Use of isoquinoline compounds and their use in the treatment of AhR imbalance

Abstract

The present invention is directed to a novel compound of formula (I), or its pharmaceutically acceptable salt, solvate or hydrate.The present invention also describes a pharmaceutical composition comprising the compound of formula (I), or its pharmaceutically acceptable salt, solvate or hydrate.The present invention is also directed to the use of the compound of formula (I) for treating the condition in mammals that is related to AhR imbalance, such as inflammatory disease or disorder.

Description

[Technical Field]

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 052,561, entitled “ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATING AhR IMBALANCE,” filed on 16 July 2020; and U.S. Provisional Application No. 63 / 052,574, entitled “ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATING AhR IMBALANCE,” filed on 16 July 2020; the contents thereof are incorporated herein by reference in their entirety. The following are prior art documents related to the invention of this application (including documents cited in the international phase after the international filing date and documents cited when the application entered the national phase in other countries): (Prior art document) (Patent Document) (Patent Document 1) International Publication No. 2011 / 156626 (Patent Document 2) U.S. Patent Application Publication No. 2013 / 0116278 (Patent Document 3) International Publication No. 2019 / 179909 (Patent Document 4) U.S. Patent No. 5,919,970 (Patent Document 5) U.S. Patent No. 6,316,495 (Patent Document 6) U.S. Patent No. 6,897,206 (Patent Document 7) U.S. Patent No. 9,604,997 (Patent Document 8) U.S. Patent No. 10,626,094 (Patent Document 9) U.S. Patent and Trademark Publication No. 2006 / 0128702 (Patent Document 10) U.S. Patent and Trademark Publication No. 2007 / 0155813 (Patent Document 11) U.S. Patent and Trademark Publication No. 2010 / 0092547 (Patent Document 12) U.S. Patent and Trademark Publication No. 2010 / 0120810 (Patent Document 13) U.S. Patent and Trademark Publication No. 2012 / 0322988 (Patent Document 14) U.S. Patent and Trademark Publication No. 2018 / 0264042 (Patent Document 15) U.S. Patent and Trademark Publication No. 2021 / 0111345 (Patent Document 16) Japanese Patent Application Publication No. 06-009392 (Patent Document 17) Japanese Patent Application Publication No. 08-337523 (Patent Document 18) International Publication No. 2011 / 156626 (Non-licensed document) (Unauthorized document 1) CANNON et al. "Targeting AhR as a Novel Therapeutic Modality Against Inflammator Diseases" 2022, International J. Molecular Sciences 23(288), retrieved from the internet: https: / / doi.org / 10.3390 / ijms23010288 (December 28, 2021) 19 Pages. (Unauthorized Document 2) CHOUDHARY et al. "Aryl Hydrocarbon Receptor Knock-out Exacerbates Choroidal Neovascularization Via Multiple Pathogenic Pathways" 2015, J. Pathology 235:101-112, DOI: 10.1002 / path.4433 (Non-patent document 3) CHOUDHARY et al. "The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Mon-Ocular Neurodegenerative Diseases" September 16, 2020, International J. Molecular Sciences 21(6777):17 DOI: 10.3390 / ijms21186777. (Non-patent document 4) DI MEGLIO et al., "Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions," Immunity, 19 Jun 2014; 40(6): 989-1001. (Non-patent document 5) DOPKINS et al. "Tryptamine Attenuates Experimental Multiple Sclerosis Through Activation of Aryl Hydrocarbon Receptor" January 25, 2021, Frontiers in Pharmacology, 11(619265):11, DOI:10.3389 / fphar.2020.619265. (Non-patent document 6) FUJINO et al. "Increased Expression Of Interleukin 17 N Inflammatory Bowel Disease" January 2003, Gut, 52(1):65-70, DOI: 10.1136 / gut.52.1.65, PMID: 12477762, PMCID: MC1773503. (Non-patent document 7) GOETTEL et al. "AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice" October 25, 2016, Cell Reports, 17:1318-1329, DOI: 10.1016 / j.celrep.2016.09.082. (Non-Patent Document 8) GRYCOVA et al. "Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice" April 13, 2022, Journal of Medicinal Chemistry, 65(9):10, DOI: 10.1021 / acs.medchem.2c00208. (Non-Patent Document 9) GUTIERREZ et al. 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(Non-Patent Document 17) LIAO et al., "Enantioselective Total Syntheses of (-)-Taiwaniaquinone H and (-)-Taiwaniaquinol B by Iridium-Catalyzed Borylation and Palladium-Catalyzed Asymmetric α-Arylation", J. Am. Chem. Soc. 2011, 133, 2088-2091. (Non-Patent Document 18) LIU et.al., "Emerging Biological Functions of IL-17A: A New Target in Chronic Obstructive Pulmonary Disease?", July 02, 2021, Frontiers in Pharmacology, 12:14 Pages, Article 695957, DOI: 10.3389 / fphar.2021.695957. (Non-Patent Document 19) MONTELEONE et al., "Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract", July 2011, Gastroenterology, 141:237-248, DOI: 10.1053 / j.jastro.2011.04.007. (Non-Patent Document 20) NAPOLITANO et al., "Role of Aryl Hydrocarbon Receptor Activation in Inflammatory Chronic Skin Diseases", Cells, Vol. 10(12): 3559 (13 pages) 16 Dec 2021 (Non-Patent Document 21) NUGENT et al. "ITE, A Novel Endogenous Nontoxic Aryl Hydrocarbon Receptor Ligand, Efficiently Suppresses EAU and T-Cell-Mediated Immunity" 2013, Investigative Ophthalmology & Visual Science, 54:7463-7469, DOI:10.1167 / ovs.12-11479. (Non-Patent Document 22) RANNUG "How the AHR Became Important in Intestinal Homeostasis - A Diurnal FICZ / AHR / CYP1A1 Feedback Controls Both Immunity and Immunopathology" August 08, 2020, International J. Molecular Sciences, 21(5681):19, DOI: 10.3390 / ijms21165681. (Non-Patent Document 23) ROTHHAMMER et al. "Type I Interferons And Microbial Metabolites Of Tryptophan Modulate Astrocyte Activity And Cns Inflammation Via The Aryl Hydrocarbon Receptor" June 2016, Nature Medicine, 22(6):586-597, DOI: 10.1038 / nm.4106. (Non-patent document 24) SMITH et al. "Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin," PLOS ONE, 12 Feb 2016, pp. 1-18. (Non-patent document 25) SMITH et al., "Tapinarof is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans," Journal of Investigative Dermatology (2017) 137, 2110-2119. (Non-patent document 26) WANG et al. "Decreased Expression of the Aryl Hydrocarbon Receptor in Ocular Behcet's Disease" June 22, 2014, Hindawi Publishing Corporation, Mediators of Inflammation, 2014:12 Pages, Article 195094, DOI:10.1155 / 2014 / 195094. (Non-Patent Document 27) West, Anthony R., "Solid State Chemistry and its Applications," Wiley, New York, 1988, pp. 358 & 365 of West (Solid State Chemistry) (Non-Patent Document 28) ZHANG et al. "Suppression of Experimental Autoimmune Uveoretinitis by Inducing Differentiation of Regulatory T Dells via Activation of Aryl Hydrocarbon Receptor" April 2010, Investigative Ophthalmology & Visual Science, 51(4):2109-2117. [Overview of the project]

[0002] Various embodiments provide compounds and compositions, as well as methods for the treatment and prevention of conditions associated with AhR imbalance, AhR-mediated diseases, and inflammatory diseases, comprising administering such compounds and compositions. The compounds described herein provide a novel class of anti-inflammatory compounds that bind to and activate aryl hydrocarbon receptors (AhRs) and have AhR-dependent cytokine regulation useful for the treatment of inflammatory disease conditions.

[0003] Some embodiments disclosed in this specification are directed to compounds of formula (I), or salts, solvates or hydrates thereof,

Chemical formula

[0004] Some embodiments are directed to a compound selected from the group consisting of

Chemical formula

[0005] Some embodiments are directed to a compound of formula (1)

Chemical formula

[0006] Some embodiments involve the compound of formula (1). [ka] , The subject is either a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0007] Some embodiments aim to provide 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or a pharmaceutically acceptable salt solvate of its hydrate.

[0008] In some embodiments, the compound of formula (II), or its salt solvate or hydrate, is described. [ka] During the ceremony R 1 and R 2 Each of these is independently OH, OR 7 Selected from the group consisting of , and H, however R 1 and R 2 At least one of them is OH or OR 7 And, R 7 This is an independently and arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Selected from the group consisting of alkyl and acyl, R 3 is arbitrarily replaced with C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 4-6Cycloalkenyl, Halo, Cyano, -C(O)OR 8 , -NR 9 R 10 -S(O)2NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 , and selected from arbitrarily substituted complex rings, n is an integer with a value of 0, 1, or 2. R 6 H is, R 8 H, and C as arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, R 9 and R 10 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, alternatively, R 9 and R 10 Together with the nitrogen atoms to which they are bonded, they form a 5-7 membered cyclic saturated or unsaturated ring. R 11 H, and C as arbitrarily substituted. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, -NR 9 R 10 , and -OR 12 Selected from the group consisting of, R 12 and R 13Each of these can independently be H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, or an optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyls, and R 6 C is a halo, hydroxyl, alkoxy, or optionally substituted C 1-6 Alkyl, alkyl halide, and optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynnyl and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0009] Some embodiments of this specification describe pharmaceutical compositions comprising a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.

[0010] Some embodiments describe methods for treating or preventing conditions in mammals associated with AhR imbalance, comprising the step of administering a therapeutically effective amount of any compound or pharmaceutical composition described herein to a mammal.

[0011] Some embodiments describe a method for treating or preventing an inflammatory disorder in a subject, comprising the step of administering a therapeutically effective amount of any compound or pharmaceutical composition described herein to the subject. In some embodiments, the inflammatory disorder is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascularization (dry) AMD, neovascularization (wet) AMD, uveitis or other inflammatory eye diseases, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease. In some embodiments, the inflammatory disease is psoriasis or atopic dermatitis. In some embodiments, the compound or pharmaceutical composition described herein is administered topically.

[0012] Some embodiments describe methods for treating or preventing psoriasis or atopic dermatitis in subjects requiring such treatment, comprising the step of administering to a subject an effective amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0013] Some embodiments of the compound of formula 8 [ka] or a process for preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, a) Compounds of formula 5 [ka] or a step of preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, 1) Alkylate 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate to obtain a compound of formula 2. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 2) Treat the ketone of formula 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent, and then remove water under acidic conditions to obtain the compound of formula 3. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 3) Hydrogenating the compound of formula 3 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain the compound of formula 4. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and 4) The preparation step includes the step of borylating a compound of formula 4 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 5, b) Compounds of formula 6 [ka] or a step of preparing a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the step of treating isoquinoline-3-ol with a triflate agent, and c) A compound of formula 6 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is coupled with a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 7. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and d) A step of demethylating a compound of formula 7 to form a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein steps a and b are the forming step, which can be carried out in different reaction vessels, in any order, or simultaneously. [Brief explanation of the drawing]

[0014] [Figure 1]Figures 1A-C show the BioMAP profile of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol compared to tapinarof and F1CZ. Figure 1A shows the BioMAP profiles of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol alone at concentrations of 1.0 μM, 0.33 μM, 0.11 μM, and 0.037 μM. Figure 1B shows the BioMAP profile of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol at 1 μM (light gray) overlaid with FICZ (330 nM; dark gray). Figure 1C shows the BioMAP profile of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol at 1 μM (light gray) overlaid with Tapionardo (1 μM; dark gray). The shaded gray areas represent normal variation. Common analytes outside the normal range of variation are annotated. [Figure 2]Figures 2A-2C show the effects of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol on IL-17A protein secretion and T cell and keratinocyte viability in primary human peripheral blood CD4+ T cells. Figure 2A shows the dose-dependent suppression of IL-17A in human peripheral blood CD4+ T cells by 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (triangle) and Tapinarov (circle) under Th17 polarized conditions. The dots represent the maximum protein expression rate compared to Th17 from six composite donors, with 3 biological replications per treatment. Error bars represent the standard error of the mean. Figure 2B shows the cell viability of human peripheral blood CD4+ T cells under increasing concentrations of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (diamond) and Tapinarov (circle) over 5 days under Th17 polarization conditions. Data are mean ± standard error from 3–9 experimental data points. Figure 2C shows cell viability in human primary keratinocytes. Cell viability was quantified after treatment with increasing concentrations of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (triangle) and Tapinarov (circle) over 5 days. Error bars represent the mean ± standard error of 10–15 biological replication. [Figure 3] Figures 3A-3B demonstrate that target involvement of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol induces the AhR target gene, CYP1A1, and reduces IL-17A expression in X-vivo human skin. Healthy donor skin samples were placed in a liquid / air interface culture system and pretreated for 24 hours with 1 or 10 μM 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (white) or GSK3038548A (gray), followed by a further 24 hours of culture under Th17 polarized conditions. Figure 3A shows the relative expression of CYP1A1 mRNA transcripts after 24 hours using qRT-PCR. Figure 3B shows the relative expression of IL-17A mRNA transcripts after 24 hours using qRT-PCR. Data are expressed as mean ± standard error from 3 or 4 biological replicas. Student's t-test was used to determine statistical significance, p<0.05. [Figure 4] Figure 4 shows the topical target engagement of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in different concentrations of cream formulation 1 and gel formulation 1. Skin samples from healthy donors placed in a liquid / air interface culture system were topically applied for 24 hours with or without 10 μM 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or 1 μM FICZ in the culture medium, or at the indicated concentration in the formulation. Relative expression of CYP1A1 mRNA transcripts is reported as a plot of the mean ± SEM of 4 biological replicas from 4 individual donors. [Figure 5]Figures 5A to 5F show the effects of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol on clinical score and epidermal thickness in an imiquimod mouse model of psoriasis. 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was applied for 3 days prior to IMQ treatment. Next, IMQ and 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in a 60% ethanol topical solution were sequentially applied to the scraped back (first IMQ, then 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, 1-2 hours later) at 0.3% for 4 days (Figures 5A-5B) or 0.3%. In the plot in Figure 5A, diamonds represent vehicle (60% EtOH 40% water) + vanilla cream, squares represent vehicle + imiquimod (5%), and × represents 0.3% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%). Other lines are not relevant to this application and are therefore not specified. In Figure 5B, epidermal thickness was measured in tissue sections of back skin taken on the last day of treatment. The triangular bars represent vehicle (60% EtOH 40% water) + vanilla cream, the oval bars represent vehicle + imiquimod (5%), and the solid bar represents 0.3% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%). In the plot in Figure 5C, the diamond represents vehicle (60% EtOH 40% water) + vanilla cream, the square represents vehicle + imiquimod (5%), the × represents 0.1% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%), the circle represents 0.3% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%), and the ◎ represents the combination of 2-isopropine (2%)-2-isoquinoline-(1)-5-ylbenzene·3-diol·(60%) + imiquimod (5%). In Figure 5D, epidermal thickness was measured using tissue sections of dorsal skin collected on the last day of treatment.The triangular bars represent vehicle (60% EtOH 40% water) + vanilla cream, the oval bars represent vehicle + imiquimod (5%), the square bars represent 0.1% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%), and the solid bar represents 0.3% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%). In Figure 5E, a second 9-day IMQ test was performed using 0.1% cream formulation 1 (square), 0.5% cream formulation 1 (×), and 1% cream formulation 1 (star). 0% cream formulation 1 + vanilla cream is represented by a diamond, and 0% cream formulation 1 + imiquimod is represented by a circle. In Figure 5F, epidermal thickness was measured on tissue sections of dorsal skin taken on the last day of treatment. Triangular bars represent vehicle (0% cream formulation 1) + vanilla cream, oval bars represent vehicle + imiquimod (5%), square bars represent 0.1% cream formulation 1 + imiquimod (5%), solid bars represent 0.5% cream formulation 1 + imiquimod (5%), and star bars represent 1% cream formulation 1 + imiquimod. [Figure 6]Figures 6A to 6E show the effects of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol on dermal and epidermal thickness in a DFNB mouse model. Figure 6A shows a schematic of the experimental design. Mice were sensitized to DNFB on day 1 and challenged with DNFB every 2-3 days starting from day 5. Topical formulations of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol were applied daily from day 5. Figure 6B shows the measured epidermal thickness, and Figure 6C shows the measured skin thickness twice daily (BID) for topical application of 1% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or 0.3% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in a 60% ethanol solution (60% EtOH, 40% water). In Figures 6B and 6C, the square bars represent the solvent (acetone / olive oil (4:1 volume:vol) + vehicle (60% EtOH, 40% water)), the diamond bar represents 0.15% DNFB (acetone / olive oil (4:1 volume:vol) + vehicle (60% EtOH, 40% water)), the star bar represents 0.15% DNFB (acetone / olive oil (4:1 volume:vol) + 1% ethanol solution of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH, 40% water)), and the solid bar represents 0.15% DNFB (acetone / olive oil (4:1 Volume:Volume)) + 0.3% ethanol solution of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH, 40% water), the hexagonal bar represents 0.15% DNFB (acetone / olive oil (4:1 volume:vol)). Figure 6D shows the measured epidermal thickness, and Figure 6E shows the dermal thickness in response to once-daily topical application of 0% cream formulation 1 or 0% cream formulation 1. In Figures 6D and 6E, the square bars represent acetone / olive oil (4:1 volume:volume) + vehicle (60% EtOH, 40% water), the diamond bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + vehicle (60% EtOH, 40% water), the round bars represent 0.15% DNFB (in acetone / olive oil), and the round bars represent 0.15% DNFB (in 0% EtOH, 40% water).The graph shows 15% DNFB (acetone / olive oil (4:1 volume:volume)) + 0% cream formulation 1, the solid bar represents 0.15% DNFB (acetone / olive oil (4:1 volume:volume)) + 0.3% cream formulation 1, and the hexagonal bar represents 0.15% DNFB (acetone / olive oil (4:1 volume:volume)) and 0.05% clobetasol cream. One-way ANOVA was used to determine statistical significance. *p<0.05, ***p<0.001, n=12 / each treatment group. [Figure 7] Figure 7 shows the amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol delivered to the epidermis (square bars in the bar set) and dermis (solid bars in the bar set) in different 1% formulations 16 hours after application. The bar graph represents the average amount ± SEM of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol from three donors, repeated 15 to 18 times. Samples were analyzed by ULC-MS / MS, and the LLOQ was 80 pg / mL. [Figure 8] Figure 8 shows the cumulative amount (ng) of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in the recipient solution over 16 hours after application of different formulations. Squares represent 1% cream formulation 3, circles represent 1% gel formulation 4, asterisks represent 1% gel formulation 3, a single vertical line represents 1% cream formulation 4, no symbol (line) represents 1% cream formulation 5, triangles represent 1% cream formulation 6, diamonds represent 1% cream formulation 7, and a thick X represents 1% cream formulation 2. The lines represent the cumulative mean amount ± SEM of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol from 15 to 18 replications from three donors. Samples were analyzed by ULC-MS / MS, and the LLOQ was set to 80 pg / mL. [Figure 9]Figure 9 shows the amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol delivered to the dermis 16 hours after application of different formulations. The bar graph represents the mean amount ± SEM of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol from 13–16 replicas from three donors. Samples were analyzed by ULC-MS / MS, and the LLOQ was 80 pg / mL*. [Figure 10] Figures 10A and 10B show the amount (μg) of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol delivered to the epidermis (square bars for each formulation) and dermis (solid bars for each formulation) 16 hours after application for different gel formulations of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. The bars represent the average amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol from 15-18 replicas ± SEM from three donors (Figure 10A) and 7-10 replicas ± SEM from one donor (Figure 10B). Samples were analyzed by ULC-MS / MS at 80 pg / mL LLOQ. [Figure 11] Figure 11 shows the cumulative amount (ng) of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in the solution 16 hours after application for different gel formulations. For gel formulation 4 (diamond), gel formulation 1 (triangle), and gel formulation 2 (square), the cumulative amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol from 15-18 replications ± SEM (N46822-2) from three donors is described. For gel formulation 4 (asterisk) and gel formulation 3 (broad X), the cumulative amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol from 7-10 replications from one donor ± is described. Samples were analyzed by ULC-MS / MS at 80 pg / mL LLOQ. [Figure 12]Figures 12A to 12C show the mean (SD) plasma concentration-time profiles of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol after a single dose in rats. In Figure 12A, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is administered intravenously (1 mg / kg). In Figure 12B, the solid squares represent subcutaneous administration of 10 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in 30% Captisol, and the open squares represent subcutaneous administration of 25 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in 30% Captisol. The solid triangle represents subcutaneous administration of 10 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in 30% Cavitron, while the open triangle represents subcutaneous administration of 25 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in 30% Cavitron. In Figure 12C, the solid circle represents the topical administration of 1% cream formulation 1 (20 mg / kg) of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, and the open square in Figure 12C represents the topical disposal of 1% gel formulation 1 (20 mg / kg) of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, as shown in Figure 12C, representing the topical disposal of 2-isopropyl-5-yl-(isoquinoline-3-yl)benzene-1,3-diol (20 mg). [Figure 13]Figures 13A and 13B show the individual epidermal / upper dermal and dermal concentration-time profiles of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol after a single topical administration in minipig subjects. In Figure 13A, the solid line and open circle represent the epidermis / upper dermis of minipig subject 1 treated with 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, and the dashed line and open circle represent the dermis of minipig subject 1 treated with 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. In Figure 13B, the solid lines and solid circles represent the epidermis / upper dermis of miniature pig subject 2 treated with 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol; and the dashed lines and solid circles represent the dermis of miniature pig subject 2 treated with 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. In Figure 13B, the solid lines and solid circles represent the epidermis / upper dermis of miniature pig subject 100 treated with 1% gel formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol; and the dashed lines and solid circles represent the dermis of miniature pig subject 100 treated with 1% gel formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. The solid line and open circle represent the epidermis / upper dermis of 102 miniature pig subjects treated with 1% gel formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol; and the dashed line and open circle represent the dermis of 102 miniature pig subjects treated with 1% gel formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. [Figure 14] Figures 14A and 14B show depth profiling and cutaneous MALDI IMS at different time points after single topical administration. 1% cream formulation 1 (Figure 14A) and 1% gel formulation 1 (Figure 14B) in minipig. [Modes for carrying out the invention]

[0015] Aryl hydrocarbon receptors (AhRs) are members of the bHLH-PAS family of transcription factors and are known to sense a diverse range of endogenous and exogenous molecules and mediate multiple biological activities as cytoplasmic ligand-activating transcription factors. Recent evidence suggests that AhRs are a highly conserved pathway that modulates inflammatory responses, and therefore the AhR pathway may be an important target for the treatment of inflammatory diseases.

[0016] AhR is widely expressed in various types of skin cells, including keratinocytes, fibroblasts, melanocytes, and cutaneous immune cells. In keratinocytes, AhR signaling regulates the expression of epidermal differentiation genes such as filaggrin, loricrin, and hornelin, promoting skin barrier formation. Furthermore, AhR has been shown to play a crucial role as a regulator of both innate and adaptive immune responses by influencing the balance between Th17 and Treg T cells. Th17-related cytokines such as IL17 contribute to the immunopathogenesis of inflammatory skin diseases such as psoriasis. Therefore, AhR has recently attracted attention as a target for the treatment and prevention of inflammatory skin diseases, while simultaneously highlighting the need for more effective topical treatments.

[0017] Compounds that bind to and activate aryl hydrocarbon receptors (AhRs), as described herein, provide a novel class of anti-inflammatory compounds that have AhR-dependent cytokine-modulating effects useful for treating inflammatory disease conditions.

[0018] Thus, the beneficial effects of AhR activation offer novel therapeutic interventions in the treatment of inflammatory disease conditions. There is a need for better topical treatment of skin diseases, particularly chronic inflammatory skin diseases. Preferably, compounds that bind to and activate aryl hydrocarbon receptors (AhRs) in multiple cell types, including human skin cells, would provide novel and useful therapeutic methods for inflammatory disease conditions. Therefore, the present invention provides a novel class of anti-inflammatory compounds having AhR-dependent cytokine regulation for the treatment of such conditions.

[0019] definition As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the components mentioned. It will be obvious to those skilled in the art that the use of the singular form includes the plural form unless otherwise specified.

[0020] The term "about" means a range of tolerance for a given parameter, as determined by those skilled in the art, which will in part depend on the method of measuring or determining the value, i.e., the limits of the measuring system. For example, "about" can mean a range of 10% of a given value. For example, about 55% means between 45% and 55%.

[0021] In this specification, "acyl" means an alkyl or aryl group bonded via a carbonyl group -C(O)-. For example, an acyl may have a carbonyl group. 1-6 Alkanoyl groups are included. Typical acyl groups include acetyl groups and benzoyl groups.

[0022] In this specification, the terms “administer” and “dosage” are used to mean any method of delivering a compound or a pharmaceutical composition thereof to a patient in a manner that provides a desired therapeutic effect in a sound medical practice. In some embodiments, the compound is contained in a pharmaceutical emulsion composition.

[0023] As used herein, the term "alkoxy" means an -O-alkyl group containing a specified number of carbon atoms. For example, C 1-6 An alkoxy means an alkoxy group containing at least one and at most six carbon atoms. Examples of “alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, buto-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.

[0024] As used herein, “alkyl” refers to a monovalent saturated hydrocarbon chain having a specified number of carbon element atoms. For example, C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be linear or branched. Typical branched alkyl groups have one, two, or three branches. Examples of alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, s-butyl, and t-butyl), and n-pentyl.

[0025] "Alkylene" refers to a linear or branched carbon chain having 1 to 6 carbon atoms and a linker having two bonding sites. Examples of C1-6 alkylene linker groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0026] As used herein, the terms "and / or" additively and alternatively cover the individual elements of such linked lists, so that these elements are understood to be selectively linked by "and" or, respectively, "or". Furthermore, terms used in the singular form also include the plural form.

[0027] As used herein, the term “apply” means any method of delivering a topical composition to a subject in order to produce a positive effect on a dermatological disorder, condition, or appearance in sound medical or cosmetic practice.

[0028] As used herein, the term "aryl" means a substituted or unsubstituted hydrocarbon aromatic ring, such as phenyl or naphthyl.

[0029] As used herein, the terms “arylalkyl” or “araalkyl” mean, unless otherwise specified, an aryl ring and a connected C such as benzene or naphthalene. 1-6 This refers to the alkyl portion, for example, -(CH2)n Phenyl, where n is 1 to 6.

[0030] As used herein, the term “compound(s) of the present invention” or “compound(s) of the present invention” means any form of the compounds defined herein, i.e., any salt or non-salt form (e.g., as a free acid or base, or as a salt, in particular a pharmaceutically acceptable salt thereof), and any physical form thereof (e.g., non-solid form (e.g., liquid or semi-solid form), and solid form (e.g., amorphous or crystalline form, certain polymorphic forms, solvate form including hydrate form (e.g., mono-, di-, and hemihydrate)), as well as mixtures of various forms.

[0031] Throughout this application, descriptions of various embodiments use the language "comprising," but in some specific examples, embodiments may alternatively be described using the language "consisting essentially of" or "consisting of."

[0032] As used herein, the term “dermatologically acceptable excipient or diluent” refers to any inert component present in a composition for use in the topical compositions described herein.

[0033] The terms “effective dose,” “pharmaceutical effective dose,” or “therapeutic effective dose” are used herein to refer to the amount of an active ingredient sufficient to have a therapeutic effect at the time of administration, for example, the amount that causes improvement or change in the condition to which it is administered. The effective dose varies depending on the specific condition being treated, the severity of the condition, the duration of treatment, the stage of progression of the condition, the body surface area affected by the clinical condition (in the case of topical administration), and the specific components of the composition. The amount is sufficient to treat one or more of a disorder, disease, or condition or its symptoms, and / or to prevent the onset of the disease or disorder, and can be determined by standard clinical techniques. The appropriate amount in any given example will be readily apparent to those skilled in the art and can be determined by routine experimentation. In some embodiments, the compositions of the present invention are generally applied topically to the affected area, i.e., topical application to the skin area where the clinical abnormality is manifest.

[0034] As used herein, the terms “haloalkyl” or “halosubstituted alkyl” mean a linear or branched saturated hydrocarbon chain containing a specific number of carbon atoms substituted with a halo atom. For example, halo C 1-6 Alkyl refers to a linear or branched alkyl group containing at least one and at most six carbon atoms, substituted with one to three halo atoms per carbon atom. Examples of “haloalkyl” as used herein include, but are not limited to, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0035] As used herein, the terms “halogen” and “halo” include fluorine, chlorine, bromine, and iodine, as well as fluoro, chloro, bromo, and iodine, respectively.

[0036] As used herein, the terms “heteroaryl ring,” “heteroaryl moiety,” and “heteroaryl” mean a monocyclic 5- to 7-membered unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen, and sulfur. Examples of heteroaryl rings include, but are not limited to, furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil. As used herein, the terms “heteroaryl ring,” “heteroaryl moiety,” and “heteroaryl” also mean a condensed aromatic ring containing at least one heteroatom selected from oxygen, nitrogen, and sulfur. Each of the condensed rings may contain five or six ring atoms. Examples of condensed aromatic rings include, but are not limited to, indolyl, isoindolyl, indazolyl, indolidinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranil, benzothiophenyl, quinolyl, isoquinolyl, quinazolinil, quinoxaline, naphthilidinyl, cinolinil, printyl, and phthalidinyl.

[0037] As used herein, the term “heteroarylalkyl” means (unless otherwise defined) the C as defined above. 1-6 This means that the alkyl group is bonded to the heteroaryl moiety as defined herein, unless otherwise specified.

[0038] As used herein, the terms “heterocyclylalkyl” or “heterocyclylalkyl” mean (unless otherwise defined) the C as defined above. 1-6 This means that the alkyl group is bonded to a heterocyclic site as defined herein, unless otherwise specified.

[0039] As used herein, the terms “heterocyclic” or “heterocyclyl” (either by itself or in any combination such as “heterocyclylalkyl”) are used herein to mean a saturated or partially unsaturated 4- to 10-membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, S, or S(O)q, and q has an integer value of 0, 1, or 2. Substantial examples include, but are not limited to, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl (including sulfur moiety oxides), pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl (including sulfur moiety oxides), or imidazolidinyl.

[0040] In this specification, when used in in vitro skin penetration studies, the term “epidermis” includes the tissue or layers up to the stratum corneum and basement membrane separated by thermal separation.

[0041] As used in in vitro skin penetration studies using X-vivo human abdominal skin with a thickness of 500 microns (±100 microns) or 750 microns (±100 microns), the term "epidermis" refers to the uppermost / outermost layer obtained by thermal separation after the washing / tape stripping procedure, while the term "dermis" refers to the lower layer.

[0042] As used herein, the term “independently” means that when multiple substituents are selected from a number of possible substituents, those substituents may be identical or different. That is, each substituent is selected separately from the entire group of possible substituents mentioned.

[0043] The terms "modulate" or "adjust" mean an increase or decrease in the quantity, quality, or effect of a particular activity.

[0044] As used herein, the term "oxo" refers to a double-bonded oxygen moiety, which, for example, forms a carbonyl moiety (C=O) when directly bonded to a carbon atom.

[0045] As used herein, the terms "hydroxy" or "hydroxyl" are intended to mean the radical -OH.

[0046] In this specification, the term "sulfinyl" refers to the oxide S(O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety.

[0047] In this specification, the term “optionally” means that the events described thereafter may or may not occur, and includes both events that occur and events that do not occur.

[0048] As used herein, “optionally replaced” means that, unless otherwise defined herein, the part is: One or more times, for example, 1 to 3 times, Independently, Halo, for example ,centre Luoro, chloro, bromo, or iodine ; hydroxy ; Hydroxysubstituted C 1-3 Alkyl ; C such as methoxy or ethoxy 1-3 Alkoxy ; Halo replacement C 1-3 Alkoxy ; For example, S(O) such as methylthio, methylsulfinyl, or methylsulfonyl m C 1-3 Alkyl ; NR 22 R 23 and , R 22 and R 23 but , independently H or C 1-3 Selected from alkyl groups, or 、 R 22 and R 23 However, along with the nitrogen to which they are bound, O, N, or S NR forms a 5 to 7 membered ring, optionally containing additional heteroatoms selected from 22 R 23 ; C 1-3 Alkyl; C 3-7 Cycloalkyl, or C3-7 Cycloalkyl C 1-3 Alkyl alkyl groups, e.g., cyclopropylmethyl; halosubstituted C 1-3 Alkyl, e.g., CF2CF2H or CF3; optionally substituted aryl such as phenyl, or optionally substituted aryl C such as benzyl or phenethyl. 1-3 Alkyl It may be replaced as needed. Here, these aryl-containing portions are halo, hydroxy, and hydroxy-substituted C. 1-3 Alkyl, C 1-3 Alkoxy, S(O) m C 1-3 Alkyl, amino, mono, and disubstituted C 1-3 Alkylamino, C 1-3 The compounds may be substituted one or two times with alkyl or CF3. Furthermore, it will be understood by those skilled in the art that the compounds of the present invention may exist in other tautomeral forms depending on further substitution. All tautomeral forms of the compounds described herein are intended to be included within the scope of the present invention. Any reference to named compounds of the present invention is understood to be intended to include all tautomers of the named compounds and any mixture of tautomers of the named compounds.

[0049] As used herein, “patient” includes human patients, including adults, teenagers, and children (e.g., pediatric patients). Pediatric patients may include teenagers under the age of 18. Children as used herein are under the age of 12.

[0050] In this specification, “pharmaceutically acceptable” means a compound, material, composition and dosage form that is suitable for use in contact with human and animal tissues, within the bounds of sound medical judgment, without excessive toxicity, irritation, or other problems or complications, and in proportion to a reasonable benefit / risk ratio. The terms “pharmaceutically acceptable” and “dermatologically acceptable” mean that they are approved by a regulatory authority or are listed in a pharmacopoeia or other generally accepted guide for use in animals, particularly humans.

[0051] The term "pharmaceutically acceptable salt" refers to a salt that is safe and effective for use in patients and possesses the desired pharmaceutically active properties. Salts encompassed by the term "pharmaceutically acceptable salt" mean non-toxic salts of the compounds of the present invention. Such salts include compounds modified by converting the parent compound into its acid salt or base salt.

[0052] As used herein, the term “skin penetration” means that a compound, preferably a compound of formula (I) or a pharmaceutically acceptable salt thereof, diffuses through the stratum corneum into the epidermis and / or dermis of the skin.

[0053] "Substantially free" of a specific ingredient refers to a composition in which the specific ingredient is present in less than approximately 1% by weight. "Free of a specific ingredient" refers to a composition in which the specific ingredient is not present at all.

[0054] As used herein, the term “substituted” in relation to a group indicates that one or more hydrogen atoms bonded to a member atom within the group are substituted with substituents selected from a defined group of substituents. The term “substituted” should be understood to imply that such substitutions are subject to the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound (i.e., one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination, and is robust enough to withstand isolation from the reaction mixture). Where it is stated that a group may contain one or more substituents, one or more (appropriate) member atoms within the group may be substituted. Furthermore, a single member atom within a group may be substituted with two or more substituents, provided that such substitutions are subject to the permissible valencies of the atom. Appropriate substituents are defined herein for each substituent or for any optionally substituted group.

[0055] The term “topical” delivery or “topical” administration refers to the application of a drug-containing formulation to the skin with the intention of substantially inducing the pharmacological effect of the drug on or within the skin in order to directly treat the skin manifestations of a skin disorder or disease. The term “topical” administration also includes transdermal administration, inhalation administration, and ocular / mental administration. “Topical” administration also refers to application to and diffusion through the stratum corneum, including but not limited to application to psoriatic lesions and broken skin.

[0056] As used herein, the terms “to treat” or “to treat” mean administering a compound or agent to a subject who has or is at risk of developing a disorder, for the purpose of curing, alleviating, reducing, improving, delaying the onset, preventing, or improving a disorder, symptoms of a disorder, disease conditions secondary to a disorder, or predisposition to a disorder. Treatment does not necessarily mean that the condition or disorder is completely cured. Useful pharmaceutical compositions, such as pharmaceutical emulsion compositions, should herein mean only those that reduce the severity of a condition or disorder, reduce the severity of associated symptoms, improve the patient’s quality of life, or delay, prevent, or suppress the onset of a condition or disorder. Treatments do not need to be effective in all members of a population, such as a population of patients with atopic dermatitis, in order to have clinical utility, as recognized in the fields of medicine and pharmacy.

[0057] Concentration, volume, solubility, and other numerical data may be presented in range form herein. Such range forms are used merely for convenience and conciseness and should be understood to be interpreted flexibly to include not only the numerical values ​​explicitly stated as limits of the range, but also all individual numerical values ​​or subranges contained within that range, as each numerical value and subrange is explicitly stated. All numerical values ​​used herein to represent quantities, percentages or proportions, and other numerical values ​​should be understood in all cases to be modified by the term “approximately”.

[0058] For example, a concentration range of 0.1–5 ng / ml should be interpreted to include not only the explicitly mentioned concentration limits of 0.1 ng / ml and 5 ng / ml, but also individual concentrations such as 0.2 ng / ml, 0.8 ng / ml, 1.0 ng / ml, 2.2 ng / ml, and 3.6 ng / mol, as well as sub-ranges such as 0.3–2.5 ng / ml and 1.8–3.2 ng / ml. This interpretation should apply regardless of the breadth of the range or the characteristics described.

[0059] Unless otherwise specified, any concentration range, percentage range, or ratio range described herein shall be understood to include any integer and fractional part thereof (e.g., one-tenth and one-hundredth) of the concentration, percentage, or ratio within that range.

[0060] Other terms used herein are intended to be defined by their meanings well known in the art.

[0061] The various alternative definitions of the groups and substituents of formulas (I), (Ia), and (II) provided herein are intended to describe each compound species disclosed herein individually, as well as groups of one or more compound species. The scope of the invention includes any combination of these group and substituent definitions.

[0062] compound In some embodiments, the present disclosure relates to compounds of formula (I). [ka] Alternatively, a salt, solvate, or hydrate thereof may be described.

[0063] Substituent R of formula (I) 1 and R 2 Each of these is independently OH, OR 7 Selected from the group consisting of , and H. However, R 1 and R 2 At least one of them is OH or OR 7 This is conditional on the following:

[0064] Substituent R of formula (I) 7 This is an independently and arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Selected from the group consisting of alkyl and acyl compounds.

[0065] Substituent R of formula (I) 3 is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, Halo, Cyano, -C(O)OR 8 , -NR 9 R 10 -S(O)2NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 The group is selected from the group consisting of , and any substituted complex algebras.

[0066] Substituent R of formula (I) 8 These are H and C, which are substituted independently. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0067] R in equation (I) 9 and R 10 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6Selected from the group consisting of alkyl groups. Alternatively, substituent R 9 and R 10 These, along with the nitrogen atoms to which they are bonded, form a 5- to 7-membered cyclic saturated or unsaturated ring.

[0068] Substituent R of formula (I) 11 These are, independently, hydrogen, and optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, -NR 9 R 10 and -OR 12 Selected from the group consisting of .

[0069] Substituent R of formula (I) 12 and R 13 Each of these can independently be H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, or an optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of siloalkyl groups.

[0070] Substituent R of formula (I) 6 C is H, halo, hydroxyl, alkoxy, or optionally substituted. 1-6 Alkyl, alkyl halide, and optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynnyl and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0071] The subscript n in expression (I) is an integer with a value of 0, 1, or 2.

[0072] The subscript s in expression (I) is an integer with a value of 0, 1, or 2.

[0073] The subscript t in expression (I) is an integer with values ​​between 0 and 6.

[0074] Substituent R of formula (I) 5 H, halo, and C as arbitrarily substituted. 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 , optionally substituted aryl, and optionally substituted -C 1-6 Selected from the group consisting of alkylaryl compounds.

[0075] Substituent R of formula (I) 14 H, and C as arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0076] Substituent R of formula (I) 15 and R 16 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of siloalkyls. Alternatively, R 15 , R 16 Together with the nitrogen atoms to which they are bonded, they form saturated or unsaturated rings of 5-7 membered rings.

[0077] Substituent R of formula (I) 4 C is a combination of H, halo, cyano, or any other substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, -(CR 18 R 19 )t COOR 8 ,-(CR 18 R 19 ) t C(O)R 8 -(CR 18 R 19 ) t NR 9 R 10 ,-(CR 18 R 19 ) t C(O)NR 9 R 10 ,-(CR 18 R 19 ) t NR 9 C(O)R 8 ,-(CR 18 r 19 ) t S(O)2NR 9 R 10 ,-(CR 18 R 19 ) t COR 11 ,-(CR 18 R 19 ) t CH(O), -(CR 18 R 19 ) t Ure 12 ,-(CR 18 R 19 ) t S(O) s R 13 , arbitrarily substituted hetero rings, and arbitrarily substituted hetero rings C 1-6 Selected from the group consisting of alkyl groups.

[0078] Substituent R of formula (I) 18 and R 19 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0079] In some embodiments, the salt is a pharmaceutically acceptable salt.

[0080] In some embodiments, R 1 and R 2 Each of them is independently OH. In some embodiments, R 1 and R 2 One of them is OH, and the other is H. In some embodiments, R 1 and R 2 One of them is OH, and the other is OR 7 And in some embodiments, R 1 and R 2 Both are OR 7 And each R 7 is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Independently selected from the group consisting of alkyls and acyls. In some embodiments, R 7 is an arbitrarily substituted C 1-4 It is alkyl. In some embodiments, R 7 is methyl or ethyl. In other embodiments, R 7 , NR 22 R 23 C that has been optionally replaced by 1-4 It is alkyl. In some embodiments, R 22 and R 23 Each of them is H and C 1-3 Alkyl, for example, is independently selected from the group consisting of -(CH2)3NH2. In some embodiments, R 1 and R 2 Each of them is methoxy. In some embodiments, R 1 OH is R 2 is OR 7 And R 7 is a substituted C 1-6 It is alkyl. In some embodiments, R 1 OH is R 2 is OR 7 And R 7 is NR 22 R 23 C replaced by1-6 It is alkyl. In some embodiments, R 1 OH is R 2 It is -O(CH2)3NH2.

[0081] R 7 If the site is arbitrarily substituted, the site to be substituted can be arbitrarily substituted, for example, once, twice, or 1 to 3 times, independently of halo, hydroxyl, or hydroxy substitution-C. 1-3 Alkyl, C 1-3 Alkoxy and halo-substituted C 1-3 Alkoxy, -S(O) m C 1-3 Here, m is an integer with a value of 0, 1, or 2, -NR 22 R 23 And here R 22 and R 23 H or C 1-3 Selected from alkyl groups, or R 22 and R 23 along with the nitrogen to which they are bound, they can optionally contain O, N, or S, C 3-7 Halo-substituted C such as cycloalkyl, CF2CF2H, or CF3 1-3 Forms a 5 to 7-membered ring containing an additional heteroatom selected from alkyl or optionally substituted aryl, where the aryl portion may also optionally be halo, hydroxyl, or hydroxy-substituted C 1-3 Alkyl, C 1-3 Alkoxy, -S(O) m C 1-3 C may be substituted once or twice with alkyl groups, where m is an integer with a value of 0, 1, or 2, and is amino, mono, or disubstituted. 1-3 Alkylamino, C 1-3 It may be alkyl or CF3.

[0082] In some embodiments, R 7 is an arbitrarily substituted C 1-6 It is alkyl. In some embodiments, R 7 , NR 22 R 23 C replaced by1-6 It is alkyl. In some embodiments, R 7 is C substituted with NH. 1-6 2 is alkyl. In some embodiments, R 7 It is -(CH2)3NH2.

[0083] In some embodiments, R 3 If the site is optionally substituted, that site may be independently substituted one or more times, for example, 1 to 3 times. In some embodiments, the site is halo, hydroxy, C 1-3 Alkoxy, C 1-3 The molecule may be independently and optionally substituted 1 to 3 times with alkyl, aryl, or arylalkyl groups.

[0084] In some embodiments, R 3 is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyl groups. In some embodiments, C 3-6 Alkyls include isopropyl, n-propyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl, n-hexyl, etc. In some embodiments, the alkyl is isopropyl or t-butyl. In some embodiments, C 3-6 The alkyl group is isopropyl. In some embodiments, C 3-6 The cycloalkyl group is cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, C 3-6 The cycloalkyl group is cyclopentyl.

[0085] In some embodiments, R 3 It is a heterocycle.

[0086] In some embodiments, R 3 It is isopropyl.

[0087] In some embodiments, R 6H, halo, hydroxyl, C 1-3 alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, and optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynnyl and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups. In some embodiments, R 6 H, halo, hydroxyl, C 1-3 alkoxy, optionally substituted C 1-3 Selected from the group consisting of alkyls and alkyl halides. In some embodiments, R 6 is selected from the group consisting of H and halo. In some embodiments, R 6 Selected from the group consisting of , H and bromo. In some embodiments, R 6 , is H.

[0088] In some embodiments, R 5 H, halo, and any substituted -C 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 , aryl and -C 1-6 Selected from the group consisting of alkylaryls. In some embodiments, R 5 H, halo, and C as arbitrarily substituted. 1-6 Alkyl, C(O)OR 14 , and C(O)NR 15 R 16 Selected from the group consisting of R 5 H, halo, and C as arbitrarily substituted. 1-6 alkyl and C(O)OR 14 Selected from the group consisting of R 5 is H and optionally substituted C 1-6 Selected from the group consisting of alkyl groups. In some embodiments, R 5 H, C(O)OR 14 , and C(O)NR 15 R 16Selected from the group consisting of R 5 , arbitrarily substituted C 1-3 It is alkyl. 5 -C which is arbitrarily replaced 1-6 In some embodiments where the alkyl portion is -C 1-6 Alkyl is independently used 1 to 3 times, halo, hydroxyl, C 1-3 Alkoxy and halo-substituted C 1-3 Alkoxy, -S(O) m C 1-3 Alkyl is optionally and independently substituted, where m is an integer having a value of 0, 1, or 2, and -NR 20 R 21 , here, R 20 and R 21 H and C 1-3 Alkyl, halo-substituted C 1-3 Alkyl, for example CF2CF2H or CF3, or aryl is independently selected from the group. In some embodiments, R 5 , is H.

[0089] In some embodiments, R 4 It is selected from the group consisting of H. -(CR 18 R 19 ) t COOR 8 ,-(CR 18 R 19 ) t C(O)NR 9 R 10 ,-(CR 18 R 19 ) t NR 9 R 10 , arbitrarily substitute C 1-6 Alkyl, -(CR 18 R 19 ) t Ure 12 ,-(CR 18 R 19 ) t S(O) s R 13 In some embodiments, R 4 H, -(CR 18 R 19) t COOR 8 , and -(CR 18 R 19 ) t C(O)NR 9 R 10 A selection is made from the group consisting of, where t is 0, R 9 H, R 10 C is optionally replaced 1-6 It is alkyl. In some embodiments, R 4 R is selected from the group consisting of H, -COOH, -COOCH3, and -CONH(CH2)2NH2. In some embodiments, R 4 , is H.

[0090] In some embodiments, t is an integer with a value of 0, 1, 2, or 3. In some embodiments, t is 0.

[0091] In some embodiments, R 9 and R 10 Each of these is H and optionally substituted C 1-6 It is independently selected from the group consisting of alkyl groups.

[0092] In some embodiments, R 11 is H, and optionally substituted C 1-6 Selected from the group consisting of alkyl groups.

[0093] In some embodiments, R 12 and R 13 Each of these is independently selected from the group consisting of H and optionally substituted alkyl groups.

[0094] In some embodiments, n is 0 or 2.

[0095] In some embodiments, R 18 and R 19 Each of these is H and optionally substituted C 1-6 It is independently selected from the group consisting of alkyl groups.

[0096] Some embodiments involve compounds of formula (I). R 1 OH and OR 7 Selected from the group consisting of R 7 is an arbitrarily substituted C 1-6 It is alkyl, R 2 OH and OR 7 Selected from the group consisting of R 7 is an arbitrarily substituted C 1-6 It is alkyl, R 3 is an arbitrarily substituted C 1-6 It is alkyl, R 4 H, -(CR 18 R 19 ) t COOR 8 ,-(CR 18 R 19 ) t C(O)NR 9 R 10 A group consisting of is selected, where t is 0, and R 8 is H and optionally substituted C 1-6 Selected from alkyl, R 9 H and R 10 is an arbitrarily substituted C 1-6 It is alkyl, R 5 H is H, and R 6 This section lists compounds where H is the element or a halo.

[0097] Some embodiments involve compounds of formula (I). R 1 OH and OR 7 A group consisting of R is selected, where R 7 It is alkyl, R 2 OH and OR 7 A group consisting of R is selected, where R 7 is NR 22 R 23 C replaced by 1-6It is alkyl, and here R 22 and R 23 H and C are independent of each other. 1-3 Selected from the group consisting of alkyl groups, R 3 is an arbitrarily substituted C 1-6 It is alkyl, R 4 These are H, -COOH, -COOCH3, and -C(O)NR 9 R 10 A group consisting of R is selected, where R 9 H is H, and R 10 is amino-substituted C 1-6 Selected from the group consisting of alkyl and -(CH2)2NHC(O)Ot-butyl, R 5 H is H, and R 6 This section describes compounds selected from the group consisting of H and halo.

[0098] Some embodiments involve compounds of formula (I). R 1 It is selected from the group consisting of OH and -OCH3, R 2 It is selected from the group consisting of OH, -OCH3, and -O-(CH2)3NH2, R 3 C 1-6 Alkyl R 4 It is selected from the group consisting of H, -COOH, -COOCH3, -C(O)NH(CH2)2NH2, and -C(O)NH(CH2)2NHC(O)Ot-butyl, R 5 H is H, and R 6 This section describes compounds selected from the group consisting of H and bromo.

[0099] Some embodiments are compounds of formula (I), R 1 It is selected from the group consisting of OH and -OCH3, R 2It is selected from the group consisting of OH, -OCH3, and -O-(CH2)3NH2, R 3 , isopropyl, R 4 It is selected from the group consisting of H, -COOH, -COOCH3, -C(O)(CH2)2NH2, and -C(O)NH(CH2)2NHC(O)Ot-butyl, R 5 H is H, and R 6 This section describes compounds selected from the group consisting of H and bromo.

[0100] In one embodiment, the present disclosure relates to a compound of formula (Ia). [ka] Alternatively, a salt, solvate, or hydrate thereof may be described.

[0101] Substituent R of formula (Ia) 1a and R 2a Each of these is independently OH, OR 7a Selected from the group consisting of , and H. However, R 1a and R 2a At least one of them is OH or OR 7a This is conditional on the following:

[0102] Substituent R of formula (Ia) 7a is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Selected from the group consisting of alkyl and acyl compounds.

[0103] Substituent R of formula (Ia) 3a is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6Alkyl, optionally substituted C 3-6 Siloalkyl, optionally substituted C 4-6 The group is selected from siloalkenyls, halos, and optionally substituted heterocycles.

[0104] Substituent R of formula (Ia) 6a C is H, halo, hydroxyl, alkoxy, or optionally substituted. 1-6 Alkyl, alkyl halide, and optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynnyl and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0105] Substituent R of formula (Ia) 5a H, halo, and C as arbitrarily substituted. 1-6 Alkyl, -C(O)OR 14a -C(O)NR 15a R 16a , optionally substituted aryl, and optionally substituted -C 1-6 Selected from the group consisting of alkylaryl compounds.

[0106] Substituent R of formula (Ia) 14a H, and C as arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 It is independently selected from the group consisting of alkyl groups.

[0107] Substituent R of formula (Ia) 15a and R 16a Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of siloalkyls. Alternatively, R 15a and R 16aTogether with the nitrogen atoms to which they are bonded, they form saturated or unsaturated rings of 5-7 membered rings.

[0108] The subscript s' in expression (Ia) is an integer with a value of 0, 1, or 2.

[0109] The subscript t' in equation (Ia) is an integer with values ​​between 0 and 6.

[0110] Substituent R of formula (Ia) 4a C is a combination of H, halo, cyano, or any other substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, -(CR 18a R 19a ) t COOR 8a ,-(CR 18a R 19a ) t OC(O)R 8a ,-(CR 18a R 19a ) t' NR9R10,-(CR 18a R 19a ) t' C(O)NR 9a r 10a ,-(CR 18a R 19a ) t' NR 9a C(O)R 8a ,-(CR 18a r 19a ) t' s(O)2NR 9a R 10a ,-(CR 18a R 19a ) t' COR 11a ,-(CR 18a r 19a ) t' CH(O),-(CR 18a R 19a ) t' Ure 12a ,-(CR18a R 19a ) t' S(O) s' R 13a , arbitrarily substituted hetero rings and arbitrarily substituted hetero rings C 1-6 Selected from the group consisting of alkyl groups.

[0111] Substituent R of formula (Ia) 18a and R 19a Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups.

[0112] Substituent R of formula (Ia) 8a H, and C as arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 It is independently selected from the group consisting of alkyl groups.

[0113] Substituent R of formula (Ia) 9a and R 10a Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups. Alternatively, substituent R 9a and R 10a These, along with the nitrogen atoms to which they are bonded, form a 5- to 7-membered cyclic saturated or unsaturated ring.

[0114] Substituent R of formula (Ia) 11a These are, independently, hydrogen, and optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, -NR 9a R 10a and -OR 12a Selected from the group consisting of .

[0115] Substituent R of formula (Ia) 12a and R 13a Each of these can independently be H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, or an optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of siloalkyl groups.

[0116] In some embodiments, the salt of formula (Ia) is a pharmaceutically acceptable salt.

[0117] In some embodiments, R 1a and R 2a Each of them is independently OH. In some embodiments, R 1a and R 2a One of them is OH and the other is H. In some embodiments, R 1a and R 2a One of them is OH, and the other is OR 7a And in some embodiments, R 1a and R 2a Each of them is independently an OR 7a Here, each R 7a These are independently and arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Selected from the group consisting of alkyl and acyl. In some embodiments, R 7a is an arbitrarily substituted C 1-4 It is alkyl. In some embodiments, R 7a It is methyl or ethyl.

[0118] In some embodiments, R 3ais an arbitrarily substituted C 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyls. In some embodiments, R 3a , arbitrarily substituted C 3-6 It is alkyl. In some embodiments, R 3a is isopropyl. In some embodiments, R 3a This is C, which has been replaced by an optional substitution. 3-6 It is a cycloalkyl compound. In some embodiments, the cycloalkyl compound is cyclopentyl.

[0119] In some embodiments, R 3a is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyl, R 1a and R 2a Each of these is independently OH. In some embodiments, R 3a is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyl, R 1a and R 2a Each of them is OH, OR 7a Independently selected from the group consisting of , and H, however R 1a and R 2a At least one of them is OH or OR 7a In another embodiment, R 3a is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyl, and R 1a and R 2a One of them is OH, and the other is H.

[0120] In some embodiments, R 4a and R 5a Each of these is independently selected from H and Halo.

[0121] In some embodiments, R4a H is R 5a H, halo, and C as arbitrarily substituted. 1-6 Alkyl, C(O)OR 14a , and C(O)NR 15a R 16a Selected from the group consisting of R 5a H is R 4a H, halo, and C as arbitrarily substituted. 1-6 Alkyl, C(O)OR 14a , and C(O)NR 15a R 16a Selected from the group consisting of .

[0122] In some embodiments, R 3a is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyl, R 1a and R 2a Both are OH, and R 4a and R 5a Each of these is selected independently from H and Halo.

[0123] In some embodiments, R 3a is an arbitrarily substituted C 3-6 It is alkyl, R 1a and R 2a Each of them is OH, and R 4a and R 5a Each of these is independently H or halo.

[0124] In some embodiments, R 6a H, halo, hydroxyl, C 1-6 alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, and optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynnyl and optionally substituted aryl C 1-6 Independently selected from the group consisting of alkyls. In some embodiments, R 6a H, halo, hydroxyl, C 1-3alkoxy, optionally substituted C 1-3 Selected from the group consisting of alkyls and alkyl halides. In some embodiments, R 6a is selected from the group consisting of H and halo. In some embodiments, R 6a H is H.

[0125] In some embodiments, R 6a The group consisting of H and halo is selected, and R 3a is an arbitrarily substituted C 3-6 It is alkyl, R 1a and R 2a Each of them is OH, and R 4a and R 5a Each of these is independently selected from the group consisting of H and halo.

[0126] In some embodiments, t is 0, and in some embodiments, t is 0, 1, 2, or 3.

[0127] Some embodiments of the present invention are [ka] , The target compounds are selected from the group consisting of salts, solvates, or hydrates thereof.

[0128] Some embodiments of the present invention relate to 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol [ka] , The subject matter includes pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0129] In some embodiments, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is a solid. In some embodiments, the solid is a crystalline solid. In some embodiments, the solid is an amorphous solid. In some embodiments, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is a non-solvated crystal. In some embodiments, isolated 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is described. In some embodiments, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is a hydrate. In some embodiments, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is an organic solvent hydrate. In some embodiments, isolated 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol organic solvent hydrate is described. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol acetonitrile / aqueous solvent. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol acetone solvate. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol N,N-dimethylformamide solvate. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol 1,4-dioxane / aqueous solution. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol butanone sorbate. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol tetrahydrofuran / aqueous solution. Some embodiments describe the ethyl acetate solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe the dimethyl carbonate solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol.Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol dimethyl sulfoxide solvate. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol 1-butanol solvate. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol tetrahydrofuran solvate. Some embodiments describe 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol methyl t-butyl ether solvate.

[0130] The present invention also includes various isomers of compounds according to any embodiment described herein, and mixtures thereof. Isomers are compounds having the same composition and molecular weight but different physical and / or chemical properties. Structural differences may be in composition (geometric isomers) or in the ability to rotate the plane of polarization (stereoisomers). Compounds according to any embodiment described herein may contain one or more asymmetric centers, also called chiral centers, and therefore may exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the present invention. Chiral centers may also be present in substituents such as alkyl groups. Where the stereochemistry of a chiral center present in a formula or in any chemical structure illustrated herein is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds according to any embodiment described herein, containing one or more chiral centers, can be used as racemic mixtures, enantiomerically concentrated mixtures, or enantiomerically pure individual stereoisomers. A mixture containing an uneven portion of enantiomers is described as having an “enantiomer excess” (ee) of either the R or S compound. An excess of one enantiomer in a mixture is often expressed as a % enantiomer excess. The ratio of enantiomers can also be defined by “optical purity,” which compares the degree to which the mixture of enantiomers rotates plane-polarized light to that of the individual optically pure R and S compounds. The compounds may also be substantially pure (+) or (-) enantiomers of the compounds described herein. In some embodiments, a composition may contain substantially pure enantiomers of the compounds according to any embodiment described herein, i.e., one enantiomer of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In certain embodiments, a composition may contain substantially pure enantiomers of the compounds according to any embodiment described herein, which are at least 99.5% of one enantiomer.

[0131] Individual stereoisomers of compounds according to any embodiment described herein, which contain one or more asymmetric centers, can be decomposed by methods known to those skilled in the art. For example, such decomposition can be carried out by (1) the formation of diastereoisomer salts, complexes or other derivatives, (2) by selective reaction with stereoisomer-specific reagents, for example by enzymatic oxidation or reduction, or (3) by gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica bound to a chiral ligand or in the presence of a chiral solvent. Those skilled in the art will understand that if a desired stereoisomer is converted to another chemical entity by one of the separation procedures described above, further steps are required to release the desired form. Alternatively, a particular stereoisomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation to convert one enantiomer to the other. Further embodiments include prodrugs of compounds according to any embodiment described herein, i.e., compounds that release the active compound according to any embodiment described herein in vivo when administered to a mammalian subject. A prodrug is a pharmacologically active compound, more typically an inactive compound, that is converted into a pharmacologically active agent by metabolic transformation. Prodrugs of compounds according to any embodiment described herein are prepared by modifying a functional group present in the compound so that the modification can be cleaved in vivo to release the parent compound. In vivo, the prodrug readily undergoes a chemical change under physiological conditions (e.g., by hydrolysis or by action by naturally occurring enzymes) to release the pharmacologically active agent. Prodrugs include compounds according to any embodiment described herein in which a hydroxyl group, an amino group, or a carboxyl group is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, an amino group, or a carboxyl group, respectively.Examples of prodrugs include, but are not limited to, esters of compounds according to any embodiment described herein (e.g., acetate, formate, and benzoate derivatives), or any other derivatives that are converted to the active parent drug when brought to physiological pH or by enzymatic action. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the Art.

[0132] Some of the compounds of the present invention can form salts with one or more equivalent amounts of acid (if the compound contains a basic moiety) or base (if the compound contains an acidic moiety). The present invention includes, within its scope, all possible stoichiometric and non-stoichiometric salt forms.

[0133] If the compound of the present invention contains a basic moiety, the desired salt form can be prepared by any suitable method known in the art, including treatment with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or treatment with an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, or pyranosidylic acids such as glucuronic acid, galacturonic acid, or α-hydroxy acids such as citric acid, tartaric acid, or amino acids such as aspartic acid, glutamic acid, or aromatics such as benzoic acid, cinnamic acid, or combinations with sulfonic acids such as plutenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid.

[0134] Suitable addition salts are formed from acids that form non-toxic salts, and examples include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, tartrate, borate, calcium edate, camusylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estrate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucept, gluconic acid, glutamate, glycolate, glycolylsanylic acid, hexylresorcinic acid, hydrobromide, hydrochloride, dihydrochloride, hydrogen fumarate, hydrogen phosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, and lac. Examples include tate, lactobionate, laurate, malate, mandelate, mesylate, methyl sulfate, monopotasmalate, mucate, napsilate, nitrate, N-methylglucamine, schuzarate, oxaltate, oxaloacetate, pamela, mesylate, mesylate, napsilate, napsilate, napsilate, napsilate, napsilate, mesylate, mesylate oxaloacetate, pamoate (embonate), palmitate, pantothenate, phosphate / disphosphate, pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theocrate, tosylate, triethiodate, trifluoroacetate, and valilate.

[0135] Other exemplary acid addition salts include pyrosulfates, sulfites, bisulfites, decanoates, caprylates, acrylates, isobutyrates, caproates, heptanoates, propioates, oxalates, malons, sverates, sebacates, butyn-1,4-geoate, hexyn-1,6-geoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, phenylacetate, phenylpropionate, phenylbutyrate, lactate, gamma-hydroxybutyrate, mandelates, and sulfonates (such as xylenesulfonic acid, propanesulfonic acid, naphthalene-1-sulfonic acid, and naphthalene-2-sulfonic acid).

[0136] When the basic compound of the present invention is isolated as a salt, the corresponding free base form of the compound is an inorganic or organic base, preferably with a pK higher than that of the free base form of the compound. a It can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic base having [a specific compound].

[0137] If the compound of the present invention contains an acidic moiety, the desired salt can be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal, or an alkaline earth metal hydroxide. Examples of suitable salts include Celite salts derived from amino acids such as glycine and arginine, ammonia; primary, secondary, and tertiary amines; salts of cyclic amines such as N-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine; and inorganic salts consisting of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0138] The compounds of the present invention having both a basic and an acidic site may be in the form of a zwitterion, an acid addition salt of the basic site, or a basic salt of the acidic site.

[0139] For its potential use in medicine, the salts of the compounds of the present invention are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are known to those skilled in the art.

[0140] These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or they may be prepared by separately treating the purified compound in the form of a free acid or free base with an appropriate base or acid, respectively.

[0141] In certain embodiments, the compounds of the present invention may contain acidic functional groups and, therefore, can be treated with a suitable base to form pharmaceutically acceptable base addition salts. Examples of such bases, but not limited to these, include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc, and b) aliphatic amines, aromatic amines, aliphatic diamines, and first, second, and third amines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine, as well as hydroxyalkylamines.

[0142] In certain embodiments, the compounds of the present invention may contain basic functional groups and, therefore, can be treated with a suitable acid to form pharmaceutically acceptable acid addition salts. Suitable acids include pharmaceutically acceptable inorganic and organic acids. Typical pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

[0143] The present invention also provides a method for converting one pharmaceutically acceptable salt of the compound of the present invention to another pharmaceutically acceptable salt of the compound of the present invention.

[0144] Compounds according to any embodiment described herein may exist in solid or liquid form. In the solid state, they may exist in crystalline or amorphous form, or as a mixture thereof. Those skilled in the art will understand that pharmaceutically acceptable solvates may be formed from crystalline compounds in which solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may contain, but are not limited to, non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, and may also contain water as the solvent incorporated into the crystal lattice. Solvates in which the solvent incorporated into the crystal lattice is water are commonly called “hydrates.” Hydrates include stoichiometric hydrates as well as compositions in which the amount of water is varied. The present invention includes all such solvates.

[0145] Those skilled in the art will understand that, with respect to solvates of compounds according to any embodiment described herein, which are in crystalline form, including solvates of salts of compounds according to any embodiment described herein, pharmaceutically acceptable solvates may be formed in which solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and RINKAN, or they may include water as the solvent incorporated into the crystal lattice. Solvates in which the solvent incorporated into the crystal lattice is water are commonly referred to as “hydrates.” Hydrates include not only stoichiometric hydrates but also compositions containing a variable amount of water. The present invention encompasses all such solvates.

[0146] Those skilled in the art will understand that compounds according to any embodiment described herein, existing in crystalline forms including their various solvates, may exhibit polymorphism (i.e., the ability to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The present invention encompasses all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of their crystalline solid state. Thus, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will understand that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or reagents used in the production of the compound. For example, changes in temperature, pressure, or solvent may result in polymorphism. Also, under certain conditions, one polymorph may spontaneously transform into another.

[0147] The subject invention also includes isotope-labeled compounds, which are identical to those described in the compounds of the present invention, except that one or more atoms are substituted by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts, solvates, or hydrates include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I is included.

[0148] Compounds according to any embodiment described herein, and pharmaceutically acceptable salts, solvates, or hydrates of such compounds containing the aforementioned isotopes and / or other atomic isotopes, are within the scope of the present invention. Examples of isotope-labeled compounds of the present invention include, 3 H, 14 Radioactive isotopes such as 13C are incorporated into assays for the tissue distribution of drugs and / or substrates. Tritium, i.e., 3 H, and carbon 14, that is, 14 Isotopes of 1C are particularly preferred in terms of ease of preparation and detectability. 11 C and 18 The F isotope is particularly useful in PET (positron emission tomography). 125 Isotopes I are particularly useful in SPECT (Single-Photon Emission Computed Tomography) and are also useful in brain imaging. Furthermore, heavier isotopes such as deuterium, i.e., 2 Substitution with H may provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or reduced dosage requirements, and is therefore preferred in some situations. Isotope-labeled compounds according to any embodiment described herein can generally be prepared by performing the procedures disclosed in the following schemes and / or examples, by substituting readily available isotope-labeled reagents with non-isotope-labeled reagents.

[0149] The present invention also includes isolated compounds. Isolated compounds are compounds that represent at least 10%, preferably at least 20%, more preferably at least 50%, and most preferably at least 80% of the compounds present in the mixture.

[0150] Since the compounds according to any embodiment described herein are intended for use in pharmaceutical compositions, it will be readily apparent that they are preferably provided in a substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, more preferably at least 85% pure, and especially at least 98% pure (percentages are on a weight-to-weight basis). In some embodiments, the compounds according to any embodiment described herein are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure. Impurity preparations of the compounds can be used to prepare a purer form for use in pharmaceutical compositions.

[0151] Pharmaceutical composition In some embodiments, pharmaceutical compositions comprising a compound according to any embodiment described herein, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof; and a pharmaceutically acceptable carrier or diluent are described. The pharmaceutical compositions can be prepared by methods well known in pharmaceutical technology and can be administered by various routes depending on whether topical or systemic treatment is desired and the site of treatment.

[0152] While any compound described in any embodiment of this specification may be administered as a bulk substance, it is preferable to present the compound in a pharmaceutical formulation, for example, in a state in which the activator is mixed with a pharmaceutically acceptable carrier selected with respect to the intended route of administration and standard pharmaceutical practice.

[0153] In particular, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any embodiment described herein, and optionally, a pharmaceutically acceptable carrier.

[0154] In some embodiments, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol [ka] Alternatively, pharmaceutical compositions comprising a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent are described.

[0155] In some embodiments, N-(2-aminoethyl)-3-[3,5-dihydroxy-4-(propan-2-yl)phenyl]isoquinoline-6-carboxamide [ka] Alternatively, pharmaceutical compositions comprising a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent are described.

[0156] In some embodiments, 3-(3-aminopropoxy)-5-(isoquinoline-3-yl)-2-(propan-2-yl)phenol [ka] The following describes a pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent. In one embodiment, the salt is trifluoroacetate [ka] That is the case.

[0157] Treatment method Vitiligo is a depigmentation disorder caused by the selective destruction of melanocytes. In melanocytes, AhR links UVB sunlight to skin pigmentation. Reduced risk of vitiligo associated with certain mutations in the AhR gene has been reported, and the authors have further found that AhR mutations promote AhR transcriptional activity, enhance interaction with the SP1 transcription factor, and increase AhR expression and IL-10 production in humans.

[0158] AhR-activating ligands suppress inflammation in the lesional skin of psoriasis patients, while AhR antagonists exacerbate the disease. AhR signaling via FICZ suppressed inflammation in imiquimod-induced mice, and AhR-deficient mice showed disease exacerbation compared to wild-type controls. Furthermore, it is noteworthy that keratinocytes were suggested to be involved in the inflammatory response.

[0159] Furthermore, activation of the AhR pathway has been shown to lead to inflammatory skin lesions such as atopic dermatitis and exacerbation of inflammatory diseases after occupational or environmental exposure to heterologous organisms. Coal tar, an AhR agonist, has been shown to completely restore the expression of major skin barrier proteins.

[0160] Early dry age-related macular degeneration (AMD) is a leading cause of vision loss in older adults. AhR activity and protein levels in human retinal pigment epithelial cells decrease with age, and AhR(- / -) mice exhibit decreased visual function and a dry AMD-like condition. Another group has shown that AhR(- / -) mice exhibit subretinal microglia accumulation and localized atrophy of retinal pigment epithelial cells, which are phenotypes observed in AMD.

[0161] The Malek lab discovered that AhR is also involved in wet AMD. They showed that in choroidal neovascular lesions experimentally induced in AhR(- / -) mice, there were lesions with a high number of ionized calcium-binding adapter molecule 1-positive (Iba1(+)) microglia and high levels of collagen type IV deposition, all of which are also observed in human wet AMD.

[0162] There are many other indications where the activation or antagonism of AhR may influence disease severity or progression. Furthermore, there is growing evidence that targeting AhR is beneficial in other disease conditions, such as the treatment of intestinal inflammation including irritable bowel disease (IBD), colitis, and Crohn's disease. AhR has also been shown to play a crucial role in protecting the lungs from allergen-induced inflammation by modulating MSC recruitment and immunosuppressive activity.

[0163] Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by severe itching. The causes of atopic dermatitis are multifactorial, with genetic factors, environmental factors, impaired skin barrier function, and a weakened immune response being the most significant contributing factors. This weakened immune response is characterized by activation of T-helper type 2 (Th2) cells accompanied by increased IgE production. Overexpression of eotaxin-3, IL-2, IL-5, and IL-13 is also observed in skin lesions. While the inflammatory components of atopic dermatitis are generally thought to be mediated primarily by the Th2 T-cell activation pathway, a shift to the T-helper type 1 (Th1)-driven pathway has been reported in chronic atopic dermatitis skin lesions. Atopic dermatitis frequently occurs in families with a history of other atopic diseases, supporting the hypothesis of a genetic link.

[0164] Atopic dermatitis is characterized by impaired skin barrier function, which is a key factor in its pathogenesis. Symptoms of atopic dermatitis may include itching, burning, lichenification, erythema, exudate, crusting, erosion, and scaling. Atopic dermatitis often significantly impacts quality of life due to both the stigma associated with visible skin lesions and the intense, persistent itching that can lead to sleep deprivation.

[0165] Currently, there is no cure for atopic dermatitis. In pediatric and adult patients, the primary goal of treatment is to stabilize the disease and reduce the frequency and severity of relapses. Patients require treatment during acute exacerbations and, if persistent, long-term maintenance therapy. In atopic dermatitis, topical therapy for skin inflammation, as well as symptom relief of itching, is a crucial element of disease management. While several topical therapy options exist, there is still a need for a topical therapy that combines high efficacy with a safety profile acceptable in adults and children, and can be applied to a wide body surface area without limitations on treatment duration. For acute exacerbations of atopic dermatitis, topical corticosteroids (TCS) are generally used as the standard treatment. However, TCS are generally not suitable for long-term use due to the potential for local and systemic adverse events (e.g., skin atrophy and increased risk of systemic exposure). In particular, current treatment options for atopic dermatitis in children are limited, considering safety concerns regarding long-term use (2-4 weeks or more) and application to sensitive areas such as the face and between the eyelashes.

[0166] Without wishing to be bound by any theory, the compounds according to the embodiments described herein are thought to have a different mechanism of action than topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs) and are expected to have an improved safety profile with superior efficacy compared to TCIs. The compounds according to the embodiments described herein would benefit children who: do not respond well to TCS; are intolerant to TCS; or are unsuitable for TCS (e.g., due to lesion site or treatment duration). Having an effective option for safe topical treatment can delay the transition to systemic treatment and limit the significant risks and costs associated with treatment for patients.

[0167] Psoriasis vulgaris is a chronic autoimmune inflammatory skin disease caused by the interaction of genetic, environmental, and systemic factors, affecting 2-3% of the Caucasian population. Abnormalities in the immune system are involved in the pathogenesis, including abnormal cell infiltration, production of inflammatory mediators, and keratinization. At the core of this process are Th17 cytokines (IL-17A, IL-17F, and IL-22), which (i) promote keratinocyte overgrowth and chemokine production, and (ii) perpetuate further recruitment of leukocytes.

[0168] The compounds according to the embodiments described herein may be used for the treatment of mild to moderate psoriasis. While there are numerous new biological treatment options for severe psoriasis, recent innovations in treatment options for patients with mild to moderate disease are limited. Given the significant contraindications of TCS treatment (long-term use and use in sensitive areas), a safe and effective topical treatment would be of great benefit to patients with mild to moderate psoriasis.

[0169] Accordingly, the present invention provides a method for treating a disorder related to the above-mentioned disease or disorder, comprising the step of administering to a subject in need of such treatment at least one compound described in any embodiment herein, and therefore in an effective amount.

[0170] In some embodiments, the present disclosure provides methods for preventing or treating conditions associated with AhR imbalance.

[0171] In some embodiments, the Disclosure provides a method for treating or preventing an AhR-mediated disease in a subject requiring such treatment, comprising administering to the subject an effective amount of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; or a pharmaceutical composition according to any embodiment described herein. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0172] Some embodiments include protection from ischemia or reperfusion injury occurring during clinical transplantation (such as organ transplantation, acute transplantation, xenotransplantation, or allotransplantation (as used in burn treatment) rejection), myocardial infarction, stroke, etc., and induction of transplant resistance; arthritis (such as rheumatoid arthritis, psoriatic arthritis, or osteoarthritis); IBD, including multiple sclerosis, ulcerative colitis, and Crohn's disease; lupus (systemic lupus erythematosus); graft-versus-host disease; T-cell-mediated hypersensitivity, such as contact hypersensitivity, eczema, delayed-type hypersensitivity, and gluten-induced irritable bowel syndrome (celiac disease); psoriasis; contact dermatitis (including that caused by poison ivy); Hashimoto's disease; autoimmune hyperthyroidism such as Sjögren's syndrome and Graves' disease; Addison's disease (an autoimmune disease of the adrenal gland); autoimmune polygranular disease (autoimmune polygranular syndrome and The present invention describes methods for treating or preventing morphea, including, as described herein; autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypospecific severity; Guillain-Barré syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; Uchikaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis), skin allergies; scleroderma; mycosis fungoides; acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia-reperfusion injury); dermatomyositis; hirsutism; chronic actinic dermatitis; eczema; Behçet's disease; palmoplantar pustulosis; pyoderma gangrenosum; Sézary syndrome; atopic dermatitis; systemic sclerosis; and morphea, comprising the step of administering an effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable pharmaceutically acceptable composition thereof, according to any embodiment described herein.

[0173] In some embodiments, a method is described for treating or preventing an allergic disease or disorder, an inflammatory disease or disorder, or an autoimmune disease or disorder in a subject requiring such treatment, comprising the step of administering to the subject an effective amount of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0174] Several embodiments describe methods for treating or preventing inflammatory diseases or disorders in subjects requiring such treatment, comprising the step of administering an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0175] In some embodiments, the inflammatory disease or disorder is an inflammatory skin disease or disorder. In some embodiments, the inflammatory skin disease or disorder is a chronic inflammatory skin disease or disorder, acne, psoriasis, rosacea, or aging skin. In some embodiments, the chronic inflammatory skin disease is dermatitis, such as atopic dermatitis, contact dermatitis, eczetra dermatitis, or seborrheic dermatitis.

[0176] In some embodiments, the inflammatory disease or disorder is selected from the group consisting of psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, or seborrheic dermatitis and acne. In some embodiments, the inflammatory disease or disorder is selected from the group consisting of psoriasis, atopic dermatitis, and acne. In some embodiments, the inflammatory disease or disorder is psoriasis. In some embodiments, the inflammatory disease or disorder is atopic dermatitis. In some embodiments, the inflammatory disease or disorder is acne.

[0177] Several embodiments describe methods for treating or preventing dermatological conditions or disorders in subjects requiring such treatment, comprising the step of administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0178] In some embodiments, a dermatological condition or disorder is a skin disease. In some embodiments, a skin disease is 1) a skin disorder of persistent inflammation, cell dynamics, and differentiation (e.g., psoriasis, psoriatic arthritis, exfoliative dermatitis, pityriasis rosea, lichen planus, lichen nitride, or porokeratosis); 2) a skin disorder of epidermal aggregation, vesicles, and vesicles (e.g., pemphigus, bullous pemphigus, acquired epidermolysis bullosa, or palmoplantar pustulosis); 3) a skin disorder of epidermal appendages and related disorders (e.g., hair disorders, nail disorders, alcohol disorders). 5) Skin disorders such as epidermal and adnexal dermatitis or follicular syndrome; 6) Skin disorders of inflammatory and neoplastic disorders of the dermis (e.g., perioral dermatitis or follicular syndrome); 7) Skin disorders of inflammatory and neoplastic disorders of the dermis (e.g., exudative 1) Skin disorders with reactive changes (e.g., urticaria, telangiectasia, graft-versus-host disease, allergic contact dermatitis, autosensitization dermatitis, atopic dermatitis, or seborrheic dermatitis); 2) Skin changes due to mechanical and physical factors (e.g., burns, radiation dermatitis, keratosis, or calluses); 3) Photoirritation (e.g., acute and chronic ultraviolet irradiation, or photosensitization); or 4) Skin disorders due to microbial agents (e.g., leprosy, Lyme borreliosis, onychomycosis, rubella, measles, herpes simplex, Epstein-Barr virus (EBV), human papillomavirus (HPV, e.g., HPV6 and 7), warts, or prions).

[0179] Several embodiments describe methods for treating or preventing radiation dermatitis in subjects requiring such treatment, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, radiation dermatitis is chronic radiation dermatitis. In some embodiments, radiation dermatitis is acute radiation dermatitis. In some embodiments, radiation dermatitis is acute erythema, desquamation, desquamation, fibrosis, telangiectasia and skin atrophy or a combination thereof. In some embodiments, radiation dermatitis is acute erythema, desquamation, or desquamation or a combination thereof. In some embodiments, radiation dermatitis is fibrosis, telangiectasia and skin atrophy or a combination thereof.

[0180] Several embodiments describe methods for treating or preventing inflammatory mucosal conditions in subjects requiring such treatment, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, inflammatory mucosal conditions are induced by radiation or chemotherapy for cancer. In some embodiments, inflammatory mucosal conditions include oral mucositis, lichen planus, and pemphigus vulgaris. In some embodiments, inflammatory mucosal conditions include oral mucositis such as oral lichen planus, erythema multiforme, mucosal pemphigus, pemphigus vulgaris, and bullous epidermolysis bullosa. In some embodiments, oral mucositis is induced by radiation or chemotherapy for cancer. In some embodiments, oral mucositis is induced by radiation or chemotherapy for cancer of the head and / or neck. In some embodiments, oral mucositis is induced by radiation therapy for cancer of the head and / or neck.

[0181] Some embodiments describe a method for treating atopic dermatitis in a subject requiring it, comprising the step of administering a therapeutically effective amount of the compound of formula (1) to the subject. [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition thereof.

[0182] Some embodiments are methods for treating psoriasis in a subject requiring the treatment, comprising: a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol [ka] The present invention describes a method comprising the step of administering a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition thereof.

[0183] Some embodiments are methods for treating atopic dermatitis in subjects requiring the treatment of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol [ka] The description includes a step of administering a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition thereof.

[0184] Some embodiments describe a method for treating atopic dermatitis or psoriasis, comprising the step of administering to a subject in need of such treatment a topical cream containing a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0185] Some embodiments describe a method for treating atopic dermatitis or psoriasis, comprising the step of administering to a subject in need of such treatment a topical gel containing a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0186] Some embodiments describe a method for treating atopic dermatitis or psoriasis, comprising the step of administering to a subject in need of such treatment a topical lotion containing a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0187] In some embodiments, the compound is an agonist of an AhR ligand. In some embodiments, the compound is an antagonist of an AhR ligand.

[0188] Compounds according to any embodiment described herein may be used in a veterinary or medical setting. It is recognized that the subject or patient may be an animal, such as a mammal, including horses, cattle, pigs, sheep, poultry, fish, cattle, dogs, and zoo animals. In some embodiments, the subject is an animal.

[0189] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the human is an adult or a pediatric patient. In some embodiments, the human is a pediatric patient. In some embodiments, the pediatric patient is a child. In some embodiments, the pediatric patient is between 3 months and 2 years of age. In some embodiments, the human is an adult.

[0190] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for therapeutic use. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0191] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for use in the treatment or prevention of conditions related to AhR imbalance. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0192] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for use in the treatment or prevention of AhR-mediated diseases. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0193] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for use in the treatment or prevention of inflammatory diseases or disorders. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0194] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for use in the treatment or prevention of dermatological conditions or disorders. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0195] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for use in the treatment or prevention of psoriasis. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0196] In some embodiments, compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, are described for use in the treatment or prevention of atopic dermatitis. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0197] Several embodiments describe the use of compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, in the manufacture of pharmaceuticals for conditions related to AhR imbalance, in subjects requiring such use. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0198] Several embodiments illustrate the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, in the manufacture of a medicament for the treatment of AhR-mediated diseases in subjects requiring such treatment. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0199] Several embodiments illustrate the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, in the manufacture of pharmaceuticals for the treatment or prevention of inflammatory disorders in subjects requiring such treatment or prevention. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0200] Several embodiments illustrate the use of compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, in the manufacture of pharmaceuticals for the treatment or prevention of dermatological conditions or disorders in subjects requiring such treatment or prevention. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Several embodiments describe the use of compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, in the manufacture of pharmaceuticals for the treatment or prevention of psoriasis in subjects requiring such treatment or prevention. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0201] Several embodiments describe the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, in the manufacture of a medicament for the treatment or prevention of atopic dermatitis in subjects requiring such treatment or prevention. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0202] Several embodiments illustrate the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, for the treatment or prevention of conditions associated with AhR imbalance in subjects requiring such treatment or prevention. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0203] Several embodiments illustrate the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, for the treatment or prevention of AhR-mediated diseases. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0204] Several embodiments illustrate the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, for the treatment or prevention of inflammatory diseases or disorders. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0205] Several embodiments illustrate the use of compounds, or pharmaceutically acceptable salts, solvates, or hydrates thereof, according to any embodiment described herein, in the manufacture of pharmaceuticals for the treatment or prevention of dermatological conditions or disorders. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0206] In some embodiments, the use of compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, in the manufacture of a medicament for the treatment or prevention of psoriasis is described. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0207] In some embodiments, the use of compounds according to any embodiment described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, in the manufacture of a medicament for the treatment or prevention of atopic dermatitis is described. In some embodiments, the compound is a compound of formula (I) or formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0208] combination With respect to the pharmaceutical compositions and methods / uses described herein, the compounds of any embodiment described herein may be administered in combination with one or more other therapeutic agents and / or activators. In some embodiments, the compounds of any embodiment described herein are administered in combination with a second agent for a disorder or disease described herein, simultaneously with, before, or after the administration of the second agent. In some embodiments, the second agent is contained in the same formulation as the compound of any embodiment described herein. In some embodiments, the second agent is in a separate formulation. The second therapeutic agent may be administered via the same route as the compound of any embodiment described herein, or via a different route than the compound of any embodiment described herein. For example, the compound of any embodiment described herein may be administered topically, and the second agent may be administered topically, orally, intravenously, intramuscularly, ophthalmologically, vaginally, rectally, etc. In some embodiments, the second agent is administered simultaneously with the compound of the present invention. In some embodiments, the second agent is administered before the compound of the present invention. In some embodiments, the second agent is administered after the compound of the present invention.

[0209] In other words, the compounds according to any embodiment described herein can be administered together, simultaneously, or sequentially, in any order, to the administration site or the desired site of action. The order of administration is not considered necessary. However, when administered topically, it may be preferable that two or more activators be in contact together at the administration site or the desired site of action at some point in time. Alternatively, it is preferable that the timing for the appropriate mode of action of the activators be appropriate in terms of the delivery time of the activators. If both are present in the same vehicle, they provide ease of administration to the patient and may improve compliance, but this is not necessary for the inventions described herein.

[0210] When a compound according to any embodiment described herein is administered in combination with one or more other therapeutic agents and / or active agents described herein, each of the active agent components (i.e., the compound of the present invention and the second agent) is contained in an effective dose.

[0211] In some embodiments, the second agent is an agent for treating or preventing conditions associated with an AhR imbalance.

[0212] In some embodiments, other agents(s) are useful for the prevention or treatment of allergic diseases, inflammatory diseases, or autoimmune diseases. In some embodiments, the agents(s) are antigen immunotherapies; antihistamines; corticosteroids, e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, and flunisonide; NSAIDs; leukotriene modulators (montelukast, zafirlukast, pranlukast, etc.); iNOS inhibitors; tryptase inhibitors; IKK2 inhibitors p38 inhibitors; Syk inhibitors; protease inhibitors; elastase inhibitors; integrin antagonists, e.g., β2 integrin antagonists; adenosine A2α agonists; mediator release inhibitors, e.g., sodium cromograate; 5-lipoxygenase inhibitors (zyflo); DP1 antagonists; DP2 antagonists; PI3K delta inhibitors; ITK inhibitors; LP (lysophosphatidic) inhibitors; or FLAP (5-lipoxygenase activator Protein inhibitors, e.g., 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridine-3-yl)benzyl)-5-((5-methylpyridine-2-yl)methoxy)-1H-indole-2-yl)-2,2-dimethylpropanoate sodium); bronchodilators, e.g., muscarinic antagonists and β2 agonists; methotrexate and similar agents; anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 This includes monoclonal antibody therapies such as and similar drugs, cytokine receptor therapies such as etanercept and similar drugs; and antigen-nonspecific immunotherapies such as interferon or other cytokines / chemokines, chemokine receptor modulators such as CCR3, CCR4, or CXCR2 antagonists, agonists or antagonists of other cytokines / chemokines, TLR agonists and similar drugs.

[0213] In some embodiments, the other(s) are drugs to assist transplantation, such as cyclosporine, tacrolimus, mycophenolate mofetil, prednisone, azathioprine, sirolimus, daclizumab, basiliximab, or OKT3.

[0214] In some embodiments, other drugs(s) may include drugs for treating diabetes, such as metformin (biguanide), meglitinoids, sulfonylurea, DPP-4 inhibitors, thiazolidinediones, or α-glucosidase inhibitors, amylin mimetic drugs, incretin mimetic drugs, or insulin.

[0215] In some embodiments, the other(s) are antihypertensive agents such as diuretics, ACE inhibitors, ARBS, calcium channel blockers, and beta-blockers.

[0216] Accordingly, in further embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable derivative thereof according to any embodiment described herein; a second activator; and an optionally pharmaceutically acceptable carrier.

[0217] When incorporated into the same formulation, it will be understood that two or more compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation in the manner known for such compounds in the art.

[0218] Preservatives, stabilizers, colorants, and flavorings may be provided in any pharmaceutical composition described herein. Examples of preservatives include sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0219] For combinations involving biologics such as monoclonal antibodies or fragments, appropriate excipients will be employed to prevent aggregation and stabilize the antibody or fragment in solution with low endotoxin for parenteral administration, such as intravenous administration. See, for example, *Formulation and Delivery Issues for Monoclonal Antibody Therapeutics*, Daugherty et al., in *Current Trends in Monoclonal Antibody Development and Manufacturing*, Part 4, 2010, Springer, New York, pp. 103-129.

[0220] Route of administration and unit dosage form Compounds according to any embodiment described herein and pharmaceutical compositions incorporating such compounds can be conveniently administered by any route conventionally used for drug administration, e.g., orally, topically, transdermally, parenterally, or by inhalation. The compounds can be administered in conventional dosage forms prepared by combining the compounds according to any embodiment described herein with a standard pharmaceutical carrier according to conventional procedures. The compounds according to any embodiment described herein may also be administered in conventional doses in combination with a known second therapeutically active compound, as further described herein. These procedures may include mixing, granulating, and compressing or dissolving the components to suit the desired preparation. It will be understood that the pharmaceutically acceptable properties or form and properties of the diluent are determined by the amount of the active ingredient combined with it, the route of administration, and other well-known variables. The carrier(s) must be “acceptable” in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient.

[0221] Compounds according to any embodiment described herein may be administered topically, i.e., non-systemically. This includes external application of the compound to the epidermis or cheek cavity, or insulation of such compound into the ears, eyes, and nose, such that the compound does not significantly enter the bloodstream. Systemic administration, in contrast, refers to oral administration, intravenous administration, intraperitoneal administration, and intramuscular administration, etc.

[0222] Formulations suitable for topical administration include liniments, lotions, creams, gels, solutions, ointments, pastes, and drops suitable for application to the skin, eyes, ears, and nose, as well as liquid or semi-liquid formulations suitable for penetration from the skin to the site of inflammation.

[0223] The lotions according to the present invention include those suitable for application to the skin, ears, nose, or eyes. Eye lotions optionally consist of a sterile aqueous solution containing a disinfectant and can be prepared in a manner similar to that of eye drops. Lotions or liniments for application to the skin may contain agents to accelerate drying and cool the skin, such as alcohol or acetone, and / or moisturizers such as glycerol, and oils such as castor oil or arachis oil.

[0224] The creams, gels, ointments, or pastes according to the present invention are semi-solid formulations of active ingredients for external use. They can be prepared by mixing finely divided or powdered active ingredients (i.e., compounds according to any embodiment described herein) alone or as a solution or suspension in an aqueous or non-aqueous fluid with an oily or non-oily base with the help of appropriate machinery. The base may consist of fatty acids such as steric acid or oleic acid, together with hard, soft, or liquid paraffin, hydrocarbons such as glycerol, beeswax, or metallic soap, mucilage, naturally derived oils such as almond, corn, arachis, castor, or olive oil, wool fat or its derivatives, or alcohols or macrogels such as propylene glycol. The formulations can incorporate any suitable surfactant, such as anionic, cationic, or nonionic surfactants such as sorbitan esters or their polyoxyethylene derivatives. Suspensioning agents such as inorganic materials such as natural gum, cellulose derivatives, or silicic silica, and other components such as lanolin may also be included.

[0225] The dropper according to the present invention comprises a sterile aqueous or oily solution or suspension and can be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericide and / or fungicide and / or any other suitable preservative, preferably including a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, sealed, and sterilized by autoclaving or maintaining at 98-100°C for 30 minutes. Alternatively, the solution may be filtered and sterilized, and then transferred to a container using aseptic techniques. Examples of bactericides and fungicides suitable for inclusion in the dropper include phenyl nitrate or phenyl acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing the oily solution include glycerol, diluting alcohol, and propylene glycol.

[0226] In some embodiments, the compounds according to any embodiment described herein are administered topically as a cream, gel ointment, paste, drop, or lotion. In some embodiments, the compounds according to any embodiment described herein are administered as a gel or cream. In some embodiments, the compounds according to any embodiment described herein are administered as a gel. In some embodiments, the compounds according to any embodiment described herein are administered as a cream.

[0227] In some embodiments, the pharmaceutical formulation comprises the compound according to any embodiment described herein, and pharmaceutically acceptable excipients or diluents and antioxidants, preservatives, gelling agents, pH adjusters, or stabilizers, or mixtures thereof, that are suitably adapted for topical administration to the patient's skin, eyes, or ears.

[0228] In some embodiments, the composition is a cream or gel composition, and the compound of formula (I) is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol.

[0229] In some embodiments, the composition is a cream formulation. In some embodiments, the composition is a cream formulation 1 comprising the following: [Table 1]

[0230] It will be understood that if 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is present in a cream formulation 1 at a specific concentration (in the range of 0 to 1%), the formulation may be called X% cream formulation 1. For example, in some embodiments, the composition is cream formulation 1 containing 1% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (1% cream formulation 1). Thus, 1% cream formulation 1 is configured as follows: [Table 2]

[0231] In some embodiments, the composition is a 0.5% cream formulation comprising a 0.5% cream formulation 1. [Table 3]

[0232] In some embodiments, the composition is a 0.1% cream formulation 1 comprising the following: [Table 4]

[0233] In some embodiments, the composition is a cream formulation 2 comprising the following: [Table 5]

[0234] In some embodiments, the composition is a cream formulation 3 comprising the following: [Table 6]

[0235] In some embodiments, the composition is a 1% cream formulation 3 comprising the following: [Table 7]

[0236] In some embodiments, the composition comprises a 0.5% cream formulation 3. [Table 8]

[0237] In some embodiments, the composition is a cream formulation 4 comprising the following: [Table 9]

[0238] In some embodiments, the composition is a cream formulation 5 comprising the following: [Table 10]

[0239] In some embodiments, the composition is a cream formulation 6 comprising the following: [Table 11]

[0240] In some embodiments, the composition is a cream formulation 7 comprising the following: [Table 12]

[0241] In some embodiments, the composition is a gel formulation (gel formulation 1) comprising the following: [Table 13]

[0242] In some embodiments, the composition is a gel formulation (1% gel formulation 1) comprising the following: [Table 14]

[0243] In some embodiments, the composition is a gel formulation (gel formulation 2) comprising the following: [Table 15]

[0244] In some embodiments, the composition is a gel formulation (gel formulation 3) comprising the following: [Table 16]

[0245] In some embodiments, the composition is a gel formulation (gel formulation 4) comprising the following: [Table 17]

[0246] While topical application is the preferred route of administration, the compounds according to any embodiment described herein may also be administered parenterally, i.e., intravenously, intramuscularly, subcutaneously, intranasally, rectally, vaginally, or intraperitoneally. Subcutaneous and intramuscular parenteral administration is generally preferred. Suitable dosage forms for such administration can be prepared by conventional art. The compounds according to any embodiment described herein can also be administered by inhalation, i.e., intranasally and orally. Suitable dosage forms for such administration, such as aerosol formulations or metered-dose inhalers, can be prepared by conventional art.

[0247] The dosage of the compound as the active ingredient of the present invention, according to any embodiment described herein, can be varied to obtain an appropriate dosage form. The active ingredient may be administered to subjects (animals and humans) requiring such treatment in a dosage that provides optimal pharmaceutically effective efficacy. The selected dosage depends on the desired therapeutic effect, route of administration, and duration of treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the patient's weight, any special diet the patient is following at the time, any concomitant medications, and other factors that a person skilled in the art would recognize.

[0248] In some embodiments, the amount of compound administered may be between about 0.1 and about 100 mg / kg / day. Generally, doses between 0.1 and 10 mg / kg body weight per day are administered to patients, e.g., humans. In some embodiments, the therapeutic effective dose is defined as a lower limit of approximately 0.1 mg / kg body weight, approximately 0.2 mg / kg body weight, approximately 0.3 mg / kg body weight, approximately 0.4 mg / kg body weight, approximately 0.5 mg / kg body weight, approximately 0.6 mg / kg body weight, approximately 0.7 mg / kg body weight, approximately 0.8 mg / kg body weight, approximately 0.9 mg / kg body weight, approximately 1 mg / kg body weight, approximately 5 mg / kg body weight, approximately 10 mg / kg body weight, approximately 15 mg / kg body weight, approximately 20 mg / kg body weight, approximately 25 mg / kg body weight, approximately 30 mg / kg body weight, approximately 35 mg / kg body weight, approximately 40 mg / kg body weight, approximately 45 mg / kg body weight, approximately 50 mg / kg body weight, approximately 55 mg / kg body weight, approximately 60 mg / kg body weight, approximately 65 mg / kg body weight, approximately 70 mg / kg body weight, approximately 75 mg / kg body weight, approximately 80 mg / kg body weight, approximately 85 mg / kg body weight, approximately 80 mg / kg body weight, approximately 95 mg / kg body weight, and approximately 100 mg / kg body weight, and an upper limit of 100 mg / kg body weight. The daily weights per kilogram include approximately 95 mg / kg, 90 mg / kg, 85 mg / kg, 80 mg / kg, 75 mg / kg, 70 mg / kg, 65 mg / kg, 60 mg / kg, 55 mg / kg, 50 mg / kg, 45 mg / kg, 40 mg / kg, 35 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 15 mg / kg, 10 mg / kg, 5 mg / kg, 1 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, 0.6 mg / kg, 0.5 mg / kg, 0.4 mg / kg, 0.3 mg / kg, 0.2 mg / kg, and 0.1 kg / kg.

[0249] In some embodiments, the compounds according to any embodiment described herein are administered to the subject in a total daily dose of about 0.01 to about 1000 mg / day. In some embodiments, the total daily dose is about 0.1 to about 100 mg / day. In some embodiments, the total daily dose ranges from about 0.01 mg / day, about 0.05 mg / day, about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, Approx. 190mg / day, Approx. 200mg / day, Approx. 210mg / day, Approx. 220mg / day, Approx. 230mg / day, Approx. 240mg / day, Approx. 250mg / day, Approx. 240mg / day, Approx. 260mg / day, Approx. 270mg / day, Approx. 280mg / day, Approx. 0mg / day, about 310mg / day, about 320mg / day, about 330mg / day, about 340mg / day, about 350mg / day, about 360mg / day, about 370mg / day, about 340mg / day, about 350mg / day, about 260mg / day, about 370mg / day, about 380mg / day Approximately 390mg / day, approximately 400mg / day, approximately 410mg / day, approximately 420mg / day, approximately 430mg / day, approximately 440mg / day, approximately 450mg / day, approximately 460mg / day, approximately 470mg / day, approximately 480mg / day, approximately 490mg / day, approximately 500mg / day, approximately 510mg / day, approximately 520mg / day, approximately 530mg / day, approximately 540mg / day, approximately 550mg / day, approximately 560mg / day, approximately 570mg / day, approximately 580mg / day, approximately 590mg / day, approximately 600mg / day, approximately 610mg / day, approximately 620mg / day, approximately 670mg g / day, approximately 670 mg / day, approximately 670 mg / day, approximately 680 mg / day, approximately 500 mg / day, approximately 60 mg / day, approximately 40 mg / day, approximately 70 mg / day, approximately 70 mg / day, approximately 70 mg / day, approximately 670 mg / day, approximately 620 mg / day, approximately 630 mg / day, approximately 640 mg / day, approximately 650 mg / day, approximately 660 mg / day, approximately 670 mg / day, approximately 680 mg / day, approximately 690 mg / day, approximately 700 mg / day, approximately 710 mg / day, approximately 720 mg / day, approximately 730 mg / day, approximately 740 mg / day, approximately 750 mg / day, approximately 760 mg / day,Approximately 770 mg / day, approximately 780 mg / day, approximately 790 mg / day, approximately 800 mg / day, approximately 810 mg / day, approximately 820 mg / day, approximately 830 mg / day, approximately 840 mg / day, approximately 850 mg / day, approximately 860 mg / day, approximately 870 mg / day, approximately 880 mg / day, approximately 770 mg / day, approximately 790 mg / day, approximately 770 mg / day, approximately 770 mg / day, approximately 770 mg / day, approximately 770 mg / day, approximately 770 mg / day, approximately 770 mg / day, approximately 770 mg / day, approximately 780 mg / day, approximately 890 mg / day, approximately 900 mg / day, approximately 910 mg / day, approximately 920 mg / day, approximately 930 mg / day The daily doses are approximately 940mg / day, 950mg / day, 960mg / day, 970mg / day, 980mg / day, 990mg / day, and 1000mg / day, with upper limits of 1000mg / day, 990mg / day, 970mg / day, 960mg / day, 950mg / day, 940mg / day, 930mg / day, 920mg / day, 910mg / day, 900mg / day, 890mg / day, 880mg / day, 870mg / day, 860mg / day, 850mg / day, 840mg / day, 830mg / day, 820mg / day, 810mg / day, and 800mg / day. mg / day, approximately 790 mg / day, approximately 780 mg / day, approximately 770 mg / day, approximately 760 mg / day, approximately 750 mg / day, approximately 740 mg / day, approximately 730 mg / day, approximately 720 mg / day, approximately 710 mg / day, approximately 700 mg / day, approximately 690 mg / day, approximately 680 mg / day, approximately 670 mg / day, approximately 660 mg / day, approximately 650 mg / day, approximately 640 mg / day, approximately 630 mg / day, approximately 620 mg / day, approximately 610 mg / day, approximately 600 mg / day, approximately 590 mg / day, approximately 580 mg / day, approximately 570 mg / day, approximately 560 mg / day, approximately 550 mg / day, approximately 540 mg / day, approximately 530 mg / day, 5 20mg / day, approximately 540mg / day, approximately 510mg / day, approximately 500mg / day, approximately 490mg / day, approximately 480mg / day, approximately 470mg / day, approximately 460mg / day, approximately 450mg / day, approximately 440mg / day, approximately 430mg / day, approximately 420mg / day, 410mg / day, approximately 400mg / day, approximately 390mg / day, approximately 380mg / day, approximately 370mg / day, approximately 360mg / day, approximately 350mg / day, approximately 340mg / day, approximately 330mg / day, approximately 320mg / day, approximately 310mg / day, approximately 300mg / day, approximately 290mg / day, approximately 280mg / day, approximately 270mg / day, approximately 240mg / day,Approximately 240mg / day, approximately 30mg / day, approximately 260mg / day, approximately 250mg / day, approximately 240mg / day, approximately 230mg / day, approximately 220mg / day, approximately 210mg / day , about 200 mg / day, about 190 mg / day, about 180 mg / day, about 170 mg / day, about 160 mg / day, about 150 mg / day, about 140 mg / day, about 180 mg The daily doses are approximately 130 mg / day, 120 mg / day, 110 mg / day, 100 mg / day, 90 mg / day, 80 mg / day, 70 mg / day, 60 mg / day, 50 mg / day, 40 mg / day, 30 mg / day, 10 mg / day, 1 mg / day, 0.5 mg / day, 0.1 mg / day, and 0.01 mg / day.

[0250] It will be understood that the pharmaceutical compositions disclosed herein do not necessarily need to contain the entire amount of the compound effective to treat a disorder, since such an effective amount can be achieved by multiple divided doses of such pharmaceutical compositions. The compound may be administered as a single dose per day, or in a regimen of multiple doses per day (e.g., two, three, four, five, or more) of small doses, such that the total daily dose is the same. The effective amount of its salt may be determined as a percentage of the effective amount of the compound according to any embodiment described herein. Similar doses should also be appropriate for the treatment of other conditions referred to herein for treatment. In general, determining an appropriate dose can be easily achieved by those skilled in the art of medicine or pharmacy.

[0251] The active ingredient, i.e., the compound according to any embodiment described herein, may be for topical administration, administered at a concentration of approximately 0.001% w / w to approximately 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein may be at a concentration of 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, or 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein may be at a concentration of 1% w / w to 2% w / w of the formulation. A daily topical administration regimen may involve administering approximately 0.1 mg to 150 mg of the compound according to any embodiment described herein, 1 to 4 times a day.In some embodiments, the daily topical dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg , 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg , 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg The initial doses were one of the following: 115 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, or 150 mg. The initial dose can also be estimated from invisibility data using animal models. Animal models useful for testing the efficacy of compounds that treat or prevent the various diseases mentioned above are well known in the art.The compound can be administered once a week, several times a week (e.g., every other day), once a day, or multiple times a day, at the discretion of the prescribing physician.

[0252] Those skilled in the art will recognize that the optimal doses and intervals of individual doses of the compounds, or their pharmaceutically acceptable salts, solvates, or hydrates, according to any embodiment described herein, are determined by the nature and severity of the condition being treated, the form, route, and site of administration, and the patient being treated, and that such optimal values ​​can be determined by the prior art. Furthermore, it will be understood that the optimal course of treatment, i.e., the daily dose of the compounds, or their pharmaceutically acceptable salts, solvates, or hydrates, according to any embodiment described herein, over a specified number of days, can be determined by those skilled in the art using conventional treatment course determination tests.

[0253] Method for preparing the compound of formula (8) Some embodiments of the compound of formula 8 [ka] or a step for preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising the compound of formula 7. [ka] The present invention describes a method comprising the step of demethylating a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0254] In some embodiments, the process involves compounding the compound of formula 6. [ka] The compound of formula 5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [ka] The process further comprises coupling with a pharmaceutically acceptable salt, solvate, or hydrate thereof to form the compound of formula 7.

[0255] In some embodiments, the process involves compounding the compound of formula 4. [ka] The process further comprises a step of borylating a pharmaceutically acceptable salt, solvate, or hydrate thereof to form the compound of formula 5.

[0256] In some embodiments, this step involves compounding the compound of formula 3. [ka] The process further comprises a step of hydrogenating a pharmaceutically acceptable salt, solvate, or hydrate thereof to form the compound of formula 4.

[0257] In some embodiments, the process involves the ketone of formula 2. [ka] The process includes treating a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent, and then removing water under acidic conditions to form the compound of formula 3.

[0258] In some embodiments, the process further includes the step of alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate to form a compound of formula 2.

[0259] In some embodiments, demethylating the compound of formula 7 to form the compound of formula 8 includes the step of treating the compound of formula 7 with boron tribromide.

[0260] In some embodiments, the demethylation of the compound of formula 7 to form the compound of formula 8 is performed by a) treating the compound of formula 7 with boron tribromide to form the compound of formula 7-1. [ka] and b) a step of hydrogenating the compound of formula 7-1 to form the compound of formula 8.

[0261] In some embodiments, the demethylation of the compound of formula 7 to form the compound of formula 8 includes the step of treating the compound of formula 7 with hydrobromic acid.

[0262] Some embodiments of the compound of formula 8 [ka] A process for preparing, a) Compounds of formula 6 [ka] A compound of the same, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and the compound of formula 5. [ka] The steps include coupling a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 7, and b) A step comprising demethylating a compound of formula 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 8.

[0263] In some embodiments, the compound of formula 6 [ka] Alternatively, any pharmaceutically acceptable salt, solvate, or hydrate thereof obtained by any process described herein may be prepared by treating isoquinoline-3-ol with a triflate agent.

[0264] In some embodiments, the compound of Formula 5 or its pharmaceutically acceptable salt, solvate, or hydrate by any process described herein includes the following steps: a) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate to form a compound of formula 2. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, b) Treat the ketone of formula 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent, and then remove water under acidic conditions to obtain the compound of formula 3. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, c) Hydrogenating a compound of formula 3 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain a compound of formula 4. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and d) Prepared by borylating a compound of formula 4 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0265] Some embodiments of the compound of formula 8 [ka] or a process for preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, a) Compounds of formula 5 [ka] or a step of preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, 1) Alkylate 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate to obtain a compound of formula 2. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 2) Treat the ketone of formula 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent, and then remove water under acidic conditions to obtain the compound of formula 3. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 3) Compounds of formula 3 [ka] The steps include: and hydrogenating a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 4, 4) The preparation step comprising the step of borylating a compound of formula 4 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, b) Compounds of formula 6 [ka] or a step of preparing a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising treating isoquinoline-3-ol with a triflate agent, and c) A compound of formula 6 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is coupled with a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 7. [ka] or to the extent that it forms a pharmaceutically acceptable salt, solvate, or hydrate thereof, and d) A step of demethylating a compound of formula 7 to form a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein steps a and b can be carried out in different reaction vessels, in any order, or simultaneously, and the step of forming the compound.

[0266] In some embodiments of any process described herein, the process further includes a step of purifying the compound of formula 8. In some embodiments, the purification includes a step of crystallizing the compound of formula 8.

[0267] The appropriate amount in any given example will be readily apparent to those skilled in the art and can be determined by routine experimentation. The composition is generally applied topically to the affected area, that is, topically to the area of ​​skin where the clinical abnormality is manifest.

[0268] Unless otherwise specified, all percentages are based on the weight percentage of the final prepared composition, and all totals equal 100 weight percent. [Examples]

[0269] Examples While the present invention has been described in considerable detail with reference to certain preferred embodiments, other versions are also possible. Therefore, the spirit and scope of the appended claims should not be limited to the descriptions and preferred versions contained herein. Various embodiments of the present invention are described with reference to the following non-limiting embodiments. The following embodiments are for illustrative purposes only and should not be construed as limiting the invention in any way. [Table 18]

[0270] LCMS standard A LC conditions: ULC analysis was performed at 50°C using a Waters Acquity BEH C18 2x50mm 1.7m column. • 0.5 μL of sample was injected using a partial loop (with needle overfill) injection mode. The gradient used is Mobile phase A: Water + 0.20% v / v formic acid Mobile phase B: Acetonitrile + 0.15% v / v formic acid ·Time%A%B flow rate ·min95 5 1 ml / min ·1.10 minutes 1 99 1 ml / min ·1.50 min 1 99 1 ml / min The sum of absorbance signals in the 210-350nm range is scanned at 40Hz, and UV detection is performed. • MS requirements. • Equipment: Waters Acquity • Serial number: C07SQD043W • Scan mode: Positive / Negative alternating electrospray • Scan range: 125-1000 AMU • Scan time: 105 msec • Interscan delay: 20 msec • Other information All equipment was provided by Waters Corp, Milford, MA. • Quality control samples are performed and analyzed at least once a day.

[0271] LCMS standard B Mobile phase A: Water (0.01% TFA) B: ACN (0.01% TFA). • Gradient: Increased from 5%B to 95%B within 1.5 minutes. • 95% B for 1.8 min, 5% B for 0.01 min • Flow rate 2.0 ml / min • Column: SunFire C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50°C Detection: UV (280, 140 nm) and MS (ESI, Pos mode, 110-1000 amu)

[0272] LCMS standard C ·Mobile phase A: Water (10mM NH4HCO3) B: ACN • Gradient: Increased from 5%B to 95%B within 2 minutes. • Back to 5% B in 0.01 min of 95% B for 1.3 min • Flow rate 1.8 ml / min • Column: XBridgeC18, 4.6 x 50 mm, 3.5 μm Column temperature: 40°C Detection: UV (280, 140 nm) and MS (ESI, Pos mode, 110-1000 amu)

[0273] Synthesis example Those skilled in the art will understand that if a substituent described herein is not suitable for the synthetic method described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at an appropriate point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art. In some embodiments, substituents may be specifically selected to be reactive under the reaction conditions used. In such circumstances, the reaction conditions may convert the selected substituent into another substituent that is useful as an intermediate compound or is a desired substituent in the target compound.

[0274] The synthesis of general formula compounds and their pharmaceutically acceptable salts, solvates, or hydrates described in the following schemes (multiple schemes are possible) can be carried out in general terms as follows.

[0275] Abbreviations are as defined in the Examples section. Starting materials are commercially available or prepared from commercially available starting materials using methods known to those skilled in the art. All temperatures are given in Celsius, all solvents are of the highest purity available, and all reactions are carried out under anhydrous conditions in an argon atmosphere unless otherwise specified.

[0276] The compounds described herein can be obtained by using the synthetic procedures shown in the following scheme or by utilizing the knowledge of a skilled organic chemist. The synthesis shown in this scheme is applicable to producing the compounds of the present invention with various different substituents, using suitable precursors that are appropriately protected as needed to achieve compatibility with the reactions outlined herein. By deprotecting as needed, compounds as generally disclosed can be obtained. Although this scheme is shown only for the compound of formula (I), it illustrates the processes that may be used to produce the compounds of the present invention.

[0277] The intermediates (compounds used in the preparation of the compounds of the present invention) may also exist as salts, solvates, or hydrates. Therefore, with respect to the intermediates, the expression "compound(s) of formula(s)" means the compound having that structural formula, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0278] The present invention also includes various deuterated forms of the compound of formula (I). Each available hydrogen atom bonded to a carbon atom may be independently substituted with a deuterium atom. In some embodiments, one or more hydrogen atoms of the compound according to any embodiment described herein are substituted with deuterium. Those skilled in the art will know how to synthesize the deuterated forms of the compound of formula (I).

[0279] As will be further explained in this specification, the scheme is given by general formula (I) [ka] Here, R 1 -R6 This is as previously defined for equation (I). [ka]

[0280] The compound of formula (I) may also be prepared by carbon-carbon formation, such as a transition metal-catalyzed cross-coupling. This reaction may also be carried out by Suzuki-Miyaura coupling in the presence of a catalyst of a halogen or pseudohalide such as PdCl2(dppf), Pd(PPh4)4, Pd(OAc)2, Pd2(dba)3, NiCl2(dppf), and NiCl2(PCy3)2, an organoboronic acid, or a boronic acid ester, or potassium trifluoroboronate and triflate, but not limited to these. Such coupling reactions are carried out in a suitable solvent such as toluene, dioxane, tetrahydrofuran, dimethoxyethane, or dimethylformamide, in the presence of a mild base such as K2CO3 and Na2CO3, NaHCO3, Cs2CO3, K3PO4, or KF. The selection of appropriate bases, ligands, solvents, and reaction conditions, such as time, temperature, pressure, and atmosphere (e.g., inertness), as well as the reaction procedure and purification, are known to those skilled in the art.

[0281] One aspect of the present invention is a process for producing the compound of formula (I). The final compound of formula (I) can be prepared by deprotecting its precursor, if any protecting group is employed during the transformation. A suitable hydroxyl protecting group, well known to those skilled in the art, can be found in Greene (vide supra). One such example of demethylation can also be performed using boron tribromide in a suitable organic solvent such as methylene chloride at -78°C to +20°C, preferably about -20°C to 0°C, for about 0.5 to 72 hours. The progress of the reaction is monitored by thin-layer chromatography or high-pressure liquid chromatography. Once the reaction is complete, the mixture is slowly quenched with a suitable solvent, e.g., methyl alcohol, at -78°C to +20°C, preferably -20°C to 10°C, and stirred at room temperature for about 1 to 4 hours. The addition of water is optional thereafter. The excess solvent is removed by distillation. The residue obtained here is purified by typical chromatography, normal-phase or reverse-phase, and recrystallization in a suitable solvent.

[0282] Compounds of formula (I) can be obtained by hydrogenating a precursor of formula (I), such as formula (A) described herein, in a suitable organic solvent such as methanol, ethanol, isopropanol, ethyl acetate, or tetrahydrofuran, at ambient temperature under a hydrogen atmosphere, in the presence of a suitable catalyst such as 5 or 10% palladium on carbon. [ka]

[0283] Step 1. 3,5-dihydroxy-4-isopropylbenzoate triethylamine salt 3,5-Dihydroxybenzoic acid (40 g, 0.26 mol, 1.0 equivalent) was placed in a 1 L three-neck round-bottom flask, and concentrated sulfuric acid (160 mL, 4 volumes) was added at room temperature. Water (20 mL, 0.5 volumes) was added while stirring. The suspension was heated to 60-65°C, and 2-propanol (25.0 mL, 0.32 mol, 1.25 equivalent) was added dropwise to the reaction mixture over 10 minutes. This clear reaction mixture was stirred at 60-65°C for 4-8 hours and then cooled to room temperature (~20°C). The reaction mixture was slowly transferred to a 10°C aqueous sodium hydroxide solution in a second 3 L three-neck round-bottom flask (RBF) equipped with an overhead stirrer. The temperature of the aqueous sodium hydroxide solution was maintained between 10-30°C in the second RBF. The reaction mixture flask was washed with water and completely transferred, and tert-butyl methyl ether (TBME, 320 mL, 8 vols) was added. The mixture was heated to 20-25°C and stirred for approximately 30 minutes. The two layers were separated, and the aqueous layer was extracted with TBME (2 x 160 mL, 4 vols). The TBME layer, combined with sodium potassium tartrate solution, was charged (1N, 160 mL, 4 vols) and stirred at 20-25°C for at least 40 minutes. The two layers were separated, and the organic layer was passed through activated carbon DARUCO G-60, -100 mesh, and the carbon cake was washed with TBME. 2-propanol (90 mL, 2.25 vols) was charged into the TBME layer, and triethylamine (36.2 mL, 1.0 equivalent) was dropwise charged into the mixture (TBME layer + 2-propanol solution) over approximately 15 minutes at 20-25°C and stirred for at least 2.5 hours. The product was separated by filtration, and the cake was washed with TBME. The title product was dried overnight in an oven at 40-50°C. Purity by HPLC: 98%.

[0284] Step 2. 3,5-Diacetoxy-4-isopropylbenzoic acid 50.0 g, 0.17 mol, 1.0 equivalent of 3,5-dihydroxy-4-isopropylbenzoate triethylamine salt was placed in a 1 L three-neck round-bottom flask (RBF), followed by the addition of tert-butyl methyl ether (TBME, 250 mL) and 2-methyltetrahydrofuran (2 Me-THF, 125 mL) at room temperature. Acetic anhydride (38.1 mL, 0.4 mol, 2.4 equivalents) and triethylamine (46.9 mL, 0.34 mol, 2.0 equivalents) were added to the mixture with stirring. The suspension was heated to 60-65°C and stirred for 6-20 hours, or until the reaction was considered complete by FastLC for 3 minutes. The mixture was cooled to room temperature (~20°C), and 6N hydrochloric acid (6NHCl, 175 mL) was slowly added while maintaining the temperature of the reaction mixture at 20-30°C, and stirred for at least 15 minutes. The two layers were separated, the organic layer was washed with water (100 mL), and evaporated under reduced pressure until approximately 3.0 volumes remained in the flask. Toluene (200 mL) was added and evaporated until approximately 2 volumes remained in the flask. Toluene (75 mL) was added, and the mixture was heated to 75-80°C and stirred for at least 30 minutes. The suspension of the product was cooled to room temperature (~20°C), cyclohexane (200 mL) was added, and the mixture was stirred at 15-20°C for at least 3 hours. The product was isolated by filtration, and the cake was washed with cyclohexane. The product was dried overnight in an oven at 40-50°C. ¹H NMR (400MHz, DMSO-d6) δppm: 13.07-13.40 (br.s, 1H), 7.54 (s, 2H), 3.07-3.23 (Sep., 1H), 2.35 (s, 6H), 1.18 (d, J=7Hz, 6H). Purified by HPLC: 97%. [ka]

[0285] The title compound was prepared according to the method reported in the literature (Xuebin Liao, Levi M. Stanley and John F. Hartwig, J. Am. Chem. SOC. 2011, 133, 2088-2091). [ka]

[0286] The title compound was prepared by the method reported in U.S. Patent No. 5,919,970. [ka]

[0287] Process 1 Methoxymethyl chloride (5.96 ml, 78 mmol) was added to a stirred solution of 4-bromo-3,5-dihydroxybenzoic acid (4.06 g, 17.42 mmol) and N,N-diisopropylethylamine (17.65 ml, 101 mmol) in DCM (45.9 mL) at 0°C. The reaction mixture was heated to rt and stirred for 30 minutes, then quenched with saturated aqueous ammonium chloride (40 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 x 40 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified using an 80 g Isco brand silica column and eluted with 10–100% toluene / heptane (60 mL / min) to obtain the target compound as a colorless amorphous solid. 1 HNMR(400MHz,CHLOROFORM-d)δppm7.54(s,2H)~5.50(s,2H)~5.33(s,4H)~3.57(s,3H)~3.55(s,6H);LCMS Method A:t R =0.8 min, 92%;MS(ESI):m / z clear mass.

[0288] Process 2 DIBAL-H (Hexane, 8.67 ml, 8.67 mmol) was added to a stirred solution of 4-bromo-3,5-bis(methoxymethoxy)benzoate (1.055 g, 2.89 mmol) in dichloromethane (DCM ~20.64 ml) at ~78°C. The reaction mixture was warmed to 0°C and stirred for 30 minutes, followed by repeated quenching with toluene (1 mL) and then MeOH (4 mL). Saturated aqueous potassium sodium tartrate (40 mL) was added, and the resulting mixture was vigorously stirred overnight. The layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 24 g Isco brand silica column and eluted with 10-100% toluene / heptane (35 mL / min) to obtain the desired product as a colorless oil. 1 HNMR (400MHz, CHLOROFORM-d) δppm6.87(s, 2H), 5.28(s, 4H), 4.66(s, 2H), 3.54(s,6H); LCMS Method A:t R =0.64 min, 94%; MS(ESI): m / z clear mass.

[0289] Process 3 A solution of (4-bromo-3,5-bis(methoxymethoxy)phenyl)methanol (490 mg, 1.595 mmol) and manganese dioxide (1387 mg, 15.95 mmol) in dichloromethane (DCM, 31.908 mL) was stirred at rt for 12 hours. The filtrate was concentrated to obtain the desired compound pure product as a colorless amorphous solid. LCMS Method A:t R =0.78 min, 100%;MS(ESI):m / z307.35(M+2) + .

[0290] Process 4 In a sealed tube, 4-bromo-3,5-bis(methoxymethoxy)benzaldehyde (322 mg, 1.055 mmol), 2-(cyclopento-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 μl, 1.583 mmol), 1N sodium bicarbonate (3590 μl), 1,4-dioxane (8974 μl), and tetrakis(triphenylphosphine)palladium (0) (51.7 mg, 0.045 mmol) were added. The reaction mixture was heated overnight at 100°C, cooled, and partitioned between ethyl acetate and water. The organic phase was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 12-gram Isco brand silica column and eluted with 10–100% acetone / heptane (30 mL / min) to obtain the target product as a bright yellow amorphous solid. 1 HNMR (400MHz, CHLOROFORM-d) δppm9.92(s, 1H), 7.32(s, 2H), 5.88(t, J=2Hz,1H), 5.22(s, 4H), 3. 50(s, 6H), 2.66-2.77(m, 2H), 2.77(m, 2H), 2.57(ddd, J=10,5,2Hz, 2H), 2.04(t, J=7Hz, 2H);LCMS Method A:t R =0.94min, 98%;MS(ESI):m / z293.5(M+H) +

[0291] Process 5 4-(cyclopento-1-en-1-yl)-3,5-bis(methoxymethoxy)benzaldehyde (252 mg, 0.862 mmol) was dissolved in a mixture of methanol (3451 μl) containing a catalytic amount of ammonium chloride (4.61 mg, 0.086 mmol) and orthoformate trimethyl (2382 μl, 21.55 mmol). The mixture was stirred at 65°C for 2.5 hours, or until the benzaldehyde was consumed as measured by NMR. The reaction mixture was cooled to rt and treated dropwise with triethylamine (481 μl, 3.45 mmol). After stirring at rt for 5 minutes, water (1.5 mL) was added and the mixture was diluted with diethyl ether (1.5 mL). The organic phase was separated and the aqueous phase was extracted with diethyl ether (3 x 10 mL). The organic phase was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (3451 μl) and stirred for 17.5 hours under a hydrogen atmosphere (40 psi) in the presence of palladium on 10% carbon (22.93 mg, 0.216 mmol). By LC-MS, the conversion rate to the target product was approximately 28%, and the residual material was approximately 59%. Additional carbon-palladium (22.93 mg, 0.216 mmol) was added, and the reaction mixture was re-immersed in a hydrogen atmosphere (40 psi) for a further 6.5 hours (total 24 hours). The reaction mixture was filtered and evaporated. The crude residue was dissolved in a 1:1 mixture of tetrahydrofuran (THF, 2.374 ml) and 2NH2SO4 (2.374 ml) and stirred at rt for 2 hours. The mixture was diluted with SiO2 (1.5 mL) and water (1.5 mL), and the organic phase was separated. The aqueous phase was extracted with toluene (3 x 10 mL), the organic phase was washed with water (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 12 g Isco brand silica column and eluted with 0-100% toluene / heptane (30 mL / min) to obtain the target product as a colorless amorphous solid. 1HNMR (400MHz, CHLOROFORM-d) δppm9.89(s, 1H), 7.30(s, 2H), 5.26(s, 4H), 3.77(m, 1H), 3.52(s, 6H), 1.0( LCMS Method A:t R =1.01 min, 92%;MS(ESI):m / z295.5(M+H) +

[0292] Process 6 To a solution of 4-cyclopentyl-3,5-bis(methoxymethoxy)benzaldehyde (100 mg, 0.340 mmol) in anhydrous dichloromethane (833 μL), mCPBA (64.5 mg, 0.374 mmol) in anhydrous dichloromethane (DCM, 3.331 mL) was slowly added. The reaction mixture was heated to rt and refluxed for 12 hours. After cooling to rt, the solution was extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated sodium bicarbonate aqueous solution and 10% sodium thiosulfate aqueous solution (10 mL), dried over sodium sulfate, filtered, and concentrated.

[0293] The residue was redissolved in methanol (0.67 ml), 10% sodium hydroxide (0.679 ml, 16.99 mmol) was added, and the mixture was stirred at rt for 3 hours. The pH was adjusted to 2 with 1N HCl, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 4 g Isco brand silica column and eluted with 0-100% siRNA / heptane (18 mL / min) to obtain the target compound as a yellow amorphous solid. 1 HNMR(400MHz,CHLOROFORM-d)δppm6.35(s, 2H), 5.15(s, 4H), 4.63(s, 1H), 3.5 9(m, 1H), 3.50(s, 6H), 1.62(m, 1H), 1.72-1.98(m, 6H), 1.61-1.72(m, 2H); LCMS Method A:t R =0.89min, 95%;MS(ESI):m / z283.5(M+H)+

[0294] Process 7 To a solution of 4-cyclopentyl-3,5-bis(methoxymethoxy)phenol (25.1 mg, 0.089 mmol) in N,N-dimethylformamide (DMF, 323 μl), triethylamine (24.78 μl, 0.178 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (47.6 mg, 0.133 mmol) were added. The mixture was stirred at rt for 1 hour. After 1 hour, the progress of the reaction was analyzed by LC-MS, confirming the complete consumption of the starting materials and their conversion to the product. Next, the reaction mixture was concentrated, the crude product was diluted with Et2O (2.5 mL), washed with water (3 x 5 mL) and saturated sodium chloride aqueous solution (5 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 4 g ISCO silica gel column (eluted with 5-100% Â / heptane) to obtain the target product as a colorless oil. 1 LCMS Method A R =1.18 min, 100%;MS(ESI):m / z413.4(MH) - [ka]

[0295] Process 1 To a solution of isoquinoline-3-ol (300 mg, 2.067 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (923 mg, 2.58 mmol) in DCM (20 mL), TEA (0.864 mL, 6.20 mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with water (25 mL), and extracted with DCM (30 mL x 2). The DCM solutions were combined, washed with brine, dried, and concentrated. The crude substance was purified by preparative TLC (eluting with petroleum ether / ethyl acetate = 50 / 1) to obtain isoquinoline-3-yltrifluoromethanesulfonic acid (350 mg, 1.136 mmol, 55.0% yield) as a colorless liquid. LCMS Method A:t R =1.77 min, 100%;MS:m / z277.8(M+H) +

[0296] Process 2 Under a nitrogen atmosphere, a mixture of isoquinoline-3-yltrifluoromethanesulfonate (100 mg, 0.361 mmol) and 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (133 mg, 0.433 mmol) in toluene (2 mL) and water (0.500 mL) was mixed with Na2CO3 (76 mg, 0.721 mmol). The reaction mixture was stirred at 80°C for 5 hours, cooled, and purified by reverse-phase chromatography (Combi Flash 50 g reverse-phase C18 column; 20-50% MeOH gradient in water containing 0.01% TFA over 30 minutes). The fractions were combined and concentrated. The residue was recrystallized with water and freeze-dried to obtain 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (90 mg, 0.190 mmol, 52.8% yield) as a white solid. LCMS Method A:t R =1.81 min, 61%;MS:m / z307.9(M+H) +

[0297] Step 3a Method A To a solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (90 mg, 0.293 mmol) in dichloromethane (DCM, 2 mL), BBr3 (0.138 mL, 1.464 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour and purified by reverse-phase chromatography (Combi Flash 50 g reverse-phase C18 column; loaded with MeOH; eluted over 30 minutes with 20-50% MeOH / Water containing 10 mMTFA). Appropriate fractions containing the product were combined, recrystallized with water, and lyophilized to obtain the title compound, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (80 mg, 0.272 mmol, 93% yield), as a yellow solid. 1 LCMS Method A:t R =1.79min, 100%;MS:m / z280.2(M+H) + [ka]

[0298] Process 3b-1 To a solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (3.8 g, 12.36 mmol) in dichloromethane (DCM, 2 mL), BBr3 (5.84 mL, 61.8 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour. The solution was concentrated under vacuum, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organic matter was washed with brine, dried over NaSO4, concentrated, and the desired compound was obtained without further purification. LCMS Method B:t R =1.88 min, 53%;MS(ESI):m / z359.5(M+2) +

[0299] Process 3b-2 A solution of 4-bromo-2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (3.4 g, 9.49 mmol) in methanol (30 mL) was mixed with 10% Pd / C (400 mg). The mixture was stirred at room temperature for 1 hour under an H2 atmosphere. The reaction mixture was filtered and concentrated under vacuum to obtain 2.7 g of crude product, which was purified by reverse-phase chromatography (C18 column; mobile phase, A: 10 mM T3-yl aqueous solution; B: MeOH; gradient: 10 min, 9-71% B) to find that 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol can be obtained as a gray solid. 1 LCMS Method B:t R =2.08 min, 98.4%;MS(ESI):m / z280.0(M+H) + [ka]

[0300] Stage 0 Isoquinoline-3-yltrifluoromethanesulfonate DCM (6 volumes) was added to the reactor, followed by isoquinoline-3-ol (1.0 equivalent), Et3N (1.45 equivalent), and N-benzyl-bis-trifluoromethanesulfonimide (1.1 equivalent). The reaction mixture was stirred at 20-35°C for 2-3 hours. After completion, water (10 volumes) was added to the reaction mixture and stirred for 15 minutes. The organic layer and aqueous layer were separated. The organic layer was washed with water (10 volumes). The organic layer and aqueous layer were separated, and the organic layer was dried over Na2SO4. Next, the organic layer was filtered and dried over NaSO4. 24The residue was removed, and the mixture was concentrated under reduced pressure at 35-40°C to obtain a crude product as a black liquid. This crude product was charged into a reactor. Ethyl acetate (6.0 vol.) and then charcoal (0.1 w / w) were added. The contents were heated at 55-60°C for 30 minutes, and then cooled to 20-35°C. The contents were filtered through Celite and washed with ethyl acetate (5 vol.). The combined organic layers were concentrated under reduced pressure at 40-45°C to obtain a dark brown liquid. This dark brown liquid was added to the reactor, and then heptane (20 vol.) was added and heated at 60-65°C for 1 hour. The heptane layer was concentrated under reduced pressure at 40-45°C to obtain the desired product, compound 6, as a pale yellow liquid that solidifies at 2-8°C.

[0301] Stage 1 1-(2,6-dimethoxyphenyl)ethanone 2,6-dihydroxyacetophenone (1.0 equivalent) and potassium carbonate (5.0 equivalents) were incorporated into acetone (14 vols) and heated to 20-35°C. Dimethyl sulfate (2.5 equivalents) was added to the contents at the same temperature. The contents were heated to 60-65°C (reflux) for 2-3 hours and monitored by IPC-HPLC. The reaction mixture was cooled to 20-35°C, the salt was filtered, and washed with acetone (5 vols). The combined organic layer was concentrated under reduced pressure to obtain the crude liquid product. Water (30 vols) was added to this crude liquid and stirred at 20-35°C for 1 hour. The obtained solid was filtered and washed with water (5 vols), and the wet cake was transferred to a round-bottom flask. Saturated NaHCO3 (10 vols) was added and the contents were stirred for 1 hour. The contents were filtered to remove the solid, and the solid was washed with water (Lot-3, 5 vols) to obtain product compound 2 as an off-white solid. Next, this solid was dried at 40-45°C until the KF measurement showed <1%.

[0302] Stage 2 1,3-Dimethoxy-2-(prop-1-en-2-yl)benzene MeMgBr (1.4 M, 1.5 equivalents) was added to a round-bottom flask under nitrogen at 20-35°C. The contents were cooled to 0-10°C. Next, a solution of compound 2 (1.0 equivalent) dissolved in THF (10 volumes) was added to the cooled Grignard solution while maintaining the temperature at 0-10°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. After 2 hours, the reaction mixture was cooled to 0-10°C. Ethyl acetate (7 volumes) was then added and stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3.5 volumes). The organic fractions were combined and washed with water (10 volumes). The layers were separated, the aqueous layer was discarded, and the organic layer was washed again with water (10 volumes). The layers were separated, the aqueous layer was discarded, and the organic layer was washed with sat.NaHCO3. Washed with NaHCO3 (10 volumes). This layer was separated again, the sat.NaHCO3 layer was discarded, and the organic layer was finally washed with water (10 vol). The organic layer was dried over Na2SO4. After drying, sodium sulfate was filtered off, and the solvent was removed under reduced pressure at 40-45°C to obtain 1,3-dimethoxy-2-(prop-1-en-2-yl)benzene compound 3 as crude solution, which was used directly in the next stage.

[0303] Stage 3 2-Isopropyl-1,3-dimethoxybenzene Ethyl acetate (10 vol.) was added to the reactor, followed by 1,3-dimethoxy-2-(prop-1-en-2-yl)benzene (1.0 equivalent), and the mixture was stirred at 25-35°C until the solution became clear. 10% Pd / C (0.1 w / w) was added to the reactor, the contents were purged under vacuum, and then placed under H2. The contents were then stirred at 25-35°C for 4 hours. After this, the reaction mixture was filtered through Celite and washed with ethyl acetate (5 vol.). The combined organic fraction was reduced under vacuum at 40-45°C to obtain 2-isopropyl-1,3-dimethoxybenzene compound 4 as crude solution, which was used directly in the next step.

[0304] Stage 4 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane THF (7 vol.) was added to the reactor and degassed with N2 for 30 minutes. Iridium catalyst (0.0081 equivalent), catalyst ligand (0.017 equivalent), bispinacolatodiborone (1.0 equivalent), and 2-isopropyl-1,3-dimethoxybenzene (1.0 equivalent) were added to the reactor in sequence. The reaction mixture was refluxed at 80°C for 60 hours, and the contents were filtered through Celite (0.5 w / w) and washed with ethyl acetate (2.5 vol.). The combined organic layers were reduced under vacuum at 40-45°C to obtain the crude product as a concentrated black syrup, which was crystallized with hexane (5 vol.) to obtain 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane compound 5 as a light brown solid.

[0305] Stage 5 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline 1,4-Dioxane (8 vols) and water (2 vols) were charged into the reactor and degassed for 20 minutes. Compound 6 (1.3 equivalents) was added to the reactor and degassed for 10 minutes. 2-(4-Isopropyl-3,5-Dimethoxyphenyl)-4,4,5,5-Tetramethyl-1,3,2-Dioxaborolane (Compound 5, Stage 4 product, 1.0 equivalent) was added, and after degassing for another 10 minutes, palladium catalyst (0.1 equivalent) was added. The reaction mixture was cooled to 20-35°C, water (20 vols) was added to the reactor, and the contents were stirred for 1-2 hours. The contents were filtered through a Buchner funnel and washed with water (5 vols) to produce a crude black solid. This solid was taken into ethyl acetate (10 vols) and charged into the reactor. After cooling to 20-35°C, it was filtered through Celite and the solid was washed with ethyl acetate (2.5 vols). This organic layer was concentrated under reduced pressure at 40-45°C to obtain a viscous liquid. Heptane (1.0 volume) was added to this liquid and distilled. Heptane (0.5 volume) was added and distilled again to obtain 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline compound 7 as a brown solid.

[0306] Stage 6 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol 1.0 equivalent of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol compound 7 was added to the reactor, and 15 volumes of 33% HBr in acetic acid were added at 20-35°C. The mixture was then heated at 95-100°C for 24 hours. Next, the contents were transferred to a second reactor containing 25 volumes of water and stirred at 20-35°C for 2 hours. The resulting salt was filtered through a Buchner funnel and washed with 5 volumes of water. This moist salt cake was added to the reactor. 10 volumes of ethyl acetate was added to the reactor, followed by 10 volumes of sat.NaHCO3soln. The contents were stirred at 20-35°C for 30 minutes. The stirring was stopped and the layers were separated. The aqueous layer was decanted off, and the organic layer was washed with 10 volumes of water. The phases were separated, the aqueous layer was removed, and the organic layer was dried over Na2SO4. Sodium sulfate was filtered and rinsed with ethyl acetate (5 vol). The combined organic layer was reduced in volume under vacuum at 40-45°C to obtain crude free base as a dark solid. The crude free base was placed in the reactor, and ethyl acetate (6.7 vol), silica (1.0 w / w), and finally carbon (1.0 w / w) were added at 20-35°C. The contents were heated at 60-70°C for 1 hour and cooled at 20-35°C. The contents were filtered through Celite (0.5 w / w) and washed with ethyl acetate (3.35 vol). The combined organic layer was distilled under reduced pressure to obtain a gummy solid. Heptane (1.34 vol) was charged into the reactor, and the contents were again distilled to reduce the volume. Heptane (1.34 vol) was again charged into the reactor, and the contents were distilled to obtain a light brown solid. 1,4-dioxane (10 vol.), silica (1.0 w / w), and carbon (1.0 w / w; Noret CGP) were charged into a reactor at 20-35°C. The contents were heated to 60-70°C for 1 hour, then cooled to 20-35°C. The contents were filtered through Celite (0.5 w / w) and washed with 1,4-dioxane (lot-2, 3 × 5 vol.). The combined organic layers were reduced under vacuum at 40-45°C to obtain 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, the compound of formula 8, as an off-white solid.

[0307] Stage 7 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol The compound 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, of formula 8, was placed in a reactor, followed by the addition of isopropyl alcohol at 20-35°C. This heterogeneous mixture was heated to 65-70°C until it became a clear solution, and then heptane was slowly added over 20-30 minutes at 65-70°C (16 volumes). This solid was filtered at 20-35°C and washed with heptane (2 volumes) to obtain 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol as an off-white solid. [Examples]

[0308] Example 2: 3-(3-aminopropoxy)-2-isopropyl-5-(isoquinoline-3-yl)phenol, bis-trifluoroacetate A solution of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (185 mg, 0.662 mmol) in N,N-dimethylformamide (DMF, 4 mL) was mixed with a 60% sodium hydride oil dispersion (35 mg, 0.875 mmol) at room temperature while magnetically stirred. After hydrogen evolution ceased, tert-butyl(3-bromopropyl)carbamate (178 mg, 0.748 mmol) was added. The resulting mixture was heated overnight at 50°C. LC-MS revealed a mixture of the starting material, monoalkylation, and dialkylation products (approximately 1:1:1). The mixture was cooled, quenched with water (25 mL), filtered, and a greenish-gray solid was collected. The crude substance was dissolved in MeOH and purified by Gilson prep-HPLC [using Luna acid on an Agilent Eclipse plus C18 column (5 μm, 30 x 50 mm), gradient 30-60%, % acetonitrile / water, 0.1% TFA, flow rate 47 mL / min, 14 min runtime, fraction collection 3.5 min to 4.2 min]. The m / z ratio was obtained from the evaporation of the corresponding fraction by LC-MS at 437.5 (M+1). + The residue was dissolved in DCM (5 mL) and treated overnight with TFA (1 mL) at rt. The reaction mixture was concentrated to dryness under reduced pressure to obtain the desired compound as a yellow amorphous solid. 1HNMR(400MHz,METHANOL-d4)ppm9.76(s, 1H), 8.61(s, 1H), 8.48(d, J=8Hz, 1H), 8.29(d, J=8H) z, 1H), 8.19(t, J=7Hz, 1H), 7.97(t, J=7Hz, 1H), 6.98-7.11(m, 2H), 4.0-4.5(m, 1H), 5.5-5.5 (m, 1H), 6.5-5.5(m, 1H), 6.5-5.5(m, 1H), 6.5-5.5(m, 1H)26(t, J=6Hz, 2H), 3.69(dt, J=14, 7 Hz, 1H), 3.24(t, J=8Hz,2H), 2.18-2.35(m,2H), 1.37(d, J=7Hz, 6H);LC / MS:m / z=337.3(M+1) + t R = 0.52 min, 100%. [Examples]

[0309] Example 3: N-(2-aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide [ka]

[0310] Process 1 A mixture of 6-bromoisoquinoline-3(2H)-one (5 g, 22.32 mmol), PdCl2 (dppf) (1.633 g, 2.232 mmol), and Et3N (6.22 mL, 44.6 mmol) in methanol (10 mL) was charged into a pressure vessel. The vessel was purged three times with nitrogen, carbon monoxide was charged at 300 kPa, and the mixture was heated at 100 °C for 20 hours. The reaction mixture was cooled and concentrated to obtain crude methyl 3-oxo-2,3-dihydroisoquinoline-6-carboxylate as a yellow solid, which was used directly in the next step. LCMS: m / z = 204.0, t R =1.19 minutes.

[0311] Process 2 A sealed tube solution of 3-oxo-2,3-dihydroisoquinoline-6-carboxylate (1 g, 2.461 mmol) and pyridine (0.389 g, 4.92 mmol) in POCl3 (5 mL) was stirred at 160°C for 16 hours, then cooled and poured into ice water (20 mL). The solid was filtered and dissolved in ethyl acetate (30 mL). The filtrate was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with water / brine, dried over Na2SO4, and concentrated by vacuum. The residue was purified by column chromatography over petroleum ether / dichloromethane / methanol (1 / 1 / 0.05) on silica gel (30 g) to obtain methyl 3-chloroisoquinoline-6-carboxylate (130 mg, 0.557 mmol, 22.64% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δppm=9.34(s, 1H), 8.67(s, 1H), 8.30(d, J=12.0, 2H), 8.14(d, J=8.8, 1H), 3.96(s, 3H);LCMS:m / z=221.9, t R =1.57 minutes.

[0312] Process 3 A mixture of methyl 3-chloroisoquinoline-6-carboxylate (100 mg, 0.451 mmol), 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (145 mg, 0.474 mmol), Na2CO3 (143 mg, 1.354 mmol), and PdCl2 (dppf) (33.0 mg, 0.045 mmol) was stirred in 1,4-dioxane (10 mL) and water (1.0 mL) under nitrogen at 100°C for 16 hours. The solvent was removed under reduced pressure. LCMS: m / z = 365.9 (M+1) + ,t R = 1.94 min, 80%. The crude product (150 mg) was used directly in the next step.

[0313] Process 4 A mixture of methyl 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylate (150 mg, 0.410 mmol) and NaOH (49.3 mg, 1.231 mmol) in THF (4 mL) and water (4.00 mL) was stirred at rt under nitrogen for 16 hours and then diluted with water (10 mL). The mixture was washed with ethyl acetate (15 mL x 3), adjusted to pH 1-2 with 1N HCl, and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylic acid (100 mg) as a pale yellow solid. This crude product was used in the next step. LCMS: m / z = 351.9 (M+1) + t R =1.72 minutes, 82%.

[0314] Process 5 A solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylate (100 mg, 0.285 mmol), HATU (162 mg, 0.427 mmol), and DIEA (0.149 mL, 0.854 mmol) in N,N-dimethylformamide (DMF, 5 mL) was stirred under nitrogen at rt for 1 hour. Tert-butyl(2-aminoethyl)carbamate (54.7 mg, 0.341 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours, quenched with ice water (10 mL), and extracted with ethyl acetate (15 mL x 5). The combined organic phase was washed with water / brine, dried over Na2SO4, and concentrated by vacuum. The residue was purified by preparative HPLC (GeminiC18 150 x 21.2 mm, 5 μm, single injection mobile phase). Tert-butyl(2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxamide)ethyl)carbamate (70 mg, 0.135 mmol, 47.3% yield) was obtained as a pale yellow solid using ACN-H2O with a gradient of 10-60%. 1HNMR(400MHz,DMSO-d6)δppm=9.47(s, 1H), 8.79(t, 1H), 8.56(s, 1H), 8.53(s, 1H), 8.22(d, J=8.8,1H), 8.04(d, J=8.4,1H), 7.49(s, 2H), 6.98(t, 1H), 3.91(s, 6H), 3.64-3.57(m, 1H), 3.37(dd, 2H), 3.17(d, J=5.6,2H),1.39(s, 9H), 1.28(d, J=7.2, 6H);LCMS:m / z=493.8(M+1) + t R =1.77 minutes, 95%.

[0315] Process 6 A solution of tert-butyl(2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxamide)ethyl)carbamate (60 mg, 0.122 mmol) in DCM (10 mL), stirred at -30°C under a nitrogen atmosphere, was mixed with BBr3 (0.575 mL, 6.08 mmol). The reaction mixture was stirred at 25°C for 3 hours, poured onto ice, neutralized with NaOH (1N) to pH=7, and extracted with ELISA (10 mL x 5). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The pale yellow residue was purified by preparative HPLC (Gemini C18 150 x 21.2 mm 5 μm, mobile phase). N-(2-aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide (30 mg, 0.080 mmol, 66.2% yield) was obtained as a yellow solid using ACN-H2O containing 0.1% TFA (gradient: 10-30%). 1HNMR (400MHz, DMSO) δppm9.42(s, 1H), 9.26(s, 1H), 8.56(s, 1H), 8.41(s, 2H), 8 .20(d, J=8.4, 1H), 8.11(s, 1H), 8.05(d, J=8.4,1H), 8.05(d, J=8.4, 1H), 8.05( s, J=8.3,1H), 8.46(s, 1.4,1H), 8.56(s, 2H, 1H)4, 1H), 7.15(s, 2H), 4.20(brs, 2H), 3.54-3.47(m,3H), 3.00(s, 2H), 1.29(d,J=6.8,6H);LCMS:m / z=365.9(M+1) + t R =1.200 minutes, 98.7%. [Examples]

[0316] Example 4: Screening of the crystalline form of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol A crystal form screening was performed on 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. This screening consisted of approximately 160 experiments using 60 solvent systems, and the following 16 crystal forms were identified: a non-solvate (group A), two hydrates (groups M and H), eight stable organic solvent hydrates, and five presumed organic solvent hydrates that are unstable at room temperature and convert to other forms.

[0317] Of the 160 experiments conducted, a solid for analysis was obtained in 83. Of these, 39 yielded non-solvated compounds (Group A, also called Group 2), 22 yielded amorphous compounds, only 5 yielded hydrates (3 from Group H and 2 from Group M), and the remaining 17 yielded one of the remaining 13 observed morphologies. These results are visually represented in Tables 1 and 2 below. [Table 19] [Table 20] [Table 21]

[0318] Some embodiments involve compounds of formula (A). [ka] The present invention describes a process for producing a compound of formula (I), which includes a step of processing the salt thereof. R 3 is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, Halo, Cyano, -C(O)OR 8 , -NR 9 R 10 -S(O)2NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 , selected from the group consisting of arbitrarily substituted complex rings, R 8 These are H and C, which are substituted independently. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, R 9 and R 10 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, or instead, R 9 and R 10 However, they are selected from a group consisting of those that form a 5-7 membered cyclic saturated or unsaturated ring together with the nitrogen atom to which they are bonded. R11 is independently H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted aryl, optionally substituted arylC 1-6 alkyl, optionally substituted C 3-6 silylalkyl, -NR 9 R 10 and -OR 12 selected from the group consisting of, R 12 and R 13 each independently is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted arylC 1-6 alkyl, and optionally substituted C 3-6 silylalkyl selected from the group consisting of, R 6 is H, halo, hydroxyl, alkoxy, optionally substituted C 1-6 alkyl, halogenated alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted arylC 1-6 alkyl selected from the group consisting of, n is an integer having a value of 0, 1, or 2, s is an integer having a value of 0, 1, or 2, t is an integer having a value from 0 to 6, R 5c is H, halo, optionally substituted C 1-6 alkyl, -C(O)OR 14 -C(O)NR 15 R 16 aryl, and -C 1-6 alkylaryl selected from the group consisting of, R 14 is independently H, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, and optionally substituted arylC1-6 selected from the group consisting of alkyl, R 15 and R 16 each independently is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, and optionally substituted C 3-6 cycloalkyl, selected from the group consisting of; alternatively, R 15 and R 16 together with the nitrogen to which they are attached form a 5- to 7-membered saturated or unsaturated ring, R 4c is H, halo, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, -(CR 18 R 19 ) t COOR 8 、-(CR 18 R 19 ) t OC(O)R 8 、-(CR 18 R) 19 ) t [[ID=]]NR 9 R 10 、-(CR 18 R 19 ) t C(O)NR 9 R 10 、-(CR 18 R 19 ) t NR 9 C(O)R 8 、-(CR 18 R<00009)) 19 ) t S(O)2NR 9 R 10 、-(CR 18 R 19 ) t COR 11 、-(CR18 R 19 ) t CH(O), -(CR 18 R 19 ) t Ure 12 ,-(CR 18 R 19 ) t S(O) s R 13 , arbitrarily substituted hetero rings, and arbitrarily substituted hetero rings C 1-6 Alkyl, and R 18 and R 19 Each of these is H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Independently selected from the group consisting of alkyls, Boron tribromide dissolved in a suitable organic solvent such as methylene chloride can be mixed with a suitable alcohol such as CH3OH while stirring for a sufficient amount of time and temperature to obtain the compound of formula (I), where R 6 It is hydrogen.

[0319] Another aspect of the present invention relates to a compound of formula (B). [ka] A process for producing a compound of formula (I), comprising the step of processing a salt thereof, During the ceremony R 3 is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, Halo, Cyano, -C(O)OR 8 , -NR 9 R 10 -S(O)2NR 9 R10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 , and selected from the group consisting of arbitrarily substituted heteroalgebras, R 8 These are H and C, which are substituted independently. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, R 9 and R 10 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, or alternatively, R 9 and R 10 However, they are selected from a group consisting of those that form a 5-7 membered cyclic saturated or unsaturated ring together with the nitrogen atom to which they are bonded. R 11 These are H and C, which are substituted independently. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, -NR 9 R 10 , and -OR 12 Selected from the group consisting of R 12 and R 13 Each of these can independently be H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, or an optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of siloalkyl groups, n is an integer with a value of 0, 1, or 2. s is an integer with a value of 0, 1, or 2. t is an integer with values ​​between 0 and 6. R 5b H, halo, and C as arbitrarily substituted. 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 , aryl and -C 1-6 Selected from the group consisting of alkylaryls, R 14 These are H and C, which are substituted independently. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, R 15 and R 16 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of cycloalkyls, alternatively, R 15 and R 16 They form a 5-7 membered cyclic saturated or unsaturated ring with the nitrogen they bond to. R 4b C is a combination of H, halo, cyano, or any other substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Siloalkyl, -(CR 18 R 19 ) t COOR 8 ,-(CR 18 R 19 ) t OC(O)R 8 ,-(CR 18 R 19 ) tNR 9 R 10 ,-(CR 18 R 19 ) t C(O)NR 9 R 10 ,-(CR 18 R 19 ) t NR 9 C(O)R 8 ,-(CR 18 R 19 ) t S(O)2NR 9 R 10 ,-(CR 18 R 19 ) t COR 11 ,-(CR 18 R 19 ) t CH(O), -(CR 18 R 19 ) t Ure 12 ,-(CR 18 R 19 ) t S(O) s R 13 , arbitrarily substituted hetero rings, and arbitrarily substituted hetero rings C 1-6 Alkyl, and R 18 and R 19 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, and The hydrogenation process was carried out at ambient temperature under a hydrogen atmosphere in a suitable organic solvent such as methanol, ethanol, isopropanol, ethyl acetate, or tetrahydrofuran, with 5-10% palladium on the carbon atoms, to obtain the compound of formula (I), where R 6 It is hydrogen.

[0320] Another aspect of the present invention is formula (II) [ka] It is a novel intermediate compound, During the ceremony R 1 and R 2 Each of these is independently OH, OR 7 Selected from the group consisting of , and H, however R 1 and R 2 At least one of them is -OH or -OR 7 And, R 7 This is an independently and arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, aryl C 1-6 Selected from the group consisting of alkyl and acyl, R 3 is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, Halo, Cyano, -C(O)OR 8 , -NR 9 R 10 -S(O)2NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 , and selected from the group consisting of arbitrarily substituted hetero rings, R 8 H, and C as arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, R 9 and R 10 Each of these is independently H, and C which is arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6Cycloalkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, or alternatively, R 9 and R 10 However, together with the nitrogen atoms to which they are bonded, they form a 5-7 membered cyclic saturated or unsaturated ring. R 11 These are H and C, which are substituted independently. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, -NR 9 R 10 , and -OR 12 Selected from the group consisting of, R 12 and R 13 Each of these can independently be H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, or an optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Selected from the group consisting of siloalkyl groups, R 6 C is H, halo, hydroxyl, alkoxy, or optionally substituted. 1-6 Alkyl, alkyl halide, and optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynnyl and optionally substituted aryl C 1-6 Selected from the group consisting of alkyl groups, n is an integer that can have the value 0, 1, or 2.

[0321] In some embodiments, R of formula II 3 When is an arbitrarily substituted site, that site may be independently substituted once or multiple times. In some embodiments, R of formula II 3When the site is optionally substituted, that site may be independently substituted 1 to 3 times. In some embodiments, the site is halo, hydroxy, C 1-3 Alkoxy, C 1-3 The molecule may be independently and optionally substituted 1 to 3 times with alkyl, aryl, or arylalkyl groups.

[0322] In one embodiment, R of formula II 3 is an arbitrarily substituted C 3-6 Alkyl or optionally substituted C 3-6 It is a cycloalkyl. In one embodiment, C 3-6 The alkyl group is selected from the group consisting of isopropyl, n-propyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl, n-hexyl, etc. In one embodiment, the alkyl group is isopropyl or t-butyl. In another embodiment, the alkyl group is isopropyl. In one embodiment, the cycloalkyl group is cyclopropyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl group is cyclopentyl.

[0323] In some embodiments, R of formula II 6 H is H.

[0324] Biodata As described above, the compounds according to any embodiment described herein are AhR regulators and are useful for the treatment or prevention of human diseases exhibiting inflammatory components.

[0325] The biological activity of the compounds in any embodiment described herein can be determined using any suitable assay for determining the activity of candidate compounds as agonists or antagonists of AhR, as well as using tissue and in vivo models.

[0326] The biological activity of the compounds in any embodiment described herein is demonstrated by the following tests. [Examples]

[0327] Example 5: CYP1A1-bla LS-180 AhR agonist assay The AhR activation ability of compounds was characterized using LS-180 cells (referred to as CYP1A1-bla LS-180 cells) stably transfected with a β-lactamase gene reporter construct bound to the CYP1A1 promoter. AhR activity was easily measured using a LiveBLAzer assay kit, which involves placing a β-lactamase (bla) reporter gene downstream of the CYP1A1 promoter and emitting fluorescence upon substrate metabolism. In the agonist assay, CYP1A1-bla LS-180 cells were treated with compounds at increasing concentrations over a 100,000-fold range.

[0328] CYP1A1-bla LS-180 cells in the exponential growth phase were washed twice with DPBS, seeded into 96-well microplates (50,000 cells / well), and allowed to adhere. The prepared compound (at twice the working concentration in complete medium) was then added to the wells, and the cells were cultured for 20 hours. LiveBLAzer FRET B / G β-lactamase substrate was added at the final time of culture, and the resulting blue / green fluorescence was measured using a 96-well microplate reader.

[0329] AhR activity was measured as a function of β-lactamase expression by readout using fluorescence resonance energy transfer. TCDD and FICZ were used as controls to validate the system. As expected, CYP1A1-bla LS-180 cells treated with TCDD showed the conventional dose-response relationship, and TCDD was found to be in accordance with Invitrogen's report (pEC 50 (pEcucC = 9.70) Similar titer (pEcucC 50 FICZ-treated CYP1A1-bla LS-180 cells also showed a normal dose-response relationship, and as predicted from the literature, FICZ had much lower potency (pEC) than TCDD. 50 This showed a result of =6.82.

[0330] For these experiments, the compounds of the present invention represented as Examples 1-3 are considered to have a positive reaction with a pEC of ≥6.0. 50 (EC 50 This demonstrated that ≤1 μM (representing ≤ 1 μM) was achieved. [Examples]

[0331] Example 6: CYP1A1-bla LS-180 AhR Antagonist Assay A similar assay was used to evaluate the antagonistic ability of the compounds. CYP1A1-bla LS-180 cells in the exponential growth phase were washed twice with DPBS, seeded in 96-well microplates (50,000 cells / well), and allowed to adhere. Either FICZ or TCDD was added as an agonist, and the prepared compound (at twice the working concentration in complete medium) was added 2 hours later. After culturing the cells for approximately 20 hours, the ability of the compounds to compete for FICZ- or TCDD-induced AhR activation was tested as a means of evaluating allosteric or partial agonist activity. LiveBLAzer FRET B / G β-lactamase substrate was added at the final time of incubation, and the resulting blue / green fluorescence was measured using a 96-well microplate reader as described above.

[0332] The compound of the present invention, represented as 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, was found to be negative in this assay. [Examples]

[0333] Example 7: CD4+ T cell IL17 assay AhR activation has been shown to modify transcriptional regulation of the immune system, potentially affecting the differentiation of Th17 and Treg cells in particular. Therefore, the compound will be evaluated for its ability to reduce IL-17 production from CD4+ T cells stimulated under Th17 impalement conditions. Cryopreserved human CD4 +T cells (AllCells, LLC, Alameda, CA and Stemcell Technologies, Inc., Vancouver, Canada) were differentiated into the Th17 subtype by culturing for 5 days on CD3-coated tissue culture plates (2 μg / mL) in Iscove-modified Dulbecco's medium (IMDM) containing 10% HI-FBS, 55 μM 2-mercaptoethanol, and soluble anti-CD28 (3 μg / mL). Th17 skinning was measured in the presence or absence of serially diluted compounds of the Th17 skinning cocktail [IL-1β (10 ng / mL), IL-6 (30 ng / mL), TGFβ (0.5 ng / mL), IL-21 (10 ng / mL), IL-23 (10 ng / mL), anti-IFNγ (10 μg / mL), and anti-IL-4 (10 μg / mL)]. After exposure to a Th17 polarizing reagent for 5 days, with or without the presence of the compound, IL-17 secretion from polarized CD4+ T cells was measured in the culture medium using an MSD (Meso Scale Discovery) detection system.

[0334] In these experiments, all compounds of the present invention were considered to have a positive response to IL-17 inhibition, with pIC values ​​of 6.0 or higher. 50 (I C 50 This indicates that ≤1 μM was represented. [Examples]

[0335] Example 8: In vivo anti-inflammatory activity model using IMQ-mice The efficacy of AhR agonist compounds has been observed in mouse models of psoriasis, specifically in imiquimod (IMQ)-treated mouse models (see Di Meglio et al., (2014) Immunity, 40(6):989-1001, and Smith et al, (2017) J Invest Dermatol, 137(10), 2110-2119). The biological activity of the compound of formula (I) was tested in this mouse model for evidence of in vivo anti-inflammatory activity.

[0336] Female BALB / c mice (BALB / cByJRj) were purchased from Janvier, France. The mice were fed a standard diet A04C from SAFE, France, and could take Adlivitamin orally. BALB / c JByRj female mice (8 weeks old at the start of the study) were treated with imiquimod (IMQ) cream (5%) or vanilla cream (a non-inflammatory, inactive cream). After 3 days of pretreatment, 100 μL of the compound was applied topically to the same skin site daily (2 hours before each IMQ treatment) until the end of the study. Mice were monitored for changes in clinical symptoms throughout the study period. The dorsal skin of the affected area was examined by histology and qPCR to confirm evidence of the compound's efficacy.

[0337] The bioactivity of the compound represented by formula (I), 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, was tested in this mouse model for evidence of in vivo anti-inflammatory activity. Histological analysis of the skin demonstrated that it could reduce imiquimod-induced epidermal thickening. Gene expression data from the skin revealed that the expression of IL-17A and IL-17F was significantly suppressed by this compound. [Examples]

[0338] Example 9: Mechanism of action of the compound of the present invention as an AhR agonist and similarity to Tapinarov Tapinarof is a first-in-class topical agent under development for the treatment of atopic dermatitis and psoriasis. Tapinarof's biological profile differs from other anti-inflammatory and immunomodulatory molecules currently used to treat inflammatory skin diseases, including TCS, TCI, vitamin D analogues, and other immunosuppressants. All data available to date indicate that tapinarof exerts its pharmacological effects in the skin through a novel mechanism involving dual activation of the AhR and Nrf2 anti-inflammatory pathways, thereby identifying tapinarof as an AhR modulator (TAMA). Tapinarof has been shown to specifically suppress inflammatory mediators downstream of AhR pathway activation, such as interleukin [IL]-6, IL-17A, and eotaxin-3. Furthermore, administration of tapinarof reduced reactive oxygen species in keratinocytes subjected to chemical redox stress and induced apoptosis in the micromolar region.

[0339] The direct relationship between AhR and anti-inflammatory activity is not fully understood, and while other compounds may drive AhR-mediated debt, there is no definitive way to identify safe TAMAs. Therefore, the known activities of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol and tapinarov were evaluated. The following is an overview of this mechanism study.

[0340] 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was evaluated for its activity in key "hits" identified in tapinarof mechanism studies (Table 3). Indeed, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol showed similar efficacy across AhR, Nrf2, and CB2 screening assays, as well as IL-17A inhibition in CD4+ T cells cultured under Th17 polarized conditions. [Table 22] [Examples]

[0341] Example 10: BioMAP profiling of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol 10:2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was profiled at multiple doses of 1M, 330nM, 110nM, and 37nM using the DiscoverRx BioMAP® Diversity Plus System®. The BioMAP system evaluates 148 biomarkers associated with multiple inflammatory diseases in 12 primary human cell culture platforms and compares the biomarker profiles to the biological response patterns of other compounds, biologics, and approved drugs in the BioMAP reference database. Of 3000 experimental agents, 10:2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (which was found to exhibit antiproliferative activity against B cells and reduce various cytokines / chemokines) was the analyte tested. Includes M-CSF, sIL-17A, sIL-2, sIL-6, sIL-10, Eot3, sTNFα, MCP-1, VCAM-1, MIP-1, IL8, IL1α, sPGE2, ICAM-1, E-Selection n Increased (Figure) 1A Similar to Tapinarov, the endogenous AhR agonist 6-formylindro(3,2-b)carbazole (FICZ) was the only compound identified from the BioMAP reference database that had a pattern of associated biological responses (Pearson correlation, r=0.71; Figure 1). B Similarly, when the profiles are superimposed, a striking similarity to that of Tapinarov is observed (Figure 1). C The most notable difference is the observation of a decrease in sIL-17 due to 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, which is not seen in Tapinarov or FICZ-treated samples. [Examples]

[0342] Example 11: Effects of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol on cytokines and cellular apoptosis. The effects of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol treatment on peripheral blood CD4+ T cells cultured under Th17-skewing conditions were evaluated. When applied throughout the culture period, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol dose-dependently reduced IL-17A production, similar to Tapinarov's approach (Figure 2A).

[0343] 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is IC 50 =5.9μM is used for T cell survival rate, IC 50 At 12.36 μM, it affected keratinocyte viability. These values ​​are similar to those of Tapinarov, supporting the idea that 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is a close expressive copy of Tapinarov's activity profile (Figures 2B, 2C). [Examples]

[0344] Example 12: Inhibitory effect of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol on reactive oxygen species (ROS) Tapinaroff has been observed to suppress chemically induced ROS in primary and immortalized (HaCat) keratinocytes, at least in part, stemming from the intrinsic ROS scavenging properties of the API (Smith et al., 2017, ibid). Importantly, the observed reduction in ROS is a key differentiating factor between tapinaroff and TCDD, a known environmental toxin that leads to elevated ROS levels. Therefore, we tested whether 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol has the ability to reduce ROS. Oxygen radical absorption capacity (ORAC) tests showed that tapinaroff scavenges all common reactive oxygen species, including peroxynitrite, superoxide anion, singlet oxygen, peroxyl radical, and hydroxyl radical. 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol showed a similar profile, reducing the levels of peroxynitrite, singlet oxygen, peroxyl radicals, and hydroxyl radicals (Table 4). [Table 23] [Examples]

[0345] Example 13: Demonstration of biological activity (involvement with the target) after local administration. sRICA: A previously reported model of cutaneous commensal immune cell activation involves liquid-air interface skin excision cultures accompanied by in situ activation of immune cells (Smith et al, (2016) PLoS One, 11(2)). This assay can induce a cytokine profile specific to inflammatory skin diseases, including Th17 cytokines, IL17A, IL17F, and IL22. Reduction of biomarkers in this assay indicates the biological activity of the test substance.

[0346] In vitro human skin obtained from abdominal reconstructive surgery was processed to remove fat and dermatomed to approximately 750 microns. The dermatomed skin was washed twice consecutively with room temperature PBS containing an antibiotic / antifungal solution for 5–10 minutes each.

[0347] From this point onward, the skin was treated as a non-receptor, and all subsequent procedures were performed in a Class II biosafety cabinet. Skin sections were cut into 10 mm diameter circular sections using a disposable biopsy punch and placed in the upper chamber of a 0.4 μm PCF membrane transwell (MilliCell #PIHP01250) containing 30 μm of bovine collagen solution (2:1 collagen / Koni medium). Care was taken to remove any air bubbles at the bottom of the transwell, as these would inhibit the penetration of the culture medium into the tissue.

[0348] Skin samples were placed on a collagen solution in a humidified chamber at 37°C for 30 minutes. After 30 minutes of incubation at 37°C to allow time for the collagen solution to solidify, the skin samples on the Transwell were transferred to a 6-well plate (1 sample per well), and the lower chamber was filled with 1 mL of complete medium (Cornification Media) + / -2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (0 μM, 1 μM, 10 μM). The plates were then left to stand overnight (16-18 hours) at 37°C.

[0349] The following day, the culture medium was aspirated from the lower chamber and replaced with 1 mL of complete medium containing a Th17 cocktail (CD3 (1 ug / ml), CD28 (2 ug / ml), anti-IL-4 (1 ug / ml), anti-INFg (1 ug / ml), IL-1b (10 ng / ml), IL-6 (10 ng / ml), TGFb (1 ng / ml), IL-21 (10 ng / ml)). 24-hour and 48-house cultures were then performed. A total of three biological replicas were used for each treatment group.

[0350] Cultures were collected 24 and 48 hours after stimulation. After harvesting, skin samples were minced with a razor and transferred to a 1.5 mL RNAse-free tube containing 1 mL RNAlater solution, and later analyzed by RT-PCR.

[0351] RNA isolation and qRT-PCR The collected skin tissue was stored in RNAlater until use. Total RNA was isolated from the tissue using Qiagen's Mini RNA Isolation kit (Cat # 74106). The skin tissue was first minced into fragments smaller than 1x1x1 mm and added to tubes containing 2.8 mm and 1.4 mm ceramic beads (mixed in one vial). Cells were lysed on ice for 300 μL of RLT buffer with 1% 2-Beta-Mercapto-Ethanol for 4 cycles (6300 rpm, 90 s) in a Precellys Tissue Homogenizer, with 30 seconds between cycles. Next, cells were added to 590 μL of water containing 10 μL of Proteinase K and incubated at 55°C for 20 minutes. The samples were then spun down at 10,000 X g for 3 minutes, and the supernatant was used for RNA isolation using Qiagen's RNeasy mini columns according to the manufacturer's protocol. RNA was diluted to 23.6 ng / µl (total of 100 ng RNA), and a 10 µl PCR volume was used as a template with the Applied Biosciences RNA-to-CT 1 Step kit (AB Catalog # 4392938) and a TaqMan probe corresponding to the gene being quantified. The Applied Biosciences Master Mix includes an internal control of ROX dye. A OneStepPlus PCR machine was used for the RT step and 40 amplification cycles.

[0352] The RNA-level relative expression was calculated using the Delta-Delta CT formula.

number

[0353] RNA was isolated from tissues collected 24 and 48 hours after stimulation, and gene expression was evaluated by quantitative PCR. Data and statistical analysis were performed using Microsoft Excel 7 and Prism GraphPad 6.

[0354] The involvement of the target pathway by 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, in this case AhR pathway activation measured by cyp1a1 gene induction, was confirmed after exposure of skin excisions to 1 μM or 10 μM of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in basal culture medium (Figure 3A). Next, the effects on inflammatory mediators were evaluated, showing that 10 μM of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol inhibited IL17A message expression by ~45% (Figure 3B). In this study, the RORg inverse agonist compound GSK3038548A was used as a positive control for inhibition of Il17a gene expression.

[0355] Adapting the sRICA model to the Franz cell apparatus made it possible to demonstrate two specific results in local administration: (i) the test substance maintains its biological activity in the formulation, and (ii) the test substance penetrates the skin barrier to reach skin targets and induce biological effects. The local target involvement of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was evaluated at multiple concentrations in cream formulation 1 and gel formulation 1. Importantly, these target involvement assays utilize customized Franz cells sandwiching the skin edge, preventing leakage of the local formulation into the lower chamber of the gas-liquid interface culture. Cyp1a1 gene expression was used as an indicator of AhR pathway activation. Therefore, activation of resident skin immune cells under Th17 conditions, as is typically seen in Th17-sRICA described above, was not performed. Rather, 12 mm skin sections were clamped between the upper (donor) and lower (receive) chambers of a customized Franz cell system, and the lower chamber was filled with 2.0 mL of complete culture medium ("corni"), ensuring that the bottom and sides were immersed in the medium and free of air bubbles. After resting at 37°C for approximately 2 hours, the cells were checked again for leakage by simple inversion, and then the topical formulation (8.4 μl) was applied to the dry stratum corneum using a positive pressure displacement pipette. The Franz cells were then placed in a humidified incubator at 37°C for a further 21 hours. Cyp1a1 levels were assessed in approximately half of each skin section by comparison with 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (10 μM) applied base-to-lateral, and the remaining half was used to measure the concentration of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Samples containing at least 0.1% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in cream formulation 1 showed strong cyp1a1 gene induction without observable dose-dependency (Figure 4). This data indicates that in this system, the greatest observable biological response is induced at the lowest formulation concentration. [Examples]

[0356] Example 14: In vivo efficacy in a mouse model Systemic administration of FICZ to target the AhR pathway has been shown to positively impact the clinical scores of imiquimod (IMQ)-treated mice (Di Meglio et al., (2014) ibid.). Furthermore, tapinaroff exhibits anti-inflammatory properties in multiple mouse models, including an ear eczema model, an IMQ mouse model of psoriasis, and a hapten-induced, Th2-dominant challenge model, the DNFB-challenge model. 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was also tested in two inflammation models: IMQ mice and DNFB mice.

[0357] IMQ Mouse Model 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was applied topically daily in a simple ethanol solution (60% EtOH:40% H2O) and tested prophylactically in an IMQ mouse model. Three days after the initial treatment, IMQ cream was applied daily for 4 days (Study A) or 10 days (Study B). Clinical scoring was monitored daily (Figure 5A). ~ 5 D After the study, the treated skin was evaluated histologically and by qPCR for induced cytokine gene expression. Treatment with 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol resulted in a decrease in clinical score, reduced epidermal thickening, and decreased cytokine gene expression compared to vehicle-treated mice (N=10 mice per group, Figure 5A~). 5D (and Table 5).

[0358] Study A- Three groups of 10 mice (BALB / cByJRJ female mice) were treated as follows: Day 1, Day 2-1 (3 days before imiquimod application), Days 0, 1, 2, and 3 (4-day study). On the shaved backs of the mice, either vehicle (100 μL of 60% EtOH / 40% water) or 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (0.3% in 60% EtOH / 40% water) was administered daily. On Days 0, 1, 2, and 3, two hours after application of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or vehicle, vanicream or 5% imiquimod cream (5% Aldara cream) was applied topically to the shaved backs daily and massaged in with fingers until absorbed. Days 0, 1, 2, and 3: We focused on visual assessment of the skin and clinical scores for psoriasis.

[0359] Psoriasis reactions (erythema and plaques) were reported on a scale of 0-4 in ascending order of severity, as shown below, with the results in Figure 5. A show. [Table 24]

[0360] On the final day of treatment, a 6mm punch sample of the skin at the treatment site is taken onto an aluminum sheet (to keep the skin flat), placed in a tube containing formalin solution (neutral buffered 10% (SIGMA HT501320-9 5L)), and histological analysis is performed (Figure 5). B ).

[0361] Study B Ten mice (BALB / cByJRJ female mice) were divided into four groups and treated as follows: Day 1, Day 2-1 (3 days before imiquimod application), Days 0, 1, 2, 3, 5, 6, 7, 8, and 9 (10-day study). The mice were administered daily to their shaved backs a vehicle (60% EtOH / 100 μL of 40% water), 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH / 0.1% of 40% water), and 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol (60% EtOH / 0.3% of 40% water). On days 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9, Vanilla Cream or 5% Imiquimod Cream (5% Aldara Cream) was applied topically to the shaved back for 2 hours after application of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or vehicle, and massaged in with fingers until absorbed. On days 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9, visual assessment of the skin and clinical scores for psoriasis were recorded.

[0362] Psoriasis reactions (erythema and plaques) were reported on a scale of 0-4 in ascending order of severity, as shown below, with the results in Figure 5. C This will be shown. [Table 25]

[0363] On the final day of treatment, a 6mm punch sample of the skin at the treatment site is taken onto an aluminum sheet (to keep the skin flat) and placed in a tube containing formalin solution (neutral buffered 10% (SIGMA HT501320-9 5L)) for histological analysis (Figure 5). D ).

[0364] In another study (Study C), 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in cream formulation 1 was re-tested in the IMQ mouse model. In this final study, excessive redness was induced by IMQ in all treatment groups, and no change in clinical scores was observed with compound treatment. Nevertheless, when 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was applied in cream formulation 1, a decrease in epidermal thickness was observed (Figure 5). A-5F ), and a significant decrease in IL17A and IL17F levels (over 80% at the highest dose tested) was observed. [Table 26]

[0365] DNFB Mouse Model Next, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was tested in a dinitrofluorobenzene (DNFB) mouse model (Figure 6). A~6E (See reference). DNFB is a small chemical hapten that induces a delayed-type hypersensitivity reaction similar to that of human atopic dermatitis. Similar to the IMQ challenge trial, 0.3% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was initially tested in a simple ethanol formulation, and when applied twice daily, demonstrated a 20% and 34% reduction in epidermal and dermal thickness, respectively (Figure 6B). ~6C This effect was not observed in a second study in which 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was incorporated into cream formulation 1 and applied only once daily throughout the study (Figure 6). D~6E). This may indicate a decrease in exposure to the compound in the second trial, but further data would be needed to understand whether this discrepancy is a result of different dosing strategies (qd vs bid), limitations of cream formulation 1, or other reasons. However, considering the results in conjunction with the IMQ mouse model, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is expected to have broad anti-inflammatory activity that would be beneficial to patients with both atopic dermatitis and psoriasis.

[0366] Second study Healthy female CDl mice (Crl:CDl(ICR)) had their abdomens and napes shaved under 3-5% isoflurane anesthesia.

[0367] After weighing, the animals were assigned to the test group according to the treatment schedule below. The study was divided into two arms, separated by a one-week interval, to accommodate in-life monitoring of scratch monitoring. Half of the animals (6 animals) from each group were assigned to arm1 and arm2, respectively. [Table 27]

[0368] For each topical treatment, 100 mg of cream or 100 μL of liquid was applied to the nape skin of mice using a solvent pipette. When using cream, it was spread with a finger and massaged into the skin until completely absorbed.

[0369] On day 1, 100 μL of acetone / olive oil (4:1 volume:volume) or 0.15% DNFB (2,4-dinitrofluorobenzeneacetone / olive oil (4:1 volume:volume)) was topically applied to the shaved abdomen (sensitization phase). On days 5, 8, 12, and 15, 100 μL each of acetone / olive oil or 0.15% DNFB was topically applied to the shaved nape of the neck (induction phase). From day 5 to day 17, 100 mg of 0.3% cream formulation 1 (group 4), 0% cream formulation 1 (group 3, placebo cream), or 0.05% clobetasol cream (group 5) was applied once daily to the nape of the neck 2 hours before the DNFB challenge.

[0370] Mice were culled on day 17, 4 hours after the last topical treatment and 48 hours after the last DNFB or acetone / olive oil challenge, under 3-5% isoflurane anesthesia. Nape skin samples were collected in formalin solution (10% neutral buffer) for histological analysis. Epidermis (Figure 6) D ) and the thickness of the dermis (Figure 6) E ) was measured. [Examples]

[0371] Example 15: In vitro evaluation of human skin permeability The in vitro human skin penetration and distribution of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was evaluated using a custom-designed (ChanneL) flow-through diffusion cell setup and ex-vivo human skin (from abdominal wall reconstruction) with skin incisions of 500 ± 100 μm. Skin distribution (epidermis and dermis) and cumulative volume in the recipient fluid over 16 hours (representative of unbound drug that penetrated to 500 μm or less) were evaluated using a purpose-adapted LC-MS / MS with a limit of quantification (LLOQ) of 80 pg / mL to determine the transdermal delivery profile of the formulation prototype. The biological target of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol is the epidermis / epithelium, and the formulation ranking focused on the dermal level due to the low cumulative volume in the recipient fluid. Epidermal samples were not included in the ranking because they may contain residual drug that did not penetrate the stratum corneum.

[0372] In the initial formulation development stage, eight topical formulations (six creams and two gels) containing 1.0% 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol were evaluated in in vitro human skin penetration studies using three donors. Figure 7 shows the delivery of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol to the epidermis and dermis after 16 hours. The amount delivered to the dermis ranged from 0.4 to 2.6 μg, and only low cumulative amounts (less than 20 ng at 16 hours, Figure 8) were quantified in the recipient solution.

[0373] The statistical significance of dermal volume was evaluated using Student's t-test, and formulations not connected by the same letter ("A" to "C") were shown to be statistically different (p<0.05, Table 6). Formulations 3 (1% cream) and 4 (1% gel) delivered more drug to the dermis. [Table 28]

[0374] Furthermore, due to improved physical stability, Cream Formulation 2 and Cream Formulation 1, a similar formulation with a lower transcatol-P level, were also advanced to dose-proportional studies. Based on the dermal volume shown in Figure 9, 1% Cream Formulation 3 and 1% Cream Formulation 1 yielded the best dose-proportional results, with the latter exhibiting comparable delivery to the dermis and an improved stability profile.

[0375] To further evaluate the potential of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol gels (specifically those with less than 15% propylene glycol), two additional formulations (gel formulation 1 and gel formulation 2) were evaluated by in vitro skin penetration assays. None of the gels delivered significantly more 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol to the dermis than the other test products (Figure 10). Cumulative amounts were measured but not considered in the ranking (Figure 11).

[0376] Furthermore, the spatial localization of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol within the skin layer was demonstrated using matrix-assisted laser desorption / ionization imaging mass spectrometry (MALDI IMS). In this study, 1% cream formulation 1 was selected in addition to 0.5% cream formulation 3 and 1% gel formulation 4. These prototypes delivered equal amounts of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol to the dermis during dose-proportional testing. Single doses of the three formulations were applied to full-thickness human skin, and samples were collected at 6 and 24 hours. After collection and preparation, the samples were sent to MALDI. After 6 hours (Table 7), the amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol delivered to the dermal level was 5.0 to 7.0 times higher in the 1% gel formulation 4 compared to the 0.5% cream formulation 3 and the 1% cream formulation 1; however, after 24 hours, this difference was approximately 2.0 times.

[0377] The drug concentrations obtained from in vitro human skin penetration studies and MALDI IMS studies were compared, and the results are shown in Table 7. To calculate the concentration in each compartment using the skin penetration study data, (i) the volume of each compartment was calculated using an administration area of ​​1 cm². 2 The calculations were based on the following assumptions: (ii) the estimated thickness of the epidermis and dermis was 150 μm and 350 μm, respectively; (iii) the assumption that the drug distribution within each compartment was uniform; and (iv) the assumption that the tissue density was 1 g / mL. The concentration did not consider bound or unbound drug fractions.

[0378] The concentrations of the two creams observed in the epidermis were, on average, 2.4 times higher in the 16-hour in vitro human skin penetration study than at the 6-hour MALDI time point. However, the amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol delivered to the epidermis by the gel in the 6-hour MALDI study was comparable to that in the in vitro skin penetration study. At the 24-hour MALDI time point, the amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol delivered was 3.0 to 6.5 times higher in the in vitro human skin penetration study (16 hours) than in the MALDI experiment (24 hours). These variations in concentration are thought to be due to differences in the research protocols used between the two assays, including skin thickness, skin donor, and analytical methods. [Table 29] [Examples]

[0379] Example 16: Absorption, distribution, metabolism, and excretion 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol showed high binding affinity to plasma proteins, with unbound fraction values ​​of 3.06%, 1.98%, and 1.08% at 2 μM in rats, minipigs, and humans, respectively (Table 8). Skin binding of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was tested in human whole skin, epidermal, and dermal homogenates at three concentrations (25, 50, and 100 ng / mL, 0.089, 0.179, and 0.358 μM, respectively), showing mean unbound fraction values ​​of 21.9±0.72%, 51.3±1.1%, and 34.1±11.5%, respectively. Blood-to-plasma ratios were similar across species (1.22-1.36, Table 9). 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was stable in plasma and blood. [Table 30] [Table 31]

[0380] 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was rapidly metabolized by hepatic microsomes and hepatocytes in all species, including mouse, rat, miniature pig, dog, rabbit, and human, suggesting high in vitro clearance. Intrinsic metabolic clearance in hepatocytes was 2.1 to 11.6 times higher than intrinsic clearance in hepatic microsomes in rat, miniature pig, and human (Table 10), and the in vitro-to-in vivo extrapolation ratio (IVIVE) measured in pharmacokinetic studies in rat and miniature pig showed good correlations (0.45 for rats and 0.27 for miniature pigs) (see "Animal Pharmacokinetic Studies" below). [Table 32]

[0381] After incubating human or rat liver microsomes with glutathione (GSH) and glutathione ethyl ester (GSEE) for 1 hour, the active metabolite of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was detected by an in vitro GSH trapping assay (Table 11). These results suggest that 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol may form reactive metabolites. However, given the low systemic exposure levels in vivo from topical administration in rats and miniature pigs (see Animal Pharmacokinetics section below) and the low estimated plasma concentrations in humans (see Estimated Human Plasma Concentrations section below), there is considered to be no safety risk. [Table 33] [Examples]

[0382] Example 17: Animal Pharmacokinetics The preclinical pharmacokinetic profile of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was characterized by high clearance, high distribution volume, and a short half-life in rats and miniature pigs (Table 12, Figure 12). The plasma pharmacokinetics of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol after subcutaneous administration to rats were nearly linear at 10–25 mg / kg for both the 30% captisol and 30% cavitron formulations. The 30% captisol formulation showed a higher plasma exposure (AUC) compared to the 30% cavitron formulation. 24h ) was equivalent (less than 17%), but C maxThe bioavailability was 3.2 to 4.1 times higher (Table 13). Bioavailability was 46.5% for the 30% captisol formulation and 41.0% for the 30% cavitron formulation. In a 7-day subcutaneous administration study in rats, the 30% captisol formulation was selected. Bioavailability after a single oral administration of 5 mg / kg with DMSO in miniature pigs was also examined. The bioavailability after a single oral administration of 5 mg / kg using the Coriofoa HS15:hydroxypropyl-β-cyclodextrin (10:10:80) vehicle was 0.1%, suggesting that the oral route is not suitable for evaluating the systemic safety of minipig. [Table 34] [Table 35]

[0383] When rats were given a single local dose of 20 mg (2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol) / kg covering 10% of their body surface area, 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol was found in 1% cream 1(C max 3.) and 1% gel formulation 1 (C5.18 ng / mL, AUC32.1 ng * Equivalent amounts were observed to be transferred into the bloodstream at hr / mL. 83 ng / mL and AUC 24h 32.1 ng*hr / mL) and 1% gel formulation 1(C max 5.18 ng / mL and AUC 24h The formulations showed similar plasma exposure levels (46.0 ng*hr / mL). Bioavailability was very low, at 1.7% for 1% cream formulation 1 and 2.4% for 1% gel formulation 1 (Table 14). Furthermore, when 15 mg (2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol) / kg of 1% of the body surface area was applied topically to miniature pigs, the plasma exposure (limit of quantification at 87% was ≤50 pg / mL) was very low, suggesting a low systemic safety risk from topical application. [Table 36]

[0384] The cutaneous pharmacokinetics of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol were investigated in Gottchingen miniature pigs over 7 days after a single topical administration of either a 1% cream formulation or a 1% gel formulation. The formulations were administered at a dose of 1 g / 44 cm². 2 The formulations were administered, and skin biopsies were performed at different time points up to 168 hours. Pharmacokinetic (epidermal and dermal tissue homogenate levels) and MALDI IMS (matrix-assisted laser desorption / ionization imaging mass spectrometry) analysis were conducted. Higher concentrations of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol were observed in the epidermis / upper dermis (0-500 μm) compared to the dermis (500-1500 μm) for both formulations (Table 15, Figure 13). Formulation 1 of the 1% cream showed similar results in the epidermis / upper dermis (C max 23.4 μg / g and AUC 168h 2026 μg * hr / mL) and dermis (C max 0.74 μg / g and AUC 168h Achieved 37.5 μg / mL. 5 μg * Exposure to hr / mL was compared to the exposure observed with 1% gel formulation 1, with epidermal (C) exposure. max 18.0 μg / g and AUC 168h 1729 μg * hr / mL) and dermis (C max 0.39 μg / g and AUC 168h 34.7 μg *Exposure to hr / mL increased. Depth profiling by MALDI IMS at different time points for minipig groups was consistent with pharmacokinetic data. The maximum concentrations observed in the epidermis (0–100 μm) and upper dermis (100–500 μm) for 1% cream formulation 1 were 9.4 μg / g at 48 hours and 1.37 μg / g at 72 hours, respectively, for 1% gel formulation 1, and 21.8 μg / g and 1.66 μg / g at 8 hours (Table 16). Some MALDI images for 1% cream formulation 1 (e.g., 8 hours) and 1% gel formulation 1 (e.g., 48 hours) also showed drug penetration via hair follicles, suggesting that the cutaneous appendage pathway may contribute to systemic exposure (Figure 12). MALDI IMS signals decreased to below the detection limit (approximately 500 ng / g) around a depth of 500 μm. [Table 37] [Table 38] [Examples]

[0385] Example 18: Estimation of human plasma concentration after local administration Human plasma concentration (Css) after topical application of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol ,human)は、 Assuming that topically applied drugs are absorbed through the skin at a constant rate, the following predictions were made:

number

[0386] Plasma clearance was estimated from in vitro and preclinical pharmacokinetic studies (CL human ). Using allometric scaling based on in vivo clearance in rats and miniature pigs, hepatic blood flow method, and the IVIVE approach with a Well-Stirred model (assuming hepatic metabolic clearance is the primary excretion pathway), CL humanThe predicted clearance was 6–25 mL / min / kg. To assess the potential systemic safety risk of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol in humans, the lowest predicted clearance (6 mL / min / kg, predicted from allometric scaling corrected for plasma protein binding) was selected.

[0387] In an in vitro human skin permeability evaluation of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol using 0.1% cream formulation 1, 0.5% cream formulation 1, and 1% cream formulation 1, the amount of fluid received remained below the lower limit of quantification (LLOQ; 80 pg / mL) for 16 hours, making it impossible to calculate the skin flux value. Therefore, assuming a 2-hour time lag, the amount of fluid received obtained every 2 hours was calculated using the LLOQ value for 16 hours, resulting in 0.048 ng / cm³. 2 The result was / h, and the estimated skin flux value was calculated.

[0388] Healthy skin is an effective protective barrier against most xenobiotics. Therefore, the validity of flux values ​​obtained from X-vivo skin penetration assays using healthy human skin from abdominal reconstructive surgery may not be consistent with those observed after application to unhealthy skin. Thus, considering skin barrier damage, a 10-fold increase in flux was incorporated into the initial prediction of human systemic exposure from topical administration of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Furthermore, calculations were also performed for human systemic exposure in the worst-case scenario where the flux increased 100-fold. This estimation assumes a human body surface area of ​​10% (1800 cm²). 2 ) was used. Therefore, considering the conditions described here for the purpose of estimating the safety margin, the estimated Css ,humanは The value is 0.34 ng / mL, and the corresponding AUCss ,24h The value was 8.2 ng*h / mL. In clinical practice, local treatment of apical dermatitis is possible up to 50% BSA (9000 cm2), so the corresponding estimated Css when flux increases tenfold is... ,human and AUCss ,24hThe values ​​were 0.17 ng / mL and 4.1 ng*h / mL. Different simulation scenarios are summarized in Table 17. [Table 39] [Examples]

[0389] Example 19: Integration of preclinical target involvement studies to select dosage for humans Based on a combination of in vitro efficacy, XVivo's target engagement and penetration into human skin, and miniature pig skin PK data, it is predicted that daily administration of 1% cream formulation 1 will deliver sufficient concentrations of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol to the target site of the skin (surviving epidermis and upper dermis), thereby inducing AhR target engagement.

[0390] The free drug concentrations in the skin, obtained after topical application of 1% cream formulation 1 and calculated from X-Vivo human and mini-pig skin PK studies (via MALDI-IMS analysis), were sufficient to cover the effective concentrations obtained in in vitro efficacy studies (50% of AhR activation in a fluorescence-based reporter assay for CYP1A1 gene expression and 50% of IL-17A production inhibition in human primary peripheral blood CD4+ T cells) as shown in Table 18. These calculations assumed identical skin binding between humans and mini-pigs and 100% transcutaneous bioavailability after correcting for unbound skin fractions. [Table 40]

[0391] Additional embodiments of the present invention are as follows:

[0392] Embodiment A: A compound which is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, and formula [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0393] Embodiment B. The compound of Embodiment A, wherein the formula is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. [ka]

[0394] Embodiment C: A pharmaceutical composition comprising a therapeutically effective amount of the compound according to either Embodiment A or B, and a pharmaceutically acceptable carrier or diluent.

[0395] Embodiment D. The pharmaceutical composition according to Embodiment C, wherein the pharmaceutically acceptable carrier or diluent is suitable for topical administration.

[0396] Embodiment E: The pharmaceutical composition according to Embodiment C, wherein the carrier or diluent is suitable for topical gel administration.

[0397] Embodiment F: The pharmaceutical composition according to Embodiment C, wherein the carrier or diluent is suitable for topical administration in cream form.

[0398] Embodiment G: A method for treating a condition in a mammal associated with AhR imbalance, comprising the step of administering a therapeutically effective amount of a compound according to either Embodiment A or B to the mammal.

[0399] Embodiment H: A method for treating an inflammatory disorder in a subject requiring the treatment thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound according to either Embodiment A or B.

[0400] Embodiment I: The method according to Embodiment H, wherein the inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascularization (dry) AMD, neovascularization (wet) AMD, uveitis or other inflammatory eye diseases, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

[0401] Embodiment J: The method according to Embodiment I, wherein the compound, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered topically.

[0402] Embodiment K: A method for treating or preventing radiation dermatitis in a subject requiring it, comprising administering to the subject a therapeutically effective amount of a compound according to either Embodiment A or B.

[0403] Embodiment L: The method according to Embodiment K, wherein the radiation dermatitis is chronic radiation dermatitis.

[0404] Embodiment M: The method according to Embodiment K, wherein the radiation dermatitis is acute radiation dermatitis.

[0405] Embodiment N: The method according to Embodiment K, wherein radiation dermatitis is selected from the group consisting of acute erythema, scabbing, desquamation, fibrosis, telangiectasia and skin atrophy, or a combination thereof.

[0406] Embodiment O: The method according to Embodiment N, wherein radiation dermatitis is selected from the group consisting of fibrosis, telangiectasia and cutaneous atrophy, or a combination thereof.

[0407] Embodiment P: A method for treating or preventing an inflammatory mucosal condition in a subject requiring such treatment, comprising administering a therapeutically effective amount of a compound according to either Embodiment A or B to the subject.

[0408] Embodiment Q: The method according to Embodiment P, wherein an inflammatory mucosal condition is induced by radiation therapy or chemotherapy for cancer.

[0409] Embodiment R: The method according to Embodiment P, wherein the inflammatory mucosal condition is selected from the group consisting of oral mucositis, lichen planus, and pemphigus vulgaris.

[0410] Embodiment S: The method according to Embodiment R, wherein the oral mucositis is selected from oral lichen planus, erythema multiforme, pemphigus mucosa, pemphigus vulgaris, and bullous epidermolysis bullosa.

[0411] Embodiment T: The method according to Embodiment R, wherein oral mucositis is induced by radiotherapy for head and neck cancer.

[0412] Embodiment U. A method for treating a dermatological condition or disorder in a subject requiring such treatment, comprising administering to the subject a therapeutically effective amount of a compound according to either Embodiment A or B.

[0413] Embodiment V: A method for treating psoriasis or atopic dermatitis in a subject requiring the treatment thereof, comprising administering to the subject an effective amount of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0414] Embodiment W: Compound of Formula 8 [ka] A process for preparing, a) Compounds of formula 6 [ka] Alternatively, a pharmaceutically acceptable salt, solvate, or hydrate thereof is coupled with formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form the compound of formula 7. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, b) A process comprising the step of dimethylating a compound of formula 7 to form a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0415] Embodiment X: Compound of Formula 8 [ka] or a process for preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, a) Compounds of formula 5 [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 1) Alkylate 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate to obtain a compound of formula 2. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 2) Treat the ketone of formula 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent, and then remove water under acidic conditions to obtain the compound of formula 3. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 3) Hydrogenating the compound of formula 3 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain the compound of formula 4. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and 4) The preparation step comprising the step of borylating a compound of formula 4 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, b) Compounds of formula 6 [ka] or a step of preparing a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the step of treating isoquinoline-3-ol with a triflate agent, and c) A compound of formula 6 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is coupled with a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 7. [ka] or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and d) Demethylate the compound of formula 7 to form the compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, where steps a) and b) can be carried out in different reaction vessels in any order or simultaneously.

[0416] Embodiment Y: A process according to Embodiment X, further comprising purifying the compound of Formula 8.

[0417] Embodiment Z: The process according to Embodiment Y, wherein the purification includes crystallization.

[0418] Embodiment AA: A compound of either Embodiment A or B having a purity of at least 90% by weight.

[0419] Embodiment BB: A compound of either Embodiment A or B having a purity of at least 95% by weight.

[0420] Embodiment CC: A compound of either Embodiment A or B having a purity of at least 98% by weight.

[0421] Embodiment DD: A compound according to either Embodiment A or B, having a purity of at least 99% by weight.

[0422] All publications, including but not limited to patents and patent applications cited herein, are incorporated by reference herein in such a manner as if each individual publication were described in its entirety, as is shown specifically and individually.

[0423] The present invention, including its preferred embodiments, is fully disclosed. Modifications and improvements to the embodiments specifically disclosed herein fall within the scope of the following claims. Those skilled in the art will likely be able to make the most of the present invention using the foregoing description without further detail. Therefore, the examples herein should be construed as illustrative only and not to limit the scope of the invention in any sense. Embodiments of the present invention that claim exclusive characteristics or privileges are defined as follows:

Claims

1. A compound of formula (I), or a salt, solvate, or hydrate thereof, 【Chemistry 1】 During the ceremony R1 is selected from the group consisting of OH and -OCH3. R2 is selected from the group consisting of OH, -OCH3, and -O-(CH2)3NH2. R3 is isopropyl, R4 is selected from the group consisting of H, -COOH, COOCH3, -C(O)NH(CH2)2NH2, and -C(O)NH(CH2)2NHC(O)O-t-butyl. R5 is H, and, R 6 is selected from the group consisting of H and bromo. A compound of formula (I), or a salt, solvate, or hydrate thereof. 【Request Item 2】 【Chemistry 2】 【change】 A compound selected from the group consisting of its salt, solvate, or hydrate.

3. A compound that is 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. 【Request Item 4】 【Chemistry 3】 A compound of, or a salt, solvate, or hydrate thereof.

5. The compound according to claim 2, wherein the compound is 【Chemistry 4】 It is a compound.

6. A composition comprising the compound described in claim 4, wherein the compound has a purity of at least 90% by weight.

7. A composition comprising the compound described in claim 4, wherein the compound has a purity of at least 95% by weight.

8. A composition comprising the compound described in claim 4, wherein the compound has a purity of at least 98% by weight.

9. A composition comprising the compound described in claim 4, wherein the compound has a purity of at least 99% by weight.

10. A pharmaceutical composition comprising the compound according to claim 1 or 2 and a pharmaceutically acceptable carrier or diluent.

11. A pharmaceutical composition comprising a compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a composition according to any one of claims 6 to 9, and a pharmaceutically acceptable carrier or diluent.

12. A pharmaceutical composition according to claim 11, wherein the carrier or diluent is suitable for oral, topical, parenteral, transdermal, intranasal, or oral inhalation administration.

13. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in the treatment or prevention of a mammalian condition associated with AhR imbalance.

14. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in the treatment or prevention of inflammatory diseases.

15. The compound according to claim 14, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascularization (dry) AMD, neovascularization (wet) AMD, uveitis or other inflammatory eye diseases, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

16. The pharmaceutical composition according to claim 10, for use in the treatment or prevention of a condition in mammals related to AhR imbalance.

17. The pharmaceutical composition according to claim 10, for use in the treatment or prevention of inflammatory diseases.

18. The pharmaceutical composition according to claim 17, wherein the inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascularization (dry) AMD, neovascularization (wet) AMD, uveitis or other inflammatory eye diseases, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

19. A compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in the treatment or prevention of inflammatory diseases.

20. The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascularization (dry) AMD, neovascularization (wet) AMD, uveitis or other inflammatory eye diseases, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

21. The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, uveitis, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

22. A compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in the treatment or prevention of psoriasis or atopic dermatitis.

23. Compound of formula 8 【Transformation 5】 or a process for preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, a) Compound of formula 6 【Transformation 6】 Alternatively, a pharmaceutically acceptable salt thereof may be used as the compound of formula 5. 【Transformation 7】 Alternatively, coupling it with a pharmaceutically acceptable salt thereof to form the compound of formula 7. 【Transformation 8】 or a step of forming a pharmaceutically acceptable salt thereof, b) A step of demethylating the compound of formula 7 to form the compound of formula 8, and optionally a step of converting the compound of formula 8 to a pharmaceutically acceptable salt, solvate, or hydrate thereof. A process that includes this.

24. The process according to claim 23, wherein the compound of formula 6, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is prepared by treating isoquinoline-3-ol with a triflate agent.

25. The compound of formula 5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, a) Alkylate 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt thereof to obtain the compound of formula 2. 【Chemistry 9】 or a step of forming a pharmaceutically acceptable salt thereof, b) Treat the compound of formula 2 or a pharmaceutically acceptable salt thereof with a Grignard reagent, and then remove water under acidic conditions to obtain the compound of formula 3. 【Chemistry 10】 or a step of forming a pharmaceutically acceptable salt thereof, c) Hydrogenating the compound of formula 3 or a pharmaceutically acceptable salt thereof to obtain the compound of formula 4 【Chemistry 11】 or a step of forming a pharmaceutically acceptable salt thereof, and d) A step of borylating the compound of formula 4 or a pharmaceutically acceptable salt thereof to form the compound of formula 5 or a pharmaceutically acceptable salt thereof, The process according to claim 23, which is prepared by a process including the following.

26. The aforementioned demethylation is a) Treat the compound of formula 7 with boron tribromide to obtain the compound of formula 7-1. 【Chemistry 12】 The process of forming, and b) A step of hydrogenating the compound of formula 7-1 to form the compound of formula 8, The process according to claim 23, including the process described in claim 23.

27. The process according to claim 23, further comprising the step of purifying the compound of formula 8.

28. The process according to claim 27, wherein the purification step includes crystallization.

29. Compound of formula 8 【Chemistry 13】 or a process for preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, a) Compound of formula 5 【Chemistry 14】 or a step of preparing a pharmaceutically acceptable salt, solvate, or hydrate thereof, 1) Alkylate 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate to obtain a compound of formula 2. 【Chemistry 15】 or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 2) Treat the ketone of formula 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent, and then remove water under acidic conditions to obtain the compound of formula 3. 【Chemistry 16】 or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, 3) Hydrogenating the compound of formula 3 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain the compound of formula 4. 【Chemistry 17】 or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and 4) The preparation step includes the step of borylating the compound of formula 4 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form the compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, b) Compound of formula 6 [Chemistry 18] or a step of preparing a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the step of treating isoquinoline-3-ol with a triflate agent, and c) Coupling a compound of formula 6 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a compound of formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to form a compound of formula 7. 【Chemistry 19】 or a step of forming a pharmaceutically acceptable salt, solvate, or hydrate thereof, and d) A step of demethylating the compound of formula 7 to form the compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein steps a and b can be carried out in different reaction vessels, in any order or simultaneously, and the forming step, A process that includes this.

30. The process according to claim 29, further comprising the step of purifying the compound of formula 8.

31. The process according to claim 30, wherein the purification step includes crystallization.

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