Azacyclobutane derivatives used to treat integrin-related diseases

Abstract

This invention relates to the ability of formula (I) to function as α v Novel compounds of β6 integrin antagonists, their use in treating diseases, methods of their manufacture, and compositions comprising said compounds for this purpose, wherein R 1 Selected from: R 1a 、-C(O)R 1a -C(O)OR 1a -C(O)NHR 1a 、-C(O)N(R 1a )2、-SO2R 1a , where R 1a Each is independently selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or alkylheteraryl, wherein each can be optionally substituted; R 2 Selected from: hydrogen, halogen, optionally substituted alkyl or optionally substituted alkoxy; R 2a Each is independently selected from: hydrogen, halogen, optionally substituted alkyl or optionally substituted alkoxy; R 3 Selected from: hydrogen, optionally substituted alkyl, or optionally substituted alkoxy; R 4 For hydroxyl group; Ar 1 It is optionally substituted heteroaryl or bicyclic heteroaryl; and L is a linker; or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This invention relates to the ability to act as α v Novel compounds of β6 integrin antagonists, the use of the novel compounds in the treatment of diseases, methods for manufacturing the novel compounds, and compositions comprising the compounds for this use. Background Art

[0002] Integrins are cell adhesion receptors composed of a group of heterodimeric glycoprotein complexes formed by α and β subunits. They play a role in signal transduction pathways. Integrins typically function in conjunction with other receptors to control cell interactions and synergize with a range of ligands, such as fibronectin and laminin.

[0003] Integrin receptors are known to play a role in the etiology of a range of different diseases. Of particular note is RGD-integrin (which contains an arginine-glycine-aspartic acid motif in its sequence). For example, α... v β3 is considered an important drug target because its abnormal expression is associated with diseases such as angiogenesis, cancer, and inhibition of bone resorption in the body.

[0004] DB Whitman et al., Bioorg. Med. Chem. Lett., 2004, 14, 4411-4415, describe an effective α v β3 receptor antagonist compounds are considered effective in treating osteoporosis. Similarly, US2018 / 0008583 discloses a series of compounds that, due to their binding to α... v β3 and α v β5 integrin receptors, these compounds are considered effective in treating various cancers. WO2018 / 089355 identified a series of nitrogen-containing heterocyclic butane compounds for the treatment of multiple diseases; these compounds are α... v β1, α v β3, α v β5, α v β6 and α v A potential antagonist for any integrin in β8 integrins. Furthermore, WO2015 / 048819 discloses a series of antagonists related to α... v Compounds that effectively bind to β1 receptors are considered effective in treating various forms of fibrosis. However, the binding affinity of compounds to different receptors can vary considerably between compounds. Furthermore, a compound that effectively binds to one receptor may not effectively bind to another.

[0005] Previous attempts have focused on targeting these integrins to enhance disease treatment. For example, WO2016 / 046230 discloses various compounds suitable for targeting these proteins. Furthermore, WO2016 / 04624, WO2014 / 154725, and WO2016 / 046225 have also shown similar results.

[0006] However, despite these efforts, there is still a need for novel alternative compounds that can provide effective treatment for a variety of integrin-regulated diseases and / or offer improved efficacy in the treatment of a range of known diseases.

[0007] The present invention aims to overcome or at least improve this problem. Summary of the Invention

[0008] In a first aspect of the invention, a compound of formula (I) is provided:

[0009]

[0010] in,

[0011] R 1 Selected from: R 1a -C(O)R 1a -C(O)OR 1a -C(O)NHR 1a -C(O)N(R) 1a )2、-SO2R 1a , where R 1a Each is independently selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or alkylheteraryl, wherein each can be optionally substituted; R 2 Selected from: hydrogen, halogen, or optionally substituted alkyl groups; R 2a Each is independently selected from: hydrogen or optionally substituted alkyl groups; R 3 Selected from: hydrogen or optionally substituted alkyl groups; R 4 For hydroxyl group; Ar 1 , which can be optionally substituted heteroaryl or bicyclic heteroaryl; and, L, which is a linker. Pharmaceutically acceptable salts of the compound are also envisioned.

[0012] The inventors discovered that compound (I) reacts with α v They are particularly effective at binding to the β6 receptor. Without being bound by theory, it is assumed that the stiffness of the four-membered ring structure plays a significant role in the observed efficacy of these compounds.

[0013] The term "alkyl" is intended to take its usual meaning in the art. Specifically, alkyl groups may be optionally substituted and may be C1 to C2. 12An alkyl group, in which one or more hydrogen atoms can be replaced by a halogen, such as fluorine or chlorine (usually fluorine), to form, for example, a monohalogenated or dihalogenated alkyl group, such as –CHF2. Typically, the length of the alkyl group is from C1 to C2. 10 Within the range, more typically within the C1 to C8 range, even more typically within the C1 to C7 range, more typically still within the C1 to C6 range, and generally within the C1 to C4 range. The alkyl group can be cyclic, branched, or straight-chain (though usually straight-chain) and is generally selected from: methyl, ethyl, and propyl. Similarly, the term "alkoxy" is intended to take its usual meaning in the art. That is, an alkyl group as described above, bonded by an oxygen atom. The term "alkylalkoxy" means an alkyl group (as described above) attached to an alkoxy group (as described above). The alkoxy group can be attached to any alkyl carbon (although usually it is attached to the terminal carbon). The length of the alkyl group present in an alkylalkoxy group is generally within the C1 to C8 range. 10 Within the range of; more usually within the range of C1 to C8; more usually within the range of C1 to C4; and most usually C1 or C2.

[0014] The term "alkenyl" is intended to be used in its usual sense within the field. Specifically, an alkenyl group can be an alkyl group as defined above, containing one or more carbon-carbon double bonds. Typically, an alkenyl group will contain one double bond. Sometimes, an alkenyl group will include two or three double bonds.

[0015] The term "alkynyl" is intended to be used in its usual sense in the field. Specifically, an alkynyl group can be an alkyl group as described above, containing one or more carbon-carbon triple bonds. Typically, an alkynyl group will contain one triple bond. Sometimes, an alkynyl group may include two or three triple bonds.

[0016] The term "aryl" is intended to be used in its usual sense in the art. Typically, the ring structure will be a fully aromatic structure. The term is also intended to cover fused ring structures containing two or more rings. Thus, fused rings consisting of two, three, four, five, or six rings may be included. Aryl fused ring structures may contain non-aromatic rings combined with at least one aromatic ring or partially aromatic ring. These rings can be selected from three- to eight-membered rings. Typically, these rings will be selected from four-, five-, six-, and seven-membered rings. Even more typically, these rings will be five- or six-membered rings. Typically, the aryl group will include at least one six-membered ring. As mentioned above, the aryl group may include one or more optional substituents. Common substituents that replace one or more hydrogen atoms include, but are not limited to: halogens (such as chlorine and fluorine, typically fluorine), hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, carboxylic acids, amines, amides, cyano, sulfonyl (e.g., SO2Me), or combinations thereof. There is no particular limit to the number of substituents, but typically each ring will have four or fewer substituents, more commonly three or fewer, and even more commonly two or fewer. Usually, only one substituent is present per ring.

[0017] The term "heteroaryl" is intended to be used in its usual sense in the art. Specifically, it refers to an aryl group as described above, in which one or more ring carbons are replaced by heteroatoms, typically selected from nitrogen, sulfur, or combinations thereof. Typically, the heteroatom will be selected from nitrogen, oxygen, or combinations thereof; most commonly, the heteroatom is nitrogen. Typically, fewer than four heteroatoms are used per ring, and more commonly two or fewer. Most heteroaryl substituents contain two heteroatoms.

[0018] The term "alkylaryl" is intended to be used in its usual sense in the art. In particular, it can refer to an alkyl group as described above, which is also covalently bonded to an aryl group as described above. The aryl group can be bonded to any alkyl carbon, but it is usually bonded to a terminal carbon. Similarly, the term "alkylheteroaryl" is intended to be used in its usual sense in the art. In particular, it can refer to an alkyl group as described above, which is also covalently bonded to a heteroaryl group as described above. The heteroaryl group can be bonded to any alkyl carbon, but it is usually bonded to a terminal carbon. The length of the alkyl group present in alkylaryl or alkylheteroaryl groups is generally between C1 and C2. 10 Within the range; more usually within the range of C1 to C8; more usually within the range of C1 to C4; most usually C1 or C2.

[0019] The term "halogen" as used in this article is intended to include fluorine, chlorine, bromine, iodine and combinations thereof; usually fluorine, chlorine, bromine and combinations thereof; more usually fluorine, chlorine and combinations thereof; and most usually fluorine.

[0020] As used herein, the term "optionally substituted" is intended to take its usual meaning in the art. That is, one or more hydrogen atoms are substituted by another substance. Unless otherwise specified herein, optional substituents (which may be the same or different in the presence of multiple substituents) include, but are not limited to: halogens, such as fluorine and chlorine; lower alkyl substances, such as straight-chain, branched, or cyclic C1 to C4 alkyl groups; lower alkoxy groups, such as C1 to C4 alkoxy groups (e.g., –OMe); saturated or unsaturated cycloalkyl groups, such as C1-C6 cycloalkyl groups, typically C6 cycloalkyl groups in which one or more carbon atoms are optionally substituted by heteroatoms such as oxygen or nitrogen or combinations thereof. Other optional substituents include hydroxyl, cyano, nitro, amine, -CONR 11 R 12 、-OR 13 -SO2R 13 -OSO2R 13 , where R 11 and R 12 Each can be represented independently as H or C 1-6 Alkyl group; wherein the R 11 and R 12 The group may optionally be replaced by one or more substituents, which may be the same or different, and these substituents are selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 1-6 The group consisting of alkoxy, cyano, amino, =O, or trifluoromethyl groups; and wherein R 13 C represents optional substitution 1-6 Alkyl groups, such as halogenated or amino-substituted alkyl groups, or optionally substituted aryl groups.

[0021] The “pharmaceutically acceptable salts” described herein are those salts familiar to those skilled in the art, i.e., any form of salt that can be safely administered to a patient. These salts can be acidic or basic, and can be organic or inorganic. Common inorganic salts include alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium, etc.

[0022] Furthermore, the present invention is not limited to a specific form of the compound. Various polymorphs of the compound are contemplated, including crystalline and amorphous forms. Additionally, complexes comprising the compound, and one or more hydrated water or other solvents, are also contemplated.

[0023] In some implementation schemes, R 1 Selected from: R 1a -C(O)R 1a -C(O)OR 1a or -SO2R 1a R 1 It could be -C(O)R 1a or -SO2R 1aIn some cases, R 1 Yes - SO2R 1a R 1a Selected from: alkyl, alkenyl, aryl, heteroaryl, alkylalkoxy, alkylaryl, or alkylheteraryl, each of which can be optionally substituted. In some embodiments, R 1a It is an alkyl or alkenyl group, such as optionally substituted cycloalkyl or optionally substituted cycloalkenyl. In these cases, R 1a Typically, they are optionally substituted cycloalkyl groups containing 4-8 carbons, usually 5 or 7 carbons, and most commonly 6 carbons. On the other hand, R... 1a It can be an optionally substituted cycloalkenyl group containing 4-8 carbons, usually 5 or 7 carbons, and most commonly 6 carbons and one or more double bonds.

[0024] Or, R 1a It can be an aryl or heteroaryl group as described above. In these embodiments, R 1a It typically contains at least one ring structure, usually containing 5-10 atoms in the ring, more commonly 5 or 6 atoms, and most commonly 6 atoms. Sometimes R 1a The ring contains an aryl or heteroaryl group with 5 atoms. Typically, R... 1a It comprises one or more rings selected from: pyrazolyl, thiophenyl, furanyl, pyridyl, imidazolyl, phenyl, naphthyl, quinolinyl, or combinations thereof, each of which can be optionally substituted. Typically, R 1a It comprises phenyl, pyrazolyl, thiophene, or combinations thereof, each of which can be optionally substituted. Typically, R 1a It contains phenyl, pyrazolyl, or combinations thereof, each of which can be optionally substituted. Typically, R 1a It can contain single-ring structures, but it can also have double-ring structures such as indene. However, when it exists as a single-ring structure, R... 1a Typically, it is an optionally substituted phenyl or an optionally substituted pyridine.

[0025] Similarly, R 1a It can also be alkylalkoxy, alkylaryl, or alkylheteroaryl, but more commonly alkylaryl or alkylheteroaryl.

[0026] Typically, each ring structure provides fewer than three substituents. Typical aryl substituents are as described above. In some embodiments, R... 1aIt is an optionally substituted phenyl group having substituents such as C1 to C4 alkyl (usually methyl or ethyl), and at least partially fluorinated C1 to C4 alkyl (usually methyl or CF3), C1 to C4 alkoxy (usually methoxy), at least partially fluorinated C1 to C4 alkoxy, -OCF3 fluorine, chlorine, sulfonyl (e.g., SO2Me), aryl, amide, nitrile, ether, heteroaryl, or combinations thereof. Typically, where optional substituents are present, four or fewer substituents are provided, more usually three or fewer substituents are provided, more usually two or fewer substituents are still provided, and most usually one or two substituents are provided.

[0027] Typically, R 2 Selected from hydrogen, halogen, hydroxyl, optionally substituted alkyl, or optionally substituted alkoxy. In some cases, R 2 Selected from hydrogen or optionally substituted alkyl groups. Wherein R 2 It is an optionally substituted alkyl and / or optionally substituted alkoxy group, typically a C1 to C6 alkyl or alkoxy group, more commonly a C1 to C4 alkyl or alkoxy group, and most commonly a C1 to C3 alkyl or alkoxy group. Typically, R 2 Selected from hydrogen, hydroxyl, fluorine, methyl, ethyl, methoxy, ethoxy, or combinations thereof. In some cases, R 2 Selected from hydrogen, methyl, ethyl, or combinations thereof; most commonly, R 2 Selected from hydrogen, methyl, or combinations thereof. Additionally, R 2 It can also be hydrogen.

[0028] In some cases, R 2a Each is independently selected from hydrogen or optionally substituted alkyl groups. Wherein R 2a It is an optionally substituted alkyl group, typically a C1 to C6 alkyl or alkoxy group, more commonly a C1 to C4 alkyl or alkoxy group, and most commonly a C1 to C3 alkyl or alkoxy group. Typically, R... 2a Each is independently selected from hydrogen, methyl, ethyl, or combinations thereof. Most typically, R... 2a Each is independently selected from hydrogen, methyl, or combinations thereof. Additionally, R 2a It can also be hydrogen. Typically, there are at least two Rs. 2a The groups are identical; more typically, at least three R groups are present. 2a The groups are the same; most typically, all four R groups are the same. 2a The functional groups are all the same.

[0029] Typically, R 3 Selected from hydrogen, optionally substituted alkyl, or optionally substituted alkoxy. In some cases, R 3 Selected from hydrogen or optionally substituted alkyl groups. Wherein R 3It is an optionally substituted alkyl and / or optionally substituted alkoxy group, typically a C1 to C6 alkyl group, more commonly a C1 to C4 alkyl group, and most commonly a C1 to C3 alkyl group. Typically, R... 3 Selected from hydrogen, methyl, ethyl, or combinations thereof. In some cases, R 3 Selected from hydrogen, methyl, ethyl, or combinations thereof; most commonly, R 3 Selected from hydrogen, methyl, or combinations thereof. Additionally, R 3 It can also be hydrogen.

[0030] R 4 It is a hydroxyl group. Without being bound by theory, it is generally accepted that the -OH group or deprotonated -O... - The hydroxyl group plays a crucial role in the binding or coordination of key components of integrins. Therefore, in an alternative embodiment, the hydrogen atom of the hydroxyl group can be replaced by a suitable counterion, such as sodium or potassium (i.e., -O). - Na + or -O - K + ).

[0031] The term "joint" is intended to take its usual meaning in this field. It is a term used to refer to the material Ar. 1 A group covalently linked to the remainder of the compound shown in formula (I) above. This linker has no fixed length, and, as those skilled in the art will understand, the Ar group... 1 The spacing between the linker and the rest of the molecule can be altered by changing the length of the linker. Linker lengths range from two to 20 bond lengths, more typically in the range of 2 to 12 bond lengths, and even more typically in the range of 3 to 7 bond lengths.

[0032] Typically, the connector is selected from any one of formulas (II) to (VIII):

[0033]

[0034]

[0035] Het is a 4, 5, 6, or 7-membered saturated heterocycle containing N, O, S, or C linked by N or C, typically selected from: aziridine, pyrrolidine, piperidine, morpholine, thiomorpholine, homomorpholine, homopiperazine, and aziridine-heptane; R 2 As mentioned above; R 5 R 6 and R 7Each is independently selected from: hydrogen or optionally substituted alkyl groups; I, m, n, and p are each independently an integer in the range of 0 to 10. The positions marked with “*” and “**” represent the left and right sides of the connector, respectively, as shown in formula (I) above. Therefore, the connector is usually oriented such that the left side (*) of the connector is attached to Ar in formula (I). 1 (Tetrahydronaphthylidine). In formula (VIII), "aryl or heteroaryl" can be substituted as previously described.

[0036] where R 2 It is part of the connector (i.e., part of any of the constituent formulas (II) to (VIII)), usually R 2 Selected from hydrogen, halogen, hydroxyl, or optionally substituted alkyl groups. In some cases, R 2 Selected from hydrogen or optionally substituted alkyl groups. Wherein R 2 It is an optionally substituted alkyl group, typically a C1 to C6 alkyl group, more commonly a C1 to C4 alkyl group, and most commonly a C1 to C3 alkyl group. Generally, R... 2 Selected from hydrogen, hydroxyl, fluorine, methyl, ethyl, or combinations thereof. In some cases, R 2 Selected from hydrogen, methyl, ethyl, or combinations thereof; most commonly, R 2 Selected from hydrogen, methyl, or combinations thereof. Additionally, R 2 It can also be hydrogen. Typically, R... 5 R 6 and R 7 Each is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted alkoxy. In some cases, R 5 R 6 and R 7 Each is independently selected from hydrogen or optionally substituted alkyl groups. The alkyl or alkoxy group is typically C1 to C6 alkyl or alkoxy, more commonly C1 to C4 alkyl or alkoxy, and most commonly C1 to C3 alkyl or alkoxy. Typically, R... 5 R 6 and R 7 Each is independently selected from hydrogen, methyl, ethyl, or combinations thereof. In some cases, R 5 R 6 and R 7 Each is independently selected from hydrogen, methyl, ethyl, or combinations thereof; most commonly, R 5 R 6 and R 7 Each is independently selected from hydrogen, methyl, or combinations thereof. R 5 R 6 and R 7 They can also be hydrogen on their own.

[0037] In equation (VII), R 5 and R 7 They can be connected together. Typically, when R... 5 and R 7 When linked together, they will form an optionally substituted ring structure. Typically, this will include four-, five-, six-, seven-, or eight-membered rings; five- or six-membered rings are most common. Typically, the ring will form an optionally substituted cycloalkyl ring, but the ring structure may also include one or more alkenyl groups.

[0038] Generally, "I" and "m" are each independently an integer in the range of 1 to 9, more commonly 1 to 6, even more commonly 1 to 4, and most commonly still 1 to 3. Usually, "I" is 1 or 2; usually "I" is 2. In some cases, "m" is 1 or 2; and usually 1. Regarding "p" and "n", they are each generally an integer in the range of 1 to 9, more commonly 2 to 8, even more commonly 3 to 7, and most commonly still 4 to 6. "p" may be an integer in the range of 4 to 5, most commonly "p" is 5. Usually, "n" is an integer in the range of 4 to 5, most commonly "n" is 4. Usually, "q" is 1 or 2; usually 2.

[0039] In one embodiment, the connector has the structure shown in formula (II), (III), (V), or (VII); more generally, it has the structure shown in formula (II), (V), or (VII). The connector may have the structure shown in formula (V) or (VII). Typically, compounds of formula (II) or (V) are used. However, compounds of formula (VI) or (VIII) may also be used. If the connector has the structure shown in formula (II), (V), (VI), or (VII), then the NR unit (i.e., formula (II)) is NR. 5 Unit, Equation (V) is NR 6 Unit, Equation (VI) is NR 5 Unit, Equation (VII) is NR 5 and NR 7 One or both of the units typically have the following structure:

[0040]

[0041] Despite the above, R 6 It is usually hydrogen or alkyl, and alkyl is usually methyl, ethyl or propyl.

[0042] Despite Ar 1 It may contain a single, optionally substituted heteroaryl ring structure, but Ar 1It can also be a fused ring structure containing at least one optionally substituted heteroaryl group (as described above). Typically, Ar... 1 It contains at least one partial or complete aromatic ring structure. 1 It typically includes two ring structures. These ring structures are usually quinary or hexagram rings; more commonly, they are all hexagram rings. Furthermore, Ar... 1 It typically comprises an aromatic ring and a non-aromatic ring. The aromatic ring is usually an optionally substituted heterocyclic compound, typically an optionally substituted pyridine; the non-aromatic ring is usually a non-aromatic heterocycle that may contain one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof. The non-aromatic ring may be selected from piperidine, piperazine, thiazide, dithiazide, tetrahydropyranyl, dioxane, morpholine, or thiomorpholine, each of which can be optionally substituted. Typically, the non-aromatic group is an optionally substituted piperidine. 1 The optionally substituted aryl or optionally substituted heteroaryl compounds are typically selected from: pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, furan, thiophene, or combinations thereof, each of which can be optionally substituted. Generally, Ar... 1 The heteroaryl compounds are selected from pyridine, pyrimidine, and pyrazine. Most commonly, Ar... 1 The optional substituted heteroaryl substance is pyridine.

[0043] Typically, Ar 1 It can function as a bidentate ligand. Without being bound by theory, the inventors believe that Ar... 1 The presence of two donor atoms in the group facilitates efficient binding with integrins. Therefore, Ar 1 It typically contains at least two donor atoms, ideally with at least two bond lengths between them. Typically, Ar... 1 It consists of two ring structures, each containing a donor atom, typically nitrogen. The rings can be fused together and may include additional rings attached or fused thereto. See pages 3 and 5 of WO2018 / 089353 for details regarding those marked "R". 1 The “arginine analogue section” shows some suitable Ar 1 Examples of functional groups.

[0044] For example, Ar 1 It may have the structure shown according to equations (IXa) to (IXi), as follows:

[0045]

[0046] in,

[0047] X 1 and X 2 Each atom is an independent donor atom, usually nitrogen;

[0048] * indicates Ar 1 Possible connection points between the above-mentioned connectors;

[0049] Each of rings A to D is an aromatic heterocycle or a non-aromatic heterocycle, provided that at least one ring is an aromatic ring.

[0050] R 9 and R 10 Each can be independently selected from: hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylalkoxy, optionally substituted heteroaryl, optionally substituted alkylaryl, or optionally substituted alkylheteraryl, or combinations thereof. Typically R 9 and R 10 Each is independently selected from hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkoxy, typically R 9 and R 10 Each group is independently selected from hydrogen or halogen. Each group includes only one connection point for the junction portion attached to the * position.

[0051] Typically, compounds of formulas (IXa) to (IXd) are used; more commonly, compounds of formula (IXa) are used.

[0052] Typically, Ar 1 Selected from one of the groups shown in formulas (Xa) to (Xr):

[0053]

[0054]

[0055] in,

[0056] R 8 Selected from: hydrogen or optionally substituted alkyl groups, usually hydrogen; and

[0057] R 9 and R 10 As stated above.

[0058] Normally, Ar 1 It is a group represented by formula (XIa), (XIb), or (XIc), usually a group represented by formula (XIa):

[0059]

[0060] in,

[0061] R 8 R 9 and R 10 As stated above; and

[0062] * indicates a connection point connected to the connector.

[0063] where R 8 It is an optionally substituted alkyl group, which is typically a C1 to C6 alkyl group, more commonly a C1 to C4 alkyl group, and most commonly a C1 to C3 alkyl group. Typically, R... 8 Selected from hydrogen, methyl, ethyl, or combinations thereof. In some cases, R 8 Selected from hydrogen, methyl, ethyl, or combinations thereof; most commonly, R 8 Selected from hydrogen, methyl, or combinations thereof. Additionally, R 8 It can also be hydrogen.

[0064] Regarding R 9 and R 10 Each of these is typically selected independently from: hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, or combinations thereof. More commonly, R... 9 and R 10 Each is independently selected from: hydrogen, halogen, optionally substituted alkyl groups, or combinations thereof. In some embodiments, R 9 and R 10 Each is hydrogen on its own.

[0065] These compounds may be provided in enantiomerically pure form or as mixtures of enantiomers, including racemic mixtures. Typically, these compounds are optically pure, but racemic mixtures may be used in certain cases. As those skilled in the art will understand, the term "enantiomerically pure" is not limited to its literal meaning. In cases where optically pure compounds are provided, other enantiomers, diastereomers, or other isomers are typically provided in amounts less than 10%, usually less than 5%, and sometimes even less than 1%.

[0066] In the compound of formula (I), R 1 It might be -SO2R 1a , where R 1a Each is independently selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, or alkylheteraryl, wherein each can be optionally substituted; R 2 Selected from: hydrogen, halogen, optionally substituted alkyl or optionally substituted alkoxy; R 2a Each is independently selected from: hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy; R 3 Selected from: hydrogen, optionally substituted alkyl, or optionally substituted alkoxy; R 4 For hydroxyl group; Ar 1 For (XIa):

[0067]

[0068] where R 8 Selected from: hydrogen or optionally substituted alkyl groups; R 9 and R 10 Each can be independently selected from: hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylalkoxy, optionally substituted heteroaryl, optionally substituted alkylaryl, or optionally substituted alkylheteroaryl, or combinations thereof; and L is a linker selected from any one of formulas (II), (V), and (VI):

[0069]

[0070] or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the compound has the structure shown in formula (Ia):

[0072] in,

[0073] R 1 As stated above.

[0074] The compound in this example has a chiral center (marked as * in formula Ia above). This chiral center can be R or S, but is usually S.

[0075] To avoid ambiguity, the present invention also includes derivatives of the compounds of the present invention and / or prodrugs of the compounds of the present invention.

[0076] A second aspect of the invention provides compositions comprising the compounds described in the first aspect of the invention. As will be understood by those skilled in the art, various excipients and other ingredients may be added to the compounds described in the first aspect of the invention to alter the physical properties of the compositions or formulations containing the compounds. Such alterations may be for various reasons, such as: improving the stability of the compound (in vitro and / or in vivo), enhancing the solubility of the compound, or improving the delivery of the compound to a specific site in the body. Common additives that may be introduced into the compositions of the invention include, but are not limited to: solvents, surfactants, fillers, buffers, flavoring agents, pharmaceutically acceptable carriers, diluents or fillers, binders, disintegrants, lubricants, colorants, and preservatives.

[0077] The compounds of the present invention can be used to treat a variety of different conditions, some of which are more suitable for administration via a single route than others. Therefore, while there are no particular limitations on the type of compositions or formulations used in the present invention, generally, the compositions are suitable for oral, inhalation, injection, transdermal delivery, topical, sublingual, ocular, rectal, vaginal, or parenteral administration routes. Of these methods, oral administration and inhalation are most preferred. In particular, inhaled formulations are often desirable in cases of lung diseases requiring treatment. In some cases, combinations of multiple routes may be used. The compounds of the present invention have been found to be particularly suitable for oral administration.

[0078] This compound is typically provided in composition form at therapeutically effective amounts. Those skilled in the art will understand that a “therapeutically effective amount” is generally a concentration sufficient to achieve a detectable reduction in disease, i.e., it brings at least some relief from disease symptoms and / or the disease itself. Typically, it does not include doses that would have adverse effects on the patient.

[0079] This compound can be present in the composition in a range of dosages. Moreover, it will be apparent to those skilled in the art that different dosages are often required to treat different diseases, different patients, and different dosage regimens. The usual dosage is the daily dose. However, the amount of the compound (or its pharmaceutical salt) is typically in the range of 0.01 to 3000 mg, more typically in the range of 100 to 2000 mg. The dosages provided herein are for oral administration. The purity of the compound is typically at least 80%, more typically at least 90%, and even more typically at least 95%.

[0080] There are no particular limitations on how the composition is formulated, and the composition can be formulated as a solid, such as a powder, tablet, or capsule as is known to those skilled in the art. Alternatively, it can be a liquid formulation, for example, for ocular administration or topical application, depending on the method of administration.

[0081] The compositions of the present invention may also provide additional pharmaceutically active agents, such as other antifibrotic or anticancer drugs.

[0082] In a third aspect of the invention, the use of the compounds described in the first aspect of the invention or the compositions described in the second aspect of the invention in a therapeutic context is also provided. Specifically, for the treatment of integrin-related diseases. As mentioned above, the binding and interaction of compounds and integrins are considered important in the regulation of many biological functions. Furthermore, in many cases, disrupting or otherwise affecting these integrins can provide valuable treatment for a range of diseases. In this example, the compounds described in the first aspect of the invention can effectively bind to several integrins. In particular, these compounds typically bind at least to α-integrins. v β6 integrin binds effectively, especially as α vAntagonist of β6 integrin. This compound can also bind effectively to other integrins, such as α-integrin. v β1, α v β3, α v β5 and α v One or more of β8.

[0083] There are no particular limitations on the diseases for which these compounds are suitable for treatment, and any of the following can be selected: cancer, ischemic diseases, fibrosis, osteoporosis, and postoperative restenosis. Diseases that are particularly effectively treated by the compounds of the present invention include cancer and fibrosis. There are no particular limitations on the types of cancer or fibrosis that can be treated with the compounds of the present invention. Fibrosis generally encompasses diseases caused by the formation of excessive connective tissue in the body. Examples of fibrotic diseases that are particularly effectively treated by the compounds and compositions of the present invention include, but are not limited to: pulmonary fibrosis (such as cystic fibrosis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, progressive massive fibrosis, and ARDS-related fibrosis, etc.), renal fibrosis (such as diabetic nephropathy, lupus nephritis, IgA nephropathy, drug- or hypertension-induced nephropathy, focal segmental glomerulosclerosis, etc.), liver fibrosis (e.g., virus-induced fibrosis, autoimmune hepatitis, cirrhosis, alcoholic liver disease, non-alcoholic fatty liver disease, congenital liver fibrosis, sclerosing cholangitis, etc.), and skin fibrosis (proliferative scarring). This invention relates to various fibrotic conditions, including scleroderma, keloids, dermatomyositis, eosinophilic fasciitis, bilateral renal contracture, Ehlers-Danlos syndrome, Peyronie's disease, bullous epidermolysis bullosa, oral submucosal fibrosis, ocular fibrosis (age-related macular degeneration, diabetic macular edema, dry eye, glaucoma), cardiac fibrosis (congenital heart failure, atherosclerosis, myocardial infarction, endocardial fibrosis, hypertrophic cardiomyopathy), Crohn's disease, myelofibrosis, uterine leiomyomas, or combinations thereof. In particular, the compounds of this invention are used to treat idiopathic pulmonary fibrosis.

[0084] Regarding cancer, there are no particular limitations on the types of cancer that the compounds of this invention may be effective in treating. Generally, cancer refers to the following cancers: skin cancer, lung cancer, liver cancer, breast cancer, colon cancer, cervical cancer, pancreatic cancer, or ovarian cancer.

[0085] Although this article refers to the “treatment” of the disease, the invention also includes preventive applications for the disease and symptoms.

[0086] A fourth aspect of the invention provides a method for preparing the compound according to the first aspect of the invention, comprising the following steps:

[0087] i) The first compound shown in formula (XII): Compared with the second compound shown in formula (XIII): To carry out the reaction;

[0088] in,

[0089] R 1 R 2 R 3 R 4 In the middle, R 4 It is a protected carboxylic acid (e.g., ester), L and Ar 1 As described in the first aspect of the invention above. An example of the synthetic route for L, as shown in structure (II), is shown below. Those skilled in the art will recognize that variations of this route are applicable to the other examples and claims herein.

[0090]

[0091] Intermediate B can be prepared by reacting intermediate A with an aqueous base (e.g., lithium hydroxide or sodium hydroxide) in a mixture of a suitable alcohol solvent (e.g., methanol or an ether solvent such as tetrahydrofuran) and water at room temperature.

[0092] Intermediate D can be prepared by reacting intermediate B with commercially available intermediate C in the presence of a suitable coupling agent (e.g., T3P, or HATU, or EDC.HCl) and in a suitable base (e.g., NMM or NEM) and a suitable solvent (e.g., THF, acetonitrile, or DMF) at room temperature.

[0093] Intermediate E can be prepared by reacting intermediate D on activated carbon in the presence of a hydrogenation catalyst (e.g., Pd) at a ratio of 10% in the presence of hydrogen and a pressure of 15 to 45 psi in a suitable solvent. Alternatively, intermediate E can be prepared by reacting intermediate D on activated carbon in the presence of a hydrogen transfer agent (e.g., ammonium formate) and a catalyst (e.g., Pd) at a ratio of 10% in an alcohol solvent (e.g., ethanol) at a suitable temperature (e.g., 60°C–80°C).

[0094] Intermediate G can be prepared from commercially available intermediate F and a suitable reagent (e.g., sulfonyl chloride) in a mixture of diethyl ether in the presence of a suitable base (e.g., aqueous sodium hydroxide solution) at a temperature between 0°C and 20°C.

[0095] Intermediate H can be prepared by reacting intermediates E and G in the presence of a suitable coupling agent (e.g., T3P, or HATU, or EDC.HCl) in the presence of a suitable base (e.g., NMM or NEM) in a suitable solvent at a temperature between 0°C and 20°C.

[0096] Intermediate I can be prepared by reacting intermediate H with a reagent (e.g., trifluoroacetic acid) in a suitable solvent (e.g., dichloromethane) at a temperature between 0°C and 20°C.

[0097] Compounds such as those of formula J can be prepared by reacting intermediate I in a suitable alcohol solvent (e.g., ethanol) at a temperature between 0°C and 20°C in the presence of a suitable base (e.g., an aqueous solution of sodium hydroxide).

[0098] Typically, the connector is as described above with respect to the first aspect of the invention.

[0099] As those skilled in the art will understand, many different synthetic routes for intermediate compounds exist in the fourth aspect of this invention. Furthermore, a range of reaction conditions can be employed to perform the steps described above. The steps of the method described in the fourth aspect of this invention do not necessarily need to be performed sequentially, and the method may include one or more purification stages at any or all steps of the synthetic process. Those skilled in the art will understand the necessary filtration techniques required to separate the intermediates and compounds of this invention.

[0100] In another aspect of the invention, a method for treating integrin-related diseases as described above is provided according to a third aspect of the invention, comprising the step of administering a compound according to a first aspect of the invention or a composition according to a second aspect of the invention. Attached Figure Description

[0101] To facilitate understanding, the invention will now be described in conjunction with the accompanying drawings and the following illustrative examples; however, the invention is not limited to these examples.

[0102] Figure 1 The racemic product of Example 4 was analyzed for chirality using supercritical fluid chromatography.

[0103] Figure 2 Chiral analysis of the chiral enriched products of Example 6 was performed using supercritical fluid chromatography.

[0104] Figure 3 Chiral analysis of the first peak (peak 1, 140.3 mg) of a portion of Example 6 obtained by supercritical fluid chromatography;

[0105] Figure 4 Chiral analysis of the second peak (peak 2, 32.6 mg) of a portion of Example 6 obtained by supercritical fluid chromatography;

[0106] Figure 5 It is intermediate 73 1 H NMR spectrum (400MHz; DMSO-d6);

[0107] Figure 6It is Example 24. 1 1H NMR spectrum (600MHz; DMSO-d6);

[0108] Figure 7 It is Example 25. 1 1H NMR spectrum (600MHz; DMSO-d6);

[0109] Figure 8 It is Example 26 1 1H NMR spectrum (600MHz; DMSO-d6);

[0110] Figure 9 It is Example 28. 1 HNMR spectrum (600MHz; DMSO-d6);

[0111] Figure 10 It is Example 31 1 1H NMR spectrum (600MHz; DMSO-d6);

[0112] Figure 11 It is Example 32 1 1H NMR spectrum (600MHz; DMSO-d6);

[0113] Figure 12 It is intermediate 77. 1 H NMR spectrum (400MHz; DMSO-d6);

[0114] Figure 13 It is Example 36 1 H NMR spectrum (400MHz; DMSO-d6);

[0115] Figure 14 It is intermediate 81 1 H NMR spectrum (400MHz; DMSO-d6);

[0116] Figure 15 It is Example 37 1 H NMR spectrum (400MHz; DMSO-d6);

[0117] Figure 16 It is Example 38 1 H NMR spectrum (400MHz; DMSO-d6);

[0118] Figure 17 It is intermediate 83 1 H NMR spectrum (400MHz; DMSO-d6);

[0119] Figure 18 It is Example 391 H NMR spectrum (400MHz; DMSO-d6); and

[0120] Figure 19 It is Example 40. 1 1H NMR spectrum (400MHz; DMSO-d6). Detailed Implementation

[0121] NMR spectra of diluted solutions at ambient temperature were recorded on Bruker AVII+ (600 MHz), Bruker AV-500 (500 MHz), Bruker DPX-400 (400 MHz), Bruker AV-400 (400 MHz), or Bruker DPX-300 (300 MHz) spectrometers. Chemical shifts are expressed in ppm (parts per million), and multiplicity is expressed as: s (singlet), d (doublet), dt (doublet-triplet), t (triplet), td (triplet-doublet), tdd (triplet-doublet-doublet), q (quartet), quin (quintet), and m (multiplicity). Slight impurity or residual solvent peaks were observed in some spectra; only peaks belonging to the product were reported. No exchangeable protons (e.g., NH, NH₂, CONH, OH, CO₂H) were observed in many spectra.

[0122] Mass spectra were recorded on a Bruker MicroTOF system using electrospray ionization (ESI) technology, which was operated in both positive and negative ion modes.

[0123] Routine analysis of compounds is performed using liquid chromatography-mass spectrometry (LCMS). Typical conditions are as follows.

[0124] LC conditions:

[0125] UPLC analysis was performed at 40°C on an Acquity UPLC CSH C18 column (50 mm × 2.1 mm inner diameter; 1.7 μm packing diameter). Solvents used included:

[0126] A = 10 mM ammonium bicarbonate aqueous solution, with pH adjusted to 10 using ammonia solution.

[0127] B = Acetonitrile.

[0128] The gradient used is:

[0129] Time (minutes) Flow rate (mL / min) ％A ％B 0.00 1 97 3 0.05 1 97 3 1.50 1 5 95 1.90 1 5 95 2.00 1 97 3

[0130] UV detection yields a summed signal with wavelengths from 210 nm to 350 nm. Injection volume: 0.3 μL

[0131] MS conditions

[0132] MS: Waters ZQ

[0133] Ionization mode: Alternating scan of positive and negative electrospray

[0134] Scan range: 100 to 1000 AMU

[0135] Scan time: 0.27 seconds

[0136] Inter-scan delay: 0.10 seconds

[0137] Purification conditions

[0138] Example 36 uses reversed-phase preparative HPLC (Reveleris, 10% ammonium carbonate aqueous solution with MeCN content of 0-100%) for purification.

[0139] Under the following conditions, quality-guided automated preparative reversed-phase HPLC (MDAP) is used in the following examples.

[0140] For Examples 23-32: Waters XSelect CSH C18 19×100mm 5μm columns were prepared using acetonitrile water containing ammonium carbonate modifier, or Xterra RP18 columns were prepared and eluted with ammonium carbonate modified MeCN:H2O (15-55%) for 20 minutes.

[0141] For Example 33: Xterra RP18 preparation column, elution was performed for 30 minutes with ammonium carbonate-modified MeCN:H2O (25-55%).

[0142] For Examples 34 and 35: Xbridge prepared C18 columns and eluted with ammonium carbonate-modified MeCN:H2O (25-55%) for 30 minutes.

[0143] For Examples 37-40: Waters XSelect CSH C18 19×100mm 5μm column, elution was performed using acetonitrile water containing ammonium carbonate modifier.

[0144] Other compounds were purified by rapid chromatography, as described in the following paragraphs.

[0145] Rapid chromatographic chromatography was performed on Puriflash silica gel columns and aminopropyl silica gel columns. Gasoline ether refers to light petroleum (bp 40-60℃).

[0146] In some examples, a water:methanol mixture was used as the eluent, and separation was performed using Waters Oasis HLB.

[0147] Reagents are obtained from standard commercial suppliers (e.g., Fluka, Fluorochem, Sigma-Aldrich, Acros) and, unless otherwise specified, can be used without purification.

[0148] Abbreviations:

[0149] EtOAc (ethyl acetate)

[0150] MeCN Acetonitrile

[0151] EtOH (ethanol)

[0152] MeOH (methanol)

[0153] EDC·HCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0154] HOBt 1-hydroxybenzotriazole hydrate

[0155] NMM 4-methylmorpholine

[0156] NEM 4-Ethylmorpholine

[0157] DMAP 4-Dimethylaminopyridine

[0158] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0159] Route 1

[0160]

[0161] Example 1: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(4-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0162] (a) Intermediate 1: 5-(1,8-naphthid-2-yl)valeric acid

[0163]

[0164] Ethyl 5-(1,8-naphthid-2-yl)valerate (5 g, 20.47 mmol) (CAS: 678986-15-7 Bioorg. Med. Chem. Lett., 2004, 14, 1049-1052) was dissolved in THF (100 mL) and water (25 mL). LiOH (1 g, 41.75 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and the residue was dissolved in brine (60 mL). 2 M hydrochloric acid (15 mL) was added dropwise until pH 4 was reached. The precipitate was collected by filtration and dried in a vacuum desiccator for 36 hours to give intermediate 1 (2.9 g). 1 H NMR (400MHz; DMSO-d6) δ12.1(br,1H),9.07(dd,1H),8.42(dd,1H),8.35(d,1H),7.55(m,2H),2.96(t,2H),2.27(t,2H),1.79(quin,2H),1.57(quin,2H). C 13 H 14 HRMS[M+H] of N2O2+H + The calculated value is 231.1134, and the measured value is 231.1151.

[0165] (b) Intermediate 2: Ethyl 3-(5-(1,8-naphthid-2-yl)pentanoylamino)-2-((benzyloxycarbonyl)amino)propionate

[0166]

[0167] Intermediate 1 (0.5 g, 2.17 mmol) was dissolved in dry MeCN (20 mL). Ethyl 3-amino-2-((benzyloxycarbonyl)amino)propionate hydrochloride (0.580 g, 2.17 mmol) (CAS: 179237-70-8, WO9610022), HOBt (0.290 g, 2.17 mmol), EDC·HCl (0.572 g, 2.6 mmol), and NMM (0.72 mL, 6.51 mmol) were added, and the reaction mixture was stirred at room temperature for 22 hours. The solvent was removed to obtain an orange oil, which was dissolved in dichloromethane (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was dried and the solvent was removed under reduced pressure to obtain an orange oil. Purification was performed on a 40 g silica gel column using EtOAc:EtOH (0-10%) as the eluent to obtain a clear / green oil. LCMS showed a small peak for the subtitle compound plus impurities. The oily substance was dissolved in dichloromethane and loaded onto a 28 g aminopropane column. Elution with EtOAc:EtOH (12:1) yielded a clear oily substance (335 mg). Further elution with EtOH (3 × 200 mL) gave intermediate 2 (combined yield, 0.632 g), which was also a clear oily substance. 1 H NMR(400MHz; CD3OD)δ9.07(d,1H),8.16(d,1H),8.08(d,1H),7.75(br,1H),7.73(d,1H),7.36(d,1H),7.28(s,5H),6.80(d,1H),5 .03(s,2H),4.50-4.45(m,1H),4.16(q,,2H),3.81(br,2H),3.07(t,2H),2.34(t,2H),1.95(quin,2H),1.74(q,2H),1.23(t,3H). C 26 H 30 HRMS[M+H] of N2O2+H + The calculated value is 479.2294, and the measured value is 479.2076.

[0168] (c) Intermediate 3: Ethyl 2-amino-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0169]

[0170] Intermediate 2 (632 mg, 1.26 mmol) was dissolved in EtOH (20 mL), and Pd / C (100 mg, 0.94 mmol) was added. The reaction mixture was evacuated under reduced pressure and placed under nitrogen. The reaction mixture was then evacuated under reduced pressure and placed under a hydrogen balloon. The reaction mixture was stirred at room temperature for 58 hours and filtered. The filtrate was collected and the solvent was removed to give intermediate 3 (350 mg), which was a clear green oil. 1 H NMR(270MHz; CDCl3)δ7.14(d,1H),6.60(s,1H),6.35(d,1H),6.17(br,1H),4.29(q,2H),3.71-3.64(m,1H),3.61(dd,1H) ,3.43(t,2H),3.38-3.32(m,1H),2.71(t,2H),2.26(t,2H),2.60(t,2H),1.19(quin,2H),1.74-1.67(m,4H),1.28(t,3H). C 18 H 28 HRMS[M+H] of N4O3+H + The calculated value is 349.2240, and the measured value is 349.2237.

[0171] (d) Intermediate 4: 1-(4-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0172]

[0173] 3-azacyclobutanecarboxylic acid (1 g, 9.9 mmol) was dissolved in diethyl ether:water (1:1, 40 mL). 4-Toluenesulfonyl chloride (1.88 g, 9.9 mmol) and NaOH (79.9 mL, 19.8 mmol) were added to the solution after vigorous stirring for 24 hours. Diethyl ether:water (1:1, 20 mL) was added, and the aqueous layer was acidified to pH 2 with 2 M hydrochloric acid and extracted with EtOAc (3 × 50 mL). The organic layer was collected and the solvent removed to give intermediate 4 (1.5 g), a colorless solid. 1 H NMR (400MHz; CDCl3) δ7.7(d,2H),7.4(d,2H),4.0(m,4H),3.3(tt,1H),2.5(s,3H). C 11 H 13 HRMS of NO4S+Na[M+H] + The calculated value is 278.0463, and the measured value is 278.0448.

[0174] (e) Intermediate 5: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(4-methylbenzenesulfonyl)azacyclobutane-3-formylamino)ethyl propionate

[0175]

[0176] Intermediate 3 (300 mg, 0.86 mmol) was dissolved in dry MeCN (15 mL). DMAP (104 mg, 0.86 mmol), EDC·HCl (220 mL, 1.0 mmol), intermediate 4 (219 mg, 0.86 mmol), and NEM (0.29 mL, 1.7 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours and the solvent was removed to give a yellow oil, which was dissolved in dichloromethane (30 mL) and washed with saturated sodium bicarbonate aqueous solution (3 × 50 mL). The organic layer was collected, dried, and the solvent was removed to give a yellow oil. This yellow oil was purified by column chromatography using a 12 g silica gel column with EtOAc:EtOH (0-8%) as the eluent to give intermediate 5 (170 mg), which was a colorless solid. 1 H NMR (400MHz; acetic acid-d4) δ7.74(d,2H),7.46(d,1H),7.43(d,2H),6.50(d,1H),4.66(dd,1H),4.15(m,2H ),3.88(t,4H),3.66(dd,1H),3.58(dd,1H),3.49(t,2H),3.33(quin,1H),2.77(t,2H),2.72(2H,br s),2.45(3H,s),2.28(t,2H)1.91(br,2H),1.65(br,4H),1.22(t,3H). C 29 H 39 HRMS[M+H] of N5O6S+H + The calculated value is 586.2699, and the measured value is 586.2693.

[0177] (f) Example 1: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(4-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0178]

[0179] Intermediate 5 (130 mg, 0.22 mmol) was dissolved in EtOH (4 mL), and 2 M NaOH (0.4 mL, 0.88 mmol) was added. The reaction mixture was stirred for 24 hours. The solvent was removed to obtain an emulsion solid. The emulsion solid was dissolved in 5 mL of water and loaded onto a 12 g Oasis column and eluted with water:MeOH (0-50%) to give 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(4-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid, which was a colorless solid (102 mg). 1 H NMR(400MHz; CD3OD)δ7.65(d,2H),7.39(d,2H),7.08(d,1H),6.31(d,1H),4.19(dd,1H),3.80-3.69(m,4H),3.52(dd,1H),3.38- 3.34(m,1H),3.25(m,2H),3.12(m,1H),2.63(t,2H),2.45(t,2H),2.39(s,3H),2.10(t,2H),1.81(quin,2H),1.56-1.50(m,4H). C 27 H 35 HRMS[M+H] of N5O6S+H + The calculated value is 558.2386, and the measured value is 558.2376.

[0180] Example 2: 2-(1-(4-fluorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0181] (a) Intermediate 6: 1-(4-fluorobenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0182]

[0183] Intermediate 6 (970 mg) was prepared using 4-fluorobenzenesulfonyl via the method of intermediate 4, and was obtained as a colorless solid. 1 HNMR (400MHz; CDCl3) δ7.9(m,2H),7.3(m,2H),4.1(t,4H),3.3(m,1H). C 10 H 10 HRMS[M+H] of FNO4S+H + The calculated value is 260.0393, and the measured value is 260.0391.

[0184] (b) Intermediate 7: ethyl 2-(1-(4-fluorobenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0185]

[0186] Intermediate 7 (140 mg) was prepared by using intermediate 6 (372 mg, 1.44 mmol) and intermediate 3 (500 mg, 1.43 mmol) via the method of intermediate 5, and was a colorless gel. 1 H NMR(400MHz; CDCl3)δ7.85(m,2H),7.26(m,2H),7.12(d,1H)6.47(d,1H),4.54(ddd,1H),4.21(m,2H),3.92(m,4H),3.76(m,1H),3.55(m, 1H),3.49(t,2H),3.31(m,1H),2.72(t,2H),2.61(s,2H),2.29(m,1H),2.18(s,1H),2.03(d,1H),1.96(m,2H),1.69(s,3H),1.26(t,3H). C 28 H 36 HRMS[M+H] of FN5O6S+H + The calculated value is 590.2449, and the measured value is 590.2477.

[0187] (c) Example 2: 2-(1-(4-fluorobenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0188]

[0189] 2-(1-(4-fluorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)propionic acid (60 mg) was prepared by the method of Example 1(f) using intermediate 7 (140 mg, 0.243 mmol) as a colorless colloid. 1 H NMR(500MHz; CD3OD)δ7.92(m,2H),7.40(dd,3H),6.49(d,1H),4.27(t,1H),3.87(m,4H),3.4 8(m,4H),3.29(m,1H),2.78(t,2H),2.63(t,2H),2.23(quin,2H),1.95(m,2H),1.67(m,4H). C26 H 32 HRMS[M+H] of FN5O6S+H + The calculated value is 562.2136, and the measured value is 562.2159.

[0190] Example 3: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(2-methylbenzenesulfonylazine-3-formylamino)propionic acid

[0191] (a) Intermediate 8: 1-(2-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0192]

[0193] Intermediate 8 (695 mg) was prepared by the method of intermediate 4 using 2-toluenesulfonyl chloride (0.72 mL, 4.95 mmol) and 3-azacyclobutanecarboxylic acid (500 mg, 4.95 mmol), and was a colorless solid. 1 ¹H NMR (400MHz; CDCl₃) δ 7.97 (dt, ¹H), 7.51 (td, ¹H), 7.35 (t, 2H), 4.20–4.03 (m, 4H), 3.43 (tt, ¹H), 2.67 (s, 3H). (b) Intermediate 9: ethyl 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(2-methylbenzenesulfonyl)azacyclobutane-3-carboxyamino)propionate

[0194]

[0195] Intermediate 9, which can be used directly in the next step, was prepared using intermediate 8 (368 mg, 1.44 mmol) and intermediate 3 (500 mg, 1.43 mmol) via the method of intermediate 5.

[0196] (c) Example 3: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(2-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0197]

[0198] 3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(2-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid (150 mg) was prepared using intermediate 9 (300 mg, 0.513 mmol) by the method of Example 1(f). 1H NMR(400MHz; CD3OD)δ7.90(dd,1H),7.54(td,1H),7.45(dt,1H),7.43-7.34(m,2H),6.50(d,1H),4.39-4.27(m,1H),4.10-3.98(m,2H),3 .93(ddd,2H),3.57(dd,2H),3.50-3.39(m,3H),2.78(t,2H),2.70-2.59(m,5H),2.31-2.16(m,2H),1.98-1.87(m,2H),1.74-1.59(m,4H).

[0199] Example 4: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0200] (a) Intermediate 10: 1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0201]

[0202] Intermediate 10 (940 mg) was prepared by the method of intermediate 4 using 3-toluenesulfonyl chloride (0.73 mL, 4.95 mmol) and 3-azacyclobutanecarboxylic acid (500 mg, 4.95 mmol), and was a colorless flaky solid. 1 H NMR (400MHz; CDCl3) δ7.69-7.64(m,2H),7.49-7.46(m,2H),4.00(quin,4H),3.29(m,1H),2.47(s,3H). C 11 H 13 HRMS[MH] of NO4S–H + The calculated value is 254.0487, and the measured value is 254.0485.

[0203] (b) Intermediate 11: ethyl 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionate

[0204]

[0205] Intermediate 11 (220 mg) was prepared by using intermediate 10 (367.6 mg, 1.44 mmol) and intermediate 3 (500 mg, 1.43 mmol) via the method of intermediate 5, and was a colorless network solid. 1H NMR(400MHz; DMSO-d6)δ8.27(d,1H),7.85(t,1H),7.62-7.57(m,2H),7.03(d,1H),6.25(d,1H),4.24(q,1H),4.02(q,2H),3.83-3.70(m ,4H),3.33(m,2H),3.26-3.18(m,3H),2.60(t,2H),2.44(s,3H),2.40(t,2H),2.02(t,2H),1.75(t,2H),1.54-1.42(m,4H),1.13(t,3H). C 29 H 39 HRMS[M+H] of N5O6S+H + The calculated value is 586.2699, and the measured value is 586.2705.

[0206] (c) Example 4: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0207]

[0208] 3(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid was prepared using intermediate 11 by the method of Example 1(f), and was a transparent, colorless glassy substance (95 mg). 1 H NMR (400MHz; CD3OD) δ7.68-7.64(m,2H),7.56-7.54(m,2H),7.45(d,1H),6.51(d,1H),4.28(t,1H),3.97-3.86(m,4H),3.55-3 .53(m,2H),3.46(t,2H),3.30-3.24(m,1H),2.79(t,2H),2.66(t,2H),2.49(s,3H),2.23(t,2H),1.94(quin,2H),1.68(m,4H). C 27 H 35 HRMS[M+H] of N5O6S+H + The calculated value is 558.2386, and the measured value is 558.2404.

[0209] Example 5: 2-(1-(3-fluorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0210] (a) Intermediate 12: 3-(3-fluorobenzenesulfonyl)cyclobutane-1-carboxylic acid

[0211]

[0212] Intermediate 12 (1.08 g) was prepared by the method of intermediate 4 using 3-fluorobenzenesulfonyl chloride (936 mg, 4.95 mmol) and 3-azacyclobutanecarboxylic acid (500 mg, 4.95 mmol), which was a colorless glassy substance. 1 H NMR (400MHz; CDCl3) δ7.68(dt,1H),7.60(m,2H),7.40(tdd,1H),4.04(m,4H),3.34(tt,1H). C 10 H 10 HRMS[MH] of FNO4S–H - The calculated value is 258.0236, and the measured value is 258.0242.

[0213] (b) Intermediate 13: ethyl 2-(1-(3-fluorobenzenesulfonyl)azacyclobutane-3-carboxylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0214]

[0215] A solution of intermediate 12 (372 mg, 1.43 mmol) and intermediate 3 (500 mg, 1.43 mmol) in acetonitrile (150 mL) was cooled to 3 °C, and propylphosphonic anhydride (≥50 wt.% in ethyl acetate, 1.2 mL, 2.00 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.44 mmol) were added dropwise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in a saturated aqueous bicarbonate solution (75 mL) and extracted with dichloromethane (4 × 50 mL). The organic extracts were combined and washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Intermediate 13 (400 mg) was obtained by silica gel chromatography, eluting with ethyl acetate and triethylamine (98:2 to 91:9), as a colorless gel. 1H NMR(400MHz; CDCl3)δ7.94(d,1H),7.63(dt,1H),7.55(m,2H),7.35(tdd,1H),7.13(m,1H),6.33(d,1H),4.46(d,1H),4.14(dd,2H), 3.93(m,4H),3.61(m,2H),3.40(t,2H),3.25(m,1H),2.71(t,2H),2.53(m,2H),2.20(t,2H),1.90(m,2H),1.66(m,4H),1.23(t,3H). C 28 H 36 HRMS[M+H] of FN5O6S+H + The calculated value is 590.2449, and the measured value is 590.2475.

[0216] (c) Example 5: 2-(1-(3-fluorobenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0217]

[0218] 2-(1-(3-fluorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)propionic acid (180 mg) was prepared using intermediate 13 by the method of Example 1(f), and was a colorless gel. 1 H NMR(400MHz; CD3OD)δ(400MHz,MeOD)7.93-7.06(m,5H),6.42(d,1H),4.40-4.20(m,2H),4.08-3.78(m,4H),3.71-3.35(m,4 H),3.34-3.13(m,2H),2.73(t,2H),2.57(t,2H),2.18(heptet,2H),1.89(quin,2H),1.73-1.55(m,4H),1.42-1.18(m,2H). C 26 H 32 HRMS[M+H] of FN5O6S+H + The calculated value is 562.2136, and the measured value is 562.2164.

[0219] Route 2

[0220]

[0221] Example 6A: (S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0222] (a) Intermediate 14: (S)-3-(5-(1,8-naphthid-2-yl)valerylamino)-2-(2-phenylacetamido)propionate methyl ester

[0223]

[0224] To a stirred solution of intermediate 1 (6.85 g, 29.7 mmol), HOBT·H₂O (5.6 g, 35.6 mmol) and EDC·HCl (6.79 g, 35.6 mmol) were added. After 5 minutes, methyl 2-(S)-[N-benzyloxy]amino-3-aminopropionate hydrochloride (8.6 g, 29.7 mmol) (CAS: 35761-27-4) and N,N-diisopropylethylamine (12.2 mL, 71.2 mmol) were added, and the resulting solution was stirred at room temperature for 18 hours. The solution was concentrated to approximately 20 mL, water (100 mL) was added, and the solution was extracted with dichloromethane (5 × 100 mL). The combined organic phases were washed with sodium bicarbonate (3 × 100 mL) and brine (140 mL), dried, and concentrated to obtain the residue, which was purified by chromatographic chromatography with ethyl acetate:methanol (2.5%–10%) to give intermediate 14 (13.79 g). 1 H NMR(400MHz; CDCl3)δ9.1(m,1H),8.19(d,1H),8.10(m,1H),7.9(d,1H),7.44(m1H),7.38(m,1H),7.29-7.24(m,5H),6 .95(d,1H),5.04(s,2H),4.53(m,1H),3.86(m,2H),3.72(s,3H),3.10(m,2H),2.37(m,2H),1.98(m,2H),1.79(m,2H).

[0225] (b) Intermediate 15: Methyl (S)-2-amino-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0226]

[0227] A methanol solution (100 mL) of intermediate 14 (5.8 g, 12.5 mmol) was added to a suspension of Pd / C (10%) (4.5 g) in ethyl acetate (20 mL). The suspension was degassed three times with argon and stirred for 18 hours under a hydrogen atmosphere. The mixture was filtered, and the filtrate was evaporated to give intermediate 15, a light brown oily substance (3.43 g), which was allowed to solidify. 1 H NMR (400MHz; CD3OD) δ7.31(d,1H),6.48(d,1H),3.78(s,3H),3.54(m,2H),3. 44(m,2H),2.76(m,2H),2.61(m,2H),2.25(m,2H),1.92(m,2H),1.65(m,4H).

[0228] (c) Intermediate 16: (S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonylazine-3-formylamino)propionate

[0229]

[0230] Intermediate 10 (331.8 mg, 1.30 mmol), propylphosphonic anhydride solution (50 wt% in EtOAc, 1.21 mL, 1.44 mmol), and N,N-diisopropylethylamine (0.66 mL, 1.73 mmol) were added to a solution of intermediate 15 (500 mg, 1.30 mmol) in acetonitrile (25 mL). The solution was stirred at room temperature under nitrogen for 16 hours, and the solvent was removed under reduced pressure. The resulting oil was dissolved in dichloromethane (50 mL) and washed with saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (20 mL, then 30 mL). The organic layers were combined and washed with saturated aqueous bicarbonate solution (50 mL). The combined organic layers were then dried (MgSO4) and the solvent was removed under reduced pressure to produce a colorless solid. The crude product was purified by rapid chromatography on silica (40 g) and eluted with methanol-dichloromethane (5:95) to give intermediate 16 (340 mg), which was a colorless solid. 1HNMR (400MHz; CDCl3) δ7.68-7.64(m,2H),7.49-7.45(m,2H),7.15(d,1H),6.37(d,1H),4.54(q,1H),3.98-3.89(m,4H),3.73(s,3H) ,3.65(d,2H),3.44(t,2H),3.20(quin,1H),2.74(t,2H),2.57(t,2H),2.48(s,3H),2.25(t,2H),1.94(quin,2H),1.69-1.60(m,4H). C 28 H 37 The calculated HRMS[MH] value for N5O6S–H is 570.2386, while the measured value is 570.2368.

[0231] (d) Example 6A: (S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0232]

[0233] To a solution of intermediate 16 (150 mg, 0.26 mmol) in ethanol (5 mL), 2 M sodium hydroxide aqueous solution (0.26 mL, 0.52 mmol) was added, and the mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure, and the resulting colorless solid was dissolved in water (2 mL) and eluted from an Oasis column using water-methanol. Selected fractions were combined and the solvent was removed under reduced pressure to give (S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid, as a clear, colorless glassy substance (55 mg). 1 H NMR (300MHz; CD3OD) δ7.68-7.62(m,2H),7.56-7.53(m,2H),7.46(d,1H),6.51(d,1H),4.27(t,1H),3.97-3.86(m,4H),3.53( d,2H),3.46(t,2H),3.28(quin,1H),2.79(t,2H),2.66(t,2H),2.48(s,3H),2.22(m,2H),1.93(quin,2H),1.76-1.60(m,4H). C 27 H 35 HRMS[M+H] of N5O6S+H + The calculated value is 558.2386, and the measured value is 558.2368.

[0234] Chiral analysis of the racemic product of Example 4 was performed using supercritical fluid chromatography, and as expected, two components were shown (…). Figure 1 ).

[0235] Chiral analysis conditions:

[0236] Waters: UPC2

[0237] Column details: Lux C1 (4.6mm × 250mm, 5um)

[0238] Column temperature: 40℃

[0239] Flow rate: 4 mL / min

[0240] Detector wavelength: 210-400nm

[0241] Injection volume: 1.0uL

[0242] BPR: 125 BarG

[0243] Isotropic conditions: 40:60 MeOH:CO2

[0244] Chiral analysis of the product from Example 6 under the same conditions showed that the product was not 100% chiral pure, but rather enriched in the first elution peak (see...). Figure 2 The chromatogram showed that the first elution peak was the desired S isomer.

[0245] A portion (198 mg) of Example 6 was chirally purified using supercritical fluid chromatography to yield two products. Peak 1: 140.3 mg ( Figure 3 Peak 2: 32.6 mg Figure 4 ).

[0246] Chiral purification conditions:

[0247] Sepiatec 100Prep SFC

[0248] Column details: Lux C1 (21.2mm × 250mm, 5um)

[0249] Column temperature: 40℃

[0250] Flow rate: 50 mL / min

[0251] BPR: 125 BarG

[0252] Detector wavelength: 210nm

[0253] Injection dosage: 500uL (25mg)

[0254] Isotropic conditions: 40:60 MeOH:CO2

[0255] Peak 1: Example 6A: (S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid - see Figure 3 .

[0256] Peak 2: Example 6B: 6: (R)-3-(5-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)pentanoic acid (see below) - see Figure 4 .

[0257]

[0258] Route 3

[0259]

[0260] Example 7: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethylbenzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0261] (a) Intermediate 17: Lithium 5-(8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoate

[0262]

[0263] Lithium hydroxide monohydrate (1.33 g, 31.6 mmol) was added to a solution of tert-butyl 7-(5-methoxycarbonylpentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (10 g, 28.7 mmol) in tetrahydrofuran (60 mL) and water (20 mL). The reaction mixture was stirred at room temperature for 36 hours, concentrated under reduced pressure, and azeotropically treated with toluene (10 × 25 mL) to give intermediate 17 (11.5 g, 118% solvent residue), which was a creamy foam. 1 H NMR (300MHz; CD3OD) δ7.47(d,1H),6.99(d,1H),3.74(t,2H),2.77(t,2H),2.75(t,2H),2.21(t,2H),1.92(q,2H),1.81-1.64(m,4H),1.52(s,9H). C 18 H 25 HRMS of N2O4 [M] - The calculated value is 333.1820, and the measured value is 333.1807.

[0264] (b) Intermediate 18: 9-tert-butyl-7-(5-((2-((benzyloxycarbonyl)amino)-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid ester

[0265]

[0266] Ethyl 3-amino-2-((benzyloxycarbonyl)amino)propionate (8.67 g, 28.7 mmol) was added to an acetonitrile (500 mL) solution of intermediate 17 (9.77 g, 28.7 mmol). N,N-diisopropylethylamine (9.83 mL, 57.4 mmol) and propylphosphonic anhydride solution (50% w / w in EtOAc, 20.5 mL, 34.44 mmol) were added to this solution, and the reaction was carried out at 0 °C for 10 min. The reaction mixture was stirred at room temperature for 24 h, and the solvent was removed under reduced pressure. The resulting oil was dissolved in dichloromethane (200 mL) and washed with saturated sodium bicarbonate solution (200 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 200 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The obtained oily substance was separated into 4 batches and purified by rapid chromatographic chromatography on a silica gel column (200g, 50μm). The elution was with methanol-ethyl acetate (5:95) to give intermediate 18 (10.5g), which was a clear and colorless oily substance. 1 H NMR(300MHz; CDCl3)δ7.37-7.30(m,6H),6.82(d,1H),5.09(s,2H),4.35(m,1H),4.15(t,2H),3.75(q,2H),3.68-3 .57(m,2H),2.74(t,2H),2.72(t,2H),2.24(t,2H),1.92(quin,2H),1.80-1.64(m,4H),1.53(s,9H),1.25(t,3H). C 31 H 42 HRMS[M+H] of N4O7+H + The calculated value is 583.3132, and the measured value is 583.3152.

[0267] b1) Intermediate 19: 7-(5-((2-amino-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0268]

[0269] To a solution of intermediate 18 (4.55 g, 7.82 mmol) in ethanol (450 mL), palladium carbon (10% w / w, 455 mg) was added and the mixture was placed under nitrogen. The flask was evacuated, placed under hydrogen, and stirred at room temperature for 48 hours. The hydrogen in the flask was evacuated and replaced with air. The reaction mixture was filtered through glass fiber filter paper, and the solid phase was washed with ethanol (50 mL). The filtrate was evaporated under reduced pressure to yield intermediate 19 (3.11 g), which was a clear, colorless oil. 1 H NMR(300MHz; CDCl3)δ7.30(d,1H),6.82(d,1H),4.18(q,2H),3.78-3.70(m,3H),3.62-3.28 (m,4H),2.73(m,4H),2.25(t,2H),1.93(quin,2H),1.75(m,4H),1.53(s,9H),1.25(t,3H). C 23 H 36 HRMS[M+H] of N4O5+H + The calculated value is 449.2758, and the measured value is 449.2757.

[0270] (c) Intermediate 20: 1-(3-(trifluoromethyl)benzenesulfonyl)azacyclobutane-3-carboxylic acid

[0271]

[0272] Intermediate 20 (650 mg) was prepared by the method of intermediate 4 using 3-(trifluoromethyl))benzenesulfonyl chloride (0.69 mL, 4.30 mmol) and aziridine-3-carboxylic acid (500 mg, 4.95 mmol), which was a white flaky solid. 1 H NMR (500MHz; CDCl3) δ8.14(s,1H),8.08(d,1H),7.94(d,1H),7.77(t,1H),4.07(dt,4H),3.39-3.33(m,1H). C 11 H 10 HRMS[M+H] of F3NO4S+H + The calculated value is 310.0361, and the measured value is 310.0366. (d) Intermediate 21: 7-(5-((3-ethoxycarbonyl-2-(1-(3-(trifluoromethyl)benzenesulfonyl)azacyclobutane-3-formylamino)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0273]

[0274] Intermediate 20 (364 mg, 1.12 mmol) was added to a solution of intermediate 19 (500 mg, 1.12 mmol) in acetonitrile (30 mL). N,N-diisopropylethylamine (390 μL, 2.24 mmol) and propylphosphonic anhydride (0.80 mL, 1.34 mmol) were added to this solution, and the reaction was carried out at 0 °C for 10 min. The reaction mixture was stirred under nitrogen at room temperature for 48 h, and the solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane (25 mL) and washed with saturated sodium bicarbonate solution (25 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 25 mL). The organic matter was combined, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The resulting oily substance was purified by rapid chromatographic chromatography using silica (40 g) and eluted with methanol-dichloromethane (5:95) to give intermediate 21 (680 mg), which was a colorless oily substance. 1 H NMR(500MHz; CDCl3)δ8.07(s,1H),8.01(d,1H),7.88(d,1H),7.72(t,1H),7.33 (d,1H),6.83(d,1H),4.33(td,1H),4.08-4.00(m,2H),3.91(dt,4H),3.75-3.71 (m,2H),3.59-3.53(m,1H),3.47-3.43(m,1H),3.14(quin,1H),2.74-2.68(m,4 H),2.20(td,2H),1.91(quin,2H),1.73-1.59(m,4H),1.49(s,9H),1.15(t,3H). C 34 H 44 HRMS[M+H] of F3N5O8S+H + The calculated value is 740.2935, and the measured value is 740.2938.

[0275] (e) Intermediate 22: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethyl)benzenesulfonyl)azacyclobutane-3-carboxylamino)ethyl propionate

[0276]

[0277] Trifluoroacetic acid (2.5 mL) was added to a solution of intermediate 21 (500 mg, 0.68 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 24 hours, and toluene (5 mL) was added. The solvent was removed under reduced pressure and the product was dissolved in dichloromethane (20 mL), and washed with saturated sodium bicarbonate solution (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 10 mL). The organic compounds were combined, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give intermediate 22 (360 mg), which was a white solid. 1 H NMR (500MHz; CDCl3) δ8.11(s,1H),8.05(d,1H),7.91(t,1H),7.75(t,1H),7.18(d,1H),6.37(d,1H),4.47(m,1H),4.16(m,2H),3.97( m,4H),3.63(m,2H),3.44(t,2H),3.21(quin,1H),2.74(t,2H),2.56(t,2H),2.24(t,2H),1.93(quin,2H),1.66(m,4H),1.25(t,3H). C 29 H 36 HRMS[M+H] of F3N5O6S+H + The calculated value is 640.2411, and the measured value is 640.2394.

[0278] (f) Example 7: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethyl)benzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0279]

[0280] Add 0.23 mL of 2M sodium hydroxide aqueous solution (0.47 mmol) to an ethanol solution (150 mg, 0.23 mmol) of intermediate 22. Stir the reaction mixture at room temperature for 24 hours, then remove the solvent under reduced pressure. Elute the crude product from an Oasis column using methanol-water. Combine selected fractions of sufficient purity, remove the solvent under reduced pressure, and give 3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethyl)benzenesulfonyl)azacyclobutane-3-carboxyamino)propionic acid (80 mg), a white solid. 1H NMR(400MHz; CD3OD)δ8.13(d,1H),8.09(s,1H),8.05(d,1H),7.89(t,1H),7.31(d,1H),6.44(d,1H),4.28(t,1H),4.01-3.88(m,4H),3.62 -3.57(m,1H),3.51-3.46(m,1H),3.42(t,2H),3.33(quin,1H),2.74(t,2H),2.60(t,2H),2.20(t,2H),1.89(quin,2H),1.69-1.59(m,4H). C 27 H 32 HRMS[M+H] of F3N5O6S+H + The calculated value is 612.2098, and the measured value is 612.2066.

[0281] Example 8: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethoxy)benzenesulfonyl)azacyclobutane-3-carboxylic acid)propionic acid (a) intermediate 23: 1-(3-(trifluoromethoxy)benzenesulfonyl)azacyclobutane-3-carboxylic acid

[0282]

[0283] Intermediate 23 (500 mg) was obtained by using 3-(trifluoromethoxy)benzenesulfonyl chloride (0.84 mL, 4.95 mmol) and 3-azacyclobutanecarboxylic acid (500 mg, 4.95 mmol) via intermediate 4. It was a colorless glassy substance. 1 H NMR (500MHz; CDCl3) δ7.81(d,1H),7.71(s,1H),7.67(t,1H),7.53(d,1H),4.03(dt,4H),3.36-3.29(m,1H). C 11 H 10 HRMS[M+H] of F3NO5S+H + The calculated value is 326.0305, and the measured value is 326.0310. (b) Intermediate 24: 7-(5-((3-ethoxycarbonyl-2-(1-(3-(trifluoromethoxy)benzenesulfonyl)azacyclobutane-3-formylaminopropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0284]

[0285] Intermediate 24 (480 mg) was prepared using intermediate 23 (346 mg, 1.12 mmol) and intermediate 19 (500 mg, 1.12 mmol) via the method of intermediate 21. 1 H NMR(500MHz; CDCl3)δ7.79(d,1H),7.69(s,1H),7.64(t,1H),7.50(d,1H),7.36(d, 1H),6.86(d,1H),4.35(dt,1H),4.13-4.02(m,2H),3.97-3.89(m,4H),3.77(dt,2H) ,3.62-3.57(m,1H),3.50-3.46(m,1H),3.14(quin,1H),2.79-2.73(m,4H),2.25(t d,2H),1.94(quin,2H),1.75(quin,2H),1.65(quin,2H),1.53(s,9H),1.19(t,3H). C 34 H 44 HRMS[MH] of F3N5O9S–H - The calculated value is 754.2739, and the measured value is 754.2731.

[0286] (c) Intermediate 25: ethyl 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-trifluoromethoxy)benzenesulfonyl)azacyclobutane-3-formylamino)propionate

[0287]

[0288] Intermediate 25 (380 mg) was prepared using intermediate 24 (450 mg, 0.60 mmol) via the method of intermediate 22, and was a white solid. 1 H NMR(500MHz; CDCl3)δ7.78(d,1H),7.69(s,1H),7.64(t,1H),7.51(d,1H) ,7.08(d,1H),6.33(d,1H),4.49-4.46(m,1H),4.19-4.12(m,2H),3.97-3. 87(m,4H),3.63-3.60(m,2H),3.38(t,2H),3.19(quin,1H),2.70(t,2H),2 .49(t,2H),2.19(t,2H),1.89(quin,2H),1.67-1.57(m,4H),1.23(t,3H). C 29 H 36 HRMS[M+H] of F3N5O7S+H+ The calculated value is 656.2360, and the measured value is 656.2356.

[0289] (d) Example 8: 3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethoxy)benzenesulfonyl)azacyclobutane-3-formylamino)propionic acid

[0290]

[0291] 3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-(trifluoromethoxy)benzenesulfonyl)azacyclobutane-3-carboxyamino)propionic acid (100 mg) was prepared using intermediate 25 (150 mg, 0.23 mmol) by the method of Example 7(f), and was a white solid. 1 H NMR(300MHz; DMSO-d6)δ7.95(d,1H),7.86-7.72(m,3H),7.10(d,1H),6.28(d,1H),4.07-4.00(m,1H),3.88-3.73(m,5H ),3.34-3.20(m,3H),3.14(quin,1H),2.62(t,2H),2.42(t,2H),2.05-1.99(m,2H),1.76(quin,2H),1.54-1.42(m,4H). C 27 H 32 HRMS of F3N5O7S+Na[M+Na] + The calculated value is 650.1867, and the measured value is 650.1850. Example 9: 2-(1-(benzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0292] (b) Intermediate 26: 1-(benzenesulfonyl)azacyclobutane-3-carboxylic acid

[0293]

[0294] Intermediate 26 (1.99 g) was prepared by the method of intermediate 4 using benzenesulfonyl chloride (1.27 mL, 9.9 mmol) and 3-azacyclobutanecarboxylic acid (1 g, 9.9 mmol), and was a colorless solid. 1H NMR (400MHz; CD3OD) δ7.90-7.85(m,2H),7.78–7.72(m,1H),7.71-7.66(m,2H),3.99(t,2H),3.93-3.84(m,2H),3.32-3.24(m,1H). C 10 H 11 HRMS of NO4S–H [M] - The calculated value is 240.0336, and the measured value is 240.0336. (c) Intermediate 27: 7-(5-((3-ethoxycarbonyl-2-(1-(phenylsulfonyl)azacyclobutane-3-carboxamido)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0295]

[0296] N,N-diisopropylethylamine (0.76 mL, 4.45 mmol) and HATU (0.67 g, 1.78 mmol) were added to a solution of intermediate 26 (0.24 g, 0.89 mmol) in acetonitrile (10 mL). The initial solution was pale green, turning dark brown after a few minutes. The solution was stirred at room temperature under an inert atmosphere for 5 hours. The resulting dark brown solution was dissolved in ethyl acetate (100 mL) and washed with a saturated sodium bicarbonate aqueous solution (5 × 50 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give a crude product as a brown oil. The resulting oil was purified on a silica gel filter (25 g, 50 μL) and eluted with 100% ethyl acetate to give intermediate 27 (0.42 g), which was a pale yellow oil. 1 H NMR(400MHz; CDCl3)δ7.82(d,2H),7.62(t,1H),7.56(t,2H),7.34(d,1H) ,6.84(d,1H),4.35-4.31(m,1H),4.10-3.99(m,2H),3.91-3.84(m,4H),3. 78-3.71(t,2H),3.63-3.40(m,2H),3.07(quin,1H),2.76-2.71(m,4H),2. 22(td,2H),1.92(quin,2H),1.78-1.60(m,4H),1.51(s,9H),1.17(t,3H). C 33 H 45 HRMS[M] of N5O8S + The calculated value is 671.2989, and the measured value is 672.3058.

[0297] (d) Intermediate 28: ethyl 2-(1-(phenylthioyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0298]

[0299] Intermediate 28 (0.24 g) was prepared using intermediate 27 (0.38 g, 0.57 mmol) via the method of intermediate 22. 1 H NMR(400MHz; CDCl3)δ7.88-7.85(m,2H),7.69-7.64(m,1H),7.61-7.57(m,2H) ,7.09(d,1H),6.35(d,1H),4.49(dt,1H),4.20-4.17(m,2H),3.96-3.73(m,4H ),3.70–3.56(m,2H),3.41-3.38(m,2H),3.19–3.12(m,1H),2.71(t,2H),2.51 (t,2H),2.22-2.20(m,2H),1.94–1.88(m,2H),1.72-1.60(m,4H),1.25(t,3H). C 28 H 37 HRMS[M+H] of N5O6S+H + The calculated value is 572.2537, and the measured value is 572.2536.

[0300] (e) Example 9: 2-(1-(benzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0301]

[0302] By the method of Example 7(f), 2-(1-(benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.15 g) was obtained from intermediate 28 (0.24 g, 0.42 mol), which was a colorless solid. 1H NMR(400MHz; CD3OD)δ7.80(d,2H),7.68(t,1H),7.61(t,2H),7.29(d,1H),6.41(d,1H),4.21(t,1H),3.93-3.77(m,4H),3.55-3.4 0(m,2H),3.40-3.35(m,2H),3.24-3.14(m,1H),2.70(t,2H),2.55(t,2H),2.22-2.07(m,2H),1.86(quin,2H),1.60-1.59(m,4H). C 26 H 33 HRMS[M] of N5O6S + The calculated value is 543.2152, and the measured value is 544.2226.

[0303] Example 10: 2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0304] (a) Intermediate 29: 1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0305]

[0306] Intermediate 29 (0.89 g) was obtained by means of intermediate 4 using 3,5-dichlorobenzenesulfonyl chloride (0.73 g, 1.97 mmol) and 3-azacyclobutanecarboxylic acid (0.3 g, 3.97 mmol), which was a colorless solid. 1 H NMR (400MHz; CD3OD) δ7.86(t,1H),7.82(d,2H),4.08(t,2H),3.95(dd,2H),3.38-3.30(m,1H). C 10 HRMS of H9Cl2NO4S–H [MH] - The calculated value is 307.9557, and the measured value is 307.9556.

[0307] (b) Intermediate 30: 7-(5-((2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamido)-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0308]

[0309] Intermediate 30 (0.54 g), which is a clear oily substance, was obtained by using intermediate 29 (0.33 g, 1.08 mmol) and intermediate 19 (0.44 g, 0.98 mmol) via the method of intermediate 21. 1 H NMR(400MHz; CDCl3)δ7.69(d,2H),7.59(t,1H),7.33(d,1H),6.83(d,1H),4.34(dt,1H),4.07-4.01(m,2H),3.99-3.88(m,4H),6.76-3.73(m,2 H),3.63-3.42(m,2H),3.20-3.09(m,1H),2.76-2.71(m,4H),2.28-2.19(m,2H),1.92(quin,2H),1.76-1.61(m,4H),1.51(s,9H),1.17(t,3H). C 33 H 43 HRMS[M+H] of Cl2N5O8S+H + The calculated value is 740.2288, and the measured value is 740.2282.

[0310] (c) Intermediate 31: ethyl 2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0311]

[0312] Intermediate 31 (0.18 g) was obtained using intermediate 31 (0.51 g, 0.69 mmol) via the method of intermediate 22. It is a colorless solid. 1 H NMR(400MHz; CDCl3)δ7.70(d,2H),7.60(t,1H),7.07(d,1H),6.33(d,1H),4.50(td,1H),4.21-4.15(m,2H),4.05-3.86(m,4H),3.74-3.5 3(m,2H),3.44-3.32(m,2H),3.19(quin,1H),2.69(t,2H),2.50(t,2H),2.10-1.93(m,2H),1.90(dt,2H),1.75-1.53(m,4H),1.25(t,3H). C 28 H 35 HRMS[M+H] of Cl2N5O6S+H + The calculated value is 640.1758, and the measured value is 640.1755.

[0313] (d) Example 10: 2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0314]

[0315] By the method of Example 7(f), 2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.08 g) was obtained as a colorless solid using intermediate 31 (0.18 g, 0.28 mmol). 1 H NMR (400MHz; CD3OD) δ7.83(t,1H),7.76(d,2H),7.59(d,1H),6.64(d,1H),4.54-4.50(m,1H),4.05-3.85(m,4H),3.73-3.6 8(m,1H),3.55-3.47(m,2H),3.43-3.36(m,2H),2.82(t,2H),2.72(t,2H),2.28(t,2H),1.95(quin,2H),1.74-1.60(m,4H). C 26 H 31 HRMS[M+H] of Cl2N5O6S+H + The calculated value is 612.1445, and the measured value is 612.1430.

[0316] Example 11: 2-(1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0317] (a) Intermediate 32: 1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0318]

[0319] Intermediate 32 (1.75 g) was obtained by using 3,5-dimethylbenzenesulfonyl chloride (2.0 g, 9.89 mmol) and aziridine-3-carboxylic acid (1 g, 9.89 mmol) via the method of intermediate 4, and was a white solid. 1 H NMR (400MHz; CD3OD) δ7.47(s,2H),7.40(s,1H),3.92(m,4H),3.27(m,1H),2.44(s,6H). C 12 H 15HRMS of NO4S+Na[M+Na] + The calculated value is 292.0619, and the measured value is 292.0616.

[0320] (b) Intermediate 33: 7-(5-((2-(1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-formamido)-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0321]

[0322] Intermediate 33 (0.363 g), a brown oily substance, was obtained by using intermediate 32 (0.4 g, 1.485 mmol) and intermediate 19 (0.6 g, 1.35 mmol) via the method of intermediate 27. 1 H NMR(400MHz; CD3OD)δ7.52(d,1H),7.45(s,2H),7.39(s,1H),7.01(d,1H),4.43(m,1H),4.14(m,2H),3.86(m,4H),3.77(m,2H),3.5 2(m,2H),3.22(m,1H),2.79(t,2H),2.73(t,2H),2.43(s,6H),2.21(t,2H),1.94(quin,2H),1.68(m,4H),1.53(s,9H),1.23(t,3H). C 35 H 49 HRMS[M+H] of N5O8S+H + The calculated value is 700.3380, and the measured value is 700.3363.

[0323] (c) Intermediate 34: ethyl 2-(1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0324]

[0325] Intermediate 34 (0.2 g), which is a brown foamy substance, was obtained by using intermediate 33 (0.363 g, 0.052 mmol) via intermediate 22. 1H NMR (400MHz; CD3OD) δ7.45(s,2H),7.38(s,1H),7.29(d,1H),6.46(d,1H),4.47(dd,1H),4.14(m,2H),3.88(m,4H),3.47- 3.41(m,4H),3.24(m,1H),2.75(t,2H),2.58(t,2H),2.45(s,6H),2.20(t,2H),1.91(quin,2H),1.63(m,4H),1.24(t,3H). C 30 H 41 HRMS[M+H] of N5O6S+H + The calculated value is 600.2856, and the measured value is 600.2853.

[0326] (d) Example 11: 2-(1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0327]

[0328] Using the method of Example 7(f), intermediate 34 (0.2 g, 0.333 mmol) yielded 2-(1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid, which was a white gel. 1 H NMR(400MHz; CD3OD)δ7.61(m,1H),7.45(m,2H),7.40(s,1H),6.67(d,1H),4.54(m,1H),3.89(m,4H),3.74-3.63(m,1H),3.61-3.5 (m,2H),3.46-3.41(m,1H),3.29-3.21(m,1H),2.84(t,2H),2.74(t,2H),2.44(s,6H),2.30(m,2H),1.97(quin,2H),1.68(m,4H). C 28 H 37 HRMS[M+H] of N5O6S+H + The calculated value is 572.2543, and the measured value is 572.2526. Example 12: 2-(1-(3-(methylsulfonyl)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (a) intermediate 35: 1-(3-(methylsulfonyl)benzenesulfonyl)azacyclobutane-3-carboxylic acid

[0329]

[0330] Intermediate 35 (0.35 g) was obtained by using 3-(methylsulfonyl)benzenesulfonyl chloride (0.5 g, 1.97 mmol) and aziridine-3-carboxylic acid (0.2 g, 1.97 mmol) via the method of intermediate 4. It was a white gel. 1 H NMR (400MHz; CD3OD) δ8.39(s,1H),8.33(d,1H),8.21(d,1H),7.96(t,1H),4.00(m,4H),3.30(m,1H),3.24(s,3H). C 11 H 13 HRMS of NO6S2+Na [M+Na] + The calculated value is 342.0082, and the measured value is 342.0069. (b) Intermediate 36: 7-(5-((3-ethoxycarbonyl-2-(1-(3-(methanesulfonyl)benzenesulfonyl)azacyclobutane-3-formylamino)-propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0331]

[0332] Intermediate 36 (0.418 g), a brown oily substance, was obtained by using intermediate 35 (0.340 g, 1.07 mmol) and intermediate 19 (0.480 g, 1.07 mmol) via the method of intermediate 27. 1 H NMR(400MHz; CDCl3)δ8.40(s,1H),8.21(d,H),8.12(d,1H),7.81(t,2H),7.49(d,1H),7.39(d,1H),7.02(m,1H),6.88(d,1H),4.30(m,1H ),4.00(m,6H),3.77(m,2H),3.53(m,2H),3.13(s,4H),2.76(m,4H),2.24(m,2H),1.95(quin,2H),1.68(m,4H),1.52(s,9H),1.18(t,3H). C 34 H 47 N5O 10 HRMS[M+H] of S2+H + The calculated value is 750.2843, and the measured value is 750.2826.

[0333] (c) Intermediate 37: 2-(1-(3-(methylsulfonyl)benzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0334]

[0335] Intermediate 37 (0.254 g), which is a collapsed foam, was obtained by using intermediate 36 (0.388 g, 0.519 mmol) via intermediate 22. 1 H NMR(400MHz; CDCl3)δ8.42(s,1H),8.23(d,1H),8.14(d,1H),7.95(d,1H),7 .83(t,1H),7.17(d,1H),6.57(s,1H),6.37(d,1H),4.44(m,1H),4.16(q,2H ),3.97(m,4H),3.63(m,2H),3.44(m,2H),3.25(m,1H),3.25(s,3H),2.74(t ,2H),2.56(t,2H),2.24(m,2H),1.94(quin,2H),1.66(m,4H),1.25(t,3H). C 29 H 39 HRMS[M+H] of N5O8S2+H + The calculated value is 650.2318, and the measured value is 650.2308.

[0336] (d) Example 12: 2-(1-(3-(methylsulfonyl)benzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0337]

[0338] Using the method of Example 7(f), intermediate 37 (254 mg, 0.39 mmol) yielded 2-(1-(3-(methylsulfonyl)benzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)propionic acid (37 mg), which was a pale yellow gel. 1H NMR(400MHz; CD3OD)δ8.36(s,1H),8.32(d,1H),8.20(d,1H),7.95(t,1H),7.48(d,1H),6.53(d,1H),4.22(t,1H),3.9 8(m,4H),3.49(m,4H),3.36(m,1H),3.26(s,3H),2.80(t,2H),2.67(t,2H),2.23(t,2H),1.94(quin,2H),1.69(m,4H). C 27 H 35 HRMS[M+H] of N5O8S2+H + The calculated value is 622.2005, and the measured value is 622.1981.

[0339] Example 13: 2-(1-(3-chloro-5-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (a) intermediate 38: 1-(3-chloro-5-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0340]

[0341] Intermediate 38 (0.32 g) was obtained by means of intermediate 4 using 3-chloro-5-methylbenzenesulfonyl chloride (0.44 g, 1.96 mmol) and aziridine-3-carboxylic acid (0.2 g, 1.97 mmol), which was a colorless oil. 1 H NMR (400MHz; CDCl3) δ7.65-7.62(m,1H),7.62-7.58(m,2H),4.05-4.01(m,2H),3.92-3.88(m,2H),3.38(quin,1H),2.48(s,3H). C 11 H 12 The calculated HRMS [MH] value for ClNO4S–H was 288.0097, and the measured value was 288.0103. (b) Intermediate 39: 7-(5-((2-(1-(3-chloro-5-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0342]

[0343] Intermediate 39 (0.05 g) was obtained by using intermediate 38 (0.17 g, 0.59 mmol) and intermediate 19 (0.26 g, 0.59 mmol) via the method of intermediate 27. It is a yellow oily substance. 1 H NMR (400MHz; CDCl3) δ7.62-7.58(m,1H),7.51-7.50(m,1H),7.41-7.40(m,1H),7.54-7. 33(m,1H),6.98-6.87(m,1H),4.39(dt,1H),4.10-3.99(m,2H),3.95-3.84(m,4H),3.82- 3.75(m,2H),3.63-3.45(m,2H),3.13(dt,1H),2.79-2.70(m,4H),2.43(s,3H),2.30-2.1 5(m,2H),1.96(quin,2H),1.76(quin,2H),1.70-1.58(m,2H),1.53(s,9H),1.19(t,3H). C 34 H 46 HRMS[M+H] of ClN5O8S+H + The calculated value is 720.2834, and the measured value is 720.2801.

[0344] (c) Example 13: 2-(1-(3-chloro-5-methylbenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0345]

[0346] Add 2 mL of trifluoroacetic acid to a solution of intermediate 39 (0.075 g, 0.10 mmol) in dichloromethane (3 mL). Stir the solution at room temperature under an inert atmosphere for 20 hours. Add 20 mL of toluene to the resulting red reaction mixture and remove the solvent under reduced pressure. Dissolve the resulting oil in ethyl acetate (30 mL) and wash with a saturated aqueous solution of sodium bicarbonate (3 × 30 mL). Dry the organic layer and filter. Remove the solvent under reduced pressure to give a red oil that can be used without purification or complete characterization. Dissolve the crude product in ethanol (5 mL) and add sodium hydroxide (2 M, 0.08 mL, 0.16 mmol). Stir the reaction mixture for 4 hours. Remove the solvent under reduced pressure and add water (20 mL). Add hydrochloric acid (1 M) dropwise until the pH of the solution is 5. The solution was extracted with dichloromethane (3 × 30 mL) to remove the solvent, yielding 2-(1-(3-chloro-5-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.04 g), which was a colorless solid. 1 H NMR (400MHz; CDCl3) δ7.63-7.54(m,4H),6.65(d,1H),4.54-4.46(m,1H),4.01-3.81(m,4H),3.73-3.6(m,1H),3.53-3. 45(m,3H),3.40-3.35(m,1H),2.82(t,2H),2.72(t,2H),2.47(s,3H),2.32(t,2H),1.94(quin,2H),1.77-1.58(m,4H). C 27 H 34 HRMS[M+H] of ClN5O6S+H + The calculated value is 592.1991, and the measured value is 592.1987.

[0347] Example 14: 2-(1-(3-ethylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0348] (a) Intermediate 40: 1-(3-ethylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0349]

[0350] Intermediate 40 (0.28 g) was obtained by using 3-ethylbenzenesulfonyl chloride (0.365 g, 1.84 mmol) and aziridine-3-carboxylic acid via the method of intermediate 4. It was a pale white gel. 1H NMR (400MHz; CD3OD) δ7.68(m,2H),7.59(m,2H),3.93(m,4H),3.26(tt,1H),2.80(q,2H),1.31(t,3H).

[0351] (b) Intermediate 41: 7-(5-((3-ethoxycarbonyl-2-(1-(3-ethylbenzenesulfonyl)azacyclobutane-3-formylamino)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0352]

[0353] Intermediate 41 (0.504 g), a light brown oily substance, was obtained by using intermediate 40 (0.280 g, 1.04 mmol) and intermediate 19 (0.466 g, 1.04 mmol) via the method of intermediate 27. 1 H NMR (400MHz; CDCl3) δ7.65(m,2H),7.48(m,2H),7.39(m,2H),7.04(t,1H),6.87(d,1H),4.39(m,1H),4.08(m,2H),3.89(m,4H),3.77( t,2H),3.56(m,2H),3.11(quin,1H),2.76(m,6H),2.25(t,2H),1.95(quin,2H),1.70(m,4H),1.53(s,9H),1.29(t,3H),1.20(t,3H). C 35 H 49 HRMS[M+H] of N5O8S+H + The calculated value is 700.3380, and the measured value is 700.3362.

[0354] (c) Intermediate 42: ethyl 2-(1-(3-ethylbenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0355]

[0356] Intermediate 42 (0.372 g) was obtained by using intermediate 41 (0.5 g; 0.72 mmol) via the method of intermediate 22. It was a light brown oily substance. 1H NMR (400MHz; CDCl3) δ7.78(d,1H),7.67(m,2H),7.49(d,2H),7.12(d,1H),6.52(t,1H),4.50(m,1H),4.16(m,2H),3.91(m,4H),3.64( t,2H),3.42(m,2H),3.18(quin,1H),2.73(m,4H),2.54(t,2H),2.22(t,2H),1.92(quin,2H),1.67(m,4H),1.29(t,3H),1.25(t,3H). C 30 H 41 HRMS[M+H] of N5O6S+H + The calculated value is 600.2856, and the measured value is 600.2832.

[0357] (d) Example 14: 2-(1-(3-ethylbenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0358]

[0359] By the method of Example 7(f), 2-(1-(3-ethylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.13 g), a colorless oil, was obtained using intermediate 42 (0.37 g, 0.618 mmol). 1 H NMR (400MHz; CD3OD) δ7.67(m,2H),7.58(m,2H),7.28(d,1H),6.53(d,1H),4.28(t,1H),3.92(m,4H),3.53(m,2H ),3.47(t,2H),3.28(m,1H),2.80(m,4H),2.68(t,2H),2.24(m,2H),1.94(quin,2H),1.69(m,4H),1.30(t,3H). C 28 H 37 HRMS[M+H] of N5O8S+H + The calculated value is 572.2543, and the measured value is 572.2514.

[0360] Example 15: 2-(3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (a) intermediate 43: methyl 1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid

[0361]

[0362] Triethylamine (3.3 mL, 24 mmol) was added to a solution of methyl 3-oxobutane-3-carboxylate hydrochloride (1.26 g, 8.3 mmol) and 3-methylbenzenesulfonyl chloride (1.32 g, 8.3 mmol) in dichloromethane (20 mL) over 0.25 hours and cooled in an ice bath. The resulting turbid yellow solution was stirred under nitrogen for 21 hours. The solution was dissolved in dichloromethane (50 mL), and the organic layer was extracted with a saturated aqueous solution of sodium bicarbonate (4 × 50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give intermediate 43 (1.66 g), which was a pale yellow oil. 1 H-NMR (400MHz; CDCl3) δ7.75-7.59(m,2H),7.55-7.43(m,2H),4.08-3.89(m,4H),3.65(s,3H),3.27(tt,1H),2.48(s,3H). C 12 H 15 HRMS of NO4S+H [M+H] + The calculated value is 270.0795, and the measured value is 270.0793. (b) Intermediate 44: methyl 3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid ester

[0363]

[0364] At -72°C, sodium bis(trimethylsilyl)amino (1M in tetrahydrofuran, 10.0 mL, 10 mmol) was added to an anhydrous tetrahydrofuran (20 mL) solution of intermediate 43 (800 mg, 3.0 mmol), and the resulting pale yellow solution was stirred for 0.5 h. A solution of methyl iodine (1.60 mL, 26 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added dropwise to the stirred solution, and the resulting solution was stirred at -72°C for 3 h. Hydrochloric acid solution (1M, 20 mL) was added to the solution at -72°C, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The separated organic layer was washed with brine (2 × 50 mL), filtered, and the solvent was removed under reduced pressure. The resulting oil was purified by rapid chromatography on a silica gel column (40 g) using petroleum ether:ethyl acetate (65:35) as elution. The fractions containing the product were combined and the solvent was removed under reduced pressure to give intermediate 44 (0.37 g), which was an orange solid. 1 H-NMR (400MHz; CDCl3) δ7.68-7.60(m,2H),7.50-7.42(m,2H),4.05(d,2H),3.62-3.57(m,5H),2.46(s,3H),1.39(s,3H). C 13 H 17 HRMS of NO4S+H [M+H] + The calculated value is 284.0951, and the measured value is 284.0947.

[0365] (c) Intermediate 45: 7-(5-((3-ethoxycarbonyl-2-(3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0366]

[0367] Intermediate 44 (370 mg, 1.3 mmol) was added to a solution of THF (10 mL), water (3.5 mL), and methanol (3.5 mL). Lithium hydroxide (45 mg, 1.9 mmol) was added, and the resulting pale yellow solution was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, and residual water was removed by azeotropic mixing with toluene (5 × 10 mL) to give lithium 3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylate (356 mg), which was a white, creamy, condensed foam.

[0368] Under a nitrogen atmosphere and at 0 °C, N,N-diisopropylethylamine (1.13 mL, 6.6 mmol) and HATU (1000 mg, 2.6 mmol) were slowly added to a solution of intermediate 19 (590 mg, 1.3 mmol) and lithium 3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylate (350 mg, 1.3 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 68 hours. The resulting solution was dissolved in ethyl acetate (100 mL), and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (6 × 50 mL). The organic layer was washed with brine (50 mL), dried, filtered, and the solvent was removed under reduced pressure. The crude product was purified by rapid chromatography on a silica gel column (40 g) and eluted with ethyl acetate (100%). The fractions containing the product were combined, and the solvent was removed under reduced pressure to give intermediate 45 (0.630 g), which was a light brown gel. 1 H-NMR (400MHz; CDCl3) δ7.68-7.58(m,3H),7.46-7.38(m,2H),7.33(d,1H),7.24-7.18(m,1 H),6.84(d,1H),4.32-4.23(m,1H),4.08-3.99(m,4H),3.79-3.71(m,2H),3.65-3.54(m,1H ),3.51(d,2H),3.48-3.40(m,1H),2.78-2.67(m,4H),2.44(s,3H),2.34-2.17(m,2H),1.98 -1.87(m,2H),1.84-1.72(m,2H),1.72-1.59(m,2H),1.52(s,9H),1.34(s,3H),1.16(t,3H). C 35 H 49 HRMS[M+H] of N5O8S+H + The calculated value is 700.3375, and the measured value is 700.3362.

[0369] (d) Intermediate 46: ethyl 2-(3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0370]

[0371] Intermediate 46 (0.460 g), an orange gel, was obtained using intermediate 45 (600 mg, 0.86 mmol) via the method of intermediate 22. 1H-NMR(400MHz; CDCl3)δ7.70-7.57(m,3H),7.46-7.38(m,2H),7.05(d,1H),6.61(bt,1H), 6.31(d,1H),4.98(bs,1H),4.43-4.36(m,1H),4.16-4.09(m,2H),4.09-4.02(m,2H),3.62- 3.55(m,2H),3.52(d,2H),3.41-3.34(m,2H),2.67(t,2H),2.55-2.48(m,2H),2.43(s,3H) ,2.23-2.14(m,2H),1.93-1.82(m,2H),1.69-1.56(m,4H),1.36(s,3H),1.29-1.17(m,3H). C 30 H 41 HRMS[M+H] of N5O6S+H + The calculated value is 600.2856, and the measured value is 600.2850.

[0372] Example 15: 2-(3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0373]

[0374] Using the method of Example 7(f), intermediate 46 (420 mg, 0.70 mmol) yielded 2-(3-methyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.18 g), which was a yellow oil. 1 H-NMR (400MHz; CD3OD) δ7.67-7.58(m,2H),7.56-7.49(m,2H),7.50-7.44(m,1H),6.51(d,1H),4.28-4.23(t,1H),4.05(dd,2H),3.5 9-3.40(m,6H),2.77(t,2H),2.69-2.61(m,2H),2.45(s,3H),2.29-2.14(m,2H),1.95-1.86(m,2H),1.75-1.59(m,4H),1.27(s,3H). C 28 H 37 HRMS[MH] of N5O6S-H -The calculated value is 570.2392, and the measured value is 570.2400. Example 16: 2-(3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0375] (a) Intermediate 47: methyl 3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid ester

[0376]

[0377] Intermediate 47 (0.540 g), a yellow oily substance, was obtained by using intermediate 43 (940 mg, 3.5 mmol) and ethyl iodine (2.75 mL, 34 mmol) via the method of intermediate 44. 1 H-NMR (400MHz; CDCl3) δ7.67-7.60(m,2H),7.46-7.43(m,2H),3.99(d,2H),3.63(d,2H),3.60(s,3H),2.45(s,3H),1.76(q,2H),0.76(t,3H). C 14 H 19 HRMS of NO4S+H [M+H] + The calculated value is 298.1113, and the measured value is 298.1108.

[0378] (b) Intermediate 48: 7-(5-((3-ethoxycarbonyl-2-(3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidium-1(2H)-carboxylic acid tert-butyl ester

[0379]

[0380] Using intermediate 45, 3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid lithium (490 mg) was obtained using intermediate 47 (500 mg, 1.7 mmol) and lithium hydroxide (60 mg, 2.5 mmol), which was a fat-collapsed foam. Intermediate 48 (0.440 g) was obtained using a portion of it (410 mg, 1.4 mmol) and intermediate 19 (544 mg, 1.2 mmol), which was a light brown gel. 1H-NMR (400MHz; CDCl3) δ7.69-7.57(m,3H),7.46-7.37(m,2H),7.35-7.24(m,2H),6.83( d,1H),4.30-4.21(m,1H),4.07-3.98(m,3H),3.94(d,1H),3.78-3.71(m,2H),3.64-3.49 (m,3H),3.48-3.39(m,1H),2.80-2.64(m,4H),2.43(s,3H),2.35-2.16(m,2H),1.98-1. 85(m,2H),1.82-1.71(m,2H),1.71-1.59(m,4H),1.51(s,9H),1.14(t,3H),0.75(t,3H). C 36 H 51 HRMS[M+H] of N5O8S+H + The calculated value is 714.3531, and the measured value is 714.3515.

[0381] (c) Intermediate 49: 2-(3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0382]

[0383] Intermediate 49 (0.29 g), a yellow oily substance, was obtained by using intermediate 48 (440 mg, 0.62 mmol) via the method of intermediate 22. 1 H-NMR(400MHz; CDCl3)δ7.68(bd,1H),7.65-7.57(m,2H),7.44-7.37(m,2H),7.04(d,1H), 6.73-6.65(m,1H),6.30(d,1H),5.04(bs,1H),4.42-4.34(m,1H),4.16-4.05(m,2H),4.01( d,2H),3.61-3.50(m,4H),3.42-3.33(m,2H),2.66(t,2H),2.54-2.47(m,2H),2.42(s,3H) ,2.24-2.13(m,2H),1.91-1.83(m,2H),1.75-1.55(6H,m),1.27-1.16(m,3H),0.76(t,3H). C 31 H 43 HRMS[M+H] of N5O6S+H +The calculated value is 614.3012, and the measured value is 614.3007.

[0384] Example 16: 2-(3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0385]

[0386] Using the method of Example 7(f), intermediate 49 (260 mg, 0.42 mmol) yielded 2-(3-ethyl-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.22 g), which was a yellow oil. 1 H-NMR (400MHz; CD3OD) δ7.65-7.58(m,2H),7.58-7.48(m,3H),6.62(d,1H),4.48(dd,1H),3.99(dd,2H),3.64-3.40( 6H,m),2.79(t,2H),2.71(t,2H),2.46(s,3H),2.28-2.20(m,2H),2.00-1.85(m,2H),1.75-1.47(6H,m),0.69(t,3H). C 29 H 39 HRMS[MH] of N5O6S–H - The calculated value is 584.2548, and the measured value is 584.2562.

[0387] Example 17: 2-(3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0388] (a) Intermediate 50: Methyl 3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylic acid ester

[0389]

[0390] At -72°C, sodium bis(trimethylsilyl)amino (5.2 mL, 5.2 mmol) was added to an anhydrous tetrahydrofuran (20 mL) solution of intermediate 43 (700 mg, 2.6 mmol), and the resulting pale yellow solution was stirred for 0.5 h. An anhydrous tetrahydrofuran (15 mL) solution of N-fluorobenzenesulfonylimide (1.23 g, 3.9 mmol) was added to the stirred solution, and the resulting solution was stirred at -72°C for 4 h. The solution was heated to room temperature, and a white solid precipitated from the solution. The mixture was stirred at room temperature for 15 h. Hydrochloric acid (1 M, 30 mL) was added to the resulting solution, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine (2 × 30 mL), dried, filtered, and the solvent was removed under reduced pressure to give a brown oil. The formed oil was purified by rapid chromatography on a silica gel column (40 g) using petroleum ether:ethyl acetate (65:35) as elution. The fractions containing the product were combined and the solvent was removed under reduced pressure to obtain intermediate 50 (0.250 g), which is a yellow oily substance. 1 H-NMR (400MHz; CDCl3) δ7.99-7.92(m,2H),7.55-7.43(m,2H),4.27(ddd,2H),4.06(ddd,2H),3.76(s,3H),2.46(s,3H). C 12 H 14 HRMS[M+H] of FNO4S+H + The calculated value is 288.0700, and the measured value is 288.0693.

[0391] (b) Intermediate 51: 7-(5-((3-ethoxycarbonyl-2-(3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0392]

[0393] Using intermediate 45, 105 mg of lithium 3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxylate was obtained from intermediate 50 (100 mg, 0.35 mmol) and lithium hydroxide (12 mg, 0.53 mmol), which was a pale yellow oil. This oil was ready for use without purification and was reacted with intermediate 19 (202 mg, 0.45 mmol) to give intermediate 51 (45 mg), which was a pale brown gel. 1H-NMR (400MHz; CDCl3) δ8.03-7.92(m,1H),7.67-7.57(m,2H),7.48-7.40(m,2H),7.36(d,1H) ),7.00(bt,1H),6.84(d,1H),4.43-4.36(m,1H),4.25-4.14(m,2H),4.12-4.07(m,2H),4.06- 3.89(m,2H),3.78-3.72(m,2H),3.61-3.50(m,2H),2.77-2.68(m,4H),2.43(s,3H),2.27-2.1 3(m,2H),1.95-1.87(m,2H),1.76-1.68(m,2H),1.65-1.56(m,2H),1.50(s,9H),1.17(t,3H). C 34 H 46 HRMS[M+H] of FN5O8S+H + The calculated value is 704.3124, and the measured value is 704.3114.

[0394] (c) Intermediate 52: ethyl 2-(3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionate

[0395]

[0396] Intermediate 52 (30 mg) was obtained using intermediate 51 (45 mg, 0.06 mmol) via the method of intermediate 22. It was a yellow oily substance. 1 H-NMR (400MHz; CDCl3) δ7.99-7.92(m,1H),7.71-7.58(m,2H),7.50-7.40(m,2H) ,7.07(d,1H),6.54(bs,1H),6.31(d,1H),5.51(bs,1H),4.49(td,1H),4.33-3.94 (m,6H),3.77-3.52(m,2H),3.45-3.33(m,2H),2.69(t,2H),2.55-2.49(m,2H),2. 44(s,3H),2.19(t,2H),1.95-1.84(m,2H),1.69-1.56(m,4H),1.30-1.15(m,3H). C 29 H 38 HRMS[M+H] of FN5O6S+H + The calculated value is 604.2605, and the measured value is 604.2601.

[0397] (d) Example 17: 2-(3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0398]

[0399] By the method of Example 7(f), 2-(3-fluoro-1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (25 mg) was obtained from intermediate 52 (30 mg, 0.05 mmol), which was a pale yellow oil. 1 H-NMR (400MHz; CD3OD) δ7.71-7.62(m,2H),7.59-7.50(m,2H),7.48(d,1H),6.51(d,1H),4.32-4.18(m,3H),4.02-3.87(m,2H),3.60 (qd,2H),3.49-3.42(m,2H),2.78(t,2H),2.69-2.59(m,2H),2.47(s,3H),2.24-2.14(m,2H),1.97-1.87(m,2H),1.77-1.55(m,4H). C 27 H 34 HRMS[MH] of FN5O6S–H - The calculated value is 574.2141, and the measured value is 574.2150.

[0400] Example 18: 2-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0401] (a) Intermediate 53: methyl 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-carboxylic acid ester

[0402]

[0403] Methyl aziridine-3-carboxylate (350 mg, 3.05 mmol) was dissolved in tetrahydrofuran (10 mL). Triethylamine (0.45 mL, 6.10 mmol) was added, and the reaction mixture was cooled in an ice bath. 1-Methyl-1H-imidazolium-4-sulfonyl chloride (550 mg, 3.05 mmol) was added, and the reaction mixture was brought to room temperature and stirred for 18 hours. Triethylamine (0.45 mL, 6.10 mmol) and acetonitrile (2 mL) were added, and the reaction mixture was stirred for another 4 hours at room temperature. The reaction mixture was concentrated under vacuum, and the residue was dissolved in sodium bicarbonate solution (saturated, 70 mL) and extracted with dichloromethane (5 × 20 mL). Sodium hydroxide solution (2 M, 1 mL) was added to the aqueous solution, and then extracted with dichloromethane (6 × 20 mL). The organic compounds were combined and concentrated under vacuum to give intermediate 53 (0.440 g), which was a white solid. 1 H NMR (400MHz; CD3OD) δ7.86(s,1H),7.84(d,1H),4.11-4.00(m,4H),3.87(s,3H),3.67(s,3H),3.40-3.31(m,1H). C9H 13 HRMS[M+H] of N3O4S+H + The calculated value is 260.0705, and the measured value is 260.0699.

[0404] (b) Intermediate 54: 1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-carboxylic acid lithium

[0405]

[0406] Intermediate 53 (420 mg, 1.62 mmol) was dissolved in tetrahydrofuran (9 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (78 mg, 3.24 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. Toluene (3 × 5 mL) was added, and the reaction mixture was concentrated three times under vacuum to give intermediate 54 (0.48 g), which was a colorless oil. 1 H NMR (400MHz; CD3OD) δ7.79(d,1H),7.77(d,1H),3.97(d,2H),3.95(d,2H),3.83(s,3H),3.11-3.02(m,1H). C8H 10 HRMS[MH] of LiN3O4S–H - The calculated value is 244.0392, and the measured value is 244.0399.

[0407] (c) Intermediate 55: 7-(5-((3-ethoxycarbonyl-2-(1-(((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamido)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0408]

[0409] Intermediate 19 (300 mg, 0.67 mmol) and intermediate 54 (147 mg, 0.67 mmol) were dissolved in acetonitrile (10 mL). NN-diisopropylethylamine (0.32 mL, 3.35 mmol) and HATU (764 mg, 2.01 mmol) were added, and the reaction mixture was brought to room temperature and stirred for 66 hours. The reaction mixture was concentrated under vacuum, and the residue was separated between a saturated sodium bicarbonate aqueous solution (50 mL) and ethyl acetate (3 × 40 mL). The organic layer was collected, washed with brine (3 × 30 mL), dried, filtered, and concentrated under vacuum to a yellow oil (760 mg). The crude product was then purified by rapid chromatography, eluting with methanol:ethyl acetate at a ratio of 0:100 to 10:80 to give intermediate 55 (350 mg), which was a yellow oil. 1 H NMR(400MHz; CDCl3)δ7.57(d,1H),7.52(d,1H),7.39-7.31(m,2H),6.97(t,1H),6.86(d, 1H),4.43-4.37(m,1H),4.14-4.04(m,4H),4.02-3.95(m,2H),3.78(s,3H),3.77-3.72(m ,2H),3.65-3.55(m,1H),3.53-3.45(m,1H),3.20-3.06(m,1H),2.78-2.70(m,4H),2.22( t,2H),1.93(quin,2H),1.78-1.69(m,2H),1.68-1.59(m,2H),1.50(s,9H),1.20(t,3H). C 31 H 45 HRMS[MH] of N7O8S–H - The calculated value is 674.2978, and the measured value is 674.2986.

[0410] (d) Intermediate 56: 2-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0411]

[0412] Intermediate 56 (0.178 g), a yellow oily substance, was obtained by using intermediate 55 (234 mg, 0.35 mmol) via the method of intermediate 22. 1 H NMR(400MHz; CDCl3)δ7.93(d,1H),7.55(d,1H),7.52(d,1H),7.12(d,1H),6.58(s,1H) ,6.35(d,1H),5.51(s,1H),4.52-4.45(m,1H),4.21-4.13(m,4H),4.06-3.97(m,2H),3 .78(s,3H),3.69-3.63(m,2H),3.44-3.38(m,2H),3.30-3.20(m,1H),2.71(t,2H),2.5 8-2.51(m,2H),2.27-2.20(m,2H),1.95-1.87(m,2H),1.72-1.61(m,4H),1.26(t,3H). C 26 H 37 HRMS[MH] of N7O6S–H - The calculated value is 574.2453, and the measured value is 574.2473.

[0413] (e) Example 18: 2-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0414]

[0415] By the method of Example 7(f), 2-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.123 g) was obtained from intermediate 56 (163 mg, 0.28 mmol), which was a colorless cracked glassy substance. 1H NMR(400MHz; CH3OD)δ7.81(s,1H),7.79(d,1H),7.22(d,1H),6.40(d,1H),4.29-4.24(m,1H),4.04-3.89(m,4H),3.83(s,3H),3.58(dd,1H),3 .46(dd,1H),3.43-3.38(m,2H),3.28-3.19(m,1H),2.72(t,2H),2.59- 2.53(m,2H),2.23-2.15(m,2H),1.93-1.85(m,2H),1.68-1.57(m,4H). C 24 H 33 HRMS[MH] of N7O6S–H - The calculated value is 546.2140, and the measured value is 546.2159.

[0416] Example 19: 2-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0417] (a) Intermediate 57: yields 1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)azacyclobutane-3-carboxylic acid

[0418]

[0419] 1-Methyl-1H-pyrazole-4-sulfonyl chloride (536 mg, 2.97 mmol) was dissolved in diethyl ether (5 mL) and water (5 mL). Azacyclobutane-3-carboxylic acid (300 mg, 2.97 mmol) and 2M (3 mL, 6 mmol) sodium hydroxide solution were added, and the reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (10 mL) was added, the aqueous layer was separated, and acidified to pH 6 with hydrochloric acid solution (2 M). Because extraction in the organic solvent failed, the aqueous layer was concentrated under vacuum, and the product was prepared with gasoline to give intermediate 57 (879 mg), a white viscous solid. 1 H NMR (400MHz; CD3OD) δ8.20(s,1H),7.81(s,1H),3.98(s,3H),3.90-3.76(m,4H),3.14-3.03(m,1H). C8H 11 LRMS[MH] of N3O4S–H - The calculated value is 244.04, and the measured value is 244.04.

[0420] (b) Intermediate 58: 7-(5-((3-ethoxycarbonyl-2-(1-(((1-methyl-1H-pyrazol-4-yl)sulfonyl)azacyclobutane-3-formamido)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0421]

[0422] Intermediate 58 (0.28 g), a yellow oily substance, was obtained by using intermediate 19 (300 mg, 0.67 mmol) and intermediate 57 (164 mg, 0.37 mmol) via the method of intermediate 27. 1 H NMR (400MHz; CD3OD) δ8.21(s,1H),7.81(s,1H),7.50(d,1H),6.99(d,1H),4.42(dd,1H),4.21-4.07(m,2H),3.98(s,3H),3.89-3.69(m,6H),3.58( dd,1H),3.45(dd,1H),3.27-3.19(m,1H),2.78(t,2H),2.72(t,2H),2.20 (t,2H),1.96-1.89(m,2H),1.75-1.60(m,4H),1.51(s,9H),1.24(t,3H). C 31 H 45 HRMS[MH] of N7O8S–H - The calculated value is 674.2972, and the measured value is 674.2978.

[0423] (c) Intermediate 59: 2-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0424]

[0425] Intermediate 59 (0.133 g), a yellow oily substance, was obtained by using intermediate 58 (155 mg, 0.23 mmol) via the method of intermediate 22. 1H NMR(400MHz; CDCl3)δ7.86(s,1H),7.83(d,1H),7.81(s,1H),7.10(d,1H),6.34(d,1H ),6.30(s,1H),4.49(td,1H),4.18(qd,2H),3.98(s,3H),3.93-3.83(m,4H),3.74-3. 65(m,1H),3.64-3.56(m,1H),3.42-3.37(m,2H),3.24-3.15(m,1H),2.70(t,2H),2.5 5-2.49(m,2H),2.26-2.19(m,2H),1.94-1.86(m,2H),1.69-1.61(m,4H),1.25(t,3H). C 26 H 37 HRMS[MH] of N7O6S–H - The calculated value is 574.2453, and the measured value is 574.2461.

[0426] (d) Example 19: 2-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0427]

[0428] By the method of Example 7(f), 2-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azacyclobutane-3-carboxamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamide)propionic acid (73 mg) was obtained from intermediate 59 (117 mg, 0.20 mmol), which was a colorless cracked glassy substance. 1 H NMR(400MHz; CD3OD)δ8.22(s,1H),7.82(s,1H),7.34(d,1H),6.45(d,1H),4.26(t,1H),3.99(s,3H),3.89-3.81(m,4H),3.57(dd,1H),3.4 9(dd,1H),3.45-3.40(m,2H),3.30-3.22(m,1H),2.75(t,2H),2.64-2.57(m,2H),2.27-2.14(m,2H),1.95-1.86(m,2H),1.72-1.59(m,4H). C 24 H 33 HRMS[MH] of N7O6S–H -The calculated value is 546.2140, and the measured value is 546.2141.

[0429] Example 20: 2-(1-((5-chlorothiophene-2-yl)sulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0430] (a) Intermediate 60: methyl 1-((5-chlorothiophen-2-yl)sulfonyl)azacyclobutane-3-carboxylic acid ester

[0431]

[0432] Intermediate 60 (0.63 g) was obtained by using methyl 3-azacyclobutane-carboxylate (265 mg, 1.75 mmol) and 5-chlorothiophene-2-sulfonyl chloride (500 mg, 2.30 mmol) via the method of intermediate 53. It was an orange oil. 1 H NMR (400MHz; CDCl3) δ7.44(d,1H),7.06(d,1H),4.10-3.97(m,4H),3.68(s,3H),3.36-3.27(m,1H).

[0433] (b) Intermediate 61: 1-((5-chlorothiophen-2-yl)sulfonyl)azacyclobutane-3-carboxylic acid lithium

[0434]

[0435] Intermediate 61 (0.69 g), a pink solid, was obtained by using intermediate 60 (630 mg, 2.13 mmol) and lithium hydroxide (102 mg, 4.26 mmol) via the method of intermediate 54. 1 H NMR (400MHz; CD3OD) δ7.51(d,1H),7.21(d,1H),3.94(m,4H),3.13(tt,1H).

[0436] (c) Intermediate 62: 7-(5-((2-(1-(((5-chlorothiophen-2-yl)sulfonyl)azacyclobutane-3-formamido)-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0437]

[0438] Intermediate 62 (0.37 g), which is a yellow oily substance, was obtained by using intermediate 61 (185 mg, 0.67 mmol) and intermediate 19 (300 mg, 0.67 mmol) via the method of intermediate 55.1 H NMR(400MHz; CDCl3)δ7.46(s,1H),7.41(d,1H),7.35(s,1H),7.03(d,1H),6.96-6 .88(m,2H),4.43-4.37(m,1H),4.15-4.04(m,2H),3.99-3.88(m,4H),3.82-3.77( m,2H),3.63-3.47(m,2H),3.23-3.11(m,1H),2.81-2.74(m,4H),2.24(td,2H),1. 98-1.92(m,2H),1.80-1.72(m,2H),1.69-1.60(m,2H),1.53(s,9H),1.20(t,3H). C 31 H 42 HRMS[M+H] of ClN5O8S2+H + The calculated value is 712.2236, and the measured value is 712.2224.

[0439] (d) Intermediate 63: 2-(1-((5-chlorothiophen-2-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0440]

[0441] Intermediate 63 (0.186 g), a yellow oily substance, was obtained by using intermediate 62 (370 mg, 0.52 mmol) via the method of intermediate 22. 1 H NMR(400MHz; CDCl3)δ7.89(d,1H),7.42(d,1H),7.15(d,1H),7.04(d,1H), 6.36(d,1H),4.55-4.48(m,1H),4.17(qd,2H),4.04-3.90(m,4H),3.70-3.6 2(m,2H),3.45-3.40(m,2H),3.30-3.20(m,1H),2.72(t,2H),2.58-2.51(m, 2H),2.29-2.20(m,2H),1.96-1.88(m,2H),1.70-1.63(m,4H),1.25(t,3H). C 26 H 34 HRMS[MH] of ClN5O6S2–H - The calculated value is 610.1566, and the measured value is 610.1567.

[0442] (e) Example 20: 2-(1-((5-chlorothiophen-2-yl)sulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0443]

[0444] Using the method of Example 7(f), intermediate 63 (186 mg, 0.30 mmol) yielded 2-(1-((5-chlorothiophen-2-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.165 g), which was a yellow, cracked glassy substance. 1 H NMR(400MHz; CD3OD)δ7.59(d,1H),7.53(d,1H),7.24(d,1H),6.65(d,1H),4.56-4.49(m,1H),4.02-3.92(m,4H),3.74-3.60(m,1H),3.53 -3.49(m,2H),3.49-3.43(m,1H),3.42-3.36(m,1H),2.82(t,2H),2.73(t,2H),2.31-2.25(m,2H),1.98-1.94(m,2H),1.75-1.60(m,4H). C 24 H 30 HRMS[MH] of ClN5O6S2–H - The calculated value is 582.1253, and the measured value is 582.1257.

[0445] Example 21: 2-(1-(pyridin-3-ylsulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0446] (a) Intermediate 64: methyl 1-(pyridin-3-ylsulfonyl)azacyclobutane-3-carboxylic acid ester

[0447]

[0448] Intermediate 64 (250 mg) was obtained by using methyl 3-azacyclobutane-carboxylate (269 mg, 2.34 mmol) and pyridine-3-sulfonyl chloride (500 mg, 2.34 mmol) via the method of intermediate 53. It was a yellow oily substance. 1H NMR (400MHz; CDCl3) δ9.06(d,1H),8.88(d,1H),8.14(dt,1H),7.54(ddd,1H),4.11-4.03(m,2H),4.00-3.93(m,2H),3.63(s,3H),3.36-3.26(m,1H).

[0449] (b) Intermediate 65: Lithium 1-(pyridin-3-ylsulfonyl)azacyclobutane-3-carboxylate

[0450]

[0451] Intermediate 65 (0.160 g), a white solid, was obtained by using intermediate 64 (181 mg, 0.71 mmol) and lithium hydroxide (34 mg, 1.42 mmol) via the method of intermediate 54. 1 H NMR (400MHz; CD3OD) δ8.97(dd,1H),8.84(dd,1H),8.26(ddd,1H),7.70(ddd,1H),3.99-3.92(m,2H),3.92-3.85(m,2H),3.15-3.05(m,1H). C9H 10 HRMS of N2O4S–H [MH] - The calculated value is 241.0289, and the measured value is 241.0294.

[0452] (c) Intermediate 66: 7-(5-((3-ethoxycarbonyl-2-(1-(pyridin-3-ylsulfonyl)azacyclobutane-3-formylamino)propyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0453]

[0454] Intermediate 66 (170 mg) was obtained by using intermediate 65 (151 mg, 0.61 mmol) and intermediate 19 (274 mg, 0.61 mmol) via the method of intermediate 55, and was a yellow oily substance. 1H NMR(400MHz; CDCl3)δ9.03(dd,1H),8.85(dd,1H),8.14-8.10(ddd,1H),7.52(ddd,1H),7.4 2(s,2H),6.96(s,1H),6.90(d,1H),4.39-4.32(m,1H),4.18-4.02(m,2H),4.00-3.88(m,4H ),3.81-3.73(m,2H),3.61-3.43(m,2H),3.20-2.70(m,1H),2.81-2.70(m,4H),2.28-2.18( m,2H),2.00-1.90(m,2H),1.80-1.70(m,2H),1.70-1.60(m,2H),1.53(s,9H),1.18(t,3H). C 32 H 44 HRMS[MH] of N6O8S–H - The calculated value is 671.2863, and the measured value is 671.2914.

[0455] (d) Intermediate 67: 2-(1-(pyridin-3-ylsulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0456]

[0457] Intermediate 67 (0.112 g), a yellow oily substance, was obtained by using intermediate 66 (160 mg, 0.24 mmol) via the method of intermediate 22. 1 H NMR(400MHz; CDCl3)δ9.05(dd,1H),8.86(dd,1H),8.13(ddd,1H),7.87(d,1H),7.52(ddd,1H ),7.09(d,1H),6.39-3.60(m,2H),4.51-4.42(m,1H),4.25-4.10(m,2H),4.02-3.90(m,4H), 3.71-3.62(m,1H),3.62-3.53(m,1H),3.43-3.35(m,2H),3.24-3.14(m,1H),2.73-2.67(m,2 H),2.57-2.48(m,2H),2.25-2.18(m,2H),1.97-1.87(m,2H),1.72-1.59(m,4H),1.24(t,3H). C 27 H 36 HRMS[MH] of N6O6S–H -The calculated value is 571.2344, and the measured value is 571.2345.

[0458] (e) Example 21: 2-(1-(pyridin-3-ylsulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0459]

[0460] Using the method of Example 7(f), intermediate 67 (112 mg, 0.20 mmol) yielded 2-(1-(pyridin-3-ylsulfonyl)azacyclobutane-3-carboxamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (56 mg), which was a colorless cracked glassy substance. 1 H NMR(400MHz; CD3OD)δ8.98(s,1H),8.85(d,1H),8.26(dt,1H),7.70(dd,1H),7.36(d,1H),6.46(d,1H),4.26-4.20(m,1H),3.99-3.89(m,4H), 3.58-3.47(m,2H),3.46-3.40(m,2H),3.33-3.29(t,1H),2.75(t,2H), 2.61(t,2H),2.23-2.15(m,2H),1.95-1.86(m,2H),1.71-1.58(m,4H). C 25 H 32 HRMS[MH] of N6O6S–H - The calculated value is 543.2031, and the measured value is 543.2029.

[0461] Example 22: 2-(1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (a) intermediate 68: 1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-carboxylic acid methyl ester

[0462]

[0463] Intermediate 68 (0.670 g) was obtained by using methyl 3-azacyclobutane-carboxylate (389 mg, 2.57 mmol) and 1,2-dimethyl-1H-imidazolium-4-sulfonyl chloride (500 mg, 2.57 mmol) via the method of intermediate 53. It was a colorless crystal. 1H NMR (400MHz; CDCl3) δ7.43(s,1H),4.18-4.06(m,4H),3.67(s,3H),3.65(s,3H),3.28(tt,1H),2.41(s,3H). C 10 H 15 HRMS[M+H] of N3O4S+H + The calculated value is 274.0856, and the measured value is 274.0854. (b) Intermediate 69: 1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-carboxylic acid lithium

[0464]

[0465] Intermediate 69 (0.52 g), a white solid, was obtained by using intermediate 68 (500 mg, 1.83 mmol) and lithium hydroxide (88 mg, 3.66 mmol) via the method of intermediate 54. 1 H NMR (400MHz; CD3OD) δ7.67(s,1H),3.99-3.90(m,4H),3.71(s,3H),3.11-3.01(m,1H),2.41(s,3H). C9H 13 HRMS[MH] of N3O4S - The calculated value is 258.0554, and the measured value is 258.0562.

[0466] (c) Intermediate 70: 7-(5-((2-(1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-ethoxycarbonylpropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0467]

[0468] Intermediate 70 (0.330 g), a yellow oily substance, was obtained by using intermediate 69 (178 mg, 0.67 mmol) and intermediate 19 (300 mg, 0.67 mmol) via the method of intermediate 55. 1H NMR(400MHz; CDCl3)δ7.43(s,1H),7.36(d,1H),7.30(d,1H),7.01(t,1H),6.86(d,1H) ,4.42-4.36(m,1H),4.15-3.92(m,6H),3.78-3.73(m,2H),3.64(s,3H),3.62-3.55(m, 1H),3.53-3.45(m,1H),3.16-3.06(m,1H),2.78-2.70(m,4H),2.40(s,3H),2.23(t,2H ),1.97-1.89(m,2H),1.78-1.69(m,2H),1.69-1.59(m,2H),1.51(s,9H),1.20(t,3H). C 32 H 47 HRMS[MH] of N7O8S–H - The calculated value is 688.3134, and the measured value is 688.3138. (d) Intermediate 71: 2-(1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)ethyl propionate

[0469]

[0470] Intermediate 71 (0.297 g), a yellow oily substance, was obtained by using intermediate 70 (310 mg, 0.45 mmol) via the method of intermediate 22. 1 H NMR(400MHz; CDCl3)δ7.75(d,1H),7.44(s,1H),7.11(d,1H),6.55(s,1H),6.34(d,1 H),4.53-4.47(m,1H),4.21-4.14(m,2H),4.14-4.08(m,2H),4.05-3.95(m,2H),3.72 -3.59(m,5H),3.44-3.38(m,2H),3.27-3.17(m,1H),2.71(t,2H),2.56-2.50(m,2H) ,2.41(s,3H),2.26-2.19(m,2H),1.94-1.87(m,2H),1.70-1.60(m,4H),1.26(t,3H). C 27 H 39 HRMS[MH] of N7O6S–H - The calculated value is 588.2604, and the measured value is 588.2610.

[0471] (e) Example 22: 2-(1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0472]

[0473] By the method of Example 7(f), 2-(1-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (0.140 g) was obtained from intermediate 71 (270 mg, 0.46 mmol), which was a colorless cracked glassy substance. 1 H NMR (400MHz; CD3OD) δ7.68(s,1H),7.14(d,1H),6.37(d,1H),4.26(dd,1H),4.02-3.85(m,4H),3.71(s,3H),3.59(dd,1H),3.43(dd,1H),3. 40-3.36(m,2H),3.25-3.17(m,1H),2.70(t,2H),2.54-2.49(m,2H),2 .41(s,3H),2.20-2.15(m,2H),1.91-1.84(m,2H),1.65-1.55(m,4H). C 25 H 35 HRMS[MH] of N7O6S–H - The calculated value is 560.2291, and the measured value is 560.2278.

[0474] Route 4

[0475]

[0476] Example 23: (S)-2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0477] (a) Intermediate 73: (S)-7-(5-((2-(1-((benzyloxy)carbonyl)azacyclobutane-3-formylamino)-3-(tert-butoxy)-3-oxopropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester

[0478]

[0479] In a 500 mL round-bottom flask, 1-((benzyloxy)carbonyl)azacyclobutane-3-carboxylic acid (2.78 g, 11.82 mmol), intermediate 72 (European patent EP 3275883) (5.12 g, 10.74 mmol), HATU (4.49 g, 11.81 mmol), dichloromethane (100 mL), and DIPEA (7 mL, 40.1 mmol) were added and stirred at room temperature for 30 minutes. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (200 mL) and brine (50 mL) and extracted with dichloromethane (2 × 150 mL). The organic layers were combined and concentrated under vacuum to give a brown oily crude product. The crude product was loaded onto a 120 g high-speed silica gel column and purified with 0–25% EtOH:EtOAc for 35 minutes. The relevant fraction was concentrated under vacuum to give intermediate 73 (10 g), a yellow oily substance that could be used without further purification. C 37 H 51 MS[M+H] of N5O8+H + The calculated value is 694.38, and the measured value is 694.6. 1 H NMR (400MHz; DMSO-d6) Figure 5 As shown.

[0480] (b) Intermediate 74: (S)-7-(5-((2-(azacyclobutane-3-formamido)-3-(tert-butoxy)-3-oxopropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0481]

[0482] A solution of intermediate 73 (10 g, 14.41 mmol) in ethanol (144 mL) was added to 10% Pd / C (1.534 g, 1.441 mmol), and the mixture was stirred overnight (16 H) in the presence of H2 gas. The reaction mixture was filtered through diatomaceous earth, washed with ethanol (3 × 200 mL), and concentrated under vacuum to give intermediate 74, which was a yellow oil and could be used without further purification. 29 H 45 MS[M+H] of N5O6+H + The calculated value is 560.34, and the measured value is 560.3.

[0483] (c) Intermediate 75: (S)-2-(azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0484]

[0485] Intermediate 74 (4.56 g, 8.14 mmol) was dissolved in dichloromethane (80 mL). TFA (15 mL, 195 mmol) was added to the reaction mixture, and the mixture was stirred at 20 °C for 6 hours. LC-MS showed the reaction was complete, and the mixture was concentrated under vacuum. The crude product was purified using a 120 g C18 column, eluting with ammonium carbonate-modified MeCN:H2O (0-25%) for 35 min. The relevant fraction was concentrated under vacuum to give an impure white solid. The crude product was purified again using a 120 g C18 column, eluting with ammonium carbonate-modified MeCN:H2O (0-25%) for 50 min. The relevant fraction was concentrated under vacuum to give intermediate 75 (1.03 g), a white solid. 1 H NMR (400MHz; CD3OD) δ7.20(d,1H),6.40(d,1H),4.36(d,1H),4.26-4.18(m,1H),4.18-4.08(m,3H),3.74(d,1H),3.71(d,1H),3. 68-3.59(m,1H),3.50(dd,1H),3.43-3.39(m,2H),2.73(t,2H),2.56(t,2H),2.22(t,2H),1.94-1.86(m,2H),1.69-1.60(m,4H). C 20 H 30 MS[M+H] of N5O4+H + The calculated value is 404.23, and the measured value is 404.2.

[0486] Example 23: (S)-2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0487]

[0488] A solution of intermediate 75 (50 mg, 0.124 mmol), THF (1 mL), and Na₂CO₃ (180 μL, 0.180 mmol) was cooled to 0 °C. 3,5-Dichlorobenzenesulfonyl chloride (9 μL, 0.124 mmol) was added to the reaction mixture, and the suspension was stirred at 0 °C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was acidified with 2 M HCl (100 μL) and then purified using an Xterra RP18 preparative column, eluting for 20 min with ammonium carbonate-modified MeCN:H₂O (15–55%). The relevant fraction was concentrated under vacuum to give (S)-2-(1-(3,5-dichlorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (55.1 mg), a white solid. 1 H NMR(400MHz; DMSO-d6)δ8.09(t,1H),8.05(d,1H),7.85-7.80(m,2H),7.80-7.7 5(m,1H),7.32(br.s.,1H),7.14(d,1H),6.31(d,1H),4.21-4.13(m,1H),3.95-3 .87(m,2H),3.85-3.78(m,2H),3.42-3.30(m,2H),3.27(t,2H),3.21-3.13(m,1 H),2.63(t,2H),2.44(t,2H),2.04(qd,2H),1.77(quin,2H),1.57-1.43(m,4H). C 26 H 31 MS [M+H] of Cl2N5O6S+H + The calculated value is 612.14, and the measured value is 612.1.

[0489] Example 24-32

[0490]

[0491] Examples 24-32 were prepared using the method of Example 23 with aromatic sulfonyl chlorides, wherein the R groups are listed in the table below. The crude products were purified by mass-oriented reversed-phase HPLC on a Waters XSelect CSH C18 19×100 mm 5 μm column with ammonium carbonate modifier, or by purification using an Xterra RP18 preparative column, eluting with ammonium carbonate modified MeCN:H2O (15-55%) for 20 min.

[0492]

[0493] Example 24: (S)-2-(1-(3,5-dimethylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0494] 1 H NMR (600MHz; DMSO-d6) Figure 6 As shown.

[0495] Example 25: (S)-2-(1-(3-chloro-5-methylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0496] 1 H NMR (600MHz; DMSO-d6) Figure 7 As shown.

[0497] Example 26: (S)-2-(1-(3-ethylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0498] 1 H NMR (600MHz; DMSO-d6) Figure 8 As shown.

[0499] Example 27: (S)-2-(1-(3-chlorobenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0500]

[0501] 1H NMR(400MHz; CDCl3)δ10.12(br.s.,1H),7.86(t,1H),7.80-7.73(m,1H),7.68-7.61(m,1H),7 .59-7.50(m,1H),7.27(s,1H),7.03(d,1H),6.97(br.s.,1H),6.31(d,1H),4.38-4.29(m,1H) ,4.05-3.93(m,4H),3.61-3.52(m,1H),3.49(t,3H),3.32-3.20(m,1H),2.80-2.66(m,3H),2. 61-2.50(m,1H),2.36-2.21(m,2H),1.99-1.90(m,2H),1.89-1.78(m,1H),1.75-1.59(m,3H).

[0502] Example 28: (S)-2-(1-(3-methoxybenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0503] 1 H NMR (600MHz; DMSO-d6) Figure 9 As shown.

[0504] Example 29: (S)-2-(1-(3-(difluoromethyl)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0505]

[0506] 1 H NMR(400MHz; CDCl3)δ9.25(br.s.,1H),8.03-7.91(m,2H),7.80(d,1H),7.75- 7.64(m,2H),7.63-7.53(m,1H),7.34(d,1H),6.75(t,1H),6.39(d,1H),4.37( br.s.,1H),4.04-3.86(m,4H),3.61-3.43(m,4H),3.30-3.18(m,1H),2.75(t, 2H),2.71-2.56(m,2H),2.25(br.s.,2H),1.99-1.87(m,2H),1.66(br.s.,4H).

[0507] Example 30: (S)-2-(1-(3-cyclopropylbenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0508]

[0509] 1 H NMR (400MHz; CDCl3) δ10.30-10.08(m,1H),7.64(d,1H),7.58-7.54(m,1H),7.52-7.44(m,1H),7.38(s,1H),7.27(m,1H),6.97-6.87(m,1H),6.82 -6.70(m,1H),6.31(d,1H),4.33(td,1H),4.04-3.90(m,4H),3.60(td,1H),3.50(t,2H),3.36(d,1H),3.28-3.15(m,1H),2.80- 2.69(m,3H),2.62-2.49(m,1H),2.39-2.21(m,2H),2.07-1.83(m,4H),1.74-1.60(m,3H),1.11-1.02(m,2H),0.84-0.75(m,2H).

[0510] Example 31: (S)-2-(1-((2,3-dihydro-1H-inden-5-yl)sulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0511] 1 H NMR (600MHz; DMSO-d6) Figure 10 As shown.

[0512] Example 32: (S)-2-(1-(3,4-dimethoxybenzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0513] 1 H NMR (600MHz; DMSO-d6) Figure 11 As shown.

[0514] Example 33: (S)-2-(1-((3-(3,6-dihydro-2H-pyran-4-yl)benzenesulfonyl)azacyclobutane-3-formylamino)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (a) intermediate 76: (S)-7-(5-((2-(1-(3-bromobenzenesulfonyl)azacyclobutane-3-formylamino)-3-(tert-butoxy)-3-oxopropyl)amino)-5-oxopentyl)-3,4-dihydro-1,8-naphthidin-1(2H)-carboxylic acid tert-butyl ester

[0515]

[0516] A solution of intermediate 74 (820 mg, 1.465 mmol), Na₂CO₃ (3.6 mL, 3.60 mmol), and THF (21 mL) was cooled to 0 °C. 3-Bromobenzenesulfonyl chloride (412 mg, 1.612 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 10 minutes. The reaction mixture was acidified with 2 M HCl (3 mL), concentrated under vacuum, and then diluted with water (20 mL) and brine (5 mL). The aqueous layer was extracted with EtOAc (3 × 25 mL), the organic layers were combined, and concentrated under vacuum to give intermediate 76 (990 mg), which was a pale yellow oil. 35 H 48 Br 79 MS[M+H] of N5O8S+H + The calculated value is 778.24, and the measured value is 778.4.

[0517] Example 33: (S)-2-(1-((3-(3,6-dihydro-2H-pyran-4-yl)benzenesulfonyl)azacyclobutane-3-formamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0518]

[0519] A solution of intermediate 76 (120.2 mg, 0.154 mmol), 2'-(dimethylamino)-2-biphenyl]palladium(II)-dibornelphosphine complex (8.65 mg, 0.015 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (64.9 mg, 0.309 mmol), and K₂CO₃ (64.0 mg, 0.463 mmol) in THF (0.7 mL) and water (0.7 mL) was purged with nitrogen and heated in a microwave oven at 100 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, washed with EtOAc (3 × 10 mL), and concentrated under vacuum to give an orange gelatinous crude product dissolved in dichloromethane (2 mL). TFA (0.3 mL, 3.89 mmol) was added and the mixture was stirred overnight (16 hours) at room temperature. TFA (0.18 mL, 2.336 mmol) was added, and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under vacuum to give a black oil. The crude mixture was purified using an Xterra RP18 preparative column, eluted with ammonium carbonate-modified MeCN:H2O (25–55%) for 30 min. The relevant fraction was concentrated under vacuum to give (S)-2-(1-((3-(3,6-dihydro-2H-pyran-4-yl)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (27.9 mg), which was a colorless solid. 1 H NMR (400MHz; CDCl3) δ10.12(br.s.1H),7.86(t,1H),7.75(d,1H),7.70-7.64(m,1H),7. 61-7.53(m,1H),7.27(s,1H),7.11(br.s.1H),7.02(d,1H),6.35-6.22(m,2H),4.39-4.2 7(m,3H),4.04-3.91(m,6H),3.58-3.44(m,4H),3.24(quin,1H),2.80-2.66(m,3H),2.61 -2.50(m,3H),2.3-2.21(m,2H),1.99-1.89(m,2H),1.86-1.76(m,1H),1.7-1.57(m,3H). C 31 H 39 MS[M+H] of N5O7S+H + The calculated value is 626.2, and the measured value is 626.4.

[0520] Example 34: (S)-2-(1-(3-(piperazin-1-yl)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0521]

[0522] Piperazine (72.2 mg, 0.838 mmol) was added to a toluene (1.2 mL) solution of intermediate 76 (94.2 mg, 0.121 mmol), RuPhosPdG4 (Sigma-Aldrich) (16.3 mg, 0.019 mmol), and Cs₂CO₃ (164.3 mg, 0.504 mmol). The reaction mixture was purged with N₂ and heated in a microwave oven at 100 °C for 4 hours. LC-MS showed residual starting materials, so piperazine (52.1 mg, 0.605 mmol) was added, and the reaction mixture was heated in a microwave oven at 100 °C for 3 hours. The reaction mixture was filtered and washed with MeOH (3 × 10 mL). The reaction mixture was concentrated under vacuum to give a yellow gel, which was dissolved in dichloromethane (2 mL), and TFA (0.3 mL, 3.89 mmol) was added. The reaction mixture was stirred overnight (16 hours) at room temperature. The reaction mixture was concentrated under vacuum to give an orange solid, which was purified using an Xbridge prep C18 column by elution with ammonium carbonate-modified MeCN:H2O (25-55%) for 30 min. The relevant fractions were combined and concentrated under vacuum to give (S)-2-(1-(3-(piperazin-1-yl)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (10.5 mg), which was a white solid. 1 H NMR (400MHz; CD3OD) δ7.54(dd,1H),7.38-7.28(m,4H),6.44(d,1H),4.18(t,1H),3.97-3.91(m,2H),3.91-3.84(m,2H),3.55-3.45(m ,6H),3.45-3.39(m,2H),3.29-3.22(m,5H),2.79-2.72(m,2H),2.59(t,2H),2.23-2.17(m,2H),1.95-1.88(m,2H),1.70-1.60(m,4H). C 30 H 41 MS[M+H] of N7O6S+H + The calculated value is 628.2, and the measured value is 628.4.

[0523] Example 35: (S)-2-(1-((3-(2-(dimethylamino)ethoxy)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid

[0524]

[0525] To a solution of intermediate 76 (103.2 mg, 0.133 mmol), RockPhosPdG3 (Sigma-Aldrich) (11.11 mg, 0.013 mmol), and Cs₂CO₃ (71.2 mg, 0.219 mmol) in toluene (1.3 mL), 2-(dimethylamino)ethane-1-ol (0.053 mL, 0.530 mmol) was added. The reaction mixture was purged with N₂ and heated in a microwave oven at 100 °C for 4 hours. The reaction mixture was filtered and washed with MeOH (3 × 10 mL). The reaction mixture was concentrated under vacuum to give an orange gel dissolved in dichloromethane (3.00 mL), and TFA (0.26 mL, 3.37 mmol) was added. The reaction mixture was stirred overnight (16 hours) at room temperature. Then, TFA (0.3 mL, 3.89 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum to give a yellow solid, which was purified using an Xbridge prep C18 column by elution with ammonium carbonate-modified MeCN:H2O (25-55%) for 30 min. The relevant fractions were combined and concentrated under vacuum to give (S)-2-(1-((3-(2-(dimethylamino)ethoxy)benzenesulfonyl)azacyclobutane-3-formamide)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanoylamino)propionic acid (8.5 mg), which was a white solid. 1 H NMR(400MHz; CDCl3)δ10.06(br s.,1H),7.54-7.36(m,3H),7.26(s,1H),7.25-7.19(m,1H),7.02(br.s.,1H),6.96-6.87 (m,1H),6.31(d,1H),4.36-4.26(m,1H),4.17(t,2H),4.05-3.91(m,4H),3.61-3.53(m,1H ),3.52-3.39(m,3H),3.22(quin,1H),2.81(t,2H),2.75(t,3H),2.62-2.49(m,1H),2.43- 2.36(m,6H),2.34-2.17(m,2H),2.00-1.89(m,2H),1.89-1.77(m,1H),1.74-1.57(m,3H). C30 H 42 MS[M+H] of N6O7S+H + The calculated value is 631.76, and the measured value is 631.4.

[0526] Route 5

[0527]

[0528] Example 36: N4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)-N2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-carbonyl)-L-asparagine

[0529] Intermediate 77: (4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)but-3-en-1-yl)tert-butyl carbamate

[0530]

[0531] To a stirred mixture of triphenyl((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)phosphonium bromide (WO 2016 / 046225) (6.71 g, 13.71 mmol) and sodium tert-butoxide (2 M in THF) (8.91 mL, 17.82 mmol) in dichloromethane (25 mL), tert-butyl (3-oxopropyl)carbamate (2.5 g, 13.71 mmol) was added and stirred at room temperature (5 min). LCMS showed a large amount of the expected product. The mixture was stirred further (2.5 h) and then left overnight (16 h). The mixture was dissolved in dichloromethane (about 30 mL); Florisil (10 g) was added, the mixture was concentrated under vacuum and dried, and purified by column chromatography (340 g silica gel column, 30-100% EtOAc in cyclohexane). The purest product fraction was concentrated under vacuum to obtain a yellow, gelatinous intermediate 77 (3.36 g), which is a mixture of geometric isomers and can be used without further purification. C 17 H 25 MS[M+H] of N3O2+H + The calculated value is 304.20, and the measured value is 304.2. 1 H NMR (400MHz; DMSO-d6) Figure 12 As shown.

[0532] Intermediate 78: (E)-4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)but-3-en-1-amine

[0533]

[0534] Trifluoroacetic acid (7 mL, 91 mmol) was added to a solution of intermediate 77 (3.36 g, 9.86 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature to obtain a yellow solution (2 hours). LCMS showed that the desired intermediate 78 was a mixture of regioisomers and could be used without further purification. 12 H 17 N3+H of MS[M+H] + The calculated value is 204.15, and the measured value is 204.2.

[0535] Intermediate 79: (E)-N2-((benzyloxy)carbonyl)-N4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)but-3-en-1-yl)-L-asparagine tert-butyl ester

[0536]

[0537] 2,4,6-Tripropyl-1,3,5,2,4,6-trioxotriphosphonane (0.320 mL, 0.537 mmol) was added to a 3 mL solution of N-benzyloxycarbonyl-(L)-aspartic acid monotert-butyl ester (Combi-Blocks) (165 mg, 0.537 mmol) in ethyl acetate and stirred (20 °C, 30 min). Triethylamine (0.6 mL, 4.30 mmol) was added to a 3 mL solution of intermediate 78 (332 mg, 0.735 mmol) in ethyl acetate and stirred (30 min), then heated to reflux (90 °C). The activated acid of the previous mixture in ethyl acetate was added and stirred (1 min). The mixture was cooled to room temperature with stirring (1 h). The mixture was washed with water (2 × 20 mL), the aqueous layers were combined and extracted with ethyl acetate (approximately 10 mL). The organic layers were combined and washed with an aqueous solution of ammonium carbonate (approximately 5 mL). The solvent was then evaporated through a hydrophobic glass frit under a nitrogen stream (40 °C) to obtain intermediate 79 (210 mg), which was ready for use without further purification. 28 H 36 MS[M+H] of N4O+H + The calculated value is 509.27, and the measured value is 509.2.

[0538] Intermediate 80: N4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)-L-asparagine tert-butyl ester

[0539]

[0540] The intermediate 79 (210 mg, 0.43 mmol) in a methanol (10 mL) solution was hydrogenated using the H-Cube technique (5 bar, 30 °C, 1 mL / min, palladium on carbon (10%) (43.9 mg, 0.413 mmol). The product solution was then concentrated under vacuum to give intermediate 80 (126 mg), which was ready for use without purification. 20 H 32 MS[M+H] of N4O3+H + The calculated value is 377.25, and the measured value is 377.3.

[0541] Example 36: N4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)-N2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-carbonyl)-L-asparagine

[0542]

[0543] A solution of intermediate 10 (26.1 mg, 0.102 mmol), HATU (45.3 mg, 0.119 mmol), and DIPEA (0.054 mL, 0.311 mmol) in DMF (0.4 mL) was stirred at room temperature (15 min). Intermediate 80 (1.45 mL, 0.104 mmol) was added to the previous solution as a 0.0716 M DMF (2.9 mL) suspension and stirred at room temperature (20 °C, 1.5 h). LCMS showed residual raw materials. Additional HATU (13 mg, 0.034 mmol), intermediate 10 (6 mg, 0.024 mmol), and DIPEA (0.02 mL, 0.115 mmol) were added, and the mixture was stirred overnight (16 h). The reaction mixture was evaporated under a nitrogen stream (40 °C). Trifluoroacetic acid (0.200 mL, 2.60 mmol) was added to a dichloromethane (1.0 mL) solution of the residue and stirred (20 °C, 19 H). Additional trifluoroacetic acid (0.200 mL, 2.60 mmol) was added and stirred (16 H). The mixture was concentrated to dryness under a nitrogen stream. The sample was purified by reversed-phase HPLC (Reveleris, 0-100% MeCN in 10% ammonium carbonate aqueous solution). Appropriate fractions were combined and concentrated to dryness under vacuum to give N4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)-N2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-carbonyl)-L-asparagine (23.9 mg), a yellow solid. 27 H 35 MS[M+H] of N5O6S+H + The calculated value is 558.23, and the measured value is 558.3.1 H NMR (400MHz; DMSO-d6) Figure 13 As shown.

[0544] Route 6

[0545]

[0546] Example 37: (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-carboxyamino)butyric acid (a) intermediate 81: (S)-2-amino-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)butyric acid methyl ester

[0547]

[0548] A solution of (S)-2-((tert-butoxycarbonyl)amino)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)butyrate (715 mg, 0.987 mmol) (WO20120120197973653, page 108) in dichloromethane (5 mL) with hydrochloric acid (4 M in 1,4-dioxane) (2 mL, 8.00 mmol) was stirred at room temperature for 3 hours. LCMS showed that the reaction was nearing completion. The reaction mixture was stirred for another 30 minutes and then washed with saturated aqueous NaHCO3 solution (20 mL) and saturated aqueous NaCl solution (20 mL). LCMS of the aqueous solution showed the presence of the product. The aqueous solution was extracted with dichloromethane (3 × 10 mL) and EtOAc (3 × 10 mL). The combined organic compounds were passed through a hydrophobic glass buffer and concentrated under vacuum to obtain a yellow gel, which was dissolved in trifluoroacetic acid (1 mL, 12.98 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to give an orange oil, which was dissolved in MeOH (20 mL) and eluted with MeOH through an aminopropyl ion exchange column (50 g). Suitable fractions were combined and concentrated under vacuum to give intermediate 81 (265 mg), which was an orange gel. 18 H 30 MS[M+H] of N4O2+H + The calculated value is 335.23, and the measured value is 335.3. 1 H NMR (400MHz; DMSO-d6) Figure 14 As shown.

[0549] Example 37: (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)butyric acid

[0550]

[0551] A solution of intermediate 10 (65.2 mg, 0.255 mmol), HATU (115 mg, 0.187 mmol), and DIPEA (0.148 mL, 0.851 mmol) in dichloromethane (0.4 mL) was stirred for 15 minutes, followed by the addition of intermediate 81 (219 mg, 0.170 mmol) in DMF (0.4 mL). The resulting solution was stirred at room temperature for 1 hour. LCMS showed that amide coupling was complete, yielding the desired methyl ester intermediate. The reaction mixture was concentrated under vacuum and then dissolved in a mixture of methanol (0.3 mL) and sodium hydroxide (2 M) (0.3 mL, 0.600 mmol). The resulting mixture was stirred at room temperature for 66 hours. LCMS showed no further reaction progress. The mixture was concentrated under vacuum to remove DMF and MeOH and then redissolved in methanol (0.3 mL) and sodium hydroxide (2 M) (0.3 mL, 0.600 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under vacuum, then dissolved in DMSO (0.2 mL) and purified by MDAP. Suitable fractions were combined and concentrated under vacuum to give (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formamide)butyric acid (27 mg), a white solid. 28 H 39 MS[M+H] of N5O5S+H + The calculated value is 558.2, and the measured value is 558.3. 1 H NMR (400MHz; DMSO-d6) Figure 15 As shown.

[0552] Example 38: (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(1-(benzenesulfonyl)azacyclobutane-3-formylamino)butyric acid

[0553]

[0554] A solution of intermediate 26 (61.6 mg, 0.255 mmol), HATU (115 mg, 0.187 mmol), and DIPEA (0.148 mL, 0.851 mmol) in dichloromethane (0.4 mL) was stirred for 15 minutes, followed by the addition of intermediate 81 (219 mg, 0.170 mmol) and DMF (0.4 mL). The resulting solution was stirred at room temperature for 1 hour. LCMS showed that amide coupling was complete, yielding the desired methyl ester intermediate. The reaction mixture was concentrated under vacuum and then dissolved in methanol (0.3 mL), with sodium hydroxide (2 M) (0.3 mL, 0.600 mmol) added. The resulting mixture was stirred at room temperature for 66 hours, concentrated under vacuum to remove DMF and MeOH, and redissolved in methanol (0.3 mL) and sodium hydroxide (2 M) (0.3 mL, 0.600 mmol). The reaction mixture was stirred at room temperature for 8 hours, concentrated under vacuum, dissolved in DMSO (0.2 mL), and purified by MDAP. The appropriate fractions were combined and concentrated under vacuum to give (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(1-(benzenesulfonyl)azacyclobutane-3-carboxyamino)butyric acid (59 mg), which was a white solid. 27 H 37 MS[M+H] of N5O5S+H + The calculated value is 544.25, and the measured value is 544.3. 1 H NMR (400MHz; DMSO-d6) Figure 16 As shown.

[0555] Route 7

[0556]

[0557] Example 39: (S)-2-(1-((3-chlorophenyl)sulfonyl)azacyclobutane-3-formamido)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)butyric acid

[0558] (a) Intermediate 82: (S)-3-((1-methoxy-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-1-oxobut-2-yl)carbamoyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0559]

[0560] A solution of 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylic acid (140 mg, 0.697 mmol), HATU (429 mg, 0.697 mmol), and DIPEA (0.552 mL, 3.17 mmol) in dichloromethane (2 mL) was stirred for 15 minutes, and then a solution of intermediate 81 (212 mg, 0.634 mmol) in dichloromethane (2 mL) was added. LCMS showed that the reaction was complete. The reaction mixture was concentrated under vacuum, then dissolved in dichloromethane (2 mL) and placed in a 28 g KP-NH filter cartridge for purification by rapid chromatography, eluting with 0-100% EtOAc in cyclohexane, followed by 0-100% 3:1 EtOAc:EtOH in cyclohexane. Appropriate fractions were combined and concentrated under vacuum to give intermediate 82 (108 mg) as an orange solid, which was ready for use without purification. 27 H 43 MS[M+H] of N5O5+H + The calculated value is 517.32, and the measured value is 518.4.

[0561] (b) Intermediate 83: (S)-2-(azacyclobutane-3-formamido)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)methyl butyrate·methyl trifluoroacetate

[0562]

[0563] A solution of intermediate 82 (108 mg, 0.209 mmol) and trifluoroacetic acid (0.161 mL, 2.086 mmol) in dichloromethane (2 mL) was stirred at room temperature for 24 hours. LC-MS showed that the reaction was nearing completion. The reaction mixture was concentrated under vacuum to give intermediate 83, which was an orange gel. 22 H 35 MS[M+H] of N5O3+H + The calculated value is 418.28, and the measured value is 418.4. 1 HNMR (400MHz; DMSO-d6) Figure 17 As shown.

[0564] Example 39: (S)-2-(1-((3-chlorophenyl)sulfonyl)azacyclobutane-3-formamido)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)butyric acid

[0565]

[0566] A solution of intermediate 83 (57 mg, 0.075 mmol), THF (1 mL), and sodium hydroxide (2 M) (0.301 mL, 0.603 mmol) was cooled to 0 °C. 3-Chlorobenzenesulfonyl chloride (0.013 mL, 0.090 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 2 hours. LC-MS showed that the reaction was not yet complete. Another 0.013 mL of 3-chlorobenzenesulfonyl chloride (0.090 mmol) was added, and the reaction mixture was stirred for another 1.5 hours. The reaction mixture was concentrated under vacuum to give a yellow solid, which was dissolved in a 1:1 DMSO:water solution and then purified using MDAP. The appropriate fractions were combined and concentrated under vacuum, then dried under a nitrogen stream (40 °C) to give (S)-2-(1-((3-chlorophenyl)sulfonyl)azacyclobutane-3-formamido)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)amino)butyric acid (10 mg), which is a white solid. 27 H 36 MS[M+H] of ClN5O5S+H + The calculated value is 578.2, and the measured value is 578.3. 1 H NMR (400MHz; DMSO-d6) Figure 18 As shown.

[0567] Example 40: (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(4-methylbenzenesulfonylazonylbutane-3-formylamino)butyric acid

[0568]

[0569] A solution of intermediate 83 (57 mg, 0.075 mmol), THF (1 mL), and sodium hydroxide (2 M) (0.301 mL, 0.603 mmol) was cooled to 0 °C. 4-Methylbenzenesulfonyl chloride (17.23 mg, 0.090 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under vacuum to give a yellow solid, which was dissolved in 1:1 DMSO:water and purified by MDAP. Appropriate fractions were combined and concentrated under vacuum, then dried under a nitrogen stream (40 °C) to give (S)-4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)amino)-2-(4-methylbenzenesulfonylazonylbutane-3-formylamino)butyric acid (10.5 mg), a white solid. 28 H 39 MS[M+H] of N5O5S+H + The calculated value is 557.26, and the measured value is 558.3. 1H NMR (400MHz; DMSO-d6) Figure 19 As shown.

[0570] Cell adhesion data

[0571] The determination was performed as described in the literature (PA Procopiou, NA Anderson, J. Barrett, TN Barrett, MHJ Crawford, BJ Fallon, APH Hancock, J. Le, S. Lemma, RP Marshall, J. Morrell, JMP Ritchard, JERowedder, P. Saklatvala, RJS Lack, SLS Sollis, CJS Buckling, LRT Horp, G. Vitulli, et al., J. Med. Chem., 2018, 61, 8417-443; SBL Udbrook, ST Barry, CJ Delves, CMTHorgan, Horgan, Biochem. J., 2003, 369, 311-318).

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581] Unless a stereochemistry is specified, these compounds are racemic.

[0582]

[0583] Comparison of Example 6A and GSK3008348

[0584]

[0585] Chromatography logD

[0586] Chromatographic logD is a measure of a compound's lipophilicity (RJ Young et al., Drug Discovery Today, 2011, 116, 882-830). Lipophilicity is a key physicochemical property that plays a crucial role in determining ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the overall suitability of candidate drugs. Growing evidence suggests that controlling physicochemical properties such as lipophilicity within defined optimal ranges can improve compound quality and the likelihood of therapeutic success (JA Arnott and SLPlaney, Expert Opinion on Drug Discovery, 2012, 7:10, 863-875).

[0587] hERG Q-membrane

[0588] The human ether-a-go-go-related gene (hERG) encodes a cardiac inward rectifier voltage-gated potassium channel (IKr) involved in cardiac repolarization. Inhibition of hERG currents leads to QT interval prolongation, resulting in a potentially fatal ventricular tachycardia known as torsade de Pointes. Due to these cardiotoxic effects, some drugs have been withdrawn from late-stage clinical trials, making it crucial to identify inhibitors early in drug discovery (W. Haverkamp et al., Eur Heart J., 2000, 21(15), 1216). This low potency in screening favors compound development.

[0589] The data and description of the measurements for GSK3008348 can be found in J.Med.Chem., 2018, 61, 8417-8443.

Claims

1. A compound selected from:

2. A compound selected from:

3. A compound, said compound being (S)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)-2-(1-(3-methylbenzenesulfonyl)azacyclobutane-3-formylamino)pentanoic acid.

4. A composition comprising the compound according to any one of claims 1-3.

5. The composition according to claim 4, wherein, The composition is suitable for inhalation.

6. Use of the compound according to any one of claims 1 to 3 or the composition according to claim 4 or 5 in the preparation of a medicament for treating integrin-related diseases.

7. The use according to claim 6, wherein, The integrin is α v β6.

8. The use according to claim 6, wherein, The diseases mentioned are selected from: cancer, ischemic diseases, fibrosis, osteoporosis, postoperative restenosis, or combinations thereof.

9. The use according to claim 6, wherein, The disease in question is idiopathic pulmonary fibrosis.

10. The use according to claim 6, wherein, The disease in question is renal fibrosis.

11. The use according to claim 6, wherein, The disease in question is liver fibrosis.

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