JP2023506118A - Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and lichen planus (LP) - Google Patents

Abstract

The present application provides a method for doing so in a patient in need of treating a disease selected from cutaneous lupus erythematosus (CLE) and lichen planus (LP), and provides such a patient with a JAK1 selective inhibitor, or and administering the pharmaceutically acceptable salt thereof in a therapeutically effective amount.

Description

The present application provides methods for the treatment of cutaneous lupus erythematosus and/or lichen planus (LP) using compounds that modulate the activity of Janus kinase (JAK) 1.

Cutaneous lupus erythematosus (CLE) is an inflammatory autoimmune skin disease with heterogenic subtypes that varies from focal discoid plaques to severe, widespread erythrosquamous lesions in affected patients (e.g. , Kuhn & Landmann, J. Autoimmun.2014, 48-49:14-19). This disease is typically histologically termed "interfacial dermatitis" (ID), consisting of colloidal bodies and anti-epithelial cytotoxic lymphocytic infiltrates at the epidermal-dermal junction organized by IFN-regulated inflammatory cytokines. Patterns are characterized (see, eg, Wenzel & Tuting, J. Invest. Dermatol. 2008, 128:2392-2402 and Wenzel et al, Br. J. Dermatol. 2007, 157:752-757).

CLE is multifactorial in origin and includes both genetic and environmental risk factors (eg Kunz et al, Exp. Dermatol. 2015, 24:510-515, Sinha & Dey-Rao, J. Proc., 2017, 18:S75-S80 and Szczech et al, Lupus, 2017, 26:791-807). Ultraviolet radiation, in particular, promotes cell damage, apoptosis and the release of DNA-containing blebs. Clearance of cellular debris is impaired and is thought to be associated with secondary necrosis (eg, Kuhn et al, Arthritis Rheum. 2006, 54:939-950, Caricchio et al, The Journal of Immunology 2003, 171 : 5778-5786, and Mahajan et al, Front Immunol. 2016, 7). In some cases, such as familial chilliform lupus, TREX1 gene mutations may be the underlying cause, leading to TREX1 exonuclease dysfunction and hyperaccumulation of cytoplasmic DNA (see, e.g., Gunther et al, J. Am. Acad. 2013, 69: e179-81, Grieves et al, Proc. Natl. Acad. 162-166, and Peschke et al, J. Invest. Dermatol. 2014, 134:1456-1459).

When nuclear components such as endogenous nucleic acid motifs are released out of the nucleus due to cell damage, they can be recognized as damage-associated molecular patterns (DAMPs) (e.g. Scholtissek et al, J. Invest. Dermatol. 2017 , 137:1484-1492). In CLE, keratinocytes, particularly plasmacytoid dendritic cells (pDCs), respond inappropriately to DAMPs, with massive type I IFN production via TLR-dependent or TLR-independent pathways. There is evidence (e.g., Mustelin et al, Front. Immunol. 2019, 10:238, Wollenberg et al, J. Invest. Dermatol. 2002, 119:1096-1102, Wenzel et al, Arch. Dermatol. Res. 2009, 301:83-86, Yu et al, J. Autoimmun.2013, 41:34-45, and Katayama et al, J. Invest.Dermatol.DOI:10.1016/j.jid.2019.02.035 ). Once the autocrine loop occurs, IFN binds to IFN-α/β receptors on keratinocytes, which activates the JAK/STAT pathway and the expression of inflammatory mediators such as CXCL10. CXCL10 is known to recruit CXCR3+ effector cells and pDCs to skin lesions (see, eg, Wenzel et al, Arch. Dermatol. Res. 2009, 301:83-86, and Wenzel et al, J. Pathol. 2005, 205:435-442). These effector cells are associated with keratinocyte necroptosis (see, e.g., Lauffer et al, J. Invest. Dermatol. 2018, 138:1785-1794), cytokine release and sustained cytotoxicity as a hallmark of chronic inflammation. Inducing "self-recruitment" (see, eg, Meller et al, Arthritis Rheum. 2005, 52:1504-1516).

This ring can put a heavy burden on the quality of life (eg Samotij et al, Postepy Dermatol. Alergol. 2018, 35:192-198 and Ogunsanya et al, Int. J. Womens Dermatol. 2018, 4:152 -158). According to current guidelines, corticosteroids and antimalarials have been established as first-line treatments for CLE. However, corticosteroids are limited by side effects that can make long-term treatment difficult, especially in antimalarial drug-resistant patients. In addition, there are no drugs specifically approved for CLE, and only a few clinical trials have been conducted, especially due to clinical heterogeneity and the resulting difficulty in trial design (e.g., Chen et al. , F1000 Res. 2019, 8).

The American College of Rheumatology (ACR) has established a scheme of 11 clinical and laboratory criteria intended to distinguish systemic lupus erythematosus (SLE) from other autoimmune diseases. Although the ACR guidelines require that 4 of 11 criteria be met for the diagnosis of SLE, only 4 of those criteria are actually relevant to the skin (cheek rash, discoid lesion, mucosal ulcer). , and photosensitivity), so coexisting skin pathology is not essential for the diagnosis of SLE. Conversely, cutaneous lupus erythematosus (CLE) subtypes can occur in the absence of systemic disease (SLE), and CLE is two to three times more frequent than SLE (e.g., Tebbe & Orfanos, Lupus, 1997, 6). 2):96-104).

Given these limitations, new treatment options are medically needed. The present application is directed to this and other needs.

The present application provides a method of doing so in a patient in need of treating a disease selected from cutaneous lupus erythematosus (CLE) and lichen planus (LP), comprising administering to the patient JAK1 as provided herein. This includes administering a therapeutically effective amount of a selective inhibitor.

無発現から

強発現までのスコアリングによって半定量的に記録したｐＪＡＫ１の発現を示す（例えば、Ｗｅｎｚｅｌ ｅｔ ａｌ．Ｊ．Ｐａｔｈｏｌ．２００５，２０５：４３５－４４２を参照のこと）。全ての棒は、平均±ＳＥＭ、

（クラスカル・ワリス検定）を示す。
ＣＬＥの皮膚病変におけるＪＡＫ１発現の機能的役割を示す。健常対照者（ＨＣ）と比較した、ＣＬＥ病変皮膚におけるＩＦＮ関連遺伝子の発現上方制御を示す（２倍、ｐ＜０，０１；ウェルチのｔ検定）。 ＣＬＥの皮膚病変におけるＪＡＫ１発現の機能的役割を示す。ＣＬＥで上方制御されているＫＥＧＧパスウェイを示す。ＫＥＧＧパスウェイの分類は、Ｄａｔａｂａｓｅ ｆｏｒ Ａｎｎｏｔａｔｉｏｎ，Ｖｉｓｕａｌｉｚａｔｉｏｎ ａｎｄ Ｉｎｔｅｇｒａｔｅｄ Ｄｉｓｃｏｖｅｒｙ（ＤＡＶＩＤ ｖｅｒ．６．８）を使用して行った。ＥＡＳＥ ＳｃｏｒｅでＰ値を生成した。カウント：ＫＥＧＧパスウェイそれぞれの内部でＣＬＥにおいて２倍を超えて上方制御されている遺伝子の数。 培養角化細胞における、炎症性サイトカイン発現及びＩＦＮ関連遺伝子調節に対する薬理学的ＪＡＫ１阻害の効果を示す。刺激されたＨａＣａＴ（ｅＮＡ）、刺激され、かつ阻害剤処理されたＨａＣａＴ（ｅＮＡ＋ＪＡＫ１阻害剤｛１－｛１－［３－フルオロ－２－（トリフルオロメチル）イソニコチノイル］ピペリジン－４－イル｝－３－［４－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１Ｈ－ピラゾール－１－イル］アゼチジン－３－イル｝アセトニトリル（すなわち、ＩＮＣＢ０３９１１０）；ｅＮＡ＋ＪＡＫ１／２、阻害剤：ルキソリチニブ）、及び未刺激ＨａＣａＴ（Ｃ－培地）における、抗ｐＪＡＫ１抗体染色の面積強度平均をピクセル値で示す。Ｆｉｊｉソフトウェアを使用して測定を実施した。細胞群（ｅｎｔｉｔｙ）ごとの測定値（ｎ＝５）。散布図はいずれも、

を示す（マン－ホイットニーのＵ検定）。
培養角化細胞における、炎症性サイトカイン発現及びＩＦＮ関連遺伝子調節に対する薬理学的ＪＡＫ１阻害の効果を示す。ｅＮＡで刺激され、未処理か（ｅＮＡ）または阻害剤処理（ｅＮＡ＋ＪＡＫ１、阻害剤：ＩＮＣＢ０３９１１０；ｅＮＡ＋ＪＡＫ１／２、阻害剤：ルキソリチニブ）されたＨａＣａＴ細胞、及び未刺激ＨａＣａＴ細胞（培地対照）の代表的な免疫蛍光顕微鏡写真を示す。抗ｐＪＡＫ１抗体染色は赤、核のＤＡＰＩ染色は青、元の拡大率：４００倍。 培養角化細胞における、炎症性サイトカイン発現及びＩＦＮ関連遺伝子調節に対する薬理学的ＪＡＫ１阻害の効果を示す。ｅＮＡで刺激されたＮＨＥＫ（＋、４試料）内でのＣＬＥに典型的な遺伝子の発現、及びＪＡＫ１選択的ＩＮＣＢ０３９１１０による刺激ＮＨＥＫの処理（ＪＡＫ１；４試料）後に２倍を超えて下方制御された発現（ｐ＜０，０５；ウェルチのｔ検定）を示す。 培養角化細胞における、炎症性サイトカイン発現及びＩＦＮ関連遺伝子調節に対する薬理学的ＪＡＫ１阻害の効果を示す。２４時間のインキュベーション後の、刺激されたＨａＣａＴでのＣＸＣＬ１０発現に対する異なるＪＡＫ阻害剤の効果を示す。細胞を、ＪＡＫ１選択的ＩＮＣＢ０３９１１０（ＪＡＫ１）、ＪＡＫ１／２選択的ルキソリチニブ（ＪＡＫ１／２）及びＪＡＫ３選択的ＦＭ－３８１（ＪＡＫ３）で処理した。ＥＬＩＳＡにより測定した。全ての棒は、

（マン－ホイットニーのＵ検定）を示す。
培養角化細胞における、炎症性サイトカイン発現及びＩＦＮ関連遺伝子調節に対する薬理学的ＪＡＫ１阻害の効果を示す。刺激された細胞（ｅＮＡ、ｎ＝３）及び刺激後にＪＡＫ１阻害剤（ＩＮＣＢ０３９１１０）で処理された細胞（ｅＮＡ＋ＪＡＫ１、ｎ＝３）におけるＣＸＣＬ１０の発現を表す顕微鏡写真（元の拡大率：４００倍）、及び対応するＣＸＣＬ１０発現スコアを示す。全ての棒は、平均±ＳＥＭ、

（マン－ホイットニーのＵ検定）を示す。
ループス易発性のＴＲＥＸ１^－／－マウスモデルにおけるインビボでの薬理学的ＪＡＫ１阻害を示す。ＵＶ刺激（－３日目に開始；３ｘ４５０ｍＪ／ｃｍ^２で１１５秒間）を受けたＴＲＥＸ１^－／－マウス（ｎ＝８）の、ベースライン時（０日目、処置の開始）ならびにＪＡＫ１選択的ＩＮＣＢ０３９１１０またはプラセボによる処置から４日後及び７日後の臨床所見を示す。 ループス易発性のＴＲＥＸ１^－／－マウスモデルにおけるインビボでの薬理学的ＪＡＫ１阻害を示す。マウスに適応させて修正したＣＬＥ疾患の面積・重症度指数（マウスＲＣＬＡＳＩ）の平均スコア±ＳＥＭ（群あたりｎ＝４のマウス）を示す。 ループス易発性のＴＲＥＸ１^－／－マウスモデルにおけるインビボでの薬理学的ＪＡＫ１阻害を示す。病変皮膚の組織学的（Ｈ＆Ｅ）及び免疫組織学的（ＣＤ４５）顕微鏡写真（元の拡大率：４００倍）を示す。プラセボ処置マウス及びＪＡＫ１阻害剤処置マウスの病変皮膚における対応するＣＤ４５発現の炎症スコア。全ての棒は、平均±ＳＥＭ、

（マン－ホイットニーのＵ検定）を示す。 Functional role of JAK1 expression in CLE skin lesions. Patients with different inflammatory skin disorders (subacute cutaneous lupus erythematosus (SCLE, n=5), chronic discoid lupus erythematosus (CDLE, n=5), lichen planus (LP, n=6) and healthy controls (HC, Representative immunohistochemical sections (anti-phospho-JAK1 staining) from skin samples of n=5)) are shown (original magnification: ×200). Functional role of JAK1 expression in CLE skin lesions.

from no expression

Expression of pJAK1 recorded semiquantitatively by scoring to strong expression is shown (see, eg, Wenzel et al. J. Pathol. 2005, 205:435-442). All bars are mean ± SEM,

(Kruskal-Wallis test).
Functional role of JAK1 expression in CLE skin lesions. Expression upregulation of IFN-related genes in CLE lesional skin compared to healthy controls (HC) (2-fold, p<0.01;Welch's t-test). Functional role of JAK1 expression in CLE skin lesions. KEGG pathways upregulated in CLE. The KEGG pathways were classified using Database for Annotation, Visualization and Integrated Discovery (DAVID ver.6.8). P values were generated with the EASE Score. Counts: Number of genes upregulated >2-fold in CLE within each KEGG pathway. Effect of pharmacological JAK1 inhibition on inflammatory cytokine expression and IFN-related gene regulation in cultured keratinocytes. Stimulated HaCaT (eNA), Stimulated and inhibitor-treated HaCaT (eNA + JAK1 inhibitor {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (i.e., INCB039110); eNA + JAK1/2, inhibitor: ruxolitinib) and unstimulated HaCaT (C-medium) are shown as area intensity averages of anti-pJAK1 antibody staining in pixel values. Measurements were performed using Fiji software. Measured values for each cell group (entity) (n=5). Both scatterplots are

(Mann-Whitney U test).
Effect of pharmacological JAK1 inhibition on inflammatory cytokine expression and IFN-related gene regulation in cultured keratinocytes. Representative of eNA-stimulated, untreated (eNA) or inhibitor-treated (eNA+JAK1, inhibitor: INCB039110; eNA+JAK1/2, inhibitor: ruxolitinib) HaCaT cells and unstimulated HaCaT cells (medium control). Immunofluorescence micrographs are shown. Anti-pJAK1 antibody staining in red, nuclear DAPI staining in blue, original magnification: ×400. Effect of pharmacological JAK1 inhibition on inflammatory cytokine expression and IFN-related gene regulation in cultured keratinocytes. Expression of CLE-typical genes in eNA-stimulated NHEKs (+, 4 samples) and downregulated more than 2-fold after treatment of stimulated NHEKs with JAK1-selective INCB039110 (JAK1; 4 samples) Expression (p<0,05;Welch's t-test) is shown. Effect of pharmacological JAK1 inhibition on inflammatory cytokine expression and IFN-related gene regulation in cultured keratinocytes. Effect of different JAK inhibitors on CXCL10 expression in stimulated HaCaT after 24 hours of incubation. Cells were treated with JAK1-selective INCB039110 (JAK1), JAK1/2-selective ruxolitinib (JAK1/2) and JAK3-selective FM-381 (JAK3). Measured by ELISA. all bars are

(Mann-Whitney U test).
Effect of pharmacological JAK1 inhibition on inflammatory cytokine expression and IFN-related gene regulation in cultured keratinocytes. Photomicrographs depicting CXCL10 expression in stimulated cells (eNA, n=3) and cells treated with a JAK1 inhibitor (INCB039110) after stimulation (eNA+JAK1, n=3) (original magnification: ×400). and corresponding CXCL10 expression scores. All bars are mean ± SEM,

(Mann-Whitney U test).
In vivo pharmacological JAK1 inhibition in a lupus-prone TREX1 ^−/− mouse model. TREX1 ^−/− mice (n=8) receiving UV stimulation (beginning on day −3; 3×450 mJ/cm ² for 115 sec) at baseline (day 0, start of treatment) as well as JAK1-selective INCB039110 or clinical findings after 4 and 7 days of treatment with placebo. In vivo pharmacological JAK1 inhibition in a lupus-prone TREX1 ^−/− mouse model. Shown are mean scores ± SEM (n = 4 mice per group) of the mouse-adapted and corrected CLE Disease Area and Severity Index (Mouse RCLASI). In vivo pharmacological JAK1 inhibition in a lupus-prone TREX1 ^−/− mouse model. Histological (H&E) and immunohistological (CD45) photomicrographs of lesional skin (original magnification: ×400) are shown. Corresponding CD45 expression inflammation scores in lesional skin of placebo- and JAK1 inhibitor-treated mice. All bars are mean ± SEM,

(Mann-Whitney U test).

In particular, the present application provides methods of doing so in a patient in need of treating a disease selected from cutaneous lupus erythematosus (CLE) and lichen planus (LP), a JAK1 selective inhibitor, or a pharmaceutical agent thereof. administration of a therapeutically effective amount of a therapeutically acceptable salt. In some embodiments, the disease is cutaneous lupus erythematosus (CLE). In some embodiments, cutaneous lupus erythematosus (CLE) is selected from acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus erythematosus. In some embodiments, the cutaneous lupus erythematosus (CLE) is acute cutaneous lupus erythematosus. In some embodiments, the cutaneous lupus erythematosus is selected from subacute cutaneous lupus erythematosus (SCLE) and chronic discoid lupus erythematosus (CDLE). In some embodiments, the cutaneous lupus erythematosus is subacute cutaneous lupus erythematosus (SCLE). In some embodiments, the cutaneous lupus erythematosus is chronic discoid lupus erythematosus (CDLE). In some embodiments, the disease is lichen planus (LP).

As used herein, "cutaneous lupus" refers to a form of the disease in which symptoms are limited to those affecting the skin. For example, a patient may be diagnosed with cutaneous lupus, but that does not mean that the patient has SLE that affects multiple parts of the body. Similarly, if a patient has SLE, it does not necessarily mean that the patient has cutaneous lupus. To that end, the Cutaneous Lupus Area and Severity Index (CLASI) scoring system, which quantitatively measures disease activity and damage, has been devised (e.g., Albrecht et al., J. Invest. Dermatol. 2005, Nov. ; 125(5):889-94). This index takes into account lesion morphology and anatomic location and is subsequently validated by reliability tests for both dermatologists and rheumatologists.

Cutaneous lupus is divided into several subtypes, including acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus erythematosus. Acute cutaneous LE typically begins in the third decade of life and is frequently associated with active SLE. The most typical form of acute cutaneous lupus is a cheek rash, in which the skin on the flat parts of the face is red and resembles a sunburn (eg Fabbri et al., Am. J. Clin. Dermatol. 2003, 4). (7):449-65). These lesions are typically transient, sun-induced, and non-scarring. Cheek rash is present in about 50% of SLE patients at diagnosis, and clinical rash activity has been reported to correspond with systemic disease activity (e.g., Rothfield et al., 2006, Sep-Oct;24(5):348-62).

Chronic cutaneous lupus includes discoid LE (DLE), deep LE (LEP), chilblain LE (CHLE), and neoplastic LE (LET). In some embodiments, chronic cutaneous lupus is selected from discoid lupus erythematosus (DLE), deep lupus erythematosus (LEP), chilblain lupus erythematosus (CHLE), and neoplastic lupus erythematosus (LET).

Discoid LE lesions are the most common lesions of chronic cutaneous lupus erythematosus (CCLE) and appear as discoid round lesions. DLE frequently occurs in women in their 30s and 40s. Patients with DLE generally have a more benign disease course than those with other CLE subtypes, with only the majority of patients (approximately 90-95%) developing other organ system lupus (SLE) symptoms. (see, e.g., Crowson & Magro, J. Cutan. Pathol. 2001, 28(1):1-23, Chong et al., Br. J. Dermatol. 2012, 166(1):29-35 ). Sores usually appear on the scalp and face, but may also appear on other parts of the body. Discoid lupus erythematosus lesions are often red, scaly and thickened. Lesions are usually painless and nonpruritic. Histological examination of active DLE lesions reveals hyperkeratosis, keratin-filled dilated dense follicles, empty basal keratinocyte degeneration, and intense inflammatory cutaneous infiltrates.

Deep LE (LEP), or panniculitis, is characterized by painful, firm subcutaneous nodules that appear in areas of increased fat deposition, such as the upper arms and legs, face, and chest. LEP tends to follow a chronic course characterized by remissions and flares, ultimately leaving atrophic scars (eg Fabbri et al., Am. J. Clin. Dermatol. 2003, 4(7): 449-65). Histology shows lobular panniculitis with dense lymphocytic infiltration.

Chiliform lupus (CHLE) is a rare form of CCLE that resembles frostbite. Lesions appear as painful purplish plaques and nodules at sites exposed to cold. Central erosions or ulceration may occur on extremity surfaces such as fingers, toes, heels, nose, and ears. Chilblain lupus occurs when there is a drop in temperature and can be difficult to distinguish from frostbite. Pathology shows epidermal atrophy, interfacial vacuolation, and perivascular mononuclear cell infiltration. Approximately 80% of CHLE patients do not develop SLE (see, eg, Hedrich et al., Clin. Rheumatol. 2008, 27(8):949-54).

Neoplastic lupus is a subtype of CCLE characterized by extreme photosensitivity and a favorable course that preferentially occurs in males, unlike SLE, which occurs predominantly in females. Clinically, these lesions present on the face as well-demarcated, raised, smooth-surfaced, erythematous, edematous, urticarial, multicyclic plaques.

Predominantly in young to middle-aged women, subacute cutaneous lupus (SCLE) lesions are described as having a scaly red annular (“ring”) flare with central healing. Lesions may also be polycyclic, ie, have the appearance of multiple rings clustered together. There are two morphological subtypes of SCLE: annular and papulosquamous. The cyclic variant is characterized by scaly annular erythematous plaques that tend to fuse to give rise to polycyclic rows (e.g. Walling & Sontheimer, Am. J. Clin. Dermatol. 2009, 10(6): 365-81). The papulosquamous variant can resemble eczema and in some cases pityriasis (eg Caproni et al. Int. J. Dermatol. 2001, 40(1):59- 62). SCLE lesions occur at light-exposed sites such as the upper chest (“V” distribution), upper back, and extensor surfaces of the arms and forearms. Approximately 10% of SLE patients present with SCLE lesions, and patients with systemic disease tend to have only mild symptoms in other organ compartments. Pathological examination of SCLE lesions reveals vacuolar degeneration of basal keratinocytes, dermal edema, hyperkeratosis, keratin plugs, and sparse superficial inflammatory infiltrates (eg, Fabbri et al., Am. J. Clin 2003, 4(7):449-65).

The first evidence for a functional role of type I IFNs in lupus erythematosus (i.e., LE) came from clinical observations of patients with carcinoid tumors who were treated with recombinant IFNα and who developed SLE due to this therapy. (See, eg, Ronnblom et al, Acta Oncol. 1991, 30:537-540). This was supported by the findings of multiple sclerosis patients who developed CLE-like lesions after subcutaneous application of recombinant IFNβ to the side of the injection site (e.g. Arrue et al, J. Cutan. Pathol. 2007, 34, Suppl 1:18-21). Gene expression analysis in both SLE and CLE revealed strong expression of type I IFN-related inflammatory cytokines in blood and skin that were associated with disease activity (see, eg, Kuhn et al, Semin. Immunopathol. 2016, 38:97-112, and Mikita et al, J. Dermatol.2011, 38:839-849). These findings are supported by the data presented herein demonstrating high IFN-regulated gene expression and immune pathways within CLE skin lesions (see, eg, FIGS. 1A-1D).

Previous reports describing a strong IFN-signature prompted the development of anti-IFN targeted therapeutic strategies in LE patients. Anti-IFNα agents (eg, Sifalimumab, Rontalizumab) were the first drugs tested in clinical trials. These agents reduced the IFN signature in blood, but had limited effect on disease activity. Without wishing to be bound by theory, this may have been due to the high diversity of different type I IFNs, including not only IFNα, but also IFNβ and IFNκ that bind to the same receptor (e.g. 2016, 75: 196-202, Merrill et al, Ann. Rheum. Dis. 2011, 70: 1905-1913, and Sarkar et al, Ann. Rheum. : 1653-1664). Targeting the common receptor is therefore more effective, and the anti-IFN αβ receptor antibody aniflorumab significantly reduced CLASI skin scores in patients with SLE in a recent clinical trial (e.g., Furie et al. al, Arthritis & Rheumatology, 2017, 69:376-386). Alternative strategies focused on 'indirect' inhibition of the IFN system by (i) targeting IFN-producing cells or (ii) targeting the intracellular IFN pathway. In skin and blood, plasmacytoid DCs are considered the major IFN-producing cells (see, e.g., Saadeh et al, Exp. Dermatol. 2016, 25:415-421), and the pDC-specific antibody BIIB059 and VIB7734 are currently in clinical trials, with initial results showing decreased CLASI activity scores (see, e.g., Furie et al, Ann. Rheum. Dis. 2017, 76 (Suppl 2):857). ).

The JAK family consists of four non-receptor tyrosine kinases (JAK1-3, TYK2) that transduce signals from cytokines such as growth factors and type I/III IFNs. JAK inhibitors were originally developed for the treatment of hematological disorders with defined JAK mutations and have shown anti-clonal activity (eg Morgan et al, Annu. Rev. Med. 2008, 59:213-222). , and Pardanani et al, Leukemia 2008, 22:23-30), but they also produce significant immunosuppressive effects (e.g., Santos & Verstovsek, Expert Opin. Pharmacother. 2014, 15:1465-1473; Schwartz et al, Nat. Rev. Drug Discov.2017, 16:843-862, Schwartz et al, Nat. Rev. Rheumatol.2016, 12:25-36, and Howell et al, Ann. 120:367-375).

Previous studies have revealed activation of the JAK/STAT pathway and expression of JAK proteins in CLE and related skin disorders (e.g. Scholtissek et al, J. Invest. Dermatol. 2017, 137:1484-1492, Alves de Medeiros et al, PLoS ONE 2016, 11:e0164080, and Wenzel et al, J. Am. Acad. Dermatol. 2008, 58:437-442). JAK inhibitors are useful in, for example, graft-versus-host disease (see, e.g., Spoerl et al, Blood, 2014, 123:3832-3842), dermatomyositis (e.g., Hornung et al, N. Engl. J. Med. 2014, 371:2537-2538, and Hornung et al, N. Engl. J. Med. : 1281-1283, and Brian et al, Ann. Rheum. 2017, 47:1096-1107 and Shreberk-Hassidim et al, J. Am. Acad. Dermatol. 2017, 76:745-753.e19). have a beneficial effect on interfacial dermatitis, contained in addition to In CLE, the JAK1/2 inhibitor ruxolitinib (eg, Wenzel et al, J. Invest. Dermatol. 2016, 136:1281-1283, Briand et al, Ann. Rheum. Dis. 2019, 78:431-433, and Klaeschen et al, Exp. Dermatol. 2017, 26:728-730) and baricitinib (see, for example, Zimmerman et al, JAMA Dermatol. 3 inhibitor tofacitinib (see, eg, Konig et al, Ann. Rheum. Dis. 2017, 76:468-472) has been reported to be successful in treating patients, and these drugs are effective in treating CLE. significantly reduced the expression of chemokines typical of in vitro (for example, Klaeschen et al, Exp. Dermatol. 2017, 26:728-730 and Srivastava et al, Acta. Derm. Venereol. 2018, 98:772). -775). One of the potential drawbacks of these drugs are side effects, including anemia and thrombocytopenia, which may occur in some patients. Side effects are associated with inhibition of JAK2 and JAK3.

Of note, recent reports of double-blind, placebo-controlled trials for the treatment of SLE suggest that baricitinib was not effective compared to placebo (e.g., Wallace et al, Lancet , 2018, 392(10143):222-231 and Werth & Merrill, Br. J. Dermatol. 2019, 180(5):964-965). Baricitinib (2 mg or 4 mg) was administered once daily for 24 weeks. Eligible patients were 18 years of age or older, diagnosed with systemic lupus erythematosus (SLE), and had active disease affecting the skin or joints. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at 24 weeks, as defined by the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K).

Exploratory endpoints assessed the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and baricitinib did not improve the CLASI activity score. Unlike SLEDAI, the CLASI scoring system is a well-validated skin-specific endpoint for SLE and has been used successfully in several phase II clinical trials for SLE and CLE. Recent reports have also agreed that the CLASI scoring system should be used as a skin outcome for lupus testing for skin reactivity (eg Albrecht J, et al. 2011, 147:203-8, Furie et al., Arthritis Rheumatol.2017, 69:376-86, van Vollenhoven. et al., The Lancet 2018, 392:1330-9, Khamashta et al., Ann. Rheumat. Dis.2016, 75:1909-16, and Concha et al., J. Invest. /doi.org/10.1016/j.jid.2018.08.017).

The methods provided herein utilize compounds or salts that are JAK1 inhibitors (eg, JAK1 selective inhibitors). In some embodiments, the compound is selected from:
{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[ 4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide,
[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidine-4 -yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile,
4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro- N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide,
((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H -pyran-2-yl)acetonitrile,
3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 - yl]propanenitrile,
3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4- yl)-1H-pyrazol-1-yl]propanenitrile,
4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl) carbonyl]-3-fluorobenzonitrile,
4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl) carbonyl]-3-fluorobenzonitrile,
[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidine -4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile,
{trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl]butanenitrile,
5-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropyl pyrazine-2-carboxamide,
4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5 -difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide,
5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropyl pyrazine-2-carboxamide,
{1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl) -1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl) -1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, and {trans-3-(4-{[4-( 2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound or salt is selective for JAK1 over JAK2, JAK3 and TYK2. For example, some of the compounds described herein, or pharmaceutically acceptable salts thereof, selectively inhibit JAK1 over one or more of JAK2, JAK3, and TYK2. JAK1 plays a central role in many cytokine and growth factor signaling pathways whose dysregulation can lead to or contribute to disease states. For example, IL-6 levels are elevated in rheumatoid arthritis, a disease in which IL-6 has been suggested to have detrimental effects (see, eg, Fonesca, et al., Autoimmunity Reviews, 8:538-42). , 2009). Since IL-6 signals, at least in part, through JAK1, IL-6 may be indirectly JAK1-mediated, with potential clinical benefits (see, eg, Guschin, Embo J 14:1421, 1995, and Smolen, et al. Lancet 371:987, 2008). In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also contribute to the disease and/or associated symptoms. Patients with such diseases may therefore benefit from inhibition of JAK1. Selective inhibitors of JAK1, as described herein, can be effective while avoiding the unnecessary and undesirable effects of inhibiting other JAK kinases.

In some embodiments, the compound or salt selectively inhibits JAK1 over JAK2 (eg, a JAK2/JAK1 _IC50 ratio greater than 1). In some embodiments, the compounds or salts provided herein are about 10-fold selective for JAK1 over JAK2. In some embodiments, the compounds or salts provided herein are about 3- _fold , about 5-fold, about 10-fold, about 15-fold, or about 20-fold selective (see Example 1).

＋は、１０ｎＭ未満を意味する（アッセイ条件については実施例１を参照のこと）
＋＋は、１００ｎＭ以下を意味する（アッセイ条件については実施例１を参照のこと）
＋＋＋は、３００ｎＭ以下を意味する（アッセイ条件については実施例１を参照のこと）
^ａエナンチオマー１のデータ
^ｂエナンチオマー２のデータ In some embodiments, the JAK1 inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof. The compounds in Table 1 are JAK1 selective inhibitors (eg, more selective than JAK2, JAK3, and TYK2). _IC50 values obtained by the method of Example 1 at 1 mM ATP are shown in Table 1.

+ means less than 10 nM (see Example 1 for assay conditions)
++ means 100 nM or less (see Example 1 for assay conditions)
+++ means ≤300 nM (see Example 1 for assay conditions)
Data for ^enantiomer 1
^b Enantiomer 2 data

In some embodiments, the JAK1 inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the JAK1 inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl]azetidin-3-yl}acetonitrile and its adipate salt are described, for example, in US Patent Publication No. 2011/0224190, filed March 9, 2011, September 2012. 6, and U.S. Patent Publication No. 2014/0256941, filed March 5, 2014, each of which is incorporated herein by reference in its entirety. incorporated into the book.

In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine -1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine -1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.

In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine -1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrochloride.

In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine -1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide hydrobromide.

In some embodiments, the JAK1 inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine -1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide sulfate.

4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro- Synthesis and preparation of N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and its phosphate are described, for example, in US Patent Publication No. US2014, filed May 16, 2014 /0343030, each of which is incorporated herein by reference in its entirety.

In some embodiments, the JAK1 inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2 -b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the JAK1 inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2 -b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.

((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H -pyran-2-yl)acetonitrile and characterization of its anhydride and monohydrate forms are described in US Patent Publication Nos. 2014/0121198 filed Oct. 31, 2013 and Apr. 29, 2015. and US Patent Publication No. 2015/0344497, filed on May 1, 2015, each of which is hereby incorporated by reference in its entirety.

In some embodiments, the compounds of Table 1 are represented in U.S. Patent Publication No. 2011/0224190, filed March 9, 2011, May 2014, each of which is incorporated herein by reference in its entirety. U.S. Patent Publication No. 2014/0343030 filed Oct. 16, U.S. Patent Publication No. 2014/0121198 filed Oct. 31, 2013, U.S. Patent Publication No. 2010/ 0298334, U.S. Patent Publication No. 2011/0059951 filed Aug. 31, 2010, U.S. Patent Publication No. 2012/0149681 filed Nov. 18, 2011, filed Nov. 18, 2011 U.S. Patent Publication No. 2012/0149682, U.S. Patent Publication No. 2013/0018034 filed Jun. 19, 2012, U.S. Patent Publication No. 2013/0045963 filed Aug. 17, 2012, and 2013 prepared by the synthetic methods described in US Patent Publication No. 2014/0005166, filed May 17, 2014.

In some embodiments, the JAK1 inhibitor is US Patent Publication No. 2011/0224190, filed March 9, 2011, May 16, 2014, each of which is incorporated herein by reference in its entirety. U.S. Patent Publication No. 2014/0343030 filed on Oct. 31, 2013; U.S. Patent Publication No. 2014/0121198 filed on Oct. 31, 2013; U.S. Patent Publication No. 2011/0059951 filed Aug. 31, 2010; U.S. Patent Publication No. 2012/0149681 filed Nov. 18, 2011; U.S. Patent Publication No. 2012/0149682, U.S. Patent Publication No. 2013/0018034 filed Jun. 19, 2012, U.S. Patent Publication No. 2013/0045963 filed Aug. 17, 2012, and 2013 selected from the compounds of US Patent Publication No. 2014/0005166, filed May 17, or a pharmaceutically acceptable salt thereof;

またはその薬学的に許容される塩であり、式中、
ＸはＮまたはＣＨであり、
ＬはＣ（＝Ｏ）またはＣ（＝Ｏ）ＮＨであり、
Ａは、フェニル、ピリジニル、またはピリミジニルであり、その各々は、１つまたは２つの独立して選択されたＲ^１基で任意選択で置換されており、
各Ｒ^１は、独立して、フルオロ、またはトリフルオロメチルである。 In some embodiments, the JAK1 inhibitor is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein
X is N or CH;
L is C(=O) or C(=O)NH;
A is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted with one or two independently selected R ¹ groups;
Each R ¹ is independently fluoro or trifluoromethyl.

In some embodiments, the compound of Formula I is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1 -{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.

またはその薬学的に許容される塩であり、式中、
Ｒ^２は、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－６シクロアルキル、またはＣ_３－６シクロアルキル－Ｃ_１－３アルキルであり、前記Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、及びＣ_３－６シクロアルキル－Ｃ_１－３アルキルはそれぞれ、フルオロ、－ＣＦ_３、及びメチルから独立して選択される１つ、２つ、または３つの置換基で任意選択で置換されており、
Ｒ^３はＨまたはメチルであり、
Ｒ^４はＨ、Ｆ、またはＣｌであり、
Ｒ^５はＨまたはＦであり、
Ｒ^６はＨまたはＦであり、
Ｒ^７はＨまたはＦであり、
Ｒ^８はＨまたはメチルであり、
Ｒ^９はＨまたはメチルであり、
Ｒ^１０はＨまたはメチルであり、
Ｒ^１１はＨまたはメチルである。 In some embodiments, the JAK1 inhibitor is a compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein
R ² is C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, or C _3-6 cycloalkyl-C _1-3 alkyl, and said C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl-C _1-3 alkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, —CF ₃ and methyl has been
^R3 is H or methyl;
^R4 is H, F, or Cl;
^R5 is H or F;
^R6 is H or F;
^R7 is H or F;
^R8 is H or methyl;
^R9 is H or methyl;
R ¹⁰ is H or methyl;
R ¹¹ is H or methyl.

In some embodiments, the compound of Formula II is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) Azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

またはその薬学的に許容される塩であり、式中、
Ｃｙ^４は、テトラヒドロ－２Ｈ－ピラン環であり、ＣＮ、ＯＨ、Ｆ、Ｃｌ、Ｃ_１－３アルキル、Ｃ_１－３ハロアルキル、ＣＮ－Ｃ_１－３アルキル、ＨＯ－Ｃ_１－３アルキル、アミノ、Ｃ_１－３アルキルアミノ、及びジ（Ｃ_１－３アルキル）アミノから独立して選択される１つまたは２つの基で任意選択で置換されており、ここで、前記Ｃ_１－３アルキル及びジ（Ｃ_１－３アルキル）アミノは、Ｆ、Ｃｌ、Ｃ_１－３アルキルアミノスルホニル、及びＣ_１－３アルキルスルホニルから独立して選択される１つ、２つ、または３つの置換基で任意選択で置換されており、
Ｒ^１２は、－ＣＨ_２－ＯＨ、－ＣＨ（ＣＨ_３）－ＯＨ、または－ＣＨ_２－ＮＨＳＯ_２ＣＨ_３である。 In some embodiments, the JAK1 inhibitor is a compound of formula III

or a pharmaceutically acceptable salt thereof, wherein
Cy ⁴ is a tetrahydro-2H-pyran ring, CN, OH, F, Cl, C _1-3 alkyl, C _1-3 haloalkyl, CN—C _1-3 alkyl, HO—C _1-3 alkyl, amino , C _1-3 alkylamino, and di(C _1-3 alkyl)amino, wherein said C _1-3 alkyl and di(C _1-3 alkyl)amino optionally with 1, 2 or 3 substituents independently selected from F, Cl, C _1-3 alkylaminosulfonyl and C _1-3 alkylsulfonyl is replaced by the selection,
R ¹² is -CH ₂ -OH, -CH(CH ₃ )-OH, or -CH ₂ -NHSO ₂ CH ₃ .

In some embodiments, the compound of Formula III is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3, 2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

One or more constituent atoms of the compounds described herein can be replaced or substituted with isotopes of atoms in their natural or unnatural abundance. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compound contains 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound are replaced or can be replaced by deuterium atoms.

Synthetic methods for including isotopes in organic compounds are known in the art (see Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971, Jens Atzrodt, Ｖｏｌｋｅｒ Ｄｅｒｄａｕ，Ｔｈｏｒｓｔｅｎ Ｆｅｙ ａｎｄ Ｊｏｃｈｅｎ ＺｉｍｍｅｒｍａｎｎによるＴｈｅ Ｒｅｎａｉｓｓａｎｃｅ ｏｆ Ｈ／Ｄ Ｅｘｃｈａｎｇｅ，Ａｎｇｅｗ．Ｃｈｅｍ．Ｉｎｔ．Ｅｄ．２００７，７７４４－７７６５、Ｊａｍｅｓ Ｒ．ＨａｎｓｏｎによるＴｈｅ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ ｏｆ Ｉｓｏｔｏｐｉｃ Ｌａｂｅｌｌｉｎｇ，Ｒｏｙａｌ Ｓｏｃｉｅｔｙ ｏｆ Ｃｈｅｍｉｓｔｒｙ，２０１１） Isotopically-labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and/or assays.

Substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or decreased dosage requirements, and thus It may be preferable in some circumstances. (See, e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210, R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312.) . In particular, substitutions at one or more sites of metabolism may result in one or more of the therapeutic benefits.

Thus, in some embodiments, a JAK1 inhibitor (e.g., a JAK1 selective inhibitor) is a compound, or a pharmaceutically acceptable It is a salt that

As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. It should be understood that substitution at a given atom is limited by valency.

As used herein, the term "C _nm alkyl" used alone or in combination with other terms, refers to a straight or branched chain having n to m carbon atoms. refers to the saturated hydrocarbon group obtained. In some embodiments, alkyl groups have 1 to 6, or 1 to 3 carbon atoms. Examples of alkyl moieties are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl. , 1,2,2-trimethylpropyl, and the like, but are not limited to these.

As used herein, the term “alkylene,” used alone or in combination with other terms, refers to a branched or straight chain in which two substituents may be attached at any position of the alkylene linking group. Refers to a divalent alkyl linking group, which can be a chain. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, and the like.

As used herein, the term "HO-C _1-3 -alkyl" refers to a group of formula -alkylene-OH, said alkylene group having from 1 to 3 carbon atoms.

As used herein, the term "CN--C _1-3 alkyl" refers to C _1-3 alkyl substituted with a cyano group.

As used herein, the term "amino" refers to a group of formula _-NH2 .

As used herein, the term “di(C _1-3 -alkyl)amino” refers to compounds of the formula —N(alkyl) ₂ in which the two alkyl groups each independently have from 1 to 3 carbon atoms. refers to the group of

As used herein, the term “C _1-3 alkylamino” refers to a group of formula —NH(alkyl), where the alkyl group has 1-3 carbon atoms.

As used herein, the term “di(C _1-3 alkyl)aminosulfonyl” refers to a group of the formula —S(O) ₂ N(alkyl) ₂ , wherein each alkyl group is independently 1 It has ∼3 carbon atoms.

As used herein, the term “C _1-3 alkylsulfonyl” refers to a group of formula —S(O) ₂ -alkyl, wherein the alkyl group has 1-3 carbon atoms.

As used herein, "halo" or "halogen", used alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo groups are fluoro or chloro.

As used herein, the term "C _n-m haloalkyl" used alone or in combination with other terms may be up to {2(n-m)+1} the same or different C _nm alkyl group having a halogen atom. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1-6 or 1-3 carbon atoms. Examples of haloalkyl groups include _CF3 , _C2F5 , _CHF2 , _CCl3 , _{CHCl2 , C2Cl5 ,} and the like. In some embodiments, haloalkyl groups are fluoroalkyl groups.

As used herein, the term “C _1-3 fluoroalkyl” refers to a C _1-3 alkyl group which may be partially or fully substituted with fluoro atoms.

As used herein, the term “C _3-6 cycloalkyl”, used alone or in combination with other terms, optionally includes one or more alkenylene groups as part of the ring structure. Refers to non-aromatic monocyclic hydrocarbon moieties having 3 to 6 carbon atoms, which may be contained. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form a carbonyl bond. Exemplary C _3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like. In some embodiments, the cyclopropyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “C _3-6 cycloalkyl-C _1-3 alkyl” refers to a group of formula —C _1-3 alkylene-C _3-6 cycloalkyl.

Compounds described herein may be asymmetric (eg, possess one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds containing an asymmetrically substituted carbon atom may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, eg, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins, C═N double bonds, etc., may also exist in the compounds described herein, and all such stable isomers are contemplated in this application. Geometric cis and trans isomers are described for the compounds of the present application and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R) configuration. In some embodiments, the compounds have the (S) configuration.

Resolution of racemic mixtures of compounds can be accomplished by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids that are optically active, salt-forming organic acids. Resolving agents suitable for fractional recrystallization include, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, optically active acids such as the D- and L-forms of lactic acid, or various β-camphorsulfonic acids. It is an optically active camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include α-methyl-benzyl-amine in stereomerically pure forms (eg S and R forms, or diastereomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (eg dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

特許請求の範囲は両方の互変異性体を網羅することが意図されている。 The compounds described herein also include tautomeric forms. Tautomeric forms arise from simultaneous rearrangements of protons in conjunction with permutations of single and adjacent double bonds. Tautomeric forms include prototropic tautomers, which are isomeric protonation states that have the same empirical formula and overall charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and protons can occupy more than one position in a heterocyclic system. Cyclic forms such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. For example, it will be appreciated that the pyrazole ring below can form two tautomers.

The claims are intended to cover both tautomers.

All compounds, and their pharmaceutically acceptable salts, can be found or isolated together with other substances such as water and solvents (eg hydrates and solvates).

In some embodiments, the compounds described herein or salts thereof are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or found. Partial separation can include, for example, compositions enriched in the compounds described herein. Substantial separation includes at least about 50% weight percent, at least about 60% weight percent, at least about 70% weight percent, at least about 80% weight percent, at least about 90% weight percent of the compounds described herein, or salts thereof. % by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight. Methods of isolating compounds and their salts are routine in the art.

The phrase "pharmaceutically acceptable" is used herein to mean, within the scope of sound medical judgment, human and animal health without undue toxicity, irritation, allergic reaction, or other problems or complications. is used to refer to compounds, materials, compositions, and/or dosage forms that are suitable for use in contact with the tissue of the body and commensurate with a reasonable benefit/risk ratio.

The expressions "ambient temperature" and "room temperature" or "rt" as used herein are understood in the art and generally refer to temperature, e.g. Near a temperature, for example a temperature of about 20°C to about 30°C.

This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety to its salt form. there is Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts of the present application include conventional non-toxic salts of the parent compounds, eg, formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present application can be synthesized from a parent compound that contains either basic or acidic moieties by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with stoichiometric amounts of the appropriate base or acid in water or an organic solvent, or a mixture of both. and generally non-aqueous media such as ether, ethyl acetate, alcohols (eg, methanol, ethanol, isopropanol, or butanol) or acetonitrile (ACN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, Pa.; , 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is hereby incorporated by reference in its entirety.

As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" a JAK with a compound of the present invention includes administration of a compound of the present application to an individual or patient, such as a human having JAK, as well as, for example, administering a compound of the present invention to a cell containing a JAK. Introduction to samples containing preparations or purified preparations is included.

As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to mammals, preferably mice, rats, other rodents, rabbits, dogs, cats. , pigs, cattle, sheep, horses, primates, and most preferably humans. In some embodiments, a "subject," "individual," or "patient" is in need of said treatment.

In some embodiments, inhibitors are administered in therapeutically effective amounts. As used herein, the phrase "therapeutically effective amount" refers to the biological response or It refers to the amount of active compound or pharmaceutical agent that elicits a pharmaceutical response.

As used herein, the term "treating" or "treatment" means (1) inhibiting a disease, e.g., experiencing or exhibiting the pathology or symptomatology of a disease, condition or disorder. (2) ameliorating the disease, e.g., the pathology of the disease, condition or disorder, or ameliorating a disease, condition or disorder in an individual experiencing or exhibiting the symptomatology (i.e., ameliorating the pathology and/or symptomatology), e.g., reducing the severity of the disease, or ( 3) refers to one or more of preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but who has not yet experienced or exhibited the pathology or symptomatology of the disease. . In some embodiments, treating refers to inhibiting or ameliorating a disease. In some embodiments, treating is to prevent disease.

Combination Therapy The methods described herein can further comprise administering one or more additional therapeutic agents. The one or more additional therapeutic agents can be administered to the patient simultaneously or sequentially.

In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim sulfamethoxazole, erythromycin, metronidazole, rifampicin, moxifloxacin, dapsone, or a combination thereof. In some embodiments, the antibiotic is clindamycin, doxycycline, minocycline, trimethoprim sulfamethoxazole, or erythromycin in combination with metronidazole. In some embodiments, the antibiotic is a combination of rifampin, moxifloxacin, and metronidazole. In some embodiments, the antibiotic is a combination of moxifloxacin and rifampin.

In some embodiments, the additional therapeutic agent is a retinoid. In some embodiments, the retinoid is etretinate, acitretin, or isotretinoin.

In some embodiments the additional therapeutic agent is a steroid. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the steroid is triamcinolone, dexamethasone, fluocinolone, cortisone, prednisone, prednisolone, flumetholone, or the like.

In some embodiments, the additional therapeutic agent is an anti-TNF-alpha agent. In some embodiments, the anti-TNF-alpha agent is an anti-TNF-alpha antibody. In some embodiments, the anti-TNF-alpha agent is infliximab or etanercept, or adalimumab.

In some embodiments, the additional therapeutic agent is an immunosuppressant. In some embodiments, the immunosuppressive agent is methotrexate or cyclosporine A. In some embodiments, the immunosuppressive agent is mycophenolate mofetil or mycophenolate sodium.

In some embodiments, the additional therapeutic agent is finasteride, metformin, adapalene, or azelaic acid.

In some embodiments, the method further comprises administering an additional therapeutic agent selected from IMiDs, anti-IL-6 agents, hypomethylating agents, and biological response modifiers (BRMs).

In general, BRMs are substances made by the body to treat disease, and may occur naturally in the body or be made in a laboratory. Examples of BRMs include IL-2, interferons, various types of colony stimulating factors (CSF, GM-CSF, G-CSF), monoclonal antibodies such as abciximab, etanercept, infliximab, rituximab, trastuzumab, high-dose ascorbate. is mentioned.

In some embodiments, the hypomethylating agent is a DNA methyltransferase inhibitor. In some embodiments, the DNA methyltransferase inhibitor is selected from 5-azacitidine and decitabine.

In general, IMiDs are immunomodulators. In some embodiments, the IMiD is selected from thalidomide, lenalidomide, pomalidomide, CC-11006, and CC-10015.

In some embodiments, the method further comprises anti-thymocyte globulin, recombinant human granulocyte colony stimulating factor (G CSF), granulocyte monocyte CSF (GM-CSF), erythropoiesis stimulating factor (ESA), and cyclosporine. administering an additional therapeutic agent selected from

In some embodiments, the method further comprises administering to the patient an additional JAK inhibitor. In some embodiments, the additional JAK inhibitors are JAK2 inhibitors (e.g., selective JAK2 inhibitors), JAK1/JAK2 inhibitors, JAK3 inhibitors (e.g., selective JAK3 inhibitors), and JAK1/JAK3 selected from inhibitors, or pharmaceutically acceptable salts of any of the foregoing.

In some embodiments, the additional JAK inhibitor is a JAK1/JAK2 inhibitor. In some embodiments, the JAK1/JAK2 inhibitors are selective for JAK1 and JAK2 over JAK3 and TYK2. In some embodiments, the JAK1/JAK2 inhibitor is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propane A nitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1/JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 - yl]propanenitrile (ruxolitinib), or a pharmaceutically acceptable salt thereof. Ruxolitinib has an IC ₅₀ at 1 mM ATP of less than 10 nM in JAK1 and JAK2. 3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and ruxolitinib are herein incorporated by reference in their entirety. It can be made by the procedure (Example 67) described in US 7,598,257 filed Dec. 12, 2006, which is incorporated. In some embodiments, the JAK1/JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl]propanenitrile phosphate. Phosphates can be made as described in US Pat. No. 8,722,693, which is incorporated herein by reference in its entirety. In some embodiments, the JAK1/JAK2 inhibitor is barcitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1/JAK2 inhibitor is barcitinib.

In some embodiments, the additional JAK1 inhibitor is a JAK1/JAK3 inhibitor. In some embodiments, the JAK1/JAK3 inhibitor is tofacitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1/JAK3 inhibitor is tofacitinib.

In some embodiments, the JAK1/JAK2 inhibitor can be an isotopically labeled compound, or a pharmaceutically acceptable salt thereof. An "isotopically" or "radiolabeled" compound has an atomic mass or mass in which one or more atoms is different from the atomic mass or mass number typically found in nature (i.e., naturally occurring) A compound that is replaced or substituted by atoms having a number. Suitable radionuclides that can be incorporated into compounds of the present disclosure include ² H (also written as D for deuterium), ³ H (also written as T for tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I are not limited to these. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced by deuterium atoms, eg, —CH ₃ is replaced with —CD ₃ ).

Thus, in some embodiments, a JAK1/JAK2 inhibitor is a compound, or a pharmaceutically acceptable salt thereof, in which one or more hydrogen atoms are replaced by deuterium atoms.

In some embodiments, the JAK1/JAK2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, in which one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the JAK1/JAK2 inhibitor is any of the compounds described in U.S. Pat. No. 9,249,149, which is incorporated herein by reference in its entirety, or a pharmaceutically acceptable It is the salt that is used. In some embodiments, the inhibitor of JAK1/JAK2 is CTP-543, or a pharmaceutically acceptable salt thereof.

またはその薬学的に許容される塩であり、式中、
Ｒ^１はＨ及びＤから選択され、
各Ｒ^２はＨ及びＤから独立して選択されるが、但し、共通の炭素に結合している各Ｒ^２が同じであることを条件とし、
各Ｒ^３はＨ及びＤから独立して選択されるが、但し、共通の炭素に結合している各Ｒ^３が同じであることを条件とし、
Ｒ^４はＨ及びＤから選択され、
各Ｒ^５は同じであり、Ｈ及びＤから選択され、
Ｒ^６、Ｒ^７、及びＲ^８は、それぞれ独立してＨ及びＤから選択され、但し、Ｒ^１がＨであり、各Ｒ^２及び各Ｒ^３がＨであり、Ｒ^４がＨであり、Ｒ^６、Ｒ^７、及びＲ^８が各々Ｈである場合には、各Ｒ^５はＤであることを条件とする。 In some embodiments, the JAK1/JAK2 inhibitor is a compound of Formula IV

or a pharmaceutically acceptable salt thereof, wherein
R ¹ is selected from H and D;
each ^R2 is independently selected from H and D, provided that each ^R2 attached to a common carbon is the same;
each R ³ is independently selected from H and D, provided that each R ³ attached to a common carbon is the same;
^R4 is selected from H and D;
each ^R5 is the same and is selected from H and D;
R ⁶ , R ⁷ and R ⁸ are each independently selected from H and D with the proviso that R ¹ is H, each R ² and each R ³ is H, R ⁴ is H; provided that if R ⁶ , R ⁷ and R ⁸ are each H, then each R ⁵ is D;

In some embodiments, the inhibitor of JAK1 and/or JAK2 is a compound of formula IV selected from compounds 100-130 of the table below, wherein R ⁶ , R ⁷ and R ⁸ are each H ), or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK1/JAK2 inhibitor is a compound of Formula IV selected from compounds 200-231 of the table below, wherein R ⁶ , R ⁷ and R ⁸ are each D, or It is a pharmaceutically acceptable salt thereof.

In some embodiments, the JAK1/JAK2 inhibitor is baricitinib, or a pharmaceutically acceptable salt thereof, in which one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the JAK1/JAK2 inhibitor is any of the compounds described in U.S. Pat. No. 9,540,367 (incorporated herein by reference in its entirety), or pharmaceutical compounds thereof. is an acceptable salt for

In some embodiments, the additional JAK inhibitor is baricitinib, tofacitinib, oclacitinib, filgotinib, gandotinib, restortinib, momelotinib, bacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, cucurbitacin I, ATI- 501 (Aclaris), ATI-502 (Aclaris), JTE-052 (ie delgocitinib; Leo Pharma and Japan Tobacco), and CHZ868.

For the treatment of cutaneous lupus erythematosus (CLE), anti-inflammatory agents, immunosuppressants, PI3Kδ inhibitors, mTor inhibitors, Bcr-Abl inhibitors, Flt-3 inhibitors, RAF inhibitors, and FAK kinase inhibitors such as , WO2006/056399, which is incorporated herein by reference in its entirety), or other agents in combination with the JAK1 inhibitors described herein, including but not limited to can be done. One or more additional agents can be administered to the patient simultaneously or sequentially.

Examples of Bcr-Abl inhibitors are disclosed in US Pat. No. 5,521,184, WO04/005281, and US Pat. No. 60/578,491, all of which are incorporated herein by reference in their entireties. and pharmaceutically acceptable salts thereof.

Examples of suitable Flt-3 inhibitors include compounds such as those disclosed in WO03/037347, WO03/099771, and WO04/046120, all of which are hereby incorporated by reference in their entirety, and their pharmacological properties. including legally acceptable salts.

Examples of suitable RAF inhibitors include compounds and pharmaceutically acceptable compounds such as those disclosed in WO00/09495 and WO05/028444, both of which are herein incorporated by reference in their entirety. Contains salt.

Examples of suitable FAK inhibitors are disclosed in WO04/080980, WO04/056786, WO03/024967, WO01/064655, WO00/053595, and WO01/014402, all of which are incorporated herein by reference in their entirety. and pharmaceutically acceptable salts thereof.

In some embodiments, one or more of the JAK1 inhibitors described herein are combined with one or more other inhibitors, particularly to treat patients resistant to imatinib or other kinase inhibitors. of kinase inhibitors such as imatinib.

In some embodiments, the additional therapeutic agent is fluocinolone acetonide (Retisert®) or rimexolone (AL-2178, Vexol, Alcon).

In some embodiments, the additional therapeutic agent is cyclosporine (Restasis®).

In some embodiments, the additional therapeutic agent is Dehydrex™ (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemmedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101 (T) (Testosterone, Argentis), AGR1012 (P) (Argentis), Ecabet sodium (Senju-Ista), Gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE ), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals), cyclosporin A (Nova22007, Novagali), oxytetracycline (duramycin, MOLI1901, LantiF1o) (CiF1io) 2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis), RX-10045 (synthetic resolvin analogue, Resolvyx), DYN15 (Dynamis Therapeutics), riboglitazone (DE011, Daiichixi (Resolvyx), SBano) OPH-01 (Opthalmis Monaco), PCS101 (Pericor Science), REV1-31 (Evolutec), Lacritin (Senju), Rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and ), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals), de selected from hydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (Torrey Pines Therapeutics), actemra, gemcitabine, oxaliplatin, L-asparaginase, or thalidomide.

In some embodiments, the additional therapeutic agent is an anti-angiogenic agent, a cholinergic agent, a TRP-1 receptor modulator, a calcium channel blocker, a mucin secretagogue, a MUC1 stimulant, a calcineurin inhibitor, a corticosteroid , P2Y2 receptor agonists, muscarinic receptor agonists, or mTOR inhibitors. In some embodiments, the additional therapeutic agent is a tetracycline derivative (eg, minocycline or doxycline). In some embodiments, the additional therapeutic agent binds to FKBP12.

In some embodiments, the additional therapeutic agent is an alkylating or DNA cross-linking agent; an antimetabolite/demethylating agent (e.g., 5-fluorouracil, capecitabine or azacytidine); an anti-hormonal therapy (e.g., hormone receptor antagonists, SERMs, or aromatase inhibitors); mitotic inhibitors (e.g. vincristine or paclitaxel); topoisomerase (I or II) inhibitors (e.g. mitoxantrone and irinotecan); apoptosis inducers (e.g. Nucleic acid therapy (eg, antisense or RNAi); nuclear receptor ligands (eg, agonists and/or antagonists: all-trans retinoic acid or bexarotene); epigenetic targeting agents, such as histones deacetylase inhibitors (e.g. vorinostat), hypomethylating agents (e.g. decitabine); modulators of protein stability, e.g. Hsp90 inhibitors, ubiquitin and/or ubiquitin-like binding or unbinding molecules; or EGFR inhibition. drug (erlotinib).

In some embodiments, the additional therapeutic agents are selected from antibiotics, antiviral agents, antifungal agents, anesthetic agents, anti-inflammatory agents (e.g., steroidal and non-steroidal anti-inflammatory agents), and anti-allergic agents. selected. Examples of suitable drugs include aminoglycosides such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin. chloramphenicol; neomycin; paramomycin; colistimate; bacitracin; vancomycin; tetracyclines; phosphate; amphotericin; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; but not limited to these.

Pharmaceutical Formulations and Dosage Forms JAK1 inhibitors provided herein can be administered in the form of pharmaceutical compositions when used as pharmaceuticals. These compositions can be prepared in a manner well known in the pharmaceutical art and administered by a variety of routes depending on whether local or systemic treatment is desired and on the area to be treated. can do. Administration may be topical (including intradermal, transdermal, epidermal, ophthalmic, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation of a powder or aerosol, such as by nebulizer, or by insufflation; intratracheal or intranasal), orally or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, eg intrathecal or intracerebroventricular administration. Parenteral administration can be in the form of a single bolus dose or can be by, for example, a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration include transdermal patches, skin patches, solutions, suspensions, foams, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions, and powders. be done. Conventional pharmaceutical carriers, aqueous bases, powder bases or oily bases, thickeners and the like may be necessary or desirable. In some embodiments, the compositions are topical via transdermal patches, skin patches, solutions, suspensions, gels, creams, ointments, lotions, sprays, foams, liquids, drops, suppositories, and powders. formulated for administration. In some embodiments, compositions are formulated for topical administration via a transdermal patch. In some embodiments, compositions are formulated for topical administration via a skin patch. In some embodiments, the composition is formulated as a foam (eg, for topical administration).

For the treatment of skin disorders such as cutaneous lupus erythematosus (CLE), topical agents that can cross the skin barrier and limit systemic effects are of particular importance.

Topical (dermal/intradermal) formulations are typically solutions, suspensions, gels, creams, ointments, lotions, sprays and foams. Preferred topical formulations should be physically and chemically stable, should not cause skin irritation, and should contain active agents (e.g., selective JAK1 inhibitors, as described herein). , or a pharmaceutically acceptable salt thereof) should be delivered to the appropriate layers of the skin in concentrations that provide a therapeutic response with limited systemic exposure.

In some embodiments, administration is topical and consists of a formulation with one or more pharmaceutically (eg, dermatologically) acceptable excipients. Examples of dermatologically acceptable additives include pH adjusters, chelating agents, preservatives, co-solvents, membrane permeability enhancers, wetting agents, thickening agents, gelling agents, thickening agents, Including, but not limited to, surfactants, propellants, flavoring agents, coloring agents, or any combination or mixture thereof. In some embodiments, topical formulations are administered locally to a patient (eg, administered to a lesion site).

In some embodiments, pH adjusting agents are selected from acids, acid salts, bases, basic salts, and buffers, or any mixture thereof. Exemplary acids include, but are not limited to, lactic, acetic, citric, and benzoic acids and salts thereof. Exemplary bases include, but are not limited to, trolamine, tromethamine, and salts thereof. Exemplary buffers include, but are not limited to, citrate/citric acid, acetate/acetic acid, edetate/edetate, lactate/lactic acid, and the like.

In some embodiments, the chelating agent is the single additive. In some embodiments, the chelating agent is a mixture of two or more chelating agents. Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), or salts thereof. In some embodiments, the chelating agent comprises a mixture of chelating agents and antioxidants, wherein the chelating agents and antioxidants prevent, minimize, or reduce oxidative degradation reactions in the composition. Let Exemplary antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, and propyl gallate.

In some embodiments, the composition includes one or more preservatives. In some embodiments, the composition comprises a mixture of two or more preservatives. In some embodiments, the composition comprises 1-5 preservatives. Exemplary preservatives include, but are not limited to, benzyl alcohol, phenonyexthanol, methylparaben, ethylparaben, propylparaben, butylparaben, and imidazolidinyl urea.

In some embodiments, the composition includes one or more co-solvents. In some embodiments, the composition comprises a mixture of two or more co-solvents. In some embodiments, the composition comprises 1-5 co-solvents. Exemplary solvents include water, propylene glycol, diethylene glycol monoethyl ether, dimethyl isosorbide, ethyl alcohol, isopropyl alcohol, benzyl alcohol, propanediol, propylene glycol, polyethylene glycols (e.g., polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 etc.), but are not limited to these. In some embodiments, the solvent is a water-insoluble drug. Exemplary water-insoluble agents include, but are not limited to, diethyl sebacate, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, and medium chain triglycerides.

In some embodiments, the composition comprises one or more membrane permeability enhancers. In some embodiments, the composition comprises a mixture of two or more membrane permeability enhancers. In some embodiments, the composition comprises 1-5 membrane permeability enhancers. A membrane permeability enhancer can act as both a solvent and a membrane permeability enhancer. Exemplary membrane permeability enhancers include, but are not limited to, fatty acids, fatty acid esters, fatty alcohols, pyrrolidones, sulfoxides, alcohols, diols and polyols, or any mixture thereof. In some embodiments, co-solvents provided herein are membrane permeability enhancers.

In some embodiments, the composition comprises one or more thickening agents, gelling agents, or thickening agents. In some embodiments, the composition comprises a mixture of two or more thickening agents, gelling agents, or thickening agents. In some embodiments, the composition comprises 1-5 thickening, gelling, or thickening agents. Exemplary thickening, gelling, or thickening agents include cellulose derivatives such as hydroxyethylcellulose (HEC), carboxymethylcellulose, hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC), and polyvinyl Examples include, but are not limited to, pyrrolidone (PVP).

Surfactants are compounds that lower the surface tension between two liquids or between a liquid and a solid. A surfactant may be a mixture of two or more surfactants. Exemplary surfactants include ethoxylated fatty alcohol ethers (eg, steareth-2, steareth-10, steareth-20, ceteareth-2, ceteareth-10, etc.), PEG esters (eg, PEG-4 dilaurate, stearic acid PEG-20, etc.), glyceryl esters or derivatives thereof (e.g., glyceryl dioleate, glyceryl stearate, etc.), polymeric ethers (e.g., poloxamer 124, poloxamer 181, poloxamer 182, etc.), sorbitan derivatives (e.g., polysorbate 80, sorbitan monostearate, etc.), fatty alcohols (e.g., cetyl alcohol, stearyl alcohol, cetearyl alcohol, etc.), and emulsifying waxes (e.g., emulsifying wax NF, a mixture of a mixture of cetearyl alcohol and polysorbate 60, etc.). , but not limited to.

In some embodiments, administration is topical administration to the skin.

In some embodiments, administration is oral.

In some embodiments, administration of a topical composition comprising a selective JAK1 inhibitor provided herein to a patient results in a steady-state systemic exposure (C _max ) of less than about 5% of the applied dose. , for example, less than about 4%, less than about 3%, less than about 2%, less than about 1%, etc. In some embodiments, administration of a topical composition comprising a selective JAK1 inhibitor provided herein to a patient results in a steady state systemic exposure ( _Cmax ) of less than about 1% of the applied dose. be

The present invention includes a medicament containing a JAK1 inhibitor provided herein or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (additives). Compositions are also included. In some embodiments, compositions are suitable for topical administration. In making the compositions of this invention, the active ingredient is typically mixed with excipients, diluted by excipients, or in a carrier such as, for example, in the form of a capsule, sachet, paper or other container. is enclosed in Excipients can be solid, semi-solid, or liquid substances that, when used as diluents, act as vehicles, carriers, or medium for the active ingredient. Thus, compositions may be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either as solid or liquid media), ointments, e.g. , containing up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. When the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

JAK1 inhibitors provided herein may be milled using known milling procedures, such as wet milling, to obtain particle sizes suitable for tableting and other dosage forms. Finely divided (nanoparticulate) preparations of JAK1 inhibitors can be prepared by methods known in the art (see, eg, International Application No. WO2002/000196).

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose. , water, syrup, and methylcellulose. Formulations may additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl benzoate and propyl hydroxybenzoate; be able to. Compositions of the invention can be formulated to provide immediate, sustained, or delayed release of the active ingredient after administration to the patient by using methods known in the art.

In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% (w/w) microcrystalline cellulose and about 2% (w/w) silicon dioxide.

In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. It is a thing. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, hydroxypropylmethylcellulose, and poly It contains at least one component selected from ethylene oxide. In some embodiments, a composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropylmethylcellulose . In some embodiments, a composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropylmethylcellulose is hydroxypropylmethylcellulose 2208 K4M (eg, Methocel K4 M Premier™) and/or hydroxypropylmethylcellulose 2208 K100LV (eg, Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (eg, Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to manufacture the composition. In some embodiments, a dry granulation process is used to manufacture the composition.

The compositions may be formulated in unit dosage form, each dose containing from about 1 to about 1,000 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, and from about 1 mg to about 10 mg of active ingredient. contains. Preferably, the dosage is from about 1 mg to about 50 mg or from about 1 mg to about 10 mg of active ingredient. In some embodiments, each dose contains about 10 mg of active ingredient. In some embodiments, each dose contains about 50 mg of active ingredient. In some embodiments, each dose contains about 25 mg of active ingredient. The term "dosage unit form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit, in combination with suitable excipients, to produce the desired therapeutic effect. It contains a predetermined amount of active substance calculated as follows.

In some embodiments, the composition comprises from about 1 to about 1,000 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, and from about 1 mg to about 10 mg of active ingredient. Preferably, the composition contains from about 1 mg to about 50 mg or from about 1 mg to about 10 mg of active ingredient. One skilled in the art will appreciate that this embodies a compound or composition comprising from about 1 mg to about 10 mg, from about 1 mg to about 20 mg, from about 1 mg to about 25 mg, from about 1 mg to about 50 mg of active ingredient. deaf.

The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, the amount of compound actually administered will usually depend on the relevant circumstances, e.g., the condition to be treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the patient's It will be understood that it will be determined by a doctor according to the severity of symptoms and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present application. Where these preformulation compositions are referred to as homogeneous, the active ingredient is typically contained in such a manner that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. , distributed evenly throughout the composition. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present application (eg, a JAK1 inhibitor provided herein). be.

The tablets or pills of the present application can be coated or otherwise compounded to provide a dosage form that allows for the advantage of prolonged action. For example, a tablet or pill may contain an inner dose and an outer dose component, the latter in the form of an envelope enclosing the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and serves to allow the inner component to pass intact into the duodenum or be released with delay. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. is included.

Liquid forms in which the compounds and compositions of this application can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, as well as cottonseed, sesame, coconut, or Emulsions flavored with edible oils such as peanut oil, as well as elixirs and similar pharmaceutical vehicles are included.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

Topical (e.g., intradermal) administration treats skin disorders locally, minimizes potential adverse events associated with systemic exposure, and allows easy discontinuation of treatment if necessary. It provides the advantage of Additionally, some topical formulations, such as creams, ointments, and gels, have the advantage of additives that can act as emollients or occlusive agents, increasing patient well-being and compliance during treatment. can. Other routes of administration, such as oral, parenteral, and inhalation, can result in systemic drug concentrations substantially in excess of therapeutic effect, increased potential for adverse events, drug-drug interactions, and formation of active/toxic metabolites. Yes, and can lead to treatment discontinuation and poor patient compliance.

Topical formulations intended for dermal delivery are typically solutions, suspensions, gels, creams, ointments, lotions, sprays and foams containing one or more conventional carriers as described herein. can do. A pharmaceutical composition should be prepared to deliver the active ingredients to the appropriate layer(s) of the skin, to minimize systemic exposure, and to prevent skin irritation. Furthermore, pharmaceutical compositions should be physically and chemically stable. Depending on the dosage form of choice, one or more additional additives as described herein, such as pH adjusting agents, chelating agents, preservatives, co-solvents, membrane permeability enhancers, wetting agents, Thickeners, gelling agents, thickeners, surfactants, propellants, flavoring agents, coloring agents, or any combination or mixture thereof may be required.

In some embodiments, topical formulations can contain one or more conventional carriers described herein. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected, for example, from liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, and the like. The carrier composition of the cream can be based on water, combined with glycerol and one or more other ingredients such as glycerin monostearate, PEG-glycerin monostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other ingredients such as glycerol, hydroxyethylcellulose and the like. In some embodiments, the topical formulation contains at least about 0.1%, at least about 0.25%, at least about 0.5%, at least about 1%, at least about 2%, or at least about It contains 5% by weight of a compound of the invention. The topical formulations may be suitably packaged in tubes, eg, 100 g tubes, optionally accompanied by instructions for the treatment of cutaneous lupus erythematosus (CLE).

The amount of compound or composition administered to a patient varies depending on what is being administered, the purpose of administration such as prophylaxis or therapy, the condition of the patient, the method of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from cutaneous lupus erythematosus (CLE) in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. . Effective dosages will vary according to the disease state being treated and at the discretion of the attending physician depending on factors such as the severity of the disease, the age, weight and general condition of the patient.

The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or can be lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that the use of certain excipients, carriers, or stabilizers described above will result in the formation of pharmaceutical salts.

Therapeutic dosages of the compounds of the present application may vary according to, for example, the particular application for which treatment is being performed, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on many factors, including dosage, chemical properties (eg, hydrophobicity), and route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing from about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg/kg body weight to about 1 g/kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg/kg body weight to about 100 mg/kg body weight per day. Dosage will depend on variables such as the type and degree of progression of the disease or disorder, the general health of the particular patient, the relative biological efficacy of the selected compound, the formulation of excipients, and its route of administration. may vary depending on Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

Compositions of the invention can further include one or more additional pharmaceutical agents, examples of which are previously listed herein.

Kits The present application also includes pharmaceutical kits useful, for example, in the treatment and/or prevention of cutaneous lupus erythematosus (CLE), comprising a therapeutically effective amount of a JAK1 inhibitor as described herein. One or more containers are included in which the composition is contained. Such kits may also optionally include one or more of the various conventional pharmaceutical kit components, e.g., one or more pharmaceutically acceptable components, as will be readily apparent to those skilled in the art. A container containing the carrier to be administered, additional containers, and the like may be included. Instructions, either as inserts or labels, indicating quantities of ingredients to be administered, guidelines for administration, and/or guidelines for mixing the ingredients can also be included in the kit.

The invention will be described in more detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially the same results.

All statistical analyzes of in vitro experiments were performed with GraphPad prism software (version 7) using the Kruskal-Wallis test and the Mann-Whitney U test. Gene expression was analyzed with Partek Flow genomic analysis software and Subio Platform software v1.22.5266 using Welch's t-test. Confidence intervals were determined at 95%. P<0.05 was considered "significant" ( ^* ) and p<0.01 "extremely significant" ( ^** ). The KEGG pathway was mapped to differentially expressed genes using DAVID v6.8 (Database for Annotation, Visualization and Integrated Discovery).

Example 1. In Vitro JAK Kinase Assay JAK1 inhibitors, which can be used to treat cytokine-related diseases or disorders, are tested for inhibitory activity of JAK targets by Park et al. , Analytical Biochemistry 1999, 269, 94-104. Catalytic domains of human JAK1 (amino acids 837-1142), JAK2 (amino acids 828-1132), and JAK3 (amino acids 781-1124) with N-terminal His-tags are expressed using baculovirus in insect cells and purified. . The catalytic activity of JAK1, JAK2, or JAK3 was assayed by measuring phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by homogeneous time-resolved fluorescence (HTRF). 40 microL containing enzyme, ATP, and 500 nM peptide in 50 mM Tris (pH 7.8) buffer containing 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA The _IC50 of the compound is determined for each kinase in 3 reactions. For an _IC50 measurement of 1 mM, the ATP concentration in the reaction is 1 mM. The reaction is performed at room temperature for 1 hour and then stopped with 20 μL of 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 assay buffer (Perkin Elmer, Boston, Mass.). Binding to europium-labeled antibody was allowed for 40 minutes and HTRF signal was measured with a Fusion plate reader (Perkin Elmer, Boston, Mass.). The compounds in Table 1 were tested in this assay and shown to have the _IC50 values in Table 1.

Example 2. Activated JAK1 is strongly expressed in human CLE skin lesions. Lichen (LP) and healthy controls were compared. All punch biopsies of different inflammatory skin disorders (N=34) were obtained from active skin lesions for diagnostic purposes. Healthy controls (N=9) were obtained from unaffected skin obtained from plastic surgery. Skin samples were fixed overnight in 4% formalin or frozen nitrogen and proceeded to immunohistochemical staining or RNA isolation. RNA was processed by the Next Generation Sequencing (NGS) Core Facility of the University of Bonn using the QuantSeq 3'-mRNA Library Prep Kit by Lexogen. An Illumina HiSeq 2500 was used for RNA sequencing (50 cycles of standard 3' RNA sequencing)

In CLE skin lesions, pJAK1 expression was significantly increased in keratinocytes from the basal to granular layers and in dermal-infiltrating immune cells. It was also observed that pJAK1 was significantly enhanced in lichen planus, an autoimmune disease that shares common histological features with CLE.

（Ｗｅｎｚｅｌ ｅｔ ａｌ．Ｊ．Ｐａｔｈｏｌ．２００５，２０５：４３５－４４２）まで半定量的に記録した。抗ウサギＲｈｏｄａｍｉｎｅ Ｒｅｄ－Ｘ（７１１－２９５－１５２；Ｊａｃｋｓｏｎ ＩｍｍｕｎｏＲｅｓｅａｒｃｈ，Ｂａｌｔｉｍｏｒｅ，ＭＤ，ＵＳＡ）及びＤＡＰＩ（Ｄ９５４２、Ｓｉｇｍａ－Ａｌｄｒｉｃｈ）によって検出されたＪＡＫ１リン酸化の免疫蛍光分析を、高解像度顕微鏡（Ａｘｉｏ Ｏｂｓｅｒｖｅｒ Ｚ１，Ｚｅｉｓｓ，Ｇｅｒｍａｎｙ）を使用して実施した。 Example 2. JAK/STAT-related natural inflammatory pathways are markedly activated in human CLE skin. gone. Immunohistochemical staining was performed using Fast Red (Agilent, Santa Clara, USA) on plastids, pJAK (ABIN196869, antibodies-online), CXCL10 (ab9807, Cambridge, UK), MxA (M143, Haller, Freiburg, Germany). and CD45 (550539, BD, New Jersey) using REAL™ Detection Systems. expression,

(Wenzel et al. J. Pathol. 2005, 205:435-442). Immunofluorescence analysis of JAK1 phosphorylation detected by anti-rabbit Rhodamine Red-X (711-295-152; Jackson ImmunoResearch, Baltimore, Md., USA) and DAPI (D9542, Sigma-Aldrich) was performed by high-resolution microscopy (Axio Observer). Z1, Zeiss, Germany).

Expression analysis in CLE lesional skin revealed significant activation of genes associated with both innate and adaptive immune pathways compared to healthy controls. In particular, LE-associated proinflammatory chemokines (CXCL10, 9, 11) and other IFN regulatory proteins (OASL, OAS2, Mx1) and major drivers in cell death and B cell activation (CXCR3, CASP10, AIM2, TRAIL, BLyS) genes were highly expressed. Since JAK/STAT signaling is a key regulator of inflammatory gene transcription, STAT1 gene expression was also significantly increased in LE lesions, as shown in FIG. 1C. Innate immune pathways that were upregulated in response to individual genes included the JAK/STAT pathway and related cytokine-/chemokine signaling pathways and upstream TLR-dependent and TLR-independent pathways, as shown in Figure 1D. The DAMP recognition pathway was included.

Example 3. INCB039110 Significantly Inhibits JAK1 Phosphorylation in Cultured Immortalized Human Keratinocytes To analyze the functional principle and effects of JAK inhibition, the following established in vitro model of CLE was used. Immortalized keratinocytes (HaCaT) were obtained from CLS Cell Lines Service GmbH, Eppelheim, Germany) and normal human epidermal keratinocytes (NHEK, FC-0025) and human epidermal equivalents (epiCS, CS-1001) were obtained from CellSystems. , Troisdorf, Germany. These cell lines were cultured according to the manufacturer's protocol. Cultured keratinocytes were treated with endogenous nucleic acid (eNA, 1.25 μg/mL) isolated from unstimulated keratinocytes using the “Genomic DNA from tissue” kit (Machery-Nagel, Dueren, Germany). stimulated me. Lipofectamine 2000 (Invitrogen, Carlsbad, USA) served as transfection reagent (2.5 μL/mL). INCB039110, and ruxolitinib (Selleckchem, Eching, Germany) were added at a final concentration of 1 μM and JAK3-selective FM-381 was used (100 nm) as recommended (eg, Forster et al, Cell Chem. Biol. 2016, 23:1335-1340). All experiments were performed in biological triplicates. Enzyme-linked immunosorbent assay of human CXCL10 (DY266-05 R&D systems) was performed using the DuoSet Ancillary Reagent Kit 2 (DY008 R&D systems) according to the protocol provided, and Synergy HT Multi-Detection Multiplate Winooski, VT, USA) and read with Gen5 software (version 1.11.5).

JAK1 phosphorylation was strongly enhanced in immortalized keratinocytes (HaCaT) after stimulation with eNA, consistent with the above findings in CLE skin lesions (see Examples 2, 3). ). As shown in FIGS. 2A and 2B, JAK1-specific INCB039110 and JAK1/2-specific ruxolitinib significantly reduced JAK1 activation in stimulated cells.

^ａＫＥＧＧパスウェイは、Ｄａｔａｂａｓｅ ｆｏｒ Ａｎｎｏｔａｔｉｏｎ，Ｖｉｓｕａｌｉｚａｔｉｏｎ ａｎｄ Ｉｎｔｅｇｒａｔｅｄ Ｄｉｓｃｏｖｅｒｙ（ＤＡＶＩＤ ｖｅｒ．６．８）を使用して分類された。ＥＡＳＥ ＳｃｏｒｅでＰ値を生成した。カウント：ＫＥＧＧパスウェイそれぞれの内部でＮＨＥＫにおいてＩＮＣＢ０３９１１０により２倍を超えて下方制御されている遺伝子の数。 Example 4. Pharmacological JAK1 inhibition blocks the expression of molecules of inflammatory cytokines and pathways typical of CLE in vitro. In vitro analysis of cells and (iii) 3D epidermal equivalents in three different CLE models was performed. As shown in FIG. 2C, pharmacological JAK1 inhibition resulted in increased IFN-regulated chemokines (CXCL10, CXCL11), cell death (TRAIL, AIM2) in primary keratinocytes (NHEK) compared to untreated eNA inflammatory cells. , TREX1) and crosstalk to adaptive immune cells (BlyS). Associated downregulated KEGG pathways are shown in Table A. These results were confirmed in HaCaT cells, where both JAK1 and JAK1/2 inhibitors significantly reduced CXCL10 protein expression.

^a KEGG pathways were classified using the Database for Annotation, Visualization and Integrated Discovery (DAVID ver.6.8). P values were generated with the EASE Score. Counts: number of genes downregulated >2-fold by INCB039110 in NHEKs within each of the KEGG pathways.

The in vitro data disclosed herein demonstrate that JAK1-selective inhibitors are as potent as JAK1/2 inhibitors in suppressing the typical cytokines of CLE and reducing inflammation, as shown in FIG. 2D. Inducible chemokines (CXCL10, 11), lymphocyte activation factor (BLyS) (see e.g. Wenzel et al, Exp. Dermatol. 2018, 27:95-97) and cell death promoters (TRAIL (e.g. Zahn et al, Br. J. Dermatol. Interestingly, as shown in Figure 2D, inhibition of JAK3 did not result in a reduction of CXCL10 expression, a central mediator of the "interfacial dermatitis" typical of CLE. Without being bound by theory, this may explain the early failure of the JAK3/SYK blocker R333 in CLE clinical trials (e.g., Presto et al, Br. J. Dermatol .2018, 178:1308-1314). In the 3D epidermal equivalent, as shown in FIG. 2E, exposure of a JAK1-selective inhibitor to stimulated epiCS revealed a marked decrease in CXCL10 protein expression, consistent with the above findings.

Example 5. In vivo topical application of INCB039110 remits CLE-like lesions in lupus-prone TREX1 ^−/− mice TREX1 ^−/− mice (established on a C57BL/6J background; Cancer Research Institute, London, UK) They were bred and reared under specific pathogen-free conditions at Bonn's Animal Core Facility (HET, Bonn, Germany). The backs of TREX1 ^−/− mice (n=8) were shaved and treated with 0,2% DNFB (1-fluoro-2,4-dinitrobenzol, Sigma Aldrich). After 4 days, UV irradiation was performed for 3 consecutive days starting with 450 mJ/cm ² UVB per day for 115 seconds using a UV801KL (Waldmann, Villingen-Schwenningen, Germany). 1% INCB039110 dissolved in DMSO and olive oil (50 μL/mouse) or vehicle was topically applied for 7 days. Mice were photographed on consecutive days and weighed every two days.

TREX1 ^−/− mice spontaneously developed CLE-like erythrosquamous, partially ulcerated skin lesions at a certain age and enhanced after challenge with UVB. As shown in FIGS. 3A and 3B, topical treatment with JAK1-specific INCB039110 for 7 days resulted in continuous improvement in lesional skin in terms of erythema, induration, scale and size compared to placebo-treated mice, and lupus-skin -Activity-score (adapted CLASI score) resulted in a significant decrease. Furthermore, as shown in FIG. 3C, distinct histological features such as epidermal thickness and infiltrating dermal immune cells were greatly improved by JAK1 inhibition.

The data disclosed in Examples 2-5 demonstrate that JAK1-specific inhibition markedly reduces the expression of inflammatory cytokines typical of CLE in vitro and in vivo. Topical application of JAK1-selective inhibitors was highly effective in treating CLE-like lesions in lupus-prone mice, supporting their potential use in human CLE.

Various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited within this disclosure, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited within this disclosure, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.
The present application also includes the following aspects.
[Aspect 1]
A method of doing so in a patient in need of treating a disease selected from cutaneous lupus erythematosus (CLE) and lichen planus (LP), comprising:
{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[ 4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide,
[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidine-4 -yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile,
4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro- N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide,
((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H -pyran-2-yl)acetonitrile,
3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 - yl]propanenitrile,
3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4- yl)-1H-pyrazol-1-yl]propanenitrile,
4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl) carbonyl]-3-fluorobenzonitrile,
4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl) carbonyl]-3-fluorobenzonitrile,
[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidine -4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile,
{trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl]butanenitrile,
5-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropyl pyrazine-2-carboxamide,
4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5 -difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide,
5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropyl pyrazine-2-carboxamide,
{1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl) -1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile {trans-3-(4-{[4-({[ (2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, and
{trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
or a pharmaceutically acceptable salt of any of the foregoing, in a therapeutically effective amount to said patient.
[Aspect 2]
2. The method of aspect 1, wherein the JAK1 selective inhibitor, or a pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2, JAK3, and TYK2.
[Aspect 3]
The JAK1 selective inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.
[Aspect 4]
Said pharmaceutically acceptable salt is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.
[Aspect 5]
The JAK1 selective inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl ]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof, according to aspect 1 or 2. Method.
[Aspect 6]
The pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine-1 -yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate.
[Aspect 7]
wherein the JAK1 selective inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.
[Aspect 8]
wherein the JAK1 selective inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate.
[Aspect 9]
9. The method of any one of aspects 1-8, further comprising administering an additional therapeutic agent to said patient.
[Aspect 10]
10. The method of aspect 9, wherein said additional therapeutic agent is selected from a JAK1/JAK2 inhibitor, a JAK1/JAK3 inhibitor, a TYK2 inhibitor, or a pharmaceutically acceptable salt of any of the foregoing.
[Aspect 11]
11. The method of aspect 10, wherein said additional therapeutic agent is a JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof.
[Aspect 12]
12. The method of aspect 10 or 11, wherein said JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof, is selective for JAK1 and JAK2 over JAK3 and TYK2.
[Aspect 13]
13. The method of any one of aspects 10-12, wherein said JAK1/JAK2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof.
[Aspect 14]
14. The method of aspect 13, wherein said method comprises topical administration of said ruxolitinib, or a pharmaceutically acceptable salt thereof, to said patient.
[Aspect 15]
14. The method of aspect 13, wherein said method comprises oral administration of said ruxolitinib, or a pharmaceutically acceptable salt thereof, to said patient.
[Aspect 16]
16. The method of any one of aspects 13 or 15, wherein said pharmaceutically acceptable salt is ruxolitinib salt.
[Aspect 17]
according to any one of aspects 10-12, wherein said JAK1/JAK2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by deuterium atoms Method.
[Aspect 18]
11. The method of aspect 10, wherein said additional therapeutic agent is a JAK1/JAK3 inhibitor, or a pharmaceutically acceptable salt thereof.
[Aspect 19]
19. The method of aspects 10 or 18, wherein said JAK1/JAK3 inhibitor is tofacitinib, or a pharmaceutically acceptable salt thereof.
[Aspect 20]
20. The method of any one of aspects 1-19, wherein said method comprises topical administration of said JAK1 selective inhibitor to said patient.
[Aspect 21]
20. The method of any one of aspects 1-19, wherein said method comprises oral administration of said JAK1 selective inhibitor to said patient.
[Aspect 22]
22. The method of any one of aspects 1-21, wherein said disease is cutaneous lupus erythematosus (CLE).
[Aspect 23]
23. The method of aspect 22, wherein the cutaneous lupus erythematosus (CLE) is selected from subacute cutaneous lupus erythematosus (SCLE) and chronic discoid lupus erythematosus (CDLE).
[Aspect 24]
22. The method of any one of aspects 1-21, wherein the disease is lichen planus (LP).

Claims (24)

A method of doing so in a patient in need of treating a disease selected from cutaneous lupus erythematosus (CLE) and lichen planus (LP), comprising:
{1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[ 4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide,
[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidine-4 -yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile,
4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro- N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide,
((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H -pyran-2-yl)acetonitrile,
3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 - yl]propanenitrile,
3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4- yl)-1H-pyrazol-1-yl]propanenitrile,
4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl) carbonyl]-3-fluorobenzonitrile,
4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl) carbonyl]-3-fluorobenzonitrile,
[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidine -4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile,
{trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl]butanenitrile,
5-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropyl pyrazine-2-carboxamide,
4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5 -difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide,
5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropyl pyrazine-2-carboxamide,
{1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile,
{trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine- 1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
{trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl) -1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile {trans-3-(4-{[4-({[ (2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, and {trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridine- 2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile,
or a pharmaceutically acceptable salt of any of the foregoing, in a therapeutically effective amount to said patient. 2. The method of claim 1, wherein the JAKl selective inhibitor, or a pharmaceutically acceptable salt thereof, is selective for JAKl over JAK2, JAK3, and TYK2. The JAK1 selective inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof. Said pharmaceutically acceptable salt is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate. The JAK1 selective inhibitor is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl ]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide or a pharmaceutically acceptable salt thereof, according to claim 1 or 2. the method of. The pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine-1 -yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphate. wherein the JAK1 selective inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof. wherein the JAK1 selective inhibitor is ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile monohydrate. 9. The method of any one of claims 1-8, further comprising administering an additional therapeutic agent to the patient. 10. The method of claim 9, wherein said additional therapeutic agent is selected from a JAK1/JAK2 inhibitor, a JAK1/JAK3 inhibitor, a TYK2 inhibitor, or a pharmaceutically acceptable salt of any of the foregoing. 11. The method of claim 10, wherein said additional therapeutic agent is a JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof. 12. The method of claim 10 or 11, wherein said JAK1/JAK2 inhibitor, or a pharmaceutically acceptable salt thereof, is selective for JAK1 and JAK2 over JAK3 and TYK2. The method of any one of claims 10-12, wherein the JAK1/JAK2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof. 14. The method of claim 13, wherein said method comprises topical administration of said ruxolitinib, or a pharmaceutically acceptable salt thereof, to said patient. 14. The method of claim 13, wherein said method comprises oral administration of said ruxolitinib, or a pharmaceutically acceptable salt thereof, to said patient. 16. The method of any one of claims 13 or 15, wherein the pharmaceutically acceptable salt is ruxolitinib salt. 13. The JAK1/JAK2 inhibitor according to any one of claims 10-12, wherein the JAK1/JAK2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by deuterium atoms. the method of. 11. The method of claim 10, wherein said additional therapeutic agent is a JAK1/JAK3 inhibitor, or a pharmaceutically acceptable salt thereof. 19. The method of claim 10 or 18, wherein said JAK1/JAK3 inhibitor is tofacitinib, or a pharmaceutically acceptable salt thereof. 20. The method of any one of claims 1-19, wherein said method comprises topical administration of said JAK1 selective inhibitor to said patient. 20. The method of any one of claims 1-19, wherein said method comprises oral administration of said JAK1 selective inhibitor to said patient. The method of any one of claims 1-21, wherein the disease is cutaneous lupus erythematosus (CLE). 23. The method of claim 22, wherein the cutaneous lupus erythematosus (CLE) is selected from subacute cutaneous lupus erythematosus (SCLE) and chronic discoid lupus erythematosus (CDLE). The method of any one of claims 1-21, wherein the disease is lichen planus (LP).

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