Inhibitors of fatty acid-binding proteins (FABPs), methods of use, and methods of manufacture

Abstract

This specification discloses FABP inhibitor compounds and their use in pharmaceutical compositions for treating diseases that highly express any of these FABPs, including cancers, particularly triple-negative breast cancer (TNBC), and other pro-inflammatory diseases, including cardiovascular diseases, obesity or obesity-related disorders, diabetes, dyslipidemia, impaired glucose tolerance or impaired fasting blood glucose, vitiligo, psoriasis, autoimmune disorders, pain, and dementia. This specification also discloses methods for preparing the disclosed compounds.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to U.S. Provisional Application No. 63 / 471,207, filed on 5 June 2023, and this patent application constitutes a part of this specification by reference.

[0002] This disclosure relates to compounds that inhibit fatty acid-binding proteins, such as FABP3, FABP4, FABP5, and / or FABP7, pharmaceutical compositions containing these inhibitory compounds, and the use of these compounds and compositions for treating or preventing cancers that highly express any of these FABPs, particularly triple-negative breast cancer (TNBC), autoimmune diseases and autoimmune disorders, viral infections, and other diseases associated with chronic inflammation, including cardiovascular diseases, obesity or obesity-related disorders, diabetes, dyslipidemia, impaired glucose tolerance or impaired fasting blood glucose, vitiligo, psoriasis, pain, and dementia. [Background technology]

[0003] Fatty acid-binding proteins (FABPs) are a family of small (12 kDa–15 kDa) soluble proteins that contribute to the transport of fatty acids within the cytosolic compartment of cells. These proteins are a multigene family, highly conserved, and non-catalytic, but they transport hydrophobic fatty acids to various destinations within the aqueous environment of the cytosol, enabling fatty acid oxidation, membrane homeostasis, or nuclear signaling. Furthermore, they are involved in signaling processes that are not yet fully understood [1–4]. Structurally, all members of the FABP family share a β-barrel structure consisting of a water-filled cavity and a site that binds to a specific lipid ligand unique to each member. FABPs have distinct tissue expression patterns, with the exception of FABP5, which is ubiquitous in most tissues. However, tissues with active lipid metabolism generally tend to express two or more isoforms. FABP3 is mainly expressed in muscle tissue, particularly in the heart and neurons. FABP4 is highly expressed in adipose tissue, macrophages, and endothelial cells. FABP5 is expressed in macrophages and endothelial cells, as well as in skin, adipocytes, neurons, glial cells, and several other tissues [2, 5, 6]. FABP7 is expressed in the brain, specifically in glial cells and astrocytes. Recent patient data have shown that FABP5 is highly upregulated in breast tumors, particularly TNBC tumors. This protein has been reported to induce TNBC cell growth and metastasis, and high levels of this protein are associated with low survival rates in TNBC patients. Genetic ablation of FABP5 in the breast cancer mouse model MMTV-NeuT significantly delayed tumor formation and inhibited their growth rate [7]. Similarly, in a xenograft model, chemical inhibition of FABP5 suppressed tumor growth [8, 9]. These data suggest that inhibition of FABP5 is a promising novel approach for the treatment of TNBC and possibly other cancers that highly express this protein.

[0004] TNBC is the most aggressive and deadly subtype of breast cancer, accounting for 10-20% of all breast cancer cases. Women diagnosed with TNBC are four times more likely to have cancer cells spread or metastasize to other organs within five years compared to patients with other types of breast cancer. TNBC is a heterogeneous group of breast tumors that is still poorly characterized at the molecular level and lacks definitive prognostic markers and selective targets for treatment. This makes the treatment and management of TNBC a significant clinical challenge, and there is an urgent need for novel targeted therapies for this disease. Current standard treatment for TNBC includes neoadjuvant systemic therapies such as anthracyclines, taxanes, and cyclophosphamide. Platinum-based chemotherapy has been proposed but is not yet recommended in available guidelines. Currently, there are no approved targeted therapies for TNBC in a neoadjuvant setting.

[0005] Genetic deletions of FABP4 and FABP5 in mice improve insulin sensitivity, lower glucose levels, and prevent atherosclerosis [4]. In a clamp test in ob / ob mice, a specific FABP4 inhibitor (BMS309403) showed decreased hepatic glucose production, increased glucose uptake in muscle and adipose tissue, and reduced hepatic steatosis, but no changes in body weight or energy expenditure. Furthermore, this compound showed reduced atherosclerotic plaque formation in ApoE KO mice [2, 3]. In humans, plasma levels of FABP4 are elevated in patients with metabolic syndrome and atherosclerosis

[10] . In addition, there is growing evidence of FABP4 involvement in angiogenesis

[11] and the growth of certain tumors

[12] . The global prevalence of obesity is exploding. Obesity causes a range of health problems, shortens life expectancy, and costs more than US$100 billion per year. More than a quarter of the population suffers from a variety of comorbidities, including obesity, atherosclerosis, insulin resistance, dyslipidemia, coagulation disorders, hypertension, and a pro-inflammatory condition known as metabolic syndrome. Individuals with metabolic syndrome are at high risk for atherosclerosis, as well as type 2 diabetes and other health problems. Similar to obesity, treatment options for atherosclerosis are very limited.

[0006] Atherosclerosis is a leading cause of death in the United States. At the heart of this syndrome are dysregulation of lipid metabolism and abnormal inflammatory responses. While the mechanistic role of fatty acids has been proposed in the formation of obesity and diabetes by altering not only the inflammatory cascade but also glucose and lipid metabolism, little is known about the mechanisms by which fatty acid or other lipid signaling is linked to inflammatory responses and the formation of atherosclerotic lesions.

[0007] The ability to modulate the immune system offers potential for treating a wide range of conditions, including those caused by chronic inflammation and cancer. Beyond its established role in vaccine development, immunomodulation has therapeutic potential for autoimmune and cancer, as well as various conditions including inflammatory, fibrous, and infectious diseases.

[0008] Immune cells play a crucial role in the tumor microenvironment (TME). Tumor-infiltrating immune cells are involved in regulating tumor development, progression, and response to treatment. The cellular and molecular profiles of the immune TME influence disease response to treatment and its outcome by modulating the balance between suppressive and cytotoxic responses in the tumor periphery

[13] . Certain immune cells, such as T cells and natural killer cells, can help suppress tumor growth and contribute to the elimination of cancer cells. Conversely, the accumulation of immunosuppressive immune cells, such as regulatory T cells and myeloid suppressor cells, may create an environment that allows tumor growth and progression. The balance between immunostimulatory and immunosuppressive cells in the tumor microenvironment is critical to the success of immunotherapy and other cancer treatments. Therefore, the ability to manipulate the complex interactions between immune cells and the tumor microenvironment is crucial for developing more effective cancer therapies.

[0009] Targeting immune cells in the tumor microenvironment is a promising strategy for improving the effectiveness of cancer treatment [13-15]. This approach aims to shift the balance of immune cells in the microenvironment from pro-tumor to anti-tumor. One way to do this is by increasing the activity of immune cells that can recognize and eliminate cancer cells, such as T cells, natural killer cells, and pro-inflammatory M1 macrophages (classical activated macrophages). This can generally be achieved through the use of immune checkpoint inhibitors that release the brakes preventing immune cells from attacking tumors. Another strategy is to reduce the number or activity of immune cells that suppress the immune response, such as regulatory T cells, myeloid suppressor cells, or anti-inflammatory M2 macrophages (alternative activated macrophages). This can be achieved through the use of drugs that specifically target these cell types. Combining these and other approaches, such as vaccines or CAR-T cell therapy, may provide a more comprehensive and effective way to target immune cells in the tumor microenvironment and improve cancer treatment outcomes.

[0010] One mechanism by which FABPs modulate immune cells has been suggested to be through their role in mediating immune cell metabolism, which is crucial for the proper functioning of the immune system. By influencing fatty acid utilization, FABPs regulate signaling pathways involved in energy production, as well as the activation and function of immune cells. For example, FABP5 has been found to modulate T cell lipid metabolism and function in TMEs by mediating the uptake and oxidation of long-chain fatty acids (FAs) within cells. Activated T cells rely primarily on aerobic glycolysis to promote their proliferation and antitumor function. However, tumor-infiltrating T lymphocytes (TILs) expressing high FABP5 levels typically exhibit an exhausted phenotype and impaired antitumor activity due to limited glucose availability and high levels of long-chain FAs. Therefore, inhibition of FABP5 in TILs is expected to activate the cells' antitumor activity by shifting their energy balance [16, 17].

[0011] Another example of immune cell regulation by FABP5 and FABP4 is the regulation of tissue-resident T cells (Trm). Trm cells are a subset of memory T cells that remain autonomous for long periods in non-lymphoid tissues such as the intestines, lungs, reproductive tract, and skin without circulating, providing a first line of defense against antigens and pathogens through rapid recall responses [18-20]. Trm cells have the ability to regulate local immune homeostasis in tissues and to participate in immune responses mediated by pathogens, cancer, and possibly autoantigens in autoimmunity

[21] . In recent years, this unique population of T cells has been shown to contribute to the pathogenesis of autoimmune disorders such as psoriasis, vitiligo, autoimmune hepatitis, and rheumatoid arthritis

[19] . Due to their specialized function and location within tissues, the gene expression signature of Trm cells, as well as their metabolic requirements, differ from those of other types of T cells [20, 22-24]. One of the most prominent characteristics of Trm cells is their dependence on exogenous free fatty acids (FFAs), which are internalized from the surrounding environment, metabolized within the cell, and used to produce ATP necessary for their maintenance and survival

[20] . Recently, it has been reported that Trm cells selectively express fatty acid-binding proteins FABP4 and FABP5, which are essential for FFA uptake into cells

[20] . T cell-specific deficiency of FABP4 / 5 impaired FFA uptake by Trm cells and significantly reduced their lifespan and survival in vivo, but did not affect the survival of central memory T (TCM) cells in lymph nodes

[20] . Therefore, FABP4 / 5 inhibitors can be used to specifically target Trm cells in autoimmune diseases.

[0012] FABP4 and FABP5 are expressed in macrophages and have been shown to regulate their functions by promoting intracellular fatty acid and lipid uptake and metabolism

[25] . FABP4 is expressed in Ly6C - MHCII - CD36 +FABP4 / 5 is highly expressed in circulating monocytes / macrophages and promotes oxidized lipid uptake, foam cell formation, angiogenesis, tissue remodeling, and tumor-promoting functions

[25] . FABP5 is highly expressed in Ly6C+MHCII+CD36- macrophages, which have been shown to be involved in lipid droplet (LD) formation in macrophages

[26] , and in CD11c+ macrophages, which have been shown to promote the secretion of the pro-inflammatory cytokine IL-1b [27, 28], causing ER stress, exhaustion, and ferroptosis [28, 29], thereby influencing the fate of immune cells and disease progression. This suggests that inhibition of FABP4 / 5 in macrophages may be beneficial in the treatment of multiple diseases. It is expected to enhance the antitumor response in cancer, block foam cell formation and chronic inflammation in obesity and atherosclerosis, and promote the anti-inflammatory response in inflammatory and autoimmune diseases and infections. In viral infections, FABP4 has been shown to be involved in the replication and propagation of SARS-CoV-2 (COVID-19) and OCT43 (common cold coronavirus) viruses

[30] . FABP4 has been shown to be recruited to the ER membrane in infected cells, and its inhibition has been shown to reduce viral replication and viral load in cell culture models and improve disease symptoms in vivo

[30] . Overall, the role of FABP in immune cell modulation highlights the importance of lipid metabolism in regulating the immune system and suggests that targeting FABP could be a promising strategy for improving immune cell function and treating immune-related diseases.

[0013] The following describes FABP inhibitor compounds in the relevant technical field. Patent Document 1 (Sulsky et al.) describes certain pyridazinon compounds that inhibit FABP aP2 (FABP4), and the use of these compounds for the treatment of type 2 diabetes and related diseases. Patent Document 2 (Lengyel et al.) describes a method for reducing or inhibiting cancer, comprising administering an inhibitor of FABP4 and / or FABP5 to a subject, wherein the inhibitor is selected from a list of known compounds including carbazolebutanoic acid, arylsulfonamide, sulfonylthiophene, 4-hydroxypyrimidine, 2,3-dimethylindole, benzoylbenzene, biphenyl-alkanoic acid, 2-oxazole-alkanoic acid, tetrahydropyrimidone, pyridone, pyrazinon, arylcarboxylic acid, tetrazole, triazolopyrimidinone, indole, or BMS480404. Patent Document 3 (Shipps, Jr. et al.) describes certain heterocyclic compounds that inhibit FABP, and the use of these compounds for the treatment of diseases or disorders including cardiovascular disease, metabolic disorders, obesity, diabetes, dyslipidemia, and impaired glucose tolerance. Patent Document 4 (Buettelmann, et al.) describes certain urea derivative compounds that inhibit FABP4 and / or FABP5, and the use of these compounds for the treatment of diseases or disorders including type 2 diabetes, atherosclerosis, chronic kidney disease, and cancer. Patent Document 5 (Levi, et al.) describes certain aniline derivative compounds that inhibit FABP4 and / or FABP5, and the use of these compounds for the treatment of diseases related to fatty acid metabolism, including cancer.

[0014] There remains a need for improved FABP inhibitor compounds, including compounds that inhibit one or more of FABP3, FABP4, FABP5, and FABP7, and for the use of these compounds in the treatment of diseases and disorders, including cancer. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] U.S. Patent No. 6,919,323 [Patent Document 2] U.S. Patent No. 8,748,470 [Patent Document 3] U.S. No. 8,815,875 [Patent Document 4] U.S. Patent No. 9,278,918 [Patent Document 5] International Publication No. 2023043803 [Overview of the Initiative]

[0016] This disclosure generally relates to compounds based on substituted 2-aminothiophene structures that are inhibitors of one or more of FABP3, FABP4, FABP5, and FABP7 (i.e., “FABP3 / 4 / 5 / 7 inhibitors”), as well as the uses of these inhibitors, methods for preparing these inhibitors, and the use of these inhibitors in pharmaceutical compositions for treating diseases related to fatty acid metabolism. This summary is intended to introduce the subject matter of this disclosure but does not exhaust all of the embodiments, combinations, or variations discussed and described within this disclosure. Further embodiments are discussed and described in the detailed description, drawings, and claims disclosure.

[0017] In at least one embodiment, the present disclosure relates to structural formula I: [ka] (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3Combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4-alkyl, methoxy, or fluoro. X is the following formula:

Chemical formula

[0018] In at least one embodiment of the compound of structural formula I of the present disclosure, the compound excludes the specific compounds shown in Table 1 (shown elsewhere in this specification).

[0019] In at least one embodiment of the compound of structural formula I of the present disclosure, position R 1 The chemical group in is a cyano group, and the compound has structural formula Ia: [ka] It holds.

[0020] In at least one embodiment, the compound of structural formula Ia is a compound having a structural formula selected from Ij, Ik, Il, Im, In, Io, Ip, Iq, Ir, Is, and It, as shown in Table 2 (otherwise in this specification).

[0021] In at least one embodiment of the compound of structural formula I of the present disclosure, position R 2 and R 3 The chemical substituents in the compound combine to form a 5- to 8-membered aryl or heteroaryl ring, and the compound has structural formula Ib [ka] (In the formula, R 10 and R 11 Each element independently comprises hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, and cyclobutyl.

[0022] In at least one embodiment, the compound of structural formula Ib is a compound having a structural formula selected from Iu, Iv, and Iw shown in Table 3 (otherwise in this specification).

[0023] In at least one embodiment of the compound of structural formula I of the present disclosure, R 1 The chemical group in is a 5-membered heteroaryl ring (e.g., 3-substituted 1,2,4-oxadiazole), and the compound is Ic, Id, Ie, If, Ig, Ih, and Ii: [Table A] (In the formula, R 12It has a structural formula selected from hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, and phenyl.

[0024] In at least one embodiment, the compounds of structural formulas Ic, Id, Ie, If, Ig, Ih, and Ii include, but are not limited to, compounds having structural formulas Ix, Iy, Iz, Iaa, Ibb, Icc, Idd, Iee, Iff, Igg, Ihh, Iii, Ijj, Ikk, Ill, Imm, Inn, Ioo, Ipp, Iqq, and Irr, as shown in Table 5 (and elsewhere in this specification).

[0025] Structural Formula I, Structural Formula Ia, Structural Formula Ib, Structural Formula Ic, Structural Formula Id, Structural Formula Ie, Structural Formula If, Structural Formula Ig, Structural Formula Ih, Structural Formula II, Structural Formula Ij, Structural Formula Ik, Structural Formula Il, Structural Formula Im, Structural Formula In , Structural Io, Structural Ip, Structural Iq, Structural Ir, Structural Is, Structural It, Structural Iu, Structural Iv, Structural Iw, Structural Ix, Structural Iy, Structural Iz, Structural Iaa, Structural Ibb, Structure In at least one embodiment of the compounds of formula Icc, structural formula Idd, structural formula Iee, structural formula Iff, structural formula Igg, structural formula Ihh, structural formula III, structural formula Ijj, structural formula Ikk, structural formula Ill, structural formula Imm, structural formula Inn, structural formula Ioo, structural formula Ipp, structural formula Iqq, and structural formula Irr, the X portion is selected from the exemplary portions shown in Table 6, Table 7, or Table 8 (otherwise in this specification).

[0026] In at least one embodiment, the present disclosure relates to structural formula II: [ka] (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4 alkyl, methoxy, or fluoro. Y is a heteroatom selected from -S- and -O-, or -CR 8 R 9 -and here, R 8 and R 9 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They come together to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring. R 4 , R 5 , R 6 and R 7 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, and / or R 4 and R 5 They are together, or R 6 and R 7 They combine to form a cyclopropyl ring or a cyclobutyl ring, or R 5 and R 6 The present invention provides FABP3 / 4 / 5 / 7 inhibitor compounds (which together form a 5- to 6-membered carbocyclic or heterocyclic ring having Y as a ring member) and any pharmaceutically acceptable salts thereof.

[0027] In at least one embodiment of the compound of structural formula II of this disclosure, the compound excludes the compounds shown in Table 1.

[0028] In at least one embodiment of the compound of structural formula II, position R 1 The chemical group in this compound is a cyano group, and the compound has structural formula IIa. [ka] (In the formula, the chemical group R 2 , chemical group R 3 , chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 (as defined for the compound of structural formula II). In at least one embodiment, a compound having the substructure of structural formula IIa may have structural formulas IIj, IIk, IIl, IIm, IIn, IIo, IIp, IIq, IIr, IIs, or IIt as shown in Table 9 (otherwise in this specification).

[0029] In at least one embodiment of the compound of structural formula II, position R 1 The chemical group in R is a cyano group, 2 and R 3 They combine to form a 6-membered aryl ring, and the compound has structural formula IIb. [ka] (In the formula, the chemical group R 2 , chemical group R 3 , chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 This is as defined for the compound of structural formula II, and R 10 and R 11 Each of these elements independently comprises hydrogen, a halogen, a C1-C4 linear or branched alkyl group, cyclopropyl, and cyclobutyl. In at least one embodiment, the compound of structural formula IIb may have structural formulas IIu, IIv, or IIw as shown in Table 10 (otherwise in this specification).

[0030] In at least one embodiment of the compound of structural formula II, position R 1 The chemical group in is a 5-membered heteroaryl ring, R 2 and R 3 The chemical groups in each are independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl, and the compounds are of structural formulas IIc, IId, IIe, IIf, IIg, IIh, or III. [Table B] (In the formula, the chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 This is as defined for the compound of structural formula II, and the chemical group R 12 The compound has hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, or phenyl. In at least one embodiment, the compounds of structural formulas IIc, IId, IIe, IIf, IIg, IIh, and IIi are compounds having structural formulas IIx, IIy, IIz, IIaa, IIbb, IIcc, IIdd, IIee, IIff, IIgg, IIhh, IIii, IIjj, IIkk, IIll, IImm, IInn, IIoo, IIpp, IIqq, IIrr, and IIss, as shown in Table 12 (otherwise in this specification).

[0031] In at least one embodiment of a compound of structural formula I or structural formula II of the present disclosure, the compound is an exemplary compound shown in Table 13 (otherwise in this specification): compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 28, compound 2 9. Select from any of the following: compound 30, compound 31, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 40, compound 41, compound 42, compound 43, compound 44, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61, compound 62, compound 63, compound 64, and compound 65.

[0032] In another embodiment, the disclosure provides a pharmaceutical composition comprising a compound of structural formula I or structural formula II and one or more auxiliary components.

[0033] In another embodiment, the disclosure provides the use of FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II in a method for producing a drug or pharmaceutical composition for the treatment of a disease or condition affected by one or more of the FABPs FABP3, FABP4, FABP5, and FABP7 (i.e., a “condition affected by FABP3 / 4 / 5 / 7”).

[0034] In another embodiment, the Disclosure provides a method for treating a subject having a disease or condition affected by FABP3 / 4 / 5 / 7, the method comprising administering to the subject in need a therapeutically effective amount of a compound of structural formula I or structural formula II, or a pharmaceutical composition comprising a compound of structural formula I or structural formula II and one or more auxiliary components.

[0035] In at least one embodiment, the compounds of structural formula I or structural formula II can be used therapeutically in subjects affected by FABP3 / 4 / 5 / 7, including atherosclerosis, coronary artery atherosclerosis, arteriofibrosis, pulmonary hypertension, heart failure, obesity, type 2 diabetes, type 1 diabetes, gestational diabetes, polycystic ovary syndrome, endometriosis, conditions affected by lipid metabolism and serum free fatty acid levels, metabolic disorders, fatty liver disease, renal fibrosis, systemic inflammation, acute inflammation, allergic inflammation, respiratory inflammation, viral infections (e.g., COVID-19, common cold), skin diseases (e.g., vitiligo, psoriasis, atopic dermatitis, allergic contact dermatitis, mycosis fungoides, alopecia areata, scarring alopecia, graft-versus-host disease (GvHD), contact dermatitis, chronic eczema, Herpetiform dermatitis, cutaneous lupus, scleroderma, dermatomyositis, vasculitis, pemphigus, epidermolysis bullosa, linear IgA, bullous diseases), neurological conditions and neurological diseases (e.g., pain, multiple sclerosis (MS), Parkinson's disease), autoimmune diseases (e.g., experimental autoimmune encephalomyelitis (EAE), asthma, type 1 diabetes, autoimmune lung disease, autoimmune hepatitis, rheumatoid arthritis (RA), spondyloarthritis, bullous stomatitis) The following conditions may be selected: lupus infection, multiple sclerosis (MS), lupus nephritis, Crohn's disease, ulcerative colitis, and food allergies; ischemic stroke; graft-versus-host disease (GvHD); and cancer (e.g., breast cancer, prostate cancer, ovarian cancer, skin cancer, gastric cancer, glioma, cholangiocarcinoma, bladder cancer, multiple myeloma, colorectal cancer, hepatocellular carcinoma, cervical cancer, oral squamous cell carcinoma, and / or non-small cell lung cancer (NSCLC)).

[0036] In another embodiment, the disclosure also provides a method for preparing a compound of structural formula I or structural formula II, the method comprising (a) in a solvent, formula III: [ka] (In the formula, Y, R 4 , R 5 , R 6 and R 7 The substituted anhydride compounds of formulas I and II are defined above, as follows: [ka] (wherein, R 1 , R 2 and R 3 are as defined above for the compounds of Formula I and Formula II), and combining with a substituted 2-amino-thiophene compound, and (b) removing the solvent to obtain a compound having Structural Formula I or Structural Formula II.

[0037] In at least one embodiment of the compound of Formula IV, the compound has Structural Formula IVa: [Chemical Formula] (wherein, chemical group R 2 , chemical group R 3 , chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 are as defined for the compound of Structural Formula II). In at least one embodiment, the compound of Structural Formula IVa is selected from Compound 4a, Compound 4b, Compound 4c, Compound 4d, Compound 4e, Compound 4f, Compound 4g, Compound 4h, Compound 4i, Compound 4j, and Compound 4k shown in Table 14 and Table 15 (elsewhere in this specification).

[0038] In at least one embodiment of the compound of Formula IV, the compound has Structural Formula IVb: [Chemical Formula] (wherein, chemical group R 2 , chemical group R 3 , chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 are as defined for the compound of Structural Formula II, and R 10 and R 11Each of these elements independently comprises hydrogen, a halogen, a C1-C4 linear or branched alkyl group, cyclopropyl, and cyclobutyl. In at least one embodiment, the compound of structural formula IVb is selected from compound 4l, compound 4m, and compound 4n shown in Table 16 (otherwise in this specification).

[0039] In at least one embodiment of the compound of formula IV, R 1 The chemical group in is a five-membered heteroaryl ring (e.g., a 3-substituted 1,2,4-oxadiazole), and the compound is selected from the compounds of structural formulas IVc, IVd, IVe, IVf, IVg, IVh, and IVi shown in Table 17 (otherwise in this specification). In at least one embodiment, the compounds of structural formulas IVc, IVd, IVe, IVf, IVg, IVh, and IVi are selected from the compounds 4o, 4p, 4q, 4r, 4s, 4t, 4u, 4v, 4w, 4x, 4y, 4z, 4aa, 4bb, 4cc, 4dd, 4ee, 4ff, 4gg, 4hh, and 4ii shown in Table 18 (otherwise in this specification).

[0040] The novel features and advantages of this disclosure will be better understood by referring to the following embodiments for carrying out the invention and the accompanying drawings (and further, "figure" and "FIG." as used herein) which describe exemplary embodiments in which the principles of the present invention are utilized. [Brief explanation of the drawing]

[0041] [Figure 1]This plot shows the results indicating that inhibitor compounds FTS005, FTS030, FTS031, FTS037, and FTS039 do not activate transcription by PPARα, PPARγ, or PPARδ. This is a transcriptional activation assay in COS7 cells co-transfected with vectors encoding either PPARα (Figure 1A), PPARγ (Figure 1B), or PPARδ (Figure 1C) along with a PPAR response element (PPRE) and a vector containing β-galactosidase acting as a transfection control. Cells were treated with either the PPAR-specific agonists Wy-134643 (5 μM), rosiglitazone (5 μM), and GW0742 (5 μM), or one of the compounds FTS005, FTS030, FTS031, FTS037, and FTS039 (10 μM). The data are the mean ± SD from three independent experiments. [Figure 2-1] This plot shows that FTS005, a FABP3 / 4 / 5 / 7 inhibitor compound that exhibits specificity for FABP4 / 5, inhibits TNBC cell growth in a FABP5-dependent manner and more efficiently than SBF-I26, a FABP5 / 7 inhibitor. In all experiments, cells were treated for 4 days with one of the compounds indicated at the stated concentrations. Cell confluence was measured using Incucyte software. Figure 2A: Results showing that various concentrations of compound FTS005 inhibit the proliferation of MB-231 and BT-549 cell lines. IC50 values ​​were calculated using the GraphPad fitting algorithm. Figure 2B: Plot showing that various concentrations of compound FTS005 inhibit the proliferation of wild-type MB-231 cell lines, but not the proliferation of cells that stably express FABP5 shRNA ("shF5"). Figure 2C: Plot showing that compound FTS005 at various concentrations inhibits the proliferation of the MB-231 cell line more effectively than the commercially available FABP5 / 7 inhibitor SBFI-26. Data are mean ± SD from three independent experiments. [Figure 2-2] Same as above [Figure 3-1]This plot shows results demonstrating that the FABP3 / 4 / 5 / 7 inhibitor compound FTS005 inhibits the growth of mouse mammary gland cell lines expressing high levels of FABP5 compared to those expressing low levels of the gene. In all experiments, cells were treated with the compound at the indicated concentrations for 4 days. Cell confluence was measured using Incucyte software. Figure 3A: Levels of FABP5 mRNA in the provided (indicated) cell lines were measured by QPCR. Figure 3B: Results demonstrating that compound FTS005 inhibits the proliferation of MB-231 and 4T1 cell lines in correlation with the FABP5 expression level in cells. IC50 values ​​were calculated using the GraphPad fitting algorithm. Figure 3C: Results demonstrating that compound FTS005 inhibits cell proliferation only in cells expressing FABP5. Data are mean ± SD from three independent experiments. [Figure 3-2] Same as above [Figure 4-1] This plot shows the results demonstrating that FABP3 / 4 / 5 / 7 inhibitor compounds FTS005, FTS040, FTS041, FTS042, FTS043, FTS044, FTS045, and FTS049 inhibit the proliferation of ovarian cancer cells (OVCAR8). In all experiments, cells were treated with the indicated concentration of the compound for 4 days. Cellular confluence was measured using Incucyte software. Figure 4A: Results showing that compounds FTS005, FTS040, FTS041, FTS042, FTS043, FTS044, FTS045, and FTS049 inhibit the proliferation of the OVCAR8 cell line. Figure 4B: IC50 values ​​for all compounds were calculated using the GraphPad fitting algorithm. Data are mean ± SD from three independent experiments. [Figure 4-2] Same as above [Figure 5-1]This figure shows results demonstrating that the FABP3 / 4 / 5 / 7 inhibitor FTS005 inhibits neuroblastoma growth and sensitizes cells to all-trans retinoic acid (atRA) treatment. NPG human neuroblastoma cells were treated with the indicated concentrations of FTS005 for 4 days in the presence or absence of retinoic acid (1 mM). Cell confluence was measured using Incucyte software. Figure 5A: Results showing that compound FTS005 inhibits NPG cell proliferation but shows a synergistic effect when combined with atRA. Figures 5B and 5C: Results showing that compound FTS005 combined with atRA inhibits cell proliferation more efficiently than atRA alone. IC50 values ​​were calculated using the GraphPad fitting algorithm. Data are mean ± SD from three independent experiments. [Figure 5-2] Same as above [Figure 6-1] This figure shows results demonstrating that the FABP3 / 4 / 5 / 7 inhibitor FTS005 suppresses tumor growth in vivo in a xenograft model. Figure 6A: Tumor growth in the MB-231 xenograft model. MB-231 cells (5 × 10⁶) were transplanted into the right flank of 7-week-old female NOD scid gamma (NSG) mice. One day later, FTS005 treatment (20 mg / kg or 40 mg / kg) or vehicle treatment was initiated five times a week by forced oral administration. Tumor growth was monitored twice a week. Mean ± SD (n=5) (unpaired t-test). Figure 6B: Plotted data represent the tumor weight of each mouse at the endpoint (day 24). In all experiments, statistical significance between control mice and treated mice was evaluated using Student's t-test. Figure 6C: Representative histological sections of paraffin-embedded sections derived from tumors stained with antibodies against Ki67, VEGFA, and F4 / 80. Figures 6D, 6E, and 6F: Plots showing the intensity of immunohistochemical staining for each sample. Figure 6G: Expression levels of the indicated PPARδ target genes in the collected tumor-derived samples. Data in Figures 5C, 5D, and 5G are mean ± SD for 3 animals / group. Statistical analysis was performed using a two-sided Student's t-test. *p<0.05, **p<0.1 (0.01). [Figure 6-2] Same as above [Figure 6-3] Same as above [Figure 7-1] This figure shows results demonstrating that the FABP3 / 4 / 5 / 7 inhibitor FTS005 suppresses tumor growth in vivo in a syngeneic mouse model. Figure 7A: Tumor growth in a 4T1 syngeneic xenograft model. 4T1 cells (1 × 10⁵) were transplanted into the mammary fat pads of 7-week-old female BALB / c mice. After 1 day, FTS005 treatment (40 mg / kg) by forced oral administration or vehicle treatment was initiated 5 times per week. Tumor growth was monitored twice per week. Mean ± SD (n=4) (unpaired t-test). Figure 7B: Plotted data represent the weight of individual tumors in each mouse at the endpoint (day 32). In all experiments, statistical significance between control mice and treated mice was assessed using Student's t-test. Figure 7C: Expression levels of VEGFA, ACSL1, and PLIN2, known PPARδ direct targets involved in tumor growth and FA storage and oxidation, in tumor samples collected from treated and untreated mice. Figure 7D: Representative histological sections of treated and untreated paraffin-embedded tumor sections stained with antibodies against the growth markers Ki67 and VEGFA. Figures 7E and 7F: Plots showing the percentage of positive immunohistochemical staining for Ki67 (Figure 7E) and VEGFA (Figure 6F (Figure 7F)) relative to the total section area for each sample. *p<0.05. [Figure 7-2] Same as above [Figure 8-1]This figure shows the results of metabolomics analysis of glycolysis, the TCA cycle, FA oxidation, long-chain fatty acids, and ADP and ATP metabolites, measured by LC / MS / MS in tumor samples collected from treated and untreated mice. Figure 8A: Amount of long-chain fatty acids in tumor cells. Figure 8B: Amount of TCA cycle metabolites in treated and untreated tumors. Figure 8C: Amount of ADP and ATP and their calculated ratios in treated and untreated tumors. Figure 8D: Amount of glycolysis metabolites in treated and untreated tumors. Data are mean ± SD for 3 mice / group. Statistical analysis was performed using a two-sided Student's t-test. *p<0.05, **p<0.1 (0.01). [Figure 8-1] Same as above [Figure 8-2] Same as above [Figure 9] This figure shows results demonstrating that the FABP3 / 4 / 5 / 7 inhibitor FTS005 modulates tumor-associated macrophages in the tumor microenvironment in a 4T1 syngeneic mouse model. Figures 9A, 9B, and 9C: Representative histological sections of treated and untreated tumor-derived paraffin-embedded sections stained with antibodies against F4 / 80 (Figure 9A), CD68 (Figure 9B), and CD163 (Figure 9C). Figures 9D, 9E, and 9F: Plots showing the percentage of positive immunohistochemical staining with each antibody for each sample. Data in Figures 9D, 9E, and 9F are mean ± SD for 3 mice / group. Statistical analysis was performed using a two-sided Student's t-test. *p<0.05. [Figure 10-1]This figure shows results demonstrating that the FABP3 / 4 / 5 / 7 inhibitor FTS005 modulates T cells in the tumor microenvironment in a 4T1 syngeneic mouse model. Figure 10A: Representative histological sections of paraffin-embedded sections from treated and untreated tumors, stained with antibodies against CD3 (A), CD4 (B), and CD8 (C). Figure 10B: Plots showing the percentage of positive immunohistochemical staining with each antibody for each sample. Data are mean ± SD for 3 mice / group. Statistical analysis was performed using a two-sided Student's t-test. *p<0.05. Figures 10C and 10D: Plots showing the frequency of CD4 and CD8 spleen T cells (Figure 10C) and activated CD4 and CD8 T cells (TNFα + CD4 / CD8 T cells) (Figure 10D) from untreated and treated syngeneic mice. Figure 10E: Collected splenocytes were stimulated in vitro (IVS) with Luc2 peptide (2 μg / mL) in T cell medium (5 × 10⁶ cells / well) supplemented with 20 ng / mL IL-7 and 20 U / mL IL-2. Cells were counted 2 weeks after IVS (n=5). Figure 10F: After 2 weeks of IVS, splenocytes were co-cultured overnight with 4T1Luc2-CFSE high (target, derived from Balb / c) and F420Luc2-CFSE low (control, derived from B6) (target:effector = 1:5). The following day, live CFSE+ cells were counted by flow cytometry, and the percentage of specific lysis was calculated using the formula (%) = 100(1 - live CFSE high / live CFSE low) and normalized by the control. Statistical significance was measured by a two-way Student's t-test: ns, non-specific (no significant difference), *p<0.05. [Figure 10-2] Same as above [Figure 11]This figure shows the results of immune cell profiling performed using the nCounter PanCancer Immune Profiling Panel, demonstrating that treatment with the FABP3 / 4 / 5 / 7 inhibitor FTS005 modulates multiple immune cells within the tumor microenvironment in a 4T1 syngeneic mouse model. Figure 11: Immune cell profiles showing all immune cell types found to be significantly different in the analysis (P-value < 0.05, magnification change > 1.5). [Figure 12] This figure shows results demonstrating that FTS005 inhibits lipid uptake in cell culture models of fatty degenerated and mature adipocytes. Figure 12A: Plot showing the intensity of Nile Red staining in liver HepG2 cells treated with a specified concentration of FTS005 or a known FABP4 inhibitor, BMS309403, for 4 hours, followed by oleic acid treatment (OA) (1 mM, 24 hours). Lipid accumulation was measured only in viable cells that were Dapi-stain positive. Total lipid uptake was quantified using a Biotech Cytation 5 plate reader. Figure 12B: Histogram showing the color intensity of Nile Red staining in viable mature adipocytes after treatment with FTS005. 3T3-L1 preadipocytes were differentiated in culture. Cells were treated with FTS005 or a known FABP4 inhibitor, BMS309403 (BMS), on day 6 and stained with Nile Red on day 12. [Figure 13-1]This figure shows results demonstrating that the FABP inhibitor FTS005 modulates macrophage differentiation in culture. Figures 13A, 13C, and 13D: Frequencies of the M1 marker MHC-II (Figure 13A) and the M2 markers CD36 (Figure 13C) and CD206 (Figure 13D) in naive macrophages after differentiation into M1 or M2 macrophages. Figures 13B and 13E: Levels of cytokines IL-12 (Figure 13B) and IL-10 (Figure 13E) secreted from M1 and M2 macrophages, respectively, during differentiation. Figures 13F, 13G, and 13H: Expression levels of CD206 (Figure 13F) and levels of IL-10 (Figure 13G) and IL-12 (Figure 13H) in macrophages differentiated from naive to M2 macrophages in the absence and presence of the FABP4 / 5 inhibitor FTS005. Figures 13I, 13J, and 13K: Frequency (Figure 13I) and expression level (Figure 13J) of CD206, and level (Figure 13K) of IL-12, in cells differentiated from M1 macrophages to M2 macrophages in the absence and presence of FTS005. [Figure 13-2] Same as above [Figure 13-3] Same as above [Modes for carrying out the invention]

[0042] In this specification and the appended claims, many terms will be used as references, and these terms shall be defined as follows:

[0043] comprehensive definition In this specification and the appended claims, many terms will be used as references, and these terms shall be defined as follows:

[0044] All percentages, ratios, and proportions in this specification shall be given by weight unless otherwise specified. All temperatures shall be given in degrees Celsius (°C) unless otherwise specified.

[0045] The terms "a" and "an" are defined as one or more unless expressly required otherwise by this disclosure.

[0046] In this specification, ranges are sometimes given that are "approximately" from one particular value to and / or "approximately" another particular value. Where such ranges are given, the alternative aspects include the range from one particular value to and / or other particular values. Similarly, where a value is indicated as an approximation by the use of "approximately" at the beginning, it will be understood that this particular value forms an alternative aspect. It will further be understood that each endpoint of these ranges is significant, whether in relation to other endpoints or independently of other endpoints.

[0047] The terms “comprise” (and any form of comprise, such as “comprises” and “comprising”) are unrestricted linking verbs, as are “have” (and any form of have, such as “has” and “having”), “include” (and any form of include, such as “includes” and “including”), and “contain” (and any form of contain, such as “contains” and “containing”). As a result, a device that “comprises,” “has,” “includes,” or “contains” one or more elements has one or more of those elements, but is not limited to having only those elements. Similarly, a method that “comprises,” “has,” “includes,” or “contains” one or more steps has one or more of those steps, but is not limited to having only those one or more steps.

[0048] Any embodiment of any of the disclosed methods or compositions may consist of or essentially consist of any of the described steps, elements, and / or features, rather than merely comprise, include, contain, or have any of them. Accordingly, in any of the claims, the terms “consisting of” or “consisting essentially of” may be replaced with any of the unrestricted linking verbs listed above in order to change the scope of the claim that would otherwise be granted using unrestricted linking verbs.

[0049] Unless specifically prohibited by the nature of this disclosure or the embodiments, one or more features of one embodiment may be applied to other embodiments, even if not described or illustrated.

[0050] Any embodiment of any of the disclosed compounds or methods may consist of or essentially consist of any of the described steps, elements, and / or features, rather than merely comprise, include, contain, or have any of them. Accordingly, in any of the claims, the terms "consisting of" or "consisting essentially of" may be replaced with any of the unrestricted linking verbs listed above in order to change the scope of the claim that would otherwise be granted using unrestricted linking verbs.

[0051] Unless specifically prohibited by the nature of this disclosure or the embodiments, one or more features of one embodiment may be applied to other embodiments, even if not described or illustrated.

[0052] As used herein, the term “subject” means a human or animal that is expected to benefit from administration of any of the FABP3 / 4 / 5 / 7 inhibitor compounds discussed herein, for example, those suffering from a disease affected by the expression of one or more of the FABPs FABP3, FABP4, FABP5, and FABP7, malregulated free fatty acid serum levels, cancer, metabolic syndrome, or atherosclerosis.

[0053] As used herein, terms such as “treat,” “treating,” and “treatment” refer to reducing or improving a disorder and / or its associated symptoms. It will be understood, though not excluded, that treatment of a disorder or condition does not require the complete elimination of the disorder, condition, or its associated symptoms.

[0054] As used herein, terms such as "prevent," "preventing," "preventive measures," etc., are encompassed within the term "treat" and refer to reducing the probability of developing a disability or condition in subjects who do not have a disability or condition but are at risk of developing one, or who are prone to developing one.

[0055] As used herein, “pharmaceutically acceptable” means physiologically acceptable for either human or veterinary use. In addition, “pharmaceutically acceptable” means a material that is not biologically or otherwise undesirable; that is, it can be administered to a subject without causing any undesirable biological effects or adverse interactions with any other components of the pharmaceutical composition containing it. Essentially, pharmaceutically acceptable materials are non-toxic to the recipient. The carrier will, of course, be selected to minimize any degradation of the active ingredient and any adverse side effects in the subject, as is well known to those skilled in the art. For a discussion of pharmaceutically acceptable carriers and other components of pharmaceutical compositions, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, 1990.

[0056] As used herein, “test active substance” or “test compound” refers to the active substance or compound screened in one or more assays described herein. Test active substances include a wide variety of common types of compounds, including, but are not limited to, small organic molecules, known pharmaceuticals, polypeptides; carbohydrates such as oligosaccharides and polysaccharides; polynucleotides; lipids or phospholipids; fatty acids; steroids; or amino acid analogs. Test active substances can be obtained from libraries such as natural product libraries and combinatorial libraries. In addition, methods are known for automating assays that enable the screening of thousands of compounds in a short time.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. Any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the invention described herein, but preferred methods and materials are described herein. All publications referenced herein constitute part of this specification by reference to disclose and describe the methods and / or materials in relation to the methods and / or materials referenced in those publications.

[0058] Details relating to the embodiments described above and other embodiments are described below.

[0059] The aryl, heterocyclic, and heteroaryl units disclosed herein may be substituted with one or more hydrogen atoms. Non-limiting examples of hydrogen substitution include:

[0060] Examples of substituted and unsubstituted linear, branched, or cyclic alkyl units include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (C4), tert-butyl (C4), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6). Examples of substituted linear, branched, or cyclic alkyls include, but are not limited to, hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-difluoroethyl (C2), 2,2,2-trifluoroethyl (C3), 3-carboxypropyl (C3), and 2,3-dihydroxycyclobutyl (C4).

[0061] Examples of substituted and unsubstituted linear, branched, or cyclic alkenyls include ethenyl (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) (C3), and buten-4-yl (C4). Non-exclusive examples of substituted linear or branched alkenyls include 2-chloroethenyl (also 2-chlorovinyl) (C2), 4-hydroxybuten-1-yl (C4), 7-hydroxy-7-methylocta-4-en-2-yl (C9), and 7-hydroxy-7-methylocta-3,5-dien-2-yl (C9).

[0062] Examples of substituted and unsubstituted linear or branched alkynyls include ethinyl (C2), propa-2-inyl (also propargyl) (C3), propyne-1-yl (C3), and 2-methylhexa-4-in-1-yl (C7). Non-exclusive examples of substituted linear or branched alkynyls include 5-hydroxy-5-methylhexa-3-inyl (C7), 6-hydroxy-6-methylhepta-3-in-2-yl (C8), and 5-hydroxy-5-ethylhepta-3-inyl (C9).

[0063] As used herein, substituted and unsubstituted "alkoxys" are of the general formula -OR 100 (In the formula, R 100 In this specification, represents a unit having an alkyl, alkylenyl (alkenyl), or alkynyl unit as defined above (for example, methoxy, methoxymethyl, or methoxymethyl).

[0064] As used herein, substituted and unsubstituted "haloalkyl" refers to alkyl units in which a hydrogen atom is substituted by one or more halogen atoms, such as trifluoromethyl, 1,2-dichloroethyl, and 3,3,3-trifluoropropyl.

[0065] As used herein, the term “aryl” refers to a cyclic organic unit comprising at least one benzene ring having a conjugated aromatic six-membered ring, non-limiting examples of which include phenyl(C6), naphthylene-1-yl(C6).10 ), naphthylene-2-yl(C 10 Examples include: ) One or more hydrogen atoms of the aryl ring may be substituted by another organic or inorganic radical. Non-limiting examples of substituted aryl rings include 4-fluorophenyl (C6), 2-hydroxyphenyl (C6), 3-methylphenyl (C6), 2-amino-4-fluorophenyl (C6), 2-(N,N-diethylamino)phenyl (C6), 2-cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), and 8-hydroxynaphthylene-2-yl (C6). 10 ), 4,5-dimethoxynaphthylene-1-yl(C 10 ), and 6-cyanonaphthylene-1-yl(C 10 ) are some examples.

[0066] The term “heteroaryl” refers to an organic unit comprising a five- or six-membered conjugated aromatic ring in which at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen, or sulfur. A heteroaryl ring may include a single ring, for example, a ring having five or six atoms in which at least one of the ring atoms is a heteroatom not limited to nitrogen, oxygen, or sulfur, such as a pyridine ring, a furan ring, or a thiofuran ring. A “heteroaryl” may also be a condensed polycyclic heteroaromatic ring system in which at least one of the rings is an aromatic ring, and at least one atom of the aromatic ring is a heteroatom containing nitrogen, oxygen, or sulfur. The following are non-limiting examples of heteroaryl rings as provided in this disclosure: [ka]

[0067] The term "heterocyclic ring" refers to a ring system having 3 to 10 atoms, where at least one of the ring atoms is a heteroatom not limited to nitrogen, oxygen, or sulfur. The ring can be a single ring, a fused ring, or a bicyclic ring. Non-restrictive examples of heterocyclic rings include: [ka]

[0068] All of the heteroaryl or heterocycles described above may be optionally substituted with one or more substituents to hydrogen, as further described herein.

[0069] Throughout this disclosure, the terms spelled "thiophene-2-yl and thiophene-3-yl" are interpreted as follows: [ka] While heteroaryl units having these rings are used to describe them, when naming the compounds of this disclosure, the chemical nomenclature of these parts is usually spelled "thiophen-2-yl and thiophen-3-yl," respectively. In this specification, the terms "thiophen-2-yl and thiophen-3-yl" are used merely to clarify to those skilled in the art which rings are referred to herein when describing these rings as units or parts constituting the compounds of this disclosure.

[0070] The following is hydrocarbyl (C1~C 20 These are non-limiting examples of units in which hydrogen atoms can be substituted on linear, branched, or cyclic alkyl, aryl, heterocyclic, or heteroaryl rings: i) Linear, branched, or cyclic alkyl, alkenyl, and alkynyl compounds, such as methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), cyclopropyl (C3), propylene-2-yl (C3), propargyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), cyclobutyl (C4), n-pentyl (C5), cyclopentyl (C5), n-hexyl (C6), and cyclohexyl (C6); ii) Substituted or unsubstituted aryl compounds, for example, phenyl, 2-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 2-aminophenyl, 3-hydroxyphenyl, 4-trifluoromethylphenyl, and biphenyl-4-yl; iii) Substitutive or non-substitutive heteroalgae, examples of which are given herein; iv) Substituted or unsubstituted heteroaryls, examples of which are shown herein below; v) LC, e.g., -OH, -CH2OH, -OCH3, -CH2OCH3, -OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; vi) keto, for example -COCH3, -CH2COCH3, -OCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3, and -CH2COCH2CH2CH3; vii) Alkylcarboxyls, e.g., -CO2CH3, -CH2CO2CH3, -CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3, and -CH2CO2CH2CH2CH3; viii) Alkylamides, e.g., -CONH2, -CH2CONH2, -CONHCH3, -CH2CONHCH3, -CON(CH3)2, and -CH2CON(CH3)2; ix) Alkyl carbamates, e.g., -OC(O)NH2, -CH2OC(O)NH2, -OC(O)NHCH3, -CH2OC(O)NHCH3, -OC(O)N(CH3)2, and -CH2OC(O)N(CH3)2; x) Alkylaminos, e.g., -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3); xi) Halogens -F, -Cl, -Br, and -I; xii)-CH m X n (In the formula, X is a halogen, m is between 0 and 2, and m+n=3), for example, -CH2F, -CHF2, -CF3, -CCl3, or -CBr3; xiii) Alkyl cyanosides, e.g., -CN, -CH2CN, and -CH2CH2CN; xiv) Alkyl-nitro, e.g., -NO2, -CH2NO2, and -CH2CH2NO2; xv) Alkylene sulfonyl alkyl, e.g., -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; xvi) Alkylene sulfonic acid, e.g., -SO3H, -CH2SO3H; xvii) A hydroxyl group or a thiol group; or xviii) Amino group, monosubstituted amino or disubstituted amino.

[0071] For the purposes of this disclosure, the terms “compound,” “analog,” and “composition of matter” equally and adequately represent all HIF-1α-prolyl hydroxylase enzyme inhibitors described herein, including all enantiomers, diastereomers, salts, etc., and the terms “compound,” “analog,” and “composition” are used without distinction throughout this specification.

[0072] The compounds disclosed herein include all salt forms, e.g., salts of basic groups, particularly amines, and salts of acidic groups, particularly carboxylic acids. The following are non-limiting examples of anions that can form pharmaceutically acceptable salts with basic groups: chloride ion, bromide ion, iodide ion, sulfate ion, bisulfate ion, carbonate ion, bicarbonate ion, phosphate ion, formate ion, acetate ion, propionate ion, butyrate ion, pyruvate ion, lactate ion, oxalate ion, malonate ion, maleate ion, succinate ion, tartrate ion, fumarate ion, citrate ion, etc. The following are non-limiting examples of cations that can form pharmaceutically acceptable salts of anionic acidic substituents on the compounds described herein: sodium ion, lithium ion, potassium ion, calcium ion, magnesium ion, zinc ion, bismuth ion, etc.

[0073] FABP3 / 4 / 5 / 7 inhibitor compounds This specification discloses compounds that inhibit one or more of FABP3, FABP4, FABP5, and FABP7 (i.e., "FABP3 / 4 / 5 / 7 inhibitors"). The FABP3 / 4 / 5 / 7 inhibitor compounds of this disclosure have general structural formula I: [ka] (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4 alkyl, methoxy, or fluoro. X is given by the following formula: [ka] (In the formula, Y is a heteroatom selected from -S- and -O-, or -CR 8 R 9 -and here, R 8 and R 9 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They come together to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring. R 4 , R 5 , R 6 and R 7Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, and / or R 4 and R 5 They are together, or R 6 and R 7 They combine to form a cyclopropyl ring or a cyclobutyl ring, or R 5 and R 6 It is based on a substituted thiophene ring that has a portion that together forms a 5- to 6-membered carbon ring or heterocycle with Y as a ring member.

[0074] In at least one embodiment, the compound of structural formula I comprises any pharmaceutically acceptable salt thereof.

[0075] In at least one embodiment, the compounds of structural formula I of the present disclosure exclude the compounds shown in Table 1 below.

[0076] [Table 1]

[0077] In at least one embodiment of a FABP3 / 4 / 5 / 7 inhibitor compound having structural formula I, position R 1 The chemical group in is a cyano group. For example, a compound of formula I can have formula Ia: [ka]

[0078] Exemplary compounds of formula Ia include, but are not limited to, compounds having structural formulas Ij, Ik, Il, Im, In, Io, Ip, Iq, Ir, Is, and It as shown in Table 2 below.

[0079] [Table 2]

[0080] In at least one embodiment, position R 2 and position R 3 The chemical substituents in these compounds combine to form a 5- to 8-membered aryl or heteroaryl ring. For example, compounds of formula I can form a compound of formula Ib [ka] (In the formula, R 10 and R 11 Each of these elements can independently have hydrogen, a halogen, a C1-C4 linear or branched alkyl group, cyclopropyl, and cyclobutyl.

[0081] Exemplary compounds of formula Ib include, but are not limited to, compounds having structural formulas Iu, Iv, and Iw, as shown in Table 3 below.

[0082] [Table 3]

[0083] In at least one embodiment of a FABP3 / 4 / 5 / 7 inhibitor compound having structural formula I, R 1 The chemical group in is a five-membered heteroaryl ring (e.g., a 3-substituted 1,2,4-oxadiazole). For example, the compound of formula I is structural formula Ic, structural formula Id, structural formula Ie, structural formula If, structural formula Ig, structural formula Ih, or structural formula Ii (wherein R is present in the formula) of the compounds shown in Table 4 below. 12 (This can be selected from hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, and phenyl.)

[0084] [Table 4]

[0085] Exemplary compounds of Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, Formula Ih, or Formula Ii include, but are not limited to, compounds having the structural formulas Ix, Iy, Iz, Iaa, Ibb, Icc, Idd, Iee, Iff, Igg, Ihh, Iii, Ijj, Ikk, Ill, Imm, Inn, Ioo, Ipp, Iqq, and Irr shown in Table 5 below.

[0086]

Table 5-1

Table 5-2

[0087] The FABP3 / 4 / 5 / 7 inhibitor compounds having the structural formula I of the present disclosure include a moiety X attached to the amine group of thiophene. The moiety X has the following formula:

Chemical formula

[0088] In at least one embodiment of the compound of structural formula I, the chemical group Y of the X portion is selected from -S- or -O-, and R 4 , R 5 , R 6 and R 7 Each of these is independently a hydrogen atom or a C1-C4 linear or branched alkyl group.

[0089] An exemplary X portion where Y is a sulfur atom (-S-) may include any of the portions shown in Table 6 below.

[0090] [Table 6]

[0091] An exemplary X portion where Y is an oxygen atom (-O-) may include any of the portions shown in Table 7 below.

[0092] [Table 7]

[0093] In at least one embodiment of the compound of structural formula I, the chemical group Y of the X portion is -CR 8 R 9 -and here, R 8 and R 9 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They combine to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring, at position R 4 , position R 5 , position R6 and position R 7 Each chemical group in this compound is independently either hydrogen or a C1-C4 linear or branched alkyl group.

[0094] Y is -CR 8 R 9 The exemplary portion X may include any of the portions shown in Table 8 below.

[0095] [Table 8]

[0096] The various inhibitor compounds of structural formula I provided in this disclosure include a series of compounds combining various substituted thiophene ring moieties with various X moieties. Various FABP3 / 4 / 5 / 7 inhibitor compounds are structural formula II: [ka] (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4 alkyl, methoxy, or fluoro. Y is a heteroatom selected from -S- and -O-, or -CR 8 R 9 -and here, R 8 and R 9is independently selected from hydrogen, C1-C4 straight-chain or branched alkyl, phenyl, and benzyl, or R 8 and R 9 together form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring, R 4 、R 5 、R 6 and R 7 are each independently selected from hydrogen, C1-C4 straight-chain or branched alkyl, phenyl, and benzyl, and / or, R 4 and R 5 together, or R 6 and R 7 together form a cyclopropyl ring or a cyclobutyl ring, or, R 5 and R 6 together form a 5- to 6-membered carbocyclic or heterocyclic ring having Y as a ring member), and can be represented as a compound thereof and any pharmaceutically acceptable salt thereof.

[0097] In at least one embodiment, the compound of Structural Formula II of the present disclosure excludes the compounds of Table 1 (see above).

[0098] Similar to the FABP3 / 4 / 5 / 7 inhibitor compounds of Structural Formula I, the compounds of Structural Formula II include a series of compounds represented by a partial structure. For example, in at least one embodiment of the FABP3 / 4 / 5 / 7 inhibitor compound having Structural Formula II, the chemical group at position R 1 is a cyano group, and the compound has Structural Formula (IIa)

Chemical Formula

[0099] In at least one embodiment, the compound having the substructure of structural formula IIa is the structural formulas IIj, IIk, IIl, IIm, IIn, IIo, IIp, IIq, IIr, IIs, and IIt (wherein the chemical group R) shown in Table 9 below. 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 It may have the following properties (as defined for the compound of structural formula II).

[0100] [Table 9-1] [Table 9-2]

[0101] In at least one embodiment of a FABP3 / 4 / 5 / 7 inhibitor compound having structural formula II, position R 1 The chemical group in R is a cyano group, 2 and R 3 They combine to form a 6-membered aryl ring, and the compound has the structural formula (IIb) [ka] (In the formula, the chemical group R 2 , chemical group R 3 , chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 This is as defined for the compound of structural formula II, and R 10 and R 11 Each element independently comprises hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, and cyclobutyl.

[0102] In at least one embodiment, a compound having the substructure of structural formula IIb may have structural formulas IIu, IIv, and IIw as shown in Table 10 below.

[0103] [Table 10]

[0104] In at least one embodiment of the compound of structural formula II, position R 1 The chemical group in is a 5-membered heteroaryl ring (e.g., 3-substituted 1,2,4-oxadiazole), R 2 and R 3 The chemical groups in each are independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl. For example, in at least one embodiment, the compound is structural formula IIc, structural formula IId, structural formula IIe, structural formula IIf, structural formula IIg, structural formula IIh, and structural formula III (wherein the chemical group R) shown in Table 11 below. 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 This is as defined for the compound of structural formula II, and the chemical group R in IIc, IId, IIe, IIf, IIg, and IIh. 12 (This can be hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, or phenyl.)

[0105] [Table 11]

[0106] In at least one embodiment, a compound having the substructures of structural formulas IIc, IId, IIe, IIf, IIg, and IIh can have the structural formulas IIx, IIy, IIz, IIaa, IIbb, IIcc, IIdd, IIee, IIff, IIgg, IIhh, IIii, IIjj, IIkk, IIll, IImm, IInn, IIoo, IIpp, IIqq, IIrr, and IIss shown in Table 12 below.

[0107] [Table 12-1] [Table 12-2]

[0108] Structural formula IIa, structural formula IIb, structural formula IIc, structural formula IId, structural formula IIe, structural formula IIf, structural formula IIg, structural formula IIh, structural formula IIi, structural formula IIj, structural formula IIk, structural formula IIl, structural formula IIm, structural formula IIn, structural formula I Io, Structural Formula IIp, Structural Formula IIq, Structural Formula IIr, Structural Formula IIs, Structural Formula IIt, Structural Formula IIu, Structural Formula IIv, Structural Formula IIw, Structural Formula IIx, Structural Formula IIy, Structural Formula IIz, Structural Formula IIaa, Structural Formula IIbb, Structural Formula IIcc In each of the various substructure embodiments of the compounds of structural formula II, including the compounds of structural formula IIdd, structural formula IIee, structural formula IIff, structural formula IIgg, structural formula IIhh, structural formula IIii, structural formula IIjj, structural formula IIkk, structural formula IIll, structural formula IImm, structural formula IInn, structural formula IIoo, structural formula IIpp, structural formula IIqq, structural formula IIrr, and structural formula IIss, the atom or chemical group represented by Y may be -S- or -O-, and the chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7Each of these is intended to be independently hydrogen or a C1-C4 linear or branched alkyl group. Therefore, the exemplary FABP3 / 4 / 5 / 7 inhibitor compounds of structural formulas I and II are shown in Table 13 below: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 309, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 26 The compounds include substance 31, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 40, compound 41, compound 42, compound 43, compound 44, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61, compound 62, compound 63, compound 64, and compound 65, but these are linear.

[0109] [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6]

[0110] As described elsewhere in this Specification, those skilled in the art will understand that the FABP3 / 4 / 5 / 7 compounds provided herein may exist in a variety of known, closely related forms and / or equivalent forms not expressly described by their chemical structures and formulas. The FABP3 / 4 / 5 / 7 inhibitor compounds of structural formulas I and II of this Disclosure (including the compounds in Tables 2 to 5 and Tables 9 to 13, and the compounds described in the Examples) are intended to include these closely related forms of the compounds defined by their chemical structures and formulas, including, but not limited to, pharmaceutically acceptable salts of the compounds, mixtures of stereoisomers of the compounds, single stereoisomers of the compounds, tautomer forms of the compounds, and / or prodrug forms of the compounds.

[0111] Preparation of FABP3 / 4 / 5 / 7 inhibitor compounds This disclosure also provides a process for preparing the FABP3 / 4 / 5 / 7 inhibitor compounds disclosed herein, including the compounds of structural formulas I and II (as defined elsewhere herein), which is outlined in Scheme A and described in more detail below. [ka] Scheme A

[0112] A mixture (1:0.75 molar ratio) of the substituted anhydride compound of structural formula III and the substituted 2-aminothiophene compound of structural formula IV is purged with argon and then dissolved in a dry solvent. The reaction mixture is then stirred at a temperature ranging from room temperature to the reflux temperature of the chosen solvent. The progress of the reaction can be tracked by one or more analytical methods, such as thin-layer chromatography (TLC) or gas chromatography. After the starting material, 2-aminothiophene IV or substituted anhydride III, is considered to have been consumed, the solvent is removed under vacuum to obtain the desired FABP3 / 4 / 5 / 7 inhibitor of structural formula II.

[0113] In at least one embodiment, the process for preparing the FABP3 / 4 / 5 / 7 inhibitor compound disclosed by structural formula II is: (a) In a solvent, Formula III: [ka] (In the formula, Y is a heteroatom selected from -S- and -O-, or -CR) 8 R 9 -and here, R 8 and R 9 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They combine to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring, R 4 , R 5 , R 6 and R 7 Each is independently selected from hydrogen, C1-C4 linear or branched alkyl, phenyl, and benzyl, and / or R 4 and R 5 They are together, or R 6 and R 7 They combine to form a cyclopropyl ring or a cyclobutyl ring, or R 5 and R 6 These compounds together form a substituted anhydride (a 5- to 6-membered carbon ring or heterocycle having Y as a ring member), formula IV: [ka] (In the formula, R 1 R is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. 2 and R 3 Each of these is independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl, or R 2 and R 3These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4-alkyl, methoxy, or fluoro, and are combined with a substituted 2-amino-thiophene compound. (b) Remove the solvent and structural formula II: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 The goal is to obtain a compound having the following characteristics (as defined above): Includes.

[0114] In at least one embodiment of the substituted anhydride of formula III, chemical group Y is a sulfur atom. In another embodiment of the anhydride of formula III, chemical group Y is an oxygen atom. In a further embodiment of the anhydride of formula III, chemical group Y is -CR 5 R 6 -and here, R 5 and R 6 Each of these is independently selected from hydrogen, a C1-C4 linear or branched alkyl group. In a further embodiment, Y is -CR 5 R 6 -If R 5 and R 6 Each is independently selected from C1-C4 linear alkyl groups, R 5 and R 6 These can come together to form a spirocyclic ring having 4 to 7 atoms. In a further embodiment, if Y is sulfur or oxygen, R 1 and R 4These can combine to form a heterocycle having 4 to 6 carbon atoms. A series of specific anhydrides of formula III that can be used to prepare compounds of formula II will be further described in the examples.

[0115] In at least one embodiment of a substituted 2-aminothiophene compound of formula IV, the compound has structural formula IVa: [ka] (In the formula, R 2 and R 3 The chemical groups in each are compounds independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl, and optionally substituted with one or two substituents selected from C1-C4 alkyl, methoxy, chloro, or fluoro. Exemplary compounds of such structural formula IVa include, but are not limited to, compounds 4a, 4b, 4c, 4d, 4e, and 4f shown in Table 14 below.

[0116] [Table 14]

[0117] In at least one embodiment of the substituted 2-amino-thiophene compound of formula IVa, position R 2 and position R 3 The chemical substituents in this structure combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring. Exemplary compounds of such structural formula IVa include, but are not limited to, compounds 4g, 4h, 4i, 4j, and 4k shown in Table 15 below.

[0118] [Table 15]

[0119] In at least one embodiment of the substituted 2-amino-thiophene compound of formula IVa, position R 2 and position R 3 The chemical substituents in the structure collectively form a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4 alkyl, methoxy, or fluoro, as shown in structural formula IVb: [ka] (In the formula, R 10 and R 11 Each of these compounds is independently represented by a compound (selected from hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, and cyclobutyl). Compounds of such structural formula IVb include, but are not limited to, compounds 4l, 4m, and 4n shown in Table 16 below.

[0120] [Table 16]

[0121] In at least one embodiment of the substituted 2-aminothiophene compound of formula IV, R 1 The chemical group in is a 5-membered heteroaryl ring (e.g., 3-substituted 1,2,4-oxadiazole), and the compounds are structural formulas IVc, IVd, IVe, IVf, IVg, IVh, and IVI (wherein R is shown in Table 17 below) 2 and R 3 The chemical groups in each are independently selected from hydrogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl, or R 2 and R 3Together, they form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C1-C4-alkyl, methoxy, or fluoro, R 12 The chemical group in is selected from compounds of hydrogen, halogen, C1-C4 linear or branched alkyl, cyclopropyl, cyclobutyl, and phenyl. Such compounds of structural formulas IVc, IVd, IVe, IVf, IVg, IVh, and IVi include, but are not limited to, compounds 4o, 4p, 4q, 4r, 4s, 4t, 4u, 4v, 4w, 4x, 4y, 4z, 4aa, 4bb, 4cc, 4dd, 4ee, 4ff, 4gg, 4hh, and 4ii shown in Table 18 below.

[0122] [Table 17]

[0123] [Table 18-1] [Table 18-2]

[0124] Methods for synthesizing 2-aminothiophene of structural formula IV have been previously reported, for example, in U.S. Patent No. 9,353,102, U.S. Patent Application Publication No. 2015 / 0175594, and PCT International Publication No. 2014 / 040938, which are incorporated herein by reference. These previously reported synthesis methods can be used to prepare useful starting materials in the synthetic routes for preparing the compounds of structural formula II described herein and in the following examples. In particular, these starting materials are useful in the preparation of intermediate compounds of structural formula IVa, IVb, IVc, IVd, IVe, IVf, IVg, or IVh shown above.

[0125] For example, the compound with structural formula IVd can be synthesized using the route shown in scheme B below. [ka] Scheme B

[0126] Another route for synthesizing the compound of structural formula IVd has been described by J. Sarvanan, et al., (Indian Journal of Heterocyclic Chemistry 1998, 7, 285-288), and is shown in scheme C below. [ka] Scheme C

[0127] A route for synthesizing the compound of structural formula IVe starting from 2-amino-3-cyanothiophene is described by RW Sabnis et al. (J. Het. Chem. 1992, 4, 285-288) and is shown in scheme D below. [ka] Scheme D

[0128] Another synthetic route for synthesizing the compound of structural formula IVe has been described by JK Augustine et al., (Tetrahedron 2009, 65, 9989-9996) and is shown in scheme E below. [ka] Scheme E Lawesson reagent or P2S5

[0129] Another useful method for introducing the 1,3,4-thiadiazole ring compound of structural formula IVe is reported in V. Polshettiwar et al., Tetrahedron Lett., 2008, 49, 879.

[0130] An exemplary synthetic route that can prepare the compound of structural formula IVf starting from 2-amino-3-cyanothiophene is illustrated in scheme F below. [ka] Scheme F

[0131] Alternative synthetic routes that can prepare the compound of structural formula IVf are exemplified in scheme G below. [ka] Scheme G

[0132] Exemplary synthetic routes for preparing compounds of structural formula IVg or structural formula IVh starting from 2-amino-3-cyanothiophene are illustrated in scheme H below (see also, e.g., ZP Demko et al., J. Org. Chem., 2001, 66, 7945-7950). [ka] Scheme H or

[0133] As shown in the reaction scheme above, in some cases it may be advantageous to protect the 2-amino substituent of the 2-aminothiophene precursor with a Boc group using standard methods before proceeding with further reactions.

[0134] A schematic synthetic route for preparing the compound of structural formula IVc is illustrated in the examples (see, for example, Scheme 21). Furthermore, specific 2-aminothiophene compounds of formula VI that can be used in the preparation of the compound of formula II are described in the examples.

[0135] A non-limiting example of a schematic procedure for preparing the disclosed FABP3 / 4 / 5 / 7 inhibitors. A mixture of substituted anhydride III and substituted 2-aminothiophene (1:0.75 molar ratio) is purged with argon and then dissolved in dry dichloromethane. The reaction mixture is stirred at room temperature for 24 hours. The solvent is removed using a rotary evaporator. The residue is then dissolved in 5 mL of ice-cold dichloromethane and transferred to a glass drum vial. The vial is then cooled on dry ice until visible crystals form. The resulting crystals are isolated by vacuum filtration and rinsed with ice-cold dichloromethane. The crystals are air-dried by vacuum filtration for 30 minutes. A small sample of the isolated crystals is dissolved in acetone and its purity is confirmed by silica thin-layer chromatography using a solvent system of 40% ethyl acetate in hexane containing 0.1% acetic acid. The plate is stained with PMA, a common stain, and the formation of carboxylic acid is confirmed by bromocresol green staining. The structure of the purified crystals is 1 Confirmation is made by 1H NMR. The crystals are transferred to a clean, pre-weighed glass drum vial, and the yield is calculated. A series of specific synthesis procedures and reagents useful for preparing compounds of structural formulas I and II, including the specific compounds in Table 1, are presented in the following examples.

[0136] Treatment, Use, and Method As described elsewhere in this specification, the FABP3 / 4 / 5 / 7 inhibitor compounds of structural formulas I and II of this disclosure have been shown to potentially provide therapeutic effects in many conditions and diseases based on in vitro studies, preclinical studies, or clinical studies. Accordingly, this disclosure is intended to show that the inhibitor compounds of this disclosure can be used in compositions and methods for the treatment of diseases and / or conditions known to be affected by FABP3, FABP4, FABP5, and / or FABP7. In general, a method of treating a subject having a disease or condition affected by FABP3, FABP4, FABP5, and / or FABP7 using the FABP3 / 4 / 5 / 7 inhibitor compounds of this disclosure comprises administering to the subject in need a therapeutically effective amount of the compounds of structural formulas I and II, or a pharmaceutical composition comprising such compounds with one or more pharmaceutically acceptable adjuncts.

[0137] Therapies using FABP3 / 4 / 5 / 7 inhibitor compounds of structural formulas I and II are intended for use in conditions and diseases known to be affected by one or more of FABP4, FABP5, FABP3, and FABP7, including atherosclerosis, coronary artery atherosclerosis, arterial fibrosis, pulmonary hypertension, heart failure, obesity, type 2 diabetes, type 1 diabetes, gestational diabetes, polycystic ovary syndrome, endometriosis, conditions affected by lipid metabolism and serum levels of free fatty acids, metabolic disorders, fatty liver disease, renal fibrosis, systemic inflammation, acute inflammation, allergic inflammation, respiratory inflammation, viral infections (e.g., COVID-19, common cold), skin diseases (e.g., vitiligo, psoriasis, atopic dermatitis, allergic contact dermatitis, mycosis fungoides, alopecia areata, scarring alopecia, graft-versus-host disease (GvHD), contact dermatitis, etc.). Chronic eczema, herpetiform dermatitis, cutaneous lupus, scleroderma, dermatomyositis, vasculitis, pemphigus, epidermolysis bullosa, linear IgA, bullous diseases), neurological conditions and neurological diseases (e.g., pain, multiple sclerosis (MS), Parkinson's disease), autoimmune diseases (e.g., experimental autoimmune encephalomyelitis (EAE), asthma, type 1 diabetes, autoimmune lung disease, autoimmune hepatitis, rheumatoid arthritis (RA), spondyloarthritis, bullous stomatitis virus) This includes, but is not limited to, infections (multiple sclerosis (MS), lupus nephritis, Crohn's disease, ulcerative colitis, and food allergies), ischemic stroke, graft-versus-host disease (GvHD), and cancer (e.g., breast cancer, prostate cancer, ovarian cancer, skin cancer, gastric cancer, glioma, cholangiocarcinoma, bladder cancer, multiple myeloma, colorectal cancer, hepatocellular carcinoma, cervical cancer, oral squamous cell carcinoma, and / or non-small cell lung cancer (NSCLC)). Further specific descriptions of the various uses and therapeutic indications of the FABP3 / 4 / 5 / 7 inhibitor compounds of structural formulas I and II are presented below.

[0138] A. Cancer treatment As described elsewhere in this specification, inhibition of FABP5 provides a method to inhibit the metastasis of cancer cells in humans. Triple-negative breast cancer (TNBC) accounts for approximately 10% to 20% of all breast cancers. The term "triple-negative breast cancer" refers to the fact that cancer cells do not produce sufficient estrogen receptors or progesterone receptors, or sufficient amounts of the protein human epidermal growth factor receptor 2 (HEGR-2). Because TNBC tumors lack definitive prognostic markers and selective targets for treatment, the treatment and management of this disease is a significant clinical problem, and there is an urgent need for a direct approach that inhibits the biological processes that regulate tumor development and metastasis. While we do not wish to be bound by theory, the data disclosed herein demonstrate that the disclosed FABP inhibitor compounds can result in inhibition of FABP5, thereby modulating TNBC levels.

[0139] Accordingly, in at least one embodiment, the FABP3 / 4 / 5 / 7 inhibitor compounds of structural formulas I and II can be used in a method to treat cancer in a subject, the method comprising administering to a subject in need a composition comprising (a) an effective amount of one or more of the disclosed FABP3 / 4 / 5 / 7 inhibitors or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component. In at least one embodiment of the method, the subject has been diagnosed with, is suffering from, and / or is receiving treatment for one or more cancers selected from breast cancer, prostate cancer, ovarian cancer, skin cancer, gastric cancer, glioma, cholangiocarcinoma, bladder cancer, multiple myeloma, colorectal cancer, hepatocellular carcinoma, cervical cancer, oral squamous cell carcinoma, and / or non-small cell lung cancer (NSCLC). In one embodiment of the disclosed cancer treatment, the method relates to breast cancer. In another embodiment of the disclosure, the method relates to preventing the metastasis of TNBC cells in a subject diagnosed with cancer.

[0140] Another further embodiment of the disclosed method relates to a method for treating cancer in a subject, comprising administering a composition to a subject as needed, wherein the composition comprises (a) one or more disclosed FABP3 / 4 / 5 / 7 inhibitors or a pharmaceutically acceptable salt thereof in an effective amount, and (b) a pharmaceutically acceptable carrier or other auxiliary component. In at least one embodiment of the method for treating cancer, the cancer is selected from breast cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma, multiple myeloma, neuroblastoma, lung adenocarcinoma, or gastric carcinoma. In one example, the cancer is breast cancer. In a further example, the cancer is prostate cancer. In another example, the cancer is ovarian cancer. In yet another example, the cancer is hepatocellular carcinoma. In yet another example, the cancer is multiple myeloma. In yet another example, the cancer is neuroblastoma. In yet another example, the cancer is lung adenocarcinoma. In yet another example, the cancer is gastric carcinoma.

[0141] In at least one embodiment, the FABP3 / 4 / 5 / 7 inhibitors of this disclosure are intended to be used in a method for sensitizing cancer cells to treatment with other chemotherapeutic agents. Such chemotherapeutic agents may include, but are not limited to, standard chemotherapeutic compounds such as doxorubicin, gemcitabine, cisplatin, paclitaxel, all-trans retinoic acid (atRA), PARP inhibitor compounds, and immune checkpoint inhibitor compounds, including but not limited to antibodies targeting PD-1 or PD-L1. Accordingly, in at least one embodiment, this disclosure provides a method for sensitizing cancer cells to treatment with other chemotherapeutic agents, the method comprising contacting cancer cells with one or more of the disclosed FABP3 / 4 / 5 / 7 inhibitors and contacting the cells with one or more chemotherapeutic agents. The method is intended to be carried out by contacting the cancer cells with the FABP3 / 4 / 5 / 7 inhibitors before, concurrently with, or after contacting the cancer cells with the chemotherapeutic agents.

[0142] In at least one embodiment, the disclosure also provides the use of a FABP3 / 4 / 5 / 7 inhibitor compound of structural formula I or structural formula II, or a pharmaceutical composition containing such compound, for the manufacture of a drug for treating cancer in a subject. In at least one embodiment, the cancer to be used or treated by the drug is selected from breast cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma, multiple myeloma, neuroblastoma, lung adenocarcinoma, or gastric carcinoma.

[0143] B. Fatty acid regulation One aspect of the disclosed use and method relates to a method for inhibiting one or more of FABP3, FABP4, FABP5, and FABP7 in a subject, the method comprising administering to a subject in need of such inhibition a composition comprising (a) an effective amount of one or more FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0144] Further embodiments of the disclosed uses and methods relate to a method for controlling free fatty acid serum levels in a subject, the method comprising administering to a subject in need of such control a composition comprising (a) an effective amount of one or more disclosed FABP3 / 4 / 5 / 7 inhibitors of structural formula I or structural formula II or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0145] In at least one embodiment, the Disclosure also provides the use of a pharmaceutical composition comprising one of the FABP3 / 4 / 5 / 7 inhibitor compounds of the Disclosure, or a FABP3 / 4 / 5 / 7 inhibitor compound of structural formula I or structural formula II, for the manufacture of a drug for treating a disease or condition affected by FABP3 / 4 / 5 / 7 in a subject. In at least one embodiment, the disease or condition is related to the control of free serum fatty acid levels in the subject.

[0146] C. Treatment of metabolic disorders Furthermore, FABP4 and FABP5 are members of a family of small, soluble proteins that contribute to the transport of fatty acids within the cytosolic compartment of cells. While these proteins do not possess catalytic function, they transport hydrophobic fatty acids to various destinations within the aqueous environment of the cytosol, enabling fatty acid oxidation, membrane homeostasis, or nuclear signaling. Moreover, they are involved in signaling processes that are not yet fully understood. FABP4 is highly expressed in adipose tissue, macrophages, and endothelial cells. FABP5 is expressed in macrophages, adipocytes, and endothelial cells, as well as in the skin and several other tissues.

[0147] While we don't want to be bound by theory, in humans, plasma levels of FABP4 are elevated in patients with metabolic syndrome and atherosclerosis. In addition, there is evidence that FABP4 is involved in angiogenesis. More than a quarter of the population has a variety of comorbidities, including obesity, atherosclerosis, insulin resistance, dyslipidemia, coagulation disorders, hypertension, and the pro-inflammatory condition known as metabolic syndrome. Patients with metabolic syndrome are at increased risk of atherosclerosis and type 2 diabetes, as well as other health problems. As with obesity, treatment options for atherosclerosis are very limited.

[0148] Further embodiments of the disclosed method relate to a method for controlling insulin sensitivity in a subject, comprising administering a composition to a subject as needed, wherein the composition comprises (a) one or more FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0149] Further embodiments of the disclosed method relate to a method for treating type 2 diabetes in a subject, comprising administering a composition to a subject in need thereof, wherein the composition comprises (a) one or more FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0150] Further embodiments of the disclosed method relate to a method relating to glucose plasma levels in a subject, comprising administering a composition to a subject requiring such a composition, wherein the composition comprises (a) one or more FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0151] Further embodiments of the disclosed method relate to a method for treating atherosclerosis in a subject, comprising administering a composition to a subject in need thereof, wherein the composition comprises (a) an effective amount of one or more FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0152] Further embodiments of the disclosed method relate to a method for treating fatty liver in a subject, comprising administering a composition to a subject in need thereof, wherein the composition comprises (a) one or more FABP3 / 4 / 5 / 7 inhibitor compounds of structural formula I or structural formula II or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or other auxiliary component.

[0153] In at least one embodiment, the Disclosure also provides the use of a FABP3 / 4 / 5 / 7 inhibitor compound of structural formula I or structural formula II, or a pharmaceutical composition comprising a FABP3 / 4 / 5 / 7 inhibitor compound of the Disclosure, for the manufacture of a drug for treating a metabolic disorder in a subject.

[0154] D. Regulation of immune cell activity and immune cell populations As described elsewhere in this specification, FABPs are involved in regulating immune cell activity. While not intended to be limited by mechanism, FABPs are thought to mediate immune cell metabolism crucial for the proper functioning of the immune system. More specifically, FABP activity influences fatty acid utilization, thereby regulating energy production and signaling pathways involved in immune cell activation and function. For example, FABP5 has been found to regulate T cell lipid metabolism and function in the tumor microenvironment (TME) by mediating the uptake and oxidation of long-chain FAs within cells. Furthermore, tumor-infiltrating T lymphocytes (TILs) expressing high FABP5 levels typically exhibit an exhausted phenotype and impaired antitumor activity due to limited glucose availability and high levels of long-chain FAs. Therefore, inhibition of FABP5 in TILs is expected to activate the cellular antitumor activity. FABP4 is related to Ly6C - MHCII - CD36 + FABP4 / 5 is highly expressed in circulating monocytes / macrophages, promoting oxidized lipid uptake, foam cell formation, angiogenesis, tissue remodeling, and tumorigenic functions. This high expression suggests that inhibition of FABP4 enhances the antitumor immune response in cancer cells and may also block foam cell formation and chronic inflammation in obesity. Another function of FABP4 / 5 in immune cells is their role in maintaining CD8+ tissue-resident memory T cells (Trm). Specifically, cutaneous Trm cells, which depend on fatty acids as an energy source, have been reported to express high levels of FABP4 / 5, which is necessary for the uptake of fatty acids into cells and their transport to mitochondria for metabolism. The energy produced in this process is necessary for the survival of Trm cells. Targeting Trm cells by inhibiting FABP4 / 5 is expected to have therapeutic effects in autoimmune diseases. Overall, the role of FABPs in immune cell modulation highlights the importance of lipid metabolism in regulating the immune system, suggesting that targeting FABPs could be a promising strategy for improving immune cell function and treating a wide range of diseases and conditions caused by chronic inflammation and cancer.

[0155] A method for modulating an immune cell population and / or immune cell activity in a subject requiring such modification comprises administering to the subject requiring such modification a therapeutically effective amount of a compound of structural formula I or structural formula II, or a pharmaceutical composition of such compound. In at least one embodiment, the subject requiring such modification has a disease or disorder caused by, affected by, and / or characterized by an immune cell population and / or immune cell activity, for example, in which the immune cells are M2 macrophages or tumor-associated macrophages (TAMs). In at least one embodiment, the subject requiring treatment to modulate an immune cell population and / or immune cell activity is diagnosed with, suffering from, or undergoing treatment for cancer. In another embodiment, the subject requiring treatment to modulate an immune cell population and / or immune cell activity is intended to have an autoimmune disease or autoimmune disorder.

[0156] Pharmaceutical composition This disclosure also provides uses and methods for administering FABP4 / 5 inhibitor compounds, such as compounds of structural formula I or structural formula II, to a subject in the form of a pharmaceutical composition. In such embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an FABP3 / 4 / 5 / 7 inhibitor compound (e.g., the compounds in Table 11), or a pharmaceutically acceptable salt or ester of such compound, and one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions can be prepared using methods well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)). Methods for preparing pharmaceutical compositions of FABP3 / 4 / 5 / 7 inhibitor compounds are described in this disclosure, including the examples disclosed herein.

[0157] In at least one embodiment, the disclosure provides a pharmaceutical composition comprising an effective amount of one or more disclosed FABP3 / 4 / 5 / 7 inhibitors, such as compounds of structural formula I or structural formula II, and one or more auxiliary components, such as pharmaceutically acceptable carriers. The disclosed composition may contain one or more disclosed FABP3 / 4 / 5 / 7 inhibitors in an amount of about 10% to about 95% by weight. In another embodiment, the composition contains one or more disclosed FABP3 / 4 / 5 / 7 inhibitors in an amount of about 10% to about 80% by weight. In yet another embodiment, the composition contains one or more disclosed FABP3 / 4 / 5 / 7 inhibitors in an amount of about 20% to about 50% by weight. In yet another embodiment, the composition contains one or more disclosed FABP3 / 4 / 5 / 7 inhibitors in an amount of about 50% to about 90% by weight. In yet another embodiment, the composition contains one or more disclosed FABP3 / 4 / 5 / 7 inhibitors in an amount of about 70% to about 90% by weight. In further embodiments, the composition contains about 80% to about 95% by weight of one or more of the disclosed FABP3 / 4 / 5 / 7 inhibitors. In further embodiments, the composition contains about 90% to about 95% by weight of one or more of the disclosed FABP3 / 4 / 5 / 7 inhibitors.

[0158] Generally, pharmaceutical compositions can be prepared by diluting an active ingredient(s) with excipients and / or encapsulating them in a carrier in the form of a capsule, pouch, paper, or other container. When the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material (as described above) and serves as a vehicle, carrier, or medium for the active ingredient. Thus, pharmaceutical compositions(s) suitable for administration in the methods of the present disclosure may be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments, soft gelatin capsules and hard gelatin capsules containing up to 10% by weight of the active compound, sterile injections, and sterile packaged powders.

[0159] Carriers used in the preparation of pharmaceutical compositions may include excipients, such as inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Excipients suitable for use in pharmaceutical compositions containing the cerastrol derivatives of this disclosure are well known in the art and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The pharmaceutical compositions may further contain lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavorings.

[0160] In terms of therapeutic use and methods, pharmaceutical compositions containing FABP3 / 4 / 5 / 7 inhibitor compounds, such as compounds of structural formula I, are intended to be administered as single doses or multiple doses, and by any of the acceptable methods of administration of the active ingredient having similar utility. For example, pharmaceutical compositions containing cerastrol derivatives can be administered using a variety of methods, including oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intrafocal administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreous administration, intraosseous administration, intracerebral administration, intra-arterial administration, intra-articular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, inhalation administration, suppository administration, inhalation administration, or subcutaneous administration.

[0161] The pharmaceutical compositions comprising the FABP3 / 4 / 5 / 7 inhibitor compounds of this disclosure can be used in a series of therapeutic methods, and a series of dosages are considered for the administration of a pharmaceutically effective amount. The dosage and frequency (single or multiple doses) of the pharmaceutical composition administered to a subject may be modified depending on a series of factors, e.g., the route of administration; the subject's physique, age, sex, health status, weight, and / or diet; the state of the disease being treated; whether the subject has any other diseases, and any concurrent treatments. Those skilled in the art will understand that adjustments to the established dosage (e.g., frequency and duration) to obtain a therapeutically effective dose may be necessary depending on the subject. Typically, the amount of the pharmaceutical composition containing the FABP3 / 4 / 5 / 7 inhibitor compound administered to a subject in a therapeutic method will be determined by a physician, taking into account the relevant circumstances of the subject being treated, the chosen route of administration, and, of course, age, weight, severity of symptoms, the individual's response to treatment, etc.

[0162] Generally, a therapeutically effective dose is an amount of administered composition sufficient to achieve the desired therapeutic objective compared to the absence of the compound. For example, a therapeutically effective dose may be an amount deemed sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease. Methods for determining the dose that provides a therapeutically effective amount of a compound are well known to those skilled in the art and are usually based on analysis of the amount determined in cell assays and / or animal models. For example, a dose for administration to humans may be formulated to reach a concentration that has been observed to be therapeutically effective in animal models. Doses in pharmaceutical compositions for human use may be further adjusted by monitoring efficacy and making adjustments up or down. Those skilled in the art can adjust the dose in the pharmaceutical compositions of this disclosure to achieve maximum therapeutic efficacy in humans using methods known in the art.

[0163] Generally, therapeutic treatment methods are developed by starting with a pharmaceutical composition containing a FABP3 / 4 / 5 / 7 inhibitor compound at a dose less than the optimal dose. The dosage of the compound is then gradually increased until optimal efficacy is achieved. A key factor considered when finding the optimal dose is the ratio of toxicity to the therapeutic efficacy of the active ingredient. This ratio, referred to as the therapeutic index of the compound, is usually the LD50 of the active ingredient. 50 (The amount of a compound that causes death in 50% of the population) and its ED 50 This is described as a ratio to (the amount of the compound effective in 50% of the population). Typically, a higher therapeutic index of the compound is preferable. Therapeutic index data can be obtained from cell culture assays and / or animal model studies and can then be used to determine a safe dose range for the active ingredient in a pharmaceutical composition for administration to humans. Ideally, the determined dose should exhibit little to no toxicity and be ED 50 The active ingredient is delivered to the subject at a specific level.

[0164] Examples of pharmaceutical composition in solid form include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The solid carrier may be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrant, and may also be an encapsulating material.

[0165] In powder form, the carrier is a fine solid present in a mixture with a fine active ingredient, such as the disclosed FABP3 / 4 / 5 / 7 inhibitor. In tablet form, the active ingredient is mixed in an appropriate proportion with a carrier having the required binding properties and compressed into the desired shape and size. Solid formulations of the pharmaceutical compositions of this disclosure may contain about 0.5% to about 10% by weight of the binder. Non-limiting examples of binders suitable for use in the disclosed compositions are selected from polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers, and mixtures thereof. In one embodiment, the binder is methylcellulose, ethylcellulose, hydroxymethylcellulose, or hydroxyethylcellulose. In one non-limiting example, the binder is ethylcellulose.

[0166] In some embodiments, the solid composition may contain about 0.5% to about 10% by weight of a carrier. Non-limiting examples of solid carriers include starch, e.g., tapioca starch, corn starch, potato starch, gelatin, dextrin, inulin, cyclodextrin, oxidized starch, starch ester, starch ether, cross-linked starch, α-starch, octenyl succinate ester, and modified starch obtained by treating starch with acid, heat or enzyme, or emulsifiers, e.g., gum arabic, modified starch. Starch, pectin, xanthan gum, ghati gum, tragacanth gum, fenugreek gum, mesquite gum, monoglycerides and diglycerides of long-chain fatty acids, sucrose monoester, sorbitan ester, polyethoxylated glycerol, stearic acid, palmitic acid, monoglycerides, diglycerides, propylene glycol ester, lecithin, lactylated monoglycerides and diglycerides, propylene glycol monoester, polyglycerol ester, diacetylated tartaric acid ester of monoglycerides and diglycerides, citrate ester of monoglycerides, stearoyl-2-lactic acid ester, polysorbate, succinyl monoglycerides, acetylated monoglycerides, ethoxylated monoglycerides, quillaja, whey Examples include protein isolates, casein, soy protein, plant protein, pullulan, sodium alginate, guar gum, locust bean gum, tragacanth gum, tamarind gum, carrageenan, furcellan, gellan gum, psyllium, curdlan, konjac mannan, agar, and cellulose derivatives, as well as combinations thereof, or sugar alcohols that may optionally have moisturizing properties, such as ethylene glycol, glycerol, erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, sucrose, fructose, isomalt, maltitol, lactitol, sorbitol, dextrose, or inositol, and combinations thereof.

[0167] The disclosed composition may contain about 25 mg to about 1200 mg of one or more of the disclosed FABP3 / 4 / 5 / 7 inhibitors. In one embodiment, the disclosed single-dose composition of the disclosed FABP3 / 4 / 5 / 7 inhibitor may contain any amount from about 25 mg to about 500 mg.

[0168] In a further embodiment, the disclosed single-dose composition of the disclosed FABP3 / 4 / 5 / 7 inhibitor may contain an amount of approximately 100 mg to approximately 500 mg. In yet another embodiment, the disclosed single-dose composition of the disclosed FABP3 / 4 / 5 / 7 inhibitor may contain an amount of approximately 500 mg to approximately 1000 mg.

[0169] A single-dose composition may contain an amount of approximately 25 mg to approximately 250 mg of any of the FABP3 / 4 / 5 / 7 inhibitors. For example, the disclosed composition contains one or more of the disclosed FABP3 / 4 / 5 / 7 inhibitors in doses of 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 mg, 219 mg, 220 mg, 221 mg, 222 mg, 223 mg, 224 mg, 225 mg, 226 mg, 227 mg, 228 mg, 229 mg, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, or 250 mg.

[0170] Pharmaceutical compositions in liquid form may include, for example, solutions, suspensions, and emulsions suitable for oral or parenteral administration. Examples of liquid compositions suitable for parenteral administration include sterile aqueous solutions of the active ingredient, or sterile solutions of the active ingredient in solvents containing water, buffer water, saline, PBS, ethanol, or propylene glycol. The composition may contain pharmaceutically acceptable auxiliary substances as needed to approximate physiological conditions, such as pH adjusters and buffers, isotonic agents, wetting agents, and cleaning agents. In at least one embodiment, the disclosed liquid composition may contain about 5% to about 25% by weight of the liquid carrier.

[0171] In liquid embodiments of this composition, target cells, such as cancer cells or tumor cells, can be brought into contact with an aqueous solution containing about 0.5 μg / mL to about 250 μg / mL. In one embodiment, the composition may contain about 1 μg / mL to about 100 μg / mL. In another embodiment, the composition may contain about 10 μg / mL to about 100 μg / mL. In yet another embodiment, the composition may contain about 5 μg / mL to about 20 μg / mL. In yet another embodiment, the composition may contain about 1 μg / mL to about 50 μg / mL. In yet yet another embodiment, the composition may contain about 1 μg / mL to about 10 μg / mL. In yet another embodiment, the composition may contain about 15 μg / mL to about 50 μg / mL. In yet another embodiment, the composition may contain about 20 μg / mL to about 200 μg / mL.

[0172] The disclosed composition can provide a single-dose dose of the disclosed FABP3 / 4 / 5 / 7 inhibitor based on the body weight of the subject being treated. Therefore, the single-dose dose of the disclosed FABP3 / 4 / 5 / 7 inhibitor can range from about 0.35 mg to about 20 mg per kg of body weight of the subject. In one embodiment, the amount of the disclosed FABP3 / 4 / 5 / 7 inhibitor in a single dose is about 1 mg to about 8 mg per kg of body weight of the subject. In another embodiment, the amount of the disclosed FABP3 / 4 / 5 / 7 inhibitor in a single dose is about 2 mg to about 5 mg per kg of body weight of the subject. In a further embodiment, the amount of the disclosed FABP3 / 4 / 5 / 7 inhibitor in a single dose is about 1.5 mg to about 4 mg per kg of body weight of the subject. In yet another embodiment, the amount of the disclosed FABP3 / 4 / 5 / 7 inhibitor in a single dose is about 4 mg to about 10 mg per kg of body weight of the subject. In further embodiments, the amount of the disclosed FABP3 / 4 / 5 / 7 inhibitor in a single dose is approximately 5 mg to 8 mg per kg of the subject's body weight.

[0173] For example, the dose may consist of any amount between approximately 0.5 mg and approximately 10 mg per kg of body weight of the subject being treated. For example, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, 5.1 mg, 5.2 mg per kg of body weight. mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. [Examples]

[0174] Various features and embodiments of this disclosure are illustrated in the following representative examples, which are for illustrative purposes only and not limiting. Those skilled in the art will readily understand that specific embodiments are merely illustrative of the invention, as they are described more fully in the appended claims. All embodiments and features described herein are to be understood to be interchangeable and combinable with all embodiments contained herein.

[0175] The following examples illustrate the synthesis method of the compound of Formula 1.

[0176] Example 1: Preparation of 2-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)acetic acid (compound FTS001) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS001 by the synthesis method of Scheme 1 shown below. [ka] Scheme 1

[0177] Materials and methods 1,4-Oxatian-2,6-dione (0.552 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.552 mmol) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethyl)thio)acetic acid (137 mg, 80%).

[0178] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ: 1.75 ppm (4H, t, J= 6.0 Hz), 2.59 ppm (2H, m, J=6.0Hz), 3.41 ppm (2H,s), 3.55 ppm (2H,s) 11.68 (1H, s), 12.66 (1H, s).

[0179] Example 2: Preparation of 2-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS003) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS003 by the synthesis method of Scheme 2 shown below. [ka] Scheme 2 Dry CH2Cl2

[0180] Materials and methods 3,3-dimethyl-1,4-oxatian-2,6-dione (2.13 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1.58 mmol, 0.75 equivalents) were placed in a 100 mL round-bottom flask. The flask was purged with argon, and 50 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a white powder (355 mg, 66.4%).

[0181] NMR analysis confirmed the preparation of the desired product.1 H NMR (400 MHz, DMSO-d6) δ: 1.43 (s,4H), 1.75 (m,4H), 2.59 (m, 4H), 3.70 (s, 2H), 11.71 (s, 1H), 12.66 (s, 1H). 13 C NMR (125 MHz): 175.3, 167.7, 146.7, 131.2, 128, 114.5, 93.2, 47.43, 33.59, 25.95, 23.95, 23.77, 23.05, 22.16.

[0182] Example 3: Preparation of 2-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS005) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS005 by the synthesis method of Scheme 3 shown below. [ka] Scheme 3 Dry CH2Cl2

[0183] Materials and methods 3,3-dimethyl-1,4-oxatian-2,6-dione (2.13 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1.58 mmol, 0.75 equivalents) were placed in a 100 mL round-bottom flask. The flask was purged with argon, and 50 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a white powder (355 mg, 66.4%).

[0184] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ: 1.43 (s,4H), 1.75 (m,4H), 2.59 (m, 4H), 3.70 (s, 2H), 11.71 (s, 1H), 12.66 (s, 1H). 13 C NMR (125 MHz): 175.3, 167.7, 146.7, 131.2, 128, 114.5, 93.2, 47.43, 33.59, 25.95, 23.95, 23.77, 23.05, 22.16.

[0185] Example 4: Preparation of 2-((1-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-1-oxopropan-2-yl)thio)propanoic acid (compound FTS007) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS007 by the synthesis method of Scheme 4 shown below. [ka] Scheme 4 Dry CH2Cl2

[0186] Materials and methods 3,5-dimethyl-1,4-oxatian-2,6-dione (0.357 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.226 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-((1-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-1-oxopropan-2-yl)thio)propanoic acid (26 mg, 34%).

[0187] NMR analysis confirmed the preparation of the desired product. 1 H NMR (500 MHz, DMSO-d6) δ: 1.33 (d, 3H, J=7.13 MHz), 1.43 (d, 3H, J=6.99 MHz), 1.75 (s, 4H), 2.36-2.63 (m, 4H), 3.56 (q, 1H, J=7.12 MHz), 4.05 (q, 1H, J=6.97MHz), 11.74 (s, 1H), 12.65 (s, 1H)

[0188] Example 5: Preparation of 5-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)tetrahydrothiophen-2-carboxylic acid (compound FTS009) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS009 by the synthesis method of Scheme 5 shown below. [ka] Scheme 5 Dry CH2Cl2

[0189] Materials and methods 3-Oxa-8-thiabicyclo[3.2.1]octane-2,4-dione (0.312 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.219 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 5-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)tetrahydrothiophene-2-carboxylic acid (20 mg, 27.2%).

[0190] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ:1.75 (s, 4H), 2.05 (m, 2H), 2.38 (m, 2H), 2.58 (m, 2H), 4.04 (t, 1H), 4.30 (t, 1H), 11.70 (s, 1H), 12.67 (s, 1H)

[0191] Example 6: Preparation of 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)acetic acid (compound FTS011) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS011 by the synthesis method of Scheme 6 shown below. [ka] Scheme 6 Dry CH2Cl2

[0192] Materials and methods 1,4-Dioxan-2,6-dione (0.968 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.907 mmol) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethoxy)acetic acid (152 mg, 57%).

[0193] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ: 1.72 ppm ( 2H, dt, J=5.7 Hz), 1.76 (2H, dt, J=5.7 Hz), 2.60 ppm ( 4H, m, J=5.7 Hz), 4.19 (2H, s), 4.35 (2H, s), 11.41 ppm (1H, s), 12.81 ppm (1H, s).

[0194] Example 7: Preparation of 5-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)tetrahydrofuran-2-carboxylic acid (compound FTS013) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS013 by the synthesis method of Scheme 7 shown below. [ka] Scheme 7 Dry CH2Cl2

[0195] Materials and methods 3,8-Dioxabicyclo[3.2.1]octane-2,4-dione (0.191 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.176 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 5-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)tetrahydrofuran-2-carboxylic acid (30 mg, 53.2%).

[0196] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ: 2.65-2.76 ppm,( 6H, m), 3.0- 3.14 ppm (6H, m), 3.34 ppm (2H, t, J=4.98 Hz), 5.41-5.47 ppm (2H, dt, J=8.45 Hz), 12.25 ppm (1H, s), 14.40 ppm (1H, s).

[0197] Example 8: Preparation of 5-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-5-oxopentanoic acid (compound FTS015) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS015 by the synthesis method of Scheme 8 shown below. [ka] Scheme 8 Dry CH2Cl2

[0198] Materials and methods Dihydro-2H-pyran-2,6(3H)-dione (1.07 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.75 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 5-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-5-oxopentanoic acid (83 mg, 37.8%).

[0199] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ: 1.68-1.82 ppm (6H, m), 2.22-2.28 (4H, dt, J= 5.8 Hz), 2.58 ppm (4H, t, J=4.45 Hz), 11.53 ppm (1H, s), 12.38 ppm (1H, s).

[0200] Example 9: Preparation of 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)-2-methylpropanoic acid (compound FTS027) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS027 by the four-step synthesis method of Scheme 9 shown below. [ka] Scheme 9 Process 1 Morpholine 16 hours Process 2 Dioxane room temperature Process 3 Process 4 LiOH aqueous solution 1 hour

[0201] Materials and methods Step 1-2 Synthesis of amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile: In a 250 mL dry, round-bottom flask under a nitrogen atmosphere, cyclohexanone (5.0 g, 50.9 mmol) was dissolved in dioxane (100 mL), and malononitrile (3.37 g, 50.9 mmol) and sulfur (1.633 g, 50.9 mmol) were added. The mixture was heated to 50°C, morpholine (4.44 g, 50.9 mmol) was added, and the mixture was stirred at the same temperature for 16 hours. The progress of the reaction was monitored by LC-MS and TLC. After the completion of the reaction, the reaction mixture (RM) was concentrated using a rotary evaporator, and the resulting residue was diluted with water (80 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated to obtain the crude compound. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 10% ethyl acetate in petroleum ether) to obtain pure 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile as a pale yellow crystalline solid.

[0202] NMR analysis confirmed the preparation of the desired intermediate compound in step 1. 1 H NMR: 400 MHz DMSO-d6δ: 6.94 (s, 2H), 2.42-2.39 (m, 2H), 2.35-2.32 (m, 2H), 1.73-1.68 (m, 4H).

[0203] Step 2 - Synthesis of 2-chloro-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide: In a 100 mL dry, round-bottom flask under a nitrogen atmosphere, 2-chloroacetyl chloride (1.521 g, 13.46 mmol) was added to a stirred solution of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carbonitrile (2.0 g, 11.22 mmol) in dioxane (25 mL), and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC (20% siRNA in hexane, 0.7 rf). After the completion of the reaction, hexane was added to the reaction mixture and stirred for 10 minutes. The resulting solid was filtered through a Buchner funnel and washed with hexane to obtain pure 2-chloro-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide.

[0204] NMR analysis confirmed the preparation of the desired intermediate compound in step 2. 1 H NMR: 400 MHz DMSO-d6δ: 11.91 (s, 1H), 4.46 (s, 2H), 2.61-2.51 (m, 2H), 2.51-2.50 (m, 2H), 1.77-1.75 (m, 4H).

[0205] Step 3: Synthesis of methyl 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)-2-methylpropanoate: To a stirred solution of methyl 2-hydroxy-2-methylpropanoate (0.464 g, 3.93 mmol) in THF (25 mL) in a 100 mL dry, round-bottom flask under a nitrogen atmosphere, 2-chloro-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (0.500 g, 1.963 mmol) was added and the mixture was heated at 70°C for 16 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane, 0.4 rf). After the reaction was complete, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated to obtain the crude compound. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted in 15% ethyl acetate in petroleum ether) to obtain pure methyl 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)-2-methylpropanoate as an orange solid.

[0206] NMR analysis confirmed the preparation of the desired intermediate compound in step 3. 1 H NMR: 400 MHz DMSO-d6δ: 10.96 (s, 1H), 4.25 (s, 2H), 3.68 (s, 3H), 2.61-260 (m, 2H), 2.51-2.50 (m, 2H), 1.76 (s, 4H), 1.42 (s, 6H).

[0207] Step 4-2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)-2-methylpropanoic acid: In a 100 mL dry, round-bottom flask under a nitrogen atmosphere, methyl 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)-2-methylpropanoate (0.180 g, 0.535 mmol) was dissolved in THF (5 mL). Water (3 mL) and lithium hydroxide hydrate (0.067 g, 1.605 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC (0.5% MeOH in DCM). Upon completion of the reaction, the reaction mixture was diluted with water (5 mL) and washed with ethyl acetate (25 mL). The aqueous layer was acidified with citric acid and extracted with 10% MeOH (3 × 20) in DCM. The organic layer was dried over sodium sulfate and concentrated in a rotary evaporator to obtain pure 2-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethoxy)-2-methylpropanoic acid as an off-white solid.

[0208] NMR analysis confirmed the preparation of the desired product. 1 H NMR: 400 MHz DMSO-d6δ: 12.95 (s, 1H), 11.17 (s, 1H), 4.23 (s, 2H), 2.70-2.51 (m, 4H), 1.76 (s, 4H), 1.40 (s, 6H).

[0209] Example 10: Preparation of 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylic acid (compound FTS028) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS028 by the seven-step synthesis method of Scheme 10 shown below. [ka] [ka] Scheme 10 Process 1 Process 2 Process 3 Process 4 Process 5 Process 6 Process 7

[0210] Materials and methods Step 1: Synthesis of ethyl 2-((bis(4-methoxyphenyl)(phenyl)methyl)thio)acetate: To a solution of ethyl 2-sulfanyl acetate (10.0 g, 83.22 mmol, 1.0 equivalent) in DCM (120 mL), NaHCO3 (8.3 g, 99.86 mmol, 1.2 equivalents) was added. The mixture was stirred at 25°C for 20 minutes. 1-[chloro-(4-methoxyphenyl)-phenyl-methyl]-4-methoxybenzene (28.20 g, 83.22 mmol, 1 equivalent) was added, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched by adding H2O (120 mL) and extracted with DCM (120 mL x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0% → 10%) to obtain ethyl 2-((bis(4-methoxyphenyl)(phenyl)methyl)thio)acetate (10.0 g, 23.67 mmol, yield 58.8%) as an off-white oily substance.

[0211] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, CDCl3) δ = 7.34 (d, J = 8.0 Hz, 2H), 7.26-7.16 (m, 6H), 7.15-7.14 (m, 1H), 6.76-6.73 (m, 4H), 4.00-3.95 (m, 2H), 3.72 (s, 6H), 2.90 (s, 2H), 1.31 (t, J = 6.8 Hz, 3H).

[0212] Step 2: Synthesis of ethyl 1-((bis(4-methoxyphenyl)(phenyl)methyl)thio)cyclopropanecarboxylate: To a solution of ethyl 2-[bis(4-methoxyphenyl)-phenyl-methyl]sulfanyl acetate (10.0 g, 23.67 mmol, 1.0 equivalent) in THF (100 mL), LDA (2 M, 29.58 mL, 2.5 equivalents) was added dropwise at -60°C. After stirring at -60°C for 1.5 hours, 1,3,2-dioxathiolane 2,2-dioxide (4.41 g, 35.50 mmol, 1.5 equivalents) in THF (17 mL) was added dropwise at -60°C, followed by DMPU (4.55 g, 35.50 mmol, 4.29 mL, 1.5 equivalents) at -60°C. The mixture was stirred at 25°C for 16 hours. After cooling to -60°C, saturated NH4Cl (200 mL) was added. The mixture was extracted with SiO2 (400 mL). The organic layer was washed with brine (400 mL), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0% → 10%) to obtain ethyl 1-((bis(4-methoxyphenyl)(phenyl)methyl)thio)cyclopropanecarboxylate (7.6 g, 16.94 mmol, yield 73.6%) as a yellow oil.

[0213] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 7.2 Hz, 2H), 7.26-7.20 (m, 3H), 7.19-7.17 (m, 4H), 6.72 (d, J = 9.2 Hz, 4H), 3.73 (s, 3H), 3.60 (m, 2H), 1.29 (m, 2H), 1.09 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).

[0214] Step 3 - Synthesis of ethyl 1-mercaptocyclopropanecarboxylate: Triethylsilane (933.2 mg, 8.03 mmol, 1.28 mL, 1.2 equivalents) was added at 0°C to a solution of ethyl 1-[bis(4-methoxyphenyl)-phenyl-methyl]sulfanylcyclopropanecarboxylate (3.0 g, 6.69 mmol, 1.0 equivalent) in DCM (30 mL). After addition, TFA (762.5 mg, 6.69 mmol, 495.16 μL, 1.0 equivalent) was added, and the mixture was stirred at 25°C for 16 hours. The resulting solution was used directly in the next step.

[0215] Step 4: Synthesis of ethyl 1-((2-(tert-butoxy)-2-oxoethyl)thio)cyclopropanecarboxylate: To the above solution, THF (300 mL), K2CO3 (4.4 g, 32.49 mmol, 5.0 equivalents), and tert-butyl 2-bromoacetate (1.3 g, 6.50 mmol, 960.12 μL, 1.0 equivalent) were added at 0°C. The mixture was stirred at 25°C for 16 hours, filtered, and concentrated to obtain ethyl 1-((2-(tert-butoxy)-2-oxoethyl)thio)cyclopropanecarboxylate (1.6 g, 6.49 mmol, crude) as a brown oily substance. This was used in the next step without further purification.

[0216] Step 5 - Synthesis of 2-((1-(ethoxycarbonyl)cyclopropyl)thio)acetic acid: To a solution of ethyl 1-(2-tert-butoxy-2-oxo-ethyl)sulfanylcyclopropanecarboxylate (1.6 g, 6.49 mmol, 1.0 equivalent) in DCM (10 mL), TFA (15.4 g, 135.06 mmol, 10 mL, 20.8 equivalents) was added. The mixture was stirred at 25°C for 1 hour, filtered, and concentrated to obtain 2-((1-(ethoxycarbonyl)cyclopropyl)thio)acetic acid (1.3 g, 6.51 mmol, crude) as a yellow oil. This was used in the next step without further purification.

[0217] Step 6: Synthesis of ethyl 2-(1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropyl)-2-oxoacetate: To a solution of 2-(1-ethoxycarbonylcyclopropyl)sulfanylacetic acid (1.15 g, 5.61 mmol, 5.0 equivalents) in DMF (2.0 mL), DIEA (1.16 g, 8.98 mmol, 1.56 mL, 8.0 equivalents) was added. After stirring at 25°C for 10 minutes, HATU (639.9 mg, 1.68 mmol, 1.5 equivalents) and 2-amino-4,5,6,7-tetrahydrobenzothiophen-3-carbonitrile (200 mg, 1.12 mmol, 1.0 equivalent) were added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched by adding H2O (20 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (25 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0% → 10%) to obtain ethyl 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylate (405.0 mg, 1.11 mmol, yield 99.0%) as a yellow solid. This was used directly in the next step.

[0218] LCMS analysis confirmed the preparation of the desired intermediate compound. t = 0.454 min (0.8 min chromatography), 5 → 95 AB, ESI C 17 H 20 Calculated value for N2O3S2Na [M+Na] + 387.1, actual measured value 387.0.

[0219] Step 7-1-Synthesis of ((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylic acid (FTS028): To a solution of ethyl 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylate (400 mg, 1.10 mmol, 1.0 equivalent) in a mixed solvent of MeOH (5 mL) and H2O (1 mL), LiOH·H2O (230.2 mg, 5.49 mmol, 5.0 equivalent) was added. The mixture was stirred at 25°C for 16 hours, filtered, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water(FA)-ACN]; B%: 35%→65%, 8 min) to obtain 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylic acid (78.5 mg, 233.33 μmol, yield 21.2%) as a white solid.

[0220] Analysis using NMR, LC-MS, and HPLC confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 3.66 (s, 2H), 2.68-2.53 (m, 4H), 1.75-1.72 (m, 4H), 1.46-1.43 (m, 2H), 1.19-1.12 (m, 2H). LCMS R t = 1.455 min (3 minute chromatography), 5 → 95 AB, ESI C 15 H 16 Calculated value for N2O3S2Na [M+Na] + 359.1, measured value 358.9. HPLC purity 98.8%, R t = 2.967 minutes (6.0 minutes chromatography), 10 → 80 AB 6 minutes.

[0221] Example 11: Preparation of 2-(1-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)cyclopropyl)acetic acid (compound FTS029) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS029 by the synthesis method of Scheme 11 shown below. [ka] Scheme 11 Dry CH2Cl2

[0222] Materials and methods 6-Oxaspiro[2,5]octane-5,7-dione (0.638 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.488 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-(1-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethyl)cyclopropyl)acetic acid as an amorphous white powder (23 mg, 14.8%).

[0223] NMR analysis confirmed the preparation of the desired product. 1 H NMR (500 MHz, DMSO-d6) δ = 12.13 (bs, 1H), 11.41 (s, 1H), 2.73 (s, 2H), 2.44 (m, 2H), 2.34 (m, 2H), 2.27 (s, 2H), 1.77-1.65 (m, 4H), 0.53 (d, 2H), 0.43 (d, 2H)

[0224] Example 12: Preparation of 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylic acid (compound FTS030) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS030 by the four-step synthesis method of Scheme 12 shown below. [ka] Scheme 12 Process 1 Process 2 Process 3 Process 4

[0225] Materials and methods Step 1: Synthesis of ethyl 1-((2-(tert-butoxy)-2-oxoethyl)thio)cyclobutanecarboxylate: To a solution of ethyl 1-bromocyclobutanecarboxylate (2.0 g, 9.66 mmol, 1.56 mL, 1.0 equivalent) in THF (10 mL), tert-butyl 2-sulfanyl acetate (1.43 g, 9.66 mmol, 1.0 equivalent) and KOH (541.9 mg, 9.66 mmol, 1.0 equivalent) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with ELISA (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain ethyl 1-((2-(tert-butoxy)-2-oxoethyl)thio)cyclobutanecarboxylate (2.6 g, 9.48 mmol, quantitative) as an off-white liquid. This was used in the next step without further purification.

[0226] Step 2-2-((1-(ethoxycarbonyl)cyclobutyl)thio)acetic acid: To a solution of ethyl 1-(2-tert-butoxy-2-oxo-ethyl)sulfanylcyclobutane carboxylate (1.0 g, 3.64 mmol, 1.0 equivalent) in DCM (15 mL), TFA (5.9 g, 51.94 mmol, 3.85 mL, 14.2 equivalents) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain 2-((1-(ethoxycarbonyl)cyclobutyl)thio)acetic acid (0.79 g, 4.58 mmol, quantitative) as an off-white liquid. This was used in the next step without further purification.

[0227] Step 3: To a solution of 2-(1-ethoxycarbonylcyclobutyl)sulfanylacetic acid (0.75 g, 3.44 mmol, 1.0 equivalent) in ethyl 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylate:DMF (1 mL), DIEA (2.22 g, 17.18 mmol, 2.99 mL, 5.0 equivalent) was added. After stirring at 25°C for 0.5 hours, HATU (1.96 g, 5.15 mmol, 1.5 equivalent) and 2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carbonitrile (612.5 mg, 3.44 mmol, 1.0 equivalent) were added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched by adding H2O (20 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (25 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0% → 10%) to obtain ethyl 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutenecarboxylate (0.8 g, 2.11 mmol, yield 61.5%) as a yellow solid. This was used directly in the next step.

[0228] LCMS analysis confirmed the preparation of the desired intermediate compound. t= 0.475 min (0.8 min chromatography), 5 → 95 AB, ESI C 18 H 22 Calculated values ​​for N2O3S2 [M+H] + 379.1, measured value 379.1.

[0229] Step 4-1-Synthesis of ((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylic acid: LiOH·H2O (443.4 mg, 10.57 mmol, 5.0 equivalents) was added to a solution of ethyl 1-[2-[(3-cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)amino]-2-oxoethyl]sulfanylcyclobutanecarboxylate (800.0 mg, 2.11 mmol, 1.0 equivalent) in a mixed solvent of MeOH (10 mL) and H2O (2 mL). The mixture was stirred at 50°C for 2 hours, filtered, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; B%: 40%→70%, 10 min) to obtain 1-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylic acid (63.6 mg, 181.48 μmol, yield 8.5%) as a yellow solid.

[0230] Analysis using NMR, LC-MS, and HPLC confirmed the preparation of the desired product. 1 H NMR (400 MHz, CDCl3) δ = 9.98 (s, 1H), 3.56 (s, 2H), 2.80-2.70 (m, 2H), 2.65-2.54 (m, 4H), 2.32-2.14 (m, 3H), 2.04-1.92 (m, 1H), 1.87-1.77 (m, 4H). LCMS R t = 1.548 min (3-minute chromatography), 5 → 95 AB, ESI C 16 H 18 Calculated value for N2O3S2Na [M+Na] +373.1, measured value 373.0. HPLC purity 97.6%, R t = 3.008 minutes (6.0 minutes chromatography), 10 → 80 AB 6 minutes.

[0231] Example 13: Preparation of 3-((2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)oxetane-3-carboxylic acid (FTS035) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS035 by the four-step synthesis method of Scheme 13 shown below. [ka] Scheme 13 Process 1 Ethyl 3-bromooxetane-3-carboxylate Process 2 Process 3 Process 4

[0232] Materials and methods FTS035 was prepared using the same general synthetic process as described in Example 12 for the preparation of FTS030, except that the starting compound ethyl 1-bromocyclobutane carboxylate was replaced with ethyl 3-bromooxetane-3-carboxylate, the starting compound shown in Scheme 13.

[0233] Example 14: Preparation of 2-(1-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)cyclobutyl)acetic acid (compound FTS031) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS031 by the synthesis method of Scheme 14 shown below. [ka] Scheme 14 Dry CH2Cl2

[0234] Materials and methods 7-Oxaspiro[3,5]nonane-6,8-dione (0.275 mmol) and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.236 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 10 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. The solvent was removed by rotary evaporation. The crude mixture was purified by preparative TLC in 2.5:1 hexane:siRNA + 0.1% acetic acid to obtain 2-(1-(2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-2-oxoethyl)cyclobutyl)acetic acid (15 mg, 19.1%).

[0235] Example 15: Preparation of (1s,3s)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylic acid (compound FTS032) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS032 by the two-step synthesis method of Scheme 15 shown below. [ka] Scheme 15 Process 1 0~room temperature 16 hours Process 2 room temperature 1 hour

[0236] Materials and methods Step 1: Synthesis of methyl(1s,3s)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylate: In a 100 mL dry two-necked round-bottom flask under a nitrogen atmosphere, 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carbonitrile (200 mg, 1.122 mmol) was dissolved in DCM (40 mL). To this reaction mixture, (1s,3s)-3-(methoxycarbonyl)cyclobutan-1-carboxylic acid (266 mg, 1.683 mmol) and DIPEA (1.176 mL, 6.73 mmol) were added at 25°C under a nitrogen atmosphere. The reaction mixture was then cooled to 0°C, POCl3 (0.314 mL, 3.37 mmol) was added dropwise, and the mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction was monitored by TLC (20% ethyl acetate in petroleum ether, 0.3 rf). After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution (100 mL). The reaction mixture was extracted with DCM (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 18% ethyl acetate in petroleum ether) to obtain pure methyl (1s,3s)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylate as a yellow solid.

[0237] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ = 11.46 (s, 1H), 3.61 (s, 3H), 3.39 (dd, J = 9.60, 18.00 Hz, 1H), 3.17 (t, J = 8.80 Hz, 1H), 2.68 (s, 4H), 2.36 (t, J = 8.80 Hz, 4H), 1.75 (s, 4H).

[0238] Step 2 - Synthesis of (1s,3s)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid: Methyl (1s,3s)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate (150 mg, 0.471 mmol) was dissolved in THF (10 mL) and water (5 mL) in a 100 mL dry, round-bottom flask under a nitrogen atmosphere. Lithium hydroxide monohydrate (59.4 mg, 1.413 mmol) was added to this reaction mixture at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The progress of the reaction was monitored by TLC (10% MeOH in DCM, 0.2 rf). After the reaction was complete, the reaction mixture was concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator. The reaction mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then acidified with citric acid (pH=5~6). The reaction mixture was extracted with 10% MeOH (3 × 50 mL) in DCM. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator, and freeze-dried to obtain pure (1s,3s)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylic acid as a white solid.

[0239] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 12.11(s, 1H), 11.50 (s, 1H), 3.52 (t, J = 7.60 Hz, 1H), 3.05-3.01 (m, 1H), 2.68 (t, J = 1.60 Hz, 2H), 2.51 (t, J = 1.60 Hz, 2H), 2.42-2.34 (m, 4H), 1.75 (s, 4H).

[0240] Example 16: Preparation of (1r,3r)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclo-butan-1-carboxylic acid (compound FTS033) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS033 by the two-step synthesis method of Scheme 16 shown below. [ka] Scheme 16 Process 1 0~room temperature 16 hours Process 2 room temperature 1 hour

[0241] Materials and methods Step 1: Synthesis of methyl(1r,3r)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylate: In a 100 mL dry two-necked round-bottom flask under a nitrogen atmosphere, 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carbonitrile (400 mg, 2.244 mmol) was dissolved in DCM (15 mL). To this reaction mixture, (1r,3r)-3-(methoxycarbonyl)cyclobutan-1-carboxylic acid (426 mg, 2.69 mmol) and DIPEA (2.352 mL, 13.46 mmol) were added at 25°C under a nitrogen atmosphere. The reaction mixture was then cooled to 0°C, POCl3 (0.629 mL, 6.73 mmol) was added dropwise, and the mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction was monitored by TLC (20% ethyl acetate in petroleum ether, 0.6 rf). After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution (100 mL). The reaction mixture was extracted with DCM (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 15% ethyl acetate in petroleum ether) to obtain pure methyl (1r,3r)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylate as a yellow solid.

[0242] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ= 11.50 (s, 1H), 4.09-4.03 (m, 1H), 3.76 (dt, J = 4.80, Hz, 1H), 3.74 (s, 3H), 3.73 (t, J = 4.80 Hz, 1H), 3.16-3.13 (m, 1H), 2.68 (t, J = 2.00 Hz, 2H), 2.51-2.43 (m, 4H), 1.75 (s, 4H).

[0243] Step 2 - Synthesis of (1r,3r)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylic acid: Methyl (1r,3r)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylate (48 mg, 0.151 mmol) was dissolved in THF (2 mL) and water (1 mL) in a 50 mL dry, one-necked round-bottom flask under a nitrogen atmosphere. LiOH monohydrate (19 mg, 0.452 mmol) was added to this reaction mixture at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The progress of the reaction was monitored by TLC (20% ethyl ether, 0.1 rf). After the reaction was complete, the reaction mixture was concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator. The reaction mixture was extracted with ethyl acetate (30 mL). The combined aqueous layer was then acidified with citric acid (2 gm, pH=1~2). The reaction mixture was extracted with 10% MeOH (3 × 30 mL) in DCM. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator, and freeze-dried to obtain pure (1r,3r)-3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)cyclobutan-1-carboxylic acid as a white solid.

[0244] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ= 12.21 (s, 1H), 11.53 (s, 1H), 3.52 (t, J = 7.60 Hz, 1H), 3.05-3.01 (m, 1H), 2.68 (t, J = 1.60 Hz, 2H), 2.51 (t, J = 1.60 Hz, 2H), 2.42-2.34 (m, 4H), 1.75 (s, 4H).

[0245] Example 17: Preparation of 3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-carboxylic acid (compound FTS034) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS034 by the two-step synthesis method of Scheme 17 shown below. [ka] Scheme 17 Process 1 0~room temperature 16 hours Process 2 room temperature 1 hour

[0246] Materials and methods Step 1: Synthesis of methyl 3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate: In a 100 mL dry two-necked round-bottom flask under nitrogen, 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carbonitrile (200 mg, 1.122 mmol) was dissolved in CH2Cl2 (10 mL). To this reaction mixture, 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (229 mg, 1.346 mmol) and DIPEA (1.176 mL, 6.73 mmol) were added at 25°C under a nitrogen atmosphere. The reaction mixture was cooled to 0°C, POCl3 (0.315 mL, 3.37 mmol) was added dropwise, and the mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction was monitored by TLC (20% ethyl acetate in petroleum ether, 0.6 rf). After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution (100 mL). The reaction mixture was extracted with 10% MeOH (3 × 50 mL) in DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 10% ethyl acetate in petroleum ether) to obtain pure methyl 3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-carboxylate as a white solid.

[0247] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ= 11.30 (s, 1H), 3.74 (s, 3H), 2.76 (s, 2H), 2.68 (s, 2H), 2.40 (s, 2H), 2.35 (d, J = 6.40 Hz, 2H), 2.25 (s, 2H), 1.78 (d, J = 14.40 Hz, 4H).

[0248] Step 2-3 - Synthesis of ((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-carboxylic acid: In a 25 mL dry, one-necked round-bottom flask under a nitrogen atmosphere, methyl 3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-carboxylate (100 mg, 0.303 mmol) was dissolved in THF (3.00 mL), water (3 mL), and MeOH (1 mL). To this reaction mixture, LiOH (21.74 mg, 0.908 mmol) was added at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The progress of the reaction was monitored by TLC (10% MeOH in DCM, 0.4 rf). After the reaction was complete, the reaction mixture was concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator. The reaction mixture was washed with ethyl acetate (10 mL), the aqueous layer was acidified with 1.5N HCl solution (pH=1~2), and extracted with 10% MeOH (3 × 20 mL) in DCM. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator, and freeze-dried to obtain pure 3-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-carboxylic acid as a white solid.

[0249] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ= 12.43 (bs, 1H), 11.27 (bs, 1H), 2.6 (dd, J = 5.60, 12.80 Hz, 4H), 2.29 (s, 6H), 1.75 (t, J = 2.40 Hz, 4H).

[0250] Example 18: Preparation of 1-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylic acid (compound FTS036) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS036 by the two-step synthesis method of Scheme 18 shown below. [ka] Scheme 18 Process 1 Process 2

[0251] Materials and methods Step 1: Synthesis of ethyl 1-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylate: To a solution of 2-(1-ethoxycarbonylcyclopropyl)sulfanylacetic acid (1.0 g, 4.93 mmol, 5.0 equivalents) in DMF (2 mL), DIEA (891.5 mg, 6.90 mmol, 1.20 mL, 7.0 equivalents) was added. After stirring at 25°C for 10 minutes, HATU (562.0 mg, 1.48 mmol, 1.5 equivalents) and 2-amino-4,5-dimethylthiophen-3-carbonitrile (150 mg, 985.44 μmol, 1.0 equivalent) were added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched by adding H2O (20 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (25 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0% → 10%) to obtain ethyl 1-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylate (290.0 mg, 103.68 μmol, yield 10.5%) as a yellow solid. This was used directly in the next step.

[0252] LCMS analysis confirmed the preparation of the desired intermediate compound. t = 0.438 min (0.8 min chromatography), 5 → 95 AB, ESI C 15 H 18Calculated value for N2O3S2Na [M+Na] + 361.1, actual measured value 361.0.

[0253] Step 2-1 - Synthesis of ((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclopropanecarboxylic acid (FTS036): To a solution of ethyl 1-[2-[(3-cyano-4,5-dimethyl-2-thienyl)amino]-2-oxoethyl]sulfanylcyclopropanecarboxylate (290 mg, 856.86 μmol, 1.0 equivalent) in a mixed solvent of MeOH (5 mL) and H2O (1 mL), LiOH·H2O (179.8 mg, 4.28 mmol, 5.0 equivalents) was added. The mixture was stirred at 25°C for 16 hours, filtered, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water(FA)-ACN]; B%: 40%→70%, 10 min) to obtain the desired compound (14.4 mg, 46.39 μmol, yield 5.4%) as a yellow solid.

[0254] Analysis using NMR, LC-MS, and HPLC confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 3.70-3.62 (s, 2H), 2.23 (s, 3H), 2.10 (s, 3H), 1.48-1.42 (m, 2H), 1.19-1.11 (m, 2H). LCMS R t = 1,300 min (3 minute chromatography), 5 → 95 AB, ESI C 13 H 14 Calculated value for N2O3S2Na [M+Na] + 333.0, measured value 332.9. HPLC purity 98.8%, R t = 2.568 minutes (6.0 minutes chromatography), 10 → 80 AB 6 minutes.

[0255] Example 19: Preparation of 1-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylic acid (compound FTS037) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS037 by the two-step synthesis method of Scheme 19 shown below. [ka] Scheme 19 Process 1 Process 2

[0256] Materials and methods Step 1: Synthesis of ethyl 1-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylate: To a solution of 2-(1-ethoxycarbonylcyclobutyl)sulfanylacetic acid (358.4 mg, 1.64 mmol, 5.0 equivalents) in DMF (1 mL), DIEA (212.26 mg, 1.64 mmol, 286.07 μL, 5.0 equivalents), HATU (187.35 mg, 492.72 μmol, 1.5 equivalents) and 2-amino-4,5-dimethylthiophen-3-carbonitrile (50.0 mg, 328.4 μmol, 1.0 equivalent) were added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched by adding H2O (20 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (25 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0% → 16%) to obtain ethyl 1-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylate (70.0 mg, 198.6 μmol, yield 60.4%) as a yellow solid. This was used directly in the next step.

[0257] LCMS analysis confirmed the preparation of the desired intermediate compound. t = 0.445 min (0.8 min chromatography), 5 → 95 AB, ESI C 16 H 21 Calculated values ​​for N2O3S2 [M+H] + 353.1, measured value 352.9.

[0258] Step 2-1 - Synthesis of ((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)cyclobutanecarboxylic acid (FTS037): To a solution of ethyl 1-[2-[(3-cyano-4,5-dimethyl-2-thienyl)amino]-2-oxoethyl]sulfanylcyclobutanecarboxylate (70.0 mg, 198.6 μmol, 1.0 equivalent) in a mixed solvent of MeOH (1 mL) and H2O (0.2 mL), LiOH·H2O (41.6 mg, 992.9 μmol, 5.0 equivalents) was added. The mixture was stirred at 50°C for 2 hours, filtered, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water(FA)-ACN]; B%: 28%→58%, 10 min) to obtain the desired compound (25.3 mg, 77.99 μmol, yield 39.2%) as a yellow solid.

[0259] Analysis using NMR, LC-MS, and HPLC confirmed the preparation of the desired product. 1 H NMR (400 MHz, CDCl3) δ = 9.95 (s, 1H), 3.55 (s, 2H), 2.79-2.72 (m, 2H), 2.81-2.71 (m, 1H), 2.33-2.27 (m, 1H), 2.26 (s, 3H), 2.22 (m, 1H), 2.20-2.17 (m, 1H), 2.16 (s, 3H), 2.02-1.95 (m, 1H). LCMS R t = 1.406 min (3-minute chromatography), 5 → 95 AB, ESI C 14 H 16 Calculated value for N2O3S2Na [M+Na] +347.1, measured value 347.0. HPLC purity 99.4%, R t = 2.640 minutes (6.0 minutes chromatography), 10 → 80 AB 6 minutes.

[0260] Example 20: Preparation of 2-((2-((3-cyano-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS038) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS038 by the synthesis method of Scheme 20 shown below. [ka] Scheme 20 Dry CH2Cl2

[0261] Materials and methods 3,3-dimethyl-1,4-oxatian-2,6-dione (0.281 mmol) and 2-amino-4,5-dimethylthiophene-3-carbonitrile (0.213 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 15 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. The crude mixture was purified by dissolving impurities in ethyl acetate and acetone. The resulting white powder was filtered and further washed with ethyl acetate to obtain 2-((2-((3-cyano-4,5-dimethylthiophene-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a pale yellow powder.

[0262] NMR analysis confirmed the preparation of the desired product. 1 H NMR (500 MHz), DMSO-d6δ: 12.65 (s, 1H), 11.66 (s, 1H), 4.15, 3.69 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 1.42 (s, 6H)

[0263] Example 21: Preparation of 2-((2-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS039) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS039 by the three-step synthesis method of Scheme 21 shown below. [ka] Scheme 21 Process 1 toluene Process 2 Process 3 Dry CH2Cl2

[0264] Materials and methods Step 1: 2-Butanone (0.680 mmol), 2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)acetonitrile (1.36 mmol, 2 equivalents), and ammonium acetate (1.36 mmol, 2 equivalents) were placed in a 100 mL two-necked round-bottom flask. The flask was purged with argon, and 10 mL of dry toluene was added. The reaction mixture was heated under reflux for 18 hours. The reaction mixture was cooled and poured into 30 mL of 10% NaHCO3 aqueous solution and 30 mL of toluene. The aqueous layer was separated and extracted again with 30 mL of toluene. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Excess solvent was removed by rotary evaporation. The crude mixture was purified by silica column chromatography in ethyl acetate with 90% hexane to obtain a mixture of (Z)-2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-3-methylpent-2-ennitrile and (E)-2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-3-methylpent-2-ennitrile.

[0265] Step 2: A mixture of (Z)-2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-3-methylpent-2-ennitrile and (E)-2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-3-methylpent-2-ennitrile (1.12 mmol), DBU (2.8 mmol, 2.5 equivalents), and elemental sulfur (1.12 mmol, 1 equivalent) was placed in a 100 mL two-necked round-bottom flask. The flask was purged with argon and 20 mL of dry ethanol. The reaction mixture was heated under reflux at 65°C for 2 hours. The reaction mixture was cooled and then poured into 30 mL of 10% NaHCO3 aqueous solution and 30 mL of ethyl acetate. The aqueous layer was separated and extracted again with 30 mL of ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Excess solvent was removed by rotary evaporation. The crude mixture was purified by silica column chromatography in 90% hexane in ethyl acetate to obtain 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine as a pale yellow powder (42 mg, 15.9%).

[0266] Step 3: 3,3-dimethyl-1,4-oxathian-2,6-dione (0.227 mmol) and 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine (0.170, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon and 15 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. The crude mixture was purified by preparative TLC in a 2.5:1 hexane:ethyl acetate + 0.1% acetic acid mixture to recover 2-((2-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a pale yellow powder (5 mg, 7.4%).

[0267] NMR analysis confirmed the preparation of the desired product. 1H NMR (500 MHz, DMSO-d6) δ = 12.67 (bs), 3.64 (s, 2H), 1.83 (m, 3H), 1.73 (m, 3H), 1.52 (m, 1H), 1.24 (m, 2H), 0.83 (m, 2H)

[0268] Example 22: Preparation of (1s,3s)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid (compound FTS040) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS040 by the four-step synthesis method of Scheme 22 shown below. [ka] Scheme 22 Process 1 Dioxane 3 hours reflux Process 2 Morpholine 16 hours Process 3 0~room temperature Process 4 room temperature 1 hour

[0269] Materials and methods Step 1-2 Synthesis of (3-cyclopropyl-1,2,4-oxadiazole-5-yl)acetonitrile: In a dry, one-necked round-bottom flask under a nitrogen atmosphere, 0.5 g, 3.06 mmol of 3-(3,5-dimethyl-1H-pyrazole-1-yl)-3-oxopropanenitrile was stirred in 25 mL of dioxane. N-hydroxycyclopropanecarboximamide (0.368 g, 3.68 mmol) was added and the mixture was heated at 105°C for 3 hours. The reaction was monitored by TLC (10% HCl in petroleum ether, 0.5 rf). After the reaction was complete, the reaction mixture was concentrated under reduced pressure in a rotary evaporator to obtain crude 2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)acetonitrile as an orange liquid. TLC (10% HCl in petroleum ether)R f =0.5. LCMS method C, 1.44 min, 19.12%, measured value [MH] 148.1.

[0270] Step 2-3 Synthesis of (3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine: In a dry, one-necked round-bottom flask under a nitrogen atmosphere, 2-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)acetonitrile (1 g crude) was stirred in ethanol (30 mL). Butane-2-one (0.218 g, 3.06 mmol) and sulfur (0.097 g, 3.06 mmol) were added, the mixture was heated to 50°C, and morpholine (0.263 mL, 3.06 mmol) was added at 50°C. The mixture was stirred at 50°C for 16 hours. The progress of the reaction was monitored by TLC (10% ethyl ether in petroleum ether, 0.7 rf). After the reaction was complete, the reaction mixture was concentrated under reduced pressure using a rotary evaporator (rotavapour), and the resulting residue was diluted with water (80 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated to obtain the crude compound. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 10% ethyl acetate in petroleum ether) to obtain 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine as an off-white solid.

[0271] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ = 7.41 (s, 2H), 2.19 (s, 3H), 2.14-2.09 (m, 4H), 2.14-2.09 (m, 4H).

[0272] Step 3: Synthesis of methyl(1s,3s)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate: To a stirred solution of 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine (200 mg, 0.850 mmol) dissolved in DCM (40 mL), (1s,3s)-3-(methoxycarbonyl)cyclobutan-1-carboxylic acid (202 mg, 1.275 mmol) and DIPEA (0.891 mL, 5.10 mmol) were added in a dry two-necked round-bottom flask under nitrogen at 25°C. The reaction mixture was cooled to 0°C, and POCl3 (0.238 mL, 2.55 mmol) was added dropwise at 0°C. The mixture was stirred under a nitrogen atmosphere at 25°C for 16 hours. The progress of the reaction was monitored by TLC (20% Â in petroleum ether, 0.5 rf). After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution (100 mL). The reaction mixture was extracted with DCM (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 10% ethyl acetate in petroleum ether) to obtain pure methyl (1s,3s)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate as a brown solid.

[0273] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ= 11.12 (s, 1H), 3.62 (s, 3H), 3.42-3.35 (m, 1H), 3.28-3.21 (m, 1H), 2.51 (s, 5H), 2.37-2.27 (m, 5H), 2.26-2.22 (m, 1H), 1.22-1.16 (m, 2H), 1.13-1.04 (m, 2H).

[0274] Step 4 - Synthesis of (1s,3s)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid: To a stirred solution of methyl(1s,3s)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate (0.120 g, 0.320 mmol) dissolved in THF (6 mL) and water (5 mL), lithium hydroxide monohydrate (0.040 g, 0.959 mmol) was added in a dry, round-bottom flask and the mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The TLC results were deemed acceptable. After the completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL). The aqueous layer was acidified with citric acid and extracted with 10% MeOH / DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator (rotavapour) to obtain pure (1s,3s)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid (0.080 g, 0.221 mmol, yield 69.1%) as a white solid.

[0275] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 12.24 (s, 1H), 11.13 (s, 1H), 3.37 (s, 1H), 3.35-3.10 (m, 1H), 2.51-2.47 (m, 4H), 2.46-2.41 (m, 6H), 2.21 (s, 1H), 1.17-1.14 (m, 2H), 1.06-1.03 (m, 2H).

[0276] Example 23: Preparation of (1r,3r)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid (compound FTS041) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS041 by the two-step synthesis method of Scheme 23 shown below. [ka] Scheme 23 Process 1 0~room temperature 16 hours Process 2 room temperature 1 hour

[0277] Materials and methods Step 1: Synthesis of methyl(1r,3r)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate: 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine (0.170 g, 0.722 mmol) was dissolved in DCM (10 mL) in a 50 mL dry two-necked round-bottom flask under nitrogen. To this reaction mixture, (1r,3r)-3-(methoxycarbonyl)cyclobutan-1-carboxylic acid (0.137 g, 0.867 mmol) and DIPEA (0.560 g, 4.33 mmol) were added at 25°C under a nitrogen atmosphere. The reaction mixture was cooled to 0°C, POCl3 (0.332 g, 2.167 mmol) was added dropwise, and the mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The progress of the reaction was monitored by TLC (20% Â in petroleum ether, 0.6 rf). After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution (50 mL). The reaction mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product was eluted with 15% ethyl acetate in petroleum ether) to obtain pure methyl (1r,3r)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate (0.060 g, 0.160 mmol, yield 22.12%).

[0278] NMR analysis confirmed the preparation of the desired intermediate compound. 1H NMR (400 MHz, DMSO-d6) δ= 11.13 (s, 1H), 3.66 (s, 3H), 3.40-3.50 (m, 1H), 3.12-3.25 (m, 1H), 2.52-2.50 (m, 4H), 2.30-2.29 (m, 7H), 1.16-1.14 (m, 2H), 1.05-1.03 (m, 2H).

[0279] Step 2 - Synthesis of (1r,3r)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid: In a 25 mL dry, round-bottom flask under a nitrogen atmosphere, methyl (1r,3r)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylate (0.050 g, 0.133 mmol) was dissolved in THF (3 mL) and water (2 mL), lithium hydroxide (9.57 mg, 0.400 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC (5% MeOH in DCM). After the completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL). The aqueous layer was acidified with citric acid and extracted with 10% MeOH / DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator (rotavapor) to obtain pure (1r,3r)-3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)cyclobutan-1-carboxylic acid as a white solid.

[0280] NMR analysis confirmed the preparation of the desired product. 1H NMR (400 MHz, DMSO-d6) δ = 11.06 (s, 1H), 3.44-3.40 (m, 1H), 3.08 (s, 1H), 2.49 (s, 4H), 2.34-2.33 (m, 6H), 2.30-2.22 (m, 1H), 1.17-1.15 (m, 2H), 1.05-1.03 (m, 2H).

[0281] Example 24: Preparation of 3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)-bicyclo[1.1.1]pentan-1-carboxylic acid (compound FTS042) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS042 by the synthesis method of Scheme 24 shown below. [ka] Scheme 24 Process 1 0~room temperature 16 hours Process 2 room temperature 1 hour

[0282] Materials and methods Step 1: Synthesis of methyl 3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate: 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine (500 mg, 2.125 mmol) was dissolved in DCM (15 mL) in a 100 mL dry two-necked round-bottom flask under nitrogen. To this reaction mixture, 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (542 mg, 3.19 mmol) and DIPEA (1.856 mL, 10.62 mmol) were added at 25°C under a nitrogen atmosphere. The reaction mixture was cooled to 0°C, POCl3 (0.596 mL, 6.37 mmol) was added dropwise, and the mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The progress of the reaction was monitored by TLC (20% ethyl ether in petroleum ether, 0.4 rf).

[0283] After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution (250 mL). The reaction mixture was extracted with DCM (3 × 200 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure (bath temperature 45°C) using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using EtOAC and petroleum ether as the eluent system (the product eluted with 15% EtOAC in petroleum ether) to obtain pure methyl 3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate as a pale yellow solid.

[0284] NMR analysis confirmed the preparation of the desired product. 1H NMR (400 MHz, DMSO-d6) δ = 11.29 (s, 1H), 3.67 (s, 3H), 2.46 (s, 6H), 2.30 (s, 6H), 2.28 (t, J = Hz, 1H), 1.14 (d, J = 8.00 Hz, 2H), 1.12 (d, J = 6.00 Hz, 2H).

[0285] Step 2-3 - Synthesis of ((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylic acid: In a 50 mL dry, one-necked round-bottom flask under a nitrogen atmosphere, methyl 3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)bicyclo[1.1.1]-pentane-1-carboxylate (250 mg, 0.645 mmol) was dissolved in water (5 mL), THF (5 mL), and MeOH (1 mL). To this reaction mixture, lithium hydroxide monohydrate (81 mg, 1.936 mmol) was added at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The reaction was monitored by TLC (20% ethyl acetate in petroleum ether, 0.2 rf). After the reaction was complete, the reaction mixture was concentrated under reduced pressure (bath temperature 45°C) in a rotary evaporator. The reaction mixture was washed with ethyl acetate (10 mL). The aqueous layer was then acidified with citric acid (pH 5-6). The reaction mixture was extracted with 10% MeOH (3 × 20 mL) in DCM. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure (bath temperature 45°C) in a rotary evaporator, and freeze-dried to obtain pure 3-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)carbamoyl)-bicyclo[1.1.1]pentane-1-carboxylic acid as a white solid.

[0286] NMR analysis confirmed the preparation of the desired product. 1H NMR (400 MHz, DMSO-d6) δ = 12.73 (s, 1H), 11.30 (s, 1H), 2.35 (s, 3H), 2.22 (s, 1H), 2.13 (s, 6H), 1.93 (s, 3H), 1.21-1.17 (m, 2H), 1.10-1.06 (m, 2H).

[0287] Example 25: Preparation of 2-(1-(2-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-yl)amino)-2-oxoethyl)cyclopentyl)acetic acid (compound FTS043) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS043 by the synthesis method of Scheme 25 shown below. [ka] Scheme 25 room temperature 48 hours

[0288] Materials and methods To a stirred solution of 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophene-2-amine (0.100 g, 0.425 mmol) dissolved in DCM (10 mL), 8-oxaspiro[4.5]decane-7,9-dione (0.086 g, 0.510 mmol) was added in a dry, one-necked round-bottom flask under a nitrogen atmosphere and stirred at room temperature for 48 hours. The progress of the reaction was monitored by TLC (20% siRNA in hexane, 0.3 rf). TLC indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (Isolera) using ethyl acetate and petroleum ether as eluents (the product eluted with 15% ethyl acetate in petroleum ether). The product peaks were pooled and concentrated to obtain pure 2-(1-(2-((3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-4,5-dimethylthiophen-2-yl)amino)-2-oxoethyl)cyclopentyl)acetic acid as a white solid.

[0289] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 12.05 (s, 1H), 11.16 (s, 1H), 2.69 (s, 2H), 2.38 (s, 2H), 2.29 (d, J = 7.20 Hz, 6H), 2.26-2.21 (m, 1H), 1.67-1.58 (m, 8H), 1.15-1.12 (m, 4H).

[0290] Example 26: Preparation of 2-((2-((3-cyanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS044) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS044 by the two-step synthesis method of Scheme 26 shown below. [ka] Scheme 26 Process 1 Dioxane room temperature 16 hours Process 2

[0291] Materials and methods Step 1 - Synthesis of 2-chloro-N-(3-cyanobenzo[b]thiophen-2-yl)acetamide: In a dry, one-necked round-bottom flask under a nitrogen atmosphere, 2-aminobenzo[b]thiophen-3-carbonitrile (0.200 g, 1.148 mmol) was dissolved in dioxane (10 mL), and 2-chloroacetyl chloride (0.130 g, 1.148 mmol) was added at room temperature. The mixture was stirred at the same temperature for 16 hours. The completion of the reaction was monitored by TLC. Hexane (10 mL) was added to the reaction mixture and stirred for 10 minutes. A solid was observed in the reaction mixture. The solid was filtered through a Buchner funnel and washed with hexane. The solid was dried under reduced pressure to obtain pure 2-chloro-N-(3-cyanobenzo[b]thiophen-2-yl)acetamide as an off-white solid.

[0292] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ = 12.43 (s, 1H), 8.04 (d, J = 8.00 Hz, 1H), 7.71 (d, J = 8.00 Hz, 1H), 7.56-7.51 (m, 1H), 7.45-7.41 (m, 1H), 4.58 (s, 2H).

[0293] Step 2 - Synthesis of 2-((2-((3-cyanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid: To a stirred solution of 2-chloro-N-(3-cyanobenzo[b]thiophen-2-yl)acetamide (0.220 g, 0.878 mmol), methyl 2-mercapto-2-methylpropanoate (0.141 g, 1.053 mmol) and cesium carbonate (0.572 g, 1.755 mmol) were added in a 50 mL dry, round-bottom flask under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The completion of the reaction was monitored by TLC (20% SiO in petroleum ether). Next, THF (5 mL), water (5.00 mL), and lithium hydroxide (0.017 g, 0.717 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (5 mL), washed with ethyl acetate (15 mL), the aqueous layer was acidified with citric acid (pH approximately 4), and extracted with 10% MeOH / DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure using a rotary evaporator to obtain pure 2-((2-((3-cyanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as an off-white solid.

[0294] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 12.69 (s, 1H), 12.20 (s, 1H), 8.00 (d, J = 8.00 Hz, 1H), 7.69 (d, J = 8.00 Hz, 1H), 7.52 (t, J = 7.20 Hz, 1H), 7.41 (t, J = 7.20 Hz, 1H), 3.83 (s, 2H), 1.46 (s, 6H).

[0295] Example 27: Preparation of 2-((2-((6-chloro-3-cyanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS045) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS045 by the three-step synthesis method of Scheme 27 shown below. [ka] Scheme 27 Process 1 2 hours Process 2 Dioxane room temperature 16 hours Process 3

[0296] Materials and methods Step 1-2 Synthesis of 2-amino-6-chlorobenzo[b]thiophene-3-carbonitrile: Sodium hydride (0.660 g, 16.51 mmol) was added in small amounts to a solution of 2-(4-chloro-2-fluorophenyl)acetonitrile (2.0 g, 11.79 mmol) in DMSO (30.0 mL) at room temperature under N2 (slightly exothermic). After 30 minutes, the reaction mixture was cooled to 15°C in a cold water bath, and O-ethyl carbonisothiocyanatidate (1.530 mL, 12.97 mmol) was added dropwise. After 1 hour, the reaction mixture was heated at 100°C for 2 hours. The progress of the reaction was monitored by TLC (30% siRNA in petroleum ether) and LC-MS. After the completion of the reaction, the reaction mixture was quenched with water to obtain a solid. The solid was filtered, washed with water, and dried under vacuum to obtain the title compound as a crude yellow solid. The crude product was purified by column chromatography (Isolera) using butyl and petroleum ether as eluents (the product was eluted in 30% butyl in petroleum ether) to obtain 3-amino-6-chlorobenzo[b]thiophene-2-carbonitrile as a solid.

[0297] NMR analysis confirmed the preparation of the desired intermediate compound. 1H NMR (400 MHz, DMSO-d6) δ = 7.96 (br s, 2H), 7.83 (d, J = 2.00 Hz, 1H), 7.32 (dd, J = 2.00, 8.40 Hz, 1H), 7.26 (d, J = 8.40 Hz, 1H).

[0298] Step 2 - Synthesis of 2-chloro-N-(6-chloro-3-cyanobenzo[b]thiophen-2-yl)acetamide: 2-chloroacetyl chloride (379 mg, 3.35 mmol) was added at room temperature to a solution of 2-amino-6-chlorobenzo[b]thiophen-3-carbonitrile (350 mg, 1.677 mmol) in dioxane (10.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC (30% siRNA in petroleum ether) and LC-MS. After the completion of the reaction, the mixture was diluted with hexane. The resulting solid was filtered, washed with hexane, and dried under vacuum to obtain the title compound, 2-chloro-N-(6-chloro-3-cyanobenzo[b]thiophen-2-yl)acetamide (400 mg, 1.019 mmol, yield 60.8%), as a white solid.

[0299] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ = 12.53 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.80 Hz, 1H), 7.55 (dd, J = 2.00, 8.80 Hz, 1H), 4.59 (s, 2H).

[0300] Step 3 - Synthesis of 2-((2-((6-chloro-3-cyanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid: Methyl 2-mercapto-2-methylpropanoate (176 mg, 1.315 mmol) was added to a solution of 2-chloro-N-(6-chloro-3-cyanobenzo[b]thiophen-2-yl)acetamide (250 mg, 0.877 mmol) and cesium carbonate (428 mg, 1.315 mmol) in ACN (15.0 mL). The resulting mixture was stirred at room temperature for 16 hours. Monitoring of the reaction by TLC and LCMS showed the formation of intermediate 7. THF (10.0 mL) was added to the same reaction mixture, followed by lithium hydroxide monohydrate (184 mg, 4.38 mmol) in water (3.0 mL). The resulting mixture was continued to stir at room temperature for 16 hours. The reaction was monitored by TLC (30% ethyl acetate + 0.5 mL acetic acid in petroleum ether) and LC-MS. After the reaction was complete, the reaction mixture was quenched with water. The reaction mixture was extracted with ethyl acetate (2 × 30 mL). The separated aqueous layer was acidified with 6N HCl aqueous solution and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using DCM and methanol as the eluent system (the product was eluted at 3% in DCM → 5% MeOH) to obtain pure 2-((2-((6-chloro-3-cyanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (28.6 mg, 0.877 mmol, yield 8.84%) as a white solid.

[0301] NMR analysis confirmed the preparation of the desired product. 1H NMR (400 MHz, DMSO-d6) δ = 12.70 (br s, 1H), 12.31 (br s, 1H), 8.18 (s, 1H), 7.67 (d, J = 8.40 Hz, 1H), 7.54 (d, J = 8.40 Hz, 1H), 3.82 (s, 2H), 1.46 (s, 6H).

[0302] Example 28: Preparation of 2-((2-((3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS046) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS046 by the synthesis method of Scheme 28 shown below. [ka] Scheme 28 Dry CH2Cl2

[0303] Materials and methods 3,3-dimethyl-1,4-oxatian-2,6-dione (0.911 mmol) and 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (0.684 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 15 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-((2-((3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a gray powder (95 mg, 42.8%).

[0304] NMR analysis confirmed the preparation of the desired product. 11H NMR (400 MHz), DMSO-d6δ: 1.43 (s, 6H), 2.36 (quintet, 2H), 2.72 (t, 2H), 2.82 (t, 2H), 3.70 (s, 2H), 11.71 (s, 1H), 12.66 (s, 1H).

[0305] Example 29: Preparation of 2-((2-((3-cyano-4,5,6,7-tetrahydro-4,7-methanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS047) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS047 by the synthesis method of Scheme 29 shown below. [ka] Scheme 29 Dry CH2Cl2

[0306] Materials and methods 3,3-dimethyl-1,4-oxatian-2,6-dione (0.697 mmol) and 2-amino-4,5,6,7-tetrahydro-4,7-methanobenzo[b]thiophene-3-carbonitrile (0.523 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 20 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. The reaction mixture was extracted with saturated NaHCO3. Concentrated HCl was added to the aqueous layer, followed by extraction with CH2Cl2, washed with brine, and dried over anhydrous sodium sulfate. Excess solvent was removed by rotary evaporation to obtain 2-((2-((3-cyano-4,5,6,7-tetrahydro-4,7-methanobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a white powder (19 mg, 10.4%).

[0307] Example 30: Preparation of 2-((2-((3-cyano-4-cyclopropylthiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS048) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS048 by the synthesis method of scheme 30 shown below. [ka] Scheme 30 Dry CH2Cl2

[0308] Materials and methods 3,3-dimethyl-1,4-oxatian-2,6-dione (0.787 mmol) and 2-amino-4-cyclopropylthiophene-3-carbonitrile (0.590 mmol, 0.75 equivalents) were placed in a 50 mL round-bottom flask. The flask was purged with argon, and 15 mL of dry dichloromethane was added. The mixture was stirred overnight under positive argon pressure. Recrystallization by rapid cooling formed a white powder, which was isolated by vacuum filtration and washed with cold CH2Cl2. The residual solvent was removed by rotary evaporation to obtain 2-((2-((3-cyano-4-cyclopropylthiophene-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid as a white powder (45 mg, 23.4%).

[0309] NMR analysis confirmed the preparation of the desired product. 1 H NMR (500 MHz), DMSO-d6δ: 0.66 (dd, 2H), 0.917 (dd, 2H), 1.437 (s, 6H), 1.84 (m, 1H), 3.72 (s, 2H), 6.65 (s, 1H), 11.76 (s, 1H), 12.67 (s, 1H).

[0310] Example 31: Preparation of 2-((2-((3-cyano-4-methyl-5-phenylthiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (compound FTS049) [ka] This example describes the preparation of the FABP3 / 4 / 5 / 7 inhibitor compound FTS049 by the synthesis method of Scheme 31 shown below. [ka] Scheme 31 Process 1 room temperature 3 hours Process 2 16 hours

[0311] Materials and methods Step 1 - Synthesis of 2-chloro-N-(3-cyano-4-methyl-5-phenylthiophen-2-yl)acetamide: To a solution of 2-amino-4-methyl-5-phenylthiophen-3-carbonitrile (500 mg, 2.333 mmol) in THF (15 mL), Et3N (826 mg, 8.17 mmol) was added, followed by the addition of 2-chloroacetyl chloride (659 mg, 5.83 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC (10% ethyl acetate in petroleum ether) and LCMS. After the completion of the reaction, the reaction mixture was quenched with water. The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using siRNA and petroleum ether as eluents (the product was eluted in petroleum ether at 5% → 10% siRNA) to obtain pure 2-chloro-N-(3-cyano-4-methyl-5-phenylthiophen-2-yl)acetamide (290 mg, 0.997 mmol, yield 43%) as a brown solid.

[0312] NMR analysis confirmed the preparation of the desired intermediate compound. 1 H NMR (400 MHz, DMSO-d6) δ = 12.16 (s, 1H), 7.39-7.51 (m, 5H), 4.52 (s, 2H), 2.30 (s, 3H).

[0313] Step 2 - Synthesis of 2-((2-((3-cyano-4-methyl-5-phenylthiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid: Methyl 2-mercapto-2-methylpropanoate (242 mg, 1.806 mmol) was added to a solution of 2-chloro-N-(3-cyano-4-methyl-5-phenylthiophen-2-yl)acetamide (350 mg, 1.204 mmol) and cesium carbonate (588 mg, 1.806 mmol) in ACN (15.0 mL). The resulting mixture was stirred at room temperature for 16 hours. Monitoring of the reaction by TLC and LCMS showed the formation of intermediate 5. THF (10.0 mL) was added to the same reaction mixture, followed by lithium hydroxide monohydrate (253 mg, 6.02 mmol) in water (3.0 mL). The resulting mixture was continued to stir at room temperature for 16 hours. The reaction was monitored by TLC [30% (10 mL) EA in petroleum ether + 0.5 mL acetic acid] and LC-MS. After the reaction was complete, the reaction mixture was quenched with water. The reaction mixture was extracted with ethyl acetate (2 × 30 mL). The separated aqueous layer was acidified with 6N aqueous HCl and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (Isolera) using DCM and methanol as the eluent system (the product was eluted at 3% in DCM → 5% MeOH) to obtain pure 2-((2-((3-cyano-4-methyl-5-phenylthiophen-2-yl)amino)-2-oxoethyl)thio)-2-methylpropanoic acid (48.10 mg, 0.128 mmol, yield 10.67%) as a white solid.

[0314] NMR analysis confirmed the preparation of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ = 12.67 (br s, 1H), 11.97 (br s, 1H), 7.44-7.51 (m, 4H), 7.38-7.42 (m, 1H), 3.76 (s, 2H), 2.29 (s, 3H), 1.44 (s, 6H).

[0315] Example 32: Screening of FABP3 / 4 / 5 / 7 inhibitor compounds This example describes a two-step fluorescence binding assay study used to determine the binding affinity of various inhibitor compounds disclosed herein to various FABPs, namely FABP3, FABP4, FABP5, and FABP7. Compounds exhibiting high binding affinity to FABPs were subjected to further secondary screening studies based on their ability to activate nuclear receptors PPARα, PPARγ, or PPARδ.

[0316] Materials and methods A. Binding assay Binding assays for FABP3, FABP4, FABP5, and FABP7 were performed by fluorescence titration. His-tagged FABPs were expressed in E. coli bacteria, purified using Ni Sepharose beads, and the equilibrium dissociation constant (Kd) characterizing interactions with various inhibitor compounds was measured by fluorescence competitive assay. This method involves two steps, as described, for example, in Lin, Q. et al., "Ligand selectivity of the peroxisome proliferator-activated receptor alpha," Biochemistry 38, 185-190, doi:10.1021 / bi9816094 [pii] (1999). In the first step, the Kd for binding of the protein to the fluorescent fatty acid probe ANS was measured. The protein (2 μM) was titrated with ANS from a concentrated solution in DMSO. Ligand binding was monitored by tracking the increase in ligand fluorescence upon binding to the protein, and the Kd for binding of ANS to each FABP was calculated by computer from the titration curve, as described, for example, in Norris, AW & Li, E., "Fluorometric titration of the CRABPs," Methods Mol Biol 89, 123-139 (1998). In the second step, the Kd for binding of non-fluorescent ligands was measured by monitoring the ability to displace ANS in the protein's binding pocket. Each FABP was pre-complexed with ANS in a 1:1 molar ratio and titrated with various compounds whose binding was reflected by a decrease in probe fluorescence. Kd was calculated from the EC of the competitive curve. 50 These were extracted from Kd measured for ANS.

[0317] B. Transcriptional activation assay COS-7 cells were cultured in 6-well plates and co-transfected with a 3-copy PPRE-driven luciferase reporter and an expression vector for either PPARδ, PPARα, or PPARγ, along with a vector containing β-galactosidase cDNA serving as a transfection control. To test whether FABP4 or FABP5 mediates the activation of their respective congener receptors, PPARγ and PPARδ, the cells were also co-transfected with plasmids containing either the FABP4 or FABP5 sequence. Eighteen hours after transfection, the cells were placed in serum-free medium and treated with an agonist / compound. After another eighteen hours, the cells were lysed and luciferase activity was assayed (Promega, WI, USA), correcting for transfection efficiency by β-galactosidase activity.

[0318] result The results of the binding assays between FABP5, FABP4, FABP3, and FABP7 and the disclosed compounds FTS001, FTS003, FTS005, FTS007, FTS009, FTS011, FTS013, FTS017, FTS019, FTS026, FTS029, FTS030, FTS031, FTS032, FTS033, FTS034, FTS037, FTS039, FTS040, FTS041, FTS042, FTS043, FTS044, FTS045, FTS046, FTS048, and FTS049 are summarized in Table 19 below. None of these tested compounds activated PPARα, PPARγ, or PPARδ.

[0319] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5] [Table 19-6] [Table 19-7] [Table 19-8] Compound: compound Inhibitor Specificity:

[0320] Example 33: Biological studies of FABP3 / 4 / 5 / 7 inhibitor compounds FTS005, FTS030, FTS031, FTS037, and FTS039 This example describes the study of the biological functions of FTS005, FTS030, FTS031, FTS037, and FTS039, which are FABP3 / 4 / 5 / 7 inhibitor compounds, in cancer models and metabolic disease models.

[0321] Materials and methods A. Cell COS-7, MDA-MB-231, NPG, HepG2, and 3T3-L1 cells were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (Invitrogen Life Sciences, Carlsbad, CA). 4T1, 4T01, NR67, MDA-MB-157, MB-549, and OVCAR8 cells were cultured in L-glutamine-containing RPMI medium supplemented with 10% fetal calf serum (Invitrogen Life Sciences, Carlsbad, CA).

[0322] B. Transcriptional activation assay The transcriptional activation assay was performed using COS7 cells as described above.

[0323] C. Real-time PCR Cells were treated with the compound for 6 hours, then lysed, and RNA was extracted using Trizol according to the manufacturer's instructions. cDNA was generated using GeneAmp RNA PCR (Applied Biosystems). qPCR was performed using TaqMan Chemistry and Assays-on-Demand probes (Applied Biosystems). 18s(4352930)rRNA was used for normalization. Relative expression was 2 -DDCT It was calculated as follows.

[0324] D. Growth assay 2000 cells were seeded into each well of a 96-well plate. The following day, the cells were treated with a compound and incubated in an Incucyte for 4 days. Images taken every 4 hours during this period were analyzed, and the percentage of confluence corresponding to the treatment was calculated. Growth inhibition was calculated as 1 - (percentage of viable cells among untreated cells).

[0325] E. Lipid uptake assay 1) HepG2 cells: 5000 cells were seeded in a 96-well plate. The following day, the cells were treated with the test compound for 4 hours, followed by a further 24-hour treatment with 1 mM oleic acid. The cells were then stained with Nile Red and Dapi, and the lipid content was quantified using Cytation 5 (Agilent).

[0326] 2) 3T3-L1: Mouse 3T3-L1 cells were differentiated in culture according to the ATCC protocol to mature adipocytes. Treatment with the compound was initiated on day 6 of differentiation. On the same day, the cells were stained with Nile Red, and the color intensity of each cell was measured and compared with Dapi staining.

[0327] F. Xenotransplantation experiment A 7-week-old female NSG had a 5x10 plaque on her right flank. 6Individual MB-231 cells were subcutaneously injected with Matrigel in a 1:1 ratio. Treatment was initiated five days a week starting the day after cell injection. Mice were orally treated by forced oral administration of either a vehicle (sesame oil) or 20 mg / kg or 40 mg / kg of FTS005 dissolved in the vehicle. Tumor size was assessed twice a week using a digital caliper. Tumor volume was measured by measuring the length (l) and width (w) of the tumor, and the volume (V = lw) was calculated. 2 The result was obtained by calculating ( / 2). Mice were sacrificed 24 days after injection. Statistical significance between control and treated mice in both experiments was assessed using Student's t-test. The mouse experiments were conducted after approval from the Institutional Animal Care and Use Committee of Case Western Reserve University.

[0328] G.TNBC Similar Mouse Model In the mammary fat pads of 7-week-old BALB / c female mice, 1 × 10⁶ 5 Four T1 cells were subcutaneously injected with Matrigel in a 1:1 ratio. Treatment was initiated five days a week starting the day after cell injection. Mice were orally treated by forced oral administration of either a vehicle (sesame oil) or 40 mg / kg FTS005 dissolved in a vehicle. Tumor size was assessed twice a week using a digital caliper. Tumor volume was measured by measuring the length (l) and width (w) of the tumor, and the volume (V = lw) was calculated. 2 The result was obtained by calculating ( / 2). Mice were sacrificed 32 days after injection. Statistical significance between control and treatment mice in both experiments was assessed using Student's t-test. Mouse experiments were conducted after approval from the Animal Experiments Committee of Case Western Reserve University.

[0329] Isolation of primary T cells (H.) T cells were collected from the splenocytes of control BALB / c mice with 4T1 tumors, or from mice treated with FABP3 / 4 / 5 / 7 inhibitors.

[0330] I. Metabolomics analysis of tumor samples A 50 mg tumor sample was dissolved in 500 μL of PBS, and the protein concentration was measured. The sample was subjected to LC / MS / MS using a C18 (Gemini 5 μM, 2 × 150 mm, Phenomnex) column. The mobile phases were as follows: 1) For detection of TCA metabolites: A) Water + 5 mM AmAc, and B) Methanol + 5 mM AmAc, flow rate 0.3 mL / min; 2) For detection of glycolysis, fatty acid, and arachidonic acid oxidation metabolites: A) Water + 0.1% acetic acid, and B) Methanol / CAN (1 / 1) + 0.1% acetic acid, flow rate 0.3 mL / min.

[0331] result A. Compounds FTS005, FTS030, FTS031, FTS037, and FTS039 do not activate PPAR-mediated transcription. Transcriptional activation assays were performed using COS7 cells to rule out the possibility that the thiophene compounds FTS005, FTS030, FTS031, FTS037, and FTS039 are ligands for the nuclear receptors PPARα, PPARγ, or PPARδ that activate transcription by these transcription factors. For comparison, Wy-14643 (Figure 1A), rosiglitazone (Figure 1B), and GW0742 (Figure 1C) (all 5 mM), which are known specific agonist compounds for PPARα, PPARγ, or PPARδ, were also assayed, respectively. As shown by the plots of data in Figures 1A, 1B, and 1C, none of the tested compounds FTS005, FTS030, FTS031, FTS037, and FTS039 activated transcription, unlike these known agonist compounds which induced activation of their respective receptors.

[0332] B. Compound FTS005 suppresses the growth of FABP5-expressing TNBC cells more effectively than the commercially available inhibitor SBF-I26. The efficacy of compound FTS005 in inhibiting cancer cell proliferation was calculated using TNBC cell lines MB-231 and BT-549. Cells were treated with serial dilutions of the compound, and proliferation was measured by calculating the percentage of confluence every 4 hours over 4 days using Incucyte. As shown in Figure 2A, FTS005 very effectively inhibited the proliferation of the two human TNBC lines MB-231 and BT-549, and the calculated IC50 was high. 50 The concentrations were 0.145 mM and 0.25 mM, respectively.

[0333] To verify that the inhibitory effect of FTS005 on TNBC cells is mediated via FABP5, we used the MB-231 cell line, which stably expresses FABP5 shRNA. As shown in Figure 2B, FTS005 inhibited the proliferation of WT MB-231 and BT-549 cell lines that express FABP5, but did not affect the proliferation of F5_KD MB-231 cell lines with low levels of FABP5.

[0334] The efficiency of FTS005 in inhibiting MB-231 cell proliferation was also compared with that of SBF-I26, a known FABP5 / 7 inhibitor compound. As shown in Figure 2C, the data clearly demonstrate that treatment of MB-231 cells with the thiophene compound suppresses TNBC cell proliferation 10 to 20 times more effectively than SBF-I26.

[0335] Furthermore, the effects of FTS005 were also tested on the proliferation of mouse mammary carcinoma cell lines 67NR, 4T07, and 4T1, which serve as models for human TNBC. Cell lines 4T07 and 4T1 are derived from NR67, with 4T1 being the most metastatic and aggressive of the three. FABP5 expression levels were measured in all cell lines and compared to those of the human cell line MB-231. FABP5 levels were found to be positively correlated with cellular aggressiveness, with MB-231 having the highest levels, followed by 4T1 and 4T07. As shown in Figure 3A, FABP5 was not detected in 67NR cells. As expected, treatment of mouse carcinoma cells with FTS005 inhibited their proliferation, but not more efficiently than in MB-231 cells (see results in Figures 3B and 3C). This indicates that the effect of the inhibitor depends on the FABP5 expression level. 67NR cells were not affected by FTS005 at all (Figure 3C).

[0336] C. Compounds FTS005, FTS040, FTS041, FTS042, FTS043, FTS044, FTS045, and FTS049 inhibit the growth of human ovarian cancer cells OVCAR8. The efficacy of compounds FTS005, FTS040, FTS041, FTS042, FTS043, FTS044, FTS045, and FTS049 in inhibiting ovarian cancer cell proliferation was calculated using the ovarian cancer cell line OVCAR8. Cells were treated with serial dilutions of the compounds, and proliferation was measured by calculating the percentage of confluence every four hours over four days using Incucyte. As shown in Figure 4A, all compounds very effectively inhibited the proliferation of the cancer cell line. The calculated ICs are shown in Figure 4B. 50 The concentration ranged from 0.602 μM (FTS044) to 1.1 μM (FTS042) across all compounds, showing similar efficacy.

[0337] D. Compound FTS005 inhibits the growth of neuroblastoma (NB) cells and increases their sensitivity to all-trans retinoic acid (atRA) in combination therapy. When available intracellularly, FABP5 has been shown to bind to atRA, deliver it to PPARδ, and activate its nuclear receptor. Activation of PPARβ by atRA shifts the signaling of this vitamin from its homologous receptor RAR, which is known to have anti-oncogenic activity in several cancers, to the pro-oncogenic PPARδ. Therefore, inhibition of FABP5 is expected to sensitize cancer cells to atRA by shifting cancer cell signaling back to RAR. Accordingly, the effect of FABP5 inhibitors in combination with atRA on cell proliferation was tested using human NPG cells, which are a type of NB. Cells were treated with FTS005 in the presence or absence of atRA.

[0338] As shown in Figure 5A, treatment of cells with FTS005 significantly inhibited cell proliferation, and this tendency was enhanced when the compound was combined with atRA. Furthermore, combination therapy with FTS005 and atRA significantly improved the sensitivity of cells to atRA (see results in Figures 5B and 5C).

[0339] E. Compound FTS005 suppresses tumor growth and limits macrophage infiltration into TNBC tumors in an in vivo xenograft model. The efficacy of FTS005 in suppressing tumor growth in vivo was tested using a TNBC xenograft model. 5 × 10 6MB-231 cells were subcutaneously injected into the right flank of NSG mice. Mice were treated five times a week with FTS005 (20 mg / kg or 40 mg / kg) or a vehicle by forced oral administration, and tumor growth was monitored. As shown in Figure 6A, FTS005 significantly inhibited the growth of MB-231 tumors, as determined by tumor volume and tumor weight (Figures 6A and 6B). Molecular analysis of the tumors showed that the level of the growth marker Ki67 was significantly reduced in tumors of mice treated with FTS005 (Figures 6C and 6D). Similarly, the level of the angiogenesis marker VEGFA, which is also a known PPARδ target gene, was significantly lower in the treated tumors (Figures 6C, 6E, and 6G). Surprisingly, staining for the macrophage marker F4 / 80 in tumors showed a significant decrease in the total number of tumor-associated macrophages (TAMs) in treated tumors compared to untreated controls (Figure 6C and Figure 6F). This indicated that inhibition of FABP5 affected the immune cell population in the tumor microenvironment. QPCR measurements of the ACSL1 and PLIN2 genes, which are involved in FA metabolism and lipid accumulation and are also known PPARδ targets, revealed that their levels were significantly reduced in treated tumors (Figure 6G).

[0340] F. Compound FTS005 suppresses TNBC tumor growth in vivo in a syngeneic mouse model. The efficacy of FTS005 in suppressing tumor growth in vivo in an immunocompromised model was tested using 4T1 cells in a TNBC syngeneic model. 1 × 10⁻¹⁶ 5 Four T1 cells were injected into the mammary fat pad of BALB / c mice. The mice were treated five times a week with FTS005 (40 mg / kg) or a vehicle by forced oral administration, and tumor growth was monitored.

[0341] As shown in Figure 7A, FTS005 significantly inhibited the growth of 4T1 tumors, as determined by tumor volume and tumor weight (see Figures 7A and 7B). QPCR measurement of the expression level of the angiogenesis marker VEGFA, which is also a known PPARδ target gene, revealed that it was significantly lower in treated tumors (Figure 7C). Similarly, levels of the genes ACSL1 and PLIN2, which are involved in FA metabolism and lipid accumulation and are also known PPARδ targets, were significantly reduced in treated tumors (Figure 7C). Immunohistochemical staining of the tumors showed that protein levels of the growth markers Ki67 and VEGFA were significantly reduced in tumors of mice treated with FTS005 (see Figures 7D, 7E, and 7F, respectively).

[0342] G. Compound FTS005 reprograms fatty acid metabolism in the tumor microenvironment (TME). 4T1 tumor samples treated with or untreated with FTS005 were analyzed for the levels of various fatty acid-related metabolites. More specifically, LC / MS / MS analysis was used to measure TCA cycle, glycolysis, long-chain fatty acids, arachidonic acid oxidation, and ATP / ADP metabolites, which were quantified based on protein concentrations in each sample. As can be seen in Figure 8, the metabolite profiles measured in tumors treated with FTS005 changed significantly after treatment. The amount of long-chain fatty acids measured in treated tumors (Figure 8A) was significantly lower than in untreated tumors, and similarly, lower levels of TCA cycle metabolites were detected (Figure 8B). Conversely, the amount of glycolysis metabolites increased after treatment (Figure 8D), indicating that FTS005 treatment induces reprogramming of fatty acid metabolism and a shift in energy use from fatty acids to glycolysis in tumors. Significantly higher levels of ADP were measured in tumors treated with ADP, and no difference in ATP levels was observed. However, significantly higher levels of ADP resulted in lower ATP / ADP ratios, which are known markers of lower proliferation rates and cell death (Figure 8C).

[0343] H. Compound FTS005 modulates immune cell populations in the tumor microenvironment (TME). The effects of FTS005 treatment on immune cells in tumor-infiltrating macrophages (TMEs) were further investigated using samples derived from tumors generated in immunocompetent BALB / c mice injected with 4T1 cells. To evaluate the effect of FTS005 on tumor-infiltrating macrophages (TAMs), tumors were stained with TAM markers F4 / 80 and CD68, as well as the specific M2 marker CD163 (Figures 9A, 9B, and 9C). As shown by the staining for F4 / 80 and CD68 (Figures 9A, 9B, 9D, and 9E), the levels of total macrophages were not regulated by FTS005 treatment, but the levels of the M2 marker CD163 were significantly lower in treated tumors (Figures 9C and 9F). The data suggest that the FABP5 inhibitor FTS005 restricts immunosuppressive M2 macrophages in tumors, thereby inducing an autoimmune response against tumor cells.

[0344] To evaluate the effect of FTS005 on tumor-infiltrating T cells, tumor samples were stained with T cell markers CD3, CD4, and CD8. Notably, levels of CD3, DC4 (CD4), and CD8 were significantly higher in treated tumors than in untreated controls (Figures 10A and 10B). The number of CD4 T cells and CD8 T cells was also measured by flow cytometry between cells isolated from the spleens of mice. No significant difference was observed in the frequency of either CD4 or CD8 in spleen cells collected from treated mice versus untreated mice (Figure 10C), but activated TNFα +The amount of CD8 T cells was significantly higher in spleen cells collected from treated mice (Figure 10D). The 4T1 cells used in this experiment stably expressed Luc2, and therefore, to stimulate an immune response by the collected spleen cells, the collected cells were treated with Luc2 peptide in growth medium for two weeks and the cell count was measured. As shown in Figure 10E, the number of T cells collected from spleens treated with FTS005 was significantly higher than that collected from untreated mice, indicating that the treated T cells proliferated more in response to Luc2 antigen exposure. To test the cytotoxic activity of T cells, spleen T cells were co-cultured overnight with 4T1Luc2-CFSE high (target, derived from Balb / c) and F420Luc2-CFSE low (control, derived from B6) (target:effector = 1:5). The following day, live CFSE+ cells were counted by flow cytometry and the percentage of lysed cells was calculated. As shown in Figure 10F, the number of lysed cells was significantly higher after incubation with T cells isolated from treated mice. Therefore, the data suggest that treatment with the FABP3 / 4 / 5 / 7 inhibitor FTS005 stimulates the formation of memory T cells.

[0345] To evaluate the effects of FTS005 on multiple immune cells and tumor immune function, comprehensive profiling of the immune response was performed using the nCounter PanCancer Immune Profiling Panel with RNA samples extracted from untreated and treated tumors. As shown in Figure 11, treatment of tumor-bearing mice with FTS005 resulted in changes in the immune cell profile in the tumors. Based on this analysis, a larger number of CD45 cells, macrophages, B cells, dendritic cells, cytotoxic cells, T cells, CD8 T cells, NK cells, and NK CD56dim cells were found in the treated tumors, indicating more immunoactive TMEs. In summary, data collected from mice treated with FTS005 suggest that inhibition of FABP3 / 4 / 5 / 7 modulates immune cells in TMEs in two ways: 1) by suppressing immunosuppressive M2 tumor-associated macrophages, and 2) by stimulating tumor-infiltrating lymphocytes (TILs), including activated CD4 and CD8 cells, NK cells, cytotoxic cells, and dendritic cells, into tumors. All of these are known to activate immunosuppressed tumors and transform them into "hot" tumors that can be recognized by the immune system.

[0346] F.FTS005 inhibits lipid uptake into hepatocytes in an in vitro model of hepatic steatosis. HepG2 cells were used to test the effect of FTS005 on lipid uptake into hepatocytes in an in vitro hepatic steatosis model. Cells were treated with oleic acid (OA) (1 mM) in or without the presence of an aniline compound or a known FABP4 inhibitor, BMS-309403 (BMS), and intracellular lipid accumulation was quantified using Nile Red. Lipid uptake into hepatocytes treated with FTS005 was significantly inhibited (Figure 12A). The inhibition of lipid uptake was more efficient with FTS005 than with BMS. For comparison, the lipid accumulation in cells after treatment with 5 μM FTS005 was equivalent to that established after treatment with 25 μM BMS (Figure 12A), indicating that thiophene compounds are more efficient than BMS.

[0347] G.FTS005 inhibits lipid uptake into mature adipocytes. Mouse 3T3-L1 cells were differentiated into mature adipocytes by culture. Various concentrations of the compound FTS005 or the known FABP4 inhibitor BMS were added to the cells starting on day 6 of differentiation. On day 12, lipid droplets were stained with Nile Red and quantified (Figure 12B). Lipid uptake into hepatocytes treated with FTS005 was significantly inhibited (Figure 12A). The inhibition of lipid uptake was more efficient with FTS005 than with BMS. For comparison, the lipids accumulated in cells after treatment with 10 μM FTS005 were equivalent to those established after treatment with 30 μM BMS (Figure 12B), demonstrating that thiophene compounds are more efficient than BMS.

[0348] Example 34: Biological study of the effects of FABP3 / 4 / 5 / 7 inhibitor compounds on immune cell populations This example describes a study of the biological effects of the FABP inhibitor compound FTS005 on immune cell populations in a cancer model.

[0349] Materials and methods A. Isolation and differentiation of mouse myeloid macrophages (BMDMs) BMDM was isolated from C57BL6 mice. Briefly, bone marrow was flushed with RPMI medium and cells were lysed using AKL buffer. The harvested cells were plated in growth medium (DMEM, 10% HI FBS, 1% pen / strep, 25 ng / mL M-CSF) for 7 days (Mφ macrophages). To promote macrophage differentiation in culture, Mφ cells were treated with LPS (10 pM) and INF (20 ng / mL) to promote differentiation to M1 macrophages, or with IL-4 (20 ng / mL) and IL-13 (20 ng / mL) to promote differentiation to M2 macrophages. Cells were incubated with cytokines in or out of the presence of FABP3 / 4 / 5 / 7 inhibitors for 3 days, then lysed and immunostained for further analysis.

[0350] B. Fluorescence-activated cell sorting (FACS) Macrophages were fixed and then stained. Live cells were identified using the LIVE / DEAD® Fixable Aqua Dead Cell Stain Kit according to the manufacturer's protocol. To measure macrophage frequency, cells were stained with the markers F4 / 80 (total macrophages), CD11b (total macrophages), MHC-II (M1 macrophages), CD36 (M2 macrophages), and CD206 (M2 macrophages). To assess T cell frequency, the following markers were used: CD4, CD8, CD25, and FoxP3 (Treg), as well as TNFα (activated T cells). Data were analyzed using FlowJo software.

[0351] Determination of C.IL-10 and IL-12 The levels of interleukin-10 (IL-10) and interleukin-12 p70 (IL-12), cytokines secreted from macrophages, were measured in the culture medium of treated cells using an ELISA assay kit according to the manufacturer's protocol.

[0352] result A. Treatment of differentiating macrophages with FABP3 / 4 / 5 / 7 inhibitors suppresses the M2 phenotype while supporting the M1 phenotype. Myeloid macrophages (BMDMs) were isolated from mice and differentiated in culture. Cells treated with M-CSF for 7 days were established as naive macrophages (Mφ). Naive macrophages were then treated with LPS and IFNg to promote differentiation into M1 macrophages, or with IL-4 and IL-13 to promote differentiation into M2 macrophages. This was done in or without FABP3 / 4 / 5 / 7 inhibitors. M1 polarization of macrophages was examined using high frequencies of the marker MHC-II (Figure 13A) and high levels of IL-12 (Figure 13B). M2 polarization of macrophages was examined using high frequencies of the markers CD36 (Figure 13C) and CD206 (Figure 13D), as well as high levels of IL-10 (Figure 13E). CD206 expression levels in macrophages differentiated to the M2 state in the presence of either the FABP inhibitor FTS005 or the commercially available inhibitor BMS480404 were significantly lower than in M2 controls (Figure 13F). Similarly, in cells differentiated in the presence of FABP3 / 4 / 5 / 7 inhibitors, levels of IL-10, which is well known to be secreted by M2 macrophages, were significantly reduced (Figure 13G), while levels of IL-12, which is known to be secreted by M1 macrophages, were significantly increased (Figure 13H). Therefore, the data indicate that FABP3 / 4 / 5 / 7 inhibitors can be used to block macrophage differentiation from the naive to the M2 state, as indicated by both cell surface markers and secreted cytokines. To test the effect of FABP3 / 4 / 5 / 7 inhibitors on macrophage differentiation from the M1 to the M2 state, cells were first differentiated into M1 macrophages and then into M2 macrophages in the presence of FABP3 / 4 / 5 / 7 inhibitors. The frequency of CD206+ macrophage populations (Figure 13I) and CD206 expression levels in differentiated cells (Figure 13J) were significantly reduced in the presence of FABP3 / 4 / 5 / 7 inhibitors, while IL-12 levels were significantly increased (Figure 13K). In summary, the data suggest that FABP3 / 4 / 5 / 7 inhibitors can be used to modulate M1 and M2 macrophage cell populations.

[0353] While the foregoing disclosure of the present invention is described in some detail with examples and illustrations for the purposes of clarity and understanding, the examples, descriptions, and embodiments described herein are for illustrative purposes only and are intended to be illustrative and should not be construed as limiting the disclosure. It will be apparent to those skilled in the art that various modifications or changes to the examples, descriptions, and embodiments described herein are possible and are included in the spirit and scope of the disclosure and the appended claims. Furthermore, those skilled in the art will recognize numerous methods and procedures equivalent to those described herein. Such equivalents are understood to be within the scope of the disclosure and are covered by the appended claims.

[0354] Additional embodiments of the present invention are described in the appended claims.

[0355] All publications, patent applications, patents, or other documents referenced herein are expressly part of this Specified by reference in their entirety, as if each individual publication, patent, patent application, or other document were explicitly indicated to be part of this Specified by their entirety for any purpose, and as if each were individually clearly indicated to be included in the Specified. In case of any conflict, including the designated terms, this Specified shall prevail. [Explanation of Symbols]

[0356] reason Figure 1A Activation (RLU / b-gal) Activation (RLU / b-gal) untreated Figure 1B Activation (RLU / b-gal) Activation (RLU / b-gal) untreated Rosiglitazone Figure 1C Activation (RLU / b-gal) Activation (RLU / b-gal) untreated Figure 2A % confluency % confluency MB-231 cells IC 50 MB-231 cell IC 50 549 cells IC 50 549 cell IC 50 Figure 2B % Confluency % Confluency 231 cells 231 cells 549 cells 549 cells Figure 2C % confluency % confluency Figure 3A Cell line cell line Figure 3B % confluency % confluency MB-231 cells MB-231 cells 4T1 cells 4T1 cells MB-231 cells IC 50 MB-231 cell IC 50 4T1 cells IC 50 4T1 cell IC 50 Figure 3C % confluency % confluency Figure 4A % confluency % confluency [compound] (μM) [compound](μM) Figure 4B % confluency % confluency [compound] (μM) [compound](μM) Figure 5A % confluency % confluency Figure 5B % confluency % confluency Figure 5C % confluency % confluency Figure 6A Tumor volume (mm 3 ) Tumor volume (mm 3 ) control (Days) (Number of days) Figure 6B Tumor weight (mg) untreated Figure 6D %(positive staining / slide area) Control Figure 6E %(positive staining / slide area) Control Figure 6F %(positive staining / slide area) Control Figure 6G Expression ration (mRNA / 18S) PPARδ targets PPARδ targets control Figure 7A Tumor volume (mm 3 ) Tumor volume (mm 3 ) Untreated (Days) (Number of days) Figure 7B Tumor weight (mg) Control Figure 7C Expression ratio (mRNA / 18S) PPARδ targets PPARδ targets Control Treated (Processed) Figure 7E %(positive staining / slide area) control Processed Figure 7F % positive staining / slide area control Processed Figure 8A pmol / mg protein pmol / mg protein Figure 8B Citrate & Isocitrate pmol / mg protein pmol / mg protein untreated Succinate Figure 8C pmol / mg protein pmol / mg protein untreated Figure 8D Glucose pmol / mg protein pmol / mg protein untreated Lactate Pyruvate Figures 9A, 9B, and 9C Untreated Figure 9D % positive staining / section area % positive staining / section area control Processed Figure 9E % positive staining / section area % positive staining / section area control Processed Figure 9F % positive staining / section area % positive staining / section area control Processed Figure 10A Untreated Figure 10B %(positive staining / slide area) control Processed Figures 10C and 10D Frequency of Parents (%) Control Figure 10E Splenic T cell Splenic T cell Cell number (x105 ) Number of cells (×10 5 ) Control Figure 10F Cell lysis (%) Cell lysis (%) Control Figure 11 Immune Cell Profiles Neutrophils Macrophages B-cells B-cells Exhausted CD8 Th1 cells Th1 cells Mast cell Cytotoxic cells CD8 T cells CD8 T cells NK CD56dim cells NK CD56dim cells NK cells NK cells T-cells T-cells control Processed Figure 12A Fold intensity intensity magnification Figure 12B Fold intensity intensity magnification Differentiated Figure 13A Freq of MHCII + / CD206 - MHCII + / CD206 - frequency Figure 13C Freq of MHCII - / CD36 + MHCII - / CD36 +frequency Figure 13D Freq of MHCII + / CD206 + MHCII + / CD206 + frequency Figure 13F CD206 intensity CD206 intensity M2-untreated Figure 13G M2-untreated Figure 13H M2-untreated Figure 13I Freq of MHCII + / CD206 + MHCII + / CD206 + frequency M1 to M2 Figure 13J CD206 intensity CD206 intensity M1 to M2 Figure 13K M1 to M2 References 1. 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Claims

1. Structural formula I: 【Chemistry 1】 (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3 each independently is hydrogen, C 1 -C 4 linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3 together form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbocyclic or heterocyclic ring, or a 5- to 8-membered aryl or heteroaryl ring, where the carbocyclic, heterocyclic, aryl, or heteroaryl ring is optionally substituted with one or two substituents selected from C 1 -C 4 -alkyl, methoxy, or fluoro, X is given by the following formula: 【Chemistry 2】 (In the formula, Y is a heteroatom selected from -S- and -O-, or -CR 8 R 9 -and here, R 8 and R 9 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They come together to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring. R 4 , R 5 , R 6 and R 7 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, phenyl, and benzyl, and / or R 4 and R 5 They are together, or R 6 and R 7 They combine to form a cyclopropyl ring or a cyclobutyl ring, or R 5 and R 6 A compound of which is a part of which (together, Y forms a 5- to 6-membered carbon ring or heterocycle having Y as a ring member) or a pharmaceutically acceptable salt thereof, However, the compound of structural formula I is the following compound: Table 1 Excluding the compound of structural formula I or a pharmaceutically acceptable salt thereof.

2. R 1 The compound according to claim 1, wherein the compound is cyano.

3. Structural formula Ia: 【Transformation 3】 The compound according to claim 1, having the following characteristics.

4. Ij, Ik, Il, Im, In, Io, Ip, Iq, Ir, Is, and It: Table 2 The compound according to claim 3, having a structural formula selected from the following.

5. Ib: 【Chemistry 4】 (In the formula, R 10 and R 11 These are, independently, hydrogen, halogen, and C. 1 ~C 4 The compound according to claim 1, having a structural formula selected from linear or branched alkyl, cyclopropyl, and cyclobutyl.

6. Iu, Iv, and Iw: Table 3 The compound according to claim 5, having a structural formula selected from the following.

7. R 1 It is a 5-membered heteroaryl ring, and R 2 and R 3 Each of them independently consists of hydrogen and C 1 ~C 4 The compound according to claim 1, selected from linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl.

8. Formulas Ic, Id, Ie, If, Ig, Ih, and Ii: Table 4 (In the formula, R 12 is hydrogen, halogen, C 1 ~C 4 The compound according to claim 1, having a structural formula selected from linear or branched alkyl, cyclopropyl, cyclobutyl, and phenyl.

9. Ix, Iy, Iz, Iaa, Ibb, Icc, Idd, Iee, Iff, Igg, Ihh, Iii, Ijj, Ikk, Ill, Imm, Inn, Ioo, Ipp, Iqq, and Irr: Table 5-1 Table 5-2 The compound according to claim 8, having a structural formula selected from the following.

10. Y is selected from -S- or -O-, R 4 , R 5 , R 6 and R 7 Each of them independently contains hydrogen or C 1 ~C 4 A compound according to any one of claims 1 to 9, which is linear or branched alkyl.

11. The aforementioned X portion is as follows: Table 6 A compound selected from any one of claims 1 to 9.

12. The aforementioned X portion is as follows: Table 7 A compound selected from any one of claims 1 to 9.

13. The aforementioned X portion is as follows: Table 8 A compound selected from any one of claims 1 to 9.

14. Structural formula II: 【Transformation 5】 (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbon ring or heterocyclic ring, or a 5- to 8-membered aryl ring or heteroaryl ring, where the carbon ring, heterocyclic, aryl ring, or heteroaryl ring is C 1 ~C 4 -Optionally substituted with one or two substituents selected from alkyl, methoxy, or fluoro, Y is a heteroatom selected from -S- and -O-, or -CR 8 R 9 -and here, R 8 and R 9 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They come together to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring. R 4 , R 5 , R 6 and R 7 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, phenyl, and benzyl, and / or R 4 and R 5 They are together, or R 6 and R 7 They combine to form a cyclopropyl ring or a cyclobutyl ring, or R 5 and R 6 A compound of which (together form a 5- to 6-membered carbon ring or heterocycle having Y as a ring member) or a pharmaceutically acceptable salt thereof, However, the compound of structural formula II is the following compound: Table 9 Excluding the compound of structural formula II or a pharmaceutically acceptable salt thereof.

15. R 1 The compound according to claim 13, wherein is cyano.

16. Structural formula IIa: 【Transformation 6】 (In the formula, the chemical group R 2 , chemical group R 3 , chemical group R 4 , chemical group R 5 , chemical group R 6 and chemical group R 7 The compound according to claim 13, having (as defined for the compound of structural formula II).

17. IIj, IIk, IIl, IIm, IIn, IIo, IIp, IIq, IIr, IIs, and IIt: Table 10 The compound according to claim 16, having a structural formula selected from the following.

18. Structural formula IIb: 【Transformation 7】 (wherein the chemical group R 2 , the chemical group R 3 , the chemical group R 4 , the chemical group R 5 , the chemical group R 6 and the chemical group R 7 are as defined for the compound of the structural formula II, and R 10 and R 11 are each independently hydrogen, halogen, C 1 - C 4 linear or branched alkyl, cyclopropyl, and cyclobutyl), the compound according to claim 13.

19. IIu, IIv, and IIw: Table 11 The compound according to claim 18, having a structural formula selected from the following.

20. Formulas IIc, IId, IIe, IIf, IIg, IIh, and IIi: Table 12 (wherein, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined for the compound of Structural Formula II, and R 12 is hydrogen, halogen, C 1 -C 4 straight-chain or branched alkyl, cyclopropyl, cyclobutyl, or phenyl), the compound according to claim 13 having a structural formula selected from).

21. IIx, IIy, IIz, IIaa, IIbb, IIcc, IIdd, IIee, IIff, IIgg, IIhh, IIIi, IIjj, IIkk, IIll, IImm, IInn, IIoo, IIpp, IIqq, IIrr, and IIss: Table 13-1 Table 13-2 The compound according to claim 20, having a structural formula selected from the following.

22. Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound Substance 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 40, compound 41, compound 42, compound 43, compound 44, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61, compound 62, compound 63, compound 64, and compound 65: Table 14-1 Table 14-2 Table 14-3 Table 14-4 Table 14-5 Table 14-6 Table 14-7 A compound selected from any one of claims 1 to 21.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and one or more auxiliary components.

24. A method for treating a subject having a disease or condition affected by FABP3 / 4 / 5 / 7, comprising administering to the subject in need a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

25. Diseases or conditions affected by FABP3 / 4 / 5 / 7 include atherosclerosis, coronary artery atherosclerosis, arteriofibrosis, pulmonary hypertension, heart failure, obesity, type 2 diabetes, type 1 diabetes, gestational diabetes, polycystic ovary syndrome, endometriosis, conditions affected by lipid metabolism and serum free fatty acid levels, metabolic disorders, fatty liver disease, renal fibrosis, systemic inflammation, acute inflammation, allergic inflammation, respiratory inflammation, viral infections (e.g., COVID-19, common cold), skin diseases (e.g., vitiligo, psoriasis, atopic dermatitis, allergic contact dermatitis, mycosis fungoides, alopecia areata, scarring alopecia, graft-versus-host disease (GvHD), contact dermatitis, chronic eczema, herpetiform dermatitis, cutaneous lupus, scleroderma, dermatomyositis, vasculitis, pemphigus, epidermal The method according to claim 24, selected from bullous diseases, linear IgA, bullous diseases), neurological conditions and neurological diseases (e.g., pain, multiple sclerosis (MS), Parkinson's disease), autoimmune diseases (e.g., experimental autoimmune encephalomyelitis (EAE), asthma, type 1 diabetes, autoimmune lung disease, autoimmune hepatitis, rheumatoid arthritis (RA), spondyloarthritis, bullous stomatitis virus infection, multiple sclerosis (MS), lupus nephritis, Crohn's disease, ulcerative colitis, and food allergies), ischemic stroke, graft-versus-host disease (GvHD), and cancer (e.g., breast cancer, prostate cancer, ovarian cancer, skin cancer, gastric cancer, glioma, cholangiocarcinoma, bladder cancer, multiple myeloma, colorectal cancer, hepatocellular carcinoma, cervical cancer, oral squamous cell carcinoma, and / or non-small cell lung cancer (NSCLC)).

26. A method for controlling free fatty acid serum levels in a subject requiring such control, comprising administering to the subject requiring such control a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

27. The method according to claim 26, wherein the subject has a disease or condition caused by, affected by, and / or characterized by a lack of control of free fatty acid serum levels in the subject.

28. A method for treating a subject who has cancer or has been diagnosed with cancer, comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

29. The method according to claim 28, wherein the cancer is selected from breast cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma, multiple myeloma, neuroblastoma, lung adenocarcinoma, or gastric carcinoma.

30. The method according to claim 28 or 29, wherein the cancer is characterized by metastasis of TNBC cells.

31. A method for sensitizing cancer cells in a subject having cancer to additional treatment, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23, to a subject requiring such treatment.

32. The method according to claim 31, wherein the additional treatment comprises the administration of a chemotherapeutic agent, optionally selected from doxorubicin, gemcitabine, cisplatin, paclitaxel, PARP inhibitor compounds, all-trans retinoic acid (atRA), and immune checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 antibodies.

33. A method for treating a subject diagnosed with metabolic syndrome and / or atherosclerosis, comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

34. The method according to claim 33, wherein the subject has been diagnosed with type 2 diabetes.

35. A method for regulating an immune cell population and / or immune cell activity in a subject requiring such regulation, comprising administering to the subject requiring such regulation a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

36. The method according to claim 35, wherein the subject has a disease or disorder caused by, affected by, and / or characterized by an immune cell population and / or immune cell activity.

37. The method according to claim 36, wherein the immune cell is an M2 macrophage.

38. The method according to claim 36, wherein the disease or disorder is cancer.

39. The method according to claim 38, wherein the immune cells are tumor-associated macrophages (TAMs).

40. The method according to claim 36, wherein the disease or disorder is an autoimmune disease or autoimmune disorder.

41. Use of a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23, for the manufacture of a drug for treating a subject according to any one of claims 24 to 40.

42. Structural formula II: 【Transformation 8】 (In the formula, R 1 It is selected from hydrogen, cyano, and a 5-membered heteroaryl ring. R 2 and R 3 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbon ring or heterocyclic ring, or a 5- to 8-membered aryl ring or heteroaryl ring, where the carbon ring, heterocyclic, aryl ring, or heteroaryl ring is C 1 ~C 4 -Optionally substituted with one or two substituents selected from alkyl, methoxy, or fluoro, Y is a heteroatom selected from -S- and -O-, or -CR 8 R 9 -and here, R 8 and R 9 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, phenyl, and benzyl, or R 8 and R 9 They come together to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or an oxetanyl ring. R 4 , R 5 , R 6 and R 7 Each of them is independently of hydrogen and C 1 ~C 4 Selected from linear or branched alkyl, phenyl, and benzyl, and / or R 4 and R 5 They are together, or R 6 and R 7 They combine to form a cyclopropyl ring or a cyclobutyl ring, or R 5 and R 6 (Together, they form a 5- to 6-membered carbon ring or heterocycle that has Y as a ring member.) A process for preparing the compound, (a) In a solvent, Formula III: 【Chemistry 9】 (In the formula, Y, R 4 , R 5 , R 6 and R 7 The substituted anhydride compound of (as defined above) is given by formula IV: 【Chemistry 10】 (In the formula, R 1 , R 2 and R 3 (As defined above) is to be combined with a substituted 2-aminothiophene compound, (b) Removing the solvent to obtain a compound having structural formula II, A process that includes this.

43. The aforementioned compound has the structural formula (IVa): 【Chemistry 11】 (In the formula, R 2 and R 3 The chemical groups in each are independently hydrogen and C. 1 ~C 4 Selected from linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbon ring or heterocyclic ring, or a 5- to 8-membered aryl ring or heteroaryl ring, where the carbon ring, heterocyclic, aryl ring, or heteroaryl ring is C 1 ~C 4 The process according to claim 42, wherein the compound is optionally substituted with one or two substituents selected from alkyl, methoxy, or fluoro.

44. The compound is Compound 4a, Compound 4b, Compound 4c, Compound 4d, Compound 4e, Compound 4f, Compound 4g, Compound 4h, Compound 4i, Compound 4j, and Compound 4k: Table 15 The process according to claim 43, selected from the following.

45. The compound has structural formula IVb: 【Chemistry 12】 (In the formula, R 10 and R 11 These are, independently, hydrogen, halogen, and C. 1 ~C 4 The process according to claim 42, wherein the compound is selected from linear or branched alkyl, cyclopropyl, and cyclobutyl.

46. The aforementioned compounds are compound 4l, compound 4m, and compound 4n: Table 16 The process according to claim 45, selected from the following.

47. The aforementioned compound has structural formulas IVc, IVd, IVe, IVf, IVg, and IVh: Table 17 (In the formula, R 2 and R 3 The chemical groups in each are independently hydrogen and C. 1 ~C 4 Selected from linear or branched alkyl, cyclopropyl, cyclobutyl, phenyl, and benzyl, or R 2 and R 3 These combine to form a 5- to 8-membered monocyclic, bicyclic, or spirocyclic carbon ring or heterocyclic ring, or a 5- to 8-membered aryl ring or heteroaryl ring, where the carbon ring, heterocyclic, aryl ring, or heteroaryl ring is C 1 ~C 4 -Optionally substituted with one or two substituents selected from alkyl, methoxy, or fluoro, R 12 The chemical groups in this context are hydrogen, halogen, and C 1 ~C 4 The process according to claim 42, wherein the compound is selected from linear or branched alkyl, cyclopropyl, cyclobutyl, and phenyl compounds.

48. The compounds are Compound 4o, Compound 4p, Compound 4q, Compound 4r, Compound 4s, Compound 4t, Compound 4u, Compound 4v, Compound 4w, Compound 4x, Compound 4y, Compound 4z, Compound 4aa, Compound 4bb, Compound 4cc, Compound 4dd, Compound 4ee, Compound 4ff, Compound 4gg, Compound 4hh, and Compound 4ii: Table 18-1 Table 18-2 The process according to claim 47, selected from the following.

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