N-Tetrazolylarylurea Derivatives, Method for Producing the Same, and Use Thereof

Abstract

The present invention relates to the field of biopharmaceuticals. An N-tetrazolylarylurea derivative, a method for producing the same, and use thereof are disclosed. The present invention has recently discovered an N-tetrazolylarylurea derivative, and further found that the compound has antagonist activity against the bradykinin B1 receptor. Therefore, the compound can be used as a novel bradykinin B1 receptor antagonist, and further can be used to treat or prevent related diseases caused by abnormal expression of the bradykinin B1 receptor. In particular, the present invention has recently found that the N-tetrazolylarylurea derivative has a preventive or therapeutic effect against coronavirus disease 2019, pulmonary edema, diabetic complications, allergic conjunctivitis, and the like.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceuticals, and particularly to N-tetrazolylarylurea derivatives as bradykinin B1 receptor antagonists, methods for producing these derivatives, pharmaceutical compositions containing these derivatives, and their use as medicaments for treating and preventing diseases caused by abnormal expression of the bradykinin B1 receptor.

Background Art

[0002] Endogenous bradykinin B1 receptor agonists are produced by the activated kallikrein-kinin system, which includes des-Arg9-BK and Lys-des-Arg9-BK of bradykinin. Bradykinin is a vasoactive peptide produced by the activation of prekallikrein via the action of kallikrein during the inflammatory response. Bradykinin can specifically bind to bradykinin receptors, thereby activating the inflammatory signal transduction pathway and promoting a series of biological responses such as vasodilation, increased vascular permeability, contraction of non-vascular smooth muscle, inflammatory response, and pain. Currently, there are two known subtypes of bradykinin receptors, namely B1 receptor and B2 receptor (B1R and B2R). These two receptors have the structure of G protein-coupled receptors (GPCRs), and they play many various biological functions in the human body (Non-Patent Document 1, Non-Patent Document 2).

[0003] Under physiological conditions, the B1 receptor is scarcely expressed in healthy tissues, and its expression is induced only by endogenous stimulators such as endotoxins, cytokines, and growth factors produced during tissue injury. For example, the expression of the B1 receptor has been found to be upregulated in the inflammatory pathologies of various diseases (e.g., asthma, pneumonia, arthritis, diabetes, endometriosis, ulcerative colitis, Crohn's disease, etc.) and some neurological diseases (e.g., epilepsy, stroke, and multiple sclerosis, etc.). IL-1β can directly upregulate the bradykinin B1 receptor (Non-Patent Document 3). However, when the bradykinin B2 receptor is activated, this further induces the upregulation of the B1 receptor through the activation of NF-κB, leading to the expression of IL-1β in fibroblasts (Non-Patent Document 2). When upregulated, the bradykinin B1 receptor is mainly expressed in macrophages, neutrophils, fibroblasts, neurons, smooth muscle cells, and vascular endothelial cells (Non-Patent Document 4). This is distinguished from the B2 receptor, which is continuously expressed at high levels in healthy tissues such as vascular smooth muscle, non-vascular smooth muscle, and heart tissue.

[0004] Activation of the bradykinin B1 receptor causes pain, promotes the inflammatory response, increases vascular permeability, and promotes tissue fibrosis. In contrast to the bradykinin B2 receptor, the bradykinin B1 receptor does not undergo internalization and desensitization of cells even under repeated stimulation by agonists. Activation of the bradykinin B1 receptor causes self-induction, which may lead to the amplification and persistence of the processes of inflammation and pain (Non-Patent Document 3, Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7).

[0005] One of the mechanisms of action of the bradykinin B1 receptor is to induce the gene expression and production of interleukins such as IL-6 and IL-8, promote the production of PGE2 (prostaglandin 2), thereby activating the inflammation-related prostaglandin signaling pathway, and phosphorylating and upregulating the TRPV1 (transient receptor potential vanilloid 1) receptor. These receptors further cause a pain response, enhance pain conduction, and induce neurogenic inflammation by releasing neuropeptides in inflamed tissues (Non-Patent Document 8, Non-Patent Document 9).

[0006] Bradykinin B1 receptor plays an important role in many diseases, especially chronic inflammatory lesions. In animal models, the anti-inflammatory and analgesic effects by blocking bradykinin B1 receptor have been clarified, which supports the potential pharmacological effects of bradykinin B1 receptor antagonists (Non-Patent Document 10, Non-Patent Document 11, Non-Patent Document 12, Non-Patent Document 13, Non-Patent Document 14, Non-Patent Document 15, Non-Patent Document 16, Non-Patent Document 17, Non-Patent Document 18). Considering that bradykinin B1 receptor is not expressed in normal tissues and is only expressed and upregulated in cases of tissue damage and lesions, thus, bradykinin B1 receptor inhibitors have therapeutic safety.

[0007] Therefore, there has been an ongoing demand to develop newer bradykinin B1 receptor antagonists.

Prior Art Documents

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Summary of the Invention

[0009] The present invention provides an N-tetrazolylarylurea derivative, a method for producing this derivative, and the use of this derivative. The inventors of the present invention newly discovered a class of N-tetrazolylarylurea derivatives and found that such compounds have antagonist activity against the bradykinin B1 receptor. Therefore, this compound is useful as a novel bradykinin B1 receptor antagonist and is further useful for treating or preventing related diseases caused by abnormal expression of the bradykinin B1 receptor.

[0010] Specific technical solutions of the present invention are as follows.

[0011] In one aspect, the present invention relates to Formula I:

Chemical formula

[0012] In formula I, R 1 and R 2 together with the N atom to which they are attached may form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom. Optionally, the 3- to 8-membered heterocyclic group may be substituted by one to three identical or different functional groups A, where the functional group A may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, and cycloamino.

[0013] On the other hand, R 1 and R 2 together with the N atom to which they are attached may form an 8- to 12-membered bicyclic heterocyclic group containing zero, one, or two heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2 in addition to at least one nitrogen atom. The 8- to 12-membered bicyclic heterocyclic group may include a spiro heterocyclic group, a bridged bicyclic heterocyclic group, and a fused bicyclic heterocyclic group. Optionally, the 8- to 12-membered bicyclic heterocyclic group may be substituted by one to three identical or different functional groups B, where the functional group B may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0014] On the other hand, each of R 1 and R 2 is the following group: (i) H, C1-C10 alkyl, C2-C 10 alkenyl, and C2-C 10 alkynyl (optionally, C1-C 10 alkyl, C2-C 10 alkenyl, or C2-C 10 alkynyl may be substituted by one to three identical or different functional groups C, where the functional group C may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino), or, (ii) phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, and 5- to 7-membered heterocyclic group (where the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains one, two, or three heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, or 5- to 7-membered heterocyclic group may be substituted by one to three identical or different functional groups D, where the functional group D may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino) may be independently selected from the group consisting of.

[0015] In formula I, Ar 1 may be selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, and C9-C 10 dicycloalkyl, where the 5- to 6-membered heteroaryl contains one or two heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, or C9-C10 The dicycloalkyl may be substituted by one to three identical or different functional groups E, where the functional group E may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0016] In formula I, Z is phenyl, a 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, a 5- to 7-membered heterocyclic group, C9-C 10 dicycloalkyl, a 9- to 10-membered fused bicyclic heterocyclic group,

Chemical formula

[0017] R 3It may be selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, and 5- to 6-membered heteroaryl. Optionally, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, or 5- to 6-membered heteroaryl may be substituted by one to three identical or different functional groups G, where the functional group G is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0018] Y may be selected from the group consisting of O or NH.

[0019] Ar 2 is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C 10 -C 20 condensed cyclic group, C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, and C1-C6 alkoxy. The 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains one, two, or three heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl, 5- to 6-membered heteroaryl, C 10 -C 20 condensed cyclic group, C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, or C1-C6 alkoxy may be substituted by one to three identical or different functional groups H, where the functional group H is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0020] In another aspect, the present invention provides an N-tetrazolylarylurea derivative which is a compound represented by formula I: [Chemical formula] or a cis-trans isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0021] In the formula, R 1 and R 2 together with the N atom to which they are attached form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom, wherein the above group is substituted by one to three identical or different functional groups A, and the functional group A is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, or cycloamino, or R 1 and R 2 together with the N atom to which they are attached form an 8- to 12-membered bicyclic group containing zero, one, or two heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2 in addition to at least one nitrogen atom, wherein the bicyclic group includes spirocycloalkyl, bridged bicycloalkyl, and fused bicycloalkyl, and the above group is substituted by one to three identical or different functional groups B, and the functional group B is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, or R 1 and R 2 each is the following group: (i) H, C1-C10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl (wherein the above groups excluding H are substituted by one to three identical or different functional groups C, and the functional group C is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (ii) phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group (wherein the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains one, two, or three heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, and the phenyl, heteroatom, or heteroatom-containing group is substituted by one to three identical or different functional groups D, and the functional group D is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino) is independently selected from the group consisting of Ar 1 is phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, C9-C 10Selected from the group consisting of a condensed bicyclic group, wherein the 5- to 6-membered heteroaryl contains one or two heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, and the phenyl, heteroatom, or heteroatom-containing group is substituted by one to three identical or different functional groups E, and the functional group E is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, Z is the following group: (i) phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group, C9-C 10 condensed bicyclic group, 9- to 10-membered condensed heterobicyclic group (wherein the 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, or 9- to 10-membered condensed heterobicyclic group contains one, two, or three heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, and the phenyl, heteroatom, or heteroatom-containing group is substituted by one to three identical or different functional groups F, and the functional group F is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino, or on the other hand, the functional group F forms a 5- to 8-membered heterocyclic ring), or, (ii) [Chemical formula] (wherein X is selected from the group consisting of O or NH, and R 3is selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, and the above groups are substituted by 1 to 3 identical or different functional groups G, and the functional group G is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or, (iii) [Chemical formula] (wherein Y is selected from the group consisting of O or NH, and Ar 2 is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C 10 -C 20 fused cyclic group, C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, C1-C6 alkoxy, wherein the above groups are substituted by 1 to 3 identical or different functional groups H, and the functional group H is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, and the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2) selected from the group consisting of.

[0022] The present inventors have newly discovered that the above-mentioned N-tetrazolyl aryl urea derivatives have antagonist activity against the bradykinin B1 receptor. Therefore, this compound is useful as a new class of bradykinin B1 receptor antagonists, and is further useful for treating or preventing related diseases caused by abnormal expression of the bradykinin B1 receptor. Preferably, the above-mentioned N-tetrazolyl aryl urea derivatives have better selectivity for B1R than for the bradykinin B2 receptor (B2R). Compared with many B1 antagonists reported so far, the above-mentioned N-tetrazolyl aryl urea derivatives of the present invention are characterized by containing the structure of a urea functional group. When the present inventors searched through SciFinder, they found that there is no report in the prior art that N-tetrazolyl aryl urea derivatives have activity against B1.

[0023] In a third aspect, the present invention provides a method for producing the above-mentioned N-tetrazolyl aryl urea derivatives, the method comprising the steps shown below.

[0024] Method 1: For a compound represented by formula I, wherein R 1 and R 2 are non-hydrogen groups, or R 1 and R 2 together with the N atom to which they are attached form a heterocyclic group containing at least one nitrogen atom, the production method is shown below.

[0025] The 2-halogenated 5-nitroaromatic carbonitrile represented by formula a is coupled with the Z-B(OH)₂ boronic acid represented by formula b under alkaline conditions to obtain a compound represented by formula c. Sodium azide is added to the cyano group in the compound represented by formula c to obtain a tetrazolyl intermediate represented by formula d. The tetrazolyl intermediate is protected with a Trt group to obtain an intermediate represented by formula e. Subsequently, the nitro group is reduced to obtain an amino compound represented by formula f. The amino compound is converted into an isocyanate compound represented by formula g. The isocyanate compound is reacted with an amine to produce a urea compound represented by formula h. Finally, the Trt group is removed from the urea compound to obtain the target compound.

Chemical formula

[0026] Compounds 1 to 14, Compound 18, and Compounds 59 to 62 in the examples were produced according to the above Method 1.

[0027] Method 2: For the compound represented by formula I, wherein Z is a substituted or unsubstituted phenoxy, the production method is shown below.

[0028] The 2-halogenated 5-nitroaromatic carbonitrile represented by formula a is subjected to a nucleophilic substitution reaction with a substituted phenol represented by formula b2 under alkaline conditions to obtain a phenolic ether intermediate represented by formula c2. The remaining steps are the same as steps 2, 3, 4, 5, 6, and 7 described in Method 1, and finally the corresponding target compound is obtained.

Chemical formula

[0029] Compounds 63 and 64 in the examples were produced according to the above Method 2.

[0030] Method 3: For the compound represented by formula I, wherein Z is [Chemical] For the compound that is, in Method 1, replace the compound represented by Formula c with [Chemical] Perform Steps 2, 3, 4, 5, 6, and 7 described in Method 1, except for the replacement, to finally obtain the target product.

[0031] Compounds 15 and 17 in the examples were produced according to the above Method 3.

[0032] Method 4: For the compound represented by Formula I, in which one of R 1 or R 2 is a hydrogen atom, first perform Steps 1, 2, 3, and 4 in Method 1 to obtain an amino intermediate represented by Formula f. Then, react the amino intermediate directly with an isocyanate compound to produce a urea compound represented by Formula h1. Finally, subject the urea compound to Trt-deprotection to obtain the target compound. [Chemical]

[0033] Compounds 58 - 62 and 66 - 71 in the examples were produced according to the above Method 4.

[0034] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the above-described N-tetrazolylarylurea derivative, a pharmaceutically acceptable carrier or additive, and optionally another therapeutic agent.

[0035] In a fifth aspect, the present invention provides the use of the above-described N-tetrazolylarylurea derivative in the manufacture of a bradykinin B1 receptor antagonist.

[0036] In a sixth aspect, the present invention provides the use of the above-mentioned N-tetrazolylarylurea derivatives as bradykinin B1 receptor antagonists.

[0037] In a seventh aspect, the present invention provides the use of the above-mentioned N-tetrazolylarylurea derivatives alone or in combination with other drugs in the manufacture of a medicament for preventing or treating a disease mediated by the bradykinin B1 receptor.

[0038] In an eighth aspect, the present invention provides the above-mentioned N-tetrazolylarylurea derivatives alone or in combination with other drugs for use in preventing or treating a disease mediated by the bradykinin B1 receptor.

[0039] In a ninth aspect, the present invention provides a method for preventing or treating a disease mediated by the bradykinin B1 receptor in a subject, comprising administering to the subject an effective amount of the above-mentioned N-tetrazolylarylurea derivative or pharmaceutical composition.

[0040] Examples of the above-mentioned diseases mediated by the bradykinin B1 receptor include, but are not limited to, respiratory diseases, digestive diseases, cardiovascular diseases, urinary diseases, skin diseases, ophthalmic diseases, joint and bone diseases, central and peripheral nervous system diseases, infectious diseases, pain, diabetic complications, trauma, and ophthalmic inflammatory diseases.

[0041] As non-limiting examples, the above-mentioned diseases mediated by the bradykinin B1 receptor can be selected from the group consisting of acute pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19, diabetic retinopathy, age-related macular degeneration, diabetic neuropathy, allergic conjunctivitis, chronic conjunctivitis, and uveitis.

[0042] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0043] (1) The present inventors newly discovered a class of N-tetrazolylarylurea derivatives, which are structurally novel selective B1R antagonists, and have high anti-target activity, strong selectivity, particularly strong selectivity over B2R, good stability in vivo, and have been proven to have no inhibitory or inductive effects on various CYPs. Therefore, this compound may further be useful for treating or preventing related diseases caused by abnormal expression of the bradykinin B1 receptor.

[0044] (2) The present inventors newly discovered that N-tetrazolyl aryl urea derivatives are effective in the prevention or treatment of diseases such as COVID-19, pulmonary edema, diabetes-related complications, and ophthalmic inflammatory diseases. Pharmacodynamic studies in the present invention have revealed that a medicament containing such a compound can inhibit the production and secretion of various inflammatory factors by IMR-90 cells induced by des-Arg9-BK of bradykinin. In a mouse model of LPS-induced acute lung injury and ARDS, this compound can reduce lung injury and pulmonary edema in mice and improve the downward trend of blood oxygen partial pressure and oxygen saturation. In a rat model of diabetic retinopathy, such a compound can not only improve the retinal inflammatory response caused by diabetes, but also reduce the permeability and osmotic pressure of retinal blood vessels and the number of stagnant retinal leukocytes. In a mouse model of allergic conjunctivitis, such a compound can significantly improve ocular clinical symptoms such as conjunctival edema, conjunctival congestion, eyelid congestion and edema, and tearing, improve inflammatory cell infiltration and conjunctival tissue, significantly reduce the degranulation of mast cells in the allergic response, and reduce the expression of allergic markers of IL-4 and IgE. Therefore, the compound or pharmaceutical composition of the present invention is expected to be useful for treating or preventing pneumonia and pulmonary edema caused by COVID-19, reducing the risk of developing acute respiratory distress syndrome, and improving the survival rate of patients. The compound or pharmaceutical composition of the present invention is also expected to be useful for treating and preventing diabetic retinopathy and age-related macular degeneration. In addition, the compound or pharmaceutical composition of the present invention is also expected to be useful for treating or preventing ophthalmic inflammatory diseases such as allergic conjunctivitis, chronic conjunctivitis, and uveitis.

Brief Description of the Drawings

[0045]

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Modes for Carrying Out the Invention

[0046] Terms Unless otherwise specified, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs.

[0047] Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of one of ordinary skill in the art are used in this disclosure. Unless otherwise specified, the nomenclature, as well as the experimental procedures and techniques used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are known in the art. The above-mentioned techniques and procedures are generally known in the art and can be carried out in accordance with conventional methods described in various general and more specific references.

[0048] The term "alkyl" refers to an aliphatic hydrocarbon group which may be a branched or straight-chain alkyl group. Depending on the structure, the alkyl group can be a monovalent or divalent group (i.e., an alkylene group).

[0049] The term "alkoxy" refers to an -O-alkyl group where alkyl is as defined herein.

[0050] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, the cycloalkyl group can be a monovalent or divalent group (e.g., a cycloalkylene group).

[0051] The term "dicycloalkyl" refers to a group having two rings and containing only carbon and hydrogen.

[0052] The term "heteroaryl" refers to an aromatic ring in which one or more of the atoms constituting the ring are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0053] As used herein, the term "heterocyclic group" refers to a non-aromatic ring in which one or more of the atoms constituting the ring are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A heterocycloalkyl ring can be a monocyclic group or a polycyclic group formed by 3, 4, 5, 6, 7, 8, 9, or 10 or more atoms.

[0054] As used herein, the term "bicyclic heterocyclic group" refers to a heterocyclic group having two rings, wherein one ring contains at least one nitrogen atom and the other ring contains 0, 1, or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. As non-limiting examples, bicyclic heterocyclic groups can be azaspirodecyl or octahydrofurano[2,3-c]pyridyl (e.g.,

Chemical formula

[0055] The term "spiro heterocyclic group" refers to a heterocyclic group having two rings sharing one carbon atom, wherein one or more of the atoms constituting the rings are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The term "bridged bicyclic heterocyclic group" refers to a heterocyclic group having two rings sharing two non-adjacent carbon atoms, wherein one or more of the atoms constituting the rings are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The term "fused bicyclic heterocyclic group" refers to a heterocyclic group having two rings sharing two adjacent carbon atoms, wherein one or more of the atoms constituting the rings are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0056] The term "cis-trans isomer" refers to diastereomers having different spatial arrangements of groups due to the presence of cyclohexyl in the compound represented by formula Ib.

[0057] The term "solvate" refers to a solvated compound formed when a compound is dissolved in a solvent and the solvent molecules combine with the compound, thereby changing the original state of the compound.

[0058] The term "optionally" means that the event(s) described thereafter may or may not occur, including both the event(s) that occur and the event(s) that do not occur. The terms "optionally substituted" or "substituted" mean that the group referred to may be substituted with one or more additional groups.

[0059] Hereinafter, the present invention will be further described in conjunction with embodiments.

[0060] Comprehensive Embodiments In one aspect, the present invention provides a compound represented by formula I:

Chemical formula

[0061] In formula I, R 1 and R 2 together with the N atom to which they are attached, may form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom. Optionally, the 3- to 8-membered heterocyclic group may be substituted with one to three identical or different functional groups A, where the functional group A may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, and cycloamino.

[0062] On the other hand, R 1 and R 2can, together with the N atom bonded thereto, form an 8- to 12-membered bicyclic heterocyclic group containing 0, 1, or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2 in addition to at least one nitrogen atom. The 8- to 12-membered bicyclic heterocyclic group may include a spiro heterocyclic group, a bridged bicyclic heterocyclic group, and a fused bicyclic heterocyclic group. Optionally, the 8- to 12-membered bicyclic heterocyclic group may be substituted by 1 to 3 identical or different functional groups B, where the functional group B may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0063] On the other hand, each of R 1 and R 2 is one of the following groups: (i) H, C1-C 10 alkyl, C2-C 10 alkenyl, and C2-C 10 alkynyl (optionally, C1-C 10 alkyl, C2-C 10 alkenyl, or C2-C 10 alkynyl may be substituted by 1 to 3 identical or different functional groups C, where the functional group C may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino), or, (ii) phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, and 5- to 7-membered heterocyclic group (wherein the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, or 5- to 7-membered heterocyclic group may be substituted by 1 to 3 identical or different functional groups D, and the functional group D may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino) may be independently selected from the group consisting of

[0064] In formula I, Ar 1 is phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, and C9-C 10 bicycloalkyl, and can be selected from the group consisting of, wherein the 5- to 6-membered heteroaryl contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, or C9-C 10 bicycloalkyl may be substituted by 1 to 3 identical or different functional groups E, where the functional group E may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0065] In formula I, Z is phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group, C9-C 10 bicycloalkyl, 9- to 10-membered fused bicyclic heterocyclic group, [Chemical formula] can be selected from the group consisting of, wherein the 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, or 9- to 10-membered fused bicyclic heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group, C9-C 10 dicycloalkyl, or 9- to 10-membered fused bicyclic heterocyclic group may be substituted by 1 to 3 identical or different functional groups F, wherein the functional group F is hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino, or on the other hand, the functional group F is a 5- to 8-membered heterocyclic ring fused to phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group, C9-C 10 dicycloalkyl, or a 9- to 10-membered fused bicyclic heterocyclic group can be formed.

[0066] R 3may be selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, and 5- to 6-membered heteroaryl. Optionally, the C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, or 5- to 6-membered heteroaryl may be substituted with one to three identical or different functional groups G, where the functional group G may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0067] Y may be selected from the group consisting of O and NH.

[0068] Ar 2 is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C 10 -C 20 condensed cyclic group, C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, and C1-C6 alkoxy. The 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains one, two, or three heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, the phenyl, 5- to 6-membered heteroaryl, C 10 -C 20 condensed cyclic group, C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, or C1-C6 alkoxy may be substituted with one to three identical or different functional groups H, where the functional group H may be selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

[0069] In another aspect, the present invention provides an N-tetrazolylarylurea derivative which is a compound represented by Formula I: [Chemical Formula] or a cis-trans isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0070] In the formula, R 1 and R 2 together with the N atom to which they are attached form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom, wherein the above group is substituted by one to three identical or different functional groups A, and the functional group A is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, or cycloamino, or R 1 and R 2 together with the N atom to which they are attached form an 8- to 12-membered bicyclic group containing zero, one, or two heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2 in addition to at least one nitrogen atom, wherein the bicyclic group includes spirocycloalkyl, bridged bicycloalkyl, and fused bicycloalkyl, and the above group is substituted by one to three identical or different functional groups B, and the functional group B is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, or R 1 and R 2 each is the following group: (i) H, C1-C 10 alkyl, C2-C10 Alkenyl, C2-C 10 Alkynyl (wherein the above groups excluding H are substituted by 1 to 3 identical or different functional groups C, and the functional group C is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (ii) phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group (wherein the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, and the phenyl, heteroatom, or heteroatom-containing group is substituted by 1 to 3 identical or different functional groups D, and the functional group D is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino) is independently selected from the group consisting of Ar 1 is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, C9-C 10 fused bicyclic group, wherein the 5- to 6-membered heteroaryl contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, and the phenyl, heteroatom, or heteroatom-containing group is substituted by 1 to 3 identical or different functional groups E, and the functional group E is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, Z is the following group: (i) phenyl, 5- to 6-membered heteroaryl, C5-C7 cycloalkyl, 5- to 7-membered heterocyclic group, C9-C 10 fused bicyclic group, 9- to 10-membered fused heterobicyclic group (wherein the 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, or 9- to 10-membered fused heterobicyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, and the phenyl, heteroatom, or heteroatom-containing group is substituted by 1 to 3 identical or different functional groups F, and the functional group F is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C1-C6 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino, or on the other hand, the functional group F forms a 5- to 8-membered heterocyclic ring), or, (ii) [Chemical formula] (wherein X is selected from the group consisting of O or NH, and R 3 is selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, and the above groups are substituted by 1 to 3 identical or different functional groups G, and the functional group G is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or, (iii) [Chemical formula] (wherein Y is selected from the group consisting of O or NH, and Ar 2 is phenyl, 5- to 6-membered heteroaryl, C 10~C 20 Selected from the group consisting of a condensed ring group, C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, and C1-C6 alkoxy, wherein the above groups are substituted by 1 to 3 identical or different functional groups H, and the functional group H is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, and the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2) Selected from the group consisting of.

[0071] In a preferred embodiment, in the N-tetrazolylarylurea derivative represented by formula I of any of the above aspects, R 1 and R 2 together with the N atom to which they are attached can form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom. Optionally, the 3- to 8-membered heterocyclic group may be substituted by 1 to 3 identical or different functional groups A, where the functional group A is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy, or R 1 and R 2Together with the N atoms attached thereto, it may form an 8- to 12-membered bicyclic heterocyclic group containing 0, 1, or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2 in addition to at least one nitrogen atom. The 8- to 12-membered bicyclic heterocyclic group may include spirocycloalkyl, bridged bicycloalkyl, and fused bicycloalkyl. Optionally, the 8- to 12-membered bicyclic heterocyclic group may be substituted by 1 to 3 identical or different functional groups B, where the functional group B may be selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy, or, R 1 and each of R 2 is one of the following groups: (i) H and C1-C6 alkyl (wherein the C1-C6 alkyl may be optionally substituted by 1 to 3 identical or different functional groups C, where the functional group C may be selected from the group consisting of C1-C6 alkoxy and halogenated C1-C6 alkoxy), (ii) phenyl and C5-C7 cycloalkyl (phenyl or C5-C7 cycloalkyl may be optionally substituted by 1 to 3 identical or different functional groups D, where the functional group D may be selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy) and is independently selected from the group consisting of.

[0072] Ar 1may be selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl may contain one or two heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl or 5- to 6-membered heteroaryl may be substituted with one to three identical or different functional groups E, wherein the functional group E may be selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0073] Z may be selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, 9- to 10-membered fused bicyclic heterocyclic group,

Chemical formula

[0074] In a preferred embodiment, in the N-tetrazolylarylurea derivative represented by formula I of any of the above aspects, R 1 and R 2 together with the N atom to which they are attached can form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom. Optionally, the 3- to 8-membered heterocyclic group may be substituted by one to three identical or different functional groups A, where the functional group A can be selected from the group consisting of C1-C6 alkyl and halogenated C1-C6 alkyl, or R 1 and R 2can form, together with the N atoms attached thereto, an 8- to 12-membered bicyclic heterocyclic group containing 0, 1, or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2, in addition to at least one nitrogen atom. The 8- to 12-membered bicyclic heterocyclic group includes spirocycloalkyl and fused bicycloalkyl, or, R 1 can be selected from the group consisting of H and C1-C6 alkyl. R 2 can be selected from the group consisting of phenyl and C5-C7 cycloalkyl. Optionally, phenyl or C5-C7 cycloalkyl may be substituted by 1 to 3 identical or different functional groups D, where the functional group D is selected from the group consisting of C1-C6 alkyl and halogenated C1-C6 alkyl.

[0075] Ar 1 can be selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl contains 1 or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2. Optionally, phenyl may be substituted by 1 to 3 identical or different halogens, Z is phenyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, 9- to 10-membered fused bicyclic heterocyclic group,

Chemical formula

[0076] In a preferred embodiment, in the N-tetrazolylarylurea derivative represented by formula I of any of the above aspects, R 1 and R 2can, together with the N atom to which they are attached, form a piperidyl. Optionally, the piperidyl may be substituted with a substituent (s) selected from the group consisting of methyl, tert-butoxy, and trifluoromethyl, or, R 1 and R 2 can, together with the N atom to which they are attached, form an azaooxaspirodecyl or octahydrofurano-pyridyl, or, R 1 can be selected from the group consisting of H and methyl, and R 2 can be selected from the group consisting of phenyl and cyclohexyl. Optionally, the phenyl may be substituted with trifluoromethyl. Optionally, the cyclohexyl may be substituted with methyl or tert-butyl.

[0077] Ar 1 can be selected from the group consisting of phenyl and pyridyl. Optionally, the phenyl may be substituted with a fluorine atom.

[0078] Z can be selected from the group consisting of phenyl, phenoxy, pyridyl, indazolyl, imidazolyl, tetrahydropyranyl, tetrahydropyranyloxy, dihydropyranyl,

Chemical formula

[0079] In a preferred embodiment, the N - tetrazolylarylurea - based derivative represented by formula I of any of the above aspects is a compound represented by formula Ia, formula Ib, or formula Ic:

Chemical formula

[0080] In the compound represented by formula Ia: Each of A and B may independently be a carbon atom or a nitrogen atom, Z is phenyl, pyridyl, indazolyl, imidazolyl, tetrahydropyranyl, dihydropyranyl,

Chemical formula

[0081] R 7 、R 6a 、and R 6 Each of can independently be selected from the group consisting of H, methyl, tert - butoxy, and trifluoromethyl, or, R 7is a hydrogen atom, and R 6 and R 6a together with the carbon atoms to which they are attached may form an oxolane ring, or R 6a is a hydrogen atom, and R 6 and R 7 together with the carbon atoms to which they are attached may form an oxolane ring.

[0082] In the compound represented by formula Ib: Each of A and B may independently be a carbon atom or a nitrogen atom, Z may be selected from the group consisting of phenyl, phenoxy, pyridyl, dihydropyranyl, tetrahydropyranyl, and tetrahydropyranyloxy. Phenyl or phenoxy may be optionally substituted with one or two methoxy groups or may be optionally condensed with a dioxolane ring. Optionally, pyridyl may be substituted with ethoxy, R 8 may be tert-butyl or methyl, R 9 may be H or methyl.

[0083] In the compound represented by formula Ic: Each of A and B may independently be a carbon atom or a nitrogen atom, Z may be selected from the group consisting of phenyl, phenoxy, pyridyl, dihydropyranyl, tetrahydropyranyl, and tetrahydropyranyloxy. Phenyl or phenoxy may be optionally substituted with one or two methoxy groups or may be optionally condensed with a dioxolane ring. Optionally, pyridyl may be substituted with ethoxy, R 10 may be trifluoromethyl, R 11 may be H.

[0084] Preferably, in the N-tetrazolylarylurea derivative represented by the formula I according to any of the above aspects, Ar 1 is one of the following phenyl, pyridyl, and pyrazinyl groups: [Chemical formula] (wherein the above groups are substituted by 1 to 3 identical or different functional groups I, and the functional group I is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino).

[0085] Preferably, the N-tetrazolylarylurea derivative according to any of the above aspects is a compound represented by the formula Ia or the formula Ib: [Chemical formula] or a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof.

[0086] In the compound represented by the formula Ia: Each of A and B is independently a carbon atom or a nitrogen atom, Z is one of the following groups: (i) phenyl, pyridyl, pyrazolyl, imidazolyl, indazolyl (wherein the above groups are substituted by 1 to 3 identical or different functional groups J, and the functional group J is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C1-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C4 alkyl, C1-C4 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, or alternatively, the functional group J forms a 5-membered heterocyclic ring), or (ii) [Chem.] (wherein, R 3 is selected from the group consisting of C1-C6 alkyl, C1-C6 cycloalkyl, C3-C7 cycloalkyl, C3-C7 aryl, 5- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, provided that the above groups are substituted by one to three identical or different functional groups K, and the functional group K is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iii) a phenoxy group (wherein, this group is substituted by one to three identical or different functional groups L, and the functional group L is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, C1-C3 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iv) [Chem.] group (wherein, R 10is selected from the group consisting of C1-C6 alkyl, 5- to 7-membered cycloalkyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclic group, wherein the above groups are substituted by 1 to 3 identical or different functional groups M, and the functional group M is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C4 alkyl, C1-C4 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, and the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of NH, N, O, S, SO, and SO2) is selected from the group consisting of R 6a is a hydrogen atom, and R 6 and R 7 each independently is selected from the group consisting of C1-C6 alkyl, C1-C6 cycloalkyl, C3-C 10 cycloalkyl, wherein the above groups are substituted by 1 to 3 identical or different functional groups N, and the functional group N is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, or R 6a is a hydrogen atom, and R 6 and R 7 together with the two carbon atoms to which they are attached form a 4- to 8-membered cyclic group, or a 4- to 8-membered bicyclic heterocyclic group containing 1 heteroatom or heteroatom-containing group independently selected from the group consisting of NH, N, O, S, SO, and SO2, wherein the above groups are substituted by 1 to 3 identical or different functional groups O, and the functional group O is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, or R 7 is a hydrogen atom, and R 6 and R 6atogether with the two carbon atoms attached thereto, forms a 4- to 8-membered cyclic group, or a 4- to 8-membered heterocyclic group containing one heteroatom or a heteroatom-containing group independently selected from the group consisting of NH, N, O, S, SO, and SO2, wherein the above group is substituted by one to three identical or different functional groups P, and the functional group P is selected from the group consisting of hydroxyl, halogen, amino, cyano, and nitro.

[0087] In the compound represented by Formula Ib: Each of A and B is independently a carbon atom or a nitrogen atom, Z is the following group: (i) phenyl, pyridyl, pyrazolyl, imidazolyl, indazolyl (wherein the above groups are substituted by one to three identical or different functional groups Q, and the functional group Q is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C4 alkyl, C1-C4 fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or, (ii)

Chemical formula

[0088] More preferably, the N-tetrazolyl aryl urea derivative is the following compound: 4-(tert-Butyl)-N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide, N-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-oxa-8-azaspiro[4.5]decane-1-carboxamide, N-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)hexahydrofuro[2,3-c]pyridine-6(2H)-carboxamide, N-(4-(6-Ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(6-ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(6’-ethoxy-3-(2H-tetrazol-5-yl)-[2,3’-bipyridyl]-5-yl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(6-ethoxypyrid-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(2-fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide, N-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4,4-dimethylpiperidine-1-carboxamide, 4-(tert-Butyl)-N-(4’-methoxy-3’-methyl-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(3’-chloro-4’-methoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide, Cyclohexyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, Cyclohexyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-fluoro-6-(2H-tetrazol-5-yl)benzoate, Ethyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-fluoro-6-(2H-tetrazol-5-yl)benzoate, 4-(tert-Butyl)-N-(3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenyl)piperidine-1-carboxamide, N-(2-Fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide, 4-Methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-Methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, Cyclohexyl 2-fluoro-4-(4-methylpiperidine-1-formamido)-6-(2H-tetrazol-5-yl)benzoate, Ethyl 2-fluoro-4-(4-methylpiperidine-1-formamido)-6-(2H-tetrazol-5-yl)benzoate, N-(4-(6-Ethoxypyrid-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(2-Fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(3’-Chloro-4’-methoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide, Cyclohexyl 2-fluoro-6-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)piperidine-1-formamido)benzoate, Ethyl 2-fluoro-6-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)piperidine-1-formamido)benzoate, N-(4-(6-Ethoxypyrid-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide, 4-(tert-Butyl)-N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(3’-chloro-2-fluoro-4’-methoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide, N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(6-(3,4-dimethoxyphenyl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(6-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide, Ethyl 5-(4-(tert-butyl)piperidine-1-formamido)-3-(2H-tetrazol-5-yl)pyridylcarboxylate, Cyclohexyl 5-(4-(tert-butyl)piperidine-1-formamido)-3-(2H-tetrazol-5-yl)pyridylcarboxylate, N-(4-(Benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(tert-butyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(3,4-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(6-(difluoromethyl)pyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, Cyclopentyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, Tetrahydrofuran-3-yl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, Ethyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, 4-(tert-Butyl)-N-(4-(cyclopentylaminocarbonyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-((5-methylpyrid-2-yl)aminocarbonyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(5-methoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(6-isopropoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(5-methoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(6-methylpyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(2-methylpyridin-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(cyclopentylaminocarbonyl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(3-fluoro-4-((5-methylpyridin-2-yl)aminocarbonyl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(3-fluoro-4-(6-methylpyridin-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(3-fluoro-4-(6-isopropoxypyridin-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-Butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 1-(4-(tert-Butyl)cyclohexyl)-3-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)urea, 1-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-((cis)-4-methylcyclohexyl)urea, 1-(3’,4’-Dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-((trans)-4-methylcyclohexyl)urea, 1-(4-(3,4-Dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-methylcyclohexyl)urea, 1-(4-(3,4-Dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-((trans)-4-(tert-Butyl)cyclohexyl)-3-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-methylurea, 1-(4-(3,6-Dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-((cis)-4-Methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea, 1-((trans)-4-Methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea, 1-(4-(Benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-(4-(Benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-(tert-butyl)cyclohexyl)urea, 1-(4-(6-Ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-((cis)-4-Methylcyclohexyl)-3-(4-(tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea, 1-(trans)-4-methylcyclohexyl-3-(4-tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea, or can be selected from the group consisting of their cis-trans isomers, or their pharmaceutically acceptable salts or solvates.

[0089] In a third aspect, the present invention provides a method for producing the above-mentioned N-tetrazolylarylurea derivatives.

[0090] Method 1: For a compound represented by formula I, wherein R 1 and R 2 are non-hydrogen groups, or R 1 and R 2 together with the N atom to which they are attached form a heterocyclic group containing at least one nitrogen atom, the production method of the present invention comprises coupling a 2-halogenated 5-nitroaromatic carbonitrile represented by formula a with Z-B(OH)2 boric acid represented by formula b under alkaline conditions to obtain a compound represented by formula c; adding sodium azide to the cyano group in the compound represented by formula c to obtain a tetrazolyl intermediate represented by formula d; performing Trt-protection to obtain an intermediate represented by formula e; then reducing the nitro group to obtain an amino compound represented by formula f; then converting the amino compound to an isocyanate compound represented by formula g; reacting the isocyanate compound with an amine to produce a urea compound represented by formula h; and finally performing Trt-deprotection to obtain the target compound.

Chemical formula

[0091] Compounds 1 to 14, Compound 18, and Compounds 59 to 62 in the examples were produced according to the above Method 1.

[0092] Method 2: In the compound represented by formula I, wherein Z is a substituted or unsubstituted phenoxy, the production method of the present invention is Subjecting a 2-halogenated 5-nitroaromatic carbonitrile represented by formula a to a nucleophilic substitution reaction with a substituted phenol represented by formula b2 under alkaline conditions to obtain a phenolic ether intermediate represented by formula c2; and performing Step 2, Step 3, Step 4, Step 5, Step 6, and Step 7 described in Method 1 to finally obtain the corresponding target compound.

Chemical formula

[0093] Compound 63 and Compound 64 in the examples were produced according to the above Method 2.

[0094] Method 3: In the compound represented by formula I, wherein Z is

Chemical formula

Chemical formula

[0095] Compound 15 and Compound 17 in the examples were produced according to the above Method 3.

[0096] Method 4: In the compound represented by formula I, wherein one of R 1 or R 2 is a hydrogen atom, the production method of the present invention is First, perform Step 1, Step 2, Step 3, and Step 4 in Method 1 to obtain an amino intermediate represented by formula f, then directly react the amino intermediate with an isocyanate compound to produce a urea compound represented by formula h1, and finally subject it to Trt-deprotection to obtain the target compound, which may be included.

Chemical formula

[0097] Compounds 58 to 62 and Compounds 66 to 71 in the examples were prepared according to the above Method 4.

[0098] In a fourth aspect, the present invention provides a pharmaceutical composition that may include the above-described N-tetrazolylarylurea-based derivative, a pharmaceutically acceptable carrier or additive, and optionally another therapeutic agent.

[0099] The pharmaceutical composition of the present invention can include at least one active ingredient and one or more pharmaceutically acceptable carriers or additives, and the active ingredient can include at least one of the compound represented by formula I, its cis-trans isomers, and their pharmaceutically acceptable salts or solvates.

[0100] Preferably, the pharmaceutically acceptable salt can be an alkali metal salt, an alkaline earth metal salt, or an ammonium salt.

[0101] More preferably, the alkali metal salt may be a sodium salt, a potassium salt, or a lithium salt, and the alkaline earth metal salt may be a calcium salt or a magnesium salt.

[0102] Even more preferably, the pharmaceutically acceptable salt can be a sodium salt or a potassium salt.

[0103] Preferably, the carrier or additive may include one or more of conventional diluents, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorbent carriers, lubricants, flavoring agents, and sweeteners in the pharmaceutical field.

[0104] Preferably, the pharmaceutical composition of the present invention can be in the form of tablets, capsules, patches, emulsions, suspensions, gels, powders, granules, oral preparations, eye drops, or injections. Preferably, the pharmaceutical composition of the present invention can be in the form of injections, oral preparations, or eye drops. The pharmaceutical composition in the above form can be manufactured according to conventional methods in the pharmaceutical field.

[0105] Typically, the pharmaceutical composition of the present invention can be formulated according to techniques known in the art. The pharmaceutical composition can be in any form suitable for oral administration, parenteral administration, topical administration, intranasal administration, intratracheal administration, sublingual administration, ocular administration, otic administration, rectal administration, vaginal administration, or transdermal administration. When parenteral administration is intended for the composition, this may be formulated for intravenous administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, or may be directly delivered to the target organ or target tissue by injection, drip, or other delivery methods. In the present invention, the administration route is preferably injection, oral administration, or ocular administration.

[0106] In a fifth aspect, the present invention provides the use of the above-mentioned N-tetrazolylarylurea derivatives in the manufacture of bradykinin B1 receptor antagonists.

[0107] In a sixth aspect, the present invention provides the use of the above-mentioned N-tetrazolylarylurea derivatives as bradykinin B1 receptor antagonists.

[0108] Preferably, the bradykinin B1 receptor antagonist or the medicament includes at least one active ingredient and one or more pharmaceutically acceptable carriers or additives, and the active ingredient is at least one of a compound represented by formula I, its cis-trans isomers, and pharmaceutically acceptable salts or solvates thereof.

[0109] In a seventh aspect, the present invention provides the use of the above-described N-tetrazolyl aryl urea derivatives alone or in combination with other drugs in the manufacture of a medicament for preventing or treating a disease mediated by bradykinin B1 receptor.

[0110] In an eighth aspect, the present invention provides the above-described N-tetrazolyl aryl urea derivatives alone or in combination with other drugs for use in the prevention or treatment of a disease mediated by bradykinin B1 receptor.

[0111] In a ninth aspect, the present invention provides a method for preventing or treating a disease mediated by bradykinin B1 receptor in a subject, which comprises administering to the subject an effective amount of the above-described N-tetrazolyl aryl urea derivative or pharmaceutical composition.

[0112] The amount of the N-tetrazolyl aryl urea derivative used in the present invention may also depend on the condition of the subject to which the N-tetrazolyl aryl urea derivative is administered, the dosage form, etc. Specifically, the dosage administered may depend on the condition, body weight, age, gender, etc. of the patient, and cannot be generalized. The dosage administered can be determined empirically by a qualified physician.

[0113] Examples of the above-described diseases mediated by bradykinin B1 receptor include, but are not limited to, respiratory diseases, digestive diseases, cardiovascular diseases, urinary diseases, skin diseases, ophthalmic diseases, joint and bone diseases, central nervous system and peripheral nervous system diseases, infectious diseases, pain, diabetic complications, trauma, and ophthalmic inflammatory diseases.

[0114] Preferably, the disease, or its syndrome, condition, or symptom, is associated with an inflammatory response caused by an infectious disease, including pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19 infection, pneumonia and type I hypersensitivity caused by respiratory syncytial virus, shock caused by bacterial sepsis and septicemia, or complications caused by diabetes, including retinal edema and lesions, macular degeneration, neuralgia, diabetic foot ulcers, or ophthalmic inflammatory diseases, including allergic conjunctivitis, chronic conjunctivitis, and uveitis.

[0115] As a non-limiting example, the above-mentioned diseases mediated by the bradykinin B1 receptor can be selected from the group consisting of acute pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19, diabetic retinopathy, age-related macular degeneration, diabetic neuralgia, allergic conjunctivitis, chronic conjunctivitis, and uveitis.

[0116] The above-mentioned N-tetrazolyl aryl urea derivatives of the present invention can be manufactured, studied, and used alone or in combination as therapeutic or prophylactic agents in a wide range of disease areas. Based on its mechanism of action of suppressing inflammatory responses and pain, the compounds of the present invention are mainly expected to be used clinically for the following indications, including but not limited to, prophylactic and therapeutic uses in these listed diseases.

[0117] Respiratory diseases: All known and unknown respiratory and lung inflammations caused by viral infections such as pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19, all inflammatory events related to airway diseases such as chronic obstructive pulmonary disease, asthma, emphysema, respiratory distress syndrome, bronchitis, pneumonia, cough, lung injury, pulmonary fibrosis, allergic rhinitis, vasomotor rhinitis, and angioedema.

[0118] Gastrointestinal diseases: Inflammatory bowel diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, and pancreatitis, etc.

[0119] Cardiovascular diseases: including congestive heart failure, myocarditis (including infectious myocarditis and non-infectious myocarditis), pericarditis, and Takayasu arteritis, etc.

[0120] Urinary diseases: nephritis, cystitis (interstitial cystitis), painful bladder syndrome, and overactive bladder.

[0121] Skin diseases: including pruritus, inflammatory skin diseases, psoriasis, atopic dermatitis (eczema), neurodermatitis, and herpes zoster, etc.

[0122] Ophthalmic diseases: allergic conjunctivitis, chronic conjunctivitis, uveitis, diabetic retinopathy (DR), age-related macular degeneration (AMD), and pathological choroidal or retinal angiogenesis and inflammation resulting from any mechanism, retinal vein occlusion, ocular trauma, postoperative-induced edema, cystoid macular edema, ocular ischemia, retinopathy of prematurity, hypertensive retinopathy, and glaucoma, etc.

[0123] Joint and bone diseases: including rheumatoid arthritis, gout, osteoarthritis, and ankylosing spondylitis.

[0124] Central nervous system and peripheral nervous system diseases: neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, migraine, stroke, closed head injury, and multiple sclerosis.

[0125] Infectious diseases: including HIV infection and tuberculosis, COVID-19 virus, respiratory syncytial virus, herpes zoster virus, hantavirus, rhinovirus, septic shock caused by bacterial infectious sepsis and sepsis, periodontitis, parasitic infections such as malaria and schistosomiasis, etc.

[0126] Pain: visceral pain such as pain associated with pancreatitis, interstitial cystitis, painful bladder syndrome, renal colic or prostatitis, chronic pelvic pain, or infiltrative endometriosis, diabetic pain and cancer pain, herpes zoster neuralgia, trigeminal neuralgia, postoperative pain syndrome, bone and joint pain (osteoarthritis), spinal pain, toothache, neuropathic pain such as chronic pelvic pain, or inflammatory pain due to various causes (including, but not limited to, pain associated with osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, gout, ankylosing spondylitis, and bursitis).

[0127] Complications of diabetes: diabetic foot ulcers, diabetic nephropathy, diabetic retinopathy, etc.

[0128] Trauma: edema including cerebral edema, burns, sunburn, contusions, or fractures.

[0129] Ophthalmic inflammatory diseases: including allergic conjunctivitis, chronic conjunctivitis, and uveitis.

[0130] Others: including primary peritonitis, secondary peritonitis, septic shock, sepsis, etc.

[0131] Furthermore, the compounds of the present invention were verified for their main pharmacological effects and pharmacodynamic effects through animal tests. The compounds of the present invention may be useful mainly for acute pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19, diabetic indications such as diabetic retinopathy, age-related macular degeneration, diabetic neuropathy, etc., ophthalmic inflammatory diseases such as allergic conjunctivitis, chronic conjunctivitis, uveitis, etc. The main mechanism of action revealed is explained as follows.

[0132] The mechanism of action of bradykinin B1 receptor antagonist in pneumonia caused by COVID-19 is shown below.

[0133] As confirmed by recent literature, the spike protein of COVID-19 binds to angiotensin-converting enzyme 2 (ACE2) and internalizes it, thereby reducing the expression level and function of ACE2, leading to dysfunction of the renin-angiotensin system (RAS system). When the efficacy of the retroegulation of the bradykinin system is lost, the inflammatory induction response of the bradykinin system is continuously amplified and enhanced, further causing an increase in vascular permeability and pulmonary edema. As verified by animal experiments, injection of the spike protein of SARS or COVID-19 (without infectivity) downregulates the level and function of ACE2, while lung injury deteriorates further, causing pulmonary edema. Also, the use of recombinant ACE2 protein (hrsACE2) effectively blocks the spike protein on the surface of COVID-19, thereby maintaining the normal level of ACE2 on the surface of lung cells, suppressing virus entry, and has also been reported to be useful as an emergency prophylaxis against infection after exposure to COVID-19. These research results suggest that the level of ACE2 on the surface of lung cells is negatively correlated with the degree of pulmonary edema.

[0134] Meanwhile, ACE2 is also an important signal control enzyme for cross-talk between the RAS system and the kallikrein-kinin system (KKS system). In the KKS system, ACE2 is an agonist specific to bradykinin receptor 1 (B1R) and can degrade and inactivate des-Arg9-BK and Lys-des-Arg9-BK of endogenous bradykinin, which is closely related to the persistent inflammatory response. According to the molecular mechanism of the KKS system, when COVID-19 binds to ACE2, invades alveolar epithelial cells, and causes local damage to lung tissue, it is speculated that bradykinin (BK) and pancreatic kinin (Lys-BK) (agonists specific to bradykinin receptor 2 (B2R)) are first released to activate B2R involved in the acute inflammatory response. Subsequently, these two B2R-specific bradykinins are hydrolyzed by ACE1 to become B1R-specific bradykinin. Since this is involved in the upregulation and activation of B1R (while downregulating B2R), the release of a large number of inflammatory factors, increased capillary permeability, and vascular leakage are caused. At the same time, the inflammatory factors subsequently upregulate the B1R level in a positive feedback manner, further exacerbating the inflammatory response, thereby causing pulmonary edema. Due to the dysfunction of ACE2 caused by COVID-19 infection, the hydrolysis and inactivation of B1R-specific bradykinin are impaired, so that B1R is in a persistent activated state, thereby exacerbating pulmonary edema and ultimately causing acute respiratory distress syndrome, threatening life.

[0135] Based on the above-mentioned KKS molecular mechanism, the research group clinically used icatibant (trade name: Firazyr), an antagonist based on the B2R peptide, to treat pulmonary edema in COVID-19 patients (9 patients in the drug group and 18 patients in the placebo group). These results have revealed that icatibant can significantly improve the hypoxic condition caused by pulmonary edema in COVID-19 patients. In a case-control study of 30 patients with severe COVID-19, compared with the standard treatment group for pneumonia caused by COVID-19, although icatibant did not shorten the clinical recovery time, it was found that it could significantly improve the lung CT score and increase eosinophils in the blood. From the above limited clinical research data, although B2R antagonists can partially improve the pulmonary edema caused by COVID-19, their efficacy is not great. This may be related to the biological characteristics of B2R. Although B2R is also involved in the inflammatory response, due to repeated activation by bradykinin, B2R is quickly desensitized, internalized, and its function is lost, so this is limited to the initial stage of inflammation. Furthermore, B2R is expressed in normal tissues, and inhibition will result in side effects related to the cardiovascular system. Therefore, B2R has great limitations as a target for the treatment of pneumonia caused by COVID-19. In contrast, when B1R is upregulated in inflamed tissues, repeated stimulation does not cause desensitization or internalization. Therefore, B1R may be continuously involved in the process of the inflammatory response. Furthermore, B1R is only expressed in inflamed tissues and not in normal tissues. Therefore, administering this can avoid side effects on normal tissues. Based on the above-mentioned summarized KKS molecular mechanism and the clinical trial results of icatibant, it is speculated that B1R antagonists have a better therapeutic effect on pneumonia and pulmonary edema caused by COVID-19, especially in severe cases.Furthermore, by administering this agent at an early stage, it is possible to prevent the excessive inflammatory response caused by COVID-19 infection, avoid the occurrence of pulmonary edema, reduce the incidence of severe illness, and have stronger specificity and safety. Unfortunately, there are currently no clinically useful B1R antagonist drugs at home and abroad.

[0136] In the pharmacodynamic study of the compound as a B1R antagonist, it has been demonstrated that this compound can inhibit the production and secretion of various inflammatory factors by IMR-90 cells induced by des-Arg9-BK of bradykinin, and can suppress inflammatory pulmonary edema in rats induced by des-Arg9-BK and IL-1β. In animal models of LPS-induced acute lung injury and ARDS, this compound can reduce lung injury and pulmonary edema in mice and improve the downward trend of blood oxygen partial pressure and oxygen saturation.

[0137] Therefore, the pharmaceutical preparation containing the compound of the present invention is expected to be useful for treating and preventing pneumonia and pulmonary edema caused by COVID-19, reducing the risk of developing acute respiratory distress syndrome, and improving the survival rate of patients.

[0138] The mechanism of action of bradykinin B1 receptor antagonist in diabetes-related complications is shown below.

[0139] Diabetic retinopathy (DR) is the most common microvascular complication of the eyes in diabetic patients and is a major cause of blindness in adults. With the increase in the number of diabetic patients and the extension of survival period, DR has become a major cause of severe visual impairment in the population aged 20 to 79 years in China and is one of the main diseases causing blindness in the middle-aged and elderly population. According to the research report on the epidemiological survey of Chinese residents from 1990 to 2020, the incidence rates of diabetic retinopathy in the normal population and diabetic patients were 1.7% and 22.4% respectively (Deng Yuxuan 2020).

[0140] Currently, the treatment of DR is limited to the late stage of diabetic retinopathy, at which point the retinal blood vessels and optic nerve have suffered irreversible damage. In addition to drug treatment for blood glucose level control, blood pressure control, and reduction of blood lipid levels, as well as laser therapy and surgical treatment, the treatment methods are limited to intravitreal injection of anti-vascular endothelial growth factor (VEGF) monoclonal antibodies or glucocorticoids. These treatment methods are invasive and have low patient compliance. Furthermore, these treatments can only prevent the progression of DR and can hardly restore the lost vision. Taking intravitreal injection of vascular endothelial growth inhibitors as an example, in addition to insufficient clinical improvement or drug resistance in some patients, long-term repeated intravitreal injections may cause serious adverse effects including endophthalmitis, vitreous hemorrhage, retinal detachment, traumatic cataract, and increased intraocular pressure. Therefore, clinically, there is a need for more effective therapeutic and prophylactic drugs for intervening in the early stage of DR. In the present invention, the compound or preparation used as a B1R antagonist is administered alone or in combination with other drugs by intravitreal injection or eye drops to treat and prevent fundus inflammation in the early stage of DR and retinal changes in the middle and late stages of DR.

[0141] The treatment of DR with B1R antagonists is mediated through a mechanism in which the expression and upregulation of B1 receptors are induced under pathological conditions caused by inflammatory cytokines and hyperglycemia-related oxidative stress. Studies have shown that B1 receptors activate iNOS by activating the Gαi / ERK / MAPK signaling pathway, thereby triggering a series of inflammatory responses in the early stages of DR. Therefore, when B1 receptors are activated as upstream signals, the expression of iNOS is promoted, while the inflammatory response continuously deteriorates, leading to increased vascular leakage and proliferation through self-induction and positive feedback amplification, ultimately potentially damaging retinal nerves. In the literature, it has been reported that inhibition of B1 receptors can reduce the oxidative stress response, decrease vascular permeability, control inflammatory responses such as reduced leukocyte infiltration, and reverse the expression levels of inflammatory mediators such as B1R, iNOS, IL-1b, COX-2, VEGF-A, VEGF-R2, and HIF-1a, thereby reducing changes in vascular structure, retinal edema, and other irreversible damages. Therefore, B1 receptor inhibitors as drug targets for the treatment and prevention of DR are expected to fill a major gap in this treatment area.

[0142] Manufacturing Example 1 Synthesis of 4-(tert-butyl)-N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide (Compound 1):

Chemical Structure

[0143] Procedure 1: Synthesis of 3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-carbonitrile (1c): 2.04 g (9.00 mmol) of 2-bromo-5-nitrobenzonitrile, 1.97 g (10.80 mmol) of 3,4-dimethoxyphenylboronic acid, 2.48 g (18.00 mmol) of potassium carbonate, 0.01 g (0.045 mmol) of palladium acetate, 100 mL of N,N-dimethylformamide, and 20 mL of water were added to a reaction flask, and the mixture was stirred at room temperature for 6 hours under nitrogen protection. After the reaction was completed, 500 mL of water was added. The resulting mixture was adjusted to be acidic with dilute hydrochloric acid and then extracted with dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 2.08 g of 1c. Yield: 81%.

[0144] Procedure 2: Synthesis of 5-(3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-yl)-2H-tetrazole (1d): After adding 1.71 g (6.00 mmol) of 3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-carbonitrile and 90 mL of toluene to a reaction flask, 1.17 g (18.00 mmol) of sodium azide and 2.89 g (21.00 mmol) of triethylammonium chloride were sequentially added. The reaction was carried out at 90 °C for 15 hours. After the reaction was completed, the mixture was adjusted to pH 2 by adding dilute hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.58 g of 1d. Yield: 80%.

[0145] Step 3: Synthesis of 5-(3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-yl)-2-trityl-2H-tetrazole (1e): 5.06 g (15.47 mmol) of 5-(3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-yl)-2H-tetrazole, 4.53 g (16.24 mmol) of triphenylchloromethane, 1.64 g (16.24 mmol) of triethylamine, and 225 mL of tetrahydrofuran were added to a reaction flask. The reaction was carried out at 40 °C for 3 hours. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 5.0 g of 1e. Yield: 57%.

[0146] Step 4: Synthesis of 3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-amine (1f): 1.16 g (2.04 mmol) of 1e, 45 mL of 1,4-dioxane, and 2.94 g (12.24 mmol) of sodium sulfide nonahydrate were added to a reaction flask. The reaction was carried out under reflux for 4 hours. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.88 g of 1f. Yield: 80%.

[0147] Step 5: Synthesis of 5-(4-isocyanato-3’,4’-dimethoxy-[1,1’-biphenyl]-2-yl)-2-trityl-2H-tetrazole (1g): 0.30 g (0.56 mmol) of 1f, 0.08 g (0.28 mmol) of triphosgene, and 30 mL of anhydrous toluene were added to a reaction flask. The reaction was carried out under reflux for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was used directly in the next step.

[0148] Step 6: Synthesis of 4-(tert-butyl)-N-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide (2a): 0.099 g (0.56 mmol) of 4-tert-butylpiperidine hydrochloride, 0.06 g (0.56 mmol) of triethylamine, and 20 mL of anhydrous DCM were added to a reaction flask. After cooling the mixture to 0 °C, 0.32 g (0.56 mmol) of 1 in 15 mL of anhydrous DCM was added. After the addition was complete, the mixture was cooled to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:EA:MeOH = 120:1:1, v / v) to obtain 0.23 g of 2a. Yield through two steps: 58%.

[0149] Step 7: Synthesis of 1-(4-(tert-butyl)cyclohexyl)-3-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)urea (1): 0.12 g (0.16 mmol) of 2a and 12 mL of methanol were added to a reaction flask. Then, concentrated hydrochloric acid was added dropwise to adjust the pH to 1 - 2. The reaction was carried out at 45 °C for 1 hour. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.03 g of 1. Yield: 30%.

[0150] ESI-MS: m / z = 465 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.12 (s, 1H), 8.77 (s, 1H), 7.82 - 7.70 (m, 2H), 7.46 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.61 - 6.54 (m, 2H), 4.27 - 4.20 (m, 2H), 3.74 (s, 3H), 3.59 (s, 3H), 2.77 - 2.65 (m, 2H), 1.69 (d, J = 12.3 Hz, 2H), 1.26 - 1.17 (m, 1H), 1.17 - 1.05 (m, 2H), 0.86 (s, 9H).

[0151] Production Example 2 Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 2):

Chemical Structure

[0152] Step 1: Synthesis of N-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (13a): The synthesis was carried out according to Step 6 of Example 1, except that 4-tert-butylcyclohexylamine was replaced with 4-(trifluoromethyl)piperidine. Yield after two steps: 39%.

[0153] Step 2: Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (2): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 13a. Yield: 49%.

[0154] ESI-MS: m / z = 477 [M+H] + .1 H NMR (500 MHz, DMSO-d6) δ 16.10 (s, 1H), 8.88 (s, 1H), 7.83 - 7.67 (m, 2H), 7.53 - 7.37 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.67 - 6.49 (m, 2H), 4.25 (d, J = 13.4 Hz, 2H), 3.74 (s, 3H), 3.59 (s, 3H), 2.93 - 2.79 (m, 2H), 2.71 - 2.55 (m, 1H), 1.91 - 1.81 (m, 2H), 1.50 - 1.28 (m, 2H).

[0155] Production Example 3 Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-oxa-8-azaspiro[4.5]decane-1-carboxamide (Compound 3):

Chemical Structure

[0156] Step 1: Synthesis of N-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxamide (14a): 0.09 g (0.56 mmol) of 1-oxa-8-azaspiro[4.5]decane hydrochloride, 0.12 g (1.23 mmol) of triethylamine, and 20 mL of anhydrous DCM were added to a reaction flask. The mixture was cooled to 0 °C. Then, 0.32 g (0.56 mmol) of 1g in 15 mL of anhydrous DCM solution was added. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:EA = 10:1, volume / volume) to obtain 0.14 g of 14a. Yield through two steps: 35%.

[0157] Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-oxa-8-azaspiro[4.5]decane-1-carboxamide (3): Synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 14a. Yield: 63%.

[0158] ESI-MS: m / z = 465 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.14 (s, 1H), 8.81 (s, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.49 - 7.42 (m, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.61 - 6.54 (m, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.74 (s, 3H), 3.67 - 3.60 (m, 2H), 3.59 (s, 3H), 3.41 - 3.34 (m, 2H), 1.92 - 1.85 (m, 2H), 1.72 - 1.67 (m, 2H), 1.55 (t, J = 5.6 Hz, 4H).

[0159] Production Example 4 Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)hexahydrofuro[2,3-c]pyridine-6(2H)-carboxamide (Compound 4):

Chemical formula

[0160] Step 1: Synthesis of N-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)hexahydrofuro[2,3-c]pyridine-6(2H)-carboxamide (Compound 23a): Synthesis was carried out according to Step 6 of Example 1, except that 1-oxazole-8-azaspiro[4.5]decane hydrochloride was replaced with octahydrofuro[2,3-c]pyridine hydrochloride. Yield: 88%.

[0161] Step 2: Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)hexahydrofuro[2,3-c]pyridine-6(2H)-carboxamide (Compound 4): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 23a. Yield: 54%.

[0162] ESI-MS: m / z = 451 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.15 (s, 1H), 8.88 (s, 1H), 7.82 - 7.71 (m, 2H), 7.50 - 7.41 (m, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.9 Hz, 2H), 4.51 - 4.39 (m, 1H), 4.36 - 4.27 (m, 1H), 3.86 - 3.78 (m, 2H), 3.73 (s, 3H), 3.58 (s, 3H), 3.15 - 3.08 (m, 1H), 2.82 - 2.72 (m, 1H), 2.67 (t, J = 12.0 Hz, 1H), 2.10 - 1.93 (m, 2H), 1.65 - 1.51 (m, 1H), 1.48 - 1.27 (m, 2H).

[0163] Production Example 5 Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide (Compound 5):

Chemical Structure

[0164] Step 1: Synthesis of 4-methylpiperidine-1-carbonyl chloride (25c): 0.99 g (10.00 mmol) of 25a, 1.24 g (4.30 mmol) of 25b, and 40 mL of anhydrous DCM were added to a reaction flask. 1.12 g (8.80 mmol) of DIEPA was added dropwise at 0 °C. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, the mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step.

[0165] Step 2: Synthesis of 2-(6-ethoxypyridin-3-yl)-5-nitrobenzonitrile (24b): The synthesis was carried out according to Step 1 of Example 1, except that 1b was replaced with 24a. Yield: 81%.

[0166] Step 3: Synthesis of 2-ethoxy-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (24c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 24b. Yield: 58%.

[0167] Step 4: Synthesis of 2-ethoxy-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (24d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 24c. Yield: 75%.

[0168] Step 5: Synthesis of 4-(6-ethoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (24e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 24d. Yield: 87%.

[0169] Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide (25d): 0.22 g (0.42 mmol) of 24e, 0.11 g (0.68 mmol) of 25c, and 8 mL of anhydrous pyridine were added to a reaction flask. Then, 0.20 g (0.04 mmol) of DIPEA was added dropwise. Next, the mixture was warmed to 65 °C and the reaction was carried out for 10 hours. After the reaction was completed, the mixture was diluted with water, adjusted to a pH of 6 - 7 by the addition of dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under pressure. The residue was purified by silica gel column chromatography (DCM:EA = 10:1, volume / volume) to obtain 0.10 g of 25d. Yield: 37%.

[0170] Synthesis of N-(4'-ethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (5): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 25d. Yield: 62%.

[0171] ESI-MS: m / z = 408 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.31 (s, 1H), 8.79 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.5, 2.3 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.15 - 4.06 (m, 2H), 2.84 - 2.73 (m, 2H), 1.69 - 1.61 (m, 2H), 1.61 - 1.53 (m, 1H), 1.31 (t, J = 7.0 Hz, 3H), 1.07 - 0.99 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H).

[0172] Production Example 6 Synthesis of 4-(tert-butyl)-N-(4-(6-ethoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 6):

Chemical formula

[0173] Step 1: Synthesis of 2-ethoxy-5-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (26a): The synthesis was carried out according to Step 4 of Example 1, except that 1f was replaced with 24e, and the resulting residue was used directly in the next step.

[0174] Step 2: Synthesis of 4-(tert-butyl)-N-(4-(6-ethoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (26b): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 26a and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 37%.

[0175] Step 3: Synthesis of 4-(tert-butyl)-N-(4-(6-ethoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (6): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 26b. Yield: 42%.

[0176] ESI-MS: m / z = 450[M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.33 (s, 1H), δ 8.84 (s, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.5, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.33 - 4.19 (m, 4H), 2.71 (t, J = 11.8 Hz, 2H), 1.69 (d, J = 11.5 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.19 - 1.15 (m, 1H), 1.14 - 1.08 (m, 2H), 0.86 (s, 9H).

[0177] Production Example 7 Synthesis of 4-(tert-butyl)-N-(6’-ethoxy-3-(2H-tetrazol-5-yl)-[2,3’-bipyridin]-5-yl)piperidine-1-carboxamide (Compound 7): [Chemical]

[0178] Step 1: Synthesis of 6'-ethoxy-5-nitro-[2,3'-bipyridyl]-3-carbonitrile (27b): 820 mg (4.46 mmol) of 27a, 900 mg (5.39 mmol) of 24a, 157 mg (0.22 mmol) of Pd(PPh3)2Cl2, 1.80 g (13.04 mmol) of potassium carbonate, 20 mL of 1,4-dioxane, and 10 mL of water were added to a reaction flask. The reaction was carried out under reflux for 3 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 4:1, volume / volume) to obtain 0.55 g of 27b. Yield: 46%.

[0179] Step 2: Synthesis of 6'-ethoxy-5-nitro-3-(2H-tetrazol-5-yl)-2,3'-bipyridine (27c): Synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 27b. Yield: 93%.

[0180] Step 3: Synthesis of 6'-ethoxy-5-nitro-3-(2-trityl-2H-tetrazol-5-yl)-2,3'-bipyridine (27d): Synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 27c. Yield: 89%.

[0181] Step 4: Synthesis of 6'-ethoxy-3-(2-trityl-2H-tetrazol-5-yl)-[2,3'-bipyridyl]-5-amine (27e): Synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 27d. Yield: 81%.

[0182] Step 5: Synthesis of 6'-ethoxy-5-isocyanato-3-(2-trityl-2H-tetrazol-5-yl)-2,3'-bipyridine (27f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 27e, and the residue was used directly in the next step.

[0183] Step 6: Synthesis of 4-(tert-butyl)-N-(6'-ethoxy-3-(2-trityl-2H-tetrazol-5-yl)-[2,3'-bipyridin]-5-yl)piperidine-1-carboxamide (27g): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 27f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 48%.

[0184] Step 7: Synthesis of 4-(tert-butyl)-N-(6'-ethoxy-3-(2H-tetrazol-5-yl)-[2,3'-bipyridin]-5-yl)piperidine-1-carboxamide (7): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 27g. Yield: 41%.

[0185] ESI-MS: m / z = 451 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.21 (s, 1H), δ 8.81 - 8.76 (m, 2H), 8.06 (d, J = 2.5 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.6, 2.5 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 4.32 - 4.21 (m, 4H), 2.72 (t, J = 11.8 Hz, 2H), 1.69 (d, J = 11.9 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.20 - 1.10 (m, 3H), 0.86 (s, 9H).

[0186] Production Example 8 Synthesis of 4-(tert-butyl)-N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 8):

Chemical formula

[0187] Step 1: Synthesis of 2-bromo-3-fluoro-5-nitrobenzonitrile (28b): 1.00 g (5 mmol) of 28a was added to a reaction flask. Subsequently, 2 mL of concentrated sulfuric acid was added. After cooling the mixture to 0 °C - 5 °C, 0.48 mL (7.5 mmol) of concentrated nitric acid was added dropwise. After the addition was complete, the mixture was kept warm and the reaction was carried out for 1 hour. Then, the reaction mixture was warmed to room temperature and the reaction was carried out for an additional 2 hours. After the reaction was complete, the reaction solution was poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 4:1, volume / volume) to obtain 328 mg of 28b. Yield: 31%.

[0188] Step 2: Synthesis of 2-(6-ethoxypyridin-3-yl)-3-fluoro-5-nitrobenzonitrile (28c): Synthesis was carried out according to Step 1 of Example 1, except that 27a was replaced with 28b. Yield: 88%.

[0189] Step 3: Synthesis of 2-ethoxy-5-(2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)pyridine (28d): Synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 28c. Yield: 83%.

[0190] Step 4: Synthesis of 2-ethoxy-5-(2-fluoro-4-nitro-6-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (28e): Synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 28d. Yield: 89%.

[0191] Step 5: Synthesis of 4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2-trityl-2H-tetrazol-5-yl)phenylamine (28f): The synthesis was carried out according to the procedure of Step 4 of Example 1, except that 1e was replaced by 28e. Yield: 79%.

[0192] Step 6: Synthesis of 2-ethoxy-5-(2-fluoro-4-isocyanato-6-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (28g): The synthesis was carried out according to the procedure of Step 5 of Example 1, except that 1f was replaced by 28f, and the residue was used directly in the next step.

[0193] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (28h): The synthesis was carried out according to the procedure of Step 6 of Example 1, except that 1g was replaced by 28g and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 46%.

[0194] Step 8: Synthesis of 4-(tert-butyl)-N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (8): The synthesis was carried out according to the procedure of Step 7 of Example 1, except that 1h was replaced by 28h. Yield: 64%.

[0195] ESI-MS: m / z = 468 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 16.13 (s, 1H), δ 9.05 (s, 1H), 7.91 - 7.84 (m, 1H), 7.81 - 7.66 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 4.33 - 4.17 (m, 4H), 2.73 (t, J = 12.6 Hz, 2H), 1.70 (d, J = 13.3 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.21 - 1.17 (m, 1H), 1.16 - 1.08 (m, 2H), 0.86 (s, 9H).

[0196] Production Example 9 Synthesis of 4-(tert-butyl)-N-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 9):

Chemical formula

[0197] Step 1: Synthesis of 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-nitrobenzonitrile (30b): The synthesis method of 30b was the same as that of 27b except that 27a was replaced by 1a and 24a was replaced by 30a. Yield: 73%.

[0198] Step 2: Synthesis of 5-(2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-nitrophenyl)-2H-tetrazole (30c): The synthesis method of 30c was the same as that of 1d except that 1c was replaced by 30b. Yield: 78%.

[0199] Step 3: Synthesis of 5-(2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-nitrophenyl)-2-trityl-2H-tetrazole (30d): The synthesis method of 30d was the same as that of 1e except that 1d was replaced by 30c. Yield: 89%.

[0200] Step 4: Synthesis of 4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (30e): The synthesis method of 30e was the same as that of 1f except that 1e was replaced by 30d. Yield: 79%.

[0201] Step 5: Synthesis of 5-(2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-isocyanatophenyl)-2-trityl-2H-tetrazole (30f): The synthesis method of 30f was the same as that of 1g except that 1f was replaced by 30e, and the residue was directly used in the next step.

[0202] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (30g): The synthesis method of 30g was the same as that of 1h except that 1g was replaced by 30f and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 38%.

[0203] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (9): The synthesis method of 9 was the same as that of 1 except that 1h was replaced by 30g. Yield: 39%.

[0204] ESI-MS: m / z = 449 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 16.08 (s, 1H), δ 8.75 (s, 1H), 7.76 - 7.65 (m, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.98 (s, 1H), 4.82 - 4.68 (m, 1H), 4.28 - 4.15 (m, 2H), 2.75 - 2.64 (m, 2H), 2.43 - 2.28 (m, 4H), 1.81 - 1.71 (m, 2H), 1.70 - 1.63 (m, 2H), 1.20 - 1.16 (m, 1H), 1.13 - 1.04 (m, 2H), 0.85 (s, 9H).

[0205] Production Example 10 Synthesis of 4-(tert-butyl)-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 10): [Chemical formula]

[0206] Step 1: Synthesis of 2-(1-methyl-1H-indazol-5-yl)-5-nitrobenzonitrile (33b): The synthesis method of 33b was the same as that of 27b except that 27a was replaced with 27a and 24a was replaced with 33a. Yield: 89%.

[0207] Step 2: Synthesis of 1-methyl-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)-1H-indazole (33c): The synthesis method of 33c was the same as that of 1d except that 1c was replaced with 33b. Yield: 91%.

[0208] Step 3: Synthesis of 1-methyl-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)-1H-indazole (33d): The synthesis method of 33d was the same as that of 1e except that 1d was replaced with 33c. Yield: 87%.

[0209] Step 4: Synthesis of 4-(1-methyl-1H-indazol-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (33e): The synthesis method of 33e was the same as that of 1f except that 1e was replaced with 33d. Yield: 89%.

[0210] Step 5: Synthesis of 5-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)-1-methyl-1H-indazole (33f): The synthesis method of 33f was the same as that of 1g except that 1f was replaced with 33e, and the residue was directly used in the next step.

[0211] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (33g): The synthesis method of 33g was the same as that of 1h except that 1g was replaced with 33f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 40%.

[0212] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (10): The synthesis method of 10 was the same as that of 1 except that 1h was replaced with 33g. Yield: 63%.

[0213] ESI-MS: m / z = 459 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.02 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 - 7.46 (m, 3H), 6.97 (dd, J = 8.5, 1.7 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.03 (s, 3H), 2.76 - 2.68 (m, 2H), 1.72 - 1.66 (m, 2H), 1.25 - 1.19 (m, 1H), 1.17 - 1.08 (m, 2H), 0.86 (s, 9H).

[0214] Production Example 11 Synthesis of 4-(tert-butyl)-N-(2-fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide (Compound 11):

Chemical formula

[0215] Step 1: Synthesis of 6-fluoro-3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-carbonitrile (36a): The synthesis method of 36a was the same as that of 27b except that 27a was replaced with 28b and 27a was replaced with 1b. Yield: 92%.

[0216] Step 2: Synthesis of 5-(6-fluoro-3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-yl)-2H-tetrazole (36b): The synthesis method of 36b was the same as that of 1d except that 1c was replaced with 36a. Yield: 89%.

[0217] Step 3: Synthesis of 3:5-(6-Fluoro-3’,4’-dimethoxy-4-nitro-[1,1’-biphenyl]-2-yl)-2-trityl-2H-tetrazole (36c): The synthesis method of 36c was the same as that of 1e except that 1d was replaced by 36b. Yield: 94%.

[0218] Step 4: Synthesis of 2-Fluoro-3’,4’-dimethoxy-6-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-amine (36d): The synthesis method of 36d was the same as that of 1f except that 1e was replaced by 36c. Yield: 89%.

[0219] Step 5: Synthesis of 5-(6-Fluoro-4-isocyanato-3’,4’-dimethoxy-[1,1’-biphenyl]-2-yl)-2-trityl-2H-tetrazole (36e): The synthesis method of 36e was the same as that of 1g except that 1f was replaced by 36d, and the residue was directly used in the next step.

[0220] Step 6: Synthesis of 4-(tert-Butyl)-N-(2-fluoro-3’,4’-dimethoxy-6-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide (36f): The synthesis method of 36f was the same as that of 1h except that 1g was replaced by 34e and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 41%.

[0221] Step 7: Synthesis of 4-(tert-Butyl)-N-(2-fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxamide (11): The synthesis method of 11 was the same as that of 1 except that 1h was replaced by 36f. Yield: 62%.

[0222] ESI-MS: m / z = 483 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 16.13 (s, 1H), δ 8.99 (s, 1H), 7.76 (dd, J = 12.8, 2.2 Hz, 1H), 7.62 (s, 1H), 6.94 - 6.82 (m, 1H), 6.68 - 6.52 (m, 2H), 4.23 (d, J = 13.0 Hz, 2H), 3.74 (s, 3H), 3.59 (s, 3H), 2.85 - 2.64 (m, 2H), 1.69 (d, J = 12.2 Hz, 2H), 1.23 - 1.17 (m, 1H), 1.17 - 1.08 (m, 2H), 0.86 (s, 9H).

[0223] Production Example 12 Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4,4-dimethylpiperidine-1-carboxamide (Compound 12):

Chemical Structure

[0224] Step 1: Synthesis of N-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4,4-dimethylpiperidine-1-carboxamide (37a): The synthesis was carried out according to Step 6 of Example 1, except that 1f was replaced with 1g and 4-tert-butylcyclohexylamine was replaced with dimethylpyridine. Yield after two steps: 40%.

[0225] Step 2: Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4,4-dimethylpiperidine-1-carboxamide (12): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 37a. Yield: 72%.

[0226] ESI-MS: m / z = 437 [M+H] + . 11H NMR (600 MHz, DMSO-d6) δ 16.05 (s, 1H), 8.74 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.60 - 6.55 (m, 2H), 3.74 (s, 3H), 3.59 (s, 3H), 3.48 - 3.44 (m, 4H), 1.34 - 1.29 (m, 4H), 0.97 (s, 6H).

[0227] Production Example 13 Synthesis of 4-(tert-butyl)-N-(4'-methoxy-3'-methyl-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (Compound 13):

Chemical Structure

[0228] Step 1: Synthesis of 4'-methoxy-3'-methyl-4-nitro-[1,1'-biphenyl]-2-carbonitrile (38b): 2.00 g (8.81 mmol) of 1a, 1.75 g (10.57 mmol) of 38a, 20 mg (0.088 mmol) of Pd(OAc)2, 2.43 g (17.62 mmol) of potassium carbonate in 12 mL of aqueous solution, and 60 mL of DMF were added to a reaction flask. The reaction was carried out at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with EA and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1, volume / volume) to obtain 1.89 g of 38b. Yield: 80%.

[0229] Step 2: Synthesis of 5-(4'-methoxy-3'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)-2H-tetrazole (38c): The synthesis method of 38c was the same as that of 1d except that 1c was replaced with 38b. Yield: 87%.

[0230] Step 3: Synthesis of 5-(4'-methoxy-3'-methyl-4-nitro-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (38d): The synthesis method of 38d was the same as that of 1e except that 1c was replaced by 38c. Yield: 84%.

[0231] Step 4: Synthesis of 4'-methoxy-3'-methyl-2-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-amine (38e): The synthesis method of 38e was the same as that of 1f except that 1e was replaced by 38d. Yield: 87%.

[0232] Step 5: Synthesis of 5-(4-isocyanato-4'-methoxy-3'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (38f): The synthesis method of 38f was the same as that of 1g except that 1f was replaced by 38e, and the residue was directly used in the next step.

[0233] Step 6: Synthesis of 4-(tert-butyl)-N-(4'-methoxy-3'-methyl-2-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (38g): The synthesis method of 38g was the same as that of 1h except that 1g was replaced by 36f and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 45%.

[0234] Step 7: Synthesis of 4-(tert-butyl)-N-(4'-methoxy-3'-methyl-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (13): The synthesis method of 13 was the same as that of 1 except that 1h was replaced by 38g. Yield: 55%.

[0235] ESI-MS: m / z = 449 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.11 (s, 1H), 8.76 (s, 1H), 7.79 - 7.73 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 4.28 - 4.20 (m, 2H), 3.76 (s, 3H), 2.74 - 2.67 (m, 2H), 2.08 (s, 3H), 1.72 - 1.64 (m, 2H), 1.25 - 1.18 (m, 1H), 1.16 - 1.06 (m, 2H), 0.86 (s, 9H).

[0236] Production Example 14 Synthesis of 4-(tert-butyl)-N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (Compound 14): [Chemical formula]

[0237] Step 1: Synthesis of 3'-chloro-4'-methoxy-4-nitro-[1,1'-biphenyl]-2-carbonitrile (39b): The synthesis was carried out according to the procedure of Step 2 in Example 1, except that 27a was replaced with 1a and 24a was replaced with 29a. Yield: 73%.

[0238] Step 2: Synthesis of 5-(3'-chloro-4'-methoxy-4-nitro-[1,1'-biphenyl]-2-yl)-2H-tetrazole (39c): The synthesis was carried out according to the procedure of Step 2 in Example 1, except that 1c was replaced with 39b. Yield: 90%.

[0239] Step 3: Synthesis of 5-(3'-chloro-4'-methoxy-4-nitro-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (39d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 39c. Yield: 87%.

[0240] Step 4: Synthesis of 3'-chloro-4'-methoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-amine (39e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 39d. Yield: 71%.

[0241] Step 5: Synthesis of 5-(3'-chloro-4-isocyanato-4'-methoxy-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (39f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 39e, and the residue was used directly in the next step.

[0242] Step 6: Synthesis of 4-(tert-butyl)-N-(3'-chloro-4'-methoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (39g): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 39f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 52%.

[0243] Step 7: Synthesis of 4-(tert-butyl)-N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (14): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 39g. Yield: 63%.

[0244] ESI-MS: m / z = 470 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.01 (s, 1H), δ 8.80 (s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.6, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.89 (dd, J = 8.5, 2.3 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.84 (s, 3H), 2.75 - 2.67 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0245] Production Example 15 Synthesis of cyclohexyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (Compound 15):

Chemical formula

[0246] Step 1: Synthesis of cyclohexyl 4-nitro-2-(2H-tetrazol-5-yl)benzoate (42b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 42a. Yield: 86%.

[0247] Step 2: Synthesis of cyclohexyl 4-amino-2-(2H-tetrazol-5-yl)benzoate (42c): 482 mg (1.52 mmol) of 42b, 593 mg (10.64 mmol) of iron powder, and 244 mg (4.56 mmol) of ammonium chloride, 9 mL of ethanol, and 3 mL of water were added to a reaction flask. The reaction was carried out under reflux for 0.5 h. After the reaction was completed, the mixture was filtered while hot. The filter cake was washed with ethyl acetate. The filtrates were combined, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 42c. Yield: 81%.

[0248] Step 3: Synthesis of cyclohexyl 4-isocyanato-2-(2H-tetrazol-5-yl)benzoate (42d): 368 mg (1.28 mmol) of 42c and 5 mL of anhydrous dichloromethane were added to a reaction flask. The mixture was cooled to 0 °C. Then, a solution of 191 mg (0.64 mmol) of triphosgene in 3 mL of anhydrous dichloromethane was slowly added dropwise, and then 143 mg (1.41 mmol) of triethylamine was slowly added. Then, the mixture was warmed to room temperature and the reaction was carried out for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 42d, which was used directly in the next step.

[0249] Step 4: Synthesis of cyclohexyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (15): 228 mg (1.28 mmol) of 4-(tert-butyl)piperidine hydrochloride, 10 mL of anhydrous dichloromethane, and 260 mg (2.57 mmol) of triethylamine were added to a reaction flask. The mixture was cooled to 0 °C. A solution of 42d in 10 mL of anhydrous dichloromethane was slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH:TEA = 30:2:1, v / v) to obtain 226 mg of 15. Yield after two steps: 39%.

[0250] ESI-MS: m / z = 401 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.49 (s, 1H), 9.09 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 4.23 (d, J = 13.1 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.72 (t, J = 12.1 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.26 - 1.17 (m, 1H), 1.15 - 1.08 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.85 (s, 9H).

[0251] Production Example 16 Synthesis of ethyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (Compound 16):

Chemical Structure

[0252] Step 1: Synthesis of ethyl 4-nitro-2-(2H-tetrazol-5-yl)benzoate (40b): The synthesis was carried out according to the procedure of Step 2 in Example 1, except that 1c was replaced with 40a. Yield: 92%.

[0253] Step 2: Synthesis of ethyl 4-amino-2-(2H-tetrazol-5-yl)benzoate (40c): 400 mg (1.52 mmol) of 40b, 593 mg (10.64 mmol) of iron powder, 244 mg (4.56 mmol) of ammonium chloride, 9 mL of ethanol, and 3 mL of water were added to a reaction flask. The reaction was carried out under reflux for 0.5 h. After the reaction was completed, the mixture was filtered while hot. The filter cake was washed with ethyl acetate. The filtrates were combined, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 40c. Yield: 85%.

[0254] Step 3: Synthesis of ethyl 4-isocyanato-2-(2H-tetrazol-5-yl)benzoate (40d): 300 mg (1.28 mmol) of 40c and 5 mL of anhydrous dichloromethane were added to a reaction flask. The mixture was cooled to 0 °C. Then, a solution of 191 mg (0.64 mmol) of triphosgene in 3 mL of anhydrous dichloromethane was slowly added dropwise, and then 143 mg (1.41 mmol) of triethylamine was slowly added. Then, the mixture was warmed to room temperature and the reaction was carried out for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 40d, which was used directly in the next step.

[0255] Step 4: Synthesis of ethyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (17): 228 mg (1.28 mmol) of 4-(tert-butyl)piperidine hydrochloride, 10 mL of anhydrous dichloromethane, and 260 mg (2.57 mmol) of triethylamine were added to a reaction flask. After cooling the mixture to 0 °C, a solution of 40d in 10 mL of anhydrous dichloromethane was slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH:TEA = 30:2:1, v / v) to obtain 170 mg of 16. Yield over two steps: 33%.

[0256] ESI-MS: m / z = 401 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.49 (s, 1H), 9.09 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 4.23 (d, J = 13.1 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.72 (t, J = 12.1 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.26 - 1.17 (m, 1H), 1.15 - 1.08 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.85 (s, 9H).

[0257] Production Example 17 Synthesis of cyclohexyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-fluoro-6-(2H-tetrazol-5-yl)benzoate (Compound 17):

Chemical Structure

[0258] Step 1: Synthesis of cyclohexyl 2-cyano-6-fluoro-4-nitrobenzoate (43c): 1.00 g (10.00 mmol) of cyclohexanol, 2.52 g (12.00 mmol) of 2-cyano-6-fluoro-4-nitrobenzoic acid, and 3.15 g (12.00 mmol) of triphenylphosphine were dissolved in 20 mL of anhydrous tetrahydrofuran. After cooling the solution to 0 °C, 2.43 g (12.00 mmol) of diisopropyl azodicarboxylate was added. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 2.42 g of 43c. Yield: 83%.

[0259] Step 2: Synthesis of cyclohexyl 2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)benzoate (43d): Synthesis was carried out according to Step 1 of Example 16, except that 1c was replaced with 43c. Yield: 85%.

[0260] Step 3: Synthesis of cyclohexyl 4-amino-2-fluoro-6-(2H-tetrazol-5-yl)benzoate (43e): Synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 43d. Yield: 79%.

[0261] Step 4: Synthesis of cyclohexyl 2-fluoro-4-isocyanato-6-(2H-tetrazol-5-yl)benzoate (43f): Synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 43e.

[0262] Step 5: Synthesis of cyclohexyl 4-(4-(tert-butyl)piperidine-1-formamide)-2-fluoro-6-(2H-tetrazol-5-yl)benzoate (17): Synthesis was carried out according to Step 4 of Example 16, except that 40d was replaced with 43f. Yield after two steps: 36%.

[0263] ESI-MS: m / z = 474 [M+H] +。 1 1H NMR (500 MHz, DMSO-d6) δ 16.31 (s, 1H), 8.61 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.1, 1.5 Hz, 1H), 4.73 - 4.61 (m, 1H), 4.25 (d, J = 13.1 Hz, 2H), 2.75 (t, J = 12.5 Hz, 2H), 1.74 (d, J = 12.2 Hz, 4H), 1.63 - 1.53 (m, 2H), 1.49 - 1.38 (m, 1H), 1.34 - 1.26 (m, 2H), 1.24 - 1.09 (m, 6H), 0.86 (s, 9H).

[0264] Production Example 18 Synthesis of 4-(tert-butyl)-N-(3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenyl)piperidine-1-carboxamide (Compound 18):

Chemical Structure

[0265] Step 1: Synthesis of 3-fluoro-5-nitro-2-(6-(trifluoromethyl)pyrid-3-yl)benzonitrile (41b): 900 mg (3.67 mmol) of 28b, 840 mg (5.39 mmol) of 2-trifluoromethyl-5-pyridineboronic acid, 129 mg (0.22 mmol) of Pd(PPh3)2Cl2, and 1.52 g (13.04 mmol) of potassium carbonate, 16 mL of 1,4-dioxane, and 8 mL of water were added to a reaction flask. The reaction was carried out under reflux for 2 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1, volume / volume) to obtain 650 mg of 41b. Yield: 57%.

[0266] Step 2: Synthesis of 5-(2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)-2-(trifluoromethyl)pyridine (41c): The synthesis was carried out according to Step 1 of Example 16, except that 1c was replaced with 41b. Yield: 85%.

[0267] Step 3: Synthesis of 3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenylamine (41d): The synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 41c. Yield: 90%.

[0268] Step 4: Synthesis of 5-(2-fluoro-4-isocyanato-6-(2H-tetrazol-5-yl)phenyl)-2-(trifluoromethyl)pyridine (41e): The synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 41d, and the residue was directly used in the next step.

[0269] Step 5: Synthesis of 4-(tert-butyl)-N-(3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenyl)piperidine-1-carboxamide (18): The synthesis was carried out according to Step 4 of Example 16, except that 40d was replaced with 41e. Yield after two steps: 35%.

[0270] ESI-MS: m / z = 492 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.83 (s, 1H), 9.13 (s, 1H), 8.55 (s, 1H), 7.93 - 7.85 (m, 3H), 7.83 (dd, J = 12.8, 2.1 Hz, 1H), 4.25 (d, J = 13.1 Hz, 2H), 2.75 (t, J = 12.1 Hz, 2H), 1.71 (d, J = 11.8 Hz, 2H), 1.28 - 1.18 (m, 1H), 1.18 - 1.07 (m, 2H), 0.86 (s, 9H).

[0271] Manufacturing Example 19 Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-sulfamide (Compound 19): [Chemical formula]

[0272] Step 1: Synthesis of N-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-sulfamide (19a): 53 mg (0.1 mmol) of 1f, 12 mg (0.1 mmol) of 4-DMAP, and 2 mL of pyridine were added to a reaction flask, and then 20 mg (0.1 mmol) of 4-methylpiperidine-1-sulfonyl chloride was added. After the addition was complete, the mixture was warmed to 80 °C and the reaction was carried out for 10 hours. After the reaction was complete, the mixture was diluted with DCM and washed with dilute hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 55 mg of 19a. Yield: 78%.

[0273] Step 2: Synthesis of N-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-sulfamide (19): Synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 19a. Yield: 55%.

[0274] ESI-MS: m / z = 459 [M+H] + . 11H NMR (500 MHz, chloroform-d) δ 11.43 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.4, 2.5 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.83 (dd, J = 8.2, 2.1 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 3.95 (s, 3H), 3.85 (d, J = 12.2 Hz, 2H), 3.80 (s, 3H), 2.92 - 2.80 (m, 2H), 1.77 - 1.68 (m, 2H), 1.54 - 1.46 (m, 1H), 1.28 - 1.25 (m, 2H), 0.95 (d, J = 6.5 Hz, 3H).

[0275] Production Example 20 Synthesis of N-(2-Fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (Compound 20): [Chemical formula]

[0276] Step 1: Synthesis of N-(2-Fluoro-3’,4’-dimethoxy-6-(2-triphenyl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (45a): Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 36e and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield: 45%.

[0277] Synthesis of Engineering 2: N-(2-Fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (20): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced by 45a. Yield: 60%.

[0278] ESI-MS: m / z = 441 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.16 (s, 1H), 8.77 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.71 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (dt, J = 7.5, 1.7 Hz, 1H), 7.16 (t, J = 1.8 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 4.24 - 4.18 (m, 2H), 3.71 (s, 3H), 3.57 (s, 3H), 2.75 - 2.63 (m, 2H), 1.68 (d, J = 12.3 Hz, 2H), 1.26 - 1.17 (m, 1H), 1.17 - 1.05 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H).

[0279] Production Example 21 Synthesis of 4-Methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 21):

Chemical Structure

[0280] Step 1: Synthesis of 4-methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (46a): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 33f and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield: 43%.

[0281] Step 2: Synthesis of 4-methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (21): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 46a. Yield: 58%.

[0282] ESI-MS: m / z = 417 [M+H] + 。 1 H NMR (600 MHz, DMSO-d6) δ 16.02 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 - 7.46 (m, 3H), 6.97 (dd, J = 8.5, 1.7 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.03 (s, 3H), 2.76 - 2.68 (m, 2H), 1.70 - 1.64 (m, 2H), 1.23 - 1.17 (m, 1H), 1.15 - 1.06 (m, 2H), 0.94 (d, J = 6.5 Hz, 3H).

[0283] Production Example 22 Synthesis of N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (Compound 22):

Chemical Structure

[0284] Step 1: Synthesis of N-(3'-chloro-4'-methoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (47a): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 39f and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield: 45%.

[0285] Step 2: Synthesis of N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide (22): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 47a. Yield: 62%.

[0286] ESI-MS: m / z = 428 [M+H] + 。 1 H NMR (600 MHz, DMSO-d6) δ 16.01 (s, 1H), δ 8.80 (s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.6, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.89 (dd, J = 8.5, 2.3 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.84 (s, 3H), 2.75 - 2.67 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.96 (d, J = 6.1 Hz, 3H).

[0287] Production Example 23 Synthesis of cyclohexyl 2-fluoro-4-(4-methylpiperidine-1-formamide)-6-(2H-tetrazol-5-yl)benzoate (Compound 23):

Chemical formula

[0288] Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 43 f and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield: 47%.

[0289] ESI-MS: m / z = 474 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 8.1, 1.5 Hz, 1H), 4.73 - 4.61 (m, 1H), 4.25 (d, J = 13.1 Hz, 2H), 2.75 (t, J = 12.5 Hz, 2H), 1.74 (d, J = 12.2 Hz, 4H), 1.63 - 1.53 (m, 2H), 1.49 - 1.38 (m, 1H), 1.34 - 1.26 (m, 2H), 1.24 - 1.09 (m, 6H), 0.94 (d, J = 6.1 Hz, 3H).

[0290] Production Example 24 Synthesis of ethyl 4-(4-methylpiperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (Compound 24):

Chemical formula

[0291] Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 40 d and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield: 44%.

[0292] ESI-MS: m / z = 359 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.51 (s, 1H), 9.01 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 8.9, 2.3 Hz, 1H), 7.76 (d, J = 2.8 Hz, 1H), 4.24 (d, J = 13.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.75 (t, J = 12.1 Hz, 2H), 1.69 (d, J = 11.4 Hz, 2H), 1.24 - 1.15 (m, 1H), 1.14 - 1.06 (m, 2H), 1.02 (t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H).

[0293] Production Example 25 Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 25):

Chemical Structure

[0294] Step 1: Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2-trimethyl-2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (50a): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 28 g and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield: 45%.

[0295] Step 2: Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (PE-050): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 50a. Yield: 62%.

[0296] ESI-MS: m / z = 480 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.10 (s, 1H), δ 9.09 (s, 1H), 7.95 - 7.88 (m, 1H), 7.84 - 7.69 (m, 2H), 7.41 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 4.39 - 4.21 (m, 4H), 2.79 (t, J = 12.6 Hz, 2H), 1.78 (d, J = 13.3 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H), 1.25 - 1.19 (m, 1H), 1.19 - 1.09 (m, 2H).

[0297] Production Example 26 Synthesis of N-(2-Fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 26):

Chemical Structure

[0298] Step 1: Synthesis of N-(2-Fluoro-3’,4’-dimethoxy-6-(2-triphenyl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (51a): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 36e and 4-tert-butylcyclohexylamine was replaced with 4-trifluoromethylpiperidine. Yield: 47%.

[0299] Step 2: Synthesis of N-(2-Fluoro-3’,4’-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (26): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 51a. Yield: 59%.

[0300] ESI-MS: m / z = 495 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.18 (s, 1H), δ 8.92 (s, 1H), 7.79 (dd, J = 12.8, 2.2 Hz, 1H), 7.61 (s, 1H), 6.98 - 6.83 (m, 1H), 6.69 - 6.58 (m, 2H), 4.24 (d, J = 13.0 Hz, 2H), 3.72 (s, 3H), 3.60 (s, 3H), 2.86 - 2.65 (m, 2H), 2.61 - 2.50 (m, 1H), 1.71 (d, J = 12.2 Hz, 2H), 1.17 - 1.08 (m, 2H).

[0301] Production Example 27 Synthesis of N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 27):

Chemical Structure

[0302] Step 1: Synthesis of N-(4-(1-methyl-1H-indazol-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (52a): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 33f and 4-tert-butylcyclohexylamine was replaced with 4-trifluoromethylpiperidine. Yield: 47%.

[0303] Synthesis of N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 27): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 52a. Yield: 59%.

[0304] ESI-MS: m / z = 471 [M+H] + 。 1 1H NMR (600 MHz, DMSO-d6) δ 16.02 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 - 7.46 (m, 3H), 6.97 (dd, J = 8.5, 1.7 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.03 (s, 3H), 2.79 - 2.73 (m, 2H), 2.70 - 2.53 (m, 1H), 1.70 - 1.64 (m, 2H), 1.15 - 1.06 (m, 2H).

[0305] Production Example 28 Synthesis of N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 28):

Chemical Structure

[0306] Step 1: Synthesis of N-(3'-chloro-4'-methoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (53a): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 39f and 4-tert-butylcyclohexylamine was replaced with 4-trifluoromethylpiperidine. Yield: 44%.

[0307] Step 2: Synthesis of N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide (28): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced by 53a. Yield: 59%.

[0308] ESI-MS: m / z = 481 [M+H] + 。 1 H NMR (600 MHz, DMSO-d6) δ 16.05 (s, 1H), δ 8.87 (s, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.3, 2.3 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.90 (dd, J = 8.1, 2.4 Hz, 1H), 4.25 - 4.21 (m, 2H), 3.87 (s, 3H), 2.78 - 2.66 (m, 2H), 2.71 - 2.55 (m, 1H), 1.75 - 1.69 (m, 2H), 1.18 - 1.09 (m, 2H).

[0309] Production Example 29 Synthesis of cyclohexyl 2-fluoro-6-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)piperidine-1-formamido)benzoate (Compound 29):

Chemical Structure

[0310] The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced by 43f and 4-tert-butylcyclohexylamine was replaced by 4-trifluoromethylpiperidine. Yield: 45%.

[0311] ESI-MS: m / z = 485 [M+H]+ 。 1 H NMR (500 MHz, DMSO-d6) δ 16.36 (s, 1H), 8.90 (s, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.57 (dd, J = 8.1, 1.5 Hz, 1H), 4.73 - 4.61 (m, 1H), 4.25 (d, J = 13.1 Hz, 2H), 2.75 (t, J = 12.5 Hz, 2H), 2.71 - 2.55 (m, 1H), 1.74 (d, J = 12.2 Hz, 4H), 1.63 - 1.53 (m, 2H), 1.34 - 1.26 (m, 2H), 1.23 - 1.09 (m, 6H).

[0312] Production Example 30 Synthesis of ethyl 2-fluoro-6-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)piperidine-1-carboxamide)benzoate (Compound 30):

Chemical formula

[0313] Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 40 d and 4-tert-butylcyclohexylamine was replaced with 4-trifluoromethylpiperidine. Yield: 47%.

[0314] ESI-MS: m / z = 413 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.40 (s, 1H), 9.03 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.87 (dd, J = 8.7, 2.3 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 4.26 (d, J = 13.1 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.75 (t, J = 12.0 Hz, 2H), 2.71 - 2.55 (m, 1H), 1.68 (d, J = 11.3 Hz, 2H), 1.17 - 1.09 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[0315] Production Example 31 Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide (Compound 31): [Chemical formula]

[0316] Step 1: Synthesis of 2-(6-ethoxypyridin-3-yl)-3-fluoro-5-nitrobenzonitrile (56a): The synthesis was carried out according to the procedure of Step 1 of Example 1, except that 1a was replaced with 28b and 1b was replaced with 24a. Yield: 85%.

[0317] Step 2: Synthesis of 2-ethoxy-5-(2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)pyridine (56b): The synthesis was carried out according to the procedure of Step 2 of Example 1, except that 1c was replaced with 56a. Yield: 90%.

[0318] Step 3: Synthesis of 2-ethoxy-5-(2-fluoro-4-nitro-6-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (56c): The synthesis was carried out according to the procedure of Step 3 of Example 1, except that 1d was replaced with 56b. Yield: 89%.

[0319] Step 4: Synthesis of 4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2-triphenyl-2H-tetrazol-5-yl)phenylamine (56d): The synthesis was carried out according to the procedure of Step 4 in Example 1, except that 1e was replaced with 56c. Yield: 88%.

[0320] Step 5: Synthesis of 2-ethoxy-5-(2-fluoro-4-isocyanato-6-(2-triphenyl-2H-tetrazol-5-yl)phenyl)pyridine (56e): The synthesis was carried out according to the procedure of Step 5 in Example 1, except that 1f was replaced with 56d.

[0321] Step 6: Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2-triphenyl-2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide (56f): The synthesis was carried out according to the procedure of Step 6 in Example 1, except that 1g was replaced with 56e and 4-tert-butylcyclohexylamine was replaced with 4-methylpiperidine. Yield after two steps: 43%.

[0322] Step 7: Synthesis of N-(4-(6-ethoxypyridin-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide (31): The synthesis was carried out according to the procedure of Step 7 in Example 1, except that 1h was replaced with 56f. Yield: 67%.

[0323] ESI-MS: m / z = 426[M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 16.34 (s, 1H), δ 8.84 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.5, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.31 - 4.15 (m, 4H), 2.73 (t, J = 11.8 Hz, 2H), 1.67 (d, J = 11.5 Hz, 2H), 1.36 (t, J = 7.4 Hz, 3H), 1.21 - 1.17 (m, 1H), 1.14 - 1.09 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H).

[0324] Production Example 32 Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 32): [Chemical formula]

[0325] Step 1: Synthesis of 3-fluoro-2-(1-methyl-1H-indazol-5-yl)-5-nitrobenzonitrile (57a): The synthesis was carried out according to Step 1 of Example 1, except that 27a was replaced with 28b and 24a was replaced with 33a. Yield: 91%.

[0326] Step 2: Synthesis of 5-(2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)-1-methyl-1H-indazole (57b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 57a. Yield: 90%.

[0327] Step 3: Synthesis of 5-(2-fluoro-4-nitro-6-(2-triphenyl-2H-tetrazol-5-yl)phenyl)-1-methyl-1H-indazole (57c): The synthesis was carried out according to the procedure of Step 3 in Example 1, except that 1d was replaced with 57b. Yield: 93%.

[0328] Step 4: Synthesis of 3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2-triphenyl-2H-tetrazol-5-yl)phenylamine (57d): The synthesis was carried out according to the procedure of Step 4 in Example 1, except that 1e was replaced with 57c. Yield: 86%.

[0329] Step 5: Synthesis of 5-(2-fluoro-4-isocyanato-6-(2-triphenyl-2H-tetrazol-5-yl)phenyl)-1-methyl-1H-indazole (57e): The synthesis was carried out according to the procedure of Step 5 in Example 1, except that 1f was replaced with 57d.

[0330] Step 6: Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2-triphenyl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (57f): The synthesis was carried out according to the procedure of Step 6 in Example 1, except that 1g was replaced with 57e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 42%.

[0331] Step 7: Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (32): The synthesis was carried out according to the procedure of Step 7 in Example 1, except that 1h was replaced with 57f. Yield: 71%.

[0332] ESI-MS: m / z = 478 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.12 (s, 1H), 8.80 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 - 7.46 (m, 3H), 6.97 (dd, J = 8.6, 1.5 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.05 (s, 3H), 2.78 - 2.69 (m, 2H), 1.73 - 1.68 (m, 2H), 1.27 - 1.21 (m, 1H), 1.19 - 1.08 (m, 2H), 0.86 (s, 9H).

[0333] Production Example 33 Synthesis of 4-(tert-butyl)-N-(3'-chloro-2-fluoro-4'-methoxy-6-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (Compound 33): [Chemical formula]

[0334] Step 1: Synthesis of 3'-chloro-6-fluoro-4'-methoxy-4-nitro-[1,1'-biphenyl]-2-carbonitrile (58a): The synthesis was carried out according to Step 1 of Example 7, except that 27a was replaced with 28b and 24a was replaced with 39a. Yield: 81%.

[0335] Step 2: Synthesis of 5-(3'-chloro-6-fluoro-4'-methoxy-4-nitro-[1,1'-biphenyl]-2-yl)-2H-tetrazole (58b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 58a. Yield: 88%.

[0336] Step 3: Synthesis of 5-(3'-chloro-6-fluoro-4'-methoxy-4-nitro-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (58c): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 58b. Yield: 91%.

[0337] Step 4: Synthesis of 3'-chloro-2-fluoro-4'-methoxy-6-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-amine (58d): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 58c. Yield: 87%.

[0338] Step 5: Synthesis of 5-(3'-chloro-6-fluoro-4-isocyanato-4'-methoxy-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (58e): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 58d.

[0339] Step 6: Synthesis of 4-(tert-butyl)-N-(3'-chloro-2-fluoro-4'-methoxy-6-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (58f): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 58e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 46%.

[0340] Step 7: Synthesis of 4-(tert-butyl)-N-(3'-chloro-2-fluoro-4'-methoxy-6-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide (33): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 58f. Yield: 69%.

[0341] ESI-MS: m / z = 488 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.12 (s, 1H), δ 8.80 (s, 1H), 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.86 (dd, J = 8.5, 2.3 Hz, 1H), 4.25 - 4.20 (m, 2H), 3.81 (s, 3H), 2.74 - 2.66 (m, 2H), 1.73 - 1.67 (m, 2H), 1.24 - 1.18 (m, 1H), 1.16 - 1.08 (m, 2H), 0.85 (s, 9H).

[0342] Production Example 34 Synthesis of N-(3-Fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (Compound 34): [Chemical formula]

[0343] Step 1: Synthesis of N-(3-Fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2-triphenyl-2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (59a): Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 57e and 4-tert-butylcyclohexylamine was replaced with 4-trifluoromethylpiperidine. Yield: 48%.

[0344] Step 2: Synthesis of N-(3-Fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide (34): Synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 59a. Yield: 72%.

[0345] ESI-MS: m / z = 478 [M+H] + 。 1 1H NMR (600 MHz, DMSO-d6) δ 16.15 (s, 1H), 8.89 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 8.5, 2.3 Hz, 1H), 7.56 - 7.47 (m, 3H), 6.98 (dd, J = 8.6, 1.5 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.05 (s, 3H), 2.78 - 2.69 (m, 2H), 2.67 - 2.55 (m, 1H), 1.73 - 1.68 (m, 2H), 1.19 - 1.08 (m, 2H).

[0346] Production Example 35 Synthesis of 4-(tert-butyl)-N-(6-(3,4-dimethoxyphenyl)-5-(2H-tetrazol-5-yl)pyridin-3-yl)piperidine-1-carboxamide (Compound 35):

Chemical Structure

[0347] Step 1: Synthesis of 2-(3,4-dimethoxyphenyl)-5-nitronicotinonitrile (60a): The synthesis was carried out according to Step 1 of Example 1, except that 1b was replaced with 24a. Yield: 56%.

[0348] Step 2: Synthesis of 2-(3,4-dimethoxyphenyl)-5-nitro-3-(2H-tetrazol-5-yl)pyridine (60b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 60a. Yield: 91%.

[0349] Step 3: Synthesis of 2-(3,4-dimethoxyphenyl)-5-nitro-3-(2-trityl-2H-tetrazol-5-yl)pyridine (60c): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 60b. Yield: 89%.

[0350] Step 4: Synthesis of 6-(3,4-dimethoxyphenyl)-5-(2-trityl-2H-tetrazol-5-yl)pyridin-3-amine (60d): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 60c. Yield: 85%.

[0351] Step 5: Synthesis of 2-(3,4-dimethoxyphenyl)-5-isocyanato-3-(2-trityl-2H-tetrazol-5-yl)pyridine (60e): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 60d.

[0352] Step 6: Synthesis of 4-(tert-butyl)-N-(6-(3,4-dimethoxyphenyl)-5-(2-trityl-2H-tetrazol-5-yl)pyrid-3-yl)cyclohexane-1-carboxamide (60f): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 60e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 44%.

[0353] Step 7: Synthesis of 4-(tert-butyl)-N-(6-(3,4-dimethoxyphenyl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide (35): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 60f. Yield: 71%.

[0354] ESI-MS: m / z = 467 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.15 (s, 1H), 8.88 (s, 1H), 7.83 - 7.67 (m, 2H), 7.53 - 7.37 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.67 - 6.49 (m, 1H), 4.27 - 4.20 (m, 2H), 2.75 - 2.67 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.85 (s, 9H).

[0355] Production Example 36 Synthesis of 4-(tert-butyl)-N-(6-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide (Compound 36):

Chemical Structure

[0356] Step 1: Synthesis of 2-(1-methyl-1H-indazol-5-yl)-5-nitronicotinonitrile (61a): The synthesis was carried out according to Step 1 of Example 1, except that 24a was replaced with 33a. Yield: 61%.

[0357] Step 2: Synthesis of 1-methyl-5-(5-nitro-3-(2H-tetrazol-5-yl)pyrid-2-yl)-1H-indazole (61b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 61a. Yield: 89%.

[0358] Step 3: Synthesis of 1-methyl-5-(5-nitro-3-(2-triphenyl-2H-tetrazol-5-yl)pyrid-2-yl)-1H-indazole (61c): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 61b. Yield: 88%.

[0359] Step 4: Synthesis of 6-(1-methyl-1H-indazol-5-yl)-5-(2-trityl-2H-tetrazol-5-yl)pyridin-3-amine (61d): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced by 61c. Yield: 85%.

[0360] Step 5: Synthesis of 5-(5-isocyanato-3-(2-triphenyl-2H-tetrazol-5-yl)pyridin-2-yl)-1-methyl-1H-indazole (61e): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced by 61d.

[0361] Step 6: Synthesis of 4-(tert-butyl)-N-(6-(1-methyl-1H-indazol-5-yl)-5-(2-trityl-2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide (61f): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced by 61e and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 46%.

[0362] Step 7: Synthesis of 4-(tert-butyl)-N-(6-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide (36): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced by 61f. Yield: 69%.

[0363] ESI-MS: m / z = 461 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.12 (s, 1H), 8.99 (s, 1H), 8.01 (s, 1H), 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 - 7.46 (m, 3H), 6.97 (dd, J = 8.5, 1.7 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.07 (s, 3H), 2.76 - 2.68 (m, 2H), 1.79 - 1.68 (m, 2H), 1.27 - 1.16 (m, 1H), 1.18 - 1.08 (m, 2H), 0.85 (s, 9H).

[0364] Production Example 37 Synthesis of Ethyl 5-(4-(tert-butyl)piperidine-1-carboxamido)-3-(2H-tetrazol-5-yl)pyridinecarboxylate (Compound 37): [Chemical Formula]

[0365] Step 1: Synthesis of Ethyl 5-nitro-3-(2H-tetrazol-5-yl)pyridinecarboxylate (62b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 62a. Yield: 83%.

[0366] Step 2: Synthesis of Ethyl 5-amino-3-(2H-tetrazol-5-yl)pyridinecarboxylate (62c): The synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 62b. Yield: 81%.

[0367] Step 3: Synthesis of Ethyl 5-isocyanato-3-(2H-tetrazol-5-yl)pyridinecarboxylate (62d): The synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 62c.

[0368] Step 4: Synthesis of ethyl 5-(4-(tert-butyl)piperidine-1-carboxamido)-3-(2H-tetrazol-5-yl)pyridinecarboxylate (37): Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 62 d and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 40%.

[0369] ESI-MS: m / z = 402 [M+H] + 。 1 1H NMR (500 MHz, DMSO-d6) δ 16.31 (s, 1H), 9.03 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 4.21 (d, J = 13.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.73 (t, J = 12.1 Hz, 2H), 1.65 (d, J = 11.4 Hz, 2H), 1.29 - 1.18 (m, 1H), 1.16 - 1.07 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H), 0.86 (s, 9H).

[0370] Production Example 38 Synthesis of cyclohexyl 5-(4-(tert-butyl)piperidine-1-carboxamido)-3-(2H-tetrazol-5-yl)pyridinecarboxylate (Compound 38):

Chemical Structure

[0371] Step 1: Synthesis of Intermediate 63b: Synthesis was carried out according to Step 1 of Example 16, except that 1c was replaced with 63a. Yield: 81%.

[0372] Step 2: Synthesis of (63c): Synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 63b. Yield: 85%.

[0373] Step 3: Synthesis of (63d): Synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 63c.

[0374] Step 4: Synthesis of cyclohexyl 5-(4-(tert-butyl)piperidine-1-carboxamido)-3-(2H-tetrazol-5-yl)pyridinecarboxylate (38): Synthesis was carried out according to Step 7 of Example 1, except that 1g was replaced with 63c and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 43%.

[0375] ESI-MS: m / z = 457 [M+H] + 。 1 1H NMR (500 MHz, DMSO-d6) δ 16.01 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.74 (dd, J = 7.5, 1.7 Hz, 1H), 4.76 - 4.66 (m, 1H), 4.25 (d, J = 12.1 Hz, 2H), 2.76 (t, J = 11.4 Hz, 2H), 1.68 (d, J = 12.2 Hz, 4H), 1.60 - 1.49 (m, 2H), 1.47 - 1.37 (m, 1H), 1.33 - 1.23 (m, 2H), 1.22 - 1.05 (m, 6H), 0.86 (s, 9H).

[0376] Production Example 39 Synthesis of N-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(tert-butyl)piperidine-1-carboxamide (Compound 39):

Chemical Structure

[0377] Step 1: Synthesis of 5-(2-(benzo[d][1,3]dioxin-5-yl)-5-isocyanatophenyl)-2-triphenyl-2H-tetrazole (64a): The synthesis was carried out according to the procedure of Step 5 in Example 1, except that 1f was replaced by 21e.

[0378] Step 2: Synthesis of N-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2-triphenyl-2H-tetrazol-5-yl)phenyl)-4-(tert-butyl)piperidine-1-carboxamide (64b): The synthesis was carried out according to the procedure of Step 6 in Example 1, except that 1g was replaced by 64a and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 49%.

[0379] Step 3: Synthesis of N-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(tert-butyl)piperidine-1-carboxamide (39): The synthesis was carried out according to the procedure of Step 7 in Example 1, except that 1h was replaced by 64b. Yield: 69%.

[0380] ESI-MS: m / z = 450 [M+H] + 。 1 H NMR (500 MHz, chloroform-d) δ 16.23 (s, 1H), 8.62 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 8.4, 2.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 6.48 - 6.37 (m, 1H), 6.14 (d, J = 7.8 Hz, 1H), 6.01 (s, 2H), 4.27 - 4.20 (m, 2H), 2.75 - 2.67 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0381] Manufacturing Example 40 Synthesis of 4-(tert-butyl)-N-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 40):

Chemical formula

[0382] Step 1: Synthesis of 4-(tert-butyl)-N-(4-(3,6-dihydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)cyclohexane-1-carboxamide (65a): Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 20a, and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield: 45%.

[0383] Step 2: Synthesis of 4-(tert-butyl)-N-(4-(tetrahydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)cyclohexane-1-carboxamide (65b): 0.12 g (0.19 mmol) of 65a was dissolved in 3 mL of methanol. The reaction was carried out at room temperature for 5 hours under a hydrogen pressure of 1 MPa. After the reaction was completed, Pd / C was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 65b. Yield: 83%.

[0384] Step 3: Synthesis of 4-(tert-butyl)-N-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (40): Synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 65b. Yield: 65%.

[0385] ESI-MS: m / z = 414 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.51 (s, 1H), δ 8.45 (s, 1H), 7.64 (s, 1H), 7.47 (dd, J = 8.6, 2.4 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.94 - 3.85 (m, 2H), 3.31 - 3.25 (m, 2H), 3.10 - 2.94 (m, 1H), 2.75 - 2.67 (m, 2H), 1.90 - 1.81 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0386] Production Example 41 Synthesis of 4-(tert-butyl)-N-(4-(3,4-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (41): [Chemical Formula]

[0387] Step 1: Synthesis of 2-(3,4-dihydro-2H-pyran-4-yl)-5-nitrobenzonitrile (66b): The synthesis was carried out according to Step 1 of Example 18, except that 28b was replaced with 1a and 41a was replaced with 66a. Yield: 81%.

[0388] Step 2: Synthesis of 5-(2-(3,4-dihydro-2H-pyran-4-yl)-5-nitrophenyl)-2H-tetrazole (66c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 67b. Yield: 83%.

[0389] Step 3: Synthesis of 5-(2-(3,4-dihydro-2H-pyran-4-yl)-5-nitrophenyl)-2-trityl-2H-tetrazole (66d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 66c. Yield: 85%.

[0390] Step 4: Synthesis of 4-(3,4-dihydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (66e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 66d. Yield: 87%.

[0391] Step 5: Synthesis of 5-(2-(3,4-dihydro-2H-pyran-4-yl)-5-isocyanatophenyl)-2-triphenyl-2H-tetrazole (66f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 66e.

[0392] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(3,4-dihydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (66g): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 66f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 45%.

[0393] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(3,4-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (41): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 66g. Yield: 63%. ESI-MS: m / z = 412 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.31 (s, 1H), 8.58 (s, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.64 - 7.56 (m, 2H), 6.40 (dd, J = 11.0, 1.8 Hz, 1H), 5.68 (dd, J = 10.8, 6.2 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.31 - 3.25 (m, 2H), 3.10 - 2.94 (m, 1H), 2.75 - 2.67 (m, 2H), 1.90 - 1.81 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0394] Production Example 42 Synthesis of 4-(tert-butyl)-N-(4-(6-(difluoromethyl)pyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 42): [Chemical formula]

[0395] Step 1: Synthesis of 2-(6-(difluoromethyl)pyridin-3-yl)-5-nitrobenzonitrile (67b): The synthesis was carried out according to Step 1 of Example 1, except that 1b was replaced with 67a. Yield: 81%.

[0396] Step 2: Synthesis of 2-(difluoromethyl)-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (67c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 67b. Yield: 89%.

[0397] Step 3: Synthesis of 2-(difluoromethyl)-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (67d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 67c. Yield: 86%.

[0398] Step 4: Synthesis of 4-(6-(difluoromethyl)pyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (67e): The synthesis was carried out according to the procedure of Step 4 in Example 1, except that 1e was replaced with 67d. Yield: 85%.

[0399] Step 5: Synthesis of 2-(difluoromethyl)-5-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (67f): The synthesis was carried out according to the procedure of Step 5 in Example 1, except that 1f was replaced with 67e.

[0400] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(6-(difluoromethyl)pyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (67g): The synthesis was carried out according to the procedure of Step 6 in Example 1, except that 1g was replaced with 67f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 43%.

[0401] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(6-(difluoromethyl)pyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (42): The synthesis was carried out according to the procedure of Step 7 in Example 1, except that 1h was replaced with 67g. Yield: 65%.

[0402] ESI-MS: m / z = 457 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.08 (s, 1H), 8.66 (d, J = 1.5 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.77 (dd, J = 7.5, 0.7 Hz, 1H), 7.72 (dd, J = 7.5, 1.5 Hz, 1H), 7.55 (dd, J = 7.5, 1.5 Hz, 1H), 4.27 - 4.20 (m, 2H), 2.75 - 2.67 (m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.85 (s, 9H).

[0403] Production Example 43 Synthesis of cyclopentyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (Compound 43): [Chemical formula]

[0404] Step 1: Synthesis of cyclopentyl 2-cyano-4-nitrobenzoate (68c): The synthesis was carried out according to the procedure of Step 1 of Example 17, except that 43a was replaced with 68a and 43b was replaced with 68b. Yield: 71%.

[0405] Step 2: Synthesis of cyclopentyl 4-nitro-2-(2H-tetrazol-5-yl)benzoate (68d): The synthesis was carried out according to the procedure of Step 2 of Example 1, except that 1c was replaced with 68c. Yield: 85%.

[0406] Step 3: Synthesis of cyclopentyl 4-amino-2-(2H-tetrazol-5-yl)benzoate (68e): The synthesis was carried out according to the procedure of Step 2 of Example 16, except that 40b was replaced with 68d. Yield: 89%.

[0407] Step 4: Synthesis of Cyclopentyl 4-isocyanato-2-(2H-tetrazol-5-yl)benzoate (68f): The synthesis was carried out according to the procedure of Step 3 of Example 16, except that 40c was replaced with 43e.

[0408] Step 5: Synthesis of Cyclopentyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (43): The synthesis was carried out according to the procedure of Step 6 of Example 1, except that 1g was replaced with 68f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 45%.

[0409] ESI-MS: m / z = 442 [M+H] + 。 1 1H NMR (500 MHz, DMSO-d6) δ 16.31 (s, 1H), 9.08 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.88 (dd, J = 8.6, 2.3 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 4.78 - 4.66 (m, 1H), 4.24 (d, J = 13.1 Hz, 2H), 2.76 (t, J = 12.5 Hz, 2H), 1.69 (d, J = 12.2 Hz, 4H), 1.60 - 1.49 (m, 2H), 1.47 - 1.37 (m, 1H), 1.33 - 1.23 (m, 2H), 1.22 - 1.05 (m, 4H), 0.85 (s, 9H).

[0410] Production Example 44 Synthesis of Tetrahydrofuran-3-yl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (Compound 44):

Chemical Structure

[0411] Step 1: Synthesis of tetrahydrofuran-3-yl 2-cyano-4-nitrobenzoate (69b): The synthesis was carried out according to the procedure of Step 1 in Example 17, except that 43a was replaced by 68a and 43b was replaced by 69a. Yield: 74%.

[0412] Step 2: Synthesis of tetrahydrofuran-3-yl 4-nitro-2-(2H-tetrazol-5-yl)benzoate (69c): The synthesis was carried out according to the procedure of Step 2 in Example 1, except that 1c was replaced by 69b. Yield: 89%.

[0413] Step 3: Synthesis of tetrahydrofuran-3-yl 4-amino-2-(2H-tetrazol-5-yl)benzoate (69d): The synthesis was carried out according to the procedure of Step 2 in Example 16, except that 40b was replaced by 69c. Yield: 84%.

[0414] Step 4: Synthesis of tetrahydrofuran-3-yl 4-isocyanato-2-(2H-tetrazol-5-yl)benzoate (69e): The synthesis was carried out according to the procedure of Step 3 in Example 16, except that 40c was replaced by 69d.

[0415] Step 5: Synthesis of tetrahydrofuran-3-yl 4-(4-(tert-butyl)piperidine-1-formamide)-2-(2H-tetrazol-5-yl)benzoate (44): The synthesis was carried out according to the procedure of Step 6 in Example 1, except that 1g was replaced by 69e and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 43%.

[0416] ESI-MS: m / z = 444 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.31 (s, 1H), 8.64 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.75 (dd, J = 7.5, 1.6 Hz, 1H), 5.39 - 5.30 (m, 1H), 4.27 - 4.20 (m, 2H), 4.08 - 4.00 (m, 2H), 3.80 (td, J = 7.2, 1.9 Hz, 2H), 2.75 - 2.67 (m, 2H), 2.31 - 2.22(m, 2H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0417] Production Example 45 Synthesis of ethyl 4-(4-(tert-butyl)piperidine-1-carboxamido)-2-(2H-tetrazol-5-yl)benzoate (Compound 45): [Chemical formula]

[0418] Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 40 d. Yield: 44%. ESI-MS: m / z = 359 [M+H] + . 11H NMR (500 MHz, DMSO-d6) δ 16.51 (s, 1H), 9.01 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 8.9, 2.3 Hz, 1H), 7.76 (d, J = 2.8 Hz, 1H), 4.24 (d, J = 13.1 Hz, 2H), 4.23 (d, J = 13.1 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.72 (t, J = 12.1 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.26 - 1.17 (m, 1H), 1.15 - 1.08 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.85 (s, 9H).

[0419] Production Example 46 Synthesis of 4-(tert-butyl)-N-(4-(cyclopentylaminocarbonyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 46): [Chemical formula]

[0420] Step 1: Synthesis of 2-cyano-N-cyclopentyl-4-nitrobenzamide (71b): 0.50 g (2.60 mmol) and 0.22 g (2.60 mmol) of cyclopentylamine were dissolved in 10 mL of anhydrous DMF, and then 0.39 g (3.90 mmol) of triethylamine and 1.04 g (2.73 mmol) of HATU were added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1, volume / volume) to obtain 0.50 g of 71b. Yield: 74%.

[0421] Step 2: Synthesis of N-cyclopentyl-4-nitro-2-(2H-tetrazol-5-yl)benzamide (71c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 71b. Yield: 83%.

[0422] Step 3: Synthesis of 4-amino-N-cyclopentyl-2-(2H-tetrazol-5-yl)benzamide (71d): The synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 71c. Yield: 84%.

[0423] Step 4: Synthesis of N-cyclopentyl-4-isocyanato-2-(2H-tetrazol-5-yl)benzamide (71e): The synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 71d.

[0424] Step 5: Synthesis of 4-(tert-butyl)-N-(4-(cyclopentylaminocarbonyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (46): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 71e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 43%.

[0425] ESI-MS: m / z = 441 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.01 (s, 1H), 8.65 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.32 (d, J = 9.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.74 (dd, J = 7.5, 1.7 Hz, 1H), 4.76 - 4.65 (m, 1H), 4.22 (d, J = 13.1 Hz, 2H), 2.71 (t, J = 12.5 Hz, 2H), 1.68 (d, J = 12.2 Hz, 4H), 1.60 - 1.49 (m, 2H), 1.47 - 1.37 (m, 1H), 1.33 - 1.23 (m, 2H), 1.22 - 1.05 (m, 4H), 0.85 (s, 9H).

[0426] Production Example 47 Synthesis of 4-(tert-butyl)-N-(4-((5-methylpyridin-2-yl)aminocarbonyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 47): [Chemical formula]

[0427] Step 1: Synthesis of 2-cyano-N-(5-methylpyridin-2-yl)-4-nitrobenzamide (72b): The synthesis was carried out according to Step 1 of Example 47, except that 71a was replaced with 72a. Yield: 80%.

[0428] Step 2: Synthesis of N-(5-methylpyridin-2-yl)-4-nitro-2-(2H-tetrazol-5-yl)benzamide (72c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 72b. Yield: 83%.

[0429] Step 3: Synthesis of 4-amino-N-(5-methylpyridin-2-yl)-2-(2H-tetrazol-5-yl)benzamide (72d): The synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 72c. Yield: 86%.

[0430] Step 4: Synthesis of 4-isocyanato-N-(5-methylpyridin-2-yl)-2-(2H-tetrazol-5-yl)benzamide (72e): The synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 72d.

[0431] Step 5: Synthesis of 4-(tert-butyl)-N-(4-((5-methylpyridin-2-yl)aminocarbonyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (47): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 72e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 46%.

[0432] ESI-MS: m / z = 441 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.01 (s, 1H), 8.64 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8.07 (dd, J = 1.5, 0.7 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.65 - 7.59 (m, 1H), 4.27 - 4.20 (m, 2H), 2.75 - 2.67 (m, 2H), 2.56 (s, 1H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0433] Production Example 48 Synthesis of 4-(tert-butyl)-N-(4-(5-methoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 48):

Chem.

[0434] Step 1: Synthesis of 2-(5-methoxypyridin-3-yl)-5-nitrobenzonitrile (73b): The synthesis was carried out according to Step 1 of Example 1, with 1b replaced by 73a. Yield: 83%.

[0435] Step 2: Synthesis of 3-methoxy-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (73c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced by 73b. Yield: 87%.

[0436] Step 3: Synthesis of 3-methoxy-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (73d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced by 73c. Yield: 86%.

[0437] Step 4: Synthesis of 4-(5-methoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (73e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced by 73d. Yield: 79%.

[0438] Step 5: Synthesis of 3-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)-5-methoxypyridine (73f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced by 73e.

[0439] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(5-methoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (73 g): Synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 73 f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 41%.

[0440] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(5-methoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (48): Synthesis was carried out according to Step 7 of Example 1, except that 1 h was replaced with 73 g. Yield: 66%.

[0441] ESI-MS: m / z = 437 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.33 (s, 1H), δ 8.84 (s, 1H), 7.93 (d, J = 2.9 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.78 (dd, J = 8.1, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.33 - 4.19 (m, 5H), 2.75 (t, J = 11.8 Hz, 2H), 1.59 (d, J = 11.5 Hz, 2H), 1.24 - 1.17 (m, 1H), 1.16 - 1.09 (m, 2H), 0.86 (s, 9H).

[0442] Production Example 49 Synthesis of 4-(tert-butyl)-N-(4-(6-isopropoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 49):

Chemical Structure

[0443] Step 1: Synthesis of 2-(6-isopropoxypyridin-3-yl)-5-nitrobenzonitrile (74b): The synthesis was carried out according to Step 1 of Example 1, with 24a replaced by 74a. Yield: 86%.

[0444] Step 2: Synthesis of 2-isopropoxy-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (74c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced by 74b. Yield: 91%.

[0445] Step 3: Synthesis of 2-isopropoxy-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (74d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced by 74c. Yield: 85%.

[0446] Step 4: Synthesis of 4-(6-isopropoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (74e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced by 74d. Yield: 82%.

[0447] Step 5: Synthesis of 5-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-isopropoxypyridine (74f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced by 74e.

[0448] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(6-isopropoxypyridin-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (74g): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced by 74f and 4-tert-butylcyclohexylamine was replaced by 4-tert-butylpiperidine hydrochloride. Yield after two steps: 42%.

[0449] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(6-isopropoxypyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (49): Synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 74g. Yield: 67%.

[0450] ESI-MS: m / z = 465 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.33 (s, 1H), 8.56 (s, 1H), 8.46 - 8.42 (m, 2H), 8.09 (dd, J = 7.5, 1.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.73 (dd, J = 7.5, 1.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.27 - 4.20 (m, 2H), 2.75 - 2.67 (m, 2H), 1.71 - 1.65 (m, 2H), 1.35 (d, J = 6.8 Hz, 6H), 1.25 - 1.18 (m, 1H), 1.17 - 1.07 (m, 2H), 0.86 (s, 9H).

[0451] Production Example 50 Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(5-methoxypyridin-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 50):

Chemical Structure

[0452] Step 1: Synthesis of 3-fluoro-2-(5-methoxypyridin-3-yl)-5-nitrobenzonitrile (75a): Synthesis was carried out according to Step 1 of Example 1, except that 1a was replaced with 28a and 1b was replaced with 73a. Yield: 74%.

[0453] Step 2: Synthesis of 3-(2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)-5-methoxypyridine (75b): The synthesis was carried out according to the procedure of Step 2 in Example 1, except that 1c was replaced with 75a. Yield: 87%.

[0454] Step 3: Synthesis of 3-(2-fluoro-4-nitro-6-(2-trityl-2H-tetrazol-5-yl)phenyl)-5-methoxypyridine (75c): The synthesis was carried out according to the procedure of Step 3 in Example 1, except that 1d was replaced with 75b. Yield: 85%.

[0455] Step 4: Synthesis of 3-fluoro-4-(5-methoxypyrid-3-yl)-5-(2-trityl-2H-tetrazol-5-yl)phenylamine (75d): The synthesis was carried out according to the procedure of Step 4 in Example 1, except that 1e was replaced with 75c. Yield: 81%.

[0456] Step 5: Synthesis of 3-(2-fluoro-4-isocyanato-6-(2-trityl-2H-tetrazol-5-yl)phenyl)-5-methoxypyridine (75e): The synthesis was carried out according to the procedure of Step 5 in Example 1, except that 1f was replaced with 75d.

[0457] Step 6: Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(5-methoxypyrid-3-yl)-5-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (75f): The synthesis was carried out according to the procedure of Step 6 in Example 1, except that 1g was replaced with 75e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 41%.

[0458] Step 7: Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(5-methoxypyrid-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (50): The synthesis was carried out according to the procedure of Step 7 in Example 1, except that 1h was replaced with 75f. Yield: 61%.

[0459] ESI-MS: m / z = 455 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.23 (s, 1H), δ 8.84 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.78 (dd, J = 8.1, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.33 - 4.19 (m, 5H), 2.75 (t, J = 11.8 Hz, 2H), 1.65 (d, J = 11.5 Hz, 2H), 1.27 - 1.19 (m, 1H), 1.16 - 1.09 (m, 2H), 0.86 (s, 9H).

[0460] Production Example 51 Synthesis of 4-(tert-butyl)-N-(4-(6-methylpyridin-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 51):

Chemical Structure

[0461] Step 1: Synthesis of 2-(6-methylpyridin-3-yl)-5-nitrobenzonitrile (76b): The synthesis was carried out according to Step 1 of Example 1, except that 1b was replaced with 76a. Yield: 86%.

[0462] Step 2: Synthesis of 2-methyl-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (76c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 76b. Yield: 88%.

[0463] Step 3: Synthesis of 3:2-methyl-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (76d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 76c. Yield: 91%.

[0464] Step 4: Synthesis of 4-(6-methylpyrid-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (76e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 76d. Yield: 83%.

[0465] Step 5: Synthesis of 5-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-methylpyridine (76f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 76e.

[0466] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(6-methylpyrid-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (76g): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 76f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 48%.

[0467] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(6-methylpyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (51): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 76g. Yield: 58%.

[0468] ESI-MS: m / z = 421 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 16.33 (s, 1H), δ 8.84 (s, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.5, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.33 - 4.19 (m, 2H), 2.71 (t, J = 11.8 Hz, 2H), 2.44 (s, 1H), 1.69 (d, J = 11.5 Hz, 2H), 1.19 - 1.15 (m, 1H), 1.14 - 1.08 (m, 2H), 0.86 (s, 9H).

[0469] Production Example 52 Synthesis of 4-(tert-butyl)-N-(4-(2-methylpyridin-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 52): [Chemical formula]

[0470] Step 1: Synthesis of 2-(2-methylpyridin-4-yl)-5-nitrobenzonitrile (77b): The synthesis was carried out according to Step 1 of Example 1, except that 1b was replaced with 77a. Yield: 86%.

[0471] Step 2: Synthesis of 2-methyl-4-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (77c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 77b. Yield: 90%.

[0472] Step 3: Synthesis of 2-methyl-4-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (77d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 77c. Yield: 89%.

[0473] Step 4: Synthesis of 4-(2-methylpyridin-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (77e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 77d. Yield: 83%.

[0474] Step 5: Synthesis of 4-(4-isocyanato-2-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-methylpyridine (77f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 77e.

[0475] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(2-methylpyridin-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (77g): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 77f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 48%.

[0476] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(2-methylpyridin-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (52): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 77g. Yield: 71%.

[0477] ESI-MS: m / z = 421 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 16.23 (s, 1H), δ 8.89 (s, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.35 - 4.21 (m, 2H), 2.74 (t, J = 11.8 Hz, 2H), 2.51 (s, 1H), 1.65 (d, J = 11.5 Hz, 2H), 1.24 - 1.17 (m, 1H), 1.15 - 1.09 (m, 2H), 0.86 (s, 9H).

[0478] Production Example 53 Synthesis of 4-(tert-butyl)-N-(4-(cyclopentylaminocarbonyl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 53): [Chemical formula]

[0479] Step 1: Synthesis of 2-cyano-N-cyclopentyl-6-fluoro-4-nitrobenzamide (78a): The synthesis was carried out according to Step 1 of Example 46, except that 68a was replaced with 43a. Yield: 73%.

[0480] Step 2: Synthesis of N-cyclopentyl-2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)benzamide (78b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 78a. Yield: 93%.

[0481] Step 3: Synthesis of 3:4-amino-N-cyclopentyl-2-fluoro-6-(2H-tetrazol-5-yl)benzamide (78c): The synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 78b. Yield: 82%.

[0482] Step 4: Synthesis of N-cyclopentyl-2-fluoro-4-isocyanato-6-(2H-tetrazol-5-yl)benzamide (78d): The synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 78c.

[0483] Step 5: Synthesis of 4-(tert-butyl)-N-(4-(cyclopentylaminocarbonyl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (53): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 78d and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 50%.

[0484] ESI-MS: m / z = 459 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.21 (s, 1H), 8.65 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.74 (dd, J = 7.5, 1.7 Hz, 1H), 4.76 - 4.65 (m, 1H), 4.22 (d, J = 13.1 Hz, 2H), 2.75 (t, J = 12.5 Hz, 2H), 1.69 (d, J = 12.2 Hz, 4H), 1.63 - 1.52 (m, 2H), 1.48 - 1.39 (m, 1H), 1.34 - 1.25 (m, 2H), 1.23 - 1.09 (m, 4H), 0.85 (s, 9H).

[0485] Production Example 54 Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-((5-methylpyridin-2-yl)aminocarbonyl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 54): [Chemical formula]

[0486] Step 1: Synthesis of 2-cyano-6-fluoro-N-(5-methylpyridin-2-yl)-4-nitrobenzamide (79a): The synthesis was carried out according to Step 1 of Example 46, except that 68a was replaced with 43a and 71a was replaced with 72a. Yield: 69%.

[0487] Step 2: Synthesis of 2-fluoro-N-(5-methylpyridin-2-yl)-4-nitro-6-(2H-tetrazol-5-yl)benzamide (79b): The synthesis was carried out according to Step 2 of Example 16, except that 1c was replaced with 79a. Yield: 90%.

[0488] Step 3: Synthesis of 4-amino-2-fluoro-N-(5-methylpyridin-2-yl)-6-(2H-tetrazol-5-yl)benzamide (79c): The synthesis was carried out according to Step 2 of Example 16, except that 40b was replaced with 79b. Yield: 83%.

[0489] Step 4: Synthesis of 2-fluoro-4-isocyanato-N-(5-methylpyridin-2-yl)-6-(2H-tetrazol-5-yl)benzamide (79d): The synthesis was carried out according to Step 3 of Example 16, except that 40c was replaced with 79c.

[0490] Step 5: Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-((5-methylpyridin-2-yl)aminocarbonyl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (54): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 79 d and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 47%.

[0491] ESI-MS: m / z = 441 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 16.23 (s, 1H), 8.69 (s, 1H), 8.34 (d, J = 1.5 Hz, 1H), 8.01 (dd, J = 1.5, 0.7 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.64 - 7.55 (m, 1H), 4.27 - 4.20 (m, 2H), 2.79 - 2.68 (m, 2H), 2.56 (s, 1H), 1.71 - 1.65 (m, 2H), 1.25 - 1.18 (m, 1H), 1.18 - 1.07 (m, 2H), 0.86 (s, 9H).

[0492] Production Example 55 Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(6-methylpyridin-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 55):

Chemical Structure

[0493] Step 1: Synthesis of 3-fluoro-2-(6-methylpyridin-3-yl)-5-nitrobenzonitrile (80a): The synthesis was carried out according to Step 1 of Example 1, except that 1a was replaced with 28b and 1b was replaced with 76a. Yield: 87%.

[0494] Step 2: Synthesis of 5-(2-Fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)-2-methylpyridine (80b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 80a. Yield: 91%.

[0495] Step 3: Synthesis of 5-(2-Fluoro-4-nitro-6-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-methylpyridine (80c): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 80b. Yield: 93%.

[0496] Step 4: Synthesis of 3-Fluoro-4-(6-methylpyrid-3-yl)-5-(2-trityl-2H-tetrazol-5-yl)phenylamine (80d): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 80c. Yield: 48%.

[0497] Step 5: Synthesis of 5-(2-Fluoro-4-isocyanato-6-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-methylpyridine (80e): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 80d.

[0498] Step 6: Synthesis of 4-(tert-Butyl)-N-(3-fluoro-4-(6-methylpyrid-3-yl)-5-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (80f): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 80e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 46%.

[0499] Step 7: Synthesis of 4-(tert-Butyl)-N-(3-fluoro-4-(6-methylpyrid-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (55): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 80f. Yield: 61%.

[0500] ESI-MS: m / z = 439 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.31 (s, 1H), δ 8.81 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.5, 2.3 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.6, 2.6 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 4.33 - 4.19 (m, 2H), 2.71 (t, J = 11.8 Hz, 2H), 2.44 (s, 1H), 1.69 (d, J = 11.5 Hz, 2H), 1.25 - 1.19 (m, 1H), 1.14 - 1.11 (m, 2H), 0.86 (s, 9H).

[0501] Production Example 56 Synthesis of 4-(tert-butyl)-N-(3-fluoro-4-(6-isopropoxypyridin-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 56):

Chemical Structure

[0502] Step 1: Synthesis of 3-fluoro-2-(6-isopropoxypyridin-3-yl)-5-nitrobenzonitrile (81a): The synthesis was carried out according to Step 1 of Example 1, except that 1a was replaced with 28b and 1b was replaced with 74a. Yield: 82%.

[0503] Step 2: Synthesis of 5-(2-fluoro-4-nitro-6-(2H-tetrazol-5-yl)phenyl)-2-isopropoxypyridine (81b): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 81a. Yield: 91%.

[0504] Step 3: Synthesis of 5-(2-Fluoro-4-nitro-6-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-isopropoxypyridine (81c): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 81b. Yield: 86%.

[0505] Step 4: Synthesis of 3-Fluoro-4-(6-isopropoxypyrid-3-yl)-5-(2-trinitro-2H-tetrazol-5-yl)phenylamine (81d): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 81c. Yield: 81%.

[0506] Step 5: Synthesis of 5-(2-Fluoro-4-isocyanato-6-(2-trityl-2H-tetrazol-5-yl)phenyl)-2-isopropoxypyridine (81e): The synthesis was carried out according to Step 5 of Example 1, except that 1g was replaced with 81d.

[0507] Step 6: Synthesis of 4-(tert-Butyl)-N-(3-fluoro-4-(6-isopropoxypyrid-3-yl)-5-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (81f): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 81e and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 41%.

[0508] Step 7: Synthesis of 4-(tert-Butyl)-N-(3-fluoro-4-(6-isopropoxypyrid-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (56): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 81f. Yield: 65%.

[0509] ESI-MS: m / z = 483 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 16.33 (s, 1H), 8.56 (s, 1H), 8.46 - 8.42 (m, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.73 (dd, J = 7.5, 1.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.27 - 4.20 (m, 2H), 2.73 - 2.67 (m, 2H), 1.78 - 1.66 (m, 2H), 1.38 (d, J = 6.8 Hz, 6H), 1.29 - 1.19 (m, 1H), 1.16 - 1.07 (m, 2H), 0.86 (s, 9H).

[0510] Production Example 57 Synthesis of 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 57):

Chemical Structure

[0511] Step 1: Synthesis of 2-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-nitrobenzonitrile (82c): 1.00 g (5.44 mmol) of 2,3-difluoro-5-nitrobenzonitrile, 0.56 g (4.53 mmol) of 4-tert-butylimidazole, and 1.88 g (13.58 mmol) of potassium carbonate were added to a reaction flask. Then, 20 mL of dimethyl sulfoxide was added. The mixture was warmed to 90 °C and the reaction was carried out for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 0.87 g of 82c. Yield: 67%.

[0512] Step 2: Synthesis of 5-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-nitrophenyl)-2H-tetrazole (82d): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 82c. Yield: 81%.

[0513] Step 3: Synthesis of 5-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-nitrophenyl)-2-trityl-2H-tetrazole (82e): The synthesis was carried out according to Step 3 of Example 1, except that 1c was replaced with 82c. Yield: 91%.

[0514] Step 4: Synthesis of 4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-(2-trityl-2H-tetrazol-5-yl)phenylamine (82f): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 81e. Yield: 81%.

[0515] Step 5: Synthesis of 5-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-isocyanatophenyl)-2-trityl-2H-tetrazole (82g): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 81f.

[0516] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (82h): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 82g and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 41%.

[0517] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (57): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced by 82h. Yield: 61%.

[0518] ESI-MS: m / z = 470 [M+H] + 。 1 H NMR (600 MHz, DMSO-d6) δ 16.02 (s, 1H), δ 8.57 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.71 (dd, J = 8.0, 1.5 Hz, 1H), 4.28 - 4.22 (m, 2H), 2.76 - 2.68 (m, 2H), 1.72 - 1.66 (m, 2H), 1.33 (s, 9H), 1.25 - 1.19 (m, 1H), 1.17 - 1.08 (m, 2H), 0.86 (s, 9H).

[0519] Production Example 58 Synthesis of 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (Compound 58):

Chemical Structure

[0520] Procedure 1: Synthesis of 2-(4-(tert-butyl)-1H-imidazol-1-yl)-5-nitrobenzonitrile (83b): 1.00 g (8.05 mmol) of 4-tert-butylimidazole was dissolved in 20 mL of anhydrous DMF. The solution was cooled to 0 °C, and 0.39 g (9.66 mmol) of sodium hydride (60%) was added portionwise. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 0.5 h. Then, 2.20 g (12.08 mmol) of 2-chloro-5-nitrobenzonitrile was added. The reaction was carried out for an additional 1 h. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 1.50 g of 83b. Yield: 69%.

[0521] Procedure 2: Synthesis of 5-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-5-nitrophenyl)-2H-tetrazole (83c): The synthesis was carried out according to the procedure of step 2 of Example 1, except that 1c was replaced with 83b. Yield: 87%.

[0522] Procedure 3: Synthesis of 5-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-5-nitrophenyl)-2-trityl-2H-tetrazole (83d): The synthesis was carried out according to the procedure of step 3 of Example 1, except that 1d was replaced with 83c. Yield: 91%.

[0523] Procedure 4: Synthesis of 4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (83e): The synthesis was carried out according to the procedure of step 4 of Example 1, except that 1e was replaced with 83d. Yield: 81%.

[0524] Procedure 5: Synthesis of 5-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-5-isocyanatophenyl)-2-trityl-2H-tetrazole (83f): The synthesis was carried out according to the procedure of step 5 of Example 1, except that 1f was replaced with 83e.

[0525] Step 6: Synthesis of 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (83 g): The synthesis was carried out according to Step 6 of Example 1, except that 1 g was replaced with 83 f and 4-tert-butylcyclohexylamine was replaced with 4-tert-butylpiperidine hydrochloride. Yield after two steps: 43%.

[0526] Step 7: Synthesis of 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide (58): The synthesis was carried out according to Step 7 of Example 1, except that 1 h was replaced with 83 g. Yield: 65%.

[0527] ESI-MS: m / z = 452 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 16.08 (s, 1H), δ 8.75 (s, 1H), 7.76 - 7.65 (m, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.98 (s, 1H), 4.28 - 4.15 (m, 2H), 2.75 - 2.64 (m, 2H), 1.70 - 1.63 (m, 2H),1.39 (s, 9H) 1.20 - 1.16 (m, 1H), 1.13 - 1.04 (m, 2H), 0.85 (s, 9H).

[0528] Production Example 59 Synthesis of 1-(4-(tert-butyl)cyclohexyl)-3-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)urea (Compound 59):

Chemical Structure

[0529] 0.12 g (0.16 mmol) of 1h and 12 mL of methanol were added to a reaction flask. Concentrated hydrochloric acid was added dropwise until the pH reached 1 - 2. The reaction was carried out at 45 °C for 1 hour. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.03 g of 59. Yield: 40%.

[0530] ESI-MS: m / z = 479 [M+H] + 。

[0531] Production Example 60 Synthesis of 1-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-(trifluoromethyl)phenyl)urea (Compound 60):

Chemical formula

[0532] Step 1: Synthesis of 1-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-(trifluoromethyl)phenyl)urea (3a): 0.50 g (0.92 mmol) of 1f, 20 mL of DCM, and 0.09 g (0.92 mmol) of triethylamine were added to a reaction flask. The mixture was cooled to 0 °C. A solution of 0.17 g (0.92 mmol) of 4-trifluoromethylphenyl isocyanate in 5 mL of DCM was added dropwise. After the addition was completed, the mixture was warmed to room temperature. The reaction was carried out for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 0.28 g of 3a. Yield: 42%.

[0533] Process 2: Synthesis of 1-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-(trifluoromethyl)phenyl)urea (Compound 60): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced by 3a. Yield: 71%.

[0534] ESI-MS: m / z = 485 [M+H] + 。 1 1H NMR (500 MHz, chloroform-d) δ 16.21 (s, 1H), δ 9.23 (s, 1H), 9.13 (s, 1H), 7.80 (s, 1H), 7.75 - 7.59 (m, 5H), 7.53 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.65 - 6.52 (m, 2H), 3.74 (s, 3H), 3.59 (s, 3H).

[0535] Production Example 61 Synthesis of 1-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-methylcyclohexyl)urea (Compound 61):

Chemical Structure

[0536] Step 1: Synthesis of 1-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-methylcyclohexyl)urea (4a): The synthesis was carried out according to Step 6 of Example 1, except that 4-tert-butylcyclohexylamine was replaced by 4-methylcyclohexylamine. Yield: 39%.

[0537] Process 2: Synthesis of 1-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-methylcyclohexyl)urea (61): The synthesis was carried out according to the procedure of Step 7 of Example 1, except that 1h was replaced by 4a. Yield: 53%.

[0538] ESI-MS: m / z = 437[M+H] + 。

[0539] Production Example 62 Synthesis of 1-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-((trans)-4-methylcyclohexyl)urea (Compound 62):

Chemical Structure

[0540] Step 1: Synthesis of 1-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-methylcyclohexyl)urea (5a): The synthesis was carried out according to the procedure of Step 1 of Example 60, except that 4-trifluoromethylphenyl isocyanate was replaced by trans-4-methylcyclohexyl isocyanate. Yield: 42%.

[0541] Step 2: Synthesis of 1-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-3-(4-methylcyclohexyl)urea (62): The synthesis was carried out according to the procedure of Step 7 of Example 1, except that 1h was replaced by 5a. Yield: 61%.

[0542] ESI-MS: m / z = 437[M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.26 (s, 1H), 8.50 (s, 1H), 8.16 (d, J = 2.7 Hz, 1H), 7.48 (dd, J = 9.0, 2.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 5.99 (d, J = 7.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.41 - 3.35 (m, 1H), 1.94 - 1.80 (m, 2H), 1.75 - 1.62 (m, 2H), 1.44 - 1.23 (m, 1H), 1.20 - 1.10 (m, 2H), 1.04 - 0.93 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H).

[0543] Production Example 63 Synthesis of 1-(4-(3,4-dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-methylcyclohexyl)urea (Compound 63):

Chemical formula

[0544] Step 1: Synthesis of 2-(3,4-dimethoxyphenoxy)-5-nitrobenzonitrile (9b): Synthesis was carried out according to Step 1 of Example 1 except that 7b was replaced with 9a, and the residue was recrystallized from ethyl acetate. Yield: 62%.

[0545] Step 2: Synthesis of 5-(2-(3,4-dimethoxyphenoxy)-5-nitrophenyl)-2H-tetrazole (9c): Synthesis was carried out according to Step 2 of Example 1 except that 1c was replaced with 9b. Yield: 68%.

[0546] Step 3: Synthesis of 5-(2-(3,4-dimethoxyphenoxy)-5-nitrophenyl)-2-trityl-2H-tetrazole (9d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 9c. Yield: 78%.

[0547] Step 4: Synthesis of 4-(3,4-dimethoxyphenoxy)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (9e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 9d. Yield: 73%.

[0548] Step 5: Synthesis of 5-(2-(3,4-dimethoxyphenoxy)-5-isocyanatophenyl)-2-trityl-2H-tetrazole (9f): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 9e, and the residue was used directly in the next step.

[0549] Step 6: Synthesis of 1-(4-(3,4-dimethoxyphenoxy)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-methylcyclohexyl)urea (9g): The synthesis was carried out according to Step 6 of Example 1, except that 4-tert-butylcyclohexylamine was replaced with 4-methylcyclohexylamine. Yield after two steps: 33%.

[0550] Step 7: Synthesis of 1-(4-(3,4-dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-methylcyclohexyl)urea (63): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 9g. Yield: 42%.

[0551] ESI-MS: m / z = 453 [M+H] + 。

[0552] Production Example 64 Synthesis of 1-(4-(3,4-dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (Compound 64): [Chemical]

[0553] Step 1: Synthesis of 1-(4-(3,4-dimethoxyphenoxy)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-methylcyclohexyl)urea (10a): The synthesis was carried out according to Step 1 of Example 60, except that 1f was replaced by 9e and 4-trifluoromethylphenyl isocyanate was replaced by trans-4-methylcyclohexyl isocyanate. Yield: 36%.

[0554] Step 2: Synthesis of 1-(4-(3,4-dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (64): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced by 10a. Yield: 59%.

[0555] ESI-MS: m / z = 453 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 16.26 (s, 1H), 8.50 (s, 1H), 8.16 (d, J = 2.7 Hz, 1H), 7.48 (dd, J = 9.0, 2.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 5.99 (d, J = 7.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.42 - 3.35 (m, 1H), 1.93 - 1.79 (m, 2H), 1.75 - 1.56 (m, 2H), 1.38 - 1.25 (m, 1H), 1.24 - 1.10 (m, 2H), 1.04 - 0.92 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H).

[0556] Production Example 65 Synthesis of 1-((trans)-4-(tert-butyl)cyclohexyl)-3-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-methylurea (Compound 65):

Chemical Structure

[0557] Step 1: Synthesis of 4-(tert-butyl)-N-methylcyclohexyl-1-amine (12b): 0.30 g (1.94 mmol) of 12a and 10 mL of methanol were added to a reaction flask, and then a 30% solution of 0.7 g (5.82 mmol) of methylamine in methanol was added. The reaction was carried out at room temperature for 1 hour. Then, the reaction solution was cooled to -78 °C, and 0.08 g (2.13 mmol) of sodium borohydride was added. The reaction was carried out for 1 hour while maintaining the mixture at this temperature. Then, the mixture was slowly warmed to room temperature, and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step.

[0558] Step 2: Synthesis of 3-(3’,4’-dimethoxy-2-(2-trityl-2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-methyl-1-(4-methylcyclohexyl)urea (12c): The synthesis was carried out according to Step 6 of Example 1, except that 4-tert-butylcyclohexylamine was replaced with 12b. Yield after two steps: 29%.

[0559] Step 3: Synthesis of 1-((trans)-4-(tert-butyl)cyclohexyl)-3-(3’,4’-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)-1-methylurea (65): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 12c. Yield: 54%.

[0560] ESI-MS: m / z = 493 [M+H]+ . 1 1H NMR (500 MHz, DMSO-d6) δ 16.14 (s, 1H), 8.51 (s, 1H), 7.83 - 7.74 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.61 - 6.54 (m, 2H), 4.01 - 3.92 (m, 1H), 3.74 (s, 3H), 3.59 (s, 3H), 2.82 (s, 3H), 1.81 (d, J = 12.5 Hz, 2H), 1.72 - 1.61 (m, 2H), 1.54 - 1.41 (m, 2H), 1.16 - 1.07 (m, 2H), 1.04 - 0.95 (m, 1H), 0.86 (s, 9H).

[0561] Production Example 66. Synthesis of 1-(4-(3,6-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (Compound 66): [Chemical formula]

[0562] Step 1: Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrobenzonitrile (17b): 1.00 g (4.40 mmol) of 1a, 1.23 g (4.62 mmol) of 17b, 1.21 g (8.81 mmol) of potassium carbonate, 0.16 mg (0.22 mmol) of Pd(dppf)Cl2, 30 mL of 1,4-dioxane, and 7 mL of water were added to a reaction flask. The reaction was carried out at 90 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature. Then, the obtained mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1, volume / volume) to obtain 0.93 g of 17b. Yield: 92%.

[0563] Step 2: Synthesis of 5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl)-2H-tetrazole (17c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 17b. Yield: 85%.

[0564] Step 3: Synthesis of 5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl)-2-trityl-2H-tetrazole (17d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 17c. Yield: 67%.

[0565] Step 4: Synthesis of 4-(3,6-dihydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (17e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 17d. Yield: 74%.

[0566] Step 5: Synthesis of 1-(4-(3,6-dihydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-methylcyclohexyl)urea (17f): The synthesis was carried out according to Step 1 of Example 60, except that 1f was replaced with 17e and 4-trifluoromethylphenyl isocyanate was replaced with 4-methylcyclohexyl isocyanate. Yield after two steps: 43%.

[0567] Step 6: Synthesis of 1-(4-(3,6-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (66): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 17f. Yield: 46%.

[0568] ESI-MS: m / z = 383 [M+H] + 。 11H NMR (500 MHz, chloroform-d) δ 16.41 (s, 1H), 8.55 (s, 1H), 7.68 (s, 1H), 7.48 (dd, J = 8.5, 2.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.10 (d, J = 7.8 Hz, 1H), 5.36 (s, 1H), 4.00 (d, J = 2.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.36 - 3.34 (m, 1H), 2.04 - 1.99 (m, 2H), 1.90 - 1.82 (m, 2H), 1.70 - 1.61 (m, 2H), 1.36 - 1.25 (m, 1H), 1.16 - 1.07 (m, 2H), 1.03 - 0.92 (m, 2H), 0.86 (d, J = 6.5 Hz, 3H).

[0569] Production Example 67 Synthesis of 1-((cis)-4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea (Compound 67):

Chemical Structure

[0570] Step 1: Synthesis of 1-(4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)urea (18a): 0.10 g (0.19 mmol) of 17f was dissolved in 3 mL of methanol. The reaction was carried out at room temperature for 5 hours under a hydrogen pressure of 1 MPa. After the reaction was completed, Pd / C was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 18a, and the residue was purified by silica gel column chromatography to obtain 18a. Yield: 88%.

[0571] Process 2: Synthesis of 1-((cis)-4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea (67): The synthesis method of 67 was the same as that of 1 except that 1h was replaced by 18a. Yield: 65%.

[0572] ESI-MS: m / z = 385 [M+H] + 。

[0573] Production Example 68 Synthesis of 1-((trans)-4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea (Compound 68):

Chemical Structure

[0574] Process 1: Synthesis of 5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-isocyanatophenyl)-2-trityl-2H-tetrazole (20a): 100 mg (0.20 mmol) of 17e, 31 mg (0.10 mmol) of triphosgene, and 10 mL of anhydrous toluene were added to a reaction flask. The reaction was carried out under reflux for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 20a, which was used directly in the next step.

[0575] Step 2: Synthesis of 1-(4-(3,6-dihydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-methylcyclohexyl)urea (20b): 23 mg (0.20 mmol) of trans-p-methylcyclohexylamine, 5 mL of DCM, and 21 mg (0.20 mmol) of triethylamine were added to a reaction flask. The mixture was cooled to 0 °C. Then, a solution of 20a in DCM (1 mL) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and the reaction was carried out for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 65 mg of 20b. Yield through two steps: 41%.

[0576] Step 3: Synthesis of 1-(4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)urea (20c): The synthetic method of 20c was the same as that of 18a except that 17f was replaced with 20b. Yield: 83%.

[0577] Step 4: Synthesis of 1-((trans)-4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea (68): The synthetic method of 68 was the same as that of 1 except that 1h was replaced with 20c. Yield: 63%.

[0578] ESI-MS: m / z = 385 [M+H] + 。 11H NMR (600 MHz, DMSO-d6) δ 16.51 (s, 1H), δ 8.45 (s, 1H), 7.64 (s, 1H), 7.47 (dd, J = 8.6, 2.4 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.07 (d, J = 7.8 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.40 - 3.34 (m, 1H), 3.31 - 3.25 (m, 2H), 3.10 - 2.94 (m, 1H), 1.90 - 1.81 (m, 2H), 1.71 - 1.62 (m, 4H), 1.61 - 1.53 (m, 2H), 1.37 - 1.28 (m, 1H), 1.20 - 1.09 (m, 2H), 1.05 - 0.93 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H).

[0579] Production Example 69 Synthesis of 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (Compound 69): [Chemical formula]

[0580] Step 1: Synthesis of 2-(benzo[d][1,3]dioxolan-5-yl)-5-nitrobenzonitrile (21b): 1.00 g (4.41 mmol) of 1a, 0.88 g (5.29 mmol) of 21a, 0.05 g (0.22 mmol) of palladium acetate, 30 mL of DMF, and 1.21 g (8.81 mmol) of an aqueous solution of potassium carbonate in 6 mL were added to a reaction flask. The reaction was carried out at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.04 g of 21b. Yield: 88%.

[0581] Step 2: Synthesis of 5-(2-(benzo[d][1,3]dioxolan-5-yl)-5-nitrophenyl)-2H-tetrazole (21c): The synthesis was carried out according to Step 2 of Example 1, except that 17b was replaced with 21b. Yield: 72%.

[0582] Step 3: Synthesis of 5-(2-(benzo[d][1,3]dioxolan-5-yl)-5-nitrophenyl)-2-trityl-2H-tetrazole (21d): The synthesis was carried out according to Step 3 of Example 1, except that 17c was replaced with 21c. Yield: 79%.

[0583] Step 4: Synthesis of 4-(benzo[d][1,3]dioxolan-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (21e): The synthesis was carried out according to Step 4 of Example 1, except that 17d was replaced with 21d. Yield: 85%.

[0584] Step 5: Synthesis of 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-methylcyclohexyl)urea (21f): The synthesis was carried out according to Step 1 of Example 60, except that 17e was replaced with 21e. Yield after two steps: 42%.

[0585] Step 6: Synthesis of 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (69): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 21f. Yield: 61%.

[0586] ESI-MS: m / z = 421 [M+H] + 。 11H NMR (500 MHz, chloroform-d) δ 16.23 (s, 1H), 8.62 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 8.4, 2.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 6.48 - 6.37 (m, 1H), 6.14 (d, J = 7.8 Hz, 1H), 6.01 (s, 2H), 3.47 - 3.36 (m, 1H), 1.94 - 1.78 (m, 2H), 1.73 - 1.60 (m, 2H), 1.40 - 1.24 (m, 1H), 1.23 - 1.08 (m, 2H), 1.06 - 0.92 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H).

[0587] Production Example 70 Synthesis of 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-(tert-butyl)cyclohexyl)urea (Compound 70):

Chemical Structure

[0588] Step 1: Synthesis of 5-(2-(benzo[d][1,3]dioxolan-5-yl)-5-isocyanatophenyl)-2-trityl-2H-tetrazole (22a): The synthesis was carried out according to Step 5 of Example 1, except that 17e was replaced with 21e, and the residue was used directly in the next step.

[0589] Step 2: Synthesis of 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-(tert-butyl)cyclohexyl)urea (22b): The synthesis was carried out according to Step 6 of Example 1, except that 20a was replaced with 22a and trans-4-methylcyclohexylamine was replaced with 4-tert-butylcyclohexylamine. Yield after two steps: 52%.

[0590] Step 3: Synthesis of 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-(tert-butyl)cyclohexyl)urea (70): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 22b. Yield: 75%.

[0591] ESI-MS: m / z = 463 [M+H] + 。

[0592] Production Example 71 Synthesis of 1-(4-(6-ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (Compound 71):

Chemical Structure

[0593] Step 1: Synthesis of 2-(6-ethoxypyrid-3-yl)-5-nitrobenzonitrile (24b): The synthesis was carried out according to Step 1 of Example 1, except that 1b was replaced with 24a. Yield: 81%.

[0594] Step 2: Synthesis of 2-ethoxy-5-(4-nitro-2-(2H-tetrazol-5-yl)phenyl)pyridine (24c): The synthesis was carried out according to Step 2 of Example 1, except that 1c was replaced with 24b. Yield: 58%.

[0595] Step 3: Synthesis of 3:2-ethoxy-5-(4-nitro-2-(2-trityl-2H-tetrazol-5-yl)phenyl)pyridine (24d): The synthesis was carried out according to Step 3 of Example 1, except that 1d was replaced with 24c. Yield: 75%.

[0596] Step 4: Synthesis of 4-(6-ethoxypyrid-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (24e): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 24d. Yield: 87%.

[0597] Step 5: Synthesis of 1-(4-(6-ethoxypyrid-3-yl)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)-3-(4-methylcyclohexyl)urea (24f): The synthesis was carried out according to Step 1 of Example 60, except that 1f was replaced with 24e. Yield: 46%.

[0598] Step 6: Synthesis of 1-(4-(6-ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea (71): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 24f. Yield: 47%.

[0599] ESI-MS: m / z = 422 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 16.41 (s, 1H), 8.66 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.5, 2.4 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.6 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.16 (d, J = 7.7 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.45 - 3.36 (m, 1H), 1.93 - 1.83 (m, 2H), 1.71 - 1.64 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.22 - 1.09 (m, 2H), 1.07 - 0.93 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H).

[0600] Production Example 72 Synthesis of 1-(cis)-4-methylcyclohexyl-3-(4-(tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea (Compound 72): [Chemical formula]

[0601] Step 1: Synthesis of 5-nitro-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (7c): 1.00 g (9.79 mmol) of tetrahydro-2H-pyran-4-ol and 20 mL of anhydrous DMF were added to a reaction flask. After cooling the mixture to 0 °C, 0.47 g (11.75 mmol) of 60% sodium hydride was added. The mixture was maintained at this temperature and the reaction was carried out for 0.5 h. Then, 1.79 g (10.77 mmol) of 2-fluoro-5-nitrobenzonitrile was added. After the addition was complete, the mixture was warmed to room temperature. The reaction was carried out for 1 h. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1, volume / volume) to obtain 1.92 g of 7c. Yield: 79%.

[0602] Step 2: Synthesis of 5-(5-nitro-2-(((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2H-tetrazole (7d): 0.50 g (2.01 mmol) of 7c, 0.39 g (6.03 mmol) of sodium azide, 0.83 g (6.03 mmol) of triethylamine hydrochloride, and 15 mL of anhydrous toluene were added to a reaction flask. The reaction was carried out at 100 °C for 12 h. After the reaction was complete, the mixture was diluted with water, acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.46 g of 7d. Yield: 79%.

[0603] Step 3: Synthesis of 5-(5-nitro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-trityl-2H-tetrazole (7e): The synthesis was carried out according to the procedure of Step 3 of Example 1, except that 1d was replaced with 7d. Yield: 65%.

[0604] Step 4: Synthesis of 4-((tetrahydro-2H-pyran-4-yl)oxy)-3-(2-trityl-2H-tetrazol-5-yl)phenylamine (7f): The synthesis was carried out according to Step 4 of Example 1, except that 1e was replaced with 7e. Yield: 95%.

[0605] Step 5: Synthesis of 5-(5-isocyanato-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-trityl-2H-tetrazole (7g): The synthesis was carried out according to Step 5 of Example 1, except that 1f was replaced with 7f, and the residue was used directly in the next step.

[0606] Step 6: Synthesis of 1-(4-methylcyclohexyl)-3-(4-((tetrahydro-2H-pyran-4-yl)oxy)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)urea (7h): The synthesis was carried out according to Step 6 of Example 1, except that 1g was replaced with 7g. Yield after two steps: 36%.

[0607] Step 7: Synthesis of 1-(cis)-4-methylcyclohexyl-3-(4-(tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea (72): The synthesis was carried out according to Step 7 of Example 1, except that 1h was replaced with 7h. Yield: 50%.

[0608] ESI-MS: m / z = 401[M+H] + 。

[0609] Production Example 73 Synthesis of 1-(trans)-4-methylcyclohexyl-3-(4-tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea (Compound 73):

Chemical Structure

[0610] Step 1: Synthesis of 1-(4-Methylcyclohexyl)-3-(4-((tetrahydro-2H-pyran-4-yl)oxy)-3-(2-trityl-2H-tetrazol-5-yl)phenyl)urea (8a): The synthesis was carried out according to the procedure of Step 1 in Example 60, except that 4-trifluoromethylphenyl isocyanate was replaced with trans-4-methylcyclohexyl isocyanate and 1f was replaced with 7f. Yield: 44%.

[0611] Step 2: Synthesis of 1-(trans)-4-Methylcyclohexyl-3-(4-tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea (73): The synthesis was carried out according to the procedure of Step 7 in Example 1, except that 1h was replaced with 8a. Yield: 58%.

[0612] ESI-MS: m / z = 401[M+H] + 。 1 H NMR (500 MHz, chloroform-d) δ 15.87 (s, 1H), 8.36 (s, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.52 (dd, J = 9.0, 2.8 Hz, 1H), 7.23 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 7.8 Hz, 1H), 4.70 - 4.43 (m, 1H), 3.87 - 3.59 (m, 2H), 3.44 - 3.37 (m, 2H), 3.37 - 3.34 (m, 1H), 2.03 - 1.80 (m, 4H), 1.79 - 1.58 (m, 4H), 1.43 - 1.24 (m, 1H), 1.20 - 1.07 (m, 2H), 1.03 - 0.91 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H).

[0613] Biological Evaluation Test Example 1. FLIPR Assay for Inhibitory Activity against Human B1R and Human B2R The inhibitory activities of the compounds against the human B1R channel and the human B2R channel were determined by a calcium ion flux assay (FLIPR method) using a fluorescence imaging plate reader. For the method, see the literature of Lee, Chen et al. [Lee et al. 2008][Chen et al. 2011].

[0614] 1. Cell culture: HEK293 recombinant cell lines (WuXi AppTec, Shanghai, China) stably expressing human B1R and human B2R were cultured in DMEM (Invitrogen, catalog number 11965) medium containing 10% fetal bovine serum (Excellbio, catalog number FSP500), 5 μg / ml geneticin (Invitrogen, catalog number 10131), and penicillin / streptomycin (Invitrogen, catalog number 15140). The incubator conditions were 37 °C and ambient humidity with 5% CO2.

[0615] 2. Preparation of cell assay plates: B1R cells and B2R cells were seeded in a 384-well assay plate (Greiner, catalog number 781090) at a density of 20,000 cells per well (20 μl per well) and cultured overnight at 37 °C in an incubator containing 5% CO2. The next day, Fluo-4 Direct (trademark) loading buffer containing 2×(8 μM) Fluo-4 Direct (Invitrogen, catalog number F10471) (containing 5 mM probenecid) was added to each well. The cells were cultured at 37 °C for 50 minutes and then at room temperature for 10 minutes.

[0616] 3. Preparation of Compound Assay Plates: Compounds were dissolved in 100% DMSO to make 30 mM stock solutions, which were stored at -20 °C. On the day of use, the compound stock solutions were thawed at room temperature. Each compound was serially diluted 1:5 (in DMSO culture medium) at an initial concentration of 30 μM over nine concentration points on a 384-well plate. Each compound was diluted in duplicate for each test. [Des-Arg10]-HOE140 was used as a positive control compound and was diluted in the same manner at an initial concentration of 3 μM.

[0617] 4. FLIPR Assay: The cell assay plates were placed in a FLIPR instrument (Molecular Probes). The compounds in the compound assay plates were added to the corresponding wells (10 μL per well) on the cell assay plates using an automated program. To determine whether the compounds could have agonist activity, the fluorescence signal of calcium ions was recorded. After 10 minutes, the B1R agonist [Lys-des-Arg9]-bradykinin 2 (10 μL per well) with a final concentration of 4.6 nM (EC80) was added to each well to stimulate the generation of intracellular calcium ion flux signals. Ca ++ The Ca-dependent fluorescence signal was continuously monitored at a wavelength of 538 nm to analyze the inhibitory activity of the compounds.

[0618] 5. Data Analysis: The data were collected and analyzed by the FLIPR program. The inhibitory (or agonist) activity of the compounds at each concentration was evaluated by fluorescence peaks. The IC 50 values of the compounds were calculated using EXCEL and PRISM programs.

[0619] 6. Test Results: The inhibitory activities (FLIPR method) of the compounds of Examples 1 to 73 of the present invention against B1R are shown in Table 1.

[0620] TIFF2025519544000106.tif135170

[0621] From the data in the above table, it can be confirmed that the compounds of Examples 1 to 73 (Table 1) have inhibitory activity against B1R. In contrast, these compounds have low inhibitory activity against B2R, with an IC 50 > 30000 nM (FLIPR method). Therefore, it can be shown that all of these compounds have good selectivity for B1R.

[0622] Furthermore, in the present invention, it has been demonstrated for the first time that the stereochemical configuration of cyclohexylurea included in the scope of formula Ib also has a certain effect on B1 antagonist activity. For example, in the case of Compound 61 and Compound 62, the activity of the trans-configured Compound 62 is higher than that of the cis-configured Compound 61.

[0623] Test Example 2. In Vivo Pharmacokinetics and In Vitro Hepatic Microsome Metabolism in Rats 1. Administration to animals: SD rats were used, and the compounds were administered by intravenous injection (3 mg / kg) or oral administration (30 mg / kg). Blood samples were collected in EDTA blood sample collection tubes at various time points after administration. Plasma was separated by centrifugation and stored at -20 °C for subsequent analysis.

[0624] 2. Handling of blood samples and LC-MS / MS analysis: Preparation and treatment of standard curves and quality control samples: The stock solutions of the compounds were diluted with an aqueous methanol solution of 50% to form standard curve working solutions containing each compound at concentrations of 40 ng / mL to 20,000 ng / mL, and quality control working solutions of 120 ng / mL, 1200 ng / mL, and 16,000 ng / mL. 47.5 μL of blank rat plasma was collected respectively and added into 2.50 μL of the standard curve working solution or quality control working solution to formulate standard curve samples containing the compounds at concentrations of 2.00 ng / mL to 1000.00 ng / mL, and quality control samples with concentrations of 6.00 ng / mL, 600.00 ng / mL, and 800.00 ng / mL. 400 μL of acetonitrile (containing 5 ng / mL of verapamil as an internal standard) was added respectively. The samples were vortexed for 3 minutes and centrifuged at 20,000 rcf at 4°C for 15 minutes. The supernatant was collected for LC-MS / MS analysis.

[0625] 3. Compound treatment of blood samples: 5 μL of plasma samples were collected, 95 μL of blank rat plasma was added thereto, and 800 μL of acetonitrile (containing 5 ng / mL of verapamil as an internal standard) was added. The samples were vortexed for 3 minutes and centrifuged at 15,000 rcf at 4°C for 10 minutes. The supernatant was collected for LC-MS / MS analysis (chromatographic column: ACQUITY UPLC (trademark) BEH C18 (2.1×50 mm 1.7 μm), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 0.35 mL / min).

[0626] 4. Analysis of results: Pharmacokinetic parameters, mainly including kinetic parameters such as Tmax, t 1 / 2 , Cmax, AUC0-t, AUC0-∞, Cl, Vd, F, etc., were fitted and calculated using the statistical matrix method by WinNonlin software. Pharmacokinetic data such as the mean and standard deviation were calculated and processed using Microsoft Excel. The results are shown in Table 2A.

[0627] Furthermore, the LC-MS / MS method was used to determine the substrate metabolites of five major subtypes of human liver microsomal CYP450 enzymes (including CYP1A2, CYP2D6, CYP2C8, CYP2C9, and CYP3A4). The substrate method was used to determine the activity of human liver microsomal CYP450 enzymes. The established incubation system was verified using known inhibitors to investigate the inhibitory effect of the compound on CYP450 enzymes. For the enzyme induction test, a primary cultured human hepatocyte incubation system was used. 3-Methylcholanthrene, phenobarbital, and rifampicin were used as positive control inducers for CYP1A2, CYP2B6, and CYP3A4, and phenacetin, bupropion, and testosterone were used as substrates for CYP1A2, CYP2B6, and CYP3A4. The CYP450 enzyme activity was calculated by measuring the production rates of three specific substrate metabolites in the incubation solution. On the other hand, total RNA was extracted from human hepatocytes after incubation, and real-time fluorescence quantitative PCR was used to determine the mRNA expression levels of CYP1A2, CYP2B6, and CYP3A4. Using enzyme activity and mRNA transcription levels as endpoints, the induction effect of the compound on CYP1A2, CYP2B6, and CYP3A4 of human liver P450 isoenzymes was investigated. Taking Compound 8 as an example, the in vitro liver microsomal metabolism parameters are shown in Table 2B.

[0628] TIFF2025519544000107.tif81170

[0629] TIFF2025519544000108.tif41170

[0630] Test Example 3. Effect of the Compound in a Rat Model of Acute Lung Injury 1. Experimental Animals: SPF-grade male Wistar rats weighing 180 g to 220 g and 6 to 8 weeks old.

[0631] 2. Drugs and reagents: LPS (0000120154, SIGMA), dexamethasone (WXBD5583V, SIGMA), Compound 71, Compound 8, Evans blue: (C2130098, Aladdin).

[0632] 3. Establishment of animal model: Rats were adaptively fed for one week. After the animals were anesthetized, 3 mg / kg of LPS (B8) was injected intratracheally to prepare a rat model of acute lung injury.

[0633] 4. Animal grouping and administration: The animals were randomly divided into six groups (12 rats per group): a negative control group (LPS replaced with physiological saline), a model control group, a positive control group (sodium dexamethasone phosphate injection, 5 mg / ml), a Compound 71 group, and a Compound 8 group. Two hours before modeling (before intratracheal injection of LPS), the test drug (30 mg / kg, vehicle was 0.3% DMSO in saline) was injected intraperitoneally. One hour after modeling, the test drug was administered again (at the same dose). The animals were sacrificed 12 hours after modeling, and samples were collected for testing various indicators.

[0634] 5. Experimental methods 5.1 Test for pulmonary vascular permeability: Five animals were randomly assigned to each group. Thirty minutes before sacrificing the animals, Evans blue (20 mg / kg) was injected via the tail vein. Thirty minutes after the injection, the animals were sacrificed immediately. 10 mL of cold PBS was perfused into the heart to wash out the blood in the pulmonary vessels. The upper lobe of the left lung was weighed. The lung tissue was minced and added to formamide at 3 mL per 100 mg of lung tissue and incubated at 37°C for 24 hours. The absorbance was measured at 620 nm using a microplate reader. On the other hand, solutions of Evans blue in formamide at various concentrations were prepared to create a standard curve. The content of Evans blue in the lung tissue was calculated.

[0635] 5.2 ELISA method: Five rats per group. Serum, bronchoalveolar lavage fluid, and tissue homogenates from one lung of each rat were subjected to ELISA assay to determine the levels of TNF-α and IL-6.

[0636] 6. Experimental results 6.1 Vascular permeability in the rat model: From the results of the vascular permeability test, it can be confirmed that the vascular permeability increased rapidly in the model group. When the model group was used as the control group, the vascular permeability was significantly decreased in both the test drug group and the positive control group of dexamethasone, as shown in Table 3 and Figure 1.

[0637] TIFF2025519544000109.tif60170

[0638] 6.2 Expression levels of IL-6 and TNF-α in the rat model: TNF-α and IL-6, as representative inflammatory factors, were measured by ELISA to observe the degree of systemic inflammatory response (in serum) and the degree of local inflammatory response in lung tissue. From the results, as shown in Table 4, Figure 2, Table 6, and Figure 3, it can be confirmed that Compounds 8 and 71 can effectively reduce the expression levels of IL-6 and TNF-α, indicating that they are effective in controlling the inflammatory response.

[0639] TIFF2025519544000110.tif81170

[0640] TIFF2025519544000111.tif86170

[0641] The above data support that the test compound can significantly improve the increase in LPS-induced vascular permeability in rats and reduce the levels of IL-6 and TNF-α in blood, bronchoalveolar fluid, and lung tissue, thereby confirming the therapeutic effect of the B1R inhibitor in acute pulmonary edema.

[0642] Test Example 4. Effects of compounds in a rat model of diabetic retinopathy 1. Analysis of Drug Concentration in Rat Retina after Intravitreal Injection of Compounds 1.1 Experimental Animals: Male Wistar rats of SPF grade weighing 180 g to 220 g.

[0643] 1.2 Drugs and Reagents: Compound 71, Sodium Chloride Injection (Shandong Qidu Pharmaceutical Co., Ltd., batch number: 3B151014124), Acetonitrile (chromatography purity, TEDIA, USA), Methanol (chromatography purity, product of SIGMA-ALDRICH), Triethylamine (analytical purity, Hangzhou Gaojing Fine Chemical Co., Ltd.).

[0644] 1.3 Grouping and Administration of Experiments: According to the sampling time, 33 male Wistar rats were divided into 11 groups: (1) control group, (2) 0 hour, (3) 2 hours, (4) 6 hours, (5) 24 hours, (6) 48 hours, (7) 72 hours, (8) 5 days, (9) 7 days, (10) 10 days, (11) 14 days (3 rats in each group). Solvent (sterile physiological saline) was intravitreally injected into 3 rats in the control group, and Compound 71 was intravitreally injected into the remaining 30 rats at a concentration of 0.5% using a 5 μL microinjector, with 5 μL of drug injected per eyeball.

[0645] 1.4 Sampling of Samples and Detection Indicators: The retinas of rats in the control group were sampled on the 14th day (14 days), and the retinas of the remaining 30 rats were sampled at the corresponding time points. After freezing the retinas in liquid nitrogen, subsequent HPLC detection was performed.

[0646] 1.5 HPLC Detection Method: 1.5.1 Chromatography Conditions: The mobile phase was chromatographic grade acetonitrile - water = 25 - 75 (volume / volume). The flow rate was 0.5 mL / min. The column temperature was 25°C. The UV detection wavelength was 254 nm. The injection volume was 20 μL.

[0647] 1.5.2 Sample treatment and preparation: The rat retina samples were taken out from an ultra-low temperature (-80 °C) refrigerator, accurately weighed, put into a glass homogenizer, and ethyl acetate as a pre-cooled organic solvent in a 4 °C refrigerator was added at a ratio of 100 mL / g. The homogenizer was placed in an ice bath for homogenization. After homogenization, all the homogenates were poured into 5 mL screw-capped centrifuge tubes. Centrifugation was carried out at a low temperature of 4 °C for 5 minutes (5000 revolutions per minute). All of the organic phase as the upper layer was accurately taken out and put into a glass tube with a conical bottom. The remaining residue of the retina was extracted repeatedly once with 2 mL of ethyl acetate. After centrifugation, the two organic phases were combined. Then, the centrifuge tube with a conical bottom was dried by blowing in a nitrogen stream in a 45 °C water bath. The residue was redissolved with 0.1 mL of methanol for chromatography, vortex mixed for 1 minute, and centrifuged at a high speed of 18000 revolutions per minute for 5 minutes. 20 μL of the supernatant was collected and analyzed in a high performance liquid chromatography system.

[0648] 1.5.3 Sample measurement: After 5 μL of 0.5% compound 71 was injected intravitreally, the retinas were collected at various time points to analyze the drug content of the test compound in the retina.

[0649] 1.5.4 Experimental results and conclusions: According to the retinal drug concentration-time curve, this is consistent with a non-absorptive two-compartment model. According to the non-absorptive two-compartment model theory of pharmacokinetics, the pharmacokinetic parameters of the drug were calculated. The results are shown in Table 6.

[0650] TIFF2025519544000112.tif29170

[0651] After intravitreally injecting 0.5% compound 71 (5 μL per eye) into rats on the 7th day, the retinal drug concentration of compound 2 was 1.54 μM on the 7th day, which was 23 times higher than its IC 50 value. On the 14th day, the retinal concentration was 1.24 μM, which was its IC 50It was 19 times higher than the value. Therefore, the pharmacokinetic parameters for Compound 71 in the eye can meet the preliminary requirements for long-term efficacy in the case of administration by intraocular injection.

[0652] 2. Analysis of Intraocular Drug Concentration and Retinal Drug Concentration in Rats after Administration of Compounds by Eye Drops 2.1 Experimental animals: SPF-grade male SD rats weighing 180 g to 200 g were used and fed adaptively for one week.

[0653] 2.2 Drugs and reagents: Compound 71 and Compound 8, sodium chloride injection (Guangxi Yuyuan Pharmaceutical Co., Ltd.), sterilizing filter (Millex) with a pore size of 0.22 μm.

[0654] 2.3 Grouping of experimental animals: The animals were randomly divided into three groups (6 rats per group): a negative control group (physiological saline), a Compound 71 group, and a Compound 8 group.

[0655] 2.4 Administration method and sample collection: 2% compound (10 μl) dissolved in physiological saline (after filtration) was dropped onto the surface of each rat's eye for 10 seconds using a pipette. The eye drops were applied twice a day for a total of 7 days. Samples were collected 1 hour and 16 hours after the second administration on the 7th day of administration to determine the intraocular distribution concentration of the drug.

[0656] 2.5 Detection of porphyrin secretion: 16 hours after the second administration on the 7th day of administration to the rats, before sacrificing the rats, the eyes were rinsed with physiological saline using a pipette. The rinsing solution was frozen at -80°C, and subsequently, the irritant inflammatory response on the surface of the eyeball was detected.

[0657] 2.6 Measurement of drug content in eye tissues by HPLC: Batch of the first sample: 1 hour after the second eye drop on the 7th day: Three rats (two males and one female) were selected from each group. The eyeballs were removed and carefully rinsed three times with physiological saline using a pipette. The washing solution was quickly dried with qualitative filter paper. The cornea, vitreous body, and retina were separated under a stereomicroscope and then frozen at -80 °C for subsequent measurement.

[0658] Batch of the second sample: In the morning of the 8th day, that is, 16 hours after the second eye drop on the 7th day: The remaining three rats (one male and two females) were selected from each group. The eyeballs were removed and carefully rinsed three times with physiological saline using a pipette. The washing solution was quickly dried with qualitative filter paper. The cornea, vitreous body, and retina were separated under a stereomicroscope and then frozen at -80 °C for subsequent detection.

[0659] 2.7 Experimental Results and Conclusions 2.7.1 Ophthalmological Observation of Animals: After eye drops, no abnormalities were shown in the eyes of rats in the negative control group and the test compound group, and no redness, swelling, congestion, etc. were shown.

[0660] 2.7.2 Measurement Results of Porphyrin Secretion: The ELISA assay of free protoporphyrin (FEP) in red blood cells was used to further determine whether inflammation or bleeding occurred in the eyes after eye drops. As the results showed, the level of FEP in the samples of eye washings was at a low concentration level for both the rats in the test drug group and the negative control group. No significant difference was found (P>0.05). The results are shown in Table 7.

[0661] TIFF2025519544000113.tif39170

[0662] 2.7.3 Results of HPLC measurement of drug content in eye tissues: Under the chromatographic conditions selected for analysis, drug impurities were sufficiently separated. Chromatograms of samples of the standard solution, samples of the blank homogenate, samples of the blank homogenate added with Compound 71 or Compound 8, and samples of the retinal homogenate were compared. As a result of the comparison, it was revealed that no interference peaks occurred at the corresponding retention times of the drug. Under the selected HPLC measurement conditions, the average recovery rates for both of the two compounds under test exceeded 90%. Since both the within-day coefficient of variation and the between-day coefficient of variation were less than 10%, this indicates that test drugs such as Compound 71 and Compound 8 under test have good recovery rates in the retinal homogenate. This accuracy can meet the measurement criteria. As shown by the accuracy results, the accuracy in all cases of quality control (QC) samples spiked into the retina at high, medium, and low concentrations within the drug curve range was higher than 95%. After sample collection, the drug content in the eye tissues was measured by HPLC, and the results are shown in Table 8 and Figure 4.

[0663] TIFF2025519544000114.tif58170

[0664] As shown by the results, the content of the test compound was highest in the cornea, followed by the retina, and lowest in the vitreous. On the other hand, the content of Compound 71 and Compound 8 in these three tissues 16 hours after administration was significantly lower than that 1 hour after administration.

[0665] 2.7.4 Conclusion: The test compound showed good safety without obvious ocular irritation when administered via eye drops. On the other hand, from the test results of this experiment, the compound of the present invention entered the eye through the eye drops, reached the expected site of action in the retina, and the level of the compound measured after 16 hours of persistence was much higher than its effective concentration (IC 50 ). It was confirmed from the test results that this compound may exhibit a therapeutic effect when administered via eye drops.

[0666] 3. Effects of the compound in a rat model of diabetic retinopathy 3.1 Experimental animals: SPF-grade male Wistar rats weighing 180 g to 220 g.

[0667] 3.2 Drugs and reagents: Test compounds include Compound 65, Compound 71, Compound 8, and Compound 11; STZ (MACKLIN, Catalog number: S817944), Dexamethasone (MACKLIN, Catalog number: D829854), Evans blue: aladdin (Catalog number E104208), Concanavalin A / FITC (SIGMA, Catalog number: C7642), Albumin (SIGMA, Catalog number: A6414), Hematoxylin (Sigma, Catalog number: H9627), Eosin (Sigma, Catalog number: E6003), RNA rapid extraction kit (Generay, Catalog number: GK3016), Reverse transcription kit HiScript-II Q RT SuperMix for qPCR (Vazyme, Catalog number: R222-01), qPCR reagent ChamQ SYBR Color qPCR Master Mix (Vazyme, Catalog number: Q411-02); Experimental primers were synthesized and purified by Shanghai Sunny Biotechnology Co., Ltd., and the remaining reagents were domestic analytical reagents.

[0668] 3.3 Animal model and grouping: After one week of adaptive feeding, 134 male Wistar rats (weighing 220 g to 260 g) were administered 65 mg / kg of STZ by a single intraperitoneal injection to establish a rat model of type I diabetes. The rats were fasted, but water was allowed ad libitum for 15 hours at night. The formulated STZ solution was injected intraperitoneally according to body weight. One hour later, feeding was resumed, and blood glucose was measured at 72 hours. Diabetic rats that successfully modeled (120 rats) were selected to continue feeding and randomly divided into the following 6 groups (20 rats per group) according to blood glucose, and a group of normal rats not injected with STZ was used as the negative control group. See Table 9.

[0669] TIFF2025519544000115.tif53170

[0670] 3.4 Administration: The rats were continuously fed, and their blood glucose was measured once before administration. After the blood glucose reached the standard, the drug was injected into the vitreous body, and the indicators were tested 14 days later. The blood glucose was measured once before sample collection.

[0671] 3.5 Evans blue staining method (7 groups, 6 rats per group): Evans blue was injected intravenously. Two hours later, physiological saline was perfused into the left ventricle. The retina was collected, and the vascular permeability of the retina was examined by comparing the stained area with the non-stained area.

[0672] 3.6 Retinal leukocyte stasis detection method (7 groups, 6 rats per group): PBS was perfused into the left ventricle for 1 minute to remove red blood cells and other substances. Concanavalin A (FITC (Sigma, C7642)) was perfused (20 μg / ml in PBS, 5 mg / kg) to label adherent leukocytes. 4% PFA was perfused for 4 minutes for fixation. 1% albumin (Sigma, A6414) (in PBS) was perfused for 1 minute, and then PBS was perfused for 2 minutes. The retina was collected for whole-mounted specimens. Subsequently, the stasis of leukocytes on the vascular endothelium was observed under a fluorescence microscope.

[0673] 3.7 qPCR method (7 groups, 6 rats per group): The retina of the left eye was separated. Total RNA was extracted and reverse-transcribed into cDNA. qPCR was used to examine the levels of B1R, COX-2, VEGF-A, VEGF receptor type 2, IL-1b, and iNOS.

[0674] 3.8 Experimental results and conclusions 3.8.1 Observation of animals and measurement of blood glucose: After STZ administration, the blood glucose of all experimental animals increased significantly and remained at a stable high level until the retina was removed for sample collection. As shown in Table 10 and Table 11, it was found that the establishment of the diabetic rat model was successful.

[0675] TIFF2025519544000116.tif85170

[0676] TIFF2025519544000117.tif79170

[0677] Blood glucose was measured on the third day after STZ injection. This blood glucose level was significantly higher than that of the animals not injected with STZ. After confirming the successful establishment of the diabetes model, feeding of the animals was continued. After 8 weeks of feeding, the rats in the normal group had a transparent lens, clear fundus, etc., and no bleeding or leakage was observed. In the model group, conditions such as posterior subcapsular opacity and anterior subcapsular opacity of the lens were occasionally observed. Most rats showed no obvious external pathological changes. As a result of blood glucose tests before sample collection after administration, the blood glucose concentrations in each of the administration group and the model group were significantly higher than that in the control group, and no significant difference was found compared with that before administration.

[0678] 3.8.2 Evans blue staining: As shown in Table 12 and Figure 5, the negative control group had almost no permeability, and the retinal permeability of the rats in the model group was significantly increased compared with that of the negative control group. Based on this, injection of dexamethasone as a positive drug or the drug to be tested can reduce the permeability in model rats, and dexamethasone as a positive drug has the most significant effect.

[0679] TIFF2025519544000118.tif81170

[0680] Furthermore, as shown in the fluorescence staining results in Figure 6, almost no vascular permeability was observed in the retinas of the rats in the negative control group. Compared with the negative control group, the retinal vascular permeability in the rats in the model group was significantly increased. Based on this, intravitreal injection of dexamethasone, or Compound 65, Compound 71, Compound 8, or Compound 11 significantly decreased the retinal vascular permeability in rats.

[0681] 3.8.3 Detection of retinal leukocyte stasis: As shown in Table 13 and Figure 7, the number of retinal leukocytes in rats in the negative control group was very small. Compared with the negative control group, the number of retinal leukocytes in rats in the model group increased significantly. Based on this, after intravitreal injection of dexamethasone, or compound 65, compound 71, compound 8, or compound 11 under test, the number of retinal leukocytes in model rats decreased significantly.

[0682] TIFF2025519544000119.tif79170

[0683] Furthermore, as shown in the fluorescence staining results in Figure 8, almost no stasis of fluorescently stained leukocytes was observed in the retinas of rats in the negative control group. Compared with the negative control group, the stasis of leukocytes in the retinas of rats in the model group increased significantly. Based on this, after intravitreal injection of dexamethasone, or compound 65, compound 71, compound 8, or compound 11, the number of leukocyte stasis in the retinas of rats decreased significantly.

[0684] 3.8.4 Expression levels of inflammation-related factors: As shown in Figure 9, the mRNA expression levels of retinal inflammation-related factors B1R, COX2, IL-1β, iNOS, VEGF-A, and VEGFR2 in rats in the model group recovered to varying degrees compared with the control group. However, the degree of recovery was relatively lower than that of the dexamethasone group.

[0685] 3.8.5 Conclusion: As the results showed, the levels of retinal vascular permeability, the number of retinal leukocyte stasis, and important related factors causing inflammation in rats in the diabetic model group were significantly increased compared with the negative control group, respectively, and were reduced after treatment with dexamethasone as a drug, or compound 65, compound 71, compound 8, or compound 11 under test.

[0686] In summary, the above compounds and dexamethasone can not only improve the retinal inflammatory response caused by diabetes, but also reduce retinal vascular permeability, infiltration, and the number of retinal leukocyte stasis.

[0687] Test Example 5. Study of the in vivo efficacy of the compound in a mouse model of butaxa pollen-induced allergic conjunctivitis 1. Experimental method: SPF-grade Balb / c mice (half male and half female, 6 to 8 weeks old) were used as experimental animals. On day 0 and day 6, a butterbur pollen plantar injection was subcutaneously injected into the plantar of the mice for sensitization (65 μl per mouse). From day 10 to day 14, in the model group, an eye drop of butterbur pollen was applied to both eyes of the mice once a day (10 μl per mouse). The eye drops were applied continuously for 5 days to induce local allergic conjunctivitis (Wu B, et al., Frontiers in Immunology, 2021, 12:4754). Eye drops of compound 8 at concentrations of 0.5% and 2%, and an eye drop of 0.1% dexamethasone as a positive control drug were administered twice a day for 14 consecutive days. On day 14, within 30 minutes from the last challenge, the clinical symptoms of the mice's eyes were observed under a microscope and scored according to the scoring criteria reported by Magone et al. (MerayoLloves J, et al., J Allergy Clin Immunol (1996) 97(5):1129-40, Magone MT, et al., Clin Immunol Immunopathol (1998) 87(1):75-84). An allergic response of the eyes including conjunctival edema, conjunctival hyperemia, eyelid hyperemia, and edema, as well as tearing, was observed for four indicators. The score was recorded as 0 to 3 points according to the severity (none, mild, moderate, and severe). The detailed scoring criteria are shown in Table 14. The left eyes of the mice were collected together with the eyelids (the conjunctiva remained intact), fixed with paraformaldehyde, sectioned in paraffin, and subjected to hematoxylin-eosin staining (HE staining) and toluidine blue staining (for detection of mast cells). Photographs were taken to analyze the infiltration of inflammatory cells in the conjunctival tissue, and it was observed whether the mast cells in the conjunctiva were aggregated and whether degranulation occurred. The expression of IL-4 and IgE, which are allergic indicators in the conjunctival tissue, was detected by immunohistochemistry.

[0688] TIFF2025519544000120.tif92170

[0689] 2. Experimental results: 2.1 Observation of Ocular Clinical Symptoms Within 30 minutes after the last challenge, the ocular clinical symptoms were observed and scored under a microscope. Compared with the mice in the normal control group, it was confirmed that in the eyes of the mice in the model group, there were statistically significant more severe conjunctival edema and congestion, tearing beyond the eyelid margin, and severe local eyelid congestion and edema. After treatment with 0.1% dexamethasone or 0.5% compound 8 as positive controls, the conjunctival edema and congestion improved mildly to moderately, with diffuse mild eyelid congestion and edema and accumulation of lacrimal glands in the lacrimal caruncle, which was significantly different from the model group. After treatment with 2% compound 8, mild local conjunctival edema or accumulation of lacrimal glands in the lacrimal caruncle was observed in some rats, but the symptoms of conjunctival congestion, eyelid congestion, and edema disappeared and recovered to normal levels, and the improvement of symptoms was significantly superior to that of the positive control dexamethasone group (P<0.0001). As the results showed, compound 8 improved the ocular clinical symptoms in a concentration-dependent manner (see Table 15 and Figure 10).

[0690] TIFF2025519544000121.tif66170

[0691] 2.2 Hematoxylin-Eosin Staining and Toluidine Blue Staining In the normal control group, the conjunctival tissue structure was intact, there were no findings of mast cell aggregation and degranulation, no obvious lesions were seen, and bleeding was shown in some samples. In some samples, thinning of the conjunctival epithelium and obvious inflammatory cell infiltration were seen. In the model group, inflammatory cell infiltration and loosening of the tissue structure in the conjunctival stroma were seen in most samples, accompanied by obvious mast cell degranulation and bleeding, and thinning of epithelial cells was shown in some samples. In the positive control group treated with dexamethasone, loosening of the conjunctival tissue was still shown in most samples, but there was a significant improvement in the overall inflammatory cell infiltration, no obvious mast cell degranulation was seen, and bleeding and epithelial thinning were shown in only a few samples. In the 0.5% compound 8 group, inflammatory cell infiltration was still observed, epithelial thinning was seen in some samples, and obvious mast cell degranulation was shown in some samples. In the 2% compound 8 group, dilation, congestion of capillaries, and loosening of the tissue structure were shown in some samples, but improvement was seen in the inflammatory cell infiltration and mast cell degranulation was not observed. This indicates that compound 8 improves inflammatory cell infiltration and conjunctival tissue in a dose-dependent manner, and 2% compound 8 significantly reduces mast cell degranulation in the allergic response (P<0.05). The results of HE staining and toluidine blue staining are shown in Figures 11 and 12, and the results of the number of inflammatory cells are shown in Figures 13 and 14.

[0692] 2.3 Measurement of the expression of IL-4 and IgE, which are allergic indicators in the conjunctival tissue, by immunohistochemistry The eyes including the eyelids of the mice (the conjunctiva was intact) were deparaffinized and then sectioned, and antigen activation and serum blocking were performed. Diluted IL-4 antibody or IgE antibody was added and incubated overnight. After incubation with the secondary antibody, DAB staining was performed, followed by counterstaining with hematoxylin. Then, the slide glass was mounted, observed under an electron microscope, and photographed. Semi-quantitative analysis was performed using Image-J software. Based on the cumulative optical density and area value of each image, the average optical density was calculated to detect the positive expression of IL-4 or IgE.

[0693] As shown by the expression of IL-4 in eye tissues, the expression of IL-4 in the eye tissues of the model group was higher (0.38 ± 0.08, about 1.8 times) compared with that in the normal control group (0.2 ± 0.04). After treatment with dexamethasone or 2% compound 8 as positive controls, the IL-4 levels decreased to levels similar to those in the normal control group (0.23 ± 0.09 and 0.24 ± 0.06, respectively). Furthermore, compound 8 showed a concentration-dependent effect on the expression of IL-4 in tissues. Although no significant difference was found in the overall statistical analysis, a significant trend was observed in terms of degree.

[0694] As shown by the IgE expression in eye tissues, the IgE expression in the eye tissues of the model group was higher (1.05 ± 0.17, about 2 times) compared with that in the normal control group (0.52 ± 0.06), and there was a statistically significant difference (P < 0.05). Both dexamethasone or 2% compound 8 as positive controls significantly decreased the levels of IgE in tissues to levels equivalent to those of IL-4 in the normal control group (0.53 ± 0.11 and 0.54 ± 0.06, respectively) (P < 0.05). 0.5% compound 8 was also able to decrease the expression of IgE to a certain extent (0.72 ± 0.12). The efficacy of compound 8 was dose-dependent with respect to the concentration of IgE in tissues. The measurement results of IL-4 and IgE by immunohistochemistry are shown in Figures 15 and 16, respectively.

[0695] 3. Conclusions of the experiment In summary, dexamethasone as a positive control had a therapeutic effect on allergic conjunctivitis, and compound 8 had a therapeutic effect on allergic conjunctivitis in a dose-dependent manner. The efficacy of 2% compound 8 was equivalent to that of dexamethasone.

[0696] The raw materials and equipment used in the present invention are all raw materials and equipment commonly used in the art unless otherwise specified. The methods used in the present invention are all conventional methods in the art unless otherwise specified.

[0697] The above description is merely a preferred embodiment of the present invention and does not limit the scope of the present invention. Any simple changes, modifications, and equivalent alterations added to the above embodiment in accordance with the technical idea of the present invention are still included within the protection scope of the technical solutions described in the claims.

Industrial Applicability

[0698] The present invention provides an N-tetrazolylarylurea derivative that can be used as a bradykinin B1 receptor antagonist and is useful in the prevention or treatment of diseases mediated by the bradykinin B1 receptor. Therefore, this derivative can be formulated into a corresponding pharmaceutical suitable for industrial use.

[0699] Although the present invention has been described in detail herein, the present invention is not limited thereto, and those skilled in the art in the field of the present invention can make changes based on the principles of the present invention. Therefore, any changes made in accordance with the principles of the present invention shall be construed as being included within the protection scope of the present invention.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ and R ２ together with the N atom bonded thereto form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom, wherein the 3- to 8-membered heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups A, and the functional groups A are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, and cycloamino; or R １ and R ２ together with the N atom bonded thereto, comprise at least one nitrogen atom plus NH, N, O, S, SO, and SO ２ wherein the 8- to 12-membered bicyclic heterocyclic group includes a spiro heterocyclic group, a bridged bicyclic heterocyclic group, and a fused bicyclic heterocyclic group, and the 8- to 12-membered bicyclic heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups B, and the functional group B is selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino; or R １ and R ２ Each of the following groups: (i) H, C １ ~C １０ Alkyl, C ２ ~C １０ Alkenyl, and C ２ ~C １０ Alkynyl (wherein C １ ~C １０ Alkyl, C ２ ~C １０ Alkenyl, or C ２ ~C １０ The alkynyl is optionally substituted with one to three identical or different functional groups C, and the functional groups C are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino); (ii) phenyl, 5- to 6-membered heteroaryl, C ５ ~C ７ Cycloalkyl, and 5- to 7-membered heterocyclic groups, wherein the 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclic group is selected from NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, the C ５ ~C ７ The cycloalkyl or the 5- to 7-membered heterocyclic group is optionally substituted with one to three identical or different functional groups D, and the functional groups D are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino are independently selected from the group consisting of Ar １ is phenyl, 5- to 6-membered heteroaryl, C ５ ~C ７ Cycloalkyl, and C ９ ~C １０ dicycloalkyl, wherein said 5- to 6-membered heteroaryl is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, the C ５ ~C ７ cycloalkyl, or the C ９ ~C １０ The dicycloalkyl is optionally substituted with one to three identical or different functional groups E, and the functional groups E are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino; Z is phenyl, 5- to 6-membered heteroaryl, C ５ ~C ７ cycloalkyl, 5- to 7-membered heterocyclic group, C ９ ~C １０ dicycloalkyl, a 9- to 10-membered fused bicyclic heterocyclic group, 【Chemistry 2】 is selected from the group consisting of wherein the 5- to 6-membered heteroaryl, the 5- to 7-membered heterocyclic group, or the 9- to 10-membered fused bicyclic heterocyclic group is selected from NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, the C ５ ~C ７ cycloalkyl, the 5- to 7-membered heterocyclic group, the C ９ ~C １０ The dicycloalkyl or the 9- to 10-membered fused bicyclic heterocyclic group is optionally substituted with one to three identical or different functional groups F, and the functional groups F are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ or wherein the functional group F is selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino, or wherein the functional group F is selected from the group consisting of a 5- to 8-membered heterocyclic ring fused to a phenyl, a 5- to 6-membered heteroaryl, C ５ ~C ７ cycloalkyl, 5- to 7-membered heterocyclic group, C ９ ~C １０ forming a dicycloalkyl or a fused 9- to 10-membered bicyclic heterocyclic group; R ３ is C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ is selected from the group consisting of cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, and 5- to 6-membered heteroaryl, and １ ~C ６ alkyl, the C ３ ~C ７ cycloalkyl, the C ３ ~C ７ The cycloalkenyl, the 5- to 7-membered heterocyclic group, the phenyl, or the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 identical or different functional groups G, and the functional groups G are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ selected from the group consisting of alkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino; Y is selected from the group consisting of O or NH, and Ar ２ is phenyl, 5- to 6-membered heteroaryl, C １０ ~C ２０ fused cyclic group, C １ ~C ６ alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic groups, and C １ ~C ６ alkoxy, wherein said 5- to 6-membered heteroaryl or said 5- to 7-membered heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, the C １０ ~C ２０ fused cyclic group, １ ~C ６ alkyl, the 5- to 7-membered cycloalkyl, the 5- to 7-membered heterocyclic group, or the C １ ~C ６ The alkoxy is optionally substituted with one to three identical or different functional groups H, and the functional groups H are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, halogenated C １ ~C ６ aryl urea derivatives, characterized in that they are compounds represented by the formula (I) or (II), or cis-trans isomers thereof, or pharmaceutically acceptable salts or solvates thereof.

2. In formula I, R １ and R ２ together with the N atom bonded thereto, form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom, wherein the 3- to 8-membered heterocyclic group is substituted with 1 to 3 identical or different functional groups A, and the functional groups A are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ３ Alkyl, C １ ~C ３ Alkenyl, C １ ~C ３ Alkynyl, C １ ~C ３ Alkoxy, halogenated C １ ~C ３ Alkyl, C １ ~C ３ selected from the group consisting of fluoroalkoxy, alkylamino, dialkylamino, acetylamino, or cycloamino; R １ and R ２ together with the N atom bonded thereto, comprise at least one nitrogen atom plus NH, N, O, S, SO, and SO ２ and forming an 8- to 12-membered bicyclic heterocyclic group containing 0, 1, or 2 heteroatoms or heteroatom-containing groups independently selected from the group consisting of: wherein the 8- to 12-membered bicyclic heterocyclic group includes spirocycloalkyl, bridged bicycloalkyl, and fused bicycloalkyl, and the 8- to 12-membered bicyclic heterocyclic group is substituted with 1 to 3 identical or different functional groups B, and the functional groups B are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, C １ ~C ６ selected from the group consisting of fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino; R １ and R ２ Each of the following groups: (i) H, C １ ~C １０ Alkyl, C ２ ~C １０ Alkenyl, C ２ ~C １０ Alkynyl (wherein the C １ ~C １０ alkyl, the C ２ ~C １０ alkenyl, or the C ２ ~C １０ The alkynyl is substituted with one to three identical or different functional groups C, and the functional groups C are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, C １ ~C ６ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (ii) phenyl, 5- to 6-membered heteroaryl, C ５ ~C ７ cycloalkyl, 5- to 7-membered heterocyclic groups (wherein the 5- to 6-membered heteroaryl or the 5- to 7-membered heterocyclic group is NH, N, O, S, SO, and SO ２ and wherein the phenyl, the heteroatom, or the heteroatom-containing group is substituted with one to three identical or different functional groups D, and the functional groups D are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, C １ ~C ６ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino) are independently selected from the group consisting of Ar １ is phenyl, 5- to 6-membered heteroaryl, C ５ ~C ７ Cycloalkyl, C ９ ~C １０ fused bicyclic groups, wherein said 5- to 6-membered heteroaryl is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the phenyl, the heteroatom, or the heteroatom-containing group is substituted with one to three identical or different functional groups E, and the functional groups E are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, C １ ~C ６ selected from the group consisting of fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino; Z is the following group: (i) phenyl, 5- to 6-membered heteroaryl, C ５ ~C ７ cycloalkyl, 5- to 7-membered heterocyclic group, C ９ ~C １０ Fused bicyclic groups, 9- to 10-membered fused heterobicyclic groups (wherein the 5- to 6-membered heteroaryl, the 5- to 7-membered heterocyclic group, or the 9- to 10-membered fused heterobicyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the phenyl, the heteroatom, or the heteroatom-containing group is substituted with one to three identical or different functional groups F, and the functional groups F are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl, C １ ~C ６ or wherein the functional groups F are selected from the group consisting of fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino, or wherein the functional groups F form a 5- to 8-membered heterocyclic ring; or (ii) 【Transformation 3】 wherein X is selected from the group consisting of O or NH, and R ３ is C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ cycloalkenyl, 5- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, and １ ~C ６ alkyl, the C ３ ~C ７ cycloalkyl, the C ３ ~C ７ The cycloalkenyl, the 5- to 7-membered heterocyclic group, the phenyl, or the 5- to 6-membered heteroaryl is substituted with 1 to 3 identical or different functional groups G, and the functional groups G are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, halogenated C １ ~C ３ Alkyl, C １ ~C ３ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iii) 【Chemistry 4】 wherein Y is selected from the group consisting of O or NH, and Ar ２ is phenyl, 5- to 6-membered heteroaryl, C １０ ~C ２０ fused cyclic group, C １ ~C ６ Alkyl, 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic group, C １ ~C ６ alkoxy, wherein said phenyl, said 5- to 6-membered heteroaryl, said C １０ ~C ２０ fused cyclic group, １ ~C ６ alkyl, the 5- to 7-membered cycloalkyl, the 5- to 7-membered heterocyclic group, or the C １ ~C ６ The alkoxy is substituted with 1 to 3 identical or different functional groups H, and the functional groups H are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, halogenated C １ ~C ３ Alkyl, C １ ~C ３ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, and said 5- to 6-membered heteroaryl or said 5- to 7-membered heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the heteroatom or heteroatom-containing group is independently selected from the group consisting of: The N-tetrazolylarylurea derivative according to claim 1, wherein the N-tetrazolylarylurea derivative is selected from the group consisting of:

3. Ar １ represents the following phenyl group, pyridyl group, pyrazinyl group: 【Transformation 5】 wherein the group is substituted with one to three identical or different functional groups I, and the functional groups I are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, halogenated C １ ~C ３ Alkyl, C １ ~C ３ 3. The N-tetrazolylaryl urea derivative according to claim 1, wherein the aryl group is selected from the group consisting of fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, and cycloamino.

4. Formula Ia or Formula Ib: 【Transformation 6】 or a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof, In compounds represented by formula Ia: Each of A and B is independently a carbon atom or a nitrogen atom; Z is the following group: (i) phenyl, pyridyl, pyrazolyl, imidazolyl, indazolyl, wherein the group is substituted with one to three identical or different functional groups J, and the functional groups J are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ４ Alkyl, C １ ~C ４ or wherein the functional group J is selected from the group consisting of fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, or wherein the functional group J forms a 5-membered heterocyclic ring; or (ii) 【Transformation 7】 (In the formula, R ３ is C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ aryl, a 5- to 7-membered heterocyclic group, phenyl, a 5- to 6-membered heteroaryl, wherein said C １ ~C ６ alkyl, the C １ ~C ６ cycloalkyl, the C ３ ~C ７ cycloalkyl, the C ３ ~C ７ The aryl, the 5- to 7-membered heterocyclic group, the phenyl, or the 5- to 6-membered heteroaryl is substituted with 1 to 3 identical or different functional groups K, and the functional groups K are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, halogenated C １ ~C ３ Alkyl, C １ ~C ３ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iii) phenoxy, wherein the phenoxy is substituted with one to three identical or different functional groups L, and the functional groups L are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, halogenated C １ ~C ３ Alkyl, C １ ~C ３ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iv) 【Transformation 8】 (In the formula, R １０ is C １ ~C ６ alkyl, 5- to 7-membered cycloalkyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, wherein said C １ ~C ６ The alkyl, the 5- to 7-membered cycloalkyl, the 5- to 6-membered heteroaryl, or the 5- to 7-membered heterocyclic group is substituted with 1 to 3 identical or different functional groups M, and the functional groups M are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ４ Alkyl, C １ ~C ４ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, and said 5- to 6-membered heteroaryl or said 5- to 7-membered heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the heteroatom or heteroatom-containing group is independently selected from the group consisting of: is selected from the group consisting of R ６ａ is a hydrogen atom, and R ６ and R ７ is C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, C ３ ~C １０ cycloalkyl, wherein said C １ ~C ６ alkyl, the C １ ~C ６ cycloalkyl, or the C ３ ~C １０ cycloalkyl is substituted with 1 to 3 identical or different functional groups N, and the functional groups N are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, or R ６ａ is a hydrogen atom, and R ６ and R ７ together with the two carbon atoms attached thereto form a 4- to 8-membered cyclic group, or NH, N, O, S, SO, and SO ２ wherein said 4- to 8-membered bicyclic heterocyclic group is substituted with one to three identical or different functional groups O, and said functional groups O are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, or R ７ is a hydrogen atom, and R ６ and R ６ａ together with the two carbon atoms attached thereto form a 4- to 8-membered cyclic group, or NH, N, O, S, SO, and SO ２ wherein the 4- to 8-membered cyclic group or the 4- to 8-membered heterocyclic group is substituted with 1 to 3 identical or different functional groups P, and the functional groups P are selected from the group consisting of hydroxyl, halogen, amino, cyano, and nitro; In compounds represented by formula Ib: Each of A and B is independently a carbon atom or a nitrogen atom; Z is the following group: (i) phenyl, pyridyl, pyrazolyl, imidazolyl, indazolyl (wherein the phenyl, pyridyl, pyrazolyl, imidazolyl, or indazolyl is substituted with 1 to 3 identical or different functional groups Q, and the functional groups Q are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ４ Alkyl, C １ ~C ４ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (ii) 【Chemistry 9】 (In the formula, R ３ is C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ aryl, wherein said C １ ~C ６ alkyl, the C １ ~C ６ cycloalkyl, the C ３ ~C １０ cycloalkyl, or the C ３ ~C １０ The aryl is substituted with 1 to 3 identical or different functional groups R, and the functional groups R are hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ４ Alkyl, C １ ~C ４ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iii) phenoxy, wherein the phenoxy is substituted with one to three identical or different functional groups S, and the functional groups S are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ４ Alkyl, C １ ~C ４ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino), or (iv) 【Chemistry 10】 (In the formula, R １０ is C １ ~C ６ alkyl, 5- to 7-membered cycloalkyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, wherein said C １ ~C ６ The alkyl, the 5- to 7-membered cycloalkyl, the 5- to 6-membered heteroaryl, or the 5- to 7-membered heterocyclic group is substituted with 1 to 3 identical or different functional groups T, and the functional groups T are selected from the group consisting of hydroxyl, halogen, amino, cyano, nitro, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ４ Alkyl, C １ ~C ４ fluoroalkoxy, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, or cycloamino, and said 5- to 6-membered heteroaryl or said 5- to 7-membered heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the heteroatom or heteroatom-containing group is independently selected from the group consisting of: is selected from the group consisting of R ８ is C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, C ３ ~C １０ aryl, wherein said C １ ~C ６ alkyl, the C １ ~C ６ cycloalkyl, or the C ３ ~C １０ the aryl is substituted with one to three identical or different functional groups U, and the functional groups U are selected from the group consisting of hydroxyl, halogen, amino, cyano, and nitro; R ９ is C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, C ３ ~C １０ aryl, wherein said C １ ~C ６ alkyl, the C １ ~C ６ cycloalkyl, or the C ３ ~C １０ The N-tetrazolyl aryl urea derivative according to claim 1 or 2, characterized in that the aryl is substituted with one to three identical or different functional groups V, and the functional groups V are selected from the group consisting of hydroxyl, halogen, amino, cyano, and nitro.

5. R １ and R ２ together with the N atom bonded thereto form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom, wherein the 3- to 8-membered heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups A, and the functional group A is C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy; or R １ and R ２ together with the N atom bonded thereto, comprise at least one nitrogen atom plus NH, N, O, S, SO, and SO ２ wherein the 8- to 12-membered bicyclic heterocyclic group includes spirocycloalkyl, bridged bicycloalkyl, and fused bicycloalkyl, and the 8- to 12-membered bicyclic heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups B, and the functional group B is selected from the group consisting of C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy; or R １ and R ２ Each of the following groups: (i) H and C １ ~C ６ Alkyl (where C １ ~C ６ The alkyl is optionally substituted with 1 to 3 identical or different functional groups C, and the functional groups C are C １ ~C ６ Alkoxy and halogenated C １ ~C ６ alkoxy), (ii) phenyl and C ５ ~C ７ Cycloalkyl (wherein the phenyl or the C ５ ~C ７ The cycloalkyl is optionally substituted with 1 to 3 identical or different functional groups D, and the functional groups D are C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy) are independently selected from the group consisting of Ar １ is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein said phenyl or said 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 identical or different functional groups E, and said functional groups E are selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy; Z is phenyl, a 5- to 6-membered heteroaryl, a 5- to 7-membered heterocyclic group, a 9- to 10-membered fused bicyclic heterocyclic group, 【Chemistry 11】 is selected from the group consisting of wherein the 5- to 6-membered heteroaryl, the 5- to 7-membered heterocyclic group, or the 9- to 10-membered fused bicyclic heterocyclic group is selected from NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, the 5- to 7-membered heterocyclic group, or the 9- to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups F, and the functional groups F are selected from the group consisting of halogen, C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy, or the functional group F forms a 5- to 8-membered heterocyclic ring fused to phenyl; R ３ is C １ ~C ６ Alkyl, C ３ ~C ７ is selected from the group consisting of cycloalkyl, 5- to 7-membered heterocyclic groups, and 5- to 6-membered heteroaryl, and １ ~C ６ alkyl, the C ３ ~C ７ The cycloalkyl or the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 identical or different functional groups G, and the functional groups G are C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy; Y is O and Ar ２ is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclic groups, wherein said 5- to 6-membered heteroaryl or said 5- to 7-membered heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, or the 5- to 7-membered heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups H, and the functional group H is selected from the group consisting of C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ 3. The N-tetrazolylarylurea derivative according to claim 1, wherein the aryl group is selected from the group consisting of alkoxy.

6. R １ and R ２ together with the N atom bonded thereto form a 3- to 8-membered heterocyclic group containing at least one nitrogen atom, wherein the 3- to 8-membered heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups A, and the functional group A is C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkyl; or R １ and R ２ together with the N atom bonded thereto, comprise at least one nitrogen atom plus NH, N, O, S, SO, and SO ２ wherein said 8- to 12-membered bicyclic heterocyclic group includes spirocycloalkyl and fused bicycloalkyl; or R １ is H and C １ ~C ６ alkyl, and R ２ is phenyl and C ５ ~C ７ cycloalkyl, wherein said phenyl or said C ５ ~C ７ The cycloalkyl is optionally substituted with 1 to 3 identical or different functional groups D, and the functional groups D are C １ ~C ６ Alkyl and halogenated C １ ~C ６ is selected from the group consisting of alkyl, Ar １ is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heteroaryl is selected from the group consisting of NH, N, O, S, SO, and SO ２ and said phenyl is optionally substituted with 1 to 3 of the same or different halogens; Z is phenyl, a 5- to 6-membered heteroaryl, a 5- to 7-membered heterocyclic group, a 9- to 10-membered fused bicyclic heterocyclic group, 【Chemistry 12】 wherein said 5- to 6-membered heteroaryl, said 5- to 7-membered heterocyclic group, or said 9- to 10-membered fused bicyclic heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and wherein the phenyl, the 5- to 6-membered heteroaryl, the 5- to 7-membered heterocyclic group, or the 9- to 10-membered fused bicyclic heterocyclic group is optionally substituted with 1 to 3 identical or different functional groups F, and the functional groups F are selected from the group consisting of halogen, C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkoxy and halogenated C １ ~C ６ alkyl, or the functional group F forms a 5- to 8-membered heterocyclic ring fused to phenyl; R ３ is C １ ~C ６ Alkyl, C ３ ~C ７ is selected from the group consisting of cycloalkyl, 5- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and ３ ~C ７ The cycloalkyl, the 5- to 7-membered heterocycloalkyl, or the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 identical or different functional groups G, and the functional group G is C １ ~C ６ is selected from the group consisting of alkyl, Ar ２ is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclic groups, wherein said 5- to 6-membered heteroaryl or said 5- to 7-membered heterocyclic group is selected from the group consisting of NH, N, O, S, SO, and SO ２ and said phenyl, said 5- to 6-membered heteroaryl, or said 5- to 7-membered heterocyclic group contains 1, 2, or 3 heteroatoms or heteroatom-containing groups independently selected from the group consisting of: １ ~C ６ Alkyl and C １ ~C ６ The N-tetrazolylarylurea derivative according to claim 5, which is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkoxy.

7. R １ and R ２ together with the N atom to which they are attached form a piperidyl, which is optionally substituted with substituent(s) selected from the group consisting of methyl, tert-butoxy, and trifluoromethyl, or R １ and R ２ together with the N atom to which they are attached form an azaoxaspirodecyl or octahydrofuranopyridyl; R １ is selected from the group consisting of H and methyl, and R ２ is selected from the group consisting of phenyl and cyclohexyl, wherein said phenyl is optionally substituted with trifluoromethyl, and said cyclohexyl is optionally substituted with methyl or tert-butyl; Ar １ is selected from the group consisting of phenyl and pyridyl, wherein said phenyl is optionally substituted with a fluorine atom; Z is phenyl, phenoxy, pyridyl, indazolyl, imidazolyl, tetrahydropyranyl, tetrahydropyranyloxy, dihydropyranyl, 【Chemistry 13】 wherein the phenyl, the pyridyl, the indazolyl, the imidazolyl, the tetrahydropyranyl, or the dihydropyranyl is optionally substituted with 1 to 3 identical or different functional groups F, and the functional groups F are selected from the group consisting of methyl, tert-butyl, methoxy, ethoxy, isopropoxy, cyclobutyl, -Cl, difluoromethyl, and trifluoromethyl, or the functional groups F form a dioxolane ring fused to the phenyl, and the phenoxy is optionally substituted with 1 to 2 methoxy groups; R ３ The N-tetrazolylarylurea derivative according to claim 5, wherein is selected from the group consisting of ethyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and pyridyl optionally substituted with methyl.

8. Formula Ia, Formula Ib, or Formula Ic: 【Chemistry 14】 or a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof, In compounds represented by formula Ia: Each of A and B is independently a carbon atom or a nitrogen atom; Z is phenyl, pyridyl, indazolyl, imidazolyl, tetrahydropyranyl, dihydropyranyl, 【Chemistry 15】 wherein the phenyl, the pyridyl, the indazolyl, the imidazolyl, the tetrahydropyranyl, or the dihydropyranyl is optionally substituted with one to three identical or different functional groups F, and the functional groups F are selected from the group consisting of methyl, tert-butyl, methoxy, ethoxy, isopropoxy, cyclobutyl, -Cl, difluoromethyl, and trifluoromethyl, or the functional groups F form a dioxolane ring fused to the phenyl, and R ３ is selected from the group consisting of ethyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and pyridyl optionally substituted with methyl; R ７ , R ６ａ , and R ６ each is independently selected from the group consisting of H, methyl, tert-butoxy, and trifluoromethyl; or R ７ is a hydrogen atom, and R ６ and R ６ａ together with the carbon atoms attached thereto form an oxolane ring, or R ６ａ is a hydrogen atom, and R ６ and R ７ together with the carbon atoms attached to them form an oxolane ring, In compounds represented by formula Ib: Each of A and B is independently a carbon atom or a nitrogen atom; Z is selected from the group consisting of phenyl, phenoxy, pyridyl, dihydropyranyl, tetrahydropyranyl, and tetrahydropyranyloxy, wherein said phenyl or said phenoxy is optionally substituted with one to two methoxy groups or is optionally fused to a dioxolane ring, said pyridyl is optionally substituted with ethoxy, and R ８ is tert-butyl or methyl, R ９ is H or methyl, In compounds represented by formula Ic: Each of A and B is independently a carbon atom or a nitrogen atom; Z is selected from the group consisting of phenyl, phenoxy, pyridyl, dihydropyranyl, tetrahydropyranyl, and tetrahydropyranyloxy, wherein said phenyl or said phenoxy is optionally substituted with one to two methoxy groups or is optionally fused to a dioxolane ring, said pyridyl is optionally substituted with ethoxy, and R １０ is trifluoromethyl, R １１ The N-tetrazolylarylurea derivative according to claim 1 or 2, wherein is H.

9. The following compounds: 4-(tert-butyl)-N-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide, N-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1-oxy-8-azaspiro[4.5]decane-1-carboxamide, N-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)hexahydrofuro[2,3-c]pyridine-6(2H)-carboxamide, N-(4-(6-ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(6-ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(6′-ethoxy-3-(2H-tetrazol-5-yl)-[2,3′-bipyridyl]-5-yl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(6-ethoxypyrid-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(2-fluoro-3',4'-dimethoxy-6-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide, N-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4,4-dimethylpiperidine-1-carboxamide, 4-(tert-butyl)-N-(4'-methoxy-3'-methyl-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)piperidine-1-carboxamide, cyclohexyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, cyclohexyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-fluoro-6-(2H-tetrazol-5-yl)benzoate, ethyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-fluoro-6-(2H-tetrazol-5-yl)benzoate, 4-(tert-butyl)-N-(3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(3-fluoro-5-(2H-tetrazol-5-yl)-4-(6-(trifluoromethyl)pyrid-3-yl)phenyl)piperidine-1-carboxamide, N-(2-fluoro-3',4'-methoxy-6-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-methylpiperidine-1-carboxamide, 4-methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-methyl-N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, cyclohexyl 2-fluoro-4-(4-methylpiperidine-1-formamido)-6-(2H-tetrazol-5-yl)benzoate, ethyl 2-fluoro-4-(4-methylpiperidine-1-formamido)-6-(2H-tetrazol-5-yl)benzoate, N-(4-(6-ethoxypyrid-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(2-fluoro-3',4'-methoxy-6-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(4-(1-methyl-1H-indazol-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide, N-(3'-chloro-4'-methoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)piperidine-1-carboxamide, cyclohexyl 2-fluoro-6-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)piperidine-1-formamido)benzoate, ethyl 2-fluoro-6-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)piperidine-1-formamido)benzoate, N-(4-(6-ethoxypyrid-3-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)-4-methylpiperidine-1-carboxamide, 4-(tert-butyl)-N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(3′-chloro-2-fluoro-4′-methoxy-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)piperidine-1-carboxamide, N-(3-fluoro-4-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)phenyl)-4-(trifluoromethyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(6-(3,4-dimethoxyphenyl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(6-(1-methyl-1H-indazol-5-yl)-5-(2H-tetrazol-5-yl)pyrid-3-yl)piperidine-1-carboxamide, ethyl 5-(4-(tert-butyl)piperidine-1-formamido)-3-(2H-tetrazol-5-yl)pyridylcarboxylate, cyclohexyl 5-(4-(tert-butyl)piperidine-1-formamido)-3-(2H-tetrazol-5-yl)pyridylcarboxylate, N-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-4-(tert-butyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(3,4-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(6-(difluoromethyl)pyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, cyclopentyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, tetrahydrofuran-3-yl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, ethyl 4-(4-(tert-butyl)piperidine-1-formamido)-2-(2H-tetrazol-5-yl)benzoate, 4-(tert-butyl)-N-(4-(cyclopentylaminoformyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-((5-methylpyridin-2-yl)aminoformyl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(5-methoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(6-isopropoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(5-methoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(6-methylpyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(2-methylpyridin-4-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(cyclopentylaminoformyl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(3-fluoro-4-((5-methylpyridin-2-yl)aminoformyl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(3-fluoro-4-(6-methylpyrid-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(3-fluoro-4-(6-isopropoxypyrid-3-yl)-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-fluoro-5-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 4-(tert-butyl)-N-(4-(4-(tert-butyl)-1H-imidazol-1-yl)-3-(2H-tetrazol-5-yl)phenyl)piperidine-1-carboxamide, 1-(4-(tert-butyl)cyclohexyl)-3-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)urea, 1-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-3-((cis)-4-methylcyclohexyl)urea, 1-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-3-((trans)-4-methylcyclohexyl)urea, 1-(4-(3,4-dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-methylcyclohexyl)urea, 1-(4-(3,4-dimethoxyphenoxy)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-((trans)-4-(tert-butyl)cyclohexyl)-3-(3',4'-dimethoxy-2-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1-methylurea, 1-(4-(3,6-dihydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-((cis)-4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea, 1-((trans)-4-methylcyclohexyl)-3-(4-(tetrahydro-2H-pyran-4-yl)-3-(2H-tetrazol-5-yl)phenyl)urea, 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-(4-(benzo[d][1,3]dioxolan-5-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((cis)-4-(tert-butyl)cyclohexyl)urea, 1-(4-(6-ethoxypyrid-3-yl)-3-(2H-tetrazol-5-yl)phenyl)-3-((trans)-4-methylcyclohexyl)urea, 1-(cis)-4-methylcyclohexyl-3-(4-(tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea, 1-(trans)-4-methylcyclohexyl-3-(4-tetrahydropyran-4-yl)oxy)-3-(2H-tetrazol-5-yl)phenyl)urea, 3. The N-tetrazolylarylurea derivative according to claim 1, wherein the N-tetrazolylarylurea derivative is selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

10. The method for producing the N-tetrazolylaryl urea derivative according to claim 1 or 2, which is represented by formula I, wherein R １ and R ２ is a non-hydrogen group, or R １ and R ２ For compounds in which, together with the N atom to which they are bonded, form a heterocyclic group containing at least one nitrogen atom, the preparation method further comprises: Step 1: A 2-halogenated 5-nitroaromatic carbonitrile represented by formula a is converted under alkaline conditions into Z—B(OH) ２ coupling with boronic acid to obtain a compound represented by formula c; Step 2: Adding sodium azide to the cyano group in the compound of formula c to give a tetrazolyl intermediate of formula d; Step 3: Trt-protection to give intermediates of formula e; Step 4: reducing the nitro group to give an amino compound represented by formula f; Step 5: converting the amino compound into an isocyanate compound represented by formula g; Step 6: reacting the isocyanate compound with an amine to produce a urea compound represented by formula h; Step 7: Trt-deprotection of the urea of ​​formula h to obtain the target compound; 【Chemistry 16】 or For compounds represented by formula I, wherein Z is substituted or unsubstituted phenoxy, the process comprises: subjecting the 2-halogenated 5-nitroaromatic carbonitrile represented by formula a to a nucleophilic substitution reaction with a substituted phenol represented by formula b2 under alkaline conditions to obtain a phenol ether intermediate represented by formula c2; carrying out steps 2 to 7 to finally obtain the corresponding target compound; 【Chemistry 17】 or Represented by formula I, wherein Z is [Chemistry 18] For a compound wherein: The compound represented by formula c obtained in step 1 is 【Chemistry 19】 by carrying out steps 2 to 7 above to finally obtain the target product; or Represented by formula I, wherein R １ or R ２ For compounds in which one of the groups is a hydrogen atom, the production method is carrying out steps 1 to 4 above to obtain an amino intermediate represented by formula f; reacting the amino intermediate directly with an isocyanate compound to produce a urea compound represented by formula h1; Trt-deprotection of the urea represented by formula h1 to obtain the target compound; 【Chemistry 20】 A method comprising:

11. A pharmaceutical composition comprising the N-tetrazolylarylurea derivative according to claim 1, a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is an injection, an oral preparation, or an eye drop.

13. A pharmaceutical composition according to claim 11 or 12 for preventing or treating a disease mediated by the bradykinin B1 receptor.

14. 14. The pharmaceutical composition of claim 13, wherein the disease or syndrome, pathology, or symptom thereof is associated with an inflammatory response caused by an infectious disease, including pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19 infection, pneumonia and type I hypersensitivity syndrome caused by respiratory syncytial virus, bacterial sepsis and shock caused by septicemia, or intestinal inflammation, including colitis, or complications caused by diabetes, including retinal edema and lesions, macular degeneration, neuralgia, diabetic hand and foot ulcers caused by diabetes, or ophthalmic inflammatory disease.

15. The pharmaceutical composition according to claim 14, characterized in that the disease is selected from the group consisting of acute pneumonia, pulmonary edema, and acute respiratory distress syndrome caused by COVID-19, diabetic retinopathy, age-related macular degeneration, diabetic neuralgia, allergic conjunctivitis, chronic conjunctivitis, and uveitis.

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