2-substituted 3, 4a, 5, 7, 8, 8a-hexahydro-4H-thiapyrano [4, 3-d] pyrimidine-4-ketone compound for wound treatment

Abstract

The invention provides compounds, pharmaceutical compositions comprising the compounds, methods of making the compounds, and methods of using the compounds and compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a PCT international application, which claims and enjoys the benefit of U.S. Provisional Application No. 63 / 417,257 filed on October 18, 2022, U.S. Provisional Application No. 63 / 418,947 filed on October 24, 2022, and U.S. Provisional Application No. 63 / 418,956 filed on October 24, 2022; the contents of each application are hereby incorporated by reference in their entirety into the present invention. Field of the Invention

[0002] The present invention provides compounds, pharmaceutical compositions comprising the compounds, methods for preparing the compounds, and methods for treating wounds using the compounds and compositions, particularly methods for enhancing tissue regeneration after wound treatment. The present invention also provides methods for treating a disease in a mammal associated with Wnt transcripts or Wnt signaling pathway activity, comprising administering a therapeutically effective amount of the compound or composition to the mammal. Background of the Invention

[0003] The Wnt pathway has been shown to play a key role in dermal fibrosis and scar formation. The Wnt pathway is an evolutionarily conserved pathway that regulates key aspects of embryonic development, including cell fate determination, cell polarity, cell migration, neural patterning, and organogenesis. This pathway helps ensure the normal development of embryonic tissues and the maintenance of adult tissues. Wnt signaling is involved in the initial stages of skin development, after gastrulation, when embryonic cells from the ectoderm and mesoderm differentiate into the epidermis and dermis, respectively.

[0004] Although the signal transduction process involves at least three different Wnt signaling pathways, the canonical (or β-catenin-dependent) Wnt pathway is the best understood. β-catenin is a key effector molecule produced by canonical Wnt pathway signal transduction, and its protein level is regulated by the "destruction complex." In the absence of Wnt signals, the transcriptional activator β-catenin is actively degraded in cells through the action of a protein complex called the "destruction complex." In this complex, Axin-1 (Axin 1) and Axin-2 form a scaffold structure with adenomatous polyposis coli, which promotes β-catenin phosphorylation through casein kinase 19a and glycogen synthase kinase 3β. Phosphorylated β-catenin is recognized and ubiquitinated, resulting in its proteomic degradation. Tankryase I and Tankryase II (TK1 and TK2) are both poly (ADP-ribose) polymerases (PARPs) whose function is to parsylate and destabilize Axin-1 and Axin-2 proteins, thereby destabilizing the β-catenin destruction complex. Once the stability of the destruction complex is destroyed, β-catenin is dephosphorylated and then stabilized, accumulating in the cytoplasm and entering the nucleus, where it interacts with members of the Tcf / Lef family. β-catenin converts Tcf proteins into potent transcriptional activators by recruiting coactivators, thereby ensuring the effective activation of Wnt target genes. Once the Wnt pathway is activated by the Wnt family of natural ligands, it upregulates TNK1 and TNK2, thereby helping to destabilize the destruction complex. Studies have shown that both TNK1 and TNK2 are key regulators of canonical Wnt signaling.

[0005] XAV939 is a small molecule that inhibits TNK1 and TNK2 (IC in cell-free assays). 50 11nM / 4nM), thereby selectively inhibiting Wnt / β-catenin-mediated transcription, regulating axin levels, and not affecting CRE, F-κB, or TGF-β. Topical application of XAV939 in a mouse ear perforation test showed that XAV939 can significantly improve wound closure rate while reducing fibrosis (scar formation) (Bastakoty, D. et al. FASEB J., 2015, 29 (12): 4881-4892). However, XAV939 is dissolved in dimethyl sulfoxide (DMSO) and is only used as a "research tool" compound because of its very low water solubility (<1μg / mL). The problem with this method is that humans cannot tolerate the use of DMSO.

[0006] Matrix components comprising graphene oxide (GO) and hyaluronic acid (HA) have been shown to effectively provide a supportive matrix for XAV939 and allow the use of XAV939 as a therapeutic agent for wound healing in humans and animals, see, for example, US20210000959, wherein XAV939 in a GO-HA matrix significantly improves the quality of wound healing; specifically, it allows the tissue to follow the fibrotic healing pathway and limit scar formation. In addition, it has been observed that, for example, 2 mm biopsy punch wounds made in the center of the cartilage region of C57Bl / CJ mice treated with XAV939 increased cartilage regeneration and healing after acute injury (Bastakoty, D. et al. FASEB J., 2015, 29(12): 4881–4892, and WO2023 / 039298).

[0007] Although XAV939 has demonstrated therapeutic utility, it has poor solubility in aqueous solutions. Therefore, there is a need for Wnt inhibitors with improved / different properties, such as increased aqueous solubility, enhanced Wnt inhibition, enhanced bioavailability, and / or improved biostability. Abstract

[0008] In a first aspect, the present invention provides a compound of formula (I), or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and / or tautomer thereof: in R 1 is H, deuterium, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, -CH2OH, or -B(OH)2; R 1a is H, deuterium, or C1-C3 alkyl; R 2 yes (a) a phenyl group, wherein the phenyl group is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; (b) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a group substitution; (c) phenyl, optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 Substituted, wherein -phenyl-R3 The phenyl group in the 3a group substitution; (d) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; (e) a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a group substitution; (f) a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(heteroaryl consisting of 5 or 6 atoms)-R 3 substituted, wherein –(5 or 6 atoms composed of heteroaryl)-R 3 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a group substitution; (g) a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is replaced by R 3 and optionally substituted with 1 or 2 R 3a group substitution; (h) a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a group substitution; (i) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group is R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a group substitution; (j) a heterocycloalkyl group consisting of 3 to 8 atoms, wherein the heterocycloalkyl group consisting of 3 to 8 atoms is substituted by a phenyl group or a heteroaryl group consisting of 5 or 6 atoms, wherein the phenyl group and the heteroaryl group consisting of 5 to 6 atoms are each replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; (k)-CH=CH-R 5 , where R5 is phenyl, or a heteroaryl consisting of 5 or 6 atoms, wherein the phenyl and the heteroaryl consisting of 5 or 6 atoms are each replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; R 3 Independently selected from -B(OH)2, cyano, halogen, halo-C1-C6 alkyl, -(C0-C6 alkylene)-OR 4 , or a heterocyclic group consisting of 5 to 10 atoms, wherein the heterocyclic group consisting of 5 to 10 atoms is optionally substituted by cyano; or when R 2 If (a) is true, then R 3 and an R 3a , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form wherein the * represents the carbon atom shared with the phenyl ring, and wherein the remaining optional R on the phenyl moiety 3a are defined as follows, and each R 7a are independently H or C1-C6 alkyl; Each R 3a are independently selected from cyano, halogen, -OH, C1-C6 alkyl, halo-C1-C6 alkyl, and C1-C6 alkoxy; R 4 is hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, or C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl; and Provided that the compound is not: 2-(4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-(4-methoxyphenyl)piperazin-1-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-(2-methoxyphenyl)piperazin-1-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-chlorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(5-(trifluoromethyl)pyridin-2-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(3-(Trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(3-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; or 2-(5-chlorothien-3-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; In some embodiments, the present invention provides a compound represented by formula (I) (or any embodiment thereof) or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0009] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) (or any embodiment thereof), or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and / or tautomer thereof; and a pharmaceutically acceptable carrier. In one or more embodiments, the present invention provides a compound of formula (I) (or any embodiment thereof), or a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0010] In a third aspect, the present invention provides a method for inhibiting the activity of a Wnt transcript or Wnt signaling pathway in a subject, the method comprising contacting an effective amount of a compound shown in formula (I) (or any embodiment thereof), or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and / or tautomer thereof. In some embodiments, the compound shown in formula (I) (or any embodiment thereof) is provided in the form of a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof.

[0011] In a fourth aspect, the present invention provides a method for treating a disease, disorder, or condition associated with a Wnt transcript or Wnt signaling pathway activity in a mammal in need thereof, the method comprising administering a compound shown in formula (I) (or any embodiment thereof) or administering a pharmaceutical composition comprising a compound shown in formula (I) or any prodrug thereof, a pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and / or tautomer. In some embodiments, the compound shown in formula (I) (or any embodiment thereof) is provided in the form of a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof. In some embodiments, the method is used to stimulate tissue regeneration at a wound in a mammal in need thereof.

[0012] In a fifth aspect, the present invention provides a method for inducing antibacterial activity associated with Wnt transcripts or Wnt signaling pathway activity in a mammal in need thereof, comprising administering XAV939 or its tautomers and / or pharmaceutically acceptable salts thereof to a mammal in need thereof, optionally as a pharmaceutical composition thereof; administering a compound of formula (I) (or any embodiment thereof), or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; or administering the pharmaceutical composition described in the second aspect (or any embodiment thereof).

[0013] In a sixth aspect, the present invention provides a compound represented by any one of the following formulae or a salt thereof and / or a stereoisomer or a mixture of stereoisomers thereof: in LG 1 is a leaving group, such as fluorine, chlorine, bromine, iodine, triflate, mesylate, triazole, pyrazole, boronic acid, boronate ester, or aryl trifluoroborate; R 1 is H, deuterium, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, -CH2OH, or -B(OH)2; R 1a is H, deuterium, or C1-C3 alkyl; R 20 is an alkyl group, preferably a methyl group or an ethyl group; or CD3; R 2 'yes (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a group substitution; (c1) phenyl, optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a group substitution; (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a group substitution; (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, wherein -(5 or 6 atoms consisting of heteroaryl)-LG 1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a group substitution; (h1) C3-C6 cycloalkyl, which is substituted with NH2 or OH and further optionally substituted with 1 or 2 R 3a group substitution; or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group is substituted by a LG 1 and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a and provided that the compound is not: 4-Oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or a salt thereof and / or a stereoisomer or a mixture of stereoisomers thereof.

[0014] In a seventh aspect, the present invention provides a method for preparing a compound represented by formula (I), comprising: a) making a compound represented by formula (A): With R 2 -C(O)H contact; or b) making a compound represented by formula (B): With R 2 -C(NH)NH2 contact, where R 20 is Me or CD3; or c) making a compound represented by formula (C): With R 2 -H contact, where LG 1 is fluorine, chlorine, bromine, iodine, triflate, mesylate, triazole, pyrazole, boronic acid, boric acid ester, or trifluoroaryl borate; and optionally isolating the compound represented by formula (I). In one or more embodiments, the contacting is performed under basic conditions (in the presence of a base). BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The inhibition of the Wnt transcriptional signaling pathway activity by the compound represented by formula (I) (Compound 1) is shown compared with the compound represented by formula (I) and GO-HA (GO-HA+Compound 1) (Biological Example 3).

[0016] Figure 2 The inhibition of the Wnt transcriptional signaling pathway activity by the compound represented by formula (I) (Compound 7) is shown compared with the compound represented by formula (I) and GO-HA (GO-HA+Compound 7) (Biological Example 3).

[0017] Figure 3 The inhibition of the Wnt transcriptional signaling pathway activity by the compound represented by formula (I) (Compound 8) is shown compared with the compound represented by formula (I) and GO-HA (GO-HA+Compound 8) (Biological Example 3).

[0018] Figure 4 Results from a rabbit ear study (Biological Example 5) are shown, comparing three specimens at eight lesion sites (L1, L2, L3, L4, R5, R6, R7, and R8) at day 0 (top panel) and day 23 (bottom panel). The specimens were treated with saline (as a control) and a compound of formula (I) (Compound 8 or Compound 18). Saline was administered via a spray, Compound 8 (1 mg / mL) via a phospholipid spray, and Compound 18 (1 mg / mL) via a phospholipid spray (Biological Example 5).

[0019] Figure 5A Ear closure rates from day 1 to day 21 are shown (Test 1). A physiological saline control was compared with compounds of formula (I) (Compound 8 and Compound 18) (Biological Example 5).

[0020] Figure 5B Ear closure rates from day 14 to day 39 are shown (Test 1). A saline control was compared with compounds of formula (I) (Compound 8 and Compound 18) (Biological Example 5).

[0021] Figure 6 Shown are the ear closure rates from day 14 to day 39 (Test 2). A saline control was compared with compounds of formula (I) (Compound 8 and Compound 18).

[0022] Figure 7 (Top) Shows the location of the embedded incision in the center of the healing wound for tissue processing following a cartilage regeneration experiment (rabbit ear study, see Biological Example 5). Figure 7 (Bottom) shows a slide of a tissue cross section located at the center of the wound. Figure 9-11 as shown in the image.

[0023] Figure 8 Shown are the average distances (mm) between opposing cartilage endplates in a cartilage regeneration assay (rabbit ear study) after 45 days. Data were obtained from Safranin O-stained cross-sections of healed ear perforation wounds treated with saline (control) or a compound of Formula (I) (Compound 8 or Compound 18) for 45 days.

[0024] Figure 9 Shown are representative samples of cross sections after being processed with normal saline (control) in the cartilage regeneration test (biological embodiment 5) collected at the 45th day.Analysis result is illustrated at 9 to 10mm away from wound edge.Gray line represents wound edge, and the upper figure is 0.3 times of magnification, and the middle figure is 2.5 times of magnification, and the figure below is 10 times of magnification.The gray square in the middle figure represents the image shown in the figure below.Gray arrow represents cartilage regeneration zone in the figure below.

[0025] Figure 10Shown are representative samples of cross sections after treatment with a compound (compound 8) shown in formula (I) in a cartilage regeneration test (biological example 5) collected on the 45th day. Analytical results are shown at 9 to 10 mm from the wound edge. The gray line represents the wound edge, and the upper figure is a 0.3 times magnification, the middle figure is a 2.5 times magnification, and the lower figure is a 10 times magnification. The gray square in the middle figure represents the image shown in the figure below. In the figure below, the gray arrow represents the cartilage regeneration area.

[0026] Figure 11 Shown are representative samples of cross sections after treatment with a compound (compound 18) shown in formula (I) in a cartilage regeneration test (biological example 5) collected on the 45th day. Analytical results are shown at 9 to 10 mm from the wound edge. The gray line represents the wound edge, and the upper figure is a 0.3 times magnification, the middle figure is a 2.5 times magnification, and the lower figure is a 10 times magnification. The gray square in the middle figure represents the image shown in the figure below. In the figure below, gray arrows represent cartilage regeneration areas.

[0027] Figure 12 Schematic diagram showing the location of mammalian (pig) wound sites in a full-thickness excisional wound healing study.

[0028] Figure 13 (Top) Shown is the suture formation process of a simple interrupted closure used in full-thickness excisional wound healing studies (see Biological Example 6), showing the first suture 3401, the second suture 3403, and the portion of the wound closed by the interrupted suture 3405. Figure 13 (Bottom) shows a cross-sectional view of a portion of a wound closed by interrupted sutures 3405.

[0029] Figure 14A The results of full-thickness open excisional wound healing and epidermal ridge formation using the compound represented by formula (I) and GO-HA (Compound 8+GO-HA), a saline control, and unwounded skin are shown.

[0030] Figure 14B The results of epidermal ridge formation in full-thickness open excision wound healing using the compounds represented by formula (I) (Compound 7, Compound 8), the compounds represented by formula (I) and GO-HA (Compound 7+GO-HA, Compound 8+GO-HA), saline control, and GO-HA alone are shown (excluding the highest outlier) (p*>0.05; p**>0.01; and p***>0.001).

[0031] Figure 15Depicted are the results of a third degree burn wound healing study (Biological Example 6) comparing a compound of formula (I) (Compound 8) with a saline control. Wound area (cm2) was measured every 2-6 days. 2 ). It shows the results from day 16 to day 22.

[0032] Figure 16 Depicted are the results of a third degree burn wound healing study (Biological Example 6) comparing a compound of formula (I) (Compound 7) to a saline control. Wound area (cm2) was measured every 2-6 days. 2 ). It shows the results from day 16 to day 22.

[0033] Figure 17 Depicted are the results of a third-degree burn wound healing study (Biological Example 6) comparing the compound of formula (I) and GO-HA (Compound 8 + GO-HA) to a saline control. Wound area (cm2) was measured every 2-6 days. 2 ). It shows the results from day 16 to day 22.

[0034] Figure 18 Depicted are the results of a third-degree burn wound healing study (Biological Example 6) comparing the compound of formula (I) and GO-HA (Compound 7 + GO-HA) to a saline control. Wound area (cm2) was measured every 2-6 days. 2 ). It shows the results from day 16 to day 22.

[0035] Figure 19 Results from a closed excisional wound study (Biological Example 6) are shown: saline control, serum control (also known as serum preparation control), and GO-HA control were used from day 1 to day 21. Sutures were removed on day 13.

[0036] Figure 20 The results of a closed excisional wound study (Biological Example 6) are shown: Compounds of Formula (I) (Compound 1, Compound 8, and Compound 10) were used from day 1 to day 21. Sutures were removed on day 13.

[0037] Figure 21 The results of a closed excisional wound study (Biological Example 6) are shown: Compounds of Formula (I) and GO-HA (Compound 1 + GO-HA, Compound 8 + GO-HA, and Compound 10 + GO-HA) were used from day 1 to day 21. Sutures were removed on day 13.

[0038] Figure 22Results from a closed excisional wound study (Biological Example 6) are shown: cross-sectional tissue specimens stained with Trichrome Blue. This study compared wound sites treated with a saline control, a serum preparation control, a GO-HA control, compounds of Formula (I) (Compound 1, Compound 8, and Compound 10), and a compound of Formula (I) plus GO-HA (Compound 1 + GO-HA, Compound 8 + GO-HA, and Compound 10 + GO-HA).

[0039] Figure 23 Results from a closed excisional wound study (see Biological Example 6) are shown: cross-sectional tissue specimens under a polarizing microscope. This study compared wound sites treated with a saline control, a serum preparation control, a GO-HA control, compounds of Formula (I) (Compound 1, Compound 8, and Compound 10), and a compound of Formula (I) plus GO-HA (Compound 1 + GO-HA, Compound 8 + GO-HA, and Compound 10 + GO-HA).

[0040] Figure 24 Results of polarized images of collagen infiltration in closed excisional wounds are shown (see Biological Example 6). The figure shows the amount of collagen infiltrated wounds in the following groups of scars: A - saline (also known as saline control); B - serum (also known as serum preparation control); C - GO-HA (also known as GO-HA control); D - compound 1; E - compound 1 + GO-HA; F - compound 8; G - compound 8 + GO-HA; H - compound 10; and J - compound 10 + GO-HA.

[0041] Figure 25 Results from a third-degree burn wound healing study (Biological Example 6) are presented, comparing compounds of Formula (I) (Compound 7, Compound 7 + GO-HA, Compound 8, and Compound 8 + GO-HA) with saline and GO-HA controls. Histological analysis demonstrated that the compounds promoted tissue regeneration (improved reticular collagen organization and epidermal ridge formation) and reduced scar formation compared to saline and GO-HA controls. Detailed Description of the Invention

[0042] The present invention provides novel compounds, compositions and methods of administering the same for: inducing wound healing, burn healing (including first, second and third degree burns), or lesion healing (including lesions caused by HPV and / or viruses selected from the Poxviridae family); treating inflammatory dermatitis, cartilage diseases, bone diseases, organ fibrosis, or cancer; inducing tissue regeneration (including but not limited to regeneration of damaged elastic cartilage); inducing bacteriostasis; inducing bacterial growth inhibition; maintaining bacteriostasis; inducing antifungal activity; inducing neovascularization (in tissues in need); inducing reinnervation (in denervated body parts); inhibiting osteoclast differentiation; enhancing osteoblast differentiation; and / or inhibiting bone destruction associated with breast cancer.

[0043] The wound or wound may include, but is not limited to, one or more selected from the group consisting of: chronic wounds, acute wounds, and corneal alkali burn wounds. The inflammatory dermatitis disease may include, but is not limited to, one or more selected from the group consisting of: acne, psoriasis, rosacea, and scleroderma. The cartilage disease may include, but is not limited to, one or more selected from the group consisting of: osteoarthritis, rheumatoid arthritis, internal joint derangement, and degenerative cartilage disease. The bone disease may include, but is not limited to, bone diseases in which bone formation is impaired, such as osteoporosis.

[0044] The organ fibrosis may include, but is not limited to, one or more selected from the group consisting of: pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and kidney fibrosis.

[0045] The cancer may include, but is not limited to, melanoma, breast cancer, and / or prostate cancer.

[0046] The present invention further provides compounds, pharmaceutical compositions comprising the compounds, methods for preparing the compounds, and methods for treating wounds using the compounds and compositions, particularly methods for enhancing tissue regeneration after wound treatment. The present invention also provides methods for treating diseases associated with Wnt transcripts or Wnt signaling pathway activity in mammals, comprising administering to the mammal a therapeutically effective amount of the compound or composition. In one or more embodiments, the mammal is a human. definition

[0047] When referring to the compounds provided by the present invention, unless otherwise stated, the following terms have the following meanings. Unless otherwise defined, all technical terms and scientific terms used in the present invention all have the same meaning as those of ordinary skill in the art are generally understood. If the present invention term has multiple definitions, unless otherwise stated, the definitions in this section shall prevail. Unless otherwise specified, when a term is defined as being substituted, the groups in the substituent list themselves are all unsubstituted. For example, unless otherwise stated, the alkyl group substituted may be substituted by, for example, a cycloalkyl group, and the cycloalkyl group is not further substituted.

[0048] References herein to "about" values or parameters include (and describe) variations with respect to the values or parameters themselves. For example, a description of "about X" includes a description of "X." Unless otherwise indicated, the terms "about" and "approximately" as used herein, when used in conjunction with the temperature, dose, amount, or weight percentage of an ingredient of a composition or dosage form, refer to a dose, amount, or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. Specifically, when used herein, the terms "about" and "approximately" refer to a dose, amount, or weight percentage that is within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percentage.

[0049] Unless the context clearly indicates otherwise, the term "a / kind" used in the present invention means one / kind or more / kind. For example, a "pharmaceutically acceptable carrier" includes one or more components provided by the present invention.

[0050] As used herein with respect to the GO-HA linker, "alkyl" refers to a straight or branched hydrocarbon group. The alkyl group can be straight, branched, cyclic, or a combination thereof, and can contain, for example, 1 to 60 carbon atoms, and in some embodiments, 2-25 carbon atoms. Examples of alkyl groups include, but are not limited to, ethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl isomers (e.g., n-butyl, isobutyl, tert-butyl, etc.), cyclobutyl isomers (e.g., cyclobutyl, methylcyclopropyl, etc.), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, and the like.

[0051] For compounds of formula (I), the term "alkyl" as used herein, unless otherwise indicated, refers to a saturated straight or branched, monovalent hydrocarbon group. In one or more embodiments, the alkyl group is a primary, secondary or tertiary hydrocarbon. The alkyl group may be straight or branched and may contain, for example, 1 to 8 carbon atoms. In one or more embodiments, the alkyl group has 1 to 6 carbon atoms, i.e., a C1-C6 alkyl group. In one or more embodiments, the alkyl group is C 1-3 Alkyl. In one or more embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl isomers (e.g., n-butyl, isobutyl, tert-butyl, etc.), pentyl isomers, hexyl isomers, and the like.

[0052] As used herein with respect to the GO-HA linker, the term "linear alkyl" refers to a chain consisting of carbon and hydrogen atoms (eg, ethane, propane, butane, pentane, hexane, etc.).

[0053] As used herein with respect to the GO-HA linker, the term "branched alkyl" refers to a chain composed of carbon and hydrogen atoms, free of double or triple bonds, and characterized by forking, branching, and / or splitting. "Branching" refers to the divergence of the carbon chain, while "substituted" refers to the presence of non-carbon / non-hydrogen atoms in the moiety.

[0054] The term "alkylene" as used herein, unless otherwise indicated, refers to a divalent alkyl group, as defined herein for the GO-HA linker or as defined for the compound of formula (I), as applicable.

[0055] As used herein with respect to the GO-HA linker, the term "cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro manner. Cycloalkyl groups may be unsubstituted, substituted, branched, and / or unbranched. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent may be an alkyl group (but not a substituted alkyl group), or selected from those described above for substitution of alkyl groups, unless otherwise indicated. Unless otherwise indicated (e.g., substituted cycloalkyl groups, heterocyclic groups, cycloalkoxy groups, halocycloalkyl groups, cycloalkylamines, thiocycloalkyl groups, etc.), alkyl groups contain only carbon and hydrogen atoms. In some or any embodiments, the cycloalkyl group comprises 3 to 6 carbon atoms, i.e., a C3-C6 cycloalkyl group. In some or any embodiments, the cycloalkyl group has 3, 4, 5, or 6 (C3-6 ); 3, 4, or 5 (C 3-5 ); 3 or 4 (C 3-4 ); 3 (C3); 4 (C4); or 5 (C5) carbon atoms. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In one or more embodiments, the cycloalkyl group is cyclobutyl.

[0056] For the compound represented by formula (I), the term "C3-C 10 "-cycloalkyl" refers to a monovalent, saturated, monocyclic hydrocarbon group or a bicyclic (fused, bridged or spiro) ring. In some or any embodiments, the terms "fused cycloalkyl" and "spirocycloalkyl" are specific embodiments of cycloalkyl groups. In some or any embodiments, the cycloalkyl group includes 3 to 6 carbon atoms, i.e., C3-C6 cycloalkyl. In some or any embodiments, the cycloalkyl group has 3, 4, or 5 (C 3-5 ); 3 or 4 (C 3-4 ); 3 (C3); 4 (C4); or 5 (C5) carbon atoms. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In some or any embodiments, the cycloalkyl group is cyclopropyl. In some or any embodiments, the cycloalkyl group is cyclobutyl. In some or any embodiments, the cycloalkyl group is cyclopentyl. In some or any embodiments, the cycloalkyl group is bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, or adamantyl. In one or more embodiments, the cycloalkyl group is cyclobutyl.

[0057] As used herein, the terms "alkoxy" and "alkyloxy" refer to the group -OR', unless otherwise indicated, where R' is an alkyl group. In one or more embodiments, the alkoxy group is C 1-6 In one or more embodiments, the alkoxy group is C 1-3 Alkoxy. In one or more embodiments, alkoxy and alkyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0058] For compounds of formula (I), the term "alkoxyalkyl" as used herein, unless otherwise indicated, refers to an alkyl group as defined herein substituted with one or two -OR' groups, wherein each R' is an alkyl group as defined herein and is independently selected. In some or any embodiments, the alkoxyalkyl is a C1-C6 alkoxy-C1-C6 alkyl.

[0059] For compounds of formula (I), the term "alkoxycarbonyl-NH-alkyl" as used herein, unless otherwise indicated, refers to an alkyl group substituted with -NH-C(O)O(alkyl), wherein alkyl is as defined herein. In some or any embodiments, alkoxycarbonyl-NH-alkyl is C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl.

[0060] With respect to the GO-HA linker used in the present invention, the "alkenyl" used in the present invention refers to a straight-chain or branched hydrocarbon group having at least 2 carbon atoms, which contains at least one carbon-carbon double bond.

[0061] With respect to the GO-HA linker used in the present invention, the "alkynyl group" used in the present invention refers to a straight-chain or branched hydrocarbon group having at least 2 carbon atoms, which contains at least one carbon-carbon triple bond.

[0062] For the GO-HA linker used in the present invention, the "amine" or "amino group" used in the present invention is represented by the formula -NA1A2, wherein A1 and A2 are each independently H or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group, wherein each group is as defined for the GO-HA linker in the present invention. In one or more embodiments, the amine (or amino) group refers to any one of NH2, NH(alkyl), NH(aryl), N(alkyl)2, N(alkyl)(aryl), and N(aryl)2.

[0063] The term "aryl" as used herein, unless otherwise specified, refers to a monovalent C6-C 15 Carbocyclic ring systems, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic. The aryl group may be attached to the main structure through any of its rings, i.e., any aromatic or non-aromatic ring. In some or any embodiments, the aryl group may be a bridged (where chemically feasible) or non-bridged, spirocyclic (where chemically feasible) or non-spirocyclic, and / or fused or non-fused polycyclic group. In some or any embodiments, the aryl group is C6-C 10Aryl. In some or any embodiments, the aryl group is a C6 aryl group, i.e., phenyl. In some or any embodiments, the aryl group is phenyl, naphthyl, indanyl, fluorenyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulyl, or tetrahydronaphthyl. When the aryl group is substituted, it may be substituted on any ring, i.e., on any aromatic or non-aromatic ring comprised by the aryl group.

[0064] The term "haloalkyl", as used herein, unless otherwise indicated, refers to an alkyl group substituted with 1, 2, 3, 4, or 5 halogen groups. In some or any embodiments, the haloalkyl group is a haloC 1-6 In some or any embodiments, the haloalkyl group is -CF3, -CH2F, -CHF2, or -CH2CF3.

[0065] As used herein, the terms "halogen" and "halo / halo", unless otherwise indicated, are synonymous and refer to chlorine, bromine, fluorine, or iodine.

[0066] The term "heteroaryl", as used herein, unless otherwise indicated, refers to a monocyclic aromatic ring system or a polycyclic aromatic ring system, wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms are independently selected from O, S(O), 0-2 , NH and N heteroatoms, the remaining ring atoms are carbon atoms, and wherein the ring can be optionally substituted as described herein. The heteroaryl group is connected to the rest of the molecule through any atom in the ring system, where its valence rules permit. In some or any embodiments, each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less and each ring contains at least 1 carbon atom. In some or any embodiments, the heteroaryl group has 5-20, 5-15, 5-6 ring atoms, or 5-10 ring atoms. When a heteroaryl group is substituted, it may be substituted on any ring. In one or more embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 10 atoms. In one or more embodiments, the heteroaryl group is a heteroaryl group consisting of 5 or 6 atoms. In one or more embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms. In one or more embodiments, the heteroaryl group is in represents the point of attachment of the heteroaryl group to the rest of the molecule.

[0067] In some or any embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In some or any embodiments, bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzotriazolyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, or quinazolinyl. In some or any embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, furidinyl, phenanthrolinyl, phenanthridinyl and phenazinyl. In some or any embodiments, heteroaryl is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl or pyrazolyl; each of which is optionally substituted with 1, 2, 3 or 4 groups as defined throughout this specification, including, in some embodiments, independently selected from C 1-6 Alkyl, hydroxy, halogen, halogenated C 1-6 Alkyl, C 1-6 It is substituted with an alkoxy, cyano, or phenyl group.

[0068] The term "heterocyclyl" or "heterocycle", as used herein, unless otherwise indicated, refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system comprising at least one non-aromatic ring; wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the monocyclic non-aromatic ring atoms are independently selected from O, S(O), 0-2 and N heteroatoms, and the remaining ring atoms are carbon atoms; and wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the atoms in any ring of the polycyclic ring system are independently selected from O, S(O), 0-2In some or any embodiment, the heterocycle comprises 1 or 2 heteroatoms, each of which is independently selected from nitrogen-atoms and oxygen-atoms. In some or any embodiment, the heterocycle comprises 1 or 2 heteroatoms, each of which is an oxygen-atoms. In some or any embodiment, the heterocycle comprises 1 or 2 heteroatoms, each of which is a nitrogen-atoms (wherein the nitrogen-atoms are substituted as described in any aspect or embodiment of the present invention). In some or any embodiment, the heterocycle comprises one heteroatom, each of which is a nitrogen-atoms (wherein the nitrogen-atoms are substituted as described in any aspect or embodiment of the present invention). In some or any embodiment, the heterocycle comprises one heteroatom, each of which is a non-aromatic ring, or one heteroatom, each of which is an aromatic ring, or two heteroatoms, each of which is an aromatic ring and another of which is a non-aromatic ring. In some or any embodiments, the heterocyclyl or heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In one or more embodiments, the heterocyclyl or heterocycle is a heterocyclyl or heterocycle consisting of 4-10 atoms. In one or more embodiments, the heterocyclyl or heterocycle is a heterocyclyl or heterocycle consisting of 5-10 atoms. In some or any embodiments, the heterocyclyl or heterocycle is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some or any embodiments, the heterocyclyl or heterocyclic group can be a bridged or non-bridged, spirocyclic or non-spirocyclic, and / or fused or non-fused polycyclic group. One or more of the nitrogen atoms and sulfur atoms can be optionally oxidized, one or more of the nitrogen atoms can be optionally quaternized, and one or more of the carbon atoms can be optionally quaternized. Replacement. Some rings can be partially or fully saturated, or aromatic, provided that the heterocyclic group or heterocycle is not fully aromatic. The monocyclic heterocycle and polycyclic heterocycle can be connected to the main structure at any heteroatom or carbon atom that produces a stable compound. The polycyclic heterocyclic group or heterocycle can be connected to the main structure through any of its rings, including any aromatic or non-aromatic rings, regardless of whether the ring contains heteroatoms. In some or any embodiments, the heterocyclic group or heterocycle is a "heterocycloalkyl", which is 1) a saturated monovalent monocyclic group containing at least one ring heteroatom as described in the present invention, or 2) a saturated monovalent bicyclic group or tricyclic group, wherein at least one ring contains at least one heteroatom as described in the present invention. In some or any embodiments, the heterocyclic group or heterocycle is a heterocycloalkyl consisting of 3-6 atoms. In some or any embodiments, the heterocyclic group or heterocycle is a heterocycloalkyl consisting of 3-8 atoms. In some or any embodiments, the heterocyclic group or heterocycle is a heterocycloalkyl consisting of 3-9 atoms. When the heterocyclyl or heterocycle and heterocycloalkyl groups are substituted, they may be substituted on any ring, ie, on any aromatic or non-aromatic ring encompassed by the heterocyclyl or heterocycle and heterocycloalkyl groups.In some or any embodiments, such heterocyclyls or heterocycles include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepenyl, 1,3-dihydroisobenzofuranyl, benzofuranonyl, chromenonyl, chromenyl, dihydrobenzofuranyl, chromanyl, tetrahydrothiophene, 2,2-dioxo-1,3-dihydrobenzo[c]thiophene, chromenyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzimidazolinyl (including but not limited to 2-oxo-1,3-dihydro-2H-benzo[d]imidazol-1-yl), dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolane, 1,4-dithianyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuranyl thiophene, isochromanyl, isochromanyl, isocoumarinyl, isoindolinyl (isoindolinyl), 1-oxo-isoindolinyl, 1,3-dioxo-isoindolinyl, isothiazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxoxadiazolyl (including but not limited to 5-oxo-1,2,4-oxadiazol-3-yl), oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiomorpholinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthenyl, 1,3,5-trithianyl, or 1,3-dihydroimidazopyridin-2-onyl.In some or any embodiments, the heterocyclyl or heterocycle is benzo-1,4-dioxanyl, benzodioxolyl, indolinyl, 2-oxo-indolinyl, pyrrolidinyl, piperidinyl, 2,3-dihydrobenzofuranyl, decahydroquinolinyl, dihydrocyclopentapyridinyl, dihydropyranopyridinyl, tetrahydronaphthyridinyl, 2,2-dioxo-3,4-dihydrothiopyranopyridinyl, dihydrofuropyridinyl, dihydropyrrolopyridinyl, 2,2-dioxo-1,3-dihydrothienopyridinyl, or tetrahydrocyclopropanecyclopentapyridinyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout this specification, including, in some or any embodiments, substitution with groups independently selected from halogen, alkyl, and phenyl. In some embodiments, heterocycloalkyl is pyrrolidinyl. In some embodiments, the heterocycloalkyl group is an N-linked heterocycloalkyl group.

[0069] The term "hydroxyalkyl" or "hydroxyalkyl" as used herein, unless otherwise indicated, refers to an alkyl group as defined herein that is substituted with 1, 2, or 3 hydroxy groups. In one or more embodiments, the hydroxy group is a primary, secondary, or tertiary alcohol. In one or more embodiments, the hydroxyalkyl group comprises 1 to 10 carbon atoms, i.e., C1-C 10 In one or more embodiments, the hydroxyalkyl group includes 1 or 2 alcohol (hydroxy) groups, provided that they are not located on the same carbon atom. In one or more embodiments, the hydroxyalkyl group is a hydroxy C 1-6 In one or more embodiments, the hydroxyalkyl group is a hydroxy C 1-3 In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl. In one or more embodiments, the hydroxyalkyl group is C 1-6 Hydroxyalkyl. In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropan-2-yl, and 2-hydroxypropan-2-yl.

[0070] The term "oxo" as used herein, unless otherwise indicated, refers to a keto group (C=O). An oxo group as a substituent of a non-aromatic carbon converts -CH2- to -C=O. An oxo group as a substituent of an aromatic carbon converts -CH- to -C=O. When the substituent is oxo, two hydrogen atoms on the atom are replaced. When an oxo group replaces an aromatic molecular moiety, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted by an oxo group is pyridone. One of ordinary skill in the art will understand that in some embodiments, such groups, for example, pyridone and 2,4(1H,3H)-dioxo-pyrimidinyl, may exist in their tautomeric forms, for example, hydroxypyridine and 2,4-dihydroxypyrimidinyl, respectively.

[0071] As used herein, "regeneration" refers to the regeneration or growth of damaged or inactivated tissue from the remaining tissue. This is the body's attempt to repair itself and, in the context of wounds, refers to the migration, differentiation, or replication of cells, or the conversion of progenitor cells into the desired cell types for the corresponding tissue. These cell types may include sebocytes, hair follicles, nerve cells, and chondrocytes.

[0072] As used herein, "wound" or "wound" refers to tissue or skin damage caused by scrapes, cuts, abrasions, surgery (e.g., minimally invasive surgery, laparoscopic surgery, robotic surgery, incisional biopsy, general surgery, and cosmetic surgery), peeling skin, burns, ulcers (e.g., diabetic ulcers, ulcers caused by vascular insufficiency, pressure sores, and burns), or other skin problems (e.g., allergies). The extent of the wound or wound can range from superficial (e.g., affecting only the epidermis) to more traumatic (e.g., affecting lesions of the skin layer or tissue deep below the epidermis). The wound or wound can be of any length or shape, for example, in some embodiments, the wound or wound is straight, jagged, or curved.

[0073] In some embodiments, the term "pharmaceutically acceptable carrier" includes any and all and / or one or more solvents, cosolvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, excipients, diluents, disintegrants, lubricants, adjuvants, and the like that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, their use in therapeutic compositions is also encompassed. Supplementary active ingredients may also be incorporated into the composition. In addition, various adjuvants, such as those commonly used in the art, may also be included. These and other such compounds are described in the literature, for example, in the Merck Index (Merck & Company, Rahway, NJ), which describes considerations for including various components in pharmaceutical compositions (e.g., Gilman et al. (Eds.), 2010, Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies).

[0074] In some embodiments, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds provided by the present invention and is not biologically or otherwise undesirable. In many cases, the compounds provided by the present invention are capable of forming acid and / or base salts by virtue of the presence of an amino and / or carboxyl group or a group similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297.

[0075] In some embodiments, the term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, refers to any salt of the compounds provided herein that retains its biological properties and is non-toxic or otherwise desirable for pharmaceutical use. Such salts can be derived from various organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid , cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid and (2) when an acidic proton is present in the parent compound, (a) it is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxide, or ammonia, or (b) it is coordinated with an organic base, such as an aliphatic, alicyclic or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, tris(hydroxymethyl)-aminomethane, piperazine, tetramethylammonium hydroxide and the like to form a base addition salt.

[0076] In some embodiments, pharmaceutically acceptable salts further include, in some or any embodiments, but not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, and the like. When the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides such as hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandelates, phthalates , laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, pivalate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminosulfonate, quinate, muconate, etc.

[0077] In some embodiments, a "therapeutically effective amount" or "pharmaceutically effective amount" of a compound provided herein refers to an amount sufficient to achieve the desired effect and may vary depending on the nature and severity of the disease condition and the efficacy of the compound. A "therapeutically effective amount" is also intended to include one or more compositions of the present invention so as to increase cartilage regeneration after acute injury. The combination of compounds is preferably a synergistic combination. As described in the prior art (e.g., Chou, 2010, Canc. Res. 70(2): 440-446), a synergistic effect occurs when the effect of the compound when administered in combination is greater than the additive effect of the compound when administered alone as a monotherapy. In general, synergistic effects are most pronounced at suboptimal concentrations of the compounds. The amount may also depend on the patient's height, weight, sex, age, and medical history.

[0078] The term "mammal" specifically includes humans, cows, horses, dogs, and cats, but also includes many other mammalian species, such as pigs, rats, mice, primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees, and humans). In some embodiments, the mammal is a human.

[0079] The term "subject" refers to a mammal, as well as a cell or biological sample provided herein.

[0080] With respect to a composition, the term "substantially free" or "substantially absent" of a stereoisomer means that the composition comprises at least 85% or 90% by weight, and in some or any embodiments, 95%, 98%, 99%, or 100% by weight of a given stereoisomer of the compound in the composition. In some or any embodiments, the methods and compounds provided herein are substantially free of stereoisomers.

[0081] Likewise, with respect to a composition, the term "isolated" means that the composition comprises at least 85%, 90%, 95%, 98%, 99% to 100% by weight of a particular compound, with the remainder comprising other chemical species or stereoisomers.

[0082] As used herein, the term "isotopic composition," unless otherwise indicated, refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. Atoms having their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise indicated, references to atoms in the compounds of the present invention are intended to represent any stable isotope of that atom. For example, when a position is specifically designated as "H" or "hydrogen," that position is understood to be a hydrogen having its natural isotopic composition, unless otherwise indicated.

[0083] The term "isotopic enrichment" as used herein, unless otherwise indicated, refers to the percentage of incorporation of a specific isotope at a given atom in a molecule in place of the natural isotopic abundance of the atom. In some or any embodiments, a deuterium enrichment of 1% at a given position refers to 1% of the molecules in a given sample containing deuterium at the specified position. Since the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be measured using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0084] As used herein, the term "isotopically enriched," unless otherwise indicated, refers to atoms having an isotopic composition other than the natural isotopic composition of the atoms. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of the atoms.

[0085] Unless otherwise specified, the term "IC 50 "" refers to the amount, concentration, or dose of a particular test compound that achieves a 50% inhibition of the maximal response in an assay measuring such response.

[0086] In some embodiments, the terms "therapeutic agent" and "therapeutic drug / agent" refer to any drug / agent that can be used to treat or prevent a disease / condition or one or more symptoms thereof. In some or any embodiments, the term "therapeutic agent" includes compounds provided herein. In some or any embodiments, a therapeutic agent is a drug / agent that is known to be useful, has been used, or is currently being used to treat or prevent a disease / condition or one or more symptoms thereof.

[0087] In some embodiments, "treatment" or "treating" of any condition or disease refers to, in some or any embodiments, improving the condition or disease present in a subject. In another embodiment, "treatment" or "treating" includes improving at least one physical parameter, which may be imperceptible to the subject. In yet another embodiment, "treatment" or "treating" includes regulating the condition or disease physically (e.g., stabilizing discernible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In yet another embodiment, "treatment" or "treating" includes delaying the onset of the condition or disease. In yet another embodiment, "treatment" or "treating" includes reducing or eliminating the condition or one or more symptoms of the condition, or slowing the progression of the condition or one or more symptoms of the condition, or alleviating the severity of the condition or one or more symptoms of the condition. Compound

[0088] The present invention provides compounds that can induce improved wound healing and tissue regeneration. The present invention provides compounds that can treat wounds and / or conditions associated with Wnt transcripts or Wnt signaling pathway activity, and in particular can enhance tissue regeneration after wound treatment.

[0089] The present invention further provides compounds capable of regulating the Wnt signaling pathway or Wnt transcription (product) activity. The compounds can be prepared as described in the present invention and used to treat diseases related to Wnt transcription products or Wnt signaling pathway activity. In one or more embodiments, the condition associated with Wnt transcripts or Wnt signaling pathway activity is a chronic wound, an acute wound, an alkali burn corneal wound, a burn, a lesion (including a lesion caused by HPV and / or a virus selected from the Poxviridae family), an inflammatory dermatitis disease (including acne, psoriasis, rosacea, and scleroderma), a cartilage disease (including osteoarthritis, rheumatoid arthritis, internal joint disorders, and degenerative cartilage diseases), a bone disease (including osteoporosis), an organ fibrosis (including pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis), a cancer (including melanoma, breast cancer, and prostate cancer), a denervated body part requiring reinnervation, a tissue requiring regeneration (including damaged elastic cartilage), a bacterial growth requiring inhibition, a fungal growth requiring inhibition, a tissue requiring neovascularization, an osteoclast differentiation requiring inhibition, an osteoblast differentiation disorder (wherein osteoblast differentiation is required to be inhibited), and / or bone destruction associated with breast cancer.

[0090] The present invention arises from a novel and unexpected discovery: the compound represented by formula (I) (or any embodiment thereof, including compound 1, compound 7, or compound 8 in some embodiments) has significant Wnt inhibitory effects and has improved properties compared to prior art Wnt inhibitors (e.g., XAV939). These improved properties may include improved wound healing and tissue regeneration after trauma in mammals, including the quantity of regeneration and the quality of tissue regeneration and regrowth.

[0091] Aspects and embodiments of the present invention include the compounds and pharmaceutically acceptable salts and / or isomers thereof. For example, aspects and embodiments of the present invention include single stereoisomers or mixtures of stereoisomers thereof, and / or pharmaceutically acceptable salts thereof.

[0092] The present invention encompasses all stereoisomers of the compounds, including diastereomers and enantiomers, if chemically possible. The present invention also encompasses mixtures of possible stereoisomers in any proportion, including but not limited to racemic mixtures. Unless the stereochemistry at a particular atom is explicitly indicated in a structure, the structure is intended to encompass all possible stereoisomers of the compound. If the stereochemistry of one or more parts of a molecule is explicitly indicated, but the stereochemistry of other parts or parts of the molecule is not, the structure is intended to encompass all possible stereoisomers of the part or parts for which the stereochemistry is not explicitly indicated. Obviously, some structures will list specific stereochemistry at specific atoms.

[0093] A composition for inhibiting Wnt transcription products or Wnt signaling pathway activity, comprising: a matrix component comprising a graphene oxide (GO) and hyaluronic acid (HA) conjugate (GO-HA), wherein GO and HA are covalently linked via a linker; polyethylene glycol (PEG), wherein the PEG is optional; a thickener, wherein the thickener is optional; a compound according to any one of claims 1 to 39; and water, wherein the compound optionally accounts for about 0.001 wt% to about 5 wt% of the total weight of the composition.

[0094] In one or more embodiments, the compound of formula (I) is a potent inhibitor of the Wnt pathway.

[0095] Embodiment 1: In one or more embodiments of formula (I), the compound is a potent inhibitor of the Wnt pathway, and its chemical name is (4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl]boronic acid (Compound 1). The structure of Compound 1 is: In one or more embodiments, the compound represented by formula (I) is Compound 1 or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, or tautomer thereof.

[0096] Embodiment 2: In one or more embodiments of formula (I), the compound is a potent inhibitor of the Wnt pathway, and its chemical name is 2-(4-(6-bromopyridin-3-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 7). The structure of Compound 7 is: In one or more embodiments, the compound represented by formula (I) is Compound 7 or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, or tautomer thereof.

[0097] Embodiment 3: In one or more embodiments of formula (I), the compound is a potent inhibitor of the Wnt pathway, and its chemical name is 2-(4-(2-(2-hydroxyethoxy)prop-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 8). The structure of Compound 8 is: In one or more embodiments, the compound represented by formula (I) is Compound 8 or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, or tautomer thereof. Implementation Plan A

[0098] In one or more embodiments, the present invention provides a compound represented by formula (I), wherein R1 and R 1a are independently selected from H and deuterium. Implementation Plan B

[0099] In one or more embodiments, including any of the above embodiments, the present invention provides a compound of formula (I), wherein ring A is and among them represents the point of attachment to the rest of the compound represented by formula (I). R 2 This is an implementation of (a)

[0100] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a phenyl group, wherein the phenyl group is R 3 and optionally substituted by 1, 2 or 3 R 3a Group substitution.

[0101] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 3 attached to the para position of the phenyl ring; or R 3 and an R 3a , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form ring (a-1), and wherein the phenyl moiety is optionally replaced by the remaining R 3a Group substitution.

[0102] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein when R 2 If (a) is true, then R 3 Not halogen or halogenated alkyl.

[0103] In one or more embodiments, including embodiments A and B, the present invention provides compounds of formula (I), wherein when R 2 If (a) is true, then R 3 is B(O)2 or –(C0-C6 alkylene)-OR 4 .

[0104] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: In one or more embodiments, R 3 is not halogen or haloalkyl. In one or more embodiments, R 3is B(O)2 or –(C0-C6 alkylene)-OR 4 .

[0105] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: In one or more embodiments, R 2 Not for

[0106] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: In one or more embodiments, R 2 Not for R 2 This is an implementation of (b)

[0107] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a Group substitution.

[0108] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is phenyl, said phenyl being substituted at its para position by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a When the heteroaryl group of 5 or 6 atoms is a heteroaryl group of 6 atoms, then R 3 Substitution is carried out at the para position of the 6-atom heteroaryl group.

[0109] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of:

[0110] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: R 2 is an implementation plan of (c)

[0111] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is phenyl, said phenyl being optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 Substituted, wherein -phenyl-R 3 The phenyl group in the 3a Group substitution.

[0112] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is phenyl, said phenyl being optionally substituted by 1, 2 or 3 R 3a The group is substituted and the para position is also substituted by -phenyl-R 3 Substituted, wherein -phenyl-R 3 The phenyl group in the 3a Group substituted, and wherein said R 3 Located in -phenyl-R 3 The para position of the phenyl group.

[0113] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of:

[0114] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: R 2 is an implementation plan of (d)

[0115] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is R3 and optionally substituted by 1, 2 or 3 R 3a Group substituted; optionally, wherein the R 3 Located in the para position of the heteroaryl group composed of 6 atoms.

[0116] In one or more embodiments, including embodiments A and B, the present invention provides compounds of formula (I), wherein when R 2 If it is (d), then R 3 Not halogen or halogenated alkyl.

[0117] In one or more embodiments, including embodiments A and B, the present invention provides compounds of formula (I), wherein when R 2 If it is (d), then R 3 is B(O)2 or –(C0-C6 alkylene)-OR 4 .

[0118] In one or more embodiments, including embodiments A and B, the present invention provides compounds of formula (I), wherein when R 2 If it is (d), then R 3 is B(O)2 or –(C1-C6 alkylene)-OR 4 . R 2 is an implementation plan of (e)

[0119] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a Group substituted; optionally, wherein the -phenyl-R 3 Located in the para position of the 6-atom heteroaryl; and optionally, wherein the R 3 Located in the para position of the phenyl group. R 2 is an implementation of (f)

[0120] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(heteroaryl consisting of 5 or 6 atoms)-R 3substituted, wherein –(5 or 6 atoms composed of heteroaryl)-R 3 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a Group substitution; optionally, wherein the -(heteroaryl consisting of 6 atoms)-R 3 Located in the para position of the first 6-atom heteroaryl group; and optionally, wherein said R 3 Located in the para position with respect to the 6-atom heteroaryl group to which it is attached.

[0121] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 yes R 2 is an implementation plan of (g)

[0122] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is R 3 and optionally substituted with 1 or 2 R 3a Group substitution.

[0123] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 yes Optionally, wherein R 3 is a heterocyclic group consisting of 5 to 10 atoms, wherein the heterocyclic group consisting of 5 to 10 atoms is optionally substituted by cyano. R 2 is an implementation of (h)

[0124] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a Group substitution. R 2 is an implementation plan of (i)

[0125] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2is a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is substituted by a phenyl group, wherein the phenyl group is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a Group substitution. R 2 is an implementation plan of (j)

[0126] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 is a heterocycloalkyl group consisting of 3 to 8 atoms, wherein the heterocycloalkyl group consisting of 3 to 8 atoms is substituted by a phenyl group or a heteroaryl group consisting of 5 or 6 atoms, wherein the phenyl group and the heteroaryl group consisting of 5 to 6 atoms are respectively replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a Group substitution.

[0127] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: R 2 is an implementation plan of (k)

[0128] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 It is -CH=CH-R 5 , where R 5 is phenyl, or a heteroaryl consisting of 5 or 6 atoms, wherein the phenyl and the heteroaryl consisting of 5 or 6 atoms are each replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a Group substitution.

[0129] In one or more embodiments, including embodiments A and B, the present invention provides a compound of formula (I), wherein R 2 Selected from the group consisting of: Additional Implementation Plans

[0130] In one or more embodiments, including embodiments A and B and when R 2 When it is any of the embodiments provided above (a)-(k), the present invention provides a compound represented by formula (I), wherein R 3 is cyano, -B(OH)2, or -(C0-C6 alkylene)-OR 4 In one or more embodiments, the present invention provides a compound represented by formula (I), wherein R 4is a hydroxy-C1-C6 alkyl group (in some embodiments, a hydroxyethyl group). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 is C1-C6 alkoxy-C1-C6 alkyl (in some embodiments, C1-C6 alkoxy-C2 alkyl). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 It is C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl (in some embodiments, C1-C6 alkoxycarbonyl-NH-C2 alkyl).

[0131] In one or more embodiments, including embodiments A and B and when R 2 When it is any of the embodiments provided above (a)-(k), the present invention provides a compound represented by formula (I), wherein R 3 It's cyano.

[0132] In one or more embodiments, including embodiments A and B and when R 2 When it is any of the embodiments provided above (a)-(k), the present invention provides a compound represented by formula (I), wherein R 3 It is -B(OH)2.

[0133] In one or more embodiments, including embodiments A and B and when R 2 When it is any of the embodiments provided above (a)-(k), the present invention provides a compound represented by formula (I), wherein R 3 is -(C0-C6 alkylene)-OR 4 In one or more embodiments, the present invention provides a compound represented by formula (I), wherein R 4 is a hydroxy-C1-C6 alkyl group (in some embodiments, a hydroxyethyl group). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 is C1-C6 alkoxy-C1-C6 alkyl (in some embodiments, C1-C6 alkoxy-C2 alkyl). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 It is C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl (in some embodiments, C1-C6 alkoxycarbonyl-NH-C2 alkyl).

[0134] In one or more embodiments, including embodiments A and B and when R 2 When it is any of the embodiments provided above (a)-(k), the present invention provides a compound represented by formula (I), wherein R 3 Yes-(C 1-6 Alkylene)-OR 4In one or more embodiments, the present invention provides a compound represented by formula (I), wherein R 4 is a hydroxy-C1-C6 alkyl group (in some embodiments, a hydroxyethyl group). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 is C1-C6 alkoxy-C1-C6 alkyl (in some embodiments, C1-C6 alkoxy-C2 alkyl). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 It is C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl (in some embodiments, C1-C6 alkoxycarbonyl-NH-C2 alkyl).

[0135] In one or more embodiments, including embodiments A and B and when R 2 When (b), (c), (e), or (f) is any of the embodiments provided above, the present invention provides a compound of formula (I), wherein R 3 is halogen, cyano, -B(OH)2, or -(C0-C6 alkylene)-OR 4 In one or more embodiments, the present invention provides a compound represented by formula (I), wherein R 4 is a hydroxy-C1-C6 alkyl group (in some embodiments, a hydroxyethyl group). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 is C1-C6 alkoxy-C1-C6 alkyl (in some embodiments, C1-C6 alkoxy-C2 alkyl). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 It is C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl (in some embodiments, C1-C6 alkoxycarbonyl-NH-C2 alkyl).

[0136] In one or more embodiments, including embodiments A and B and any of the embodiments provided above, When R 2 (b), (c), (e), or (f), the present invention provides a compound represented by formula (I), wherein R 3 is halogen, cyano, -B(OH)2, or -(C0-C6 alkylene)-OR 4 ;or When R 2 (b), (c), (e), or (f), the present invention provides a compound represented by formula (I), wherein R 3 is cyano, -B(OH)2, or -(C0-C6 alkylene)-OR 4 . In one or more embodiments, the present invention provides a compound represented by formula (I), wherein R 4 is a hydroxy-C1-C6 alkyl group (in some embodiments, a hydroxyethyl group). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 is C1-C6 alkoxy-C1-C6 alkyl (in some embodiments, C1-C6 alkoxy-C2 alkyl). In one or more embodiments, the present invention provides a compound of formula (I), wherein R 4 It is C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl (in some embodiments, C1-C6 alkoxycarbonyl-NH-C2 alkyl).

[0137] In one or more embodiments, the present invention provides a compound of formula (I) selected from the group consisting of compounds 1-44 provided in Table 1.

[0138] In one or more embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I); and a pharmaceutically acceptable carrier. In one or more embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0139] In one or more embodiments, the pharmaceutical composition of the present invention further comprises: a matrix component comprising a conjugate of graphene oxide (GO) and hyaluronic acid (HA) (GO-HA), wherein GO and HA are covalently linked via a linker; polyethylene glycol (PEG), wherein the PEG is optional; a thickener, wherein the thickener is optional; and water, optionally, wherein the compound optionally comprises from about 0.001 wt % to about 5 wt % of the total weight of the composition.

[0140] In one or more embodiments, the present invention provides a method for inhibiting Wnt transcription products or Wnt signaling pathway activity in a subject, comprising contacting the subject with an effective amount of a compound represented by formula (I) or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0141] In one or more embodiments, the present invention provides a method for treating a disease, disorder or condition associated with Wnt transcript or Wnt signaling pathway activity in a mammal, comprising administering to a subject in need thereof a compound of formula (I) or a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof; or administering to a subject in need thereof a pharmaceutical composition according to one or more embodiments of the present invention.

[0142] In one or more embodiments, the present invention provides a method for stimulating tissue regeneration at a wound in a subject in need thereof, wherein the wound is contacted with an effective amount of a compound of formula (I) (or a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition according to one or more embodiments of the present invention.

[0143] In one or more embodiments, the disease, disorder or condition (the disease, disorder or condition to be treated in one or more embodiments of the methods of the invention) is selected from chronic wounds, acute wounds, alkali burns, corneal wounds, burns, lesions (including lesions caused by HPV and / or viruses selected from the Poxviridae family), inflammatory dermatitis diseases (including acne, psoriasis, rosacea and scleroderma), cartilage diseases (including osteoarthritis, rheumatoid arthritis, internal joint disorders and degenerative cartilage diseases), bone diseases (including osteoporosis), organ fibrosis (including pulmonary fibrosis, cardiac fibrosis, liver fibrosis and renal fibrosis), cancer (including melanoma, breast cancer and prostate cancer), denervated body parts in need of reinnervation, tissue in need of regeneration (including damaged elastic cartilage), bacterial growth in need of inhibition, fungal growth in need of inhibition, tissue in need of neovascularization, osteoclast differentiation in need of inhibition, osteoblast differentiation disorders (wherein osteoblast differentiation is required to be inhibited), and / or bone destruction associated with breast cancer.

[0144] In one or more embodiments, the present invention provides a method for inducing antibacterial activity associated with Wnt transcripts or Wnt signaling pathway activity, comprising administering XAV939 or a tautomer thereof and / or a pharmaceutically acceptable salt thereof, optionally as a pharmaceutical composition thereof, to a mammal in need thereof; administering a compound of formula (I), or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; or administering a pharmaceutical composition according to one or more embodiments of the present invention.

[0145] In one or more embodiments, the present invention provides a compound represented by any one of the following formulae or a salt thereof and / or a stereoisomer or a mixture of stereoisomers thereof: And LG 1 is a leaving group, such as fluorine, chlorine, bromine, iodine, triflate, mesylate, triazole, pyrazole, boronic acid, boronate, or aryl trifluoroborate; R 1 is H, deuterium, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, -CH2OH, or -B(OH)2; R 1a is H, deuterium, or C1-C3 alkyl; R 20 is an alkyl group, preferably a methyl group or an ethyl group, or CD3; R 2 ' is: (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a (c1) phenyl, which is optionally substituted with 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is also substituted by –(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, where –(5 or 6 atoms of heteroaryl)-LG 1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a (h1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by NH2 or OH and optionally substituted by 1 or 2 R 3a or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group being LG 1 and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R3a Group substitution; and proviso that the compound is not: 4-oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or a salt thereof and / or a stereoisomer or a mixture of stereoisomers thereof.

[0146] LG 1 This may be a suitable leaving group, for example, in a suitable nucleophilic aromatic substitution or a suitable cross coupling, not limited to a Suzuki-Miyaura coupling.

[0147] In one or more embodiments, the present invention provides a method for preparing a compound represented by formula (I), comprising: a) making a compound represented by formula (A): With R 2’ -C(O)H; or b) contacting a compound represented by formula (B): With R 2’ -C(NH)NH2 contact, where R 20 is Me or CD3; or c) a compound represented by formula (C): With R 2’ -H contact, where LG 1 is fluorine, chlorine, bromine, iodine, trifluoromethanesulfonate, mesylate, triazole, pyrazole, boronic acid, boric acid ester, or trifluoroborate aryl ester; and optionally separating the compound of formula (I); wherein R 2 ' is: (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a (c1) phenyl, which is optionally substituted with 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is also substituted by –(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, where –(5 or 6 atoms of heteroaryl)-LG1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a (h1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by NH2 or OH and optionally substituted by 1 or 2 R 3a or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group being LG 1 and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a Group substitution; and proviso that the compound is not: 4-oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or a salt thereof and / or a stereoisomer or a mixture of stereoisomers thereof. In one or more embodiments, the method for preparing the compound of formula (I) comprises contacting under alkaline conditions.

[0148] In one or more embodiments of formula (I), the compound is selected from any one of compounds 1-44 shown in Table 1 or a pharmaceutically acceptable salt thereof. In one or more embodiments of formula (I), the compound is selected from any one of compounds 1-44 shown in Table 1 or an isomer thereof. In one or more embodiments of formula (I), the compound is selected from any one of compounds 1-44 shown in Table 1 or a single stereoisomer or a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof. In one or more embodiments of formula (I), the compound is selected from any one of compounds 1-44 shown in Table 1 or a prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, or tautomer thereof.

[0149] Table 1. Compounds

[0150] In one or more embodiments, the present invention provides a compound represented by any one of the following formulae: or a salt thereof, in LG 1is a leaving group, such as fluorine, chlorine, bromine, iodine, triflate, mesylate, triazole, pyrazole, boronic acid, boronate ester, or aryl trifluoroborate; R 1 is H, deuterium, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, -CH2OH, or -B(OH)2; R 1a is H, deuterium, or C1-C3 alkyl; R 20 is an alkyl group, preferably a methyl group or an ethyl group; or CD3; R 2 'yes (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a group substitution; (c1) phenyl, optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a group substitution; (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a group substitution; (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is also substituted by –(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, where –(5 or 6 atoms of heteroaryl)-LG 1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a group substitution; (h1) C3-C6 cycloalkyl, which is substituted with NH2 or OH and further optionally substituted with 1 or 2 R 3a group substitution; or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group is substituted by a LG 1and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a and provided that the compound is not: 4-Oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or a salt or enantiomer thereof.

[0151] In one or more embodiments, the compound is selected from any one of the following compounds A1 to A6 shown in Table 2, or a prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, or tautomer thereof, and these compounds can at least be used to prepare the compound represented by formula (I).

[0152] Table 2. Intermediates

[0153] In some or any embodiments, the present invention provides: (a) Compounds of the present invention, for example, compounds of formula (I) and compounds 1-44, and pharmaceutically acceptable salts and compositions thereof; (b) the compounds of the present invention, for example, the compounds of formula (I) and compounds 1-44, and pharmaceutically acceptable salts and compositions thereof, It is used to stimulate wound regeneration in mammals; (c) compounds of the present invention, such as compounds of formula (I) and compounds 1-44, and pharmaceutically acceptable salts and compositions thereof, It is used to inhibit Wnt transcription products or Wnt signaling pathway activity; (d) methods for preparing the compounds of the present invention (e.g., compounds of formula (I) and compounds 1-44), as described in more detail elsewhere herein; (e) a pharmaceutical preparation comprising a compound of the present invention, for example, a compound of formula (I) and compounds 1-44 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (e.g., a diluent); (f) a method for treating a disease associated with Wnt transcripts or Wnt signaling pathway activity in a mammal, comprising administering a therapeutically effective amount of a compound of the present invention, for example, a compound of formula (I) and compounds 1-44, or a pharmaceutically acceptable salt or combination thereof; (g) a method for treating wounds in mammals, comprising administering a therapeutically effective amount of a compound of the present invention, for example, a compound of formula (I) and compounds 1-44, or a pharmaceutically acceptable salt or combination thereof; (h) a pharmaceutical preparation comprising a compound of the present invention, e.g., a compound of formula (I) and compounds 1-44 or a pharmaceutically acceptable salt thereof, and one or more other effective drugs for treating wounds and / or conditions regulated by Wnt transcripts or Wnt signaling pathway activity, optionally containing a pharmaceutically acceptable carrier (e.g., a diluent); (i) A method for treating a wound in a mammal, comprising administering a therapeutically effective amount of a compound of the present invention, e.g., a compound of Formula (I) and Compounds 1-44, or a pharmaceutically acceptable salt or composition thereof, in combination and / or alternating administration with one or more drugs for treating wounds and / or conditions regulated by Wnt transcripts or Wnt signaling pathway activity; (j) A method for treating a disease associated with Wnt transcription products or Wnt signaling pathway activity in a mammal, comprising administering a therapeutically effective amount of a compound of the present invention, for example, a compound of formula (I) and compounds 1-44, or a pharmaceutically acceptable salt or combination thereof, in combination and / or in alternation with one or more drugs for treating wounds; and (k) Use of any compound described herein (e.g., a compound of formula (I) and compounds 1-44) or a composition comprising any compound described herein (e.g., a compound of formula (I) and compounds 1-44, or a pharmaceutically acceptable salt or composition thereof) for treating wounds associated with the Wnt transcript or Wnt signaling pathway activity described herein, optionally in combination and / or alternating administration with one or more drugs for treating wounds. Optically active compounds

[0154] Should be understood that compound provided by the invention has several chiral centers, and can exist and be separated in optically active form and racemic form.Should be understood that any racemate, optical active form, diastereomer, tautomer or stereoisomeric form, its mixture or its combination of compound provided by the invention with useful property described in the present invention are all included within the scope of the present invention.It is well known in the art how to prepare optical active form (in some or any embodiment, racemic form is split by recrystallization technology, synthesized by optically active starting material, chiral synthesis, or by using chiral stationary phase to carry out chromatographic separation).

[0155] In some or any embodiments, methods for obtaining optically active substances are known in the art and include at least the following. i) Physical separation of crystals - a technique whereby macroscopic crystals of individual stereoisomers are separated manually. This technique can be used if crystals of individual stereoisomers are present, ie the material is an aggregate and the crystals are visually distinct. ii) simultaneous crystallization - a technique by which the individual stereoisomers are crystallized separately from a solution of the racemate, provided the latter is an aggregate in the solid state; iii) Enzymatic resolution - a technique that partially or completely separates racemates by taking advantage of the different reaction rates of stereoisomers with enzymes; iv) Enzymatic asymmetric synthesis - a synthetic technique in which an enzymatic reaction is used in at least one step of the synthesis to provide a stereomerically pure or enriched synthetic precursor of the desired stereoisomer; v) Chemical asymmetric synthesis - a synthetic technique in which the desired stereoisomer is synthesized from achiral precursors under conditions that result in asymmetry (i.e., chirality) of the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi) Diastereoisomer separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization, due to their now more pronounced structural differences, and the chiral auxiliary is subsequently removed to obtain the desired enantiomer; vii) Primary and secondary asymmetric transformations - techniques whereby the desired enantiomer is liberated from the diastereoisomers by equilibrating the diastereoisomers from the racemate to produce a predominance of the diastereoisomer over the desired enantiomer in solution, or by preferential crystallization of the diastereoisomer over the desired enantiomer, which disturbs the equilibrium so that ultimately, in principle, all of the material is converted from the desired enantiomer to the crystalline diastereoisomer. viii) Kinetic resolution - techniques that achieve partial or complete resolution of racemates (or further resolution of partially resolved compounds) due to the unequal reaction rates of stereoisomers with chiral, non-racemic reagents or catalysts under kinetic conditions; ix) Stereospecific synthesis from non-racemic precursors - synthetic techniques by which the desired stereoisomer is obtained from achiral starting materials, and wherein the stereochemical integrity is not or only minimally compromised during the synthetic process; x) Chiral liquid chromatography - a technique that allows the separation of racemic stereoisomers in a liquid mobile phase by virtue of their differential interactions with the stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral materials to induce differential interactions; xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the stereoisomers are separated by their differential interaction in a gaseous mobile phase with a chromatographic column containing a stationary non-racemic chiral adsorbent phase; xii) Chiral solvent extraction - a technique that allows the separation of stereoisomers by preferentially dissolving one stereoisomer in a specific chiral solvent; xiii) Transchiral Membrane Transport - A technique in which a racemate is exposed to a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force, such as concentration or pressure differential, results in preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one stereoisomer of the racemate to pass through.

[0156] In some or any embodiments, the present invention provides compositions of compounds comprising substantially pure specified stereoisomers of the compounds. In some or any embodiments, in the methods and compounds of the present invention, the compounds are substantially free of other stereoisomers. In some or any embodiments, the compositions comprise at least 85%, 90%, 95%, 98%, 99%, or 100% by weight of the compound of the specified stereoisomer, with the remainder comprising other chemical substances or stereoisomers. Isotopically enriched compounds

[0157] The present invention also provides isotopically enriched compounds.

[0158] It has been previously demonstrated with certain classes of drugs that isotopic enrichment (deuteration in some or any embodiments) of drugs can improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles. See, for example, Lijinsky et.al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et.al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et.al., Mutation Res. 308:33 (1994); Gordon et.al., Drug Metab. Dispos., 15:589 (1987); Zello et.al., Metabolism, 43:487 (1994); Gately et.al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[0159] In some or any embodiments, isotopic enrichment of a drug can be used to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of doses required to achieve a desired effect, (4) reduce the amount of the dose necessary to achieve a desired effect, (5) increase the formation of active metabolites (if any), and / or (6) reduce the production of deleterious metabolites in specific tissues and / or create more effective drugs and / or safer drugs for combination therapies, whether the combination therapy is intentional or unintentional.

[0160] Replacing an atom with one of its isotopes generally results in a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if a C-H bond breaks during the rate-determining step (i.e., the step with the highest transition state energy) in a chemical reaction, then replacing hydrogen with deuterium will result in a decrease in the reaction rate, and the process will slow down. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE"). See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

[0161] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken and the same reaction in which deuterium replaces hydrogen. The DKIE can range from about 1 (no isotope effect) to very large values, such as 50 or more, meaning that the reaction can be 50 times slower or more when deuterium replaces hydrogen. High DKIE values may be due in part to a phenomenon known as tunneling, which is a result of the uncertainty principle. Tunneling is attributed to the smaller mass of hydrogen atoms and occurs because transition states involving protons can sometimes form in the absence of the required activation energy. Since deuterium is more massive than hydrogen, the statistical probability of this phenomenon occurring is much lower.

[0162] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with 2 neutrons in its nucleus and an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly as T2O. Tritium decays slowly (half-life = 12.3 years) and releases low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, but it must be ingested in large quantities to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before dangerous levels are reached. Replacing hydrogen with tritium ("T") produces a stronger bond than deuterium and produces a numerically larger isotope effect. Similarly, isotope substitutions of other elements, including but not limited to, 13 C or 14 C replaces carbon, 33 S. 34 S, or 36 S replaces sulfur, 15 N replaces nitrogen, and 17 O or 18 O replaces oxygen, which can produce similar kinetic isotope effects.

[0163] For example, DKIE has been used to reduce the hepatotoxicity of halothane, presumably by limiting the generation of reactive species such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching posits that xenobiotics, when sequestered by phase I enzymes, can transiently bind and rebind in various conformations prior to a chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large number of binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can result in different ratios of known metabolites as well as novel metabolites. Such novel metabolic profiles may confer greater or lesser toxicity.

[0164] In some embodiments, the compounds described herein can be used as radiopharmaceuticals, e.g., imaging agents. In one embodiment, the radiopharmaceutical is a positron emission tomography (PET) imaging agent. In such embodiments, a radionuclide (e.g., a positron emitting isotope) replaces an atom in the compound to synthesize a radiopharmaceutical that can be used as an imaging agent. In some embodiments, the radionuclides that can be replaced in the compounds described herein include, but are not limited to, 18 F. 11 C. 13 N. 15 O. 76 Br, and 124 1. In some embodiments, the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms. In some embodiments, the compound is administered as an isotopic composition.

[0165] Animals express various enzymes to remove foreign substances such as therapeutic agents from their circulatory systems. In some or any embodiments, these enzymes include cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of drug compounds involve oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have significantly different pharmacokinetics, pharmacodynamics, and acute and long-term toxicity characteristics relative to the parent compound. For many drugs, this oxidation reaction is very fast. Therefore, these drugs usually require multiple or high-dose daily dosing.

[0166] Therefore, isotopic enrichment at certain positions of the compounds provided herein will result in a detectable KIE compared to similar compounds having a natural isotopic composition, which will affect the pharmacokinetic, pharmacological and / or toxicological characteristics of the compounds provided herein. Preparation of compounds

[0167] The compounds provided by the present invention can be prepared, isolated or obtained by any method apparent to those skilled in the art. The compounds provided by the present invention can be prepared according to the exemplary preparation schemes provided below. The reaction conditions, steps and reactants not provided in the exemplary preparation schemes are apparent to those skilled in the art and are known.

[0168] Additional steps and reagents not provided in the exemplary preparation schemes are known to those skilled in the art. For example, intermediates and compounds can be prepared using methods known to those skilled in the art or methods disclosed in U.S. Provisional Application Nos. 63 / 417,257, 63 / 418,947, and 63 / 418,956 (each of which is incorporated herein by reference in its entirety for the disclosed synthetic methods). Exemplary preparation methods are described in detail in the Examples herein.

[0169] In one or more embodiments, the present invention provides a method for preparing a compound represented by formula (I), comprising: a) making a compound represented by formula (A): With R 2’ -C(O)H; or b) contacting a compound represented by formula (B): With R 2’ -C(NH)NH2 contact, where R 20 is Me or CD3; or c) a compound represented by formula (C): With R 2’ -H contact, where LG 1 is fluorine, chlorine, bromine, iodine, trifluoromethanesulfonate, mesylate, triazole, pyrazole, boronic acid, boric acid ester, or trifluoroborate aryl ester; and optionally separating the compound of formula (I); wherein R 2 ' is: (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a (c1) phenyl, which is optionally substituted with 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is also substituted by –(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, where –(5 or 6 atoms of heteroaryl)-LG 1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a (h1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by NH2 or OH and optionally substituted by 1 or 2 R 3a or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group being LG 1 and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a Group substitution; and proviso that the compound is not: 4-oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or its salts and / or its stereoisomers or mixtures of stereoisomers. In one or more embodiments, the method for preparing a compound of formula (I) comprises contacting under alkaline conditions; and all other groups are as defined in any embodiment of the present invention; and optionally wherein R 1 and R 1a are each independently H or alkyl.

[0170] It will be understood by those skilled in the art that the order of steps of any process method described in the present invention can be changed. Other variations will be apparent to those skilled in the art, and all such variations are included within the scope of the embodiments described in the present invention. Pharmaceutical compositions and methods of administration

[0171] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any compound disclosed herein can be provided in a suitable pharmaceutical composition and administered / administered via a suitable route of administration. The present invention provides pharmaceutical compositions comprising a compound of formula (I) as described in some and any embodiments of the present invention, and a pharmaceutically acceptable carrier.

[0172] In some embodiments, the composition is a topical or local composition.

[0173] The methods provided herein comprise administering a pharmaceutical composition containing at least one compound of the present invention (including a compound of formula (I), in salt form, if appropriate) alone or in combination with one or more compatible and pharmaceutically acceptable carriers (e.g., diluents or adjuvants), or in combination with another drug for treating wounds and / or conditions regulated by Wnt transcripts or Wnt signaling pathway activity.

[0174] In addition to the compound of formula (I), the compositions of the present invention (including the GO-HA pharmaceutical compositions) may also contain other drugs or therapeutic compounds. In other words, the compositions containing the compound of formula (I) (including the GO-HA pharmaceutical compositions) can also be used as a matrix dispersion medium in which other drugs or therapeutic agents, particularly hydrophobic drugs or therapeutic agents, such as drugs or therapeutic agents for topical administration to wounds, can be dispersed. These drugs or therapeutic agents may include anti-fibrotic compounds, such as pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc.; anticancer agents, anti-inflammatory agents, analgesics, antibiotics, Wnt inhibitors, Hedgehog pathway inhibitors, TGF-β inhibitors, LOX inhibitors, etc.

[0175] In some embodiments, the composition may include a second drug or therapeutic agent for wounds, comprising one or more of the following: corticosteroids, cytotoxic drugs, antibiotics, antiseptics, nicotine, antiplatelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, anticoagulants, vasoconstrictors or immunosuppressants, growth factors, antibodies, proteases, protease inhibitors, antimicrobial peptides, adhesion peptides, hemostatic agents, living cells, honey, or nitric oxide. These therapeutic agents may be delivered as a separate dosage form from the composition of the present invention, or may be included as an additional component of the composition of the present invention, thereby being delivered together with the compound shown in formula (I) (or any embodiment thereof, in some embodiments, including compound 1, compound 7, or compound 8).

[0176] In some or any embodiments, the second drug can be formulated or packaged with the compound provided by the present invention. Of course, when, according to the judgment of those skilled in the art, such co-formulation should not interfere with the activity or administration method of any drug, the second drug will only be formulated together with the compound provided by the present invention. In some or any embodiments, the compound provided by the present invention and the second drug are formulated separately. For the convenience of practitioners in this field of technology, they can be packaged together or separately.

[0177] In clinical practice, the active agents / drugs provided by the present invention can be administered / administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (eg, in the form of an aerosol).

[0178] The composition of the present invention can be applied by applying the composition topically to a wound. If the composition is contained in a medical device comprising a substrate (e.g., a patch or a pad) according to the present invention, the medical device can be fixed to the wound so that the composition contacts the wound.

[0179] As solid compositions for oral administration, tablets, pills, hard gelatin capsules, powders or granules may be used. In these compositions, the active ingredient is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch.

[0180] These compositions may contain substances other than diluents, for example, lubricants such as magnesium stearate, or coatings for controlled release.

[0181] As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or liquid paraffin can be used. These compositions may also contain substances other than diluents, and in some or any embodiments, contain wetting agents, sweeteners or flavoring preparations.

[0182] Compositions for parenteral administration can be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil or injectable organic esters can be used as solvents or vehicles, and in some or any embodiments, ethyl oleate is used as solvent or vehicle. These compositions can also include adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, and in some or any embodiments, bacteriological filters can be used, sterilized by radiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or any other injectable sterile medium when used.

[0183] Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

[0184] Said composition can also be an aerosol. In order to use with the form of liquid aerosol, said composition can be a stable sterile solution or be dissolved in the solid composition in pyrogen-free sterilized water, saline or any other pharmaceutically acceptable solvent when in use. In order to use with the dry aerosol form that is intended to directly inhale, said active ingredient is finely separated and combined with water-soluble solid diluent or solvent, in some or any embodiment, with dextran, mannitol or lactose. In one or more embodiments, pharmaceutical composition provided by the invention is an aerosol.

[0185] In some or any embodiment, the composition provided by the present invention is a pharmaceutical composition or a single unit dosage form. The pharmaceutical composition provided by the present invention and the single unit dosage form include one or more therapeutic agents (for example, compounds provided by the present invention or other therapeutic agents) and typical one or more pharmaceutically acceptable carriers (for example, excipients) of a therapeutically effective amount. In specific embodiments and the present invention, the term "pharmaceutically acceptable" refers to a drug or carrier for animals, particularly for humans, approved by a regulatory agency of a federal or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias. In some embodiments, the term "carrier" includes diluents, disintegrants, lubricants, adjuvants (for example, Freund's adjuvant (complete and incomplete)), excipients, or vehicles used together with the therapeutic agent. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal oils, vegetable oils, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions and aqueous glucose solutions and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0186] Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy. In some or any embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is administered to a mammal and the specific active ingredient in the dosage form. If desired, the composition or single unit dosage form may also contain a small amount of a wetting agent or emulsifier, or a pH buffer.

[0187] The lactose-free compositions provided herein may include excipients known in the art, and in some or any embodiments, listed in the United States Pharmacopoeia (USP 36-NF 31S2). Typically, the lactose-free compositions include pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredient, binder / filler, and lubricant. Exemplary lactose-free dosage forms include active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0188] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, as water can promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical art as a means of simulating long-term storage in order to determine characteristics such as shelf life or the stability of a formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379-80. In fact, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be of great significance because moisture and / or humidity are often encountered during the manufacture, handling, packaging, storage, transportation, and use of formulations.

[0189] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-water content ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity is anticipated during manufacture, packaging, and / or storage.

[0190] Anhydrous pharmaceutical compositions should be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. In some or any embodiments, suitable packaging includes, but is not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0191] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds referred to as "stabilizers" herein include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0192] The present invention also provides pharmaceutical compositions and dosage forms comprising one or more chemical penetration enhancers. In some or any embodiments, chemical penetration enhancers include, but are not limited to, ethanol, amides (e.g., Ozone, Laurocapram), alkyl esters and benzoates, fatty acid esters (e.g., isopropyl myristate, propylene glycol monocaprylate, and propylene glycol monolaurate), Transcutol (trademarked name), fatty acids (oleic acid), glycols, pyrrolidones (N-methyl-2-pyrrolidone and 2-pyrrolidone), dimethyl sulfoxide (DMSO), terpenes (e.g., terpene-containing essential oils), phospholipids, and / or cyclodextrins.

[0193] The pharmaceutical composition and single unit dosage form can all take the form of solution, suspension, emulsion, tablet, pill, capsule, powder, sustained release formulation and the like. Oral formulations can include standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Such compositions and dosage forms will contain a preventive or therapeutically effective amount of a prophylactic or therapeutic agent, which in some or any embodiments is in a purified form together with an appropriate amount of carrier to provide a form suitable for administration to a mammal. The formulation should be suitable for administration. In some or any embodiments, the pharmaceutical composition or single unit dosage form is sterile and administered to a mammal in a suitable form, and in some or any embodiments, is administered to humans.

[0194] Pharmaceutical compositions are prepared to match the route of administration expected therefrom. In some or any embodiment, route of administration includes, but is not limited to, parenteral administration, such as intrathecal, epidural, local or regional peripheral nerve block, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, oral, sublingual, inhalation, intranasal, transdermal, topical / topical (including being applied to eyes, being applied to cornea in some embodiments), transmucosal, intratumoral, synovial and rectal administration. In a specific embodiment, according to conventional procedure, compositions are formulated into a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical / topical (including being applied to eyes, being applied to cornea in some embodiments) being administered to people. In a specific embodiment, according to conventional procedure, pharmaceutical compositions are formulated into a pharmaceutical composition that people are administered subcutaneously. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. If desired, the composition can also include a solubilizing agent and a local anesthetic such as lidocaine (lignocamne), to alleviate the pain at the injection site.

[0195] In some or any embodiments, dosage forms include, but are not limited to, sprays; tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; lozenges; troches; dispersions; suppositories; ointments; cataplasms (cataplasms); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to mammals, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to mammals; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to mammals.

[0196] The composition, shape and type of the dosage form provided by the present invention will generally vary according to its use. In some or any embodiment, the dosage form for the initial treatment of the disease, disorder or condition may include one or more active ingredients, which include a larger amount of active ingredients than the dosage form for maintaining the treatment of the same disease, disorder or condition. Similarly, compared with the oral dosage form for treating the same disease or condition, the parenteral dosage form may contain a smaller amount of one or more active ingredients contained therein. These and other forms of the specific dosage form included in the present invention will vary from one another, which will be apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0197] Typically, the components of the composition are provided separately or mixed together in unit dosage form, in some or any embodiments, as a dry lyophilized powder or anhydrous concentrate sealed in an airtight sealed container such as an ampoule or pouch indicating the amount of active agent. Where the composition is administered by infusion, an infusion bottle containing sterile pharmaceutical grade water or saline can be used to dispense the composition. Where the composition is administered by injection, an ampoule of sterile water or saline for injection can be provided so that the components can be mixed prior to administration.

[0198] Typical dosage forms include a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in a range of about 0.1 mg to about 1000 mg per day, administered in a single, once-a-day dose in the morning or dividedly administered throughout the day with food. Specific dosage forms may have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of active compound. Oral dosage form

[0199] Pharmaceutical compositions suitable for oral administration can be present as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and can be prepared by pharmaceutical methods well known to those skilled in the art. See generally Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0200] In some or any embodiments, the oral dosage form is solid and is prepared with anhydrous ingredients under anhydrous conditions, as described in detail herein. However, the scope of the compositions provided by the present invention can be extended to anhydrous, solid oral dosage forms. Therefore, the present invention also records other forms.

[0201] According to conventional pharmaceutical compounding technology, typical oral dosage forms are prepared by fully mixing the active ingredient with at least one adjuvant. Adjuvants can take various forms, depending on the dosage form required for administration. In some or any embodiments, adjuvants suitable for oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavorings, preservatives, and colorants. In some or any embodiments, adjuvants suitable for solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0202] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are used. If desired, tablets can be coated by standard aqueous or anhydrous techniques. Such dosage forms can be prepared by any pharmaceutical method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired form.

[0203] In some or any embodiments, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules in a suitable machine, optionally mixed with excipients. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0204] In some or any embodiments, one or more of the following may be used in the pharmaceutical composition: benzyl alcohol, butylparaben, butylated hydroxytoluene, calcium carbonate, candelilla wax, colloidal silicon dioxide, calcium stearate, calcium disodium edetate (EDTA), copovidone or copovidone, dibasic calcium phosphate dihydrate, crospovidone, calcium phosphate (diac and tribasic), emollient (glyceryl monostearate), iron oxide, ivy yellow, and iron.

[0205] In some or any embodiments, excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for pharmaceutical compositions and dosage forms include, but are not limited to, copolyvidone or copolyvidone, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., numbered 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0206] In some or any embodiments, fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical composition is typically present in an amount of about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

[0207] In some or any embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, those sold as AVICEL PH 101, AVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscosity Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A particular binder is a mixture of microcrystalline cellulose sold as AVICEL RC 581 and sodium carboxymethylcellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103, AVICEL RC 581, AVICEL PH 105, and mixtures thereof. TM and Starch 1500LM.

[0208] Disintegrants are used in the composition so that the tablet disintegrates when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant should be used to form a solid oral dosage form, and the disintegrant is neither too much nor too little to adversely change the release of the active ingredient. The amount of disintegrant used can vary depending on the type of formulation and is easily discernible for those of ordinary skill in the art. Typical pharmaceutical compositions contain about 0.5% to about 15% by weight of disintegrant, specifically about 1% to about 5% by weight of disintegrant.

[0209] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, crospovidone, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0210] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. In some or any embodiments, other lubricants include syloid silica gel (AEROSIL 200, manufactured by WR Grace, Baltimore, Maryland), condensed aerosols of synthetic silica (sold by Degussa, Plano, Texas), CAB O SIL (a pyrogenic silica product sold by Cabot, Boston, Massachusetts), and mixtures thereof. If a lubricant is used, the amount of the lubricant is typically less than about 1% by weight of the pharmaceutical composition or dosage form into which it is incorporated. GO-HA preparation (containing the compound represented by formula (I) and any embodiment thereof)

[0211] In one or more embodiments, the present invention provides a pharmaceutical composition (e.g., for treating wounds) comprising: a matrix component comprising a conjugate of graphene oxide (GO) and hyaluronic acid (HA), wherein GO and HA are covalently linked via a linker; a compound represented by formula (I) (or any embodiment thereof, in some embodiments, including compound 1, compound 7, or compound 8); and water. The covalently linked GO and HA are also referred to as GO-HA conjugates or simply GO-HA in the present invention. The GO-HA conjugate can be prepared according to methods known to those of ordinary skill in the art (including the method disclosed in US-2019-0105398-A1).

[0212] The graphene oxide (GO) used in the present invention refers to an oxidized form of graphene, which is a single-layer form of graphite. GO can be obtained by treating graphite with a strong oxidant. GO contains different amounts of carbon, oxygen, and hydrogen, depending on how it is made. In the GO plane direction, its length can be hundreds of nanometers, up to several microns, and its thickness is about 0.7-1.2nm. When prepared using sulfuric acid (e.g., Hummers method), GO can include various oxygen-containing group portions, such as epoxy groups, carboxylic acid (-COOH), phenol, etc. An example of a GO structure is shown below:

[0213] Hyaluronic acid (HA) is an anionic, highly hydrophilic, non-sulfated glycosaminoglycan that occurs naturally throughout the human body. It can be thousands of carbohydrate units long and can bind to water to form a gel with a firm, viscous texture. An example of the structure of HA is provided below:

[0214] In the compositions of the present invention, the GO is covalently linked to HA to form a matrix component (or carrier), which can be used to form a stable suspension of the compound of formula (I) (e.g., Compound 1, Compound 7, or Compound 8) while providing other benefits for wound healing. The covalent linking can be accomplished using a linker or linker group portion ("GO-HA linker"). In one or more embodiments, the GO-HA linker may comprise 2-25 carbon atoms. In one or more embodiments, the GO-HA linker is linear. In one or more embodiments, the GO-HA linker is branched. The GO-HA linker may be saturated or unsaturated.

[0215] In one or more embodiments, the GO-HA linker may comprise a C2-C 25An alkylene group, wherein the carbon atoms and hydrogen atoms in the alkylene group may be substituted with oxygen atoms or other atoms or groups (e.g., hydroxyl, carboxyl, amino, alkyl, alkoxy, alkenyl, alkynyl, nitro, etc.). In one or more embodiments, the GO-HA linker may comprise one or more -CH2CH2O- units.

[0216] In one or more embodiments, the GO-HA linker comprises -R x -R s -R y -, where R x and R y Each independently selected from the group consisting of: -CO-, -COO-, -NH-, -NH-NH-, -NH-NH-CO-, -CS-, -S-, and -O-, wherein R s (also referred to herein as a spacer group) can be an unsubstituted or substituted, saturated or unsaturated straight chain alkylene group having 2-20 main chain carbons. In one or more embodiments, R x and R y All are *-HN-HN-CO- (* indicates that the linker is far away from R s end of the ).

[0217] In one or more embodiments, the spacer group in the GO-HA linker can be an unsubstituted or substituted, saturated or unsaturated linear alkylene group with a backbone carbon number of 2-20. For purposes of illustration and not limitation, the HA can be derivatized with one of the following spacer groups: where R 101 and R 102 can be independently -CONHNH-, -S-, -NH-, -O-, or other nucleophiles, and n is an integer, for example, 1-20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. In one or more embodiments, the HA is derivatized with a spacer comprising a dihydrazide (e.g., -NHNHC(O)-alkylene-CONHNH-), such as adipic acid dihydrazide (-NHNHC(O)(CH2)4CONHNH-).

[0218] In one or more embodiments of the GO-HA pharmaceutical composition, the weight ratio of the compound of Formula (I) (e.g., Compound 1, Compound 7, or Compound 8) to GO-HA can be from about 1:100 to 100:1, for example, from about 1:2 to about 2:1. In one or more embodiments, in the GO-HA conjugate, the weight ratio of GO:HA can be from about 1:1 to about 1:20, or from about 1:6 to about 1:10.

[0219] In one or more embodiments, the GO-HA pharmaceutical composition further comprises a pharmaceutical carrier (e.g., an excipient), a compound, or a material that enables the composition to be presented as a semisolid aqueous gel that can be topically applied. For example, carboxymethyl cellulose can be used as a gel-forming agent. However, other cellulose derivatives (e.g., microcrystalline cellulose) and polysaccharides (e.g., alginates, agarose, tragacanth gum, guar gum, and xanthan gum) are also suitable as gel-forming agents. If desired, the gel can be made thicker and / or harder by adding a relatively elastic gel-forming material such as cross-linked fibrin (e.g., gelatin or collagen cross-linked with formaldehyde). In one or more embodiments, the GO-HA pharmaceutical composition can be in the form of a cream, which can include those excipients suitable for cream formulations, such as paraffin oil, petrolatum, waxes, organic esters (e.g., cetyl palmitate), etc.

[0220] In one or more embodiments, the GO-HA pharmaceutical compositions of the present invention further comprise a thickener to provide the desired viscosity for transdermal delivery. For example, the thickener may include hydroxypropyl cellulose (HPC). HPC allows the GO-HA pharmaceutical composition to form a smooth film, facilitating application. HPC also reduces evaporation, keeping wounds moist longer, a factor that has been shown to improve healing and reduce scarring. UPC is available in different grades, depending on the molecular weight of the aqueous solution or the viscosity of a given concentration.

[0221] In one or more embodiments of the GO-HA pharmaceutical composition, the compound of formula (I) (e.g., Compound 1, Compound 7, or Compound 8) may comprise from about 0.001 wt% to about 5 wt% of the total weight of the composition (including water). In one or more embodiments of the GO-HA pharmaceutical composition, the compound of formula (I) (e.g., Compound 1, Compound 7, or Compound 8) may comprise from about 0.01 wt% to about 2 wt%, from about 0.02 wt% to about 1 wt%, or from about 0.05 wt% to about 0.5 wt% of the total weight of the composition. In one or more embodiments, GO-HA comprises from about 0.001 wt% to about 5 wt% of the total weight of the composition. In one or more embodiments, GO-HA may comprise from about 0.01 wt% to about 2 wt%, from about 0.02 wt% to about 1 wt%, or from about 0.05 wt% to about 0.5 wt% of the total weight of the composition.

[0222] Generally speaking, the GO-HA pharmaceutical composition appears as a slightly dark or black viscous liquid. The compound represented by Formula (I) (e.g., Compound 1, Compound 7, or Compound 8) is uniformly dispersed in the viscous suspension and is stable for several months at room temperature. In one or more embodiments, the composition further comprises a surfactant, which can enhance the miscibility or solubility of the hydrophobic substance in water. In one or more examples, the surfactant can be a nonionic hydrophilic material, such as polyethylene glycol (PEG). The PEG can have a number average molecular weight of about 100 to about 10,000 daltons, or about 200 to about 4000 daltons, for example, about 200 to about 1000 daltons, about 200 to about 800 daltons, about 200 to about 500 daltons, about 200 to about 400 daltons, about 300 to about 400 daltons, about 350 to about 450 daltons, about 200 daltons, about 250 daltons, about 300 daltons, about 350 daltons, about 400 daltons, about 450 daltons, about 500 daltons, about 550 daltons, about 600 daltons, about 650 daltons, about 700 daltons, about 750 daltons, about 800 daltons, about 850 daltons, about 900 daltons, about 950 daltons, about 1000 daltons, and the like. In one or more embodiments, the PEG can be present in the composition in an amount of about 0.1 wt % to about 20 wt % of the total amount of the composition. For example, the PEG can be about 0.2 wt % to about 10 wt %, or about 0.5 wt % to about 10 wt %, or about 1 wt % to about 10 wt % of the total amount of the composition. Other non-ionic hydrophilic materials can also be used, such as copolymers of polyethylene glycol (PEG) and polypropylene glycol (PPG), such as poloxamers. In one embodiment, poloxamer-188 (average molecular weight of about 8400 Daltons) can be used.

[0223] In the GO-HA pharmaceutical composition of the present invention, in addition to the compound of formula (I) (e.g., Compound 1, Compound 7, or Compound 8), other drugs or therapeutic compounds may also be included. In other words, the GO-HA pharmaceutical composition containing the compound of formula (I) (e.g., Compound 1, Compound 7, or Compound 8) can also be used as a matrix dispersion medium in which other drugs or therapeutic agents, particularly hydrophobic drugs or therapeutic agents, such as drugs or therapeutic agents for topical administration to wounds, can be dispersed. These drugs or therapeutic agents may include anti-fibrotic compounds, such as pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc.; anticancer agents, anti-inflammatory agents, analgesics, antibiotics, Wnt inhibitors, Hedgehog pathway inhibitors, TGF-β inhibitors, LOX inhibitors, etc. Delayed-release dosage form

[0224] Active ingredients, such as the compounds provided herein, can be administered by controlled release or by delivery devices known to those skilled in the art. In some or any embodiments, but not limited to, U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 6,699,500; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide sustained or controlled release of one or more active ingredients, wherein in some or any embodiments, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres or combinations thereof are used to provide desired release profiles in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art (including those described herein) can be easily selected for the active ingredients provided by the present invention. Therefore, the present invention encompasses unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel capsules and caplets suitable for controlled release.

[0225] All controlled-release pharmaceutical products have the common goal of improving drug therapy / therapy, which is superior to the goal achieved by its non-controlled counterparts. Ideally, the feature of using the best designed controlled-release formulation in drug therapy is to cure or control the disease / illness in the shortest time with a minimum amount of drug substance. The advantages of controlled-release formulations include prolonged activity of the drug, reduced dosing frequency and increased compliance. In addition, controlled-release formulations can be used to influence the time of onset of action or other characteristics, such as drug blood levels, and therefore can affect the occurrence of side effects (such as adverse reactions).

[0226] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously release additional amounts of drug to maintain this level of therapeutic or preventive effect over a long period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0227] In some or any embodiments, the drug can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In some or any embodiments, a pump can be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. J. Med. 321: 574 (1989)). In another embodiment, a polymeric material can be used. In yet another embodiment, a controlled release system can be configured at an appropriate location in a mammal as determined by a technician, i.e., only a portion of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in Langer's review (Science 249: 1527-1533 (1990)). The active ingredient can be dispersed in a solid internal matrix such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, which can be coated with an external polymer. The active ingredient is then diffused through the outer polymer membrane in a release rate-controlling step. The percentage of active ingredient in such parenteral compositions is highly dependent on its specific properties and the needs of the mammal. Parenteral dosage forms

[0228] In some or any embodiments, the present invention provides parenteral dosage forms. Parenteral dosage forms can be administered to mammals by various routes, including but not limited to subcutaneous, intravenous (including bolus), intramuscular and intraarterial administration. Because its administration usually bypasses the natural defenses of mammals to pollutants, parenteral dosage forms are usually sterile or can be sterilized before being administered to mammals. In some or any embodiments, parenteral dosage forms include but are not limited to solutions prepared for injection, dry products prepared to be dissolved or suspended in a pharmaceutically acceptable solvent for injection, suspensions prepared for injection, and emulsions.

[0229] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In some or any embodiments, suitable vehicles include, but are not limited to, Water for Injection, USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and anhydrous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0230] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into parenteral dosage forms. Transdermal, topical, and mucosal dosage forms

[0231] The present invention also provides transdermal, topical and mucosal dosage forms. Transdermal, topical and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissue can be formulated as mouthwashes or oral gels. In addition, transdermal dosage forms include "reservoir-type" or "matrix-type" patches, which can be applied to the skin and worn over a specific time period to allow the desired amount of active ingredient to penetrate.

[0232] Suitable carriers (e.g., excipients and diluents) and other materials that can be used to provide the transdermal, topical, and mucosal dosage forms encompassed by the present invention are well known to those skilled in the art of pharmaceuticals and depend on the specific tissue to which a given pharmaceutical composition or dosage form will be applied. In view of this fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, which are non-toxic and pharmaceutically acceptable, and can be formed into lotions, tinctures, creams, emulsions, gels, or ointments. If desired, moisturizers or wetting agents can also be added to the pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0233] According to the specific tissue to be treated, additional components can be used before the active ingredient treatment provided, in combination or after treatment. In some or any embodiment, a penetration enhancer can be used to help deliver the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl alcohols and tetrahydrofuranyl alcohols; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinyl pyrrolidone; Kollidon grade (polyvinyl pyrrolidone, povidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[0234] The pH value of the pharmaceutical composition or dosage form or the pH value of the tissue using the pharmaceutical composition or dosage form also can be adjusted to improve the delivery of one or more active ingredients. In the same way, the polarity of the solvent carrier, its ionic strength or tension can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously change the hydrophilicity or lipophilicity of one or more active ingredients, thereby improving delivery. In this regard, stearates can be used as the lipid carrier of preparations, as emulsifiers or surfactants, and as delivery facilitators or penetration enhancers. Different salts, hydrates or solvates of the active ingredient can be used to further regulate the properties of the resulting composition. Dosage and unit dosage form

[0235] In human treatment, the physician will determine what he or she deems most appropriate posology depending on the treatment desired (e.g., prophylactic or therapeutic) and on the age, weight, stage of the disease, disorder or condition, and other factors specific to the mammal being treated. In some or any embodiments, the local dose is described as 1000 dL / cm2.2 mg per treatment site (e.g., wound) and is from about 0.001 to about 50 mg / cm 2 , or from about 0.005 to about 50 mg / cm 2 , or from about 0.01 to about 50 mg / cm 2 , or from about 0.01 to about 40 mg / cm 2 , or from about 0.01 to about 30 mg / cm 2 , or from about 0.01 to about 20 mg / cm 2 , or from about 0.01 to about 10 mg / cm 2 , or about 0.05 to about 10 mg / cm 2 , or about 0.05 to about 1 mg / cm 2 .

[0236] In some or any embodiments, the topical and non-topical dosage is from about 1 mg to about 1000 mg per day for an adult, or from about 5 mg to about 250 mg per day for an adult, or from about 10 mg to about 50 mg per day for an adult. In some or any embodiments, the dosage is from about 5 mg to about 400 mg per day for each adult, or from about 25 mg to about 200 mg per day. In some or any embodiments, a dosage rate of from about 50 mg to about 500 mg per day is also contemplated. In some or any embodiments, the dosage for subcutaneous administration is from about 1 mg to about 50 mg per day, or from about 1 mg to about 25 mg per day, or from about 1 mg to about 10 mg per day, or from about 1 mg to about 20 mg per day, or from about 5 mg to about 25 mg per day, or from about 5 mg to about 20 mg per day, or from about 10 mg to about 20 mg per day. In some or any embodiments, the oral dosage is from about 0.01 mg to about 100 mg per day, from about 0.01 mg to about 100 mg per day, or from about 0.01 mg to about 50 mg per day, from about 0.01 mg to about 25 mg per day, from about 0.01 mg to about 15 mg per day, from about 0.01 mg to about 10 mg per day, from about 0.05 mg to about 10 mg per day, from about 0.05 mg to about 5 mg per day, from about 0.05 mg to about 1 mg per day, from about 0.1 mg to about 100 mg per day, from about 0.1 mg to about 50 mg per day, from about 0.1 mg to about 25 mg per day, from about 0.1 mg to about 15 mg per day, from about 0.1 mg to about 10 mg per day, from about 0.1 mg to about 5 mg per day, from about 0.5 mg to about 1 mg per day, or from about 10 mg to about 200 mg per day. In some or any embodiments, including any of the foregoing embodiments, the daily dosage can be administered once daily. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be divided into two and administered 2 times daily. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be divided into three and administered 3 times daily.

[0237] In some embodiments, the amount of mg / day is for adults. In a further aspect, the invention provides a method for treating a disease, disease or condition associated with Wnt signaling pathway activity in a mammal by administering a therapeutic or preventive effective amount of a compound provided by the invention or a pharmaceutically acceptable salt thereof to a mammal in need. The amount of the compound or composition having a therapeutic or preventive effect in terms of treating a disease or one or more symptoms thereof will vary according to the nature and severity of the disease or condition and the route of administration of the active ingredient. Frequency and dosage will also vary according to the specific factors of each mammal, specifically depending on the specific therapy (for example, therapeutic agent or preventive agent) administered, the severity of the disease, disease or condition, route of administration, and age, weight, reaction and previous medical history of the mammal. The effective dose can be extrapolated from the dose-response curve obtained from in vitro or animal model test systems.

[0238] In some or any embodiments, exemplary dosages of the compositions include milligrams or micrograms of active compound per kilogram of mammal or sample weight (e.g., about 10 μg / kg to about 50 mg / kg, about 100 μg / kg to about 25 mg / kg, or about 100 μg / kg to about 10 mg / kg). For the compositions provided herein, in some or any embodiments, the dosage administered to a mammal is 0.01 mg / kg to 3 mg / kg of mammal body weight, or 0.10 mg / kg to 3 mg / kg of mammal body weight, based on the weight of the active compound. In some or any embodiments, the dosage administered to a mammal is between 0.20 mg / kg and 2.00 mg / kg of mammal body weight, or between 0.30 mg / kg and 1.50 mg / kg of mammal body weight. In some embodiments, the dosage is administered subcutaneously to a mammal and is between about 0.01 mg / kg and 1 mg / kg (inclusive) of mammal body weight, or between about 0.03 mg / kg and 0.5 mg / kg (inclusive) of mammal body weight, based on the weight of the active compound. In some embodiments, the dosage is orally administered to a mammal and is between about 0.10 mg / kg and 5 mg / kg (inclusive) of the mammal's body weight, or between about 0.10 mg / kg and 2 mg / kg (inclusive) of the mammal's body weight based on the weight of the active compound. In some or any embodiments, for the conditions described herein, the recommended daily topical dosage of the composition provided by the present invention ranges from about 0.01 mg / day to about 100 mg / day, administered in a single dose once daily or in divided doses throughout the day (e.g., two or three doses).

[0239] In some or any embodiment, for the disease described in the present invention, the recommended daily dose range of the composition provided by the present invention is the range of about 0.1 mg to about 1000 mg per day, with a single once-daily dose or in divided doses throughout the day. In some or any embodiment, the daily dose is administered twice a day in divided divided doses. In some or any embodiment, the daily dose is administered three times a day in divided divided doses. In some or any embodiment, the daily dose is administered four times a day in divided divided doses. In some or any embodiment, the daily dose range should be about 0.01 mg to about 400 mg per day, about 0.1 mg to about 250 mg per day, about 10 mg and about 200 mg per day, in other embodiments, about 10 mg to about 150 mg per day, and in further embodiments, between about 25 mg and about 100 mg per day. In some cases, it may be necessary to use the dosage of the active ingredient outside the scope disclosed by the present invention, which is obvious to those of ordinary skill in the art. In addition, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate treatment based on the mammalian response.

[0240] As will be readily appreciated by those skilled in the art, different therapeutically effective amounts may be applicable to different diseases and conditions. Similarly, amounts sufficient to prevent, control, treat or improve such diseases / conditions but insufficient to cause or alleviate the adverse reactions associated with compositions provided by the invention are also included in the dosage and dosage frequency schedules of the present invention. In addition, when applied to multiple doses of the compositions provided by the invention in mammals, not all dosages need be the same. In some or any embodiment, the dosage applied to a mammal may be increased to improve the preventive or therapeutic effect of the compositions, or its dosage may be reduced to reduce one or more side effects experienced by a particular mammal.

[0241] In some or any embodiments, the dosage of the composition provided herein administered to prevent, treat, control, or ameliorate a disease / disorder or one or more symptoms thereof in a mammal is about 0.01 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, or about 15 mg / kg of mammal body weight or more, based on the weight of the active compound. In another embodiment, the dosage of the composition provided herein or the composition administered for the prevention, treatment, control or improvement of a disease / disorder or one or more symptoms thereof in a mammal is selected from about 0.01 mg / kg to about 100 mg / kg, selected from about 0.1 mg to about 200 mg, selected from about 0.1 mg to about 100 mg, selected from about 0.1 mg to about 50 mg, selected from about 0.1 mg to about 25 mg, selected from about 0.1 mg to about 20 mg, selected from about 0.1 mg to about 15 mg, selected from about 0.1 mg to about 10 mg, selected from about 0.1 mg to about 7.5 mg, selected from about 0.1 mg to about 5 mg, selected from about 0.1 mg to about 25 mg A unit dose from about 0.1 mg to about 2.5 mg, selected from about 0.25 mg to about 20 mg, selected from about 0.25 mg to about 15 mg, selected from about 0.25 mg to about 12 mg, selected from about 0.25 mg to about 10 mg, selected from about 0.25 mg to about 7.5 mg, selected from about 0.25 mg to about 5 mg, selected from about 0.5 mg to about 2.5 mg, selected from about 1 mg to about 20 mg, selected from about 1 mg to about 15 mg, selected from about 1 mg to about 12 mg, selected from about 1 mg to about 10 mg, selected from about 1 mg to about 7.5 mg, selected from about 1 mg to about 5 mg, or selected from about 1 mg to about 2.5 mg.

[0242] In some or any embodiment, the compound provided by the invention or compositions of certain dose can be used to realize the steady-state concentration of active ingredient in mammalian blood or serum.Described steady-state concentration can be determined by measuring according to the available technology of technical personnel, or can be determined based on described mammalian physical characteristics such as height, body weight and age.In some or any embodiment, can repeatably administer identical compositions, and described use can be spaced at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months to carry out.In other embodiments, can repeatably administer identical preventive or therapeutic agent, and described use can be spaced at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months to carry out.

[0243] In some or any embodiments, the present invention provides a unit dose comprising a compound or a pharmaceutically acceptable salt thereof in a form suitable for administration. Such forms are described in detail herein. In some or any embodiments, the unit dose comprises 1 to 1000 mg, 1 to 100 mg, or 10 to 50 mg of active ingredient. In specific embodiments, the unit dose comprises about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of active ingredient. Such unit doses can be prepared according to techniques well known to those skilled in the art.

[0244] In some or any embodiments, the present invention provides a dosage of a second agent for use in a combination therapy. In some or any embodiments, a dosage lower than the dosage that has been or is currently used to treat the disease, disorder, or condition can be used in the combination therapy provided herein. Recommended dosages of the second agent can be obtained from the knowledge of those skilled in the art. For those second agents approved for clinical use, recommended dosages are described, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Therapeutics 9 th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57 th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ; each of which is incorporated herein by reference in its entirety.

[0245] In various embodiments, less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour apart, about 1 hour apart, about 2 hours apart, about 3 hours apart, about 3 hours apart, about 4 hours apart, about 4 hours apart, about 5 hours apart, about 5 hours apart, about 6 hours apart, about 7 hours apart, about 8 hours apart, about 9 hours apart, about 10 hours apart, about 10 hours apart, about 11 hours apart, about 12 hours apart, about 13 hours apart, about 14 hours apart, about 15 hours apart, about 16 hours apart, about 17 hours apart, about 18 hours apart, about 19 hours apart, about 20 hours apart, about 21 hours apart, about 22 hours apart, about 23 hours apart, about 24 hours apart, about 25 hours apart, about 26 hours apart, about 27 hours apart, about 28 hours apart, about 29 hours apart, about 30 hours apart, about 31 hours apart, about 32 hours apart, about 33 hours apart, about 34 hours apart, about 35 hours apart, about 36 hours apart, about 37 hours apart, about 38 hours apart, about 39 hours apart, about 40 hours apart, about 41 hours apart The treatment / therapy (for example, compound provided by the invention and the second drug) is administered at intervals of about 11 hours to about 12 hours, about 12 hours to 18 hours, about 18 hours to 24 hours, about 24 hours to 36 hours, about 36 hours to 48 hours, about 48 hours to 52 hours, about 52 hours to 60 hours, about 60 hours to 72 hours, about 72 hours to 84 hours, about 84 hours to 96 hours or about 96 hours to 120 hours. In various embodiments, the treatment / therapy is administered no more than 24 hours apart or no more than 48 hours apart. In some or any embodiment, two or more treatments / therapy are administered during the same patient's visit. In other embodiments, compound provided by the invention and the second drug are administered simultaneously.

[0246] In other embodiments, the compound provided herein and the second drug are administered about 2 to 3 days apart, about 2 to 4 days apart, about 4 to 6 days apart, about 1 week apart, about 1 to 2 weeks apart, or more than 2 weeks apart.

[0247] In some or any embodiments, the same drug can be administered repeatedly, and the administration can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, the same drug can be administered repeatedly, and the administration can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0248] In some or any embodiment, the compound provided by the present invention and the second drug are administered to the patient in a certain order and over a period of time, in some or any embodiment, administered to mammals such as humans, so that the compound provided by the present invention can work together with other drugs, to provide a greater benefit than the benefit of other administered drugs. In some or any embodiment, the second activating agent can be administered sequentially at the same time or in any order at different time points; however, if not administered simultaneously, it should be administered in time close enough to provide the desired treatment or preventive effect. In some or any embodiment, the compound provided by the present invention and the second activating agent play their role at the time of overlap. Each second activating agent can be administered separately in any suitable form and by any suitable route. In other embodiments, the compound provided by the present invention is administered before, at the same time, or after the administration of the second activating agent.

[0249] In some or any embodiment, the compound provided by the present invention and the second drug are periodically administered to the patient. Cyclic therapy includes administering a first drug (e.g., a first preventive or therapeutic agent) over a period of time, followed by administering a second drug and / or a third drug (e.g., a second and / or third preventive or therapeutic agent) over a period of time, and repeating this sequential administration. Cyclic therapy can reduce the development of drug resistance to one or more treatments, avoid or reduce the side effects of one of the treatments, and / or improve the efficacy of the treatment.

[0250] In some or any embodiment, compound provided by the invention and the second activating agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once a week.A cycle can include by administering compound provided by the invention and the second drug by infusion at each cycle for about 90 minutes, each cycle for about 1 hour, each cycle for about 45 minutes.Each cycle can include a rest of at least 1 week, a rest of at least 2 weeks, a rest of at least 3 weeks.The number of cycles administered is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

[0251] In other embodiments, the treatment course is administered to the patient simultaneously, i.e., a single dose of the second drug is administered separately over a period of time so that the compound provided by the present invention can work together with the second active agent. In some or any embodiments, a component that is administered once a week can be co-administered with other components that can be administered once every two weeks or once every three weeks. In other words, even if the drug treatments are not performed simultaneously or on the same day, the dosing regimen will be performed simultaneously.

[0252] The second drug can be added or synergistic with the compound provided by the invention. In some or any embodiment, the compound provided by the invention can be used simultaneously with one or more second drugs in the same pharmaceutical composition. In another embodiment, the compound provided by the invention is used simultaneously with one or more second drugs in different pharmaceutical compositions. In another embodiment, the compound provided by the invention is used before or after the second drug is used. It is also contemplated that by the same or different routes of administration, for example, oral and parenteral administration, the compound provided by the invention and the second drug are used. In some or any embodiment, when the compound provided by the invention is used simultaneously with the second drug that may produce adverse side effects (including but not limited to toxicity), the second active drug can advantageously be used with a dosage lower than the adverse side effect causing threshold value. Reagent test kit

[0253] The present invention also provides a kit for treating a disease, disorder or condition associated with Wnt signaling pathway activity. The kit may include a compound or composition provided by the present invention, a second drug or composition, and instructions for providing information about the disease, disorder or condition associated with Wnt signaling pathway activity to medical personnel. The instructions can be provided in printed form or in the form of an electronic medium (such as a floppy disk, CD or DVD), or in the form of a website address for obtaining such instructions. The unit dose of the compound or composition provided by the present invention, or the second drug or composition, may include this dose so that when administered to a mammal, the treatment or prevention effective plasma level of the compound or composition can be maintained in a mammal for at least 1 day. In some or any embodiments, the compound or composition may be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0254] In some or any embodiment, suitable packaging can be provided. " packaging " used by the present invention comprises solid matrix or material commonly used in the system, and it can accommodate compound provided by the invention and / or be suitable for being applied to mammalian second medicine within fixed limits. Such materials include glass and plastic (for example, polyethylene, polypropylene and polycarbonate) bottles, vials, paper, plastics and plastic foil laminated envelopes etc. If adopting electron beam sterilization technology, described packaging should have enough low density to allow content to be sterilized. How to use

[0255] The present invention provides a method for inhibiting the Wnt transcriptional signaling pathway in mammals, comprising contacting and administering an effective amount of a compound represented by formula (I), including a single stereoisomer or a mixture of stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof.

[0256] The present invention provides a method for treating a disease, disorder or condition associated with Wnt transcripts or Wnt signaling pathway activity in a mammal, comprising administering a therapeutically or prophylactically effective amount of a compound of formula (I) of the present invention or a pharmaceutical composition of the present invention. In one or more embodiments, the method is used to treat a disease, disorder or condition associated with Wnt transcripts or Wnt signaling pathway activity, comprising administering to a mammal in need thereof a compound of formula (I) (or a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition of one or more embodiments.

[0257] In one or more embodiments, the method is used to stimulate tissue regeneration at the wound of a mammal in need. In one or more embodiments, the method comprises contacting the wound with an effective amount of a compound shown in formula (I) (or a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition described in one or more embodiments. In some embodiments, the mammal is a human. In one group of embodiments, the disease, disorder or condition is a wound.

[0258] In one group of embodiments, the disease, disorder or condition is selected from chronic wounds, acute wounds, alkali burns, corneal wounds, burns, lesions (including lesions caused by HPV and / or viruses selected from the Poxviridae family), inflammatory dermatitis diseases (including acne, psoriasis, rosacea and scleroderma), cartilage diseases (including osteoarthritis, rheumatoid arthritis, internal joint disorders and degenerative cartilage diseases), bone diseases (including osteoporosis), organ fibrosis (including pulmonary fibrosis, cardiac fibrosis, liver fibrosis and renal fibrosis), cancer (including melanoma, breast cancer and prostate cancer), denervated body parts in need of reinnervation, tissues in need of regeneration (including damaged elastic cartilage), bacterial growth in need of inhibition, fungal growth in need of inhibition, tissues in need of neovascularization, osteoclast differentiation in need of inhibition, osteoblast differentiation disorders (wherein osteoblast differentiation is required to be inhibited), and / or bone destruction associated with breast cancer.

[0259] In some or any embodiments, the present invention provides a method for treating a disease, disorder or condition associated with Wnt transcripts or Wnt signaling pathway activity in a mammal. In some or any embodiments, the method comprises administering to a subject in need thereof a compound that is effective for treating a disease, disorder or condition associated with Wnt transcripts or Wnt signaling pathway activity in a therapeutic or prophylactic effective amount in combination with a second drug that is effective for treating a disorder associated with Wnt transcripts or Wnt signaling pathway activity. The compound may be any compound described herein, and the second drug may be any second drug described in the art or herein. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described in other aspects of the invention.

[0260] In some or any embodiments, the present invention provides a method for inhibiting Wnt transcription products or Wnt signaling pathway activity, comprising contacting Wnt with a compound represented by formula (I) or a compound selected from Compounds 1-44.

[0261] In one or more embodiments, the present invention provides a method for improving wound healing, the method comprising contacting the wound with an effective amount of a composition of the present invention. Wounds expected to be damaged include, but are not limited to, surgical trauma caused by physical impacts that damage the structure and function of the skin (e.g., lacerations, abrasions, cuts, scrapes, or punctures caused by knives, scalpels, bullets, or other sharp or blunt instruments). The present invention is intended to be used for wounds caused by unplanned acute injuries due to excessive (low or high) temperatures (e.g., burns, ionizing radiation, chemotherapy) or accidents or incidents. The present invention is intended to be used for chronic wounds caused by underlying diseases (e.g., diabetic ulcers).

[0262] The composition of the present invention can be applied topically to a wound. If the composition is contained in a medical device comprising a substrate (eg, a patch or pad) of the present invention, the medical device can be fixed to the wound so that the composition contacts the wound.

[0263] In the preparation method of the composition used in the present invention, the spacer group can be an unsubstituted or substituted, saturated or unsaturated linear alkylene group, the main chain carbon number of which is 2 to 20. For the purpose of illustration and not limitation, the reagent used to derivatize HA can be selected from the following: where R 101 and R 102They can each independently be -CONHNH2, -SH, -NH2, -OH, or other nucleophilic reagents, and n is an integer, for example, 1-20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. In one or more embodiments, the reagent used to derivatize HA can be a dihydrazide (e.g., -NHNHC(O)-alkylene-CONHNH2), such as adipic acid dihydrazide (-NHNHC(O)(CH2)4CONHNH2).

[0264] In one or more embodiments, the method of preparing the composition of the present invention includes obtaining GO-HA (e.g., by the method of the present invention), adding or dissolving the GO-HA conjugate in water to obtain a GO-HA aqueous solution, and adding a compound of formula (I) (or any embodiment thereof, in some embodiments, including compound 1, compound 7, or compound 8) to the GO-HA aqueous solution to form a mixture (GO-HA + compound of formula (I), or any embodiment thereof, in some embodiments, including GO-HA + compound 1, GO-HA + compound 7, or GO-HA + compound 8). In some embodiments, the method is by first adding the compound of formula (I) (or any embodiment thereof, including compound 1, compound 7, or compound 8) to or dissolving it in a non-ionic hydrophilic polymer (e.g., PEG-400 (or PEG 400, with an average molar mass of about 400)), and then adding the solution of the compound of formula (I) (or any embodiment thereof, including compound 1, compound 7, or compound 8) to the aqueous solution of the GO-HA conjugate, thereby generating GO-HA + the compound of formula (I) (or any embodiment thereof, including GO-HA + compound 1, GO-HA + compound 7, or GO-HA / compound 8).

[0265] In some or any embodiments, the wound to be improved, treated, repaired or healed is selected from one or more of the group consisting of: acute wounds, chronic wounds, lacerations, abrasions, lacerations, puncture wounds, avulsions, skin cuts, surgical wounds, thermal wounds, burns, ulcers, chemical wounds, bite wounds, stab wounds, gunshot wounds, other penetrating high-velocity projectile wounds, stings, electrical wounds, cuts, crush wounds, poison wounds, radiation wounds, scalp wounds, penetrating wounds, incisional wounds, blunt force trauma wounds, skin tears, internal wounds, open wounds, closed wounds, excoriations, infected wounds, exuding wounds, non-healing wounds, wounds associated with dressing changes, amputations, necrotizing fasciitis wounds, osteomyelitis wounds, and post-traumatic wounds.

[0266] The present invention contemplates use in chronic wounds resulting from an underlying condition (eg, diabetic ulcers).

[0267] In some or any embodiment, the wound to be improved, treated, repaired or healed is a wound in an acute care environment, including a postoperative wound. In some or any embodiment, the wound to be improved, treated, repaired or healed is a wound in an acute care environment, including a postoperative wound, and the compound is administered intravenously. In some or any embodiment, the wound to be improved, treated, repaired or healed is a surgical wound. In some or any embodiment, the wound to be improved, treated, repaired or healed is a surgical wound, and the compound is applied topically (e.g., a spray). In some or any embodiment, the wound to be improved, treated, repaired or healed is an acute or chronic wound. In some or any embodiment, the wound to be improved, treated, repaired or healed is an acute or chronic wound, and the compound is administered subcutaneously. In some or any embodiment, the wound to be improved, treated, repaired or healed is an acute or chronic wound, and the compound is administered orally.

[0268] In one set of embodiments, the wound to be improved, treated, repaired, or healed is a burn. In one or more embodiments, the burn is a thermal burn. In one or more embodiments, the burn is a chemical burn. In one or more embodiments, the burn is an electrical burn. In one or more embodiments, the burn is a thermal burn. In one or more embodiments, the wound is a radiation burn. In one or more embodiments, the wound is a first-degree burn. In one or more embodiments, the wound is a second-degree burn. In one or more embodiments, the wound is a third-degree burn.

[0269] In some or any embodiments, the compounds of the present invention are used to delay the occurrence of wounds, or reduce the severity or duration of wounds. In some or any embodiments, the compounds of the present invention are used to reduce the severity or duration of wounds associated with Wnt transcripts or Wnt signaling pathway activity. In some embodiments, the compounds of the present invention are used to delay or prevent the occurrence of wounds.

[0270] In some or any embodiments, the compounds described herein are used to prevent wounds or conditions associated with Wnt transcripts or Wnt signaling pathway activity.

[0271] In some or any embodiments, the compounds described herein are used to treat wounds or conditions associated with Wnt transcripts or Wnt signaling pathway activity. Test methods

[0272] The efficacy of a compound in treating a disease, disorder or condition associated with Wnt signaling pathway activity can be determined according to any assay method known to those skilled in the art. Exemplary assay methods are provided in other aspects of the invention. Second therapeutic agent

[0273] In some or any embodiments, the compounds and compositions provided herein can be used for methods of treating wounds and / or conditions associated with Wnt transcripts and / or Wnt signaling pathway activity, the methods comprising further administering a second drug effective for treating wounds and / or Wnt transcription-related diseases and / or conditions associated with Wnt transcripts and / or Wnt signaling pathway activity. The second drug used in the treatment method can be any drug known to those skilled in the art that is effective for treating wounds and / or Wnt transcription-related diseases and / or conditions associated with Wnt transcripts and / or Wnt signaling pathway activity, including drugs currently approved by the U.S. Food and Drug Administration or other similar agencies outside the United States. The second drug (second agent) has been previously described in the present invention and can be used in the treatment method. In some or any embodiments, the second drug is a PARP inhibitor, silver, or notich inhibitor.

[0274] In one or more embodiments, the second drug is one or more of the following: corticosteroids, cytotoxic drugs, antibiotics, antiseptics, nicotine, antiplatelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, anticoagulants, vasoconstrictor drugs or immunosuppressants, growth factors, antibodies, proteases, protease inhibitors, antimicrobial peptides, adhesion peptides, hemostatics, living cells, honey, nitric oxide, antifibrotic compounds (e.g., pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc.), anticancer agents, anti-inflammatory agents, analgesics, Wnt inhibitors, Hedgehog pathway inhibitors, TGF-β inhibitors, and / or LOX inhibitors, etc.

[0275] In some or any embodiment, the compound provided by the present invention is co-administered with a second drug. In a further embodiment, the compound provided by the present invention is co-administered with two second drugs. In a further embodiment, the compound provided by the present invention is co-administered with two or more second drugs.

[0276] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). The use of the term "combination" does not limit the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a mammal having a disease. A first therapy / treatment (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered to a mammal having a disease prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) administration of a second therapy / treatment (e.g., a prophylactic or therapeutic agent, such as a compound described herein) can be administered concomitantly or subsequently to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy / treatment (e.g., a prophylactic or therapeutic agent).

[0277] The term "synergistic" used in the present invention includes a combination / association of a compound provided by the present invention with another therapy / treatment (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, control, or treat a disease / illness, which is more effective than the additive effect of the therapy / treatment. The synergistic effect of a therapeutic combination / association (e.g., a combination / association of a prophylactic or therapeutic agent) allows the use of one or more therapies / treatments at lower doses and / or less frequent administration of the therapy / treatment to a mammal suffering from a disease. The ability to utilize a lower dose of therapy / therapy (e.g., a prophylactic or therapeutic agent) and / or less frequent administration of the therapy / treatment reduces the toxicity associated with administering the therapy / treatment to a mammal without reducing the efficacy of the therapy / treatment in preventing or treating a disease. In addition, synergism can improve the efficacy of a drug in preventing or treating an illness. Finally, the synergistic effect of a combination / combination of therapies / therapy (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce the side effects or adverse reactions associated with using any one therapy / therapy alone.

[0278] The active compounds provided herein can be combined / combined or administered alternately with another therapeutic agent, particularly a drug that is effective in treating wounds and / or Wnt transcription-related diseases and / or conditions associated with Wnt transcripts and / or Wnt signaling pathway activity. In combination therapy, effective doses of two or more drugs can be administered together, while in alternating or sequential step treatments, effective doses of each drug can be administered continuously or sequentially. The dose administered will depend on the absorption, inactivation, and excretion rates of the drug and other factors known to those skilled in the art. It is noteworthy that the dosage value will also vary with the severity of the wound or Wnt transcription-related disease to be alleviated. It should be further understood that for any particular mammal, the specific dosage regimen and schedule should be adjusted over time based on individual needs and the professional judgment of the person implementing or supervising the administration of the composition. Example

[0279] In order to illustrate certain aspects of the present invention, the present invention provides the following examples, which should not be considered as limiting the present invention in any way.

[0280] As used herein, the symbols and conventions used in the methods, synthetic schemes, and examples of the present invention, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but not by way of limitation, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimolar); μM (micromolar); Hz (hertz); MHz (megahertz); M (molar); M+1 (MS peak, C-13 isotope +1 peak present in the molecular ion); mmol (millimolar); m / z (unit charge mass); h, hr, or hrs (hours); min (minutes); eq (equivalent); RT, RT, or rt (room temperature); R t or Rt (retention time); R f or Rf (retention factor); v (V) or vol (volume); E (cis); Z (trans); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); LC-MS (liquid chromatography-mass spectrometry); 1H NMR (proton nuclear magnetic resonance); ACN or CH3CN (acetonitrile); Ac2O (acetic anhydride); AcOH (acetic acid); BPin (boronic acid (pinacol ester)); BBr3 (boron tribromide); CDCl3 (deuterated chloroform); CH2Cl2 or DCM (dichloromethane); CuBr2 (copper (II) bromide); CN (cyanide or cyano group); Cs2CO3 (cesium carbonate); DCM (dichloromethane); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EtOAc (ethyl acetate); FA (formic acid); H2 (hydrogen); HCl (hydrogen chloride or hydrochloric acid); I2 (iodine); K2CO3 (potassium carbonate); KOAc (potassium acetate); LDA (diisopropyl iodide); (lithium propylamide); LAH (lithium aluminum hydride); LHMDS or LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); MeOD (methanol-D); MeMgBr (methylmagnesium bromide); N2 (nitrogen); NaH (sodium hydride); NH2OH (hydroxylamine); Na2SO4 (sodium sulfate); NaHCO3 (sodium bicarbonate); NaHMDS (sodium bis(trimethylsilyl)amide); NaOMe (sodium methoxide); NH3 (ammonia); NH4Cl (ammonium chloride); NH4HCO3 (ammonium bicarbonate); NMP (N-methyl-2-pyrrolidone); OMe (methoxy); Pd / C (palladium on carbon); PE (petroleum ether); Ph (phenyl); -Si(tert-Bu)(Ph)2 and -Si t BuPh2 (tert-butyl-diphenylsilyl); SiO2 (silicon dioxide); THF (tetrahydrofuran); TFA (trifluoroacetic acid); tBuONO (tert-butyl nitrite); dppf (diphenylphosphine); TMS (trimethylsilyl); GO-HA (graphene oxide / hyaluronic acid); MWCO (molecular weight cutoff); RPM or rpm (revolutions per minute); N (normality) or N (newton); and CFU (colony forming units). Synthesis Example Compound 1 Synthesis of (4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid (Compound 1) Synthesis of 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0281] Option 1A

[0282] A mixture of 4-bromobenzimidamide hydrochloride (1) (22.0 g, 93.41 mmol, 1.0 equiv), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1.1 g, 102.76 mmol, 1.1 equiv) and K2CO3 (38.73 g, 280.23 mmol, 3.0 equiv) in MeOH (660 mL) was stirred at 80°C for 16 hours. The mixture was cooled and concentrated in vacuo. The solid was triturated with water (500 mL), filtered and dried to give 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (26.4 g, 81.7 mmol). LC-MS: calculated value C 13 H 11 BrN2OS: 323.2; measured value: 325.0. Synthesis of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0283] Option 1B

[0284] A degassed mixture of 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (20 g, 61.88 mmol, 1.0 equiv), (BPin)2 (31.43 g, 123.76 mmol, 2.0 equiv), Pd(dppf)Cl2 (2.26 g, 3.09 mmol, 0.05 equiv) and KOAc (30.36 g, 309.40 mmol, 5.0 equiv) in dioxane (200 mL) was stirred under argon at 100° C. for 16 h. The mixture was concentrated in vacuo. The crude product was purified by silica gel column (PE: EtOAc = 5: 1 to 1: 1) to give 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (3) (21.73 g, 58.72 mmol). LC-MS: calculated value C 19 H 23 BN2O3S:370.1; measured value:371.1.

[0285] Option 1C

[0286] A solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (3) (10.0 g, 370.27 mmol, 1.0 equiv) in 3M HCl / MeOH (100 mL) was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo to give the crude product, which was triturated with THF (150 mL) at reflux and filtered to give (4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid (Compound 1). LC-MS: Calculated C 13 H 13 BN2O3S: 288.1; Found: 289.1. 1 H NMR (400MHz, MeOD): δ7.95 (s, 4H), 3.67 (s, 2H), 3.10 (m, 2H), 3.02 (m, 2H). Compound 2 Synthesis of 2-oxo-1-((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (Compound 2) Synthesis of tert-butyl (Z)-(3-hydroxycyclobutyl)carbamate

[0287] Option 2A

[0288] A solution of tert-butyl (3-oxocyclobutyl)carbamate (1) (2.5 g, 13.5 mmol, 1.0 equiv) in 80 mL of THF was cooled to -78°C and treated with a 1N solution of lithium tri-sec-butylborohydride (L-Selectride, 16.2 mL, 16.2 mmol, 1.2 equiv) in THF. After stirring for 1 hour, the reaction was quenched with 5 mL of water and warmed to room temperature. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EA:PE = 0-50%) to give tert-butyl (Z)-(3-hydroxycyclobutyl)carbamate (2) (1.8 g). 1 HNMR (400MHz, CDC13): δ (ppm): 4.68 (brs, 1H), 4.05-3.98 (m, 1H), 3.67-3.6 5(m,1H),2.78-2.75(m,2H),2.08(brs,1H),1.81-1.78(m,2H),1.44(s,9H). Synthesis of (Z)-3-((tert-Butoxycarbonyl)amino)cyclobutylmethanesulfonate

[0289] Option 2B

[0290] Methanesulfonyl chloride (1.3 g, 11.6 mmol, 1.2 equiv) was added dropwise to a solution of tert-butyl (Z)-(3-hydroxycyclobutyl)carbamate (2) (1.8 g, 9.6 mmol, 1.0 equiv) and TEA (1.5 g, 14.8 mmol, 1.5 equiv) in dichloromethane (60 mL) at -70°C. The resulting solution was stirred at -70°C for 2 hours and then diluted with 100 mL of water. The resulting solution was extracted with dichloromethane (3 x 60 mL), and the organic layers were combined. The resulting mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give (Z)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (3) (2.5 g). 1 H NMR (400MHz, CDC13): δ (ppm): 4.75-4.67 (m, 2H), 3.85-3.82 (m, 1H), 2.98 (s, 3H), 2.93-2.88 (m, 2H), 2.22-2.14 (m, 2H), 1.44 (s, 9H). Synthesis of tert-butyl (E)-(3-cyanocyclobutyl)carbamate

[0291] Option 2C

[0292] A solution of (Z)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (3) (1.2 g, 4.5 mmol, 1.0 equiv) in DMF (30 mL) was treated with NaCN (665.7 mg, 13.6 mmol, 3.0 equiv). The reaction was heated to 120°C for 15 hours, and the mixture was diluted with 50 mL of water. The resulting solution was extracted with EA (2 x 60 mL), and the organic layers were combined. The resulting mixture was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (E)-(3-cyanocyclobutyl)carbamate (4) (730.0 mg). 1 H NMR (400MHz, CDCl3): δ (ppm): 4.77 (br s, 1H), 4.41-4.39 (m, 1H), 3.06-3.01 (m, 1H), 2.74-2.41 (m, 2H), 2.27-2.24 (m, 2H), 1.45 (s, 9H). Synthesis of tert-butyl (E)-(3-(N-hydroxycarbamimidoyl)cyclobutyl)carbamate

[0293] Plan 2D

[0294] To a solution of tert-butyl (E)-(3-cyanocyclobutyl)carbamate (4) (730.0 mg, 3.7 mmol, 1.0 equiv) in EtOH (25 mL) was added aqueous hydroxylamine (2.2 g / 2.0 mL, 33.3 mmol, 9.0 equiv) under N2 atmosphere. The mixture was heated to 80°C and stirred for 15 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give tert-butyl (E)-(3-(N-hydroxycarbamimidoyl)cyclobutyl)carbamate (5) (520.0 mg). LCMS (ESI): m / z 230.2 [M+H] + . Synthesis of tert-butyl (E)-(3-carbamimidoylcyclobutyl)carbamate

[0295] Option 2E

[0296] To a solution of tert-butyl (E)-(3-(N-hydroxycarbamimidoyl)cyclobutyl)carbamate (5) (520.0 mg, 2.3 mmol, 1.0 equiv) in MeOH (100 mL) under N2 was added Raney-Ni (200 mg, 2.3 mmol, 1.0 equiv). The suspension was degassed in vacuo and purged with H2 several times. The mixture was stirred at 0°C under H2 for 8 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (E)-(3-carbamimidoylcyclobutyl)carbamate (6) (480.0 mg). LCMS (ESI): m / z 214.2 [M+H] + . Synthesis of tert-butyl (E)-((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)carbamate

[0297] Plan 2F

[0298] To a solution of tert-butyl (E)-(3-carbamimidoylcyclobutyl)carbamate (6) (480.0 mg, 2.3 mmol, 1.0 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (7) (431.3 mg, 2.5 mmol, 1.1 equiv) in t-BuOH (30 mL) was added TEA (1.3 g, 12.8 mmol, 5.6 equiv) in one portion under N2 at 15°C. The mixture was heated to 100°C and stirred for 15 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 100% to 95%) to give tert-butyl (E)-((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)carbamate (8) (630.1 mg). LCMS (ESI): m / z 338.1 [M+H] + . Synthesis of (E)-2-((1r,3r)-3-aminocyclobutyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0299] Plan 2G

[0300] To a stirred solution of (8) (630 mg, 1.9 mmol, 1.0 equiv) in DCM (30.0 mL) was added TFA (3.0 mL, 39.5 mmol, 20.8 equiv) at 25°C. The reaction mixture was stirred at 25°C under N2 atmosphere for 5 hours. The reaction mixture was concentrated in vacuo to afford (E)-2-((1r,3r)-3-aminocyclobutyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (9) (656.5 mg). LCMS (ESI): m / z 238.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ (ppm): 8.41 (brs, 3H), 3.75-3.71 (m, 1H), 3.47 (s, 2H), 3.43-3.80 (m, 1H), 2.90-2.87 (m, 4H), 2.66-2.53 (m, 4H). Synthesis of (E)-3-nitro-4-(((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)amino)benzonitrile

[0301] Plan 2H

[0302] To a solution of (9) (443.1 mg, 1.9 mmol, 1.0 equiv) and 4-fluoro-3-nitrobenzonitrile (10) (248.3 mg, 1.5 mmol, 0.8 equiv) in DMF (30 mL) was added Cs2CO3 (1.5 g, 4.6 mmol, 2.4 equiv) in one portion at 15°C under N2. The reaction mixture was stirred at 15°C under N2 for 15 hours, and then the mixture was diluted with 50 mL of water. The resulting solution was extracted with EA (2 x 60 mL), and the organic layers were combined. The resulting mixture was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated to give (E)-3-nitro-4-(((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)amino)benzonitrile (11) (500.9 mg). LCMS (ESI): m / z 384.0 [M+H] + . Synthesis of (E)-3-amino-4-(((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)amino)benzonitrile

[0303] Plan 2J

[0304] To a solution of (11) (200.0 mg, 0.52 mmol, 1.0 equiv) and TEA (1.0 mL, 7.2 mmol, 13.8 equiv) in MeOH (200 mL) was added Pd / C (200 mg) under N2. The suspension was degassed in vacuo and purged with H2 several times. The mixture was stirred at 15°C under H2 atmosphere for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (E)-3-amino-4-(((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)amino)benzonitrile (12) (180.0 mg). LCMS (ESI): m / z 354.2 [M+H] + .

[0305] Plan 2K

[0306] A solution of (E)-3-amino-4-(((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)amino)benzonitrile (12) (180.0 mg, 0.51 mmol, 1.0 equiv) and TEA (3 mL, 21.7 mmol, 42.6 equiv) in DCM (30 mL) was treated with CDI (918.3 mg, 5.7 mmol, 11.2 equiv) and the reaction was heated to 50° C. for 15 h. The mixture was diluted with 50 mL of water. The resulting solution was extracted with EA (2×60 mL) and the organic layers were combined. The resulting mixture was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. The residue was purified by preparative HPLC to obtain (E)-2-oxo-1-((1r,3r)-3-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)cyclobutyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (Compound 2) (102.0 mg). LCMS (ESI): m / z 380.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6): δ (ppm): 11.40 (s, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.58 (dd, J = 8.0Hz, J = 1.2Hz, 1H), 7.40 (d, J = 1. 2Hz,1H),5.02-4.92(m,1H),3.47(s,2H),3.31-3.24(m,1H),3.10-3.02(m,2H),2.93-2.85(m,4H),2.71-2.63(m,2H).

[0307] Plan 2L

[0308] (Compound 2) (150 mg) was purified by chiral HPLC to obtain (Compound 2-P1) and (Compound 2-P2). LCMS (ESI): m / z 380.0 [M+H] + . 1 H-NMR (Compound 2-P1, 400 MHz, DMSO-d6): δ (ppm): 7.49 (s, 2H), 7.38 (s, 1H), 5.10-5.04 (m, 1H), 3.58-3.50 (m, 1H), 3.47 (s, 2H), 3.17-3.09 (m, 2H), 2.93-2.85 (m, 4H), 2.71-2.63 (m, 2H). 1H-NMR (Compound 2-P2, 400 MHz, DMSO-d6): δ (ppm): 12.49 (s, 1H), 11.39 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 5.02-4.92 (m, 1H), 3.47 (s, 2H), 3.31-3.24 (m, 1H), 3.10-3.01 (m, 2H), 2.93-2.90 (m, 4H), 2.71-2.63 (m, 2H). Compound 3 Synthesis of 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)-7,8-dihydro-3H-thiopyrano[4,3-d]pyrimidin-4(5H)-one (Compound 3) Synthesis of Methyl 2-Bromo-5-cyanobenzoate

[0309] Option 3A

[0310] A mixture of CuBr2 (3.04 g, 13.6 mmol, 1.2 eq) in ACN (50 mL) was added to tBuONO (1.64 g, 15.9 mmol, 1.4 eq) at 0°C. The mixture was stirred for 5 minutes. Methyl 2-amino-5-cyanobenzoate (1) (2.0 g, 11.4 mmol, 1 eq) was added portionwise. The mixture was stirred at room temperature for 16 hours and made acidic (pH = 2) by adding 1 M HCl. The mixture was extracted with EtOAc (3 x 80 mL), and the combined organic extracts were dried over Na2SO4, filtered, and evaporated to give methyl 2-bromo-5-cyanobenzoate (2) (2.7 g, crude product). Synthesis of Methyl 2-Bromo-5-Carboxamidinobenzoate

[0311] Option 3B

[0312] A mixture of methyl 2-bromo-5-cyanobenzoate (2) (2.50 g, 10.4 mmol, 1.0 equiv), ammonium chloride (0.38 g, 5.4 mmol, 2.5 equiv) and sodium methoxide (0.22 g, 5.4 mmol, 2.5 equiv) in MeOH (50 mL) was stirred at 40° C. for 16 hours. The mixture was concentrated to give methyl 2-bromo-5-carbamimidobenzoate (3) (crude). LC-MS (ESI) m / z calculated for C9H9BrN2O2+H + :257.1; measured value:256.9. Synthesis of methyl 2-bromo-5-(4-oxo-4,5,7,8-tetrahydro-3H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate

[0313] Option 3C

[0314] A solution of methyl 2-bromo-5-carbamimidobenzoate (3) (2.5 g, 9.7 mmol, 1.0 equiv), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1.7 g, 9.7 mmol, 1.0 equiv) and K2CO3 (4.0 g, 29.2 mmol, 3.0 equiv) in MeOH (50 mL) was stirred at 70°C for 16 hours. The mixture was cooled and filtered. The filtrate was added to water (300 mL). The solid was filtered and dried to give methyl 2-bromo-5-(4-oxo-4,5,7,8-tetrahydro-3H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate (4) (1.5 g, 3.9 mmol). LC-MS (ESI) m / z calculated value: C 15 H 13 BrN2O3S+H + :382.2; measured value:383.0. 5-(4-Oxo-4,5,7,8-tetrahydro-3H-thiopyrano[4,3-d]pyrimidin-2-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid Synthesis of methyl ester

[0315] Solution 3D

[0316] A mixture of methyl 2-bromo-5-(4-oxo-4,5,7,8-tetrahydro-3H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate (4) (0.60 g, 1.57 mmol, 1.0 equiv), (BPin)2 (0.80 g, 3.15 mmol, 2.0 equiv), Pd(dppf)Cl2 (115 mg, 0.16 mmol, 0.1 equiv) and KOAc (462 mg, 4.72 mmol, 3.0 equiv) in dioxane (15 mL) was stirred at 110° C. for 16 hours. The mixture was diluted with EtOAc (30 mL), washed with water (15 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column (PE: EtOAc = 5: 1 to 1: 1) to give methyl 5-(4-oxo-4,5,7,8-tetrahydro-3H-thiopyrano[4,3-d]pyrimidin-2-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5) (340 mg, 0.79 mmol). LC-MS (ESI) m / z calculated value: C 21 H 25 BN2O5S+H + :429.3; measured value:429.1.

[0317] Plan 3E

[0318] To a solution of methyl 5-(4-oxo-4,5,7,8-tetrahydro-3H-thiopyrano[4,3-d]pyrimidin-2-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5) (0.34 g, 0.79 mmol, 1.0 eq) in THF (15 mL) was added LAH (60 mg, 1.60 mmol, 2.0 eq). The mixture was stirred at 0° C. for 1 hour. The mixture was added to H2O, filtered, and concentrated in vacuo to give a crude product, which was purified by flash chromatography (H2O:CH3CN=90:10 to 50:50) to give 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 3). LC-MS (ESI) m / z calculated value: C 14 H 13 BN2O3S+H + :301.1; measured value:301.0. 1H NMR (400MHz, MeOD): δ8.09 (s, 1H), 8.03 (d, J = 7.6Hz, 1H), 7.84 (d, J = 7.6Hz, 1H), 3.54 (s, 2H), 5.07 (s, 2H), 2.95-2.85 (m, 4H). Compound 4 and Compound 43 Synthesis of 3-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Compound 4) Synthesis of 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzonitrile (Compound 43) Synthesis of 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0319] Option 4A

[0320] To a solution of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1) (5.00 g, 28.7 mmol, 1.00 equiv) and 4-bromobenzamidinium hydrochloride (6.76 g, 28.7 mmol, 1.00 equiv) in EtOH (50 mL) was added K2CO3 (7.93 g, 57.4 mmol, 2 equiv) at 20°C. The mixture was stirred at 80°C for 16 hours. LC-MS showed that (1) was completely consumed. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was suspended in water (100 mL) and then the mixture was stirred at 20°C for 4 hours. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (6.60 g, crude product), which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 8.08-8.02 (m, 2H), 7.72-7.67 (m, 2H), 3.51 (s, 2H), 2.87 (qd, J=4.4, 8.4 Hz, 4H). LC-MS: 324.3 + Br isomer (M+1). Synthesis of 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzonitrile (Compound 43)

[0321] Option 4B

[0322] To a solution of 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (4.50 g, 13.9 mmol, 1 eq) in NMP (45 mL) was added Zn(CN) (981 mg, 8.35 mmol, 530 μL, 0.6 eq) and Pd(PPh) (1.61 g, 1.39 mmol, 0.1 eq) in portions under N2 at 20°C. The mixture was stirred at 100°C for 2 hours. LC-MS showed complete consumption of (2). The resulting mixture was cooled to 20°C and diluted with saturated NaCO (120 mL) at 20°C. The mixture was then extracted with EtOAc (40 mL×3). The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzonitrile (Compound 43) (1.80 g, 6.68 mmol). 1 H NMR (400MHz, DMSO-d6): δ 13.07-12.77 (m, 1H), 8.25 (br d, J = 7.5Hz, 2H), 8.00 (d, J = 8.4Hz, 2H), 3.55 (s, 2H), 2.91 (s, 4H). LC-MS: 270.1 (M+1). Synthesis of (Z)-N'-hydroxy-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzimidamide

[0323] Option 4C

[0324] To a solution of 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzonitrile (Compound 43) (500 mg, 1.86 mmol, 1 equiv) in pyridine (5 mL) was added NH2OH.HCl (258 mg, 3.71 mmol, 2 equiv) and K2CO3 (641 mg, 4.64 mmol, 2.50 equiv) at 20°C. The mixture was stirred at 100°C for 13 hours. LC-MS showed that (Compound 43) had been consumed. After cooling to 20°C, the reaction mixture was filtered, the filter cake dried, and concentrated under reduced pressure to give a residue. The resulting residue was suspended in water (5.00 mL), and the mixture was stirred at 20°C for 4 hours. The mixture was filtered, the filter cake was dried, and concentrated under reduced pressure to afford (Z)-N'-hydroxy-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzimidamide (4) (333 mg, crude), which was used in the next step without further purification. LC-MS: 302.9 (M+1).

[0325] Plan 4D

[0326] To a solution of (Z)-N'-hydroxy-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzimidamide (4) (333 mg, 1.10 mmol, 1 eq) in pyridine (3.30 mL) was added CDI (268 mg, 1.65 mmol, 1.50 eq) at 20°C. The mixture was stirred at 110°C for 3 hours. LC-MS showed complete consumption of (4). After cooling to 20°C, the mixture was filtered, the filter cake was dried, and concentrated under reduced pressure to give a residue, which was stirred in DCM (2 mL) at room temperature for 6 hours. The mixture was filtered, the filter cake was dried, and concentrated under reduced pressure to obtain 3-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one (Compound 4). 1 H NMR (400MHz, DMSO-d6): δ 13.26-12.46 (m, 1H), 8.23 (d, J = 8.5Hz, 2H), 7.94 (d, J = 8.5Hz, 2H), 7.18 (s, 1H), 3.55 (s, 2H), 2.91 (s, 4H). LC-MS: 329.1 (M+1). Compound 5 Synthesis of (E)-(5-(2-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)vinyl)-2-(trifluoromethyl)phenyl)boronic acid (Compound 5) become Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzaldehyde

[0327] Option 5A

[0328] To a solution of 3-bromo-4-(trifluoromethyl)benzaldehyde (1) (0.50 g, 1.98 mmol, 1.00 equiv) and Pin2B2 (753 mg, 2.96 mmol, 1.50 equiv) in DMSO (10.0 mL) at 25°C under N2 atmosphere were added KOAc (1.36 g, 13.8 mmol, 7.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (161 mg, 198 μmol, 0.10 equiv). The suspension was degassed in vacuo and purged with N2 several times. The mixture was then warmed to 80°C and stirred at 80°C for 2 hours. Thin layer chromatography (TLC; petroleum ether / ethyl acetate = 20 / 1) indicated complete consumption of 3-bromo-4-(trifluoromethyl)benzaldehyde (1). The mixture was cooled to 25°C and diluted with EtOAc (5.00 mL). The mixture was filtered, and the filtrate was washed with water (5.00 mL x 2) and saturated brine (5.00 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzaldehyde (2) (0.20 g, crude product), which was used in the next step without further purification. Synthesis of 2-methyl-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0329] Option 5B

[0330] To a solution of acetamidine hydrochloride (4) (814 mg, 8.61 mmol, 1.50 equiv) in MeOH (10.0 mL) were added K2CO3 (1.98 g, 14.4 mmol, 2.50 equiv) and 4-oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester (3) (1.00 g, 5.74 mmol, 1.00 equiv). The mixture was stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 8 / 1) indicated that 4-oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester (3) was completely consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, i.e., 2-methyl-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (1.00 g, crude product), which was used in the next step without further purification. The obtained compound was purified by 1 H NMR confirmation. (E)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyran Synthesis of [4,3-d]pyrimidin-4-one

[0331] Option 5C

[0332] To a solution of 2-methyl-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (0.20 g, 666 μmol, 1.21 equiv) in Ac2O (1.00 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzaldehyde (2) (0.10 g, 549 μmol, 1.00 equiv), ZnCl2 (150 mg, 1.10 mmol, 51.4 μL, 2.00 equiv) and AcOH (65.9 mg, 1.10 mmol, 62.8 μL, 2.00 equiv) at 25° C. under N2. The mixture was stirred at 120° C. for 4 h. LC-MS (ET48116-9-P1A) showed complete consumption of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-benzaldehyde (2), with the detection of a major peak with the desired m / z. The mixture was cooled to 25°C and then concentrated under reduced pressure to remove most of the AcO. The resulting residue was dissolved in EtOAc (5.00 mL) and washed with saturated NaHCO (2.00 mL x 2). The organic layer was separated and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give (E)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (6) (0.25 g, crude).

[0333] Plan 5D

[0334] A mixture of (E)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (6) (0.25 g, 538.44 μmol, 1 eq) in HCl / H2O (4 M, 2.50 mL) was stirred at 80°C for 2 h. LC-MS showed complete consumption of the starting material (6). The reaction mixture was concentrated under reduced pressure to give a residue, which was then purified by preparative HPLC (column: Phenomenex luna C1880*40 mm*3 μm; mobile phase: [water(HCl)-ACN]; B%: 18%-48%, 7 minutes) to give (E)-(5-(2-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)vinyl)-2-(trifluoromethyl)phenyl)boronic acid (Compound 5). LC-MS: 383.0 (M+1). 1 H NMR (400MHz, DMSO-d6): δ = 7.89 (br d, J = 16.4Hz, 1H), 7.80-7.66 (m, 3H), 7.04 (br d, J = 16.3Hz, 1H), 3.51 (br s, 2H), 2.93-2.81 (m, 4H). Compound 6 Synthesis of (E)-2-(4-trifluoromethyl)phenylvinyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 6) Synthesis of 2-methyl-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0335] Plan 6A

[0336] To a solution of acetamidine / hydrochloride (814 mg, 8.61 mmol, 1.50 equiv) in MeOH (10.0 mL) was added K2CO3 (1.98 g, 14.4 mmol, 2.50 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1) (1.00 g, 5.74 mmol, 1.00 equiv). The mixture was stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 8 / 1) indicated that the starting material (1) was completely consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, 2-methyl-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (1.00 g, crude product), which was used in the next step without further purification.

[0337] Plan 6B

[0338] To a solution of 2-methyl-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (0.25 g, 1.37 mmol, 1.00 equiv) in Ac2O (2.50 mL) at 20°C was added 4-(trifluoromethyl)benzaldehyde (244 mg, 1.40 mmol, 187 μL, 1.02 equiv). The mixture was stirred at 110°C for 12 hours. The mixture was cooled to 20°C and concentrated under reduced pressure to obtain a residue. The mixture was diluted with H2O (2.00 mL) and extracted with EtOAc (2.00 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. A portion of the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40%-65%, 10 minutes) to afford (E)-2-(4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 6). LCMS: 339.1 (M+1). 1 H NMR (400MHz, DMSO-d6): δ=12.62-12.51(m,1H), 7.91-7.73(m,5H), 7.04-6.92(m,1H), 3.52-3.45(m,2H), 2.89-2.79(m,4H). Compound 7 Synthesis of 2-(4-(6-bromopyridin-3-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 7) Synthesis of 4-(6-bromopyridin-3-yl)benzonitrile

[0339] Plan 7A

[0340] A mixture of (4-cyanophenyl)boronic acid (1) (50.0 g, 340.0 mmol, 1.0 equiv), 2-bromo-5-iodopyridine (96.6 g, 340.2 mmol, 1.0 equiv) and K2CO3 (141.0 g, 1.02 mol, 3.0 equiv) in dioxane (3.2 L) and water (800 mL) was stirred at 60°C for 16 hours. The mixture was filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give 4-(6-bromopyridin-3-yl)benzonitrile (2) (63.0 g). LC-MS (ESI) m / z calculated value: C 12 H7BrN2+H + :261.0; Measured value:261.1( 81 This reaction is shown in Scheme 7A. Synthesis of 4-(6-bromopyridin-3-yl)-N-hydroxybenzamidine

[0341] Plan 7B

[0342] A mixture of 4-(6-bromopyridin-3-yl)benzonitrile (2) (60 g, 231.6 mmol, 1.0 equiv), NH2OH·HCl (40.2 g, 579 mmol, 2.5 equiv) and NaOH (23.16 g, 579 mmol, 2.5 equiv) in EtOH (500 mL) was stirred at 80°C for 3 hours. The mixture was diluted with EtOH (100 mL) and filtered. The filtrate was concentrated to give 4-(6-bromopyridin-3-yl)-N-hydroxybenzimidamide (3) (40 g, crude). LC-MS (ESI) m / z calculated value: C 12 H 10 BrN3O+H + :294.0; Measured value:294.1( 81 This reaction is shown in Scheme 7B. Synthesis of 4-(6-bromopyridin-3-yl)benzamidine

[0343] Plan 7C

[0344] A mixture of 4-(6-bromopyridin-3-yl)-N-hydroxybenzimidamide (3) (40.0 g, 136.8 mmol, 1.0 equiv), NH4Cl (146.48 g, 3.460 mol, 20 equiv) and Fe (230.04 g, 2.74 mol, 20 equiv) in EtOH (600 mL) was stirred at 80°C for 48 hours. The mixture was cooled and filtered. The solvent was removed in vacuo to give 4-(6-bromopyridin-3-yl)benzimidamide (4) (30.0 g, crude product). LC-MS (ESI) m / z calculated: C 12 H 10 BrN3+H + :276.0; Measured value:276.1( 79 This reaction is shown in Scheme 7C.

[0345] Plan 7D

[0346] A mixture of 4-(6-bromopyridin-3-yl)benzimidamide (4) (30.0 g, 108.6 mmol, 1.0 equiv), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (37.8 g, 217.2 mmol, 2 equiv) and K2CO3 (45.0 g, 325.8 mmol, 3.0 equiv) in MeOH (500 mL) was stirred at 70°C for 4 hours. The mixture was concentrated under reduced pressure. The residue was washed with water (200 mL) and filtered. The solid was triturated in MeOH (150 mL), EtOAc (150 mL) and acetone (100 mL) to remove most of the impurities. The mixture was filtered. The crude solid was triturated in aqueous NaOH solution (1% wt, 20 mL) and filtered. The solid was washed with water (50 mL) and acetone (100 mL) and dried under vacuum to give 2-(4-(6-bromopyridin-3-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 7). LC-MS (ESI) m / z calculated value: C 18 H 14 BrN3OS+H + :402.0; measured value:401.9( 81 isotopes of Br). 1H NMR (400 MHz, DMSO): δ 12.82 (brs, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 8.3 Hz, 2H), 8.14 (dd, J = 8.4, 2.4 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.4 Hz, 1H), 3.54 (s, 2H), 2.91 (brs, 4H). This reaction is shown in Scheme 7D. Compound 8 Synthesis of 2-(4-(2-(2-hydroxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 8) Synthesis of Methyl 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate

[0347] Plan 8A

[0348] To a solution of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1) (2 g, 11.48 mmol, 1 eq) in MeOH (20 mL) was added methyl 4-carbamimidobenzoate hydrochloride (1a) (3.20 g, 14.91 mmol, 1.30 eq) and K2CO3 (4.00 g, 28.94 mmol, 2.52 eq) at 25°C. The mixture was stirred at 25°C for 12 hours. The mixture was filtered and the filter cake was concentrated under reduced pressure to obtain a residue. The residue was suspended in H2O (40 mL) and the mixture was stirred at 25°C for 12 hours. The mixture was filtered and the filter cake was dried under vacuum to obtain methyl 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate (2) (1.5 g, crude). The crude product was used directly in the next step without further purification. This reaction is shown in Scheme 8A. Synthesis of 2-(4-(2-hydroxypropan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0349] Plan 8B

[0350] To a solution of methyl 4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate (2) (0.3 g, 992.24 μmol, 1 eq) in THF (3 mL) was added dropwise MeMgBr (3 M, 992.24 μL, 3 eq) under N2 and 0°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched by the addition of NH4Cl (5 mL), and the aqueous phase was extracted with 10 mL of DCM (5 mL x 2). The organic layers were combined and concentrated under reduced pressure to give a residue, namely 2-(4-(2-hydroxypropan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (3) (2 g, crude product), which was used directly in the next step without further purification. 1 H NMR: ET47629-1-P1A (400 MHz, CDCl3): δ 12.54-12.27 (m, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 3.62 (br s, 2H), 3.03-2.94 (m, 2H), 2.91-2.82 (m, 2H), 1.55 (s, 6H). This reaction is shown in Scheme 8B.

[0351] Plan 8C

[0352] To a solution of 2-(4-(2-hydroxypropan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (3) (0.12 g, 396.84 μmol, 1 eq) in ethylene glycol (5 mL) was added TosOH (82.00 mg, 476.21 μmol, 1.2 eq) at 20° C. The mixture was stirred at 20° C. for 1 hour, then heated to 80° C. and stirred at 80° C. for 12 hours. The mixture was directly purified by preparative HPLC (neutral conditions, column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 10%-50%, 10 minutes) to obtain 2-(4-(2-(2-hydroxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 8). LC-MS: 347.2 (M+1). 1H NMR: ET47430-4-P1A1 (400 MHz, CDCl3): δ 8.14 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 3.80-3.69 (m, 4H), 3.34 (t, J = 4.6 Hz, 2H), 3.14-3.06 (m, 2H), 3.01-2.93 (m, 2H), 1.62 (s, 6H). This reaction is shown in Scheme 8C. Compound 9 Synthesis of 2-(4'-bromo-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 9) Synthesis of 4'-bromo-[1,1'-biphenyl]-4-carboxamidine

[0353] Plan 9A

[0354] To a mixture of 4'-bromo-[1,1'-biphenyl]-4-carbonitrile (1) (4 g, 15.5 mmol, 1 eq) in THF (40 mL) was added dropwise NaHMDS (1 M, 18.60 mL, 1.2 eq) under N2 at 25°C. The mixture was stirred at 25°C for 1 hour to obtain a liquid. The reaction mixture was quenched by the addition of water (30 mL) at 25°C. The pH of the mixture was adjusted to 2-3 by the addition of 1 M HCl. The aqueous layer was separated and evaporated to about 15% of its original volume to obtain the desired HCl salt crystals. The mixture was filtered and the filter cake was dried under vacuum to obtain 4'-bromo-[1,1'-biphenyl]-4-carboximidamide (2) (4.53 g, 14.5 mmol, HCl). The crude product was used in the next step without further purification. 1 H NMR: (400MHz, DMSO-d6): δ9.44(s,2H),9.19(s,2H),7.94(s,4H),7.81-7.65(m,4H).

[0355] Plan 9B

[0356] To a solution of 4'-bromo-[1,1'-biphenyl]-4-carboximidamide (2) (0.066 g, 378.8 μmol, 1.1 eq) in MeOH (1.8 mL) was added methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3) (107.3 mg, 344.4 μmol, 1 eq, HCl) and K2CO3 (95.2 mg, 688.8 μmol, 2 eq) at 25°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered and the filter cake was dried under vacuum to obtain a residue. The crude product was purified by precipitation with DMSO (3 mL) to give 2-(4'-bromo-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 9). LC-MS: 399.19 (M+1). 1 H NMR: ET48394-6-P1A (400MHz, DMSO-d6): δ12.86-12.62 (m, 1H), 8.21 (d, J=8 .3Hz,2H),7.86-7.81(m,2H),7.75-7.68(m,4H),3.55(s,2H),2.91(s,4H). Compound 10 Synthesis of (4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 10) 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidine-4-yl Synthesis of ketones

[0357] Plan 10A

[0358] To a mixture of 2-(4'-bromo-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (compound 9) (0.31 g, 776.4 μmol, 1 eq) and B2Pin2 (394.3 mg, 1.55 mmol, 2 eq) in dioxane (6 mL) was added KOAc (152.4 mg, 1.55 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (63.4 mg, 77.6 μmol, 0.1 eq) in portions at 25 ° C and N2. The mixture was degassed in vacuo and purged with N2 three times. The reaction mixture was then heated to 100 ° C and stirred for 16 hours. A suspension was obtained. The crude product was triturated with water (10 mL) at 25 ° C for 2 hours. The mixture was filtered and the filter cake was washed with DCM (5 mL) and MeOH (5 mL). The filter cake was dried under reduced pressure to give 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (0.18 g), which was used in the next step without further purification.

[0359] Plan 10B

[0360] To a round-bottom flask at 25°C was added 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (0.18 g, 403.2 μmol, 1 eq) and HCl (4 M, 4 mL, 39.7 eq). The reaction mixture was stirred at 80°C for 4 h. The mixture was filtered and the filter cake was washed with DCM (5 mL) and MeOH (5 mL). The filter cake was dried under vacuum to afford (4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 10). LC-MS: 365.1 (M+1). 1 H NMR: ET48394-20 (400MHz, DMSO-d6): δ8.20 (d, J = 8.5 Hz, 2H), 7.89 (dd, J = 8.3, 19.4 Hz, 4H), 7.74 (d, J = 8.2 Hz, 2H), 3.55 (s, 2H), 2.92 (s, 4H). Compound 11 Synthesis of 2-(4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 11) Synthesis of 4-(2-chloropyrimidin-5-yl)benzonitrile

[0361] Plan 11A

[0362] To a mixture of (2-chloropyrimidin-5-yl)boronic acid (2) (9.57 g, 60.43 mmol, 1.10 equiv) and 4-bromobenzonitrile (1) (10.0 g, 54.9 mmol, 1.00 equiv) in dioxane (200 mL) and H2O (20.0 mL) was added K2CO3 (15.2 g, 110 mmol, 2.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (4.49 g, 5.49 mmol, 0.10 equiv) in one portion at 25°C under N2. The mixture was degassed with N2 and then stirred at 100°C for 16 hours. A liquid was obtained. The reaction mixture was diluted with water (200 mL) and then extracted with 600 mL of EtOAc (200 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography ( 200g Silica gel flash chromatography column, eluent: 0-20% ethyl acetate / petroleum ether, gradient elution, flow rate: 100 mL / min, R f =0.25) to give 4-(2-chloropyrimidin-5-yl)benzonitrile (3) (1.1 g), which was used as a crude product in the next step. Synthesis of 4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzonitrile

[0363] Plan 11B

[0364] To a mixture of 4-(2-chloropyrimidin-5-yl)benzonitrile (3) (0.70 g, 3.25 mmol, 1.00 equiv) in THF (4.00 mL) and ethylene glycol (4.00 mL) was added K2CO3 (897 mg, 6.49 mmol, 2.00 equiv) at 25°C under N2. The mixture was stirred at 70°C for 16 hours. A suspension was obtained. The reaction mixture was diluted with water (20 mL) and then extracted with 30 mL of EtOAc (10 mL×3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography ( 40g Silica gel flash chromatography column, eluent: 0-50% ethyl acetate / petroleum ether, gradient elution, flow rate: 40 mL / min, R f =0.27) to give 4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzonitrile (4) (540 mg, 2.24 mmol), which was used crude in the next step. Synthesis of (Z)-N'-hydroxy-4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzamidine

[0365] Plan 11C

[0366] To a mixture of 4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzonitrile (4) (0.54 g, 2.24 mmol, 1.00 equiv) in MeOH (5.00 mL) at 25° C. under N2 was added NH2OH.HCl (171 mg, 2.46 mmol, 1.10 equiv) and NaHCO3 (207 mg, 2.46 mmol, 95.8 μL, 1.10 equiv) in one portion. The mixture was stirred at 65° C. for 16 hours. A liquid was obtained. The reaction mixture was filtered and concentrated under reduced pressure to give (Z)-N′-hydroxy-4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzimidamide (5) (500 mg, crude), which was used in the next step without further purification. Synthesis of 4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzamidine

[0367] Plan 11D

[0368] To a mixture of (Z)-N'-hydroxy-4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzimidamide (5) (0.50 g, 1.82 mmol, 1.00 equiv) in AcOH (2.62 g, 43.7 mmol, 2.50 mL) at 25°C under N2 was added Ac2O (744 mg, 7.29 mmol, 683 μL, 4.00 equiv) in one portion. The mixture was stirred at 25°C for 30 min. MeOH (20 mL) and Pd / C (0.2 g, 218.76 μmol) were then added. The resulting mixture was degassed with H2 three times and stirred at 25°C under H2 (15 psi) for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give 4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzimidamide (6) (500 mg, crude), which was used in the next step without further purification.

[0369] Plan 11E

[0370] To a mixture of 4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)benzimidamide (6) (500 mg, 1.94 mmol, 1.00 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (7) (438 mg, 2.52 mmol, 1.30 equiv) in MeOH (4.00 mL) was added KCO (535 mg, 3.87 mmol, 2.00 equiv) in one portion under N2 atmosphere at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (chromatographic column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes) to obtain 2-(4-(2-(2-hydroxyethoxy)pyrimidin-5-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 11). 1 H NMR (400MHz, DMSO-d6) δ = 13.15-12.49 (m, 1H), 9.03 (s, 2H), 8.21 (br d,J=8.2Hz,2H),7.91(d,J=8.6Hz,2H),4.93(t,J=5.5Hz,1H),4.42-4.36(m, 2H), 3.76 (q, J = 5.4Hz, 2H), 3.54 (s, 2H), 2.95-2.86 (m, 4H). LCMS: 383 (M+1). Compound 12 Synthesis of 2-(4'-(2-(2-hydroxyethoxy)propan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 12) become Synthesis of 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0371] Plan 12A

[0372] To a mixture of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1) (8.00 g, 45.9 mmol, 1.00 equiv) and 4-bromobenzimidamide (3) (11.9 g, 50.5 mmol, 1.10 equiv, HCl) in EtOH (100 mL) was added KCO (12.7 g, 91.8 mmol, 2.00 equiv) in one portion at 25°C under N2. The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (15.6 g, crude product), which was used in the next step without further purification. 1 HNMR: (400MHz, DMSO-d6): δ8.19-8.13(m,2H),7.53-7.46(m,2H),3.42(s,2H),2.81-2.75(m,2H),2.74-2.67(m,2H). Synthesis of 2-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0373] Plan 12B

[0374] To a mixture of 2-(4-bromophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (2) (4.00 g, 12.4 mmol, 1.00 equiv) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (4) (2.67 g, 14.9 mmol, 1.20 equiv) in dioxane (40.0 mL) and H2O (5.00 mL) was added K2CO3 (3.42 g, 24.8 mmol, 2.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (1.01 g, 1.24 mmol, 0.10 equiv) in one portion at 25°C under N2. The mixture was degassed in vacuo and purged with N2 three times, then heated to 100°C and stirred for 16 hours. The reaction mixture was diluted with EtOAc (20.0 mL) and filtered. The filter cake was washed with water (10 mL) and MeOH (10 mL) to give 2-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (2.10 g, 5.55 mmol, crude), which was used in the next step without further purification. 1 H NMR: (400MHz, DMSO-d6): δ=13.13-12.31(m,1H),8.51-7.75(m,4H),7.75-7.15(m,4H),5.07(br d,J=3.2Hz,1H),3.54(br s,2H),2.90(br s,4H),1.78-0.88(m,6H).

[0375] Plan 12C

[0376] To a mixture of 2-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (1.50 g, 3.96 mmol, 1.00 equiv) in DMF (10.0 mL) at 25°C under N2 was added TosOH (819 mg, 4.76 mmol, 1.20 equiv) and ethylene glycol (5.55 g, 89.4 mmol, 5.00 mL, 22.6 equiv) in one portion. The mixture was stirred at 85°C for 16 hours. The mixture was cooled to room temperature and filtered. The filter cake was dissolved in DMSO and then directly purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-MEOH]; B%: 40%-65%, 8 minutes) to obtain 2-(4'-(2-(2-hydroxyethoxy)propan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 12). LCMS: 423.2 (M+1). 1 H NMR: (400MHz, chloroform-d): δ11.47-10.94(m,1H),8.14(d,J=8.4Hz,2H),7.76(d,J=8.5Hz,2H),7.67-7.61(m,2H),7.54 (d,J=8.4Hz,2H),3.80-3.69(m,4H),3.41-3.31(m,2H),3.10-3.03(m,2H),2.99-2.91(m,2H),1.66-1.62(m,6H). Compound 13 Synthesis of 2-(4-trifluoromethylphenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one-8,8-d2 (Compound 13) Synthesis of methyl-d3 4-oxotetrahydro-2H-thiopyran-3-carboxylate-3,5,5-d3

[0377] Plan 13A

[0378] A mixture of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (1) (0.9 g, 5.16 mmol, 1.0 eq) and NaH (2.1 mg, 0.051 mmol, 0.01 eq) in MeOD (13.5 mL) was stirred at 65° C. for 2 h. The crude product methyl-d3 4-oxotetrahydro-2H-thiopyran-3-carboxylate-3,5,5-d3 (2) was obtained in MeOD solution. 1 H NMR (400MHz, MeOD): δ3.23-3.07(m,1H),2.95(s,1H),2.76(s,1H),2.73(s,2H).

[0379] Plan 13B

[0380] A mixture of (2) (0.90 g, 5.07 mmol, 1.11 equiv) and 4-(trifluoromethyl)benzimidamide (0.861 g, 4.56 mmol, 1.0 equiv) in MeOD (12 mL) was stirred at 65°C for 1 hour. The mixture was concentrated to half its volume and then added to H2O (50 mL). The precipitate was filtered, washed with H2O (30 mL) and MeOH / H2O (20 mL, 1:1, v / v), and dried in vacuo to give 2-(4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one-8,8-d2 (Compound 13). LC-MS (ESI) m / z calculated value: C 14 H9D2F3N2OS+H + :315.1; Measured value:315.1. 1 H NMR (400MHz, DMSO-d6): δ8.29(d,J=8Hz,2H),7.88(d,J=8Hz,2H),3.54(s,2H),2.89(s,2H). 19 F NMR (375MHz, DMSO-d6): δ61.33 (s, 3F). Compound 14 Synthesis of (2,6-difluoro-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid (Compound 14) Synthesis of 3,5-difluorobenzamidine

[0381] Plan 14A

[0382] To a solution of 3,5-difluorobenzonitrile (1) (5.0 g, 36.0 mmol, 1.0 equiv) in MeOH (50 mL) was added MeONa (3.9 g, 71.9 mmol, 2.0 equiv); the mixture was stirred at 20°C for 4 hours. To the mixture was added NH4Cl (3.9 g, 71.9 mmol, 2.0 equiv), and the mixture was stirred at 40°C for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give 3,5-difluorobenzamidine (2) (7 g, crude product). LC-MS 157.4 [M+H] + . Synthesis of 2-(3,5-difluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0383] Plan 14B

[0384] To a mixture of 3,5-difluorobenzamidine (2) (7 g, 44.9 mmol, 1.0 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3) (6.2 g, 35.9 mmol, 0.8 equiv) in MeOH (50 mL) was added K2CO3 (12.4 g, 89.7 mmol, 2.0 equiv) under N2 atmosphere. The mixture was stirred at 75°C for 2 hours. The reaction mixture was concentrated to give 2-(3,5-difluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4), which was used directly in the next step. LC-MS 281.1 [M+H] + . Synthesis of 2-(3,5-difluorophenyl)-4-((2-methoxyethoxy)methoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine

[0385] Plan 14C

[0386] To a mixture of 2-(3,5-difluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (crude, 1.0 equiv) in DMA (50 mL) was added 1-(chloromethoxy)-2-methoxyethane (11.2 g, 89.7 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 3 hours, then poured into water (300 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with 300 mL of saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexane to give 2-(3,5-difluorophenyl)-4-((2-methoxyethoxy)methoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (5) (6 g). LC-MS: 369.2[M+H] + . Synthesis of (2,6-difluoro-4-(4-((2-methoxyethoxy)methoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid

[0387] Plan 14D

[0388] To a mixture of 2-(3,5-difluorophenyl)-4-((2-methoxyethoxy)methoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (5) (400 mg, 1.4 mmol, 1.0 equiv) in anhydrous THF (10 mL) was cooled to -78°C and LDA (2 M, 1.1 mL, 1.5 equiv) was added dropwise; the mixture was stirred at -78°C for 1 hour. Trimethyl borate (191 mg, 1.9 mmol, 1.3 equiv) was added, and the mixture was stirred at -78°C for 3 hours. The mixture was quenched with NH4Cl solution (30 mL) and then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (0-50% acetonitrile / 0.05% formic acid) to give (2,6-difluoro-4-(4-((2-methoxyethoxy)methoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid (6) (200 mg). LC-MS: 413.4 [M+H] + .

[0389] Plan 14E

[0390] A mixture of (2,6-difluoro-4-(4-((2-methoxyethoxy)methoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid (6) (200 mg, 0.48 mmol, 1.0 equiv) in FA (3 mL) was stirred at room temperature for 2 h. After concentration, the residue was purified by preparative HPLC to give (2,6-difluoro-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)boronic acid (Compound 14). LC-MS 325.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.85 (s, 1H), 8.86 (s, 2H), 7.72 (d, J = 7.2Hz, 2H), 3.54 (s, 2H), 2.90 (s, 4H). Compound 15 Synthesis of 2-(3,5-difluoro-4-(2-(2-hydroxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 15) Synthesis of Methyl 4-Cyano-2,6-Difluorobenzoate

[0391] Plan 15A

[0392] To a solution of 4-cyano-2,6-difluorobenzoic acid (1) (5.00 g, 27.31 mmol, 1.0 eq) in THF (50 mL) / MeOH (50 mL) was added TMSCHN2 (2 M, 20.48 mL, 1.5 eq) dropwise at 25°C. The mixture was stirred at 25°C for 13 hours. TLC indicated (petroleum ether / ethyl acetate = 5 / 1, R f (Compound 1) = 0.33) (1) was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a residue, namely, methyl 4-cyano-2,6-difluorobenzoate (2) (4.1 g, crude product). Synthesis of methyl 4-carbamimidoyl-2,6-difluorobenzoate

[0393] Plan 15B

[0394] To a solution of methyl 4-cyano-2,6-difluorobenzoate (2) (2.00 g, 10.15 mmol, 1.0 equiv) in THF (20 mL) at 0°C was added LiHMDS (1 M, 15.22 mL, 1.5 equiv). The mixture was stirred at 20°C for 16 hours. LC-MS (ET68120-10-P1A1) showed that (2) was completely consumed and the desired mass was detected. The reaction mixture was quenched by the addition of HCl / dioxane (4 mol / L, 8 mL) at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was triturated with MeOH (40 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was then filtered and the filter cake was dried under reduced pressure. Methyl 4-carbamimidoyl-2,6-difluorobenzoate (3) (2.6 g, crude, HCl) was used directly in the next step without further purification. Synthesis of methyl 2,6-difluoro-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate

[0395] Plan 15C

[0396] To a solution of methyl 4-carbamimidoyl-2,6-difluorobenzoate (3) (470 mg, 1.88 mmol, 1.0 equiv, HCl) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3a) (327 mg, 1.88 mmol, 1.0 equiv) in MeOH (4.7 mL) was added KCO (778 mg, 5.63 mmol, 3.0 equiv) at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS showed complete consumption of (3) and a peak of the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge Prep OBD C18 150x40mm x10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes) to give methyl 2,6-difluoro-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate (4) (180 mg). Synthesis of 2-(3,5-difluoro-4-(2-hydroxypropyl-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0397] Plan 15D

[0398] To a solution of methyl 2,6-difluoro-4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)benzoate (4) (300 mg, 887 μmol, 1.0 eq) in THF (5.0 mL) was added MeMgBr (3 M, 1.03 mL, 3.5 eq) at 0°C. The mixture was stirred at 25°C for 1 hour. TLC (petroleum ether / ethyl acetate = 1 / 1, R f (Compound 4) = 0.60) indicated that (4) was completely consumed, forming two new spots. LC-MS (ET65158-9-P1A1) indicated that (4) was completely consumed, and a main peak with the desired MS was detected. The reaction mixture was quenched by adding NH4Cl (15 ml) at 0°C, and then extracted with 45 mL of EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 1) to give 2-(3,5-difluoro-4-(2-hydroxypropan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (150 mg, crude), which was used immediately in the next step. LC-MS (ET65158-9-P1A1, Product: R t =0.575mins).

[0399] Plan 15E

[0400] To a solution of 2-(3,5-difluoro-4-(2-hydroxypropyl-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (20.0 mg, 59.11 μmol, 1.0 eq) in ethylene glycol (1.59 g, 25.62 mmol, 1.43 mL, 433.41 eq) was added TosOH (12.7 mg, 73.88 μmol, 1.25 eq) at 25°C. The mixture was stirred at 80°C for 12 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, R f (Compound 5) = 0.53) indicated complete consumption of (5), forming two new spots. After cooling to 25°C, the mixture was concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1) to obtain 2-(3,5-difluoro-4-(2-(2-hydroxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 15). LC-MS: 383.1 (M+1).1 H NMR (400MHz, DMSO-d6): δ = 7.78-7.70 (m, 2H), 4.49-4.45 (m, 1H) 3.47-3.43 (m, 4H), 3.21-3.17 (m, 2H), 2.85 ~ 2.75 (m, 4H), 1.637 (s, 6H). Compound 16 Synthesis of 2-(3,5-difluoro-4-(2-(2-methoxyethoxy)prop-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 16) become

[0401] Plan 16A

[0402] The synthesis of 2-(3,5-difluoro-4-(2-hydroxypropan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) is shown in Schemes 15A-15D.

[0403] To a solution of 2-(3,5-difluoro-4-(2-hydroxypropyl-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (50.0 mg, 147 μmol, 1.0 eq) in 2-methoxyethanol (0.5 mL) at 25°C was added TosOH (31.6 mg, 183 μmol, 1.24 eq), and the mixture was heated to 85°C and stirred for 13 hours. LC-MS showed that approximately 17% of (5) remained. LC-MS showed several new peaks, and the target compound was detected. After cooling to 25°C, the reaction mixture was purified by preparative HPLC (neutral conditions; column: Waters Xbridge BEH C18 100x30mm x 10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 25%-55%, 8 minutes) to afford 2-(3,5-difluoro-4-(2-(2-methoxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 16). LC-MS: 397.1 (M+1). 1 H NMR (400MHz, DMSO-d6): δ=7.81~7.75(m,2H),3.549(s,2H)3.53~3.38(m,2H),3.35~3.25(m,2H),3.22(s,3H),2.906(m,4H),1.653(s,6H). Compound 17 Synthesis of 2-(4-(2-(2-methoxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 17) Synthesis of 1-bromo-4-(2-(2-methoxyethoxy)prop-2-yl)benzene

[0404] Plan 17A

[0405] To a solution of 2-(4-bromophenyl)propan-2-ol (1) (2.6 g, 12.2 mmol, 1.0 equiv) in 2-methoxyethan-1-ol (20 mL) was added TsOH·H2O (2.3 g, 12.2 mmol, 1 equiv). The mixture was stirred at room temperature for 2 days, then quenched with water (100 mL) and extracted with EtOAc (3×60 mL). The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexane to give 1-bromo-4-(2-(2-methoxyethoxy)propan-2-yl)benzene (2) (2.7 g). 1 H NMR (400MHz, DMSO-d6): δ7.54-7.51(m,2H),7.38-7.35(m,2H),3.42-3.40(m,2H),3.24-3.22(m,5H),1.44(s,6H). Synthesis of 4-(2-(2-methoxyethoxy)prop-2-yl)benzonitrile

[0406] Plan 17B

[0407] To a solution of 1-bromo-4-(2-(2-methoxyethoxy)propan-2-yl)benzene (2) (1.5 g, 3.7 mmol, 1 eq) in NMP (10 mL) were added Zn(CN) (260 mg, 2.2 mmol, 0.6 eq) and Pd(PPh) (430 mg, 0.37 mmol, 0.1 eq). The resulting solution was stirred at 140° C. under argon for 2 hours. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with EtOAc (3×60 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography eluting with 0-40% EtOAc / hexane to give 4-(2-(2-methoxyethoxy)propan-2-yl)benzonitrile (3) (600 mg). 1 H NMR (400MHz, DMSO-d6): δ7.81 (d, J = 8.4Hz, 2H), 7.62 (d, J = 8.4Hz, 2H), 3.44 (t, J = 5.2Hz, 2H), 3.28-3.25 (m, 5H), 1.47 (s, 6H). Synthesis of 4-(2-(2-methoxyethoxy)prop-2-yl)benzamidine

[0408] Plan 17C

[0409] To a solution of 4-(2-(2-methoxyethoxy)propan-2-yl)benzonitrile (3) (0.6 g, 2.7 mmol, 1.0 equiv) in MeOH (5 mL) was added MeONa (295 mg, 5.5 mmol, 2.0 equiv); the mixture was stirred at room temperature for 4 hours. NH4Cl (287 mg, 5.5 mmol, 2.0 equiv) was added, and the mixture was stirred at 40°C for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give 4-(2-(2-methoxyethoxy)propan-2-yl)benzimidamide (4) (285 mg, crude). LC-MS: 237.2 [M+H] + .

[0410] Plan 17D

[0411] Under N2 atmosphere, to a solution of 4-(2-(2-methoxyethoxy)propan-2-yl)benzimidamide (4) (150 mg, 0.7 mmol, 1.0 equiv) in MeOH (5 mL) were added K2CO3 (180 mg, 1.3 mmol, 2.0 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (80 mg, 0.5 mmol, 0.7 equiv). The mixture was stirred at 70°C for 2 hours. It was then concentrated and the residue was purified by preparative HPLC to give 2-(4-(2-(2-methoxyethoxy)propan-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 17). LC-MS: 361.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.70(s,1H),8.06(d,J=8.6Hz,2H),7.54(d,J=8.6Hz,2H),3.52( s, 2H), 3.46-3.41 (m, 2H), 3.25 (d, J = 5.0Hz, 5H), 2.88 (dd, J = 7.6, 4.0Hz, 4H), 1.48 (s, 6H). Compound 18 Methyl (2-((2-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)propan-2-yl)oxy)ethyl)carbamate (Compound 18) Synthesis Synthesis of 1-bromo-4-(2-(2-nitroethoxy)prop-2-yl)benzene

[0412] Plan 18A

[0413] To a solution of 2-(4-bromophenyl)propan-2-ol (1) (2.6 g, 12.2 mmol, 1.0 equiv) in DCM (20 mL) was added TFA (2.3 g, 12.2 mmol, 1.0 equiv) and 2-nitroethan-1-ol (2) (10 mL). The mixture was stirred at room temperature for 3 days. The reaction was quenched with water (100 mL) and then extracted with EtOAc (3 x 60 mL). The organic layer was concentrated and the residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc / hexanes to give 1-bromo-4-(2-(2-nitroethoxy)propan-2-yl)benzene (3) (2.7 g). 1HNMR (400MHz, CDCl3): δ7.80 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.55 (t, J = 4.8 Hz, 2H), 3.69 (t, J = 4.8 Hz, 2H), 1.51 (s, 6H). Synthesis of 2-((2-(4-bromophenyl)propan-2-yl)oxy)ethan-1-amine

[0414] Plan 18B

[0415] To a solution of 1-bromo-4-(2-(2-nitroethoxy)propan-2-yl)benzene (3) (1.5 g, 3.7 mmol, 1.0 equiv) in EtOH / H2O (10 mL / 2 mL) were added Zn (1.2 g, 18.5 mmol, 5.0 equiv) and NH4Cl (1.0 g, 18.5 mmol, 5.0 equiv). The resulting mixture was stirred at 80°C under argon for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with EtOAc (3×60 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give 2-((2-(4-bromophenyl)propan-2-yl)oxy)ethan-1-amine (4) (1.2 g, crude). LC-MS: 258.0, 260.0 [M+H] + . Synthesis of Methyl (2-((2-(4-bromophenyl)propan-2-yl)oxy)ethyl)carbamate

[0416] Plan 18C

[0417] To a solution of 2-((2-(4-bromophenyl)propan-2-yl)oxy)ethan-1-amine (4) (1.2 g, 4.7 mmol, 1.0 equiv) in DCM (10 mL) was added TEA (707 mg, 7.0 mmol, 1.5 equiv) followed by methyl chloroformate (5) (395 mg, 4.2 mmol, 0.9 equiv). The mixture was stirred at room temperature for one day. The reaction was concentrated and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexanes to give methyl (2-((2-(4-bromophenyl)propan-2-yl)oxy)ethyl)carbamate (6) (1.0 g). LC-MS: 357.0, 359.0 [M+H+MeCN] + . Synthesis of Methyl (2-((2-(4-cyanophenyl)propan-2-yl)oxy)ethyl)carbamate

[0418] Plan 18D

[0419] To a solution of methyl (2-((2-(4-bromophenyl)propan-2-yl)oxy)ethyl)carbamate (6) (1.0 g, 3.7 mmol, 1 eq) in NMP (10 mL) was added Zn(CN) (260 mg, 2.2 mmol, 0.6 eq) followed by Pd(PPh) (430 mg, 0.37 mmol, 0.1 eq). The resulting solution was stirred at 140° C. under argon for 2 h. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-40% EtOAc / hexanes to give methyl (2-((2-(4-cyanophenyl)propan-2-yl)oxy)ethyl)carbamate (7) (600 mg). 1 H NMR (400MHz, DMSO): δ7.86–7.76(m,2H),7.64–7.58(m,2H),7.25–7.11(m,1H),3.33(s,3H),3.15–3.04(m,4H),1.46(s,6H). Synthesis of Methyl (2-((2-(4-Carbamimidophenyl)propan-2-yl)oxy)ethyl)carbamate

[0420] Plan 18E

[0421] To a solution of methyl (2-((2-(4-cyanophenyl)propan-2-yl)oxy)ethyl)carbamate (7) (0.6 g, 2.7 mmol, 1.0 equiv) in MeOH (5 mL) was added MeONa (295 mg, 5.5 mmol, 2.0 equiv); the mixture was stirred at room temperature for 4 hours. NH4Cl (287 mg, 5.5 mmol, 2.0 equiv) was added, and the mixture was stirred at 40°C for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give methyl (2-((2-(4-carbamimidophenyl)propan-2-yl)oxy)ethyl)carbamate (8) (285 mg, crude). LC-MS: 280.2 [M+H] + .

[0422] Plan 18F

[0423] To a solution of methyl (2-((2-(4-carbamimidophenyl)propan-2-yl)oxy)ethyl)carbamate (8) (285 mg, 0.7 mmol, 1.0 equiv) in MeOH (5 mL) under N2 atmosphere was added K2CO3 (180 mg, 1.3 mmol, 2.0 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (80 mg, 0.5 mmol, 0.7 equiv). The mixture was stirred at 70°C for 2 hours and then concentrated. The residue was purified by preparative HPLC to give methyl (2-((2-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)propan-2-yl)oxy)ethyl)carbamate (Compound 18). LC-MS: 404.2 [M+H] + . 1 HNMR (400MHz, DMSO): δ12.71(s,1H),8.05(d,J=8.2Hz,2H),7.56(d,J=8.4Hz,2H),7.16 (s, 1H), 3.51 (m, 5H), 3.12 (dd, J = 12.5, 5.0Hz, 4H), 2.89 (d, J = 4.0Hz, 4H), 1.47 (s, 6H). Compound 19 Synthesis of 2-(6'-bromo-[2,3'-bipyridyl]-5-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 19) Synthesis of 6'-bromo-[2,3'-bipyridine]-5-carbonitrile

[0424] Plan 19A

[0425] To a solution of 6-bromonicotinonitrile (1) (2.00 g, 10.93 mmol, 1.0 equiv) and (6-bromopyridin-3-yl)boronic acid (1a) (2.00 g, 9.91 mmol, 9.07 e-1 equiv) in dioxane (20 mL) / H2O (4 mL) was added K2CO3 (3.02 g, 21.86 mmol, 2.0 equiv) and Pd(dppf)Cl2 (799.65 mg, 1.09 mmol, 0.1 equiv) at 20° C. under N2. The mixture was stirred at 100° C. under N2 for 16 hours. After cooling to 25° C., the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give 6′-bromo-[2,3′-bipyridine]-5-carbonitrile (2) (730 mg). 1 H NMR: (400MHz, CDCl3): δ = 8.92 (dd, J = 1.8, 12.3Hz, 2H), 8.19 (dd, J = 2.5, 8.3Hz, 1H), 8.00 (dd, J=2.0, 8.3Hz, 1H), 7.81 (d, J=8.3Hz, 1H), 7.58 (d, J=8.3Hz, 1H). Synthesis of 6'-bromo-[2,3'-bipyridine]-5-carboxamidine

[0426] Plan 19B

[0427] To a solution of 6'-bromo-[2,3'-bipyridine]-5-carbonitrile (2) (280 mg, 1.08 mmol, 1.0 equiv) in THF (3 mL) was added LiHMDS (1 M, 2.69 mL, 2.5 equiv) at 0°C under N2 atmosphere. The mixture was warmed to 20°C and stirred at 20°C for 12 hours. The reaction mixture was quenched by the addition of HCl / dioxane (4 mol / L, 1 mL) at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was suspended in MeOH (7 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was then filtered and the filter cake was dried under reduced pressure to obtain 6'-bromo-[2,3'-bipyridine]-5-carboximidamide (3) (350 mg, crude, HCl), which was used immediately in the next step.

[0428] Plan 19C

[0429] To a solution of 6'-bromo-[2,3'-bipyridine]-5-carboximidamide (3) (350 mg, 1.12 mmol, 1.0 eq., HCl) in MeOH (3.5 mL) was added methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3a) (194.45 mg, 1.12 mmol, 1.0 eq.) and K2CO3 (462.79 mg, 3.35 mmol, 3.0 eq.) at 20° C. The mixture was stirred at 60° C. for 16 h. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was then purified by preparative HPLC (neutral conditions; column: Phenomenex C1875*30mm*3um; mobile phase: [water(NH4HCO3)-ACN]; B%: 25%-40%, 10 minutes) to afford 2-(6'-bromo-[2,3'-bipyridyl]-5-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 19). LC-MS: 401 (M+1). 1 H NMR: (400MHz, DMSO-d6): δ=9.27(d,J=1.3Hz,1H),8.94(d,J=2.2Hz,1H),8.43(dd,J=1.9,8.3Hz,1 H),8.27(dd,J=2.3,8.4Hz,1H),7.90(d,J=8.3Hz,1H),7.61(d,J=8.4Hz,1H),3.28(s,2H),2.61(br dd,J=5.0,15.4Hz,4H). Compound 20 Synthesis of 2-(4-(6-bromopyridin-3-yl)-3-fluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 20) Synthesis of 4-(6-bromopyridin-3-yl)-3-fluorobenzonitrile

[0430] Plan 20A

[0431] To a solution of (6-bromopyridin-3-yl)boronic acid (1a) (408.52 mg, 2.02 mmol, 1.0 equiv) in dioxane (5 mL) / H2O (1 mL) were added 3-fluoro-4-iodobenzonitrile (1) (0.5 g, 2.02 mmol, 1.0 equiv), K2CO3 (559.52 mg, 4.05 mmol, 2.0 equiv) and Pd(dppf)Cl2 (148.11 mg, 202.42 μmol, 0.1 equiv) at 20° C. under N2. The mixture was stirred at 100° C. under N2 for 16 hours. After cooling to 20° C., the mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give 4-(6-bromopyridin-3-yl)-3-fluorobenzonitrile (2) (200 mg, crude product), which was used directly in the next step. 1 HNMR: (400MHz, CDCl3): δ = 8.48 (s, 1H), 7.68 (td, J = 1.9, 8.3Hz, 1H), 7.56 (s, 1H), 7.50 (br d, J = 7.5Hz, 2H), 7.47-7.45 (m, 1H). Synthesis of 4-(6-bromopyridin-3-yl)-3-fluorobenzamidine

[0432] Plan 20B

[0433] To a solution of 4-(6-bromopyridin-3-yl)-3-fluorobenzonitrile (2) (200 mg, 721.78 μmol, 1.0 equiv) in THF (2 mL) was added LiHMDS (1 M, 1.80 mL, 2.5 equiv) at 0°C under N2. The mixture was warmed to 20°C and stirred at 20°C for 16 hours. The reaction mixture was quenched by the addition of HCl / dioxane (4 mol / L, 0.6 mL) at 0°C and then concentrated under reduced pressure to give a residue, which was suspended in MeOH (3 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was then filtered and the filter cake was dried under reduced pressure to give 4-(6-bromopyridin-3-yl)-3-fluorobenzamidine (3) (0.11 g, crude product), which was used in the next step without further purification.

[0434] Plan 20C

[0435] To a solution of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3a) (68.75 mg, 394.62 μmol, 1.06 eq) and 4-(6-bromopyridin-3-yl)-3-fluorobenzimidamide (3) (0.11 g, 373.99 μmol, 1.0 eq) in MeOH (2 mL) was added KCO (183.33 mg, 1.33 mmol, 3.55 eq) at 20° C. The mixture was stirred at 60° C. for 16 h. After cooling to 20°C, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH3H2O + NH4HCO3)-ACN]; B%: 30%-60%, 8 minutes) to obtain 2-(4-(6-bromopyridin-3-yl)-3-fluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 20). LC-MS: 417 + Br isomer (M+1). 1 H NMR: (400MHz, DMSO-d6): δ8.66(s,1H),8.13-8.06(m,2H),8.06-8.00(m,1H),7.86-7.77(m,2H),3.55(s,2H),2.91(s,4H). Compound 21 Synthesis of 2-(4-(6-bromopyridin-3-yl)-3,5-difluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 21) Synthesis of 3,5-difluoro-4-iodobenzonitrile

[0436] Plan 21A

[0437] To a solution of 3,5-difluorobenzonitrile (1) (2.00 g, 14.07 mmol, 1.0 equiv) in THF (20 mL) was added LDA (2 M, 7.86 mL, 1.12 equiv) dropwise at -70 °C. A solution of I2 (3.76 g, 14.80 mmol, 2.98 mL, 1.05 equiv) in THF (10 mL) was then added at -70 °C. The reaction mixture was slowly warmed to 15 °C and then stirred at 15 °C for 1 hour. The mixture was quenched with 10% sodium thiosulfite solution (15 mL). The reaction mixture was extracted with a 1 / 1 ethyl acetate / hexane mixture (7 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (neutral conditions; column: Welch Xtimate C18 250*70mm#10μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 40%-70%, 20 minutes) to give 3,5-difluoro-4-iodobenzonitrile (2) (2.00 g). 1 H NMR: (400MHz, CDCl3): δ=7.23-7.18 (m, 2H). Synthesis of 4-(6-bromopyridin-3-yl)-3,5-difluorobenzonitrile

[0438] Plan 21B

[0439] To a solution of (6-bromopyridin-3-yl)boronic acid (2a) (1.60 g, 7.93 mmol, 1.05 equiv) and 3,5-difluoro-4-iodobenzonitrile (2) (2.00 g, 11.32 mmol, 1.0 equiv) in dioxane (20 mL) / H2O (4 mL) at 15°C under N2 was added K2CO3 (2.09 g, 15.09 mmol, 2.0 equiv) and Pd(dppf)Cl2 (552.23 mg, 0.75 mmol, 0.1 equiv). The mixture was heated to 100°C under N2 for 16 hours. After cooling to 15°C, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give 4-(6-bromopyridin-3-yl)-3,5-difluorobenzonitrile (3) (620 mg, 210 mmol). 1 HNMR: (400MHz, CDCl3): δ = 8.43 (s, 1H), 7.63-7.55 (m, 2H), 7.34-7.26 (m, 2H). Synthesis of 4-(6-bromopyridin-3-yl)-3,5-difluorobenzamidine

[0440] Plan 21C

[0441] To a solution of 4-(6-bromopyridin-3-yl)-3,5-difluorobenzonitrile (3) (500 mg, 1.69 mmol, 1.0 equiv) in THF (5 mL) was added LiHMDS (1 M, 4.24 mL, 2.5 equiv) at 0°C under N2. The mixture was warmed to 20°C and stirred for 16 hours. The reaction mixture was quenched by the addition of HCl / dioxane (4 mol / L, 2.0 mL) at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was suspended in MeOH (8 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 4-(6-bromopyridin-3-yl)-3,5-difluorobenzamidine (4) (540 mg, crude, HCl). The obtained compound was used immediately in the next step.

[0442] Plan 21D

[0443] To a solution of 4-(6-bromopyridin-3-yl)-3,5-difluorobenzamidine (4) (440 mg, 1.41 mmol, 1.0 equiv) in MeOH (4.4 mL) was added methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (4a) (245.60 mg, 1.41 mmol, 1.0 equiv) and K2CO3 (584.52 mg, 4.23 mmol, 3.0 equiv) at 20°C. The mixture was stirred at 20°C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative HPLC (neutral conditions; column: NP-1; mobile phase: [heptane-EtOH]; B%: 10%-70%, 10 minutes) to afford 2-(4-(6-bromopyridin-3-yl)-3,5-difluorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 21). LC-MS: 438 + Br isomer (M+1). 1 H NMR: (400MHz, DMSO-d6): δ=13.06-12.89(m,1H),8.64(s,1H),8.10-8.00(m,3H),7.93(d,J=8.4Hz,1H),3.62(s,2H),2.98(s,4H). Compound 22 Synthesis of (6-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)pyridin-3-yl)boronic acid (Compound 22) Synthesis of 4-(5-bromopyridin-2-yl)benzonitrile

[0444] Plan 22A

[0445] To a solution of 5-bromo-2-iodopyridine (1) (0.5 g, 1.76 mmol, 1.0 equiv) and (4-cyanophenyl)boronic acid (1a) (388.19 mg, 2.64 mmol, 1.5 equiv) in dioxane (5 mL) / H2O (1 mL) at 20°C under N2 was added Pd(dppf)Cl2 (128.87 mg, 176.12 μmol, 0.1 equiv) and K2CO3 (486.83 mg, 3.52 mmol, 2.0 equiv). The mixture was stirred at 100°C for 13 hours. After cooling to 20°C, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give 4-(5-bromopyridin-2-yl)benzonitrile (2) (400 mg, crude), which was used immediately in the next step. 1 HNMR: (400MHz, CDCl3): δ=8.71 (d, J=2.1Hz, 1H), 8.06-8.00 (m, 2H), 7.87. Synthesis of 4-(5-bromopyridin-2-yl)benzamidine

[0446] Plan 22B

[0447] To a solution of 4-(5-bromopyridin-2-yl)benzonitrile (2) (100 mg, 385.95 μmol, 1.0 equiv) in THF (1 mL) was added LiHMDS (1 M, 964.87 μL, 2.5 equiv) at 0°C under N2. The mixture was warmed to 20°C and stirred for 16 hours. The reaction mixture was quenched by the addition of HCl / dioxane (4 mol / L, 0.3 mL) at 0°C and then concentrated under reduced pressure to give a residue. The residue was suspended in MeOH (2 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a residue, i.e., 4-(5-bromopyridin-2-yl)benzimidamide (3) (110 mg, crude, HCl salt), which was used in the next step without further purification. Synthesis of 2-(4-(5-bromopyridin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0448] Plan 22C

[0449] To a solution of 4-(5-bromopyridin-2-yl)benzimidamide (3) (100 mg, 362.15 μmol, 1.0 equiv) in MeOH (1 mL) was added methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3a) (126.18 mg, 724.29 μmol, 2.0 equiv) and K2CO3 (100.10 mg, 724.29 μmol, 2.0 equiv) at 20°C. The mixture was stirred at 60°C for 16 hours. The mixture was filtered and the filter cake was dried under reduced pressure to give 2-(4-(5-bromopyridin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (238 mg, crude), which was used immediately in the next step. 1 H NMR: (400MHz, CDCl3): δ=8.75-8.69(m,1H),8.14-8.04(m,4H),7.90-7.83(m,1 H),7.68-7.61(m,1H),3.65-3.62(m,2H),3.04-2.97(m,2H),2.92-2.86(m,2H).

[0450] Plan 22D

[0451] To a solution of 2-(4-(5-bromopyridin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (238 mg, 594.57 μmol, 1.0 eq) in dioxane (3 mL) was added B2Pin2 (181.18 mg, 713.48 μmol, 1.2 eq), KOAc (175.06 mg, 1.78 mmol, 3.0 eq) and Pd(dppf)Cl2.DCM (48.55 mg, 59.46 μmol, 0.1 eq) under N2 atmosphere. The mixture was stirred at 80°C for 13 hours. After cooling to 25°C, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 15%-45%, 8 minutes) to afford [6-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)pyridin-3-yl]boronic acid (Compound 22). LC-MS: 366.1 (M+1). 1 H NMR: (400MHz, DMSO-d6): δ = 12.83 (br s, 1H), 9.01 (s, 1H), 8.41 (s, 2H), 8.30-8.20 (m, 5H), 8.06 (d, J = 8.0Hz, 1H), 3.55 (s, 2H), 2.92 (s, 4H). Compound 23 Synthesis of 2-(4-(2-bromopyridin-4-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 23) Synthesis of 4-(2-bromopyridin-4-yl)benzonitrile

[0452] Plan 23A

[0453] To a solution of 2-bromo-4-iodopyridine (1) (2.50 g, 8.81 mmol, 1.00 equiv) and (4-cyanophenyl)boronic acid (1a) (1.42 g, 9.69 mmol, 1.10 equiv) in dioxane (25.0 mL) and H2O (5.00 mL) was added K2CO3 (2.43 g, 17.6 mmol, 2.00 equiv) at 20°C. The suspension was degassed and purged with N2 three times. Pd(dppf)Cl2 (644 mg, 881 μmol, 0.10 equiv) was then added to the mixture at 20°C and N2. The suspension was degassed and purged with N2 three times. The mixture was stirred at 100°C under N2 for 12 hours. The reaction mixture was diluted with water (10.0 mL) and then extracted with 60.0 mL of EtOAc (20.0 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 4-(2-bromopyridin-4-yl)benzonitrile (2) (950 mg). 1 H NMR: (400MHz, DMSO-d6): δ=8.57 (d, J=5.3Hz, 1H), 8.17-8.03 (m, 5H), 7.91 (dd, J=1.7, 5.2Hz, 1H). Synthesis of 4-(2-bromopyridin-4-yl)benzamidine

[0454] Plan 23B

[0455] To a solution of 4-(2-bromopyridin-4-yl)benzonitrile (2) (400 mg, 1.54 mmol, 1.00 equiv) in THF (4.00 mL) was added LiHMDS (1 M, 3.09 mL, 2.00 equiv) dropwise at 0°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with 4N HCl (4.00 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was suspended in MeOH (20.0 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was then filtered. The filtrate was concentrated under reduced pressure to give a residue, i.e., 4-(2-bromopyridin-4-yl)benzimidamide (3) (500 mg, crude product), which was used in the next step without further purification.

[0456] Plan 23C

[0457] To a solution of 4-(2-bromopyridin-4-yl)benzimidamide (3) (250 mg, 905 μmol, 1.00 equiv) and methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (3a) (166 mg, 951 μmol, 1.05 equiv) in MeOH (2.50 mL) was added KCO (313 mg, 2.26 mmol, 2.50 equiv) at 20°C. The mixture was stirred at 60°C for 16 hours. The reaction mixture was filtered. The filter cake was slurried with MeOH (0.50 mL) and H2O (1.00 mL) and then filtered. The filter cake was dried under vacuum to give a residue. The obtained residue was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water(HCl)-ACN]; B%: 35%-65%, 7 minutes) to give 2-(4-(2-bromopyridin-4-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 23). 1 H NMR (400MHz, DMSO-d6): δ = 8.48 (d, J = 5.3Hz, 1H), 8.27 (d, J = 8.4Hz, 2H), 8.07 (s, 1H), 7.99 ( d, J=8.4Hz, 2H), 7.87 (dd, J=1.2, 5.2Hz, 1H), 3.54 (s, 2H), 2.89 (s, 4H). LC-MS: 404.1 (M+1). Compound 24 Synthesis of (2-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)pyrimidin-5-yl)boronic acid (Compound 24) Synthesis of 4-(5-bromopyrimidin-2-yl)benzonitrile

[0458] Plan 24A

[0459] To a solution of 5-bromo-2-iodopyrimidine (1) (2.50 g, 8.78 mmol, 1.00 equiv) and (4-cyanophenyl)boronic acid (1a) (1.42 g, 9.65 mmol, 1.10 equiv) in dioxane (25.0 mL) and H2O (5.00 mL) was added K2CO3 (2.43 g, 17.6 mmol, 2.00 equiv) at 15°C. The suspension was degassed and purged with N2 three times. Pd(dppf)Cl2 (642 mg, 878 μmol, 0.10 equiv) was then added to the mixture at 15°C and N2. The suspension was degassed and purged with N2 three times. The mixture was stirred at 100°C under N2 for 16 hours. The reaction mixture was diluted with water (10.0 mL) and filtered. The filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was suspended in methyl tert-butyl ether (MTBE, 10.0 mL), and the mixture was stirred at 15°C for 16 hours and then filtered. The filter cake was dried under reduced pressure to obtain a residue, namely 4-(5-bromopyrimidin-2-yl)benzonitrile (2) (2.00 g, crude product), which was immediately used in the next step. 1 H NMR (400MHz, DMSO-d6): δ = 9.16 (s, 2H), 8.49 (br d, J = 8.3Hz, 2H), 8.01 (br d, J = 8.3Hz, 2H). Synthesis of 4-(5-bromopyrimidin-2-yl)benzamidine

[0460] Plan 24B

[0461] To a solution of 4-(5-bromopyrimidin-2-yl)benzonitrile (2) (0.80 g, 3.08 mmol, 1.00 equiv) in THF (8.00 mL) was added LiHMDS (1 M, 6.15 mL, 2.00 equiv) at 0°C. The mixture was stirred at 15°C for 16 hours. The reaction mixture was diluted with 4N HCl / dioxane (6.00 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was suspended in MeOH (8.00 mL), and the mixture was stirred at 15°C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue, i.e., 4-(5-bromopyrimidin-2-yl)benzamidine (3) (0.8 g, crude product), which was used in the next step without further purification. Synthesis of 2-(4-(5-bromopyrimidin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0462] Plan 24C

[0463] To a solution of 4-(5-bromopyrimidin-2-yl)benzimidamide (3) (0.80 g, 2.89 mmol, 1.00 equiv) and methyl 4-oxotetrahydrothiopyran-3-carboxylate (6) (528 mg, 3.03 mmol, 1.05 equiv) in MeOH (16.0 mL) was added K2CO3 (1.20 g, 8.66 mmol, 3.00 equiv) at 25°C. The mixture was stirred at 60°C for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting solid was suspended in water (5 mL) and the mixture was stirred at 20°C for 3 hours. The mixture was filtered and the filter cake was dried under vacuum to give 2-(4-(5-bromopyrimidin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (300 mg, crude). The crude product was used directly in the next step without further purification.

[0464] Plan 24D

[0465] To a solution of 2-(4-(5-bromopyrimidin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (0.1 g, 249.20 μmol, 1 eq) in dioxane (2 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (69.61 mg, 274.12 μmol, 1.1 eq), KOAc (48.91 mg, 498.41 μmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (20.35 mg, 24.92 μmol, 0.1 eq) at 20°C under N2. The mixture was stirred at 80°C for 12 hours under N2. The mixture was concentrated under reduced pressure to obtain a residue. The residue was suspended in MeCN / H2O (1:1, 3 mL) and the mixture was stirred at 20°C for 2 hours. The mixture was then filtered and the filter cake was dried under vacuum to obtain 2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (50 mg, crude). The crude product was suspended in HCl / H2O (4N, 3 mL) and the mixture was stirred at 20°C for 12 hours. The mixture was then diluted with DMSO (5 mL) and purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase: [water (HCl)-ACN]; B%: 15%-45%, 10 minutes) to obtain [2-(4-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)phenyl)pyrimidin-5-yl]boronic acid (Compound 24). LCMS: 367 (M+1). 1 H NMR: (400MHz, DMSO-d6): δ = 9.16 (s, 2H), 8.54 (d, J = 8.5Hz, 2H), 8.25 (d, J = 8.5Hz, 2H), 3.55 (s, 2H), 2.92 (s, 4H). Compound 25 Synthesis of (3',5'-difluoro-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 25) Synthesis of 4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-carbonitrile

[0466] Plan 25A

[0467] To a mixture of 2,6-difluoro-4-iodobenzonitrile (1) (5 g, 22.94 mmol, 1 eq) and 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a) (6.49 g, 22.94 mmol, 1 eq) in dioxane (100 mL) and water (10 mL) was added KCO (6.34 g, 45.87 mmol, 2 eq) and Pd(PPh)Cl (1.61 g, 2.29 mmol, 0.1 eq) at 20 ° C and N2. The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 ° C under N2 atmosphere for 16 hours. The mixture was cooled to 20 ° C and then diluted with water (100 mL). The mixture was then extracted with 300 mL of EtOAc (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give 4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-carbonitrile (2) (1.8 g). 1 H NMR: (400MHz, CDCl3): δ=7.57 (d, J=8.6Hz, 2H), 7.39-7.33 (m, 2H), 7.20-7.17 (m, 2H). Synthesis of 4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-carboxamidine

[0468] Plan 25B

[0469] To a solution of 4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-carbonitrile (2) (0.5 g, 1.70 mmol, 1 eq) in THF (5 mL) was added LiHMDS (1 M, 4.25 mL, 2.5 eq) dropwise at 0°C. The mixture was stirred at 15°C for 16 hours. The reaction mixture was quenched by the dropwise addition of 4N HCl / dioxane (10 mL). The mixture was concentrated under reduced pressure to obtain a residue. The residue was suspended in MeOH (10 mL) and the mixture was stirred at 20°C for 1 hour. The mixture was then filtered and the filtrate was concentrated under reduced pressure to obtain a residue, i.e., 4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-carboximidamide (3) (528 mg, crude product), which was used in the next step without further purification. Synthesis of 2-(4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0470] Plan 25C

[0471] To a mixture of 4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-carboximidamide-HCl (3) (528 mg, 1.52 mmol, 1 eq) in MeOH (10 mL) at 25°C under N2 were added K2CO3 (419.88 mg, 3.04 mmol, 2 eq) and methyl 4-oxotetrahydrothiopyran-3-carboxylate (396.97 mg, 2.28 mmol, 1.5 eq). The mixture was then stirred at 25°C under N2 for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with water (10 mL) at 25°C for 1 hour and then filtered. The filter cake was dried in vacuo to give 2-(4′-bromo-3,5-difluoro-[1,1′-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (0.9 g, crude), which was used directly in the next step. 2-(3,5-difluoro-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyran Synthesis of [4,3-d]pyrimidin-4-one

[0472] Plan 25D

[0473] To a mixture of 2-(4'-bromo-3,5-difluoro-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (150 mg, 344.60 μmol, 1 eq) in dioxane (3 mL) at 25°C was added B2Pin2 (131.26 mg, 516.90 μmol, 1.5 eq) and KOAc (101.46 mg, 1.03 mmol, 3 eq). The mixture was degassed and purged with N2 three times, and then Pd(dppf)Cl2 (28.14 mg, 34.46 μmol, 0.1 eq) was added at 25°C under N2. The mixture was stirred at 100°C under N2 for 16 hours. After cooling to 20°C, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was triturated with water (2 mL) and acetonitrile (2 ml) at 25° C. for 1 hour. The mixture was filtered and the filter cake was dried under vacuum to give 2-(3,5-difluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (120 mg).

[0474] Plan 25E

[0475] To a stirred solution of HCl / H2O (4M, 2 mL) was added 2-(3,5-difluoro-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (120 mg, 248.78 μmol, 1 eq) in portions at 20°C under N2. The mixture was then stirred at 50°C under N2 for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 25%-55%, 8 minutes) to obtain (3',5'-difluoro-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 25). LCMS: 401 (M+1). 1H NMR: (400MHz, DMSO-d6): δ=13.30-12.89(m,1H),8.19(s,2H),7.98-7.86(m,2H),7.84-7.77(m,2H),7.73-7.65(m,2H),3.55(br s,2H),2.97-2.81(m,4H). Compound 26 Synthesis of (3'-hydroxy-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 26) Synthesis of 4'-bromo-3-methoxy-[1,1'-biphenyl]-4-carbonitrile

[0476] Plan 26A

[0477] To a solution of 4-bromo-2-methoxybenzonitrile (1) (10.0 g, 47.2 mmol, 1.00 equiv) and (4-bromophenyl)boronic acid (10.4 g, 51.9 mmol, 1.10 equiv) in dioxane (50.0 mL) and water (10.0 mL) was added K2CO3 (13.0 g, 94.3 mmol, 2.00 equiv) and Pd(dppf)Cl2 (3.45 g, 4.72 mmol, 0.10 equiv) at 20°C. The mixture was heated to 75°C for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f =0.53) indicates that (1) has been completely consumed. The reaction mixture was diluted with EtOAc (50.0 mL) and H2O (20.0 mL). The organic layer was separated from the mixture and the aqueous phase was extracted with EtOAc (50.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 4'-bromo-3-methoxy-[1,1'-biphenyl]-4-carbonitrile (2) (3.30 g, 8.02 mmol). The resulting compound was used without further purification. 1 H NMR (400MHz, DMSO-d6): δ=7.86 (d, J=8.1Hz, 1H), 7.84-7.72 (m, 4H), 7.52 (d, J=1.1Hz, 1H), 7.45 (dd, J=1.4, 8.0Hz, 1H), 4.08 (s, 3H). Synthesis of 4'-bromo-3-methoxy-[1,1'-biphenyl]-4-carboxamidine

[0478] Plan 26B

[0479] To a solution of 4'-bromo-3-methoxy-[1,1'-biphenyl]-4-carbonitrile (2) (2.00 g, 6.94 mmol, 1.00 equiv) in THF (20.0 mL) was added dropwise LiHMDS (1 M, 13.9 mL, 2.00 equiv) at 0°C, and the mixture was then warmed to 20°C and stirred for 12 hours. The reaction mixture was quenched with HCl / dioxane (13.0 mL) at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was triturated with MeOH (10 mL) and filtered. The filter cake was dried under vacuum to obtain a residue, namely 4'-bromo-3-methoxy-[1,1'-biphenyl]-4-carboximidamide (3) (3.00 g, crude). The crude product was used in the next step without further purification. LC-MS: 306 (M+1). Synthesis of 2-(4'-bromo-3-methoxy-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0480] Plan 26C

[0481] To a solution of 4'-bromo-3-methoxy-[1,1'-biphenyl]-4-carboximidamide (3) (3.00 g, 9.83 mmol, 1.00 equiv) and methyl 4-oxotetrahydrothiopyran-3-carboxylate (3.43 g, 19.6 mmol, 2.00 equiv) in MeOH (45.0 mL) was added K2CO3 (5.43 g, 39.3 mmol, 4.00 equiv) at 25°C, and the mixture was heated to 50°C and stirred for 16 hours. LC-MS showed that (3) was consumed. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give a residue. The residue was triturated with H2O (30.0 mL) and stirred at 20°C for 16 hours. The mixture was then filtered and the filter cake was dried under reduced pressure to give 2-(4'-bromo-3-methoxy-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (1.5 g, crude product), which was used in the next step without further purification. LC-MS: 430.2 (+Br isomer) (M+1). 2-(3-methoxy-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyran Synthesis of [4,3-d]pyrimidin-4-one

[0482] Plan 26D

[0483] To a solution of 2-(4'-bromo-3-methoxy-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (1.00 g, 2.33 mmol, 1.00 equiv) and Pin2B2 (650 mg, 2.56 mmol, 1.10 equiv) in dioxane (50.0 mL) was added KOAc (457 mg, 4.66 mmol, 2.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (190 mg, 233 μmol, 0.10 equiv) at 20°C. The mixture was heated to 80°C and stirred for 16 hours. LC-MS indicated complete consumption of (4) with a major peak of the desired mass being detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2-(3-methoxy-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (1.60 g, crude). The crude product was used in the next step without further purification. LC-MS: 477.2 (M+1). Synthesis of (3'-methoxy-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid

[0484] Plan 26E

[0485] A mixture of 2-(3-methoxy-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (5) (1.60 g, 3.36 mmol, 1.00 equiv) in HCl (8 M, 32.0 mL, 76.2 equiv) was heated to 80°C and stirred for 16 hours. HCl (12 M, 8.00 mL, 28.6 equiv) was added to the mixture at 20°C and then heated to 80°C for 4 hours. LC-MS showed complete consumption of (5) and a major peak with the desired mass was detected. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to afford (3'-methoxy-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (6) (710 mg, crude). The crude product was used in the next step without further purification. LC-MS: 395.2 (M+1).

[0486] Plan 26F

[0487] To a solution of (3'-methoxy-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (6) (710 mg, 1.80 mmol, 1.00 equiv) in DCM (21.6 mL) was added BBr3 (1 M in DCM, 9.00 mL, 5.00 equiv) dropwise at 20°C. The mixture was heated to 20°C and stirred for 1 hour. LC-MS showed complete consumption of (6) with the detection of a peak of the desired mass. The reaction mixture was quenched by the addition of ice water (20.0 mL) at 0°C. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NXC18 (75 × 30 mm × 3 μm); mobile phase: [H₂O (0.05% NH₃H₂O + 10 mM NH₄HCO₃)-ACN]; gradient: 15%-65% B over 8.0 minutes) to obtain (3'-hydroxy-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 26). LC-MS: 381.2 (M+1). 1H NMR (400MHz, DMSO-d6): δ = 8.27 (d, J = 8.1Hz, 1H), 8.13 (s, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.32-7.19 (m, 2H), 3.55 (s, 2H), 2.93 (s, 4H). Compound 27 Synthesis of (3-hydroxy-4'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)boronic acid (Compound 27) Synthesis of 4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-carbonitrile

[0488] Plan 27A

[0489] To a solution of 1-bromo-4-iodo-2-methoxybenzene (1) (8 g, 25.56 mmol, 1 eq) and (4-cyanophenyl)boronic acid (1a) (4.51 g, 30.7 mmol, 1.20 eq) in DMF (160 mL) was added Cs2CO3 (16.7 g, 51.1 mmol, 2.00 eq) and Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.05 eq) at 25°C. The mixture was heated to 80°C and stirred under N2 atmosphere for 16 hours. LC-MS showed complete consumption of (1). The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated from the mixture, and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 4′-bromo-3′-methoxy-[1,1′-biphenyl]-4-carbonitrile (2) (4.50 g, 15.6 mmol). 1 H NMR (400MHz, DMSO-d6): δ = 8.00 (s, 4H), 7.74 (d, J = 8.2Hz, 1H), 7.46 (d, J = 2.0Hz, 1H), 7.31 (dd, J = 2.1, 8.2Hz, 1H), 4.02 (s, 3H). Synthesis of 4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-carboxamidine

[0490] Plan 27B

[0491] To a solution of 4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-carbonitrile (2) (2.00 g, 6.94 mmol, 1.00 equiv) in THF (20.0 mL) was added LiHMDS (1 M, 13.9 mL, 2.00 equiv) dropwise at 0°C. The mixture was warmed to 25°C and stirred for 12 hours. LC-MS showed that (2) was completely consumed. The reaction mixture was quenched by the dropwise addition of HCl / dioxane (4 M, 8.00 mL) at 0°C and then concentrated under reduced pressure to obtain a residue. The residue was suspended in MeOH (20.0 mL) and the mixture was stirred at 25°C for 1 hour. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give 4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-carboximidamide (3) (3.00 g, crude product), which was used directly in the next step without further purification. LC-MS: 306.1+Br isomer (M+1). Synthesis of 2-(4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one

[0492] Plan 27C

[0493] To a solution of 4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-carboximidamide (3) (1.00 g, 3.28 mmol, 1.00 equiv) and methyl 4-oxotetrahydrothiopyran-3-carboxylate (1.14 g, 6.55 mmol, 2 equiv) in MeOH (15.0 mL) was added K2CO3 (1.81 g, 13.1 mmol, 4.00 equiv) at 25°C. The mixture was heated to 50°C and stirred for 16 hours. LC-MS showed that (3) was completely consumed. The reaction mixture was filtered and the filter cake was dried under reduced pressure to obtain a residue. Water (10.0 mL) was added to the resulting residue to form a slurry, which was stirred at 20°C for 16 hours. The mixture was then filtered, and the filter cake was dried under reduced pressure to give 2-(4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one (4) (1.50 g, crude product). LC-MS: 430.2 + Br isomer (M+1). 1H NMR (400MHz, DMSO-d6): δ = 12.76 (brs, 1H), 8.26-8.20 (m, J = 8.4Hz, 2H), 7.90-7.82 (m, J = 8.4Hz, 2H), 7.68 ( d,J=8.3Hz,1H),7.42(d,J=1.9Hz,1H),7.27(dd,J=2.0,8.3Hz,1H),3.98(s,3H),3.53(s,2H),2.89(s,4H). 2-(3'-methoxy-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4H-thiopyran Synthesis of [4,3-d]pyrimidin-4-one

[0494] Plan 27D

[0495] To a solution of 2-(4'-bromo-3'-methoxy-[1,1'-biphenyl]-4-yl)-3,5,7,8-tetrahydro-4...

Claims

1. Compound represented by formula (I): or a single stereoisomer or a mixture of stereoisomers thereof; a single tautomer or a mixture of tautomers thereof; and / or a pharmaceutically acceptable salt thereof; in R 1 is H, deuterium, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, -CH2OH, or -B(OH)2; R 1a is H, deuterium, or C1-C3 alkyl; R 2 yes (a) a phenyl group, wherein the phenyl group is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; (b) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a group substitution; (c) phenyl, optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 Substituted, wherein -phenyl-R 3 The phenyl group in the 3a group substitution; (d) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; (e) a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a group substitution; (f) a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(heteroaryl consisting of 5 or 6 atoms)-R 3 substituted, wherein –(5 or 6 atoms composed of heteroaryl)-R 3 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a group substitution; (g) a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is replaced by R 3 and optionally substituted with 1 or 2 R 3a group substitution; (h) a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a group substitution; (i) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group is R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a group substitution; (j) a heterocycloalkyl group consisting of 3 to 8 atoms, wherein the heterocycloalkyl group consisting of 3 to 8 atoms is substituted by a phenyl group or a heteroaryl group consisting of 5 or 6 atoms, wherein the phenyl group and the heteroaryl group consisting of 5 to 6 atoms are each replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; (k)-CH=CH-R 5 , where R 5 is phenyl, or a heteroaryl consisting of 5 or 6 atoms, wherein the phenyl and the heteroaryl consisting of 5 or 6 atoms are each replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a group substitution; R 3 Independently selected from -B(OH)2, cyano, halogen, halo-C1-C6 alkyl, -(C0-C6 alkylene)-OR 4 , or a heterocyclic group consisting of 5 to 10 atoms, wherein the heterocyclic group consisting of 5 to 10 atoms is optionally substituted by cyano; or when R 2 If (a) is true, then R 3 and an R 3a , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form wherein the * represents the carbon atom shared with the phenyl ring, and wherein the remaining optional R on the phenyl moiety 3a are defined as follows, and each R 7a are independently H or C1-C6 alkyl; Each R 3a are independently selected from cyano, halogen, -OH, C1-C6 alkyl, halo-C1-C6 alkyl, and C1-C6 alkoxy; R 4 is hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, or C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl; and Provided that the compound is not: 2-(4-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-(4-methoxyphenyl)piperazin-1-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-(2-methoxyphenyl)piperazin-1-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(4-chlorophenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(5-(trifluoromethyl)pyridin-2-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(3-(Trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; 2-(3-(trifluoromethyl)phenyl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; or 2-(5-chlorothien-3-yl)-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d]pyrimidin-4-one, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1a are independently selected from H and deuterium.

3. The compound according to claim 1 or 2, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein Ring A is and among them represents the point of attachment to the rest of the compound represented by formula (I).

4. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Phenyl, the phenyl group is R 3 and optionally substituted by 1, 2 or 3 R 3a Group substitution.

5. The compound according to claim 4, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 3 attached to the para position of the phenyl ring; or R 3 and an R 3a , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form ring (a-1), and wherein the phenyl moiety is optionally replaced by the remaining R 3a Group substitution.

6. The compound according to any one of claims 1 to 5, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

7. The compound according to any one of claims 1 to 6, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

8. The compound according to any one of claims 1 to 7, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

9. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a Group substitution.

10. The compound according to claim 9, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, said phenyl being substituted at its para position by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a When the heteroaryl group of 5 or 6 atoms is a heteroaryl group of 6 atoms, then R 3 Substitution is carried out at the para position of the 6-atom heteroaryl group.

11. The compound according to any one of claims 1 to 3, 9 and 10, or a single stereoisomer or a mixture of stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

12. The compound according to any one of claims 1 to 3 and 9 to 11, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

13. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, said phenyl being optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 Substituted, wherein -phenyl-R 3 The phenyl group in the 3a Group substitution.

14. The compound according to claim 13, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, said phenyl being optionally substituted by 1, 2 or 3 R 3a The group is substituted and the para position is also substituted by -phenyl-R 3 Substituted, wherein -phenyl-R 3 The phenyl group in the 3a Group substituted, and wherein said R 3 Located in -phenyl-R 3 The para position of the phenyl group.

15. The compound according to any one of claims 1 to 3 and 13 to 14, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

16. The compound according to any one of claims 1 to 3 and 13 to 15, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

17. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is R 3 and optionally substituted by 1, 2 or 3 R 3a Group substituted; optionally, wherein the R 3 Located in the para position of the heteroaryl group composed of 6 atoms.

18. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-R 3 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a Group substituted; optionally, wherein the -phenyl-R 3 Located in the para position of the 6-atom heteroaryl; and optionally, wherein the R 3 Located in the para position of the phenyl group.

19. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- or 6-atom heteroaryl group, wherein the 5- or 6-atom heteroaryl group is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(heteroaryl consisting of 5 or 6 atoms)-R 3 substituted, wherein –(5 or 6 atoms composed of heteroaryl)-R 3 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a Group substitution; optionally, wherein the -(heteroaryl consisting of 6 atoms)-R 3 Located in the para position of the first 6-atom heteroaryl group; and optionally, wherein said R 3 Located in the para position with respect to the 6-atom heteroaryl group to which it is attached.

20. The compound according to any one of claims 1 to 3 and 19, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 yes 21. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is R 3 and optionally substituted with 1 or 2 R 3a Group substitution.

22. The compound according to any one of claims 1 to 3 and 21, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 yes Optionally, wherein R 3 is a heterocyclic group consisting of 5 to 10 atoms, wherein the heterocyclic group consisting of 5 to 10 atoms is optionally substituted by cyano.

23. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a Group substitution.

24. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is substituted by a phenyl group, wherein the phenyl group is replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a Group substitution.

25. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is a heterocycloalkyl group consisting of 3 to 8 atoms, wherein the heterocycloalkyl group consisting of 3 to 8 atoms is substituted by a phenyl group or a heteroaryl group consisting of 5 or 6 atoms, wherein the phenyl group and the heteroaryl group consisting of 5 to 6 atoms are respectively replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a Group substitution.

26. The compound according to any one of claims 1 to 3 and 25, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

27. The compound according to any one of claims 1 to 3, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 It is -CH=CH-R 5 , where R 5 is phenyl, or a heteroaryl consisting of 5 or 6 atoms, wherein the phenyl and the heteroaryl consisting of 5 or 6 atoms are each replaced by R 3 and optionally substituted by 1, 2 or 3 R 3a Group substitution.

28. The compound according to any one of claims 1 to 3 and 27, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

29. The compound according to any one of claims 1 to 28, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 3 is cyano, -B(OH)2, or -(C0-C6 alkylene)-OR 4 .

30. A compound according to any one of claims 1 to 7, 9 to 11 and 13 to 29, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 3 It's cyano.

31. A compound according to any one of claims 1 to 7, 9 to 11 and 13 to 29, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 3 It is -B(OH)2.

32. A compound according to any one of claims 1 to 7, 9 to 11 and 13 to 29, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 3 is -(C0-C6 alkylene)-OR 4 .

33. A compound according to any one of claims 1 to 7, 9 to 11, 13 to 29 and 32, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 3 Yes-(C 1-6 Alkylene)-OR 4 .

34. A compound according to any one of claims 1 to 7, 9 to 11, 13 to 29, 32 and 33, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 4 It is a hydroxy-C1-C6 alkyl group.

35. A compound according to any one of claims 1-7, 9-11, 13-29, 32 and 33, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 4 It is a C1-C6 alkoxy-C1-C6 alkyl group.

36. A compound according to any one of claims 1 to 7, 9 to 11, 13 to 29, 32 and 33, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 4 It is a C1-C6 alkoxycarbonyl-NH-C1-C6 alkyl group.

37. A compound according to any one of claims 1-3, 9-11, 13-16 and 18-20, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, wherein R 2 is (b), (c), (e), or (f), and R 3 is halogen, cyano, -B(OH)2, or -(C0-C6 alkylene)-OR 4 .

38. The compound of claim 1, or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds 1-44 provided in Table 1.

39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

40. The pharmaceutical composition according to claim 39, wherein The drug carrier comprises: a matrix component comprising a graphene oxide (GO) and hyaluronic acid (HA) conjugate (GO-HA), wherein GO and HA are covalently linked via a linker; polyethylene glycol (PEG), wherein the PEG is optional; a thickener, wherein the thickener is optional; and water; Optionally, the compound optionally comprises from about 0.001 wt % to about 5 wt % of the total composition.

41. A method for inhibiting Wnt signaling pathway activity in a subject, comprising contacting the subject with an effective amount of a compound according to any one of claims 1-38, or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof.

42. A method for treating a disease, disorder, or condition associated with Wnt signaling pathway activity, comprising administering to a mammal in need thereof a compound of any one of claims 1-38, or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; or administering to a mammal in need thereof a pharmaceutical composition of claim 39 or 40.

43. The method according to claim 42, wherein The method is for stimulating tissue regeneration at a wound in a mammal in need thereof, wherein the wound is contacted with an effective amount of the compound (or a single stereoisomer or a mixture of stereoisomers, a single tautomer or a mixture of tautomers, and / or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition.

44. The method of claim 42, wherein: The disease, disorder, or condition is selected from chronic wounds, acute wounds, alkali burns, corneal wounds, burns, lesions (including lesions caused by HPV and / or viruses selected from the Poxviridae family), inflammatory dermatitis diseases (including acne, psoriasis, rosacea, and scleroderma), cartilage diseases (including osteoarthritis, rheumatoid arthritis, internal joint disorders, and degenerative cartilage diseases), bone diseases (including osteoporosis), organ fibrosis (including pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis), cancer (including melanoma, breast cancer, and prostate cancer), denervated body parts requiring reinnervation, tissue requiring regeneration (including damaged elastic cartilage), bacterial growth requiring inhibition, fungal growth requiring inhibition, tissue requiring neovascularization, osteoclast differentiation requiring inhibition, osteoblast differentiation disorders (wherein osteoblast differentiation requires inhibition), and / or bone destruction associated with breast cancer.

45. A method for inducing antibacterial activity associated with Wnt signaling pathway activity, comprising administering XAV939 or a tautomer thereof and / or a pharmaceutically acceptable salt thereof, optionally containing a pharmaceutically acceptable carrier, to a mammal in need thereof; administering a compound according to any one of claims 1 to 38, or a single stereoisomer or a mixture of stereoisomers thereof, a single tautomer or a mixture of tautomers thereof, and / or a pharmaceutically acceptable salt thereof; or administering a pharmaceutical composition according to claim 39 or 40.

46. A compound, or a salt thereof and / or a stereoisomer or a mixture of stereoisomers thereof, having a structure represented by any one of the following formulae: Formula (A): Formula (B): Formula (C): Or formula (D): and in LG 1 is a leaving group, such as fluorine, chlorine, bromine, iodine, triflate, mesylate, triazole, pyrazole, boronic acid, boronate ester, or aryl trifluoroborate; R 1 is H, deuterium, C1-C3 alkyl, -OH, -O-C1-C3 alkyl, -CH2OH, or -B(OH)2; R 1a is H, deuterium, or C1-C3 alkyl; R 20 is an alkyl group, preferably a methyl group or an ethyl group; or CD3; R 2 'yes (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a group substitution; (c1) phenyl, optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a group substitution; (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a group substitution; (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, wherein -(5 or 6 atoms consisting of heteroaryl)-LG 1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a group substitution; (h1) C3-C6 cycloalkyl, which is substituted with NH2 or OH and further optionally substituted with 1 or 2 R 3a group substitution; or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group is substituted by a LG 1 and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a group substitution; and Provided that the compound is not: 4-Oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or salts thereof and / or stereoisomers or mixtures of stereoisomers thereof.

47. A method for preparing a compound of formula (I) according to any one of claims 1 to 37, comprising: a) making a compound represented by formula (A): With R 2’ -C(O)H contact; or b) making a compound represented by formula (B): With R 2’ -C(NH)NH2 contact, where R 20 is Me or CD3; or c) making a compound represented by formula (C): With R 2’ -H contact, where LG 1 is fluorine, chlorine, bromine, iodine, triflate, mesylate, triazole, pyrazole, boronic acid, boric acid ester, or trifluoroaryl borate; and optionally isolating the compound represented by formula (I); where R 2 'yes (b1) phenyl, said phenyl being substituted by a heteroaryl group consisting of 5 or 6 atoms, wherein said heteroaryl group consisting of 5 or 6 atoms is substituted by LG 1 and optionally substituted by 1, 2 or 3 R 3a substituted with 1, 2 or 3 R 3a group substitution; (c1) phenyl, optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 Substituted, wherein -phenyl-LG 1 The phenyl group in the 3a group substitution; (e1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and also substituted by -phenyl-LG 1 substituted, wherein the phenyl group is optionally further substituted with 1, 2 or 3 R 3a group substitution; (f1) a heteroaryl group consisting of 5 or 6 atoms, wherein the heteroaryl group consisting of 5 or 6 atoms is optionally substituted by 1, 2 or 3 R 3a group and is further substituted by -(5 or 6 atoms consisting of heteroaryl)-LG 1 Substituted, wherein -(5 or 6 atoms consisting of heteroaryl)-LG 1 The 5 or 6 atoms in the heteroaryl group are optionally replaced by 1, 2 or 3 R 3a group substitution; (h1) C3-C6 cycloalkyl, which is substituted with NH2 or OH and further optionally substituted with 1 or 2 R 3a group substitution; or (i1) C3-C6 cycloalkyl, the C3-C6 cycloalkyl being substituted by a phenyl group, wherein the phenyl group is substituted by a LG 1 and the phenyl group is optionally substituted with 1, 2 or 3 R 3a wherein the cycloalkyl group is optionally substituted with 1 or 2 R 3a group substitution; and Provided that the compound is not: 4-Oxotetrahydro-2H-thiopyran-3-carboxylic acid methyl ester or salts thereof and / or stereoisomers or mixtures of stereoisomers thereof.

48. The method of claim 46, wherein The contacting is performed under alkaline conditions.

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