阅读说明：本技术 Ccr6或cxcr2拮抗剂治疗泛发性脓疱型银屑病的方法 (Methods of treating generalized pustular psoriasis with CCR6 or CXCR2 antagonists ) 是由 J·J·坎贝尔 K·埃伯斯华斯 A·卡拉辛斯基 V·R·马利 J·麦克马洪 R·辛格 杨 于 2019-01-07 设计创作，主要内容包括：本公开尤其提供了通过施用有效量的趋化因子受体6(CCR6)拮抗剂和/或C-X-C基序趋化因子受体2(CXCR2)拮抗剂来治疗泛发性脓疱型银屑病(GPP)的方法。本文还提供了在有需要的受试者中调节失调的IL-36信号传导的方法和在有需要的受试者中减少嗜中性白细胞、炎性树突细胞(iDC)和/或CD4T细胞聚积的方法,所述方法包括施用有效量的趋化因子受体6(CCR6)拮抗剂和/或CXC基序趋化因子受体2(CXCR2)拮抗剂。在一些实施方式中,CCR6和/或CXCR2拮抗剂具有下式：<Image he="384" wi="700" file="DDA0002667523180000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The disclosure particularly providesMethods of treating generalized psoriasis (GPP) by administering an effective amount of a chemokine receptor 6(CCR6) antagonist and/or a C-X-C motif chemokine receptor 2(CXCR2) antagonist are provided. Also provided herein are methods of modulating dysregulated IL-36 signaling in a subject in need thereof and methods of reducing neutrophil, Inflammatory Dendritic Cell (iDC), and/or CD4T cell accumulation in a subject in need thereof, comprising administering an effective amount of a chemokine receptor 6(CCR6) antagonist and/or a CXC motif chemokine receptor 2(CXCR2) antagonist. In some embodiments, the CCR6 and/or CXCR2 antagonist has the formula:)

1. A method of treating a disease or condition in a subject in need thereof, the disease or condition selected from the group consisting of: extensive pustular psoriasis (GPP), palmoplantar psoriasis (PPP), acute generalized pustular pustulosis (age), Hidradenitis Suppurativa (HS), dermatitis herpetiformis, and pemphigus vulgaris, the method comprising administering to the subject an effective amount of a chemokine receptor 6(CCR6) and/or CXC motif chemokine receptor 2(CXCR2) antagonist.

2. The method of claim 1, wherein the disease or condition is Generalized Pustular Psoriasis (GPP).

3. The method of claim 1, wherein the disease or condition is palmoplantar psoriasis (PPP).

4. The method of claim 1, wherein the disease or condition is Acute Generalized Eruptive Pustulosis (AGEP).

5. The method of claim 1, wherein the disease or condition is Hidradenitis Suppurativa (HS).

6. The method of claim 1, wherein the disease or condition is dermatitis herpetiformis.

7. The method of claim 1, wherein the disease or condition is pemphigus vulgaris.

8. A method of modulating dysregulated IL-36 signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a chemokine receptor 6(CCR6) and/or C-X-C motif chemokine receptor 2(CXCR2) antagonist.

9. A method of reducing accumulation of neutrophils, Inflammatory Dendritic Cells (iDC), and/or CD4T cells in a subject in need thereof comprising administering to the subject an effective amount of a chemokine receptor 6(CCR6) and/or CXC motif chemokine receptor 2(CXCR2) antagonist.

10. The method of claim 9, wherein the method reduces the accumulation of neutrophils, iDC and CD4T cells.

11. The method of any one of claims 1 to 10, wherein the chemokine receptor 6(CCR6) and/or C-X-C motif chemokine receptor 2(CXCR2) is a dual CCR6/CXCR2 antagonist.

12. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

wherein

B is selected from the following group: furyl, thienyl, oxazolyl, phenyl, pyridyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with R^1a、R^1bAnd R²Substituted, R^1a、R^1bAnd R²Independently selected from the group consisting of: halogen, CN, C _1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

R³is a member selected from the group consisting of: h and D;

R⁴is a member selected from the group consisting of: H. c_1-8Alkyl, OH, -NR^aR^b、-C_1-4Alkoxy and Y; wherein, C_1-8Alkyl optionally substituted by halogen, -CN, -CO₂R^a、-CONR^aR^b、-C(O)R^a、OC(O)NR^aR^b、-NR^aC(O)R^b、-NR^aC(O)₂R^c、-NR^aC(O)NR^aR^b、-NR^aR^b、-OR^a、-S(O)₂NR^aR^b、-NR^aS(O)₂R^bAnd Y is substituted, wherein Y is a 4-to 8-membered cycloheteroalkyl or 3-to 8-membered cycloheteroalkyl or 5-or 6-membered aryl or heteroaryl, each of which is optionally substituted with 1 to four substituents selected from halo, oxo, -CN, -C_1-6Alkyl, -C_1-6Alkoxy, -C_1-6Hydroxyalkyl, -C_1-6Haloalkyl, O-C_1-6Haloalkyl, -C_1-4alkyl-O-C_1-4Alkyl, -C_1-6alkyl-NR^aR^b、-C_1-6alkyl-CO₂H、-C_1-6alkyl-CO₂R^a、-C_1-6alkyl-CONR^aR^b、-C_1-6alkyl-C (O) R^a、-C_1-6alkyl-OC (O) NR^aR^b、-C_1-6alkyl-NR^aC(O)R^b、-C_1-6alkyl-NR^aC(O)₂R^c、-C_1-6alkyl-NR^aC(O)NR^aR^b、-C_1-6alkyl-OR^a、-C_1-6alkyl-S (O)₂NR^aR^b、-C_1-6alkyl-NR^aS(O)₂R^b、-CO₂R^b、-CONR^aR^b、-C(O)R^a、-OC(O)NR^aR^b、-NR^aC(O)R^b、-NR^aC(O)₂R^c、-NR^aC(O)NR^aR^b、-NR^aR^b、-OR^a、-S(O)₂NR^aR^b、-NR^aS(O)₂R^b、-CH₂CO₂R^a(ii) a Each R^aAnd R^bIndependently selected from: hydrogen, C_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_1-4Haloalkyl, and R^cSelected from: c_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_1-4A haloalkyl group; wherein the 4 to 8 membered cycloheteroalkyl group and the 3 to 8 membered cycloalkyl group may be further optionally substituted with oxo;

R^5aand R^5bEach independently is a member selected from the group consisting of: H. halogen, C_1-4Alkyl, -C_1-4Haloalkyl, O-C_1-4Haloalkyl, C_1-4Alkoxy, CO₂H and CN;

R^6aand R^6bEach independently is a member selected from the group consisting of: H. c_1-4Alkyl radical, C _1-4Hydroxyalkyl and C_1-4A haloalkyl group; or optionally, R^6aAnd R^6bTogether form an oxo (═ O) or 4 to 6 membered cycloheteroalkyl group or a 3 to 6 membered cycloalkyl group;

R⁷is a member selected from the group consisting of: methyl, ethyl and C_1-2A haloalkyl group; and

subscript n is 1 or 2;

or any pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof.

13. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

or any salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein

B is selected from the following group: furyl, oxazolyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted by R^1a、R^1bAnd R²Substituted, R^1a、R^1bAnd R²Independently selected from the group consisting of: halogen, CN, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

R³is a member selected from H and D: (ii) a

R⁴Is selected from H, C_1-8Members of alkyl and Y; wherein, C_1-8Alkyl optionally substituted by halogen, -CN, -CO₂R^a、-CONR^aR^b、-C(O)R^a、OC(O)NR^aR^b、-NR^aC(O)R^b、-NR^aC(O)₂R^c、-NR^aC(O)NR^aR^b、-NR^aR^b、-OR^a、-S(O)₂NR^aR^b、-NR^aS(O)₂R^bAnd Y, wherein each R^aAnd R^bIndependently selected from: hydrogen, C_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_1-4Haloalkyl, R^cSelected from: c_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_1-4Haloalkyl, and Y is a 5-or 6-membered aryl or heteroaryl, optionally substituted with one to four substituents selected from halogen, -CN, -C _1-4Alkyl, -C_1-4Alkoxy, -C_1-4Hydroxyalkyl, -C_1-4Haloalkyl, OCF₃、-CO₂R^a、-CONR^aR^b、-C(O)R^a、-OC(O)NR^aR^b、-NR^aC(O)R^b、-CH₂CO₂R^aSubstituted with the substituent(s);

R^5aand R^5bEach independently selected from H, halogen, C_1-4Alkyl radical, C_1-4Alkoxy, CO₂Members of H and CN;

R^6aand R^6bEach independently is selected from H, C_1-4Alkyl radical, C_1-4Hydroxyalkyl and C_1-4A member of haloalkyl; or optionally R^6aAnd R^6bTaken together to form oxo (═ O); and

subscript n is 1 or 2.

14. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

wherein

R^1aSelected from: CH (CH)₃And Cl;

R^1bis H or CH₃；

R³Is H or D;

R⁴is H or Y;

R^5aand R^5bEach independently selected from: H. f, Cl, Br and CH₃；

R^6aAnd R^6bEach independently selected from: h and CH₃(ii) a And

R⁷is methyl or ethyl; or

A pharmaceutically acceptable salt, solvate or hydrate thereof.

15. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist is a compound of figure 1.

16. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

Or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

or a pharmaceutically acceptable salt thereof.

19. The method of any one of claims 1 to 10, wherein the CCR6 and/or CXCR2 antagonist has the formula:

or a pharmaceutically acceptable salt thereof.

20. The method of any one of claims 1 to 19, wherein the subject is a human subject.

Background

Generalized Pustular Psoriasis (GPP) is a rare disease, lacking clinical research, and has no generally accepted evidence-based guidelines for its treatment and management (Benjegrerdes et al Psoriasis (Psoriasis) (Auckl) 2016; 6: 131-44.). Biotherapeutics effective in the more common plaque form of psoriasis have not been developed in GPP (Benjegerdes et al psoriasis (Auckl), 2016; 6:131-44 Mansouri et al biotherapeutic Expert reviews (Expert Opin Biol Ther) 2013; 13(12):1715-30.), as well as treatment methods directly in line with the urgent need of GPP (Mahil et al symposium of immunopathology 2016; 38(1):11-27.Navarini et al, journal of european dermatology and venereal society (J Eur AcadDermatol vector), 2017; 31(11):1792-9.Robinson et al, journal of american dermatology phase (J Am acaddetol), 2012; 67(2): 279-88).

The present disclosure addresses the need for promising therapies to target and improve GPP symptoms, and also provides related advantages

Disclosure of Invention

The present disclosure provides methods of treating Generalized Pustular Psoriasis (GPP), palmoplantar psoriasis (PPP), acute generalized eruption (age), Hidradenitis Suppurativa (HS), dermatitis herpetiformis, and/or pemphigus vulgaris, comprising administering an effective amount of a chemokine receptor 6(CCR6) and/or CXC motif chemokine receptor 2(CXCR2) antagonist.

In another aspect, provided herein is a method of modulating dysregulated IL-36 signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of an antagonist of chemokine receptor 6(CCR6) and/or CXC motif chemokine receptor 2(CXCR 2).

In another aspect, provided herein is a method of reducing neutrophil, Inflammatory Dendritic Cell (iDC), and/or CD4T cell accumulation in a subject in need thereof, comprising administering to the subject an effective amount of a chemokine receptor 6(CCR6) and/or C-X-C motif chemokine receptor 2(CXCR2) antagonist.

In some embodiments, the CCR6 and/or CXCR2 antagonist has the formula:

the variables are explained below.

In some embodiments, the CCR6 and/or CXCR2 antagonist has the formula:

the variables are explained below.

In some embodiments, the CCR6 and/or CXCR2 antagonist is a compound as shown in figure 1.

In some embodiments, the CCR6 and/or CXCR2 antagonist is compound 1.129:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the CCR6 and/or CXCR2 antagonist is compound 1.123:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the CCR6 and/or CXCR2 antagonist is compound 1.136:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the CCR6 and/or CXCR2 antagonist is compound 1.138:

or a pharmaceutically acceptable salt thereof.

Brief description of the drawings

FIGS. 1A-1AJ provide specific structures for the compounds described herein.

FIGS. 2A-D show gating protocols for identifying iDCs, neutrophils and CD4 isolated from IL-36 treated skin (discussed in FIGS. 3, 5 and 5)⁺α β T cells. First the cells were in live CD45⁺The cell population was gated with Thy-1 and CD11b (FIG. A). Cells circled in the lower left corner gated with Ly6C and Ly6G to identify iDC and neutrophils (panel B). The cells circled in the upper left corner of FIG. A are then gated with TCR α β and TCR γ (FIG. C). Cells circulating in panel C were gated on CD8 α and CD4 to identify CD4⁺T α β cells (panel D).

Figures 3A-D show distinct inflammatory cell skin infiltration in the Imiquimod (Imiquimod) model of plaque psoriasis and the IL-36 model of GPP. FIGS. A and B show the number of cells per gram isolated from four days (each day) of mice treated with IMQ (A, horizontally striped gray bars) or IL-36 α (B, obliquely striped gray bars black bars indicate the number of cells per gram isolated from control-treated skin (topical Vaseline (VAS) (A) for the Imquimod experiment and intradermal PBS (B) for the IL-36 experiment.) FIG. C shows the relative representation of the subpopulations of leukocytes in IL-36-treated and imiquimod-treated skin: comparisons between experiments: calculation of total active CD45 for 5 imiquimod experiments and 7 IL-36 experiments (at least 5 mice per experiment) ⁺Percentage of infiltrating T cells, neutrophils, and iDC. Showing the mean (and SEM) of these experimentsAverage value. Panel D shows the percentage of T cells expressing the indicated immunophenotype isolated from mouse skin following treatment with imiquimod (horizontally striped gray bars) or IL-36 α (obliquely striped gray bars). Each bar represents the mean and SEM of ten mice from a single experiment (representing at least 5 replicates). All populations shown were first alive (AQUA alive/dead negative) and CD45⁺And a door is arranged. For panels a and b, T cells were taken as Thy-1 expressing TCR β or TCR γ⁺/CD11b^-The cells are gated. Ly6G⁺And Ly6C^hi/Ly6G^-Cells were in Thy-1^-and/Cd 11b + population range gating. For panel c, each indicated population expressed Thy-1 of TCR β or TCR γ⁺/CD11b^-And calculating the percentage of the total population.

Fig. 4A-B show multiple analyses of CCL20 and CXCL2 proteins, which demonstrated a significant increase in both proteins following 4 days of daily intradermal injection of IL-36 α. CCL20 protein levels are plotted in panel a; CXCL2 protein levels are plotted in panel B.

Figures 5A-C show that leukocytes accumulated in the skin in response to intradermal injection of IL-36 α express CCR6 and CXCR 2. Cells isolated from IL-36 treated ears of 20 mice were pooled and stained with unconjugated specific MAb (as shown above each column) or isotype matched controls, followed by secondary MAb staining using standard procedures. Unbound secondary (secondstage) was blocked by normal mouse, rat and hamster serum, followed by a directly labeled monoclonal antibody. Gating for each cell type is shown to the left of each row: myeloid cells are panel a; neutrophil granulocytes are panel B; CD 4T cells are panel C. If the percentage of cells brighter than the isotype matched control is greater than 5%, it is indicated in the flow cytometer. Pooled cell staining represents 4 replicates.

FIGS. 6A-B show that Compound 1.136 improved inflammatory swelling in the ear injected with IL-36 α. Panel A plots ear thickness of mice administered compound 1.136 (or α -IL-17RA) daily at the indicated dose during the IL-36 α -induced GPP model. After 4 days of treatment, the ear thickness was measured with a caliper. The time course of ear thickness for the experiment shown in panel B (A), compares the 90mg/kg dose of Compound 1.136 with α -IL-17 RA. Ten mice per data point. Statistics from the Whitney rank order test. Note that: titration experiments showed that the effect of α -IL-17RA was stable at 200 μ g per mouse per day, and mice in this experiment were dosed at 500 μ g per mouse per day (data not shown). n.s., not significant p 05, p 0005, p 0001.

Fig. 7A-B show ear thickness data. Panel A shows the time course of titration for Compound 1.136 (as shown in FIG. 6A). Panel B shows isotype-matched controls for anti-IL-17 RA treated IL-36 α inflamed skin. The ears of five mice per group were inflamed by daily intradermal injection of PBS or activated IL-36 α as described herein. Some groups also received intraperitoneal injections of 500. mu.g/mouse of anti-IL-17 RA or 500. mu.g/mouse of anti-IgG-17 a MAb per day of rat IgG2a isotype-matched negative controls. The mann-whitney ranking test established significant significance between anti-IL-17 RA Mab and their isotype matched controls on days 3, 4 and 5. P <0.05, p < 0.01. Although the effect of anti-IL 17RA was saturated at a dose of 200. mu.g/mouse/day (compared to 500. mu.g/mouse/day in FIG. 3), anti-IL-17 RA was compared to its isotype-matched control at a dose of 500 mg/kg/day to demonstrate that even at these very high concentrations, the effect was not isotype-nonspecific.

FIGS. 8A-D show that Compound 1.136 substantially improved the histology of the IL-36 α -injected ear. Ears were harvested from sacrificed mice 4 days after 90mg/kg IL-36 α or PBS treatment (panel A PBS + vehicle; panel B IL-36+ vehicle). During the treatment period, mice were dosed daily with 1% HPMC (vehicle for Compound 1.136; panels A & B), and Compound 1.136 in vehicle (panel C) or anti-IL 17RA (panel D). Ears were fixed and embedded using standard FFPE techniques, sectioned, and stained using hematoxylin and eosin (H & E) staining techniques. The slices shown represent at least five different slices from five different ears.

Figures 9A-B show that compound 1.136 substantially reduced the thickness of the epidermis of the ear injected with activated IL-36 a. Panel a, first row shows a section of the entire width of the ear after 4 days of IL-36 α injection. Panel a, second row shows a higher magnification image focused on the lesion region of the top image. Panel a, lines 3 and 4 show the diseased regions of compound 1.136 treated IL-36 α treated mouse ears and mouse ears injected with PBS instead of IL-36 α. The black bars represent the position of each 7 individual epidermal thickness measurements for all slices plotted in graph B. Panel B, ear thickness measurements from 8 mice from each treatment group. Each point represents the average of 7 epidermal thickness measurements for 1 mouse ear. After 4 days of activated IL-36 α (or PBS) treatment, ears were obtained from sacrificed mice. During the treatment, mice were injected subcutaneously daily with 1% HPMC (vehicle), and 90 mg/kg/day compound 1.136 (in vehicle) s.c, or with IP200 μ g/mouse/day anti-IL 17RA (in PBS). Ears were fixed and embedded using standard FFPE techniques, sectioned, and stained using hematoxylin and eosin (H & E) staining techniques. The slices shown represent at least five different slices from eight different ears. Statistics p <.05 from the mann-whitney rating test.

Figures 10A-C show that compound 1.136 significantly reduced the accumulation of CD4T cells (panel a), neutrophils (panel B), and inflammatory dendritic cells (panel C) in IL-36 treated skin. After 4 days IL-36 α (or PBS control) treatment, ears were harvested from sacrificed mice. IL-36 α -injected mice were dosed with vehicle, compound 1.136 (s.c.90mg/kg/day dorsal) or α -IL-17RA (200 μ g/mouse/day peritoneal). Statistical analysis was performed by the mann-whitney rating test. Each group of 10 mice was tested and represented 3 replicates. n.s. not significant, p < 005, p < 0001.

FIGS. 11A-E show Ly6C accumulating in skin following intradermal injection of IL-36 α^hiCharacteristics of myeloid cells. After 4 days of IL-36 α injection, cells were isolated from 20 ears, then pooled and stained with unbound specific MAb (as shown in each figure, light gray curve) or isotype matched control (dark gray curve), followed by staining with anti-Ig secondary (secondstage) polyclonal Ab using standard procedures. Unbound secondary was blocked by normal mouse, rat and hamster serum, followed by a directly conjugated MAb antibody. Panel a uses MAb specific for CD 103; panel B uses Flt 3-specific MAbs; panel C uses MAb specific for CD 205; panel D uses MAb specific for CD11 c; drawing E makes MAb specific for F4/80 was used. Myeloid cells were gated as shown in FIG. 5A. The pooled cell staining shown represents 3 replicates.

Detailed Description

General purpose

Generalized Pustular Psoriasis (GPP) is a rare inflammatory skin disease with a different etiology than the more common plaque psoriasis. GPP patients generally do not respond to the therapeutic agents commonly used for plaque psoriasis. Antagonists of CCR6 and/or CXCR2, including the compounds disclosed herein, have been previously shown to reduce inflammation in plaque psoriasis models. Surprisingly, the present disclosure demonstrates that antagonists of CCR6 and/or CXCR2 can be used to effectively treat Generalized Pustular Psoriasis (GPP). In addition to treating GPP, the methods described herein can be used to treat related diseases such as palmoplantar psoriasis (PPP), acute generalized eruptive pustulosis (PNP), Hidradenitis Suppurativa (HS), dermatitis herpetiformis, and pemphigus vulgaris.

Chemokine targeted therapy is intended to prevent the migration of inflammatory leukocytes from the peripheral blood into the tissue, thereby preventing their involvement in and amplifying any existing autoimmune lesions to dissipate the inflammatory cytokine milieu. Genetic studies have shown that GPP is closely associated with IL-36 cytokine axis dysfunction and that many aspects of GPP can be reconstituted in mice by intradermal injection of pre-activated IL-36 α cytokines. The present disclosure demonstrates that immune cells infiltrating the skin of mice injected with IL-36 α have a significantly different composition than immune cells infiltrating imiquimod (IMQ-) treated skin (a well-established model of Balb/c plaque psoriasis in mice). The findings disclosed herein indicate that CCR6 and CXCR2 antagonists may constitute a novel target class of therapeutic approaches with unique mechanisms for the treatment of GPP and related PPP, age, HS, dermatitis herpetiformis, and pemphigus vulgaris diseases.

Abbreviations and Definitions

Unless otherwise indicated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

Unless otherwise indicated, the term "alkyl", by itself or as anotherPart of the substituent means having a specified number of carbon atoms (i.e., C)_1-8Refers to a straight or branched chain hydrocarbon group of 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term "cycloalkyl" refers to a ring having the indicated number of ring atoms (e.g., C)_3-6Cycloalkyl) and fully saturated or having no more than one double bond between the ring vertices. "cycloalkyl" may also refer to bicyclic hydrocarbon rings and polycyclic hydrocarbon rings, e.g., bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, and the like.

The term "cycloheteroalkyl" refers to a cycloalkyl ring having the indicated number of ring vertices (or members) and having one to five heteroatoms selected from N, O and S in place of one to five carbon vertices, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. The cycloheteroalkyl group may be a monocyclic, bicyclic, or polycyclic ring system. Non-limiting examples of cycloheteroalkyl groups include: pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1, 4-dioxane, morpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Cycloheteroalkyl groups can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

As used herein, a wavy line intersecting a single, double, or triple bond in any of the chemical structures described herein

Represents the point of attachment of a single, double or triple bond to the rest of the molecule. Further, a bond extending to the center of a ring (e.g., a benzene ring) means a connection at any available ring vertex. One skilled in the art will appreciate that multiple substituents shown as attached to a ring will occupy the ring vertex, which provides a stable compound and additionallyAre spatially compatible. For divalent moieties, the representation is meant to include either direction (forward or reverse). For example, the group "-c (o) NH-" is meant to include bonds in either direction: -C (O) NH-or-NHC (O) -, and similarly, "-O-CH₂CH₂- "is intended to include both-O-CH₂CH₂-and-CH₂CH₂-O-。

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. In addition, for dialkylamino groups, the alkyl moieties can be the same or different and can be attached to the 3-7 membered ring through the nitrogen atom to which each is attached. Thus, groups represented by dialkylamino or NRaRb include piperidinyl, pyrrolidinyl, morpholinyl, azaridinyl and the like

Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C_1-4Haloalkyl "is meant to include trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, usually aromatic, hydrocarbon group that can be a single ring or multiple rings (up to three rings) that are fused together or linked covalently. Non-limiting examples of aryl groups include: phenyl, naphthyl, and biphenyl.

The term "heteroaryl" refers to an aryl (or ring) containing one to five heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Heteroaryl groups may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include: pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzpyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. The substituents of the heteroaryl ring may be selected from the acceptable substituents described below.

In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") can be optionally substituted. Selected substituents for each type of group are provided below.

Optional substituents for alkyl (including those groups commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) are selected from the following: halogen, -OR ', -NR' R ', -SR', -SiR 'R' ", -OC (O) R ', -C (O) R', -CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O)₂R’、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R ", -CN and-NO₂(ii) a From zero to a number of (2m '+ 1), where m' is the total number of carbon atoms in the group. R ', R ' and R ' each independently mean hydrogen, unsubstituted C_1-8Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C_1-8Alkyl radical, C_1-8Alkoxy or C_1-8Thioalkoxy or unsubstituted aryl-C_1-4An alkyl group. When R' and R "are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 3, 4, 5, 6 or 7 membered ring. For example, -NR' R "is meant to include 1-pyrrolidinyl and 4-morpholinyl.

Similarly, the aryl and heteroaryl substitutents are varied and are generallySelected from: -halogen, -OR ', -OC (O) R ', -NR ' R ", -SR ', -R ', -CN, -NO ₂、-CO₂R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R”’、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R”、-N₃Perfluoro (C)₁-C₄) Alkoxy and perfluoro (C)₁-C₄) Alkyl groups in a number ranging from zero to the total number of open valences on the aromatic ring system; and wherein R ', R ", and R'" are independently selected from: hydrogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-6Cycloalkyl radical, C_2-8Alkenyl and C_2-8Alkynyl. Other suitable substituents include the various aryl substituents described above attached to the ring atoms through an alkylene group of 1 to 4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted by a group of formula-T-C (O) - (CH)₂)_q-U-substituent, wherein T and U are independently-NH-, -O-, -CH₂-or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted by a group of formula-A- (CH)₂)_rA substituent of-B-, wherein A and B are independently-CH₂-, -O-, -NH-, -S-, -S (O) -, -S (O)2-, -S (O)2 NR' or a single bond, and r is an integer of 1 to 3. One of the single bonds of the new ring so formed may be optionally substituted by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a group of formula- (CH)₂)_s-X-(CH₂)_t-substituent (S) wherein S and t are independently an integer from 0 to 3, and X is-O-, -NR' -, -S (O) ₂-or-S (O)₂NR' -. At NR' -and-S (O)₂The substituents R 'in NR' are selected from hydrogen or unsubstituted C_1-6An alkyl group.

As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

When variable (e.g., R)¹Or R^a) When occurring more than one time in any compound or substituent, its definition at each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are Salts of amino acids such as arginine and the like, and Salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge, s.m., et al, "pharmaceutically acceptable Salts", Journal of Pharmaceutical Science (1977, 66, 1-19). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt is equivalent to the parent form of the compound for purposes of the present invention.

In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that are susceptible to chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical agent, the prodrug will slowly convert to a compound of the invention.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are intended to be included within the scope of the present invention. When a stereochemical description is shown, it refers to a compound in which one isomer is present and which is substantially free of the other isomer. By "substantially free" of the other isomer is meant at least an 80/20 ratio of the two isomers, more preferably 90/10 or 95/5 or more. In some embodiments, one of the isomers is present in an amount of at least 99%.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of isotopes can be defined from amounts found in nature to 100% of the amount made up of the atoms in question. For example, the compounds may incorporate radioactive isotopes (e.g., tritium(s) (iii))³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) Or a non-radioactive isotope (e.g. deuterium: (ll))²H) Or carbon-13 (¹³C) ). Such isotopic variations can provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may find other uses, including but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotoxic therapeutic agents. In addition, isotopic variations of the compounds of the present invention can have altered pharmacokinetic and pharmacodynamic profiles that can contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The terms "patient" or "subject" are used interchangeably and refer to a human or non-human animal (e.g., a mammal).

The terms "administering", "administration" or the like when used with respect to, for example, a subject, cell, tissue, organ or biological fluid, refer to contacting, for example, a CCR6 and/or CXCR2 antagonist, a pharmaceutical composition or diagnostic reagent comprising the same, with the subject, cell, tissue, organ or biological fluid. In the case of cells, administration includes contacting the agent with the cell (e.g., in vitro or ex vivo), and contacting the agent with a fluid, wherein the fluid is in contact with the cell.

The terms "treat," "treated," "therapy," and the like, refer to the initiation of a series of procedures (e.g., administration of a CCR6 and/or CXCR2 antagonist or a pharmaceutical composition comprising the same) after a disease, disorder or condition or symptoms thereof has been diagnosed, observed, or the like, to temporarily or permanently eliminate, alleviate, prevent, alleviate, or ameliorate at least one underlying cause of a disease, disorder, condition, or at least one symptom associated with a disease, disorder, condition in a subject. Thus, treatment includes inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms associated therewith) active disease.

As used herein, the term "in need of treatment" refers to the judgment made by a physician or other caregiver that a subject needs or will benefit from treatment. The determination is made based on a variety of factors within the expertise of the physician or caregiver.

The terms "prevent," "preventing," "prophylaxis," and the like, refer to a series of processes (such as administration of a CCR6 and/or CXCR2 antagonist or a pharmaceutical composition comprising the same) that are initiated in a manner (e.g., prior to onset of a disease, disorder, or condition, or symptoms thereof) to temporarily or permanently prevent, arrest, inhibit, or reduce the risk of a subject developing a disease, disorder, or condition, etc. (as determined by lack of clinical symptoms) or delay onset thereof, typically referring to a condition in which a subject is predisposed to the disease, disorder, or condition. In certain instances, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its development into a harmful or other undesirable condition.

As used herein, the term "in need of prophylaxis" refers to a judgment made by a physician or other caregiver that a subject needs or will benefit from. The determination is made based on a variety of factors within the expertise of the physician or caregiver.

The phrase "therapeutically effective amount" refers to an amount of an agent that, alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses, is capable of having any detectable positive effect on any symptom, aspect, or characteristic of a disease, disorder, or condition when administered to a subject. The therapeutically effective amount can be determined by measuring the relevant physiological effects and can be adjusted according to the dosing regimen and diagnostic analysis of the condition of the subject, etc. For example, measuring the serum level of CCR6 and/or CXCR2 antagonist (or e.g., metabolites thereof) at a particular time after administration can indicate whether a therapeutically effective amount has been used.

The phrase "in an amount sufficient to effect an alteration" means that there is a detectable difference between the indicator level measured before (e.g., the baseline level) and after administration of the particular therapy. The index includes any objective parameter (e.g., serum concentration) or subjective parameter (e.g., the subject's well-being).

The term "small molecule" refers to a compound having a molecular weight of less than about 10kDa, less than about 2kDa, or less than about 1 kDa. Small molecules include, but are not limited to, inorganic molecules, organic molecules containing inorganic components, molecules containing radioactive atoms, and synthetic molecules. Therapeutically, small molecules may be more permeable to cells, less susceptible to degradation, and larger molecules less likely to elicit an immune response.

The terms "inhibitor" and "antagonist", or "activator" and "agonist" refer to inhibitory or activating molecules, respectively, e.g., for activating, e.g., a ligand, receptor, cofactor, gene, cell, tissue, or organ. An inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or down regulates, for example, a gene, protein, ligand, receptor, or cell. An activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks or inactivates intrinsic activity. An "agonist" is a molecule that interacts with a target to cause or promote an increase in the activity of the target. An "antagonist" is a molecule that antagonizes the action of an agonist. Antagonists prevent, reduce, inhibit or neutralize the activity of an agonist, and antagonists may also prevent, inhibit or reduce the intrinsic activity of a target, e.g., a target receptor, even in the absence of a defined agonist.

The terms "modulate", "modulation" and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of CCR6 and/or CXCR 2. Modulators may function alone, or cofactors such as proteins, metal ions, or small molecules may be used.

The "activity" of a molecule may describe or refer to the binding of the molecule to a receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation or maturation; an antigenic activity; modulating the activity of other molecules; and so on.

As used herein, "comparable", "comparable activity", "activity comparable to …", "comparable effect", "effect comparable to …" and the like are relative terms that can be observed quantitatively and/or qualitatively. The meaning of terms is generally dependent upon their context of use. For example, two drugs that both activate a receptor may be considered to have comparable effects from a qualitative standpoint, but if the activity of one drug is only 20% of the activity of the other drug as determined in an art-accepted assay (e.g., a dose-response assay) or in an art-accepted animal model, then from a quantitative standpoint, the two drugs may be considered to lack comparable effects. "comparable" when comparing one result to another (e.g., one result to a reference standard) often (although not always) means that one result deviates from the reference standard by less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In particular embodiments, a result is comparable to a reference standard if the deviation of the result from the reference standard is less than 15%, less than 10%, or less than 5%. By way of example, and not limitation, activity or effect may refer to potency, stability, solubility, or immunogenicity.

By "substantially pure" is meant that the component comprises greater than about 50% of the total composition, and typically greater than about 60% of the total composition. More typically, "substantially pure" means that at least 75%, at least 85%, at least 90% or more of all components in the composition are the component of interest. In some cases, the component of interest will comprise greater than about 90%, or greater than about 95%, of the total content of the composition.