Inhibitors of JUN N-terminal kinases (JNK1, JNK2, and / or JNK3) and mitogen-activated protein kinases (MAPK8, MAPK9, and / or MAPK10), and methods for using them.

Abstract

This disclosure relates, in part, to compounds of formulas (I) and (II) that selectively inhibit JUN N-terminal kinases (JNK1, JNK2, and / or JNK3; also known as MAPK8, MAPK9, and / or MAPK10), their pharmaceutically acceptable compositions, and methods of using them for the treatment, prevention, and / or improvement of one or more diseases and / or disorders in a subject. In certain embodiments, the inflammatory diseases or disorders are endometriosis, arthritis, pulmonary fibrosis, cancer, type 1 and / or type 2 diabetes, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis. In certain embodiments, the methods described herein further include the step of detecting the disease and / or disorder in a subject by a preferred diagnostic method.

Description

[Technical Field]

[0001] Description of research and development funded by the federal government. This invention was made with government support under R01HD099341-01A1 and R01HD110038, awarded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The government has certain rights to the invention.

[0002] Cross-reference of related applications This application claims priority under Section 119(e) of the United States Patent Act to U.S. Provisional Patent Application No. 63 / 461,485, filed on 24 April 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0003] background Endometriosis is a common medical condition affecting approximately 10-15% of women worldwide. The two main clinical diagnoses that physicians use to select a patient for treatment are pain and infertility. In 2012, it was reported that the average annual cost per endometriosis patient seeking pain relief was nearly $12,000 higher than that of women without endometriosis, with nearly $4,000 of this cost being out-of-pocket medical expenses and the remainder attributable to physician-initiated treatment.

[0004] Currently, anti-endometriosis therapies seeking approval aim to suppress estrogen production or inhibit estrogen receptor activation, and it is hoped that this mechanism will lead to lesion regression and pain reduction. However, lesions remain, and patients treated with therapies that disrupt the endocrine axis continue to complain of pain.

[0005] There are no alternative anti-endometriosis therapies that address the underlying pathological mechanisms of the disease without interfering with the endocrine system. Innovative treatments offering novel and complementary approaches that may induce lesion regression, minimize pain, and potentially restore fertility after treatment would address the current unmet needs.

[0006] Inhibition of one or more JUN N-terminal kinases (i.e., JNK1, JNK2, and / or JNK3), also known as mitogen-activated protein kinases (i.e., MAPK8, MAPK9, and / or MAPK10), has already been validated as a target in non-human primates and humans, and can disrupt the survival and pain of endometriotic lesions without affecting normal ovarian and endometrial function. Existing JNK inhibitors have not progressed to late-stage clinical trials for endometriosis, and it is unclear whether this is due to a lack of efficacy, safety concerns, or simply a lower priority in endometriosis drug development.

[0007] Therefore, there is a need in the art for selective inhibitors of the JNK protein and methods thereof. This disclosure addresses this need and further identifies JNK-I compounds that have a more desirable target regulatory profile than any such compounds known in the art, if any. [Overview of the Initiative]

[0008] overview In one aspect, this disclosure provides a compound of formula (I), or a salt, solvate, stereoisomer, or isotopolog thereof. TIFF2026517730000001.tif16128 in formula, R 1a , R 1b , L 1 , and R 2 This is defined elsewhere in this specification.

[0009] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia), TIFF2026517730000002.tif In 25128, R 1a 、R 1b 、R 2 、R 3a 、R 3b 、R 3c 、and R 3d are defined elsewhere in this specification.

[0010] In certain embodiments, the compound of formula (I) is a compound of formula (Ib), TIFF2026517730000003.tif In 25128, R 1a 、R 1b 、R 2 、R 3a 、R 3b 、R 3c 、and R 3d are defined elsewhere in this specification.

[0011] In certain embodiments, the compound of formula (I) is a compound of formula (Ic), TIFF2026517730000004.tif In 25128, R 1a 、R 1b 、R 2 、R 3b 、R 3c 、and R 3d are defined elsewhere in this specification.

[0012] In certain embodiments, the compound of formula (I) is a compound of formula (Id), TIFF2026517730000005.tif In 23128, R 1a 、R 1b 、R 2 、R 3a 、R 3b 、R 3c 、and R 3d are defined elsewhere in this specification.

[0013] In certain embodiments, the compound of formula (I) is a compound of formula (Ie), TIFF2026517730000006.tif In 23128, R1a , R 1b , R 2 , R 3a , R 3b , R 3c , and R 3d This is defined elsewhere in this specification.

[0014] In a particular embodiment, the compound of formula (I) is the compound of formula (If), TIFF2026517730000007.tif19128In formula, R 1a , R 1b , R 2 , R 3a , R 3b , and R 3d This is defined elsewhere in this specification.

[0015] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig), TIFF2026517730000008.tif23128 formula, R 1a , R 1b , R 2 , R 3a , R 3b , R 3c , and R 3d This is defined elsewhere in this specification.

[0016] In another aspect, the present disclosure provides a compound of formula (II), or a salt, solvate, stereoisomer, or isotopolog thereof, TIFF2026517730000009.tif23128 formula, R 4 , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 6 G, X, and Z 2 This is defined elsewhere in this specification.

[0017] In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure and a pharmaceutically acceptable carrier.

[0018] In another aspect, the disclosure provides methods for treating, preventing, and / or improving inflammatory diseases in subjects. In certain embodiments, the method includes the step of administering a therapeutically effective dose of at least one compound and / or a pharmaceutically effective composition of the disclosure to a subject. In certain embodiments, JNK1 is inhibited at a similar or greater rate than JNK2 and / or JNK3.

[0019] In certain embodiments, the inflammatory disease is an inflammatory disease of the non-central nervous system (CNS). In certain embodiments, the inflammatory disease is at least one selected from the group consisting of endometriosis, arthritis, pulmonary fibrosis, cancer, type 1 diabetes, and type 2 diabetes. [Brief explanation of the drawing]

[0020] The drawings generally illustrate various aspects of the present application as examples, rather than as limitations.

[0021] [Figure 1] This paper demonstrates the use of DEC-Tec for the discovery of novel JNK inhibitors (JNK-I). The main steps for discovering JNK-I using DEC-Tec are: 1) screening a library of over 4 billion DNA-encoded drug-like compounds, each with a "barcode"; 2) affinity selection of the library for his-tagged JNK1, JNK2, and JNK3; 3) isolation of kinases and small molecules bound to beads; 4) next-generation sequencing and informatics analysis of DNA barcodes to decipher the molecular structures of selective drug-like JNK-I "hit" candidates; 5) synthesis of drug-like "hits" without DNA tags; and 6) analysis of optimized hits in vitro and in vivo. [Figure 2] The results of DEC-Tec selection using 0.05 μM JNK1 compared to a non-targeted control are shown. Specific and non-specific binders were distinguished using bentamapimod (10 μM) as a competing substance. [Figure 3A]Figures 3A-3B show enlarged DEC-Tec views of the selection results for qDOS21 (Figure 3A) and qDOS28_1 (Figure 3B) for JNK3 (0.05 μM) compared to a non-targeted control. Specific and non-specific binders were distinguished using bentamapimod (10 μM) as a competitor. The three components include C1 (bottom), C2 (middle), and C3 (top). Figure 3A: A key feature of the qDOS21 library is its high count and score criteria, which provide additional indicators of the relevance of hits (e.g., C1, C2) as well as its enrichment score. In contrast, hits from qDOS28_1 had much lower enrichment, count, and score. Specific and non-specific binders were distinguished using bentamapimod (10 μM) as a competitor for all assays. Figure 3B: The enrichment of component C3 was obtained from qDOS28_1 along with various C1 and C2 components. The concentration of each hit series is shown below each scaffold as the count / z score at 0.05 μM. [Figure 3B] Refer to the explanation in Figure 3A. [Figure 4A] Figures 4A-4D show the docking of highly enriched compounds from the qDOS21 library to the JNK3 crystal structure: CDD-2728-JNK1(PDB:4L7F) interaction (Figure 4A); CDD-2728-JNK3(PDB:4WHZ) interaction (Figure 4B); CDD-3013-JNK1(PDB:4L7F) interaction (Figure 4C); and CDD-3013-JNK3(PDB:4WHZ) interaction (Figure 4D). In the model presented herein, it is observed that the orientation of CDD-2728 (Figures 4A-4B) and CDD-3013 (Figures 4C-4D) in JNK1 (MAPK8; Figures 4A and 4C) differs from that in JNK3 (MAPK10; Figures 4B and 4D). [Figure 4B] See the explanation in Figure 4A. [Figure 4C] See the explanation in Figure 4A. [Figure 4D] See the explanation in Figure 4A. [Figure 5A]Figures 5A–5C show the KINOMEscan selectivity profiles of staurosporine (Figure 5A), bentamapimod (BEND; Figure 5B), and tandicertib (TANZ; Figure 5C) at 1 μM against 480 kinases. JNK1–3 (CMGC family) were more strongly inhibited by BEND and even more strongly by TANZ. All JNK-I kinases showed high selectivity for JNK (spot at 7 o'clock), while tandicertib weakly inhibited LATS1 (spot at 9 o'clock). Subsequent ThermoFisher Z'Lyte assays did not confirm inhibition of LATS1. Both bentamapimod and tandicertib were considered safe in the Phase 1 clinical trial population. [Figure 5B] Refer to the explanation in Figure 5A. [Figure 5C] Refer to the explanation in Figure 5A. [Figure 6A] Figure 6A shows a dendrogram summarizing the selectivity of CDD-2346 (an early analog obtained from DEC-Tec selection) in KINOMEscan. Figures 6B-6C show the concentration-dependent evaluation of CDD-2346 inhibition among "intra-pathway" MEK / JNK enzymes (Figure 6B) and "extra-pathway" (Figure 6C) kinases determined by the ThermoFisher Lantha Screen. Figure 6D shows the concentration-dependent evaluation of CDD-2346 inhibition among several additional "extra-pathway" kinases determined by the ThermoFisher TF Z'LYTE assay. Certain exemplary compounds described herein have been found to have better selectivity profiles than CDD-2346. [Figure 6B] See the explanation in Figure 6A. [Figure 6C] See the explanation in Figure 6A. [Figure 6D] See the explanation in Figure 6A. [Figure 7A]Figure 7A provides a dendrogram showing the selectivity and efficacy of optimized JNK-I CDD-2728 in Eurofins KINOMEscan. The JNK enzyme is shown at the 7 o'clock position, and MEK4 is shown at the 2 o'clock position. Figures 7B–7C show concentration-dependent inhibition of "intra-pathway" (Figure 7B) and "extra-pathway" (Figure 7C) kinases by CDD-2728 in ThermoFisher LanthaScreen (Figure 7B) and ThermoFisher Z'LYTE assays (Figure 7C). [Figure 7B] Refer to the explanation in Figure 7A. [Figure 7C] Refer to the explanation in Figure 7A. [Figure 8] The definition of "intra-pathway" versus "extra-pathway" followed the general relationship within the MAPK family, where MEK4 / 7 functions as an upstream regulator of JNK enzymes and MEK1 / 2 functions as an upstream regulator of ERK1 / 2 kinases. Enzymes outside this range of the MAPK family were referred to as "extra-pathway." [Figure 9] The study demonstrated the expected non-limiting cellular responses for each CDD-JNK inhibitor (Bora and Yaba et al. J. Obstet. Gynaecol. Res. 2021, 47(5):1610-1623). While it examined "intra-pathway" and "extra-pathway" targets and highlighted the expected non-limiting effects of JNK-I on inflammation, differentiation, apoptosis, and growth, expectations for the effects of selective JNK-I on cell proliferation, cell division, and cell cycle arrest, which are expected properties of JNK-I, were reduced. [Figure 10A]Figures 10A–10B represent data generated by the Promega NanoBRET system to confirm the effectiveness of JNK-I, as described herein, in the intracellular environment where it is expected to be an effective regulator of endometriosis pathogenesis. The graphs show the substitution of tracer K10 by several CDD-JNK-I in Promega NanoBRET per CDD hit in the JNK1 assay (Figure 10A) and JNK3 assay (Figure 10B). Figure 10C: Activity of optimized inhibitors CDD-2728, CDD-2729, and CDD-2731 against a Promega NanoBRET system expressing JNK1. Figure 10C further provides IC50 calculations for each of CDD-2728, CDD-2729, and CDD-2731. Figure 10C shows the activity of preceding analogs identified in the program for activity in NanoBRET JNK3 cells. [Figure 10B] Refer to the explanation in Figure 10A. [Figure 10C] Refer to the explanation in Figure 10A. [Figure 11] CDD-3013 was evaluated in a Promega NanoBRET panel of 192 kinase assays. The figure illustrates the principle of the BRET-based ligand substitution assay performed in live cells. [Figure 12-1] Figures 12A–12J provide graphs showing that CDD-2628 inhibits the IL-1b-stimulated inflammatory biomarker response in 12Z endometriosis cells with comparable efficacy to bentamapimod (i.e., Figures 12A–12B and 12E–12F) or with improved efficacy compared to bentamapimod (CDD-939) (IL-8, Figures 12C–12D; MMP-3, Figures 12G–12H). Similar effects were observed for the biomarker MMP-3 with CDD-2575 and CDD-2634. [Figure 12-2] See the explanation in Figure 12-1. [Figure 12-3] See the explanation in Figure 12-1. [Figure 13]Figures 13A–13B provide graphs from replicate experiments showing that CDD-2728 and CDD-2634 are selective JNK inhibitors that are more potent inhibitors of IL-8 expression than bentamapimod (CDD-939). [Figure 14-1] Figures 14A–14H provide graphs from replicate experiments showing that CDD-2728 inhibits the IL-1β-stimulated inflammatory biomarker response in 12Z endometriosis cells with similar potency to bentamapimod (CDD-939). Consistent with previous observations, CDD-2728 continues to be more potent than CDD-939 in inhibiting MMP-3 expression. Figures 14G–14H show the response of primary human endometriosis stromal cells (derived from endometrioma lesions) from endometriosis patient "50". CDD-2728 demonstrated to be a more effective inhibitor of IL-6 gene expression in these cells than CDD-939. [Figure 14-2] See the explanation in Figure 14-1. [Figure 15-1] Figures 15A–15H show replicate results of responses in primary human endometriosis stromal cells (lesion-derived) obtained from 50 endometriosis patients. In all cases, CDD-2728 was a more effective inhibitor of biomarker IL-8, MMP-3, and PTGS2 gene expression than CDD-939. In all cases, CDD-2728 inhibited the IL-1β-stimulated inflammatory biomarker response in primary endometriosis stromal cell cultures. The concentration of JNK inhibitor required to reduce the IL-1β inflammatory response in stromal cells was lower than the concentration of JNK-I in 12Z epithelial cells. [Figure 15-2] See the explanation in Figure 15-1. [Figure 16-1]Figures 16A–16F provide results obtained from cultures of human endometriosis stromal cells (i.e., from endometrioma lesions) from a second endometriosis patient, "143," demonstrating that CDD-2728 inhibits the expression of IL-8, MMP-3, and PTGS2 genes induced by IL-1β stimulation at lower doses than those required for CDD-939 to inhibit the expression of these genes. Similar to patient "50," the concentration of CDD-2728 required to reduce the IL-1β inflammatory response in stromal cells to these measured genes was lower than that in 12Z epithelial cells. [Figure 16-2] See the explanation in Figure 16-1. [Figure 17A] Figures 17A–17C provide bar graphs showing ATP consumption (% viability) of HepG2 cells administered with the CDD-JNK inhibitors CDD-2575 (Figure 17A), CDD-2728 (Figure 17B), and CDD-2634 (Figure 17C). This assay reflects cell viability. A decrease in cell viability suggests a nonspecific effect of the inhibitor on cell survival. The results suggest that CDD-2575 clearly resulted in a nonspecific decrease in cell viability at 25 μM, while CDD-2728 was tolerable even at higher concentrations (up to 75 μM). Continued improvements in JNK-I selectivity and permeability were obtained with CDD-3013, and no decrease in HepG2 cell viability was observed even at 100 μM. [Figure 17B] Refer to the explanation in Figure 17A. [Figure 17C] Refer to the explanation in Figure 17A. [Figure 18]A bar graph is provided showing ATP consumption (% viability) of HepG2 cells after administration of JNK-I CDD-3013 compared to three other kinase inhibitors. The results demonstrate no evidence of cytotoxicity in HEPG2 cells up to 100 μM. Based on the experiments described herein, the dose at which CDD-3013 is estimated to cause cytotoxicity is greater than 100 μM (e.g., 143 μM). For comparison, the IC50 for inducing a cytotoxic response is 48 μM for CDD-XX07, 34 μM for CDD-XX10, and 72 μM for CDD-XX30. This suggests that a 138-fold safety margin can be obtained at a cell culture concentration of 1 μM and a 13.8-fold safety margin can be obtained at a cell culture concentration of 10 μM of CDD-3013. [Figure 19] Figures 19A-19B provide the results of pharmacokinetic analyses of CDD-2728 concentration and clearance rate measured in plasma following oral administration of CDD-2728 at a dose of 50 mg / kg in a carboxymethylcellulose (CMC) sodium preparation in mice administered orally (Figure 19A) or intraperitoneally (Figure 19B). [Figure 20] This shows the enrichment profiles of compounds in qDOS11 that were identified to bind to JNK1 present at a concentration of 0.3 μM. In qDOS11, the methylamide in BB1 represents the DNA binding site. A series of hits were identified by di-synthone enrichment of the same BB1 ​​(blue) and BB3 (black) and various BB2 (red), as well as the same BB2 and BB3. A structure-enrichment correlation was observed with BB2, the hit with the highest z-score (i.e., 6.3). [Figure 21] Figure 21A shows the results of JNK1 biochemical assays with compounds CDD-1722, CDD-1723, CDD-2009, CDD-2010, and CD-985 (tandicertib). Figure 21B shows the concentration-dependent inhibition of JNK1 by CDD-1722 and CDD-1723. The components of CDD-1722 and CD-1723 represent alternative components that may be incorporated when optimizing the pharmaceutical properties of JNK-I. [Figure 22]Figure 22A shows the design of an in vivo model in which JNK-I was evaluated for its ability to induce regression of endometriosis in mice. The results of an in vivo disease-associated model of endometriosis in mice are shown. In this experimental design, endometriosis was induced by introducing isolated endometrial tissue from donor mice, and prepared endometrial cells were introduced into the peritoneal cavity of recipient mice. Drug treatment was initiated 14 days after the induction of endometriosis and continued for 14 days. At the end of the study (i.e., day 28), the presence or absence of endometriotic lesions was determined, and various measurements were performed. Figure 22B shows the results obtained with CDD-2728 using the endometriosis model described herein. CDD-2728 reduced the number of endometriotic lesions and caused a decrease in the size (mm3) and mass (mg) of residual lesions in mice. CDD-2728 had no effect on uterine, liver, or kidney weight, suggesting a specific effect on lesions without affecting the uterus or other organs. [Figure 23] Immunofluorescence staining of sections of residual endometriotic lesions after 14 days of treatment with intraperitoneal administration of CDD-2728 or vehicle solution (i.e., captisol) is shown. Results from these images indicate that JNK-I CDD-2728 causes a reduction in the growth rate of lesional proliferating cells (Ki67), a decrease in the presence of cells corresponding to leukocytes, platelets, and endothelial cells (CD31), and a reduction in macrophage infiltration of endometriotic lesions (F4 / 80). [Figure 24] Figures 24A-24E show the effects of CDD-3013 on regression of endometriotic lesions (Figure 24A), lesion volume (Figure 24B), and lesion mass (Figure 24C) per mouse. The effects of CDD-3013 on endometriotic lesions do not affect other tissues such as the liver (Figure 24D) or kidneys (Figure 24E), demonstrating a unique effect on the site of inflammation. Treatment of mice with CDD-3031 at 10 mg / kg significantly reduced endometriotic lesions (number, volume, and lesion mass). [Figure 25]This study shows that treatment of mice with endometriotic lesions resulted in altered proliferation rates of endometriotic cells, decreased recruitment of endothelial cells to lesions (CD31), and reduced recruitment of macrophages to lesions. This demonstrates a common mechanism among JNK-I derived from the disclosed chemical lineage and their ability to target endometriotic lesions and innate immune cells that drive inflammatory responses within the lesions. Endometriotic lesions from mice treated with CDD-2728 showed reduced cell proliferation (anti-Ki67 antibody), angiogenesis (anti-CD31 antibody), and macrophage infiltration (anti-F4 / 80 antibody). [Figure 26A]Figure 26A shows the effects of CDD-2728 and CDD-3013 on the phosphorylation of the JNK enzyme itself (i.e., representing MEK4 inhibition) and on the phosphorylation of the transcription factor Jun at pSer63 and pSer73 in immortalized human endometrial epithelial cells (iHEEC). HEEC cells are a well-characterized cell line relevant to the measurement of inflammatory endpoints and epithelial-mesenchymal transition (EMT). Compared to CDD-939 (bentamapimod), which does not inhibit MEK4 in KINOMEscan, CDD-2728 inhibits the phosphorylation of JNK1 (P46) and JNK2 (P54). In addition, CDD-2728 inhibits Jun at pSer63 and pSer73 more effectively than CDD-939. This is consistent with the relationship between the potency of CDD-2728 and bentamapimod observed in the cytokine gene expression described above in iHEEC cells and primary human stromal endometriosis cells. For comparison, a commonly used reference JNK-I (i.e., SP600125) also inhibits the MEK4-dependent phosphorylation of Jun pSer63 and pSer73, as well as JNK1 and JNK2. Although SP600125 is often described as a less selective JNK-I, in this context it provides further support for the inhibition of JNK target kinases by CDD-2728. Figure 26B shows the inhibition of Jun pSer63 and pSer73 by the JNK-I CDD-2856, which inhibits phosphorylation more effectively than tandicertib, and CDD-2856 inhibits the upstream phosphorylation of JNK1 and JNK2. These results demonstrate the common characteristics of JNK-I disclosed herein (i.e., their ability to inhibit both Jun transcription factor (primary target) and MEK4 (secondary target), an immediately upstream regulator of JNK activity), as well as the lack of efficacy of tandicertib, which has a lower IC50 compared to JNK-2. This further supports the important role of JNK-1 in the therapeutic effects of the disclosed JNK inhibitors. [Figure 26B] Refer to the explanation in Figure 26A. [Figure 27A]Figure 27A: Semi-quantitative intracellular Western blotting showed that both CDD-2728 and CDD-3013 were more effective inhibitors of Jun phosphorylation than tandicertib (CDD-985). The upper panel of the intracellular Western blotting shows pSer73, and the lower panel shows pSer63. The experiment was performed three times at three different concentrations (0.1 μM, 1 μM, and 10 μM). Figures 27B-27C: Figures summarizing the intracellular Western blotting for pSer73 (Figure 27B) and pSer63 (Figure 27C) are provided. [Figure 27B] Refer to the explanation in Figure 27A. [Figure 27C] Refer to the explanation in Figure 27A. [Figure 28A] Figures 28A–28C show the effects of JNK inhibition on cell morphology and the expression of vimentin, a surface marker, in iHEECs. These results demonstrate that JNK-I CDD-2728 can reduce the intensity of phospho-JNK staining, while vimentin staining does not undergo a dramatic change. Phospho-JNK staining in iHEECs can be either punctate staining in intracellular organelles or dispersed staining throughout the cytoplasm of cells. [Figure 28B] Refer to the explanation in Figure 28A. [Figure 28C] Refer to the explanation in Figure 28A. [Figure 29]Figures 29A–29C show the effects of JNK inhibition on the cellular expression of beta-catenin present on the cell surface and throughout the cytoplasm of iHEEC cells, where HEEC cells were treated with a vehicle (Figure 29A), IL-1β (Figure 29B), or IL-1β and 10 μM CDD-2728 (Figure 29C). The increase in cytoplasmic and membrane expression of β-catenin after exposure to IL-1β supports the role of β-catenin in promoting epithelial-mesenchymal transition. Cell morphology is consistent with that of columnar epithelial cells. iHEEC cells were treated with JNK-I or a vehicle for 30 minutes before the addition of IL-1β, followed by a further 15 minutes of cell culture. This short-term addition of IL-1β resulted in dramatic changes in beta-catenin expression in iHEEC endometriotic epithelial cells, and significant changes in phospho-JNK throughout the cytoplasm induced by IL-1β. Beta-catenin expression at intercellular contact points is increased by IL-1β and inhibited by CDD-2728. In this short-term experiment, there were no apparent changes in cell viability or cell density caused by JNK-I. [Figure 30A] Figures 30A-30B demonstrate the superior efficacy of CDD-2728 (Figure 30A) and CDD-3013 (Figure 30B) over bentamapimod in phosphorylating Jun to all Jun cells in experiments conducted using 12Z cells in the presence of the pro-inflammatory mediator IL-1β. The results demonstrate specific inhibition of Jun phosphorylation without affecting all Jun cells (Figure 30A) or cellular metabolism (GAPDH). The results in Figure 30B demonstrate undetectable changes in JNK1 or JNK2 phosphorylation by CDD-2728 or CDD-3013, indicating that inhibition of the primary target (JNK) does not lead to significant accumulation of phosphorylated JNK1 or JNK2. This suggests that inhibition of Jun JNK phosphorylation does not trigger a backup of phosphorylation events in this signaling pathway. [Figure 30B] Refer to the explanation in Figure 30A. [Figure 31A]Figures 31A-31B show the effects of CDD-3013 on cells obtained from patient-derived endometrioma lesions, illustrating the common mechanism in primary culture of endometrioma-derived stromal cells, as described above for immortalized epithelial cells (12Z cells and iHEEC cells). The results in Figure 31A demonstrate inhibition of Jun phosphorylation in cells cultured with IL-1β and increased concentrations of CDD-3013 (0.1, 1, 10 μM). Similar effects of JNK inhibition were observed in orthotopic endometrial cells (EuE) and ectopic endometrioma cells (OMA) from patient 35. In this patient, increased JNK1 phosphorylation was observed at the highest concentration tested, in contrast to decreased Jun phosphorylation. Similar inhibition of Jun phosphorylation was observed in orthotopic endometrial cells and ectopic endometrioma-derived cells from patient 92 in the presence of the inflammatory mediator IL-1β (Figure 31B). In cells obtained from patient 92, changes in JNK1 or JNK2 phosphorylation were minimal, suggesting that patients receiving JNK therapy for endometriosis are likely to have dose-dependent requirements to achieve optimal suppression of Jun while minimizing the impact on JNK1 or JNK2 phosphorylation. [Figure 31B] Refer to the explanation in Figure 31A. [Figure 32A]Figures 32A-32B demonstrate the selective effect of CDD-3013 on several intracellular kinase pathways in orthotopic and ectopic endometriosis cells. In patient 35, there was a significant difference in pSmad1,5 between orthotopic endometrium and endometrioma. Addition of a JNK inhibitor further promoted the phosphorylation of pSmad1,5 in orthotopic endometrium-derived cells, but did not inhibit this kinase activity in either orthotopic or ectopic cells. Similar decreases in the phosphorylation of Smad2, pSmad3, and Akt were observed in endometriosis-derived cells compared to orthotopic cells, with increases in pSmad2, pSmad3, and pAkt in orthotopic tissue, while CDD-3013 did not alter the phosphorylation status of these signaling proteins in ectopic endometrioma-derived cells. The enhancement of morphogenic responses (pSmad1, 2, 3, 5) in orthotopic cells, while suppression of inflammatory pathways (Jun) in both orthotopic and ectopic cells, suggests that this chemical lineage of JNK-I selectively modifies disease in lesions without adversely affecting orthotopic endometrial-derived cells. These results were largely confirmed in patient 92 (Figure 32B), where JNK-I CDD-3013 had minimal effect on pSmad1,5 in ectopic endometrioma-derived cells (OMA92) and no significant effect on orthotopic-derived cells. pSTAT3 status was unaffected in both patient 35 and patient 92. [Figure 32B] Refer to the explanation in Figure 32A. [Figure 33A]Figures 33A–33B show the phosphorylation of Jun or JNK in endometrial organoids obtained from deep-invasive lesions compared to endometrial epithelial organoids obtained from orthotopic endometrium of patient 63. Organoids are considered to represent physiologically more relevant culture conditions than primary epithelial cells cultured in flat plastic culture dishes. Under these more relevant conditions, the results demonstrate that Jun is more phosphorylated in lesion-derived epithelial organoids than in orthotopic tissue-derived organoids. Stimulation with IL-1β results in increased Jun phosphorylation in both organoid conditions (orthotopic, EuE63; deep-invasive endometriosis lesion, DiE63). Figures 33C–33D show no visible difference in JNK levels or JNK phosphorylation between orthotopic and lesion organoids. These results suggest that basal levels of Jun phosphorylation exist in DiE epithelial organoids, and that JNK inhibitors can reduce Jun phosphorylation levels without significantly affecting the activation of the upstream kinase MEK4, which triggers JNK phosphorylation. [Figure 33B] Refer to the explanation in Figure 33A. [Figure 33C] Refer to the explanation in Figure 33A. [Figure 33D] Refer to the explanation in Figure 33A. [Modes for carrying out the invention]

[0022] Detailed description of the invention The following describes in detail a particular aspect of the subject matter of disclosure, which is partially shown in the attached drawings. The subject matter of disclosure is described in relation to the enumerated claims, but it will be understood that the subject matter described as an example is not intended to limit the claims to the subject matter of disclosure.

[0023] Throughout this document, values ​​expressed in range form should be interpreted flexibly to include not only the numerical limits explicitly stated as the limits of that range, but also all individual numerical values ​​or subranges within that range, as if each numerical value and subrange were explicitly stated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only approximately 0.1% to approximately 5%, but also the individual values ​​within the indicated range (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). The expression "approximately X to Y" has the same meaning as "approximately X to approximately Y" unless otherwise specified. Similarly, the expression "approximately X, Y, or approximately Z" has the same meaning as "approximately X, approximately Y, or approximately Z" unless otherwise specified.

[0024] In this text, the terms “a,” “an,” or “the” are used to include one or more unless the context makes it clear otherwise. The term “or” is used to refer to a non-exclusive “or” unless otherwise specified. The expression “at least one of A and B” or “at least one of A or B” is synonymous with “A, B, or A and B.” In addition, any expressions or terms used herein that are not specifically defined should be understood as being for illustrative purposes only, not limitation. Wherever headings are used, they are intended to aid in the reading of the document and should not be interpreted as limitation, and information related to headings may be found both inside and outside of that particular heading. All publications, patents, and patent documents referenced herein are incorporated herein by reference as if they were incorporated individually by reference.

[0025] In the methods described herein, the actions may be performed in any order unless a temporal or operational sequence is explicitly stated. Furthermore, the specified actions may be performed simultaneously unless the language of the claim explicitly states that they are performed separately. For example, the action of performing X in a claim and the action of performing Y in a claim may be performed simultaneously within a single operation, and the resulting process would be encompassed within the scope of the process language of the claim.

[0026] explanation In one aspect, this disclosure relates to the discovery of a novel JNK inhibitor (JNK-I) useful in treating inflammatory diseases, including, but not limited to, endometriosis and associated pain.

[0027] Preclinical and clinical data on bentamapimod (BEND) generally support the premises through the demonstration of efficacy in preclinical and clinical trials. The mechanistic role of JNK-I in modulating inflammation and fibrosis has been demonstrated with tangicertib (TANZ), a JNK-I developed for the treatment of idiopathic pulmonary fibrosis (IPF). TANZ reduced inflammation, EMT, and fibrosis in preclinical models of IPF and in human IPF patients.

[0028] However, neither BEND nor TANZ progressed to Phase 3 clinical trials. TANZ was discontinued after adverse liver effects in IPF. Celgene (now Bristol-Myers Squibb) replaced TANZ with CC-90001 [NCT02510937] for IPF, while screening for liver injury [NCT03742882] and emphasizing that they are optimistic about this target while managing the risks. However, improvement in pain is not required for JNK-I for IPF. ICs have been reported for BEND and TANZ for JNK1, JNK2, and JNK3. 50 The values ​​are 80, 90, and 230 nM for BEND, and 400, 38, and 32 nM for TANZ.

[0029] This disclosure relates to one or more unexpected and / or innovative discoveries, and non-limiting examples include: (1) novel chemical scaffolds for kinase inhibition (e.g., JNK1-3); (2) unique selectivity profiles among JNK isoforms designed to limit the side effects of excessive inhibition of JNK2, maximize the impact on the inflammatory pathway (JNK1), and lower the perceived pain threshold in the CNS (JNK3); (3) unique selectivity profiles among broader kinase families that enhance inhibition of the MEK4 / JNK pathway, which broadly controls inflammation, without significantly affecting cell proliferation and / or other MEK family kinases that may cause side effects in animals and / or humans; (4) JNK-I that can reduce progesterone insensitivity in hosts with endometriotic lesions; (5) JNK inhibitors that inhibit mesenchymal-to-epithelial transition preceding epithelial-mesenchymal transition and precancerous cell formation; and (6) JNK inhibitors that can inhibit the regrowth of surgically resected and chemically treated cancers by reducing the ability of cancer stem cells to resume tumorigenesis. In one respect, the JNK inhibitors described herein represent a development strategy for kinase inhibitor selectivity profiles that have not been reported prior to this disclosure.

[0030] In one aspect, this disclosure concerns the discovery that JNK1-3 are key unifying factors in the underlying pathophysiology of endometriosis, including inflammation, epithelial-mesenchymal transition (EMT) of endometrial cells, suppression of immune-mediated clearance of endometriotic cells from their ectopic sites, and sensory integration of pain. The hypothesis that drove this effort to discover this finding is that JNK inhibitors (JNK-I) can address each of these pathological features of endometriosis.

[0031] definition As used herein, the term “about” may allow some degree of variation in a value or range, for example, within 10%, 5%, or 1% of the stated value or range limit, and includes such stated value or range.

[0032] As used herein, the term “alkenyl” refers to linear, branched, and cyclic alkyl groups as defined herein, except that they have at least one double bond between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0033] As used herein, the term "alkoxy" refers to an oxygen atom bonded to an alkyl group, including cycloalkyl groups as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, and isohexyloxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and may further contain double or triple bonds, and may also contain heteroatoms. For example, an allyloxy group or a methoxyethoxy group is an alkoxy group within the meaning of this specification, as is the methylenedioxy group in the context that two adjacent atoms in a certain structure are substituted by it.

[0034] As used herein, the term “alkyl” refers to linear and branched alkyl groups and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of linear alkyl groups include those having 1 to 8 carbon atoms, e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, non-limitingly, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Typical substituted alkyl groups may be substituted once or more with any of the groups listed herein, e.g., amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0035] As used herein, the terms “alkylene” or “alkylenyl” refer to divalent saturated aliphatic groups (e.g., particularly -CH2-, -CH2CH2-, and -CH2CH2CH2-). In certain embodiments, the terms may be considered to be moies derived from alkenes by ring-opening of a double bond, or from alkanes by the removal of two hydrogen atoms from the same (e.g., -CH2-) or different (e.g., -CH2CH2-) carbon atoms.

[0036] As used herein, the term "alkynyl" refers to linear and branched alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, 2 to 12 carbon atoms, or, in some embodiments, 2 to 8 carbon atoms. Examples include, in particular, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0037] As used herein, the term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group)3, where each group can independently be H or a non-H group, such as alkyl or aryl. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, and alkylarylamines; R2NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, and heterocyclylamines; and R3N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, and triarylamines. The term "amine" as used herein also includes ammonium ions.

[0038] As used herein, the term "amino group" refers to -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + Substituents in the form of -NR3, and non-protonable substituents. + This refers to each protonation form except for the specified one. Therefore, any compound substituted with an amino group can be considered an amine. Within the scope of the meaning of this specification, "amino group" can be a primary, secondary, tertiary, or quaternary amino group. The "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0039] As used herein, the term "aralkyl" refers to an alkyl group as defined herein, in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Typical aralkyl groups include benzyl and phenylethyl groups, as well as condensed (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein, in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0040] As used herein, the term “aryl” refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Therefore, aryl groups include, without limitation, phenyl, azlenyl, heptarenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbon atoms in the ring portion of the group. Aryl groups may be unsubstituted or substituted as defined herein. Typical substituted aryl groups may be monosubstituted or substituted more than once, and without limitation include phenyl groups in which one or more of the 2, 3, 4, 5, or 6 positions of the phenyl ring are substituted, or naphthyl groups in which one or more of the 2 to 8 positions are substituted.

[0041] As used herein, the term "cycloalkyl" refers non-limitingly to cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups may have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups further non-limitingly include polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and calenyl groups, and non-limitingly to fused rings such as dekalinyl. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined herein. Typical substituted cycloalkyl groups can be monosubstituted or substituted more than once, and are not limited to 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono, di, or trisubstituted norbornyl or cycloheptyl groups, which can be substituted with amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups, for example. The term "cycloalkenyl" alone or in combination refers to a cyclic alkenyl group.

[0042] As used herein, the terms "cycloalkylene" or "cycloalkylenyl" refer to a divalent saturated cycloalkyl group (e.g., particularly TIFF2026517730000010.tif8128). In certain embodiments, the term may be considered the product of removal of two hydrogen atoms from the corresponding cycloalkane (e.g., cyclobutyl) by removal of two hydrogen atoms from the same (e.g., TIFF2026517730000011.tif7128), different (e.g., TIFF2026517730000012.tif7128) carbon atoms.

[0043] "Disease" refers to the health state of an animal where the animal cannot maintain homeostasis and the animal's health continues to deteriorate if the disease does not improve.

[0044] In contrast, "disorder" in an animal refers to a health state where the animal can maintain homeostasis but the animal's health state is less favorable than in the absence of the disorder. A disorder does not necessarily cause a further decline in the animal's health state if left untreated.

[0045] A disease or disorder is "improved" when the severity of the symptoms of the disease or disorder, the frequency with which such symptoms are experienced by a patient, or both, are reduced.

[0046] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to an amount of a drug that is non-toxic but sufficient to produce the desired biological result. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a living system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0047] As used herein, the terms "halo," "halogen," or "halide" group, by themselves or as part of another substituent, unless otherwise specified, mean a fluorine, chlorine, bromine, or iodine atom.

[0048] As used herein, the term "haloalkyl" group includes a monohaloalkyl group, a polyhaloalkyl group in which all halo atoms may be the same or different, and a perhaloalkyl group in which all hydrogen atoms are replaced by a halogen atom such as fluorine. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0049] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, not limited to N, O, and S; for example, a heteroaryl ring may have five to about eight to twelve ring members. Heteroaryl groups are various heterocyclyl groups having aromatic electronic structures. A heteroaryl group designated as C2-heteroaryl may be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl may be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be unsubstituted or substituted with the groups considered herein. Typical substituted heteroaryl groups may be substituted once or more with groups such as those listed herein.

[0050] Examples of added aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xane Tenyl, isoindanil, benzhydryl, acridinil, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrrolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), Thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) Zolyl, 7-benzoimidazolyl, 8-benzoimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine (5H-dibenzo[b,f]azepine-1-yl, 5H-dibenzo[b,f]azepine-2-yl, 5 H-dibenzo[b,f]azepine-3-yl, 5H-dibenzo[b,f]azepine-4-yl, 5H-dibenzo[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenzo[b,It includes, indefinitely, azepine-5-yl (f), etc.

[0051] As used herein, the term “heteroarylalkyl” refers to an alkyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to a heteroaryl group as defined herein.

[0052] As used herein, the terms “heteroarylene” or “heteroarylene” refer to a divalent heteroaryl group (e.g., 2,4-pyridylene). In certain embodiments, the terms may be considered as a divalent group formed by the removal of two hydrogen atoms from one or more rings of the heteroaryl moiety, where the hydrogen atoms may be removed from the same or different rings, preferably from the same ring.

[0053] As used herein, the term “heterocycloalkyl” refers to aliphatic, partially unsaturated or fully saturated 3- to 14-membered ring systems, including monocyclic rings with 3 to 8 atoms, and dicyclic and tricyclic ring systems in which at least one carbon atom of the ring is non-limitedly replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Heterocycloalkyls may contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen heteroatom may be substituted. Representative heterocycloalkyls non-limitedly include the following exemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The terms used for heterocycloalkyl groups are C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5 heterocycloalkyl, C2-C6 heterocycloalkyl, C2-C7 heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C9 heterocycloalkyl, and C2-C 10 Heterocycloalkyl, C2~C 11Heterocycloalkyl groups can include heterocycloalkyls, such as heterocycloalkyls, with a maximum of C2 to C145. For example, a C2 heterocycloalkyl group includes a group having two carbon atoms and at least one heteroatom, non-limitingly including aziridinyl, diazetidinyl, oxyranyl, thyranyl, etc. Alternatively, for example, a C5 heterocycloalkyl group includes a group having five carbon atoms and at least one heteroatom, non-limitingly including piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, etc. Heterocycloalkyl groups are understood to be bonded via heteroatoms within the ring or via one of the carbon atoms constituting the heterocycloalkyl ring, where chemically possible. Heterocycloalkyl groups can be substituted or unsubstituted.

[0054] As used herein, the terms "heterocycloalkylene" or "heterocycloalkylenyl" refer to divalent saturated cycloalkyl groups (e.g., particularly TIFF2026517730000013.tif9128) refers to the same thing. In certain embodiments, the term is the same as (for example, TIFF2026517730000014.tif6128), different (for example, (TIFF2026517730000015.tif7128) The removal of two hydrogen atoms from a carbon atom and / or heteroatom may be considered a product of the removal of two hydrogen atoms from the corresponding heterocycloalkane (e.g., piperidine).

[0055] As used herein, the term “heterocyclyl” refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, not limited to N, O, and S. Thus, heterocyclyls can be cycloheteroalkyl or heteroaryl, or, in the case of polycyclic compounds, any combination thereof. In some embodiments, a heterocyclyl group contains 3 to about 20 ring members, while another heterocyclyl group contains 3 to about 15 ring members. A heterocyclyl group designated as a C2 heterocyclyl may be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl may be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. A heterocyclyl ring may also contain one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. The term "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. For example, the dioxolanyl ring and the benzodioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the scope of the terms used herein. This term also includes polycyclic systems containing heteroatoms, and non-limitingly, quinuclidyls, etc. Heterocyclyl groups may be unsubstituted or may be substituted as discussed herein. The heterocyclyl group includes, without limitation, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.Typical substituted heterocyclyl groups may be monosubstituted or substituted more than once, and are not limited to piperidinyl or quinolinyl groups that are 2, 3, 4, 5, or 6-substituted or disubstituted with groups such as those listed herein.

[0056] As used herein, the terms "hydrocarbon" or "hydrocarbyl" refer to molecules or functional groups containing carbon and hydrogen atoms. The terms may also refer to molecules or functional groups that typically contain both carbon and hydrogen atoms, but in which all hydrogen atoms are substituted with other functional groups.

[0057] As used herein, the term "hydrocarbyl" refers to a functional group derived from a linear, branched, or cyclic hydrocarbon, which may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. The hydrocarbyl group is (C a ~C b ) may be expressed as hydrocarbyl, where a and b are integers and it means having any number of carbon atoms from a to b. For example, (C1-C4) hydrocarbyl means that the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-C b ) Hydrocarbyl means that, in certain embodiments, the hydrocarbyl group is absent.

[0058] As used herein, the term “selected independently of ~” means that the bases referred to are the same, different, or a combination thereof, unless the context makes otherwise clear. Thus, under this definition, “X 1 , X 2 , and X 3 The expression "X is selected independently of the noble gases" is, for example, X 1 , X 2 , and X 3 Are they all the same, or X 1 , X 2 , and X 3 If they are all different, X1 and X 2 Although X is the same 3 This would include different scenarios and other types.

[0059] As used herein, the term "linker" refers to an organic moiety that connects two parts of a compound (e.g., two small molecule drugs, or a small molecule drug and an antibody). In non-limiting examples, the linker may be a direct bond, a single atom (e.g., -O-), a peptide, or a substituted or unsubstituted alkylene or heteroalkylene moiety (e.g., polyethylene glycol). Those skilled in the art will understand common linkers suitable for use in antibody-drug conjugates and methods for their preparation.

[0060] As used herein, the term "monovalent" refers to a substituent that is connected to the molecule being substituted via a single bond. When a substituent is monovalent, for example, F or Cl, it is connected to the atom being substituted by a single bond.

[0061] As used herein, the term “organic group” refers to any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo(carbonyl) groups; carboxyl groups including carboxylic acids, carboxylates, and carboxylic acid esters; sulfur-containing groups such as alkyl and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, O(O)R, C(O)N(R)2, O(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N( R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100 ) comprises hydrocarbyl, where R can be hydrogen (in examples containing other carbon atoms) or a carbon-based moiety, where the carbon-based moiety can be substituted or unsubstituted.

[0062] The terms “patient,” “subject,” or “individual” are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, to which the methods described herein are possible. In a non-limiting embodiment, patient, subject, or individual is human.

[0063] As used herein, the term “pharmaceutically acceptable” refers to a substance, such as a carrier or diluent, that does not inhibit the biological activity or properties of a compound and is relatively non-toxic; that is, the substance can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition in which it is contained.

[0064] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a administered compound prepared from a pharmaceutically acceptable, non-toxic acid or base, including an inorganic acid or base, an organic acid or base, a solvate, a hydrate, or an inclusion compound thereof.

[0065] Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and bisulfates), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharin, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0066] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts, including salts of alkali metals, alkaline earth metals, and transition metals, such as salts of calcium, magnesium, potassium, sodium, and zinc. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts may be prepared from the corresponding compounds, for example, by reacting the compounds with a suitable acid or base.

[0067] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspension, diluent, excipient, thickener, solvent, or encapsulating agent, that is involved in transporting or delivering a compound within or to a patient so that the compound described herein can perform its intended function. Typically, such a compound is transported or delivered from one organ, i.e., part of the body, to another organ, i.e., part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation, including the compound described herein, and is not harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyhydric alcohols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free substances; isotonic salines; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic and suitable substances used in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carriers” include any and all coatings, antimicrobial and antifungal agents, and absorption retarders that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. “pharmaceutically acceptable carriers” may further include pharmaceutically acceptable salts of the compounds described herein.Other additional components that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0068] As used herein, the terms "phenylene" or "phenylenyl" refer to a divalent phenyl group (e.g., 1,4-phenylene). In certain embodiments, the term may be considered a divalent group formed by the removal of two hydrogen atoms from a benzene moiety.

[0069] As used herein, the term "room temperature" refers to a temperature of about 15 °C to 28 °C.

[0070] As used herein, the term "solvent" refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicone, organic compounds, water, alcohol, ionic liquids, and supercritical fluids.

[0071] Terms such as "specifically binds" or "specifically binds" mean that a small molecule, antibody, and / or antigen-binding fragment forms a complex with a relatively stable target and / or antigen under physiological conditions. Specific binding can be characterized by an equilibrium dissociation constant (e.g., the smaller the K D the stronger the binding). Methods for determining whether two molecules specifically bind to each other are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.

[0072] As used herein, the term “substantially” means the majority or most, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term “substantially absent” may mean that the material is not present at all, or that the amount of the material present does not affect the material properties of the composition, such that the amount of the material present is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or less than or equal to about 5 wt%, or less than or equal to or greater than about 4.5 wt%, such as 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt%. The term "substantially absent" may mean that the material is present in a minute amount such as approximately 0 wt% to approximately 5 wt%, or approximately 0 wt% to approximately 1 wt%, or approximately 5 wt% or less, or less than approximately 4.5 wt%, equal to or greater than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or approximately 0.001 wt%, or approximately 0 wt%.

[0073] As used herein in conjunction with the definition of a molecule or organic group, the term “substituted” refers to a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the terms “functional group” or “substituent” refer to a group that can be substituted for or substitutes for a molecule or an organic group. Examples of substituents or functional groups include halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxyl groups including carboxylic acid groups; sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups, without limitation. Non-limiting examples of substituents that can bond to the substituted carbon (or other) atom include F, Cl, Br, I, OR, OCO(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 Includes N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R can be a hydrogen or carbon-based part; for example, R is hydrogen, (C1~C 100)It may be hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or here, two R groups bonded to a nitrogen atom or multiple adjacent nitrogen atoms may together with the nitrogen atom or multiple nitrogen atoms form a heterocyclyl.

[0074] "Therapeutic" treatment is a treatment administered to a subject presenting signs of a pathology for the purpose of reducing or eliminating those signs.

[0075] As used herein, the terms "treat", "treating", and "treatment" mean reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0076] Compounds and Compositions In one aspect, the present disclosure provides a compound of formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof, TIFF2026517730000016.tif16128wherein, R 1a is selected from the group consisting of C1-C6 alkyl, phenyl, and C2-C 10 heteroaryl, wherein the alkyl, phenyl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, OR A , N(R A )(R B ), C(=O)OR A , C(=O)N(R A )(R B ), S(=O)2N(R A )(R B ), S(=O)N(R A )(R B ), OC(=O)R A , and N(R A )C(=O)R B ; R1b This is selected from the group consisting of H and optionally substituted C1-C6 alkyl groups, or R 1a and R 1b These can combine with the nitrogen atom to which they are bonded to form substituted C2-C8 heterocycloalkyl groups; R 2 These are C2-C9 heteroaryls which may be substituted and C6-C which may be substituted. 10 Selected from the group consisting of aryls; L 1 teeth, Selected from the group consisting of TIFF2026517730000017.tif77133; R 3a , R 3b , R 3c , and R 3d These are, independently, H, a C1-C6 alkyl group which may be substituted, a halogen, CN, NO2, OR C , N(R C )(R D ), C(=O)OR C , C(=O)N(R C )(R D ), S(=O)2N(R C )(R D ), S(=O)N(R C )(R D ), OCR C , and N(R C )C(=O)R D Selected from the group consisting of; Y is selected from the group consisting of optionally substituted C1-C3 alkylenyls and optionally substituted C3-C8 cycloalkylenyls; R A , R B , R C , and R D If present, each independently comprises H, an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted C2-C6 heterocycloalkyl group, and an optionally substituted C7-C6 group.12 Aralkyl, may be substituted C6~C 10 Aryl and possibly substituted C2-C 12 Selected from the group consisting of heteroaryls, Here, R A and R B or R C and R D These can combine with the nitrogen atoms to which they are bonded to form substituted C2-C8 heterocycloalkyl groups. Here, R A and R B One or more of these can combine with L to form a C4-C8 heterocycloalkyl or C4-C6 heteroaryl, which may be substituted.

[0077] In certain embodiments, Y is 1,1-cyclopropylene, which may be substituted.

[0078] In a particular embodiment, the compound of formula (I) is formula (Ia): This is the compound TIFF2026517730000018.tif25128.

[0079] In a particular embodiment, the compound of formula (I) is: This is the compound TIFF2026517730000019.tif25128.

[0080] In a particular embodiment, the compound of formula (I) is: This is the compound TIFF2026517730000020.tif25128.

[0081] In a particular embodiment, the compound of formula (I) is: This is the compound TIFF2026517730000021.tif23128.

[0082] In a particular embodiment, the compound of formula (I) is: This is the compound TIFF2026517730000022.tif23128.

[0083] In a particular embodiment, the compound of formula (I) is formula (If): This is the compound TIFF2026517730000023.tif19128.

[0084] In a particular embodiment, the compound of formula (I) is formula (Ig): This is the compound TIFF2026517730000024.tif23128.

[0085] In a particular manner, R 1a C1-C6 alkyl, C1-C6 haloalkyl, F, OH, CN, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -(CH2) 1~3 NH(C1~C6 alkyl), -(CH2) 1~3 This is a phenyl compound substituted with at least one substituent selected from the group consisting of N(C1~C6 alkyl)2, C(=O)NH2, C(=O)NH(C1~C6 alkyl), C(=O)N(C1~C6 alkyl)2, and C(=O) (which may be substituted with C2~C8 heterocycloalkyl).

[0086] In a particular manner, R 1a C1-C6 alkyl, C1-C6 haloalkyl, F, OH, CN, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -(CH2) 1~3 NH(C1~C6 alkyl), -(CH2) 1~3 The alkyl group is substituted with at least one substituent selected from the group consisting of N(C1~C6 alkyl)2, C(=O)NH2, C(=O)NH(C1~C6 alkyl), C(=O)N(C1~C6 alkyl)2, and C(=O) (which may be substituted C2~C8 heterocycloalkyl).

[0087] In a particular manner, R 1aC1-C6 alkyl, C1-C6 haloalkyl, F, OH, CN, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -(CH2) 1~3 NH(C1~C6 alkyl), -(CH2) 1~3 It is a pyridinyl substituted with at least one substituent selected from the group consisting of N(C1~C6 alkyl)2, C(=O)NH2, C(=O)NH(C1~C6 alkyl), C(=O)N(C1~C6 alkyl)2, and C(=O) (which may be substituted C2~C8 heterocycloalkyl).

[0088] In a particular manner, R 1a C1-C6 alkyl, C1-C6 haloalkyl, F, OH, CN, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -(CH2) 1~3 NH(C1~C6 alkyl), -(CH2) 1~3 It is a pyrimidinyl substituted with at least one substituent selected from the group consisting of N(C1~C6 alkyl)2, C(=O)NH2, C(=O)NH(C1~C6 alkyl), C(=O)N(C1~C6 alkyl)2, and C(=O) (which may be substituted C2~C8 heterocycloalkyl).

[0089] In a particular manner, R 1a R is a phenyl molecule substituted with CH3. In certain embodiments, R 1a R is a phenyl molecule substituted with an OH group. In certain embodiments, R 1a R is a phenyl substituted with OCH3. In certain embodiments, R 1a is a phenyl substituted with OCF3. In certain embodiments, R 1a is a phenyl compound substituted with F. In certain embodiments, R 1a is a phenyl substituted with CN. In a particular embodiment, R 1a R is a phenyl substituted with CH2NHCH3. In a particular embodiment, R 1a R is a phenyl molecule substituted with CH2N(CH3)2. In certain embodiments, R 1aR is a phenyl molecule substituted with C(=O)NH2. In certain embodiments, R 1a R is a phenyl molecule substituted with C(=O)NHCH3. In certain embodiments, R 1a is a phenyl molecule substituted with C(=O)N(CH3)2. In certain embodiments, R 1a is a phenyl substituted with C(=O)(azetidinyl). In certain embodiments, R 1a is a phenyl compound substituted with C(=O)(piperidinyl). In certain embodiments, R 1a R is a phenyl compound substituted with C(=O)(4-methylpiperazinyl). In certain embodiments, R 1a is a phenyl substituted with C(=O)(morpholinyl). In certain embodiments, R 1a is a phenyl substituted with C(=O)NH(oxyranyl). In certain embodiments, R 1a This is a phenyl compound substituted with C(=O)NH(cyclopropylmethyl).

[0090] In a particular manner, R 1a is a pyridinyl substituted with CH3. In a particular embodiment, R 1a is a pyridinyl compound substituted with an OH group. In certain embodiments, R 1a is a pyridinyl substituted with OCH3. In certain embodiments, R 1a is a pyridinyl substituted with OCF3. In certain embodiments, R 1a is a pyridinyl substituted with F. In certain embodiments, R 1a is a pyridinyl substituted with CN. In a particular embodiment, R 1a is a pyridinyl substituted with CH2NHCH3. In a particular embodiment, R 1a This is a pyridinyl substituted with CH2N(CH3)2. In a particular embodiment, R 1a is a pyridinyl substituted with C(=O)NH2. In certain embodiments, R 1a is a pyridinyl substituted with C(=O)NHCH3. In certain embodiments, R 1ais a pyridinyl compound substituted with C(=O)N(CH3)2. In certain embodiments, R 1a is a pyridinyl substituted with C(=O)(azetidinyl). In certain embodiments, R 1a is a pyridinyl substituted with C(=O)(piperidinyl). In certain embodiments, R 1a is a pyridinyl substituted with C(=O)(4-methylpiperazinyl). In certain embodiments, R 1a is a pyridinyl substituted with C(=O)(morpholinyl). In certain embodiments, R 1a is a pyridinyl substituted with C(=O)NH(oxyranyl). In certain embodiments, R 1a This is a pyridinyl compound substituted with C(=O)NH (cyclopropylmethyl).

[0091] In a particular manner, R 1a is a pyrimidinyl substituted with CH3. In a particular embodiment, R 1a is a pyrimidinyl substituted with an OH group. In certain embodiments, R 1a is a pyrimidinyl substituted with OCH3. In certain embodiments, R 1a is a pyrimidinyl substituted with OCF3. In certain embodiments, R 1a is a pyrimidinyl substituted with F. In certain embodiments, R 1a is a pyrimidinyl substituted with CN. In a particular embodiment, R 1a is a pyrimidinyl substituted with CH2NHCH3. In a particular embodiment, R 1a This is a pyrimidinyl substituted with CH2N(CH3)2. In a particular embodiment, R 1a is a pyrimidinyl substituted with C(=O)NH2. In certain embodiments, R 1a is a pyrimidinyl substituted with C(=O)NHCH3. In certain embodiments, R 1a is a pyrimidinyl substituted with C(=O)N(CH3)2. In certain embodiments, R 1a is a pyrimidinyl substituted with C(=O)(azetidinyl). In certain embodiments, R1a is a pyrimidinyl substituted with C(=O)(piperidinyl). In certain embodiments, R 1a is a pyrimidinyl substituted with C(=O)(4-methylpiperazinyl). In certain embodiments, R 1a is a pyrimidinyl substituted with C(=O)(morpholinyl). In certain embodiments, R 1a is a pyrimidinyl substituted with C(=O)NH(oxyranil). In certain embodiments, R 1a This is a pyrimidinyl compound substituted with C(=O)NH(cyclopropylmethyl).

[0092] In a particular manner, R 1a teeth This is TIFF2026517730000025.tif10128. In a particular aspect, R 1a teeth This is TIFF2026517730000026.tif10128. In a particular aspect, R 1a teeth This is TIFF2026517730000027.tif16128. In a particular aspect, R 1a teeth This is TIFF2026517730000028.tif11128. In a particular manner, R 1a teeth This is TIFF2026517730000029.tif17128. In a particular embodiment, R 1a teeth This is TIFF2026517730000030.tif19128. In a particular aspect, R 1a teeth This is TIFF2026517730000031.tif18128. In a particular manner, R 1a teeth It is TIFF2026517730000032.tif23128. In a particular aspect, R 1a teeth It is TIFF2026517730000033.tif25128. In a particular aspect, R 1a teeth This is TIFF2026517730000034.tif25128. In a particular aspect, R 1a teeth It is TIFF2026517730000035.tif30128. In a particular aspect, R 1a teeth This is TIFF2026517730000036.tif27128. In a particular aspect, R 1a teeth This is TIFF2026517730000037.tif11128. In a particular manner, R 1a teeth This is TIFF2026517730000038.tif10128. In a particular manner, R 1a teeth This is TIFF2026517730000039.tif10128. In a particular manner, R 1a teeth This is TIFF2026517730000040.tif12128. In a particular aspect, R 1a teeth This is TIFF2026517730000041.tif11128. In a particular embodiment, R 1a teeth This is TIFF2026517730000042.tif12128. In a particular embodiment, R 1a teeth This is TIFF2026517730000043.tif14128. In a particular aspect, R 1a teeth This is TIFF2026517730000044.tif18128. In a particular embodiment, R 1a teeth This is TIFF2026517730000045.tif16128. In a particular embodiment, R 1a teeth This is TIFF2026517730000046.tif17128. In a particular embodiment, R 1a teeth This is TIFF2026517730000047.tif16128. In a particular embodiment, R 1a teeth This is TIFF2026517730000048.tif17128. In a particular embodiment, R 1a teeth This is TIFF2026517730000049.tif17128. In a particular embodiment, R 1a teeth This is TIFF2026517730000050.tif17128. In a particular manner, R 1a teeth This is TIFF2026517730000051.tif22128. In a particular aspect, R 1a teeth This is TIFF2026517730000052.tif17128. In a particular aspect, R 1a teeth This is TIFF2026517730000053.tif17128. In a particular manner, R 1a teeth This is TIFF2026517730000054.tif16128. In a particular embodiment, R 1a teeth This is TIFF2026517730000055.tif17128. In a particular aspect, R 1a teeth This is TIFF2026517730000056.tif17128. In a particular aspect, R 1a teeth The filename is TIFF2026517730000057.tif17128.

[0093] In a particular manner, R 1a This is a C1-C6 alkyl group that may be substituted.

[0094] In a particular manner, R 1a is methyl. In a particular embodiment, R 1a It is CH2CH2N(CH3)2. In a particular embodiment, R 1b H is H.

[0095] In a particular manner, R 1a and R 1bThese combine with the nitrogen atoms to which they are bonded, Forms TIFF2026517730000058.tif10128. In a particular embodiment, R 1a and R 1b These combine with the nitrogen atoms to which they are bonded, Forms TIFF2026517730000059.tif10128. In a particular embodiment, R 1a and R 1b These combine with the nitrogen atoms to which they are bonded, Forms TIFF2026517730000060.tif14128.

[0096] In a particular manner, R 2 teeth This is TIFF2026517730000061.tif13128. In a particular manner, R 2 teeth This is TIFF2026517730000062.tif17128. In a particular manner, R 2 teeth This is TIFF2026517730000063.tif18128. In a particular aspect, R 2 teeth This is TIFF2026517730000064.tif13128. In a particular aspect, R 2 teeth This is TIFF2026517730000065.tif10128. In a particular aspect, R 2 teeth This is TIFF2026517730000066.tif17128. In a particular embodiment, R 2 teeth The filename is TIFF2026517730000067.tif14128.

[0097] In a particular manner, R 3a , R 3b , R 3c , and R 3d At least one of them is H. In a particular embodiment, R 3a , R 3b, R 3c , and R 3d At least two of them are H. In a particular embodiment, R 3a , R 3b , R 3c , and R 3d At least three of them are H. In a particular embodiment, R 3a , R 3b , R 3c , and R 3d Each of them is H.

[0098] In a particular embodiment, the compound is N-methyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(isoquinoline-4-yl)-N-(p-tolyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(isoquinoline-4-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)imidazo[1,2-a]pyridine-6-carboxamide; N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 3-(2-aminopyrimidine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((dimethylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide; N-(4-(methylcarbamoyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide; N-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-methoxy-3-(morpholine-4-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-hydroxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzofuran-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-(trifluoromethoxy)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-carbamoylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-5-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(5-(dimethylcarbamoyl)-2-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carboxamide)-N,N-dimethylpicolinamide; N-(4-hydroxy-3-(pyrroridine-1-carbonyl)phenyl)-4-(1H-pyrrorol[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(azetidine-1-carbonyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(pyrimidine-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(2-(dimethylamino)ethyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-((2-(dimethylamino)ethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-hydroxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)thieno[2,3-c]pyridine-2-carboxamide; N-(4-hydroxy-3-(oxetane-3-ylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-((cyclopropylmethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-oxoisoindolin-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carbonyl)-1-phenylpiperazine-2-one; N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-cyano-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-phenyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(p-trill)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(pyridine-4-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-indole-5-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-indazole-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperidine-1-yl)methanone; (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperazine-1-yl)methanone; 1-(5-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyridine-3-yl)-N-(4 ((methylamino)methyl)phenyl)cyclopropane-1-carboxamide; N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide; N-methyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-phenyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-(trifluoromethyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; and Selected from the group consisting of N-(3-(dimethylcarbamoyl)-4-fluorophenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide.

[0099] In another aspect, the present disclosure provides a compound of formula (II), or a salt, solvate, stereoisomer, or isotopolog thereof, TIFF2026517730000068.tif24128In formula, R4 This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 heterocycloalkyl, and optionally substituted C7-C 12 Aralkyl, may be substituted C3~C 12 Heteroaralkyl, may be substituted C6~C 10 Aryl and possibly substituted C2-C 12 Selected from the group consisting of heteroaryls; R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f These are, independently, H, a C1-C6 alkyl group which may be substituted, a halogen, OR E , and N(R E )(R F Selected from the group consisting of; R 6 is, -(CH2) 1~3 C(=O)N(R G )(R H ) and; R 7a H and C(=O)OR I Selected from the group consisting of R 7b H is; X is OR J and Selected from the group consisting of TIFF2026517730000069.tif15128; G may be substituted with C1-C6 alkyl and -Z 1 -N(R 7a )(R 7b Selected from the group consisting of; Z 1 and Z 2 Each of these is independently a -(may be substituted C1-C6 alkylenyl)-; R 8 This is selected from the group consisting of H and optionally substituted C1-C6 alkyl groups; R 9a and R9b Each is independently selected from the group consisting of H and optionally substituted C1-C6 alkyl groups; R 10a and R 10b These are, independently, H, an optionally substituted C1-C6 alkyl group, and an optionally substituted C6-C6 alkyl group. 10 Selected from the group consisting of aryls; n is 1, 2, 3, 4, or 5; R E , R F , R G , R H , R I , and R J These are, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heterocycloalkyl, and optionally substituted C7-C 12 Aralkyl, may be substituted C6~C 10 Aryl and possibly substituted C2-C 12 Selected from the group consisting of heteroaryls.

[0100] In a particular manner, R 4 H is H. In a particular manner, R 4 teeth The filename is TIFF2026517730000070.tif16128.

[0101] In a particular manner, R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least one of them is H. In a particular embodiment, R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least two of them are H. In a particular manner, R 5a , R 5b , R5c , R 5d , R 5e , and R 5f At least three of them are H. In a particular manner, R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least four of them are H. In certain embodiments, R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least five of them are H. In certain embodiments, R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f Each of these is H.

[0102] In a particular manner, R 6 It is -CH2C(=O)NHCH3.

[0103] In a particular embodiment, G is CH3.

[0104] In certain embodiments, G is -Z 1 -N(R 7a )(R 7b )

[0105] In a particular manner, R 7a H is H. In a particular manner, R 7a teeth The filename is TIFF2026517730000071.tif16128.

[0106] In a particular manner, R 7b H is H.

[0107] In a particular embodiment, X is OEt. In a particular embodiment, X is The filename is TIFF2026517730000072.tif15128.

[0108] In a particular manner, R 9a H is H. In a particular manner, R 9b H is H.

[0109] In a particular embodiment, n is 3.

[0110] In a particular manner, R 10a is methyl. In a particular embodiment, R 10a It is 4-fluorophenyl.

[0111] In a particular manner, R 10b is methyl. In a particular embodiment, R 10b It is 4-fluorophenyl.

[0112] In certain embodiments, X is The filename is TIFF2026517730000073.tif16128.

[0113] In a particular manner, Z 1 It is -CH2CH2CH2-.

[0114] In a particular manner, Z 2 It is -CH2-.

[0115] In a particular embodiment, the compound is (2-((2R,6R)-6-(2-((3-((4-fluorophenyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)-4-(pyrazolo[1,5-a]pyridine-7-ylmethyl)piperazine-2-yl)ethyl)benzyl carbamate; 2-((2R,6R)-6-(2-(((benzyloxy)carbonyl)amino)ethyl)-1-(2-(methylamino)-2-oxoethyl)-4-(pyrazolo[1,5-a]pyridine-7-ylmethyl)piperazine-2-yl)ethyl acetate; (2-((2R,6R)-6-(2-((3-((4-fluorophenyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)piperazine-2-yl)ethyl)benzyl carbamate; and Selected from the group consisting of N-(3-((4-fluorophenyl)(methyl)amino)propyl)-2-((2R,6R)-6-methyl-1-(2-(methylamino)-2-oxoethyl)piperazin-2-yl)acetamide.

[0116] (Table 1) Exemplary Compounds TIFF2026517730000074.tif104146TIFF2026517730000075.tif224146TIFF2026517730000076.tif218146TIFF202 6517730000077.tif189146TIFF2026517730000078.tif185146TIFF2026517730000079.tif213146TIFF20265177300 00080.tif222146TIFF2026517730000081.tif210146TIFF2026517730000082.tif214146TIFF2026517730000083.t if210146TIFF2026517730000084.tif222146TIFF2026517730000085.tif199146TIFF2026517730000086.tif134146

[0117] In certain embodiments, the appearance of each of the optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylenyl, optionally substituted C1-C3 alkylenyl, optionally substituted C3-C8 cycloalkylenyl, optionally substituted benzyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl independently corresponds to C1-C6 alkyl, C3-C8 cycloalkyl, C2-C12 Heterocycloalkyl, C1-C6 hydroxyalkyl, halogen, CN, NO2, OR a , N(R a )(R b ), C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, aryl, heteroaryl, (C1-C6 alkylenyl)C(=O)N(R a )(R b ), (C1~C6 alkyrenyl)C(=O)OR a O(C1~C3 alkylenyl)C(=O)OR a O(C1~C3 alkylenyl)C(=O)N(R a )(R b ), C(=O)R a , C(=O)OR a ,OC(=O)R a , OC(=O)OR a , SR a , S(=O)R a , S(=O)2R a , S(=O)2N(R a )(R b ), S(=O)2NR a C(=O)NHR b , N(R a )S(=O)2R b , N(R a )C(=O)R b , and C(=O)NR a R b It may be substituted with at least one substituent selected from the group consisting of, where R a and R b These are, independently, H, -C(=O)(C1~C6 alkyl), C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 heteroalkyl, C3~C8 cycloalkyl, and C2~C 12 Heterocycloalkyl, C7~C 12 The group is selected from aralkyl, aryl, and heteroaryl.

[0118] In another aspect, the Disclosure provides a pharmaceutical composition comprising at least one compound of the Disclosure and a pharmaceutically acceptable carrier.

[0119] In certain embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0120] The compounds described herein may have one or more stereocenters, each stereocenter independently existing in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein are understood to encompass racemic, optically active, positional isomeric, and stereoisomeric forms, or combinations thereof, having the therapeutically useful properties described herein. Preparation of the optically active form is achieved in any preferred manner, including, but not limited to, separation of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The separation of compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0121] The methods and formulations described herein involve the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of any compound having the structure of any compound described herein, or metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohols (e.g., ethanol) solvates, acetates, etc. In certain embodiments, the compounds described herein exist in solvated forms with water and pharmaceutically acceptable solvents such as ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[0122] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers are included within the range of compounds presented herein.

[0123] In certain embodiments, the compounds described herein are prepared as prodrugs. “Prodrug” refers to a drug that is converted to a parent drug in vivo. In certain embodiments, at in vivo administration, the prodrug is chemically converted to a biological, pharmaceutical, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutical, or therapeutically active form of the compound by one or more steps or processes.

[0124] In certain embodiments, for example, a moiety on the aromatic ring portion of a compound described herein is susceptible to various metabolic reactions. The incorporation of appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions include, but are merely illustrative, deuterium, halogens, or alkyl groups.

[0125] The compounds described herein also include isotope-labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes suitably included in the compounds described herein are: 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 It contains S in an unrestricted manner. In certain embodiments, isotope-labeled compounds are useful for studying the tissue distribution of drugs and / or substrates. In another embodiment, substitution with heavier isotopes such as deuterium results in higher metabolic stability (e.g., increased in vivo half-life or reduced required dose). In yet another embodiment, 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N is useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds are prepared by any suitable method or process using an appropriate isotope-labeling reagent in place of the otherwise unlabeled reagent.

[0126] In certain embodiments, the compounds described herein are labeled by other means, which include, but are not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0127] The compounds described herein, and other related compounds having different substituents, are referenced herein and, for example, Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4. th The compounds are synthesized using the techniques and materials described in *Wiley 1992*, *Advanced Organic Chemistry*, 4th Ed., Vols. A and B (Plenum 2000, 2001), and *Protective Groups in Organic Synthesis*, 3rd Ed., (Wiley 1999) (all of which are incorporated by reference to such disclosures). The basic methods for preparing the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various parts found in the formulas provided herein.

[0128] The compounds described herein are synthesized using any preferred procedure starting with compounds available from the distributor, or prepared using the procedures described herein.

[0129] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxyl groups are protected to avoid their undesirable participation in a reaction. Protecting groups are used to block some or all of the reactive moiety, preventing such groups from participating in a chemical reaction until the protecting group is removed. In another embodiment, each protecting group can be removed by different means. Protecting groups that are cleaved under entirely different reaction conditions satisfy the requirements for selective removal.

[0130] In certain embodiments, protecting groups are removed by acids, bases, reducing conditions (e.g., hydrolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid-unstable and are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected by a Cbz group, which is removable by hydrolysis, and a base-unstable Fmoc group. Carboxylic acid and hydroxyl reactive moieties are blocked, non-limitingly, by base-unstable groups such as methyl, ethyl, and acetyl, in the presence of amines blocked by acid-unstable groups such as t-butyl carbamate, or by carbamates that are stable to both acids and bases but removable by hydrolysis.

[0131] In certain embodiments, the carboxylic acid and hydroxyl-reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, while the acid-hydrogen-bondable amine groups are blocked with base-unstable groups such as Fmoc. The carboxylic acid-reactive moieties are protected by conversion to simple ester compounds, such as those exemplified herein, including conversion to alkyl esters, or blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while the coexisting amino groups are blocked with fluoride-unstable silyl carbamate.

[0132] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and can subsequently be removed by a metal or pyic acid catalyst. For example, an allyl-blocked carboxylic acid can be deprotected by a palladium-catalyzed reaction in the presence of an acid-unstable t-butyl carbamate or a base-unstable amine acetate protecting group. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue remains attached to the resin, its functional group is blocked and does not react. Once released from the resin, the functional group becomes available for reaction.

[0133] Typically, the blocking / protecting group can be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t-butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (Trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC).

[0134] Detailed descriptions of other protecting groups and techniques applicable to the formation and removal of protecting groups are found in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference.

[0135] method In another aspect, the present disclosure provides a method for treating, preventing, and / or improving an inflammatory disease in a subject, comprising the step of administering a therapeutically effective amount of at least one compound and / or at least one pharmaceutical composition of the present disclosure to the subject.

[0136] In certain embodiments, JNK1 is selectively inhibited compared to JNK2 and / or JNK3.

[0137] In certain embodiments, JNK1 is inhibited at a similar rate to JNK2. In certain embodiments, JNK1 is inhibited at a higher rate than JNK2.

[0138] In certain embodiments, JNK1 is inhibited at a similar rate to JNK3. In certain embodiments, JNK1 is inhibited at a higher rate than JNK3.

[0139] In certain aspects, inflammatory diseases are inflammatory diseases of the non-central nervous system (CNS).

[0140] In a particular embodiment, the inflammatory disease is at least one selected from the group consisting of endometriosis, arthritis, pulmonary fibrosis, cancer, type 1 diabetes, and type 2 diabetes. In a particular embodiment, the inflammatory disease is endometriosis.

[0141] In certain embodiments, progesterone insensitivity in the subject is reduced and / or eliminated. In certain embodiments, pain associated with endometriosis is reduced and / or eliminated. In certain embodiments, normal reproductive function is maintained in the subject.

[0142] In certain aspects, inflammatory diseases are inflammatory diseases of the non-central nervous system (CNS).

[0143] In a particular embodiment, the inflammatory disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0144] In certain embodiments, the subject is further administered progesterone.

[0145] In certain aspects, the subject is a mammal.

[0146] In certain aspects, mammals are humans.

[0147] In certain embodiments, humans are female.

[0148] In certain embodiments, the compound selectively inhibits JNK1 rather than JNK2. In certain embodiments, the compound selectively inhibits JNK1 rather than JNK3. In certain embodiments, the compound selectively inhibits JNK2 rather than JNK1. In certain embodiments, the compound selectively inhibits JNK2 rather than JNK3. In certain embodiments, the compound selectively inhibits JNK3 rather than JNK1. In certain embodiments, the compound selectively inhibits JNK3 rather than JNK2.

[0149] In certain embodiments, the compounds of the present disclosure are suitable for reversing at least one immunodisruption that underlies the pathophysiology of the disease, which is increased in the presence of endometriosis.

[0150] In certain embodiments, the compounds of the present disclosure are suitable for treating polycystic ovary disease driven by inflammation that causes endocrine disruption and / or insulin resistance.

[0151] In certain embodiments, the compounds of the present disclosure are suitable for treating hearing loss by overcoming resistance to glucocorticoids, which normally provide protection from cochlear cell death of auditory hair cells damaged by stress.

[0152] In certain embodiments, the compounds of the disclosed herein are suitable for reducing the size or volume of endometriotic lesions. In certain embodiments, the compounds of the disclosed herein are suitable for the treatment of endometriosis while maintaining hypothalamic-pituitary-ovarian steroid control of the menstrual cycle and fertility.

[0153] In certain embodiments, the compounds of this disclosure are suitable for alleviating pain associated with endometriosis while maintaining normal reproductive function. In certain embodiments, normal reproductive function includes follicular maturation, ovulation, fertilization, embryonic development, implantation of a blastocyst into uterine decidual tissue, and / or fetal development.

[0154] In certain embodiments, the compounds of the present disclosure are suitable for reducing primordial follicle activation, resulting in extended ovarian lifespan and delaying the onset of ovarian aging.

[0155] In certain embodiments, the compounds of the present disclosure are suitable for reducing and / or preventing insulin resistance in subjects with ovarian disease.

[0156] In certain embodiments, the method further includes a step of detecting an inflammatory disease or disorder in a subject. In certain embodiments, the detection step includes performing a preferred diagnostic method on the subject.

[0157] Dosage / Prescription The administration regimen may affect the effective dose. The therapeutic agent may be administered to the subject either before or after the onset of the disease or disorder. Furthermore, several divided doses or staggered doses may be administered daily or sequentially, or the dose may be administered by continuous infusion or bolus injection. In addition, the dosage of the therapeutic agent may be increased or decreased in proportion to the urgency of the therapeutic or prophylactic situation.

[0158] The administration of the compositions described herein to patients, preferably mammals, more preferably humans, may be carried out using known procedures in doses and durations effective in treating the disease or disorder in the patient. The effective dose of the therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the state of the disease or disorder in the patient; the patient's age, sex, and weight; and the therapeutic compound's ability to treat the disease or disorder in the patient. The dosing regimen may be adjusted to produce an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be reduced in proportion to the urgency of the treatment situation. An unrestricted example of the effective dose range for the therapeutic compounds described herein is about 1 to 5,000 mg / kg body weight / day. Those skilled in the art will be able to consider the relevant factors and make a determination regarding the effective dose of the therapeutic compound without excessive experimentation.

[0159] The actual dosage levels of the active ingredient in the pharmaceutical compositions described in the specification may be modified so as to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and method of administration without being toxic to the patient.

[0160] In particular, the selected dosage level depends on a variety of factors, including the activity of the specific compound used, the timing of administration, the compound's elimination rate, the duration of treatment, other drugs, compounds, or substances used in combination with the compound, the patient's age, sex, weight, condition, overall health, and medical history, as well as similar factors well known in the medical field.

[0161] A medical doctor with ordinary skills in the art, such as a physician or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian could start with a dose of the compound described herein employed in the pharmaceutical composition at a lower level than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0162] In specific embodiments, it is particularly advantageous to formulate compounds in dosage units for ease of administration and uniformity of dosage. As used herein, dosage units refer to physically distinct units suitable as a single dose for a patient to be treated; each unit contains a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical vehicle. The dosage unit forms of the compounds described herein are determined and directly depended on (a) the specific properties of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology for formulating / manufacturing such therapeutic compounds.

[0163] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0164] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Often, it is preferable to include isotonic agents in the composition, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol and sorbitol. The inclusion of absorption-delaying agents, such as aluminum monostearate or gelatin, in the composition can result in sustained absorption of the injectable composition.

[0165] In certain embodiments, the compositions described herein are administered to a patient in doses ranging from one to five times per day or more. In other embodiments, the compositions described herein are administered to a patient in doses ranging from once a day, once every two days, once every three days to once a week, and once every two weeks, without limitation. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein will vary from individual to individual depending on many factors, including, but not limited to, age, disease or disorder to be treated, sex, overall health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to any particular administration regimen, and the exact dose and composition to be administered to any patient will be determined by the attending physician, taking into account all other factors concerning the patient.

[0166] The compounds described herein for administration are available in doses of approximately 1 μg to 10,000 mg, 20 μg to 9,500 mg, 40 μg to 9,000 mg, 75 μg to 8,500 mg, 150 μg to 7,500 mg, 200 μg to 7,000 mg, 350 μg to 6,000 mg, 500 μg to 5,000 mg, 750 μg to 4,000 mg, and 1 mg to 3,000 mg. g may range from approximately 10 mg to approximately 2,500 mg, approximately 20 mg to approximately 2,000 mg, approximately 25 mg to approximately 1,500 mg, approximately 30 mg to approximately 1,000 mg, approximately 40 mg to approximately 900 mg, approximately 50 mg to approximately 800 mg, approximately 60 mg to approximately 750 mg, approximately 70 mg to approximately 600 mg, and approximately 80 mg to approximately 500 mg, as well as any and all overall or partial increments between these ranges.

[0167] In some embodiments, the dose of the compound described herein is approximately 1 mg to approximately 2,500 mg. In some embodiments, the dose of the compound described herein used in the composition described herein is approximately less than 10,000 mg, or approximately less than 8,000 mg, or approximately less than 6,000 mg, or approximately less than 5,000 mg, or approximately less than 3,000 mg, or approximately less than 2,000 mg, or approximately less than 1,000 mg, or approximately less than 500 mg, or approximately less than 200 mg, or approximately less than 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than approximately 1,000 mg, or less than approximately 800 mg, or less than approximately 600 mg, or less than approximately 500 mg, or less than approximately 400 mg, or less than approximately 300 mg, or less than approximately 200 mg, or less than approximately 100 mg, or less than approximately 50 mg, or less than approximately 40 mg, or less than approximately 30 mg, or less than approximately 25 mg, or less than approximately 20 mg, or less than approximately 15 mg, or less than approximately 10 mg, or less than approximately 5 mg, or less than approximately 2 mg, or less than approximately 1 mg, or less than approximately 0.5 mg, as well as any and all of these overall or partial increments.

[0168] In a particular embodiment, the compositions described herein are packaged pharmaceutical compositions comprising a container for holding a therapeutically effective amount of the compound described herein alone or in combination with a second pharmaceutical product, and instructions for using the compound to treat or reduce one or more symptoms of a disease or disorder in a patient.

[0169] The formulations may be used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable method of administration known in the art. Pharmaceutical preparations may be sterilized and, if desired, mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt buffers to affect osmotic pressure, colorants, flavorings and / or aromatic substances. They may also be combined with other activators, such as other analgesics, if desired.

[0170] The routes of administration for any composition described herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical routes. The compounds for use in the compositions described herein can be formulated for administration by any preferred route, such as oral or parenteral, percutaneous, transmucosal (e.g., sublingual, tongue, (trans) buccal, (trans) urethral, ​​vagina (e.g., transvaginal and perivaginal), nasal (intra) and (trans) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0171] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0172] Oral administration For oral administration, tablets, sugar-coated tablets, liquids, drops, suppositories, or capsules, caplets, and gel caps are particularly preferred. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulators and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or coated by known techniques for aesthetic purposes or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0173] For oral administration, the compounds described herein may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets may be coated using preferred methods and coating materials such as the Opadry® film coating system (e.g., Opadry® OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and Opadry® White, 32K18400) available from Colorcon, West Point, Pa. Liquid preparations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid formulations may be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible oils); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid).

[0174] Parenteral administration For parenteral administration, the compounds described herein may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in bolus doses and / or continuous infusions. Suspensions, solutions, or emulsions in oily or aqueous vehicles may be used, which may contain other formulations such as suspending agents, stabilizers, and / or dispersants.

[0175] The sterile injection forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic and parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among other acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solutions. Sterile non-volatile oils are conventionally employed as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic mono or diglycerides, may be employed. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injections, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0176] Additional dosage forms Additional dosage forms suitable for use with the compounds and compositions described herein include those described in US Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compounds and compositions described herein also include those described in US Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compounds and compositions described herein include those described in PCT Applications Nos. WO 03 / 35041;WO 03 / 35040;WO 03 / 35029;WO 03 / 35177;WO 03 / 35039;WO 02 / 96404;WO 02 / 32416;WO 01 / 97783;WO 01 / 56544;WO 01 / 32217;WO 98 / 55107;WO 98 / 11879;WO 97 / 47285;WO 93 / 18755; and WO 90 / 11757.

[0177] Controlled-release formulations and drug delivery systems In certain embodiments, the formulations described herein may, non-limitingly, be short-release formulations, rapid-offset formulations, or controlled-release formulations, such as sustained-release formulations, delayed-release formulations, and pulsed-release formulations.

[0178] The term "sustained-release" is used in its traditional sense to refer to a drug formulation that provides a gradual release of the drug over a long period, resulting in a substantially constant blood concentration of the drug over a long period, though not necessarily. The duration may be up to one month or longer, and should be a longer release than that obtained by administering the same amount of drug in bolus form.

[0179] For sustained release, the compound may be formulated with a suitable polymer or hydrophobic material that provides the compound with sustained release properties. Therefore, the compound intended for use with the methods described herein may be administered in the form of microparticles, for example, by injection, or by embedding in the form of a wafer or disk.

[0180] In some cases, the dosage form used may provide one or more active ingredients in a sustained-release or controlled-release manner, for example, by using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof, to provide a desired release profile in various proportions. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single-unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules, and caplets adapted for controlled release, are included in the compositions and dosage forms described herein.

[0181] Most controlled-release drugs share the common objective of improving pharmacotherapy compared to what can be achieved with uncontrolled-release drugs. Ideally, the use of optimally designed controlled-release formulations in medical procedures is characterized by the use of minimal drug substance to cure or control a condition in minimal time. The advantages of controlled-release formulations include extended drug activity, reduced dosing frequency, and improved patient adherence to medication. Furthermore, controlled-release formulations may affect other characteristics such as the time of onset of action or drug blood concentration, and thus may also affect the occurrence of side effects.

[0182] Most controlled-release formulations are designed to release an initial amount of drug to rapidly produce the desired therapeutic effect, and then gradually and continuously release different amounts of the drug to maintain this therapeutic level for an extended period. To maintain this constant level of drug in the body, the drug must be released from the formulation at a rate that compensates for the amount metabolized and excreted by the body.

[0183] The controlled release of an active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release ingredient" is defined herein as a compound or compounds, non-limitingly comprising polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof, that facilitate the controlled release of an active ingredient. In some embodiments, the compounds described herein are administered to a patient alone or in combination with other agents using sustained-release formulations.

[0184] The term "delayed release" is used herein in its conventional sense to refer to a drug formulation that provides an initial release of the drug after a certain delay following drug administration, and which may include delays of approximately 10 minutes to up to approximately 12 hours, though not necessarily.

[0185] The term "pulsed release" is used herein in its conventional sense to refer to a drug formulation that provides drug release in a manner that generates a pulsed plasma profile of the drug after drug administration.

[0186] The term "immediate release" is used in its traditional sense to refer to drug formulations that provide drug release immediately after administration.

[0187] As used herein, short-term means any period of approximately 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes or less after drug administration, and any overall or partial increment of any or all of these.

[0188] As used herein, rapid elimination of action means any period of time approximately 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes or less after drug administration, as well as any overall or partial increment of any and all of these periods.

[0189] Dosage The therapeutically effective dose or amount of the compounds described herein will vary depending on the patient's age, sex, and weight, the patient's current medical condition, and the progression of the disease or disorder in the patient being treated. A person skilled in the art can determine the appropriate dose based on these and other factors.

[0190] The preferred doses of the compounds described herein may range from about 0.01 mg to about 5,000 mg per day, for example, from about 0.1 mg to about 1,000 mg per day, for example, from about 1 mg to about 500 mg, for example, from about 5 mg to about 250 mg. The dose may be administered as a single dose or as multiple doses, for example, 1 to 4 times or more per day. When multiple doses are used, each dose may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses with an interval of about 12 hours between doses.

[0191] The amount of the compound administered per day may, in non-limiting cases, be daily, every other day, every two days, every three days, every four days, or every five days. For example, in every-other-day administration, a dose of 5 mg per day may be started on Monday, followed by the first subsequent dose of 5 mg per day on Wednesday, and the second dose of 5 mg per day on Friday.

[0192] If the patient's condition improves, the administration of the compounds described herein may be optionally continued at the physician's discretion; alternatively, the dose of the administered drug may be temporarily reduced or temporarily discontinued (i.e., “drug-free period”) for a certain period. The length of the drug-free period may vary arbitrarily from 2 days to 1 year, and includes, but are not limited to, 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days. Dose reductions during drug discontinuation include 10% to 100%, and just a few examples include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0193] If the patient's condition improves, a maintenance dose is administered as needed. Subsequently, the dose, frequency, or both are reduced to a level that maintains improvement in the disease. In certain embodiments, the patient may require long-term intermittent treatment in the event of any recurrence of symptoms and / or infection.

[0194] The compounds described herein may be formulated as unit dosage forms. The term "unit dosage form" refers to a physically distinct unit suitable as a single dose for each patient receiving treatment, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect, with an optional and suitable pharmaceutical carrier. Unit dosage forms may be for a once-daily dose or for multiple daily doses (e.g., about 1 to 4 times or more per day). If multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0195] The toxicity and therapeutic efficacy of such treatment regimens are determined arbitrarily in cell cultures or experimental animals, and the LD 50 (A lethal dose for 50% of the population) and ED 50This includes, in no particular way, determining the dose that is therapeutically effective in 50% of the population. The dose-to-toxicity ratio is the therapeutic index, which is the LD (Low Life Quantitative). 50 and ED 50 It is expressed as a ratio to . Data obtained from cell culture assays and animal experiments are optionally used when formulating the dosage range for human use. The dosage of such compounds is determined with minimal toxicity and ED 50 It is preferable that the circulating concentration is within the range that includes [the substance]. The dosage can be arbitrarily varied within this range depending on the dosage form used and the route of administration used.

[0196] Those skilled in the art will recognize, or can verify by conventional experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention and are encompassed by the claims appended herein. For example, it should be understood that modifying reaction conditions, including reaction time, scale / volume of reaction, and experimental reagents, e.g., solvent, catalyst, pressure, ambient conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agent, with alternatives recognized in the art and by conventional experimentation alone is within the scope of the present application.

[0197] Where values ​​and ranges are provided herein, it should be understood that all values ​​and ranges encompassed within those values ​​and ranges are included within the scope of this disclosure. Furthermore, all values ​​that fall within these ranges, as well as any upper or lower limits on the ranges of values, are contemplated in this application.

[0198] The following embodiments further illustrate aspects of this disclosure. However, they do not limit the teachings or disclosures of this disclosure described herein. [Examples]

[0199] Various aspects of this application can be better understood by referring to the following examples provided as illustrations. The scope of this application is not limited to the examples given herein.

[0200] Example 1: Identification of JNK inhibitors using DEC-Tec library screening The selection of JNK inhibitors was performed and optimized from the BCM DEC-Tec chemical library using the method described in Figure 1, and the results are shown in Figures 2 and 3A-3B. More than 4 billion compounds were included in the selection target with the aim of identifying novel chemical scaffolds and associating these novel scaffolds with JNK inhibitors. This disclosure describes, in one aspect, the method used to identify JNK inhibitors. Seven major structures were identified from more than 3,000 positive cases using established cheminformatics and bioinformatics methods. Initial observations from DEC-Tec selection performed with 1 μM JNK1 enzyme yielded significantly fewer hits than expected. Introducing a removal step into our selection method dramatically improved the selection results.

[0201] Next, DEC-Tec selection using 0.05 μM JNK3 enzyme yielded much more manageable results. At this JNK1 concentration, significant enrichment of compounds was observed in library qDOS18_2, with a maximum enrichment of 750-fold. In qDOS21, the enrichment was approximately 150-fold. According to the target compound profile, the desired compound should have a higher affinity for JNK1 than for JNK2. Compounds from qDOS24 were enriched by JNK2, while compounds from qDOS21 were not enriched by JNK2. These results suggest that qDOS21 has unique selectivity for JNK1 compared to JNK2. Compared to JNK1, compounds in qDOS18_2 demonstrated high nonspecific binding (y-axis) relative to enrichment (x-axis). Finally, DEC-Tec selection was performed using JNK3, and the results from the two libraries with the highest enrichment are shown (Figures 3A-3B).

[0202] Library qDOS21 also showed very good enrichment of selected compounds using JNK3, and qDOS28_1 showed good enrichment, though to a lesser degree, using JNK3. Based on the overlapping scaffolds in qDOS21 shown in both JNK1 and JNK3 selections, hits from this library were resynthesized. These results are described in more detail elsewhere in this specification. Briefly, the results described herein demonstrate the use of the DEC-Tec platform to establish selectivity between JNK isoforms. Selected compounds in the library that were overexpressed in multiple selections, and certain compounds in the library containing chaotic ligands were excluded. This was the case with the qDOS18_2 hit.

[0203] The following crystal structures of human JNK1 and JNK3 (i.e., 4QTD, 4WHZ, 3ELJ, 4AWI, 4L7F, 3PZE, 4HYU, 4E73, 4IZY, 2H96, 2NO3, 2G01, 2GMX, 3TTJ, 3TTI) were superimposed to observe possible side-chain conformations. Their small molecule ligands were optimized, and a pharmacophore model was constructed from these, in addition to four other known binders described in the literature. This modeling revealed common overlaps between several compounds from the DEC-Tec selection described herein and known structures (Figures 4A-4D).

[0204] Example 2: Chemical synthesis of compounds identified in the qDOS21 and qDOS28_1 libraries TIFF2026517730000087.tif59154 Reagents and conditions. (i) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), rt, 16 hours; (ii) a. R3-boronic acid, Cs2CO3, Pd(dppf)Cl2·CH2Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex), 1,4-dioxane-H2O (3:1), 110℃, 1 hour; b. Trifluoroacetic acid (TFA), CH2Cl2, rt, 4 hours.

[0205] General procedure for amide synthesis (i.e., step (i) in Scheme 1) To a stirred solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.4 mmol, 1.0 eq) in anhydrous DMF (2 mL), the substituted amine (1.5 eq), HATU (236 mg, 0.6 mmol, 1.2 eq), and DIPEA (217 μL, 1.24 mmol, 3.0 eq) were added, and the resulting mixture was stirred at room temperature for 14 hours. After completion, water was added to quench the reaction (monitored by TLC and LC-MS), and the mixture was extracted three times with 20 mL of ethyl acetate (siRNA). The combined organic layers were washed with brine solution (NaCl), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude reaction mixture. The mixture was purified by silica gel column chromatography using hexane-Â(100-0 to 0-100) (Teledyne ISCO CombiFlash system) to obtain the desired compound in moderate to good yield (63-88%).

[0206] General procedure for the Suzuki cross-coupling reaction (i.e., step (ii) in Scheme 1) A 10 mL microwave vial, equipped with a magnetic stirring rod and oven-dried, was charged with 1.0 eq of an aryl halide intermediate, 1.2 eq of boronic acid, 2.5 eq of Cs2CO3, and 0.1 eq of Pd(dppf)Cl2·CH2Cl2, followed by the addition of 1,4-dioxane-H2O (3:1, 4 mL). The vial was sealed with a microwave cap, purged with nitrogen for 25 minutes, and then irradiated under microwave conditions at 110°C for 1 hour. After the reaction was completed (monitored by TLC and LC-MS), the crude material containing unwanted catalyst was removed by filtration using Celite. The clear solution was extracted three times with 20 mL of ethyl acetate (siRNA), the combined organic layers were washed with brine (NaCl), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude reaction mixture. The Boc-protected compound was obtained by normal-phase silica gel column chromatography (Teledyne ISCO CombiFlash system) using CH2Cl2-MeOH (100-0 to 0-10) as the eluent. Furthermore, the Boc protection was removed by reacting it with TFA in CH2Cl2, and the compound was purified by reverse-phase column chromatography (Teledyne ISCO CombiFlash system) using the solvent CH3CN-H2O (0-90 to 95-5) to obtain the desired compound in 32-72% yield.

[0207] The following exemplary compounds were prepared according to the synthesis shown in Scheme 1.

[0208] N-methyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2574) TIFF2026517730000088.tif28128 Yield 57% (63 mg); pale yellow solid; TIFF2026517730000089.tif38145

[0209] N-phenyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2485) TIFF2026517730000090.tif28128 Yield 32% (40 mg); pale yellow solid; TIFF2026517730000091.tif45140

[0210] 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(p-trill)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2288) TIFF2026517730000092.tif28128 Yield 60% (27 mg); pale yellow solid; TIFF2026517730000093.tif45143

[0211] 3-(isoquinoline-4-yl)-N-(p-trill)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2325) TIFF2026517730000094.tif23128 Yield 63% (70 mg); pale yellow solid; TIFF2026517730000095.tif57145

[0212] N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2346) TIFF2026517730000096.tif29128 Yield 53% (46 mg); pale yellow solid; TIFF2026517730000097.tif51146

[0213] 3-(isoquinoline-4-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2347) TIFF2026517730000098.tif23128 Yield 69% (80 mg); White solid; TIFF2026517730000099.tif45143

[0214] 3-(pyridine-4-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2343) TIFF2026517730000100.tif23128 Yield 62% (46 mg); White solid; TIFF2026517730000101.tif38143

[0215] 3-(1H-indole-5-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2344) TIFF2026517730000102.tif28128 Yield 63% (29 mg); pale yellow solid; TIFF2026517730000103.tif50146

[0216] 3-(1H-indazole-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2426) TIFF2026517730000104.tif28128 Yield 36% (24 mg); pale yellow solid; TIFF2026517730000105.tif51147

[0217] 3-(2-aminopyrimidine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2387) TIFF2026517730000106.tif29128 Yield 48% (22 mg); pale yellow solid; TIFF2026517730000107.tif38145

[0218] N-(4-((methylamino)methyl)phenyl)-3-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2388) TIFF2026517730000108.tif40128 Yield 46% (30 mg); pale yellow solid; TIFF2026517730000109.tif51146

[0219] 3-(1-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2489) TIFF2026517730000110.tif31128 Yield 72% (50 mg); pale yellow solid; TIFF2026517730000111.tif51146

[0220] N-(4-((dimethylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2482) TIFF2026517730000112.tif29128 Yield 58% (96 mg); pale yellow solid; TIFF2026517730000113.tif51144

[0221] N-(4-(methylcarbamoyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide (CDD-2461) TIFF2026517730000114.tif29128 Yield 38% (21 mg); pale yellow solid; TIFF2026517730000115.tif43145

[0222] 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2483) TIFF2026517730000116.tif28128 Yield 49% (23 mg); pale yellow solid; TIFF2026517730000117.tif38145

[0223] N-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (CDD-2486) TIFF2026517730000118.tif29128 Yield 69% (87 mg); pale yellow solid; TIFF2026517730000119.tif45145

[0224] (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperidine-1-yl)methanone (CDD-2484) TIFF2026517730000120.tif28128 Yield 47% (50 mg); White solid; TIFF2026517730000121.tif45146

[0225] (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperazine-1-yl)methanone (CDD-2487) TIFF2026517730000122.tif29128 Yield 65% (87 mg); White solid; TIFF2026517730000123.tif38143

[0226] TIFF2026517730000124.tif26150 Reagents and conditions. (i) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), rt, 16 hours; (ii) a. (1H-pyrrolo[2,3-b]pyridine-5-yl)boronic acid, Cs2CO3, Pd(dppf)Cl2·CH2Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex), 1,4-dioxane-H2O (3:1), 110℃, 1 hour; b. Trifluoroacetic acid (TFA), CH2Cl2, rt, 4 hours.

[0227] General procedure for amide synthesis (i.e., step (i) in Scheme 2) To a stirred solution of substituted amine (100 mg, 0.4 mmol, 1.0 eq) in anhydrous DMF (2 mL), substituted acid (1.0 eq), HATU (193 mg, 0.5 mmol, 1.2 eq), and DIPEA (222 μL, 1.27 mmol, 3.0 eq) were added, and the resulting mixture was stirred at room temperature for 14 hours. After completion, water was added to quench the reaction (monitored by TLC and LC-MS), and the mixture was extracted three times with 20 mL of ethyl acetate (siRNA). The combined organic layers were washed with brine solution (NaCl), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude reaction mixture. This was purified by silica gel column chromatography using hexane-siRNA (100-0 to 0-100) (Teledyne ISCO CombiFlash system) to obtain the desired compound in moderate to good yield (69-90%).

[0228] General procedure for the Suzuki cross-coupling reaction (i.e., step (ii) in Scheme 2) A 10 mL microwave vial, oven-dried and equipped with a magnetic stirring rod, was charged with 1.0 eq of bromo intermediate (2s-2y), 1.2 eq of (1H-pyrrolo[2,3-b]pyridine-5-yl)boronic acid, 2.5 eq of Cs2CO3, and 0.1 eq of Pd(dppf)Cl2·CH2Cl2, followed by the addition of 1,4-dioxane-H2O (3:1, 4 mL). The vial was sealed with a microwave cap, purged with nitrogen for 25 minutes, and then irradiated under microwave conditions at 110°C for 1 hour. After the reaction was completed (monitored by TLC and LC-MS), the crude material containing unwanted catalyst was removed by filtration using Celite. The clear solution was extracted three times with 20 mL of ethyl acetate (Â), the combined organic layer was washed with brine solution (NaCl), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude reaction mixture. This was purified by normal-phase silica gel column chromatography (Teledyne ISCO CombiFlash system) using CH2Cl2-MeOH (100-0 to 0-10) as the eluent to obtain the Boc-protected compound. Furthermore, this was reacted with TFA in CH2Cl2 to remove the Boc protection, and purified by reverse-phase column chromatography (Teledyne ISCO CombiFlash system) using the solvent CH3CN-H2O (0-90 to 95-5) to obtain the desired compound in 46-82% yield.

[0229] The following exemplary compounds were prepared according to the synthesis shown in Scheme 2.

[0230] 1-(5-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyridine-3-yl)-N-(4((methylamino)methyl)phenyl)cyclopropane-1-carboxamide (CDD-2519) TIFF2026517730000125.tif23128 Yield 60% (80 mg); White solid; TIFF2026517730000126.tif50144

[0231] N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (CDD-2520) TIFF2026517730000127.tif27128 Yield 46% (91 mg); White solid; TIFF2026517730000128.tif45143

[0232] N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-6-carboxamide (CDD-2488) TIFF2026517730000129.tif29128 Yield 63% (87 mg); White solid; TIFF2026517730000130.tif51146

[0233] N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2575) TIFF2026517730000131.tif28128 Yield 82% (46 mg); Light brown solid; TIFF2026517730000132.tif45143

[0234] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzofuran-2-carboxamide (CDD-2855) TIFF2026517730000133.tif41128 Yield 45% (43 mg); White solid; TIFF2026517730000134.tif51144

[0235] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide (CDD-2856) TIFF2026517730000135.tif41128 Yield 49% (28 mg); White solid; TIFF2026517730000136.tif51145

[0236] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide (CDD-3016) TIFF2026517730000137.tif29128 Yield 36% (14 mg); White solid; TIFF2026517730000138.tif31146

[0237] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)thieno[2,3-c]pyridine-2-carboxamide (CDD-3111) TIFF2026517730000139.tif40128 Yield 29% (21 mg); White solid; TIFF2026517730000140.tif50144

[0238] TIFF2026517730000141.tif28151

[0239] General procedure for amide synthesis (i.e., step (i) in Scheme 3) A substituted amine (1.0 eq) was added to a stirred solution of substituted amine (1.0 eq) in anhydrous DMF (2 mL). Substituted acid (1.0 eq), HATU (1.2 eq), and DIPEA (3.0 eq) were added, and the resulting mixture was stirred at room temperature for 16 hours. After completion, water was added to quench the reaction (monitored by TLC and LC-MS), and the mixture was extracted three times with 20 mL of ethyl acetate (Â). The combined organic layers were washed with brine solution (NaCl), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude reaction mixture. This was purified by silica gel column chromatography (Teledyne ISCO CombiFlash system) using CH2Cl2-MeOH (100-0 to 0-10) to obtain the desired compound in moderate to good yield (72-84%).

[0240] General procedure for the Suzuki cross-coupling reaction (i.e., step (ii) in Scheme 3) A 10 mL microwave vial, equipped with a magnetic stirring rod and oven-dried, was charged with 1.0 eq of an aryl halide intermediate, 1.2 eq of boronic acid, 2.5 eq of Cs2CO3, and 0.1 eq of Pd(dppf)Cl2·CH2Cl2, followed by the addition of 1,4-dioxane-H2O (3:1, 4 mL). The vial was sealed with a microwave cap, purged with nitrogen for 25 minutes, and then irradiated under microwave conditions at 110°C for 1 hour. After the reaction was completed (monitored by TLC and LC-MS), the crude material containing unwanted catalyst was removed by filtration using Celite. The clear solution was extracted three times with 20 mL of ethyl acetate (siRNA), the combined organic layers were washed with brine (NaCl), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude reaction mixture. The mixture was purified by normal-phase silica gel column chromatography (Teledyne ISCO CombiFlash system) using CH2Cl2-MeOH (100-0 to 0-10) as the eluent to obtain the desired compound in a yield of 35-72%.

[0241] The following exemplary compounds were prepared according to the synthesis shown in Scheme 3.

[0242] N-methyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2627) TIFF2026517730000142.tif29128 Yield 73% (53 mg); Light brown solid; TIFF2026517730000143.tif38144

[0243] N-phenyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2631) TIFF2026517730000144.tif29128 Yield 64% (72 mg); White solid; TIFF2026517730000145.tif44145

[0244] N-(4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (6 CDD-2629) TIFF2026517730000146.tif28128 Yield 72% (48 mg); White solid; TIFF2026517730000147.tif45141

[0245] N-(4-Methoxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2490) TIFF2026517730000148.tif28128 Yield 70% (113 mg); White solid; TIFF2026517730000149.tif45144

[0246] N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2628) TIFF2026517730000150.tif28128 Yield 74% (146 mg); pale yellow solid; TIFF2026517730000151.tif51146

[0247] N-(4-methoxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2491) TIFF2026517730000152.tif34128 Yield 60% (98 mg); White solid; TIFF2026517730000153.tif58145

[0248] N-(4-methoxy-3-(morpholine-4-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2635) TIFF2026517730000154.tif34128 Yield 68% (138 mg); White solid; TIFF2026517730000155.tif58146

[0249] N-(4-Methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2636) TIFF2026517730000156.tif33128 Yield 72% (126 mg); White solid; TIFF2026517730000157.tif65146

[0250] N-(3-(dimethylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2632) TIFF2026517730000158.tif31128 Yield 60% (78 mg); pale yellow solid; TIFF2026517730000159.tif58144

[0251] N-(3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2630) TIFF2026517730000160.tif34128 Yield 75% (163 mg); pale yellow solid; TIFF2026517730000161.tif51144

[0252] N-(4-hydroxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2634) TIFF2026517730000162.tif34128 Yield 61% (16 mg); White solid; TIFF2026517730000163.tif45146

[0253] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2728) TIFF2026517730000164.tif31128 Yield 35% (27 mg); White solid; TIFF2026517730000165.tif51146

[0254] N-(3-(dimethylcarbamoyl)-4-methylphenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2729) TIFF2026517730000166.tif31128 Yield 58% (83 mg); White solid; TIFF2026517730000167.tif51143

[0255] N-(3-(dimethylcarbamoyl)-4-(trifluoromethyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2732) TIFF2026517730000168.tif31128 Yield 42% (31 mg); White solid; TIFF2026517730000169.tif51145

[0256] N-(3-(dimethylcarbamoyl)-4-fluorophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2730) TIFF2026517730000170.tif31128 Yield 45% (63 mg); White solid; TIFF2026517730000171.tif51143

[0257] N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2731) TIFF2026517730000172.tif31128 Yield 55% (43 mg); pale yellow solid; TIFF2026517730000173.tif51146

[0258] N-(3-(dimethylcarbamoyl)-4-(trifluoromethoxy)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2857) TIFF2026517730000174.tif31128 Yield 39% (24 mg); White solid; TIFF2026517730000175.tif45143

[0259] N-(3-carbamoylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2936) TIFF2026517730000176.tif29128 Yield 31% (35 mg); Brown solid; TIFF2026517730000177.tif51145

[0260] N-(3-(dimethylcarbamoyl)-5-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2937) TIFF2026517730000178.tif31128 Yield 42% (35 mg); White solid; TIFF2026517730000179.tif51144

[0261] N-(5-(dimethylcarbamoyl)-2-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-2938) TIFF2026517730000180.tif31128 Yield 41% (35 mg); White solid; TIFF2026517730000181.tif44146

[0262] 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carboxamide)-N,N-dimethylpicolinamide (CDD-3012) TIFF2026517730000182.tif31128 Yield 50% (23 mg); White solid; TIFF2026517730000183.tif45146

[0263] N-(4-hydroxy-3-(pyrroridine-1-carbonyl)phenyl)-4-(1H-pyrrorol[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3013) TIFF2026517730000184.tif32128 Yield 46% (30 mg); Brown solid; TIFF2026517730000185.tif51145

[0264] N-(3-(azetidine-1-carbonyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3014) TIFF2026517730000186.tif31128 Yield 32% (3.5 mg); Light brown solid; TIFF2026517730000187.tif51145

[0265] N-(pyrimidine-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3015) TIFF2026517730000188.tif29128 Yield 58% (65 mg); White solid; TIFF2026517730000189.tif44142

[0266] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3017) TIFF2026517730000190.tif28128 Yield 50% (40 mg); White solid; TIFF2026517730000191.tif51144

[0267] N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3018) TIFF2026517730000192.tif29128 Yield 60% (46 mg); White solid; TIFF2026517730000193.tif50144

[0268] N-(2-(dimethylamino)ethyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3085) TIFF2026517730000194.tif28128 Yield 54% (53 mg); White solid; TIFF2026517730000195.tif45143

[0269] N-(3-((2-(dimethylamino)ethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3086) TIFF2026517730000196.tif31128 Yield 43% (46 mg); White solid; TIFF2026517730000197.tif57143

[0270] N-(4-hydroxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3087) TIFF2026517730000198.tif31128 Yield 35% (38 mg); White solid; TIFF2026517730000199.tif51145

[0271] N-(4-hydroxy-3-(oxetane-3-ylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3112) TIFF2026517730000200.tif31128 Yield 15% (10 mg); White solid; TIFF2026517730000201.tif38144

[0272] N-(3-((cyclopropylmethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3113) TIFF2026517730000202.tif31128 Yield 15% (14 mg); White solid; TIFF2026517730000203.tif51145

[0273] N-(3-oxoisoindoline-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3115) TIFF2026517730000204.tif29128 Yield 34% (60 mg); White solid; TIFF2026517730000205.tif38143

[0274] 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carbonyl)-1-phenylpiperazine-2-one (CDD-3116) TIFF2026517730000206.tif25128 Yield 43% (70 mg); White solid; TIFF2026517730000207.tif51145

[0275] N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide (CDD-3117) TIFF2026517730000208.tif34128 Yield 50% (65 mg); White solid; TIFF2026517730000209.tif51145

[0276] N-(3-cyano-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamidomide (carboxyamidemide) (CDD-3126) TIFF2026517730000210.tif29128 Yield 35% (28 mg); White solid; TIFF2026517730000211.tif51145

[0277] Example 3: Confirmation of off-DNA synthesis and JNK inhibitory activity The activity of four compounds from qDOS21 and five compounds from qDOS28_1 was synthesized "off-DNA" and tested using a JNK enzyme assay. These nine compounds represent common structural elements that emerged from DEC-Tec selection with good binding inhibitory activity.

[0278] The next step was to confirm that compounds that bind to JNK1, JNK2, or JNK3 in a competitive manner with bentamapimod are inhibitors of ATP-dependent kinase activity in the assay. In many cases, the results have been reproduced in ThermoFisher using its SelectScreen technology platform. Based on knowledge of JNK inhibitors and the results of DEC-Tec selection, a target compound profile was developed (Table 2).

[0279] (Table 2) K between BEND and TANZ d Preliminary target compound profiles for next-generation JNK inhibitors based on selection results (TCP;IC 50 nM) TIFF2026517730000212.tif35146

[0280] Example 4: Kinase and Binding Assay JNK1, JNK2, and JNK3 hydrolyze ATP to ADP even without a peptide substrate. This allows for a highly robust and rapid endpoint assay using the Kinase-Glo assay kit (V6711) from Promega to measure residual ATP concentration (BMG ClarioStar Plus plate reader). The luminescence signal produced by the catalytic conversion of firefly luciferin to oxyluciferin by luciferase is measured. Since a kinase-free assay is always included, potential luciferase inhibition (i.e., false negatives) is easily detected, and even if there is less ATP than present in this control reaction, it may indicate luciferase inhibition, but this can be ruled out by counterscreening using luciferase alone. Peptide substrate-independent luminescence assays for measuring endogenous ATPase activity have been established as reliable indicators of catalytic kinase activity.

[0281] To minimize violations of the linear initial rate principle, which are problematic in endpoint assays when performing dose-response studies, enzyme concentrations were carefully optimized within a total assay volume of 25 μL. The assay was performed in a white 384-well plate using 10 μM ATP, 0.02% Tween-20, and kinase buffer (#9802) from Cell Signaling. Kinase reactions were carried out at 30°C for 30 or 60 minutes, and residual ATP was detected according to the Promega protocol. ADP concentrations were calculated from controls that contained no kinase. Fractional activity was obtained from normalized data. The apparent K of the inhibitor was determined without assuming a specific mode of inhibition using nonlinear regression (GraphPad Prism7) and a modified Morrison equation for tight binding. i The values ​​were determined. An orthogonal coupling assay (LanthaScreen) was commissioned to ThermoFisher Scientific's SelectScreen Services for IC. 50 The value was determined.

[0282] Results for compounds synthesized and identified as being concentrated for validation of the qDOS18_2 results are provided herein (Tables 3a-3b). From this library, lower-priority compounds did not exhibit comparable activity to bentamapimod (CDD-939) or tandicertib (CDD-985).

[0283] (Table 3a) K for JNK1, JNK2, and JNK3 of compounds identified in the qDOS21 and qDOS28 libraries d (nM) value TIFF2026517730000213.tif69146TIFF2026517730000214.tif220146TIFF2026517730000215.tif138146

[0284] (Table 3b) Ki(app) values ​​of JNK inhibitors (CDD-939 and CDD-985) and compounds identified in the qDOS11 and qDOS21 libraries TIFF2026517730000216.tif42146

[0285] Example 5: Optimization of JNK inhibitor JNK inhibitors have been optimized to achieve high affinity for the JNK enzyme while simultaneously meeting isoform selectivity criteria, exhibiting high selectivity among unrelated kinases. The efficacy and selectivity of BEND and TANZ were used to define a realistic preliminary target compound profile for next-generation JNK1-3 inhibitors for endometriosis treatment (Table 2). BEND and TANZ were evaluated using Eurofins KINOMEscan® and KdSelect® assays (Figure 5 and Table 2). Presentation of results in Treespot dendrograms (Eurofins) provides a comprehensive visual understanding of the selectivity of BEND and TANZ over staurosporine (non-selective).

[0286] Using results from a series of Eurofins evaluations, we revised the medicinal chemistry goals and strategies for the synthesis of next-generation JNK inhibitors. KINOMEscan results showed that BEND was highly selective for the 480 kinases tested, but less potent than desired against JNK1-3 (Table 2, Figure 5). While TANZ's JNK-2 and JNK-3 inhibition constants were sufficient (Table 2; Figure 5), TANZ's K for JNK1 was... d This is not optimal. An unbalanced inhibition of JNK1 / JNK2 has been suggested as one of the reasons for the discontinuation of clinical development of TANZ.

[0287] CDD-2346 was one of the earliest compounds to exhibit good enzymatic activity against JNK1 and JNK3. KINOMEscan was performed on CDD-2346 to determine whether the selectivity of this chemical scaffold was satisfactory or required optimization. The results from KINOMEscan suggested that CDD-2346 had insufficient selectivity and required optimization (Figures 6A–6D). To confirm that the activity against each kinase was accurate and not false-positive, CDD-2346 was evaluated using kinase assays on the ThermoFisher SelectScreen platform. The results from these assays are provided herein (Table 4). The key and innovative steps described are the optimization of selectivity for a) JNK isoforms, b) kinases considered "intra-pathway," and c) kinases considered "extra-pathway."

[0288] (Table 4) Kinase selectivity of exemplary JNK inhibitors d (nM) profile TIFF2026517730000217.tif117146

[0289] The activity of the hit compound CDD-2346 did not meet the selectivity criteria. The importance of disclosing the lack of selectivity of CDD-2346 for JNK1-JNK3 isoforms and other kinases lies in demonstrating the intentional processes applied in this discovery effort to create selectivity among JNK inhibitors. Another discovery group has pursued strategies to identify compounds that are "panspecific" JNK inhibitors or compounds that inhibit only JNK3. While we do not wish to be limited by any theory, both of these strategies would not meet the target product profile of affecting the peripheral inflammatory components of disease and the central nervous system components of pain perception.

[0290] As seen as part of the hit optimization process described herein, CDD-2491 showed significantly improved selectivity for unrelated kinases, but failed to establish the desired selectivity for JNK1, JNK2, and JNK3. Continued optimization of the JNK inhibitor yielded CDD-2728, an inhibitor that satisfied the criteria for potency and selectivity (Figures 7A-7C).

[0291] The results demonstrate the improved selectivity of CDD-2728 achieved through optimization of the JNK inhibitor, as demonstrated on the KINOMEscan platform (Eurofins), which identified a significant improvement in selectivity for JNK subgroups compared to CDD-2346. No activity of CDD-2728 was detected against atypical, mutant, or lipid kinases. To confirm the inhibitory effects of CDD-2728 in KINOMEscan analysis, individual binding assays were performed using ThermoFisher SelectScreen against kinases bound to CDD-2728. Results from these confirmatory assays demonstrated a 7-fold selectivity for "intra-pathway" targets and a selectivity of over 500-fold for five of the "extra-pathway" kinase targets (Table 5).

[0292] (Table 5) Inhibition of JNK1, JNK2, JNK3, ERK1 / 2, MEK4, CLK2 / 3, CSNK1D, CSNK1E, and CSNK1G1 by CDD-2728 (nM, K d ) TIFF2026517730000218.tif28146

[0293] (Table 6) Selectivity ratio (SR) of CDD-2728 for JNK1 inhibition in "intra-pathway" and "extra-pathway" (Kd = 1.0 nM for JNK1) TIFF2026517730000219.tif35146 a Off-route; b Within the route

[0294] (Table 7) JNK1 IC 50 (μM) NanoBRET cell data TIFF2026517730000220.tif51146

[0295] The definition of "intra-pathway" was based on the published signaling pathways for JNK shown in Figures 11 and 12A-12J. These figures are consistent with the current interpretation that MEK4 (i.e., MKK4) activity is the primary upstream kinase for phosphorylating JNK isoforms, and MEK1 (i.e., MKK1) is the primary upstream kinase for phosphorylating ERK1 / 2 activity. ERK1 / 2 activity in this case is considered "opportunistic" given the demonstrated relevance of the MEK / ERK pathway in endometriosis and the fact that ERK1 / 2 belongs to the same MAPK family as JNK. These results position CDD-2728 as the first inhibitor of its kind that inhibits the preferred target pathways (i.e., JNK1-3 and MEK4) but only minimally inhibits ERK1 / 2, which is also known to be relevant in models of inflammation and infiltration.

[0296] This selectivity profile distinguishes CDD-2728 from several other MEK inhibitors that lack selectivity among multiple MEK isoforms. While the figures included herein indicate that MEK4 is an upstream kinase for phosphorylation of the NF-Kappa B pathway, there is little evidence to support this, or that it is a kinase associated with growth or proliferation (e.g., mTOR, Akt, and PI3K). CDD-2728 is far more selective than pazopanib among the MEK family kinases and represents a selective JNK and MEK4 inhibitor, exhibiting low activity against JNK2 but unique selectivity against JNK1 and JNK3, as defined for this target compound profile.

[0297] Of the 192 assays, only JNK1, JNK2, and JNK3 were inhibited by CDD-3013 at a concentration of 1 μM (MEK4 was not one of the 192 kinases evaluated by the NanoBRET assay) (Table 8).

[0298] (Table 8) Kinase inhibition profile of CDD-3013 at 1 μM TIFF2026517730000221.tif117146

[0299] Example 6: Demonstration of therapeutic opportunities of CDD-JNK inhibitors in cell assays The unique selectivity profile of the compounds disclosed herein allows the compounds (e.g., CDD-2728) to effectively disrupt the MEK4 / JNK pathway while avoiding overlapping selectivity for the MEK1 / 2, MEK3 / 6, and MEK5 pathways and their downstream targets. Compounds with this profile were not previously available, enabling better therapeutic control of the MEK4 / JNK pathway, which is associated with apoptosis, inflammation, and interference with cell differentiation and proliferation, including endometriotic lesions.

[0300] The results provided herein demonstrate that several JNK inhibitors synthesized to date are cell-permeable and potent with respect to endometriosis-related endpoints. Among the JNK inhibitors synthesized early in the drug discovery process, CDD-2346 was superior to staurosporine in inhibiting binding to JNK1, JNK2, and JNK3 in the Promega NanoBRET® targeted engagement intracellular kinase assay (Table 9).

[0301] (Table 9) IC2578 50 value TIFF2026517730000222.tif103146TIFF2026517730000223.tif172146

[0302] In this assay configuration, bentamapimod interferes with the tracer's assay reading via the cyano group of bentamapimod, and staurosporine is used as a reference control. IC of the various compounds described herein 50 The values ​​are summarized in Table 9. Optimization of JNK inhibitors is for JNK1 NanoBRET IC 50 This improved the binding rate by 8.5 times (CDD-2346 / CDD-2728). CDD-2731 and CDD-3013 show better cell-permeable binding to JNK1 in the NanoBRET assay, but these compounds are rapidly metabolized within liver microsomes.

[0303] These studies demonstrate that the NanoBRET assay is an innovative technological platform for measuring targeted binding of CDD JNK inhibitors to target JNK1, JNK2, or JNK3. As further evidence that JNK inhibitors address disease-related endpoints, we hereby provide the biological responses to JNK inhibitors measured in target tissue cell models. 12Z immortalized endometriosis epithelial cells and patient-derived endometriosis stromal cells were cultured with the reference compounds bentamapimod, CDD-2628, and CDD-2728. To illustrate the effects of CDD-2628 and CDD-2728 in endometrial cell cultures, gene expression reflecting inflammatory lipid synthesis (PTGS2), transformation into cells with higher migratory and invasive capabilities (MMP-3), and chemoattractant cytokines (IL-6, IL-8) that recruit pro-inflammatory immune cells was measured using qPCR (expressed as a change ratio compared to GAPDH, a housekeeping gene unaffected by culture treatment effects).

[0304] In the culture systems used in Figures 12A–12J, 13A–13B, 14A–14H, 15A–15H, and 16A–16F, cell treatment with IL-1β is employed to mimic the intraperitoneal environment in patients with endometriosis, where IL-1β is most frequently measured at higher concentrations (0.1 ng / mL–1 ng / mL) compared to women without the disease (<0.01 ng / mL). The use of IL-1β to mimic a pro-inflammatory environment is a common method in cell assays for endometriosis research. Although IL-1β concentrations in these cell cultures are higher than those measured in ascites fluid, ascites fluid contains several other pro-inflammatory cytokines that contribute to a pro-inflammatory environment.

[0305] Specifically, 12Z cells are placed in a 12-well tissue culture plate at a rate of 1 × 10⁶ 5Cells were seeded at a cell / well density, serum-starved overnight (17-18 hours), pre-treated with a vehicle (DMSO) or a JNK inhibitor for 30 minutes, and then stimulated with 10 ng / ml IL-1β for 6 hours in or without the JNK inhibitor. After 6 hours of treatment, mRNA was extracted from the cells using a Qiagen RNEasy mini-isolation kit, and 1 μg of mRNA was reverse transcribed to cDNA using qScript cDNA Supermix (Quanta Biosciences). The cDNA was amplified by quantitative real-time PCR (BioRad CFX) and SYBR Green Master Mix (Applied Biosystems) using pre-designed and validated primers (BioRad) specific to the genes encoding IL6, IL8, PTGS2 / COX2, and MMP3. The relative quantification of these specific genes was calculated by the ΔΔCt method, normalizing their abundance relative to the internal housekeeping gene GAPDH and then quantifying them against vehicle-treated cells. Statistical analysis and visualization were performed using one-way ANOVA with Tukey's multiple comparison post-hoc test on GraphPad Prism version 9.

[0306] Bentamapimod and CDD-2628 have similar effects on IL-6 and PTGS2 production, causing a concentration-dependent decrease in IL-6 and PTGS2 expression over a concentration range of 5–25 μM. The concentrations of IL-1β added to these cultures were very high, and these results indicate that CDD-2628 is effective in suppressing this inflammatory invasion of tissue in the presence of this extreme inflammatory environment. CDD-2628 suppresses IL-8 and MMP-3 expression more effectively than bentamapimod. These results suggest that CDD-2628, a representative inhibitor of the CDD JNK inhibitor series, may be more effective in suppressing epithelial-mesenchymal transition (MMP-3) and neutrophil recruitment to inflammatory sites (IL-8). These results also suggest that CDD-2628 and bentamapimod may have comparable abilities in suppressing macrophage and monocyte recruitment (IL-6, PTGS2) to lesions. Additional examples of the ability of CDD-JNK inhibitors to suppress EMT compared to bentamapimod are also exemplified by CDD-2575 and CDD-2634.

[0307] As a further example of the usefulness of CDD JNK inhibitors, 12Z endometriosis epithelial cells were cultured in the presence of IL-1β and CDD-2728. In this in vitro model of inflammation induced by IL-1β against endometriosis epithelial cells, CDD-2728 significantly and effectively suppressed IL-8 production more effectively than bentamapimod. CDD-2728 was also more effective than bentamapimod in suppressing the expression of MMP-3 and PTGS2. In this experiment, CDD-2728 and bentamapimod were equally effective in suppressing IL-6 expression.

[0308] Another target tissue for JNK inhibitors in the treatment of endometriosis is endometriotic stromal cells. To further illustrate the relevance of the discovery of novel JNK inhibitors for endometriosis, stromal cells obtained from endometriotic lesions of patients with endometriosis were cultured. The reference identifier for this patient is Eosis50. These cells represent stromal cells from ovarian endometriomas. As with the culture systems described elsewhere herein, the inflammatory environment of peritoneal endometriosis was mimicked by the addition of IL-1β, and either bentamapimod or CDD-2728 was added to these stromal cell cultures at increasing concentrations. Specifically, cells were cultured in groups of approximately 2 × 10⁶ cells. 5 Cells were cultured at cell / well density, serum-starved for 17-18 hours, pre-treated with a JNK inhibitor for 30 minutes, and then stimulated with 10 ng / ml IL-1β for 6 hours in or without the JNK inhibitor. After 6 hours, mRNA was extracted, reverse transcribed using qScript cDNA supermix, and amplified using specific pre-designed and validated primers (IL6, IL8, MMP3, and PTGS2). These results demonstrate the superior efficacy and potency of CDD-2728 compared to bentapimod for suppressing the expression of inflammatory mediators.

[0309] To confirm and further corroborate the results described herein, endometriosis stromal cell cultures were established from a second patient. For compliance purposes, this series of cell culture results is identified as Eosis143. These are stromal cells obtained from the inner lining of the ovarian endometrioma cyst wall. Similar to the findings reported above, CDD-2728 was superior to bentapimod in its inhibitory effects on IL-6, PTGS2, IL-8, and MMP-3 and in its ability to achieve inhibition.

[0310] To determine whether the responses observed in endometriosis epithelial cells and endometriosis stromal cell cultures were cytotoxic, cell viability was measured in HepG2 cells. The results highlighted CDD-2575's reduction of cellular ATP consumption as one measure of cytotoxicity. CDD-2575 was effective, but showed clear cytotoxicity at concentrations lower than those required to inhibit cytokine expression in epithelial or stromal cells. On the other hand, neither CDD-2624 nor CDD-2728 had a significant effect on ATP consumption up to a concentration of 75 μM.

[0311] The target product profile requires the delivery of JNK inhibitors as once-daily oral doses. To prioritize compounds for further development, the in vitro metabolism of several CDD JNK inhibitors was determined to estimate the plasma half-lives and metabolic rates of the compounds in vivo. The results from the compound panel are shown in Table 10. Of the optimized compounds in this list, CDD-2728 showed the highest potential to meet the TCP target (i.e., once-daily oral dose) for in vivo PK parameters.

[0312] (Table 10) Selected pharmacokinetic data for specific exemplary compounds TIFF2026517730000224.tif78146TIFF2026517730000225.tif223146TIFF2026517730000226.tif91146

[0313] Based on the stability and estimated half-life of the compound exposed to liver microsomes in vitro, CDD-2728 was selected for PK evaluation. Similar to the in vitro metabolic prediction, the half-life of CDD-2728 was predicted to be 85.2 minutes (1 hour 25 minutes), which was reasonably close to the result obtained by in vivo PK (1 hour 30 minutes). To avoid first-pass metabolism, CDD-2728 was also injected intraperitoneally, extending the half-life of CDD-2728 to 14 hours, although the absorption of the compound may have been affected by the solubility of the compound in the peritoneal cavity.

[0314] (Table 11) Exemplary pharmacokinetic data for orally administered CDD-2728 TIFF2026517730000227.tif62146

[0315] (Table 12) Plasma ALT and AST levels after oral administration of CDD-2728 (24 hours after administration) TIFF2026517730000228.tif49146

[0316] (Table 13) Exemplary pharmacokinetic data for CDD-2728 administered intraperitoneally TIFF2026517730000229.tif62146

[0317] (Table 14) Plasma ALT and AST levels after intraperitoneal administration of CDD-2728 (24 hours after administration) TIFF2026517730000230.tif28146

[0318] (Table 15) Intrinsic metabolic clearance rates in mouse liver microsomes (MLMs) and human liver microsomes (HLMs) TIFF2026517730000231.tif28146

[0319] (Table 16) Predicted half-life in mouse and human plasma based on the unique properties of CDD-3013 TIFF2026517730000232.tif21146

[0320] Example 7: Identification and evaluation of JNK inhibitors including piperazine-based scaffolds Histidine-tagged recombinant human full-length JNK1 / JNK3 (Eurofins, USA) was used for selection of stereochemically diverse piperazine-derived DECLs. Paired affinity selection was performed, with one containing 0.3 μM JNK and the other serving as a protein-free non-targeted control, to identify non-protein-specific enrichment. DEL molecules with affinity for JNK1 / JNK3 were retained using polyhistidine-bound nickel nitrilotriacetate (Ni-NTA) magnetic beads. Illumina next-generation sequencing and informatics analysis enabled decoding of isolated DNA barcode sequences, allowing for the identification of the structures of enriched drug-like compounds. The enrichment of bound compounds was measured using a normalized Z-score index. Comparison of normalized enrichment levels of library members in the dataset highlighted compound series shown in Figure 18, where reasonable structure-enrichment relationships suggest promising chemical series for further investigation.

[0321] Based on the experiment shown in Figure 18, the estimated dose at which CDD-3013 causes cytotoxicity is greater than 100 μM (i.e., 138.4 μM). For comparison, the IC50 of CDD-xx07 for inducing a cytotoxic response... 50 The concentrations are 48 μM for CDD-xx10, 34 μM for CDD-xx10, and 72 μM for CDD-xx30. This indicates that a 138-fold safety margin can be obtained at cell culture and plasma concentrations of 1 μM, and a 13.8-fold safety margin is expected at a plasma concentration of 10 μM for CDD-3013. These results suggest that plasma concentrations exceeding 10 μM may be acceptable before adverse effects are observed.

[0322] In this affinity selection, scaffolds derived from ornithine amino acids demonstrated a good structural-enrichment correlation (SER). Interestingly, one enantiomer was enriched better than the other. The selectivity identified between the enantiomers for JNK1 on DNA was subsequently confirmed using off-DNA synthesis, following the same synthetic sequence used in the DEL build.

[0323] In off-DNA chemosynthesis, selected chemical features were replaced and / or modified, including substitution of DNA binding sites with methylamides. To evaluate chirality-driven enrichment from selected experiments, compounds CDD-1723, CDD-2010, CDD-1722, CDD-272, and the enantiomer CDD-2009 were synthesized.

[0324] In certain embodiments, the compound of formula (II) (i.e., piperazine compounds) can be prepared according to the synthesis described in Scheme 4. TIFF2026517730000233.tif144151

[0325] In certain embodiments, compound 4-1 can be alkylated with haloacetate 4-2 to obtain compound 4-3, which can then be deprotected with a suitable acid (e.g., TFA) and subsequently treated with an amine to obtain amide 4-4. Compound 4-4 can be denosylated and subsequently coupled with amine 4-5 to obtain 4-6 (i.e., CDD-2010). Compound 4-6 can be reduced and aminated with aldehyde 4-7 to obtain compound 4-8 (CDD-1723). Alternatively, after denosylation, compound 4-4 can be reduced and aminated with aldehyde 4-7 to obtain compound 4-9 (i.e., CDD-1722).

[0326] When selecting exemplary compounds were evaluated for JNK1 inhibition, compound CDD-1723 showed good JNK1 inhibition, while the enantiomer compound (CDD-2009) showed 20-fold lower activity.

[0327] Numbered form The following exemplary embodiments are provided, but their numbering should not be interpreted as indicating importance.

[0328] Embodiment 1 provides the following: Compounds of formula (I), or their salts, solvates, stereoisomers, or isotopologs: TIFF2026517730000234.tif16128In formula, R 1a These are C1-C6 alkyl, phenyl, and C2-C 10 Selected from the group consisting of heteroaryls, where alkyl, phenyl, or heteroaryl may be substituted with C1-C6 alkyl, halogen, CN, NO2, OR A , N(R A )(R B ), C(=O)OR A , C(=O)N(R A )(R B ), S(=O)2N(R A )(R B ), S(=O)N(R A )(R B ), OCR A , and N(R A )C(=O)R B It may be substituted with at least one substituent selected from the group consisting of; R 1b This is selected from the group consisting of H and optionally substituted C1-C6 alkyl groups, or R 1a and R 1b These can combine with the nitrogen atom to which they are bonded to form substituted C2-C8 heterocycloalkyl groups; R 2 These are C2-C9 heteroaryls which may be substituted and C6-C which may be substituted. 10 Selected from the group consisting of aryls; L 1 teeth, Selected from the group consisting of TIFF2026517730000235.tif77128; R 3a , R 3b , R 3c , and R 3d These are, independently, H, a C1-C6 alkyl group which may be substituted, a halogen, CN, NO2, OR C , N(R C )(R D ), C(=O)OR C, C(=O)N(R C )(R D ), S(=O)2N(R C )(R D ), S(=O)N(R C )(R D ), OCR C , and N(R C )C(=O)R D Selected from the group consisting of; Y is selected from the group consisting of optionally substituted C1-C3 alkylenyls and optionally substituted C3-C8 cycloalkylenyls; R A , R B , R C , and R D If present, each independently comprises H, an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted C2-C6 heterocycloalkyl group, and an optionally substituted C7-C6 group. 12 Aralkyl, may be substituted C6~C 10 Aryl and possibly substituted C2-C 12 Selected from the group consisting of heteroaryls, Here, R A and R B or R C and R D These can combine with the nitrogen atoms to which they are bonded to form substituted C2-C8 heterocycloalkyl groups. Here, R A and R B One or more of these can combine with L to form a C4-C8 heterocycloalkyl or C4-C6 heteroaryl, which may be substituted. Embodiment 2 is, A compound according to Embodiment 1, selected from the group consisting of TIFF2026517730000236.tif78142. To provide. Embodiment 3 is, R 1aHowever, C1-C6 alkyl, C1-C6 haloalkyl, F, OH, CN, O(C1-C6 alkyl), O(C1-C6 haloalkyl), -(CH2) 1~3 NH(C1~C6 alkyl), -(CH2) 1~3 A compound of embodiment 1 or 2, which is a phenyl, pyridinyl, or pyrimidinyl compound substituted with at least one substituent selected from the group consisting of N(C1~C6 alkyl)-2, C(=O)NH2, C(=O)NH(C1~C6 alkyl), C(=O)N(C1~C6 alkyl)2, and C(=O) (which may be substituted C2~C8 heterocycloalkyl). To provide. Appearance 4 is, R 1a The compound is a phenyl, pyridinyl, or pyrimidinyl compound substituted with at least one substituent selected from the group consisting of CH3, CF3, OH, OCH3, OCF3, F, CN, CH2NHCH3, CH2N(CH3)2, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2, C(=O)(azetidinyl), C(=O)NH(oxyranyl), C(=O)(piperidinyl), C(=O)(4-methylpiperazinyl), C(=O)(morpholinyl), and C(=O)NH(cyclopropylmethyl), which is any one compound from Embodiments 1 to 3. To provide. Embodiment 5 is, R 1a but, One compound selected from the group consisting of TIFF2026517730000237.tif169144, which is one of embodiments 1 to 4. To provide. Embodiment 6 is, R 1a The compound of embodiment 1 or 2, which is a C1-C6 alkyl group that may be substituted. To provide. Embodiment 7 is, R 1a However, the compound of embodiment 6 is selected from the group consisting of methyl and CH2CH2N(CH3)2. To provide. Embodiment 8 is, R 1a and R1b However, when they combine with the nitrogen atoms to which they are bonded, Compounds of embodiment 1 or 2 that form TIFF2026517730000238.tif15128 To provide. Embodiment 9 is, R 1b However, one compound from any one of embodiments 1 to 7, wherein H is present. To provide. Embodiment 10 is, R 2 but, One compound selected from the group consisting of TIFF2026517730000239.tif20164, which is one of embodiments 1 to 9. To provide. Embodiment 11 is, At least one of the following: (a)R 3a , R 3b , R 3c , and R 3d At least one of them is H; (b)R 3a , R 3b , R 3c , and R 3d At least two of them are H; (c)R 3a , R 3b , R 3c , and R 3d At least three of them are H; and (d)R 3a , R 3b , R 3c , and R 3d Each of them is H The compound that corresponds to any one of embodiments 1 to 10 To provide. Embodiment 12 is, N-methyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(isoquinoline-4-yl)-N-(p-tolyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(isoquinoline-4-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)imidazo[1,2-a]pyridine-6-carboxamide; N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 3-(2-aminopyrimidine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((dimethylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide; N-(4-(methylcarbamoyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide; N-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-methoxy-3-(morpholine-4-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-hydroxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzofuran-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-(trifluoromethoxy)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-carbamoylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-5-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(5-(dimethylcarbamoyl)-2-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carboxamide)-N,N-dimethylpicolinamide; N-(4-hydroxy-3-(pyrroridine-1-carbonyl)phenyl)-4-(1H-pyrrorol[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(azetidine-1-carbonyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(pyrimidine-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(2-(dimethylamino)ethyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-((2-(dimethylamino)ethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-hydroxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)thieno[2,3-c]pyridine-2-carboxamide; N-(4-hydroxy-3-(oxetane-3-ylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-((cyclopropylmethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-oxoisoindolin-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carbonyl)-1-phenylpiperazine-2-one; N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-cyano-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-phenyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(p-trill)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(pyridine-4-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-indole-5-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-indazole-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperidine-1-yl)methanone; (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperazine-1-yl)methanone; 1-(5-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyridine-3-yl)-N-(4 ((methylamino)methyl)phenyl)cyclopropane-1-carboxamide; N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide; N-methyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-phenyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-(trifluoromethyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; and N-(3-(dimethylcarbamoyl)-4-fluorophenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide A compound selected from the group consisting of any one of embodiments 1 to 11 To provide. Embodiment 13 provides the following: Compounds of formula (II), or their salts, solvates, stereoisomers, or isotopologs: TIFF2026517730000240.tif24128In formula, R 4 This includes H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 heterocycloalkyl, and optionally substituted C7-C 12 Aralkyl, may be substituted C3~C 12 Heteroaralkyl, may be substituted C6~C 10 Aryl and possibly substituted C2-C 12 Selected from the group consisting of heteroaryls; R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f These are, independently, H, a C1-C6 alkyl group which may be substituted, a halogen, OR E , and N(R E )(R F Selected from the group consisting of; R 6 is, -(CH2) 1~3 C(=O)N(R G )(R H ) and; R 7a H and C(=O)OR I Selected from the group consisting of; R 7b H is; X is OR J and Selected from the group consisting of TIFF2026517730000241.tif15128; G may be substituted with C1-C6 alkyl and -Z 1 -N(R 7a )(R 7b Selected from the group consisting of; Z 1 and Z 2 Each of these is independently a -(may be substituted C1-C6 alkylenyl)-; R 8 This is selected from the group consisting of H and optionally substituted C1-C6 alkyl groups; R 9a and R 9b Each is independently selected from the group consisting of H and optionally substituted C1-C6 alkyl groups; R 10a and R 10b These are, independently, H, an optionally substituted C1-C6 alkyl group, and an optionally substituted C6-C6 alkyl group. 10 Selected from the group consisting of aryls; n is an integer selected from the group consisting of 1, 2, 3, 4, and 5; and R E , R F , R G , R H , R I , and R J These are, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heterocycloalkyl, and optionally substituted C7-C 12 Aralkyl, may be substituted C6~C 10 Aryl and possibly substituted C2-C 12Selected from the group consisting of heteroaryls. Embodiment 14 is, R 4 However, H and Compound of Embodiment 13, selected from the group consisting of TIFF2026517730000242.tif16128 To provide. Embodiment 15 is, At least one of the following: (a)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least one of them is H; (b)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least two of them are H; (c)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least three of them are H; (d)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least four of them are H; (e)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least five of them are H; and (f)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f Each of them is H Compounds of embodiment 13 or 14 to which the above applies To provide. Embodiment 16 is, R 6 However, one of the compounds in any of embodiments 13 to 15 is -CH2C(=O)NHCH3 To provide. Embodiment 17 is, A compound from any one of embodiments 13 to 16, wherein G is CH3. To provide. Embodiment 18 is, G, -Z 1 -N(R 7a )(R 7b ) one compound from any one of embodiments 13 to 16 To provide. Embodiment 19 is, R 7a However, H and A compound selected from the group consisting of TIFF2026517730000243.tif16128, one of any of embodiments 13-16 and 18. To provide. Appearance 20 is, R 7b However, one compound from any of embodiments 13-16 and 18-19 is H. To provide. Embodiment 21 is, X is a compound from any one of embodiments 13 to 20, wherein X is OEt. To provide. Embodiment 22 is, X One compound from any of embodiments 13 to 20, which is TIFF2026517730000244.tif15128 To provide. Embodiment 23 is, R 9a and R 9b Each occurrence of is independently H, one of the compounds in embodiments 13-20 and 22 To provide. Embodiment 24 is, One compound from any of embodiments 13-20 and 22-23, wherein n is 3. To provide. Embodiment 25 is, R10a and R 10b However, each is independently selected from the group consisting of 4-fluorophenyl and methyl, one of any of the compounds in embodiments 13-20 and 22-23. To provide. Embodiment 26 is, X One compound from any of embodiments 13-20 and 22-25, which is TIFF2026517730000245.tif16128 To provide. Embodiment 27 is, Z 1 However, one compound from any one of embodiments 13 to 26 is -CH2CH2CH2- To provide. Embodiment 28 is, Z 2 However, one compound from any one of embodiments 13 to 27 is -CH2- To provide. Appearance 29 is, (2-((2R,6R)-6-(2-((3-((4-fluorophenyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)-4-(pyrazolo[1,5-a]pyridine-7-ylmethyl)piperazine-2-yl)ethyl)benzyl carbamate; 2-((2R,6R)-6-(2-(((benzyloxy)carbonyl)amino)ethyl)-1-(2-(methylamino)-2-oxoethyl)-4-(pyrazolo[1,5-a]pyridine-7-ylmethyl)piperazine-2-yl)ethyl acetate; (2-((2R,6R)-6-(2-((3-((4-fluorophenyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)piperazine-2-yl)ethyl)benzyl carbamate; N-(3-((4-fluorophenyl)(methyl)amino)propyl)-2-((2R,6R)-6-methyl-1-(2-(methylamino)-2-oxoethyl)piperazine-2-yl)acetamide A compound selected from the group consisting of any one of embodiments 13 to 28 To provide. Embodiment 30 is, A pharmaceutical composition comprising at least one compound from any one of embodiments 1 to 29 and a pharmaceutically acceptable carrier. To provide. Embodiment 31 is, A pharmaceutical composition according to embodiment 30, further comprising at least one therapeutically effective agent. To provide. Embodiment 32 is, A step of administering a therapeutically effective amount to at least one compound from any one of embodiments 1 to 29 and / or a pharmaceutical composition from embodiment 30 or 31. Methods for treating, preventing, and / or improving inflammatory diseases in a subject, including To provide. Embodiment 33 is, A method of embodiment 32 in which JNK1 is inhibited at a similar or greater inhibition rate than JNK2. To provide. Embodiment 34 is, A method in embodiment 32 or 33 in which JNK1 is inhibited at a similar or greater inhibition rate than JNK3. To provide. Embodiment 35 is, The inflammatory disease is an inflammatory disease of the non-central nervous system (CNS), one of the methods in any one of embodiments 32 to 34. To provide. Embodiment 36 is, Any one of embodiments 32 to 35, wherein the inflammatory disease is at least one selected from the group consisting of endometriosis, arthritis, pulmonary fibrosis, cancer, type 1 diabetes, and type 2 diabetes. To provide. Embodiment 37 is, The inflammatory disease is endometriosis, in any one of the methods described in embodiments 32 to 36. To provide. Embodiment 38 is, Any one of embodiments 32 to 37, wherein progesterone insensitivity in a subject is reduced and / or eliminated. To provide. Embodiment 39 is, One of the methods described in embodiments 32 to 38, wherein pain associated with endometriosis is reduced and / or eliminated. To provide. Appearance 40 is, One of embodiments 32-34 and 38, wherein the inflammatory disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. To provide. Embodiment 41 is, Any one of embodiments 32-34, 38, and 40, wherein the subject is further administered progesterone. To provide. Embodiment 42 is, One of the methods described in embodiments 32 to 41, wherein normal reproductive function is maintained in the subject. To provide. Embodiment 43 is, Any one of embodiments 32 to 42 further includes a step of detecting an inflammatory disease or disorder in the subject. To provide. Appearance 44 is, The method of embodiment 43, wherein the detection step includes performing a preferred diagnostic method. To provide. Embodiment 45 is, The subject is a mammal, one of the methods described in any of embodiments 32 to 44. To provide. Embodiment 46 is, The method in which the mammal is a human being, according to aspect 45. To provide. Appearance 47 is, Method 46 in which the human is female To provide.

[0329] The terms and expressions used herein are for illustrative purposes only, not limitation, and in using such terms and expressions, there is no intention to exclude any equivalents of the features or parts thereof shown or described, and it is recognized that various modifications are possible within the scope of the embodiments of this application. Therefore, although this application describes specific embodiments and any features, it should be understood that modifications and variations of the compositions, methods, and concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the embodiments of this application.

Claims

1. Compounds of formula (I), or their salts, solvates, stereoisomers, or isotopologs: During the ceremony, R 1a is C 1 -C 6 alkyl, phenyl, and C 2 -C 10 heteroaryl selected from the group consisting of, where the alkyl, phenyl, or heteroaryl may be optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, halogen, CN, NO 2 , OR A , N(R A )(R B ), C(=O)OR A , C(=O)N(R A )(R B ), S(=O) 2 N(R A )(R B ), S(=O)N(R A )(R B ), OC(=O)R A , and N(R A )(C=O)R B ; R 1b H and C which may be substituted 1 ~C 6 Selected from the group consisting of alkyl groups, or R 1a and R 1b These may be substituted C in combination with the nitrogen atom to which they are bonded. 2 ~C 8 It can form heterocycloalkyl groups; R 2 C may be substituted 2 ~C 9 Heteroaryl and optionally substituted C 6 ~C 10 Selected from the group consisting of aryls; L 1 teeth, Selected from the group consisting of; R 3a , R 3b , R 3c , and R 3d These are H and C, which may be substituted, independently of each other. 1 ~C 6 Alkyl, halogen, CN, NO 2 , OR C , N(R C )(R D ), C(=O)OR C , C(=O)N(R C )(R D ), S(=O) 2 N(R C )(R D ), S(=O)N(R C )(R D ), OCR C , and N(R C )C(=O)R D Selected from the group consisting of; Y may be substituted for C 1 ~C 3 Alkyrenyl and possibly substituted C 3 ~C 8 Selected from the group consisting of cycloalkylenyls; R A , R B , R C , and R D If present, H and C may be substituted, respectively, independently. 1 ~C 6 Alkyl, possibly substituted C 3 ~C 8 Cycloalkyl, may be substituted C 1 ~C 6 Heteroalkyl, possibly substituted C 2 ~C 6 Heterocycloalkyl, optionally substituted C 7 ~C 12 Aralkyl, may be substituted C 6 ~C 10 Aryl, and possibly substituted C 2 ~C 12 Selected from the group consisting of heteroaryls, Here, R A and R B or R C and R D These may be substituted C in combination with the nitrogen atom to which they are bonded. 2 ~C 8 It can form heterocycloalkyl groups. Here, R A and R B One or more of which, in combination with L, may be a substituted C 4 -C 8 heterocycloalkyl or C 4 -C 6 heteroaryl can be formed.

2. A compound according to claim 1, selected from the group consisting of

2. .

3. R 1a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, F, OH, CN, O(C 1 -C 6 alkyl), O(C 1 -C 6 haloalkyl), -(CH 2 ) 1～3 NH(C 1 -C 6 alkyl), -(CH 2 ) 1～3 N(C 1 -C 6 alkyl)- 2 , C(=O)NH 2 , C(=O)NH(C 1 -C 6 alkyl), C(=O)N(C 1 -C 6 alkyl) 2 , and C(=O)(optionally substituted C 2 -C 8 heterocycloalkyl), and is phenyl, pyridinyl, or pyrimidinyl substituted with at least one substituent selected from the group consisting of, a compound according to claim 1 or 2.

4. R 1a However, CH 3 , CF 3 , OH, OCH 3 OCF 3 F, CN, CH 2 NHCH 3 CH 2 N(CH 3 ) 2 , C(=O)NH 2 , C(=O)NHCH 3 , C(=O)N(CH 3 ) 2 The compound according to any one of claims 1 to 3, which is a phenyl, pyridinyl, or pyrimidinyl substituted with at least one substituent selected from the group consisting of C(=O)(azetidinyl), C(=O)NH(oxyranyl), C(=O)(piperidinyl), C(=O)(4-methylpiperazinyl), C(=O)(morpholinyl), and C(=O)NH(cyclopropylmethyl).

5. R 1a but, A compound according to any one of claims 1 to 4, selected from the group consisting of the following.

6. R 1a However, C may be substituted. 1 ~C 6 The compound according to claim 1 or 2, wherein it is alkyl.

7. R 1a However, methyl and CH 2 CH 2 N(CH 3 ) 2 A compound according to claim 6, selected from the group consisting of the following.

8. R 1a and R 1b However, when they combine with the nitrogen atoms to which they are bonded, The compound according to claim 1 or 2, which forms a compound.

9. R 1b The compound according to any one of claims 1 to 7, wherein H is present.

10. R 2 but, A compound according to any one of claims 1 to 9, selected from the group consisting of the following.

11. At least one of the following: (a)R 3a , R 3b , R 3c , and R 3d At least one of them is H; (b)R 3a , R 3b , R 3c , and R 3d At least two of them are H; (c)R 3a , R 3b , R 3c , and R 3d At least three of them are H; and (d)R 3a , R 3b , R 3c , and R 3d Each of them is H A compound according to any one of claims 1 to 10, wherein the compound in question is the compound described above.

12. N-methyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(isoquinoline-4-yl)-N-(p-trill)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide; 3-(isoquinoline-4-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)imidazo[1,2-a]pyridine-6-carboxamide; N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 3-(2-aminopyrimidine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((dimethylamino)methyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-(methylcarbamoyl)phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carboxamide; N-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-methoxy-3-(morpholine-4-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-hydroxy-3-(piperidine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-methoxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzofuran-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-(trifluoromethoxy)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-carbamoylphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-5-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(5-(dimethylcarbamoyl)-2-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carboxamide)-N,N-dimethylpicolinamide; N-(4-hydroxy-3-(pyrroridine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(azetidine-1-carbonyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(pyrimidine-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[d]thiazole-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(3-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(2-(dimethylamino)ethyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-((2-(dimethylamino)ethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-hydroxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)thieno[2,3-c]pyridine-2-carboxamide; N-(4-hydroxy-3-(oxetane-3-ylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-((cyclopropylmethyl)carbamoyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-oxoisoindolin-5-yl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; 4-(4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophen-2-carbonyl)-1-phenylpiperazine-2-one; N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-cyano-4-hydroxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-phenyl-3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(p-trill)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(pyridine-4-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-indole-5-yl)-N-(p-tril)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-indazole-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; N-(4-((methylamino)methyl)phenyl)-3-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-((methylamino)methyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide; (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperidine-1-yl)methanone; (3-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyrazolo[1,5-a]pyridine-5-yl)(piperazine-1-yl)methanone; 1-(5-(1H-pyrrolo[2,3-b]pyridine-5-yl)pyridine-3-yl)-N-(4 ((methylamino)methyl)phenyl)cyclopropane-1-carboxamide; N-(4-((methylamino)methyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide; N-methyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-phenyl-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxyphenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(methylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(4-methoxy-3-(4-methylpiperazine-1-carbonyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide; N-(3-(dimethylcarbamoyl)-4-(trifluoromethyl)phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[b]thiophene-2-carboxamide; and N-(3-(dimethylcarbamoyl)-4-fluorophenyl)-4-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzo[b]thiophene-2-carboxamide A compound according to any one of claims 1 to 11, selected from the group consisting of the following.

13. Compounds of formula (II), or their salts, solvates, stereoisomers, or isotopologs: During the ceremony, R 4 H, and C may be substituted. 1 ~C 6 Alkyl, possibly substituted C 3 ~C 8 Cycloalkyl, may be substituted C 2 ~C 6 Heterocycloalkyl, optionally substituted C 7 ~C 12 Aralkyl, may be substituted C 3 ~C 12 Heteroaralkyl, may be substituted C 6 ~C 10 Aryl, and possibly substituted C 2 ~C 12 Selected from the group consisting of heteroaryls; R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f These are H and C, which may be substituted, independently of each other. 1 ~C 6 Alkyl, halogen, OR E , and N(R E )(R F Selected from the group consisting of; R 6 is, -(CH 2 ) 1～3 C(=O)N(R G )(R H ) and; R 7a H and C(=O)OR I Selected from the group consisting of; R 7b H is; X is OR J and Selected from the group consisting of; G may be substituted for C. 1 ~C 6 Alkyl and -Z 1 -N(R 7a )(R 7b Selected from the group consisting of; Z 1 and Z 2 These are, independently, -(C which may be substituted) 1 ~C 6 (alkirenyl)- and; R 8 H and C which may be substituted 1 ~C 6 Selected from the group consisting of alkyl groups; R 9a and R 9b These are H and C, which may be substituted, independently of each other. 1 ~C 6 Selected from the group consisting of alkyl groups; R 10a and R 10b These are H and C, which may be substituted, independently of each other. 1 ~C 6 Alkyl and optionally substituted C 6 ~C 10 Selected from the group consisting of aryls; n is an integer selected from the group consisting of 1, 2, 3, 4, and 5; and R E , R F , R G , R H , R I , and R J These are H and C, which may be substituted, independently of each other. 1 ~C 6 Alkyl, possibly substituted C 3 ~C 8 Cycloalkyl, may be substituted C 1 ~C 6 Heteroalkyl, possibly substituted C 2 ~C 6 Heterocycloalkyl, optionally substituted C 7 ~C 12 Aralkyl, may be substituted C 6 ~C 10 Aryl, and possibly substituted C 2 ~C 12 Selected from the group consisting of heteroaryls.

14. R 4 However, H and A compound according to claim 13, selected from the group consisting of the following.

15. At least one of the following: (a)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least one of them is H; (b)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least two of them are H; (c)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least three of them are H; (d)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least four of them are H; (e)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f At least five of them are H; and (f)R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f Each of them is H The compound according to claim 13 or 14, wherein the compound in question is the compound according to claim 13 or 14.

16. R 6 However, -CH 2 C(=O)NHCH 3 The compound according to any one of claims 13 to 15.

17. G, CH 3 The compound according to any one of claims 13 to 16.

18. G, -Z 1 -N(R 7a )(R 7b The compound according to any one of claims 13 to 16, which is the compound described in the previous claim.

19. R 7a However, H and A compound according to any one of claims 13 to 16 and 18, selected from the group consisting of the following.

20. R 7b The compound according to any one of claims 13 to 16 and 18 to 19, wherein H is present.

21. The compound according to any one of claims 13 to 20, wherein X is OEt.

22. X The compound according to any one of claims 13 to 20.

23. R 9a and R 9b The compound according to any one of claims 13 to 20 and 22, wherein each occurrence of is independently H.

24. The compound according to any one of claims 13 to 20 and 22 to 23, wherein n is 3.

25. R 10a and R 10b The compound according to any one of claims 13-20 and 22-23, wherein each is independently selected from the group consisting of 4-fluorophenyl and methyl.

26. X The compound according to any one of claims 13 to 20 and 22 to 25.

27. Z 1 However, -CH 2 CH 2 CH 2 - The compound according to any one of claims 13 to 26.

28. Z 2 However, -CH 2 - The compound according to any one of claims 13 to 27.

29. (2-((2R,6R)-6-(2-((3-((4-fluorophenyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)-4-(pyrazolo[1,5-a]pyridine-7-ylmethyl)piperazine-2-yl)ethyl)benzyl carbamate; 2-((2R,6R)-6-(2-(((benzyloxy)carbonyl)amino)ethyl)-1-(2-(methylamino)-2-oxoethyl)-4-(pyrazolo[1,5-a]pyridine-7-ylmethyl)piperazine-2-yl)ethyl acetate; (2-((2R,6R)-6-(2-((3-((4-fluorophenyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1-(2-(methylamino)-2-oxoethyl)piperazine-2-yl)ethyl)benzyl carbamate; N-(3-((4-fluorophenyl)(methyl)amino)propyl)-2-((2R,6R)-6-methyl-1-(2-(methylamino)-2-oxoethyl)piperazine-2-yl)acetamide A compound according to any one of claims 13 to 28, selected from the group consisting of the following.

30. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 29 and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30, further comprising at least one therapeutic agent.

32. A step of administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 29 and / or the pharmaceutical composition according to claim 30 or 31 to a target. Methods for treating, preventing, and / or improving inflammatory diseases in a subject, including [specific examples of such methods].

33. The method according to claim 32, wherein JNK1 is inhibited at a similar or greater inhibition rate than JNK2.

34. The method according to claim 32 or 33, wherein JNK1 is inhibited at a similar or greater rate than JNK3.

35. The method according to any one of claims 32 to 34, wherein the inflammatory disease is an inflammatory disease of the non-central nervous system (CNS).

36. The method according to any one of claims 32 to 35, wherein the inflammatory disease is at least one selected from the group consisting of endometriosis, arthritis, pulmonary fibrosis, cancer, type 1 diabetes, and type 2 diabetes.

37. The method according to any one of claims 32 to 36, wherein the inflammatory disease is endometriosis.

38. The method according to any one of claims 32 to 37, wherein progesterone insensitivity in the subject is reduced and / or eliminated.

39. The method according to any one of claims 32 to 38, wherein pain associated with endometriosis is reduced and / or eliminated.

40. The method according to any one of claims 32 to 34 and 38, wherein the inflammatory disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

41. The method according to any one of claims 32-34, 38, and 40, wherein the subject is further administered progesterone.

42. The method according to any one of claims 32 to 41, wherein normal reproductive function is maintained in the subject.

43. The method according to any one of claims 32 to 42, further comprising the step of detecting an inflammatory disease or disorder in a subject.

44. The method according to claim 43, wherein the detection step includes performing a preferred diagnostic method.

45. The method according to any one of claims 32 to 44, wherein the subject is a mammal.

46. The method according to claim 45, wherein the mammal is a human.

47. The method according to claim 46, wherein the person is female.

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