Imidazo[1,2-α]pyridine compounds for use in the treatment of cancer and inflammatory diseases, and methods for preparing the said compounds.

Abstract

The present invention relates to an ALDH1A inhibitor compound isoform described in formula (I) and a pharmaceutical composition comprising the said compound. A medical compound for inhibiting the activity of subtype 1A aldehyde dehydrogenase protein is provided, comprising 2,6,8-trisubstituted imidazo[1,2-a]pyridine. Pathologies and diseases resulting from the upmodulation of one or more ALDH1A isoforms can thereby be prevented or treated. TIFF2026521872000027.tif51170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of Italian Patent Application No. 10202300013581, filed on 29 June 2023, entitled "Composto medicale per l'inibizione di aldeide deidrogenasi sottotipo 1A", which is incorporated herein by reference in its entirety. [Background technology]

[0002] Aldehyde dehydrogenases are known to be NAD(P)+-dependent enzymes that catalyze the irreversible oxidation of endogenous and exogenous aldehydes to their corresponding carboxylic acids. They are widely expressed in the liver, kidneys, heart, skeletal muscle, uterus, and brain, and are located in diverse cellular compartments, including the cytosol, mitochondria, endoplasmic reticulum, and nucleus.

[0003] The ALDH1A enzyme subfamily (hereinafter collectively referred to as "ALDH1As"), including isoforms 1A1, 1A2, and 1A3, specifically converts retinal methyl phosphate to trans-retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid. Collectively, these metabolites regulate the transcription of more than 400 target genes associated with metabolism, immunity, organogenesis, and reproduction, thereby enabling ALDH1A enzymes to play key roles in multiple cellular processes. Alterations in the normal function of these enzymes, therefore, determine the onset of numerous pathologies, such as cancer, obesity, type II diabetes, pulmonary hypertension, and neointimal hyperplasia. In particular, overexpression of specific ALDH1A isoforms has been associated with poor tumor growth and prognosis in several types of malignancies, both solid and non-solid, such as those of the head and neck, thyroid, lung, pleura, gastrointestinal tract, genitourinary tract, gynecological, breast, bone and soft tissue, skin, central nervous system, rare pediatric solid tumors, lymphonematoids, and chronic and acute pediatric leukemias.

[0004] Furthermore, ALDH1As overexpression is also both a hallmark and vital element of a subset of cancer cells known as cancer stem cells (CSCs), which are responsible for tumor development and metastasis, as well as resistance to radiation and chemicals. Therefore, inhibition of ALDH1As enzymes, including isoforms 1A1, 1A2, and 1A3, represents a promising therapeutic approach for treating cancer, involving the selective eradication of CSCs.

[0005] ALDH1As activity is also important for the induction and function of Treg cells, which are mediated by retinoic acid production by multiple cell types, such as dendritic cells, macrophages, and eosinophils. Therefore, inhibition of ALDH1As may increase the ratio of effector T cells to Treg cells in tumor tissue, leading to increased tumor immunity and tumor rejection.

[0006] ALDH1As promote the proliferation of vascular smooth muscle cells and pulmonary artery cells. The resulting neointima narrows the luminal space, leading to pathologies such as neointima hyperplasia and pulmonary hypertension, which are major causes of restenosis. Therefore, inhibition of ALDH1As may reduce intimal hyperplasia and could be useful for the treatment of restenosis, coronary angioplasty, stenting and bypass surgery, and in post-transplant patients.

[0007] Overexpression of ALDH1As found in patients with type 2 diabetes identifies pancreatic beta cell dedifferentiation characterized by impaired insulin secretion and mitochondrial function. Inhibition of these enzymes reactivates beta cell differentiation and therefore represents a therapeutic strategy to reduce glucose and increase insulin secretion in diabetic patients.

[0008] Finally, since ALDH1A enzyme deficiency has been demonstrated in animal models to confer resistance to the development of diet-induced obesity, these isoenzymes are also potential targets for the development of drugs for the treatment and / or prevention of obesity.

[0009] The literature describes numerous heterocyclic derivatives as ALDH1As inhibitors. However, the compounds described in the prior art exhibit several significant drawbacks. In particular, the described compounds exhibit poor pharmacokinetic properties, including short half-lives and lack of oral bioavailability, which limits their use for intravenous or intraperitoneal administration. Furthermore, they exhibit off-target toxicity and / or lack of in vivo efficacy. To date, there are no selective inhibitors for ALDH1A enzyme isoforms that are approved for marketing as drugs or in clinical development.

[0010] Therefore, there is a clear need for potent and selective ALDH1As inhibitors that are suitable for oral administration, have minimal or no toxicity, and possess a good pharmacokinetic profile. [Overview of the Initiative]

[0011] Among other advantages that may become apparent from the description, examples, claims, and drawings of this application, the compounds described herein and pharmaceutically relevant compositions comprising such compounds are capable of inhibiting ALDH1A1, ALDH1A2, or ALDH1A3, or are selective inhibitors of ALDH1A3. The compounds and compositions described herein have uses and methods for the prevention and treatment of pathologies and diseases resulting from the upmodulation of one or more ALDH1A isoforms, including but not limited to tumors and inflammatory diseases.

[0012] In general, in one embodiment, compounds of formula I, or pharmaceutically acceptable salts or prodrugs thereof, are described herein: TIFF2026521872000002.tif56170

[0013] (In the formula, A, X, and Z are independently selected from aryl, heteroaryl, heterocyclic, or cyclic groups;

[0014] R1 is hydrogen, amino, fluoro, chloro, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxyC1-C6 alkyl, hydroxyC1-C6 Alkoxy, Hydroxy C1-C6 alkylamino, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkylamino, Amino C1-C6 alkyl, Amino C1-C6 alkoxy, C1-C6 alkylamino, Di-C1-C6 alkylamino, C1-C6-alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, Phosphate C1-C6 alkylthio, Sulfate C1-C6 alkylthio, Thio C1-C6 alkyl, Thio C1-C6 alkoxy, Thi C1-C6 alkylamino, heterocycloC1-C6 alkyl, heterocycloC1-C6 alkoxy, heterocycloC1-C6 alkylamino, phosphate C1-C6 alkylamino, sulfate C1-C6 alkylamino, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkylthioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarboxamide Mido, C1-C6 dialkylsulfonamide, C1-C6 dialkylthiocarboxamide, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 guanidine alkyl, C1-C6 cyanoalkyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, cyclic C1-C6 alkoxy, phosphate C1-C6 alkoxy, sulfate C1-C6 alkoxy, aryl C1-C6 alkylamino, heteroaryl C1-C6 alkylamino, cyclic C1-C6 alkylamino, (((3R,4S,5S,6R)-3,4,Selected from 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, aryl, heteroaryl, heterocyclic, and cyclic groups;

[0015] Furthermore, R2 and R3 are hydrogen, halogen, fluoro, chloro, bromo, iodine, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amide, acetyl, sulfonamide, acrylic, acrylaldehyde, buta-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl)vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, penta-2-en-1,4-dione, 4-oxobuta-2-enoate, N,N-dimethyl-4-oxobuta-2-enoate, ethane-1-one, and oxiran-2-ylethane-1-one, trifluoromethyl, carbamoyl, sulfamoyl, acrylamide, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxyC1-C6 alkyl, hydroxyC1-C6 alkoxy, hydroxyC1-C6 Alkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, amino C1-C6 alkyl, amino C1-C6 alkoxy, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6-alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, phosphate C1-C6 alkylthio, sulfate C1-C6 alkylthio, thio C1-C6 alkyl, thio C1-C6 alkoxy, thio C1-C6 alkyl Mino, heterocycloC1-C6 alkyl, heterocycloC1-C6 alkoxy, heterocycloC1-C6 alkylamino, phosphate C1-C6 alkylamino, sulfate C1-C6 alkylamino, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkylthioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarboxamide, C1 -C6 dialkylsulfonamide, C1-C6 dialkylthiocarboxamide, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 guanidine alkyl, C1-C6 cyanoalkyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, cyclic C1-C6 alkoxy, phosphate C1-C6 alkoxy, sulfate C1-C6 alkoxy, aryl C1-C6 alkylamino, heteroaryl C1-C6 alkylamino, cyclic C1-C6 alkylamino, (((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, independently selected from aryl, heteroaryl, heterocyclic, and cyclic groups;

[0016] Furthermore, aryl, heteroaryl, heterocyclic, and cyclic groups include hydrogen, halogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amide, acetyl, sulfonamide, acrylic, acrylaldehyde, buta-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl)vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, penta-2-en-1,4-dione, 4-oxobuta-2-enoate, N,N-dimethyl-4-oxobuta-2-enoate, ethane-1-one, and oxiran-2-ylethane-1-one, trifluoromethyl, carbamoyl, sulfamoyl, acrylamide, acrylonitrile, dichloroacetamide, (May be further functionalized with additional substituents selected from C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 alkylcarboamino, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di-C1-C6 alkylamino, aminoC1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C2-C6 alkynylcarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, C1-C6 alkylsulfonylaminocarbonyl, C1-C6 alkoxycarbonyl, arylaminocarbonyl, and C3-C7 cycloalkylaminocarbonyl.)

[0017] In some embodiments, A, X, and Z are each phenyl; R1 is selected from hydrogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, thiol, amino, amide, acetyl, sulfonamide, acrylyl, acryaldehyde, but-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl)vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, pent-2-en-1,4-dione, 4-oxobut-2-enoate, N,N-dimethyl-4-oxobut-2-enoate, ethane-1-one, and oxiran-2-yl-ethane-1-one; and R2 and R3 are each independently selected from hydrogen, halogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amide, acetyl, sulfonamide, acrylyl, acryaldehyde, but-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl)vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, pent-2-en-1,4-dione, 4-oxobut-2-enoate, N,N-dimethyl-4-oxobut-2-enoate, ethane-1-one, and oxiran-2-yl-ethane-1-one.

[0018] In some embodiments, A, X, and Z are each phenyl; R1 is selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (either direction), methyl ether, fluoro, chloro, alkoxy, methoxy, and cyano; and R2 and R3 are each independently selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (either direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano.

[0019] In some embodiments, A, X, and Z are each phenyl; R1 is selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (either direction), methyl ether, fluoro, chloro, alkoxy, methoxy, and cyano; and R2 and R3 are each independently selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (either direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano; and any aryl, heteroaryl, heterocyclic, and cyclic groups present are further functionalized with up to two additional substituents selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (either direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano.

[0020] In some embodiments, the compound is 2,6,8-triarylimidazo[1,2-a]pyridine selected from the compounds named or exemplified herein.

[0021] In some embodiments, the compound is formulated or formulated with a pharmaceutically acceptable carrier, optionally including a delivery system, such as liposomal delivery.

[0022] In general, in one embodiment, a method for producing 2,6,8-trisubstituted imidazo[1,2-a]pyridine is described herein, the method comprising reacting an alpha-aminopyridine directly bonded to bromine and iodine with a beta-carbonylalkyl halide directly bonded to a first functional group to produce an imidazo[1,2-a]pyridine core directly bonded to a first functional group, and then sequentially reacting the product with a coupling agent directly bonded to a second functional group (e.g., a boronic acid) and a coupling agent directly bonded to a third functional group; to obtain 2,6,8-trisubstituted imidazo[1,2-a]pyridine. In some embodiments, the production method results in 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one). In some embodiments, the manufacturing method results in 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile.

[0023] In general, methods for treating or preventing a pathology or disease in a subject suffering from a pathology or disease resulting from abnormal regulation of subtype 1A aldehyde dehydrogenase activity are described herein. Treatment methods include administering a therapeutically effective amount of an aldehyde dehydrogenase protein inhibitor, and prevention methods include administering a preventively effective amount of an aldehyde dehydrogenase protein inhibitor. In some embodiments, the aldehyde dehydrogenase protein inhibitor is a compound described herein. In some embodiments, the pathology or disease is cancer, for example, a tumor. In some embodiments, the pathology or disease is an inflammatory disease, for example, pneumonia. In some embodiments, the pathology or disease is selected from diabetes mellitus, psoriasis, rheumatoid arthritis, acute nephropathy, chronic nephropathy, arterial restenosis, autoimmune diseases, acute infections, ocular diseases resulting from changes in microcirculation, and endometriosis. [Brief explanation of the drawing]

[0024] [Figure 1]Figure 1 shows the confirmation of ALDH1A3 levels in breast cancer cells by Western blotting. MDA-MB-231 has low levels of ALDH1A3, and ALDH1A3 is overexpressed in the cells. MDA-MB-468 and HCC1806 have elevated ALDH1A3 levels, and ALDH1A3 is reduced by knockdown. [Figure 2A] Figure 2A is a blot showing that MDA-MB-231 natively has low levels of ALDH1A3 and ALDH1A1, but can be induced to selectively overexpress either isoform. [Figure 2B] Figure 2B shows that the pan-ALDH inhibitor DEAB (100 μM) inhibits the Aldefluor assay activity of ALDH1A3 and ALDH1A1 (blue and red solid lines) in MDA-MB-231 cells overexpressing ALDH1A3 or ALDH1A1, respectively. [Figure 2C] Figure 2C shows that compound 1 inhibits Aldefluor activity in MDA-MB-231 cells induced by ALDH1A3 overexpression. (Top) The plot of counts against Aldefluor shows that at all plotted concentrations of compound 1, compound 1 inhibits Aldefluor activity in MDA-MB-231 cells induced by ALDH1A3 overexpression, substantially overlapping with the curve for the 100uM DEAB control rather than the no-compound control condition (shaded section). (While distinguishing the colors is not necessary to understand the figure, for clarity, the data series are in the following order from left to right on the y-axis value of "47 counts": compound 1 at 10uM, compound 1 at 100nM, compound 1 at 1uM, compound 1 at 100nM, compound 1 at 100uM, DEAB at 10nM, compound 1 at 1nM). (Below) Quantitative bar graph of Aldefluor activity in the presence of a dilution series of compound 1 compared to negative and DEAB-positive control conditions, normalized to 1.0 relative to the negative control bar "0". Significance was determined by one-way Anova; p-value < 0.0001 = ****. [Figure 2D]Figure 2D shows that compound 1 does not inhibit Aldefluor activity in MDA-MD-231 cells induced by ALDH1A1 overexpression. (Top) The plot of counts for Aldefluor shows that at all plotted concentrations of compound 1, compound 1 overlaps with the no-compound control condition (shaded section) rather than the 100uM DEAB curve (red). (Bottom) Quantitative bar graph of Aldefluor activity in the presence of dilution series of compound 1 compared to negative and DEAB-positive control conditions, normalized to 1.0 relative to the negative control bar "0". Significance was determined by one-way Anova; p-value < 0.0001 = ****. [Figure 2E] Figure 2E shows the percentage inhibition of Aldefluor by compound 1 in MDA-MB-231 cells with ALDH1A3 overexpression. [Figure 3A] Figure 3A shows that compound 2 at nanomolar concentrations inhibits Aldefluor activity in MDA-MD-231 cells induced by ALDH1A3 overexpression (n=4). The bar graph quantitatively displays Aldefluor activity in the presence of a dilution series of compound 2 compared to the negative control condition, normalized to 1.0 relative to the negative control bar "0". [Figure 3B] Figure 3B shows the percentage inhibition of Aldefluor by compound 2 in MDA-MB-231 cells with ALDH1A3 overexpression. Significance was determined by one-way Anova; p-values ​​<0.01 = **, <0.0001 = ****. [Figure 4A]Figure 4A shows that micromolar concentrations of GA-11 inhibit ALDH1A3-induced Aldefluor activity in MDA-MB-231 cells with ALDH1A3 overexpression (n=3). (Top) 100uM of DEAB and GA11 are distinguishable from the control count (shaded section) in the Aldefluor count plot; all other concentration series shown are indistinguishable from the control count. (Bottom) Quantitative bar graph of Aldefluor activity in the presence of dilution series of GA11 compared to negative and DEAB-positive control conditions, normalized to 1.0 relative to the negative control bar. Significance was determined by one-way Anova; p-value < 0.0001 = ****. [Figure 4B] Figure 4B shows that micromolar concentrations of NR6 inhibit ALDH1A3-induced Aldefluor activity in MDA-MB-231 cells with ALDH1A3 overexpression (n=3). (Top) 100uM of DEAB and 100uM and 10uM of NR6 are distinguishable from the control count (shaded section) in the Aldefluor count plot; all other concentration series shown are indistinguishable from the control count. (Bottom) Quantitative bar graph of Aldefluor activity in the presence of dilution series of NR6 compared to negative and DEAB-positive control conditions, normalized to 1.0 relative to the negative control bar. Significance was determined by one-way Anova; p-value < 0.0001 = ****. [Figure 4C] Figure 4C shows the percentage inhibition of Aldefluor by NR6 in MDA-MB-231 cells with ALDH1A3 overexpression. Significance was determined by one-way Anova; p-values ​​<0.01 = **, <0.0001 = ****. [Figure 5A-5C]Figures 5A, 5B, and 5C. Compound 1 at nanomolar concentrations specifically inhibits the expression of ALDH1A3 target genes in breast cancer cells. Expression of DHRS3, RARB, ELF3, and RARRES1 in MDA-MB-231 cells with ALDH1A3 overexpression (Figure 5A), MDA-MB-468 cells (with ALDH1A3 shRNA knockdown as a control; Figure 5B), and HCC1806 cells (with ALDH1A3 shRNA knockdown as a control; Figure 5C) was determined by QPCR 24 hours after treatment with 0, 1, 10, or 100 nM of compound 1. Significance was determined by one-way Anova; p-values ​​<0.5=*, <0.01=**, <0.001=***, <0.0001=****. [Figure 6A-6B] Figures 6A and 6B. Expression of ALDH1A3 target genes, RARB, ELF3, and RARRES1 in control and ALDH1A3-overexpressing MDA-MB-231 cells (Figure 6A), and control and ALDH1A3-knockdown MDA-MB-468 cells (Figure 6B), 24 hours after treatment with compound 2. [Figure 7] Figure 7 shows the body weight of mice injected with MDA-MB-231 cells and treated with compound 1 on day 1. The mice were treated as outlined in the examples below. No significant changes were observed, as can be seen due to the substantial overlap of the data series. The arrows indicate that treatment with compound 1 was initiated on day 15. [Figure 8] Figure 8 shows the MDA-MB-231 tumor volume (OE = overexpression) in mice treated with compound 1 according to the groups described in the examples below. The arrows indicate that treatment with compound 1 was started on day 15. [Figure 9] Figure 9 shows the final MDA-MB-231 tumor volume of mice treated with compound 1. Significance was determined by one-way Anova; p-value <0.5 = *, <0.0001 = ****. [Figure 10]Figure 10 shows the final MDA-MB-231 tumor weight (g) in mice treated with compound 1. Treatment was initiated 15 days after cancer cell transplantation, and the experiment was completed on 41 days. Significance was determined by one-way Anova; p-values ​​<0.5 = *, <0.001 = ***. [Figure 11] Figure 11 shows the pharmacodynamic analysis. Compound 1 reduces ALDH1A3-induced RARB expression in MDA-MB-231 tumors. Tumors were harvested on day 41, and treatment was initiated on day 15. Significance was determined by one-way Anova; p-values ​​<0.5=*, <0.01=**, <0.0001=****. [Figure 12A] Figure 12A shows that daily treatment with compound 1 does not affect serum levels of alanine aminotransferase (ALT) in mice. Administration of compound 1 was initiated on day 15, and ALT levels were measured on day 41. [Figure 12B] Figure 12B shows that daily treatment with compound 1 does not affect serum creatinine levels in mice. Administration of compound 1 was initiated on day 15, and creatinine was measured on day 41. [Modes for carrying out the invention]

[0025] In this document, measurements, values, shapes, and geometric references (e.g., perpendicular and parallel) should be understood as being less than measurement error or manufacturing error, and / or manufacturing error, when associated with “approximately” or other similar terms, such as “nearly,” “about,” or “substantially,” and, in particular, as having a slight deviation from the associated value, measurement, shape, or geometric reference. For example, when these terms are associated with a value, they preferably indicate a difference of 10% or less from the value itself. Furthermore, when terms such as “first,” “second,” “upper,” “lower,” “higher,” “lower,” “principal,” “main,” and “secondary” are used, they do not necessarily identify order, priority in relation, or relative position; they may simply be used to more clearly distinguish between different components. Measurements and data reported in this document should be assumed to have been performed in accordance with ICAO International Standard Atmosphere (ISO 2533:1975), unless otherwise indicated.

[0026] According to one embodiment, compounds are disclosed that can be used in the prevention and treatment of pathologies resulting from abnormal modulation of the activity of subtype 1A aldehyde dehydrogenase proteins. In some preferred embodiments, the compounds are inhibitors of 1A1, 1A2, 1A3 isoforms or combinations thereof.

[0027] The compounds disclosed herein enhance inhibitory activity against aldehyde dehydrogenase proteins, particularly subtype 1A (preferably isoforms 1A1, 1A2, 1A3, and combinations thereof). In some embodiments, the compounds disclosed herein are used in the prevention and treatment of pathologies resulting from abnormal modulation of the activity of subtype 1A aldehyde dehydrogenase proteins, such as isoforms 1A1, 1A2, and 1A3.

[0028] According to one embodiment, a 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative, i.e., one or more substituted imidazo[1,2-a]pyridine derivatives having substitutions at the 2,6, and 8 positions of the imidazopyridine core, is disclosed herein.

[0029] According to one embodiment, a pharmaceutical composition comprising a compound described herein together with a pharmaceutically acceptable carrier is disclosed herein. In some embodiments, the carrier comprises one or more excipients. In some embodiments, the compound described herein is formulated into a pharmaceutically acceptable dosage form, such as tablets, granules, powders, capsules, syrups, elixirs, aqueous solutions, aqueous suspensions, oily solutions, oily suspensions, emulsions, or microemulsions, for use in oral, intramuscular, intravenous, or subcutaneous administration or topical application.

[0030] According to one embodiment, a compound of formula I is disclosed: TIFF2026521872000003.tif51170

[0031] (In the formula, A, X, and Z are independently selected from aryl, heteroaryl, heterocyclic, or cyclic groups; R1 is hydrogen, amino, fluoro, chloro, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxyC1-C6 alkyl, hydroxyC1-C6 Alkoxy, Hydroxy C1-C6 alkylamino, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkylamino, Amino C1-C6 alkyl, Amino C1-C6 alkoxy, C1-C6 alkylamino, Di-C1-C6 alkylamino, C1-C6-alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, Phosphate C1-C6 alkylthio, Sulfate C1-C6 alkylthio, Thio C1-C6 alkyl, Thio C1-C6 alkoxy, Thi C1-C6 alkylamino, heterocycloC1-C6 alkyl, heterocycloC1-C6 alkoxy, heterocycloC1-C6 alkylamino, phosphate C1-C6 alkylamino, sulfate C1-C6 alkylamino, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkylthioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarboxamide Mido, C1-C6 dialkylsulfonamide, C1-C6 dialkylthiocarboxamide, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 guanidine alkyl, C1-C6 cyanoalkyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, cyclic C1-C6 alkoxy, phosphate C1-C6 alkoxy, sulfate C1-C6 alkoxy, aryl C1-C6 alkylamino, heteroaryl C1-C6 alkylamino, cyclic C1-C6 alkylamino, (((3R,4S,5S,6R)-3,4,Selected from 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, aryl, heteroaryl, heterocyclic, and cyclic groups; and, R2 and R3 are hydrogen, hydroxy, amino, halogen, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, hydroxy C1-C6 alkylamino, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkylamino, amino C1-C6 alkyl, amino C1-C6 alkoxy, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6-alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, phosphate C1-C6 alkylthio, sulfate C1-C6 alkylthio, thio C1-C6 alkyl, thio C1-C6 alkoxy C1-C6 alkylamino, heterocycloC1-C6 alkyl, heterocycloC1-C6 alkoxy, heterocycloC1-C6 alkylamino, phosphateC1-C6 alkylamino, sulfateC1-C6 alkylamino, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkylthioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarbo Xamide, C1-C6 dialkylsulfonamide, C1-C6 dialkylthiocarboxamide, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 guanidine alkyl, C1-C6 cyanoalkyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, cyclic C1-C6 alkoxy, phosphate C1-C6 alkoxy, sulfate C1-C6 alkoxy, aryl C1-C6 alkylamino, heteroaryl C1-C6 alkylamino, cyclic C1-C6 alkylamino, (((3R,4S,5S,6R)-3,4,(5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, independently selected from aryl, heteroaryl, heterocyclic, and cyclic groups).

[0032] In some embodiments, A, X, Z, or combinations thereof may include monocyclic systems. In some embodiments, they may include bicyclic systems. In some heterocyclic embodiments of A, X, Z, or combinations thereof, there are 1 to 3 oxygen, nitrogen, phosphorus, or sulfur atoms. In some embodiments, A, X, and Z are different from each other. In some embodiments, the same parts are selected for A, X, and Z. In some embodiments, R1, R2, and R3 are different from each other. In some embodiments, the same parts are selected for R1, R2, and R3. For clarity, in some embodiments, any one of R1, R2, or R3 is all hydrogen, and the corresponding A, X, or Z is therefore "functionalized with 0 substituents". In some preferred embodiments, R1, R2, and R3 are each independently bonded to the phenyl ring at the ortho, meta, or para position, more preferably at the para position.

[0033] In some embodiments, aryl, heteroaryl, heterocyclic, and cyclic groups are hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, hydroxy, carboxy, formyl, carbamoyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 alkylcarboamino, C1-C6 alkylthio, C1-C6 alkyls The group is further functionalized with one or more substituents selected from ulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di-C1-C6 alkylamino, aminoC1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C2-C6 alkynylcarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, C1-C6 alkylsulfonylaminocarbonyl, C1-C6 alkoxycarbonyl, arylaminocarbonyl, and C3-C7 cycloalkylaminocarbonyl. The substituents may be the same or different from each other. In some embodiments, one or more R1, R2, R3 substituents or one or more substituents or both are, as appropriate, independently bonded to A, X, Z to available positions on aryl, heteroaryl, heterocyclic, or cyclic groups.

[0034] The terms “administering” or “giving” a compound should be understood to mean providing an individual with an amount of the compound of the present invention effective for prevention, treatment, or diagnosis in a form that can be introduced into the individual’s body, as appropriate. Such forms may include, for example, oral, injectable, transdermal, inhaled, and rectal forms.

[0035] The term "alkyl" refers to a monovalent saturated hydrocarbon radical having linear or branched residues, unless otherwise specified. An "alkyl" group may contain double or triple carbon-carbon bonds if it consists of two or more carbon atoms, or it may form a cyclic residue if it consists of at least three carbon atoms.

[0036] The term "alkenyl," as used herein, means a straight-chain, branched-chain, and / or cyclic hydrocarbon containing at least one carbon-carbon double bond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutyrenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, and 3-decenyl.

[0037] The term "alkoxy," as used herein, means a molecule in which an alkyl group, as defined herein, is attached to the parent molecule via an oxygen atom. Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0038] The term "alkoxycarbonyl," as used herein, means a molecule in which an alkoxy group, as defined herein, is attached to the parent molecule via a carbonyl group, as defined herein. Typical examples of alkoxycarbonyls include, but are not limited to, methoxycarbonyls, ethoxycarbonyls, and tert-butoxycarbonyls.

[0039] When used herein, the term "alkylamino" means a molecule in which an alkyl group, as defined herein, is attached to the parent molecule via an NH group. Typical examples of alkylaminos include, but are not limited to, methylamino, ethylamino, isopropylamino, and butylamino.

[0040] The term "alkylcarbonyl," as used herein, means a molecule in which an alkyl group, as defined herein, is attached to the parent molecule via a carbonyl group, as defined herein. Typical examples of alkylcarbonyls include, but are not limited to, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, and n-propylcarbonyl.

[0041] When used herein, the term "alkylsulfonyl" means a molecule in which an alkyl group, as defined herein, is attached to the parent molecule via a sulfonyl group, as defined herein. Typical examples of alkylsulfonyls include, but are not limited to, methylsulfonyl and ethylsulfonyl.

[0042] The term "alkynyl," as used herein, means a linear or branched hydrocarbon group containing 2 to 10 carbon atoms, preferably 2, 3, 4, or 5 carbon atoms, and at least one carbon-carbon triple bond. Typical examples of alkynyls include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0043] The term "amide," as used herein, means a molecule in which an amino, alkylamino, or dialkylamino group is attached to the parent molecule via a carbonyl group as defined herein. Typical examples of amides include, but are not limited to, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

[0044] As used herein, the term "amino" refers to the -NH2 group.

[0045] In this document, the term "aryl" refers, unless otherwise specified, to an aromatic monocyclic, bicyclic, or tricyclic carbocyclic system consisting of 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0046] When used herein, the term "arylalkyl" means a molecule in which an aryl group, as defined herein, is attached to the parent molecule via an alkyl group, as defined herein. Typical examples of arylalkyls include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl.

[0047] As used herein, the term "carbonyl" refers to a -C(=O)- group.

[0048] The term "carboxy" as used herein means a -COOH group, which may be protected as an ester group: -COO-alkyl.

[0049] In this specification, Cx refers to acyclic straight-chain or branched-chain hydrocarbons of the longest length x; therefore, C1-C5 include methyl, ethyl, propyl, butyl, pentyl, isopropyl, and the like.

[0050] The term "cyano," as used herein, refers to the -CN group.

[0051] As used herein, the term "cyanophenyl" means a molecule in which a -CN group is added to the parent molecule via a phenyl group, and includes, but is not limited to, 4-cyanophenyl, 3-cyanophenyl, and 2-cyanophenyl.

[0052] The term "ring" or "cyclic system" refers to a non-aromatic monocyclic, bicyclic, or tricyclic carbocyclic system that contains 0 to 3 unsaturated atoms and is formed from a minimum of 5 to a maximum of 12 members.

[0053] The term “dialkylamino,” as used herein, means a molecule in which two independent alkyl groups, as defined herein, are attached to the parent molecule via a nitrogen atom. Typical examples of dialkylaminos include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, and butylmethylamino.

[0054] The term "formyl," as used herein, refers to the -C(O)H group.

[0055] When used herein, the term "haloalkoxy" means a molecule in which at least one halogen, as defined herein, is attached to the parent molecule via an alkoxy group, as defined herein. Typical examples of haloalkoxys include, but are not limited to, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0056] The term "halogen" refers to fluorine, chlorine, bromine, or iodine unless otherwise specified.

[0057] The term "heteroaryl" refers to a heterocyclic aromatic monocyclic, bicyclic, or tricyclic carbocyclic system containing 0 to 5 unsaturated atoms, formed from a minimum of 5 to a maximum of 12 members, and containing 1 to 3 heteroatoms preferably selected from the group including N, O, S, P, SO, and SO2. Monocyclic rings may include, but are not limited to, a 6-membered aromatic ring in which 1 to 4 of the ring carbon atoms are replaced by nitrogen atoms; a 5-membered ring containing sulfur, oxygen, phosphorus, or nitrogen in the ring; a 5-membered ring containing 1 to 4 nitrogen atoms; and a 5-membered ring containing oxygen, sulfur, or phosphorus and 1 to 3 nitrogen atoms. Typical examples of 5-6 member monocyclic heteroaryl rings include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridadinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, and [1,2,4]triazolyl. Typical examples of bicyclic heteroaryl rings include, but are not limited to, indolyl, benzothienyl, benzofuranil, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthilidinyl, sinnolinyl, thieno[2,3-d]imidazole, thieno[3,2-b]pyridinyl, and pyrrolopyrimidinyl.

[0058] The term “heterocyclic” or “heterocyclic formula” refers to a non-aromatic monocyclic, bicyclic, or tricyclic carbocyclic system that contains 0 to 3 unsaturated atoms, is formed from a minimum of 5 to a maximum of 12 members, and contains 0 to 5 unsaturated atoms and 1 to 3 heteroatoms preferably selected from the group including N, O, S, P, SO, and SO2. The functional groups may be the same or different from each other. Typical examples of nitrogen-containing heterocyclics include, but are not limited to, azepanyl, azetidinyl, azilidinyl, azokanyl, dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl, morpholinyl, piperadinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, and thiomorpholinyl. Representative examples of non-nitrogen-containing non-aromatic heterocycles include, but are not limited to, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, and [1,3]dioxolanil. Examples of additional heterocycles include azetidine-2-one, azepan-2-one, isoindorin-1,3-dione, (Z)-1H-benzo[e][1,4]diazepine-5(4H)-one, pyridazine-3(2H)-one, pyridine-2(1H)-one, pyrimidine-2(1H)-one, pyrimidine-2,4(1H,3H)-dione, pyrrolidine-2-one, benzo[d]thiazole-2(3H)-one, pyridine-4(1H)-one, imidazolidine-2-one, and 1H-imidazole-2 This includes, but is not limited to, (3H)-one, piperidine-2-one, tetrahydropyrimidine-2(1H)-one, 1H-benzo[d]imidazole-2(3H)-one, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiadinol, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiadinol, and 1,5-dihydro-benzo[b][1,4]diazepine-2-one-yl.

[0059] The term "hydroxy" as used herein means the -OH group.

[0060] When used herein, the term "hydroxyalkyl" means a molecule in which at least one hydroxyl group, as defined herein, is attached to the parent molecule via an alkyl group, as defined herein. Typical examples of hydroxyalkyls include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0061] The term "imino," as defined herein, means a -C(=NH)- group.

[0062] As used herein, the term "mercapto" refers to the -SH group.

[0063] The term "nitro" as used herein means the -NO2 group.

[0064] The term "oxo," as used herein, means (=O).

[0065] Unless otherwise indicated, the term “prodrug” includes pharmaceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonic acid esters of the compounds disclosed herein. Examples of prodrugs include compounds containing a biohydrolyzable moiety (e.g., biohydrolyzable amides, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable esters, biohydrolyzable phosphates, or biohydrolyzable ureido analogs). Prodrugs of the compounds disclosed herein are readily conceived and prepared by those skilled in the art. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985; Bundgaard, hours., “Design and Application of Prodrugs,” A Textbook of Drug Design and Development, Krosgaard-Larsen and hours. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, hours., Advanced Drug Delivery Review, 1992, 8, 1-38.

[0066] The expression "racemic mixture" defines a set of two R and S enantiomers in a 50:50 ratio.

[0067] The expression “scalemic mixture” identifies a set of two enantiomers R and S in any reciprocal proportion. As a non-limiting example, it could be a mixture in which one of the two enantiomers is enriched (e.g., 70%, 80%, 90%, or 99%).

[0068] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0069] When used herein, the term "thioalkoxy" means a molecule in which an alkyl group, as defined herein, is attached to the parent molecule via a sulfur atom. Typical examples of thioalkoxys include, but are not limited to, methylthio, ethylthio, and propylthio.

[0070] In some embodiments, the compound of formula I may exist in a non-solvated form. In some embodiments, it may exist in a solvated form with a pharmaceutically acceptable solvent, such as water and ethanol. In some embodiments, the compound of formula I may exist in stereoisomer form, for example, containing one or more chiral carbon atoms, and therefore may be in an optically active form, a non-racemic mixture, or a racemic mixture. In some embodiments, the imidazo[1,2-a]pyridine derivative of formula I has one or more chiral carbon atoms, and therefore may be in an optically active form, a non-racemic mixture, or a racemic mixture.

[0071] Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. The present invention also covers individual isomers of compounds represented by formula I as mixtures with isomers in which one or more chiral centers are inverted. Similarly, in some embodiments, the compounds disclosed herein may exist in tautomer forms other than those shown in formula I, and these are also included within the scope of the present invention.

[0072] The synthesis of optically active compounds can be carried out by following methodologies commonly known in the literature, along with the references to optically inert compounds and their synthesis described herein. For example, optically active compounds can be obtained by both using optically pure compounds as starting products and by optical separation in non-racemic or racemic forms.

[0073] In some embodiments, the pharmaceutical composition comprises a compound of formula I, its stereoisomers, prodrugs, mutual drugs, hybrid compounds or pharmaceutically acceptable salts as defined herein, and a pharmaceutically acceptable carrier or delivery system; some preferred non-limiting examples of carriers or delivery systems are liposomes, lipid or protein vesicles, albumin, cyclodextrin, (gold) nanoparticles, polymers, and nanosponges.

[0074] In further non-limiting embodiments, the compound of formula I can be in the form of a salt. The salt can be derived from inorganic or organic acids, salts using amino acids, or organic or inorganic bases suitable when an acid functional group is present in the derivative. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms of salts of the pharmaceutical compounds of formula I.

[0075] In some embodiments, the compound of formula I can include all suitable isotope variations. Isotope variations of the compounds of the present invention are defined as compounds in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Certain isotope variations of the present invention, for example, those incorporating radioactive isotopes such as 3 H or 14 C are useful in drug and / or substrate tissue distribution studies. Further, isotopes such as deuterium 2Substitution with H may result in certain therapeutic benefits that lead to greater metabolic stability. Isotope variations of the compounds of the present invention can generally be prepared by conventional procedures, for example by exemplary methods using appropriate isotope variations of suitable reagents, or by the preparations described in the examples below.

[0076] In some embodiments, the pharmaceutical composition comprises at least one compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, and / or diluents. pharmaceutically acceptable salts are well known in the art. For clarity, the term “pharmaceutically acceptable salt” as used herein generally refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases, as well as organic acids and bases. Preferred pharmaceutically acceptable base addition salts include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Suitable non-toxic acids include inorganic and organic acids, such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, fluonic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Examples of specific salts include, therefore, hydrochloride salts and mesylate salts. Others are well known in the art. For example, see Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing, Easton Pa.: 1990) and Remington: The Science and Practice of Pharmacy, 19th ed. (Mack Publishing, Easton Pa.: 1995).The preparation and use of acid addition salts, carboxylate salts, amino acid addition salts, and zwitterionic salts of the compounds of the present invention may also be considered pharmaceutically acceptable if, within reasonable medical judgment, they are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, and allergic responses, etc., and are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. Such salts may also comprise various solvates and hydrates of the compounds of the present invention.

[0077] The term “excipient” or “pharmaceutically acceptable excipient” as used herein means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffering agents, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solution. In addition, other non-toxic, suitable lubricants, e.g., sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants, may also be present in the composition, at the discretion of those skilled in the art of formulation.

[0078] Unless otherwise indicated, the terms “prevention,” “prevention,” and “prevention” refer to actions taken before a patient begins to develop a specified disease or disorder, which inhibit or reduce the severity of one or more of the disease or disorder or its symptoms. The term “prevention” encompasses “prophylaxis.”

[0079] Unless otherwise indicated, the “preventive effective dose” of a compound is the amount sufficient to prevent a disease or condition, or one or more symptoms associated with a disease or condition, or to prevent their recurrence. The preventive effective dose of a compound is the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of disease. The term “preventive effective dose” may include the amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0080] Unless otherwise indicated, the “therapeutic dose” of a compound is an amount sufficient to treat a disease or condition, or one or more symptoms associated with a disease or condition.

[0081] The term "subject" is intended to include living organisms on which the disease may occur. Examples of subjects include humans, monkeys, cattle, sheep, goats, dogs, cats, mice, rats, and transgenic species of these.

[0082] In some embodiments, compounds of formula I are formulated as pharmaceutical compositions selected based on the requirements of treatment. This may mean administration to subjects requiring it in the form of tablets, capsules, oral preparations, powders, granules, pills, injections, or insoluble liquid solutions, suspensions, suppositories, syrups, elixirs, aqueous solutions, aqueous suspensions, oily solutions, oily suspensions, emulsions, or microemulsion preparations for inhalation, for use in oral, intramuscular, intravenous, subcutaneous, or topical administration.

[0083] Pharmaceutical compositions may be formulated for oral administration in solid or liquid form, parenteral intravenous, subcutaneous, intramuscular, intraperitoneal, intra-arterial, or intradermal injection, or for vaginal, nasal, topical, or rectal administration. Pharmaceutical compositions of the present invention suitable for oral administration may be provided in separate dosage forms, such as tablets, chewable tablets, caplets, capsules, liquids, and flavor syrups. Such dosage forms may contain a predetermined amount of the active ingredient and may be prepared by pharmaceutical methods well known to those skilled in the art. See, for general information, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0084] Parenteral drug formulations can be administered to patients via various routes, including subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Since these administrations typically circumvent the patient's natural defenses against contaminants, parenteral drug formulations may be particularly sterile or sterilized prior to administration to the patient. Examples of parenteral drug formulations include solutions prepared for injection, dried products prepared for dissolution or suspension in pharmaceutically acceptable media for injection, suspensions prepared for injection, and emulsions. Pharmaceutical compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, and glycerol, and suitable mixtures thereof), vegetable oils (e.g., olive oil), and organic esters for injection, such as ethyl oleate, or suitable mixtures thereof. The suitable fluidity of the composition may be maintained, for example, by coating, such as the use of lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant. These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action may be ensured by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. Sustained absorption of the pharmaceutical form for injection can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin.

[0085] In some cases, slowing the absorption of a drug via subcutaneous or intramuscular injection is often desirable to prolong its effects. This may be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The rate of drug absorption depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delaying the absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily medium.

[0086] The suspension may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methhydroxyl, bentonite, agar-agar, tragacanth, and mixtures thereof. If desired, and for more effective distribution, the compounds of the present invention may be incorporated into delayed-release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injection medium immediately before use.

[0087] Depot formulations for injection are prepared by forming a microencapsulation matrix of the drug in a biodegradable polymer, such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues. Injection formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media immediately before use.

[0088] Preparations for injection, such as sterile aqueous or oily suspensions for injection, may be formulated according to known techniques using suitable dispersing or wetting and suspending agents. Sterile preparations for injection may also be sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Additionally, sterile fixative oils have conventionally been used as solvents or suspension media. For this purpose, any branded fixative oil, including synthetic mono or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injections.

[0089] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, one or more compounds of the present invention are at least one inert, pharmaceutically acceptable carrier, e.g., sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) water-retaining agents, e.g., glycerol; d) disintegrants, e.g., agar-agar, carbonate It is mixed with calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[0090] Similar types of solid compositions may also be used as fillers in soft and rigid gelatin capsules using high molecular weight polyethylene glycol in addition to lactose or lactose. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology. They may optionally contain opacifying agents and may also be compositions that release the active ingredient only in or preferentially in a specific part of the intestinal tract in a delayed manner. Examples of materials that may be useful for delaying the release of the activator may include polymeric substances and waxes.

[0091] The compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compound of the present invention with a suitable non-irritating carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compound.

[0092] Topical formulations may include powders, sprays, ointments, and inhalants. The compounds of the present invention can be mixed under sterile conditions with pharmaceutically acceptable carriers and any necessary preservatives, buffers, or propellants as required. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are envisioned to be within the scope of the present invention. Aqueous liquid compositions containing the compounds of the present invention are also envisioned.

[0093] Liquid formulations for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid formulations may contain solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof.

[0094] In addition to inert diluents, oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The desired compounds of the present invention are mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as needed. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also assumed to be within the scope of the present invention. Ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present invention, animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0095] The powders and sprays may contain, in addition to the compounds of the present invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may also contain conventional propellants, such as chlorofluorohydrocarbons.

[0096] The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayers or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipids capable of forming liposomes may be used. The compositions of the present invention in liposome form may contain stabilizers, preservatives, and the like, in addition to the compounds of the present invention. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithin), used separately or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY, (1976), pp. 33 et seq.

[0097] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention may be modified to obtain an amount of the active compound effective in achieving the desired therapeutic effect for a particular patient, composition, and mode of administration. The selected dosage level depends on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the patient's condition and medical history. However, it is within the technical scope of the art to start with a dose of the compound at a lower level than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0098] An effective amount of one of the compounds of the present invention may be used in pure form or, where such form exists, in a pharmaceutically acceptable salt form. Alternatively, the compound may be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers. However, it is understood that the overall daily use of the compounds and compositions of the present invention is to be determined by the attending physician within reasonable medical judgment. A specific effective dose level for any particular patient depends on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, overall health, sex, and diet; the time of administration, route of administration, and rate of elimination of the specific compound used; the duration of treatment; the risk / benefit ratio; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. For example, it is well within the technical scope of the art to start with a dose of the compound at a level lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0099] The overall daily dose of the compound of the present invention administered to humans or lower animals may be in the range of about 0.0003 to about 30 mg per kg of body weight. For oral administration purposes, a more preferred dose may be in the range of about 0.0003 to about 1 mg per kg of body weight. If desired, an effective daily dose may be divided into multiple doses for administration purposes; consequently, a single-dose composition may contain such an amount or an amount that is a fraction thereof to constitute a daily dose. For oral administration, the composition of the present invention is preferably provided in the form of a tablet containing about 1.0, about 5.0, about 10.0, about 15.0, about 25.0, about 50.0, about 100, about 250, or about 500 milligrams of the active ingredient.

[0100] In some embodiments, the compounds of the present invention may be used for the treatment and / or prevention of pathological conditions, either alone as a monotherapy, by separate administrations, or in combination with other therapeutic agents by including two or more active ingredients in the same pharmaceutical formulation. The components of the treatment may be administered simultaneously, sequentially, or as a single dosage form containing both agents.

[0101] According to one embodiment, the method of treatment or prevention or the use of a compound of formula I may also include the administration (implementation) of further antitumor treatments, such as radiotherapy, immunotherapy, and chemotherapy. In some embodiments, a compound of formula I may be used in combination with or administered in combination with a known anticancer agent or drug; some preferred non-limiting examples are mitomycin C, cisplatin, etoposide, vincristine, doxorubicin, isotretinoin, temozolomide, dasatinib, and cyclophosphamide.

[0102] Some preferred non-limiting examples of imidazo[1,2-a]pyridine derivatives of formula I are reported below:

[0103] 2,6,8-triphenylimidazo[1,2-a]pyridine

[0104] 2-(4-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0105] 2-(3-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0106] 2-(2-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0107] 2-(4-bromophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0108] 2-(3-bromophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0109] 2-(2-bromophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0110] 2-(4-iodophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0111] 2-(3-iodophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0112] 2-(2-iodophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0113] 2-(4-nitrophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0114] 2-(3-nitrophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0115] 2-(2-nitrophenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0116] 6,8-diphenyl-2-(p-tolyl)imidazo[1,2-a]pyridine

[0117] 6,8-diphenyl-2-(m-tolyl)imidazo[1,2-a]pyridine

[0118] 6,8-diphenyl-2-(o-tolyl)imidazo[1,2-a]pyridine

[0119] 2-(4-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0120] 2-(3-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0121] 2-(2-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0122] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzonitrile

[0123] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzonitrile

[0124] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzonitrile

[0125] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzaldehyde

[0126] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzaldehyde

[0127] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzaldehyde

[0128] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenol

[0129] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenol

[0130] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenol

[0131] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenethiol

[0132] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenethiol

[0133] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenethiol

[0134] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)aniline

[0135] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)aniline

[0136] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)aniline

[0137] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzamide

[0138] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzamide

[0139] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzamide

[0140] 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenesulfonamide

[0141] 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenesulfonamide

[0142] 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenesulfonamide

[0143] 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)acrylaldehyde

[0144] 4-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)buta-3-en-2-one

[0145] Methyl 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)acrylate

[0146] 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)-N,N-dimethylacrylamide

[0147] 2-(4-(2-(methylsulfonyl)vinyl)phenyl)-6,8-diphenylimidazo[1,2-a]pyridinemethyl

[0148] 2-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)ethene-1-sulfonate

[0149] 2-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)ethene-1-sulfonamide

[0150] 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)acrylonitrile

[0151] 2-(4-(2-nitrovinyl)phenyl)-6,8-diphenylimidazo[1,2-a]pyridine

[0152] 1-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)penta-2-en-1,4-dione

[0153] Methyl 4-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)-4-oxobuta-2-enoate

[0154] 4-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)-N,N-dimethyl-4-oxobuta-2-enamide

[0155] 1-(3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzoyl)oxiran-2-yl)ethane-1-one

[0156] 6-(4-chlorophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0157] 6-(3-chlorophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0158] 6-(2-chlorophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0159] 6-(4-bromophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0160] 6-(3-bromophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0161] 6-(2-bromophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0162] 6-(4-iodophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0163] 6-(3-iodophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0164] 6-(2-iodophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0165] 6-(4-nitrophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0166] 6-(3-nitrophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0167] 6-(2-nitrophenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0168] 2,8-diphenyl-6-(p-tolyl)imidazo[1,2-a]pyridine

[0169] 2,8-diphenyl-6-(m-tolyl)imidazo[1,2-a]pyridine

[0170] 2,8-diphenyl-6-(o-tolyl)imidazo[1,2-a]pyridine

[0171] 6-(4-methoxyphenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0172] 6-(3-methoxyphenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0173] 6-(2-methoxyphenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0174] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0175] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0176] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0177] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzaldehyde

[0178] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzaldehyde

[0179] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzaldehyde

[0180] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenol

[0181] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenol

[0182] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenol

[0183] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenethiol

[0184] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenethiol

[0185] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenethiol

[0186] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)aniline

[0187] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)aniline

[0188] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)aniline

[0189] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzamide

[0190] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzamide

[0191] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzamide

[0192] 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenesulfonamide

[0193] 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenesulfonamide

[0194] 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenesulfonamide

[0195] 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)acrylaldehyde

[0196] 4-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)buta-3-en-2-one

[0197] Methyl 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)acrylate

[0198] 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)-N,N-dimethylacrylamide

[0199] 6-(4-(2-(methylsulfonyl)vinyl)phenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0200] Methyl 2-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)ethene-1-sulfonate

[0201] 2-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)ethene-1-sulfonamide

[0202] 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)acrylonitrile

[0203] 6-(4-(2-nitrovinyl)phenyl)-2,8-diphenylimidazo[1,2-a]pyridine

[0204] 1-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)penta-2-en-1,4-dione

[0205] Methyl 4-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)-4-oxobuta-2-enoate

[0206] 4-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)-N,N-dimethyl-4-oxobuta-2-enamide

[0207] 1-(3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzoyl)oxiran-2-yl)ethane-1-one

[0208] 8-(4-chlorophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0209] 8-(3-chlorophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0210] 8-(2-chlorophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0211] 8-(4-bromophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0212] 8-(3-bromophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0213] 8-(2-bromophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0214] 8-(4-iodophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0215] 8-(3-iodophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0216] 8-(2-iodophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0217] 8-(4-nitrophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0218] 8-(3-nitrophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0219] 8-(2-nitrophenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0220] 2,6-diphenyl-8-(p-tolyl)imidazo[1,2-a]pyridine

[0221] 2,6-diphenyl-8-(m-tolyl)imidazo[1,2-a]pyridine

[0222] 2,6-diphenyl-8-(o-tolyl)imidazo[1,2-a]pyridine

[0223] 8-(4-methoxyphenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0224] 8-(3-methoxyphenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0225] 8-(2-methoxyphenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0226] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzonitrile

[0227] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzonitrile

[0228] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzonitrile

[0229] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzaldehyde

[0230] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzaldehyde

[0231] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzaldehyde

[0232] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenol

[0233] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenol

[0234] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenol

[0235] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenethiol

[0236] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenethiol

[0237] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenethiol

[0238] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline

[0239] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline

[0240] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline

[0241] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzamide

[0242] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzamide

[0243] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzamide

[0244] 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenesulfonamide

[0245] 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenesulfonamide

[0246] 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenesulfonamide

[0247] 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)acrylaldehyde

[0248] 4-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)buta-3-en-2-one

[0249] Methyl 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)acrylate

[0250] 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)-N,N-dimethylacrylamide

[0251] 8-(4-(2-(methylsulfonyl)vinyl)phenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0252] Methyl 2-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethene-1-sulfonate

[0253] 2-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethene-1-sulfonamide

[0254] 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)acrylonitrile

[0255] 8-(4-(2-nitrovinyl)phenyl)-2,6-diphenylimidazo[1,2-a]pyridine

[0256] 1-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)penta-2-en-1,4-dione

[0257] Methyl 4-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)-4-oxobuta-2-enoate

[0258] 4-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)-N,N-dimethyl-4-oxobuta-2-enamide

[0259] 1-(3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzoyl)oxiran-2-yl)ethane-1-one

[0260] 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one)

[0261] 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0262] 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0263] 1-(4-(6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0264] 1-(4-(6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0265] 1-(4-(6-(4-Bromophenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)phenyl)ethan-1-one

[0266] 1-(4-(6-(3,5-Dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)phenyl)ethan-1-one

[0267] Dimethyl 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzoate

[0268] Methyl 4-(6-(4-Cyanophenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate

[0269] Methyl 4-(6-(3-Cyanophenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate

[0270] Methyl 4-(6-(4-Fluorophenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate

[0271] Methyl 4-(6-(4-Chlorophenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate

[0272] Methyl 4-(6-(4-Bromophenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate

[0273] Methyl 4-(6-(3,5-Dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridin-8-yl)benzoate

[0274] 6,8-Bis(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine

[0275] 4-(8-(4-Chlorophenyl)-2-phenylimidazo[1,2-a]pyridin-6-yl)benzonitrile

[0276] 3-(8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0277] 8-(4-chlorophenyl)-6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine

[0278] 6-(4-bromophenyl)-8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine

[0279] 8-(4-chlorophenyl)-6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine

[0280] 1-(4-(8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)phenyl)ethane-1-one

[0281] 3-(8-(4-acetylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile

[0282] 1-(4-(2-(4-((2-hydroxyethyl)amino)phenyl)-6-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0283] 3-(8-(4-acetylphenyl)-2-(4-((2-hydroxyethyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile

[0284] 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-hydroxyethyl)amino)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0285] 3-(8-(4-acetylphenyl)-2-(4-((2-morpholinoethyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile

[0286] 3-(8-(4-acetylphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile 3-(8-(4-acetylphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile

[0287] 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-morpholinoethyl)amino)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0288] 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)amino)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0289] 3-(8-(4-acetylphenyl)-2-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile

[0290] 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0291] 1-(4-(2-(4-(2-(Diethylamino)ethoxy)phenyl)-6-(3,5-dimethoxyphenyl)imidazo[1,2-a]pyridin-8-yl)phenyl)ethan-1-one

[0292] 3-(8-(4-Acetylphenyl)-2-(4-(2-(diethylamino)ethoxy)phenyl)imidazo[1,2-a]pyridin-6-yl)benzonitrile

[0293] 1-(4-(6-(3,5-Dimethoxyphenyl)-2-(4-((2-(piperazin-1-yl)ethyl)amino)phenyl)imidazo[1,2-a]pyridin-8-yl)phenyl)ethan-1-one

[0294] 3-(8-(4-Acetylphenyl)-2-(4-((2-(piperazin-1-yl)ethyl)amino)phenyl)imidazo[1,2-a]pyridin-6-yl)benzonitrile

[0295] 3-(8-(4-Acetylphenyl)-2-(4-(2-(piperazin-1-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-6-yl)benzonitrile

[0296] 3-(8-(4-Acetylphenyl)-2-(4-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)imidazo[1,2-a]pyridin-6-yl)benzonitrile

[0297] 1-(4-(6-(3,5-Dimethoxyphenyl)-2-(4-(2-(piperazin-1-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-8-yl)phenyl)ethan-1-one

[0298] 1-(4-(6-(3,5-Dimethoxyphenyl)-2-(4-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)imidazo[1,2-a]pyridin-8-yl)phenyl)ethan-1-one

[0299] N-(4-(8-(4-acetylphenyl)-6-(3,5-dimethoxyphenyl)imidazo[1,2-a]pyridine-2-yl)phenyl)-2-aminoacetamide

[0300] N-(4-(8-(4-acetylphenyl)-6-(3-cyanophenyl)imidazo[1,2-a]pyridine-2-yl)phenyl)-2-aminoacetamide

[0301] 4-(8-(4-acetylphenyl)-6-(3-cyanophenyl)imidazo[1,2-a]pyridine-2-yl)phenylacetate

[0302] 4-(8-(4-acetylphenyl)-6-(3,5-dimethoxyphenyl)imidazo[1,2-a]pyridine-2-yl)phenylacetate

[0303] 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-(2-(((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)ethoxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0304] 3-(8-(4-acetylphenyl)-2-(4-(2-(((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)ethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile

[0305] 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one)

[0306] 3-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile

[0307] 1-(4-(6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0308] 1-(4-(6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0309] 1-(4-(6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one

[0310] 6,8-Bis(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine

[0311] 2-phenyl-6,8-di-p-tolylumidazo[1,2-a]pyridine

[0312] 6,8-Bis(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine

[0313] 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzaldehyde

[0314] Dimethyl 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzoate

[0315] 1,1'-((2-(4-hydroxyphenyl)imidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one)

[0316] 1,1'-((2-(4-methoxyphenyl)imidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one)

[0317] According to one embodiment, a compound that can be used as a drug, and in particular a method for the synthesis of imidazo[1,2-a]pyridine derivatives of formula I and the corresponding salts are disclosed herein. More particularly, a process and method for producing the compound are disclosed herein. In some embodiments, the process may first include a cyclization step and at least one reaction step. In the cyclization step, a 2-substituted imidazo[1,2-a]pyridine derivative, i.e., an imidazopyridine nucleus having a main group at position 2 and preferably a functional group R1 bonded to the group A (these groups are defined according to formula I herein). In such a cyclization step, 5-bromo-3-iodopyridine-2-amine (II) is cyclized to obtain the corresponding 2-substituted imidazo[1,2-a]pyridine derivative (III), as described below, using phenyl as the functional group. TIFF2026521872000004.tif30170

[0318] In some embodiments, for example, 5-bromo-3-iodopyridine-2-amine is reacted with one or more halides, preferably having the following formula: R1-AC(O)CH2-halogen (wherein A and R1 are selected as given herein for formula I). ​​The cyclization step may be carried out in the presence of a base catalyst, such as sodium carbonate or potassium. The process may include at least one reaction step in which at least one imidazo[1,2-a]pyridine derivative of formula I is obtained. In this at least one reaction step, the imidazo[1,2-a]pyridine derivative of formula I is preferably obtained by reacting the 2-substituted imidazo[1,2-a]pyridine derivative III obtained in the cyclization step with at least one substituted boronic acid; throughout the at least reaction step, the molar ratio between the 2-substituted imidazo[1,2-a]pyridine and the at least one boronic acid is 1:2. In such a process, at least one substituted boronic acid comprises at least one group selected from A and preferably at least one functional group selected from R1, where each R1 is bonded to only one A group. In a specific example, at least one substituted boronic acid comprises only one A group and preferably only one R1 functional group molecularly bonded to the A group. In a further specific example, the acid may be phenylboronic acid. Preferably, in each of at least one reaction steps, a 2-substituted imidazo[1,2-a]pyridine derivative is reacted with only one of the boronic acids.

[0319] Therefore, according to one non-limiting embodiment of the process, the process comprises a single reaction step in which a 2-substituted imidazo[1,2-a]pyridine derivative is reacted with a single, substituted boronic acid in a molar ratio of 1:2 to obtain a 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative. As an exemplary reaction step, the 2-substituted imidazo[1,2-a]pyridine derivative, III, is functionalized at the 6th and 8th positions of the core using phenyl as the functional group to obtain the corresponding 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative, IV, as described below. TIFF2026521872000005.tif34170

[0320] According to one non-limiting embodiment of the process, the process comprises reacting a 2-substituted imidazo[1,2-a]pyridine derivative with a boronic acid, preferably a boronic acid having the following formulas: R2-XB(OH)2 and R3-ZB(OH)2 (wherein X and Z are selected from the X and Z groups as given herein for formula I, respectively; and R2 and R3 are selected as given herein for formula I). ​​In some embodiments, R2 and R3 are selected from the same portion. This single reaction step may be carried out in the presence of catalysts, such as palladium acetate and triphenylphosphine, and a base, such as sodium carbonate.

[0321] In some embodiments, according to one non-limiting embodiment of the process, the process comprises at least two reaction steps. In particular, in such embodiments, the process comprises a first reaction step in which a 2-substituted imidazo[1,2-a]pyridine derivative is reacted with a first substituted boronic acid in a 1:1 molar ratio to obtain a 2,8-substituted imidazo[1,2-a]pyridine derivative V; and a second reaction step in which a 2,8-substituted imidazo[1,2-a]pyridine derivative is reacted with a second substituted boronic acid in a 1:1 molar ratio to obtain a 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative. The first substituted boronic acid and the second substituted boronic acid may be the same boronic acid or may be different from each other. As an exemplary reaction step, a 2-substituted imidazo[1,2-a]pyridine derivative is reacted with an equimolar amount of a single, substituted boronic acid to obtain the corresponding 2,8-substituted imidazo[1,2-a]pyridine derivative. As a non-limiting example, as shown below, the 2-phenyl-substituted imidazo[1,2-a]pyridine derivative, III, is functionalized at the 8-position using phenyl as the functional group to obtain the corresponding 2,8-substituted imidazo[1,2-a]pyridine, V. TIFF2026521872000006.tif34170

[0322] In some embodiments, the boronic acid used above is R3-ZB(OH)2 (wherein Z is selected from the Z group as given herein for formula I; and R3 is selected as given herein for formula I). ​​This reaction step may be carried out in the presence of a catalyst, such as palladium acetate and triphenylphosphine, and a base, such as sodium carbonate or potassium. Following this first reaction step according to this embodiment of a non-limiting process, a second reaction step is carried out, in which 2,8-substituted imidazo[1,2-a]pyridine, V is coupled to an equimolar amount of a single, substituted boronic acid to obtain the corresponding 2,6,8-trisubstituted imidazo[1,2-a]pyridine. In this second reaction step, the 2,8-substituted imidazo[1,2-a]pyridine derivative, V is functionalized at the 6-position using phenyl as the functional group to obtain the 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative as described below. TIFF2026521872000007.tif43170

[0323] In some embodiments, the boronic acid used for the second reaction step given above is R3-ZB(OH)2 (wherein Z is selected from the Z group as given herein for formula I; and R3 is selected as given herein for formula I). ​​This second reaction step may be carried out in the presence of a catalyst, such as palladium acetate and triphenylphosphine or tetrakis(triphenylphosphine)palladium(O), and a base, such as sodium carbonate or potassium.

[0324] According to one embodiment, a method of production is disclosed. The method comprises the synthesis of a compound of formula I, which includes using any of the above reaction steps. In a preferred embodiment, the method includes using the following reaction scheme: TIFF2026521872000008.tif94170

[0325] According to one embodiment, methods for treatment, methods for prevention, and the use of compounds of formula I are disclosed. These involve administering compounds of formula I to subjects in need for medical purposes, more particularly for therapeutic or preventive purposes, or both, the subjects in need of aldehyde dehydrogenase proteins; in particular, inhibitors of subtype 1A (preferably isoforms 1A1, 1A2, and 1A3) for the prevention, treatment, or both of pathologies and diseases resulting from abnormal modulation of the activity of subtype 1A aldehyde dehydrogenase proteins, e.g., isoforms 1A1, 1A2, and 1A3.

[0326] In some embodiments, as a non-limiting example of the medical utility of the inhibitory activity disclosed herein, a method for treating and thus curing a tumor is disclosed, the method comprising administering a prophylactic or therapeutically effective amount (as appropriate) of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor is solid. In some embodiments, the tumor is non-solid. In some embodiments, the tumor is a cancer selected from the head and neck, thyroid, lung, pleura, gastrointestinal tract, urogenital tract, gynecological, breast, bone and soft tissue, skin, central nervous system, neuroblastoma, glioblastoma, retinoblastoma, rhabdomyosarcoma, hepatocellular carcinoma, glioblastoma multiforme, melanoma, squamous cell carcinoma, pancreatic cancer, mesothelioma, and rare pediatric solid tumors. In some embodiments, the method is applicable in hematological oncology in the treatment of lymphoblastoma, chronic leukemia, and acute leukemia in children.

[0327] In some embodiments, as non-limiting examples of the medical utility of the inhibitory activity disclosed herein, methods for the prevention or treatment of inflammatory diseases or both are disclosed, the methods comprising administering a prophylactic or therapeutically effective amount (as appropriate) of a compound of formula I. In some embodiments, the inflammatory disease affects the respiratory tree, lungs, gastrointestinal tract, bile ducts, gallbladder, or a combination thereof.

[0328] In some embodiments, as non-limiting examples of the medical utility of the inhibitory activity disclosed herein, methods for the prevention or treatment, or both, of diseases of altered expression of subtype 1A aldehyde dehydrogenase protein are disclosed, the methods comprising administering a prophylactic or therapeutically effective amount (as appropriate) of a compound of formula I. In some embodiments, diseases of altered subtype 1A aldehyde dehydrogenase protein are selected from diabetes mellitus, psoriasis, rheumatoid arthritis, acute nephropathy, chronic nephropathy, arterial restenosis, autoimmune diseases, acute infections, ocular diseases resulting from changes in microcirculation, and endometriosis.

[0329] The present invention is described below by experimental examples, but the purpose of these examples is merely to illustrate the functional details of the invention and not to limit the scope of its protection. [Examples]

[0330] Example 1 - Biological Data

[0331] The functional efficacy of the 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative of formula I was experimentally verified using in vitro and in vivo assays.

[0332] In vitro assays were performed in breast cancer cell lines MDA-MB-231, MDA-MB-468, and HCC1806. Specifically, the MDA-MB-231 cell line, characterized by low ALDH1A expression, was used either as is or after being modified to overexpress either the ALDH1A1 or ALDH1A3 isoform, while the MDA-MB-468 and HCC1806 cell lines, characterized by high ALDH1A3 expression, were used either as is or after knockdown of the ALDH1A3 isoform (Figure 1). First, the ability of compounds to specifically inhibit the activity of the ALDH1A3 isoform compared to the ALDH1A1 isoform was determined in MDA-MB-231 cells overexpressing these enzymes (Figures 2A, 2B, 2C, 2D, 2E, 3A, and 3B). Experiments were performed using the Aldefluor® assay, which is specific to aldehyde dehydrogenases.

[0333] Table 1 shows the concentrations that produce 50% of the maximum inhibitory effect for compounds 1 and 2 (whose synthesis is described below), as given as examples, IC50. 50 The data is summarized. In the experimental design, we also included two ALDH1A3 inhibitors, namely GA11 (reported as compound 3a in J.Med.Chem.2020,63,9,4603-4616,https: / / doi.org / 10.1021 / acs.jmedchem.9b01910) and NR6 (reported as compound 3h in J.Med.Chem.2020,63,9,4603-4616,https: / / doi.org / 10.1021 / acs.jmedchem.9b01910), for direct comparison (Figures 4A, 4B, 4C). Compounds 1 and 2 exhibit higher inhibitory activity against ALDH1A3 and selective activity against ALDH1A3 than GA11 and NR6: TIFF2026521872000009.tif43170

[0334] The efficacy of the test compounds compared to 4-diethylaminobenzaldehyde (DEAB), a known inhibitor of ALDH1As used as a reference standard, is shown in Table 1 above. When tested under the same experimental conditions, compounds 1 and 2 showed activity at concentrations less than 1 / 1000th of those used for DEAB (Figures 2, 3, and 4). We confirmed that the activity of compound 1 is specific to ALDH1A3, and that even at a concentration of 100 μM, compound 1 does not inhibit the homologous enzyme ALDH1A1 (Figure 2D). With respect to MDA-MB-468, no significant changes in the expression of the three target genes were observed in either native or ALDH1A3 knockdown strains (Figures 3 and 4).

[0335] Subsequently, to confirm the direct inhibitory activity of the tested compounds against the enzyme isoforms of interest, their effects on the expression of ALDH1A3 target genes, particularly RARB, DHRS3, ELF3, and RARRES1, were investigated in the aforementioned cell lines. Regarding MDA-MB-231, neither compound 1 nor compound 2 produced significant results in the native cell line 24 hours after treatment, but statistically significantly reduced the expression of target genes in MDA-MB-231 cells overexpressing the enzyme, as well as in MDA-MB-468 and HCC1806 cells (Figures 5A, 5B, 5C, 6A, and 6B).

[0336] In vivo experiments were then performed. In vivo assays were carried out using 8-week-old female NOD / SCID mice orthotopically injected with 2 × 10⁶ native or ALDH1A3 overexpressing MDA-MB-231 cells. Approximately 2,000,000 MDA-MB-231 cells were injected into the fifth mammary fat pad of 60 female NOD-SCID mice. Thirty mice were injected with MDA-MB-231 with a vector control (groups 1-3), and 30 mice were injected with MDA-MB-231 with an ALDH1A3 overexpressing vector (groups 4-6). Treatment phases were initiated on day 15 after inoculation. Groups 1 and 4 (n=10 and n=10, respectively) received 100 μL of intraperitoneal saline injections daily for 26 days. Groups 2 and 5 (n=10, 10) received 0.4 mg / kg of the drug intraperitoneally in 100 uL of saline daily for 26 days. Groups 3 and 6 (n=10, 10) received 4.0 mg / kg of the drug intraperitoneally in 100 uL of saline daily for 26 days. Tumor caliper measurements and body weight were obtained throughout the treatment phase. After 26 days, all mice were euthanized, tumors were collected, and blood was taken for analysis.

[0337] On day 15, animals were treated with compound 1, administered intraperitoneally daily at concentrations of 0.4 mg / kg or 4 mg / kg, and then continuously monitored for weight gain (Figure 7) and tumor volume (Figure 8). Once the tumors became palpable, we initiated treatment of the animals (day 15). After treatment on day 26, the animals were sacrificed, and the tumors were collected and evaluated for size (Figures 8 and 9) and weight (Figure 10). Test compound 1 was shown to statistically significantly reduce the ALDH1A3-induced increase in tumor growth in xenografted animals. Pharmacodynamic analysis of tumors collected from sacrificed animals also demonstrated the specificity of the compound to ALDH1A3 in the tumors, with animals treated with compound 1 showing a significant reduction in RARB levels (induced by ALDH1A3 overexpression) in the tumors (Figure 11).

[0338] Importantly, no detectable toxicity was induced by compound 1. This is supported by the trend in body weight over time (Figure 7), as well as by the analysis of alanine aminotransferase (ALT) and creatinine levels in serum collected from terminally ill animals (Figures 12A and 12B). The continued weight gain in mice during treatment, along with the lack of changes in creatinine (an increase in creatinine indicates nephrotoxicity) and ALT levels (an increase in ALT indicates hepatotoxicity), suggests that there is no toxicity associated with daily treatment with compound 1.

[0339] Example 2 - Synthesis Method

[0340] Unless otherwise stated below, all materials used, including the starting products, were obtained from commercial sources or prepared according to experimental protocols described in the literature.

[0341] The information reported in the synthesis procedure described below refers to the following experimental conditions:

[0342] (i) Temperature is expressed in degrees Celsius (°C);

[0343] (ii) The organic solution shall be dried over anhydrous magnesium or sodium sulfate; the evaporation of the solvent shall be carried out using a rotary evaporator and under reduced pressure;

[0344] (iii) Thin-layer chromatography (TLC) is performed on a Merck 60 F-254 plate; column chromatography is performed using silica gel as the stationary phase in flash chromatography and / or using a Biotage Isolera Prime chromatography system;

[0345] (iv) The time indicated in each step required to obtain the desired product shall be determined by TLC;

[0346] (v) The final product of each reaction is characterized by physicochemical and spectroscopic data;

[0347] (vi) The yield reported for each product indicates the yield that can be obtained by an optimally carried-out reaction, and does not necessarily correspond to such yield;

[0348] (vii) The 1H NMR spectrum was recorded at 400 MHz using a Bruker Ultrashield 400 spectrometer. The spectrum is reported in parts per million (δ scale) and internally referenced to the DMSO-d6 signal at δ 2.50 ppm. The data is reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, qi=quintet, m=multiple and / or multiple resonances, bs=single broad), coupling constant (J) in Hertz (Hz), and integral.

[0349] (viii) The purity of the final product (≧95%) was evaluated by HPLC analysis using a Shimadzu LC-20AD liquid chromatograph (PDA, 250-500 nm) and a Luna C18 column (250 mm × 4.6 mm, 5 μm, Phenomenex) with a mixture of 30% water and 70% acetonitrile and isocratic elution at a flow rate of 1.0 mL / min.

[0350] Example 3 - Synthesis of Compound 1:1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one) TIFF2026521872000010.tif68170

[0351] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-acetylphenylboronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.10(d,J=1.7Hz,1H),8.54 d,J=2.4Hz,2H),8.52(d,J=1.8Hz,1H),8.17-8.12(m,2H),8.11(d,J=8.5Hz,2H),8.08-8.00(m, 4H),7.97(d,J=1.8Hz,1H),7.49(t,J=7.7Hz,2H),7.41-7.33(m,1H),2.68(s,3H),2.65(s,3H).

[0352] Example 4 - Synthesis of Compound 2: 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile TIFF2026521872000011.tif85170

[0353] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and Na2CO3 (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The resulting 2-phenylimidazo[1,2-a]pyridine (1.00 mmol) was then suspended in ethanol / water (4:1) and added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-acetylphenylboronic acid (1.00 mmol), and Na2CO3 (2.00 mmol). The resulting mixture was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The resulting 1-(4-(6-bromo-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one (1.00 mmol) was then suspended in ethanol / water (4:1), and Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-cyanophenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol) were added. The resulting mixture was refluxed under stirring until the starting materials were eliminated (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.13(d,J=1.8Hz,1H),8.59-8.50(m,3H),8.17-8.09( m,4H),8.07-7.99(m,5H),7.49(t,J=7.7Hz,2H),7.37(t,J=7.6Hz,1H),2.68(s,3H).

[0354] Example 5 - Synthesis of Compound 3:3-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile TIFF2026521872000012.tif77170

[0355] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium tricarbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The resulting 2-phenylimidazo[1,2-a]pyridine (1.00 mmol) was then suspended in ethanol / water (4:1) and added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-acetylphenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol). The resulting mixture was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The resulting 1-(4-(6-bromo-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one (1.00 mmol) was then suspended in ethanol / water (4:1), and Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 3-cyanophenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol) were added. The resulting mixture was refluxed under stirring until the starting materials were eliminated (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.11(d,J=1.8Hz,1H),8.59-8.53(m,2H),8.52(s,1H),8.44(t,J=1.8Hz,1 H),8.23(m,1H),8.17-8.11(m,2H),8.09-8.03(m,2H),8.02(d,J=1.8Hz,1H),7.90(m,1H),7.75(t,J=7.8 Hz,1H),7.49(t,J=7.7Hz,2H),7.40-7.33(m,1H),2.68(s,3H).

[0356] Example 6 - Synthesis of Compound 4:1-(4-(6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one TIFF2026521872000013.tif94170

[0357] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The resulting 2-phenylimidazo[1,2-a]pyridine (1.00 mmol) was then suspended in ethanol / water (4:1), and Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-acetylphenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol) were added. The resulting mixture was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The resulting 1-(4-(6-bromo-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one (1.00 mmol) was then suspended in ethanol / water (4:1), and Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-fluorophenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol) were added. The resulting mixture was refluxed under stirring until the starting materials were eliminated (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.95(d,J=1.7Hz,1H),8.53(d,J=1.7Hz,1H),8.51(d,J=1.3Hz,2H),8.18-8. 09(m,2H),8.08-8.01(m,2H),7.94-7.87(m,3H),7.48(t,J=7.6Hz,2H),7.38(t,J=8.6Hz,3H),2.68(s,3H).

[0358] Example 7 - Synthesis of Compound 5: 1-(4-(6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one TIFF2026521872000014.tif85170

[0359] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The resulting 2-phenylimidazo[1,2-a]pyridine (1.00 mmol) was then suspended in ethanol / water (4:1), and Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-acetylphenylboronic acid (1.00 mmol), and Na2CO3 (2.00 mmol) were added. The resulting mixture was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The resulting 1-(4-(6-bromo-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one (1.00 mmol) was then suspended in ethanol / water (4:1), and Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-chlorophenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol) were added. The resulting mixture was refluxed under stirring until the starting materials were eliminated (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.97(d,J=1.7Hz,1H),8.52(s,1H),8.50(s,2H),8.13(d,J=8.3Hz,2H),8.06- 8.00(m,2H),7.93-7.83(m,3H),7.63-7.54(m,2H),7.48(t,J=7.5Hz,2H),7.36(t,J=7.4Hz,1H),2.67(s,3H).

[0360] Example 8 - Synthesis of Compound 6:1-(4-(6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one TIFF2026521872000015.tif94170

[0361] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The resulting 2-phenylimidazo[1,2-a]pyridine (1.00 mmol) was then suspended in ethanol / water (4:1) and added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-acetylphenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol). The resulting mixture was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The resulting 1-(4-(6-bromo-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one (1.00 mmol) was then suspended in ethanol / water (4:1) and added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 3,5-dimethoxyphenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol). The resulting mixture was refluxed under stirring until the starting materials were eliminated (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.98(d,J=2.4Hz,1H),8.55-8.46(m,3H),8.18-8.09(m,2H),8.07-8.00(m,2H),7.89(d,J= 2.8Hz,1H),7.52-7.43(m,2H),7.36(t,J=7.4Hz,1H),7.01-6.94(m,2H),6.57(d,J=2.7Hz,1H),3.85(s,6H),2.67(s,3H).

[0362] Example 9 - Synthesis of Compound 7: Methyl 4-(6-(4-cyanophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate TIFF2026521872000016.tif85170

[0363] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The resulting 2-phenylimidazo[1,2-a]pyridine (1.00 mmol) was then suspended in ethanol / water (4:1) and added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (1.00 mmol), and sodium carbonate (2.00 mmol). The resulting mixture was refluxed under stirring until the starting materials were removed (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The resulting methyl 4-(6-bromo-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate (1.00 mmol) was then suspended in ethanol / water (4:1) and added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-cyanophenylboronic acid (1.00 mmol), and sodium carbonate (2.00 mmol). The resulting mixture was refluxed under stirring until the starting materials were eliminated (TLC analysis). After cooling, the mixture was evaporated under reduced pressure to a dry state, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.13(d,J=2.4Hz,1H),8.54(d,J=7.6Hz,2H),8.15(d,J=7.6Hz,2H),8.11(d,J=8.4Hz,2H),8. 06(d,J=6.8Hz,2H),8.02(d,J=9.6Hz,2H),7.99(d,J=2.4Hz,2H),7.49(t,J=8.0Hz,2H),7.37(t,J=8.4Hz,1H),3.31(s,3H).

[0364] Example 10 - Synthesis of Compound 8:6,8-bis(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine TIFF2026521872000017.tif85170

[0365] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), 4-chlorophenylboronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.96(d,J=1.9Hz,1H),8.50(d,J=1.8Hz,1H),8.45-8.35(m,2H),8.03(d,J=7.6Hz) ,2H),7.93-7.85(m,2H),7.83(d,J=1.9Hz,1H),7.66-7.55(m,4H),7.48(t,J=7.6Hz,2H),7.37(d,J=7.3Hz,1H).

[0366] Example 11 - Synthesis of Compound 9:2,6,8-triphenylimidazo[1,2-a]pyridine TIFF2026521872000018.tif68170

[0367] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), phenylboronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.91(d,1H,J=1.6Hz),8.50(s,1H),8.32(d,2H,J=7.2Hz),8.02(d,2H,7.2Hz),7.85(d,2H,J=7.2Hz),7.75(d,2H,J=1.6 Hz),7.58-7.41(m,8H),7.36-7.33(m,1H).

[0368] Example 12 - Synthesis of Compound 10: 2-phenyl-6,8-di-p-tolylumidazo[1,2-a]pyridine TIFF2026521872000019.tif85170

[0369] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), p-trilboronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.84(d,J=1.7Hz,1H),8.47(s,1H),8.22(d,J=8.2Hz,2H),8.04-7. 96(m,2H),7.75-7.68(m,3H),7.47(t,J=7.7Hz,2H),7.40-7.29(m,5H),2.41(s,3H),2.38(s,3H).

[0370] Example 13 - Synthesis of Compound 11:6,8-bis(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine TIFF2026521872000020.tif94170

[0371] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallizing from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), (4-methoxyphenyl)boronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.78(d,J=1.9Hz,1H),8.46(d,J=1.3Hz,1H),8.37-8.29(m,2H),8.02(d,J=7.7Hz,2H),7.82-7 .72(m,2H),7.70(d,J=1.8Hz,1H),7.48(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.17-7.03(m,4H),3.87(s,3H),3.84(s,3H).

[0372] Example 14 - Synthesis of Compound 12: Dimethyl 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzaldehyde TIFF2026521872000021.tif85170

[0373] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), (4-formylphenyl)boronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.13(s,1H),10.10(s,1H),9.16(s,1H),8.62(d ,2H,J=8Hz),8.56(s,1H),8.16-8.05(m,9H),7.50(t,2H,J=7.6Hz),7.38(m,1H).

[0374] Example 15 - Synthesis of Compound 13: Dimethyl 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzoate TIFF2026521872000022.tif85170

[0375] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-phenylethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.12(d,J=1.8Hz,1H),8.57-8.49(m,3H),8.18-8.13(m,2H),8.11(d,J=8.5Hz,2H) ,8.08-8.00(m,4H),7.99(d,J=1.8Hz,1H),7.49(t,J=7.7Hz,2H),7.37(t,J=7.3Hz,1H),3.93(s,3H),3.91(s,3H).

[0376] Example 16 - Synthesis of Compound 14: 1,1'-((2-(4-hydroxyphenyl)imidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one) TIFF2026521872000023.tif85170

[0377] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-(4-hydroxyphenyl)ethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), (4-acetylphenyl)boronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.62(s,1H),9.08(s,1H),8.52(d,J=8.1Hz,2H),8.37(s,1H),8.22-8.06(m,4H ),8.03(d,J=8.2Hz,2H),7.94(s,1H),7.85(d,J=8.2Hz,2H),6.87(d,J=8.2Hz,2H),2.68(s,3H),2.65(s,3H).

[0378] Example 17 - Synthesis of Compound 15: 1,1'-((2-(4-methoxyphenyl)imidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one) TIFF2026521872000024.tif94170

[0379] A mixture of 2-amino-3-iodine-5-bromopyridine (1.00 mmol), 2-bromo-1-(4-methoxyphenyl)ethane-1-one (1.00 mmol), and sodium carbonate (1.00 mmol) in 20.0 mL of ethanol was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated to a dry state, and the resulting solid was purified by washing with water and subsequently crystallization from ethanol. The thus obtained 2-phenylimidazo[1,2-a]pyridine (1.00 mmol), suspended in ethanol / water (4:1), was then added to Pd(OAc)2 (0.10 mmol), PPh3 (0.20 mmol), (4-acetylphenyl)boronic acid (2.00 mmol), and sodium carbonate (2.00 mmol), and the resulting mixture was refluxed under stirring until the starting materials disappeared (TLC analysis). After cooling, the reaction mixture was evaporated under reduced pressure until dry, and the residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether eluate mixture). The pure product was finally characterized by physicochemical and spectroscopic data. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.08(d,J=1.8Hz,1H),8.54-8.47(m,2H),8.44(s,1H),8.18-8.12(m,2H),8.12-8.07(m,2H),8.03(d,J=8.5 Hz,2H),8.00-7.90(m,3H),7.09-6.97(m,2H),3.81(s,3H),2.67(s,3H),2.65(s,3H).

[0380] Evenly

[0381] The present invention covers variations that fall within the scope of the inventive concept as defined by the claims and as can be predicted based on the disclosures provided herein. In this context, all details can be replaced by equivalent elements, and as appropriate, materials, shapes, and dimensions can be any equivalents as can be predicted from those given herein.

Claims

1. Compounds of formula I, or its pharmaceutically acceptable salts or prodrugs: In the formula, A, X, and Z are each independently selected from aryl, heteroaryl, heterocyclic, or cyclic groups; R １ Hydrogen, amino, fluoro, chloro, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkynyl Coxy, Hydroxy C1-C6 alkylamino, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkylamino, Amino C1-C6 alkyl, Amino C1-C6 alkoxy, C1-C6 alkylamino, Di-C1-C6 alkylamino, C1-C6 alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, Phosphate C1-C6 alkylthio, Sulfate C1-C6 alkylthio, Thio C1-C6 alkyl, Thio C1-C6 alkoxy, Thio C1-C6 alkylamino, heterocycloC1-C6 alkyl, heterocycloC1-C6 alkoxy, heterocycloC1-C6 alkylamino, phosphate C1-C6 alkylamino, sulfate C1-C6 alkylamino, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkylthioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarboxamide Mido, C1-C6 dialkylsulfonamide, C1-C6 dialkylthiocarboxamide, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 guanidine alkyl, C1-C6 cyanoalkyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, cyclic C1-C6 alkoxy, phosphate C1-C6 alkoxy, sulfate C1-C6 alkoxy, aryl C1-C6 alkylamino, heteroaryl C1-C6 alkylamino, cyclic C1-C6 alkylamino, (((3R,4S,5S,6R)-3,4,Selected from 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, aryl, heteroaryl, heterocyclic, and cyclic groups; and, R ２ and R ３ Hydrogen, halogen, fluoro, chloro, bromo, iodine, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amide, acetyl, sulfonamide, acrylic, acrylaldehyde, buta-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl) vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, penta-2-en-1,4-dione, 4-oxobuta-2-enoate, N,N-dimethyl-4-oxobuta-2-enoate, ethane-1-one, and oxiran-2-ylethane-1-one, trifluoromethyl, carbamoyl, sulfamoyl, acrylamide, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, hydroxy C1-C6 Alkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, amino C1-C6 alkyl, amino C1-C6 alkoxy, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, phosphate C1-C6 alkylthio, sulfate C1-C6 alkylthio, thio C1-C6 alkyl, thio C1-C6 alkoxy, thio C1-C6 alkyl Mino, heterocycloC1-C6 alkyl, heterocycloC1-C6 alkoxy, heterocycloC1-C6 alkylamino, phosphate C1-C6 alkylamino, sulfate C1-C6 alkylamino, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkylthioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarboxamide, C1 -C6 dialkylsulfonamide, C1-C6 dialkylthiocarboxamide, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 guanidine alkyl, C1-C6 cyanoalkyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, cyclic C1-C6 alkoxy, phosphate C1-C6 alkoxy, sulfate C1-C6 alkoxy, aryl C1-C6 alkylamino, heteroaryl C1-C6 alkylamino, cyclic C1-C6 alkylamino, (((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, independently selected from aryl, heteroaryl, heterocyclic, and cyclic groups; Furthermore, the present aryl, heteroaryl, heterocyclic, and cyclic groups include hydrogen, halogen, fluoro, chloro, bromo, iodo, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amide, acetyl, sulfonamide, acrylic, acrylaldehyde, buta-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl) vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, penta-2-en-1,4-dione, 4-oxobuta-2-enoate, N,N-dimethyl-4-oxobuta-2-enoate, ethane-1-one, and oxiran-2-ylethane-1-one, trifluoromethyl, carbamoyl, sulfamoyl, acrylamide, acrylonitrile, dichloroacetate They are further functionalized with 0 or more substituents selected from mid, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 alkylcarboamino, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di-C1-C6 alkylamino, aminoC1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C2-C6 alkynylcarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, C1-C6 alkylsulfonylaminocarbonyl, C1-C6 alkoxycarbonyl, arylaminocarbonyl, and C3-C7 cycloalkylaminocarbonyl.

2. A, X, and Z are each phenyl; R １ but selected from hydrogen, fluoro, chloro, bromo, iodine, nitro, methyl, methoxy, cyano, formyl, carboxy, thiol, amino, amide, acetyl, sulfonamide, acrylic, acrylaldehyde, buta-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl)vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, penta-2-en-1,4-dione, 4-oxobuta-2-enoate, N,N-dimethyl-4-oxobuta-2-enoate, ethane-1-one, and oxiran-2-ylethane-1-one; and R ２ and R ３ The compound according to claim 1, wherein each of the following is independently selected: hydrogen, halogen, fluoro, chloro, bromo, iodine, nitro, methyl, methoxy, cyano, formyl, carboxy, hydroxy, thiol, amino, amide, acetyl, sulfonamide, acrylic, acrylaldehyde, buta-3-en-2-one, methyl acrylate, N,N-dimethyl acrylate, 2-(methylsulfonyl)vinyl, ethane-1-sulfonate, ethane-1-sulfonamide, acrylonitrile, nitrovinyl, penta-2-en-1,4-dione, 4-oxobuta-2-enoate, N,N-dimethyl-4-oxobuta-2-enoate, ethane-1-one, and oxiran-2-ylethane-1-one.

3. A, X, and Z are each phenyl; R １ is selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (in either direction), methyl ether, fluoro, chloro, alkoxy, methoxy, and cyano; and R ２ and R ３ are each independently selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (in either direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano, the compound according to claim 1.

4. The compound according to claim 3, wherein the existing aryl, heteroaryl, heterocyclic, and cyclic groups are further functionalized with up to two additional substituents selected from hydrogen, acetyl, formyl, alkyl, methyl, methyl ester (in any direction), methyl ether, halogen, fluoro, chloro, hydroxy, alkoxy, methoxy, and cyano.

5. 2,6,8-triphenylimidazo[1,2-a]pyridine, 2-(4-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(3-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(2-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(3-bromophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(2-bromophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(4-iodophenyl)-6,8-diphenyl Midazo[1,2-a]pyridine, 2-(3-iodophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(2-iodophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(4-nitrophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(3-nitrophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(2-nitrophenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 6,8-diphenyl-2-(p-tolyl)imidazo[1,2-a]pyridine, 6, 8-diphenyl-2-(m-tolyl)imidazo[1,2-a]pyridine, 6,8-diphenyl-2-(o-tolyl)imidazo[1,2-a]pyridine, 2-(4-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(3-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 2-(2-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzonitrile, 3-(6,8-diphenylimidazo[1 ,2-a]pyridine-2-yl)benzonitrile, 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzonitrile, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzaldehyde, 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzaldehyde, 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzaldehyde, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenol, 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenol, 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenol, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenethiol, 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenethiol, 2-(6,8-diphenylimidazo[1,2-a ]pyridine-2-yl)benzenethiol, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)aniline, 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)aniline, 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)aniline, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl) ) benzamide, 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzamide, 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzamide, 4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenesulfonamide, 3-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenesulfonamide, 2-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzenesulfonamide, 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)acrylaldehyde, 4-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)buta-3-en-2-one, methyl 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl) acrylate, 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)-N,N-dimethylacrylamide, 2-(4-(2-(methylsulfonyl)vinyl)phenyl)-6,8-diphenylimidazo[1,2-a]pyridinemethyl, 2-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)ethene-1-sulfonate, 2-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)ethene-1-sulfonamide, 3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)acrylonitrile, 2-(4-(2-nitrovinyl)phenyl)-6,8-diphenylimidazo[1,2-a]pyridine, 1-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)penta-2-en-1,4-dione, methyl 4-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)-4-oxobuta-2-enoate, 4-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)phenyl)-N,N-dimethyl-4-oxobuta-2-enamide, 1-(3-(4-(6,8-diphenylimidazo[1,2-a]pyridine-2-yl)benzoyl)oxiran-2-yl)ethane-1-one, 6-(4-chlorophenyl)-2,8-diphenylim Dazo[1,2-a]pyridine, 6-(3-chlorophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(2-chlorophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(4-bromophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(3-bromophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(2-bromophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(4-yo (Diphenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(3-iodophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(2-iodophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(4-nitrophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(3-nitrophenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(2-nitrophenyl)-2,8-diphenylimida Zo[1,2-a]pyridine, 2,8-diphenyl-6-(p-tolyl)imidazo[1,2-a]pyridine, 2,8-diphenyl-6-(m-tolyl)imidazo[1,2-a]pyridine, 2,8-diphenyl-6-(o-tolyl)imidazo[1,2-a]pyridine, 6-(4-methoxyphenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(3-methoxyphenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 6-(2-methoxyphenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzaldehyde, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzaldehyde, 2-(2,8-diphenylimidazo[1 ,2-a]pyridine-6-yl)benzaldehyde, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenol, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenol, 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenol, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenethiol, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenethiol, 2-(2,8-diphenylimidazo[1,2-a] Pyridine-6-yl)benzenethiol, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)aniline, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)aniline, 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)aniline, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzamide, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzamide, 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzamide Suamide, 4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenesulfonamide, 3-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenesulfonamide, 2-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzenesulfonamide, 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)acrylaldehyde, 4-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)buta-3-en-2-one, methyl 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)acrylate, 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)-N,N-dimethylacrylamide, 6-(4-(2-(methylsulfonyl)vinyl)phenyl)-2,8-diphenylimidazo[1,2-a]pyridine, methyl 2-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)ethene-1-sulfonate, 2-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)ethene-1-sulfonamide, 3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)acrylonitrile, 6-(4-(2-nitrovinyl)phenyl)-2,8-diphenylimidazo[1,2-a]pyridine, 1-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)penta-2-en-1,4-dione, methyl 4-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)-4-oxobuta-2-enoate, 4-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)phenyl)-N,N-dimethyl-4-oxobuta-2-enamide, 1-(3-(4-(2,8-diphenylimidazo[1,2-a]pyridine-6-yl)benzoyl)oxiran-2-yl)ethane-1-one, 8-(4-chlorophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(3-chlorophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(2-chlorophenyl)-2,6 -diphenylimidazo[1,2-a]pyridine, 8-(4-bromophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(3-bromophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(2-bromophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(4-iodophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(3-iodophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(2-iodophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(3-nitrophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(2-nitrophenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 2,6-diphenyl-8-(p-tolyl)imidazo[1,2-a]pyridine, 2,6-diphenyl-8-(m-tolyl)imidazo[1,2-a]pyridine, 2,6-diphenyl-8-(o-tolyl)imidazo[1,2-, a) Pyridine, 8-(4-methoxyphenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(3-methoxyphenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 8-(2-methoxyphenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzonitrile, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzonitrile, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzonitrile , 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzaldehyde, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzaldehyde, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzaldehyde, 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenol, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenol, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenol, 4-(2, 6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenethiol, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenethiol, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenethiol, 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline, 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)aniline Dazo[1,2-a]pyridine-8-yl)benzamide, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzamide, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzamide, 4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenesulfonamide, 3-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenesulfonamide, 2-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzenesulfonamide, 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)acrylaldehyde, 4-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)buta-3-en-2-one, methyl 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)acrylate, 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)-N,N-dimethylacrylamide, 8-(4-(2-(methylsulfonyl)vinyl)phenyl)-2,6-diphenylimidazo[1,2-a]pyridine, methyl 2-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethene-1-sulfonate, 2-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethene-1-sulfonamide, 3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)acrylonitrile, 8-(4-(2-nitrovinyl)phenyl)-2,6-diphenylimidazo[1,2-a]pyridine, 1-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)penta-2-en-1,4-dione, methyl 4-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)-4-oxobuta-2-enoate, 4-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)phenyl)-N,N-dimethyl-4-oxobuta-2-enamide, 1-(3-(4-(2,6-diphenylimidazo[1,2-a]pyridine-8-yl)benzoyl)oxiran-2-yl)ethane-1-one, 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl) Bis(4,1-phenylene))bis(ethane-1-one), 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(6-(4-bromophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, dimethyl 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzoate, methyl 4-(6-(4-cyanophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate, methyl 4-(6-(3-cyanophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate, methyl 4-(6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate, methyl 4-(6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate, methyl 4-(6-(4-bromophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate, methyl 4-(6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)benzoate, 6,8-bis(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine, 4-(8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 3-(8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 8-(4-chlorophenyl)-6-(4-fluorophenyl)-2- Phenylimidazo[1,2-a]pyridine, 6-(4-bromophenyl)-8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine, 8-(4-chlorophenyl)-6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine, 1-(4-(8-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(2-(4-((2-hydroxyethyl)amino)phenyl)-6-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-((2-hydroxyethyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-hydroxyethyl)amino)phenyl)imidazo[1,2-a]py Lysine-8-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-((2-morpholinoethyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 3-(8-(4-acetylphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile 3-(8-(4-acetylphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)amino (Oxatetradecyl)oxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-morpholinoethyl)amino)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)amino)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane -1-one, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(2-(4-(2-(diethylamino)ethoxy)phenyl)-6-(3,5-dimethoxyphenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-(2-(diethylamino)ethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-(piperazine-1-yl)ethyl)amino)phenyl)imidazo [1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-((2-(piperazine-1-yl)ethyl)amino)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 3-(8-(4-acetylphenyl)-2-(4-(2-(piperazine-1-yl)ethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl)benzonitrile, 3-(8-(4-acetylphenyl)-2-(4-((2-(4-methylpiperazine-1-yl)ethyl)amino)phenyl)imidazo [1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-(2-(piperazine-1-yl)ethoxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(6-(3,5-dimethoxyphenyl)-2-(4-((2-(4-methylpiperazine-1-yl)ethyl)amino)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, N-(4-(8-(4-acetylphenyl)-6-(3,5-dimethoxyphenyl) Imidazoo[1,2-a]pyridine-2-yl)phenyl)-2-aminoacetamide, N-(4-(8-(4-acetylphenyl)-6-(3-cyanophenyl)imidazo[1,2-a]pyridine-2-yl)phenyl)-2-aminoacetamide, 4-(8-(4-acetylphenyl)-6-(3-cyanophenyl)imidazo[1,2-a]pyridine-2-yl)phenylacetate, 4-(8-(4-acetylphenyl)-6-(3,5-dimethoxyphenyl)imidazo[1,2-a]pyridine-2-yl)phenylacetate, 1-(4-(6-(3,5-Dimethoxyphenyl)-2-(4-(2-(((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)ethoxy)phenyl)imidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 3-(8-(4-acetylphenyl)-2-(4-(2-(((3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)ethoxy)phenyl)imidazo[1,2-a]pyridine-6-yl), Benzonitrile, 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one), 3-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, 1-(4-(6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 1-(4-(6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl) Ethane-1-one, 1-(4-(6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-a]pyridine-8-yl)phenyl)ethane-1-one, 6,8-bis(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyridine, 2-phenyl-6,8-di-p-tolyliimidazo[1,2-a]pyridine, 6,8-bis(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine, 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzaldehyde, dimethyl The compound according to claim 1, selected from 4,4'-(2-phenylimidazo[1,2-a]pyridine-6,8-diyl)dibenzoate, 1,1'-((2-(4-hydroxyphenyl)imidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one), and 1,1'-((2-(4-methoxyphenyl)imidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one).

6. The compound according to claim 1, wherein the compound is 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one).

7. The compound according to claim 1, wherein it is 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile.

8. A method for producing 2,6,8-trisubstituted imidazo[1,2-a]pyridine, comprising: reacting alpha-aminopyridine directly bonded to bromine and iodine with a beta-carbonylalkyl halide directly bonded to a first functional group to produce an imidazo[1,2-a]pyridine core directly bonded to the first functional group; and then sequentially reacting the produced product with a boronic acid directly bonded to a second functional group and a boronic acid directly bonded to a third functional group to obtain the 2,6,8-trisubstituted imidazo[1,2-a]pyridine.

9. The method for producing the compound according to claim 8, wherein the compound obtained is 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one).

10. The method for producing the compound obtained is 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile, according to claim 8.

11. A method for treating a pathology or disease in a subject suffering from a pathology or disease resulting from abnormal regulation of subtype 1A aldehyde dehydrogenase activity, comprising administering a therapeutically effective amount of an aldehyde dehydrogenase protein inhibitor.

12. The treatment method according to claim 11, wherein the inhibitor is a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof: In the formula, A, X, and Z are each independently selected from aryl, heteroaryl, heterocyclic, or cyclic groups; R １ 、R ２ 、R ３ Hydrogen, hydroxy, amino, halogen, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, acetyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy Hydroxy C1-C6 alkylamino, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkylamino, amino C1-C6 alkyl, amino C1-C6 alkoxy, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyldiamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, phosphate C1-C6 alkylthio, sulfate C1-C6 alkylthio, thio C1-C6 alkyl, thio C1-C6 alkoxy, thio C1-C6 alkyl C1-C6 alkyl, heterocyclo C1-C6 alkoxy, heterocyclo C1-C6 alkylamino, phosphate C1-C6 alkylamino, sulfate C1-C6 alkylamino, C1-C6 alkyl sulfinyl, C1-C6 alkyl sulfonyl, C1-C6 alkyl thiocarboxamide, C1-C6 alkylcarboxamide, C1-C6 alkyl thioureyl, C1-C6 alkylureyl, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 dialkylcarboxamide, C1-C6 dialkyl Sulfonamides, C1-C6 dialkylthiocarboxamides, C1-C6 haloalkyls, C1-C6 haloalkoxys, C1-C6 guanidine alkyls, C1-C6 cyanoalkyls, aryl C1-C6 alkoxys, heteroaryl C1-C6 alkoxys, cyclic C1-C6 alkoxys, phosphate C1-C6 alkoxys, sulfate C1-C6 alkoxys, aryl C1-C6 alkylaminos, heteroaryl C1-C6 alkylaminos, cyclic C1-C6 alkylaminos, aryl, heteroaryl, heterocyclic, and cyclic groups are each independently selected; Furthermore, the present aryl, heteroaryl, heterocyclic, and cyclic groups include hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, hydroxy, carboxy, formyl, carbamoyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C1-C6 alkylcarboamino, C1-C6 alkylthio, and C1-C6 alkylsulfo They are further functionalized with one or more substituents selected from nyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di-C1-C6 alkylamino, aminoC1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkylcarbonyl, C2-C6 alkenylcarbonyl, C2-C6 alkynylcarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, C1-C6 alkylsulfonylaminocarbonyl, C1-C6 alkoxycarbonyl, arylaminocarbonyl, and C3-C7 cycloalkylaminocarbonyl.

13. The treatment method according to claim 12, wherein the compound is 1,1'-((2-phenylimidazo[1,2-a]pyridine-6,8-diyl)bis(4,1-phenylene))bis(ethane-1-one).

14. The treatment method according to claim 12, wherein the compound is 4-(8-(4-acetylphenyl)-2-phenylimidazo[1,2-a]pyridine-6-yl)benzonitrile.

15. The treatment method according to claim 11, wherein the aforementioned pathology or disease is cancer.

16. The treatment method according to claim 11, wherein the aforementioned pathology or disease is an inflammatory disease.

17. The treatment method according to claim 11, wherein the pathology or disease is a tumor selected from the head and neck, thyroid gland, lungs, pleura, gastrointestinal tract, urogenital tract, gynecology, breast, bone and soft tissue, skin, central nervous system, neuroblastoma, glioblastoma, retinoblastoma, rhabdomyosarcoma, hepatocellular carcinoma, glioblastoma multiforme, melanoma, squamous cell carcinoma, pancreatic cancer, mesothelioma, and rare pediatric tumor types.

18. The treatment method according to claim 11, wherein the pathology or disease is an inflammatory disease presenting in a body region selected from the respiratory tree, lungs, gastrointestinal tract, bile ducts, and gallbladder.

19. The treatment method according to claim 11, wherein the pathology or disease is selected from diabetes mellitus, psoriasis, rheumatoid arthritis, acute nephropathy, chronic nephropathy, arterial restenosis, autoimmune disease, acute infection, eye disease resulting from changes in microcirculation, and endometriosis.

20. A method for preventing a pathology or disease in a subject suffering from a pathology or disease resulting from abnormal regulation of subtype 1A aldehyde dehydrogenase activity, comprising administering a prophylactically effective amount of an aldehyde dehydrogenase protein inhibitor.

21. A medical compound for inhibiting the activity of subtype 1A aldehyde dehydrogenase protein, comprising at least one 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative; the derivative comprising an imidazopyridine nucleus and three main groups molecularly bonded to the imidazopyridine nucleus; and the three main groups being selected from aryl, heteroaryl, heterocyclic, or cyclic groups.

22. The medical compound according to claim 21, wherein each of the three main groups contains one, two, or three heteroatoms selected from oxygen, nitrogen, phosphorus, and sulfur.

23. The medical compound according to claim 21, comprising exactly three of the main groups directly molecularly bonded to the imidazopyridine nucleus.

24. The medical compound according to claim 21, wherein each of the aforementioned main groups contains a functional group that is directly molecularly bonded to the aforementioned main group.

25. The functional groups include hydrogen, hydroxy, amino, halogen, trifluoromethyl, cyano, nitro, carboxy, formyl, carbamoyl, sulfamoyl, mercapto, acrylaldehyde, acrylate, acrylamide, acrylonitrile, dichloroacetamide, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 A medical compound according to claim 24, selected from lucyl, amino C1-C4 alkyl, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 alkoxyaminocarbonyl, C1-C6 alkylthio, thio C1-C6 alkyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aryl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, aryl C1-C6 amino, heteroaryl C1-C6 amino, aryl, and heteroaryl.

26. The medical compound according to claim 21, as a stereoisomer or its prodrug or salt.

27. Use of the medical compound according to claim 21 for the preparation of inhibitory drugs against aldehyde dehydrogenase proteins, particularly subtype 1A.

28. Use of the medical compound according to claim 21 for the prevention and treatment of pathologies resulting from abnormal regulation of the activity of the subtype 1A aldehyde dehydrogenase protein, for example, isoforms 1A1, 1A2, and 1A3.

29. Use of the medical compound according to claim 21 for the prevention and treatment of cancer.

30. Use of the medical compound according to claim 29, either alone or in combination with further treatments including radiotherapy, immunotherapy, and chemotherapy.

31. Use of the medical compound according to claim 21 in a pharmaceutical composition or formulation.

32. Use of the medical compound according to claim 21, using a pharmaceutically acceptable carrier or delivery system.

33. The use according to claim 32, wherein the pharmaceutically acceptable carrier or delivery system comprises liposomes.

34. A manufacturing process for producing a medical compound for inhibiting the activity of subtype 1A aldehyde dehydrogenase protein, wherein the medical compound comprises at least one 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative; the derivative comprises an imidazopyridine nucleus and three main groups molecularly bonded to the imidazopyridine nucleus; each of the three main groups is selected from an aryl, heteroaryl, heterocyclic, or cyclic group, and the process comprises 5-bromo-3-iodopyridine-2-amine comprising at least one of the main groups A manufacturing process comprising: a cyclization step of reacting with another halide to obtain a 2-substituted imidazo[1,2-a]pyridine derivative; and at least one reaction step of reacting the 2-substituted imidazo[1,2-a]pyridine with at least one boronic acid substituted with at least one of the main groups to obtain at least one 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative, wherein the molar ratio of the 2-substituted imidazo[1,2-a]pyridine derivative to the at least one boronic acid is 1:2 throughout at least the entirety of the reaction step.

35. The manufacturing process according to claim 34, comprising at least one reaction step which is a single reaction step, wherein at least one 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative is obtained by reacting the 2-substituted imidazo[1,2-a]pyridine derivative with only one of at least one boronic acid in the at least one reaction step; and the molar ratio of the 2-substituted imidazo[1,2-a]pyridine derivative to the boronic acid is 1:

2.

36. The manufacturing process according to claim 34, comprising at least one reaction step comprising two reaction steps, wherein a first reaction step is obtained by reacting the derivative 2-substituted imidazo[1,2-a]pyridine with a first substituted boronic acid in a 1:1 molar ratio to obtain the 2,8-substituted imidazo[1,2-a]pyridine derivative; and a second reaction step is obtained by reacting the 2,8-substituted imidazo[1,2-a]pyridine derivative with a second substituted boronic acid in a 1:1 molar ratio to obtain the 2,6,8-trisubstituted imidazo[1,2-a]pyridine derivative.

Images