Azetidinylpyrimidine and its use as a JAK inhibitor

Abstract

Compounds useful in the treatment of JAK-related diseases are provided herein as inhibitors of Janus kinase (JAK) proteins. Azetidinylpyrimidine compounds that affect the functions of kinases and other proteins useful in the treatment of diseases are described herein. The compounds described herein have kinase regulatory activity. In some embodiments, the kinase regulatory activity includes inhibition of one or more JAK proteins. In some embodiments, the kinase regulatory activity includes inhibition of ROCK1 or ROCK2, or both.

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 356,670, filed Jun. 29, 2022, the entire content of which is incorporated herein by reference.

[0002] Sequence Listing This application includes a sequence listing having the file name 1960110_00621_SL.xml (size 3,315 bytes, created on May 30, 2023). The entire content of this sequence listing is incorporated herein by reference.

Background Art

[0003] Background Janus kinases (JAK) are a family of cytoplasmic protein tyrosine kinases. Four JAKs, JAK1, JAK2, JAK3, and TYK2, and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signaling downstream of cytokine receptors and are involved in pathologies such as autoimmune diseases, allergic diseases, and inflammatory diseases, among others. JAKs typically associate with cytokine receptors in pairs, either as homodimers or heterodimers. Specific cytokines associate with specific JAK pairs. Each of the four members of the JAK family is involved in the signaling pathway of at least one of the cytokines associated with inflammation. When a cytokine binds to a JAK-dependent cytokine receptor, receptor dimerization is induced, as a result of which tyrosine residues on the JAK kinase are phosphorylated and the JAK is activated. The phosphorylated JAK then binds to and phosphorylates various STAT proteins, dimerizes by phosphorylation, translocates to the cell nucleus, and directly regulates gene transcription, causing downstream effects such as those associated with inflammatory or autoimmune diseases, among other effects. Furthermore, there is recent evidence that the kinases ROCK1 and ROCK2 interact with STAT enzymes and as a result may downregulate IL-21 and IL-17 secretion. Inhibition of ROCK kinase has been pointed out to have not only the well-known effects of JAK inhibition but also anti-inflammatory effects. Considering the roles played by kinases in many pathological conditions, small molecule ligands that inhibit or modulate kinase activity are urgently and continuously needed.

Summary of the Invention

Means for Solving the Problems

[0004] Summary Formula:

Chemical

[0005] The use of compounds including inhibition of kinases and treatment of related diseases is also described herein.

Brief Description of the Drawings

[0006]

Figure 1

Modes for Carrying Out the Invention

[0007] Detailed Description Azetidinylpyrimidine compounds that affect the functions of kinases and other proteins useful for the treatment of diseases are described herein. Definitions

[0008] Certain terms are defined below, whether used alone or as part of a phrase or other term.

[0009] The articles "a" and "an" refer to the grammatical object of the article being one or more than one.

[0010] Numerical values regarding measurements are subject to measurement error and have limitations in their accuracy. For this reason, unless otherwise indicated, all numerical values provided herein should be understood to be modified by the term "about". Thus, the last decimal place of the numerical values provided herein indicates the degree of their accuracy. When no other error range is given, when there is no decimal point in a given numerical value, the maximum range is determined by applying the rounding rule to the last decimal place or the last significant digit.

[0011] The term "alkyl" or "alkylene" refers to a branched or straight-chain saturated hydrocarbon.

[0012] The term "alkynyl" refers to an unsaturated hydrocarbon containing at least one carbon-carbon triple bond.

[0013] The term "amelioration" means a reduction in the severity of at least one indicator of a condition or disease, such as a delay in the progression of one or more indicators of a condition or disease or slowing of its progression. The severity of an indicator can be determined by subjective or objective measures known to those of ordinary skill in the art.

[0014] The term "aryl" refers to a carbocyclic aromatic system containing one, two, three, or more rings.

[0015] The term "C n~m " refers to a moiety containing from n to m carbon atoms, where n and m are integers.

[0016] The terms "composition" and "pharmaceutical composition" refer to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are multiple techniques for administering a compound (including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, nasal, pulmonary, and topical administration).

[0017] The term "cycloalkyl" refers to a cyclic alkyl moiety containing one, two, three, or more rings.

[0018] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound, such as a compound described herein, that is effective, as a single dose or as part of a series of doses, when administered to a subject to provide the desired therapeutic effect. Generally, a therapeutically effective amount can first be estimated in either a cell culture assay or a mammalian model (e.g., non-human primates, mice, rabbits, dogs, or pigs). Also, an animal model can be used to determine the appropriate concentration range and route of administration. Then, such information can be used to determine the dosage and route of administration useful for administration in non-human and human subjects.

[0019] The term "halo" or "halogen" refers to one or more atoms independently selected from F, Br, Cl, or I.

[0020] The term "haloalkyl" refers to an alkyl moiety substituted with one or more halogens.

[0021] The term "haloaryl" refers to an aryl moiety substituted with one or more halogens.

[0022] The term "halocycloalkyl" refers to a cycloalkyl moiety substituted with one or more halogens.

[0023] The term "heteroaryl" refers to an aryl moiety containing at least one ring heteroatom selected from O, S, or N, where each ring may independently contain 1, 2, 3, or 4 ring heteroatoms independently selected from O, S, or N.

[0024] The term "heterocycloalkyl" refers to a cycloalkyl moiety containing at least one ring heteroatom selected from O, S, or N, where each ring may independently contain 1, 2, 3, or 4 ring heteroatoms independently selected from O, S, or N.

[0025] The term "heterocyclyl" refers to a ring system containing at least one heteroatom selected from O, S, or N and one or more rings, where each ring may independently contain 1, 2, 3, or 4 ring heteroatoms independently selected from O, S, or N.

[0026] The term "pharmaceutically acceptable carrier" means a liquid filling agent, solid filling agent, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, etc., a pharmaceutically acceptable material, composition, or carrier that is involved in the transport or delivery of at least one compound described in this specification into or to a patient such that the compound can exert its intended function. A given carrier must be "acceptable" in the sense that it is compatible with the other components of a particular formulation containing the compounds described in this specification and is not harmful to the patient. Other components that can be included in the pharmaceutical compositions described in this specification are known in the art and are described, for example, in ‘‘Remington’s Pharmaceutical Sciences’’ (Genaro (Ed.), Mack Publishing Co., 1985) (the entire content of which is incorporated herein by reference).

[0027] The term "refractory disease" refers to a disease that continues to progress during treatment with pharmaceutical components other than the compounds provided in this specification, partially responds to other treatments, or transiently responds to other therapies. The foregoing term can be applied to each of the diseases mentioned in this specification.

[0028] The term "treatment" or "treating" refers to the application of one or more specific procedures used for the improvement of a disease. "Preventive" treatment refers to a decrease in the rate of progression of the disease or condition being treated, a delay in the onset of the foregoing disease or condition, or a reduction in the severity of its onset.

[0029] The recitation of a range of values in this specification is intended to serve only as a convenient method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. Unless otherwise indicated or clearly contradicted by context, all of the methods described herein can be performed in any suitable order. The use of any examples, or exemplary language (e.g., "such as") provided herein is intended merely to clarify the description and does not otherwise limit the scope of the claimed subject matter. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the claimed subject matter.

[0030] The grouping of alternative elements or embodiments of the present disclosure should not be construed as a limitation. Members of each group can be referred to individually or in any combination with other members of the group or other elements found herein and can be recited in the claims. Further, for convenience or reasons of patentability, some of the recited members of a group may be included in or excluded from another recited group. In the event of any such inclusion or exclusion, the specification is to be regarded as including the modified group, thereby satisfying the written description of all Markush groups used in the appended claims.

[0031] Throughout this specification patents and printed publications are referenced, and each of these is hereby incorporated by reference in its entirety for all purposes.

[0032] It is to be understood that the embodiments of the present disclosure are illustrative. Accordingly, the present disclosure is not strictly limited to what is illustrated and described. Compound

[0033] It has been found that the compounds described herein are useful as inhibitors of kinases including JAK proteins.

[0034] Therefore, the formula: [Chemical formula] (wherein, R 5 is H or S(O)2-(C 1~6 alkyl); R 1 is H, CN, halogen, C 1~6 alkyl, O-(C 1~6 alkyl), or C 3~7 cycloalkyl); R 2 is C 6~16 aryl or C 2~15 heterocyclyl, each of which is OH, halogen, C 1~6 alkyl, (C 1~6 alkylene)-OH, O-(C 1~6 alkyl), (C 1~6 alkylene)-O-(C 1~6 alkyl), S(O)2-(C 1~6 alkyl), C 3~7 cycloalkyl, (C 1~16 alkylene)-C(O)OH, (C 1~16 alkylene)-C(O)N(H)-(C 1~6 alkyl), (C 1~16 alkylene)-C(O)N(H)-OH, or (C 1~6 alkylene)-N(C 1~6 alkyl)-(C 1~6 alkyl) and may be substituted with one or two groups independently selected from; R 3 is CN, OH, NH2, C 1~6 alkyl, C 1~6 alkynyl, C 3~7 cycloalkyl, (C 1~3 alkylene)-CN, (C 1~3 alkylene)-NH2, (C 1~3 alkylene)-N(H)C(O)-(C 3~7 cycloalkyl), (C 1~3 alkylene)-N(H)C(O)-(C2~8 heterocycloalkyl), O-(C 3~7 cycloalkyl), O-(C 1~3 alkylene)-CN, N(H)C(O)-(C 3~7 cycloalkyl), N(H)C(O)-(C 2~8 heterocycloalkyl), N(H)C(O)-(C 2~5 heteroaryl), N(H)C(O)-(C 1~3 alkylene)-(C 2~5 heteroaryl), N(H)C(O)-(C 6~10 aryl), N(H)C(O)-(C 1~3 alkylene)-(C 6~10 aryl), N(H)C(O)NH2, N(H)(C 1~6 alkyl), N(H)(C 3~7 cycloalkyl), N(C 1~6 alkyl)(C 3~7 cycloalkyl), N(H)(C 1~3 alkylene)-(C 2~8 heterocycloalkyl), N(H)(C 1~3 alkylene)-(C 2~5 heteroaryl), N(H)(C 1~3 alkylene)-(C 6~10 aryl), or C 2~15 heterocyclyl, each of which is halogen, O, OH, O-(C 1~6 alkyl), S(O)2-(C 1~6 alkyl), S(O)2-(C 1~6 haloalkyl), C(NH2)(NH), C 1~6 alkyl, C 1~6 haloalkyl, (C 1~6 alkylene)-OH, (C 1~6 alkylene)-O-(C 1~6 alkyl), (C 1~6 alkylene)-O-(C 1~6 haloalkyl), (C 1~6 alkylene)-S(O)2-(C 1~6 alkyl), (C 1~6 alkylene)-NH2, (C 1~6 alkylene)-N(H)(C 1~6 alkyl), (C1~6 (alkylene)-N(C 1~6 (alkyl)(C 1~6 (alkyl), (C 1~6 (alkylene)-(C 3~7 (cycloalkyl), (C 1~6 (alkylene)-(C 3~7 (halocycloalkyl), (C 1~6 (alkylene)-(C 2~5 (heteroaryl), (C 1~6 (alkylene)-(C 6~10 (haloaryl), NH2, N(H)(C 1~6 (alkyl), N(C 1~6 (alkyl)(C 1~6 (alkyl), N(H)-(C 1~3 (alkylene)-(C 3~7 (cycloalkyl), N(C 1~6 (alkyl)-(C 1~3 (alkylene)-(C 3~7 (cycloalkyl), N(H)C(O)O-(C 1~6 (alkyl), N(H)S(O)2-(C 1~6 (alkyl), C(O)-(C 1~6 (alkyl), C(O)-(C 1~6 (alkylene)-CN, C(O)-(C 1~6 (alkylene)-NH2, C(O)-(C 1~6 (alkylene)-N(H)(C 1~6 (alkyl), C(O)-(C 1~6 (alkylene)-N(C 1~6 (alkyl)(C 1~6 (alkyl), C(O)-(C 1~6 (alkylene)-N(H)[S(O)2-C 1~6 (alkyl)], C(O)-(C 1~6 (alkylene)-N(C 1~6 (alkyl)[S(O)2-C 1~6 (alkyl)], or C(O)O-(C 1~6 (alkyl) and may be optionally substituted with 1, 2, 3, or 4 groups independently selected therefrom; and R 4 is H, OH, C 1~6 (alkyl), (C 1~6 (alkylene)-OH, C 1~6Haloalkyl, C 3~7 Cycloalkyl, C 3~7 Halocycloalkyl, (C 1~3 Alkylene)-(C 3~7 Cycloalkyl), (C 1~6 Alkylene)CN, (C 1~6 Alkylene)-C(O)O-(C 1~6 Alkyl), (C 1~6 Alkylene)-OC(O)-(C 1~6 Alkyl), or C 2~8 Heterocycloalkyl; Alternatively, R 3 and R 4 are, together with the atoms to which they are attached, selected from 1 or 2 groups independently selected from C 3~7 Cycloalkyl, C 2~8 Heterocycloalkyl, CC(H)-(C 0~6 Alkylene)CN, halogen or (C 1~6 Alkylene)CN substituted C 3~7 Cycloalkyl, or halogen or (C 1~6 Alkylene)CN substituted C 2~8 Heterocycloalkyl to form) a compound having or a pharmaceutically acceptable salt thereof is provided herein.

[0035] In some embodiments, R 5 is H.

[0036] In some embodiments, R 2 is phenyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolinyl, isoindolinyl, indolyl, phenylmorpholinyl, phenyloxetanyl, phenylpiperazinyl, dihydrobenzoborolyl, or benzoborolyl, each of which is OH, F, Cl, Br, C 1~3 Alkyl, (C 1~3 Alkyl)-OH, C 1~6 Haloalkyl, O-(C 1~3 Alkyl), (C 1~3 Alkylene)-O-(C1~3 alkyl), S(O)2-(C 1~3 alkyl), C 3~5 cycloalkyl, (C 6~16 alkylene)-C(O)OH, (C 6~16 alkylene)-C(O)N(H)-(C 1~6 alkyl), (C 6~16 alkylene)-C(O)N(H)-OH, or (C 1~3 alkylene)-N(C 1~3 alkyl)-(C 1~3 alkyl) and may be substituted with one or two groups independently selected from

[0037] In some embodiments, R 3 is CN, OH, NH2, C 1~6 alkyl, C 1~6 alkynyl, C 3~7 cycloalkyl, (C 1~3 alkylene)-CN, or (C 1~3 alkylene)-NH2.

[0038] In some embodiments, R 3 is OH, NH2, C 1~3 alkyl, C 1~3 alkynyl, C 3~7 cycloalkyl, or (C 1~3 alkylene)-NH2, each of which is F, Cl, O, OH, O-(C 1~3 alkyl), C 1~3 alkyl, C 1~3 haloalkyl, (C 1~3 alkylene)-OH, (C 1~3 alkylene)-O-(C 1~3 alkyl), (C 1~3 alkylene)-NH2, NH2, N(H)(C 1~3 alkyl), or N(C 1~3 alkyl)(C 1~3 alkyl) and may be substituted with one, two, or three groups independently selected from

[0039] In some embodiments, R 3 is (C1~3 (alkylene)-N(H)C(O)-(C 3~7 cycloalkyl), (C 1~3 (alkylene)-N(H)C(O)-(C 2~8 heterocycloalkyl), O-(C 3~7 cycloalkyl), or O-(C 1~3 (alkylene)-CN, and each of these is F, Cl, O, OH, O-(C 1~3 alkyl), C 1~3 alkyl, C 1~3 haloalkyl, (C 1~3 (alkylene)-OH, (C 1~3 (alkylene)-O-(C 1~3 alkyl), (C 1~3 (alkylene)-NH2, NH2, N(H)(C 1~3 alkyl), or N(C 1~3 alkyl)(C 1~3 alkyl) and may be substituted with one, two, or three groups independently selected therefrom.

[0040] In some embodiments, R 3 is N(H)C(O)-(C 3~7 cycloalkyl), N(H)C(O)-(C 2~8 heterocycloalkyl), N(H)C(O)-(C 2~5 heteroaryl), N(H)C(O)-(C 1~3 (alkylene)-(C 2~5 heteroaryl), N(H)C(O)-(C 6~10 aryl), N(H)C(O)-(C 1~3 (alkylene)-(C 6~10 aryl), N(H)C(O)NH2, N(H)(C 1~6 alkyl), N(H)(C 3~7 cycloalkyl), N(C 1~6 alkyl)(C 3~7 cycloalkyl), N(H)(C 1~3 (alkylene)-(C 2~8 heterocycloalkyl), N(H)(C 1~3 (alkylene)-(C 2~5 heteroaryl), or N(H)(C 1~3(Alkylene)-(C 6~10 Aryl), and each of these is F, Cl, O, OH, O-(C 1~3 Alkyl), C 1~3 Alkyl, C 1~3 Haloalkyl, (C 1~3 Alkylene)-OH, (C 1~3 Alkylene)-O-(C 1~3 Alkyl), (C 1~3 Alkylene)-NH2, NH2, N(H)(C 1~3 Alkyl), or N(C 1~3 Alkyl)(C 1~3 Alkyl) and may be substituted with 1, 2, or 3 groups independently selected from.

[0041] In some embodiments, R 3 is F, Cl, O, OH, O-(C 1~3 Alkyl), C 1~3 Alkyl, C 1~3 Haloalkyl, (C 1~3 Alkylene)-OH, (C 1~3 Alkylene)-O-(C 1~3 Alkyl), (C 1~3 Alkylene)-NH2, NH2, N(H)(C 1~3 Alkyl), or N(C 1~3 Alkyl)(C 1~3 Alkyl) and may be substituted with 1, 2, or 3 groups independently selected from a C 2~15 Heterocyclyl.

[0042] In some embodiments, R 3 and R 4 are combined with the atoms to which they are attached to form a C 3~7 Cycloalkyl, C 2~8 Heterocycloalkyl, CC(H)-(C 0~3 Alkylene)CN, halogen or (C 1~3 Alkylene)CN and may be substituted with 1 or 2 groups independently selected from a C 3~7 Cycloalkyl, or halogen or (C 1~3C substituted with one or two groups independently selected from (alkylene)CN 2~8 forms a heterocycloalkyl.

[0043] In some embodiments, the compounds provided herein have the following formula:

Chemical Formula

[0044] In some embodiments, the compounds provided herein have the following formula:

Chemical Formula

[0045] In some embodiments, the compounds provided herein have the following formula:

Chemical Formula

[0046] In some embodiments, the compounds provided herein have the following formula: [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments of the formula provided herein, R 1 is F, Cl, Br, C 1~3 alkyl, or C 3~4 cycloalkyl. In some embodiments, R 2 is C 3~4 heteroaryl, or C 1~3 alkyl or (C 1~3 alkylene)OH-substituted C 3~4 heteroaryl. In some embodiments, R 3 is C 4~8 heterocycloalkyl, or C 1~3 alkyl, F, Cl, Br, or O(C 1~3 alkyl)-substituted C 4~8 heterocycloalkyl by one or two groups independently selected therefrom. In some embodiments, R 4 is CH2CN.

[0048] In some embodiments of the formula provided herein, one or more of A)-F) apply: A) R 5 is H, S(O)2CH3, or S(O)2CH2CH3; B) R 1 is H, CH3, CH2CH3, cyclopropyl, OCH3, F, Cl, or CN; C) R 2 is [Chemical formula] [Chemical formula] is; D)R 3 is CN, OH, NH2,

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0049] In some embodiments, the compounds provided herein are

Chem.

Chem.

[0050] In addition, the compounds described herein include isotopically labeled compounds in which one or more atoms have an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature while having the same atomic number. Examples of isotopes suitable for inclusion in the compounds described herein are 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S, including but not limited to these. In some embodiments, the isotopically labeled compounds are useful in tissue distribution studies of drugs or substrates. In another embodiment, replacement with heavier isotopes such as deuterium improves metabolic stability (e.g., extends the in vivo half-life or reduces the required dosage). In yet another embodiment, replacement with positron-emitting isotopes ( 11 C, 18 F, 15 O, and 13 N, etc.) is useful in positron emission tomography (PET) studies for testing substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or by a process using appropriate isotopically labeled reagents in place of the unlabeled reagents used in another method.

[0051] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Composition

[0052] In some embodiments, compositions comprising the compounds provided herein are provided herein. In some embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In some embodiments, the carrier is a solvent or an inert stabilizer or both. In some embodiments, the inert stabilizer provides a dehydrating effect on the composition, thereby making it possible to increase the shelf-life stability of the compounds for storing the composition. In some embodiments, the composition may further comprise additional pharmaceuticals. Method

[0053] The compounds described herein have kinase modulating activity. In some embodiments, the kinase modulating activity includes inhibition of one or more JAK proteins. In some embodiments, the kinase modulating activity includes inhibition of ROCK1 or ROCK2, or both.

[0054] Accordingly, in some embodiments, the compounds described herein are useful for the treatment of JAK-related diseases or ROCK-related diseases in a subject in need of treatment of a JAK-related disease or a ROCK-related disease. In some embodiments, provided herein is a method of treating a disease in a subject in need of treatment of the disease, the method comprising administering to the subject a therapeutically effective amount of a compound described herein.

[0055] In some embodiments, provided herein is a method of treating an eye disease in a subject in need of treatment for the eye disease, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein. In some embodiments, the eye disease includes, but is not limited to, ocular inflammatory conditions (non-infectious uveitis, retinitis, iritis, sterile conjunctivitis, keratitis, episcleritis, dry eye disease, meibomian gland dysfunction, allergic conjunctivitis, eye inflammation or dry eye syndrome associated with injury, primary or secondary Sjogren's syndrome, redness, blepharitis, dry keratoconjunctivitis, eye congestion, macular degeneration (atrophic or exudative), diabetic retinopathy, diabetic macular edema, retinal vein occlusion, age-related macular degeneration, geographic atrophy, posterior uveitis, retinal inflammation, inflammation caused by gene therapy vectors (e.g., viral vectors), graft-versus-host disease, blepharitis, Thygeson's punctate superficial keratitis, or combinations thereof).

[0056] In some embodiments, provided herein is a method of treating a disease in a subject in need of treatment for the disease, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, wherein the disease is selected from: neurodegenerative diseases or conditions (such as Alzheimer's disease); eye diseases (such as diabetic eye diseases, exudative age-related macular degeneration, or atrophic age-related macular degeneration, inflammatory eye diseases, retinal damage, and glaucoma); cardiovascular diseases; or cancer. Further examples of diseases that can be treated by administration of the compounds provided herein include bone conditions, obesity, liver diseases, kidney diseases, pancreatitis, gastric disorders, hypertension, fertility regulation, hair growth conditions, nasal congestion, neurogenic bladder conditions, gastrointestinal conditions, dermatological conditions, or respiratory manifestations.

[0057] In some embodiments, JAK-related diseases include diseases and conditions involving the immune system (e.g., including organ transplant rejection (e.g., allograft rejection and graft-versus-host disease)). Further examples of diseases or conditions related to JAK include autoimmune diseases (alopecia areata, alopecia totalis, polycythemia vera, vitiligo, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid conditions, and chronic obstructive pulmonary disease (COPD), etc.). In some embodiments, the autoimmune disease is arthritis.

[0058] Further examples of diseases or conditions related to JAK include allergic conditions such as asthma, food allergy, eczematous dermatitis, contact dermatitis, atopic dermatitis (atropic eczema), and rhinitis. Further examples of diseases or conditions related to JAK include viral diseases (such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), and human papillomavirus (HPV), etc.).

[0059] Further examples of diseases or conditions related to JAK include those characterized by solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman disease, uterine leiomyosarcoma, melanoma, etc.), hematological cancers (e.g., lymphoma, leukemia (such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), etc.), or multiple myeloma), and skin cancers (such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma, etc.). Exemplary CTCLs include Sézary syndrome and mycosis fungoides. Other examples of diseases or conditions related to JAK include pulmonary hypertension.

[0060] Other examples of diseases or conditions associated with JAK include inflammation-related cancers. In some embodiments, the cancer is associated with an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn's disease. In some embodiments, the inflammation-related cancer is a colitis-related cancer. In some embodiments, the inflammation-related cancer is colon cancer or colorectal cancer. In some embodiments, the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), adenocarcinoma, small intestine cancer, hematological cancer, or rectal cancer.

[0061] In some embodiments, provided herein is a method of treating an ocular condition in a subject in need of treatment of the ocular condition, the method comprising administering to the subject a therapeutically effective amount of a compound, composition, or pharmaceutical composition provided herein.

[0062] In some embodiments, provided herein is a method of reducing ocular inflammation in a subject in need of reduction of ocular inflammation, the method comprising administering to the subject a therapeutically effective amount of a compound, composition, or pharmaceutical composition provided herein.

[0063] In some embodiments, provided herein is a method of treating an ocular condition in a subject in need of treatment of the ocular condition, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the ocular disease or condition is dry eye.

[0065] In some embodiments, the ocular disease or condition is meibomian gland dysfunction (MGD).

[0066] In some embodiments, the ocular disease or condition is uveitis.

[0067] In some embodiments, the eye disease or condition is blepharitis.

[0068] In another aspect, provided herein is a method of reducing inflammation in a subject in need of reducing inflammation, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof provided herein.

[0069] In some embodiments of these aspects, the compound or pharmaceutical composition is administered topically to the eye of the subject.

[0070] In some embodiments, provided herein is a method of treating an eye disease or condition in a subject in need of treating the eye disease or condition, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0071] In some embodiments, provided herein is a method of treating an eye disease or condition in a subject in need of treating the eye disease or condition, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0072] In some embodiments, provided herein is a method of reducing signs or symptoms of dry eye disease (DED) or meibomian gland dysfunction (MGD) in a subject in need of reducing the signs or symptoms of DED or MGD, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0073] In some embodiments, provided herein is a method of reducing intraocular pressure in a subject in need of reducing intraocular pressure, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0074] In some embodiments of the methods provided herein, the method further comprises administering a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are beta blockers (e.g., levobunalol, timolol, betaxolol, or metipranolol), alpha-agonists (e.g., apraclonidine or brimonidine), carbonic anhydrase inhibitors (e.g., dorzolamide or brinzolamide), prostaglandins, prostaglandin-like compounds (e.g., AR-102, latanoprost, bimatoprost, tafluprost, or travoprost), miotics or cholinergic agents (e.g., pilocarpine or carbachol), epinephrine or norepinephrine compounds (e.g., dipivefrin), neuroprotective compounds or anti-inflammatory compounds (e.g., alfibercept), or corticosteroids (e.g., dexamethasone). In some embodiments, the one or more additional therapeutic agents are prostaglandins or prostaglandin-like compounds. In some embodiments, the prostaglandin-like compound is AR-102, latanoprost, bimatoprost, tafluprost, or travoprost. In another embodiment, the additional therapeutic agent is another JAK inhibitor or a corticosteroid. As described above, the administration of the compounds of the present disclosure can be simultaneous, as a mixture in a single pharmaceutical composition, or chemically conjugated to each other directly or via a linker for simultaneous administration.

[0075] Also provided herein is a method of treating an autoimmune disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, composition, or pharmaceutical composition provided herein.

[0076] In some embodiments, provided herein is a method of treating an autoimmune disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0077] In some embodiments, provided herein is a method of treating an autoimmune disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0078] In some embodiments, the autoimmune disease or condition is multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, an autoimmune thyroid condition, or chronic obstructive pulmonary disease.

[0079] In some embodiments, the subject includes a refractory disease. In some embodiments, the refractory disease includes a refractory cancer.

[0080] One of ordinary skill in the art can determine the actual route of administration of the compounds, compositions, or combinations disclosed herein by considering factors including, but not limited to, the type of JAK-related or ROCK-related disease, the location of the JAK-related or ROCK-related disease, the cause of the JAK-related or ROCK-related disease, the severity of the JAK-related or ROCK-related disease, the desired treatment period, the desired degree of alleviation, the desired alleviation period, a particular compound, composition, or combination, the excretion rate of the compound, composition, or combination used, the pharmacodynamics of the compound, composition, or combination used, the properties of other compounds included in the composition or combination, a particular route of administration, the specific characteristics of the individual, medical history, and risk factors (such as age, weight, and general health status, etc.), the response of the individual to the treatment, or any combination of these. Accordingly, one of ordinary skill in the art can readily determine the effective dosage of the compounds, compositions, or combinations disclosed herein by taking into account all criteria and using their best judgment to the benefit of the individual. Kit

[0081] In some embodiments, provided herein is a packaged compound, a packaged composition, or a packaged pharmaceutical composition that includes a container holding a therapeutically effective amount of a compound described herein and instructions for using the compound according to one or more of the methods provided herein.

[0082] The present compound and related materials can be finished as commercial products by ordinary processes practiced in the art (e.g., appropriate sterilization and packaging processes). For example, the materials can be treated by UV / vis irradiation (200 - 500 nm) using photoinitiators having different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble photoinitiators (e.g., Irgacure 2959). Such irradiation is usually carried out with an irradiation time of 1 - 60 minutes, although longer irradiation times can be applied depending on the specific method. The materials according to the present disclosure can ultimately be sterile packaged to maintain sterility until use and packaged in suitable containers (such as boxes) (e.g., by adding specific product information leaflets).

[0083] According to further embodiments, the present compound can also be provided in kit form in combination with other components necessary for administration of the material to a patient. For example, a disclosed kit for use in the treatment of cancer can further include, for example, an administration material.

[0084] The kits are designed in various forms based on the specific deficiency to be treated.

[0085] The compounds or compositions provided herein can be prepared and placed in a container for storage at ambient temperature or elevated temperature. When the compound or composition is stored in a polyolefin plastic container, compared to a polyvinyl chloride plastic container, whether dissolved or suspended in a liquid composition (e.g., an aqueous solution or an organic liquid solution), or even as a solid, discoloration of the compound or composition can be reduced. Without wishing to be bound by theory, the container can reduce the exposure of the contents of the container to electromagnetic radiation, whether it is visible light (e.g., having a wavelength of about 380 - 780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190 - 320 nm (UV B light) or about 320 - 380 nm (UV A light)). Also, some containers include the ability to reduce the adhesion or adsorption of an active agent to the surface of the container. Further, some containers include the ability to reduce the exposure of the contents of the container to infrared radiation, or a second component having such ability. Containers that can be used include polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly containers made of polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container. The container can further be placed within a second container (e.g., a container of paper, cardboard, paperboard, metal film, or foil, or combinations thereof) to further reduce the exposure of the contents of the container to UV, visible light, or infrared radiation. Compounds and compositions that benefit from reduced discoloration, decomposition, or both during storage include eye drops or implants containing the compounds or compositions provided herein. The compounds or compositions provided herein may require storage for periods up to 3 months or more; in some cases, up to 1 year or more. The container can be of any form suitable for containing the contents; e.g., a bag, bottle, or box.

[0086] The following embodiments further illustrate aspects of the present disclosure. However, the examples are in no way intended to limit the teachings or disclosures set forth herein.

Example

[0087] Example 1: ROCK and JAK assays. ROCK kinase inhibition assay. All compounds were first prepared as 10 mM stocks in anhydrous dimethyl sulfoxide (DMSO). 20 μL aliquots of the 10 mM solution were transferred to individual wells in column 1 of a 96-well polypropylene microtiter plate (Corning number 3363) and diluted with DMSO to obtain a final compound concentration of 4 mM. The test compounds were then serially diluted 1:5 with DMSO for an 11-point concentration response and further diluted with assay buffer to bring all compound concentrations to a final range of 100 μM to 10 pM in 2.5% DMSO. The assay was performed in a white 96-well flat-bottom half-area non-binding assay plate (Corning number 3642) in 20 mM HEPES (pH 7.5), 10 mM MgCl2 *It was carried out in an assay buffer consisting of 6H2O, 100 μM sodium orthovanadate, 0.05% CHAPS, and 0.1% bovine serum albumin. To each well were added 10 μL aliquots of the compounds from the intermediate dilution plates and 20 μL of a 2× substrate / enzyme solution containing the acceptor substrate (800 nM RSK2 peptide KRRRLSSLRA (SEQ ID NO: 1)), ROCK2 enzyme (10 nM), or ROCK1 enzyme, and 1,4-dithiothreitol (DTT, 2 μM). The reaction was initiated by the addition of 10 μL of a 4× stock solution of ATP (2 μM). The reactants were mixed thoroughly by hand, capped, and incubated at room temperature for 75 minutes. Protein kinase activity was quantified using Promega's Kinase-GLO (TM) luminescent kinase assay kit according to the manufacturer's instructions. The ATP concentration remaining in the test wells after the enzyme reaction was compared to that in control wells (CTRL) containing an equal volume of DMSO without inhibitor. The ATP concentrations in both the test wells and the CTRL wells were normalized to the background (BKG) ATP concentration in wells containing an inhibitor at a concentration that completely inhibits the protein kinase under investigation (i.e., a concentration that prevents any consumption of ATP during the incubation). The percent (POC) value relative to the control for each concentration of the compound tested was determined according to the following formula. POC = ((test well value - BKG) / (CTRL - BKG)) * 100 The IC50 value was calculated using the following four-parameter logistic curve fitting algorithm. f(x) = (A + ((B - A) / (1 + ((x / C)^D)))) The IC50 value was converted to the Ki value using the following Cheng-Prusoff equation. K i = IC 50 50 / (1 + ([ATP] / Km ATP))).

[0088] JAK Kinase Assay. The compound was prepared in the same manner as described in the ROCK kinase assay, except for the substrate and enzyme. The JAK2 × substrate / enzyme solution consisted of an acceptor substrate (800 nM Abl peptide EAIYAAPFAKKK (SEQ ID NO: 2)), JAK1, TYK2, JAK2, or JAK3 enzyme (10 nM), and DTT (2 μM). All other steps and solutions remained the same as in the above ROCK kinase assay. Example 2. Topical Ophthalmic Composition

[0089] A topical ophthalmic pharmaceutical composition for treating inflammation was prepared by conventional methods and formulated as shown in Table 1. [Table 1-1] [Table 1-2]

[0090] When the composition is topically administered once a day to one or both eyes, the composition reduces eye inflammation in subjects suffering from meibomian gland dysfunction (MGD) or dry eye disease (DED). Example 3. Topical Ophthalmic Composition

[0091] A topical ophthalmic pharmaceutical composition for treating inflammation was prepared by conventional methods and formulated as shown in Table 2. [Table 2]

[0092] When the composition is topically administered once a day to one or both eyes, the composition reduces eye inflammation in subjects suffering from meibomian gland dysfunction (MGD) or dry eye disease (DED). Example 4. Assay for Pharmacological Activity Against Glaucoma.

[0093] The pharmacological activity against glaucoma can be demonstrated using an assay designed to test the ability of a target compound to reduce intraocular pressure. Examples of such assays are described in the following references, which are incorporated herein by reference: C. Liljebris, G. Selen, B. Resul, J. Stjernschantz, and U. Hacksell, “Derivatives of 17-phenyl-18,19,20-trinorprostaglandin F2α Isopropyl Ester: Potential Anti-glaucoma Agents”, Journal of Medicinal Chemistry 1995, 38(2):289-304. Example 5. General Synthesis

[0094] The compounds provided herein can be synthesized by several methods including the synthetic scheme shown in Figure 1.

[0095] Although the present disclosure has been described in detail with reference to its specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present disclosure.

[0096] Alternative elements or groupings of embodiments of the present disclosure can be referenced and claimed, either individually or in any combination with other members of the group or other elements found herein.

[0097] The content of all references cited throughout this application (including literature, issued patents, published patent applications, and co-pending patent applications) is hereby incorporated by reference in its entirety. Unless otherwise defined, all technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art.

[0098] One of ordinary skill in the art can recognize or confirm many equivalents of the specific embodiments of the present invention described herein with only routine experimentation. Such equivalents are intended to be included in the following claims.

Claims

1. formula: 【Chemistry 19】 A compound having or a pharmaceutically acceptable salt thereof, wherein the formula is R ５ is H or S(O) ２ - (C １～６ It is alkyl; R １ H, CN, halogen, C １～６ Alkyl, O-(C １～６ Alkyl), or C ３～７ It is a cycloalkyl; R ２ is C ６～１６ aryl or C ２～１５ heterocyclyl, each of which may be substituted with one or two groups independently selected from OH, halogen, C １～６ alkyl, (C １～６ alkylene)-OH, O-(C １～６ alkyl), (C １～６ alkylene)-O-(C １～６ alkyl), S(O) ２ -(C １～６ alkyl), C ３～７ cycloalkyl, (C １～１６ alkylene)-C(O)OH, (C １～１６ alkylene)-C(O)N(H)-(C １～６ alkyl), (C １～１６ alkylene)-C(O)N(H)-OH, or (C １～６ alkylene)-N(C １～６ alkyl)-(C １～６ alkyl); R ３ , CN, OH, NH ２ , C １～６ Alkyl, C １～６ Alkinyl, C ３～７ Cycloalkyl, (C １～３ Alkylene)-CN, (C １～３ Alkilen)-NH ２ , (C １～３ Alkylene)-N(H)C(O)-(C ３～７ Cycloalkyl), (C １～３ Alkylene)-N(H)C(O)-(C ２～８ Heterocycloalkyl), O-(C ３～７ Cycloalkyl), O-(C １～３ Alkylene)-CN,N(H)C(O)-(C ３～７ Cycloalkyl), N(H)C(O)-(C ２～８ Heterocycloalkyl), N(H)C(O)-(C ２～５ Heteroaryl), N(H)C(O)-(C １～３ Alkylene) - (C ２～５ Heteroaryl), N(H)C(O)-(C ６～１０ Ayl), N(H)C(O)-(C １～３ Alkylene) - (C ６～１０ Ayl), N(H)C(O)NH ２ , N(H)(C １～６ Alkyl), N(H)(C ３～７ Cycloalkyl), N (C １～６ (Alkyl) (C ３～７ Cycloalkyl), N(H)(C １～３ Alkylene) - (C ２～８ Heterocycloalkyl), N(H)(C １～３ Alkylene) - (C ２～５ Heteroaryl), N(H)(C) １～３ Alkylene) - (C ６～１０ Aryl), or C ２～１５ They are heterocyclines, each of which is a halogen, O, OH, O-(C) １～６ Alkyl), S(O) ２ - (C １～６ Alkyl), S(O) ２ - (C １～６ Haloalkyl), C(NH ２ ), (NH), C １～６ alkyl, C １～６ haloalkyl, (C １～６ alkylene)-OH, (C １～６ alkylene)-O-(C １～６ alkyl), (C １～６ alkylene)-O-(C １～６ haloalkyl), (C １～６ alkylene)-S(O) ２ -(C １～６ alkyl), (C １～６ alkylene)-NH ２ , (C １～６ alkylene)-N(H)(C １～６ alkyl), (C １～６ alkylene)-N(C １～６ alkyl)(C １～６ alkyl), (C １～６ alkylene)-(C ３～７ cycloalkyl), (C １～６ alkylene)-(C ３～７ halocycloalkyl), (C<着 １～６ [[ID=上45]]alkylene)-(C ２～５ heteroaryl), (C １～６ alkylene)-(C ６～１０ haloaryl), NH ２ , N(H)(C １～６ alkyl), N(C １～６ alkyl)(C １～６ alkyl), N(H)-(C １～３ alkylene)-(C ３～７ cycloalkyl), N(C １～６ alkyl)-(C １～３ alkylene)-(C ３～７ cycloalkyl), N(H)C(O)O-(C １～６ alkyl), N(H)S(O) ２ -(C １～６ alkyl), C(O)-(C １～６ [[ID=上77]]alkyl), C(O)-(C １～６ alkylene)-CN, C(O)-(C １～６ alkylene)-NH ２ , C(O)-(C １～６ alkylene)-N(H)(C １～６ It should be noted that there may be some incorrect or unclear parts in the original text, especially in the Japanese characters which seem to be misaligned or incorrect in the provided text. This translation is based on the best understanding of the existing content.Alkyl), C(O)-(C １～６ Alkylene)-N(C) １～６ (Alkyl) (C １～６ Alkyl), C(O)-(C １～６ Alkylene)-N(H)[S(O)] ２ -C １～６ Alkyl], C(O)-(C １～６ Alkylene)-N(C) １～６ Alkyl) [S(O) ２ -C １～６ Alkyl], or C(O)O-(C １～６ It may be substituted with one, two, three, or four groups independently selected from alkyl groups; R ３ C ２～８ Heterocycloalkyl, or C １～６ Alkyl, F, Cl, Br, or O(C) １～６ C substituted with one or two groups independently selected from alkyl groups ２～８ It is heterocycloalkyl; and R ４ H, OH, C １～６ Alkyl, (C １～６ Alkylene)-OH, C １～６ Haloalkyl, C ３～７ Cycloalkyl, C ３～７ Halocycloalkyl, (C １～３ Alkylene) - (C ３～７ Cycloalkyl), (C １～６ Alkylene) CN, (C １～６ Alkylene)-C(O)O-(C １～６ (Alkyl), (C １～６ Alkylene)-OC(O)-(C １～６ Alkyl), or C ２～８ It is heterocycloalkyl; Alternatively, R ３ and R ４ These combine with the atoms they bond to, C ３～７ Cycloalkyl, C ２～８ Heterocycloalkyl, CC(H)-(C ０～６ Alkylene) CN, halogen or (C １～６ C substituted with one or two groups independently selected from alkylene CN ３～７ Cycloalkyl, or halogen or (C １～６ C substituted with one or two groups independently selected from alkylene CN ２～８ Forms heterocycloalkyl groups, A compound or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 20】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula is R １ H, F, Cl, Br, C １～６ Alkyl, or C ３～７ It is a cycloalkyl; R ２ C ２～５ Heteroaryl, or C １～６ Alkyl or (C １～６ C substituted with one or two groups independently selected from alkylene)OH ２～５ It is a heteroaryl; R ３ C ２～８ Heterocycloalkyl, or C １～６ Alkyl, F, Cl, Br, or O(C) １～６ C substituted with one or two groups independently selected from alkyl groups ２～８ It is heterocycloalkyl; and R ４ is (C １～３ Alkylene CN A compound or a pharmaceutically acceptable salt thereof.

3. formula: 【Chemistry 21】 A compound according to claim 1, having the above, or a pharmaceutically acceptable salt thereof.

4. formula: 【Chemistry 22】 A compound according to claim 1, having the above, or a pharmaceutically acceptable salt thereof.

5. formula: 【Chemistry 23】 A compound according to claim 1, having the above, or a pharmaceutically acceptable salt thereof.

6. R １ However, F, Cl, Br, C １～３ Alkyl, or C ３～４ The compound according to claim 1, wherein it is a cycloalkyl compound.

7. R ２ However, C ３～４ Heteroaryl, or C １～３ Alkyl or (C １～３ C substituted with alkylene OH ３～４ The compound according to claim 1, wherein it is a heteroaryl compound.

8. R ３ However, C ４～８ Heterocycloalkyl, or C １～３ Alkyl, F, Cl, Br, or O(C) １～３ C substituted with one or two groups independently selected from alkyl groups ４～８ The compound according to claim 1, wherein it is a heterocycloalkyl compound.

9. R ４ ga CH ２ The compound according to claim 1, wherein it is a CN.

10. formula: 【Chemistry 24】 【Chemistry 25】 A compound according to claim 2, having the same as a pharmaceutically acceptable salt thereof.

11. formula: 【Chemistry 26】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula is R ５ H, S(O) ２ CH ３ , or S(O) ２ CH ２ CH ３ And; R １ H, CH ３ ,CH ２ CH ３ cyclopropyl, OCH ３ , F, Cl, or CN; R ２ teeth, 【Chemistry 27】 【Chemistry 28】 And; R ３ , CN, OH, NH ２ , 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 and R ４ H, CH ３ ,CH ２ CH ３ Isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, OH, CH ２ OH, CH ２ CH ２ OH, CH ２ F, CH ２ CHF ２ ,CH ２ CH ２ F, CH ２ CH ２ Cl, CH ２ -Cyclopropyl, CH ２ CN, CH ２ CH ２ CN, 3-fluorocyclobuta-1-yl, tetrahydro-2H-pyran-4-yl, CH ２ C(O)OCH ３ , or CH ２ OC(O)CH ３ And; Alternatively, R ３ and R ４ They combine together with the atoms they bond to, 【Transformation 36】 to form A compound or a pharmaceutically acceptable salt thereof.

12. A composition comprising the compound described in one of claims 1 to 11.

13. The composition according to claim 12, further comprising a pharmaceutically acceptable carrier.

14. 0.30% by weight of the compound according to any one of claims 1 to 11; 0.1% by weight of citric acid; 0.3% by weight of hydroxypropyl methylcellulose; 0.77% by weight of sodium chloride; 0.12% by weight of potassium chloride; 0.05% by weight of disodium EDTA; 0.01% by weight of benzalkonium chloride; pH 4.5–6.5; and water A composition containing the following:

15. 0.30% by weight of the compound according to any one of claims 1 to 11; 0.067% by weight of citric acid; 0.48% by weight of sodium citrate dihydrate; 0.70% by weight of sodium chloride; pH 6.0; and water A composition containing the following:

16. A composition for use in a method for treating a Janus kinase (JAK)-related disease in a subject requiring treatment for the disease, wherein the composition comprises a compound according to any one of claims 1 to 11.

17. A composition for use in a method for treating an eye disease in a subject requiring treatment for an eye disease, wherein the composition comprises a compound according to any one of claims 1 to 11.

18. A composition for use in a method for inhibiting JAK activity in a subject requiring inhibition of Janus kinase (JAK) activity, wherein the composition comprises a compound according to any one of claims 1 to 11.

19. A composition for use in a method for inhibiting Janus kinase (JAK) activity in vitro, wherein the composition comprises a compound according to any one of claims 1 to 11, and the method comprises the step of contacting JAK with the compound.

20. A composition for use in a method, wherein the composition comprises a compound according to any one of claims 1 to 11, and the method comprises the step of administering the compound to a subject.

21. A kit comprising a compound according to any one of claims 1 to 11, and instructions for use thereof.

22. The compound according to any one of claims 1 to 11 in a container.

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