Isoquinoline compounds and their use in the treatment of ahR imbalance

Abstract

The present invention relates to novel compounds of Formula (I) or pharmaceutically acceptable salts, solvates or hydrates thereof. Also described are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof. The present invention also relates to the use of said compounds of Formula (I) in the treatment of disorders associated with AhR imbalance in mammals, such as inflammatory diseases or disorders.

Description

[0001] Cross-reference with related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 052,561, filed July 16, 2020, entitled "Isoquinoline compounds and their use in treating AhR imbalance" and U.S. Provisional Application No. 63 / 052,574, also filed July 16, 2020, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention

[0003] Various embodiments provide compounds, compositions, and methods for treating and preventing conditions associated with AhR imbalance, AhR-mediated diseases, and inflammatory conditions, the methods including administration of such compounds to compositions described below. The compounds described herein bind to and activate aryl hydrocarbon receptors (AhR), providing a class of novel anti-inflammatory compounds with AhR-dependent cytokine regulation that can be used to treat inflammatory disease states.

[0004] Some embodiments disclosed herein relate to a compound of formula (I) or a salt, solvate or hydrate thereof.

[0005]

[0006] in

[0007] R 1 and R 2 Each of them is independently selected from OH and OR. 7 A group consisting of H and R, provided that R is a given. 1 and R 2 At least one of them is -OH or -OR 7 ;

[0008] R 7 Independently select any freely arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, aryl C 1-6 The group consisting of alkyl and acyl groups;

[0009] R 3 Choose any C to replace it. 1-6 Alkyl, optionally substituted C 2-6alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halogen, cyano, -C(O)OR 8 -NR 9 R 10 -S(O)2NR 9 R 10 -C(O)R 11 -OR 12 -S(O) n R 13 The group consisting of optional substituted heterocyclic groups;

[0010] R 8 Choose H freely and C can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0011] R 9 and R 10 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings;

[0012] R 11 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -NR 9 R 10 and -OR 12 The group formed;

[0013] R 12 and R 13 Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups;

[0014] R 6 Choose from H, halogen, hydroxyl, alkoxy, and optionally substituted C. 1-6 Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0015] n is an integer with a value of 0, 1, or 2;

[0016] s is an integer with a value of 0, 1, or 2;

[0017] t is an integer with values ​​from 0 to 6;

[0018] R 5 Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 aryl and -C 1-6 The group consisting of alkyl aryl groups;

[0019] R 14 Choose H freely and C can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0020] R 15 and R 16 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups, or R 15 and R 16 Together with the nitrogen to which they are attached, they form 5-7 cyclic saturated or unsaturated rings;

[0021] R 4 Choose freely from H, halogen, cyano, and optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 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)2NR 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 The group consisting of alkyl groups; and

[0022] R 18 and R 19 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0023] Some embodiments involve compounds selected from the following:

[0024]

[0025] Or its salts, solvates or hydrates.

[0026] Some implementations involve compounds of the following formula

[0027]

[0028] Some implementations involve compounds of the following formula

[0029]

[0030] Or its pharmaceutically acceptable salts, solvates, or hydrates.

[0031] Some implementations involve 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0032] Some embodiments describe a compound of formula (II) or a salt, solvate, or hydrate thereof:

[0033]

[0034] in

[0035] R 1 and R 2 Each of them is independently selected from OH and OR. 7 A group consisting of H and R, provided that R is a given. 1 and R 2 At least one of them is OH or OR 7 ;

[0036] R 7 Independently select any freely arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 The group consisting of alkyl and acyl groups;

[0037] R 3 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halogen, cyano, -C(O)OR 8 -NR 9 R 10 -S(O)2NR 9 R 10 -C(O)R 11 -OR 12 -S(O) n R 13 and optionally substituted heterocycles;

[0038] n is an integer with a value of 0, 1, or 2;

[0039] R 6 It is H;

[0040] R 8 Choose H freely and C can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0041] R 9 and R 10 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings;

[0042] R 11 Choose H freely and C can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl; -NR 9 R 10 and -OR 12 The group formed;

[0043] R 12 and R 13 Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups; and

[0044] R 6 Choose from halogens, hydroxyl groups, alkoxy groups, and optionally substituted C groups. 1-6 Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0045] Some embodiments described herein describe a pharmaceutical composition comprising: a compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable carrier or diluent.

[0046] Some embodiments describe a method for treating or preventing conditions associated with AhR imbalance in mammals, the method comprising administering to the mammal a therapeutically effective amount of any compound or pharmaceutical composition described herein.

[0047] Some embodiments describe a method of treating or preventing an inflammatory condition in a subject, the method comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described herein. In some embodiments, the inflammatory condition is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascular (dry) AMD, neovascular (wet) AMD, uveitis or other inflammatory eye conditions, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease. In some embodiments, the inflammatory condition is psoriasis or atopic dermatitis. In some embodiments, the compounds or pharmaceutical compositions described herein are administered topically.

[0048] Some embodiments describe a method for treating or preventing psoriasis or atopic dermatitis in a subject in need, the method comprising administering to the subject an effective amount of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0049] Some embodiments describe a method for preparing a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0050]

[0051] The method includes:

[0052] a) Prepare a compound of formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0053]

[0054] It includes:

[0055] 1) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 2 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0056]

[0057] 2) Treat the ketone of Formula 2 or its pharmaceutically acceptable salt, solvate or hydrate with Grignard reagent, and then remove water under acidic conditions to form the compound of Formula 3 or its pharmaceutically acceptable salt, solvate or hydrate.

[0058]

[0059] 3) Hydrogenating a compound of Formula 3 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 4 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0060]

[0061] 4) Boronize 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;

[0062] b) Prepare a compound of formula 6 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0063]

[0064] This includes treating isoquinoline-3-ol with a trifluoromethanesulfonylating agent; and

[0065] c) Couple a compound of Formula 6 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a compound of Formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 7 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0066]

[0067] d) Demethylating the compound of formula 7 to form the compound of formula 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0068] Steps a and b can be performed in any order or simultaneously in different reaction vessels. Attached Figure Description

[0069] Figure 1A -C shows a biomap overview of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol compared to tapinarof and F1CZ. Figure 1A Biographies of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol at concentrations of 1.0 μM, 0.33 μM, 0.11 μM, and 0.037 μM are shown. Figure 1BA biomap overview of 1 μM 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (light gray) is shown, overlapping with FICZ (330 nM; dark gray). Figure 1C A biomap overview of 1 μM 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (light gray) is shown, overlapping with tapinalov (1 μM; dark gray). Shaded gray areas represent normal variations. Common analytes outside of normal variations are annotated.

[0070] Figures 2A to 2C The effects of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol on IL-17A protein secretion and cell survival in primary human peripheral blood CD4+ T cells were shown. Figure 2A The diagram shows that 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (triangle) and tapinarov (circle) inhibited IL-17A in human peripheral blood CD4+ T- cells in a dose-dependent manner under Th17 polarization conditions. Dots represent the highest percentage of protein expression compared to Th17 from six co-donors; each treatment was performed in triplicate. Error bars represent the standard error of the mean. Figure 2B The cell viability of human peripheral blood CD4+ T- cells is shown under Th17 polarization conditions and with gradually increasing concentrations of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (rhomboid) and tapinarov (round) for 5 days. Data are the mean ± standard error of 3 to 9 experimental data points. Figure 2C Cell viability in primary human keratinocytes is shown. Cell viability was quantified after two days of treatment with gradually increasing concentrations of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (triangular) and tapinarov (circular). Error bars represent the mean ± standard error of 10–15 biological replicates.

[0071] Figures 3A to 3B This study demonstrates that targeted binding of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol induces AhR target gene CYP1A1 and reduces IL-17A expression in ex vivo human skin. Skin samples from healthy donors were placed in a liquid / air interface culture system and pretreated for 24 h with or without 1 or 10 μM 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (white) or GSK3038548A (grey), followed by further culture for 24 h under Th17 polarization conditions. Figure 3A The relative expression of CYP1A1 mRNA transcripts 24 hours later, as determined by qRT-PCR, is shown. Figure 3BThe relative expression of IL-17A mRNA transcripts 24 hours later, as determined by qRT-PCR, is shown. Data are presented as mean ± standard error from 3 or 4 biological replicates. Statistical significance was determined using the Student's t-test, *p < 0.05.

[0072] Figure 4 Local targeted binding of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol at different concentrations in cream formulation 1 and gel formulation 1 is illustrated. Skin samples from healthy donors were placed in a liquid / air interface culture system and treated with or without 10 μM 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or 1 μM FICZ in the culture medium, or applied topically in the formulation at the indicated concentration for 24 hours. The relative expression of CYP1A1 mRNA transcripts is reported as a plot of mean ± standard error from four biological replicates from four donors.

[0073] Figures 5A to 5F The effects of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol on clinical scores and epidermal thickness in an imiquimod mouse model of psoriasis were shown. 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was administered for 3 days prior to IMQ treatment. Then, IMQ and 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in a 60% ethanol topical solution were sequentially applied to the shaved back (IMQ first, followed by 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 1–2 hours later) at a concentration of 0.3% for 4 days. Figures 5A to 5B Or apply at concentrations of 0.3% and 0.1% for 9 days. Figures 5C to 5D ).exist Figure 5A In the diagram, rhombuses represent the vehicle (60% EtOH, 40% water) + vanicream; squares represent the vehicle + imiquimod (5%); X represents 0.3% 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (60% EtOH, 40% water) + imiquimod (5%). Other lines are irrelevant to this application and therefore not identified. Figure 5B Epidermal thickness was measured on histological sections of back skin obtained on the last day of treatment. Triangular bars represent mediator (60% EtOH 40% water) + vanicream; oval bars represent mediator + imiquimod (5%); solid bars represent 0.3% 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (60% EtOH 40% water) + imiquimod (5%). Figure 5CIn the diagram, the rhombus represents the medium (60% EtOH, 40% water) + vanicream; the square represents the medium + imiquimod (5%); X represents 0.1% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (60% EtOH, 40% water) + imiquimod (5%); and the circle represents 0.3% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (60% EtOH, 40% water) + imiquimod (5%). Figure 5D Epidermal thickness was measured on histological sections of back skin obtained on the last day of treatment. Triangular bars represent mediator (60% EtOH 40% water) + vanicream; oval bars represent mediator + imiquimod (5%); square bars represent 0.1% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (60% EtOH 40% water) + imiquimod (5%); solid bars represent 0.3% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (60% EtOH 40% water) + imiquimod (5%). Figure 5E In this study, a second 9-day IMQ study was conducted using 0.1% cream formulation 1 (square), 0.5% cream formulation 1 (X), and 1% cream formulation 1 (star). 0% cream formulation 1 + vanicream was represented by a rhombus, and 0% cream formulation 1 + imiquimod was represented by a circle. Figure 5F In this study, epidermal thickness was measured on histological sections of back skin obtained on the last day of treatment. Triangular bars represent mediator (0% cream formulation 1) + vanicream; oval bars represent mediator + 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.

[0074] Figures 6A to 6E The effects of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol on dermal and epidermal thickness were shown in the DFNB mouse model. Figure 6A A schematic diagram of the experimental design is shown. Mice were sensitized with DNFB on day 1 and irritated with DNFB every 2–3 days starting from day 5. A topical formulation of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was administered daily starting from day 5. Figure 6B Measurements of epidermal thickness responding to topical application of 1% or 0.3% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in a 60% ethanol solution (60% EtOH, 40% water) twice daily (BID) are shown. Figure 6C The measurement of dermal thickness is shown. Figure 6B and 6C In the diagram, square bars represent solvent (acetone / olive oil (4:1 volume:volume)) + medium (60% EtOH, 40% water), diamond bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + medium (60% EtOH, 40% water), and star bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + 1% 2-isopropyl-5-(isoquinoline-3-) 1,3-diol (60% EtOH, 40% water) in ethanol solution; solid bars indicate 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + 0.3% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in ethanol solution (60% EtOH, 40% water); hexagonal bars indicate 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)). Figure 6D Measurements of epidermal thickness in response to once-daily topical application of 0% cream formulation 1 or 0.3% cream formulation 1 are shown. Figure 6E The measurement of dermal thickness is shown. Figure 6D and 6E In the diagram, square bars represent acetone / olive oil (4:1 volume:volume) + medium (60% EtOH, 40% water); diamond bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + medium (60% EtOH, 40% water); circle bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + 0% cream formulation 1; solid bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) + 0.3% cream formulation 1; and hexagonal bars represent 0.15% DNFB (in acetone / olive oil (4:1 volume:volume)) and 0.05% clobetasol cream. One-way ANOVA was used to determine statistical significance. *p<0.05, ***p<0.001, n=12 for each treatment group.

[0075] Figure 7 The amounts of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol delivered to the epidermis (square bars in the bar set) and dermis (solid bars in the bar set) in different 1% formulations are shown 16 hours after application. Bar values ​​represent the mean amount ± standard error of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 15–18 biological replicates from 3 donors. Samples were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS) along with a limit of least quantitation (LLOQ) of 80 pg / mL.

[0076] Figure 8The cumulative amount (ng) of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in the receiving fluid within 16 hours after administration of different formulations is shown. Squares represent 1% cream formulation 3; circles represent 1% gel formulation 4; asterisks represent 1% gel formulation 3; single vertical line represents 1% cream formulation 4; no sign (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. Lines represent the mean cumulative amount ± standard error of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 15–18 replicates from 3 donors. Samples were analyzed by UPLC-MS / MS with 80 pg / mL LLOQ.

[0077] Figure 9 The amounts of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol delivered to the dermis 16 hours after application of different formulations are shown. Bars represent the mean amount ± standard error of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 13–16 replicates from three donors. Samples were analyzed by UPLC-MS / MS with LLOQ at 80 pg / mL*.

[0078] Figures 10A to 10B The amounts (μg) of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol delivered to the epidermis (square strips for each formulation) and dermis (solid strips for each formulation) 16 hours after application of different gel formulations of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol are shown. Bar values ​​represent the mean amount ± standard error of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 15–18 replicates from 3 donors. Figure 10A ) and the mean ± standard error of 7-10 replicates from one donor. Figure 10B The sample was analyzed by UPLC-MS / MS along with 80 pg / mL LLOQ.

[0079] Figure 11The cumulative amount (ng) of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in the receiving fluid within 16 hours after application of different gel formulations is shown. For gel formulation 4 (rhombus), gel formulation 1 (triangle), and gel formulation 2 (square), the cumulative amount ± standard error (N46822-2) of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 3 donors is described. For gel formulation 4 (asterisk) and gel formulation 3 (wide X), the cumulative amount ± standard error of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 1 donor is described. Samples were analyzed by UPLC-MS / MS with 80 pg / mL LLOQ.

[0080] Figures 12A to 12C The mean (SD) plasma concentration-time curve of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol after a single dose is shown in rats. Figure 12A In this study, 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol was administered intravenously (1 mg / kg). Figure 12B In the diagram, a solid square indicates subcutaneous administration of 10 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 30% sulfobutyl-β-cyclodextrin; a hollow square indicates subcutaneous administration of 25 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 30% sulfobutyl-β-cyclodextrin; a solid triangle indicates subcutaneous administration of 10 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 30% painless piercing cone (Cavitron); and a hollow square indicates subcutaneous administration of 25 mg / kg of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol from 30% painless piercing cone. Figure 12C In the image, the solid circle indicates topical administration of a 1% cream formulation 1 (20 mg / kg) of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol, and... Figure 12C The hollow square in the image represents the topical administration of a 1% gel formulation (20 mg / kg) of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol.

[0081] Figures 13A to 13B Individual epidermal / upper dermal and dermal concentration-time curves of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol following a single topical administration in miniature pigs are shown. Figure 13AIn the diagram, solid hollow circles represent the epidermis / upper dermis of miniature pig subject 1 treated with a 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol; dashed hollow circles represent the dermis of miniature pig subject 1 treated with a 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol; solid solid circles represent the epidermis / upper dermis of miniature pig subject 2 treated with a 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol; and dashed solid circles represent the dermis of miniature pig subject 2 treated with a 1% cream formulation 1 of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol. Figure 13B In the diagram, solid circles represent the epidermis / upper dermis of miniature pig subject 101 treated with a 1% gel formulation of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol; dashed circles represent the dermis of miniature pig subject 101 treated with a 1% gel formulation of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol; solid hollow circles represent the epidermis / upper dermis of miniature pig subject 102 treated with a 1% gel formulation of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol; and dashed hollow circles represent the dermis of miniature pig subject 102 treated with a 1% gel formulation of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol.

[0082] Figure 14A -B shows the use of a 1% cream formulation 1 in miniature pigs. Figure 14A ) and 1% gel formulation 1 ( Figure 14B In-depth analysis of skin MALDI IMS at different time points after a single local application. Invention Details

[0084] The aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcription factors, is a ligand-activated cytoplasmic transcription factor that senses and mediates a wide variety of endogenous and exogenous molecules with diverse biological activities. It is best known for mediating the toxic effects of environmental pollutants such as TCDD (dioxins) and a range of other xenobiotics. Recent evidence suggests that AhR is a highly conserved pathway that modulates inflammatory responses, thus making the AhR pathway a potentially important target for the treatment of inflammatory diseases.

[0085] AhR is widely expressed in several skin cell types, including keratinocytes, fibroblasts, melanocytes, and cutaneous immune cells. In keratinocytes, AhR signaling controls the expression of epidermal differentiation genes such as filaggrin, loricrin, and keratin, thus promoting skin barrier formation. Furthermore, AhR has been shown to play a crucial role as a regulator of both innate and adaptive immune responses by influencing the balance between Th17 and Treg T cells. Th17-related cytokines, including IL-17, contribute to the immunopathogenesis of inflammatory skin diseases such as psoriasis. Therefore, AhR has recently attracted attention as a target for the treatment or prevention of inflammatory skin diseases, highlighting the need for better topical therapies.

[0086] Compounds such as those described in this article that bind to and activate the aryl hydrocarbon receptor (AhR) provide a class of novel anti-inflammatory compounds with AhR-dependent cytokine regulation that can be used to treat inflammatory disease states.

[0087] Therefore, the beneficial effects of AhR activation offer novel therapeutic interventions in the treatment of inflammatory conditions. There is a need for better topical treatment of skin diseases, particularly chronic inflammatory skin diseases. Where appropriate, compounds that bind to and activate aryl hydrocarbon receptors (AhR) in various cell types, including human skin cells, will provide new and useful treatments for inflammatory conditions. Therefore, this invention provides a class of novel anti-inflammatory compounds with AhR-dependent cytokine regulation for the treatment of inflammatory conditions.

[0088] definition

[0089] It should be understood that, when used herein, the designation of no specific number refers to "one or more" of the described components. It will be apparent to those skilled in the art that the use of the singular includes the plural, unless otherwise specified.

[0090] The term "about" refers to a range within which a particular parameter is considered acceptable by those skilled in the art, the range depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can refer to a range of 10% of a given value. For instance, about 55% means 45% to 55%.

[0091] When used herein, "acyl" refers to an alkyl or aryl group bonded via a carbonyl-C(O)- group. For example, an acyl group includes C 1-6 Alkyl group. Typical acyl groups include acetyl and benzoyl groups.

[0092] The term "administration" herein means, in sound medical practice, any method of delivering a compound or a 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.

[0093] When used herein, the term "alkoxy" refers to an -O-alkyl group containing a specified number of carbon atoms. For example, C 1-6 An alkoxy group is an alkoxy group containing at least one and at most six carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexoxy.

[0094] When used herein, "alkyl" refers to a monovalent saturated hydrocarbon chain having a specified number of carbon atoms. For example, C 1-6 Alkyl groups are alkyl groups having 1 to 6 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have 1, 2, or 3 branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, and tert-butyl), and n-pentyl, etc.

[0095] The term "alkylene" refers to a linker, which is a straight or branched carbon chain with 1 to 6 carbon atoms and two bonding sites. 1-6 Examples of alkylene linkages include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, etc.

[0096] When used in this document, the term “and / or” can refer to both addition and optionally to the individual elements in a list that are thus connected, such that these elements should be understood as being selectively connected using “and” or, correspondingly, “or”. Furthermore, terms used in the singular naturally also include the plural.

[0097] When used herein, the term "application" means any method of delivering a topical composition to a subject in a manner that has a positive effect on a skin condition, state, or appearance, in sound medical or cosmetic practice.

[0098] When used in this document, the term "aryl" refers to a substituted or unsubstituted aromatic ring of a hydrocarbon, such as phenyl, naphthyl, etc.

[0099] When used herein, unless otherwise specified, the term "arylalkyl" or "aryl" refers to an aryl ring, such as benzene or naphthalene, and a C-linked ring. 1-6 Alkyl groups, such as -(CH2) n Phenyl, where n is 1-6.

[0100] When used herein, the term “compound of the invention” means a compound in any form as defined herein, namely any salt or non-salt form (e.g., as a free acid or base, or as a salt thereof, particularly a pharmaceutically acceptable salt) and any physical form (e.g., including non-solid forms (e.g., liquid or semi-solid forms) and solid forms (e.g., amorphous or crystalline forms, specific polymorphs, solvates, including hydrate forms (e.g., monohydrates, dihydrates and hemihydrates)), as well as mixtures of various forms.

[0101] Throughout this application, the descriptions of various embodiments use the language of “comprising”; however, in certain specific cases, embodiments may optionally be described using the language of “substantially consisting of” or “consisting of”.

[0102] When used herein, the term "dermatologically acceptable excipient or diluent" refers to any inactive ingredient present in the composition used in the topical composition described herein.

[0103] "Effective amount," "pharmaceutical effective amount," or "therapeutic effective amount" are used herein to refer to the amount of active ingredient sufficient to have a therapeutic effect after administration, such as an amount that will cause improvement or alteration in the condition to which it is administered. The effective amount will vary depending on the specific condition being treated, the severity of the condition, the duration of treatment, the stage of disease progression, the body surface area affected by the clinical condition (for topical administration), and the specific components of the composition. The amount is sufficient to treat the condition, disease, or symptom, or one or more symptoms thereof, and / or sufficient to prevent the occurrence of said disease or symptom, and can be determined by standard clinical techniques. The appropriate amount in any given situation will be apparent to those skilled in the art, or can be determined by routine experiments. In some embodiments, the compositions of the present invention are typically applied topically to the affected area, i.e., to a skin area where the clinical abnormality is evident.

[0104] When used herein, the term "halogenated alkyl" or "halogen-substituted alkyl" refers to a straight-chain or branched saturated hydrocarbon chain containing a specified number of carbon atoms that has been substituted with halogen atoms. For example, halogenated C 1-6 Alkyl refers to a straight-chain or branched alkyl group containing at least one and at most six carbon atoms, each carbon atom being substituted by one to three halogen atoms. Examples of "halogenated alkyl" as used herein include, but are not limited to, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0105] When used herein, the terms “halogen” and “halogenated” include fluorine, chlorine, bromine and iodine, as well as fluorinated, chlorinated, bromine and iodinated.

[0106] When 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, furanyl, pyranyl, thiopheneyl, pyrroleyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil. When used herein, the terms "heteroaryl ring," "heteroaryl moiety," and "heteroaryl" also refer to a fused aromatic ring containing at least one heteroatom selected from oxygen, nitrogen, and sulfur. Each fused ring may contain 5 or 6 ring atoms. Examples of fused aromatic rings include, but are not limited to, indole, isoindole, indazole, indole-indole, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophene, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthidyl, cinolinyl, purinyl, and phthalazinyl.

[0107] When used herein, unless otherwise specified, the term "heteroarylalkyl" refers to a C14 group attached to a heteroaryl component as defined herein, as defined above (unless otherwise defined). 1-6 alkyl.

[0108] When used herein, unless otherwise specified, the terms “heterocyclic alkyl” or “heterocyclic alkyl” refer to a C14-C14 bond attached to a heterocyclic component as defined herein (unless otherwise defined). 1-6 alkyl.

[0109] When used herein, the terms “heterocyclic” or “heterocyclic group” (alone or in any combination such as “heterocyclic alkyl”) refer to a saturated or partially unsaturated 4- to 10-membered ring system, wherein one or more rings contain one or more heteroatoms selected from N, O, S, or the group consisting of S(O)q, where q is 0 or an integer having a value of 1 or 2. Examples include, but are not limited to, tetrahydropyrroleyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl (including the oxidized form of the sulfur component), pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl (including the oxidized form of the sulfur component), or imidazoalkyl.

[0110] When used in this paper for in vitro skin penetration studies, the term “epidermis” includes the stratum corneum and the tissue or layer extending down to the basement membrane, separated by a thermal separation process.

[0111] When used in this study for in vitro skin permeation studies using ex vivo human abdominal skin with a thickness of 500 micrometers (+ / -100 micrometers) or 750 micrometers (+ / -100 micrometers), the term “epidermis” refers to the top / superficial layer obtained after undergoing a washing / tape-off procedure followed by thermal separation, and the term “dermis” refers to the underlying layer.

[0112] When used herein, the term "independently" means that, in the case where more than one substituent is selected from a plurality of possible substituents, those substituents may be the same or different. That is, each substituent is selected individually from the set of possible substituents described herein.

[0113] The term "regulation" refers to the increase or decrease of the quantity, quality, or effect of a particular activity.

[0114] When used herein, the term “oxo” refers to the oxygen component of a double bond; for example, if directly attached to a carbon atom, it forms the carbonyl component (C=O).

[0115] When used in this document, the term "hydroxyl" refers to the group -OH.

[0116] When used herein, the term “sulfinyl” refers to the oxide of the corresponding sulfide S(O), the term “thio” refers to the sulfide, and the term “sulfonyl” refers to the fully oxidized S(O)2 component.

[0117] When used in this document, the term “optionally” means that the event described below may or may not occur, and includes both the occurrence and non-occurrence of the event.

[0118] When used herein, unless specifically defined herein, "optionally substituted" means that the component can be independently substituted once or more, for example, 1 to 3 times, by the following substituents: halogens, such as fluorine, chlorine, bromine, or iodine; hydroxyl groups; hydroxyl-substituted C-type substituents. 1-3 Alkyl; C 1-3 Alkyl groups, such as methoxy or ethoxy groups; halogen-substituted C groups 1-3 Alkyl group; S(O) m C 1-3 Alkyl groups, such as methylthio, methylsulfinyl, or methylsulfonyl; NR 22 R 23 , where R 22 and R 23 Independently selected from H or C 1-3 Alkyl, or R therein 22 and R 23 Together with the nitrogen atoms to which they are attached, they form 5 to 7-membered rings, which optionally contain additional heteroatoms selected from O, N, or S; C 1-3 Alkyl; C3-7 cycloalkyl or C 3-7 cycloalkyl C 1-3 Alkyl groups, such as cyclopropylmethyl; halogen-substituted C 1-3 Alkyl groups, such as CF2CF2H or CF3; optionally substituted aryl groups, such as phenyl groups; or optionally substituted aryl C groups. 1-3 Alkyl groups, such as benzyl or phenethyl, and wherein these aryl-containing components may also be substituted with halogens, hydroxyl groups, or C-terminal groups. 1-3 Alkyl, C 1-3 Alkoxy groups, S(O) m C 1-3 Alkyl, amino, mono-substituted or disubstituted C 1-3 Alkylamino, C 1-3 Alkyl or CF3 substitution once or twice. Furthermore, those skilled in the art will recognize that, depending on further substitution, the compounds of the present invention may exist in other tautomer forms. All tautomer forms of the compounds described herein are intended to be covered within the scope of the invention. It should be understood that any designation of the named compounds of the present invention is intended to cover all tautomers of the named compounds and any mixtures of the tautomers of the named compounds.

[0119] When used in this document, “patient” includes human patients, including adults, adolescents, and children (e.g., pediatric patients). Pediatric patients may include adolescents under the age of 18. For the purposes of this document, children are those under the age of 12.

[0120] When used herein, "pharmaceuticalally acceptable" means that, within reasonable medical judgment, it is suitable for use in human and animal tissues without excessive toxicity, irritation, or other problems or complications, in proportion to a reasonable benefit / risk ratio. The terms "pharmaceuticalally acceptable" and "dermatologically acceptable" mean that which is approved by regulatory authorities or listed in a pharmacopoeia or other recognized guidelines for use in animals, and more specifically, in humans.

[0121] The term "pharmaceutically acceptable salt" refers to a salt that can be used safely and effectively in patients and has the desired pharmaceutical activity. The term "pharmaceutically acceptable salt" encompasses non-toxic salts of the compounds of this invention. Such salts include compounds in which the parent compound is modified by forming its acid or base salt.

[0122] When used herein, the term “skin penetration” refers to the diffusion of a compound, preferably a compound of formula (I) or a pharmaceutically acceptable salt thereof, through the stratum corneum of the skin and into the epidermis and / or dermis.

[0123] "Substantially free of" a specified component means that the composition contains less than about 1% of the specified component by weight. "Free of" a specified component means that the specified component is not present in the composition.

[0124] When used herein, the term “substituted” refers to a group in which one or more hydrogen atoms of a member atom attached to the group are replaced by a substituent selected from the defined set of substituents. It should be understood that the term “substituted” includes the implicit premise that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound (i.e., a compound that does not spontaneously transform by, for example, rearrangement, cyclization, or elimination, and is robust enough to remain upon separation from the reaction mixture). When a group is stated to contain one or more substituents, one or more (as the case may) member atoms within the group may be substituted. Furthermore, a single member atom within the group may be substituted by more than one substituent, provided that such substitution conforms to the permissible valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

[0125] The term "topical" delivery or "local administration" refers to the application of a drug-containing formulation to the skin for the direct treatment of skin conditions or diseases, with the aim of directing the pharmacological effects of the drug substantially to the surface or within the skin. The term "topical" delivery also includes dermal, inhalation, and ocular / oral 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.

[0126] When used herein, the term "treatment" means administering a compound or agent to a subject who has a condition or is at risk of developing a condition, with the aim of curing, alleviating, reducing, remedying, delaying the onset of the condition, preventing or improving the condition, the symptoms of the condition, secondary disease states of the condition, or susceptibility to the condition. Treatment does not necessarily mean that the condition or symptom is completely cured. Useful pharmaceutical compositions, such as pharmaceutical emulsion compositions, may only reduce the severity of the condition or symptom, reduce the severity of associated symptoms, improve the patient's quality of life, or delay, prevent, or inhibit the onset of the condition or symptom. As is recognized in the medical and pharmaceutical fields, a treatment is not necessarily effective in every member of a population, such as a group of patients with atopic dermatitis, to have clinical applicability.

[0127] Concentration, amount, solubility, and other numerical data may be presented in range format herein. It should be understood that this range format is used solely for convenience and brevity and should be interpreted flexibly to include not only the values ​​explicitly stated as limits of the range, but also all individual values ​​or subranges covered within that range, as if each value and subrange were explicitly stated. All figures and other numerical values ​​used in this specification to express quantities, percentages, or proportions should be understood to be modified by the term "about" in all cases.

[0128] For example, a concentration range of 0.1 to 5 ng / ml should be interpreted as including 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, 3.6 ng / mol and subranges such as 0.3–2.5 ng / ml, 1.8–3.2 ng / ml, etc. This interpretation applies regardless of the width of the range or the characteristics described.

[0129] Unless otherwise specified, any concentration range, percentage range or ratio range described herein shall be understood to include any integer and fraction thereof (e.g., one-tenth and one-hundredth of an integer) of the concentration, percentage or ratio within that range.

[0130] Other terms used herein are intended to be defined by their meanings as known in the art.

[0131] The optional definitions of various groups and substituents of formulas (I), (Ia), and (II) provided throughout this application are intended to specifically describe each individual compound substance disclosed herein, as well as groups of one or more compound substances. The scope of the invention includes any combination of these group and substituent definitions.

[0132] compound

[0133] In some embodiments, this disclosure describes a compound of formula (I):

[0134]

[0135] Or its salts, solvates or hydrates.

[0136] Each substituent R in formula (I) 1 and R 2 Independently selectable OH and OR 7 A group consisting of H and R, provided that R is a given. 1 and R 2 At least one of them is OH or OR 7 .

[0137] Substituent R in formula (I) 7 Independently select any freely arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 A group consisting of alkyl and acyl groups.

[0138] Formula (I) Substituent R 3 Choose any C to replace it. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halogen, cyano, -C(O)OR 8 -NR 9 R 10 -S(O)2NR 9 R 10 -C(O)R 11 -OR 12 -S(O) n R 13 The group consisting of heterocycles with optional substitutions.

[0139] Substituent R in formula (I) 8 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0140] R in equation (I) 9 and R 10 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups. Alternatively, substituents R. 9 and R 10 Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings.

[0141] Substituent R in formula (I) 11 Independently selectable hydrogen, with optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6Alkyl, optionally substituted C 3-6 cycloalkyl, -NR 9 R 10 and -OR 12 A group that is formed.

[0142] Substituent R in formula (I) 12 and R 13 Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Group consisting of cycloalkyl groups.

[0143] Substituent R in formula (I) 6 Choose from H, halogen, hydroxyl, alkoxy, and optionally substituted C. 1-6 Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0144] In equation (I), the subscript n is an integer with a value of 0, 1, or 2.

[0145] The subscript s in equation (I) is an integer with a value of 0, 1 or 2.

[0146] In equation (I), the subscript t is an integer with a value from 0 to 6.

[0147] Substituent R in formula (I) 5 Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 Optionally substituted aryl groups and optionally substituted -C 1-6 The group consisting of alkyl aryl groups.

[0148] Substituent R in formula (I) 14 Choose H freely and C can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0149] Substituent R in formula (I) 15 and R 16 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups. Or, R 15 and R 16 Together with the nitrogen to which they are attached, they form 5-7 cyclic saturated or unsaturated rings.

[0150] Substituent R in formula (I) 4 Choose freely from H, halogen, cyano, and optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 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)2NR 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 A group composed of alkyl groups.

[0151] Substituent R in formula (I) 18 and R 19 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0152] In some embodiments, the salt is a pharmaceutically acceptable salt.

[0153] In some implementations, R 1 and R 2 Each of them is independently OH. In some embodiments, R 1 and R 2 One is OH, and the other is H. In some embodiments, R 1 and R 2 One is OH, the other is OR 7 And in some implementations, R 1 and R 2 Both are OR 7 , where each R 7 Independently select any freely arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 The group consisting of alkyl and acyl groups. In some embodiments, R 7 C is an optional substitute 1-4 Alkyl group. In some embodiments, R 7 It is methyl or ethyl. In other embodiments, R 7 Is it optional to be NR? 22 R 23 Replacement C 1-4 Alkyl group. In some embodiments, R 22 and R 23 Each of them is independently chosen from H and C. 1-3 Alkyl groups, such as those consisting of -(CH2)3NH2. In some embodiments, R 1 and R 2 Each of them is a methoxyl group. In some embodiments, R 1 It is OH and R 2 Is it OR 7 , where R 7 It is the replacement of C 1-6 Alkyl group. In some embodiments, R 1 It is OH and R 2 Is it OR 7, where R 7 It was NR 22 R 23 Replacement C 1-6 Alkyl group. In some embodiments, R 1 It is OH, and R 2 It is -O(CH2)3NH2.

[0154] When R 7 When the component is an optionally substituted component, the substituted component may be independently substituted once or more, for example, 1 to 3 times, by the following substituents: halogen; hydroxyl group; hydroxyl-substituted -C group. 1-3 Alkyl; C 1-3 Alkoxy; halogenated C 1-3 Alkyl group; -S(O) m C 1-3 , where m is an integer with a value of 0, 1, or 2; -NR 22 R 23 , where R 22 and R 23 Independently selected from H or C 1-3 Alkyl, or R therein 22 and R 23 Together with the nitrogen atoms to which they are attached, they form 5 to 7-membered rings, which optionally contain additional heteroatoms selected from O, N, or S; C 3-7 cycloalkyl; halogen-substituted C 1-3 Alkyl groups, such as CF2CF2H or CF3; or optionally substituted aryl groups, wherein the aryl component may also optionally be substituted with a halogen, a hydroxyl group, or a -C group. 1-3 Alkyl, C 1-3 Alkyl groups, -S(O) m C 1-3 Alkyl (where m is an integer having a value of 0, 1, or 2), amino, monosubstituted, and disubstituted C 1-3 Alkylamino, C 1-3 Alkyl or CF3 substitution once or twice.

[0155] In some implementations, R 7 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 7 It was NR 22 R 23 Replacement C 1-6 Alkyl group. In some embodiments, R 7 C is replaced by NH2 1-6 Alkyl group. In some embodiments, R 7 It is -(CH2)3NH2.

[0156] In some implementations, when R3 When the component is an optionally substituted component, the component can be substituted independently once or multiple times, for example, 1 to 3 times. In some embodiments, the component can optionally be substituted independently by halogens, hydroxyl groups, C... 1-3 Alkoxy, C 1-3 Alkyl, aryl, or arylalkyl are substituted 1 to 3 times.

[0157] In some implementations, R 3 Choose any C to replace it. 3-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups. In some embodiments, the C 3-6 The alkyl group is isopropyl, n-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl, n-hexyl, etc. In some embodiments, the alkyl group is isopropyl or tert-butyl. In some embodiments, the C... 3-6 The alkyl group is isopropyl. In some embodiments, the C... 3-6 The cycloalkyl group is cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, the C... 3-6 The cycloalkyl group is cyclopentyl.

[0158] In some implementations, R 3 It is a heterocyclic ring.

[0159] In some implementations, R 3 It is isopropyl.

[0160] In some implementations, R 6 Choose freely from H, halogen, hydroxyl, and C. 1-3 Alkoxy, optional substituted C 1-6 Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 The group consisting of alkyl groups. In some embodiments, R 6 Choose freely from H, halogen, hydroxyl, and C. 1-3 Alkoxy, optional substituted C 1-3 The group consisting of alkyl and haloalkyl groups. In some embodiments, R 6 The group consisting of H and halogens is selected. In some embodiments, R... 6 The group consisting of H and bromine is selected. In some embodiments, R... 6 It is H.

[0161] In some implementations, R 5 Choose from free H, halogen, or arbitrarily substituted -C 1-6 Alkyl, -C(O)OR 14 -C(O)NR15 R 16 aryl and -C 1-6 The group consisting of alkyl aryl groups. In some embodiments, R 5 Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, C(O)OR 14 and C(O)NR 15 R 16 A group consisting of [groups]. In some implementations, R 5 Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl and C(O)OR 14 A group consisting of [groups]. In some implementations, R 5 Selected from H and optionally substituted C 1-6 Alkyl group. In some embodiments, R 5 Choose freely H, C(O)OR 14 and C(O)NR 15 R 16 A group consisting of [groups]. In some implementations, R 5 C is an optional substitute 1-3 Alkyl group. In some embodiments, when R 5 It is an optional substitution of -C 1-6 When alkyl components are used, the -C 1-6 Alkyl groups may optionally be independently substituted 1 to 3 times with the following substituents: halogen; hydroxyl; C 1-3 Alkoxy; Halogenated C 1-3 Alkyl group; -S(O) m C 1-3 Alkyl group, where m is an integer having a value of 0, 1, or 2; -NR 20 R 21 , where R 20 and R 21 Independently selected from H and C 1-3 Alkyl; halogen-substituted C 1-3 Alkyl groups, such as CF2CF2H or CF3; or aryl groups. In some embodiments, R 5 It is H.

[0162] In some implementations, R 4 Choose freely H, -(CR) 18 R 19 ) t COOR 8 、-(CR 18 R 19 ) t C(O)NR 9 R 10 、-(CR 18 R 19 ) tNR 9 R 10 Optional substitution of C 1-6 Alkyl, -(CR) 18 R 19 ) t OR 12 and -(CR 18 R 19 ) t S(O) s R 13 A group consisting of [groups]. In some implementations, R 4 Choose freely H, -(CR) 18 R 19 ) t COOR 8 and -(CR 18 R 19 ) t C(O)NR 9 R 10 The group consists of t, where t is 0 and R. 9 It is H, and R 10 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 4 The group consisting of H, -COOH, -COOCH3, and –CONH(CH2)2NH2 is selected. In some embodiments, R 4 It's H.

[0163] In some implementations, t is an integer having a value of 0, 1, 2, or 3. In some implementations, t is 0.

[0164] In some implementations, R 9 and R 10 Each of them is independently chosen from H and arbitrarily substituted C. 1-6 A group composed of alkyl groups.

[0165] In some implementations, R 11 Choose H freely and C arbitrarily substituted. 1-6 A group composed of alkyl groups.

[0166] In some implementations, R 12 and R 13 Each of them is independently selected from the group consisting of H and optionally substituted alkyl groups.

[0167] In some implementations, n is 0 or 2. In some implementations, n is 0. In some implementations, n is 2.

[0168] In some implementations, R 18 and R 19Each of them is independently chosen from H and arbitrarily substituted C. 1-6 A group composed of alkyl groups.

[0169] Some embodiments describe a compound of formula (I), wherein:

[0170] R 1 Choose freely between OH and OR 7 The group consisting of R 7 C is an optional substitute 1-6 alkyl;

[0171] R 2 Choose freely between OH and OR 7 The group consisting of R 7 C is an optional substitute 1-6 alkyl;

[0172] R 3 C is an optional substitute 1-6 alkyl;

[0173] R 4 Choose freely H, -(CR) 18 R 19 ) t COOR 8 、-(CR 18 R 19 ) t C(O)NR 9 R 10 The group consists of t, where t is 0 and R. 8 Selected from H and optionally substituted C 1-6 Alkyl, R 9 It is H, and R 10 C is an optional substitute 1-6 alkyl;

[0174] R 5 It is H; and

[0175] R 6 It is H or halogen.

[0176] Some embodiments describe a compound of formula (I), wherein:

[0177] R 1 Choose freely between OH and OR 7 The group consisting of R 7 It is an alkyl group;

[0178] R 2 Choose freely between OH and OR 7 The group consisting of R 7 It was NR 22 R 23 Replacement C1-6 Alkyl; wherein R 22 and R 23 Independently choose H and C 1-3 The group consisting of alkyl groups;

[0179] R 3 C is an optional substitute 1-6 alkyl;

[0180] R 4 Choose freely from H, -COOH, -COOCH3 and -C(O)NR 9 R 10 The group consisting of R; 9 It is H, and R 10 Choose C with free amino substitution 1-6 The group consisting of alkyl groups and –(CH2)2NHC(O)O-tert-butyl groups;

[0181] R 5 It is H; and

[0182] R 6 Choose the group consisting of free hydrogen and halogens.

[0183] Some embodiments describe a compound of formula (I), wherein:

[0184] R 1 Choose the group consisting of OH and -OCH3;

[0185] R 2 Choose from the group consisting of OH, -OCH3, and -O-(CH2)3NH2;

[0186] R 3 It is C 1-6 alkyl;

[0187] R 4 Choose the group consisting of H, -COOH, -COOCH3, -C(O)NH(CH2)2NH2 and -C(O)NH(CH2)2NHC(O)O-tert-butyl;

[0188] R 5 It is H; and

[0189] R 6 Choose the group consisting of H and bromine.

[0190] Some embodiments describe a compound of formula (I), wherein:

[0191] R 1 Choose the group consisting of OH and -OCH3;

[0192] R 2Choose from the group consisting of OH, -OCH3, and –O-(CH2)3NH2;

[0193] R 3 It is isopropyl;

[0194] R 4 Choose the group consisting of H, -COOH, -COOCH3, -C(O)(CH2)2NH2 and -C(O)NH(CH2)2NHC(O)O-tert-butyl;

[0195] R 5 It is H; and

[0196] R 6 Choose the group consisting of H and bromine.

[0197] In one embodiment, this disclosure describes a compound of formula (Ia):

[0198]

[0199] Or its salts, solvates or hydrates.

[0200] Substituent R in formula (Ia) 1a and R 2a Each of them is independently selected from OH and OR. 7a A group consisting of H and R, provided that R is a given. 1a and R 2a At least one of them is OH or OR 7a .

[0201] Substituent R in formula (Ia) 7a Choose any C to replace it. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 A group consisting of alkyl and acyl groups.

[0202] Substituent R in formula (Ia) 3a Choose any C to replace it. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 The group consisting of cycloalkenyl, halogen, and optionally substituted heterocycles.

[0203] Substituent R in formula (Ia) 6a Choose from H, halogen, hydroxyl, alkoxy, and optionally substituted C. 1-6Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0204] Substituent R in formula (Ia) 5a Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, -C(O)OR 14a -C(O)NR 15a R 16a Optionally substituted aryl groups and optionally substituted -C 1-6 The group consisting of alkyl aryl groups.

[0205] Substituent R in formula (Ia) 14a Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0206] Substituent R in formula (Ia) 15a and R 16a Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups. Or, R 15a and R 16a Together with the nitrogen to which they are attached, they form 5-7 cyclic saturated or unsaturated rings.

[0207] The subscript s' in equation (Ia) is an integer with a value of 0, 1 or 2.

[0208] The subscript t' in equation (Ia) is an integer with a value from 0 to 6.

[0209] Substituent R in formula (Ia) 4a Choose freely from H, halogen, cyano, and optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -(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 、-(CR 18a R 19a ) t’ S(O) s’ R 13a ;Optionally substituted heterocycles and optionally substituted heterocycles C 1-6 A group composed of alkyl groups.

[0210] Substituent R in formula (Ia) 18a and R 19a Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0211] Substituent R in formula (Ia) 8a Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 A group composed of alkyl groups.

[0212] Substituent R in formula (Ia) 9a and R 10a Each of them is independently chosen from H and arbitrarily substituted with C. 1-6Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups. Alternatively, substituents R. 9a and R 10a Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings.

[0213] Substituent R in formula (Ia) 11a Independently selectable hydrogen, with optional substitution of C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -NR 9a R 10a and -OR 12a A group that is formed.

[0214] Substituent R in formula (Ia) 12a and R 13a Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 Group consisting of cycloalkyl groups.

[0215] In some embodiments, the salt of formula (Ia) is a pharmaceutically acceptable salt.

[0216] In some implementations, R 1a and R 2a Each of them is independently OH. In some embodiments, R 1a and R 2a One is OH, and the other is H. In some embodiments, R 1a and R 2a One is OH, the other is OR 7a And in some implementations, R 1a and R 2a Each of them is independently OR 7a , where each R 7a Independently select any freely arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 The group consisting of alkyl and acyl groups. In some embodiments, R 7a C is an optional substitute 1-4 Alkyl group. In some embodiments, R 7aIt is methyl or ethyl.

[0217] In some implementations, R 3a Choose any C to replace it. 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups. In some embodiments, R 3a C is an optional substitute 3-6 Alkyl group. In some embodiments, R 3a It is isopropyl. In some embodiments, R 3a C is an optional substitute 3-6 Cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopentyl.

[0218] In some implementations, R 3a Choose any C to replace it. 3-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups; and R 1a and R 2a Each is independently OH. In some embodiments, R 3a Choose any C to replace it. 3-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups; and R 1a and R 2a Each of them is independently selected from OH and OR. 7a A group consisting of H and R, provided that R is a given. 1a and R 2a At least one of them is OH or OR 7a In another implementation, R 3a Choose any C to replace it. 3-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups; and R 1a and R 2a One is OH, and the other is H.

[0219] In some implementations, R 4a and R 5a Each of them is independently selected from H and halogens.

[0220] In some implementations, R 4a It is H, and R 5a Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, C(O)OR 14a and C(O)NR 15a R 16a A group consisting of [groups]. In some implementations, R 5a It is H, and R 4a Choose from free H, halogen, and C with optional substitution.1-6 Alkyl, C(O)OR 14a and C(O)NR 15a R 16a A group that is formed.

[0221] In some implementations, R 3a Choose any C to replace it. 3-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups; R 1a and R 2a Both are OH, and R 4a and R 5a Each of them is independently selected from H and halogens.

[0222] In some implementations, R 3a C is an optional substitute 3-6 Alkyl, R 1a and R 2a Each of them is OH, and R 4a and R 5a Each of them is independently either H or a halogen.

[0223] In some implementations, R 6a Independently selectable from H, halogen, hydroxyl, and C 1-6 Alkoxy, optional substituted C 1-6 Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 The group consisting of alkyl groups. In some embodiments, R 6a Choose freely from H, halogen, hydroxyl, and C. 1-3 Alkoxy, optional substituted C 1-3 The group consisting of alkyl and haloalkyl groups. In some embodiments, R 6a The group consisting of H and halogens is selected. In some embodiments, R... 6a It is H.

[0224] In some implementations, R 6a Choose the group composed of H and halogens; R 3a C is an optional substitute 3-6 Alkyl, R 1a and R 2a Each of them is OH, and R 4a and R 5a Each of them is independently selected from the group consisting of H and halogens.

[0225] In some implementations, t is 0. In some implementations, t is 0, 1, 2, or 3.

[0226] Some embodiments of the present invention involve compounds selected from the following:

[0227]

[0228] Or its salts, solvates or hydrates.

[0229] Some embodiments of the present invention relate to 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol:

[0230]

[0231] Or its pharmaceutically acceptable salts, solvates, or hydrates.

[0232] In some embodiments, the 2-isopropyl-5-(isoquinoline-3-yl)phenyl-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, the 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is a non-solventizable crystal. Some embodiments describe isolated 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol. In some embodiments, the 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is a hydrate. In some embodiments, the 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is an organic solvate. Some embodiments describe an organic solvate of isolated 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol. Some embodiments describe an acetonitrile / water solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe an acetone solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe an N,N-dimethylformamide solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a 1,4-dioxane / water solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a butanone solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a tetrahydrofuran / water solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe an ethyl acetate solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a dimethyl carbonate solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a dimethyl sulfoxide solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a 1-butanol solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a tetrahydrofuran solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol. Some embodiments describe a methyl tert-butyl ether solvate of 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol.

[0233] This invention also includes various different isomers of compounds according to any embodiment described herein, and mixtures thereof. An isomer is a compound having the same composition and molecular weight but different physical and / or chemical properties. Structural differences may manifest in their construction (geometric isomers) or ability to rotate the plane of polarization (stereoisomers). Compounds according to any embodiment described herein may contain one or more asymmetric centers, also referred to as chiral centers, and thus may exist as individual enantiomers, diastereomers, or other stereoisomers, or as mixtures thereof. All such isomeric forms, including mixtures thereof, are included in this invention. Chiral centers may also be present in substituents such as alkyl groups. Where the stereochemistry of the chiral center present in any formula shown herein or in any chemical structure is not specified, the structure is intended to cover any stereoisomer and all mixtures thereof. Therefore, compounds containing one or more chiral centers according to any embodiment described herein can be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure single stereoisomers. A mixture containing unequal portions of enantiomers is described as having an “enantiomer excess” (ee) of either the R or S compound. The excess of one enantiomer in the mixture is typically described as a percentage of enantiomer excess. The ratio of enantiomers can also be defined by “optical purity,” where the degree to which the enantiomer mixture rotates plane-polarized light is compared to the individual optically pure R and S compounds. The compound can also be a substantially pure (+) or (-) enantiomer of the compound described herein. In some embodiments, the composition may comprise a substantially pure enantiomer of the compound according to any embodiment described herein, containing at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one enantiomer. In some embodiments, the composition may comprise a substantially pure enantiomer of the compound according to any embodiment described herein, containing at least 99.5% of one enantiomer.

[0234] Individual stereoisomers of compounds containing one or more asymmetric centers according to any of the embodiments described herein can be separated by methods known to those skilled in the art. For example, such separation can be performed by: (1) forming diastereomer salts, complexes, or other derivatives; (2) selectively reacting with a stereoisomer-specific reagent, such as by enzymatic oxidation or reduction; or (3) performing gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support, for example on silica gel with bound chiral ligands, or in the presence of a chiral solvent. Those skilled in the art will recognize that, in cases where the desired stereoisomer is converted to another chemical entity by one of the above separation procedures, an additional step is required to release the desired form. Alternatively, a particular stereoisomer can be synthesized by asymmetric synthesis or by asymmetric conversion of one enantiomer to another using optically active reagents, substrates, catalysts, or solvents. Other embodiments include prodrugs of compounds according to any of the embodiments described herein, i.e., compounds that, when administered to a mammalian subject, release in vivo the active compound according to any of the embodiments described herein. A prodrug is a pharmacologically active compound, or more commonly an inactive compound, that is metabolized and converted into a pharmacologically active compound. Prodrugs of compounds according to any embodiment described herein are prepared by modifying functional groups present in the compound such that the modification can be cleaved in vivo to release the parent compound. In vivo, prodrugs readily undergo chemical changes (e.g., hydrolysis or action by naturally occurring enzymes) under physiological conditions, resulting in the release of the pharmacologically active agent. Prodrugs include compounds according to any embodiment described herein in which a hydroxyl, amino, or carboxyl group is bonded to any group, which can be cleaved in vivo to regenerate the free hydroxyl, amino, or carboxyl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives) of compounds according to any embodiment described herein, or any other derivatives that are converted into an active parent drug upon reaching physiological pH or by enzymatic action. Conventional procedures for selecting and preparing suitable prodrug derivatives have been described in the art.

[0235] Certain compounds of the present invention can form salts with one or more equivalents of an acid (if the compound contains a basic component) or a base (if the compound contains an acidic component). The present invention encompasses all possible stoichiometric and non-stoichiometric salt forms within its scope.

[0236] When the compounds of the present invention contain a basic component, the desired salt form can be prepared by any suitable method known in the art, including treating the free base with the following acids: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or 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, etc.; or pyranoside, such as glucuronic acid or galacturonic acid; or α-hydroxy acids, such as citric acid or tartaric acid; or amino acids, such as aspartic acid or glutamic acid; or aromatic acids, such as benzoic acid or cinnamic acid; or sulfonic acids, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.

[0237] Suitable addition salts are formed from acids that form non-toxic salts, including acetates, p-aminobenzoates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, bicarbonates, bimethylenesalicylate, bisulfates, tartrates, borates, calcium edetate, camphorsulfonates, carbonates, clavulanates, citrates, cyclohexylaminosulfonate, edetate, ethanedisulfonate, etolate, ethanesulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, gluconate, glutamate, glycolate, p-hydroxyacetaminophenarsine, hexylresorcinol salt, hydrobromide, hydrochloride, dihydrochloride, and hydrogen fumarate. Salts, hydrogen phosphates, hydroiodates, hydrogen maleate, hydrogen succinate, hydroxynaphthyl carboxylate, hydroxyethyl sulfonate, itaconic acid salts, lactates, lacturonates, laurates, malates, maleates, mandelates, methanesulfonates, methyl sulfates, monopotassium maleate, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine, oxalates, oxaloacetate, bis(hydroxynaphthyl) salts, palmitate, palmitate, pantothenate, phosphates / bis(phosphophosphates), pyruvate, polygalacturonate, propionate, sucrose, salicylates, stearates, basic acetates, succinates, sulfates, tannins, tartrates, theochloroate, toluenesulfonate, triethyliodide, trifluoroacetate, and valerates.

[0238] Other exemplary acid addition salts include pyrosulfates, sulfites, bisulfites, decanoates, octanoates, acrylates, isobutyrates, hexanoates, heptanoates, propionates, oxalates, malonates, octanoates, sebacic acid 1,4-diacidates, hexyn-1,6-diacidates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates, lactates, γ-hydroxybutyrates, mandelates, and sulfonates such as xylenesulfonates, propanesulfonates, naphthalene-1-sulfonates, and naphthalene-2-sulfonates.

[0239] If the basic compound of the present invention is isolated as a salt, the corresponding free basic form of the compound can be prepared by any suitable method known in the art, including using inorganic or organic bases, which, where appropriate, have a higher pK than the free basic form of the compound. a The salt is treated with an inorganic or organic base.

[0240] When the compounds of the present invention contain an acidic component, the desired salt can be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary amine), an alkali metal, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include protonate salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as N-methyl-D-glucosamine, diethylamine, isopropylamine, trimethylamine, ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0241] The compounds of the present invention having both basic and acidic components can take the form of zwitterions, acid addition salts of the basic component, or basic salts of the acidic component.

[0242] Because of their potential uses in medicine, the salts of the compounds of the present invention are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are known to those skilled in the art.

[0243] These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by individually treating the purified compound, in the form of a free acid or a free base, with a suitable base or acid.

[0244] In some embodiments, the compounds of the present invention may contain acidic functional groups and are therefore capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable 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, including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxyalkylamines, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

[0245] In some embodiments, the compounds of the present invention may contain basic functional groups and are therefore capable of forming acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic and organic acids. Representative pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, glycolic 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, methanesulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, etc.

[0246] The present invention also provides a conversion of one pharmaceutically acceptable salt of the compounds of the present invention to another pharmaceutically acceptable salt of the compounds of the present invention.

[0247] The compounds according to any of the embodiments described herein may exist in solid or liquid form. In the solid state, it may exist in crystalline or amorphous form or as mixtures thereof. Those skilled in the art will recognize that pharmaceutically acceptable solvates can be formed from crystalline compounds, wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may contain non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may contain water as a solvent incorporated into the crystal lattice. Solvates in which the solvent incorporated into the crystal lattice is water are generally referred to as “hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing a variable amount of water. This invention includes all such solvates.

[0248] For solvates of compounds in crystalline form according to any embodiment described herein, including solvates of salts of compounds according to any embodiment described herein, those skilled in the art will recognize that pharmaceutically acceptable solvates can be formed in which solvent molecules are incorporated into the crystal 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 a solvent incorporated into the crystal lattice. Solvates in which the solvent incorporated into the crystal lattice is water are generally referred to as "hydrates". Hydrates include stoichiometric hydrates and compositions containing a variable amount of water. This invention includes all such solvates.

[0249] Those skilled in the art will also recognize that compounds existing in crystalline form according to any of the embodiments described herein, including their various solvates, may exhibit polymorphism (i.e., the ability to appear in different crystalline structures). These different crystalline forms are generally referred to as "polymorphs." This 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. Therefore, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will recognize 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 solvent may produce polymorphs. Furthermore, under certain conditions, one polymorph may spontaneously transform into another polymorph.

[0250] The subject matter invention also includes isotopically labeled compounds that are consistent with the compounds of the present invention and those described below, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts, solvates, or hydrates include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I.

[0251] Pharmaceutically acceptable salts, solvates, or hydrates of compounds according to any of the embodiments described herein and other isotopes containing the aforementioned isotopes and / or other atoms are within the scope of this invention. Isotope-labeled compounds of this invention, for example, those incorporating radioactive isotopes, are also included. 3 H, 14 Compounds of C can be used in the determination of drug and / or substance tissue distribution. Due to their ease of preparation and detection, tritium... 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred. 11 C and 18F isotopes are particularly useful in PET (positron emission tomography), and 125 Iodine isotopes are particularly useful in SPECT (single-photon emission computed tomography) and can also be used in brain imaging. Additionally, heavier isotopes such as deuterium are used... 2 H substitution can yield certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. Isotopically labeled compounds according to any of the embodiments described herein can generally be prepared by performing the procedures disclosed in the reaction diagrams and / or examples below, replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0252] The present invention also includes isolated compounds. Isolated compounds refer to compounds that constitute at least 10%, preferably at least 20%, more preferably at least 50%, and most preferably at least 80% of the compounds present in the mixture.

[0253] Since the compounds according to any of the embodiments described herein are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in a substantially pure form, for example, with a purity of at least 60%, more preferably at least 75%, preferably at least 85%, and particularly at least 98% (by weight). In some embodiments, the compounds according to any of the embodiments described herein have a purity of 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%. Impure preparations of the compounds may be used to prepare a purer form for use in pharmaceutical compositions.

[0254] Pharmaceutical Composition

[0255] Some embodiments describe a pharmaceutical composition comprising: a compound according to any of the embodiments described herein, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof; and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition may be prepared in a manner known in the pharmaceutical industry and may be administered via various routes, whether for local or systemic treatment as needed and depending on the area to be treated.

[0256] Although the compounds described in any of the embodiments herein may be administered as bulk substances, it is preferable to present the compounds in pharmaceutical formulations, for example, in which the active pharmaceutical agent is mixed with a pharmaceutically acceptable carrier selected according to the target route of administration and standard pharmaceutical practice.

[0257] Specifically, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any of the embodiments described herein and optionally a pharmaceutically acceptable carrier.

[0258] Some embodiments describe a pharmaceutical composition comprising 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol:

[0259]

[0260] Or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.

[0261] Some embodiments describe a pharmaceutical composition comprising N-(2-aminoethyl)-3-[3,5-dihydroxy-4-(propyl-2-yl)phenyl]isoquinoline-6-carboxamide:

[0262]

[0263] Or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.

[0264] Some embodiments describe a pharmaceutical composition comprising 3-(3-aminopropoxy)-5-(isoquinoline-3-yl)-2-(prop-2-yl)phenol:

[0265]

[0266] Or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent. In one embodiment, the salt is a trifluoroacetate:

[0267]

[0268] Treatment

[0269] Vitiligo is a depigmentation disorder caused by the selective destruction of melanocytes. In melanocytes, AhR links UVB radiation from sunlight to skin pigmentation. A reduced risk of vitiligo has been described as being associated with specific variants of the AhR gene, and in further research, these authors found that one AhR variant in humans promotes Ahr transcriptional activity, enhances its interaction with the SP1 transcription factor, leading to increased AhR expression and IL-10 production.

[0270] AhR activating ligands have been shown to reduce inflammation in the lesions of psoriatic skin, and AhR antagonists exacerbate the disease. AhR signaling via FICZ reduced inflammation in an imiquimod-induced mouse model, and AhR-deficient mice showed aggravated disease compared to WT controls. It should also be noted that keratinocytes are implied to be involved in the aforementioned inflammatory response.

[0271] It has also been shown that activation of the AhR pathway leads to inflammatory skin conditions such as atopic dermatitis and exacerbations of inflammatory diseases following exposure to occupational or environmental xenobiotics. Coal tar, an AhR agonist, has been shown to completely restore the expression of major skin barrier proteins.

[0272] Early dry age-related macular degeneration (AMD) is a leading cause of vision loss in older adults. AhR activity and protein levels in human retinal pigment epithelial cells decrease with age, and AhR(- / -) mice exhibit visual function decline and develop dry AMD-like pathology. Another research group also showed that AhR(- / -) mice exhibit subretinal microglia aggregation and focal retinal pigment epithelial cell atrophy, phenotypes observed in AMD.

[0273] Malek's lab discovered that AhR is also associated with wet AMD. They showed that in lab-induced choroidal neovascularization in AhR(- / -) mice, some lesions exhibited a greater number of ionized calcium-binding adaptor molecule 1-positive (Iba1(+)) microglia and a greater amount of type IV collagen deposition, all of which are also seen in human wet AMD.

[0274] Many other potential indications suggest that AhR agonist or antagonist effects may influence disease severity or progression. There is also mounting evidence that targeting AhR may be beneficial in other disease conditions, such as for the treatment of intestinal inflammations like irritable bowel disease (IBD), colitis, and Crohn's disease. AhR has also been shown to play a significant role in protecting the lungs from allergen-induced inflammation by modulating MSC recruitment and their immunosuppressive activity.

[0275] Atopic dermatitis (AD) is a severe, itchy, chronic, relapsing inflammatory skin disease. The etiology of atopic dermatitis is multifactorial, with genetic and environmental factors, skin barrier dysfunction, and impaired immune response being the most prominent. Impaired immune response is characterized by activation of type 2 T helper cells (Th2) and increased IgE production; overexpression of eosinophil chemokine-3, IL-2, IL-5, and IL-13 is also present in the skin lesions. It is also believed that the inflammatory components of atopic dermatitis are primarily mediated by Th2-type T cell activation pathways, although a shift to a type 1 T helper cell (Th1) driven pathway has been described in chronic atopic dermatitis lesions. The frequent occurrence of atopic dermatitis in families with other atopic conditions supports the hypothesis that it may be genetically linked.

[0276] Disorders of the skin barrier function are a key factor in the pathogenesis of atopic dermatitis. Characteristic signs and symptoms of atopic dermatitis include itching and burning, lichenification and xerosis, accompanied by erythematous papules and plaques, vesicle formation, exudation and crusting, erosion, and scaly exfoliation. Due to both the stigma associated with visible skin lesions and the intense, persistent itching that leads to sleep deprivation, atopic dermatitis often has a significant impact on quality of life.

[0277] To date, there is no cure for atopic dermatitis. For both children and adults, stabilizing the condition and reducing the frequency and severity of flare-ups are the primary goals of treatment. Patients require treatment for acute flare-ups and long-term maintenance therapy in persistent cases. Topical therapy targets skin inflammation and is a key factor in disease management, as is the relief of itching symptoms in atopic dermatitis. While several topical treatment options are available, there is a need for a topical treatment that combines high efficacy with acceptable safety in both adults and children, allowing application to a large body surface area without limiting the duration of treatment. Topical corticosteroids (TCS) are generally the standard of care for acute flare-ups of atopic dermatitis. However, TCS are generally not suitable for long-term use due to the potential for local and systemic adverse events, such as skin atrophy and an increased risk of systemic exposure. Current treatment options for atopic dermatitis in children are particularly limited due to safety concerns regarding long-term use (>2–4 weeks) or application to sensitive areas such as the face or chafed areas.

[0278] Without wishing to be limited by any theoretical constraints, the compounds of the embodiments described herein are believed to have a different mechanism of action than topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI), and are expected to have improved safety and efficacy superior to TCI. The compounds of the embodiments described herein will benefit children who: do not respond adequately to TCS; are intolerant to TCS; or are not suitable for TCS (e.g., due to lesion site or duration of treatment). Having an effective option of safe topical treatment can delay the transition to systemic therapy, thereby limiting the significant treatment-related risks and costs for patients.

[0279] Psoriasis vulgaris is a chronic autoimmune inflammatory skin disease caused by the interaction of genetic, environmental, and systemic factors, affecting 2–3% of Caucasians. Immune system dysregulation is involved in the pathogenesis of the disease and includes abnormal cell infiltration, the production of inflammatory mediators, and keratinization. A key component of this process is Th17-type cytokines (IL-17A, IL-17F, and IL-22), which (i) drive excessive proliferation of keratinocytes and chemokine production, and (ii) perpetuate further leukocyte recruitment.

[0280] The compounds disclosed herein can be used to treat mild to moderate psoriasis. While a number of new biological treatment options exist for severe psoriasis, innovation in the latest treatment options is limited for patients with mild to moderate disease. Treatment with TCS has clear contraindications (long-term use and use on sensitive areas), therefore safe and effective topical treatment would be extremely beneficial for patients with mild to moderate psoriasis.

[0281] Therefore, the present invention provides a method for treating conditions related to the aforementioned diseases or disorders, the method comprising the step of administering to a subject in need an effective amount of at least one compound described in any embodiment herein.

[0282] In some embodiments, this disclosure provides methods for preventing or treating conditions associated with AhR imbalance.

[0283] In some embodiments, this disclosure provides a method of treating or preventing AhR-mediated disease in a subject of need, the method 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 (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent.

[0284] Some embodiments describe a method for treating or preventing conditions such as: clinical transplant rejection (e.g., organ transplant, acute transplant, or xenograft or allograft rejection, e.g., used in burn treatment); protection against ischemic or reperfusion injury, e.g., during organ transplantation, myocardial infarction, stroke, or other causes; transplant tolerance induction; arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or osteoarthritis); multiple sclerosis; IBD, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosus); graft-versus-host disease; T-cell-mediated hypersensitivity disorders, including contact hypersensitivity, eczema, delayed-type hypersensitivity, and gluten-sensitive enteropathy (celiac disease); psoriasis; contact dermatitis (including poison ivy-induced dermatitis); Hashimoto's thyroiditis; Sjögren's syndrome; autoimmune hyperthyroidism, e.g., Graves' disease. Addison's disease (an autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituitarism; Guillain-Barré syndrome; other autoimmune diseases; glomerulonephritis, serum sickness; urticaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; sclerotic diseases; mycosis fungoides; acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; palmoplantar pustulosis; pyoderma gangrenosa; Sezari syndrome; atopic dermatitis; systemic sclerosis; and morphine; the method comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to any embodiment described herein.

[0285] Some embodiments describe a method for treating or preventing an allergic disease or condition, an inflammatory disease or condition, or an autoimmune disease or condition in a subject in need, the method 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 (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent.

[0286] Some embodiments describe a method for treating or preventing an inflammatory disease or condition in a subject in need, the method 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 (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent.

[0287] In some embodiments, the inflammatory disease or condition is an inflammatory skin disease or condition. In some embodiments, the inflammatory skin disease or condition is a chronic inflammatory skin disease or condition, acne, psoriasis, rosacea, or aging skin. In some embodiments, the chronic inflammatory skin disease is dermatitis, such as atopic dermatitis, contact dermatitis, eczematous dermatitis, or seborrheic dermatitis.

[0288] In some embodiments, the inflammatory disease or condition is selected from the group consisting of psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, and acne. In some embodiments, the inflammatory disease or condition is psoriasis. In some embodiments, the inflammatory disease or condition is atopic dermatitis. In some embodiments, the inflammatory disease or condition is acne.

[0289] Some embodiments describe a method for treating or preventing a dermatological condition or disease in a subject in need, the method 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 (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent.

[0290] In some implementations, the dermatological condition or symptom is a skin disease. In some embodiments, the skin disease is selected from: 1) skin conditions characterized by persistent inflammation, cellular dynamics, and differentiation (e.g., psoriasis, psoriatic arthritis, exfoliative dermatitis, pityriasis rosea, lichen planus, lichen luster, or hidradenosis); 2) skin conditions characterized by epidermal adhesions, vesicular and bullous diseases (e.g., pemphigus, bullous pemphigus, acquired epidermolysis bullosa, or pustular eruptions of the palms or soles); 3) skin conditions and related conditions of epidermal appendages (e.g., hair diseases, nail diseases, rosacea, perioral dermatitis, or follicular syndrome); 4) skin conditions such as tumors of the epidermis and its appendages (e.g., squamous cell carcinoma, basal cell carcinoma, keratoacanthoma, benign epithelial tumor, or Merkel cell carcinoma); 5) melanocyte diseases (e.g., pigmentary diseases, albinism, hypomelanosis and hypermelanosis, melanocytic nevus, or melanoma); 6) skin conditions of inflammatory and neoplastic dermal diseases. (e.g., persistent raised erythema, eosinophilic granuloma, facial granuloma, gangrenous pyoderma, malignant atrophic papules, fibrosis of the dermis and soft tissues, or Kaposi's sarcoma); 7) Subcutaneous tissue conditions (e.g., panniculitis or lipid dystrophy); 8) Skin conditions involving reactive changes in the skin (e.g., urticaria, vasculitis, graft-versus-host disease, allergic contact dermatitis, autosensitization dermatitis, atopic dermatitis, or seborrheic dermatitis); 9) Skin changes caused by mechanical and physical factors (e.g., heat injury, radiation dermatitis, corns, or calluses); 10) Photodamage (e.g., acute and chronic UV radiation or photosensitization); or 11) Skin conditions caused by microbial infectious agents (e.g., leprosy, Lyme disease, onychomycosis, tinea pedis, rubella, measles, herpes simplex, Epstein-Barr virus (EBV), human papillomavirus (HPV, e.g., HPV6 & 7), warts, or prions).

[0291] Some embodiments describe a method for treating or preventing radiation dermatitis in a subject in need, the method 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 (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof 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, ale, desquamation, fibrosis, telangiectasia, and skin atrophy, or a combination thereof. In some embodiments, the radiation dermatitis is acute erythema, ale, or desquamation, or a combination thereof. In some embodiments, the radiation dermatitis is fibrosis, telangiectasia, and skin atrophy, or a combination thereof.

[0292] Some embodiments describe a method for treating or preventing inflammatory mucosal conditions in a subject in need, the method 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 (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a combination of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another therapeutic agent. In some embodiments, the inflammatory mucosal condition is caused by cancer radiotherapy or chemotherapy. 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 pemphigoid, pemphigus vulgaris, and epidermolysis bullosa. In some embodiments, the oral mucositis is caused by radiotherapy or chemotherapy for cancer. In some embodiments, the oral mucositis is caused by radiotherapy or chemotherapy for head and / or neck cancer. In some embodiments, the oral mucositis is caused by radiotherapy for head and / or neck cancer.

[0293] Some embodiments describe a method of treating atopic dermatitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the following formula.

[0294]

[0295] Or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition thereof.

[0296] Some embodiments describe a method of treating psoriasis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol:

[0297]

[0298] Or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition thereof.

[0299] Some embodiments describe a method for treating atopic dermatitis in a subject in need, the method comprising administering 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol to the subject:

[0300]

[0301] Or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutical composition thereof.

[0302] Some embodiments describe a method for treating atopic dermatitis or psoriasis in a subject in need, the method comprising administering to the subject a topical cream comprising a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0303] Some embodiments describe a method for treating atopic dermatitis or psoriasis in a subject in need, the method comprising administering to the subject a topical gel containing a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0304] Some embodiments describe a method for treating atopic dermatitis or psoriasis in a subject in need, the method comprising administering to the subject a topical lotion comprising a therapeutically effective amount of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0305] In some embodiments, the compound is an agonist of the AhR ligand. In some embodiments, the compound is an antagonist of the AhR ligand.

[0306] The compounds according to any of the embodiments described herein can be used in a veterinary or medical context. It should be appreciated that the subject or patient can be an animal, a domesticated animal such as a mammal, including horses, cows, pigs, sheep, poultry, fish, cats, dogs, and zoo animals. In some embodiments, the subject is an animal.

[0307] 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 3 months to 2 years of age or older. In some embodiments, the human is an adult.

[0308] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for therapeutic purposes. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0309] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for the treatment or prevention of conditions associated with AhR imbalance. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0310] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for the treatment or prevention of AhR-mediated diseases. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0311] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for the treatment or prevention of an inflammatory disease or condition. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0312] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for the treatment or prevention of dermatological conditions or ailments. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0313] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for the treatment or prevention of psoriasis. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0314] Some embodiments describe a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein, for the treatment or prevention of atopic dermatitis. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0315] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for treating a condition associated with AhR imbalance in a subject of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0316] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for treating AhR-mediated diseases in subjects of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0317] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for treating or preventing an inflammatory condition in a subject of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0318] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for treating or preventing a dermatological condition or disease in a subject of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0319] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for the treatment or prevention of psoriasis in subjects of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0320] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for the treatment or prevention of atopic dermatitis in a subject of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0321] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any of the embodiments described herein in the preparation of a medicament for treating or preventing conditions associated with AhR imbalance in subjects of need. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0322] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein in the preparation of a medicament for the treatment or prevention of AhR-mediated diseases. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0323] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein in the preparation of a medicament for treating or preventing an inflammatory disease or condition. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0324] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein in the preparation of a medicament for treating or preventing dermatological conditions or diseases. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0325] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein in the preparation of a medicament for the treatment or prevention of psoriasis. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0326] Certain embodiments describe the use of a compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any embodiment described herein in the preparation of a medicament for the treatment or prevention of atopic dermatitis. In some embodiments, the compound is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0327] combination

[0328] For the pharmaceutical compositions and methods / uses described herein, the compounds of any embodiment described herein may be used in combination with one or more other therapies and / or active pharmaceutical agents. In some embodiments, the compounds of any embodiment described herein are combined with a second pharmaceutical agent suitable for the condition or disease described herein, administered concurrently with, before, or after administration of the second pharmaceutical agent. In some embodiments, the second pharmaceutical agent is in the same formulation as the compound according to any embodiment described herein. In some embodiments, the second pharmaceutical agent is in a separate formulation. The second therapeutic agent may be administered via the same route as the compound according to any embodiment described herein, or it may be administered via 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 pharmaceutical agent may be administered topically, orally, intravenously, intramuscularly, through the ear, eye, vagina, rectum, etc. In some embodiments, the second pharmaceutical agent is administered concurrently with the compound of the present invention. In some embodiments, the second pharmaceutical agent is administered before the compound of the present invention. In some embodiments, the second pharmaceutical agent is administered after the compound of the present invention.

[0329] In other words, compounds according to any of the embodiments described herein can be administered simultaneously or sequentially to the administration site or desired site of action. The order of administration is not considered necessary. However, if administered topically, it may be preferred to contact two or more active agents together at the administration site or desired site of action for a period of time. Alternatively, it may be ideal to suitably select the duration of action of the active agents based on the delivery time of the active agents. The presence of both in the same medium provides convenience for patient administration and may improve compliance, but this is not required by the present invention.

[0330] When a compound according to any of the embodiments described herein is administered in combination with one or more other therapies and / or active pharmaceutical agents described herein, each active pharmaceutical component (i.e., the compound of the present invention and the second pharmaceutical agent) is contained in an effective dose.

[0331] In some embodiments, the second agent is an agent used to treat or prevent conditions associated with AhR imbalance.

[0332] In some embodiments, the other agents may be used to prevent or treat allergic diseases, inflammatory diseases, or autoimmune diseases. In some embodiments, the agents are antigen immunotherapy agents, antihistamines, corticosteroids such as fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, cicosone, mometasone furoate, triamcinolone acetonide, and flunisolone, NSAIDs, leukotriene modifiers such as montelukast, zafirlukast, and prolukast, iNOS inhibitors, trypsin inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, surface inhibitors, elastase inhibitors, integrin antagonists such as β-2 integrin antagonists, adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3Kδ inhibitors, ITK inhibitors, LP (lysophospholipid) inhibitors, or FLAP (5-lipoxygenase activator). 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-dimethylpropionate, bronchodilators such as muscarinic antagonists and β-2 agonists, methotrexate and similar agents, monoclonal antibody therapeutics such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 antibodies and similar agents, cytokine receptor therapeutics such as etanercept and similar agents, and antigen-nonspecific immunotherapies such as interferon or other cytokines / chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar agents.

[0333] In some embodiments, the other agents are agents used to assist in transplantation, including cyclosporine, tacrolimus, mycophenolate mofetil, prednisone, azathioprine, sirolimus, dacrolimus, balithimab, or OKT3.

[0334] In some embodiments, the other agents are agents used to treat diabetes, such as metformin (biguanide), chloropicrin, sulfonylureas, DPP-4 inhibitors, thiazolidinediones or α-glucosidase inhibitors, amylin mimics, enterohepatic hormone mimics or insulin.

[0335] In some embodiments, the other agents are antihypertensive drugs such as diuretics, ACE inhibitors, ARBS, calcium channel blockers, and beta-blockers.

[0336] Therefore, on the other hand, this 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 pharmaceutical agent, and optionally a pharmaceutically acceptable carrier.

[0337] When combined in the same formulation, it should be recognized that the two or more compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation in a manner known in the art to be suitable for such compounds.

[0338] Preservatives, stabilizers, dyes, and flavorings 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.

[0339] For combinations including biologics such as monoclonal antibodies or fragments, suitable excipients will be used to prevent aggregation and stabilize the antibody or fragment in a low-endotoxin solution, typically for parenteral administration, such as intravenous administration. See, for example, “Formulation and Delivery Issues for Monoclonal Antibody Therapeutics,” Daugherty et al., in Current Trends in Monoclonal Antibody Development and Manufacturing, Part 4, 2010, Springer, New York, pp. 103-129.

[0340] Route of administration and unit dosage form

[0341] The compounds according to any of the embodiments described herein and pharmaceutical compositions incorporating said compounds may be conveniently administered via any route of administration commonly used for drug delivery, such as oral, topical, transdermal, parenteral, or inhalation. The compounds may be administered in conventional dosage forms prepared by combining the compounds according to any of the embodiments described herein with a standard pharmaceutical carrier according to conventional procedures. The compounds according to any of the embodiments described herein may also be combined with a known second therapeutically active compound further described herein for administration at a conventional dose. Depending on the desired preparation, these procedures may involve mixing, granulation, and compression or dissolving the ingredients. It should be recognized that the form and characteristics of a pharmaceutically acceptable carrier or diluent depend on the amount of active ingredient to be combined with, the route of administration, and other well-known variables. The carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the recipient.

[0342] The compounds according to any of the embodiments described herein can be administered topically, i.e., non-systemic administration. This includes applying the compound externally to the epidermis, buccal cavity, or instilling it into the ear, eye, or nose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0343] Preparations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as liniments, lotions, creams, gels, solutions, ointments, pastes, and drops suitable for administration to the skin, eyes, ears, or nose.

[0344] The lotions according to the invention include those suitable for application to the skin, ears, nose, or eyes. Eye lotions may contain a sterile aqueous solution optionally containing a bactericide and may be prepared by a method similar to that used for preparing drops. Lotions or liniments applied to the skin may also contain agents that accelerate drying and cool the skin, such as alcohol or acetone, and / or moisturizers such as glycerin or oils such as castor oil or peanut oil.

[0345] The creams, gels, ointments, or pastes according to the invention are semi-solid formulations of active ingredients for external application. They can be manufactured by mixing, with the aid of suitable machinery, the active ingredient (i.e., the compound according to any embodiment described herein) in a solution or suspension in an aqueous or non-aqueous fluid, either in fractionated or powder form, with an oily or non-oily base. The base may contain hydrocarbons such as hard, soft, or liquid paraffin, glycerin, beeswax, metallic soaps; mucilage; naturally derived oils such as almond, corn, peanut, castor, or olive oil; lanolin or derivatives thereof; or fatty acids such as stearic acid or oleic acid with alcohols such as propylene glycol or large-particle gels. The formulation may incorporate any suitable surfactant, such as anionic, cationic, or nonionic surfactants like sorbitol or its polyoxyethylene derivatives. It may also include suspending agents such as natural gums, cellulose derivatives, or inorganic materials such as silica, and other ingredients such as lanolin.

[0346] The drops according to the invention may comprise a sterile aqueous or oily solution or suspension, and may be prepared by dissolving the active ingredient in a suitable aqueous solution containing a bactericide and / or fungicide and / or any other suitable preservative and preferably a surfactant. The resulting solution may then be clarified by filtration, transferred to a suitable container, and then sealed and sterilized by pressure heat treatment or by maintaining at 98-100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container using aseptic techniques. Examples of bactericides and fungicides suitable for inclusion in the drops are nitric acid or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, dilute alcohol, and propylene glycol.

[0347] In some embodiments, the compounds according to any of the embodiments described herein are administered topically as creams, gel ointments, pastes, drops, or lotions. In some embodiments, the compounds according to any of the embodiments described herein are administered as gels or creams. In some embodiments, the compounds according to any of the embodiments described herein are administered as gels. In some embodiments, the compounds according to any of the embodiments described herein are administered as creams.

[0348] In some embodiments, the pharmaceutical formulation comprises compounds according to any of the embodiments described herein and pharmaceutically acceptable excipients or diluents, as well as antioxidants, preservatives, gelling agents, pH adjusters or stabilizers, or mixtures thereof, which are suitably modified for topical administration to a patient’s skin, eyes or ears.

[0349] In some embodiments, the composition is a cream or gel composition, and the compound of formula (I) is 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol.

[0350] In some embodiments, the composition is a cream formulation. In some embodiments, the composition is a cream formulation 1 comprising the following components:

[0351]

[0352]

[0353] QS 100: The amount required to produce 100% of the composition.

[0354] It should be understood that when 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is present in cream formulation 1 at a specific concentration (in the range of 0-1%), the formulation may be referred to as X% cream formulation 1. For example, in some embodiments, the composition is a cream formulation 1 (1% cream formulation 1) containing 1% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol. Therefore, 1% cream formulation 1 comprises:

[0355] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 1 Propylene glycol 15.0 Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 stearate 1.0 Glyceryl monostearate 1.5 stearic acid 0.15 Cetearyl alcohol 50 3.0 benzyl alcohol 1.0 BHT 0.1 water QS 100

[0356] In some embodiments, the composition is a 0.5% cream formulation 1, comprising:

[0357] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 0.5 Propylene glycol 15.0 Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 stearate 1.0 Glyceryl monostearate 1.5 stearic acid 0.15 Cetearyl alcohol 50 3.0 benzyl alcohol 1.0 BHT 0.1 water QS 100

[0358] In some embodiments, the composition is a 0.1% cream formulation 1, comprising:

[0359] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 0.1 Propylene glycol 15.0 Transcutol P 10.0 PEG400 20.0 Miglyol 810 5.0 PEG40 stearate 1.0 Glyceryl monostearate 1.5 stearic acid 0.15 Cetearyl alcohol 50 3.0 benzyl alcohol 1.0 BHT 0.1 water QS 100

[0360] In some embodiments, the composition is a cream formulation 2, which comprises the following components:

[0361] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 0-1 Propylene glycol 15.0 Transcutol P 15.0 PEG400 20.0 Miglyol 810 5.0 PEG40 stearate 1.0 Glyceryl monostearate 1.5 stearic acid 0.15 Cetearyl alcohol 50 3.0 benzyl alcohol 1.0 BHT 0.1 water QS 100

[0362] In some embodiments, the composition is a cream formulation 3, which comprises the following components:

[0363]

[0364] In some embodiments, the composition is a 1% cream formulation 3, comprising:

[0365]

[0366] In some embodiments, the composition is a 0.5% cream formulation 3, comprising:

[0367]

[0368] In some embodiments, the composition is a cream formulation 4, which comprises the following components:

[0369]

[0370]

[0371] In some embodiments, the composition is a cream formulation 5, which comprises the following components:

[0372]

[0373] In some embodiments, the composition is a cream formulation 6, which comprises the following components:

[0374]

[0375]

[0376] In some embodiments, the composition is a cream formulation 7, which comprises the following components:

[0377]

[0378] In some embodiments, the composition is a gel formulation (gel formulation 1) comprising the following components:

[0379]

[0380]

[0381] In some embodiments, the composition is a gel formulation comprising the following components (1% gel formulation 1):

[0382] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 1 Propylene glycol 10.0 Transcutol P 35.0 benzyl alcohol 2.0 BHT 0.05 Carbomer P980 0.5 Triethanolamine 0.15 water QS 100

[0383] In some embodiments, the composition is a gel formulation (gel formulation 2) comprising the following components:

[0384] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 0-1 Transcutol P 35.0 PEG400 10.0 benzyl alcohol 2.0 BHT 0.05 Carbomer P980 0.5 Triethanolamine 0.2 water QS 100

[0385] In some embodiments, the composition is a gel formulation (gel formulation 3) comprising the following components:

[0386]

[0387]

[0388] In some embodiments, the composition is a gel formulation (gel formulation 4) comprising the following components:

[0389] Formulation components Composition (% w / w) 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol 0-1 Propylene glycol 40.0 Transcutol P 15.0 benzyl alcohol 2.0 BHT 0.05 Carbomer P980 0.5 Triethanolamine 0.15 water QS 100

[0390] While topical administration is the preferred route of administration, compounds according to any of the embodiments described herein may also be administered parenterally, i.e., via intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal, or intraperitoneal administration. Subcutaneous and intramuscular parenterial administration are generally preferred. Dosage forms suitable for such administration can be prepared using conventional techniques. Compounds according to any of the embodiments described herein may also be administered by inhalation, i.e., via intranasal and oral inhalation. Dosage forms suitable for such administration, such as aerosol formulations or metered-dose inhalers, can be prepared using conventional techniques.

[0391] The dosage of the compound, which is the active ingredient of the invention according to any of the embodiments described herein, may be varied to obtain a suitable dosage form. The active ingredient may be administered to subjects (animals and humans) requiring such treatment at a dosage that provides optimal pharmaceutical efficacy. The chosen dosage depends on the desired therapeutic effect, route of administration, and duration of treatment. The dosage will vary depending on the patient, the nature and severity of the disease, the patient's weight, any specific diet subsequently followed by the patient, concomitant medications, and other factors that will be recognized by those skilled in the art.

[0392] In some embodiments, the amount of the compound to be administered can range from about 0.1 to about 100 mg / kg / day. Typically, the daily dose level administered to the patient, for example, a human, is between 0.1 and 10 mg / kg body weight. In some embodiments, the therapeutically effective amount is at doses 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, and about 20 mg / kg body weight per day. / kg body weight, approximately 25mg / kg body weight, approximately 30mg / kg body weight, approximately 35mg / kg body weight, approximately 40mg / kg body weight, approximately 45mg / kg body weight, approximately 50mg / kg body weight, 55mg / kg body weight, approximately 60mg / kg body weight, approximately 65mg / kg body weight, approximately 70mg / kg body weight, approximately 75mg / kg body weight, approximately 80mg / kg body weight, approximately 85mg / kg body weight, approximately 80mg / kg body weight, approximately 95mg / kg body weight and approximately 100mg / kg body weight The lower limit of g / kg body weight is approximately 100 mg / kg body weight, approximately 95 mg / kg body weight, approximately 90 mg / kg body weight, approximately 85 mg / kg body weight, approximately 80 mg / kg body weight, approximately 75 mg / kg body weight, approximately 70 mg / kg body weight, approximately 65 mg / kg body weight, approximately 60 mg / kg body weight, approximately 55 mg / kg body weight, 50 mg / kg body weight, approximately 45 mg / kg body weight, approximately 40 mg / kg body weight, approximately 35 mg / kg body weight, approximately 30 mg / kg body weight, approximately 2... The dosage ranges from approximately 5 mg / kg body weight, approximately 20 mg / kg body weight, approximately 15 mg / kg body weight, approximately 10 mg / kg body weight, approximately 5 mg / kg body weight, approximately 1 mg / kg body weight, approximately 0.9 mg / kg body weight, approximately 0.8 mg / kg body weight, approximately 0.7 mg / kg body weight, approximately 0.6 mg / kg body weight, approximately 0.5 mg / kg body weight, approximately 0.4 mg / kg body weight, approximately 0.3 mg / kg body weight, approximately 0.2 mg / kg body weight, and approximately 0.1 mg / kg body weight.

[0393] In some embodiments, the compound according to any of the embodiments described herein is administered to the 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 approximately 0.01 mg / day, approximately 0.05 mg / day, 0.1 mg / day, approximately 0.5 mg / day, approximately 1 mg / day, approximately 10 mg / day, approximately 20 mg / day, approximately 30 mg / day, approximately 40 mg / day, approximately 50 mg / day, approximately 60 mg / day, approximately 70 mg / day, approximately 80 mg / day, approximately 90 mg / day, approximately 100 mg / day, approximately 110 mg / day, approximately 120 mg / day, approximately 130 mg / day, approximately 140 mg / day, approximately 150 mg / day, approximately 160 mg / day, approximately 170 mg / day, approximately 180 mg / day, approximately 190 mg / day, approximately 20 mg / day, etc. 0 mg / day, approximately 210 mg / day, approximately 220 mg / day, approximately 230 mg / day, approximately 240 mg / day, approximately 250 mg / day, approximately 260 mg / day, approximately 270 mg / day, approximately 280 mg / day, approximately 290 mg / day, approximately 300 mg / day, approximately 310 mg / day, approximately 320 mg / day, approximately 330 mg / day, approximately 340 mg / day, approximately 350 mg / day, approximately 360 mg / day, approximately 370 mg / day, approximately 380 mg / day, approximately 390 mg / day, approximately 400 mg / day, approximately 410 mg / day, approximately 420 mg / day, approximately 430 mg / day, approximately 440 mg / day, approximately 450 mg / day g / day, approximately 460mg / day, approximately 470mg / day, approximately 480mg / day, approximately 490mg / day, approximately 500mg / day, approximately 510mg / day, approximately 520mg / day, approximately 530mg / day, approximately 540mg / day, approximately 550mg / day, approximately 560mg / day, approximately 570mg / day, approximately 580mg / day, approximately 590mg / day, approximately 600mg / day, approximately 610mg / day, approximately 620mg / day, approximately 630mg / day, approximately 640mg / day, approximately 650mg / day, approximately 660mg / day, approximately 670mg / day, approximately 680mg / day, approximately 690mg / day, approximately 700mg / day Approximately 710 mg / day, approximately 720 mg / day, approximately 730 mg / day, approximately 740 mg / day, approximately 750 mg / day, approximately 760 mg / day, approximately 770 mg / day, approximately 780 mg / day, approximately 790 mg / day, approximately 800 mg / day, approximately 810 mg / day, approximately 820 mg / day, approximately 830 mg / day, approximately 840 mg / day, approximately 850 mg / day, approximately 860 mg / day, approximately 870 mg / day, approximately 880 mg / day, approximately 890 mg / day, approximately 900 mg / day, approximately 910 mg / day, approximately 920 mg / day, approximately 930 mg / day, approximately 940 mg / day, approximately 950 mg / day.The lower limit of approximately 960 mg / day, approximately 970 mg / day, approximately 980 mg / day, approximately 990 mg / day, and approximately 1000 mg / day, and the lower limit of approximately 1000 mg / day, approximately 990 mg / day, approximately 980 mg / day, approximately 970 mg / day, approximately 960 mg / day, approximately 950 mg / day, approximately 940 mg / day, approximately 930 mg / day, approximately 920 mg / day, approximately 910 mg / day, approximately 900 mg / day, approximately 890 mg / day, approximately 880 mg / day, approximately 870 mg / day, approximately 860 mg / day, approximately 850 mg / day, approximately 840 mg / day, approximately 830 mg / day, approximately 820 mg / day, approximately 810 mg / day, approximately 800 mg / day, approximately 790 mg / day. g / 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, approximately 520mg / day g / 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, approximately 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 260mg / day, approximately 250mg / day The dosage ranges from approximately 240 mg / day, 230 mg / day, 220 mg / day, 210 mg / day, 200 mg / day, 190 mg / day, 180 mg / day, 170 mg / day, 160 mg / day, 150 mg / day, 140 mg / day, 130 mg / day, 120 mg / day, 110 mg / day, 100 mg / day, 90 mg / day, 80 mg / day, 70 mg / day, 60 mg / day, 50 mg / day, 40 mg / day, 30 mg / day, 10 mg / day, 1 mg / day, 0.5 mg / day, 0.1 mg / day, and the upper limit of approximately 0.01 mg / day.

[0394] It should be understood that the pharmaceutical compositions disclosed herein do not necessarily contain the full amount of compound effective in treating the stated condition, as such an effective amount can be achieved by administering multiple fractions of such pharmaceutical compositions. The compound can be administered as a single daily dose or in a multi-dose regimen (e.g., 2, 3, 4, 5, or more fractions daily) such that the total daily dose is the same. The effective amount of its salts can be determined as a proportion of the effective amount of the compound according to any embodiment described herein. Similar dosages should be suitable for treating other conditions mentioned herein. Generally, a person skilled in the medical or pharmaceutical field can readily determine a suitable dosage.

[0395] The active ingredient, i.e., the compound according to any embodiment described herein, may be administered topically at a dose of 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 is administered at 0.1% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, or 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein is administered at 1% w / w to 2% w / w of the formulation. A daily topical dosing regimen may be approximately 0.1 mg to 150 mg of the compound according to any of the embodiments described herein, administered 1 to 4 times daily.In some embodiments, the daily topical dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, or 31 mg. , 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53 mg, 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, 96 mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, The dosages are 115 mg, 116 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. Initial doses can also be estimated using animal models from in vivo data. Animal models for testing the efficacy of the compounds in treating or preventing the various diseases described above are well known in the art. The compounds can be administered once a week, several times a week (e.g., every other day), once a day, or several times a day, as determined by the prescribing physician.

[0396] Those skilled in the art will also recognize that the optimal amount and interval of a single dose of a compound or its pharmaceutically acceptable salt, solvate, or hydrate according to any embodiment described herein will be determined by the nature and extent of the condition to be treated, the form, route, and site of administration, and the patient to be treated, and that such optimal values ​​can be determined by conventional techniques. Those skilled in the art will also recognize that the optimal treatment course, i.e., the number of doses of a compound or its pharmaceutically acceptable salt, solvate, or hydrate according to any embodiment described herein administered daily over a defined number of days, can be determined by those skilled in the art using conventional treatment course determination experiments.

[0397] Method for preparing compounds of formula 8

[0398] Some embodiments describe a method for preparing a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0399]

[0400] The method includes demethylating a compound of Formula 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0401]

[0402] In some embodiments, the method further includes adding a compound of formula 6 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0403]

[0404] Coupled with a compound of formula 5 or its pharmaceutically acceptable salt, solvate or hydrate,

[0405]

[0406] Compounds of formula 7.

[0407] In some embodiments, the method further includes borating the compound of Formula 4 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0408]

[0409]

[0410] To form a compound of formula 5.

[0411] In some embodiments, the method further includes hydrogenating the compound of Formula 3 or its pharmaceutically acceptable salt, solvate, or hydrate.

[0412]

[0413] To form compounds of formula 4.

[0414] In some embodiments, the method further includes treating the ketone of Formula 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a Grignard reagent.

[0415]

[0416] Then, water is removed under acidic conditions to form a compound of formula 3.

[0417] In some embodiments, the method further includes alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 2.

[0418] In some embodiments, demethylating a compound of formula 7 to form a compound of formula 8 includes treating the compound of formula 7 with boron tribromide.

[0419] In some embodiments, demethylating a compound of formula 7 to form a compound of formula 8 includes: a) treating the compound of formula 7 with boron tribromide to form a compound of formula 7-1.

[0420]

[0421] b) Hydrogenating the compound of formula 7-1 to form the compound of formula 8.

[0422] In some embodiments, demethylating a compound of formula 7 to form a compound of formula 8 includes treating the compound of formula 7 with hydrobromic acid.

[0423] Some embodiments describe a method for preparing a compound of formula 8.

[0424]

[0425] The method includes:

[0426] a) The compound of Formula 6 or its pharmaceutically acceptable salt, solvate or hydrate.

[0427]

[0428] Coupled with Formula 5 or its pharmaceutically acceptable salt, solvate or hydrate to form a compound of Formula 7 or its pharmaceutically acceptable salt, solvate or hydrate;

[0429]

[0430] b) Demethylating a compound of formula 7 to form a compound of formula 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0431] In some embodiments, a compound of Formula 6 or a pharmaceutically acceptable salt, solvate, or hydrate thereof according to any method described herein

[0432]

[0433] It is prepared by treating isoquinoline-3-ol with a trifluoromethanesulfonylating agent.

[0434] In some embodiments, a compound of Formula 5 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, according to any of the methods described herein, is prepared by a method comprising the steps described below:

[0435] a) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 2 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0436]

[0437] b) Treat the ketone of Formula 2 or its pharmaceutically acceptable salt, solvate or hydrate with Grignard reagent and then remove water under acidic conditions to form the compound of Formula 3 or its pharmaceutically acceptable salt, solvate or hydrate.

[0438]

[0439] c) Hydrogenating a compound of formula 3 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 4 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0440]

[0441] d) Boronizing 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.

[0442] Some embodiments describe a method for preparing a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0443]

[0444]

[0445] The method includes:

[0446] a) Prepare a compound of formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0447]

[0448] It includes:

[0449] 1) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 2 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0450]

[0451] 2) Treat the ketone of Formula 2 or its pharmaceutically acceptable salt, solvate or hydrate with Grignard reagent and then remove water under acidic conditions to form the compound of Formula 3 or its pharmaceutically acceptable salt, solvate or hydrate.

[0452]

[0453] 3) Hydrogenating a compound of Formula 3 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 4 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0454]

[0455] 4) Boronize 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;

[0456] b) Prepare a compound of formula 6 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0457]

[0458] This includes treating isoquinoline-3-ol with a trifluoromethanesulfonylating agent; and

[0459] c) Couple a compound of Formula 6 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a compound of Formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 7 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0460]

[0461] d) Demethylating the compound of formula 7 to form the compound of formula 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0462] Steps a and b can be performed in any order or simultaneously in different reaction vessels.

[0463] In some embodiments of any of the methods described herein, the method further includes purifying the compound of Formula 8. In some embodiments, the purification includes crystallizing the compound of Formula 8.

[0464] The appropriate amount in any given situation will be obvious to those skilled in the art, or can be determined by routine experiments. The composition is typically applied topically to the affected area, i.e., to the skin area exhibiting clinical abnormalities.

[0465] Unless otherwise specified, all percentages are based on the weight percentage of the final composition prepared and total 100% by weight. Example

[0466] Although the invention has been described in considerable detail with reference to certain preferred embodiments, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and preferred versions contained herein. Various embodiments of the invention will be described with reference to the following non-limiting examples. The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0467] The following abbreviations may be used in experimental descriptions:

[0468]

[0469]

[0470] LCMS Standard Method A

[0471] LC conditions:

[0472] •UPLC analysis was performed on a Waters Acquity BEH C182x50mm 1.7m column at 50°C.

[0473] • Inject 0.5 μL of sample using the partial loop (needle overflow) injection mode.

[0474] The gradient used is:

[0475] • Mobile phase A: Water + 0.20% v / v formic acid

[0476] Mobile phase B: Acetonitrile + 0.15% v / v formic acid

[0477] • Time %A %B Flow Rate

[0478] 9551 ml / min

[0479] • 1.10 minutes 1991 ml / min

[0480] • 1.50 minutes 1991 ml / min

[0481] • UV detection is provided by the summed absorbance signal scanned at 40 Hz from 210 to 350 nm.

[0482] ·MS conditions:

[0483] • Instrument: Waters Acquity

[0484] · Serial Number: C07SQD043W

[0485] • Scanning mode: Alternating positive / negative electrical spray

[0486] • Scan range: 125-1000 amu

[0487] • Scan time: 105 msec

[0488] • Inter-scan delay: 20 msec

[0489] Other information

[0490] • All equipment was supplied by Waters Corp., Milford, Massachusetts.

[0491] • Run and analyze quality control samples at least once a day.

[0492] LCMS Standard Method B

[0493] • Mobile phase: A: Water (0.01% TFA) B: ACN (0.01% TFA)

[0494] • Gradient: Increases from 5% B to 95% B within 1.5 minutes.

[0495] • 95% B for 1.8 minutes, returning to 5% B within 0.01 minutes.

[0496] • Flow rate: 2.0 ml / min

[0497] ·Column: SunFire C18, 4.6X50mm, 3.5μm

[0498] Column temperature: 50℃

[0499] • Detection: UV (280, 140 nm) and MS (ESI, positive mode, 110 to 1000 amu) LCMS standard method C

[0500] • Mobile phase: A: Water (10mM NH4HCO3) B: ACN

[0501] • Gradient: Increase from 5%B to 95%B within 2 minutes.

[0502] • 95% B for 1.3 minutes, returning to 5% B within 0.01 minutes.

[0503] • Flow rate: 1.8 ml / min

[0504] ·Column: XBridge C18, 4.6X50mm, 3.5μm

[0505] Column temperature: 40℃

[0506] • Detection: UV (280, 140nm) and MS (ESI, positive mode, 110 to 1000 amu) Synthesis example

[0507] Those skilled in the art will recognize that if the substituents described herein are incompatible with the synthetic methods described herein, the substituents can be protected with suitable protecting groups that are stable under the reaction conditions. The protecting group can be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art. In some cases, the substituents can be specifically selected to be reactive under the reaction conditions used. In these cases, the reaction conditions transform the selected substituent into another substituent, which can be used as a desired substituent in the intermediate compound or the target compound.

[0508] The synthesis of compounds of the general formulas indicated in the reaction diagrams below, and their pharmaceutically acceptable salts, solvates, or hydrates, can be achieved as outlined below.

[0509] Abbreviations are as defined in the Examples section. Starting materials are commercially available or prepared from commercially available starting materials using methods known to those skilled in the art. Unless otherwise specified, all temperatures are given in degrees Celsius, all solvents are of the highest available purity, and all reactions are carried out under anhydrous conditions in an argon atmosphere.

[0510] The compounds described herein can be obtained using the synthetic procedures illustrated in the reaction diagram below or by utilizing the knowledge of a skilled organic chemist. The synthesis provided in this reaction diagram is applicable to the production of the compounds of the present invention having various substituents using suitable precursors, which are suitably protected, if necessary, to achieve compatibility with the reaction conditions outlined herein. If desired, subsequent deprotection yields compounds with generally disclosed properties. Although the reaction diagram is shown only for compounds of formula (I), it illustrates a method that can be used to prepare the compounds of the present invention.

[0511] Intermediates (compounds used in the preparation of the compounds of this invention) may also exist as salts, solvates, or hydrates. Therefore, for intermediates, the phrase "compound of formula (number)" refers to a compound having that structural formula or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0512] This invention also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. In some embodiments, one or more hydrogen atoms of the compound according to any of the embodiments described herein are replaced by deuterium. Those skilled in the art will know how to synthesize deuterated forms of compounds of formula (I).

[0513] As further described in the reaction diagram in this paper, there exists a general formula (I).

[0514]

[0515] Where R 1 -R 6 As defined in equation (I) above.

[0516] General reaction diagram:

[0517]

[0518] Compounds of formula (I) can be prepared by carbon-carbon formation, such as transition metal-catalyzed crosslinking. The reaction can be achieved by aqueous Suzuki-Miyaura coupling between an organoboronic acid or borate ester or potassium trifluoroborate and a halide or pseudohalide, such as trifluoromethanesulfonate, in the presence of a catalyst, such as Pd(0), Ni(0), Pd(II), or Ni(II) complexed with a ligand, including but not limited to PdCl2(dppf), Pd(PPh4)4, Pd(OAc)2, Pd2(dba)3, NiCl2(dppf), and NiCl2(PCy3)2. This coupling reaction is carried out in the presence of a weak base, such as K2CO3 and Na2CO3, NaHCO3, Cs2CO3, K3PO4, KF, etc., in a suitable solvent, such as toluene, dioxane, tetrahydrofuran, dimethoxyethane, and dimethylformamide. Suitable bases, ligands, solvents, and reaction conditions such as time, temperature, pressure, choice of gas (e.g., inert gas), reaction preparation, purification, etc., are known to those skilled in the art.

[0519] One aspect of the invention is a method for preparing a compound of formula (I). If any protecting group is used during the conversion, the final compound of formula (I) can be prepared by deprotecting its precursor. Suitable hydroxyl protecting groups known to those skilled in the art can be found in Greene (see above). One such example of demethylation can be using boron tribromide in a suitable organic solvent such as dichloromethane for about 0.5-72 hours at -78°C to +20°C, preferably about -20°C to 0°C. The progress of the reaction is monitored by thin-layer chromatography or high-performance liquid chromatography. When the reaction is complete, it is slowly quenched with a suitable solvent such as methanol at -78°C to +20°C, preferably -20°C to 10°C, and stirred continuously at room temperature for about 1-4 hours. Optionally, water is then added. Excess solvent is removed by distillation. The residue obtained herein is purified by typical normal-phase or reversed-phase chromatography and recrystallization in a suitable solvent.

[0520] Compounds of formula (I) can be obtained from a precursor of formula (I), such as formula (A) described herein, by hydrogenation in a suitable organic solvent such as methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, etc., in the presence of a suitable catalyst, such as 5 or 10% carbon-supported palladium, under a hydrogen atmosphere and at ambient temperature.

[0521] General intermediate 1: 3,5-diacetoxy-4-isopropylbenzoic acid

[0522]

[0523] Step 1. Triethylamine salt of 3,5-dihydroxy-4-isopropylbenzoate

[0524] 40 g (0.26 mol, 1.0 equivalent) of 3,5-dihydroxybenzoic acid was placed in a 1 L three-necked round-bottom flask (RBF), and then concentrated sulfuric acid (160 mL, 4 times the volume) was added at room temperature. Water (20 mL, 0.5 times the volume) was added to the mixture while stirring. The suspension was heated to 60–65 °C, and then 2-propanol (25.0 mL, 0.32 mol, 1.25 equivalent) was added dropwise to the reaction over a period of approximately 10 minutes. The clear reaction mixture was stirred at 60–65 °C for 4–8 hours and then cooled to room temperature (approximately 20 °C). The reaction mixture was slowly transferred to a second 3 L three-necked round-bottom flask (RBF) equipped with a top stirrer and placed in an aqueous sodium hydroxide solution at 10 °C. The temperature of the aqueous sodium hydroxide solution in the second RBF was maintained between 10–30 °C. The reaction mixture flask was rinsed with water to ensure complete transfer. Tert-butyl methyl ether (TBME, 320 mL, 8 times the volume) was added, and the mixture was heated to 20–25 °C and stirred for approximately 30 minutes. The two layers were separated, and the aqueous layer was extracted with TBME (2 x 160 mL, 4 times the volume). A potassium sodium tartrate solution (1 N, 160 mL, 4 times the volume) was added to the combined TBME layers, and the mixture was stirred at 20–25 °C for at least 40 minutes. 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 times the volume) was added to the TBME layer, and then triethylamine (36.2 mL, 1.0 equivalent) was added dropwise to the mixture (TBME layer + 2-propanol solution) over approximately 15 minutes at 20–25 °C, and the mixture was stirred for at least 2.5 hours. The product was separated by filtration, and the filter cake was washed with TBME. The title product was dried overnight in an oven at 40-50°C. HPLC purity: 98%.

[0525] Step 2.3,5-Diacetoxy-4-isopropylbenzoic acid

[0526] 50.0 g (0.17 mol, 1.0 equivalent) of triethylamine 3,5-dihydroxy-4-isopropylbenzoate was placed in a 1 L three-necked round-bottom flask (RBF), and then 250 mL of tert-butyl methyl ether (TBME) and 125 mL of 2-methyltetrahydrofuran (2Me-THF) were added at room temperature. Acetic anhydride (38.1 mL, 0.4 mol, 2.4 equivalent) and triethylamine (46.9 mL, 0.34 mol, 2.0 equivalent) were added to the mixture with stirring. The suspension was heated to 60–65 °C and stirred for 6–20 hours, or until the reaction was considered complete by 3-minute rapid liquid chromatography (LC). The mixture was cooled to room temperature (approximately 20 °C), and 175 mL of 6N hydrochloric acid (6N HCl) was slowly added while maintaining the temperature of the reaction mixture between 20–30 °C, and the mixture was stirred for at least 15 minutes. Separate the two layers. Wash the organic layer with water (100 mL) and evaporate under reduced pressure until approximately 3.0 times its volume remains in the flask. Add toluene (200 mL) and evaporate until approximately 2 times its volume remains in the flask. Add toluene (75 mL), heat the mixture to 75-80 °C and stir for at least 30 minutes. Cool the product suspension to room temperature (approximately 20 °C), add cyclohexane (200 mL) and stir at 15-20 °C for at least 3 hours. Separate the product by filtration and wash the filter cake with cyclohexane. Dry the title product in an oven at 40-50 °C overnight. 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 13.07–13.40 (br.s, 1H), 7.54 (s, 2H), 3.07–3.23 (Sep., 1H), 2.35 (s, 6H), 1.18 (d, J = 7Hz, 6H); HPLC purity: 97%.

[0527] General intermediate 2: 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dihexylpentaborane

[0528]

[0529] The title compound was prepared according to the method reported in the literature (Xuebin Liao, Levi M. Stanley and John F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2088–2091).

[0530] General intermediate 3: 5-bromo-2-(tert-butyl)phenol

[0531]

[0532] The title compound was prepared by the method reported in U.S. Patent No. 5,919,970.

[0533] General intermediate 4: 4-Cyclopentyl-3,5-bis(methoxymethoxy)phenyl trifluoromethanesulfonate

[0534] Step 1

[0535] Methoxymethyl chloride (5.96 mL, 78 mmol) was added to a stirred solution of 4-bromo-3,5-dihydroxybenzoic acid (4.06 g, 17.42 mmol) and N,N-diisopropylethylamine (17.65 mL, 101 mmol) in DCM (45.9 mL) at 0 °C. The reaction mixture was allowed to heat to rt and stirred for 30 min, then quenched with a saturated aqueous solution of 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 dehydrated on sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with 80 g of Isco silica gel and eluted with 10–100% EtOAc / heptane (60 mL / min) to give the desired compound as a colorless amorphous solid. 1 ¹H NMR (400MHz, chloroform-d) δppm 7.54(s, 2H), 5.50(s, 2H), 5.33(s, 4H), 3.57(s, 3H), 3.55(s, 6H); LCMS Method A: t R = 0.84 minutes, 92%; MS(ESI): m / z no definite quality.

[0536] Step 2

[0537] DIBAL-H (1M, in hexane, 8.67mL, 8.67mmol) was added to a stirred solution of 4-bromo-3,5-bis(methoxymethoxy)benzoate methoxymethyl ester (1.055g, 2.89mmol) in dichloromethane (DCM, 20.64mL) at -78°C. The reaction mixture was heated to 0°C and stirred for 30 minutes, then repeatedly quenched with ethyl acetate (1mL) and MeOH (4mL). A saturated aqueous solution of potassium sodium tartrate (40mL) was added, and the resulting mixture was stirred vigorously overnight. The layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 50mL). The combined organic extracts were dehydrated on sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography using a 24g Isco silica gel column and eluted with 10-100% ethyl acetate / heptane (35mL / min) to give the desired product as a colorless oil. 1 ¹H NMR (400MHz, chloroform-d) δppm 6.87(s, 2H), 5.28(s, 4H), 4.66(s, 2H), 3.54(s, 6H); LCMS Method A: t R= 0.64 minutes, 94%; MS(ESI): m / z no definite quality.

[0538] Step 3

[0539] A solution of (4-bromo-3,5-bis(methoxymethoxy)phenyl)methanol (490 mg, 1.595 mmol) and manganese dioxide (1387 mg, 15.95 mmol) in dichloromethane (DCM, 31.908 mL) was stirred at rt for 12 hours. The mixture was diluted with diethyl ether, filtered through a diatomaceous earth mat, and washed with diethyl ether. The filtrate was concentrated to give the desired compound as a colorless amorphous solid. LCMS Method A: t R = 0.78 minutes, 100%; MS(ESI): m / z 307.35 (M+2) +

[0540] Step 4

[0541] A sealed tube was loaded 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-diaxopentane (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 overnight at 100 °C, 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 dehydrated on sodium sulfate, filtered, and concentrated. The residue was purified using a 12 g Isco silica gel column and eluted with 10-100% EtOAc / heptane (30 mL / min) to obtain the desired product as a bright yellow amorphous solid. 1 ¹H NMR (400MHz, chloroform-d) δppm 9.92 (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), 2.57 (ddd, J = 10, 5, 2Hz, 2H), 2.04 (t, J = 7Hz, 2H); LCMS Method A: t R = 0.94 minutes, 98%; MS(ESI): m / z 293.5(M+H) + Step 5

[0542] 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 benzaldehyde was depleted as measured by NMR. The reaction mixture was cooled to rt and treated dropwise with triethylamine (481 μl, 3.45 mmol). After stirring at rt for 5 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 x 10 mL). The organic phase was washed with water (10 mL), dehydrated on sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (3451 μl) and stirred for 17.5 h under a hydrogen atmosphere (40 psi) in the presence of 10% carbon-supported palladium (22.93 mg, 0.216 mmol). LC-MS revealed that approximately 28% was converted to the desired product and approximately 59% was the starting material of the residue. Additional carbon-supported palladium (22.93 mg, 0.216 mmol) was added, and the reaction was repeated for another 6.5 h under a hydrogen atmosphere (40 psi) (24 h in 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 2N H₂SO₄ (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) and saturated sodium bicarbonate solution (10 mL), dehydrated on sodium sulfate, filtered, and concentrated. The residue was purified by 12 g Isco silica gel column chromatography and eluted with 0-100% EtOAc / heptane (30 mL / min) to give the desired product as a colorless amorphous solid. 1 ¹H NMR (400MHz, chloroform-d) δppm 9.89(s, 1H), 7.30(s, 2H), 5.26(s, 4H), 3.77(m, 1H), 3.52(s, 6H), 1.79–2.04(m, 6H), 1.63–1.76(m, 2H); LCMS Method A: t R = 1.01 minutes, 92%; MS(ESI): m / z 295.5(M+H) +

[0543] Step 6

[0544] A solution of 4-cyclopentyl-3,5-bis(methoxymethoxy)benzaldehyde (100 mg, 0.340 mmol) in anhydrous dichloromethane (DCM, 3.331 mL) in 833 μL was slowly added to anhydrous dichloromethane (DCM, 3.331 mL). The reaction mixture was heated to rt and then 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 solution and 10% aqueous sodium thiosulfate solution (10 mL), dehydrated on sodium sulfate, filtered, and concentrated.

[0545] The residue was redissolved in methanol (0.67 mL) and stirred at rt for 3 h with 10% sodium hydroxide aqueous solution (0.679 mL, 16.99 mmol). The pH was adjusted to 2 with 1N HCl, and the solution was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dehydrated on sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with 4 g of Isco silica gel and eluted with 0–100% EtOAc / heptane (18 mL / min) to give the desired compound as a yellow amorphous solid. 1 ¹H NMR (400MHz, chloroform-d) δppm 6.35(s, 2H), 5.15(s, 4H), 4.63(s, 1H), 3.59(m, 1H), 3.50(s, 6H), 1.72–1.98(m, 6H), 1.61–1.72(m, 2H); LCMS Method A: t R = 0.89 minutes, 95%; MS(ESI): m / z 283.5(M+H) + Step 7

[0546] Triethylamine (24.78 μl, 0.178 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (47.6 mg, 0.133 mmol) were added to a solution of 4-cyclopentyl-3,5-bis(methoxymethoxy)phenol (25.1 mg, 0.089 mmol) in N,N-dimethylformamide (DMF, 323 μl). The mixture was stirred at rt for 1 h. After 1 h, the reaction progress was analyzed by LCMS, showing that the starting material was completely consumed and converted to the product. Next, the reaction mixture was concentrated, and the crude product was diluted with Et2O (2.5 mL), washed with water (3 x 5 mL) and saturated sodium chloride aqueous solution (5 mL), dehydrated on sodium sulfate, filtered, and concentrated. The residue was purified by 4 g ISCO silica gel column chromatography (eluting with 5-100% EtOAc / heptane) to give the desired product as a colorless oil. 1¹H NMR (400MHz, chloroform-d) δppm 6.75 (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 minutes, 100%; MS(ESI): m / z 413.4 (MH) -

[0547] Example 1A 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol Method A

[0548]

[0549] Step 1

[0550] TEA (0.864 mL, 6.20 mmol) was added to a solution of isoquinoline-3-ol (300 mg, 2.067 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (923 mg, 2.58 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 2 hours, diluted with water (25 mL), and extracted with DCM (30 mL x 2). The DCM solutions were combined, washed with brine, dried, and concentrated. The crude material was purified by preparative TLC (eluting with petroleum ether / ethyl acetate = 50 / 1) to give isoquinoline-3-yltrifluoromethanesulfonate (350 mg, 1.136 mmol, 55.0% yield) as a colorless liquid. LCMS Method A: t R = 1.77 minutes, 100%; MS: m / z 277.8 (M+H) +

[0551] Step 2

[0552] In a nitrogen atmosphere, Na₂CO₃ (76 mg, 0.721 mmol) was added to a mixture of isoquinoline-3-yltrifluoromethanesulfonate (100 mg, 0.361 mmol) and 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (133 mg, 0.433 mmol) in toluene (2 mL) and water (0.500 mL). The reaction mixture was stirred at 80 °C for 5 h, cooled, and purified by reversed-phase chromatography (CombiFlash 50 g reversed-phase C18 column; gradient: 20–50% MeOH in water containing 0.01% TFA over 30 min). The fractions were combined and concentrated. The residue was recrystallized in water and dried by lyophilization to give 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (90 mg, 0.190 mmol, 52.8% yield) as a white solid. LCMS Method A: t R = 1.81 minutes, 61%; MS: m / z 307.9 (M+H) + Step 3a, Method A

[0553] BBr3 (0.138 mL, 1.464 mmol) was added to a solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (90 mg, 0.293 mmol) in dichloromethane (DCM, 2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and purified by reversed-phase chromatography (CombiFlash 50 g reversed-phase C18 column; sample loaded with MeOH; eluted with 20–50% MeOH / water and 10 mM TFA over 30 min s). Suitable fractions containing the product were combined, recrystallized in water, and dried by lyophilization to give the title compound 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (80 mg, 0.272 mmol, 93% yield) as a yellow solid. 1 LCMS

[0554] Method A: t R = 1.79 minutes, 100%; MS: m / z 280.2 (M+H) +

[0555] Step 3b, Method B

[0556]

[0557] Step 3b-1

[0558] BBr3 (5.84 mL, 61.8 mmol) was added to a solution of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline (3.8 g, 12.36 mmol) in dichloromethane (DCM, 2 mL). The reaction mixture was stirred at 0 °C for 1 h. The solution was concentrated under vacuum, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organic phase was washed with brine, dehydrated on NaSO4, and concentrated to give the desired compound, which could be used directly without further purification. LCMS Method B: t R = 1.88 minutes, 53%; MS(ESI): m / z 359.5 (M+2) +

[0559] Step 3b-2

[0560] 10% Pd / C (400 mg) was added to a solution of 3.4 g (9.49 mmol) of 4-bromo-2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in methanol (30 mL). The mixture was stirred at room temperature for 1 h under H2 atmosphere. The reaction mixture was filtered and concentrated under vacuum to give 2.7 g of crude product, which was purified by reversed-phase chromatography (C18 column; mobile phase, A: 10 mM MTFA aqueous solution; B: MeOH; gradient: 10 min, 9-71% B) to give 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol as a gray solid. 1 H NMR(500MHz,MeOD)δ9.26(s,1H),8.10(d,1H),8.06(s,1H),7.96(d,1H),7.7 9(t,1H),7.66(t,1H),6.97(s,2H),3.59(sep.,1H),1.37(d,6H); LCMS method B: t R = 2.08 minutes, 98.4%; MS(ESI): m / z 280.0(M+H) +

[0561] Example 1B 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol Method B

[0562]

[0563] Phase 0: Isoquinoline-3-yltrifluoromethanesulfonate

[0564] DCM (6 volumes) was loaded into a reactor, followed by the addition of isoquinoline-3-ol (1.0 equivalent), Et3N (1.45 equivalent), and N-benzylmethylbis-trifluoromethanesulfonylimide (1.1 equivalent). The reaction mixture was stirred at 20–35 °C for 2–3 h. After stirring, water (10 volumes) was added to the reaction mixture, and the mixture was stirred for 15 min. The organic and aqueous layers were separated. The organic layer was washed with water (10 volumes). The organic and aqueous layers were separated again, and the organic layer was dehydrated on Na2SO4. The organic layer was then filtered to remove Na2SO4 and concentrated under reduced pressure at 35–40 °C to obtain a crude product as a black liquid. The crude product was loaded into a reactor. Ethyl acetate (6.0 volumes) was added, followed by char (0.1 w / w). The contents were heated to 55–60 °C for 30 min, then cooled to 20–35 °C. The contents were filtered through diatomaceous earth and washed with ethyl acetate (5 volumes). The combined organic layers were concentrated under reduced pressure at 40-45°C to obtain a dark brown liquid. This dark brown liquid was loaded into a reactor, and heptane (20 volumes) was added. The contents were heated to 60-65°C for 1 hour. The contents were filtered through a layer of diatomaceous earth (lot-2) at 60-65°C and washed with heptane (5 volumes). The combined heptane layers were concentrated under reduced pressure at 40-45°C to give the desired product compound 6 as a light yellow liquid, which solidifies at 2-8°C. Stage 1: 1-(2,6-Dimethoxyphenyl)ethyl ketone

[0565] 2,6-Dihydroxyacetophenone (1.0 equivalent) and potassium carbonate (5.0 equivalent) were transferred to acetone (14 volumes) at 20-35 °C. Dimethyl sulfate (2.5 equivalent) was added to the inclusions at the same temperature. The inclusions were heated to 60-65 °C (reflux) for 2-3 h, monitored by IPC-HPLC. The reaction mixture was cooled to 20-35 °C, the salt was filtered off, and the mixture was washed with acetone (5 volumes). The combined organic layers were concentrated under reduced pressure to give a crude liquid product. Water (30 volumes) was added to the crude material, and the mixture was stirred at 20-35 °C for 1 h. The resulting solid was filtered off and washed with water (5 volumes), and the wet filter cake was transferred to a round-bottom flask. Saturated NaHCO3 (10 volumes) was added, and the inclusions were stirred for 1 h. The inclusions were filtered to remove the solid, and the solid was washed with water (lot-3, 5 volumes) to give product compound 2 as a grayish-white solid. The solid was then dried at 40-45°C until the KF reading showed <1%. Stage 2: 1,3-Dimethoxy-2-(prop-1-en-2-yl)benzene

[0566] MeMgBr (1.4 M, 1.5 equivalents) was added to a round-bottom flask under nitrogen atmosphere and at 20–35 °C. The contents were cooled to 0–10 °C. Then, a solution of compound 2 (1.0 equivalents) dissolved in THF (10 volumes) was added to the cooled Grignard solution while maintaining the temperature at 0–10 °C. The reaction mixture was heated to room temperature and stirred for 2 h. After 2 h, the reaction mixture was cooled to 0–10 °C. 4 N HCl solution was added, and the contents were allowed to heat to room temperature while stirring was continued for 2 h. Subsequently, ethyl acetate (7 volumes) was added, and the contents were stirred for 30 min. Layer separation was allowed, and the aqueous layer was extracted with ethyl acetate (3.5 volumes). The organic fractions were combined and washed with water (10 volumes). Layer separation was allowed, the aqueous layer was discarded, and the organic layer was washed again with water (10 volumes). Layer separation was allowed, the aqueous layer was discarded, and the organic layer was washed with saturated NaHCO3 (10 volumes). Layer separation was allowed again, the saturated NaHCO3 layer was discarded, and the organic layer was washed one last time with water (10 volumes). The organic layer was dehydrated on Na2SO4. After dehydration, sodium sulfate was filtered off, and the solvent was removed under reduced pressure at 40-45°C to obtain 1,3-dimethoxy-2-(prop-1-en-2-yl)benzene compound 3 as a liquid crude product, which was used as is in the next stage.

[0567] Stage 3: 2-Isopropyl-1,3-Dimethoxybenzene

[0568] Ethyl acetate (10 volumes) was charged into the reactor, followed by the addition of 1,3-dimethoxy-2-(prop-1-en-2-yl)benzene (1.0 equivalent). The contents were stirred at 25–35 °C until a clear solution was obtained. 10% Pd / C (0.1 w / w) was added to the reactor, and the contents were purified under vacuum and then placed under H2. The contents were then stirred at 25–35 °C for 4 h. The reaction mixture was then filtered through diatomaceous earth and washed with ethyl acetate (5 volumes). The combined organic fractions were reduced in volume under vacuum at 40–45 °C to give compound 4, 2-isopropyl-1,3-dimethoxybenzene, as a crude liquid, which was used as is in the next stage.

[0569] Stage 4: 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[0570] THF (7 volumes) was charged into the reactor and degassed with N2 for 30 minutes. Iridium catalyst (0.0081 equivalents), catalyst ligand (0.017 equivalents), bis-pinacol diborone (1.0 equivalent), and 2-isopropyl-1,3-dimethoxybenzene (1.0 equivalent) were added sequentially to the reactor. The reaction mixture was refluxed at 80°C for 60 h. The contents were filtered through diatomaceous earth (0.5 w / w) and washed with ethyl acetate (2.5 volumes). The combined organic layers were reduced in volume under vacuum at 40–45°C to give a crude product as a viscous black syrup, which was crystallized from hexane (5 volumes) to give compound 5, 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane, as a light brown solid.

[0571] Stage 5: 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline

[0572] 1,4-Dioxane (8 volumes) and water (2 volumes) were charged into the reactor and degassed for 20 minutes. Compound 6 (1.3 equivalents) was charged into the reactor and degassed for 10 minutes. 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (compound 5, stage 4 product, 1.0 equivalent) was added, and the contents were further degassed for 10 minutes, followed by the addition of palladium catalyst (0.1 equivalents). The contents were further degassed for 15 minutes, and then heated to 85-89°C for 3 hours. The reaction mixture was cooled to 20-35°C, and water (20 volumes) was charged into the reactor. The contents were stirred for 1-2 hours. The contents were filtered through a Buchner funnel and washed with water (5 volumes) to give a crude black solid. The solid was transferred to ethyl acetate (10 volumes) and charged into the reactor. 0.5 w / w of charcoal was added to the reactor, and the contents were heated to 60-70 °C for 1 h. The contents were cooled to 20-35 °C, filtered through diatomaceous earth, and the solid was washed with ethyl acetate (2.5 v / w). The combined organic layers were concentrated under reduced pressure at 40-45 °C to give a viscous liquid. Heptane (1.0 v / w) was added to the liquid and distilled. Heptane (0.5 v / w) was added and distilled again to give compound 7, 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline, as a brown solid.

[0573] Stage 6: 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol

[0574] 2-Isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol compound 7 (1.0 equivalent) was loaded into a reactor, and 33% HBr (15 volumes) in acetic acid was added at 20-35°C. The contents were heated to 95-100°C for 24 h. The contents were then transferred to a second reactor containing water (25 volumes) and stirred at 20-35°C for 2 h. The resulting salt was filtered through a Buchner funnel and washed with water (5 volumes). The wet salt filter cake was added to the reactor. Ethyl acetate (10 volumes) was added to the reactor, followed by a saturated NaHCO3 solution (10 volumes). The contents were stirred at 20-35°C for 30 min. Stirring was stopped and layer separation was allowed. The aqueous layer was discarded, and the organic layer was washed with water (10 volumes). Phase separation was allowed, the aqueous layer was removed, and the organic layer was dehydrated on Na2SO4. Sodium sulfate was filtered off, and the organic layer was washed with ethyl acetate (5 volumes). The combined organic layers were reduced in volume under vacuum at 40-45°C to obtain a crude free base as a dark black solid. The crude free base was loaded into a reactor, and then ethyl acetate (6.7 v / w), silica (1.0 w / w), and finally char (1.0 w / w) were added at 20-35°C. The contents were heated to 60-70°C for 1 h, and then cooled to 20-35°C. The contents were filtered through diatomaceous earth (0.5 w / w) and washed with ethyl acetate (3.35 v / w). The combined organic layers were reduced in volume by distillation to obtain a colloidal solid. Heptane (1.34 v / w) was loaded into the reactor, and the contents were distilled again. Heptane (1.34 v / w) was loaded into the reactor again, and the contents were distilled to obtain a light brown solid. 1,4-Dioxane (10 volumes), silica (1.0 w / w), and char (1.0 w / w; Norret CGP) were charged into a reactor at 20–35 °C. The contents were heated to 60–70 °C for 1 h and then cooled to 20–35 °C. The contents were filtered through diatomaceous earth (0.5 w / w) and washed with 1,4-Dioxane (lot-2, 3 x 5 volumes). The combined organic layers were reduced in volume under vacuum at 40–45 °C to give 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, the compound of formula 8, as a grayish-white solid.

[0575] Stage 7: 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol

[0576] Compound 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol of Formula 8 was charged into a reactor, followed by the addition of isopropanol at 20-35°C. The heterogeneous mixture was heated to 65-70°C until it became a clear solution, and then heptane (16 volumes) was slowly added over a period of 20-30 minutes at 65-70°C. The reaction mixture was maintained at 65-70°C for 1 hour, then cooled to 0-5°C and maintained for 1 hour. The solid was filtered off at 20-35°C and washed with heptane (2 volumes) to give 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol as a grayish-white solid.

[0577] Example 2 3-(3-aminopropoxy)-2-isopropyl-5-(isoquinoline-3-yl)phenol, bis-trifluoroacetate

[0578] A 60% sodium hydrosulfite oil dispersion (35 mg, 0.875 mmol) was added to a solution of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (185 mg, 0.662 mmol) in N,N-dimethylformamide (DMF, 4 mL) under room temperature and magnetic stirring. After hydrogen production ceased, tert-butyl (3-bromopropyl)carbamate (178 mg, 0.748 mmol) was added. The resulting mixture was heated overnight at 50 °C. LCMS revealed the presence of a mixture of starting material, monoalkylated and dialkylated products (approximately 1:1:1). The mixture was cooled, quenched with water (25 mL), and filtered to collect a grayish-green solid. The crude material was dissolved in MeOH and purified by Gilson prep-HPLC [acidic Luna on an Agilent Eclipse plus C18 column (5 μm, 30 x 50 mm), gradient 30–60% acetonitrile / water and 0.1% TFA, 47 mL / min flow rate, 14 min run time, fractions collected from 3.5 min to 4.2 min]. The fractions will be analyzed on LCMS at m / z = 437.5 (M+1). + The residues from the evaporation of the corresponding fractions were dissolved in DCM (5 mL) and treated overnight with TFA (1 mL) at rt. The reaction mixture was concentrated to dryness under reduced pressure to give the desired compound as a yellow amorphous solid. 1H NMR(400MHz,METHANOL-d4)ppm 9.76(s,1H),8.61(s,1H),8.48(d,J=8Hz,1H),8.29(d,J=8Hz,1H),8.19(t,J=7Hz,1H),7.97(t,J=7Hz,1H),6.98-7.11(m,2H),4 .26(t,J=6Hz,2H),3.69(dt,J=14,7Hz,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%.

[0579] Example 3: N-(2-aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide

[0580] Step 1

[0581] A mixture of 6-bromoisoquinoline-3(2H)-one (5 g, 22.32 mmol), PdCl2(dppf) (1.633 g, 2.232 mmol), and Et3N (6.22 mL, 44.6 mmol) in methanol (10 mL) was placed in a pressure vessel. The vessel was purged three times with nitrogen, filled with carbon monoxide at 300 kPa, 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-carboxylic acid as a yellow solid, which was used directly in the next step. LCMS: m / z = 204.0, t R =1.19min.

[0582] Step 2

[0583] In a sealed tube, a solution of methyl 3-oxo-2,3-dihydroisoquinoline-6-carboxylic acid (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. The mixture was cooled and poured into ice-water (20 mL). The solid was filtered and dissolved in ethyl acetate (30 mL). The filtrate was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with water / salt water, dehydrated on Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (30 g) using petroleum ether / dichloromethane / methanol (1 / 1 / 0.05) to give methyl 3-chloroisoquinoline-6-carboxylic acid (130 mg, 0.557 mmol, 22.64% yield) as a yellow solid. 1 H NMR (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 =1.57min.

[0584] Step 3

[0585] 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-dioxane (145 mg, 0.474 mmol), Na₂CO₃ (143 mg, 1.354 mmol), and PdCl₂(dppf) (33.0 mg, 0.045 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) was stirred at 100 °C for 16 h under nitrogen. 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.

[0586] Step 4

[0587] A mixture of methyl 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylic acid (150 mg, 0.410 mmol) and NaOH (49.3 mg, 1.231 mmol) in THF (4 mL) and water (4.00 mL) was stirred at rt for 16 hr under nitrogen, 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 under vacuum to give 100 mg of 3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carboxylic acid as a pale yellow solid. The crude product was used for the next step. LCMS: m / z = 351.9 (M+1) + ,t R =1.72min, 82%.

[0588] Step 5

[0589] 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 rt for 1 h under nitrogen. Tert-butyl (2-aminoethyl)carbamate (54.7 mg, 0.341 mmol) was added. The reaction mixture was stirred at 25 °C for 12 h, quenched with ice water (10 mL), and extracted with ethyl acetate (15 mL x 5). The combined organic phases were washed with water / brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by preparative HPLC (Gemini C18 150 x 21.2 mm, 5 μm, single injection, mobile phase: ACN-H2O, gradient: 10-60%) to obtain tert-butyl (2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carbamate)ethyl)carbamate as a light yellow solid (70 mg, 0.135 mmol, 47.3% yield). 1H NMR (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%.

[0590] Step 6

[0591] Under a nitrogen atmosphere, BBr3 (0.575 mL, 6.08 mmol) was added to a stirred solution of (60 mg, 0.122 mmol) of tert-butyl (2-(3-(4-isopropyl-3,5-dimethoxyphenyl)isoquinoline-6-carbamate)ethyl)carbamate in 10 mL of DCM at -30 °C. The reaction mixture was stirred at 25 °C for 3 h, poured onto ice, neutralized with NaOH (1N) until pH 7, and extracted with EtOAc (10 mL x 5). The combined organic extracts were washed with brine, dehydrated on Na2SO4, and concentrated. The yellow residue was purified by preparative HPLC (Gemini C18150 x 21.2 mm 5 μm, mobile phase: ACN-H2O and 0.1% TFA, gradient: 10-30%) to obtain N-(2-aminoethyl)-3-(3,5-dihydroxy-4-isopropylphenyl)isoquinoline-6-carboxamide (30 mg, 0.080 mmol, 66.2% yield) as a yellow solid. 1 HNMR(400MHz,DMSO)δppm 9.42(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) ,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%.

[0592] Example 4: Crystal form screening of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol

[0593] A crystal form screening was performed on 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol. The screening consisted of approximately 160 experiments using 60 solvent systems, and identified 16 different crystal forms, including: non-solventized forms (group A); two hydrated forms (groups M and H); eight stable organic solvates; and five speculative organic solvates that are unstable under environmental conditions and transform into other forms.

[0594] Of the approximately 160 experiments conducted, 83 produced solids for analysis. Of these, 39 produced a non-solventized form (also known as form 2) from group A; 22 produced amorphous materials; only 5 produced hydrates (3 from group H and 2 from group M); and the remaining 17 produced one of the remaining 13 observed forms. These results are visually presented in Tables 1 and 2 below.

[0595] Table 1: Products of slurry ripening, cooling and evaporation crystallization

[0596]

[0597]

[0598]

[0599] 1 Color change; 2 There were not enough solids available for analysis; 3 Purified off-white solids: A = non-solvent; B = MeCN / water solvate; C = acetone solvate; D = DMF solvate; E = 1,4-dioxane / water solvate; F = butanone solvate (specified); G = THF / water solvate; H = hydrate; I = EtOAc solvate (specified); J = DMC solvate (specified); K = DMSO solvate (specified); L = 1-butanol solvate; M = hydrate (when scaled up); N = THF solvate; O = THF solvate (specified); P = MTBE solvate; NS = no solids; NE = not experimental.

[0600] Table 2: Products of Solvent / Antisolvent Crystallization

[0601] # solvent antisolvent Group 1 MeOH Diethyl ether NS 2 MeOH Isopropyl ether NS 3 MeOH MTBE NS 4 IPA Diethyl ether amorphous 5 IPA Isopropyl ether NS 6 IPA MTBE NS 7 EtOAc Diethyl ether NS 8 EtOAc MTBE NS 9 EtOAc pentane A 10 DMSO water K 11 DMSO MTBE NS 12 DMSO Toluene NS

[0602] A = non-solvent; K = DMSO solvate (specified); NS = no solids

[0603] Some embodiments describe a method for preparing a compound of formula (I), the method comprising reacting a compound of formula (A) or a salt thereof.

[0604]

[0605] in,

[0606] R 3 Choose any C to replace it. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halogen, cyano, -C(O)OR 8 -NR 9 R 10 -S(O)2NR 9 R 10 -C(O)R 11 -OR 12 -S(O) n R 13 The group consisting of heterocyclic rings with optional substitutions;

[0607] R 8 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0608] R 9 and R 10 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings;

[0609] R 11 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -NR 9 R 10 and -OR 12 The group formed;

[0610] R12 and R 13 Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups;

[0611] R 6 Selected from H, halogen, hydroxyl, alkoxy, and optionally substituted C 1-6 Alkyl, haloalkyl; optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 alkyl;

[0612] n is an integer with a value of 0, 1, or 2;

[0613] s is an integer with a value of 0, 1, or 2;

[0614] t is an integer with values ​​from 0 to 6;

[0615] R 5c Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 aryl and -C 1-6 The group consisting of alkyl aryl groups;

[0616] R 14 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0617] R 15 and R 16 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups, or R 15 and R 16 Together with the nitrogen to which they are attached, they form 5-7 cyclic saturated or unsaturated rings;

[0618] R 4c Choose freely from H, halogen, cyano, and optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -(CR 18 R 19 ) t COOR 8 、-(CR 18 R 19 ) t OC(O)R 8 、-(CR 18 R 19 ) t NR 9 R 10 、-(CR 18 R 19 ) t C(O)NR 9 R 10 、-(CR 18 R 19 ) t NR 9 C(O)R 8 、-(CR 18 R 19 ) t S(O)2NR 9 R 10 、-(CR 18 R 19 ) t COR 11 、-(CR 18 R 19 ) t CH(O), -(CR) 18 R 19 ) t OR 12 、-(CR 18 R 19 ) t S(O) s R 13 Optionally substituted heterocycles and optionally substituted heterocycles C 1-6 The group consisting of alkyl groups; and

[0619] R 18 and R 19 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0620] Boron tribromide is dissolved in a suitable organic solvent, such as dichloromethane, and the mixture is stirred for a sufficient time and temperature. Then, a suitable alcohol, such as CH3OH, is added to obtain R. 6 It is a compound of formula (I) containing hydrogen.

[0621] Another aspect of the present invention is a method for preparing a compound of formula (I), the method comprising reacting a compound of formula (B) or a salt thereof.

[0622]

[0623] in,

[0624] R 3 Choose any C to replace it. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halogen, cyano, -C(O)OR 8 -NR 9 R 10 -S(O)2NR 9 R 10 -C(O)R 11 -OR 12 -S(O) n R 13 The group consisting of heterocyclic rings with optional substitutions;

[0625] R 8 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0626] R 9 and R 10 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 The group consisting of alkyl groups, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings;

[0627] R 11 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -NR 9 R 10 and -OR 12 The group formed;

[0628] R 12 and R 13 Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups;

[0629] n is an integer with a value of 0, 1, or 2;

[0630] s is an integer with a value of 0, 1, or 2;

[0631] t is an integer with values ​​from 0 to 6;

[0632] R 5b Choose from free H, halogen, and C with optional substitution. 1-6 Alkyl, -C(O)OR 14 -C(O)NR 15 R 16 aryl and -C 1-6 The group consisting of alkyl aryl groups;

[0633] R 14 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0634] R 15 and R 16 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups, or R 15 and R 16 Together with the nitrogen to which they are attached, they form 5-7 cyclic saturated or unsaturated rings;

[0635] R 4b Selected from H, halogen, cyano, or optionally substituted C 1-6Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -(CR 18 R 19 ) t COOR 8 、-(CR 18 R 19 ) t OC(O)R 8 、-(CR 18 R 19 ) t NR 9 R 10 、-(CR 18 R 19 ) t C(O)NR 9 R 10 、-(CR 18 R 19 ) t NR 9 C(O)R 8 、-(CR 18 R 19 ) t S(O)2NR 9 R 10 、-(CR 18 R 19 ) t COR 11 、-(CR 18 R 19 ) t CH(O), -(CR) 18 R 19 ) t OR 12 、-(CR 18 R 19 ) t S(O) s R 13 Optionally substituted heterocycles and optionally substituted heterocycles C 1-6 Alkyl; and

[0636] R 18 and R 19 Each of them is independently chosen from H and arbitrarily substituted with C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0637] Under hydrogenation conditions, for example with 5-10% carbon-supported palladium, in a hydrogen atmosphere and at ambient temperature, treatment in a suitable organic solvent such as methanol, ethanol, isopropanol, ethyl acetate, or tetrahydrofuran, yields R. 6 It is a compound of hydrogen with formula (I).

[0638] Another aspect of the present invention is a novel intermediate compound of formula (II).

[0639]

[0640] in

[0641] R 1 and R 2 Each of them is independently selected from OH, OR 7 A group consisting of H and R, provided that R is a given. 1 and R 2 At least one of them is -OH or -OR 7 ;

[0642] R 7 Independently select any freely arbitrarily substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, aryl C 1-6 The group consisting of alkyl and acyl groups;

[0643] R 3 Choose any C to replace it. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 4-6 Cycloalkenyl, halogen, cyano, -C(O)OR 8 -NR 9 R 10 -S(O)2NR 9 R 10 -C(O)R 11 -OR 12 -S(O) n R 13 The group consisting of heterocyclic rings with optional substitutions;

[0644] R 8 Choose H freely and C can be arbitrarily substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 Groups composed of alkyl groups;

[0645] R 9 and R 10 Each of them is independently selected from H, and optionally substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted aryl and optionally substituted aryl C 1-6 Alkyl, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form 5-7 member cyclic saturated or unsaturated rings;

[0646] R 11 Independently select H and arbitrarily substitute C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted aryl, optionally substituted aryl C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, -NR 9 R 10 and -OR 12 The group formed;

[0647] R 12 and R 13 Each of these is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryl C. 1-6 Alkyl and optionally substituted C 3-6 The group consisting of cycloalkyl groups;

[0648] R 6 Choose from H, halogen, hydroxyl, alkoxy, and optionally substituted C. 1-6 Alkyl, haloalkyl, optional substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl and optionally substituted aryl C 1-6 The group consisting of alkyl groups;

[0649] n is an integer with a value of 0, 1, or 2.

[0650] In some implementations, when R of formula II 3 When it is an optional component, the component can be substituted independently once or multiple times. In some embodiments, when R of Formula II... 3 When the component is an optionally substituted component, the component can be independently substituted 1 to 3 times. In some embodiments, the component can be independently optionally substituted with halogens, hydroxyl groups, C... 1-3 Alkoxy, C 1-3 Alkyl, aryl, or arylalkyl are substituted 1 to 3 times.

[0651] In some implementations, R of Formula II 3 C is an optional substitute 3-6 Alkyl or optionally substituted C 3-6 Cycloalkyl. In some embodiments, the C 3-6 The alkyl group is selected from the group consisting of isopropyl, n-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, 2-methylbutyl, and n-hexyl. In one embodiment, the alkyl group is isopropyl or tert-butyl. In another embodiment, the alkyl group is isopropyl. In one embodiment, the cycloalkyl group is cyclopropyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl group is cyclopentyl.

[0652] In some implementations, R of Formula II 6 It is H.

[0653] Biological data

[0654] As stated above, the compounds according to any of the embodiments described herein are modulators of AhR and can be used to treat or prevent human diseases exhibiting inflammatory components.

[0655] The biological activity of compounds according to any of the embodiments described herein can be determined using any suitable assay for determining the activity of candidate compounds as agonists or antagonists of AhR, as well as using tissue and in vivo models.

[0656] The biological activity of compounds according to any of the embodiments described herein is confirmed by the following tests.

[0657] Example 5: Assay for CYP1A1-bla LS-180AhR agonist

[0658] LS-180 cells stably transfected with a β-lactamase reporter gene construct linked to the CYP1A1 promoter (referred to as CYP1A1-bla LS-180 cells) were used to characterize the ability of compounds to activate AhR. In short, AhR activity was measured using the LiveBLAzer assay kit, which utilizes a β-lactamase (bla) reporter gene downstream of the CYP1A1 promoter to metabolize its substrate and provide a fluorescent readout. For the agonist assay, CYP1A1-bla LS-180 cells were treated with compounds at progressively increasing concentrations over a 100,000-fold range.

[0659] CYP1A1-bla LS-180 cells in exponential growth phase were washed twice with DPBS and then seeded into 96-well microplates (50,000 cells / well) and allowed to attach. The prepared compound (at 2-fold working concentration in complete medium) was then added to the wells, and the cells were incubated for approximately 20 hours. LiveBLAzer FRET B / G β-lactamase substrate was added during the last hour of incubation, and blue / green fluorescence was measured using a 96-well microplate reader.

[0660] AhR activity as a function of β-lactamase expression was measured using fluorescence resonance energy transfer-based readout. The system was validated using TCDD and FICZ as controls. As expected, CYP1A1-bla LS-180 cells treated with TCDD showed a conventional dose-response relationship, and TCDD exhibited similar response to that reported by Invitrogen (pEC... 50 =9.70) similar efficacy (pEcucC) 50 =10.34). CYP1A1-bla LS-180 cells treated with FICZ also showed a conventional dose-response relationship, and as predicted from the literature, FICZ exhibited significantly lower potency than TCDD (pEC). 50 =6.82).

[0661] For these experiments, the compounds of the present invention, represented by Examples 1-3, exhibited a pEC value of ≥6.0. 50 (representing EC) 50 A value ≤1μM is considered a positive reaction.

[0662] Example 6: Assay for CYP1A1-bla LS-180AhR Antagonist

[0663] The antagonistic activity of the compounds was assessed using a similar assay. CYP1A1-bla LS-180 cells in exponential growth phase were washed twice with DPBS and then seeded into 96-well microplates (50,000 cells / well) and allowed to attach. FICZ or TCDD was added as an agonist, and the prepared compound (at 2-fold working concentration in complete medium) was added after 2 hours. Cells were incubated for approximately 20 hours, and then the ability of the compounds to compete with FICZ or TCDD-induced AhR activation was tested as a means of assessing potential allosteric or partial agonist activity. LiveBLAzerFRET B / G β-lactamase substrate was added during the last hour of incubation as described above, and blue / green fluorescence was measured using a 96-well microplate reader.

[0664] The compounds of the present invention, represented by 2-isopropyl-5-(isoquinoline-3-yl)benzene-1,3-diol, were found to be negative in this assay.

[0665] Example 7: CD4+ T cell IL17 assay

[0666] AhR activation has been shown to alter transcriptional regulation of the immune system, specifically affecting the differentiation of Th17 and Treg cells. Therefore, the ability of compounds to reduce IL-17 production in CD4+ T cells stimulated under Th17 tilt conditions was evaluated. This was achieved by cryopreserving human CD4+ cells... + T cells (AllCells, LLC, Alameda, CA and Stem Cell Technologies Ltd., Vancouver, Canada) were cultured for 5 days in CD3-coated tissue culture plates (2 μg / mL) in Iscove modified Dulbecco medium (IMDM) containing 10% HI-FBS, 55 μM 2-mercaptoethanol and soluble anti-CD28 antibody (3 μg / mL) to differentiate into the Th17 subtype. The Th17 tilt mixture [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 antibody (10 μg / mL), and anti-IL-4 antibody (10 μg / mL)] was used, with or without serially diluted compounds. Five days after exposure to Th17 polarizing agents containing and without the compound, IL-17 secretion from polarized CD4+ T- cells in the culture medium was measured using the MSD (Meso Scale Discovery) detection system.

[0667] From these experiments, the compounds of the present invention all exhibited a pIC value of ≥6.0. 50 (representing IC) 50 ≤1μM), which is considered a positive response to IL-17 inhibition.

[0668] Example 8: IMQ mouse model with in vivo anti-inflammatory activity

[0669] The efficacy of AhR agonist compounds has been observed in mouse models of psoriasis, specifically imiquimod (IMQ)-treated mouse models (see Di Meglio et al., (2014) Immunity, 40(6):989-1001, and Smith et al., (2017) J Invest Dermatol, 137(10), 2110-2119). The biological activity of compounds of formula (I) was tested in such mouse models to obtain evidence of their in vivo anti-inflammatory activity.

[0670] Female BALB / c mice (BALB / cByJRj) were purchased from Janvier (France). Mice were allowed to consume a normal diet (A04C) from SAFE (France) and have free access to water. Female BALB / cJByRj mice (8 weeks old at the start of the study) were treated with either imiquimod (IMQ) cream (5%) or vanicream (a non-inflammatory, inert cream). For three days of pretreatment and subsequent daily treatments until the end of the study (2 hours before each IMQ application), the same skin area was topically treated with 100 μL of the compound. Changes in clinical symptoms in mice were monitored throughout the study. The affected dorsal skin was examined histologically and by qPCR to obtain evidence of the compound's efficacy.

[0671] The biological activity of compounds of formula (I), represented by 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol, was tested in this mouse model to obtain evidence of in vivo anti-inflammatory activity. Histological analysis of skin confirmed its ability to reduce imiquimod-induced epidermal thickening. Skin gene expression data revealed that the expression of IL-17A and IL-17F was significantly inhibited by the compounds.

[0672] Example 9: Mechanism of the compound of the present invention as an AhR agonist and its similarity to tpinanov

[0673] Tapinaloflav is a first-line 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 available data suggest that tapinaloflav exerts its pharmacological action in the skin through a novel mechanism involving the dual activation of the AhR and Nrf2 anti-inflammatory pathways, thus identifying tapinaloflav as a therapeutic agent. A tapinanov is an hR regulator (TAMA). It specifically inhibits pro-inflammatory mediators including interleukin [IL]-6, IL-17A, and eosinophil activation chemokine-3, which may be downstream of AhR pathway activation. Furthermore, treatment with tapinanov reduces reactive oxygen species (ROS) in chemically redox-stressed keratinocytes and induces apoptosis in the micromolar range.

[0674] The direct mechanistic link between AhR and anti-inflammatory activity is not fully elucidated, nor has the means to definitively identify safe TAMAs ​​while other compounds may drive AhR-mediated activity have been determined. Therefore, the known activities of each tapinarov of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol were evaluated. An overview of this mechanistic study is provided below.

[0675] The activity of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in the major “hit” identified in the mechanistic study of Tapinalov was evaluated (Table 3). Indeed, 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol showed similar potency in each screening assay of AhR, Nrf2, and CB2, as well as IL-17A inhibition in CD4+ T cells cultured under Th17 polarized conditions.

[0676] Table 3: Initial screening comparison of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol with the clinical lead drug tapinarov

[0677]

[0678]

[0679] Example 10: Biographic Analysis of 2-Isopropyl-5-(Isoquinoline-3-yl)phenyl-1,3-diol

[0680] Using DiscoveRx Diversity Plus System TM 2-Isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol was analyzed at multiple doses of 1 μM, 330 nM, 110 nM, and 37 nM. The BioMap system evaluated 148 biomarkers associated with various inflammatory diseases on 12 different primary human cell culture platforms, and the biomarker profiles were compared with biological response patterns of other compounds, biologics, and approved drugs from a BioMap reference database of over 3000 experimental agents. Among the analytes tested, 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol was found to have anti-proliferative effects on B cells, leading to a decrease in various cytokines / chemokines, including M-CSF, sIL-17A, sIL-2, sIL-6, sIL-10, Eot3, sTNFα, MCP-1, VCAM-1, and MIP-1, and an increase in IL8, IL1α, sPGE2, ICAM-1, and E-selectin. Figure 1A-1B Similar to tapinarov, the endogenous AhR agonist 6-formylindolo(3,2-b)carbazole (FICZ) is the only compound identified from the Biograph Reference Database with a relevant biological response pattern (Pearson correlation, r = 0.71). Figure 1C-1D). Similarly, when the curves are overlaid, a significant similarity to tapinalov is noted (Figs. 1E-1F). The most significant difference is the reduction of sIL-17 observed in 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol, which was not seen in tapinalov or FICZ-treated samples.

[0681] Example 11: Effects of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol on cytokines and apoptosis

[0682] The effects of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol treatment on peripheral blood CD4+ T cells cultured under Th17 tilt conditions were evaluated. When used throughout the culture period, 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol, similar to tapinarov, reduced IL-17A production in a dose-dependent manner. Figure 2A ).

[0683] 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol at IC50 50 =5.9μM affects T cell survival rate, and is expressed as IC50. 50 =12.36 μM affects keratinocyte survival. These values ​​are similar to those of tapinarov and support the view that 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol is a near-phenotype of tapinarov's activity profile. Figure 2B , Figure 2C ).

[0684] Example 12: Inhibition of Reactive Oxygen Species (ROS) by 2-Isopropyl-5-(Isoquinoline-3-yl)phenyl-1,3-diol

[0685] Tapinarov was observed to inhibit chemically induced ROS in primary and immortalized (HaCat) keratinocytes, at least in part due to the inherent ROS scavenging properties of the API (Smith et al., 2017, ibid.). Importantly, the observed ROS reduction is a key difference between tapinarov and TCDD, a known environmental toxin that leads to elevated ROS levels. Therefore, the ability of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol to reduce ROS was tested. Using an oxygen radical uptake capacity (ORAC) assay, tapinarov showed scavenging peroxynitrite, superoxide anion, singlet oxygen, peroxy radical, and hydroxyl radical, all common types of ROS. 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol exhibited a similar profile, reducing levels of peroxynitrite, singlet oxygen, peroxy radical, and hydroxyl radical (Table 4).

[0686] Table 4: Oxygen Radical Absorption Capacity (ORAC) as measured by Trolox Equivalent Value (TEV)

[0687]

[0688] Example 13: Confirmation of biological activity (target involvement) after local delivery

[0689] A previously reported in situ activated liquid-air interface skin explant culture with immunologically active cells, termed sRICA (skin-resident immune cell activation model) (Smith et al., (2016) PLoS One, 11(2)). In this assay, a specific cytokine profile of inflammatory skin diseases can be induced, including Th17-type cytokines, IL17A, IL17F, and IL22. The reduction of biomarkers in this assay indicates the biological activity of the tested compounds.

[0690] Human cells obtained from abdominoplasty were processed to remove fat, and the tissue was sectioned to approximately 750 micrometers using a dermabrasion scalpel. The sectioned skin was then cleaned in two consecutive 5-10 minute rinses, each in room temperature PBS containing an antibiotic / antifungal agent solution.

[0691] From this point onward, the skin is treated aseptically; all further procedures are performed in a Class II biosafety cabinet. Using a disposable biopsy punch, skin sections are cut into 10mm diameter circular sections and placed in the upper compartment of a 0.4µm PCF membrane cell migration plate (Millicell#PIHP01250) containing 30µl of bovine collagen solution (2:1 collagen / keratin medium). Any air bubbles beneath the cell migration plate are carefully removed, as they can inhibit the penetration of the culture medium into the tissue.

[0692] In a humidified incubator at 37°C, allow skin samples to coagulate on the collagen solution for 30 minutes. After incubating at 37°C for 30 minutes to allow time for the collagen solution to coagulate, transfer the skin samples from the cell migration plate to a 6-well plate (one sample per well). Add 1 mL of complete culture medium (keratin medium) + / - 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (0 μM, 1 μM, or 10 μM) to the lower compartment and allow it to rest overnight (16-18 h) at 37°C.

[0693] On the second day, the culture medium was aspirated from the lower compartment and replaced with 1 mL of complete medium containing a Th17 mixture (CD3 (1 μg / mL), CD28 (2 μg / mL), anti-IL-4 antibody (1 μg / mL), anti-INFg antibody (1 μg / mL), IL-1b (10 ng / mL), IL-6 (10 ng / mL), TGFb (1 ng / mL), IL-21 (10 ng / mL)). The medium was incubated for 24 and 48 hours. A total of three biological replicates were used for each treatment group.

[0694] Cultures were harvested at 24 and 48 hours post-stimulation. After harvesting, skin samples were minced with a razor blade and transferred to 1.5 mL RNase-free tubes containing 1 mL of RNAlater solution until subsequent analysis by RT-PCR.

[0695] RNA isolation and qRT-PCR

[0696] Harvested skin tissue was stored in RNAlater until use. Total RNA was isolated from the tissue using Qiagen's Mini RNA Isolation Kit (catalog number 74106). First, the skin tissue was minced into pieces smaller than 1x1x1 mm and added to a tube containing 2.8 and 1.4 mm ceramic beads (mixed in a small tube). Cells were lysed in a Precellys tissue homogenizer in 300 μL of RLT buffer supplemented with 1% 2-β-mercaptoethanol for 4 cycles (6300 rpm 90 s), with 30 s on ice between each cycle. Then, 590 μL of water containing 10 μL of proteinase K was added to the lysed cells, and the mixture was incubated at 55 °C for 20 min. The sample was then centrifuged at 10,000 X g for 3 min, and the supernatant was used for RNA isolation using a Qiagen RNeasy mini-column according to the manufacturer's protocol. RNA was diluted to a concentration of 23.6 ng / µl (total 100 ng RNA) and used as a template in a 10 µL PCR volume. The Applied Biosciences RNA-to-CT One-Step Kit (AB catalog number 4392938) and specific TaqMan probes for each gene to be quantified were used. The Applied Biosciences master mix contained an internal control of ROX dye. A OneStepPlus PCR machine was used for both the RT step and 40 amplification cycles.

[0697] The relative RNA levels of the genes of interest were calculated using the ΔΔCT formula.

[0698]

[0699] RNA was isolated from tissues at 24 and 48 hours post-stimulation, and gene expression was assessed by quantitative PCR. Data and statistical analysis were performed using Microsoft Excel 7 and Prism GraphPad 6.

[0700] 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is involved in the target pathway, in this case AhR pathway activation as measured by cyp1a1 gene induction, which was confirmed after exposing skin explants to 1 μM or 10 μM 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in basolateral membrane culture medium. Figure 3A Next, the effect on inflammatory mediators was evaluated, confirming that 10 μM 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol inhibited IL17A messenger expression by approximately 45%. Figure 3B In this study, the RORg inverse agonist compound GSK3038548A was used as a positive control for the inhibition of Il17a gene expression.

[0701] The sRICA model was adapted to fit the Franz diffusion cell apparatus to demonstrate two specific outcomes of local delivery: (i) the test compound retains biological activity in its formulation, and (ii) the test compound can cross the skin barrier to reach its dermal target and elicit a biological effect. Local target engagement of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol was evaluated at multiple concentrations in cream formulation 1 and gel formulation 1. Importantly, because these target engagement assays utilize a custom-designed Franz diffusion cell clamped to the skin edge, leakage of the local formulation into the lower compartment of the air-liquid interface culture is prevented. Expression of the Cyp1a1 gene was used as an indicator of AhR pathway activation. Therefore, as is typical of Th17-sRICA described above, activation of skin-resident immune cells under Th17 conditions is not performed. Instead, 12 mm skin sections were sandwiched between the upper (donor) and lower (recipient) compartments of a custom-designed Franz diffusion cell. 2.0 mL of complete culture medium (“keratin”) was then added to the lower compartment, ensuring the outer surface of the basal layer was fully immersed in the medium and free of air bubbles. After standing at 37°C for approximately 2 hours, the diffusion cell was checked again for leaks by simply inverting it. A topical formulation (8.4 μl) was then applied to the dried stratum corneum using a positive displacement pipette. The Franz diffusion cell was then incubated in a humidified incubator at 37°C for another 21 hours. Cyp1a1 levels were assessed in approximately half of each skin section relative to the outer surface of the basal layer with 10 μM of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol, while the other half was used to determine the concentration of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol. Samples containing at least 0.1% 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol in cream formulation 1 showed strong cyp1a1 gene induction without observable dose dependence. Figure 4 This data shows that the lowest formulation concentration induced the highest observable biological response in this system.

[0702] Example 14: In vivo efficacy in a mouse model

[0703] It has been confirmed that systemic FICZ treatment targeting the AhR pathway has a positive effect on the clinical scores of mice treated with imiquimod (IMQ) (Di Meglio et al., (2014) ibid.). Furthermore, tapinarov has demonstrated anti-inflammatory properties in various mouse models, including an ear eczema model, an IMQ mouse model of psoriasis, and a DNFB irritation model, the latter being a hapten-induced Th2 dominant irritation model. 2-Isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol:IMQ and DNFB mouse models were also tested in two mouse inflammation models.

[0704] IMQ mouse model

[0705] 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was tested prophylactically in an IMQ mouse model, in which 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was applied topically daily in a simple ethanol solution (60% EtOH: 40% H2O). IMQ cream was applied daily for 4 days (Study A) or 10 days (Study B), starting 3 days after the first treatment. Clinical scores were monitored daily. Figure 5A , Figure 5B At the end of the study, treated skin was assessed histologically and by qPCR to obtain induced cytokine gene expression. Compared with mice treated with the vector, 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol treatment resulted in lower clinical scores, reduced epidermal thickening, and decreased cytokine gene expression (N = 10 mice per group). Figure 5A -B and Table 5).

[0706] Research A-

[0707] Ten mice in each of the three groups (female BALB / cByJRJ mice) were treated as follows: Days -3, -2, and -1 (three days prior to imiquimod administration) and Days 0, 1, 2, and 3 (a four-day study): The shaved backs of the mice were treated daily with either a carrier (100 μL of 60% EtOH / 40% water) or 0.3% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in 60% EtOH / 40% water). On Days 0, 1, 2, and 3, vanicream or 5% imiquimod cream (5% Aldara cream) was applied topically to the shaved backs two hours after the application of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol or the carrier, and massaged in with fingers until absorbed. On Days 0, 1, 2, and 3: The skin was visually assessed and clinical psoriasis scores were recorded.

[0708] Psoriasis reactions (erythema and plaques) are reported below in ascending order of severity on a scale of 0-4, and the results are shown in Figure 5A1.

[0709] Psoriasis score ]]> ​ grade ]]> ​ No response – normal ]]> ​ 0 ]]> ​ <![CDATA[ Mild erythema ]]> <![CDATA[ 1 ]]> <![CDATA[ Moderate to severe erythema and some plaques ]]> <![CDATA[ 2 ]]> <![CDATA[ Obvious erythema and plaque ]]> <![CDATA[ 3 ]]> <![CDATA[ Very obvious erythema and plaque ]]> <![CDATA[ 4 ]]>

[0710] On the last day of treatment, 6 mm skin punches from the treated area were collected on an aluminum plate (to keep the skin flat) and placed in a test tube containing formalin solution (neutral buffer 10% (SIGMA HT501320-95L)) for histological analysis (Figure 5A2).

[0711] Research B

[0712] Four groups of 10 mice each (BALB / cByJRJ female mice) were treated as follows: Days -3, -2, -1 (3 days before imiquimod administration) and Days 0, 1, 2, 3, 5, 6, 7, 8, 9 (10-day study): The shaved backs of the mice were treated daily with a medium (100 μL 60% EtOH / 40% water), 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (0.1% in 60% EtOH / 40% water) or 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol (0.3% in 60% EtOH / 40% water). On days 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9, apply vanicream or 5% imiquimod cream (5% Aldara cream) topically to the shaved back 2 hours after application of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or the carrier, and massage with your fingers until absorbed. On days 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9: visually assess the skin and record the psoriasis clinical score.

[0713] Psoriasis reactions (erythema and plaques) are reported below in ascending order of severity on a scale of 0-4, and the results are shown in Figure 5B1.

[0714] <![CDATA[ Psoriasis score ]]> <![CDATA[ grade ]]> <![CDATA[ No response – normal ]]> <![CDATA[ 0 ]]> <![CDATA[ Mild erythema ]]> <![CDATA[ 1 ]]> <![CDATA[ Moderate to severe erythema and some plaques ]]> <![CDATA[ 2 ]]> <![CDATA[ Obvious erythema and plaque ]]> <![CDATA[ 3 ]]> <![CDATA[ Very obvious erythema and plaque ]]> <![CDATA[ 4 ]]>

[0715] On the last day of treatment, 6 mm skin punches from the treated area were collected on an aluminum plate (to keep the skin flat) and placed in a test tube containing formalin solution (neutral buffer 10% (SIGMA HT501320-95L)) for histological analysis (Figure 5B2).

[0716] In an independent study (Study C), 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in cream formulation 1 was tested again in an IMQ mouse model. In this last study, no observable changes in clinical scores were observed in all treatment groups when hyperredness was induced by IMQ. However, when 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was administered in cream formulation 1, a reduction in epidermal thickness (Figure 5) and a significant reduction in IL17A and IL17F levels (>80% at the highest dose tested) were observed.

[0717] Table 5: In an imiquimod mouse model of psoriasis, 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol reduced tissue mRNA expression of IL-17A and IL-17F (Study A corresponds to...). Figure 5A The study of B corresponds to Figure 5B )

[0718]

[0719] DNFB mouse model

[0720] Next, 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was tested in a dinitrofluorobenzene (DNFB) mouse model (see Figure 6). DNFB is a small chemical hapten that induces delayed-type hypersensitivity reactions, somewhat similar to human atopic dermatitis. As in the IMQ irritation study, 0.3% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in a simple ethanol formulation was first tested, confirming a 20% and 34% reduction in epidermal and dermal thickness, respectively, when applied twice daily. Figure 6B This effect was not observed in the second study, in which 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was formulated in 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, although further data are needed to understand whether this difference stems from the different dosing strategy (qd vs. bid), limitations of cream formulation 1, or other reasons. However, combined with the results from the IMQ mouse model, the data suggest that 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol is expected to have broad-spectrum anti-inflammatory activity, which would be beneficial for patients with atopic dermatitis and psoriasis.

[0721] Second study

[0722] Healthy female CD1 mice (Crl:CD1(ICR)) were anesthetized with 3 to 5% isoflurane and their fur was shaved on the abdomen and back of the neck.

[0723] After measuring body weight, animals were assigned to the study group according to the treatment table below. The study was divided into two groups, separated by one week, to accommodate real-life monitoring of scratching. Half of the animals from each group (6 mice) were assigned to Group 1 and Group 2, respectively.

[0724]

[0725] For each topical treatment, 100 mg of cream or 100 μL of liquid formulation was applied to the skin of the nape of the neck of the mice using a solvent pipette. When using the cream, it was spread with fingers and massaged into the skin until fully absorbed.

[0726] On day 1, acetone / olive oil (4:1 volume:volume) or 0.15% DNFB (2,4-dinitrofluorobenzene, in acetone / olive oil (4:1 volume:volume)) was applied topically to the shaved abdomen (sensitization phase) at a volume of 100 μL. On days 5, 8, 12, and 15, 100 μL of acetone / olive oil or 0.15% DNFB was applied topically to the shaved nape of the neck (initiation phase). From day 5 to day 17, 100 mg of 0.3% cream preparation 1 (group 4), 0% cream preparation 1 (group 3, placebo cream), or 100 mg of 0.05% clobetasol cream (group 5) was applied to the nape of the neck 2 hours before DNFB irritation each day.

[0727] On day 17, 4 hours after the last local treatment and 48 hours after the last DNFB or acetone / olive oil irritation, mice were sacrificed under 3- to 5% isoflurane anesthesia. Skin samples from the nape of the neck were collected in 10% neutral buffered formalin for histological analysis. Epidermal (Fig. 6C1) and dermal thickness were measured (Fig. 6C2).

[0728] Example 15: In vitro human skin penetration assessment

[0729] In vitro human skin penetration and distribution of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol were evaluated using a custom-designed (ChanneL) flow-through diffusion cell device and ex vivo human skin sections (derived from abdominoplasty) with a 500 ± 100 μm dermal blade. Skin distribution (epidermis and dermis) and accumulation in the receiver fluid (representing unbound drug penetrating below 500 μm) over 16 hours were assessed using a suitable LC-MS / MS method with a lower limit of quantitation (LLOQ) of 80 pg / mL to determine skin delivery of the formulation prototype. The biological target site for 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is the epidermis / upper dermis, and given the lower accumulation in the receiver fluid, formulation ranking focuses on the dermal level. Epidermal samples may still contain residual drug that has not penetrated the stratum corneum and were therefore not considered for ranking purposes.

[0730] In the initial formulation development phase, using three donors, eight topical formulations (six creams and two gels) loaded with 1.0% 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol were evaluated in vitro in human skin penetration assays. Delivery of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in the epidermis and dermis was demonstrated at 16 hours. Figure 7 The amount delivered to the dermis ranged from 0.4 to 2.6 μg, and only low cumulative amounts were quantified in the receiving solution (less than 20 ng within 16 hours). Figure 8 ).

[0731] The statistical significance of dermal delivery was assessed using a Student's t-test and presented in a manner that formulations not associated with the same letters ("A" through "C") showed statistical differences (p < 0.05, Table 6). Formulations 1% cream (Formulation 3) and 1% gel (Formulation 4) delivered higher amounts of drug to the dermis.

[0732] Table 6: Statistical evaluation of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol formulations based on delivery amount (μg) to the dermis

[0733]

[0734]

[0735] Furthermore, due to the improved physical stability, dosage ratio studies were also conducted on cream formulation 2 and a similar formulation, cream formulation 1, which has a lower Transcutol P level. Based on Figure 9 The dermal amounts shown in the figure, 1% cream formulation 3 and 1% cream formulation 1 produce the optimal dosage ratio, and the latter exhibits comparable delivery to the dermis and improved stability.

[0736] To further evaluate the potential of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol gels (especially gels with less than 15% propylene glycol), two additional formulations (gel formulation 1 and gel formulation 2) were evaluated in an in vitro skin penetration assay. Neither gel delivered significantly more 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol to the dermis compared to any other test sample (Figure 10). Cumulative amounts were measured but not considered in the ranking. Figure 11 ).

[0737] The spatial localization of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in the dermal layer was also confirmed using matrix-assisted laser desorption / ionization imaging mass spectrometry (MALDI-IMS). In addition to the 0.5% cream formulation 3 and the 1% gel formulation 4, a 1% cream formulation 1 was selected for this study; these prototypes delivered equivalent amounts of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol to the dermis during dose-proportioning studies. Single doses of all three formulations were applied to human full-thickness skin, and samples were collected at 6 and 24 hours. After collection and preparation, the samples were sent for MALDI. At 6 hours (Table 7), the amount of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol delivered to the dermal level was 5.0 to 7.0 times higher for 1% gel formulation 4 compared to 0.5% cream formulation 3 and 1% cream formulation 1; however, at 24 hours, this difference was approximately 2.0 times.

[0738] Drug concentrations from in vitro human skin permeation and MALDI IMS studies were compared, and the results are presented in Table 7. Several assumptions were made to calculate the concentration in each compartment using data from the skin permeation assay: (i) the volume of each compartment was 1 cm³. 2 The concentrations are calculated based on the drug delivery area; (ii) the skin thickness of the epidermis and dermis is estimated to be 150 μm and 350 μm, respectively; (iii) it is assumed that the drug distribution is uniform in each compartment; and (iv) it is assumed that the tissue density is 1 g / mL. The concentrations do not take into account whether the drug fractions are bound or unbound.

[0739] For both creams, the concentrations observed in the epidermis in the 16-hour in vitro human skin penetration study were on average 2.4 times higher than at the 6-hour MALDI timepoint; however, the amount of epidermal delivery delivered by the gel was comparable in the 6-hour MALDI study to the results in the in vitro skin penetration assay. At the 24-hour MALDI timepoint, the amount of epidermal delivery in the gel formulation decreased, resulting in a 1.5-fold higher value from the in vitro skin penetration study compared to that of the cream. The creams did not exhibit this behavior, instead showing an increase in epidermal delivery from 6 to 24 hours, becoming comparable to the amount delivered in the in vitro skin penetration study. This difference in behavior indicates a difference in formulation delivery kinetics between the gel and cream formulations. Comparison of dermal values ​​showed that the amount of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol delivered in the in vitro human skin penetration assay (16 hours) was 3.0 to 6.5 times higher than in the MALDI experiment (24 hours). These differences in concentration can be attributed to differences in the research protocols used in the two assays, including skin thickness, skin donor, and analytical methods.

[0740] Table 7: Calculated skin concentrations (μM and μg / g) in the epidermal and dermal compartments (± standard error as displayed)

[0741]

[0742] The values ​​reported for MALDI-IMS analysis of ex vivo human skin are the average of six skin sections (three sections per skin replicate) obtained from two skin permeation replicates using one skin donor.

[0743] Example 16: Absorption, Distribution, Metabolism, and Excretion

[0744] 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol showed high binding to plasma proteins, with unbound fractions of 3.06%, 1.98%, and 1.08% in rats, miniature pigs, and humans at 2 μM (Table 8). Skin binding of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in intact human skin, epidermis, and dermal homogenates was tested at three concentrations (25, 50, and 100 ng / mL, 0.089, 0.179, and 0.358 μM, respectively), showing unbound fractions of 21.9 ± 0.72%, 51.3 ± 1.1%, and 34.1 ± 11.5%, respectively. Blood-plasma ratios were similar across species (1.22–1.36, Table 9). 2-Isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is stable in plasma and blood.

[0745] Table 8: Binding of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (2 μM) in plasma proteins of rats, miniature pigs, and humans, as determined by rapid equilibration dialysis (RED) apparatus.

[0746]

[0747] Table 9. Blood-to-plasma ratios and binding of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (1 μM) to blood cells in rats, miniature pigs, and humans.

[0748]

[0749] In species including mice, rats, miniature pigs, dogs, rabbits, and humans, 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol is rapidly metabolized by hepatic microsomes and / or hepatocytes, indicating a high intrinsic in vitro clearance. In rats, miniature pigs, and humans, the intrinsic metabolic clearance in hepatocytes is 2.1 to 11.6 times higher than that in hepatic microsomes, and it correlates well with in vivo clearance measured in pharmacokinetic studies in rats and miniature pigs (see below: Animal Pharmacokinetics), with an in vitro-to-in vivo extrapolation (IVIVE) ratio of 0.45 for rats and 0.27 for miniature pigs.

[0750] Table 10. Metabolic stability of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (0.5 μM) in liver microsomes and hepatocytes in mice, rats, miniature pigs, dogs, rabbits, and humans.

[0751]

[0752] An in vitro GSH capture assay was used to detect the reactive metabolites of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol after incubation for 1 hour in human or rat liver microsomes supplemented with glutathione (GSH) and glutathione ethyl ester (GSEE) (Table 11). These results indicate that 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol has the potential to form reactive metabolites. Despite these findings, 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol is not expected to pose a safety risk due to low systemic exposure in vivo following topical administration in rats and miniature pigs (see the Animal Pharmacokinetics section below) and low estimated plasma concentrations in humans (see the Estimation of Human Plasma Concentrations section below).

[0753] Table 11: Detection of GSH-capturing reactive metabolites of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (10 μM) in liver microsomes

[0754]

[0755] P = parent; O = oxygen; GSH = glutathione

[0756] Example 17: Animal Pharmacokinetics

[0757] In rats and miniature pigs, the preclinical pharmacokinetic profile of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was characterized by high clearance, large volume of distribution, and short half-life (Table 12, Figure 12). In rats, after subcutaneous administration of both 30% sulfobutyl-β-cyclodextrin and 30% painless piercing cone formulations, the plasma pharmacokinetics of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol were approximately linear in the range of 10–25 mg / kg. 24h ), while C max The bioavailability was 3.2 to 4.1 times higher (Table 13). Bioavailability was 46.5% for 30% sulfobutyl-β-cyclodextrin and 41.0% for 30% painless piercing cones. The 30% sulfobutyl-β-cyclodextrin formulation was selected for a 7-day subcutaneous toxicity study in rats. In miniature pigs, bioavailability was 0.1% after a single oral administration of 5 mg / kg with the DMSO:Kolliphore HS15:hydroxypropyl-β-cyclodextrin (10:10:80) mediator, indicating that the oral route was not suitable for systemic safety assessment in miniature pigs.

[0758] Table 12: Pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol after a single intravenous administration in rats and miniature pigs.

[0759]

[0760] Note: For rats, mean (±SD), n=3; for miniature pigs, mean (individual).

[0761] Table 13: Effects of dosage and formulation on the pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol after subcutaneous administration in rats

[0762]

[0763] Note: Mean (±SD), n=3

[0764] In rats, following a single topical administration of 20 mg 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol / kg with 10% body surface area (BSA) coverage, 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol was used in a 1% cream formulation (C max 3.83 ng / mL, AUC 24h 32.1 ng*hr / mL) and 1% gel formulation 1 (C max 5.18 ng / mL, AUC 24h Comparable plasma exposures were observed between the 46.0 ng*hr / mL formulations. Bioavailability was very low: 1.7% for the 1% cream formulation 1 and 2.4% for the 1% gel formulation 1 (Table 14). Similarly, in miniature pigs, very low plasma exposures were observed (below the lower limit of quantitation 50 pg / mL for 87% of the time points) following a single topical administration of 15 mg 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol / kg in either the 1% cream or 1% gel formulation 1 with 10% body surface area coverage, indicating a low risk to systemic safety following topical administration.

[0765] Table 14: Plasma pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol in rats after a single topical administration of 20 mg / kg of 10% BSA.

[0766]

[0767] Note: Mean (±SD), n=4

[0768] In Gottingen miniature pigs, the skin pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol were studied for 7 days following a single topical administration of either 1% cream formulation 1 or 1% gel formulation 1. 2 The drug was administered at the specified dose rate, and skin biopsy samples were collected at different time points up to 168 hours for pharmacokinetic (tissue homogenate levels in the epidermis and dermis) and MALDI IMS (matrix-assisted laser desorption / ionization imaging mass spectrometry) analysis. For both formulations, higher concentrations of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol were observed in the epidermis / upper dermis (0-500 μm) compared to the dermis (500-1500 μm) (Table 15, Figure 13). The concentrations observed in the epidermis (C...) were higher than those observed in the 1% gel formulation 1. max 18.0 μg / g, AUC 168h 1729 μg*hr / mL) and dermis (C max 0.39 μg / g, AUC 168h Compared to 34.7 μg*hr / mL, the 1% cream formulation achieved a similar epidermal / upper dermal (C) ratio. max 23.4 μg / g, AUC 168h 2026 μg*hr / mL) and dermis (C max 0.74 μg / g, AUC 168h Exposure was 37.5 μg*hr / mL. Deep analysis of one miniature pig from each group at different time points using MALDI IMS showed consistency with pharmacokinetic data: the highest concentrations observed in the epidermis (0–100 μm) and upper dermis (100–500 μm) were 9.4 μg / g at 48 hours and 1.37 μg / g at 72 hours for 1% cream formulation 1; for 1% gel formulation 1, these figures 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). At a depth of approximately 500 μm, the MALDI IMS signal decreased below the detection limit (approximately 500 ng / g).

[0769] Table 15: Single local administration in miniature pigs (1 g formulation / 44 cm²) 2 Following this, the skin pharmacokinetics of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol

[0770]

[0771] Table 16: In miniature pigs, single local administration (1 g formulation / 44 cm²) 2 The skin levels of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol were subsequently determined by MALDI IMS.

[0772]

[0773] Example 18: Estimation of human plasma concentration after local administration

[0774] Steady-state human plasma concentration (C) after topical application of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol ss,人类 This is predicted by assuming that the locally applied drug is absorbed through the skin at a constant rate, and

[0775]

[0776] Plasma clearance rate (CL) 人类 CL was estimated from in vitro and preclinical pharmacokinetic studies. The allometric ratio method based on in vivo clearance in rats and miniature pigs, the hepatic blood flow velocity method, and the IVIVE method using a well-stirred model (assuming hepatic metabolic clearance is the primary elimination pathway) were used to predict CL. 人类 The clearance rate was between 6 and 25 mL / min / kg. The lowest predicted clearance rate (6 mL / min / kg, predicted from allosteric ratio and plasma protein binding correction) was selected to assess the potential systemic safety risk of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol in humans.

[0777] In in vitro human skin permeability assessment of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol loaded in 0.1% cream formulation 1, 0.5% cream formulation 1, and 1% cream formulation 1, the receiver fluid level was below the lower limit of quantitation (LLOQ; 80 pg / mL) within 16 hours, thus preventing the calculation of skin flux values. Assuming a lag time of 2 hours and receiver fluid levels obtained every 2 hours at the LLOQ level within 16 hours, an estimated skin flux prediction was performed, resulting in a calculated flux of 0.048 ng / cm³. 2 / h.

[0778] Healthy skin serves as an effective protective barrier for most xenobiotics; therefore, the correlation of flux values ​​derived from ex vivo skin permeability measurements using healthy human skin from abdominoplasty may not be transferable to observations after application to unhealthy skin. To account for impaired skin barrier function, 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)phenyl-1,3-diol. Human systemic exposure was also calculated using a 100-fold increase in flux to account for worst-case estimates. 10% of the human body surface area (1800 cm²) was considered. 2 ) is used for this estimation. Therefore, for the purpose of estimating the safety margin and taking into account the conditions explained in this paper, the estimated C is... ss,人类 The value was 0.34 ng / mL, and the corresponding AUC was... ss,24h The concentration was 8.2 ng / h / mL. In clinical practice, topical treatment of atopic dermatitis can achieve up to 50% BSA (9000 cm⁻¹). 2 Therefore, using a 10-fold increase in flux would improve the estimated corresponding C. ss,人类 and AUC ss,24h The values ​​are 0.17 ng / mL and 4.1 ng*h / mL. The different simulation scenarios are summarized in Table 17.

[0779] Table 17: Estimated steady-state human plasma concentrations (C1) after topical application of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol (1% cream formulation 1). ss,人类 ) and the corresponding area under the curve (AUC) within 24 hours 24h )

[0780]

[0781]

[0782] Example 19: Integration of preclinical goals into studies for human dose selection

[0783] Based on a combination of data from in vitro efficacy, target engagement and penetration in isolated human skin, and PK data from miniature pig skin, it is expected that the 1% cream formulation 1 will generate sufficient concentrations of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol at the target skin sites (living epidermis and upper dermis) after daily administration, leading to AhR target engagement.

[0784] The free drug concentrations in the skin obtained after topical application of 1% cream formulation 1 and calculated from pharmacokinetic studies of ex vivo human and miniature pig skin (analyzed by MALDI-IMS) indicate adequate coverage of the effective concentrations obtained by in vitro efficacy assays (50% AhR activation and 50% inhibition of IL-17A production in primary human peripheral blood CD4+ T- cells in a fluorescence-based reporter assay of CYP1A1 gene expression), as shown in Table 18. These calculations assume identical skin binding between humans and miniature pigs and 100% skin bioavailability after adjusting for unbound skin fractions.

[0785] Table 18: Calculated skin free concentrations (μM) of 2-isopropyl-5-(isoquinoline-3-yl)phenyl-1,3-diol in the epidermal and upper dermal compartments determined by MALDI-IMS analysis (± standard error)

[0786]

[0787] Note: In a fluorescence-based reporter assay of CYP1A1 gene expression, the EC50 for AhR activation was 0.0158 μM; the IC50 for IL-17A inhibition in primary human peripheral blood CD4+ T cells was [not specified]. 50 =0.14μM.

[0788] The values ​​reported for MALDI-IMS analysis of ex vivo human skin are the average of six skin sections (three sections per skin replicate) obtained from two skin permeation replicates using one skin donor.

[0789] Other embodiments of this application include:

[0790] Implementation Method A: A compound of the following formula: 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol:

[0791]

[0792] Or its pharmaceutically acceptable salts, solvates, or hydrates.

[0793] Implementation Method B: The compound described in Implementation Method A is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol of the following formula:

[0794]

[0795] Implementation C: A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of Implementation A or B and a pharmaceutically acceptable carrier or diluent.

[0796] Implementation method D: The pharmaceutical composition of implementation method C, wherein the pharmaceutically acceptable carrier or diluent is suitable for topical administration.

[0797] Implementation method E: The pharmaceutical composition of implementation method C, wherein the carrier or diluent is suitable for topical gel administration.

[0798] Implementation F: The pharmaceutical composition of Implementation C, wherein the carrier or diluent is suitable for topical administration as a cream.

[0799] Implementation G: A method for treating a condition associated with AhR imbalance in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to any one of Implementation A or B.

[0800] Implementation H: A method of treating an inflammatory condition in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Implementation A or B.

[0801] Implementation Method I: The method according to Implementation Method H, wherein the inflammatory condition is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascular (dry) AMD, neovascular (wet) AMD, uveitis or other inflammatory eye conditions, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

[0802] Implementation J: According to the method of Implementation I, the compound or its pharmaceutically acceptable salt, solvate or hydrate is administered topically.

[0803] Implementation K: A method for treating or preventing radiation dermatitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Implementation A or B.

[0804] Implementation method L: The method described in implementation method K, wherein the radiation dermatitis is chronic radiation dermatitis.

[0805] Implementation method M: The method described in implementation method K, wherein the radiation dermatitis is acute radiation dermatitis.

[0806] Implementation method N: The method described in implementation method K, wherein the radiation dermatitis is selected from the group consisting of acute erythema, salpingitis, desquamation, fibrosis, telangiectasia and skin atrophy or a combination thereof.

[0807] Implementation method O: The method described in implementation method N, wherein the radiation dermatitis is selected from fibrosis, telangiectasia and skin atrophy or a combination thereof.

[0808] Implementation P: A method for treating or preventing inflammatory mucosal conditions in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of implementations A or B.

[0809] Implementation Q: The method described in Implementation P, wherein the inflammatory mucosal condition is induced by cancer radiotherapy or chemotherapy.

[0810] Implementation R: The method described in Implementation P, wherein the inflammatory mucosal disease is selected from the group consisting of oral mucositis, lichen planus and pemphigus vulgaris.

[0811] Implementation S: The method described in Implementation R, wherein the oral mucositis is selected from oral lichen planus, erythema multiforme, mucosal pemphigoid, pemphigus vulgaris, and epidermolysis bullosa.

[0812] Implementation T: The method described in Implementation R, wherein the oral mucositis is caused by radiotherapy for head and / or neck cancer.

[0813] Implementation U: A method for treating a dermatological condition or disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Implementation A or B.

[0814] Implementation method V: A method for treating psoriasis or atopic dermatitis in a subject in need, the method comprising administering to the subject an effective amount of 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0815] Implementation method W: A method for preparing a compound of formula 8,

[0816]

[0817] The method includes:

[0818] a) The compound of Formula 6 or its pharmaceutically acceptable salt, solvate or hydrate.

[0819]

[0820] Coupled with a compound of Formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 7 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0821]

[0822] b) Demethylating a compound of formula 7 to form a compound of formula 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0823] Implementation method X: A method for preparing a compound of formula 8 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0824]

[0825] The method includes:

[0826] a) Prepare a compound of formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0827]

[0828] The preparation includes:

[0829] 1) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of formula 2 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0830]

[0831] 2) Treat the ketone of Formula 2 or its pharmaceutically acceptable salt, solvate or hydrate with Grignard reagent, and then remove water under acidic conditions to form the compound of Formula 3 or its pharmaceutically acceptable salt, solvate or hydrate.

[0832]

[0833] 3) Hydrogenating a compound of Formula 3 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 4 or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0834]

[0835] 4) Boronize 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;

[0836] b) Prepare a compound of formula 6 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0837]

[0838] The preparation includes treating isoquinoline-3-ol with a trifluoromethanesulfonylating agent; and

[0839] c) Couple a compound of Formula 6 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a compound of Formula 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof to form a compound of Formula 7 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0840]

[0841] d) Demethylating the compound of formula 7 to form the compound of formula 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein steps a) and b) may be performed in any order or simultaneously in different reaction vessels.

[0842] Implementation Y: The method according to Implementation X further includes purifying the compound of Formula 8.

[0843] Implementation method Z: The method according to implementation method Y, wherein the purification includes crystallization.

[0844] Implementation method AA: The compound described in any one of implementation methods A or B has a purity of at least 90% by weight.

[0845] Implementation method BB: The compound described in any one of implementation methods A or B has a purity of at least 95% by weight.

[0846] Implementation CC: The compound described in any one of Implementation A or B has a purity of at least 98% by weight.

[0847] Implementation method DD: The compound described in any one of implementation methods A or B has a purity of at least 99% by weight.

[0848] All publications referenced in this specification, including but not limited to patents and patent applications, are incorporated herein by reference as if each individual publication were specifically and individually identified as fully elaborated and incorporated herein by reference.

[0849] The foregoing description fully discloses the invention, including its preferred embodiments. Modifications and improvements to the embodiments specifically disclosed herein are within the scope of the following claims. Without further exhaustive detail, it is believed that those skilled in the art can utilize the invention to the fullest extent possible using the foregoing description. Therefore, the embodiments herein should be interpreted as merely illustrative and not in any way limiting the scope of the invention. Embodiments of the invention that claim exclusive attributes or privileges are defined below.

Claims

1. A compound of formula (I) or a salt thereof. (I) in R 1 Choose freely between OH and OR 7 The group consisting of R 7 C is an optional substitute 1-6 alkyl; R 2 Choose freely between OH and OR 7 The group consisting of R 7 C is an optional substitute 1-6 alkyl; R 3 C is an optional substitute 1-6 alkyl; R 4 Choose freely H, -(CR) 18 R 19 ) t COOR 8 and -(CR 18 R 19 ) t C(O)NR 9 R 10 The group consists of t, where t is 0 and R. 8 Choose H freely and C arbitrarily substituted. 1-6 The group consisting of alkyl groups, R 9 It is H, and R 10 C is an optional substitute 1-6 alkyl; R 5 It is H; and R 6 Choose the group composed of free hydrogen and halogens; The term C is replaced by 1-6 Alkyl refers to a C18 carbonyl group that has been substituted one or more times. 1-6 Alkyl group, wherein the substituent is independently selected from halogen; hydroxyl group; C-substituted hydroxyl group. 1-3 Alkyl; C 1-3 Alkoxy; halogenated C 1-3 Alkyl group; S(O) m C 1-3 Alkyl group, where m is an integer having a value of 0, 1, or 2; NR 22 R 23 , where R 22 and R 23 Independently selected from H or C 1-3 Alkyl, or R therein 22 and R 23 Together with the nitrogen atoms to which they are attached, they form 5- to 7-membered rings, which optionally contain additional heteroatoms selected from O, N, or S; C 1-3 Alkyl; C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-3 Alkyl groups; and halogen-substituted C groups 1-3 alkyl.

2. The compound according to claim 1, wherein: R 1 Choose freely between OH and OR 7 The group consisting of R 7 It is C 1-6 alkyl; R 2 Choose freely between OH and OR 7 The group consisting of R 7 It was NR 22 R 23 Replacement C 1-6 Alkyl, wherein R 22 and R 23 Independently choose H and C 1-3 The group consisting of alkyl groups; and R 4 Choose freely from H, -COOH, -COOCH3 and -C(O)NR 9 R 10 The group consisting of R; 9 It is H, and R 10 It is an amino-substituted C 1-6 alkyl.

3. The compound according to claim 1, wherein: R 1 Choose the group consisting of OH and -OCH3; R 2 Choose from the group consisting of OH, -OCH3, and -O-(CH2)3NH2; R 3 It is C 1-6 alkyl; R 4 Choose from the group consisting of H, -COOH, -COOCH3, and -C(O)NH(CH2)2NH2; and R 6 Choose the group composed of H and bromine.

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

5. The compound according to claim 1, wherein: R 1 Choose the group consisting of OH and -OCH3; R 2 Choose from the group consisting of OH, -OCH3, and –O-(CH2)3NH2; R 3 It is isopropyl; R 4 Choose from the group consisting of H, -COOH, -COOCH3, and -C(O)(CH2)2NH2; and R 6 Choose the group composed of H and bromine.

6. A compound selected from the group consisting of: , , , , , , and Or its salt.

7. A compound that is 2-isopropyl-5-(isoquinolin-3-yl)phenyl-1,3-diol or a pharmaceutically acceptable salt thereof.

8. A compound with the following formula: ； Or its salt.

9. The compound according to claim 6, wherein the compound is 。 10. A pharmaceutical composition comprising the compound according to claim 6, wherein the compound has a purity of at least 90% by weight.

11. A pharmaceutical composition comprising the compound according to claim 6, wherein the compound has a purity of at least 95% by weight.

12. A pharmaceutical composition comprising the compound of claim 6, wherein the compound has a purity of at least 98% by weight.

13. A pharmaceutical composition comprising the compound according to claim 6, wherein the compound has a purity of at least 99% by weight.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or diluent.

15. A pharmaceutical composition comprising the composition according to any one of claims 10 to 13 and further comprising a pharmaceutically acceptable carrier or diluent.

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. The use of the compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 14 in the preparation of a medicament for treating or preventing conditions associated with AhR imbalance in mammals, wherein the medicament comprises an effective amount of the compound or the pharmaceutical composition.

18. The use of the compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 14 in the preparation of a medicament for treating or preventing inflammatory conditions in a subject in need, wherein the medicament comprises an effective amount of the compound or the pharmaceutical composition.

19. The application according to claim 18, wherein the inflammatory condition is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascular dry AMD, neovascular wet AMD, uveitis or other inflammatory eye conditions, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

20. The use of the composition according to any one of claims 10 to 13 in the preparation of a medicament for treating or preventing inflammatory conditions in a subject in need, wherein the medicament comprises an effective amount of the compound or a pharmaceutically acceptable salt thereof.

21. The application according to claim 20, wherein the inflammatory condition is selected from the group consisting of psoriasis, atopic dermatitis, vitiligo, acne, neovascular dry AMD, neovascular wet AMD, uveitis or other inflammatory eye conditions, radiation dermatitis, COPD, asthma, multiple sclerosis (MS), and inflammatory bowel disease.

22. The application according to claim 20, wherein the inflammatory condition 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. Use of the composition according to any one of claims 10 to 13 in the preparation of a medicament for treating or preventing psoriasis or atopic dermatitis in a subject in need, wherein the medicament comprises an effective amount of the compound or a pharmaceutically acceptable salt thereof.

24. The application according to claim 20, wherein the drug is administered orally, topically, parenterally, transdermally, intranasally, or orally.

25. A method for preparing a compound of formula 8 or a pharmaceutically acceptable salt thereof, 8 The method includes: a) A compound of formula 6 or a pharmaceutically acceptable salt thereof is coupled with a compound of formula 5 or a pharmaceutically acceptable salt thereof to form a compound of formula 7 or a pharmaceutically acceptable salt thereof. 6 5 7 b) Demethylating the compound of Formula 7 to form the compound of Formula 8, and optionally converting the compound of Formula 8 into its pharmaceutically acceptable salt.

26. The method of claim 25, wherein isoquinoline-3-ol is treated with a trifluoromethanesulfonylating agent to prepare the compound of formula 6 or a pharmaceutically acceptable salt thereof.

27. The method of claim 25, wherein the compound of formula 5 or a pharmaceutically acceptable salt thereof is prepared by the following method: a) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt thereof to form a compound of formula 2 or a pharmaceutically acceptable salt thereof; 2 b) Treat the compound of formula 2 or a pharmaceutically acceptable salt thereof with Grignard reagent and then remove water under acidic conditions to form the compound of formula 3 or a pharmaceutically acceptable salt thereof; 3 c) Hydrogenating a compound of Formula 3 or a pharmaceutically acceptable salt thereof to form a compound of Formula 4 or a pharmaceutically acceptable salt thereof; 4 and d) Boronizing a compound of formula 4 or a pharmaceutically acceptable salt thereof to form a compound of formula 5 or a pharmaceutically acceptable salt thereof.

28. The method of claim 25, wherein demethylation comprises: a) Treating the compound of formula 7 with boron tribromide to form the compound of formula 7-1; 7-1 and b) Hydrogenate the compound of formula 7-1 to form the compound of formula 8.

29. The method of claim 25, further comprising purifying the compound of formula 8.

30. The method of claim 29, wherein the purification comprises crystallization.

31. A method for preparing a compound of formula 8 or a pharmaceutically acceptable salt thereof, 8 The method includes: a) Prepare a compound of formula 5 or a pharmaceutically acceptable salt thereof. 5 It includes: 1) Alkylating 2,6-dihydroxyacetophenone or a pharmaceutically acceptable salt thereof to form a compound of formula 2 or a pharmaceutically acceptable salt thereof; 2 2) Treat the ketone of Formula 2 or its pharmaceutically acceptable salt with Grignard reagent, and then remove water under acidic conditions to form the compound of Formula 3 or its pharmaceutically acceptable salt; 3 3) Hydrogenating a compound of formula 3 or a pharmaceutically acceptable salt thereof to form a compound of formula 4 or a pharmaceutically acceptable salt thereof; 4 and 4) Boronize a compound of formula 4 or a pharmaceutically acceptable salt thereof to form a compound of formula 5 or a pharmaceutically acceptable salt thereof; b) Prepare a compound of formula 6 or a pharmaceutically acceptable salt thereof. 6 This includes treating isoquinoline-3-ol with a trifluoromethanesulfonylating agent; and c) Coupling a compound of Formula 6 or a pharmaceutically acceptable salt thereof with a compound of Formula 5 or a pharmaceutically acceptable salt thereof to form a compound of Formula 7 or a pharmaceutically acceptable salt thereof; 7 and d) Demethylating the compound of formula 7 to form the compound of formula 8 or a pharmaceutically acceptable salt thereof; Steps a and b can be performed in any order or simultaneously in different reaction vessels.

32. The method of claim 31, further comprising purifying the compound of formula 8.

33. The method of claim 32, wherein the purification comprises crystallization.

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