Small molecule activators of YAP transcriptional activity for regenerative organ repair

Abstract

The present disclosure provides compounds or tautomers thereof or pharma- ceutically acceptable salts thereof that can selectively activate Yes-associated protein 1 (YAP) and pharmaceutical compositions thereof. The YAP activators of the present disclosure are useful in therapies such as wound and organ repair, including, for example, the treatment of chronic ulcers.

Description

[Technical field]

[0001] The present invention relates to small molecule activators of YAP transcriptional activity for regenerative organ repair.

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 148,868, filed February 12, 2021, the entirety of which is incorporated herein as if fully set forth herein. [Background technology]

[0003] The conserved Hippo-YAP pathway controls organ size in animals 1,2 The transcriptional effector of this pathway, Yes-associated protein 1 (YAP), when activated, promotes the expression of proliferative and anti-apoptotic gene products through nuclear interactions with TEAD transcription factors. 3 Activation of YAP leads to proliferation and loss of programmed cell death at the organ level 4 Beyond controlling organ size, YAP orchestrates the regenerative response in mammals, a process that requires the recruitment and proliferation of endogenous stem and progenitor cells. 5 .

[0004] Beyond controlling organ size, YAP orchestrates the regenerative response in mammals, a process that requires the recruitment and proliferation of endogenous stem and progenitor cells 5a The transcriptional activity of YAP is essential for pluripotent stem cells 5b , neural stem cells 5c , Lgr5+ intestinal and colonic stem cells 5d,5e , epidermal keratinocyte precursor cells 5f YAP is essential for maintaining stemness in multiple stem cell populations, including endothelial cells, endothelial cells, and other organ-resident progenitor cells. Activation of YAP allows stem and progenitor cells to repopulate damaged organs, because enhanced and sustained YAP activation promotes regenerative proliferation. 5a,5gMoreover, previous studies have demonstrated that forced expression of YAP in terminally differentiated cells, such as neurons, mammary epithelium, and pancreatic exocrine cells, reversibly converts these cells to a more stem cell-like transcriptional state, allowing for long-term ex vivo expansion and subsequent transplantation into mice. 5h Moreover, recent studies suggest that genetic activation of YAP can promote restorative proliferation in non-dividing cells. For example, inactivation of Hippo promotes cardiomyocyte proliferation in adult mice and leads to improved cardiac function in rodent models of heart failure. 5i .

[0005] Currently, attempts to pharmacologically activate YAP have focused on targeting traditionally druggable targets in the Hippo pathway, in particular the development of active site inhibitors against the MST1 / 2 and LATS1 / 2 kinases. 5j However, MST1 / 2 and LATS1 / 2 are involved in numerous cellular roles outside of Hippo signaling, including cell cycle control, stress signaling, and transcription, suggesting that even selective inhibitors of these kinases may have undesirable on-target effects. 5k~5p Thus, currently there are no drugs known to fully activate the YAP transcriptional program. Summary of the Invention

[0006] overview To address these shortcomings and others, the present disclosure provides a compound according to formula (I): [ka] or a tautomer or a pharma- ceutically acceptable salt thereof.

[0007] ring [ka] is a 5-6 membered heterocycle or heteroaryl, where 1-4 heteroatoms are independently selected from N, O and S. In various embodiments, the ring [ka] teeth, [ka] is selected from the group consisting of:

[0008] R is selected from H and C1-C6-alkyl.

[0009] R 1 is C6-C 10 -aryl, 5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S).

[0010] R 2 If present, H, C6-C 10 -aryl, 5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S).

[0011] In some embodiments, R 1 and R 2 are attached to adjacent atoms, they form a fused C6-C 10 -aryl or 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S.

[0012] In some embodiments, L is C(O), C(S) or CH2. V is NR 3 R 4 It is.

[0013] R 3is C1-C6-alkyl, -(C1-C6-alkyl)-S-(C1-C6-alkyl), -C1-C6-alkyl-(C6-C 10 -aryl), -C1-C6-alkyl-(5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S), C3-C 14 -cycloalkyl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O and S), -C1-C6-alkyl-(3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O and S).

[0014] R 4 is H, C1-C6-alkyl, -C1-C6-alkyl-(C6-C 10 -aryl), 5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S).

[0015] In some embodiments, R 3 and R 4 together with the N atom to which they are attached form a 5- to 7-membered heterocycloalkyl that is optionally fused or spirofused to a 3- to 14-membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O, and S.

[0016] In formula (I), any alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl may be selected from -CN, -OH, halo, oxo, -OR, -C, -D, -D-C, -D- ... A , -SR A , -S(O)R A , -S(O)2R A , N.R. A R B , -C(O)R A , -C(O)R A , -NR A C(O)2R B, -C(O)NR A R B , -S(O)NR A R B , -S(O)NR A R B , -NR A S(O)R B , -NR A S(O)2R B , and 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O, and S.

[0017] R A and R B are independently H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C 10 -aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C 10 -Aryl, C(O)OC1-C6-Alkyl, C6-C 10 -aryl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O, and S), -C(O)(5-10 membered heteroaryl (wherein 1-4 heteroaryl ring members are independently selected from N, O, and S).

[0018] R A and R B wherein each aryl and heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from C1-C6-alkyl, halo, C1-C6-haloalkyl, and 3- to 14-membered heterocycloalkyl, wherein 1 to 4 ring members are independently selected from N, O, and S; and each alkyl is optionally substituted with halo, NR C R D (where R C and R D are independently H, C1-C6-alkyl, C(O)C1-C6-alkyl and C(O)C6-C 10-aryl).

[0019] In another embodiment, the present disclosure provides a method for activating Yes-associated protein 1 (YAP) in a subject in need thereof, the method comprising administering to the subject a compound of formula (I), a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0020] In additional embodiments, the disclosure provides a method of treating a disease or condition having an etiology exacerbated or defined by insufficient proliferation repair in an afflicted subject, or a disease or condition that is ameliorated by induced proliferation of cells, comprising administering to the subject a compound of formula (I), a tautomer thereof, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0021] [Figure 1A] Figure 1A-1E. Figure 1A: Summary of the structure and cellular activity of compound 13. Figure 1B: Relative intensity values ​​and cell counts from 293A-TEAD-LUC cells treated with compound 13 for 24 h (n=3 biological replicates; mean and standard error). Figure 1C: Relative transcript levels of YAP-dependent genes (ANKRD1, CTGF, CYR61) and YAP itself (YAP1) from 293A cells treated with compound 13 in serum-containing or serum-deprived medium (n=3 biological replicates; mean and standard deviation). Figure 1D: Gene set enrichment analysis (GSEA) plot of the YAP-dependent gene set (curated and MSigDB:M2871) from 293A cells treated with compound 13 for 24 h (10 μM, P<0.0001, nominal P-value, GSEA). Data are from biologically independent samples. FIG. 1E: Enrichment P values ​​for GO categories upregulated by compound 13 treatment (10 μM) for 24 h. [Figure 1B]Figure 1A-1E. Figure 1A: Summary of the structure and cellular activity of compound 13. Figure 1B: Relative intensity values ​​and cell counts from 293A-TEAD-LUC cells treated with compound 13 for 24 h (n=3 biological replicates; mean and standard error). Figure 1C: Relative transcript levels of YAP-dependent genes (ANKRD1, CTGF, CYR61) and YAP itself (YAP1) from 293A cells treated with compound 13 in serum-containing or serum-deprived medium (n=3 biological replicates; mean and standard deviation). Figure 1D: Gene set enrichment analysis (GSEA) plot of the YAP-dependent gene set (curated and MSigDB:M2871) from 293A cells treated with compound 13 for 24 h (10 μM, P<0.0001, nominal P-value, GSEA). Data are from biologically independent samples. FIG. 1E: Enrichment P values ​​for GO categories upregulated by compound 13 treatment (10 μM) for 24 h. [Figure 1C] Figure 1A-1E. Figure 1A: Summary of the structure and cellular activity of compound 13. Figure 1B: Relative intensity values ​​and cell counts from 293A-TEAD-LUC cells treated with compound 13 for 24 h (n=3 biological replicates; mean and standard error). Figure 1C: Relative transcript levels of YAP-dependent genes (ANKRD1, CTGF, CYR61) and YAP itself (YAP1) from 293A cells treated with compound 13 in serum-containing or serum-deprived medium (n=3 biological replicates; mean and standard deviation). Figure 1D: Gene set enrichment analysis (GSEA) plot of the YAP-dependent gene set (curated and MSigDB:M2871) from 293A cells treated with compound 13 for 24 h (10 μM, P<0.0001, nominal P-value, GSEA). Data are from biologically independent samples. FIG. 1E: Enrichment P values ​​for GO categories upregulated by compound 13 treatment (10 μM) for 24 h. [Figure 1D]Figure 1A-1E. Figure 1A: Summary of the structure and cellular activity of compound 13. Figure 1B: Relative intensity values ​​and cell counts from 293A-TEAD-LUC cells treated with compound 13 for 24 h (n=3 biological replicates; mean and standard error). Figure 1C: Relative transcript levels of YAP-dependent genes (ANKRD1, CTGF, CYR61) and YAP itself (YAP1) from 293A cells treated with compound 13 in serum-containing or serum-deprived medium (n=3 biological replicates; mean and standard deviation). Figure 1D: Gene set enrichment analysis (GSEA) plot of the YAP-dependent gene set (curated and MSigDB:M2871) from 293A cells treated with compound 13 for 24 h (10 μM, P<0.0001, nominal P-value, GSEA). Data are from biologically independent samples. FIG. 1E: Enrichment P values ​​for GO categories upregulated by compound 13 treatment (10 μM) for 24 h. [Figure 1E] Figure 1A-1E. Figure 1A: Summary of the structure and cellular activity of compound 13. Figure 1B: Relative intensity values ​​and cell counts from 293A-TEAD-LUC cells treated with compound 13 for 24 h (n=3 biological replicates; mean and standard error). Figure 1C: Relative transcript levels of YAP-dependent genes (ANKRD1, CTGF, CYR61) and YAP itself (YAP1) from 293A cells treated with compound 13 in serum-containing or serum-deprived medium (n=3 biological replicates; mean and standard deviation). Figure 1D: Gene set enrichment analysis (GSEA) plot of the YAP-dependent gene set (curated and MSigDB:M2871) from 293A cells treated with compound 13 for 24 h (10 μM, P<0.0001, nominal P-value, GSEA). Data are from biologically independent samples. FIG. 1E: Enrichment P values ​​for GO categories upregulated by compound 13 treatment (10 μM) for 24 h. [Figure 2A]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2B]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2C]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2D]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2E]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2F]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2H]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 2I]Figures 2A-I. Compound 13 promotes epidermal keratinocyte proliferation ex vivo and in vivo. Representative images (Figure 2A) and quantification (Figure 2B) of rhodamine B stained mouse epidermal keratinocyte precursors after compound 13 treatment (10 μM; 10 days; n=3 biologically independent experiments, mean and standard deviation; scale bar=7 mm). Figure 2C: Relative expression of the YAP target transcript CYR61 in response to compound 13 treatment (10 μM; n=3 biologically independent experiments, mean and standard deviation). Figure 2D: Representative H&E-stained and anti-keratin 14 (K14)-stained tissue sections of mouse epidermis after 10 days of treatment with compound 13 (10 mg / mL; scale bar=50 μm). Epidermal thickness (Figure 2E) and keratinocyte number (Figure 2F) from wild-type or YAP knockout mice treated with compound 13 at the end of the study (n=3 animals; mean and standard deviation). Representative images (Figure 2G) and quantification (Figure 2H) of anti-KI67 histological staining of mouse epidermis at the end of the study (n=3 animals; mean and standard deviation; scale bar=50 μm). Figure 2I: Relative transcript levels of YAP target transcripts CTGF, CYR61 and ANKRD1 at the end of the study (n=3; mean and standard deviation; NS=statistically not significant). Statistical analysis was by univariate two-tailed t-test (Figures B, C, E, F, H and I). [Figure 3A] Figures 3A and 3B. Gel-based formulations of Compound 13 promote predominant epidermal hyperplasia in mice upon topical application of the drug. Quantitation (Figure 3A) and representative histological images (Figure 3B) of mice treated with the indicated formulations of Compound 13 for 10 days. [Figure 3B] Figures 3A and 3B. Gel-based formulations of Compound 13 promote predominant epidermal hyperplasia in mice upon topical application of the drug. Quantitation (Figure 3A) and representative histological images (Figure 3B) of mice treated with the indicated formulations of Compound 13 for 10 days. [Figure 4A]Figures 4A-D. Topical administration of compound 13 promotes epidermal growth in Yucatan minipigs. Figure 4A: Epidermal thickness, keratinocyte counts and representative H&E stained tissue sections at the end of the study (day 10). Representative images (Figure 4B) and quantification of nuclei counts (Figure 4C) from the dermal layer of pigs treated with the indicated concentrations of compound 13. Figure 4D: Relative transcript levels of YAP regulated genes Cyr61 and Ctgf obtained at the end of the study. [Figure 4B] Figures 4A-D. Topical administration of compound 13 promotes epidermal growth in Yucatan minipigs. Figure 4A: Epidermal thickness, keratinocyte counts and representative H&E stained tissue sections at the end of the study (day 10). Representative images (Figure 4B) and quantification of nuclei counts (Figure 4C) from the dermal layer of pigs treated with the indicated concentrations of compound 13. Figure 4D: Relative transcript levels of YAP regulated genes Cyr61 and Ctgf obtained at the end of the study. [Figure 4C] Figures 4A-D. Topical administration of compound 13 promotes epidermal growth in Yucatan minipigs. Figure 4A: Epidermal thickness, keratinocyte counts and representative H&E stained tissue sections at the end of the study (day 10). Representative images (Figure 4B) and quantification of nuclei counts (Figure 4C) from the dermal layer of pigs treated with the indicated concentrations of compound 13. Figure 4D: Relative transcript levels of YAP regulated genes Cyr61 and Ctgf obtained at the end of the study. [Figure 4D] Figures 4A-D. Topical administration of compound 13 promotes epidermal growth in Yucatan minipigs. Figure 4A: Epidermal thickness, keratinocyte counts and representative H&E stained tissue sections at the end of the study (day 10). Representative images (Figure 4B) and quantification of nuclei counts (Figure 4C) from the dermal layer of pigs treated with the indicated concentrations of compound 13. Figure 4D: Relative transcript levels of YAP regulated genes Cyr61 and Ctgf obtained at the end of the study. [Figure 5A]Figures 5A-E. Compound 13 promotes accelerated wound closure in a human skin equivalent model. Representative images of KI-67 stained sections at the end of a 6-day in vitro wound healing study using Mattek human skin equivalents (Figure 5A) and quantification of wound thickness (Figure 5B), wound diameter (Figure 5C), number of keratinocytes per wound (Figure 5D) and percentage of KI-67 positive nuclei (Figure 5E). [Figure 5B] Figures 5A-E. Compound 13 promotes accelerated wound closure in a human skin equivalent model. Representative images of KI-67 stained sections at the end of a 6-day in vitro wound healing study using Mattek human skin equivalents (Figure 5A) and quantification of wound thickness (Figure 5B), wound diameter (Figure 5C), number of keratinocytes per wound (Figure 5D) and percentage of KI-67 positive nuclei (Figure 5E). [Figure 5C] Figures 5A-E. Compound 13 promotes accelerated wound closure in a human skin equivalent model. Representative images of KI-67 stained sections at the end of a 6-day in vitro wound healing study using Mattek human skin equivalents (Figure 5A) and quantification of wound thickness (Figure 5B), wound diameter (Figure 5C), number of keratinocytes per wound (Figure 5D) and percentage of KI-67 positive nuclei (Figure 5E). [Figure 5D] Figures 5A-E. Compound 13 promotes accelerated wound closure in a human skin equivalent model. Representative images of KI-67 stained sections at the end of a 6-day in vitro wound healing study using Mattek human skin equivalents (Figure 5A) and quantification of wound thickness (Figure 5B), wound diameter (Figure 5C), number of keratinocytes per wound (Figure 5D) and percentage of KI-67 positive nuclei (Figure 5E). [Figure 5E]Figures 5A-E. Compound 13 promotes accelerated wound closure in a human skin equivalent model. Representative images of KI-67 stained sections at the end of a 6-day in vitro wound healing study using Mattek human skin equivalents (Figure 5A) and quantification of wound thickness (Figure 5B), wound diameter (Figure 5C), number of keratinocytes per wound (Figure 5D) and percentage of KI-67 positive nuclei (Figure 5E).

[0022] Detailed Description The present disclosure relates, in part, to the identification of a series of YAP-activating small molecules, which in various embodiments demonstrate their usefulness in promoting ex vivo and in vivo proliferation of keratinocytes. The compounds of the present disclosure are selective YAP activators and are therefore useful in enhancing wound repair in patients with burns or chronic ulcers, conditions that are not adequately addressed by current standard therapies. 39,40 .

[0023] An unbiased reporter-based screen identified small molecule activators of YAP-driven transcription that potently proliferated cells ex vivo and in vivo. More specifically, we used a 293A cell line that contains a stably integrated cassette (8xGTII-LUC) containing eight copies of a TEAD-binding element upstream of luciferase. These cells retain their responsiveness to contact inhibition-induced reduction of YAP transcriptional output. 6The TEAD-responsive reporter assay (referred to throughout as 293A-TEAD-LUC) was adapted to a 1536-well format and then used to screen a library of approximately 738,000 compounds for YAP-inducing activity. 98 compounds were identified that dose-dependently activated the TEAD-LUC signal, did not induce cytotoxicity (<20 μM), did not alter the enzymatic activity of luciferase in cells (<20 μM; 293A-CMV-LUC), and did not have annotated activity in the historical screen. Twenty-one of these molecules had 5-phenyl-isoxazole in their structure and were the strongest activators identified, as illustrated herein and throughout the Examples.

[0024] definition "Alkyl" means a straight or branched chain hydrocarbyl containing from 1 to about 20 carbon atoms. For example, an alkyl can have from 1 to 10 carbon atoms or from 1 to 6 carbon atoms. Exemplary alkyls include straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also branched chain isomers of straight chain alkyl groups such as, but not limited to, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2C H3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)CH(CH3)2, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Alkyl groups can be unsubstituted or, optionally, substituted with one or more substituents described herein.

[0025] The terms "halogen", "halide" and "halo" refer to -F or fluoro, -Cl or chloro, -Br or bromo, or -I or iodo, respectively.

[0026] "Haloalkyl" groups include monohaloalkyl groups, polyhaloalkyl groups (wherein all halo atoms can be the same or different), and perhaloalkyl groups (wherein all hydrogen atoms are replaced by the same or different halogen atoms, e.g., fluorine and / or chlorine atoms). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0027] The term "alkoxy" refers to an -O-alkyl group having the indicated number of carbon atoms. For example, (C1-C6)-alkoxy groups include -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl and -O-neohexyl.

[0028] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic or polycyclic 3-14 membered ring system, such as C3-C8-cycloalkyl. Cycloalkyl may be attached via any atom. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups can be unsubstituted or optionally substituted with one or more substituents described herein.

[0029] "Aryl" used alone or as part of another term means a carbocyclic aromatic group, either fused or unfused, having the number of carbon atoms indicated, or, if no number is indicated, up to 14 carbon atoms, e.g., C6-C 10 -Aryl or C6-C 14- means aryl. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, etc. (see, for example, Lang's Handbook of Chemistry (ed. Dean, JA) 13th ed. Table 7-2

[1985] ). An exemplary aryl is phenyl. An aryl group can be unsubstituted or, optionally, substituted with one or more substituents described herein.

[0030] The term "heteroatom" refers to N, O and S. Compounds of the present disclosure containing N or S atoms may be optionally oxidized to the corresponding N-oxide, sulfoxide or sulfone compounds.

[0031] "Heteroaryl," alone or in combination with any other moiety described herein, is a monocyclic aromatic ring structure containing 5-10, e.g., 5 or 6, ring atoms, or a bicyclic aromatic group having 8-10 atoms containing one or more, e.g., 1-4, 1-3, or 1-2 heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, e.g., sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or heteroatom is present at the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. Heteroaryl groups can be unsubstituted or optionally substituted with one or more substituents described herein.

[0032] "Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system having 3 to 14 atoms, e.g., 3 to 5, 3 to 6 or 3 to 7 atoms, in which 1 to 3 atoms in the ring are replaced by O, S or N heteroatoms. Heterocycloalkyls can be optionally fused to aryl or heteroaryl of 5 to 6 ring members and include oxidized S or N, e.g., sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. The attachment point of the heterocycloalkyl ring is at a carbon or heteroatom such that a stable ring is maintained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl and dihydroindolyl. Heterocycloalkyl groups can be unsubstituted or optionally substituted with one or more substituents described herein.

[0033] The terms "nitrile" and "cyano" may be used interchangeably and refer to the group --CN.

[0034] The term "oxo" refers to an =O atom bonded to an atom that is part of a saturated or unsaturated moiety. Thus, the =O atom can be bonded to a carbon, sulfur, or nitrogen atom that is part of a cyclic or acyclic moiety.

[0035] "Hydroxyl" or "hydroxy" refers to the group --OH.

[0036] One or more optional substituents on any group described herein are independently -CN, -OH, halo, oxo, -OR A , -SR A , -S(O)R A , -S(O)2R A , N.R. A R B , -C(O)R A , -C(O)R A , -NR A C(O)2RB , -C(O)NR A R B , -S(O)NR A R B , -S(O)NR A R B , -NR A S(O)R B , -NR A S(O)2R B , 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S.

[0037] R A and R B are independently H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C 10 -aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C 10 -Aryl, C(O)OC1-C6-Alkyl, C6-C 10 -aryl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O, and S), -C(O)(5-10 membered heteroaryl (wherein 1-4 heteroaryl ring members are independently selected from N, O, and S).

[0038] The compounds described herein may exist in various isomeric forms, including stereoisomers, geometric isomers, and conformational isomers (e.g., including cis or trans conformations). The compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to include all isomeric forms of the compounds of the present disclosure, including tautomeric forms of the compounds. The compounds of the present disclosure may also exist as open-chain or cyclized forms. In some cases, one or more of the cyclized forms may result from loss of water. The specific composition of the open-chain and cyclized forms may depend on how the compound is isolated, stored, or administered. For example, the compound may exist primarily in open-chain form under acidic conditions, but may cyclize under neutral conditions. All forms are included in the present disclosure.

[0039] Some compounds described herein may have asymmetric centers and therefore may exist in various enantiomeric and diastereomeric forms. Compounds described herein may be in the form of optical isomers or diastereomers. Thus, the present disclosure includes compounds described herein and their use in the form of optical isomers, diastereoisomers and mixtures thereof (including racemic mixtures). Optical isomers of compounds of the present disclosure may be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or chemical separation of stereoisomers by using optically active resolving agents.

[0040] Unless otherwise indicated, the term "stereoisomer" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of the other diastereomer of the compound. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of other stereoisomers of the compound.The above stereoisomers can be considered as compositions comprising two stereoisomers present in the respective weight percentages described herein.

[0041] In the event of a discrepancy between a depicted structure and the name given to that structure, the depicted structure shall prevail. Also, if the stereochemistry of a structure or part of a structure is not shown, for example, with bold or dashed lines, the structure or part of the structure shall be interpreted as including all stereoisomers thereof. However, in some cases, when multiple chiral centers are present, structures and names may be depicted as single enantiomers to account for the relative stereochemistry. Those skilled in the art of organic synthesis will know whether a compound is produced as a single enantiomer from the method used to produce the compound.

[0042] Unless otherwise indicated, the term "compound" as used herein is inclusive in that it includes the compound or its pharma- ceutically acceptable salts, stereoisomers and / or tautomers. Thus, for example, a compound of formula IA or formula IB includes pharma- ceutically acceptable salts of the tautomers of the compound.

[0043] In the present disclosure, a "pharmaceutically acceptable salt" is a pharma- ceutically acceptable salt of an organic or inorganic acid or base, of a compound described herein. Representative pharma- ceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, water soluble salts and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, hydrogen sulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariat, dihydrochloride, edetate, edisylate, estolate, esylate, fionalate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide ... Salts of phenylalanine, ... In this case, a pharma- ceutically acceptable salt can have more than one counter ion. Hence, a pharma- ceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0044] The terms "treat," "treat" and "treatment" refer to the amelioration or eradication of a disease or symptoms associated with a disease. In various embodiments, the term refers to minimizing the spread or worsening of a disease by administering to a patient having the disease one or more prophylactic or therapeutic compounds described herein.

[0045] The terms "prevent", "preventing" and "prevention" refer to preventing the onset, recurrence or spread of a disease in a patient by administering a compound described herein.

[0046] The term "effective amount" refers to an amount of a compound or other active ingredient described herein sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease, or to delay or minimize symptoms associated with a disease. Additionally, a therapeutically effective amount with respect to a compound described herein refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. This term, as used in connection with a compound described herein, can include an amount that improves overall treatment, or reduces or avoids the symptoms or causes of a disease, or enhances the therapeutic effect of another therapeutic agent, or acts synergistically with another therapeutic agent.

[0047] A "patient" or "subject" includes animals such as, for example, humans, cows, horses, sheep, lambs, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, the animals are mammals, such as non-primates and primates (e.g., monkeys and humans). In one embodiment, the patient is a human, such as a human infant, child, adolescent, or adult. In this disclosure, the terms "patient" and "subject" are used interchangeably.

[0048] compound In various embodiments, the present disclosure provides a compound of formula (I): [ka] or a tautomer or a pharma- ceutically acceptable salt thereof.

[0049] ring [ka] is a 5-6 membered heterocycle or heteroaryl, where 1-4 heteroatoms are independently selected from N, O and S. In various embodiments, the ring [ka] teeth, [ka] is selected from the group consisting of:

[0050] R is selected from H and C1-C6-alkyl.

[0051] R 1 is C6-C 10 -aryl, 5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S).

[0052] R 2 If present, H, C6-C 10 -aryl, 5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S).

[0053] In some embodiments, R 1 and R 2 are attached to adjacent atoms, they form a fused C6-C 10 -aryl or 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S.

[0054] In some embodiments, L is C(O), C(S) or CH2. V is NR 3 R 4 It is.

[0055] R 3 is C1-C6-alkyl, -(C1-C6-alkyl)-S-(C1-C6-alkyl), -C1-C6-alkyl-(C6-C 10 -aryl), -C1-C6-alkyl-(5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S), C3-C 14 -cycloalkyl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O and S), -C1-C6-alkyl-(3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O and S).

[0056] R 4 is H, C1-C6-alkyl, -C1-C6-alkyl-(C6-C 10 -aryl), 5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S).

[0057] In some embodiments, R 3 and R 4 together with the N atom to which they are attached form a 5- to 7-membered heterocycloalkyl that is optionally fused or spirofused to a 3- to 14-membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O, and S.

[0058] R A and R B are independently H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C 10-aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C 10 -Aryl, C(O)OC1-C6-Alkyl, C6-C 10 -aryl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O, and S), -C(O)(5-10 membered heteroaryl (wherein 1-4 heteroaryl ring members are independently selected from N, O, and S).

[0059] R A and R B wherein each aryl and heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from C1-C6-alkyl, halo, C1-C6-haloalkyl, and 3- to 14-membered heterocycloalkyl, wherein 1 to 4 ring members are independently selected from N, O, and S; and each alkyl is optionally substituted with halo, NR C R D (where R C and R D are independently H, C1-C6-alkyl, C(O)C1-C6-alkyl and C(O)C6-C 10 -aryl).

[0060] In various embodiments, which may be optionally combined with any other embodiments described herein, L is C(O).

[0061] In various embodiments, which may be optionally combined with any other embodiments described herein, R 3 is an optionally substituted C1-C6-alkyl or -C1-C6-alkyl-(5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S). In one embodiment, R 3is an optionally substituted -C1-C6-alkyl-(5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S)).

[0062] In yet another embodiment, which may be optionally combined with any other embodiment described herein, R 4 is H.

[0063] In various embodiments, which may be optionally combined with any other embodiments described herein, R 1 is an optionally substituted C-C 10 -aryl. In some embodiments, R 1 is an optionally substituted phenyl. In other embodiments, R 1 is phenyl.

[0064] In various embodiments, which may be optionally combined with any other embodiments described herein, R 2 is H.

[0065] The present disclosure provides, in some embodiments, optionally in combination with any other embodiment described herein, a compound of formula (I), a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: [ka] teeth [ka] It is.

[0066] In other embodiments, the ring [ka] teeth, [ka] is selected from.

[0067] In yet other embodiments, the ring [ka] teeth, [ka] is selected from.

[0068] In additional embodiments, the ring [ka] teeth, [ka] is selected from.

[0069] In various embodiments, which may be optionally combined with any other embodiment described herein, the present disclosure provides a compound of formula (I), a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: ring [ka] teeth, [ka] is; R 1 is phenyl or 5-6 membered heteroaryl (wherein 1-3 heteroaryl members are independently selected from N, O and S), each of which is selected from Br, Cl, F, -CN, C-C-alkyl, C-C-haloalkyl, -OC-C-alkyl, -OC-C-haloalkyl, optionally substituted phenyl, -C(O)R A optionally substituted with 1 to 3 substituents independently selected from R 2 is H; L is C(O); R 3 is -C1-C6-alkyl-(5-7 membered heteroaryl (wherein 1-3 heteroaryl members are independently selected from N, O and S)) or -C1-C6-alkyl(phenyl), where heteroaryl or phenyl is selected from Br, Cl, F, C1-C6-alkyl, -OC1-C6-alkyl, C(O)R A and -C(O)NR A R B optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 4 is H.

[0070] In additional embodiments, which may be optionally combined with any other embodiments described herein, R 1 is phenyl, and R 3 is an optionally substituted -C1-C6-alkyl-(5-membered heteroaryl (wherein 1-2 heteroaryl members are independently selected from N, O and S)) or an optionally substituted C1-C6-alkyl(phenyl).

[0071] The disclosure also provides, in various embodiments, the compounds set forth in Table 1, or a tautomer or pharma- ceutically acceptable salt thereof. [Table 1] TIFF2024508698000020.tif247151TIFF2024508698000021.tif245151TIFF2024508698000022.tif251151TIFF2024508698000023.tif158151In additional embodiments, the disclosure provides compounds set forth in Table 2, or tautomers or pharma- ceutically acceptable salts thereof. [Table 2] TIFF2024508698000025.tif247132TIFF2024508698000026.tif251133TIFF2024508698000027.tif27146Pharmaceutical Composition The present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds described herein or pharma- ceutically acceptable salts, stereoisomers and / or tautomers thereof in admixture with a pharma- ceutically acceptable carrier. In some embodiments, the compositions further contain one or more additional therapeutic substances, pharma- ceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavoring agents, in accordance with accepted practices of pharmaceutical compounding.

[0072] In one embodiment, the pharmaceutical composition comprises a compound selected from those exemplified in Table 1 and Table 2, or a pharma- ceutically acceptable salt, stereoisomer and / or tautomer thereof, and a pharma- ceutically acceptable carrier.

[0073] The pharmaceutical compositions of the present disclosure are formulated, dosed, and administered in a manner consistent with good clinical practice. Factors to consider in this regard include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0074] The "therapeutically effective amount" of the compound or its pharma- ceutically acceptable salt, stereoisomer and / or tautomer administered is determined by such considerations and is the minimum amount necessary to activate YAP transcriptional activity, promote proliferative tissue repair, and combinations thereof. Such an amount may be below an amount that is toxic to normal cells or to the subject as a whole. In general, the initial therapeutically effective amount of the compound of the present disclosure (or its pharma- ceutically acceptable salt, stereoisomer or tautomer) administered ranges from about 0.01 to about 200 mg / kg or about 0.1 to about 20 mg / kg of patient body weight per day, with a typical initial range being about 0.3 to about 15 mg / kg / day. Oral unit dosage forms such as tablets and capsules may contain about 0.1 mg to about 1000 mg of the compound of the present disclosure (or its pharma- ceutically acceptable salt, stereoisomer or tautomer). In another embodiment, such dosage forms contain about 50 mg to about 500 mg of the compound of the present disclosure (or a pharma- ceutically acceptable salt, stereoisomer, or tautomer). In yet another embodiment, such dosage forms contain about 25 mg to about 200 mg of the compound of the present disclosure (or a pharma- ceutically acceptable salt, stereoisomer, or tautomer). In yet another embodiment, such dosage forms contain about 10 mg to about 100 mg of the compound of the present disclosure (or a pharma- ceutically acceptable salt, stereoisomer, or tautomer). In another embodiment, such dosage forms contain about 5 mg to about 50 mg of the compound of the present disclosure (or a pharma- ceutically acceptable salt, stereoisomer, or tautomer). In any of the above embodiments, the dosage forms may be administered once or twice daily.

[0075] The compositions of the present disclosure may be administered orally, topically, parenterally, by inhalation or aerosol, or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[0076] Suitable oral compositions described herein include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0077] In another aspect, also included is a pharmaceutical composition suitable for single unit administration comprising a compound of the present disclosure or a pharma- ceutically acceptable stereoisomer, salt, or tautomer thereof and a pharma- ceutically acceptable carrier.

[0078] The composition of the present disclosure suitable for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.For example, the liquid formulation of the compound of the present disclosure contains one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to obtain a pharmacopoeial formulation of the compound of the present disclosure.

[0079] For tablet compositions, the compound of the present disclosure mixed with non-toxic pharma- ceutically acceptable excipients is used to manufacture tablets.Examples of such excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc.Tablets may be uncoated or may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract and provide sustained therapeutic action over a desired period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used.

[0080] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0081] In the case of aqueous suspensions, the compounds of the present disclosure are mixed with suitable excipients to maintain a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

[0082] Oral suspensions may also contain dispersing or wetting agents, such as naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0083] Oily suspensions may be formulated by suspending the compounds of the present disclosure in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.

[0084] Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0085] Dispersible powders and granules suitable for preparing aqueous suspension by adding water provide the compound of the present disclosure mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavorings and colorings, may also be present.

[0086] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and the condensation reaction products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0087] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose, and such formulations may also contain a demulcent, a preservative, a flavoring and a coloring agent.

[0088] The pharmaceutical composition may be in the form of a sterile injectable, aqueous or oleaginous suspension. The suspension (suspension) may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. Sterile fixed oils are also commonly used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Also, fatty acids such as oleic acid are useful in the preparation of injectables.

[0089] The compounds described herein can also be administered in the form of suppositories for rectal administration of drugs.These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycol.

[0090] The composition for parenteral administration is administered in a sterile medium.Depending on the vehicle used and the concentration of the drug in the formulation, the parenteral preparation can be either a solution or a suspension containing dissolved drug.Additives such as local anesthetics, preservatives and buffers can also be added to the parenteral composition.

[0091] How to use In an additional embodiment, as illustrated by the data and examples herein, the disclosure provides a method for activating Yes-associated protein 1 (YAP) in a subject in need thereof, comprising administering to the subject a compound described herein, e.g., a compound of Formula (I), a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0092] The advantage of the compounds described herein is their selectivity for reducing undesired proliferation by activating YAP.Therefore, the compounds are particularly useful in therapy, such as, for example, in the treatment of disease or condition whose etiology is aggravated or determined by insufficient proliferation repair in the affected subject.In some embodiments, the disease or condition is improved by the induction of proliferation of cells.The method includes administering to the subject a compound described herein, such as the compound of formula (I), its tautomer or its pharmaceutically acceptable salt.

[0093] In some embodiments, the method is useful for wound repair or organ repair, where the disease or condition is one requiring wound repair or one requiring organ repair. Exemplary organs include the lung, heart, liver, pancreas, liver and intestine.

[0094] In other embodiments, the disease or condition is selected from the group consisting of burns, ulcers, heart failure and inflammatory bowel disease. Examples of ulcers include chronic ulcers, diabetic foot ulcers and venous leg ulcers.

[0095] Examples of diseases and conditions that may be treated by the methods disclosed herein include: diabetic foot ulcers (DFUs), venous ulcers (stasis ulcers), pressure ulcers, full or partial thickness burns, eczema, psoriasis, cellulitis, impetigo, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acropellic peeling skin syndrome, and the like. syndrome), Blau syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, furunculosis, capillaritis, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, chronic lichen simplex, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), emphysema, silicosis, asbestosis, pneumoconiosis, aluminosis, bauxite fibrosis, beryllium disease, siderosis, stanosis, talc, Labrador lung (mixed dust pneumoconiosis), sarcoidosis pulmonary edema, hypersensitivity pneumonitis (HP) / extrinsic allergic alveolitis (EAA), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial pneumonia (LIP), idiopathic interstitial pneumonia: unspecified, eosinophilic lung disease, tuberculosis (TB), pulmonary edema, interstitial lung disease, cryptogenic organizing pneumonia (COP), electronic cigarettes, etc. Vaping-associated pulmonary illness (EVALI), Hantavirus pulmonary syndrome (HPS), histoplasmosis, legionellosis, MAC pulmonary disease, alpha-1 antitrypsin deficiency, aspergillosis, lymphangioleiomyomatosis (LAM), Middle East respiratory syndrome (MERS), nontuberculous mycobacterial pulmonary disease (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hematosiderosis, pulmonary alveolar proteinosis, pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (with or without situs inversus), Hypersensitivity pneumonitis of rare causes (all causes except farmer's lung disease and pigeon breeder's lung disease), pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT), interstitial lung disease in systemic sclerosis, interstitial lung disease in rheumatoid arthritis, interstitial lung disease in idiopathic inflammatory myopathies (polymyositis, dermatomyositis, antisynthetase syndrome), interstitial lung disease in Sjögren's syndrome, interstitial lung disease in mixed connective tissue disease (MCTD), interstitial lung disease in overlap syndrome,Interstitial lung disease in undifferentiated connective tissue disease, bronchiolitis obliterans (in non-transplant patients), infectious colitis, ulcerative colitis, Crohn's disease, ischemic colitis, radiation colitis, peptic ulcer, intestinal cancer, intestinal obstruction, rheumatoid arthritis, psoriatic arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, multiple sclerosis, Graves' disease, type 1 diabetes, psoriasis, ankylosing spondylitis, scleroderma, myositis, gout, antiphospholipid syndrome (APS), vasculitis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, systolic heart failure, diastolic heart failure (heart failure with preserved ejection fraction), atrial septal defect, atrioventricular septal defect, aortic Coarctation, double outlet right ventricle, type D transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, single ventricle, tetralogy of Fallot, total anomalous pulmonary venous return, tricuspid atresia, truncus arteriosus, ventricular septal defect, polycystic kidney disease, diabetes insipidus, Goodpasture's disease, IgA vasculitis, IgA nephropathy, lupus nephritis, adult nephrotic syndrome, childhood nephrotic syndrome, hemolytic uremic syndrome, cavernous kidney, renal dysplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, Alport syndrome, Wegener's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal fistula segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schönlein purpura, IgA nephropathy (Berge disease), interstitial nephritis, minimal change nephrotic syndrome, nephrotic syndrome, thrombotic thrombocytopenic purpura (TTP), granulomatosis with polyangiitis (GPA), adult Still's disease, agammaglobulinemia, alopecia areata, autoimmune angioedema, autoimmune autonomic dysregulation, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis , Autoimmune Retinopathy, Autoimmune Urticaria, Axonal and Neuronal Neuropathy (AMAN), Baro's Disease, Bullous Pemphigoid, Celiac Disease, Chronic Recurrent Multifocal Osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial Pemphigoid, Cogan's Syndrome, Cold Agglutinin Disease, Coxsackie Myocarditis, CREST Syndrome, Dermatitis Herpetiformis, Dermatomyositis, Devic's Disease (Neuromyelitis Optica), Discoid Lupus, Eosinophilic Esophagitis (EoE), Eosinophilic Fasciitis, Erythema Nodosum, Essential Mixed Cryoglobulinemia, Giant Cell Arteritis (Temporal Arteritis),Giant cell myocarditis, granulomatosis with polyangiitis, Guillain-Barré syndrome, Hashimoto's thyroiditis, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestation (PG), hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), Lambert-Eaton syndrome, leukocytoclastic vasculitis, linear IgA disease (LAD), microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal carcinomatosis, Motor Neuropathy (MMN) or MMNCB, Multiple Sclerosis, Myasthenia Gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis Optica, Neutropenia, Ophthalmic Cicatricial Pemphigoid, Optic Neuritis, Relapsing Rheumatism (PR), PANDAS, Paraneoplastic Cerebellar Degeneration (PCD), Paroxysmal Nocturnal Hemoglobinuria (PNH), Parry-Romberg Syndrome, Parsplanitis (Peripheral Uveitis), Parsonage-Turner Syndrome, Pemphigus, Peripheral Neuropathy, Perivenous Encephalomyelitis, Pernicious Anemia (PA), POEMS Syndrome, Nodular Multifocal Inflammatory Syndrome, Arteritis, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt's syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm and testicular autoimmunity, Stiff-person syndrome Syndrome (SPS), Subacute Bacterial Endocarditis (SBE), Susac Syndrome, Sympathetic Ophthalmia (SO), Takayasu Arteritis, Temporal Arteritis / Giant Cell Arteritis, Thrombocytopenic Purpura (TTP), Thyroid Eye Disease (TED), Alagille Syndrome, Alcohol-Related Liver Disease, Autoimmune Hepatitis, Biliary Atresia, Liver Cirrhosis, Lysosomal Acid Lipase Deficiency (LAL-D), Neonatal Jaundice, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Primary Biliary Cholangitis (PBC) and Progressive Familial Intrahepatic Cholestasis (PFIC).

[0096] Working Example Additional embodiments of the present disclosure reside in the specific examples and data described in further detail herein.

[0097] Example 1A: Synthesis of 5-phenyl-N-(3-(thiazol-2-yl)propyl)isoxazole-3-carboxamide (compound 13): [ka] To a stirred solution of 5-phenyl-1,2-oxazole-3-carboxylic acid (5.50 g, 29.1 mmol, 1.0 equiv.) and 3-(thiazol-2-yl)propan-1-amine dihydrochloride (4.13 g, 29.1 mmol, 1.0 equiv.) in dichloromethane (60.0 mL) was added triethylamine (12.6 mL, 90.1 mmol, 3.1 equiv.) at room temperature and stirred for 5 min. The solution was cooled to 0° C. and propylphosphonic anhydride (T3P, 50% solution in ethyl acetate, 59.2 mL, 93.0 mmol, 3.2 equiv.) was added. The resulting solution was stirred at room temperature for 3 h after which the reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (3×75 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography using a mobile phase gradient of 0% to 50% ethyl acetate in hexane to give 5-phenyl-N-(3-(thiazol-2-yl)propyl)isoxazole-3-carboxamide (compound 13; 5.20 g, 16.3 mmol, 56%) as a white solid.

[0098] Example 1B: Alternative synthesis of 5-phenyl-N-(3-(thiazol-2-yl)propyl)isoxazole-3-carboxamide (compound 13): 5-Phenylisoxazole-3-carboxylic acid (1.0 g, 5.3 mmol, 1.0 equiv.) was dissolved in 15 mL of anhydrous DMF and the solution was cooled in an ice bath. HATU (2.0 g, 5.3 mmol, 1.0 equiv.) was added to the solution, followed by Hunig's base (1.9 mL, 10.6 mmol, 2.0 equiv.) in portions, and the mixture was stirred for 15 min. 3-(Thiazol-2-yl)propan-1-amine (827 mg, 5.8 mmol, 1.1 equiv.) was added, and the mixture was stirred at room temperature overnight. TLC and LC-MS analysis indicated that the starting material had been consumed and converted to the desired product. The mixture was then filtered through a cotton plug, the volatiles were removed in vacuo, and the product was purified by silica gel column chromatography by dry loading the crude reaction (30-70% ethyl acetate in hexanes). For chromatography, the compound was resuspended in 10 mL of a 5:1 mixture of acetone / toluene and solubilized upon reflux. The solution was cooled to room temperature and left at -20°C overnight, and the crystallized solid was filtered through a fritted funnel, washed with ice-cold acetone and sucked dry.

[0099] Example 2: Synthesis of N-[3-(4-methylpiperazin-1-yl)propyl]-5-phenyl-1,2-oxazole-3-carboxamide (compound 127): [ka] To a stirred solution of 5-phenyl-1,2-oxazole-3-carboxylic acid (150 mg, 793 μmol, 1.0 equiv.) and 3-(4-methylpiperazin-1-yl)propan-1-amine (125 mg, 793 μmol, 1.0 equiv.) in dichloromethane (5.0 mL), triethylamine (343 μL, 2.46 mmol, 3.1 equiv.) was added at room temperature and stirred for 5 min. The solution was cooled to 0° C. and propylphosphonic anhydride (T3P, 50% solution in ethyl acetate, 1.61 mL, 2.54 mmol, 3.2 equiv.) was added. The resulting solution was stirred at room temperature for 16 h, after which the volatiles were removed in vacuo. The crude material was first purified by column chromatography using a mobile phase of 10% methanolic ammonia in dichloromethane. The resulting compound was purified again by reverse-phase preparative-scale HPLC and the desired fractions were lyophilized to give N-[3-(4-methylpiperazin-1-yl)propyl]-5-phenyl-1,2-oxazole-3-carboxamide (compound 127; 63.0 mg, 188 μmol, 24%) as an off-white solid.

[0100] Example 3: Synthesis of N-(2-(1H-pyrrol-1-yl)ethyl)-5-phenylisoxazole-3-carbothioamide (Compound 106) [ka] To a stirred solution of 5-phenyl-N-[2-(1H-pyrrol-1-yl)ethyl]-1,2-oxazole-3-carboxamide (200 mg, 711 μmol) in tetrahydrofuran (8.00 mL) was added bis(4-methoxyphenyl)-1,3,2λ 5 ,4λ 5-Dithiadiphosphetane-2,4-dithione (Lawson's reagent, 863 mg, 3 equiv., 2.13 mmol) was added at room temperature and stirred at 65° C. for 18 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by Combi Flash chromatography using a 12.0 g Redi Sep column eluting with 15-20% ethyl acetate in heptane. The desired fractions were concentrated and the resulting solid was washed with diethyl ether and dried under vacuum to give N-(2-(1H-pyrrol-1-yl)ethyl)-5-phenylisoxazole-3-carbothioamide as a pale yellow solid.

[0101] Example 4: Synthesis of Additional Compounds [ka] The synthesis of compounds 1-105 and resynthesis of certain known compounds (107-157) were carried out following the exemplary procedures outlined for compounds 13 and 127. To a stirred solution of a representative carboxylic acid (i, 1.0 equiv.) and a representative amine (ii, 1.0 equiv.) in dichloromethane, triethylamine (3.1 equiv.) was added at room temperature and stirred for 5 min. The solution was cooled to 0° C. and propylphosphonic anhydride (T3P, 50% solution in ethyl acetate, 3.2 equiv.) was added. The resulting solution was stirred at room temperature for 3 h after which the volatiles were removed in vacuo. The crude material was purified by column chromatography to give the desired compound as a powder or repurified using reverse phase preparative scale HPLC. All synthesized compounds were characterized by LC / MS and / or HPLC. 1 H NMR confirmed the purity to be greater than 95%.

[0102] Example 5: YAP activation assay To exemplify the compounds of formula (I) and those shown in Tables 1 and 2, a 5-phenyl-3-carboxamide substituted isoxazole scaffold was identified and exemplified in the thiazole substituted derivative, compound 13. This compound induced luciferase activity in 293A-TEAD-LUC cells in a dose-dependent manner in the presence or absence of serum when the cells were plated at high cell density (EC 50 = 1.5 and 1.6 μM, respectively; Figures 1A and 1B. The results indicate that compound 1 does not mimic the weakly YAP-activating properties of serum. 7 .

[0103] The magnitude of this transcriptional response is similar to that observed upon knockdown of NF2 (merlin), a key Hippo signaling protein, in reporter assays. 8 Treatment with compound 13 also promoted the association of YAP with TEAD proteins in cells in a dose-dependent manner and induced the nuclear localization of YAP in response to increasing cell density, indicating that treatment with compound 13 can overcome the YAP-inhibitory effect of Hippo pathway activation.

[0104] Additionally, treatment with compound 13 potently increased levels of YAP-regulated transcripts (i.e., ANRKD1, CYR61, CTGF) in 293A cells and other human cell lines (i.e., MCF-10A, HEK293T, H69, HaCaT), but did not increase levels of YAP itself (YAP1). This indicates that compound 1 broadly activates YAP, but does not do so via positive regulation of YAP transcripts (Figure 1C). RNA-seq-based expression profiling of 293A cells showed that compound 13 increased transcripts of previous YAP transcriptional targets and annotated YAP-bound loci by gene set enrichment analysis (GSEA). 9-11Similarly, treatment with compound 13 upregulated transcripts associated with cell growth, differentiation, and wound healing, as measured by DAVID analysis (Figure 1D and Figure 1E). Furthermore, the ability of compound 13 to activate the TEAD-LUC reporter signal and upregulate YAP-regulated transcripts was dependent on the presence of YAP protein, indicating that compound 13 is a potent and specific activator of YAP transcriptional activity acting upstream of YAP.

[0105] Additional compounds of the present disclosure were subjected to the above assays, and the results and selected characterization data are shown in Tables 3 and 4 below. [Table 3] TIFF2024508698000033.tif234167TIFF2024508698000034.tif250167TIFF2024508 698000035.tif234167TIFF2024508698000036.tif227167TIFF2024508698000037.t if230167TIFF2024508698000038.tif222167TIFF2024508698000039.tif241167TIF F2024508698000040.tif224167TIFF2024508698000041.tif250166TIFF20245086980 00042.tif227166TIFF2024508698000043.tif220166TIFF2024508698000044.tif23 5167TIFF2024508698000045.tif241168TIFF2024508698000046.tif240166TIFF202 4508698000047.tif227167TIFF2024508698000048.tif207166TIFF20245086980000 49.tif234167TIFF2024508698000050.tif249167TIFF2024508698000051.tif122168 [Table 4] TIFF2024508698000053.tif242163TIFF2024508698000054.tif198163TIFF2024508698000055.tif244163TIFF2024508698000056.tif217163TIFF2024508698000057.tif251164TIFF2024508698000058.tif245163TIFF2024508698000059.tif120163Example 6: Epidermal remodeling We evaluated the proliferation response of primary cells and tissues to treatment with compound 13. In this regard, cyclic YAP activation sustains the growth of keratin 14 (K14)-positive keratinocyte precursors in mice, thereby contributing new keratinocytes to the epidermal barrier. 12,13 Moreover, continuous genetic activation of YAP promotes hyperplasia of keratinocytes and their precursors ex vivo and in mice, indicating that YAP is essential for basal epidermal regeneration but can be enhanced to promote growth. 13 Treatment with compound 13 enhanced (approximately 10-fold) the colony-forming ability of primary mouse epidermal keratinocytes when cultured over a 10-day groWth on dermal feeder layers (Figures 2A and 2B). Treatment with compound 13 also enabled secondary replating proliferation of rhodamine B-stained keratinocytes and time-dependent expression of the YAP-driven transcript Cyr61 (Figures 2A-C).

[0106] When applied topically to the dorsal skin of wild-type adult C57BL / 6 mice for 10 days, compound 13 (10 μM) promoted a dramatic proliferation of keratinocytes and K14-positive precursors as assessed by H&E and anti-K14 histological staining at the end of the study (Figure 2D). Treatment with the compound approximately doubled the thickness of the epidermis, a result derived from an increase in the number of keratinocytes per unit length of skin (Figure 2E and Figure 2F). The increase in keratinocyte number was dependent on the presence of YAP, as conditional YAP knockout animals were insensitive to drug treatment in the absence of YAP (Figure 2E and Figure 2F). 14This observation is consistent with previous studies and with publicly available RNA-seq data from primary mouse and human skin tissues from GEO, which indicates that activity of YAP, rather than its paralogue TAZ (WW domain-containing transcriptional regulator; WWTR), predominates in the epidermis. 13 Furthermore, KI-67 positive keratinocytes were substantially increased upon drug treatment, indicating that keratinocyte proliferation was due to drug-induced proliferation (Figure 2G and Figure 2H). Compound treatment also led to a strong upregulation of the YAP-dependent transcripts Ctgf, Cyr61 and Ankrd1 at the experimental endpoint (Figure 2I). Taken together, these results indicate that compound 13, as an example of a compound disclosed herein, activates a pro-proliferative YAP-dependent transcriptional program in adult animals that can remodel the epidermis through proliferation.

[0107] Example 7: Wound healing In an exemplary embodiment, treatment with compound 13 promotes wound healing in human cells and induces a proliferation-promoting effect on keratinocytes of Yucatan minipigs, a human skin substitute species. Thus, a gel-based formulation of compound 13 was developed, which allows for its stable room temperature storage and topical delivery at high concentrations (up to about 1.5 weight percent). Topical delivery of compound 13 was found to promote epidermal thickening in mice to a significant extent more than delivery of the drug in acetone or DMSO (Figure 3). Furthermore, topical delivery of compound 13 promoted epidermal hyperplasia, dermal hyperplasia, and YAP-dependent gene expression in Yucatan minipigs (Figure 4). Additionally, treatment of human wounded skin equivalents with a 3 mm full-thickness wound with compound 13 promoted keratinocyte hyperplasia and promoted wound contraction (Figure 5).

[0108] By extensively screening a large chemical library for compounds that selectively activate YAP-driven transcription by a mechanism that does not involve direct inhibition of Hippo kinase, we identified the thiazole-substituted 3-carboxamido-5-phenyl-isoxazole PY-60. In contrast to MST1 / 2 inhibition, which only partially activates YAP-driven transcription, we found that PY-60 dramatically enhances the transcriptional output of YAP, resulting in levels of YAP activation similar to those of NF2 knockdown in cells. Treatment with PY-60 largely phenocopies the proliferative response of forced expression of a YAP transgene, resulting in serum-free growth of MCF10A cells in agar and allowing MDCK cells to circumvent contact inhibition of cell growth. These data suggest that PY-60 is a valuable in vitro tool compound, allowing the temporal and dose-dependent control of small molecule drugs to examine the cellular effects of full YAP transcription activation.

[0109] Numbered references in this disclosure are as follows:

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Claims

1. 1. A composition for use in a method for activating Yes-associated protein 1 (YAP) in a subject in need thereof, comprising: 【Chemistry 1】 [In the formula, ring 【Chemistry 2】 teeth 【Chemistry 3】 Selected from the group consisting of: R is selected from H and C1-C6-alkyl; R1 is selected from the group consisting of C6-C10-aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; R2, if present, is selected from the group consisting of H, C6-C10-aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; Alternatively, R1 and R2, when attached to adjacent atoms, together with the atoms to which they are attached, form a fused C6-C10-aryl or 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; L is C(O), C(S) or CH2; V is NR3R4; R3 is selected from the group consisting of C1-C6-alkyl, -(C1-C6-alkyl)-S-(C1-C6-alkyl), -C1-C6-alkyl-(C6-C10-aryl), -C1-C6-alkyl-(5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S), C3-C14-cycloalkyl, 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O and S), -C1-C6-alkyl-(3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O and S); R4 is selected from the group consisting of H, C1-C6-alkyl, -C1-C6-alkyl-(C6-C10-aryl), 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; or R3 and R4, together with the N atom to which they are attached, form a 5-7 membered heterocycloalkyl, optionally fused or spirofused to a 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O and S; and wherein any alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of: -CN, -OH, halo, oxo, -ORA, -SRA, -S(O)RA, -S(O)2RA, NRARB, -C(O)RA, -C(O)2RA, -NRAC(O)2RB, -C(O)NRARB, -S(O)NRARB, -S(O)2NRARB, -NRAS(O)RB, -NRAS(O)2RB, 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O, and S; RA and RB are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C10-aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C10-aryl, C(O)OC1-C6-alkyl, C6-C10-aryl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O and S), -C(O)(5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S)); Each aryl and heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from C1-C6-alkyl, halo, C1-C6-haloalkyl, and 3- to 14-membered heterocycloalkyl, where 1 to 4 ring members are independently selected from N, O, and S; and Each alkyl is optionally substituted with 1 to 3 substituents independently selected from halo, NRCRD, where RC and RD are independently selected from H, C1-C6-alkyl, C(O)C1-C6-alkyl and C(O)C6-C10-aryl. or a tautomer thereof or a pharma- ceutically acceptable salt thereof.

2. 1. A composition for use in a method of treatment of a disease or condition having an etiology exacerbated or defined by insufficient proliferation repair in an affected subject, or a disease or condition that is ameliorated by induced proliferation of cells, comprising a compound of formula (I) 【Chemistry 4】 [In the formula, ring 【Chemistry 5】 teeth 【Chemistry 6】 Selected from the group consisting of: R is selected from H and C1-C6-alkyl; R1 is selected from the group consisting of C6-C10-aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; R2, if present, is selected from the group consisting of H, C6-C10-aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; Alternatively, R1 and R2, when attached to adjacent atoms, together with the atoms to which they are attached, form a fused C6-C10-aryl or 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; L is C(O), C(S) or CH2; V is NR3R4; R3 is selected from the group consisting of C1-C6-alkyl, -(C1-C6-alkyl)-S-(C1-C6-alkyl), -C1-C6-alkyl-(C6-C10-aryl), -C1-C6-alkyl-(5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S), C3-C14-cycloalkyl, 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O and S), -C1-C6-alkyl-(3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O and S); R4 is selected from the group consisting of H, C1-C6-alkyl, -C1-C6-alkyl-(C6-C10-aryl), 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O and S; or R3 and R4, together with the N atom to which they are attached, form a 5-7 membered heterocycloalkyl, optionally fused or spirofused to a 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl ring members are independently selected from N, O and S; and wherein any alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of: -CN, -OH, halo, oxo, -ORA, -SRA, -S(O)RA, -S(O)2RA, NRARB, -C(O)RA, -C(O)2RA, -NRAC(O)2RB, -C(O)NRARB, -S(O)NRARB, -S(O)2NRARB, -NRAS(O)RB, -NRAS(O)2RB, 5-10 membered heteroaryl, where 1-4 heteroaryl members are independently selected from N, O, and S; RA and RB are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkyl-C6-C10-aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C10-aryl, C(O)OC1-C6-alkyl, C6-C10-aryl, 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl ring members are independently selected from N, O and S), -C(O)(5-10 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O and S)); Each aryl and heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from C1-C6-alkyl, halo, C1-C6-haloalkyl, and 3- to 14-membered heterocycloalkyl, where 1 to 4 ring members are independently selected from N, O, and S; and Each alkyl is optionally substituted with 1 to 3 substituents independently selected from halo, NRCRD, where RC and RD are independently selected from H, C1-C6-alkyl, C(O)C1-C6-alkyl and C(O)C6-C10-aryl. or a tautomer thereof or a pharma- ceutically acceptable salt thereof.

3. 3. The composition of claim 1 or 2, wherein L is C(O).

4. R ３ is an optionally substituted C １ -C ６ -Alkyl or -C １ -C ６ The composition of any one of claims 1 to 3, wherein the heteroaryl is -alkyl-(5 to 10 membered heteroaryl, where 1 to 4 heteroaryl members are independently selected from N, O and S).

5. R ３ is an optionally substituted -C １ -C ６ The composition of any one of claims 1 to 4, wherein the heteroaryl is -alkyl-(5 to 10 membered heteroaryl, where 1 to 4 heteroaryl members are independently selected from N, O and S).

6. R ４ The composition of any one of claims 1 to 5, wherein is H.

7. R １ is an optionally substituted C ６ -C １０ The composition according to any one of claims 1 to 6, wherein -aryl.

8. R １ The composition of any one of claims 1 to 7, wherein is optionally substituted phenyl.

9. R １ The composition of any one of claims 1 to 8, wherein is phenyl.

10. R ２ The composition of any one of claims 1 to 9, wherein is H.

11. ring 【Chemistry 7】 but 【Chemistry 8】 The composition according to any one of claims 1 to 10,

12. ring 【Chemistry 9】 but, 【Chemistry 10】 The composition according to any one of claims 1 to 10, wherein the composition is selected from the group consisting of

13. ring 【Chemistry 11】 but, 【Chemistry 12】 The composition according to any one of claims 1 to 10, wherein the composition is selected from the group consisting of

14. ring 【Chemistry 13】 but, 【Chemistry 14】 The composition according to any one of claims 1 to 10, wherein the composition is selected from the group consisting of

15. ring 【Chemistry 15】 but, 【Chemistry 16】 and R1 is phenyl or 5-6 membered heteroaryl, where 1-3 heteroaryl members are independently selected from N, O and S, each of which is optionally substituted with 1-3 substituents independently selected from Br, Cl, F, -CN, C1-C6-alkyl, C1-C6-haloalkyl, -OC1-C6-alkyl, -OC1-C6-haloalkyl, optionally substituted phenyl, -C(O)RA; R2 is H; L is C(O); R3 is -C1-C6-alkyl-(5-7 membered heteroaryl (wherein 1-3 heteroaryl members are independently selected from N, O and S)) or -C1-C6-alkyl(phenyl), where the heteroaryl or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of Br, Cl, F, C1-C6-alkyl, -OC1-C6-alkyl, C(O)RA and -C(O)NRARB; The composition of claim 1 or 2, wherein R4 is H.

16. R １ is phenyl, R ３ is an optionally substituted -C １ -C ６ -alkyl-(5-membered heteroaryl (wherein 1-2 heteroaryl members are independently selected from N, O and S)) or optionally substituted C １ -C ６ The composition of claim 15, wherein the -alkyl(phenyl).

17. 3. The composition of claim 1 or 2, wherein the compound, or a tautomer or a pharma- ceutically acceptable salt thereof, is selected from the table below. 【Table 1】

18. 3. The composition of claim 1 or 2, wherein the compound, or a tautomer or a pharma- ceutically acceptable salt thereof, is selected from the table below. 【Table 2】

19. The composition according to any one of claims 2 to 18, wherein the disease or condition requires wound repair or requires organ repair.

20. The composition of any one of claims 2 to 18, wherein the disease or condition is selected from the group consisting of burns, ulcers, heart failure and inflammatory bowel disease.

21. 21. The composition of claim 20, wherein the disease or condition is a burn.

22. 21. The composition of claim 20, wherein the disease or condition is an ulcer.

23. 23. The composition of claim 22, wherein the disease or condition is a chronic ulcer.

24. 24. The composition of claim 22 or 23, wherein the ulcer is a diabetic foot ulcer or a venous leg ulcer.

25. The composition according to any one of claims 2 to 19, wherein the disease or condition requires wound repair.

26. The composition according to any one of claims 2 to 19, wherein the disease or condition requires organ repair.

27. 27. The composition of claim 26, wherein the organ is selected from the group consisting of lung, heart, liver, pancreas, liver and intestine.

28. The disease or condition is diabetic foot ulcers (DFU), venous ulcers (stasis ulcers), pressure ulcers, full or partial thickness burns, eczema, psoriasis, cellulitis, impetigo, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acral peeling skin syndrome syndrome), Blau syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, furunculosis, capillaritis, cellulitis, corneal abrasion, corneal erosion, xeroderma, lichen planus, chronic lichen simplex, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), emphysema, silicosis, asbestosis, pneumoconiosis, aluminosis, bauxite fibrosis, beryllium disease, siderosis, stanosis, talc, Labrador lung (mixed dust pneumoconiosis), sarcoidosis, Hypersensitivity pneumonitis (HP) / Extrinsic allergic alveolitis (EAA), Desquamative interstitial pneumonia (DIP), Respiratory bronchiolitis interstitial lung disease (RBILD), Acute interstitial pneumonia (AIP), Nonspecific interstitial pneumonia (NSIP), Cryptopathic organizing pneumonia (COP = idiopathic BOOP), Secondary organizing pneumonia (BOOP), Lymphoid interstitial pneumonia (LIP), Cryptopathic interstitial pneumonia: unspecified, Eosinophilic lung disease, Tuberculosis (TB), Pulmonary edema, Interstitial lung disease, Cryptopathic organizing pneumonia (COP), E-cigarette or vape use-related lung Disorders (EVALI), Hantavirus Pulmonary Syndrome (HPS), Histoplasmosis, Legionnaires' Disease, MAC Lung Disease, Alpha-1 Antitrypsin Deficiency, Aspergillosis, Lymphangioleiomyomatosis (LAM), Middle East Respiratory Syndrome (MERS), Nontuberculous Mycobacterial Lung Disease (NTM), Pulmonary Embolism Goodpasture's Syndrome, Idiopathic Pulmonary Hemosiderosis, Pulmonary Alveolar Proteinosis, Pulmonary Amyloidosis, Primary Pulmonary Lymphoma, Primary Ciliary Dyskinesia (with or without Situs Inversus), Rare Causes (Farmer's Lung Disease and Pigeon's Lung Disease) Hypersensitivity pneumonitis in dogs (all causes except breeder's lung disease), pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT), interstitial lung disease in systemic sclerosis, interstitial lung disease in rheumatoid arthritis, interstitial lung disease in idiopathic inflammatory myopathies (polymyositis, dermatomyositis, antisynthetase syndrome), interstitial lung disease in Sjogren's syndrome, interstitial lung disease in mixed connective tissue disease (MCTD), interstitial lung disease in overlap syndrome, interstitial lung disease in undifferentiated connective tissue disease,Obliterative bronchiolitis (in non-transplant patients), infectious colitis, ulcerative colitis, Crohn's disease, ischemic colitis, radiation colitis, peptic ulcer, intestinal cancer, intestinal obstruction, rheumatoid arthritis, psoriatic arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, multiple sclerosis, Graves' disease, type 1 diabetes, psoriasis, ankylosing spondylitis, scleroderma, myositis, gout, antiphospholipid syndrome (APS), vasculitis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, systolic heart failure, diastolic heart failure (heart failure with preserved ejection fraction), atrial septal defect, atrioventricular septal defect, coarctation of the aorta, double outlet right ventricle, type D large vessel Transposition, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, single ventricle, tetralogy of Fallot, total anomalous pulmonary venous return, tricuspid atresia, truncus arteriosus, ventricular septal defect, polycystic kidney disease, diabetes insipidus, Goodpasture's disease, IgA vasculitis, IgA nephropathy, lupus nephritis, adult nephrotic syndrome, childhood nephrotic syndrome, hemolytic uremic syndrome, sponge kidney, renal dysplasia, renal artery stenosis, renal vascular hypertension, renal tubular acidosis, Alport syndrome, Wegener's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis interstitial nephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schönlein purpura, IgA nephropathy (Berge's disease), interstitial nephritis, minimal change nephrotic syndrome, nephrotic syndrome, thrombotic thrombocytopenic purpura (TTP), granulomatosis with polyangiitis (GPA), adult Still's disease, agammaglobulinemia, alopecia areata, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, Axonal and neuronal neuropathy (AMAN), Baro's disease, bullous pemphigoid, celiac disease, chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, Coxsackie myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, giant cell arteritis (temporal arteritis), giant cell myocarditis, granulomatosis with polyangiitis,Guillain-Barre syndrome, Hashimoto's thyroiditis, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestation (PG), hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), Lambert-Eaton syndrome, leukocytoclastic vasculitis, linear IgA disease (LAD), microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucher-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis , myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, types I, II, and III polyglandular syndromes, rheumatic polyarteritis Myalgia, Polymyositis, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, Progesterone Dermatitis, Pure Red Cell Aplasia (PRCA), Pyoderma Gangrenosum, Raynaud's Phenomenon, Reactive Arthritis, Reflex Sympathetic Dystrophy, Relapsing Polychondritis, Restless Legs Syndrome (RLS), Retroperitoneal Fibrosis, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleritis, Scleroderma, Sjogren's Syndrome, Sperm and Testicular Autoimmunity, Stiff Person Syndrome (SPS), Subacute Bacterial Endocarditis (SBE), Susac's Syndrome The composition according to any one of claims 2 to 18, wherein the inflammatory bowel disease is selected from the group consisting of sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Alagille syndrome, alcohol-related liver disease, autoimmune hepatitis, biliary atresia, cirrhosis, lysosomal acid lipase deficiency (LAL-D), neonatal jaundice, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis (PBC), and progressive familial intrahepatic cholestasis (PFIC).

29. A compound selected from the table below, or a tautomer or a pharma- ceutically acceptable salt thereof. 【Table 3】

30. 30. A pharmaceutical composition comprising a compound of claim 29, or a tautomer or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

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