Isoquinoline compounds and their use in treating 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 of and priority to U.S. Provisional Application No. 63 / 052,561, entitled "ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATING AhR IMBALANCE," filed July 16, 2020; and U.S. Provisional Application No. 63 / 052,574, entitled "ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATING AhR IMBALANCE," filed July 16, 2020, the contents of which are incorporated herein by reference in their entireties. Summary of the Invention

[0002] Various embodiments provide compounds and compositions, and methods for treating and preventing 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 the aryl hydrocarbon receptor (AhR) and have AhR-dependent cytokine regulation, useful for treating inflammatory disease states.

[0003] Some embodiments disclosed herein are directed to a compound of formula (I), or a salt, solvate, or hydrate thereof: [ka] During the ceremony R 1 and R 2 each independently represents OH, OR 7 and H, with the proviso that R 1 and R 2 At least one of the following is -OH or -OR 7 and R 7 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-6Cycloalkyl, optionally substituted aryl, arylC 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, optionally substituted arylC 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)NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 and optionally substituted heterocyclyl; R 8 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 9 and R 10 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl, or alternatively, R 9 and R 10 form a 5- to 7-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, R 11 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, optionally substituted aryl, optionally substituted arylC 1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, -NR 9 R 10 , and -OR 12 is selected from the group consisting of R 12 and R 13 each independently selected from 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 is selected from the group consisting of cycloalkyl, R 6 is H, halo, hydroxyl, alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, and optionally substituted aryl C 1-6 is selected from the group consisting of alkyl, 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 5 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; R 14 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 15 and R 16 each independently represents H, optionally substituted C 1-6Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 Alkyl, and optionally substituted C 3-6 cycloalkyl; Alternatively, R 15 and R 16 form a 5- to 7-membered saturated or unsaturated ring together with the nitrogen to which they are attached, R 4 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 arylC 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 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)NR 9 R 10 , -(CR 18 R 19 ) t COR 11 , -(CR 18 R 19 ) t CH(O), -(CR 18 R 19 ) tOR 12 , -(CR 18 R 19 ) t S(O) s R 13 , optionally substituted heterocycles, and optionally substituted heterocycles C 1-6 is selected from the group consisting of alkyl, and R 18 and R 19 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

[0004] Some embodiments are compounds selected from the group consisting of [ka] , The salts, solvates or hydrates thereof are also included.

[0005] Some embodiments include a compound of formula (1) [ka] , The target is.

[0006] Some embodiments include a compound of formula (1) [ka] , or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0007] Some embodiments are directed to a pharmaceutically acceptable salt solvate of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a hydrate thereof.

[0008] In some embodiments, compounds of formula (II), or salt solvates or hydrates thereof, are described: [ka] During the ceremony R 1 and R 2 each independently represents OH, OR 7 and H, with the proviso that R 1 and R 2 At least one of the following is OH or OR 7 and R 7 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 selected from the group consisting of alkyl, and acyl; R 3 is arbitrarily 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 Cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halo, cyano, -C(O)OR 8 , -NR 9 R 10 , -S(O)NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 and optionally substituted heterocycles; n is an integer having a value of 0, 1, or 2; R 6 is H, R 8 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 9 and R 10 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl; alternatively, R 9 and R 10 form, together with the nitrogen atom to which they are attached, a 5- to 7-membered saturated or unsaturated ring, R 11 is 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 Silyl alkyl, -NR 9 R 10 , and -OR 12 selected from the group consisting of R 12 and R 13 each independently selected from 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 is selected from the group consisting of cycloalkyl, and R 6 is halo, hydroxyl, alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, and optionally substituted aryl C 1-6 alkyl.

[0009] Some embodiments herein 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 a method for treating or preventing a condition in a mammal associated with AhR imbalance, comprising administering to the mammal a therapeutically effective amount of any compound or pharmaceutical composition described herein.

[0011] Some embodiments describe methods for treating or preventing an inflammatory disorder in a subject, comprising administering to the subject a therapeutically effective amount of any compound or pharmaceutical composition described herein. In some embodiments, the inflammatory disorder is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascular (dry) AMD, neovascular (wet) AMD, uveitis or other inflammatory eye disease, 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, a compound or pharmaceutical composition described herein is administered topically.

[0012] Some embodiments describe a method of treating or preventing psoriasis or atopic dermatitis in a subject in need thereof, comprising administering to the subject an effective amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0013] Some embodiments include a compound of formula 8 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: a) a compound of formula 5 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: 1) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain a compound of formula 2 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; 2) treating a ketone of formula 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with a Grignard reagent, followed by removal of water under acidic conditions to give a compound of formula 3 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; 3) 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 pharmaceutically acceptable salt, solvate, or hydrate thereof; and 4) borylating a compound of formula 4, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to form a compound of formula 5; b) a compound of formula 6 [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising treating isoquinolin-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 obtain a compound of formula 7 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; and and d) demethylating the 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 either order or simultaneously. [Brief explanation of the drawings]

[0014] [Figure 1] 1A-C show the BioMAP profile of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol compared to tapinarof and F1CZ. Figure 1A shows the BioMAP profile of 2-isopropyl-5-(isoquinolin-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-(isoquinolin-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-(isoquinolin-3-yl)benzene-1,3-diol at 1 μM (light gray) overlaid with tapionardo (1 μM; dark gray). The shaded gray area represents the normal range of variation. Common analytes outside the normal range of variation are annotated. [Figure 2]Figures 2A-2C show the effects of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on IL-17A protein secretion in primary human peripheral blood CD4+ T cells and cell viability of T cells and keratinocytes. Figure 2A shows the dose-dependent suppression of IL-17A in human peripheral blood CD4+ T cells by 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (triangles) and tapinarofen (circles) under Th17-polarizing conditions. Points represent the maximum protein expression rate relative to Th17 in six combined donors, three biological replicates 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 Th17-polarizing conditions and increasing concentrations of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (diamonds) and tapinarofumab (circles) over a 5-day period. Data are means ± 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-(isoquinolin-3-yl)benzene-1,3-diol (triangles) and tapinarofumab (circles) for 5 days. Error bars represent the mean ± standard error of 10–15 biological replicates. [Figure 3] Figures 3A-3B show that target engagement of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol induces AhR target gene, CYP1A1, and reduces IL-17A expression in ex vivo human skin. Healthy donor skin samples were placed in a liquid / air interface culture system and pretreated with 1 or 10 µM 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (white) or GSK3038548A (gray) for 24 h, followed by an additional 24 h of culture under Th17-polarizing conditions. Figure 3A shows the relative expression of CYP1A1 mRNA transcripts after 24 h using qRT-PCR. Figure 3B shows the relative expression of IL-17A mRNA transcripts after 24 h using qRT-PCR. Data are presented as mean ± standard error from 3 or 4 biological replicates. Student's t-test was used to determine statistical significance, *p<0.05. [Figure 4] Figure 4 shows the local targeting of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in different concentrations of cream and gel formulations. Healthy donor skin samples placed in a liquid / air interface culture system were treated with 10 μM 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or 1 μM FICZ, either with or without the medium or at the indicated concentrations in the formulations, for 24 hours. Relative expression of CYP1A1 mRNA transcripts is reported as a plot of the mean ± SEM of four biological replicates from four individual donors. [Figure 5]Figures 5A-5F show the effect of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on clinical score and epidermal thickness in an imiquimod mouse model of psoriasis. 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was applied for 3 days before IMQ treatment. Next, IMQ and 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in a 60% ethanolic topical solution were applied sequentially to the shaved back (IMQ first, then 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, 1–2 h later) at 0.3% for 4 days (Figures 5A–5B). In the plot in Figure 5A, diamonds represent vehicle (60% EtOH 40% water) + Vanicream, squares represent vehicle + imiquimod (5%), and crosses represent 0.3% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%). Other lines are not relevant to this application and are therefore not identified. In Figure 5B, epidermal thickness was measured on histological sections of dorsal skin taken on the final day of treatment. Triangular bars represent vehicle (60% EtOH 40% water) + Vanicream, oval bars represent vehicle + imiquimod (5%), and solid bars represent 0.3% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%). In Figure 5C, diamonds represent vehicle (60% EtOH, 40% water) + Vanicream, squares represent vehicle + imiquimod (5%), crosses represent 0.1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH, 40% water) + imiquimod (5%), circles represent 0.3% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH, 40% water) + imiquimod (5%), and ◎ represents the combination of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60%) + imiquimod (5%). In Figure 5D, epidermal thickness was measured on histological sections of dorsal skin taken on the final day of treatment.Triangular bars represent vehicle (60% EtOH 40% water) + Vanicream; oval bars represent vehicle + imiquimod (5%); square bars represent 0.1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%); and solid bars represent 0.3% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (60% EtOH 40% water) + imiquimod (5%). In Figure 5E, a second 9-day IMQ study was conducted using 0.1% Cream Formulation 1 (squares), 0.5% Cream Formulation 1 (x), and 1% Cream Formulation 1 (stars). 0% Cream Formulation 1 + Vanicream is represented by a diamond, and 0% Cream Formulation 1 + Imiquimod is represented by a circle. In Figure 5F, epidermal thickness was measured on histological sections of dorsal skin taken on the last day of treatment. Triangular bars represent vehicle (0% Cream Formulation 1) + Vanicream, 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-6E show the effects of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on dermal and epidermal thickness in the DFNB mouse model. Figure 6A shows an outline of the experimental design. Mice were sensitized to DNFB on day 1 and challenged with DNFB every 2–3 days starting on day 5. A topical formulation of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was applied daily starting on day 5. Figure 6B shows epidermal thickness measurements, and Figure 6C shows skin thickness measurements twice a day (BID) following topical application of 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or 0.3% 2-isopropyl-5-(isoquinolin-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 v:v) + vehicle (60% EtOH, 40% water)), the diamond bars represent 0.15% DNFB (in acetone / olive oil (4:1 v:v) + vehicle (60% EtOH, 40% water)), the stir bars represent 0.15% DNFB (acetone / olive oil (4:1 v:v) + 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in ethanol (60% EtOH, 40% water)), and the solid bars represent 0.15% DNFB (acetone / olive oil (4:1 v:v) + 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in ethanol (60% EtOH, 40% water)). The hexagonal bars represent 0.15% DNFB in acetone / olive oil (4:1 vol:vol). Figure 6D shows epidermal thickness measurements, and Figure 6E shows dermal thickness in response to once-daily topical application of 0% Cream Formulation 1 or 0% Cream Formulation 1. In Figures 6D and 6E, square bars represent acetone / olive oil (4:1 vol:vol) + vehicle (60% EtOH, 40% water), diamond bars represent 0.15% DNFB (in acetone / olive oil (4:1 vol:vol)) + vehicle (60% EtOH, 40% water), round bars represent 0.15% DNFB (in acetone / olive oil) + vehicle (60% EtOH, 40% water), and round bars represent 0.15% DNFB (in acetone / olive oil) + vehicle (60% EtOH, 40% water).The solid bars represent 15% DNFB in acetone / olive oil (4:1 v:v) + 0% cream formulation 1; the solid bars represent 0.15% DNFB in acetone / olive oil (4:1 v:v) + 0.3% cream formulation 1; and the hexagonal bars represent 0.15% DNFB in acetone / olive oil (4:1 v:v) + 0.05% clobetasol cream. One-way analysis of variance was used to determine statistical significance. *p<0.05, ***p<0.001, n=12 per treatment group. [Figure 7] Figure 7 shows the amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in different 1% formulations delivered to the epidermis (square bars in bar set) and dermis (solid bars in bar set) 16 hours after application. Bar graphs represent the mean amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol ± SEM from 15-18 replicates from three donors. Samples were analyzed by UPLC-MS / MS, and the LLOQ was 80 pg / mL. [Figure 8] Figure 8 shows the cumulative amount (ng) of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the recipient fluid 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, single vertical lines represent 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 thick X represents 1% cream formulation 2. The lines represent the cumulative mean amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol ± SEM from 15–18 replicates from three donors. Samples were analyzed by UPLC-MS / MS, with an LLOQ of 80 pg / mL. [Figure 9]Figure 9 shows the amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol delivered to the dermis 16 hours after application of different formulations. The bar graph represents the mean amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol ± SEM from 13-16 replicates from three donors. Samples were analyzed by UPLC-MS / MS, and the LLOQ was 80 pg / mL. [Figure 10] Figures 10A-10B show the amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (µg) 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-(isoquinolin-3-yl)benzene-1,3-diol. Bars represent the average amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 15-18 replicates ± SEM from three donors (Figure 10A) and from 7-10 replicates ± SEM from one donor (Figure 10B). Samples were analyzed by UPLC-MS / MS at an LLOQ of 80 pg / mL. [Figure 11] Figure 11 shows the cumulative amount (ng) of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the receiving fluid 16 hours after application for different gel formulations. For Gel Formulation 4 (diamonds), Gel Formulation 1 (triangles), and Gel Formulation 2 (squares), the cumulative amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 15-18 replicates ± SEM (N46822-2) from three donors is shown. For Gel Formulation 4 (asterisk) and Gel Formulation 3 (broad X), the cumulative amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol from 7-10 replicates ± SEM from one donor is shown. Samples were analyzed by UPLC-MS / MS at an LLOQ of 80 pg / mL. [Figure 12]Figures 12A-12C show the mean (SD) plasma concentration-time profiles of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol after a single dose in rats. In Figure 12A, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is administered intravenously (1 mg / kg). In Figure 12B, solid boxes represent 10 mg / kg subcutaneous administration of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Captisol, and open boxes represent 25 mg / kg subcutaneous administration of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Captisol. Solid triangles represent subcutaneous administration of 10 mg / kg 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in 30% Cavitron; open triangles represent subcutaneous administration of 25 mg / kg 2-isopropyl-5-(isoquinolin-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-(isoquinolin-3-yl)benzene-1,3-diol, and the open square in Figure 12C represents the topical administration of 1% gel formulation 1 (20 mg / kg) of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (20 mg), as shown in this Figure 12C. [Figure 13]13A-13B show individual epidermal / upper dermal and dermal concentration-time profiles of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol after a single topical administration in minipigs. In FIG. 13A, the solid line, open circle, represents the epidermis / upper dermis of minipig subject 1 treated with 1% cream formulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, and the dashed line, open circle, represents the dermis of minipig subject 1 treated with 1% cream formulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. The solid line and solid circle represent the epidermis / upper dermis of minipig subject 2 treated with 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol cream formulation 1; and the dashed line and solid circle represent the dermis of minipig subject 2 treated with 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol cream formulation 1. In Figure 13B, the solid line and solid circle represent the epidermis / upper dermis of minipig subject 100 treated with 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol gel formulation 1, and the dashed line and solid circle represent the dermis of minipig subject 100 treated with 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol gel formulation 1. Solid line, open circle, epidermis / upper dermis of minipig subject 102 treated with 1% gel formulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol; and dashed line, open circle, dermis of minipig subject 102 treated with 1% gel formulation 1 of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. [Figure 14] Figures 14A-B show depth profiling and skin MALDI IMS at different time points after a single topical administration of 1% cream formulation 1 (Figure 14A) and 1% gel formulation 1 (Figure 14B) in minipigs. DETAILED DESCRIPTION OF THE INVENTION

[0015] The aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcription factors, is a cytoplasmic ligand-activated transcription factor that senses a variety of endogenous and exogenous molecules and mediates multiple biological activities. Recent evidence suggests that the AhR is a highly conserved pathway that regulates 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 cell types in the skin, including keratinocytes, fibroblasts, melanocytes, and cutaneous immune cells. In keratinocytes, AhR signaling regulates the expression of epidermal differentiation genes, such as filaggrin, loricrin, and hornerin, promoting skin barrier formation. Furthermore, AhR plays an important role as a regulator of both innate and adaptive immune responses by influencing the balance between Th17 and Treg T cells. Th17-associated cytokines, such as IL17, contribute to the immunopathogenesis of inflammatory skin diseases, including psoriasis. Therefore, AhR has recently gained attention as a potential target for the treatment and prevention of inflammatory skin diseases, highlighting the need for better topical treatments.

[0017] Compounds that bind to and activate the aryl hydrocarbon receptor (AhR), as described herein, provide a novel class of anti-inflammatory compounds with AhR-dependent cytokine-modulating activity that are useful for the treatment of inflammatory disease states.

[0018] Thus, the beneficial effects of AhR activation provide a new therapeutic intervention in the treatment of inflammatory disease states. There is a need for better topical treatments for skin diseases, particularly chronic inflammatory skin diseases. Preferably, compounds that bind to and activate the aryl hydrocarbon receptor (AhR) in multiple cell types, including cells of human skin, would provide novel and useful treatments for inflammatory disease states. Thus, the present invention provides a novel class of anti-inflammatory compounds with AhR-dependent cytokine regulation for the treatment thereof.

[0019] definition As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the referenced component. It will be apparent to those skilled in the art that the use of the singular includes the plural unless specifically stated otherwise.

[0020] The term "about" means within an acceptable range of the specified particular parameter as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 10% of a given value. For example, about 55% means 45% to 55%.

[0021] As used herein, "acyl" refers to an alkyl or aryl group bonded through a carbonyl group -C(O)-. For example, acyl includes C 1-6 Representative acyl groups include acetyl and benzoyl groups.

[0022] As used herein, the terms "administering" and "administration" refer to any method, in sound medical practice, of delivering a compound or pharmaceutical composition thereof to a patient in a manner that provides the desired therapeutic effect. In some embodiments, the compound is in a pharmaceutical emulsion composition.

[0023] As used herein, the term "alkoxy" refers to an -O-alkyl group containing the specified number of carbon atoms. For example, C 1-6 Alkoxy means an alkoxy group containing at least 1 and at most 6 carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-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 member atoms. For example, C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, s-butyl, and t-butyl), and n-pentyl.

[0025] "Alkylene" refers to a linker having a straight or branched carbon chain of 1 to 6 carbon atoms and having two attachment sites. Examples of C alkylene linker groups include, but are not limited to, -CH-, -CHCH-, -CHCHCHCHCH-, -CHCH(CH)CH-, and the like.

[0026] As used herein, the term "and / or" covers the individual members of such a linked list in both additive and alternative ways, such that these elements are understood to be linked in the alternative by "and" or, respectively, "or." Furthermore, terms used in the singular, of course, also include the plural.

[0027] As used herein, the term "applying" refers to any method, in sound medical or cosmetic practice, of delivering a topical composition to a subject to have a positive effect on a dermatological disorder, condition, or appearance.

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

[0029] As used herein, unless otherwise indicated, the term "arylalkyl" or "araalkyl" refers to an aryl ring such as benzene or naphthalene and a connecting C 1-6 Refers to the alkyl moiety, e.g., -(CH2)n phenyl, where n is 1 to 6;

[0030] As used herein, the term "compound(s) of the invention" or "compound(s) of the invention" refers to a compound as defined herein in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof), and any physical form thereof (e.g., non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, particular polymorphic forms, solvated forms, including hydrate forms (e.g., mono-, di-, and hemihydrates)), as well as mixtures of various forms.

[0031] Throughout this application, descriptions of various embodiments use the language "comprising," although in some specific instances, 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 inactive ingredient present in a composition for use in the topical compositions described herein.

[0033] The terms "effective amount," "pharmacologically effective amount," or "therapeutically effective amount" are used herein to refer to an amount of an active ingredient sufficient to have a therapeutic effect upon administration, e.g., an amount that causes an improvement or change in the condition to which it is administered. The effective amount will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the stage of the condition, the body surface area affected by the clinical condition (in the case of topical administration), and the particular components of the composition. The amount will be sufficient to treat the disorder, disease, or condition or one or more of its symptoms and / or prevent the onset of the disease or disorder, and can be determined by standard clinical techniques. The appropriate amount in any given instance will be readily apparent to one of skill 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., to the area of ​​skin where a clinical abnormality is evident.

[0034] As used herein, the term "haloalkyl" or "halo-substituted alkyl" means a straight or branched saturated hydrocarbon chain containing the specified number of carbon atoms substituted with a halo atom. For example, haloC 1-6 Alkyl means a straight or branched chain alkyl group containing at least 1 and at most 6 carbon atoms substituted with 1 to 3 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, and fluoro, chloro, bromo and iodine, respectively.

[0036] As used herein, the terms "heteroaryl ring," "heteroaryl moiety," and "heteroaryl" refer to 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 refer to fused aromatic rings containing at least one heteroatom selected from oxygen, nitrogen, and sulfur. Each of the fused rings may contain 5 or 6 ring atoms. Examples of fused aromatic rings include, but are not limited to, indolyl, isoindolyl, indazolyl, indolizinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, quinoxaline, naphthyridinyl, cinnolinyl, purinyl, and phthalidinyl.

[0037] As used herein, the term "heteroarylalkyl" refers to a heteroaryl group as defined above (unless otherwise defined). 1-6 It is meant that the alkyl is attached to a heteroaryl moiety, also defined herein, unless otherwise indicated.

[0038] As used herein, the term "heterocyclalkyl" or "heterocyclylalkyl" refers to a heterocyclyl group as defined above (unless otherwise defined). 1-6 It is intended that the alkyl be attached to a heterocycle moiety, as defined herein unless otherwise indicated.

[0039] As used herein, the term "heterocycle" or "heterocyclyl" (by itself or in any combination, such as "heterocyclylalkyl") is 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, where q is 0 or an integer having a value of 1 or 2. Substantial examples include, but are not limited to, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl (including an oxide of the sulfur moiety), pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl (including an oxide of the sulfur moiety), or imidazolidinyl, and the like.

[0040] As used herein in in vitro skin permeation testing, the term "epidermis" includes the stratum corneum and tissue or layers up to the basement membrane separated by a heat separation process.

[0041] As used in in vitro skin penetration studies using ex vivo human abdominal skin of 500 microns (±100 microns) or 750 microns (±100 microns) thickness, the term "epidermis" refers to the top / most layer obtained by heat separation after a washing / tape stripping procedure, and the term "dermis" refers to the underlying layer.

[0042] As used herein, the term "independently" means that when multiple substituents are selected from a number of possible substituents, the substituents can be the same or different, i.e., each substituent is separately selected from the entire group of possible substituents stated.

[0043] The terms "modulate" or "regulate" refer to 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, for example, when attached directly to a carbon atom, forming a carbonyl moiety (C=O).

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

[0046] As used herein, 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) moiety.

[0047] As used herein, the term "optionally" means that the event described thereafter may or may not occur, and includes both an event that occurs and an event that does not occur.

[0048] As used herein, unless otherwise defined herein, "optionally substituted" means that moieties are independently substituted one or more times, e.g., 1 to 3 times, with halo, e.g., bromine or iodo, and optionally fluoro, chloro, bromo, or iodo, hydroxy, hydroxy-substituted C 1-3 C such as alkyl, methoxy or ethoxy 1-3 Alkoxy, halo-substituted C 1-3 Alkoxy, for example, S(O) such as methylthio, methylsulfinyl, or methylsulfonyl m C1-3 alkyl, NR 22 R 23 where R 22 and R 23 are independently H or C 1-3 alkyl, or R 22 and R 23together with the nitrogen to which they are attached form a 5- to 7-membered ring optionally containing additional heteroatoms selected from O, N, or S, C alkyl; C cycloalkyl, or C cycloalkyl C alkyl groups, e.g., cyclopropylmethyl, halo-substituted C alkyl, e.g., CF CF H, or CF , optionally substituted aryl such as phenyl, or optionally substituted aryl C alkyl such as benzyl or phenethyl, wherein these aryl-containing moieties are selected from halo, hydroxy, hydroxy-substituted C alkyl, C alkoxy, S(O) m It may be optionally substituted one to two times with C alkyl, amino, mono- and di-substituted C alkylamino, C alkyl, or CF. Furthermore, those skilled in the art will recognize that the compounds of the present invention may exist in other tautomeric forms, depending on further substitution. All tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the present invention. It is understood that any reference to a named compound of the present invention is intended to encompass all tautomers of the named compound and any mixture of tautomers of the named compound.

[0049] As used herein, "patient" includes human patients, including adults, teenagers, and children (e.g., pediatric patients). Pediatric patients can include teenagers under the age of 18. A child, as used herein, is under the age of 12.

[0050] As used herein, "pharmaceutically acceptable" means those compounds, materials, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The terms "pharmaceutically acceptable" and "dermatologically acceptable" mean approved by a regulatory authority or listed in a pharmacopoeia or other generally recognized guide, for use in animals, particularly humans.

[0051] The term "pharmaceutically acceptable salts thereof" refers to salts that are safe and effective for use in patients and possess the desired pharmacological activity. The salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention. Such salts include compounds that have been modified by making the parent compound into an acid or base salt thereof.

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

[0053] "Substantially free" of a particular component refers to a composition that contains less than about 1% by weight of the particular component. "Free" of a particular component refers to a composition in which the particular component is not present.

[0054] As used herein, the term "substituted" with respect to a group indicates that one or more hydrogen atoms bonded to a member atom within the group are replaced with a substituent selected from the defined group of substituents. The term "substituted" should be understood to include the implicit provision that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound (i.e., one that does not spontaneously undergo transformation, such as by rearrangement, cyclization, or elimination, and is robust enough to withstand isolation from a reaction mixture). Where a group is described as optionally containing one or more substituents, one or more (optional) member atoms within the group may be substituted. Furthermore, a single member atom within a group may be substituted with more than one substituent, provided such substitution is in accordance with the allowed valences of the atom. Suitable substituents are defined herein for each substituent or optionally substituted group.

[0055] The terms "topical" delivery or "topical" administration refer to the application of a drug-containing formulation to the skin with the intent of substantially directing the drug's pharmacological effects at or within the skin to directly treat cutaneous symptoms of a skin disorder or disease. The term "topical" administration also includes transdermal, inhalation, 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 term "treating" or "treatment" refers to the administration of a compound or agent to a subject having or at risk of developing a disorder with the intent to cure, alleviate, relieve, ameliorate, delay the onset of, prevent, or ameliorate the disorder, the symptoms of the disorder, a disease state secondary to the disorder, or the predisposition to the disorder. Treatment need not mean that the condition or disorder is completely cured. A useful pharmaceutical composition, e.g., a pharmaceutical emulsion composition, as used herein, need only mean reducing the severity of the condition or disorder, reducing the severity of symptoms associated therewith, improving the patient's quality of life, or delaying, preventing, or inhibiting the onset of the condition or disorder. As recognized in the medical and pharmaceutical fields, a treatment need not be effective in all members of a population, e.g., a population of atopic dermatitis patients, to have clinical utility.

[0057] Concentrations, amounts, solubilities, and other numerical data may be presented in a range format herein. It is understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values ​​expressly recited as range limits, but also all individual numerical values ​​or subranges encompassed within the range, as if each numerical value and subrange were expressly recited. All numerical values ​​expressing quantities, percentages or proportions, and other numerical values ​​used herein shall be understood to be modified in all instances by the term "about."

[0058] For example, a concentration range of 0.1-5 ng / ml should be interpreted to include not only the explicitly stated 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 subranges such as 0.3-2.5 ng / ml, 1.8-3.2 ng / ml, etc. This interpretation should apply regardless of the breadth of the range or the properties described.

[0059] Concentration ranges, percentage ranges, or ratio ranges described herein shall be understood to include any whole number and fraction thereof (e.g., tenths and hundredths) of concentrations, percentages, or ratios within the range, unless otherwise specified.

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

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

[0062] compound In some embodiments, the present disclosure provides a compound of formula (I) [ka] or a salt, solvate or hydrate thereof.

[0063] The substituent R of formula (I) 1 and R 2 each independently represents OH, OR 7 and H, wherein R 1 and R 2 At least one of the following is OH or OR 7 This is subject to the condition that:

[0064] The substituent R of formula (I) 7 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 It is selected from the group consisting of alkyl and acyl.

[0065] The 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 arylC 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)NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 , optionally substituted heterocycle.

[0066] The substituent R of formula (I) 8 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

[0067] R in formula (I) 9 and R 10 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6Alternatively, the substituent R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- to 7-membered cyclic saturated or unsaturated ring.

[0068] The substituent R of formula (I) 11 are independently hydrogen, 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 Silyl alkyl, -NR 9 R 10 AND-OR 12 is selected from the group consisting of:

[0069] The substituent R of formula (I) 12 and R 13 each independently selected from 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 is selected from the group consisting of cycloalkyl.

[0070] The substituent R of formula (I) 6 is H, halo, hydroxyl, alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, and optionally substituted aryl C 1-6 alkyl.

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

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

[0073] The subscript t in formula (I) is an integer having a value from 0 to 6.

[0074] The substituent R of formula (I) 5 is H, halo, optionally substituted C 1-6 Alkyl, -C(O)OR 14 , -C(O)NR 15 R 16 , optionally substituted aryl, and optionally substituted -C 1-6 alkylaryl.

[0075] The substituent R of formula (I) 14 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

[0076] The substituent R of formula (I) 15 and R 16 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 Alkyl and optionally substituted C 3-6 Alternatively, R 15 , R 16 , together with the nitrogen to which they are attached, form a 5- to 7-membered saturated or unsaturated ring.

[0077] The substituent R of formula (I) 4 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 arylC 1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, -(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)NR 9 R 10 , -(CR 18 R 19 ) t COR 11 ,-(CR 18 R 19 ) t CH(O), -(CR 18 R 19 ) t OR 12 , -(CR 18 R 19 ) t S(O) s R 13 , optionally substituted heterocycles, and optionally substituted heterocycles C 1-6 alkyl.

[0078] The substituent R of formula (I) 18 and R 19 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

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

[0080] In some embodiments, R 1 and R 2 Each of is independently OH. In some embodiments, R 1 and R 2 One of R 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 OR 7 and each R 7 is an arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 In some embodiments, R 7 is an arbitrarily substituted C 1-4 In some embodiments, R 7 is methyl or ethyl. In other embodiments, R 7 is NR 22 R 23 Optionally substituted C 1-4 In some embodiments, R 22 and R 23 Each of H and C 1-3 In some embodiments, R 1 and R 2 Each of R is methoxy. 1 is OH and R 2 is OR 7 and R 7 is the substituted C 1-6 In some embodiments, R 1 is OH and R 2 is OR 7 and R 7 is NR 22 R 23 C replaced with1-6 In some embodiments, R 1 is OH and R 2 is -O(CH2)3NH2.

[0081] R 7 is an optionally substituted moiety, the substituted moieties can be optionally substituted, for example, once, twice, one to three times, and can independently be selected from halo, hydroxyl, hydroxy-substituted -C 1-3 Alkyl, C 1-3 Alkoxy, halo-substituted C 1-3 Alkoxy, -S(O) m C 1-3 , where m is an integer having a value of 0, 1, or 2; -NR 22 R 23 where R 22 and R 23 are independently H or C 1-3 alkyl, or R 22 and R 23 together with the nitrogen to which they are attached, optionally O, N, or S, C 3-7 Cycloalkyl, halo-substituted C such as CF2CF2H or CF3 1-3 forming a 5- to 7-membered ring containing an additional heteroatom selected from alkyl, or optionally substituted aryl, wherein the aryl moiety is also optionally halo, hydroxyl, hydroxy-substituted -C 1-3 Alkyl, C 1-3 Alkoxy, -S(O) m C 1-3 and optionally substituted 1 to 2 times by alkyl, where m is an integer having a value of 0, 1, or 2; and optionally substituted amino, mono- and di-substituted C 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 In some embodiments, R 7 is NR 22 R 23 C replaced with1-6 In some embodiments, R 7 is C substituted with NH 1-6 2 is alkyl. In some embodiments, R 7 is -(CH2)3NH2.

[0083] In some embodiments, R 3 When is an optionally substituted moiety, the moiety may be independently substituted one or more times, e.g., 1 to 3 times. In some embodiments, the moiety is selected from halo, hydroxy, C 1-3 Alkoxy, C 1-3 It may be optionally substituted independently 1 to 3 times with alkyl, aryl or arylalkyl.

[0084] In some embodiments, R 3 is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 In some embodiments, C is selected from the group consisting of C 3-6 Alkyl is isopropyl, n-propyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl, n-hexyl, etc. In some embodiments, alkyl is isopropyl or t-butyl. In some embodiments, C 3-6 In some embodiments, C is 1 to 3; 3-6 Cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, C 3-6 Cycloalkyl is cyclopentyl.

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

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

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

[0088] In some embodiments, R 5 -H, halo, optionally substituted -C 1-6 Alkyl, -C(O)OR 14 , -C(O)NR 15 R 16 , aryl and -C 1-6 In some embodiments, R is selected from the group consisting of alkyl, aryl, and the like. 5 is H, halo, optionally substituted C 1-6 Alkyl, C(O)OR 14 , and C(O)NR 15 R 16 In some embodiments, R 5 is H, halo, optionally substituted C 1-6 Alkyl, and C(O)OR 14 In some embodiments, R 5 is H and optionally substituted C 1-6 In some embodiments, R 5 H, C(O)OR 14 , and C(O)NR 15 R 16In some embodiments, R 5 , optionally substituted C 1-3 R is alkyl. 5 -C with optional substitutions 1-6 In some embodiments, when it is an alkyl moiety, -C 1-6 Alkyl may be independently selected from 1 to 3 times, halo, hydroxyl, C 1-3 Alkoxy, halo-substituted C 1-3 Alkoxy, -S(O) m C 1-3 and optionally independently substituted alkyl, where m is an integer having a value of 0, 1, or 2; 20 R 21 , where R 20 and R 21 is H and C 1-3 Alkyl, halo-substituted C 1-3 In some embodiments, R 5 , H.

[0089] In some embodiments, R 4 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 , optionally substituted C 1-6 Alkyl, -(CR 18 R 19 ) t OR 12 , -(CR 18 R 19 ) t S(O) s R 13 In some embodiments, R 4 is H, -(CR 18 R 19) t COOR 8 , and -(CR 18 R 19 ) t C(O)NR 9 R 10 where t is 0, R 9 is H, R 10 is an optionally substituted C 1-6 In some embodiments, R 4 is selected from the group consisting of H, —COOH, —COOCH, and —CONH(CH)NH. In some embodiments, R 4 , H.

[0090] In some embodiments, t is an integer having 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 1-6 alkyl.

[0092] In some embodiments, R 11 is H and optionally substituted C 1-6 alkyl.

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

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

[0095] In some embodiments, R 18 and R 19 Each of 1-6 alkyl.

[0096] Some embodiments include a compound of formula (I) R 1 OH and OR 7 and R 7 is an arbitrarily substituted C 1-6 is alkyl, R 2 OH and OR 7 and R 7 is an arbitrarily substituted C 1-6 is alkyl, R 3 is an arbitrarily substituted C 1-6 is alkyl, R 4 is H, -(CR 18 R 19 ) t COOR 8 , -(CR 18 R 19 ) t C(O)NR 9 R 10 where t is 0 and R 8 is H and optionally substituted C 1-6 alkyl, and R 9 is H and R 10 is an arbitrarily substituted C 1-6 is alkyl, R 5 is H, and R 6 is H or halo.

[0097] Some embodiments include a compound of formula (I) R 1 OH and OR 7 where R 7 is alkyl, R 2 OH and OR 7 where R 7 is NR 22 R 23 C replaced with 1-6alkyl, where R 22 and R 23 are independently H and C 1-3 is selected from the group consisting of alkyl, R 3 is an arbitrarily substituted C 1-6 is alkyl, R 4 are H, -COOH, -COOCH3, and -C(O)NR 9 R 10 wherein R 9 is H, and R 10 is amino-substituted C 1-6 is selected from the group consisting of alkyl and —(CH)NHC(O)Ot-butyl; R 5 is H, and R 6 is selected from the group consisting of H and halo.

[0098] Some embodiments include a compound of formula (I) R 1 is selected from the group consisting of OH and —OCH3; R 2 is selected from the group consisting of OH, —OCH3, and —O—(CH2)3NH2; R 3 is C 1-6 It is an alkyl R 4 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 is H, and R 6 is selected from the group consisting of H and bromo.

[0099] Some embodiments are compounds of formula (I): R 1 is selected from the group consisting of OH and —OCH3; R 2is selected from the group consisting of OH, —OCH3, and —O—(CH2)3NH2; R 3 , isopropyl, R 4 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 is H, and R 6 is selected from the group consisting of H and bromo.

[0100] In one embodiment, the present disclosure provides a compound of formula (Ia) [ka] or a salt, solvate or hydrate thereof.

[0101] The substituent R of formula (Ia) 1a and R 2a each independently represents OH, OR 7a and H, wherein R 1a and R 2a At least one of the following is OH or OR 7a This is subject to the condition that:

[0102] The 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 arylC 1-6 It is selected from the group consisting of alkyl and acyl.

[0103] The 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 arylC 1-6Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 4-6 It is selected from the group consisting of silylalkenyl, halo and optionally substituted heterocycle.

[0104] The substituent R of formula (Ia) 6a is H, halo, hydroxyl, alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl and optionally substituted aryl C 1-6 alkyl.

[0105] The substituent R of formula (Ia) 5a is H, halo, optionally substituted C 1-6 Alkyl, -C(O)OR 14a , -C(O)NR 15a R 16a , optionally substituted aryl, and optionally substituted -C 1-6 alkylaryl.

[0106] The substituent R of formula (Ia) 14a is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

[0107] The substituent R of formula (Ia) 15a and R 16a each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 Alkyl and optionally substituted C 3-6 Alternatively, R 15a and R 16a, together with the nitrogen to which they are attached, form a 5- to 7-membered saturated or unsaturated ring.

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

[0109] The subscript t' in formula (Ia) is an integer having a value of 0-6.

[0110] The substituent R of formula (Ia) 4a 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 arylC 1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, -(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' OR 12a ,-(CR18a R 19a ) t' S(O) s' R 13a , optionally substituted heterocycles and optionally substituted heterocycles C 1-6 alkyl.

[0111] The substituent R of formula (Ia) 18a and R 19a each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

[0112] The substituent R of formula (Ia) 8a is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl.

[0113] The substituent R of formula (Ia) 9a and R 10a each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 Alternatively, the substituent R 9a and R 10a together with the nitrogen atom to which they are attached form a 5- to 7-membered cyclic saturated or unsaturated ring.

[0114] The substituent R of formula (Ia) 11a are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted arylC1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, -NR 9a R 10a AND-OR 12a is selected from the group consisting of:

[0115] The substituent R of formula (Ia) 12a and R 13a each independently selected from 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 is selected from the group consisting of cycloalkyl.

[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 is independently OH. In some embodiments, R 1a and R 2a One of R 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 the is independently OR 7a , where each R 7a are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 In some embodiments, R 7a is an arbitrarily substituted C 1-4 In some embodiments, R 7a , methyl or ethyl.

[0118] In some embodiments, R 3ais an arbitrarily substituted C 1-6 Alkyl, and optionally substituted C 3-6 In some embodiments, R is selected from the group consisting of cycloalkyl. 3a , optionally substituted C 3-6 In some embodiments, R 3a is isopropyl. In some embodiments, R 3a is an optionally substituted C 3-6 In some embodiments, the cycloalkyl is cyclopentyl.

[0119] In some embodiments, R 3a is an arbitrarily substituted C 3-6 Alkyl, and optionally substituted C 3-6 cycloalkyl; R 1a and R 2a are each independently OH. In some embodiments, R 3a is an arbitrarily substituted C 3-6 Alkyl, and optionally substituted C 3-6 cycloalkyl; R 1a and R 2a Each of the following is OH, OR 7a and H, with the proviso that R 1a and R 2a At least one of the following is OH or OR 7a In another embodiment, R 3a is an arbitrarily substituted C 3-6 Alkyl and optionally substituted C 3-6 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 is independently selected from H and halo.

[0121] In some embodiments, R4a is H and R 5a is H, halo, optionally substituted C 1-6 Alkyl, C(O)OR 14a , and C(O)NR 15a R 16a In some embodiments, R 5a is H and R 4a is H, halo, optionally substituted C 1-6 Alkyl, C(O)OR 14a , and C(O)NR 15a R 16a is 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 cycloalkyl; R 1a and R 2a are both OH and R 4a and R 5a Each of is independently selected from H and halo.

[0123] In some embodiments, R 3a is an arbitrarily substituted C 3-6 alkyl, and R 1a and R 2a Each of R is OH, 4a and R 5a Each of 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, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, and optionally substituted aryl C 1-6 In some embodiments, R 6a H, halo, hydroxyl, C 1-3Alkoxy, optionally substituted C 1-3 In some embodiments, R 6a is selected from the group consisting of H and halo. In some embodiments, R 6a is H.

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

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

[0127] Some embodiments of the present invention comprise: [ka] , or a salt, solvate or hydrate thereof.

[0128] Some embodiments of the present invention are directed to 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol [ka] , or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0129] In some embodiments, 2-isopropyl-5-(isoquinolin-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-(isoquinolin-3-yl)benzene-1,3-diol is a non-solvated crystal. In some embodiments, isolated 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is described. In some embodiments, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is a hydrate. In some embodiments, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is an organic solvate. In some embodiments, isolated 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol organic solvate is described. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol acetonitrile / water solvent. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol acetone solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol N,N-dimethylformamide solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1,4-dioxane / water solution. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol butanone sorbate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol tetrahydrofuran / water solution. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol ethyl acetate solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol dimethyl carbonate solvate.Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol dimethyl sulfoxide solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 1-butanol solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol tetrahydrofuran solvate. Some embodiments describe 2-isopropyl-5-(isoquinolin-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 that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). Compounds according to any embodiment described herein may contain one or more asymmetric centers, also referred to as 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. When 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 stereoisomers and all mixtures thereof. Thus, compounds according to any embodiment described herein containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers. A mixture containing unequal portions of enantiomers is described as having an "enantiomeric excess" (ee) of either the R or S compound. The excess of one enantiomer in a mixture is often expressed as % enantiomeric excess. The ratio of enantiomers can also be defined by "optical purity," which compares the degree to which a mixture of enantiomers rotates plane-polarized light with the individual optically pure R and S compounds. A compound can also be a substantially pure (+) or (-) enantiomer of a compound described herein. In some embodiments, a composition can comprise a substantially pure enantiomer of a compound according to any embodiment described herein, i.e., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one enantiomer. In certain embodiments, a composition can comprise a substantially pure enantiomer of a compound according to any embodiment described herein, where the enantiomer is at least 99.5% of one enantiomer.

[0131] Individual stereoisomers of compounds according to any embodiment described herein that contain one or more asymmetric centers can be resolved by methods known to those skilled in the art. For example, such resolution can be carried out (1) by the formation of diastereomeric salts, complexes, or other derivatives; (2) by selective reaction with stereoisomer-specific reagents, e.g., by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, e.g., 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 the desired stereoisomer is converted to a different chemical entity by one of the above-described separation procedures, additional steps will be required to liberate the desired form. Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to the other by asymmetric transformation. Further embodiments include prodrugs of compounds according to any embodiment described herein, i.e., compounds that release an 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 drug by metabolic transformation. Prodrugs of any of the embodiments of the compounds described herein are prepared by modifying functional groups present in the compound so that the modifications can be cleaved in vivo to release the parent compound. In vivo, the prodrug readily undergoes chemical changes under physiological conditions (e.g., hydrolysis or the action of naturally occurring enzyme(s)), liberating the pharmacologically active drug. Prodrugs include compounds according to any of the embodiments described herein in which a hydroxyl group, an amino group, or a carboxy group is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, an amino group, or a carboxy 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 derivative that is converted to the active parent drug when subjected 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 equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0133] When the compounds of the present invention contain a basic moiety, the desired salt form can be prepared by any suitable method known in the art, including treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like, or pyranosidyl 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 aromatic acids such as benzoic acid, cinnamic acid, or sulfonic acids such as butylenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like.

[0134] Suitable addition salts are formed from acids which form non-toxic salts, examples of which include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, tartrate, borate, calcium edate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucept, gluconate, glutamate, glycolate, glycolylsanilate, hexylresorcinate, hydrobromide, hydrochloride, dihydrochloride, hydrogen fumarate, hydrogen phosphate, hydrogen iodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, lactate, and the like. tate, lactobionate, laurate, malate, mandelate, mesylate, methylsulfate, monopotasmalate, mucate, napsylate, nitrate, N-methylglucamine, sulphate, oxalate, oxaloacetate, pamelate, mesylate, mesylate, napsylate, napsylate, napsiate, napsiate, mesylate, mesylate oxaloacetate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, triethiodate, trifluoroacetate, and valerate.

[0135] Other exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutyrate, lactate, gamma-hydroxybutyrate, mandelate, and sulfonates such as xylenesulfonate, propanesulfonate, naphthalene-1 sulfonate, and naphthalene-2 ​​sulfonate.

[0136] When a basic compound of the present invention is isolated as a salt, the corresponding free base form of the compound will have a higher pK than an inorganic or organic base, preferably the free base form of the compound. a The salts may be prepared by any suitable method known in the art, including treatment of the salts with an inorganic or organic base having the formula:

[0137] When 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 alkaline earth metal hydroxide, etc. Examples of suitable salts include Celite salts derived from amino acids such as glycine and arginine, ammonia; salts of primary, secondary, and tertiary amines, and cyclic amines such as N-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine; and inorganic salts of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0138] Compounds of the present invention which contain both a basic and an acidic moiety may be in the form of zwitterions, acid addition salts of the basic moiety or base salts of the acidic moiety.

[0139] Because of their potential use in medicine, the salts of the compounds of the invention are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts will be 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 compounds, or may be prepared by separately treating the purified compounds in their free acid or free base form with an appropriate base or acid, respectively.

[0141] In certain embodiments, compounds of the present invention may contain acidic functional groups and thus are capable of forming pharmaceutically acceptable base addition salts by treatment with an appropriate base. Examples of such bases include, but are not limited to, a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc, and b) primary, secondary, and tertiary amines, such as aliphatic amines, aromatic amines, aliphatic diamines, and hydroxyalkylamines, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

[0142] In certain embodiments, the compounds of the present invention may contain a basic functional group, and therefore, can be treated with a suitable acid to form a pharmaceutically acceptable acid addition salt.Suitable acids include pharmaceutically acceptable inorganic and organic acids.Representative 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, etc.

[0143] The present invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of the invention into another pharmaceutically acceptable salt of a compound of the 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. One of skill in the art will appreciate that pharmaceutically acceptable solvates may be formed from crystalline compounds where solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, and may also include water as the solvent incorporated into the crystalline lattice. Solvates where water is the solvent incorporated into the crystalline lattice are commonly referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing varying amounts of water. The present invention encompasses all such solvates.

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

[0146] Those skilled in the art will further understand that compounds according to any embodiment described herein that exist in crystalline forms, including various solvates thereof, 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 includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability, and dissolution characteristics. 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 preparation of the compound. For example, changes in temperature, pressure, or solvents can result in polymorphism. Also, under certain conditions, one polymorph may spontaneously convert to another polymorph.

[0147] The subject invention also includes isotopically labeled compounds, which are identical to the compounds described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally 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, e.g., 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 Contains I.

[0148] Compounds according to any embodiment described herein, and pharmaceutically acceptable salts, solvates or hydrates of said compounds that contain the aforementioned isotopes and / or isotopes of other atoms, are within the scope of the present invention. Isotopically labeled compounds of the present invention, e.g., 3 H, 14 Incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 The F isotope is particularly useful in PET (positron emission tomography), 125 I isotopes are particularly useful in SPECT (single photon emission computed tomography) and are also useful for brain imaging. Additionally, heavier isotopes such as deuterium, i.e. 2 Substitution with H may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds according to any embodiment described herein can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0149] The present invention also encompasses isolated compounds, which refer to 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 a mixture.

[0150] It will be readily understood that, because the compounds according to any embodiment described herein are intended for use in pharmaceutical compositions, it is preferable to provide each of them in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, preferably at least 85%, and particularly at least 98% pure (% 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 purer forms for use in pharmaceutical compositions.

[0151] Pharmaceutical Composition In some embodiments, a pharmaceutical composition is described that includes 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. The pharmaceutical composition can be prepared by methods well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated.

[0152] While it is possible for the compounds described in any embodiment herein to be administered as a bulk substance, it is preferable to present the compounds in a pharmaceutical formulation, e.g., where the active agent is present in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

[0153] In particular, the present disclosure provides pharmaceutical compositions 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-(isoquinolin-3-yl)benzene-1,3-diol [ka] or 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] or 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-(isoquinolin-3-yl)-2-(propan-2-yl)phenol [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent. In one embodiment, the salt is the trifluoroacetate salt [ka] is.

[0157] Treatment method Vitiligo is a depigmentation disorder caused by the selective destruction of melanocytes, where AhR links solar UVB radiation to skin pigmentation. A reduced risk of vitiligo has been reported in association with specific AhR gene variants. Furthermore, the authors found that AhR variants promote Ahr transcriptional activity and interaction with the SP1 transcription factor, increasing AhR expression and IL-10 production in humans.

[0158] AhR-activating ligands suppress inflammation in lesional skin of psoriasis patients, whereas AhR antagonists exacerbate the disease. FICZ-mediated AhR signaling suppresses inflammation in imiquimod-induced mice, and AhR-deficient mice exhibit exacerbated disease compared with WT controls. Notably, keratinocytes are implicated in the inflammatory response.

[0159] Activation of the AhR pathway has also been shown to contribute to the development of inflammatory skin lesions such as atopic dermatitis and the exacerbation of inflammatory diseases after occupational or environmental exposure, and the AhR agonist coal tar has been shown to fully restore the expression of key skin barrier proteins.

[0160] Early dry age-related macular degeneration (AMD) is a major cause of visual loss in the elderly. AhR activity and protein in human retinal pigment epithelial cells (RPE) decrease with age, and AhR(- / -) mice exhibit reduced visual function and dry AMD-like pathology. Another group demonstrated that Ahr(- / -) mice exhibited subretinal microglial accumulation and focal RPE atrophy, a phenotype consistent with AMD.

[0161] The Malek lab has also found that AhR is involved in wet AMD. They showed that experimentally induced choroidal neovascular lesions in AhR(- / -) mice contained increased numbers of ionized calcium-binding adaptor molecule 1-positive (Iba1(+)) microglial cells and increased amounts of collagen type IV deposition, all of which are also observed in human wet AMD.

[0162] There are numerous other indications where agonizing or antagonizing AhR may impact disease severity and progression. There is also growing evidence that targeting AhR is beneficial in other disease states, such as treating intestinal inflammation, including irritable bowel disease (IBD), colitis, and Crohn's disease. Additionally, AhR plays an important role in protecting the lung from allergen-induced inflammation by regulating MSC recruitment and immunosuppressive activity.

[0163] Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease accompanied by intense pruritus. The cause of atopic dermatitis is multifactorial, with genetic and environmental factors, impaired skin barrier function, and impaired immune response being the most important contributors. The impaired immune response is characterized by the activation of T-helper type 2 (Th2) cells accompanied by increased IgE production. Furthermore, overexpression of eosinophilic ...

[0164] Atopic dermatitis is characterized by a compromised skin barrier function, a key factor in its pathogenesis. Characteristic symptoms of atopic dermatitis include itching, burning, lichenification, erythema, exudation, crusting, erosion, and scaling. Atopic dermatitis often significantly impacts quality of life, both due to the stigma associated with having visible skin lesions and the intense, constant 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 number and severity of exacerbations. Patients require treatment during acute exacerbations and, if persistent, long-term maintenance therapy. In atopic dermatitis, topical treatments for skin inflammation, as well as symptomatic relief of pruritus, are important components of disease management. While multiple topical treatment options are available, there remains a need for topical treatments that combine high efficacy with an acceptable safety profile for adults and children and can be applied to large body surface areas without treatment duration limitations. Topical corticosteroids (TCS) are commonly used as standard treatment for acute exacerbations of atopic dermatitis. 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 pediatric atopic dermatitis are limited given safety concerns regarding long-term use (more than 2–4 weeks) and application to sensitive areas such as the face and between the eyelashes.

[0166] Without wishing to be bound by any theory, compounds according to embodiments described herein are believed 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 over TCIs. The compounds of embodiments described herein may benefit children who do not respond adequately to TCS; who are intolerant to TCS; or who are not suitable for TCS (e.g., due to lesion location or treatment duration). Having effective options for safe topical treatment can delay transition to systemic treatment, limiting significant treatment-related risks and costs to patients.

[0167] Plaque psoriasis is a chronic autoimmune inflammatory skin disease resulting from the interplay of genetic, environmental, and systemic factors, affecting 2-3% of the Caucasian population. Immune system abnormalities contribute to the pathogenesis, including abnormal cellular 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 hyperproliferation and chemokine production, and (ii) perpetuate further leukocyte recruitment.

[0168] Compounds according to embodiments described herein can be used to treat mild to moderate psoriasis. While there are many new biological treatment options for severe psoriasis, recent innovations in treatment options for patients with mild to moderate disease have been limited. Because TCS treatment has significant contraindications (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] Thus, the present invention provides a method for treating a disorder associated with the above-mentioned diseases or disorders, comprising administering to a subject in need thereof at least one compound described in any embodiment herein, in an effective amount accordingly.

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

[0171] In some embodiments, the present disclosure provides a method for treating or preventing an AhR-mediated disease in a subject in need thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0172] Some embodiments are directed to the treatment of disorders such as: protection from ischemia or reperfusion injury, induction of transplant tolerance, occurring during clinical transplantation (such as organ transplant, acute transplant, or xenograft or allograft (as employed in burn treatment) rejection), organ transplant, myocardial infarction, stroke, etc.; 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-sensitive enteropathy (celiac disease); psoriasis; contact dermatitis (including that caused by poison ivy); Hashimoto's disease; autoimmune hyperthyroidism, such as Sjogren's syndrome, Graves' disease; Addison's disease (an autoimmune disease of the adrenal gland); autoimmune polyglandular disease (including autoimmune polyglandular syndrome and and morphea; autoimmune alopecia; pernicious anemia; vitiligo; autoimmune low specific severity syndrome; Guillain-Barré syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; utilitarianism; 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, ischemia-reperfusion injury); dermatomyositis; macrotrichosis; chronic actinic dermatitis; eczema; Behcet's disease; palmoplantar pustulosis; pyoderma gangrenosum; Sezary syndrome; atopic dermatitis; systemic sclerosis; and morphea, comprising administering an effective amount of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0173] In some embodiments, methods are described for treating or preventing an allergic disease or disorder, an inflammatory disease or disorder, or an autoimmune disease or disorder in a subject in need thereof, 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. 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0174] Some embodiments describe a method for treating or preventing an inflammatory disease or disorder in a subject in need thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-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, escetotic 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 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] Some embodiments describe a method of treating or preventing a dermatological condition or disorder in a subject in need thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-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, the dermatological condition or disorder is a skin disease. In some embodiments, the skin disease is: 1) skin disorders of persistent inflammation, cell dynamics, and differentiation (e.g., psoriasis, psoriatic arthritis, exfoliative dermatitis, pityriasis rosea, lichen planus, lichen nitrite, or porokeratosis); 2) cohesive, vesicular, and bullous skin disorders of the epidermis (e.g., pemphigus, bullous pemphigus, epidermolysis bullosa acquisita, or palmoplantar pustulosis); 3) skin disorders of the epidermal appendages and associated disorders (e.g., hair disorders, nail disorders, rosacea). rash, perioral dermatitis, or hair follicle syndrome; 4) skin disorders such as epidermal and adnexal tumors (e.g., squamous cell carcinoma, basal cell carcinoma, keratoacanthoma, benign epithelial tumor, or Merkel cell carcinoma); 5) melanocyte disorders (e.g., pigmentary disorders, albinism, hypo- and hypermelanotic, melanocytic nevi, or melanoma); 6) skin disorders of inflammatory and neoplastic disorders of the dermis (e.g., exudative erythema, eosinophilia, facial granuloma, pyoderma gangrenosum, malignant atrophic papulosis, fibrous lesions of the dermis and soft tissue, or Kaposi's sarcoma; 7) disorders of the subcutaneous tissue (e.g., panniculitis or lipodystrophy); 8) skin disorders with reactive changes (e.g., urticaria, vascular ectasia, graft-versus-host, allergic contact dermatitis, autosensitization dermatitis, atopic dermatitis, or seborrheic dermatitis); 9) skin changes due to mechanical and physical factors (e.g., burns, radiation dermatitis, keratinization, or calluses); 10) photodamage (e.g., acute and chronic ultraviolet radiation, or photosensitization); or 11) 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] Some embodiments describe a method for treating or preventing radiation dermatitis in a subject in need thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the radiation dermatitis is chronic radiation dermatitis. In some embodiments, the radiation dermatitis is acute radiation dermatitis. In some embodiments, the radiation dermatitis is acute erythema, dilation, scaling, fibrosis, telangiectasia, and skin atrophy, or a combination thereof. In some embodiments, the radiation dermatitis is acute erythema, dilation, or scaling, or a combination thereof. In some embodiments, the radiation dermatitis is fibrosis, telangiectasia, and skin atrophy, or a combination thereof.

[0180] Some embodiments describe a method for treating or preventing an inflammatory mucosal condition in a subject in need thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the inflammatory mucosal condition is induced by radiation or chemotherapy treatment for cancer. In some embodiments, the inflammatory mucosal condition is oral mucositis, lichen planus, or pemphigus vulgaris. In some embodiments, the inflammatory mucosal condition is oral mucositis, such as oral lichen planus, erythema multiforme, mucosal pemphigus, pemphigus vulgaris, or bullous epidermolysis bullosa. In some embodiments, the oral mucositis is induced by radiation or chemotherapy treatment for cancer. In some embodiments, the oral mucositis is induced by radiation or chemotherapy treatment for head and / or neck cancer. In some embodiments, the oral mucositis is induced by radiation treatment for head and / or neck cancer.

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

[0182] Some embodiments provide a method of treating psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof.

[0183] Some embodiments provide a method of treating atopic dermatitis in a subject in need thereof, comprising administering to the subject 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof.

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

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

[0186] Some embodiments describe a method of treating atopic dermatitis or psoriasis in a subject in need thereof, comprising administering to the subject a topical lotion comprising a therapeutically effective amount of 2-isopropyl-5-(isoquinolin-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 the AhR ligand. In some embodiments, the compound is an antagonist of the AhR ligand.

[0188] The 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, for example, a mammal, including horses, cows, pigs, sheep, poultry, fish, cats, 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 or older. In some embodiments, the human is an adult.

[0190] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is described for use in therapy. 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0191] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is described for use in treating or preventing a condition associated with 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0192] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is described for use in treating or preventing an AhR-mediated disease. 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0193] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is described for use in treating or preventing an inflammatory disease or disorder. 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0194] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is described for use in treating or preventing a dermatological condition or disorder. 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0195] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is described for use in treating or preventing 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0196] In some embodiments, a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0197] Some embodiments describe the use of a compound according to any embodiment described herein, or its pharmaceutically acceptable salt, solvate or hydrate, in the manufacture of a medicament for treating a condition associated with AhR imbalance in a subject in need thereof.In some embodiments, the compound is a compound of Formula (I) or Formula (Ia), or its pharmaceutically acceptable salt, solvate or hydrate.In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or its pharmaceutically acceptable salt, solvate or hydrate.

[0198] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for treating an AhR-mediated disease in a subject in need 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 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0199] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for treating or preventing an inflammatory disorder in a subject in need 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 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0200] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for the treatment or prevention of a dermatological condition or disorder in a subject in need 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 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for the treatment or prevention of psoriasis in a subject in need 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 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0201] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for treating or preventing atopic dermatitis in a subject in need 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 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0202] Some embodiments describe the use of a compound according to any embodiment described herein, or its pharmaceutically acceptable salt, solvate, or hydrate, for the treatment or prevention of a condition associated with AhR imbalance in a subject in need thereof. In some embodiments, the compound is a compound of Formula (I) or Formula (Ia), or its pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or its pharmaceutically acceptable salt, solvate, or hydrate.

[0203] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0204] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0205] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for the treatment or prevention of a dermatological condition or disorder. 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0206] In some embodiments, the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0207] In some embodiments, the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate 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-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0208] combination For the pharmaceutical compositions and methods / uses described herein, the compound of any embodiment described herein may be administered in combination with one or more other therapeutic and / or active agents. In some embodiments, the compound of any embodiment described herein is administered in combination with a second agent indicated for a disorder or disease described herein, either simultaneously with, before, or after the administration of the second agent. In some embodiments, the second agent is included in the same formulation as the compound according to any embodiment described herein. In some embodiments, the second agent is in a separate formulation. The second therapeutic agent may be administered by the same route as the compound according to any embodiment described herein, or by a different route than the compound according to any embodiment described herein. For example, the compound according to any embodiment described herein may be administered topically, and the second agent may be administered topically, orally, intravenously, intramuscularly, ophthalmically, intravaginally, intrarectally, etc. In some embodiments, the second agent is administered simultaneously with the compound of the invention. In some embodiments, the second agent is administered before the compound of the invention. In some embodiments, the second agent is administered after the compound of the invention.

[0209] That is, the compounds according to any embodiment described herein can be administered simultaneously or sequentially to the administration site or desired site of action in any order. The order of administration is not considered necessary. However, when administered locally, it may be preferable for two or more active agents to be in contact with each other at the administration site or desired site of action at some point. Alternatively, it may be preferable for the time period for the appropriate mode of action of the active agent to be appropriately timed in the delivery time of the active agent. If both are present in the same vehicle, this provides ease of administration to the patient and may increase compliance, but is not required for the invention herein.

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

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

[0212] In some embodiments, the other agent(s) are useful for the prevention or treatment of allergic, inflammatory, or autoimmune diseases. In some embodiments, the agent(s) are antigen immunotherapeutics; antihistamines; corticosteroids such as fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, and flunisonide; NSAIDs; leukotriene modifiers (such as 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 A2a agonists; mediator release inhibitors, e.g., sodium cromoglanate, 5-lipoxygenase inhibitors (zyflo); DP1 antagonists; DP2 antagonists; PI3K delta inhibitors; ITK inhibitors; LP (lysophosphatidic) inhibitors; or FLAP (5-lipoxygenase activating protein) inhibitors. Protein inhibitors, such as sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate; bronchodilators, such as 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 and similar agents, cytokine receptor therapeutics, e.g., etanercept and similar agents; and antigen-nonspecific immunotherapeutics, e.g., 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 agents.

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

[0214] In some embodiments, the other agent(s) is an agent for treating diabetes, such as metformin (a biguanide), a meglitinoid, a sulfonylurea, a DPP-4 inhibitor, a thiazolidinedione, or an α-glucosidase inhibitor, an amylin mimetic, an incretin mimetic, or insulin.

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

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

[0217] It will be understood that if combined in the same formulation, the two or more compounds must be stable and compatible with each other and with the other components of the formulation. If formulated separately, they can be provided in any convenient formulation, in such a manner as is known for such compounds in the art.

[0218] Preservatives, stabilizers, dyes, and flavoring agents may be provided in any of the pharmaceutical compositions 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 including 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, typically for parenteral, e.g., intravenous, administration. See, e.g., 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 said compounds can be conveniently administered by any route conventionally used for drug administration, for example, orally, topically, transdermally, parenterally, or by inhalation. The compounds can be administered in conventional dosage forms prepared by combining a compound according to any embodiment described herein with a standard pharmaceutical carrier according to conventional procedures. Compounds according to any embodiment described herein may also be administered in conventional dosage amounts in combination with a known second therapeutically active compound, as further described herein. These procedures may include mixing, granulating, and compressing or dissolving the ingredients as appropriate for the desired preparation. It will be understood that the form and characteristics of a pharmaceutically acceptable property or diluent are dictated by the amount of active ingredient with which it is combined, the route of administration, and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0221] The compounds according to any embodiment described herein may be administered topically, i.e., by non-systemic administration. This includes external application of the compound to the epidermis, buccal cavity, or installation of such a compound in the ear, eye, and nose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration, etc.

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

[0223] Lotions according to the present invention include those suitable for application to the skin, ears, nose, or eyes. Eye lotions consist of a sterile aqueous solution, optionally containing a bactericide, and can be prepared by methods similar to those used to prepare eye drops. Lotions or liniments for application to the skin may contain agents to speed drying and cool the skin, such as alcohol or acetone, and / or moisturizing agents, such as glycerol, or oils, such as castor oil or arachis oil.

[0224] Creams, gels, ointments, or pastes according to the present invention are semi-solid formulations of the active ingredient for topical application. They can be prepared by mixing, with the aid of a suitable machine, the finely divided or powdered active ingredient (i.e., a compound 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. The base may be composed of hard, soft, or liquid paraffin; hydrocarbons such as glycerol, beeswax, or metal soaps; mucilage; naturally occurring oils such as almond, corn, arachis, castor, or olive oil; wool fat or its derivatives; or fatty acids such as steric or oleic acid, together with alcohols or macrogels such as propylene glycol. The formulations can incorporate any suitable surface-active agent, such as anionic, cationic, or nonionic surfactants, such as sorbitan esters or their polyoxyethylene derivatives. Suspending agents such as natural gums, cellulose derivatives, or inorganic materials such as silicatic silicas, and other ingredients such as lanolin, may also be included.

[0225] Drops according to the present invention comprise sterile aqueous or oily solutions or suspensions, which 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 can be sterilized by filtration and transferred to a container using aseptic techniques. Examples of bactericides and fungicides suitable for inclusion in drops include phenyl nitrate or phenyl acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted alcohol, and propylene glycol.

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

[0227] In some embodiments, the pharmaceutical formulation comprises a compound according to any embodiment described herein and a pharmaceutically acceptable excipient or diluent and an antioxidant, a preservative, a gelling agent, a pH adjuster, or a stabilizer, or a mixture thereof, suitable for topical administration to the skin, eye, or ear of a patient.

[0228] In some embodiments, the composition is a cream or gel composition and the compound of Formula (I) is 2-isopropyl-5-(isoquinolin-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: [Table 1]

[0230] It will be appreciated that when 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is present at a specific concentration (ranging from 0 to 1%) in Cream Formulation 1, the formulation may be referred to as X% Cream Formulation 1. For example, in some embodiments, the composition is Cream Formulation 1 containing 1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (1% Cream Formulation 1). Thus, 1% Cream Formulation 1 is composed as follows: [Table 2]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0246] Although topical use is the preferred route of administration, the compounds according to any embodiment described herein can also be administered parenterally, i.e., intravenously, intramuscularly, subcutaneously, intranasally, rectally, intravaginally, or intraperitoneally. Subcutaneous and intramuscular dosage forms of parenteral administration are generally preferred. Suitable dosage forms for such administration can be prepared by conventional techniques. 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 techniques.

[0247] The dosage of the compound according to any embodiment described herein as the active ingredient of the present invention can be varied to obtain a suitable dosage form. The active ingredient may be administered to subjects (animals and humans) in need of such treatment at a dosage that provides optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, the route of administration, and the 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 currently following, concurrent medications, and other factors that will be recognized by those skilled in the art.

[0248] In some embodiments, the amount of compound administered can be between about 0.1 and about 100 mg / kg / day. Generally, a dosage of between 0.1 and 10 mg / kg of body weight per day is administered to a patient, e.g., a human. In some embodiments, the therapeutically effective amount has lower limits of about 0.1 mg / kg body weight, about 0.2 mg / kg body weight, about 0.3 mg / kg body weight, about 0.4 mg / kg body weight, about 0.5 mg / kg body weight, about 0.6 mg / kg body weight, about 0.7 mg / kg body weight, about 0.8 mg / kg body weight, about 0.9 mg / kg body weight, about 1 mg / kg body weight, about 5 mg / kg body weight, about 10 mg / kg body weight, about 15 mg / kg body weight, about 20 mg / kg body weight, about 25 mg / kg body weight, about 30 mg / kg body weight, about 35 mg / kg body weight, about 40 mg / kg body weight, about 45 mg / kg body weight, about 50 mg / kg body weight, about 55 mg / kg body weight, about 60 mg / kg body weight, about 65 mg / kg body weight, about 70 mg / kg body weight, about 75 mg / kg body weight, about 80 mg / kg body weight, about 85 mg / kg body weight, about 80 mg / kg body weight, about 95 mg / kg body weight, and about 100 mg / kg body weight, and an upper limit of 100 mg / kg body weight. mg / kg body weight, about 95 mg / kg body weight, about 90 mg / kg body weight, about 85 mg / kg body weight, about 80 mg / kg body weight, about 75 mg / kg body weight, about 70 mg / kg body weight, about 65 mg / kg body weight, about 60 mg / kg body weight, about 55 mg / kg body weight, about 50 mg / kg body weight, about 45 mg / kg body weight, about 40 mg / kg body weight, about 35 mg / kg body weight, about 30 mg / kg body weight, about 25 mg / kg body weight, about 20 mg / kg body weight, about 15 mg / kg body weight, about 10 mg / kg body weight, about 5 mg / kg body weight, about 1 mg / kg body weight, about 0.9 mg / body weight, about 0.8 mg / body weight, about 0.7 mg / body weight, about 0.6 mg / body weight, about 0.5 mg / body weight, about 0.4 mg / body weight, about 0.3 mg / body weight, about 0.2 mg / body weight, about 0.1 kg / body weight per day.

[0249] In some embodiments, a compound according to any embodiment described herein is administered to a subject at 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 is, at lower limits, 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 Days, about 390mg / day, about 400mg / day, about 410mg / day, about 420mg / day, about 430mg / day, about 440mg / day, about 450mg / day, about 460mg / day, about 470mg / day, about 480mg / day, about 490mg / day, about 500mg / day, about 510mg / day, about 520mg / day, about 530mg / day, about 540mg / day, about 550mg / day, about 560mg / day, about 570mg / day, about 580mg / day, about 590mg / day, about 600mg / day, about 610mg / day, about 620mg / day, about 670mg g / day, about 670 mg / day, about 670 mg / day, about 680 mg / day, about 500 mg / day, about 60 mg / day, about 40 mg / day, about 70 mg / day, about 70 mg / day, about 70 mg / day, about 670 mg / day, about 620 mg / day, about 630 mg / day, about 640 mg / day, about 650 mg / day, about 660 mg / day, about 670 mg / day, about 680 mg / day, about 690 mg / day, about 700 mg / day, about 710 mg / day, about 720 mg / day, about 730 mg / day, about 740 mg / day, about 750 mg / day, about 760 mg / day,Approximately 770mg / day, approximately 780mg / day, approximately 790mg / day, approximately 800mg / day, approximately 810mg / day, approximately 820mg / day, approximately 830mg / day, approximately 840mg / day, approximately 850mg / day, approximately 860mg / day, approximately 870mg / day, approximately 880mg / day, approximately 770mg / day, approximately 790mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 770mg / day, approximately 780mg / day, approximately 890mg / day, approximately 900mg / day, approximately 910mg / day, approximately 920mg / day, approximately 930mg / The upper limit is 1000 mg / day, about 990 mg / day, about 970 mg / day, about 960 mg / day, about 950 mg / day, about 940 mg / day, about 930 mg / day, about 920 mg / day, about 910 mg / day, about 900 mg / day, about 890 mg / day, about 880 mg / day, about 870 mg / day, about 860 mg / day, about 850 mg / day, about 840 mg / day, about 830 mg / day, about 820 mg / day, about 810 mg / day, and about 800 mg / day. mg / day, approximately 790mg / day, approximately 780mg / day, approximately 770mg / day, approximately 760mg / day, approximately 750mg / day, approximately 740mg / day, approximately 730mg / day, approximately 720mg / day, approximately 710mg / day, approximately 700mg / day, approximately 690mg / day, approximately 680mg / day, approximately 670mg / day, approximately 660mg / day, approximately 650mg / day, approximately 640mg / day, approximately 630mg / day, approximately 620mg / day, approximately 610mg / day, approximately 600mg / day, approximately 590mg / day, approximately 580mg / day, approximately 570mg / day, approximately 560mg / day, approximately 550mg / day, approximately 540mg / day, approximately 530mg / 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 / day, about 130 mg / day, about 120 mg / day, about 110 mg / day, about 100 mg / day, about 90 mg / day, about 80 mg / day, about 70 mg / day, about 60 mg / day, about 50 mg / day, about 40 mg / day, about 30 mg / day, about 10 mg / day, about 1 mg / day, about 0.5 mg / day, about 0.1 mg / day, about 0.01 mg / day.

[0250] It will be understood that the pharmaceutical compositions of the present disclosure do not necessarily contain the entire amount of the compound effective to treat a disorder, as such an effective amount can be achieved by multiple, divided administrations of such pharmaceutical compositions. The compound can be administered in a single dose per day, or in a regimen of multiple smaller doses (e.g., 2, 3, 4, 5, or more) per day, such that the total daily dose is the same. The effective amount of the salt may be determined as a percentage of the effective amount of the compound according to any embodiment described herein. Similar dosages should also be appropriate for treating other conditions referred to herein for treatment. In general, the determination of appropriate dosages can be readily achieved by those skilled in the art of medicine or pharmacy.

[0251] The active ingredient, i.e., a compound according to any embodiment described herein, may be administered for topical administration in about 0.001% w / w to about 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein is 1% to 2% w / w of the formulation. A daily topical dosing regimen can be from about 0.1 mg to 150 mg of a compound according to any embodiment described herein, administered 1 to 4 times per day.In some embodiments, the daily topical dosage 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 dose was either 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 in vivo data using animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well known in the art.The compounds may be administered once a week, several times a week (eg, 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 also recognize that the optimal amount and interval of individual doses of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, will be determined by the nature and extent 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 conventional techniques. It will also be understood that the optimal course of treatment, i.e., the dose of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered per day for a specified number of days, can be ascertained by those skilled in the art using conventional course-of-treatment determination tests.

[0253] Method for preparing compounds of formula (8) Some embodiments include a compound of formula 8 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof.

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

[0255] In some embodiments, the process comprises reacting a compound of formula 4 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 5.

[0256] In some embodiments, the process comprises reacting a compound of formula 3 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 4.

[0257] In some embodiments, the process comprises reacting a ketone of formula 2 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof with a Grignard reagent, followed by elimination of water under acidic conditions to form a compound of formula 3.

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

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

[0260] In some embodiments, demethylating a compound of formula 7 to form a compound of formula 8 comprises the steps of: a) treating a compound of formula 7 with boron tribromide to form a compound of formula 7-1; [ka] and b) hydrogenating a compound of formula 7-1 to form a compound of formula 8.

[0261] In some embodiments, demethylating a compound of Formula 7 to form a compound of Formula 8 comprises treating a compound of Formula 7 with hydrobromic acid.

[0262] Some embodiments include a compound of formula 8 [ka] A process for preparing a) a compound of formula 6 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof with a compound of formula 5 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 7; and b) demethylating the compound of formula 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to form a compound of formula 8.

[0263] In some embodiments, a compound of Formula 6 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof by any process described herein, prepared by treating isoquinolin-3-ol with a triflating agent.

[0264] In some embodiments, the compound of formula 5, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, by any process described herein, comprises the steps of: a) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain a compound of formula 2 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; b) treating a ketone of formula 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with a Grignard reagent, followed by removal of water under acidic conditions to give a compound of formula 3 [ka] or 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 pharmaceutically acceptable salt, solvate or hydrate thereof; and and d) 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 include a compound of formula 8 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: a) a compound of formula 5 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: 1) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain a compound of formula 2 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; 2) treating a ketone of formula 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with a Grignard reagent, followed by removal of water under acidic conditions to give a compound of formula 3 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; 3) Compound of Formula 3 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 4; and 4) 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) a compound of formula 6 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising treating isoquinolin-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 obtain a compound of formula 7 [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and d) demethylating the 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 either order, or simultaneously.

[0266] In some embodiments according to any process described herein, the step further comprises purifying the compound of formula 8. In some embodiments, the purifying comprises crystallizing the compound of formula 8.

[0267] The appropriate amount in any given instance will be readily apparent to one skilled in the art and can be determined by routine experimentation. The compositions are generally applied topically to the affected area, i.e., to the area of ​​the skin where a clinical abnormality is manifest.

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

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

[0270] LCMS standard A LC conditions: UPLC analysis was performed using a Waters Acquity BEH C18 2x50mm 1.7m column at 50°C. A 0.5uL sample was injected using 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 from 210 to 350 nm is scanned at 40 Hz and UV detection is performed. · MS conditions. Instrument: Waters Acquity Serial number: C07SQD043W Scan mode: Positive / negative alternating electrospray Scan range: 125-1000 amu Scan time: 105msec Interscan delay: 20msec Other information All equipment was provided by Waters Corp, Milford, MA. · Quality control samples are run and analyzed at a minimum once per day.

[0271] LCMS standard B Mobile phase A: Water (0.01% TFA) B: ACN (0.01% TFA). Gradient: Increases from 5%B to 95%B within 1.5 minutes. 95%B for 1.8min, back to 5%B within 0.01min Flow rate 2.0ml / min Column: SunFire C18, 4.6 x 50 mm, 3.5 μm Column temperature: 50℃ 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: Increases from 5%B to 95%B within 2 minutes. 95%B for 1.3min, back to 5%B within 0.01min Flow rate 1.8ml / min Column: XBridgeC18, 4.6 x 50 mm, 3.5 μm Column temperature: 40℃ 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 compatible with the synthetic methods 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 a 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 certain embodiments, a substituent may be specifically selected to be reactive under the reaction conditions used. Under such circumstances, depending on the reaction conditions, the selected substituent may be converted into another substituent that is useful as an intermediate compound or is a desired substituent in a target compound.

[0274] The synthesis of compounds of the general formula set forth in the following scheme(s) and their pharmaceutically acceptable salts, solvates or hydrates can be generally carried out as follows.

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

[0276] The compounds of the present invention can be obtained 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 can be applied to prepare compounds of the present invention having a variety of different substituents, using appropriate precursors that are appropriately protected as necessary to achieve compatibility with the reactions outlined herein. Deprotection, as necessary, generally provides compounds as disclosed. While this scheme shows only compounds of formula (I), it is intended to illustrate processes that can be used to prepare compounds of the present invention.

[0277] Intermediates (compounds used to prepare compounds of the invention) can also exist as salts, solvates, or hydrates. Thus, with respect to intermediates, the phrase "compound(s) of formula(s)" means a compound having that structural formula, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

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

[0279] As further illustrated in the scheme herein, compounds of general formula (I) [ka] where R 1 -R6 is as defined above for formula (I). [ka]

[0280] Compounds of Formula (I) may be prepared by carbon-carbon formations such as transition metal-catalyzed cross-coupling. This reaction may be accomplished by Suzuki-Miyaura coupling in the presence of a halide or pseudohalide catalyst, such as, but not limited to, Pd(0), Ni(0), Pd(II), or Ni(II) complexes bearing ligands, such as, but not limited to, PdCl(dppf), Pd(PPh), Pd(OAc), Pd(dba), NiCl(dppf), and NiCl(PCy), organoboronic acids, or boronate esters or potassium trifluoroboronate and triflate. Such coupling reactions are carried out in the presence of a mild base, such as KCO, NaCO, NaHCO, CsCO, KPO, KF, or the like, in a suitable solvent, such as toluene, dioxane, tetrahydrofuran, dimethoxyethane, dimethylformamide, or the like. Selection of appropriate bases, ligands, solvents, and reaction conditions, such as time, temperature, pressure, choice of atmosphere (eg, inert), reaction work-up, purification, etc., are known to those skilled in the art.

[0281] One aspect of the present invention is a process for producing a compound of Formula (I). The final compound of Formula (I) can be prepared by deprotecting its precursor, if any protecting groups are employed during the conversion. Suitable hydroxyl protecting groups familiar to those skilled in the art can be found in Greene (vide supra). One such example of demethylation is possible 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. Upon completion of the reaction, the mixture is slowly quenched with a suitable solvent, such as methyl alcohol, at -78°C to +20°C, preferably about -20°C to 10°C, and stirring is continued at room temperature for about 1 to 4 hours. Water may then be added, if desired. Excess solvent is removed by distillation. The resulting residue is purified by typical normal-phase or reverse-phase chromatography and recrystallization in an appropriate solvent.

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

[0283] Step 1. 3,5-Dihydroxy-4-isopropylbenzoic acid triethylamine salt 3,5-Dihydroxybenzoic acid (40 g, 0.26 mol, 1.0 equiv) was placed in a 1 L three-neck round-bottom flask and concentrated sulfuric acid (160 mL, 4 vol) was added at room temperature. Water (20 mL, 0.5 vol) was added with stirring. The suspension was heated to 60-65 °C, and 2-propanol (25.0 mL, 0.32 mol, 1.25 equiv) was added dropwise to the reaction mixture over 10 min. The clear reaction mixture was stirred at 60-65 °C for 4-8 h 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 and 30 °C in the second RBF. The reaction mixture flask was rinsed thoroughly with water and then charged with tert-butyl methyl ether (TBME, 320 mL, 8 vol). The mixture was warmed to 20-25 °C and stirred for ~30 min. The two layers were separated, and the aqueous layer was extracted with TBME (2 x 160 mL, 4 vol). Sodium potassium tartrate solution was charged to the combined TBME layer (1N, 160 mL, 4 vol) and stirred at 20-25 °C for at least 40 min. The two layers were separated, and the organic layer was passed through Darco G-60 activated carbon (-100 mesh), and the carbon cake was washed with TBME. 2-Propanol (90 mL, 2.25 vol) was charged to the TBME layer, and triethylamine (36.2 mL, 1.0 equiv.) was charged dropwise to the mixture (TBME layer + 2-propanol solution) over ~15 min at 20-25 °C and stirred for at least 2.5 h. The product was isolated by filtration and the cake was washed with TBME. The title product was dried in an oven at 40-50°C overnight. Purity by HPLC: 98%.

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

[0285] The title compound was prepared according to a 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 US Pat. No. 5,919,970. [ka]

[0287] Process 1 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 was added methoxymethyl chloride (5.96 mL, 78 mmol). The reaction mixture was warmed to RT and stirred for 30 minutes before being 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 extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified using an 80-gram Isco brand silica column, eluting with 10–100% EtOAc / heptane (60 mL / min) to give the desired 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 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 was added DIBAL-H (1 mL, hexane, 8.67 mL, 8.67 mmol). The reaction mixture was warmed to 0 °C, stirred for 30 min, and repeatedly quenched with EtOAc (1 mL) and then MeOH (4 mL). Saturated aqueous sodium potassium tartrate (40 mL) was added, and the resulting mixture was stirred vigorously overnight. The layers were separated, and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 24-gram Isco brand silica column, eluting with 10–100% EtOAc / heptane (35 mL / min) to give 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 h. The filtrate was concentrated to give the pure desired compound as a colorless amorphous solid. LCMS Method A:t R =0.78 min, 100%;MS(ESI):m / z307.35(M+2) + .

[0290] Process 4 A sealed tube was charged with 4-bromo-3,5-bis(methoxymethoxy)benzaldehyde (322 mg, 1.055 mmol), 2-(cyclopent-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). The reaction mixture was heated at 100° C. overnight, cooled, and partitioned between EtOAc and water. The organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 12 gram Isco brand silica column eluting with 10-100% EtOAc / heptane (30 mL / min) to give the desired product as a light 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-(Cyclopent-1-en-1-yl)-3,5-bis(methoxymethoxy)benzaldehyde (252 mg, 0.862 mmol) was dissolved in a mixture of methanol (3451 μL) and trimethyl orthoformate (2382 μL, 21.55 mmol) containing a catalytic amount of ammonium chloride (4.61 mg, 0.086 mmol). The mixture was stirred at 65 °C for 2.5 h or until the benzaldehyde was consumed as determined 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 min, 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 × 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 under a hydrogen atmosphere (40 psi) in the presence of 10% palladium on carbon (22.93 mg, 0.216 mmol) for 17.5 h. LCMS indicated approximately 28% conversion to the desired product, with approximately 59% remaining material. Additional palladium on carbon (22.93 mg, 0.216 mmol) was added, and the reaction was resubmerged under a hydrogen atmosphere (40 psi) for an additional 6.5 h (24 h total). 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 h. The mixture was diluted with EtOAc (1.5 mL) and water (1.5 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 x 10 mL), and the organic phase was washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified on a 12 gram Isco brand silica column eluted with 0-100% EtOAc / heptane (30 mL / min) to give the desired 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) was slowly added mCPBA (64.5 mg, 0.374 mmol) in anhydrous dichloromethane (DCM, 3.331 mL). The reaction mixture was warmed to rt and refluxed for 12 h. After cooling to rt, the solution was extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate, 10% aqueous sodium thiosulfate (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 h. The pH was adjusted to 2 with 1 N HCl, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 4 gram Isco brand silica column, eluting with 0-100% EtOAc / heptane (18 mL / min) to give the desired 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) was added triethylamine (24.78 μL, 0.178 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (47.6 mg, 0.133 mmol). The mixture was stirred at rt for 1 h. After 1 h, the reaction progress was analyzed by LCMS, which confirmed complete consumption of the starting material and conversion to product. The reaction mixture was then concentrated, and the crude product was diluted with EtO (2.5 mL), washed with water (3 × 5 mL) and saturated aqueous sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified using a 4-gram ISCO silica gel column (eluting with 5–100% EtOAc / heptane) to give the desired product as a colorless oil. 1 HNMR(400MHz,CHLOROFORM-d)δppm6.75(s, 2H), 5.18(s, 4H), 3.66(m, 1H), 3.50(s, 6H), 1.76-1.98(m, 6H), 1.63-1.75(m, 2H);LCMS Method A:t R =1.18 min, 100%;MS(ESI):m / z413.4(MH) - [ka]

[0295] Process 1 To a solution of isoquinolin-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) was added TEA (0.864 mL, 6.20 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water (25 mL), and extracted with DCM (30 mL x 2). The combined DCM solution was washed with brine, dried, and concentrated. The crude material was purified by preparative TLC (eluted with petroleum ether / ethyl acetate = 50 / 1) to give isoquinolin-3-yltrifluoromethanesulfonic acid (350 mg, 1.136 mmol, 55.0% yield) as a colorless liquid. LCMS Method A:t R =1.77min, 100%;MS:m / z277.8(M+H) +

[0296] Process 2 To a mixture of isoquinolin-3-yl trifluoromethanesulfonate (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) under a nitrogen atmosphere was added NaCO (76 mg, 0.721 mmol). The reaction mixture was stirred at 80 °C for 5 h, 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 min). The fractions were combined and concentrated. The residue was recrystallized from water and lyophilized to give 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (90 mg, 0.190 mmol, 52.8% yield) as a white solid. LCMS Method A: 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) was added BBr3 (0.138 mL, 1.464 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and purified by reverse-phase chromatography (Combi Flash 50 g reverse-phase C18 column; loaded with MeOH; eluted with 20-50% MeOH / Water containing 10 mM TFA over 30 min). The appropriate fractions containing the product were combined, recrystallized from water, and lyophilized to afford the title compound, 2-isopropyl-5-(isoquinolin-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) was added BBr3 (5.84 mL, 61.8 mmol). The reaction mixture was stirred at 0 °C for 1 h. The solution was concentrated in vacuo, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organics were washed with brine, dried over NaSO4, and concentrated to give the desired compound, which was used without further purification. LCMS Method B:t R =1.88 min, 53%;MS(ESI):m / z359.5(M+2) +

[0299] Process 3b-2 To a solution of 4-bromo-2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (3.4 g, 9.49 mmol) in methanol (30 mL) was added 10% Pd / C (400 mg). The mixture was stirred at room temperature under an atmosphere of H for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give 2.7 g of crude product, which was purified by reverse-phase chromatography (C18 column; mobile phase, A: 10 mM TFA in water; B: MeOH; gradient: 10 min, 9-71% B) to give 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 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 Isoquinolin-3-yl trifluoromethanesulfonate DCM (6 vol) was charged to the reactor, followed by the addition of isoquinolin-3-ol (1.0 eq), EtN (1.45 eq), and N-benzyl-bis-trifluoromethanesulfonimide (1.1 eq). The reaction mixture was stirred at 20-35°C for 2-3 hours. Upon completion, water (10 vol) was charged to the reaction mixture and stirred for 15 minutes. The organic and aqueous layers were separated. The organic layer was washed with water (10 vol). The organic and aqueous layers were separated and the organic layer was dried over NaSO. The organic layer was then filtered and washed with NaSO. 24The solvent was removed and concentrated under reduced pressure at 35-40°C to give the crude product as a black liquid. This crude product was charged to a reactor. Ethyl acetate (6.0 vol) was added, followed by charcoal (0.1 w / w). 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 give a dark brown liquid. This dark brown liquid was then charged to a reactor, followed by heptane (20 vol) and heating at 60-65°C for 1 hour. The heptane layer was concentrated under reduced pressure at 40-45°C to give the desired product, compound 6, as a pale yellow liquid that solidified at 2-8°C.

[0301] Stage 1 1-(2,6-dimethoxyphenyl)ethanone 2,6-Dihydroxyacetophenone (1.0 equiv.) and potassium carbonate (5.0 equiv.) were taken in acetone (14 vol.) and heated to 20-35°C. Dimethyl sulfate (2.5 equiv.) was added to the contents at this 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, and the salts were filtered and washed with acetone (5 vol.). The combined organic layers were concentrated under reduced pressure to give the crude liquid product. Water (30 vol.) was added to the crude liquid and stirred at 20-35°C for 1 hour. The resulting solid was filtered and washed with water (5 vol.), after which the wet cake was transferred to a round-bottom flask. Saturated NaHCO3 (10 vol.) was added, and the contents were stirred for 1 hour. The contents were filtered to remove the solid, which was then washed with water (Lot-3, 5 vol.) to give the product compound 2 as an off-white solid. The solid was then dried at 40-45°C until the KF measured <1%.

[0302] Stage 2 1,3-Dimethoxy-2-(prop-1-en-2-yl)benzene MeMgBr (1.4 M, 1.5 equiv) 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 equiv) dissolved in THF (10 vol) was added to the cooled Grignard solution, maintaining the temperature at 0-10°C. The reaction mixture was warmed to room temperature and stirred for 2 h. After 2 h, the reaction mixture was cooled to 0-10°C. Ethyl acetate (7 vol) was then added and stirred for 30 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3.5 vol). The organic fractions were combined and washed with water (10 vol). The layers were separated, the aqueous layer was discarded, and the organic layer was washed again with water (10 vol). The layers were separated, the aqueous layer was discarded, and the organic layer was washed with saturated NaHCO3 (10 vol). The layers were again separated, the saturated NaHCO layer was discarded, and the organic layer was finally washed with water (10 vol). The organic layer was dried over NaSO. After drying, the sodium sulfate was filtered, and the solvent was removed under reduced pressure at 40-45 °C to give 1,3-dimethoxy-2-(prop-1-en-2-yl)benzene compound 3 as a crude liquid, which was used directly in the next stage.

[0303] Stage 3 2-Isopropyl-1,3-dimethoxybenzene Ethyl acetate (10 vol) was charged to the reactor, followed by 1,3-dimethoxy-2-(prop-1-en-2-yl)benzene (1.0 equiv.) and stirred at 25-35 °C until the solution became clear. 10% Pd / C (0.1 w / w) was added to the reactor, and the contents were purged under vacuum and then placed under H2. The contents were then stirred at 25-35 °C for 4 h. After this time, the reaction mixture was filtered through Celite and washed with ethyl acetate (5 vol). The combined organic fractions were depressurized under vacuum at 40-45 °C to give 2-isopropyl-1,3-dimethoxybenzene compound 4 as a crude liquid, 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 charged to the reactor and degassed with N for 30 min. The iridium catalyst (0.0081 equiv), catalytic ligand (0.017 equiv), bis-pinacolatodiboron (1.0 equiv), and 2-isopropyl-1,3-dimethoxybenzene (1.0 equiv) were added to the reactor in that order. The reaction mixture was refluxed at 80 °C for 60 h, and the contents were filtered through Celite (0.5 w / w) and washed with ethyl acetate (2.5 vol). The combined organic layers were evaporated under vacuum at 40-45 °C to give the crude product as a thick black syrup, which was crystallized from hexane (5 vol) to give 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 vol) and water (2 vol) were charged to a reactor and degassed for 20 minutes. Compound 6 (1.3 eq) was charged 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 eq) was added and degassed for an additional 10 minutes before the palladium catalyst (0.1 eq) was charged. The reaction mixture was cooled to 20-35°C, water (20 vol) was charged 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 vol), yielding a crude black solid. This solid was taken up in ethyl acetate (10 vol) and charged to the reactor. After cooling to 20-35°C, the mixture was filtered through Celite and the solid was washed with ethyl acetate (2.5 vol). The organic layer was concentrated under reduced pressure at 40-45°C to give a viscous liquid. Heptane (1.0 volume) was added to the liquid and distilled. Heptane (0.5 volume) was added and distilled again to give 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline compound 7 as a brown solid.

[0306] Stage 6 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol Compound 7 (1.0 equiv.) was charged to a reactor, and 33% HBr in acetic acid (15 vol.) was added at 20-35°C, followed by heating at 95-100°C for 24 hours. The contents were then transferred to a second reactor containing water (25 vol.) and stirred at 20-35°C for 2 hours. The resulting salt was filtered through a Buchner funnel and washed with water (5 vol.). This wet salt cake was added to the reactor. Ethyl acetate (10 vol.) was added to the reactor, followed by saturated NaHCO3 soln. (10 vol.). The contents were stirred at 20-35°C for 30 minutes. The stirring was stopped, and the layers were allowed to separate. The aqueous layer was decanted off, and the organic layer was washed with water (10 vol.). The phases were separated, the aqueous layer was drained, and the organic layer was dried over Na2SO4. The sodium sulfate was filtered and rinsed with ethyl acetate (5 vol). The combined organic layers were reduced in volume under vacuum at 40-45°C to give the crude free base as a dark solid. The crude free base was charged to a reactor, and ethyl acetate (6.7 vol), silica (1.0 w / w), and finally charcoal (1.0 w / w) were added at 20-35°C. The contents were heated at 60-70°C for 1 hour and cooled to 20-35°C. The contents were filtered through Celite (0.5 w / w) and washed with ethyl acetate (3.35 vol). The combined organic layers were distilled to a reduced pressure, yielding a gummy solid. Heptane (1.34 vol) was charged to the reactor, and the contents were again distilled to a reduced volume. Heptane (1.34 vol) was again charged to the reactor, and the contents were distilled to a light brown solid. 1,4-Dioxane (10 vol), silica (1.0 w / w), and charcoal (1.0 w / w; Noret CGP) were charged to a reactor at 20-35°C. The contents were heated to 60-70°C for 1 hour and 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 x 5 vol). The combined organic layers were reduced under vacuum at 40-45°C to give 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, a compound of Formula 8, as an off-white solid.

[0307] Stage 7 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, a compound of Formula 8, was charged to a reactor, followed by isopropyl alcohol at 20-35°C. The heterogeneous mixture was heated to 65-70°C until a clear solution was obtained, and then heptane was added slowly (16 volumes) at 65-70°C over 20-30 minutes. The solid was filtered at 20-35°C and washed with heptane (2 volumes) to give 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol as an off-white solid. [Example]

[0308] Example 2 3-(3-aminopropoxy)-2-isopropyl-5-(isoquinolin-3-yl)phenol, bis-trifluoroacetate To a solution of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (185 mg, 0.662 mmol) in N,N-dimethylformamide (DMF, 4 mL) was added 60% sodium hydride oil dispersion (35 mg, 0.875 mmol) at room temperature with magnetic stirring. After hydrogen evolution ceased, tert-butyl (3-bromopropyl)carbamate (178 mg, 0.748 mmol) was added. The resulting mixture was heated at 50 °C overnight. LCMS revealed a mixture of starting material, mono- and di-alkylated products (approximately 1:1:1). The mixture was cooled, quenched with water (25 mL), and filtered to collect a greenish-gray solid. The crude material was dissolved in MeOH and purified by Gilson prep-HPLC [Agilent Eclipse plus C18 column (5 μm, 30 × 50 mm) using lunic acid, gradient 30–60% acetonitrile / water, 0.1% TFA, flow rate 47 mL / min, run time 14 min, fraction collection 3.5–4.2 min]. Evaporation of the corresponding fraction gave m / z = 437.5 (M+1) by LCMS. + The residue was dissolved in DCM (5 mL) and treated with TFA (1 mL) at rt overnight. The reaction mixture was concentrated to dryness under reduced pressure to give 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 =0.52min, 100%. [Example]

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

[0310] Process 1 A mixture of 6-bromoisoquinolin-3(2H)-one (5 g, 22.32 mmol), PdCl(dppf) (1.633 g, 2.232 mmol), and EtN (6.22 mL, 44.6 mmol) in methanol (10 mL) was placed in a pressure vessel. The vessel was purged with nitrogen three times, charged with 300 kPa of carbon monoxide, and heated at 100 °C for 20 h. The reaction mixture was cooled and concentrated to give 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 h, 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 × 3). The combined organic phase was washed with water / brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30 g) with petroleum ether / dichloromethane / methanol (1 / 1 / 0.05) to give 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), NaCO (143 mg, 1.354 mmol), and PdCl(dppf) (33.0 mg, 0.045 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) was stirred at 100 °C under nitrogen for 16 h. 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 room temperature 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 phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 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-carboxylic acid (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 at room temperature under nitrogen 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 NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini C18 150x21.2 mm, 5 µm, single injection mobile phase). ACN-H2O, gradient: 10-60%, afforded tert-butyl (2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxamido)ethyl)carbamate (70 mg, 0.135 mmol, 47.3% yield) as a pale yellow solid. 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 To a solution of tert-butyl (2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxamido)ethyl)carbamate (60 mg, 0.122 mmol) in DCM (10 mL) stirred at −30° C. under nitrogen atmosphere was added 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 EtOAc (10 mL × 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 150×21.2 mm 5 um, mobile phase). ACN-H2O with 0.1% TFA, gradient: 10-30%, afforded N-(2-aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide (30 mg, 0.080 mmol, 66.2% yield) as a yellow solid. 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%. [Example]

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

[0317] Of the 160 total experiments, 83 yielded solids suitable for analysis. Of these, 39 yielded the non-solvated Group A (also referred to as Group 2), 22 yielded amorphous, only 5 yielded hydrates (3 Group H, 2 Group M), and the remaining 17 yielded one of the remaining 13 observed forms. These results are visually presented in Tables 1 and 2 below. [Table 19] [Table 20] [Table 21]

[0318] Some embodiments include a compound of formula (A) [ka] or a 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 arylC 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)NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 , and optionally substituted heterocycles; R 8 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 9 and R 10 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 alkyl, or alternatively, R 9 and R 10 which, together with the nitrogen atom to which they are attached, form a 5- to 7-membered saturated or unsaturated ring; R11 are 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 Silyl alkyl, -NR 9 R 10 , and -OR 12 selected from the group consisting of R 12 and R 13 each independently selected from 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 is selected from the group consisting of cycloalkyl, R 6 is H, halo, hydroxyl, alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, and optionally substituted aryl C 1-6 is selected from the group consisting of alkyl, 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; R 14 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC1-6 is selected from the group consisting of alkyl, R 15 and R 16 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 Alkyl, and optionally substituted C 3-6 cycloalkyl; alternatively R 15 and R 16 form a 5- to 7-membered saturated or unsaturated ring together with the nitrogen to which they are attached, 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 arylC 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 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)NR 9 R 10 , -(CR 18 R 19 ) t COR 11 , -(CR18 R 19 ) t CH(O), -(CR 18 R 19 ) t OR 12 ,-(CR 18 R 19 ) t S(O) s R 13 , optionally substituted heterocycles, and optionally substituted heterocycles C 1-6 alkyl, and R 18 and R 19 Each of 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 independently selected from the group consisting of alkyl, Boron tribromide dissolved in a suitable organic solvent, such as methylene chloride, can be added with stirring for a sufficient time and temperature to provide a compound of formula (I), where R 6 is hydrogen.

[0319] Another aspect of the present invention is a compound of formula (B) [ka] 1. A process for preparing a compound of formula (I), comprising treating 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 arylC 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)NR 9 R10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 and optionally substituted heterocycles; R 8 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 9 and R 10 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 alkyl, or alternatively, R 9 and R 10 which, together with the nitrogen atom to which they are attached, form a 5- to 7-membered saturated or unsaturated ring; R 11 are 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 Cycloalkyl, -NR 9 R 10 , and -OR 12 is selected from the group consisting of: R 12 and R 13 each independently selected from 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 is selected from the group consisting of cycloalkyl, 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 5b 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; R 14 are independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 15 and R 16 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted arylC 1-6 Alkyl, and optionally substituted C 3-6 cycloalkyl; alternatively, R 15 and R 16 form a 5- to 7-membered saturated or unsaturated ring together with the nitrogen to which they are attached, R 4b 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 arylC 1-6 Alkyl, optionally substituted C 3-6 Silyl alkyl, -(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)NR 9 R 10 , -(CR 18 R 19 ) t COR 11 , -(CR 18 R 19 ) t CH(O), -(CR 18 R 19 ) t OR 12 , -(CR 18 R 19 ) t S(O) s R 13 , optionally substituted heterocycles, and optionally substituted heterocycles C 1-6 alkyl, and R 18 and R 19 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, and Hydrogenation conditions such as 5-10% palladium on carbon in a suitable organic solvent such as methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, etc. under a hydrogen atmosphere at ambient temperature provide compounds of formula (I), where R 6 is hydrogen.

[0320] Another aspect of the present invention is a compound of formula (II) [ka] is a novel intermediate compound of During the ceremony R 1 and R 2 each independently represents OH, OR 7 and H, with the proviso that R 1 and R 2 At least one of the following is -OH or -OR 7 and R 7 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, arylC 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 arylC 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)NR 9 R 10 , -C(O)R 11 , -OR 12 , -S(O) n R 13 and optionally substituted heterocycles; R 8 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 is selected from the group consisting of alkyl, R 9 and R 10 each independently represents H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6Cycloalkyl, optionally substituted aryl, and optionally substituted arylC 1-6 alkyl, or alternatively, R 9 and R 10 form a 5- to 7-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, R 11 are 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 Cycloalkyl, -NR 9 R 10 , and -OR 12 selected from the group consisting of R 12 and R 13 each independently selected from 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 is selected from the group consisting of cycloalkyl, R 6 is H, halo, hydroxyl, alkoxy, optionally substituted C 1-6 Alkyl, alkyl halide, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, and optionally substituted aryl C 1-6 is selected from the group consisting of alkyl, n is an integer having a value of 0, 1 or 2.

[0321] In some embodiments, R of Formula II 3 When R is an optionally substituted moiety, the moiety may be independently substituted one or more times. 3When is an optionally substituted moiety, the moiety may be independently substituted 1 to 3 times. In some embodiments, the moiety is selected from halo, hydroxy, C 1-3 Alkoxy, C 1-3 It may be optionally substituted independently 1 to 3 times with alkyl, aryl or arylalkyl.

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

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

[0324] Biodata As noted above, the compounds according to any embodiment described herein are modulators of AhR and are useful in the treatment or prevention of human diseases that exhibit an inflammatory component.

[0325] The biological activity of the compounds according to any embodiment described herein can be determined using any suitable assay for determining the activity of a candidate compound as an agonist or antagonist of AhR, and using tissue and in vivo models.

[0326] The biological activity of the compounds according to any embodiment described herein is demonstrated by the following tests. [Example]

[0327] Example 5: CYP1A1-bla LS-180 AhR agonist assay We characterized the AhR activation ability of compounds using LS-180 cells stably transfected with a β-lactamase gene reporter construct linked to the CYP1A1 promoter (referred to as CYP1A1-bla LS-180 cells). The β-lactamase (bla) reporter gene was placed downstream of the CYP1A1 promoter, and AhR activity was simply measured using the LiveBLAzer assay kit, which metabolizes and fluoresces the substrate. For the agonist assay, CYP1A1-bla LS-180 cells were treated with increasing concentrations of compounds over a 100,000-fold concentration range.

[0328] Exponentially growing CYP1A1-bla LS-180 cells were washed twice with DPBS and seeded (50,000 cells / well) into 96-well microplates and allowed to adhere. Compounds (2x working concentrations in complete medium) were then added to the wells, and the cells were incubated for 20 hours. LiveBLAzer FRET B / G β-lactamase substrate was added at the end of incubation, 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 using a fluorescence resonance energy transfer readout. TCDD and FICZ were used as controls to validate the system. As expected, TCDD treatment of CYP1A1-bla LS-180 cells showed a conventional dose-response relationship, with TCDD showing a dose-response response greater than that reported by Invitrogen (pEC 50 =9.70) and a similar titer (pEcucC 50 FICZ-treated CYP1A1-bla LS-180 cells also showed the usual dose-response relationship, with FICZ exhibiting a much lower potency (pEC 50 =6.82).

[0330] For these experiments, compounds of the invention represented as Examples 1-3 had a pEC of ≥ 6.0, which was considered a positive response. 50 (EC 50 ≦1 μM). [Example]

[0331] Example 6: CYP1A1-bla LS-180 AhR antagonist assay A similar assay was used to assess the antagonist potential of compounds. Exponentially growing CYP1A1-bla LS-180 cells were washed twice with DPBS and then seeded (50,000 cells / well) into 96-well microplates and allowed to adhere. Either FICZ or TCDD was added as an agonist, followed 2 hours later by the addition of prepared compounds (2x working concentration in complete medium). Cells were cultured for approximately 20 hours, after which the ability of compounds to compete with FICZ- or TCDD-induced AhR activation was tested as a means of assessing allosteric or partial agonist activity. LiveBLAzer FRET B / G β-lactamase substrate was added at the end of the incubation period, and the resulting blue / green fluorescence was measured using a 96-well microplate reader as described above.

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

[0333] Example 7 CD4+ T Cell IL17 Assay Activation of AhR has been shown to modify transcriptional regulation of the immune system, potentially affecting Th17 and Treg cell differentiation in particular. Therefore, compounds are evaluated for their ability to reduce IL-17 production from CD4+ T cells stimulated under Th17-stimulating 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 in Iscove's modified Dulbecco's medium (IMDM) containing 10% HI-FBS, 55 μM 2-mercaptoethanol, and soluble anti-CD28 (3 μg / mL) at 2 μg / mL. The Th17 response 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)] was measured in the presence or absence of serially diluted compounds. After 5 days of exposure to Th17 polarizing reagents with or without compounds, IL-17 secretion from polarized CD4+ T cells was measured in the culture medium using an MSD (Meso Scale Discovery) detection system.

[0334] For these experiments, all compounds of the present invention had a pIC of 6.0 or greater, which is considered a positive response for IL-17 inhibition. 50 (I C 50 ≦1 μM). [Example]

[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 the imiquimod (IMQ)-treated mouse model (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 compounds 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). Mice were fed a normal diet, A04C, from SAFE (France), and allowed to drink ad libitum. BALB / c JByRj female mice (8 weeks old at the start of the study) were treated with imiquimod (IMQ) cream (5%) or Vanicream (a non-inflammatory, inert cream). After a 3-day pretreatment, 100 μL of compound was applied topically to the same skin site every day (2 hours before each IMQ treatment) until the end of the study. Mice were monitored for changes in clinical symptoms throughout the study. The affected dorsal skin was examined for evidence of compound efficacy by histology and qPCR.

[0337] The biological activity of compound (I), represented by 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, was tested in this mouse model for evidence of in vivo anti-inflammatory activity. Skin histological analysis demonstrated that it was able to reduce imiquimod-induced epidermal thickening. Skin gene expression data revealed that the expression of IL-17A and IL-17F was significantly suppressed by this compound. [Example]

[0338] Example 9: Mechanism of action of the compounds of the present invention as AhR agonists and similarity to tapinarof Tapinarof is a first-in-class topical medication under development for the treatment of atopic dermatitis and psoriasis. Its biological profile differs from other anti-inflammatory and immunomodulatory molecules currently used to treat inflammatory skin diseases, including TCS, TCI, vitamin D analogs, and other immunosuppressants. All current data indicate that tapinarof exerts its pharmacological action in the skin through a novel mechanism involving dual activation of the AhR and Nrf2 anti-inflammatory pathways, thereby identifying it as an AhR modulator (TAMA). Tapinarof specifically suppresses inflammatory mediators downstream of AhR pathway activation, including interleukin (IL)-6, IL-17A, and eosinophil-3. Furthermore, tapinarof administration reduced reactive oxygen species in keratinocytes subjected to chemical redox stress and induced cell apoptosis at the micromolar level.

[0339] The direct relationship between AhR and anti-inflammatory activity is not fully understood, and while other compounds may drive AhR-mediated activity, there is no definitive means of identifying safe TAMAs. Therefore, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, tapinarofen, was evaluated for its known activity. A summary of this mechanistic study is provided below.

[0340] 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was evaluated for activity on the key "hits" identified in the mechanistic studies of tapinarof (Table 3). Indeed, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol demonstrated similar potency across each of the AhR, Nrf2, and CB2 screening assays, as well as IL-17A inhibition in CD4+ T cells cultured under Th17-polarizing conditions. [Table 22] [Example]

[0341] Example 10: BioMAP profiling of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol 10:2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was profiled at multiple doses: 1M, 330nM, 110nM, and 37nM using the DiscoveRx BioMAP™ Diversity Plus System™. The BioMAP system evaluates 148 biomarkers associated with multiple inflammatory diseases in 12 primary human cell culture platforms and compares biomarker profiles with the biological response patterns of other compounds, biologics, and approved drugs in the BioMAP reference database. Of the 3,000 experimental drugs tested, 10:2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (which was found to exhibit antiproliferative properties on B cells and reduce various cytokines / chemokines) was the only analyte tested. These included M-CSF, sIL-17A, sIL-2, sIL-6, sIL-10, Eot3, sTNFα, MCP-1, VCAM-1, and MIP-1, and increased IL8, IL1α, sPGE2, ICAM-1, and E-selectin (Figure 1A-1B). Similar to tapinarof, the endogenous AhR agonist 6-formylindolo(3,2-b)carbazole (FICZ) was the only compound identified from the BioMAP reference database with a related pattern of biological responses (Pearson correlation, r = 0.71; Figure 1C-1D). Similarly, when the profiles are overlaid, striking similarity to tapinarof is observed (Figure 1E-1F). The most striking difference is the observed reduction of sIL-17 by 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, which is not seen in tapinarof or FICZ-treated samples. [Example]

[0342] Example 11: Effects of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on cytokines and cellular apoptosis We evaluated the effect of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol treatment on peripheral blood CD4+ T cells cultured under Th17-skewing conditions. When applied throughout the culture period, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol dose-dependently reduced IL-17A production, similar to tapinarofen (Figure 2A).

[0343] 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is IC 50 IC = 5.9 μM for T cell viability 50 = 12.36 μM. These values ​​are similar to those of tapinarofen, supporting the idea that 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol closely mirrors the activity profile of tapinarofen (Figure 2B, Figure 2C). [Example]

[0344] Example 12: Inhibitory effect of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol on reactive oxygen species (ROS) Tapinarof was observed to suppress chemically induced ROS in primary and immortalized (HaCat) keratinocytes, resulting, at least in part, from the intrinsic ROS-scavenging properties of the API (Smith et al., 2017, ibid.). Importantly, the observed reduction in ROS is a key differentiator between tapinarof and TCDD, a known environmental toxin that elevates ROS levels. Therefore, we tested the ability of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol to reduce ROS. Oxygen radical absorbance capacity (ORAC) assays demonstrated that tapinarof scavenged all common reactive oxygen species: peroxynitrite, superoxide anion, singlet oxygen, peroxyl radical, and hydroxyl radical. 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol showed a similar profile, reducing the levels of peroxynitrite, singlet oxygen, peroxyl radical, and hydroxyl radical (Table 4). [Table 23] [Example]

[0345] Example 13: Demonstration of biological activity (target engagement) after local administration A liquid-air interface skin excision culture with in situ activation of immune cells, called sRICA: Skin-Resident Immune Cell Activation Model, has previously been reported (Smith et al., (2016) PLoS One, 11(2)). This assay can induce a specific cytokine profile of inflammatory skin diseases, including Th17-type cytokines, IL17A, IL17F, and IL22. Reduction of biomarkers in this assay indicates biological activity of the test substance.

[0346] Ex vivo human skin obtained from abdominoplasty surgery was processed to remove fat and the tissue was dermatomed to ~750 microns. The dermatomed skin was washed twice consecutively with room temperature PBS containing antibiotic / antimycotic solution for 5-10 minutes each.

[0347] From this point on, the skin was treated as a non-recipient, and all subsequent manipulations 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 μl of bovine collagen solution (2:1 collagen / Cohn's medium). Care was taken to remove any air bubbles below the transwell, as these would prevent the medium from penetrating the tissue.

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

[0349] The next day, the 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-IFN-γ (1 ug / ml), IL-1b (10 ng / ml), IL-6 (10 ng / ml), TGF-β (1 ng / ml), and IL-21 (10 ng / ml)). Cultures were performed for 24 h and 48 h. A total of three biological replicates were used for each treatment group.

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

[0351] RNA isolation and qRT-PCR The harvested skin tissue was stored in RNAlater until use. Total RNA was isolated from the tissue using Qiagen's Mini RNA Isolation kit (Cat # 74106). Skin tissue was first minced into fragments measuring 1x1x1mm or less and added to a tube containing 2.8mm and 1.4mm ceramic beads (combined in one vial). Cells were lysed using a Precellys Tissue Homogenizer with 300µL of RLT buffer supplemented with 1% 2-Beta-Mercapto-Ethanol for four cycles (6300 rpm, 90s), with 30 seconds between cycles, on ice. Next, 590µL of water containing 10µL of Proteinase K was added to the lysed cells and incubated at 55°C for 20 minutes. The sample was then spun down at 10,000xg 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 used as template in a 10 µL PCR volume with the Applied Biosciences RNA-to-CT 1 Step kit (AB Catalog # 4392938) and TaqMan probes appropriate for the gene being quantified. The Applied Biosciences Master Mix contains an internal control of ROX dye. A OneStepPlus PCR machine was used for the RT step and 40 amplification cycles.

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

number

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

[0354] Engagement of target pathways by 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, in this case AhR pathway activation as measured by cyp1a1 gene induction, was confirmed after exposing skin excisions to 1 µM or 10 µM 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in the basolateral medium (Figure 3A). Next, we assessed the effects on inflammatory mediators and showed that 10 µM 2-isopropyl-5-(isoquinolin-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] By adapting the sRICA model to the Franz cell device, we were able to demonstrate two specific outcomes of topical administration: (i) test substances maintain their biological activity within the formulation, and (ii) test substances penetrate the skin barrier to reach their cutaneous targets and induce biological effects. Topical target engagement of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was evaluated at multiple concentrations in cream and gel formulations 1. Importantly, these target engagement assays utilize customized Franz cells that clamp the skin edges, preventing leakage of the topical formulation into the lower chamber of the air-liquid interface culture. Cyp1a1 gene expression was used as an indicator of AhR pathway activation. Therefore, activation of skin-resident immune cells under Th17 conditions, as typically seen in the 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. The lower chamber was filled with 2.0 mL of complete medium ("Cornui"), ensuring that the bottom-to-side was submerged in the medium and free of air bubbles. After approximately 2 hours of rest at 37°C, the cells were checked for leaks again by simple inversion, and then topical formulation (8.4 μl) was applied to the dried stratum corneum using a positive pressure displacement pipette. The Franz cells were then placed in a humidified incubator at 37°C for an additional 21 hours. Cyp1a1 levels were assessed in approximately one-half of each skin section relative to 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (10 μM) applied basolaterally, while the other half was used to measure 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol concentrations. Samples containing at least 0.1% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in cream formulation 1 showed strong cyp1a1 gene induction without observable dose-dependence (Figure 4). This data indicates that in this system, the greatest observable biological response is induced at the lowest formulation concentration. [Example]

[0356] Example 14: In vivo efficacy in a mouse model Targeting the AhR pathway through systemic administration of FICZ has been shown to positively impact clinical scores in imiquimod (IMQ)-treated mice (Di Meglio et al., (2014) supra). Furthermore, tapinarofen exhibits anti-inflammatory properties in multiple mouse models, including the ear eczema model, the IMQ mouse model of psoriasis, and the DNFB-challenge model, a hapten-induced, Th2-dominant challenge model. 2-Isopropyl-5-(isoquinolin-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-(isoquinolin-3-yl)benzene-1,3-diol was applied topically daily in a simple ethanol solution (60% EtOH:40% HO) and tested prophylactically in the IMQ mouse model. Starting 3 days after the first treatment, IMQ cream was applied daily for 4 days (Study A) or 10 days (Study B). Clinical scoring was monitored daily (Figure 5A, Figure 5B). After the study, treated skin was evaluated by histology and qPCR for induced cytokine gene expression. 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol treatment led to reduced clinical scores, reduced epidermal thickening, and decreased cytokine gene expression compared to vehicle-treated mice (N = 10 mice per group, Figure 5A-B and Table 5).

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

[0359] Psoriatic responses (erythema and plaques) were reported according to a scale of 0-4 in ascending order of severity as shown below, and the results are shown in Figure 5A1. [Table 24]

[0360] On the last day of treatment, a 6 mm punch of the skin from the treatment site was taken onto an aluminum sheet (to keep the skin flat) and placed in a tube containing formalin solution (neutral buffered 10% (SIGMA HT501320-9 5 L)) for histological analysis (Figure 5A2).

[0361] Study B Four groups of 10 mice (BALB / cByJRJ female mice) were treated as follows: days -2-1 (3 days before imiquimod application), days 0, 1, 2, 3, 5, 6, 7, 8, and 9 (10-day study). Each day, mice were treated on the shaved back with vehicle (100 μL in 60% EtOH / 40% water), 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (0.1% in 60% EtOH / 40% water), or 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (0.3% in 60% EtOH / 40% water). Vanicream or 5% imiquimod cream (5% Aldara Cream) was applied topically to the shaved back daily, massaged with the fingers until absorbed, 2 hours after application of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or vehicle 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] Psoriatic reactions (erythema and plaques) were reported according to a scale of 0-4 in ascending order of severity as shown below, and the results are shown in Figure 5B1. [Table 25]

[0363] On the last day of treatment, a 6 mm punch of the skin from the treated area was taken onto an aluminum sheet (to keep the skin flat) and placed in a tube containing formalin solution (neutral buffered 10% (SIGMA HT501320-9 5 L)) for histological analysis (Figure 5B2).

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

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

[0366] Second Study Healthy female CDl mice (Crl:CDl(ICR)) were anesthetized with 3-5% isoflurane and had their abdomen and nape shaved.

[0367] After weighing, the animals were assigned to the test groups according to the treatment table below. The test was divided into two arms with a one-week interval to accommodate in-life scratch monitoring. Half of the animals (6 animals) from each group were assigned to arm 1 and arm 2, respectively. [Table 27]

[0368] For each topical treatment, 100 mg of cream or 100 μL of solution was applied to the nape of the mouse skin using a solvent pipette. If cream was used, it was spread with the fingers and massaged into the skin until completely absorbed.

[0369] On day 1, 100 μL of acetone / olive oil (4:1 v:v) or 0.15% DNFB (2,4-dinitrofluorobenzene in acetone / olive oil (4:1 v:v)) was applied topically to the shaved abdomen (sensitization phase). On days 5, 8, 12, and 15, 100 μL of acetone / olive oil or 0.15% DNFB was applied topically to the shaved nape skin (challenge phase). From days 5 to 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 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. Epidermal (Figure 6C1) and dermal thickness (Figure 6C2) were measured. [Example]

[0371] Example 15: In vitro human skin permeability evaluation In vitro human skin permeation and distribution of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were evaluated using a custom-built (ChanneL) flow-through diffusion cell setup and ex vivo human skin (from abdominoplasty) with a 500 ± 100 μm skin incision. Skin distribution (epidermis and dermis) and cumulative amounts in the receptor fluid over 16 hours (representative of unbound drug that penetrated below 500 μm) were assessed using a fit-for-purpose LC-MS / MS method with a lower limit of quantitation (LLOQ) of 80 pg / mL to determine the transdermal delivery profile of formulation prototypes. Because the biological target of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is the epidermis / epithelium, formulation ranking focused on the dermal level due to the low cumulative amounts in the receptor fluid. Epidermal samples were not included in the ranking due to the possibility of residual drug that did not penetrate the stratum corneum.

[0372] During early formulation development, eight topical formulations (six creams and two gels) containing 1.0% 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were evaluated in an in vitro human skin permeation study using three donors. The epidermal and dermal delivery of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol after 16 hours is shown in Figure 7. 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 fluid.

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

[0374] Additionally, due to improved physical stability, Cream Formulation 2 and a similar formulation with lower Transquatr P levels, Cream Formulation 1, were also advanced to dose proportionality studies. Based on the dermal volumes shown in Figure 9, 1% Cream Formulation 3 and 1% Cream Formulation 1 were found to provide the best dose proportionality, with the latter demonstrating comparable delivery to the dermis and an improved stability profile.

[0375] To further evaluate the potential of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol gels (specifically those containing less than 15% propylene glycol), two additional formulations (Gel Formulation 1 and Gel Formulation 2) were evaluated in an in vitro skin penetration assay. None of the gels delivered significantly more 2-isopropyl-5-(isoquinolin-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 rankings (Figure 11).

[0376] We also used matrix-assisted laser desorption / ionization imaging mass spectrometry (MALDI IMS) to demonstrate the spatial localization of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol within skin layers. For this study, we selected 1% cream formulation 1, along with 0.5% cream formulation 3 and 1% gel formulation 4. These prototypes delivered equivalent amounts of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol to the dermis during dose proportionality testing. Single doses of the three formulations were applied to full-thickness human skin, and samples were collected 6 and 24 hours later. After collection and preparation, the samples were sent for MALDI analysis. After 6 hours (Table 7), the amount of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol delivered to the dermal level was 5.0-7.0 times higher in the 1% gel formulation 4 compared to the 0.5% cream formulation 3 and the 1% cream formulation 1, but after 24 hours, this difference was approximately 2.0 times.

[0377] The drug concentrations obtained from the in vitro human skin permeation study and the MALDI IMS study were compared, and the results are shown in Table 7. To calculate the concentration in each compartment using the data from the skin penetration study, (i) the volume of each compartment was determined by dividing the administration area by 1 cm 2 (ii) the epidermal and dermal skin thicknesses were estimated to be 150 μm and 350 μm, respectively; (iii) drug distribution within each compartment was assumed to be uniform; and (iv) tissue density was assumed to be 1 g / mL. The concentrations did not take into account the bound or unbound drug fractions.

[0378] The concentrations of the two creams observed in the epidermis were, on average, 2.4-fold higher in the 16-hour in vitro human skin penetration study than at the 6-hour MALDI time point. However, the epidermal volumes delivered by the gels in the 6-hour MALDI study were comparable to those in the in vitro skin penetration study. At the 24-hour MALDI time point, the epidermal volumes of the gel formulations decreased, resulting in a 1.5-fold increase in the in vitro skin penetration values. The creams did not exhibit this behavior, instead increasing their epidermal volumes from 6 to 24 hours, demonstrating a similar level of the dose delivered in the in vitro skin penetration study. This difference in behavior suggests differences in the delivery rates of the gel and cream formulations. Comparing the dermal values ​​indicated that 3.0- to 6.5-fold higher amounts of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were delivered in the in vitro human skin penetration study (16 hours) than in the MALDI experiment (24 hours). The variation between these concentrations may be due to differences in the research protocols used between the two assays, including skin thickness, skin donors, and analytical methods. [Table 29] [Example]

[0379] Example 16: Absorption, Distribution, Metabolism, and Excretion 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol exhibited high binding to plasma proteins, with unbound fractions at 2 μM being 3.06%, 1.98%, and 1.08% in rats, minipigs, and humans, respectively (Table 8). Skin binding of 2-isopropyl-5-(isoquinolin-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), yielding mean unbound fractions of 21.9 ± 0.72%, 51.3 ± 1.1%, and 34.1 ± 11.5%. Blood-to-plasma ratios were similar across species (1.22-1.36, Table 9). 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was stable in plasma and blood. [Table 30] [Table 31]

[0380] 2-Isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was rapidly metabolized by liver microsomes and hepatocytes in all species: mice, rats, minipigs, dogs, rabbits, and humans, suggesting high in vitro clearance. The intrinsic metabolic clearance in hepatocytes was 2.1- to 11.6-fold higher than that in liver microsomes in rats, minipigs, and humans (Table 10). The in vitro-to-in vivo extrapolation ratios (IVIVE) measured in pharmacokinetic studies in rats and minipigs were 0.45 and 0.27, respectively, which showed good correlation (see the "Animal Pharmacokinetic Studies" section below). [Table 32]

[0381] After 1 hour of incubation in human or rat liver microsomes supplemented with glutathione (GSH) and glutathione ethyl ester (GSEE), active metabolites of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were detected in an in vitro GSH trapping assay (Table 11). These results suggest that 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol may form reactive metabolites. However, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol is not considered to pose a safety risk due to its low systemic exposure in vivo following topical administration in rats and minipigs (see Animal Pharmacokinetics section below) and its low estimated plasma concentrations in humans (see Estimated Human Plasma Concentrations section below). [Table 33] [Example]

[0382] Example 17: Animal Pharmacokinetics The preclinical pharmacokinetic profile of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was characterized by high clearance, a high volume of distribution, and a short half-life in rats and minipigs (Table 12, Figure 12). The plasma pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol following subcutaneous administration to rats was nearly linear at 10-25 mg / kg for both the 30% Captisol and 30% Cavitron formulations. The 30% Captisol formulation showed significantly higher plasma exposure (AUC ) than the 30% Cavitron formulation. 24h ) were similar (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. The 30% Captisol formulation was selected for a 7-day subcutaneous administration study in rats. Bioavailability was also investigated in minipigs after a single oral dose of 5 mg / kg administered with DMSO. Bioavailability was 0.1% following a single oral dose of 5 mg / kg administered with a Coriphor HS15:hydroxypropyl-β-cyclodextrin (10:10:80) vehicle, suggesting that the oral route is not suitable for evaluating the systemic safety of minipigs. [Table 34] [Table 35]

[0383] When 20 mg (2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol) / kg was administered topically to rats in a single dose covering 10% of the body surface area, 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was administered topically to rats in a single dose covering 10% of the body surface area. max 3.) and 1% gel 1 (C 5.18 ng / mL, AUC 32.1 ng * The same amount of steroids was transferred to the blood at AUC 83ng / mL and AUC 24h 32.1ng*hr / mL) and 1% gel formulation 1 (C max 5.18 ng / mL and AUC 24h The plasma exposure levels were similar between the formulations (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 1% cream formulation 1 or 1% gel formulation 1 was applied topically to minipigs at 15 mg (2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol) / kg over 10% of the body surface area, the plasma exposure level (below the lower limit of quantification, 50 pg / mL, at 87% of the time point) was very low, suggesting that the systemic safety risk from topical application is low. [Table 36]

[0384] The dermal pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol was studied in Göttingen minipigs over a 7-day period following a single topical administration of 1% cream formulation 1 or 1% gel formulation 1. The formulations were administered at a dose of 1 g / 44 cm. 2 The 1% cream formulation was administered at a dose of 0.01 mg / mL, and skin biopsies were taken at different time points up to 168 hours for pharmacokinetic (epidermal and dermal tissue homogenate levels) and MALDI IMS (matrix-assisted laser desorption / ionization imaging mass spectrometry) analysis. Higher concentrations of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol were found in the epidermis / upper dermis (0-500 μm) compared to the dermis (500-1500 μm) for both formulations (Table 15, Figure 13). The 1% cream formulation 1 showed similar concentrations in the epidermis / upper dermis (C max 23.4 μg / g and AUC 168h 2026μg * hr / mL) and dermis (C max 0.74 μg / g and AUC 168h 37.5μg / mL) was achieved. * hr / mL) compared to exposure observed with 1% gel formulation 1. max 18.0 μg / g and AUC 168h 1729μg * hr / mL) and dermis (C max 0.39 μg / g and AUC 168h 34.7μg *hr / mL). Depth profiling by MALDI IMS at different time points in each group of minipigs was consistent with the 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, and for 1% gel formulation 1, they were 21.8 μg / g and 1.66 μg / g at 8 hours, respectively (Table 16). Some MALDI images of 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 skin appendage pathway may contribute to systemic exposure (Figure 12). The MALDI IMS signal decreased below the detection limit (approximately 500 ng / g) at a depth of approximately 500 μm. [Table 37] [Table 38] [Example]

[0385] Example 18: Estimation of human plasma concentrations after topical administration Human plasma concentrations (Css) of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol after topical application ,human)は、 The prediction was made assuming that the topically applied drug is absorbed through the skin at a constant rate, and was calculated as follows:

number

[0386] Plasma clearance was estimated from in vitro and preclinical pharmacokinetic studies (CL human CL was calculated using allometric scaling based on in vivo clearance in rats and minipigs, hepatic blood flow method, and an IVIVE approach (assuming hepatic metabolic clearance is the major excretion pathway) using a well-stirred model. humanThe predicted clearance was 6-25 mL / min / kg. To assess the potential systemic safety risk of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol in humans, the lowest predicted clearance (6 mL / min / kg predicted by allometric scaling with correction for plasma protein binding) was selected.

[0387] In an in vitro human skin permeation evaluation of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol loaded with 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 quantitation (LLOQ; 80 pg / mL) for 16 hours, making it impossible to calculate the skin flux value. Therefore, assuming a time lag of 2 hours, the amount of fluid received every 2 hours was calculated using the LLOQ value for 16 hours, resulting in a value of 0.048 ng / cm. 2 / h, and the estimated skin flux value was calculated.

[0388] Healthy skin is an effective barrier against most xenobiotics. Therefore, the validity of flux values ​​obtained from ex vivo skin penetration assays using healthy human skin from abdominal plastic surgery may not be consistent with those observed after application to unhealthy skin. Therefore, to account for the damage to the skin barrier, a 10-fold increase in flux was incorporated into the initial prediction of human systemic exposure following topical administration of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. We also calculated the human systemic exposure for a 100-fold increase in flux, assuming a worst-case scenario. This estimate included a 10% (1800 cm) coverage area of ​​the human body surface. 2 ) was used. Therefore, for the purpose of estimating the safety margin, taking into account the conditions described here, the estimated Css ,humanは 0.34ng / mL, and the corresponding AUCss ,24h In clinical practice, topical treatment of apical dermatitis is possible with up to 50% BSA (9000 cm2), so the corresponding estimated Css for a 10-fold increase in flux is ,human and AUCss ,24hwere 0.17 ng / mL and 4.1 ng*h / mL. The different simulation scenarios are summarized in Table 17. [Table 39] [Example]

[0389] Example 19: Integration of preclinical target engagement studies to select human dosage Based on the combination of in vitro efficacy, ex vivo human skin target engagement and penetration, and minipig skin PK data, it is predicted that after daily administration, 1% cream formulation 1 will deliver sufficient concentrations of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol to target sites in the skin (viable epidermis and upper dermis) to cause AhR target engagement.

[0390] Free drug concentrations in the skin obtained after topical application of 1% cream Formulation 1 and calculated from ex vivo human skin and minipig skin PK studies (via MALDI-IMS analysis) demonstrated sufficient coverage for the effective concentrations obtained in the in vitro efficacy studies (50% AhR activation in a fluorescence-based reporter assay of CYP1A1 gene expression and 50% inhibition of IL-17A production in human primary peripheral blood CD4+ T cells) shown in Table 18. These calculations assume identical human and minipig skin binding and 100% dermal bioavailability after correcting for the unbound skin fraction. [Table 40]

[0391] Additional embodiments of the present application are as follows.

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

[0393] Embodiment B. A compound of embodiment A which is of the formula: 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol. [ka]

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

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

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

[0397] Embodiment F: The pharmaceutical composition of embodiment C, wherein the carrier or diluent is suitable for topical administration as a cream.

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

[0399] Embodiment H: A method of treating an inflammatory disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any of embodiments A or B.

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

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

[0402] Embodiment K: A method of treating or preventing radiation dermatitis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any of Embodiments A or B.

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

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

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

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

[0407] Embodiment P: A method of treating or preventing an inflammatory mucosal condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any of embodiments A or B.

[0408] Embodiment Q: The method of embodiment P, wherein the inflammatory mucosal condition is induced by radiation or chemotherapy treatment for cancer.

[0409] Embodiment R: The method of 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 of embodiment R, wherein the oral mucositis is selected from oral lichen planus, erythema multiforme, mucosal pemphigus, pemphigus vulgaris, and bullous epidermolysis bullosa.

[0411] Embodiment T: The method of embodiment R, wherein the oral mucositis is induced by head and neck cancer radiation therapy.

[0412] Embodiment U. A method of treating a dermatological condition or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any of embodiments A or B.

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

[0414] Embodiment W: Compound of Formula 8 [ka] 1. A process for preparing a) a compound of formula 6 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof with Formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof to obtain a compound of Formula 7 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; b) 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 pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: a) a compound of formula 5 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, 1) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain a compound of formula 2 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; 2) treating a ketone of formula 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with a Grignard reagent, followed by removal of water under acidic conditions to give a compound of formula 3 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; 3) 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 pharmaceutically acceptable salt, solvate or hydrate thereof; and 4) 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) a compound of formula 6 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising treating isoquinolin-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 obtain a compound of formula 7 [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof; and d) demethylating the 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 either order or simultaneously in different reaction vessels.

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

[0417] Embodiment Z: The process of embodiment Y, wherein the purification comprises crystallization.

[0418] Embodiment AA: The compound of either embodiment A or B which is at least 90% pure by weight.

[0419] Embodiment BB: The compound of any of Embodiments A or B which is at least 95% pure by weight.

[0420] Embodiment CC: The compound of any of Embodiments A or B which is at least 98% pure by weight.

[0421] Embodiment DD: The compound of any of Embodiments A or B, which is at least 99% pure by weight.

[0422] All publications, including but not limited to patents and patent applications, cited in this specification are specifically and individually indicated to be incorporated by reference in this specification to the same extent as if each individual publication was fully set forth.

[0423] The foregoing description fully discloses the present invention, including preferred embodiments thereof. Variations and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the examples herein are to be construed as merely illustrative and not as limiting the scope of the present invention in any way. Embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

Claims

1. A compound of formula (I) or a salt, solvate or hydrate thereof, 【Chemical 1】 During the ceremony R1 is selected from the group consisting of OH and OR7; ７ is an optionally substituted C １－６ is alkyl, R 2 is selected from the group consisting of OH and OR 7 , where R 7 is optionally substituted C 1-6 alkyl; R ３ is an optionally substituted C １－６ is alkyl, R 4 is selected from the group consisting of H, —(CR 18 R 19 ) t COOR 8 , and —(CR 18 R 19 ) t C(O)NR 9 R 10 , wherein t is 0, R 8 is selected from the group consisting of H and optionally substituted C 1-6 alkyl, R 9 is H, and R 10 is optionally substituted C 1-6 alkyl; R 5 is H; R 6 is selected from the group consisting of H and halo, and The optionally substituted C 1-6 alkyl refers to a C 1-6 alkyl substituted one or more times with substituents independently selected from the group consisting of halo, hydroxy, hydroxy-substituted C 1-3 alkyl, C 1-3 alkoxy, halo-substituted C 1-3 alkoxy, S(O) m C 1-3 alkyl, NR 22 R 23 where R 22 and R 23 are independently selected from H or C 1-3 alkyl, or where R 22 and R 23 together with the nitrogen to which they are attached form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S, C 1-3 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkylC 1-3 alkyl group, halo-substituted C 1-3 alkyl, substituted aryl, or optionally substituted arylC 1-3 alkyl. alkyl, the aryl-containing moiety of which is optionally substituted one to two times with halo, hydroxy, hydroxy-substituted C 1-3 alkyl, C 1-3 alkoxy, S(O) m C 1-3 alkyl, amino, mono- and di-substituted C 1-3 alkylamino, C 1-3 alkyl, or CF 3 ; A compound of formula (I) or a salt, solvate or hydrate thereof.

2. In the compound according to claim 1, R 1 is selected from the group consisting of OH and OR 7 , wherein said R 7 is C 1-6 alkyl; R 2 is selected from the group consisting of OH and OR 7 , wherein said R 7 is C 1-6 alkyl substituted with NR 22 R 23 , wherein each of said R 22 and R 23 is independently selected from H and C 1-3 alkyl; and R 4 is selected from the group consisting of H, —COOH, —COOCH 3 , and —C(O)NR 9 R 10 , where R 9 is H and R 10 is selected from the group consisting of amino-substituted C 1-6 alkyl, and —(CH 2 ) 2 NHC(O)O-t-butyl; compound.

3. In the compound according to claim 1, R 1 is selected from the group consisting of OH and —OCH 3 ; R 2 is selected from the group consisting of OH, —OCH 3 , and —O—(CH 2 ) 3 NH 2 ; R 3 is C 1-6 alkyl; R 4 is selected from the group consisting of H, —COOH, —COOCH 3 , —C(O)NH(CH 2 ) 2 NH 2 , and —C(O)NH(CH 2 ) 2 NHC(O)O-t-butyl; R 5 is H, and R 6 is selected from the group consisting of H and bromo; compound.

4. The compound according to claim 1, wherein R 3 is isopropyl or t-butyl.

5. The compound according to claim 1, R 1 is selected from the group consisting of OH and —OCH 3 ; R 2 is selected from the group consisting of OH, —OCH 3 , and —O—(CH 2 ) 3 NH 2 ; R 3 is isopropyl; R 4 is selected from the group consisting of H, —COOH, COOCH 3 , —C(O)NH(CH 2 ) 2 NH 2 , and —C(O)NH(CH 2 ) 2 NHC(O)O-t-butyl; R 5 is H, and R 6 is selected from the group consisting of H and bromo; compound. 【Request 6】 【Chemical 2】 【change】 A compound selected from the group consisting of a salt, solvate or hydrate thereof.

7. A compound which is 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol, or a pharmaceutically acceptable salt, solvate or hydrate thereof. 【Request 8】 【Chemical 3】 or a salt, solvate or hydrate thereof.

9. 7. The compound of claim 6, wherein the compound is 【Chemistry 4】 A compound.

10. A composition comprising the compound of claim 6, wherein the compound is at least 90% pure by weight.

11. A composition comprising the compound of claim 6, wherein the compound is at least 95% pure by weight.

12. A composition comprising the compound of claim 6, wherein the compound is at least 98% pure by weight.

13. A composition comprising the compound of claim 6, wherein the compound is at least 99% pure by weight.

14. 10. A pharmaceutical composition comprising a compound of claim 1 or 6 and a pharmaceutically acceptable carrier or diluent.

15. A pharmaceutical composition comprising a compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a composition according to any one of claims 10 to 13, and a pharmaceutically acceptable carrier or diluent.

16. 16. The pharmaceutical composition of claim 15, wherein the carrier or diluent is suitable for oral, topical, parenteral, transdermal, intranasal, or oral inhalation administration.

17. A compound according to claim 1 or 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 14, for use in the treatment or prevention of a condition in a mammal associated with AhR imbalance.

18. 15. A compound according to claim 1 or 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 14, for use in the treatment or prevention of an inflammatory disease.

19. 19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or pharmaceutical composition thereof, wherein the inflammatory disease is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascular (dry) AMD, neovascular (wet) AMD, uveitis or other inflammatory eye disease, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

20. A compound according to any one of claims 7 to 13, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the treatment or prevention of an inflammatory disease.

21. 21. The compound of claim 20, 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, neovascular (dry) AMD, neovascular (wet) AMD, uveitis or other inflammatory eye disease, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

22. 21. The compound of claim 20, 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.

23. A compound according to any one of claims 7 to 13, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the treatment or prevention of psoriasis or atopic dermatitis.

24. Compound of Formula 8 【Chemistry 5】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: a) a compound of formula 6 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, by reacting a compound of formula 5 【Chemistry 7】 or a pharmaceutically acceptable salt thereof to form a compound of formula 7 【Chemistry 8】 or a pharmaceutically acceptable salt thereof; b) demethylating the compound of formula 7 to form a compound of formula 8, and optionally converting the compound of formula 8 to a pharmaceutically acceptable salt, solvate, or hydrate thereof; The process includes:

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

26. The compound of formula 5, or a pharmaceutically acceptable salt, solvate or hydrate thereof, a) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt thereof to produce a compound of formula 2 【Chemistry 9】 or a pharmaceutically acceptable salt thereof; b) treating a compound of formula 2 or a pharmaceutically acceptable salt thereof with a Grignard reagent, followed by removal of water under acidic conditions to give a compound of formula 3 【Chemistry 10】 or a pharmaceutically acceptable salt thereof; c) hydrogenating a compound of formula 3 or a pharmaceutically acceptable salt thereof to obtain a compound of formula 4 【Chemistry 11】 or a pharmaceutically acceptable salt thereof; and d) borylating a compound of formula 4, or a pharmaceutically acceptable salt thereof, to form a compound of formula 5, or a pharmaceutically acceptable salt thereof; 25. The process of claim 24, wherein the compound is prepared by a process comprising:

27. The demethylation may be carried out by a) Treating a compound of formula 7 with boron tribromide to give a compound of formula 7-1 【Chemistry 12】 forming a b) hydrogenating a compound of formula 7-1 to form a compound of formula 8; 25. The process of claim 24, comprising:

28. 25. The process of claim 24, further comprising purifying the compound of formula 8.

29. 30. The process of claim 28, wherein the purifying step comprises crystallization.

30. Compound of Formula 8 【Chemistry 13】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: a) a compound of formula 5 【Chemistry 14】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising: 1) alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate, or hydrate thereof to obtain a compound of formula 2 【Chemistry 15】 or a pharmaceutically acceptable salt, solvate or hydrate thereof; 2) treating a ketone of formula 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with a Grignard reagent, followed by removal of water under acidic conditions to give a compound of formula 3 【Chemistry 16】 or a pharmaceutically acceptable salt, solvate or hydrate thereof; 3) hydrogenating a compound of formula 3 or a pharmaceutically acceptable salt, solvate or hydrate thereof to obtain a compound of formula 4 【Chemistry 17】 or a pharmaceutically acceptable salt, solvate or hydrate thereof; and 4) 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) a compound of formula 6 【Chemistry 18】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising treating isoquinolin-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 obtain a compound of formula 7 【Chemistry 19】 or a pharmaceutically acceptable salt, solvate or hydrate thereof; and d) demethylating the 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 either order, or simultaneously; The process includes:

31. 31. The process of claim 30, further comprising purifying the compound of formula 8.

32. 32. The process of claim 31 , wherein the purifying step comprises crystallization.

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