4 It can be methyl. R 4 It can be ethyl.

[0123] R 5 It can be independently selected from: tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz). R 5 It can be tert-butoxycarbonyl (Boc). R 5 It can be benzyloxycarbonyl (Cbz).

[0124] R may 2 It's Cbz, R 5 It's Cbz, R 3 It's benzyl. Possibly R 2 It's Boc, R 5 It's Boc, R3 It is tert-butyl.

[0125] You can choose R 2 R 3 and R 5 This makes R 2 R 3 and R 5 Each of them cleaves under the same conditions. For example, R 2 R 3 and R 5 Each of these can be cracked by catalytic hydrogenation (e.g., where R...). 2 R 5 and R 3 (It consists of benzyl and Cbz groups). Or, R 2 R 3 and R 5 Each of them can be cleaved using Brønsted acid (e.g., where R...). 2 R 5 and R 3 (It consists of tert-butyl and Boc groups).

[0126] Alternatively, you can choose R. 2 R 3 and R 5 This causes them to cleave under different conditions, or causes R to... 2 R 3 and R 5 Any two of them in the equation split into R under different conditions. 2 R 3 and R 5 The remaining one. Therefore, R can be chosen. 2 R 3 and R 5 This makes R 2 and R 5 In causing R 3 It is not pyrolyzed under pyrolysis conditions.

[0127] R 7 It can be -OR 7a For example, -O-CH3, -O-CH2CH3, -CH2CH2CH3, or OC(CH3)3. R7 can be OC(CH3)3. 7 It can be -O-benzyl. Or, R 7 It can be N(R) 4 )CH2CH2NR 4 R 5 For example, N(R) 4 )CH2CH2NR 4 Cbz or N(R) 4 )CH2CH2NR4 Boc.

[0128] R 8a R 8b Or R 8c They can be independently selected from BF3K, -B(OH)2, -B(OCH3)2,

[0129] In certain embodiments of any of the first, second, or third aspects, the compound of formula (IV) is a compound of formula (IVa):

[0130]

[0131] In certain embodiments of any of the first, second, or third aspects, the compound of formula (V) is a compound of formula (Va):

[0132]

[0133] X can be independently selected from Cl, Br, and I. X can be Cl. X can be Br.

[0134] In each occurrence of R 9a The time could be H. Therefore, R 8a It might be B(OH)2.

[0135] The reaction of compound (I) with compound (II) can be carried out in the presence of an inorganic base (such as NaHCO3). The reaction of compound (I) with compound (II) can be carried out in a mixture of water and C1-C4 alcohols (such as methanol). The reaction of compound (I) with compound (II) can be carried out in a mixture of water and aromatic hydrocarbons (such as toluene).

[0136] The reaction of compound (III) with compound (V) can be carried out by first converting compound (III) to an acyl chloride, followed by reacting the acyl chloride with an amine (V). Oxaloyl chloride, for example in the presence of DMAP or DMF, can be used to convert compound (III) to an acyl chloride. Alternatively, thionyl chloride can be used, for example in the presence of DMAP or DMF. The reaction of the acyl chloride with the amine (V) can be carried out in the presence of a base (e.g., an inorganic base, such as NaHCO3).

[0137] The reaction of compound (III) with compound (V) can be achieved using a suitable amide coupling agent (e.g., propanephosphonic anhydride). This reaction can be carried out in the presence of a suitable organic base (e.g., triethylamine). The reaction can be carried out in acetonitrile.

[0138] Hydrogenation catalyzed by palladium, for example using H2 and Pd / C, can convert compounds of formula (VI) to compounds of formula (IV). This reaction can be carried out in the presence of NH3 and methanol. This reaction can be carried out in 1,4-dioxane. This reaction can be carried out in polyfluorinated C1-C4 alcohols (e.g., 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-2-propanol).

[0139] The reaction of compound (VII) with compound (VIII) is usually carried out in the presence of a base (such as NaH). This reaction can be carried out in THF.

[0140] A can be Na.

[0141] R 8b may be

[0142] The reaction between compounds of formula (I) and (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 can be carried out in the presence of XPhos Pd G2, Pd(PPh3)4, or Pd(dppf)Cl2. The reaction can also be carried out in the presence of an inorganic base (e.g., K3PO4). The reaction can be carried out in 1,4-dioxane.

[0143] R 7 Possibly selected from -OC 1-6 -alkyl or -O-CH2-aryl. R 7 It can be selected from -O-tert-butyl and O-benzyl. When R 7 Selected from -OC 1-6 When -alkyl or -O-CH2-aryl, R is preferred. 2 and R 3 This makes them compatible with R 7 It will not be cleaved under the same conditions. R 7 It can be -OC 1-6 -alkyl, such as -O-tert-butyl. Where R 7 Yes - OC 1-6 -alkyl, such as -O-tert-butyl, R 2 The preferred choice is Cbz, R 3 Benzyl is preferred. R may be present. 7 It is -O-CH2-aryl, for example -O-benzyl. Where R... 7 It is -O-CH2-aryl, for example -O-benzyl, R 2 The preferred choice is Boc, R 3 The preferred option is tBu.

[0144] When R 7When the molecule is -O-tert-butyl, the conversion of compound (Xa) to compound (III) can be carried out in the presence of a Brønsted acid (e.g., TFA). The conversion can be performed in a DCM.

[0145] When R 7 When the radical is -O-benzyl, palladium-catalyzed hydrogenation, for example using H2 and Pd / C, can be used to convert the compound of formula (Xa) to the compound of formula (III). This reaction can be carried out in the presence of NH3 and methanol. This reaction can also be carried out in 1,4-dioxane.

[0146] R 7 It can be N(R) 4 )CH2CH2NR 4 R 5 For example, N(R) 4 )CH2CH2NR 4 Cbz or N(R) 4 )CH2CH2NR 4 Boc. R 7 It could be N(Me)CH2CH2NMeR 5 For example, N(Me)CH2CH2NMeCbz or N(Me)CH2CH2NMeBoc.

[0147] 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 acyl chloride, followed by reacting the acyl chloride with an amine (V). Oxaloyl chloride can be used, for example, in the presence of DMAP or DMF, to convert formula (XI) to an acyl chloride. Alternatively, thionyl chloride can be used, for example, in the presence of DMAP or DMF. The reaction of the acyl chloride with the amine (V) can be carried out in the presence of a base (e.g., an inorganic base, such as NaHCO3).

[0148] The reaction between compound (XIII) and compound (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., Ag₂CO₃). The reaction can be carried out in the presence of a copper salt. The copper salt can be a Cu(I) salt, such as Cs₂CO₃ / CuBr, Cu₂O / 1,10-phenanthroline, or Cu(I)thiophene-2-carboxylate. The copper salt can be a Cu(II) salt, such as Cu(OAc)₂. The reaction can be carried out in 1,4-dioxane.

[0149] The reaction of compound (XVIII) with compound (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 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.

[0150] The reaction between compounds of formula (XV) and (VIII) is typically carried out in the presence of a base (such as NaH). This reaction can also be conducted in THF.

[0151] The reaction of compound (XVI) with compound (V) can be carried out in the presence of HBTU. This reaction can be performed in a DCM. Detailed Implementation

[0152] The chemical terms used in this specification have their generally accepted meanings in the art.

[0153] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0154] The term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon chain. For example, C1-C6-alkyl can refer to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Alkyl groups can be unsubstituted or substituted with one or more substituents.

[0155] The term "alkylene" refers to a linear, saturated divalent hydrocarbon chain. Alkylenes can be unsubstituted or substituted with one or more substituents.

[0156] The term "haloalkyl" refers to a hydrocarbon group substituted with at least one halogen atom, which, each time it appears, is independently selected from fluorine, chlorine, bromine, and iodine. The halogen atom can 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 fluoroalkyl, i.e., a hydrocarbon chain substituted with at least one fluorine atom. Therefore, a haloalkyl group can have any number of halogen substituents. The group can contain a single halogen substituent, it can have two or three halogen substituents, or it can be saturated with halogen substituents.

[0157] The term "alkenyl" refers to a branched or straight-chain hydrocarbon group containing at least one double bond. The double bond can exist as an E or Z isomer. The double bond can be in any possible position on the hydrocarbon chain; for example, "C2-C6-alkenyl" can refer to vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. The alkenyl group can be unsubstituted or substituted with one or more substituents.

[0158] The term "alkynyl" refers to a branched or straight-chain hydrocarbon chain containing at least one triple bond. The triple bond can be in any possible position on the hydrocarbon chain. For example, "C2-C6-alkynyl" can refer to ethynyl, propynyl, butynyl, pentyynyl, and hexynyl. The alkynyl group can be unsubstituted or substituted with one or more substituents.

[0159] 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, or cyclohexyl. Cycloalkyl groups can be unsubstituted or substituted with one or more substituents.

[0160] The term "heterocyclic alkyl" can refer to a monocyclic or bicyclic saturated or partially saturated group having a specified number of atoms in the ring system and containing one or two heteroatoms independently selected from O, S, and N (in other words, the one or two atoms forming the ring system are selected from O, S, and N). Partial saturation means that the ring may contain one or two double bonds. This is particularly true for monocyclic rings with 5 to 6 members. Double bonds are typically between two carbon atoms, but can also be between one carbon atom and one nitrogen atom. Examples of heterocyclic alkyl groups include: piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, and aziridine. Heterocyclic alkyl groups can be unsubstituted or substituted with one or more substituents.

[0161] The term "aryl" can refer to any aromatic carbocyclic system (i.e., a ring system containing 2(2n+1)π electrons). An aryl group can have 6 to 12 carbon atoms in a ring system. Aryl groups are typically phenyl. Aryl groups can also be naphthyl or biphenyl.

[0162] The term "heteroaryl" or "heteroarylene" refers to any 5- to 10-membered ring system (i.e., a ring system containing two (2n+1)π electrons) containing one to four heteroatoms independently selected from O, S, and N (in other words, the one to four atoms forming the ring system are selected from O, S, and N). Therefore, any heteroaryl can be independently selected from: 5-membered heteroaryls, where the heteroarylene ring is substituted by 14 heteroatoms independently selected from O, S, and N; and 6-membered heteroaryls, where the heteroarylene ring is substituted by 1 to 3 (e.g., 1 to 2) nitrogen atoms; 9-membered bicyclic heteroaryls, where the heteroarylene system is substituted by 1 to 4 heteroatoms independently selected from O, S, and N; and 10-membered bicyclic heteroaryls, where the heteroarylene system is substituted by 1 to 4 nitrogen atoms. Specifically, the heteroaryl group can be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, thiazole, isothiazole, oxadiazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzothiazole, benzoisoxazole, benzofuran, purine, quinoline, isoquinoline, cinnamoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthidine, carbazole, phenazine, benzoisoquinoline, pyridopyrazine, thiophene-furan, 2H-furanpyrazine, 5H-pyridoxazine, 1H-pyrazoloxazole, 4H-imidazothiazole, pyrazolopyrazine, imidazothiazole, imidazotriazine.

[0163] As used herein, the term "protecting group" is given its general meaning, which is readily understood by those skilled in the art. It is used herein to refer to a group suitable for protecting nitrogen or oxygen. Exemplary protecting groups suitable for protecting nitrogen include tert-butoxycarbonyl (Boc group), benzyloxycarbonyl (Cbz), tert-butyl (… t Bu), p-methoxybenzyl (PMB), and phthalimide. Exemplary protecting groups suitable for protecting oxygen include benzyl (Bn) and tert-butyl (Bn). t Bu).

[0164] When multiple protecting groups are present on the same compound, the protecting groups can be orthogonal or non-orthogonal to each other (i.e., if the first protecting group can be removed while the second protecting group is not removed, then the two groups are said to be orthogonal). In the method of the present invention, the protecting groups are generally non-orthogonal to each other.

[0165] The compounds disclosed herein containing one or more asymmetric carbon atoms can exist in two or more stereoisomers. Geometric cis / trans (or Z / E) isomers are possible if the compound contains a double bond, such as a C=C or C=N group. Tautomerism occurs when the structural isomers interconvert via low-barrier transformations. In the compounds disclosed herein containing, for example, imino, ketone, or oxime groups, this can take the form of proton tautomerism, or in compounds containing aromatic moieties, it can take the form of so-called valence tautomerism. Thus, a compound may exhibit more than one isomerism.

[0166] Included within the scope of this invention are all stereoisomers, geometric isomers, and tautomers of compounds produced in the method of this invention, including compounds exhibiting more than one type of isomerism, and mixtures thereof.

[0167] The compounds produced in the methods of this invention can be obtained, 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, aminosulfonic acid, and hydrobromic acid, or salts of agronomically 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, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, p-aminobenzenesulfonic acid, aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid. Suitable salts also include salts of inorganic and organic bases, such as counterions like Na, Ca, K, Li, Mg, ammonium, and trimethylsulfonium. These compounds can also be obtained, stored, and / or used in the form of N-oxides. It also includes acid addition salts or base salts in which the counterion is optically active; for example, d-lactate or l-lysine, or racemic; for example, dl-tartrate or dl-arginine.

[0168] Pharmaceutically acceptable salts of the compounds produced in the method of the present invention can be prepared, for example, by one or more of the following methods:

[0169] (i) Reacting the compound with the desired acid or base;

[0170] (ii) by removing a protecting group that is unstable to acids or bases from a suitable precursor of the compound of the invention, or by using a suitable cyclic precursor, such as a lactone or lactam, to open the ring with the desired acid or base; or

[0171] (iii) To convert one salt of a compound into another salt by reacting it with a suitable acid or base or by passing it through a suitable ion exchange column.

[0172] These methods are typically carried out in solution. The resulting salt can precipitate and be collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can range from fully ionized to almost unionized.

[0173] Cis / trans isomers can be separated using conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0174] Conventional techniques for preparing / separating individual enantiomers when necessary include chiral synthesis or resolution of racemates (or racemates of salts or derivatives) from suitable optically pure precursors using, for example, chiral high-performance liquid chromatography (HPLC). Therefore, the chiral compounds (and their chiral precursors) of the present invention can be obtained in enantiomer-enriched form using chromatography, typically HPLC, on an asymmetric resin having a mobile phase composed of hydrocarbons, typically heptane or hexane, containing 0 to 50% by volume isopropanol, typically 2% to 20%, and, in certain instances, 0 to 5% by volume alkylamines, such as 0.1% diethylamine. Concentration of the eluent provides an enriched mixture.

[0175] Alternatively, the racemic mixture (or racemic precursor) may react with a suitable optically active compound, such as an alcohol, or, in the case where the compound of the present invention contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers may be separated by chromatography and / or fractional crystallization, and one or both diastereomers may be converted into the corresponding pure enantiomers by methods well known to those skilled in the art.

[0176] When any racemic mixture crystallizes, two different types of crystals are possible. The first type is the racemic compound mentioned above (a true racemate), in which a homogeneous form of crystal is produced, containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or aggregate, in which two forms of crystal are produced in equimolar amounts, each containing one enantiomer.

[0177] Although the two crystal forms present in a racemic mixture have the same physical properties, 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 Elle Liel and S. Wilen (Wiley, 1994).

[0178] Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in J. March, John Wiley, and Sons, "Advanced Organic Chemistry," 7th edition, New York, 2013).

[0179] This invention also includes compounds produced in the methods of this invention as defined herein, which contain one or more isotopic substitutions. For example, H can be any isotopic form, including... 1 H, 2 H(D) and 3 H(T); C can be any isotopic form, including 12 C 13 C and 14 C and O can be in any isotopic form, including 16 O and 18 O, etc. Similarly, isotopic variants of nitrogen, sulfur, and phosphorus can be utilized.

[0180] The steps described above as individual steps may be performed in series. In other words, reaction products from one step may not be isolated and purified before the next step. Once the reaction of the first step is complete, the reagents used in that step can be added immediately to the reaction mixture obtained in the previous step. For example, after hydrogenolysis, when the reaction sequence includes a Suzuki reaction (e.g., step a) or the first aspect of the invention), once that reaction is complete, H2 can simply be added to the reaction mixture of the Suzuki reaction.

[0181] Throughout this specification and claims, the words “comprising” and “including” and variations thereof mean “including, but not limited to”, and do not exclude other parts, additives, ingredients, wholes, or steps. Throughout the description and claims, the singular form includes the plural form unless the context requires otherwise. In particular, where the indefinite article is used, the specification should be understood to consider both the plural and singular forms unless the context requires otherwise.

[0182] The features, wholes, properties, compounds, chemical parts or groups described in connection with a particular aspect, embodiment or example of the invention shall be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith.

[0183] Readers should note all papers and documents submitted concurrently with or prior to this specification in connection with this application, which are made publicly available for examination along with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0184] Example

[0185] The following examples illustrate specific methods for producing (IV) compounds.

[0186] Routine experiment

[0187] The following abbreviations were used:

[0188] Bn-Benzyl

[0189] Cbz-benzyloxycarbonyl

[0190] DCM-dichloromethane

[0191] DIPEA-N,N-Diisopropylethylamine

[0192] DMAP-N,N-dimethyl-1-4-aminopyridine

[0193] DMF-N,N-dimethylformamide

[0194] DMSO-dimethyl sulfoxide

[0195] HBTU-N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate

[0196] HFIP-1,1,1,3,3,3-hexafluoro-2-propanol

[0197] T3P-propylphosphoanhydride

[0198] TFA-trifluoroacetic acid

[0199] TFE-2,2,2-trifluoroethanol

[0200] THF-Tetrahydrofuran

[0201] XPhos-2-Dicyclohexylphosphine-2′,4′,6′-Triisopropylbiphenyl

[0202] XPhos Pd G2-chloro(2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0203] Analytical methods

[0204] all 1 H- 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 solvent-dependent. Coupling constants (J) are expressed in Hertz (Hz).

[0205] LC-MS was obtained on Waters Alliance ZQ (methods A and B) or Waters Alliance Acquity H-class UPLC (method C) using the methods detailed below. The wavelengths were 254 and 210 nm.

[0206] Method A

[0207] Column: YMC-Triart C18, 2.0 × 50 mm, 5 μm. Flow rate: 0.8 mL / min. Injection volume: 6 μL.

[0208] Mobile phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% formic acid.

[0209] initial 90 5 5 4.0 0 95 5 6.0 0 95 5

[0210] Method B

[0211] Column: YMC-Triart C18, 2.0 × 50 mm, 5 μm. Flow rate: 0.8 mL / min. Injection volume: 6 μL.

[0212] Mobile phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% formic acid.

[0213] initial 95 0 5 2.0 95 0 5 12.0 0 95 5 14.0 0 95 5

[0214] Method C

[0215] Column: CSH C18, 2.1 x 50 mm, 1.7 μm. Flow rate: 1.0 mL / min. Injection volume: 5 μL.

[0216] Mobile phase: A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid.

[0217] initial 98 2 0.2 98 2 2.5 2 98 3.0 2 98 3.1 98 2 3.5 98 2

[0218] intermediate synthesis

[0219] Intermediate 1: N-methyl-N-[2-(methylamino)ethyl]carbamate benzyl ester

[0220]

[0221] Under argon atmosphere, a solution of N-(benzyloxycarbonyloxy)succinimide (60 g, 241 mmol) in DCM (500 mL) was added dropwise to a cooled (0 °C) solution of N,N′-dimethylethane-1,2-diamine (130 mL, 1.20 mol) in DCM (500 mL) over approximately 90 minutes, and the mixture was stirred at room temperature for another 2.5 hours.

[0222] Separation and Purification Experiment A: Separation of HCl Salt

[0223] 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), the combined organic matter was washed with brine (500 mL), 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 (78.2 mL, 313 mmol) dissolved in 1,4-dioxane was added dropwise to the stirred solution. The precipitate was separated by filtration, washed with ethyl acetate, and then washed with petroleum ether to give the desired hydrochloride (49.1 g, 79%) as a white solid.

[0224] 1 H NMR(500MHz,DMSO-d6)δ9.19-8.97(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).

[0225] Separation and Purification Test B: Distillation of Free Alkali

[0226] The reaction mixture was concentrated under reduced pressure, then water (300 mL) was added and the mixture was extracted in diethyl ether (2 × 300 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to dryness. The resulting yellow oil was purified by short-path distillation (the product was distilled at 116 °C and 0.45 mbar) to give the desired colorless oily free base (36 g, 64%).

[0227] 1 H NMR (500MHz, CDCl3) δ7.39-7.28(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).

[0228] Intermediate 2: N-chlorosulfonyl carbamate benzyl ester

[0229]

[0230] 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 mixture was then heated to room temperature and stirred for 1 hour. The mixture was evaporated to approximately 50% of the solvent volume, and petroleum ether was added under vigorous stirring until the solid was broken up. The resulting slurry was stirred for 20 minutes, then filtered and dried under a nitrogen stream for 1 hour to give the desired white solid product (79 g, 91%).

[0231] 1 H NMR (500MHz, CDCl3) δ8.88 (br s, 1H), 7.40 (s, 5H), 5.31 (s, 2H).

[0232] Example 1 – Synthesis of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-aminosulfonyl-pyrrole-2-carboxylic acid

[0233]

[0234] Step 1: Benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrole-1-yl)sulfonylazasodium

[0235] Under a nitrogen atmosphere, a suspension of sodium hydride (60% in mineral oil, 23.6 g, 589 mmol) in anhydrous THF (200 mL) was cooled to -10 °C, followed by the dropwise addition of a solution of 3-bromo-1H-pyrrole-2-carboxylic acid benzyl ester (55 g, 196 mmol) in anhydrous THF (200 mL) over 45 minutes, ensuring the temperature remained below -5 °C. The reaction mixture was heated to room temperature and stirred for 1 hour, then cooled again to -10 °C. Over 30 minutes, N-chlorosulfonylcarbamate benzyl ester (53.9 g, 216 mmol) was added to the reaction mixture in portions, ensuring the temperature remained below -5 °C. The reaction mixture was heated to room temperature and stirred for 2 hours, then cooled again to -10 °C and quenched by the dropwise addition of a 50:50 water:salt solution (250 mL). The mixture was extracted into ethyl acetate (3 × 100 mL), the combined organic phases were washed with brine (200 mL), dried over magnesium sulfate, the solution was decanted and concentrated to dryness. The residue was ground in diethyl ether (200 mL), filtered and dried, then resaturated in diethyl ether (250 mL), filtered and dried to give the desired white solid product (99.8 g, 98%).

[0236] 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).

[0237] Step 2: 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid

[0238] A solution of benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrole-1-yl)sulfonylazasodium (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 min, and then 10% palladium / activated carbon (Type 58, standard, reduced, nominally 50% wetted water, 2.07 g, 0.97 mmol) was added. The mixture was then evacuated under vacuum and the air was purged three times with nitrogen. A degassed solution of sodium bicarbonate (6.52 g, 77.6 mmol) in water (100 mL) (30 min, nitrogen) was slowly added to the reaction mixture. After the addition was complete, the reaction mixture was evacuated under vacuum and the atmosphere was purged with nitrogen, then heated to 80 °C overnight. After cooling to room temperature, the mixture was... The reaction mixture was filtered through a pad (pretreated with water), the pad was washed with water (2 × 100 mL), and the combined filtrates were extracted with diethyl ether (2 × 100 mL). Over approximately 1 hour, the aqueous layer was added in a slow, steady stream to a mixture of acetic acid (30 mL) and water (270 mL) stirred at 50 °C. After the addition was complete, the resulting slurry was stirred at 50 °C for 10 minutes, then cooled to room temperature and stirred for another hour. The precipitated solid was separated by filtration, washed with water (2 × 50 mL), and dried under vacuum at 60 °C to give the desired white solid product (17.0 g, 80%).

[0239] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.84 (d, J = 8.2Hz, 2H), 7.43–7.39 (m, 3H), 7.36–7.30 (m, 5H), 7.29–7.25 (m, 5H), 6.42 (d, J = 2.6Hz, 1H), 5.19 (s, 2H), 5.00 (s, 2H). LC-MS (Method A): R T =3.42 min, m / z = 533.8 [MH] - .

[0240] Step 3: 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester

[0241] DMF (43 μL, 0.56 mmol) was added to a suspension of 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrolo-3-yl]benzoic acid (15.0 g, 28.0 mmol) in ethyl acetate (150 mL), followed by the dropwise addition of oxaloyl chloride (2.68 mL, 30.9 mmol). The resulting suspension was heated to 40 °C and held for 1 hour, 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 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 adding 2 M HCl aqueous solution (100 mL). The layers were separated, and the organic phase was washed with 2M HCl aqueous solution (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to approximately 100 mL. It was heated to 60 °C, and then cyclohexane (200 mL) was slowly added. After stirring at 60 °C for 15 minutes, the resulting suspension was cooled to room temperature and stirred overnight. The precipitated solid was separated by filtration, washed with cyclohexane (2 × 50 mL), and dried to obtain the desired white solid product (17.0 g, 82%).

[0242] 1 ¹H NMR (500MHz, 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 =3.70min, m / z = 739.9 [M+H] + .

[0243] Step 4: 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-aminosulfonyl-pyrrole-2-carboxylic acid (compound IVa)

[0244] 10% palladium / activated carbon (Type 58, standard, reduced, nominal 50% wetted water, 720 mg, 0.34 mmol) was added to a solution of 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester (5.00 g, 6.77 mmol) purged (vacuum purged, then purged three times with nitrogen) in a mixture of methanol (17.5 mL) and 1,4-dioxane. The reaction mixture was purged three times with vacuum / nitrogen, and a methanol solution of 7M ammonia (7.73 mL, 54.1 mmol) was added. The reaction mixture was purged once with vacuum, the air was replaced with hydrogen (1 atm), and the mixture was stirred overnight at room temperature. The reaction mixture was then passed through… The mixture was filtered through a pad (pretreated with a 7M ammonia in methanol solution) and washed with 50 mL of the same solution. The combined filtrates were diluted with 50 mL of methanol and concentrated under reduced pressure, removing approximately 50 mL of solvent in three separate applications. The mixture was then stirred at room temperature for 1 hour. The resulting precipitate was separated by filtration and dried under vacuum at 60 °C overnight to give the desired product as a white solid (2.20 g, 85%).

[0245] 1 ¹H NMR (500MHz, D₂O) δ 7.51 (br d, J = 7.9Hz, 2H), 7.44 (d, J = 7.9Hz, 1.5H), 7.37 (br d, J = 7.9Hz, 0.5H), 7.19 (d, J = 3.1Hz, 1H), 6.41 (d, J = 3.0Hz, 1H), 3.81 (t, J = 5.7Hz, 1.5H), 3.69–3.65 (m, 0.5H), 3.31 (t, J = 5.7Hz, 1.5H), 3.15 (t, J = 6.3Hz, 0.5H), 3.05 (s, 0.8H), 3.01 (s, 2.2H), 2.72 (s, 2.2H), 2.53 (s, 0.8H). Multiple rotational isomers were observed. LC-MS (Method B): R T =4.93 min, m / z = 379.7 [MH] - .

[0246] Alternative conditions for step 3 of Example 2-Example 1: Synthesis of benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid ester

[0247]

[0248] Before stirring at 20°C for 20 minutes, triethylamine (78.2 mL, 561 mmol) was added to a suspension of N-methyl-N-[2-(methylamino)ethyl]carbamate benzyl hydrochloride (25.4 g, 98.2 mmol) and 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid (50.0 g, 93.5 mmol) in acetonitrile (125 mL). Propionic anhydride (50%, in ethyl acetate, 82.7 mL, 140 mmol) was added over 1 hour, ensuring the temperature was maintained below 25°C, and then stirred for another 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (500 mL) and 5% citric acid aqueous solution (500 mL), and then stirred for 15 minutes. The layers were separated, and the organic phase was washed successively with 5% citric acid aqueous solution (500 mL) and 1M sodium bicarbonate aqueous solution (500 mL). The organic phase was concentrated to a final volume of 100 mL to form a flowing slurry, which was diluted with ethyl acetate (150 mL) and stirred overnight at 20 °C. Over 4 hours, n-heptane (100 mL) was added to the slurry, and the mixture was stirred overnight. The product was separated by filtration, washed with a 1:3 mixture of ethyl acetate:n-heptane (100 mL) and n-heptane (100 mL), and dried under vacuum at 40 °C overnight to give the desired white solid product (63.0 g, 91%).

[0249] The analyzed data are consistent with those reported in step 3 of Example 1.

[0250] Alternative conditions for step 4 of Example 3-Example 1: Synthesis of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-aminosulfonyl-pyrrole-2-carboxylic acid

[0251]

[0252] A mixture of 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester (100 g, 135 mmol) and 10% palladium / activated carbon (Type 58, standard, reduced, nominally 50% wetted water, 4.50 g, 2.13 mmol) in HFIP (500 mL) was purged three times with vacuum / nitrogen, then three times with hydrogen, and then pressurized to ~850 mbar hydrogen. The reaction mixture was maintained at this pressure at 20 °C for 24 h, then purged with nitrogen, filtered through a Solka-floc pad (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 filtrates were concentrated to a final volume of 200 mL under reduced pressure, then water (100 mL) and methanol (100 mL) were added, followed by product seed crystals (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, the filter cake was washed with an 80:20 methanol:water solution (2 × 300 mL), and dried under vacuum at 30 °C overnight to give a crude product as a white solid (44.5 g, 87% crude yield).

[0253] Recrystallization step: The suspension of crude product (40.6 g, 107 mmol) in DMSO (160 mL) was stirred at 20 °C until a solution was formed. Water (200 mL) was added over 1 hour, maintaining the temperature below 25 °C, and the resulting slurry was stirred for 1 hour. Methanol (240 mL) was added over 1 hour, and the mixture was stirred overnight. The resulting slurry was filtered, the filter cake was washed with an 80:20 methanol:water mixture (2 × 120 mL), and dried on a filter under vacuum. The wet filter cake was then slurried at 20 °C in a mixture of methanol (400 mL) and water (40 mL) for 20 hours, separated by filtration, washed with an 80:20 methanol:water mixture (240 mL), and dried under vacuum at 30 °C overnight to give the desired white solid product (37.1 g, 91% recrystallization yield, 79% overall yield).

[0254] The analyzed data are consistent with those reported in step 4 of Example 1.

[0255] Example 4 - Alternative conditions for step 4 of Example 1: Synthesis of 3-[4-[methyl-[2-(methylamino)ethyl]carbamoyl]phenyl]-1-aminosulfonyl-pyrrole-2-carboxylic acid

[0256]

[0257] A mixture of 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester (20 g, 27 mmol) and 10% palladium / activated carbon (nominal 50% wetted water, 2.0 g, 0.94 mmol) in TFE (1000 mL) was purged twice with vacuum / nitrogen, then purged three times with hydrogen, and then pressurized to 2–4 atm hydrogen. The reaction mixture was kept at this pressure at room temperature for 16 hours, then purged with nitrogen and filtered, and washed with TFE (20 mL). The combined filtrates were concentrated to a final volume of 160 mL under reduced pressure, stirred for 6 hours, and then separated by filtration of the precipitated solid. The solid was resuspended in methanol (400 mL), stirred for 2 hours, filtered, 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 hours. The solid was separated by filtration, washed with methanol (60 mL), and dried under vacuum at 40 °C for 8 hours to obtain the desired white solid product (7.2 g, 70%).

[0258] The analyzed data are consistent with those reported in step 4 of Example 1.

[0259] Example 5 – Alternative synthetic route for 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid (via sodium salt)

[0260]

[0261] Step 1: Sodium [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-{4-[(tert-butoxy)carbonyl]phenyl}-1H-pyrrolo-1-yl}sulfonyl)aza

[0262] Sodium benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrole-1-yl)sulfonylaza (35.0 g, 67.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate (22.7 g, 74.7 mmol), and XPhos PdG2 (2.67 g, 3.40 mmol) in a stirred suspension in 1,4-dioxane were degassed and purged with nitrogen, followed by the addition of 3M K3PO4 aqueous solution (67.9 mL, 204 mmol). After heating at 45 °C for 2 hours, 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 ~60 mL. Dilute with diethyl ether (150 mL), and add the resulting solution dropwise to petroleum ether while stirring vigorously. Separate the precipitated solid by filtration and dry to obtain the desired grayish-white solid product (40.4 g, 97%).

[0263] 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).LC-MS(Method A): R T =3.93 min, m / z = 589.6 [MH] - .

[0264] Step 2: 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid

[0265] TFA (73 mL, 0.99 mol) was added to a stirred solution of [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-{4-[(tert-butoxy)carbonyl]phenyl}-1H-pyrrolo-1-yl}sulfonyl)aza compound (40.5 g, 65.8 mmol) in DCM (300 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to dryness. The residue was milled with isopropanol, filtered, and blotted dry to give the desired off-white solid product (25.0 g, 71%). This was used in subsequent steps without further removal of residual salts.

[0266] 1H 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).LC-MS(Method A): R T =3.20 min, m / z = 533.5 [MH] - .

[0267] Compound IVa was synthesized from 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid according to steps 3 and 4 of Example 1.

[0268] Example 6 – Alternative synthetic route for 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid (via free sulfonamide)

[0269]

[0270] Step 1: 1-(benzyloxycarbonylaminosulfonyl)-3-(4-tert-butoxycarbonylphenyl)pyrrole-2-carboxylic acid benzyl ester

[0271] In a similar manner to that described above, benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrole-1-yl)sulfonylazasodium (51.9 g, 101 mmol) was converted to [(benzyloxy)carbonyl]({2-[(benzyloxy)carbonyl]-3-{4-[(tert-butoxy)carbonyl]phenyl})-1H-pyrrole-1-yl}sulfonyl)azasodium. It was redissolved in DCM (500 mL), washed with an aqueous HCl solution (500 mL), dried over Na₂SO₄, filtered, and concentrated to dryness to give the desired off-white solid product (58.0 g, 96%).

[0272] LC-MS (Method A): R T =4.12 min, m / z = 589.6 [MH] - .

[0273] Step 2: 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid

[0274] TFA (109 mL, 1.47 mol) was added to a stirred solution of 1-(benzyloxycarbonylaminosulfonyl)-3-(4-tert-butoxycarbonylphenyl)pyrrole-2-carboxylic acid benzyl ester (58.0 g, 98.2 mmol) in DCM (300 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated to dryness. The residue was ground with isopropanol, filtered, and dried to give the desired off-white solid product (39.2 g, 75%).

[0275] 1 H NMR (500MHz, CDCl3) δ8.68(br s,1H),7.94(br d,J=7.6Hz,2H),7.65(br s,1H),7.40-7.21(m,10H),7.00(br d,J=7.0Hz,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] - .

[0276] Compound IVa was synthesized from 4-[2-benzyloxycarbonyl-1-(benzyloxycarbonylaminosulfonyl)pyrrole-3-yl]benzoic acid according to steps 3 and 4 of Example 1.

[0277] Example 7 - Alternative synthetic route for 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester

[0278]

[0279] Step 1: N-methyl-N-[2-[methyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoyl]amino]ethyl]benzyl carbamate

[0280] DMF (6 μL, 81 μmol) was added to a suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoic acid (1.0 g, 4.03 mmol) in ethyl acetate (10 mL). After cooling to 0 °C, thionyl chloride (0.32 mL, 4.43 mmol) was added dropwise, and the reaction mixture was heated to room temperature and stirred overnight. The resulting solution was concentrated under reduced pressure to about half its volume, and then solid sodium bicarbonate (745 mg, 8.87 mmol) was added, followed by dropwise addition of a solution of 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 ~5 mL, and then petroleum ether (40 mL) was added and stirred for 10 minutes. The precipitated solid was separated by filtration and dried to give the desired white solid product (1.44 g, 79%).

[0281] 1 ¹H NMR (500MHz, 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 =3.65min, m / z = 453.6 [M+H] + .

[0282] Step 2: 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester

[0283] Before adding benzyloxycarbonyl-(2-benzyloxycarbonyl-3-bromo-pyrrole-1-yl)sulfonylazasodium (2.00 g, 3.88 mmol) and N-methyl-N-[2-[methyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoyl]amino]ethyl]carbamate (2.28 g, 5.05 mmol) to 1,4-dioxane (10 mL), 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 minutes. The mixture was degassed and placed under a nitrogen atmosphere, then 3M K3PO4 aqueous solution (3.88 mL, 11.6 mmol) was added and the mixture was heated to 60 °C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (~100 mL) and washed with water (2 × 60 mL) and brine (~60 mL). The organic phase was dried with Na₂SO₄, filtered, and concentrated to dryness. The residue was then further concentrated with IPA, ground with diethyl ether, and filtered for separation. The separated solid was redissolved in DCM with methanol and acidified by washing with 1 M HCl aqueous solution. The organic phase was dried with Na₂SO₄, filtered, and concentrated to dryness. The mixture of DCM and petroleum ether was then further concentrated to give the desired off-white solid product (2.55 g, 88%).

[0284] 1 H NMR (500MHz, CDCl3) δ8.64 (br s, 1H), 7.55 (d, J = 3.1Hz, 1H), 7.39-7.20 (m, 17H), 7.10-7.01 (br m,2H),6.25(d,J=2.4Hz,1H),5.20-4.95(m,6H),3.76(br t,J=5.5Hz,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(brm,1H).LC-MS (Method A): R T =3.31min, m / z = 739.5[M+H] + .

[0285] According to step 4 of Example 1, compound IVa was synthesized from benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester.

[0286] Example 8 - Alternative synthetic route for benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester (via coupling with chloride)

[0287]

[0288] Step 1: Benzyloxycarbonyl-(2-benzyloxycarbonyl-3-chloro-pyrrole-1-yl)sulfonylazasodium

[0289] Under a nitrogen atmosphere, a suspension of sodium hydride (60% in mineral oil, 25.2 g, 630 mmol) in anhydrous THF (200 mL) was cooled to -10 °C, followed by the dropwise addition of a solution of 3-chloro-1H-pyrrole-2-carboxylic acid benzyl ester (49.5 g, 210 mmol) in anhydrous THF (200 mL) over 60 minutes, ensuring the temperature remained below -5 °C. The reaction mixture was heated to room temperature and stirred for 1 hour, then cooled again to -10 °C. Over 45 minutes, N-chlorosulfonylcarbamate benzyl ester (57.7 g, 231 mmol) was added to the reaction mixture in portions, ensuring the temperature remained below -5 °C. The reaction mixture was heated to room temperature and stirred for 2 hours, then cooled again to -10 °C and quenched by the dropwise addition of a 50:50 water:salt solution (250 mL). The mixture was extracted into ethyl acetate (3 × 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 ground in diethyl ether (200 mL), filtered and dried to give the desired white solid product (94.5 g, 96%).

[0290] 1 ¹H NMR (500MHz, 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 =3.48min,m / z=447.2 / 449.2[MH] - .

[0291] Step 2: 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester

[0292] A mixture of benzyloxycarbonyl-(2-benzyloxycarbonyl-3-chloro-pyrrole-1-yl)sulfonylazasodium (500 mg, 1.06 mmol) and benzyl N-methyl-N-[2-[methyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoyl]amino]ethyl]carbamate (606 mg, 1.34 mmol) in 1,4-dioxane (4 mL) was degassed by bubbling under nitrogen for 5 min, and then a solution of XPhos Pd G2 (88 mg, 0.11 mmol) and K3PO4 (711 mg, 3.35 mmol) in water (1 mL) was added. The reaction mixture was then heated to 50 °C for 2 h under a nitrogen atmosphere. Afterward, the reaction mixture was cooled to room temperature, diluted with a 50:50 water:sweet solution (3 mL), and extracted into ethyl acetate (3 × 3 mL). The combined organic phases were washed with 2M HCl aqueous solution (5 mL) and brine (5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate, elution gradient from 90:10 to 0:100) to give the desired pale yellow solid product (280 mg, 36% yield).

[0293] 1 ¹H NMR (500MHz, 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 =3.73min, m / z = 740.0 [M+H] + .

[0294] According to step 4 of Example 1, compound IVa was synthesized from benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester.

[0295] Example 9 – Alternative synthetic route for benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester

[0296]

[0297] Step 1: N-{2-[1-(4-ethynylphenyl)-N-methylformamido]ethyl}-N-methylcarbamate benzyl ester

[0298] HBTU (23.1 g, 61.0 mmol) was added to a mixture of 4-ethynylbenzoic acid (6.86 g, 46.9 mmol) and N-methyl-N-[2-(methylamino)ethyl]carbamate benzyl ester hydrochloride (13.4 g, 51.6 mmol) in DCM (150 mL), followed by the addition of DIPEA (36.1 mL, 211 mmol), and the mixture was stirred at 20 °C for 3 days. The reaction mixture was concentrated to dryness, redissolved in ethyl acetate (400 mL), and washed with 2 M HCl aqueous solution (2 × 200 mL), water (200 mL), saturated sodium bicarbonate aqueous solution (2 × 200 mL), water (200 mL), and brine (100 mL). The organic phase was dried with MgSO4, filtered, concentrated to dryness, and purified by column chromatography (silica gel, petroleum ether: ethyl acetate, elution gradient from 100:0 to 0:100) to obtain the desired straw-colored gelatinous product (16.0 g, 97%).

[0299] 1 H NMR (500MHz, CDCl3) δ7.47(br d,J=7.8Hz,2H),7.40-7.25(m,7H),5.20-4.90(m,2H),3.74(t,J=5.2Hz,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 =1.76min, m / z = 351.2[M+H] + .

[0300] Step 2: 3-{4-[(2-{[(benzyloxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]phenyl}-1H-pyrrole-2-carboxylic acid benzyl ester

[0301] Under an argon atmosphere, a mixture of 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. Before reheating at 100 °C for 2 hours, a solution of 2-isocyanoacetate (2.10 g, 12.0 mmol) in anhydrous 1,4-dioxane (10 mL) was added dropwise to the heated suspension (via syringe pump ~80 min). After cooling to room temperature, the reaction mixture was diluted with diethyl ether (200 mL) and stirred for 10 min, then... Filter. Concentrate the filtrate until dry to obtain the desired yellow gelatinous product (4.26 g, 81%).

[0302] 1 H NMR (500MHz, CDCl3) δ9.28 (br s, 1H), 7.54 (br d, J = 7.8Hz, 2H), 7.40-7.25 (m, 12H), 6.95 (t, J = 2.7Hz, 1H), 6.34 (br s,1H),5.24(s,2H),5.20-4.92(m,2H),3.76(br s,1H),3.69-3.26(br m,3H),3.20-2.82(br m,5H),2.75-2.55(br m,1H).LC-MS (Method C): R T =1.98min, m / z = 526.3 [M+H] + .

[0303] Step 3: 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester

[0304] Under an argon atmosphere, a suspension of sodium hydride (60% in mineral oil, 228 mg, 5.71 mmol) in anhydrous THF (5 mL) was cooled to -10 °C, followed by the dropwise addition of a solution of 3-{4-[(2-{[(benzyloxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]phenyl}-1H-pyrrole-2-carboxylic acid benzyl ester (1.00 g, 1.90 mmol) in anhydrous THF (5 mL) over 30 minutes. The reaction mixture was heated to room temperature and stirred for 60 minutes, then cooled again to -10 °C. N-chlorosulfonylcarbamate benzyl ester (523 mg, 2.09 mmol) was added to the reaction mixture in portions over 25 minutes, and the mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was recooled to -10°C, carefully quenched with a 1:1 brine:water solution (20 mL), acidified with a 2 M HCl aqueous solution (50 mL), and extracted into ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to dryness to give a colorless, colloidal crude product (1.29 g, 92%).

[0305] 1H NMR (500MHz, CDCl3) δ8.67 (br s, 1H), 7.55 (d, J = 3.2Hz, 1H), 7.40-7.20 (m, 17H), 7.05 (br s, 2H), 6.15 (br d,J=2.3Hz,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 =2.17min, m / z = 739.3 [M+H] + .

[0306] According to step 4 of Example 1, compound IVa was synthesized from benzyl 3-[4-[2-[benzyloxycarbonyl(methyl)amino]ethyl-methyl-carbamoyl]phenyl]-1-(benzyloxycarbonylaminosulfonyl)pyrrole-2-carboxylic acid benzyl ester.

Claims

1. A method for forming a formula (IV) compound or a pharmaceutically acceptable salt thereof, the method comprising: (a) In the presence of Pd / C, the compound of formula (I) reacts with the compound of formula (II) to form the compound of formula (III): ;and (b) Formation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof from a compound of formula (III): in x is independently selected from Cl, Br, I, N2 + or OSO2CF3; R 2 is a protecting group; R 3 Independently selected from -CH2-aryl or tert-butyl; Each R 4 It is C independently each time it appears. 1-4 alkyl; R 8a Is it BF3K or B(OR)? 9a )2; where R 9a It is either H or C each time it appears. 1-4 Alkyl; or two R 9a Substituents together form (CR) a R b ) n Or two Rs 9a Substituents together form -C(O)-(CR) a R b )-N(R c )-(CR a R b )-C(O)-; R a R b and R c Each time it appears, it is independently selected from H and C. 1-4 alkyl; n is 2 or 3; and A is independently selected from H or cations.

2. The method of claim 1, wherein step (b) comprises the following steps: (i) Reacting compound (III) with compound (V) to form compound (VI): ； and (ii) Cleavage of R from compound of formula (VI) 2 R 3 and R 5 Substituent-forming (IV) compounds or their pharmaceutically acceptable salts: in R 5 It is a protecting group.

3. The method according to claim 2, wherein R 5 It is benzyloxycarbonyl (Cbz).

4. The method according to claim 1, wherein the compound of formula (I) is formed by reacting the compound of formula (VII) with the compound of formula (VIII) to form the compound of formula (I): ， Where R 6 Independently selected from F, Cl, Br, I or .

5. The method of claim 1, wherein X is Br.

6. The method of claim 1, wherein R 8a It is B(OR) 9a )2.

7. The method of claim 6, wherein R 8a It is B(OH)2.

8. The method according to claim 1, wherein R 3 It is Bn.

9. The method of claim 1, wherein R 2 It is benzyloxycarbonyl (Cbz).

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