Azetidinylpyrimidines and uses thereof

Abstract

Provided herein are azetidine pyrimidine compounds.In particular, provided herein are compounds that affect the function of kinases in cells and are useful as therapeutic agents or together with therapeutic agents.Provided herein are compounds that are useful in treating various diseases and conditions, including inflammatory eye diseases, such as uveitis, cardiovascular diseases, inflammatory diseases, and diseases characterized by abnormal growth, such as cancer.Also provided herein are compositions that include azetidine pyrimidine compounds.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 217,607, filed July 1, 2021, the entire contents of which are incorporated herein by reference. Sequence Listing

[0002] This application contains a Sequence Listing with filename 1959002-00345_ST26.xml, which is 3,320 bytes in size and was created on Jun. 29, 2022. The entire contents of this Sequence Listing are incorporated herein by reference.

[0003] Field The present disclosure relates to azetidinylpyrimidine compounds that affect the function of kinases and other proteins in cells and are useful as or in conjunction with therapeutic agents.In particular, these compounds are useful for treating cardiovascular disease, autoimmune-related disease, and as anti-inflammatory agents for diseases characterized by abnormal growth, such as cancer, ophthalmic diseases, such as non-infectious uveitis or chorioretinitis, iritis, sterile conjunctivitis, keratitis, episcleritis, dry eye, meibomian gland dysfunction, allergic conjunctivitis, glaucoma, and retinal diseases. [Background technology]

[0004] background Various hormones, neurotransmitters and biologically active substances control, regulate or modulate the functions of living organisms through specific receptors located on the cell membrane. Many of these receptors mediate the transmission of intracellular signals by activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Such receptors are commonly referred to as G protein-coupled receptors (GPCRs) and include, among others, α-adrenergic receptors, β-adrenergic receptors, interleukin receptors, opioid receptors, cannabinoid receptors and prostaglandin receptors. The biological effects of activating or inhibiting these receptors are not direct but are mediated by a host of intracellular proteins. The importance of these secondary proteins has been recognized and modulation of this class is currently being investigated as a point of intervention in disease states. One of the most important classes of these downstream effectors is the "kinase" class.

[0005] Kinases play an important role in the regulation of various physiological functions.For example, kinases are related to several disease states, including but not limited to cardiac symptoms such as angina pectoris, essential hypertension, myocardial infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes, respiratory symptoms such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction, upper respiratory tract symptoms such as rhinitis, seasonal allergies, inflammatory diseases, autoimmune diseases, inflammation in response to injury, and rheumatoid arthritis.The importance of p38 MAPK inhibitors as new drugs, especially for rheumatoid arthritis, is reflected by the large number of compounds that have been developed over the past few years (J. Westra and PC Limburg Mini-Reviews in Medicinal Chemistry Volume 6, Number 8, August 2006). Other conditions include chronic inflammatory bowel disease, glaucoma, retinal geographic atrophy, age-related macular degeneration, hypergastrinemia, gastrointestinal symptoms such as acid / peptide conditions, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastrointestinal reflux, peptic ulcer, Zollinger-Ellison syndrome, pain, obesity, bulimia nervosa, depression, obsessive-compulsive conditions, organ malformations (e.g. cardiac malformations), neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, multiple sclerosis, Epstein-Barr virus infection and cancer (Nature Reviews Drug Discovery 2002, 1: 493-502).In other disease conditions, the role of kinases is only recently becoming clear.

[0006] The retina is a complex tissue consisting of many interconnected cell layers, highly specialized in converting light and color into electrical signals that are perceived by the brain. Damage or death of the photoreceptors, the primary light-sensing cells, causes devastating effects in vision. Despite the identification of many mutations that cause inherited retinal degeneration, the cellular and molecular mechanisms that lead to primary mutations in photoreceptor apoptosis are not well understood, but may involve the wnt pathway (AS Hackam "The Wnt Signaling Pathway in Retinal Degeneration" IUBMB Life Volume 57, Number 6 / June 2005).

[0007] Janus kinases (or JAKs) are a family of cytoplasmic protein tyrosine kinases. The JAK family plays a role in the cytokine-dependent regulation of proliferation and functions of cells involved in immune responses. Currently, four JAK family members are known: JAK1, JAK2, JAK3 and TYK2. JAKs usually 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 associated with at least one signaling pathway of cytokines associated with inflammation. Binding of cytokines to JAK-dependent cytokine receptors induces receptor dimerization, which results in phosphorylation of tyrosine residues in JAK kinases and results in JAK activity. Phosphorylated JAKs then bind to and phosphorylate various STAT proteins, which dimerize, translocate to the cell nucleus, and directly modulate gene transcription, resulting in downstream effects associated with inflammation and / or autoimmune diseases, among other effects. There is recent evidence that the kinases ROCK1 and ROCK2 may also be involved in similar interactions with STAT enzymes, resulting in downregulation of IL-21 and IL-17 secretion. Thus, inhibition of ROCK kinases is recognized to have anti-inflammatory effects and the well-known effects of JAK inhibition. In view of the role that kinases play in many disease states, there is an urgent and continuing need for small molecule ligands that inhibit or modulate the activity of kinases.Without wishing to be bound by theory, it is believed that the modulation of the activity of kinases, particularly ROCK, JAK or a combination of ROCK and JAK kinases, by the compounds of the present disclosure is at least partially responsible for their beneficial effects. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] J. Westra and PC Limburg Mini-Reviews in Medicinal Chemistry Volume 6, Number 8, August 2006 [Non-Patent Document 2] Nature Reviews Drug Discovery 2002, 1: 493-502 [Non-Patent Document 3] AS Hackam "The Wnt Signaling Pathway in Retinal Degeneration" IUBMB Life Volume 57, Number 6 / June 2005 Summary of the Invention [Means for solving the problem]

[0009] overview It has been found that the compounds described herein are useful as inhibitors of kinases, including JAK proteins.

[0010] Thus, in one aspect, a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0011] In one aspect, the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to the present disclosure and a pharma- ceutically acceptable excipient.

[0013] In another embodiment, the pharmaceutical compositions described herein can be housed in a package or container that is opaque, translucent or transparent to visible light. If necessary, such a package or container can be formed to prevent light from certain parts of the electromagnetic spectrum, including UV light, from penetrating into the interior of the container or package. Furthermore, such a package or container can be formed from one or more polyolefin resins, one or more polyester resins, or any combination thereof, which delays or slows the decrease in stability of the composition when exposed to external effects, such as light, particularly ultraviolet light, elevated humidity of at least about 25%, at least about 40% and at least about 65%, elevated temperature of at least about 2°C to about 8°C, at least about 25°C, at least about 30°C and at least about 40°C, or any combination thereof, for 1, 2 or 3 months or longer. As a result, the survival rate, i.e., the amount of active contained in such compositions, after exposure to an external effect may be at least 70%, at least 80%, at least 90%, at least 95% or at least 98%, or more, compared to the amount of active in the composition prior to such exposure to the external effect.

[0014] In addition to the above materials, the packaging or container for the pharmaceutical composition of the present disclosure can be made of glass or metal.The pharmaceutical composition of the present disclosure can be contained in a primary packaging material, which itself can be contained in a secondary packaging material.The secondary packaging material can be made of paper, such as cardboard.

[0015] In another aspect, the disclosure provides a method of treating an ophthalmic disease or condition in a subject in need thereof, comprising administering to the subject a compound or composition according to the disclosure.

[0016] In another aspect, the disclosure provides a method of reducing inflammation in a subject in need thereof, comprising administering to the eye of the subject a compound or composition according to the disclosure.

[0017] In another aspect, the disclosure provides a kit comprising a compound or composition according to the disclosure and instructions for use. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 shows a general scheme for the synthesis of the azetidinylpyrimidine compounds described herein.

[0019] [Diagram 2] FIG. 2 shows an exemplary synthetic scheme (Scheme 1) that can be used to prepare the compounds described herein.

[0020] [Diagram 3] FIG. 3 shows another exemplary synthetic scheme (Scheme 1′) that can be used to prepare the compounds described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Detailed Description Publications and patents are referenced throughout this disclosure. All U.S. patents and published applications cited herein are incorporated by reference in their entirety. All percentages, ratios and proportions used herein are expressed as weight percent unless otherwise specified.

[0022] Provided herein are azetidinyl pyrimidine compounds.

[0023] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0024] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0025] Numerical values ​​relating to measurements are subject to measurement errors that place limits on their accuracy. Therefore, all numerical values ​​provided herein should be understood to be modified by the term "about" unless otherwise indicated. Thus, the last decimal place of the numerical values ​​provided herein indicates the degree of accuracy. If no other error tolerance is given, the maximum tolerance is ascertained by applying a rounding conversion to the last decimal place or to the last significant figure if no decimals are present in the given numerical value.

[0026] As used herein, the term "alkyl" or "alkylene" refers to saturated aliphatic hydrocarbons, including straight-chain and branched-chain groups. "Alkyl" may be exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. 1~6 "Alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted, including independent substitution with alkenyl, alkynyl, alkoxyl, amino, amido, carboxyl, carboxamidyl, carboxyhydroxamidyl, cycloalkyl, halo, heterocycloalkyl, hydroxyl, polycyclyl, aryl, heteroaryl, nitrile, boronyl, or cyano groups. The substituents may themselves be substituted.

[0027] The term "alkynyl" refers to an unsaturated hydrocarbon containing at least one carbon-carbon triple bond.

[0028] The term "amelioration" refers to a reduction in the severity of at least one indicator of a condition or disease, such as a delay or slowing of the progression of one or more indicators of a condition or disease. The severity of an indicator can be determined by subjective or objective measurements known to those of skill in the art.

[0029] The term "aryl" refers to a carbocyclic aromatic system containing one, two, three or more rings.

[0030] The term “C n~m " refers to a moiety containing n to m carbon atoms, where n and m are integers.

[0031] The terms "composition" and "pharmaceutical composition" refer to a mixture of at least one compound described herein with a pharma- ceutical acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques for administering compounds, including but not limited to intravenous, oral, aerosol, parenteral, ocular, nasal, pulmonary and topical administration.

[0032] As used herein, the term "contacting a cell" is used to mean contacting a cell in vitro or in vivo, i.e., within a subject, e.g., a mammal, including a human, non-human primate, rabbit, cat, and dog.

[0033] As used herein, the term "controlling a disease or condition" is used to mean altering the activity of one or more kinases to affect the disease or condition.

[0034] The term "cycloalkyl" refers to a cyclic alkyl moiety containing one, two, three or more rings.

[0035] As used herein, the term "disease or condition associated with kinase activity" is used to mean a disease or condition treatable in whole or in part by the inhibition of one or more kinases.

[0036] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound, such as a compound described herein, that is administered to a subject either as a single dose or as part of a series of doses and is effective to produce a desired therapeutic effect.In general, a therapeutically effective amount can be estimated first in cell culture assays or in mammalian models, such as non-human primates, mice, rabbits, dogs or pigs.Animal models can also be used to determine appropriate concentration ranges and routes of administration.This information can then be used to determine useful doses and routes of administration in non-human and human subjects.

[0037] As used herein, the term "excipient" includes physiologically compatible additives useful in the preparation of pharmaceutical compositions. A non-limiting number of examples of pharma- ceutically acceptable carriers and excipients can be found, for example, in Remington Pharmaceutical Science, 16 th It can be found in Ed.

[0038] As used herein, the phrase "ocular disease or condition" includes, but is not limited to, ocular inflammatory conditions, such as non-infectious uveitis, chorioretinitis, iritis, sterile conjunctivitis, keratitis, episcleritis, dry eye, meibomian gland dysfunction, allergic conjunctivitis, MGD, injury-related ocular inflammation or dry eye syndrome, primary and secondary Sjogren's syndrome, redness, blepharitis, keratoconjunctivitis sicca, ocular hyperemia, macular degeneration (wet and dry), diabetic retinopathy, DME, RVO, age-related macular degeneration, geographic atrophy, posterior uveitis, retinal inflammation, inflammation due to gene therapy vectors (e.g., viral vectors), graft versus host disease, blepharitis, Thygeson's superficial punctate keratitis (TSPK), or combinations thereof.

[0039] The term "halo" or "halogen" refers to one or more atoms independently selected from F, Br, Cl, or I. In some embodiments, the halogen is fluoro, chloro, or bromo. In some embodiments, the halogen is fluoro.

[0040] The term "haloalkyl" refers to an alkyl moiety substituted with one or more halogens.

[0041] The term "haloaryl" refers to an aryl moiety substituted with one or more halogens.

[0042] The term "halocycloalkyl" refers to a cycloalkyl moiety substituted with one or more halogens.

[0043] As used herein, the term "heteroalkyl" refers to a non-aromatic carbocyclic radical having one or more heteroatoms in the carbocyclic ring.

[0044] The term "heteroaryl" refers to an aryl moiety that contains at least one ring heteroatom selected from O, S, or N, and each ring can independently contain 1, 2, 3, or 4 ring heteroatoms independently selected from O, S, or N.

[0045] The term "heterocycloalkyl" refers to a cycloalkyl moiety containing at least one ring heteroatom selected from O, S, or N, and each ring can independently contain 1, 2, 3, or 4 ring heteroatoms independently selected from O, S, or N.

[0046] The term "heterocyclyl" refers to a ring system containing at least one heteroatom selected from O, S or N, one or more rings, and each ring can independently contain 1, 2, 3, or 4 ring heteroatoms independently selected from O, S or N.

[0047] The term "pharmaceutical acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid filler, solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in transporting or delivering at least one compound described herein into or to a patient so that the compound can perform its intended function. A given carrier must be "acceptable" in that it is compatible with the other ingredients of a particular formulation containing the compound described herein and is not harmful to the patient. Non-limiting examples of other ingredients that may be included in the pharmaceutical compositions described herein are known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (Ed.), Mack Publishing Co., 1985), the entire contents of which are hereby incorporated by reference herein.

[0048] As used herein, the term "polycyclic" refers to a non-aromatic radical having two or more rings in its structure. Polycyclic rings include tricyclic and bicyclic rings, as well as rings that are spirocyclic. Polycyclic rings can contain heteroatoms or can be completely carbocyclic. Polycyclic rings can have substituents, including alkyl substituents, non-ring heteroatoms, and halogens.

[0049] As used herein, the superscript "R" and the subscript "R" refer to the same moiety, thus R and R 1 refers to the same group, and R and R 2 And so on. In some depictions, superscripts may be used, and in other depictions, subscripts are used.

[0050] The term "refractory disease" refers to a disease that continues to progress during treatment with a pharmaceutical ingredient other than the compound provided herein, or that responds partially to other treatments, or that responds temporarily to other treatments. The term can be applied to each of the diseases mentioned herein.

[0051] The term "treatment" or "treating" refers to the application of one or more specific procedures used to ameliorate a disease. "Prophylactic" treatment refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset.

[0052] The recitation of ranges of values ​​herein is intended only to serve as a shorthand method of referring individually to each separate value within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "such as"), are intended only to better illuminate the described subject matter and do not limit the scope of the subject matter unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to practicing the described subject matter.

[0053] Groupings of alternative elements or embodiments of the present disclosure should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, stated members of a group may be included in or excluded from another stated group for reasons of convenience or patentability. When any such inclusion or exclusion occurs, the specification is deemed to contain the group modified to satisfy all Markush group descriptions used in the appended claims.

[0054] It is to be understood that the embodiments of the present disclosure are illustrative, and therefore, the present disclosure is not limited to that precisely as shown and described. compound

[0055] It has surprisingly and unexpectedly been discovered that the compounds described herein are useful as inhibitors of kinases, including JAK proteins.

[0056] Thus, in one aspect, a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof: [In the formula, J 5 is H or S(O)2-(C 1~6 alkyl); R 1 H, CN, halogen, C 1~6 Alkyl, O-(C 1~6 Alkyl) or C 3~7 is cycloalkyl; A is C 6~16 Aryl or C 2~15 heterocyclyl, each of which is selected from the group consisting of 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); J 3 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, (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), 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 selected from 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 1~6Alkyl), (C 1~6 alkylene)-NH2, (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 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); R4 is 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 Heterocycloalkyl; Or J 3 and R 4 combine with the atoms to which they are attached to form C 3~7 Cycloalkyl, C 2~8 Heterocycloalkyl, CC(H)-(C 0~6 Alkylene)CN, halogen or (C 1~6 C substituted with 1 or 2 groups independently selected from alkylene)CN 3~7 Cycloalkyl, or halogen or (C 1~6 C substituted with 1 or 2 groups independently selected from alkylene)CN 2~8 forming a heterocycloalkyl] are provided herein.

[0057] In some embodiments, J 5 is H.

[0058] In one aspect, the formula: [ka] or a pharma- ceutically acceptable salt thereof: [In the formula, R 1 is H, F, Cl, Br, I, -CN, -NH2, -OH, -OCF3, -OCH2CF3, C 1~6 Alkyl, C 3~7 Cycloalkyl or C1~6 is haloalkyl; R 2 and R 3 are independently H, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl or R 2 and R 3 combine to form a heteroalkyl or polycyclic ring of at least 4 member atoms and at most 8 member atoms; R 4 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl, CH2CN, CH2CH2CN, CH2CH2CH2CN, C3-C7 cycloalkyl, alkylenecycloalkyl, alkylenecyclopropyl or hydroxyl; A is phenyl or a monocyclic C ring having 1 to 3 heteroatoms. 3~5 heteroaryl, where each heteroatom is independently N, O or S, as provided herein.

[0059] In some embodiments of the formulas provided herein, J 3 teeth, [ka] and R 2 and R 3 is as defined herein.

[0060] In some embodiments of the formulas provided herein, J 5 is H.

[0061] In some embodiments of the formulae provided herein, A is phenyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolinyl, isoindolinyl, indolyl, phenylmorpholinyl, phenyloxetanyl, phenylpiperazinyl, dihydrobenzoborolyl, or benzoborolyl, each of which is selected from the group consisting of OH, F, Cl, Br, C, C-C ...1~3 Alkyl, (C 1~3 Alkyl)-OH, C 1~6 Haloalkyl, O-(C 1~3 Alkyl), (C 1~3 alkylene)-O-(C 1~3 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).

[0062] In some embodiments of the formulas provided herein, J 3 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.

[0063] In some embodiments of the formulas provided herein, J 3 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)(C1~3 alkyl).

[0064] In some embodiments of the formulas provided herein, J 3 is (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) or O-(C 1~3 alkylene)-CN, 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).

[0065] In some embodiments of the formulas provided herein, J 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 3~7Cycloalkyl), 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), 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).

[0066] In some embodiments of the formulas provided herein, J 3 is C 2~15 Heterocyclyl, 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).

[0067] In some embodiments of the formulas provided herein, J 3 and R 4 combine with the atoms to which they are attached to form C 3~7 Cycloalkyl, C 2~8 Heterocycloalkyl, CC(H)-(C0~3 Alkylene)CN, halogen or (C 1~3 C substituted with 1 or 2 groups independently selected from alkylene)CN 3~7 Cycloalkyl, or halogen or (C 1~3 C substituted with 1 or 2 groups independently selected from alkylene)CN 2~8 Forms a heterocycloalkyl.

[0068] In one aspect, the formula: [ka] or a pharma- ceutically acceptable salt thereof: [In the formula, R 1 are H, F, Cl, Br, I, CN, NH2, OH, OCF3, OCH2CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 2 and R 3 are independently H, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl or R 2 and R 3 combine to form a heteroalkyl or polycyclic ring of at least 4 member atoms and at most 8 member atoms; R 4 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 Haloalkyl, -CHCN, -CHCHCN, -CHCHCHCN, C3-C7 cycloalkyl, C 1~12 alkylenecycloalkyl, alkylenecyclopropyl, or hydroxyl; R 5 is C 1~12 Alkyl, C 3~6 Cycloalkyl, C 1~12 Heteroalkyl or C 1~12haloalkyl, -CHOH, -CHCHOH, -CHCHCHOH, alkylenecycloalkyl, alkylenecyclopropyl or methoxy are provided herein.

[0069] In some embodiments of the formulas provided herein, the compound is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments of the formulas provided herein, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 1 are H, F, Cl, Br, I, CN, NH2, OH, OCF3, OCH2CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 2 and R 3 , H, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl or R 2 and R 3 combine to form a heteroalkyl or polycyclic ring of at least 4 member atoms and at most 10 member atoms; R 4 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl, CH2CN, CH2CH2CN, CH2CH2CH2CN, C3-C7 cycloalkyl, alkylenecycloalkyl, alkylenecyclopropyl or hydroxyl; R 6 is C 1~12 Alkyl, C 1~12 Heteroalkyl or C 1~12 haloalkyl, CH2OH, CH2CH2OH, CH2CH2CH2OH, alkylenecycloalkyl, alkylenecyclopropyl or methoxy.

[0071] In some embodiments of the formulas provided herein, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 1 are H, F, Cl, Br, I, CN, NH2, OH, OCF3, OCH2CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 2 and R 3 , H, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl or R 2 and R 3 combine to form a heteroalkyl or polycyclic ring of at least 4 member atoms and at most 10 member atoms; R 4 is C 1~6 Alkylene, C 1~6 Heteroalkyl or C 1~6 haloalkyl, CH2CN, CH2CH2CN, CH2CH2CH2CN, C3-C7 cycloalkyl, alkylenecycloalkyl, alkylenecyclopropyl or hydroxyl; X is CH, N or CR 7 and R 7 and R 8 are independently H, amino, aminoalkyl, C 1~12 Alkyl, C 1~12 Heteroalkyl or C 1~12 haloalkyl, halo, CHOH, CHCHOH, CHCHCHOH, alkylenecycloalkyl, alkylenecyclopropyl or methoxy, sulfonyl, sulfonamylin, or R 7 and R 8 combine to form a heteroalkyl ring of at least four member atoms and at most eight member atoms.

[0073] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 1 are H, F, Cl, Br, I, CN, OCF3, OCH2CF3, C 1~3 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 4 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl, CH2CN, CH2CH2CN, CH2CH2CH2CN, C3-C7 cycloalkyl, alkylenecycloalkyl, alkylenecyclopropyl or hydroxyl; R 9 , H, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl or R 4 and R 9 combine to form a carbocyclic, polycyclic, or heteroalkyl ring of at least 4 member atoms and at most 10 member atoms; A is phenyl or a monocyclic C ring having 1 to 3 heteroatoms. 3~5 heteroaryl, where each heteroatom is independently N, O or S.

[0078] In some embodiments of the formulas provided herein, R 1 is H, F, Cl, Me, CN, cyclopropyl or C 1~3 is alkyl; R 2 is H or C 1~3 is alkyl; or R 7 is H, F or C 1~3 It is an alkyl.

[0079] In some embodiments of the formulae provided herein, R2 and R 3 combine to form a heteroalkyl ring of six member atoms.

[0080] In some embodiments of the formulae provided herein, R 4 is -CHCN.

[0081] In some embodiments of the formulae provided herein, R 4 is -CH2-CH2CN.

[0082] In some embodiments of the formulae provided herein, R 4 is -OH.

[0083] In some embodiments of the formulae provided herein, R 6 is a substituted or unsubstituted C 1~14 Alkyl, alkenyl, alkynyl, alkylenearyl, alkylenecycloalkyl.

[0084] In some embodiments of the formulae provided herein, A is pyridyl.

[0085] In some embodiments of the formulae provided herein, A is not phenyl.

[0086] In some embodiments of the formulae provided herein, R 7 is alkyleneamino.

[0087] In some embodiments of the formulae provided herein, R 1 is H.

[0088] In some embodiments of the formulae provided herein, R 8 is alkyleneamino.

[0089] In some embodiments of the formulae provided herein, R 8 is cyclopropyl.

[0090] In some embodiments of the formulae provided herein, R 8 is a monocyclic C ring having 1 to 3 nitrogen atoms 3~5 It is heteroaryl.

[0091] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0093] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof: [In the formula, R 1 are H, F, Cl, CN, CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 2 is H, amino, amidyl, aminosulfonyl, hydroxyl, cycloalkyl, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl, heterocyclyl, heteroaryl, or R 3 can be linked to form a ring; R 3 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 Haloalkyl, CH2CCH, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CO2R 4, CH2CO2H, CH2CH2OH, CH2CH2F, CH2CH2Cl, CH2CHF2, CH2CF3, or R 3 can be linked to form a ring; R 4 is C 1~3 is alkyl; and R 5 is C 1~12 Alkyl, C 3~6 Cycloalkyl, C 1~12 Heteroalkyl or C 1~12 haloalkyl, CH2OH, CH2CH2OH, CH2CH2CH2OH, alkylenecycloalkyl, alkylenecyclopropyl or methoxy.

[0094] In some embodiments, the compound is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0095] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof: [In the formula, R 1 are H, F, Cl, CN, CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 2 is H, amino, amidyl, aminosulfonyl, cycloalkyl, C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 haloalkyl, heterocyclyl, heteroaryl, or R 3 can be linked to form a ring; R3 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 Haloalkyl, CH2CCH, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CO2R 4 , CH2CO2H, CH2CH2OH, CH2CH2F, CH2CH2Cl, CH2CHF2, CH2CF3, or R 3 can be linked to form a ring; R 4 is C 1~3 is alkyl; R 5 and R 6 are each independently 1~12 Alkyl, C 3~6 Cycloalkyl, C 1~12 Heteroalkyl or C 1~12 haloalkyl, CHOH, CHCHOH, CHCHCHOH, alkylenecycloalkyl, alkylenecyclopropyl, methoxy, or R 5 and R 6 can combine to form rings of 5 to 7 member atoms; X is CH or N.

[0096] In some embodiments, R 5 and R 6 are each H.

[0097] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0100] In one aspect, the formula: [ka] or a pharma- ceutically acceptable salt thereof: [In the formula, R 1 are H, F, Cl, CN, CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 is haloalkyl; R 3 is C 1~6 Alkyl, C 1~6 Heteroalkyl or C 1~6 Haloalkyl, CH2CCH, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CO2R 4 , CH2CO2H, CH2CH2OH, CH2CH2F, CH2CH2Cl, CH2CHF2, CH2CF3; R 4 is C 1~3 is alkyl; n is an integer between 0 and 4; X is CR for n=0 and n=1 5 R 6 If n>1, then X is a CR 5 R 6 or O, or NR 4 It could be; R 5 and R 6 are each independently H, F, Cl, CN, OCH3, CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl or C 1~6 Haloalkyl, C 1~6 Heteroalkyl or R 5 and R 6can be linked to form a ring of 3 to 5 member atoms; A is heteroaryl] is provided herein.

[0101] In some embodiments, the compound has the formula: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments of the formulas provided herein, R 1 is H, F, Cl, Me, CN, cyclopropyl or C 1~3 is alkyl; R 2 is a substituted piperidyl; or R 5 is hydroxymethyl or C 1~3 It is an alkyl.

[0103] In some embodiments of the formulae provided herein, R 1 is methyl.

[0104] In some embodiments of the formulae provided herein, R 3 is -CHCN.

[0105] In some embodiments of the formulae provided herein, R 3 is -CH2CH2CN.

[0106] In some embodiments of the formulae provided herein, R 3 is -CH2CH2F.

[0107] In some embodiments of the formulae provided herein, R 5 is SO2Me.

[0108] In some embodiments of the formulae provided herein, X is a nitrogen atom.

[0109] In some embodiments of the formulae provided herein, R 2 is an alkyleneamino, e.g. (C 1~3 alkylene)-amino.

[0110] In some embodiments of the formulae provided herein, R 1 is H.

[0111] In some embodiments of the formulae provided herein, R 3 is an alkyleneamino, e.g. (C 1~3 alkylene)-amino.

[0112] In some embodiments of the formulae provided herein, R 3 is cyclopropyl.

[0113] In some embodiments of the formulae provided herein, R 2 is a monocyclic C ring having 1 to 3 nitrogen atoms 3~5 It is heteroaryl.

[0114] In some embodiments, the compound is [ka] It is. synthesis

[0115] The method of synthesizing the compounds described herein will be obvious to those skilled in the art.The synthetic chemistry transformation and protective group methodology (protection and deprotection) that are useful for synthesizing compounds are known in the art, and include, for example, those described in R. LaRock, Comprehensive Organic Transformations, VCH Publishers (1989);TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991);L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);And L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and later editions.

[0116] In general, the compounds provided herein can be prepared according to the general scheme shown in Figure 1. For example, in some embodiments, the compounds are synthesized by first coupling an azetidine to a pyrimidine at the 4-position of the pyrimidine, followed by addition of a heteroaryl or arylamine. Figure 2 shows an exemplary synthesis using this route.

[0117] Preparation of tert-butyl 3-(cyanomethyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (E2): To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (E1, 200 mg, 1.030 mmol) in MeOH (1.3 mL) was added 1-methylpiperazine (172 μL, 1.545 mmol). The reaction was stirred at room temperature until the starting material was consumed as judged by TLC (5% MeOH / DCM, iodine stain). The reaction was poured into saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. Compound E2 was purified by column chromatography (0-5% MeOH:DCM) to give a white solid (E2, 96%).

[0118] Preparation of 2-(3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile trifluoroacetate (E3): To a solution of tert-butyl 3-(cyanomethyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (E2, 110 mg, 0.374 mmol) in dichloromethane (3.7 mL) was added trifluoroacetic acid (0.4 mL). The reaction was stirred at room temperature until the starting material was consumed based on TLC (5% MeOH / DCM, stained with KMnO4). The solution was concentrated under reduced pressure and the clear, colorless crude oil (E3) was carried on to the next step.

[0119] Preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile (E4): To a solution of 2,4-dichloro-5-methylpyrimidine (73 mg, 0.449 mmol) in methanol (2 mL) was added triethylamine (0.5 mL, 3.74 mmol). E3 was added slowly to the solution and the vial was rinsed with methanol (0.5 mL x 3). The reaction was stirred at room temperature overnight or until E3 was consumed as judged by LC / MS. The reaction was poured into saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. Compound E4 was purified by column chromatography (0-5% MeOH:DCM) to give a white solid (69% over two steps).

[0120] Preparation of 2-(1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)-3-(4-methyl-piperazin-1-yl)azetidin-3-yl)acetonitrile (E5): To a microwave vial was added E4 (100 mg, 0.312 mmol), 3-methylisothiazol-5-amine (39 mg, 0.343 mmol), Pd2(dba)3 (14 mg, 5 mol%), Xantphos (27 mg, 15 mol%), K2CO3 (172 mg, 1.25 mmol) and dioxane (3.1 mL). The reaction was heated to 150 °C for 20 min in an Anton Paar Monowave. The reaction mixture was filtered through Celite into a 1M aqueous HCl solution in a separatory funnel. The Celite was washed with ethyl acetate. The aqueous layer was washed with ethyl acetate to remove the intense yellow color. Saturated NaHCO3 was then added to the aqueous layer until basic, forming a precipitate. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. Compound E5 was purified by column chromatography (0-5% MeOH:DCM) to give a white solid (37%). [ka]

[0121] Alternative preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile (E4): A dry vial was charged with intermediate (6) (100 mg; 0.45 mmol; 1.0 equiv) and DBU (671 μL; 2.25 mmol; 10.0 equiv) in dry ACN (0.6 mL). To this solution was added 1-methylpiperazine (76 μL; 0.68 mmol; 1.5 equiv). The solution turned red. After 30 min the reaction was complete by TLC and LC. The reaction mixture was poured into saturated sodium bicarbonate and sodium chloride and extracted with DCM:IPA (3:1). The combined organics were dried over sodium sulfate, filtered and then evaporated. The crude residue was purified by column chromatography (DCM:EtOH) to give intermediate (E4) in 70% yield.

[0122] Using the above-described scheme and adjusting the protecting groups etc. as necessary, the compounds E5 to E52 in Table 1 were synthesized. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19]

[0123] Using essentially the same procedures described above, with appropriate modifications, compounds E53-E79 (Tables 2-5) can be prepared. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 3] [Table 4] [Table 5] Scheme 2. [ka]

[0124] Preparation of 2-(1-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(4-methyl-piperazin-1-yl)azetidin-3-yl)acetonitrile (E80): 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile (E4, 74 mg, 0.23 mm) under nitrogen ol, 1.0 equiv) was charged with 4-amino-1-methyl-pyrazole hydrochloride (41 mg, 0.24 mmol, 1.05 equiv), palladium(II) acetate (2 mg, 0.01 mmol, 5 mol%), BINAP (19 mg, 0.03 mmol, 15 mol%) and potassium carbonate (127 mg, 0.92 mmol, 4.0 equiv), followed by dioxane and tert-butyl alcohol (2 mL, 1:1). The reaction mixture was heated at 100° C. overnight. The reaction mixture was poured into saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, then filtered and evaporated. The crude residue was purified by column chromatography (DCM:EtOH) to give 2-(1-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile (E80) in 24% yield (21 mg, 0.06 mmol).

[0125] Using procedures similar to those shown above for Scheme 2, substituting the appropriate starting materials, compounds E80-82 (Table 6) were made. Compounds E83-109 in Tables 7-10 can be synthesized. [Table 6] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 8] [Table 9] [Table 10] Scheme 3. [ka]

[0126] Preparation of 2-(3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-1-(5-methyl-2-((2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E111): 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azetidin-3-yl)acetonitrile (E110, 58 mg) under nitrogen To 2-methyl-2,3-dihydro-1H-isoindol-5-amine dihydrochloride (37 mg, 0.17 mmol, 1.05 equiv.), palladium(II) acetate (2.2 mg, 0.01 mmol, 5 mol%), BINAP (15 mg, 0.02 mmol, 15 mol%) and potassium carbonate (231 mg, 0.63 mmol, 4.0 equiv.) was charged, followed by dioxane and tert-butyl alcohol (1.6 mL, 1:1). The reaction mixture was heated at 100° C. overnight. The reaction mixture was poured into saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3:1 DCM / IPA. The combined organic layers were dried over sodium sulfate, then filtered and evaporated. The crude residue was purified by column chromatography (hexane:EtOAc then DCM:EtOH) to give 2-(3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-1-(5-methyl-2-((2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile in 33% yield (E111, 25 mg, 0.05 mmol).

[0127] Using procedures related to those set forth above for Schemes 1-3, substituting the appropriate starting materials, compounds E111-119 (Table 11) were made. Compounds E120-144 and the compounds in Tables 12-15 can be synthesized. [Table 11-1] [Table 11-2] [Table 11-3] [Table 12-1] [Table 12-2] [Table 12-3] [Table 13] [Table 14] [Table 15] Scheme 4. [ka]

[0128] Preparation of tert-butyl ((1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)methyl)carbamate (E145).

[0129] To 2,4-dichloro-5-methylpyrimidine (196 mg, 1.2 mmol) in DMF (3.9 mL) was added tert-butyl ((3-methylazetidin-3-yl)methyl)carbamate hydrochloride (1.05 equiv.) and DIPEA (2 equiv.) and the solution was heated to 50 °C. After 2 h, the solution was cooled and extracted with EtOAc and NaHCO3. The organics were dried (Na2SO4), filtered and evaporated. Column chromatography (0-100% EtOAc-hexanes) afforded tert-butyl ((1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)methyl)carbamate (E145, 89%).

[0130] Preparation of tert-butyl ((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate (E146).

[0131] To tert-butyl ((1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)methyl)carbamate (E145, 104 mg, 0.32 mmol) in dioxane (6.9 mL) was added 3-methylisothiazol-5-amine (37.5 mg, 0.33 mmol), BINAP (39.8 mg, 0.06 mmol), Cs2CO3 (156 mg, 0.48 mmol) and Pd(OAc)2 (7.1 mg, 0.03 mmol)) in a pressure tube and the mixture was sparged with N2 for 1 min. The pressure tube was capped and heated to 129 °C for 1.5-2 h, cooled and the mixture was extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (0-5% MeOH—CH2Cl2) afforded tert-butyl ((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate (E146, 51%).

[0132] Preparation of N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E147).

[0133] To tert-butyl ((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate (E146, 67 mg, 0.17 mmol) in CHCl (0.9 mL) was added HCl (4N in dioxane, 0.33 mL, 1.33 mmol) and the solution was stirred for 3 h and evaporated. The compound was taken up in water and 2-methyl-THF. NaHCO3 (sat.) and K2CO3 were added until pH 10 (pH paper) and the aqueous solution was extracted with 2-methyl-THF. NaCl was added and the mixture was further extracted with 2-methyl-THF. Column chromatography (0-90% (EtOH / 10% 2N NH3-MeOH)-CH2Cl2) afforded N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E147, 39 mg, 75%).

[0134] Preparation of N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)ethanesulfonamide (E148).

[0135] To N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E147, 17 mg, 0.06 mmol) in CHCl (4 mL) and DMF (0.2 mL) was added DIPEA (9.7 μL, 0.06 mmol) and the reaction was cooled to 0° C. Ethanesulfonyl chloride was added and the reaction was allowed to warm to room temperature. The reaction was extracted with EtOAc, dried (NaSO), filtered and evaporated. Column chromatography (0-10% MeOH—CH2Cl2) afforded N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)ethanesulfonamide (E148, 15.1 mg, 68%). Scheme 5. [ka]

[0136] Preparation of (S)-2,2-difluoro-N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)cyclopropane-1-carboxamide (E149): To N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E147, 20.4 mg, 0.07 mmol) in DMF (0.35 mL) was added (S)-2,2-difluorocyclopropane-1-carboxylic acid (9.8 mg, 0.08 mmol), EDC (22 mg, 0.11 mmol), DMAP (1.6 mg, 0.01 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was poured into EtOAc / NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (0-10% MeOH-CH2Cl2) afforded pure (S)-2,2-difluoro-N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)cyclopropane-1-carboxamide (E149, 11.5 mg, 43%). Scheme 6. [ka]

[0137] Preparation of tert-butyl (S)-3-(2,2-difluorocyclopropane-1-carboxamide)-3-methylazetidine-1-carboxylate (E151): To tert-butyl 3-amino-3-methylazetidine-1-carboxylate (E150, 400 mg, 2.1 mmol) in DMF (7 mL) was added (S)-2,2-difluorocyclopropane-1-carboxylic acid (313 mg, 2.6 mmol), EDC (659 mg, 3.4 mmol) and DMAP (52 mg, 0.4 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was poured into EtOAc and HCL (1N), extracted with EtOAc, dried (Na2SO4) and filtered. Column chromatography (0-50% EtOAc-hexanes) afforded pure tert-butyl (S)-3-(2,2-difluorocyclopropane-1-carboxamide)-3-methylazetidine-1-carboxylate (E151, 519 mg, 84%).

[0138] Preparation of (S)-2,2-difluoro-N-(3-methylazetidin-3-yl)cyclopropane-1-carboxamide trifluoroacetate (E152): To tert-butyl (S)-3-(2,2-difluorocyclopropane-1-carboxamide)-3-methylazetidine-1-carboxylate (E151, 519 mg, 1.79 mmol) in CHCl (13 mL) was added TFA (2 mL) and the solution was stirred overnight. The solvent was evaporated and the residue was azeotroped with toluene to give (S)-2,2-difluoro-N-(3-methylazetidin-3-yl)cyclopropane-1-carboxamide trifluoroacetate (E152, 492 mg, 90%).

[0139] Preparation of N-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (E153): To (S)-2,2-difluoro-N-(3-methylazetidin-3-yl)cyclopropane-1-carboxamide trifluoroacetate (E152, 492 mg, 1.6 mmol) in DMF (5.2 mL) was added DIPEA (0.57 mL, 3.2 mmol) and 2,4-dichloro-5-methylpyrimidine (264 mg, 1.6 mmol) and the solution was heated to 30° C. overnight. The reaction mixture was cooled, poured into EtOAc and NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Automated column (0-80% EtOAc-hexane) afforded pure N-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (E153, 315 mg, 61%).

[0140] Preparation of 2,2-difluoro-N-(3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E154): In a pressure tube, add 2,2-difluoro-N-(3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E154) in dioxane (4.9 mL). To (3-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E153, 73 mg, 0.23 mmol) was added 3-methylisothiazol-5-amine (27.4 mg, 0.24 mmol), BINAP (28.4 mg, 0.05 mmol), Cs2CO3 (111 mg, 0.34 mmol) and Pd(OAc)2 (5.1 mg, 0.02 mmol) and the mixture was sparged with N2 for 1 min. The tube was capped and heated to 129 °C for 1.5-2 h, cooled and the mixture was extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (0-5% MeOH—CH2Cl2) afforded 2,2-difluoro-N-(3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E154, 50 mg, 56%).

[0141] Using the above schemes S1-S6, with appropriate modifications, the following compounds E155-E182 (Table 16) were synthesized. Compounds E183-E207 (Table 17) can be synthesized. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4]

[0142] Preparation of tert-butyl 3-(cyanomethyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (E2): To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (E1, 200 mg, 1.030 mmol) in MeOH (1.3 mL) was added 1-methylpiperazine (172 μL, 1.545 mmol). The reaction mixture was stirred at room temperature until the starting material was consumed as judged by TLC (5% MeOH / CHCl, iodine stain). The reaction was poured into saturated NaHCO and extracted with CHCl. ​​The organic layer was dried over MgSO and then concentrated under reduced pressure. Compound E2 was purified by column chromatography (0-5% MeOH:CHCl) to give a white solid (E2, 94%).

[0143] Preparation of 2-(3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile trifluoroacetate (E3): To a solution of tert-butyl 3-(cyanomethyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (E2, 285 mg, 0.97 mmol) in dichloromethane (9.7 mL) was added trifluoroacetic acid (0.97 mL). The reaction was stirred at room temperature until the starting material was consumed based on TLC (5% MeOH / CH2Cl2, stained with KMnO4). The solution was concentrated under reduced pressure and the clear, colorless crude oil (E3) was carried on to the next step.

[0144] Preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile (E4): To a solution of E3 (188 mg, 0.97 mmol) in DMF (3 mL) at 0 °C was added 2,4-dichloro-5-methylpyrimidine (150 mg, 0.92 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. Compound E4 was purified by column chromatography (0-5% MeOH:CH2Cl2) to give a white solid in quantitative yield.

[0145] Preparation of 2-(1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)-3-(4-methyl-piperazin-1-yl)azetidin-3-yl)acetonitrile (E5): To a microwave vial was added E4 (100 mg, 0.312 mmol), 3-methylisothiazol-5-amine (39 mg, 0.328 mmol), Pd(OAc)2 (3.5 mg, 5 mol%), BINAP (29 mg, 15 mol%), K2CO3 (173 mg, 1.25 mmol) and dioxane:tert-butyl alcohol (1:1, 3.1 mL). The reaction mixture was heated at 110° C. overnight. The reaction mixture was filtered through Celite into a 1 M aqueous HCl solution in a separatory funnel. The Celite was washed with ethyl acetate. The aqueous layer was washed with ethyl acetate to remove the intense yellow color. Saturated aqueous NaHCO3 was then added to the aqueous layer until basic, which resulted in the formation of a precipitate. The aqueous layer was then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. Compound E5 was purified by column chromatography (0-5% MeOH:CH2Cl2) to give a white solid (37%). [ka]

[0146] Alternative preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)azetidin-3-yl)acetonitrile (E4): A dry vial was charged with the intermediate (100 mg; 0.45 mmol; 1.0 equiv) and DBU (671 μL; 2.25 mmol; 10.0 equiv) in dry ACN (0.6 mL). To this solution was added 1-methylpiperazine (76 μL; 0.68 mmol; 1.5 equiv). The solution turned red. After 30 min the reaction was complete by TLC and LC. The reaction mixture was poured into saturated sodium bicarbonate and sodium chloride and extracted with CHCl:IPA (3:1). The combined organics were dried over sodium sulfate, filtered, and then evaporated. The crude residue was purified by column chromatography (CH2Cl2:EtOH) to give intermediate (E4) in 70% yield. [ka]

[0147] 2,4-Dichloro-5-methyl-pyrimidine (58 mL, 1.75 mmol, 1.0 equiv) and E117-J (300 mg, 1.83 mmol, 1.05 equiv) in 7 mL of dry DMF were charged with DIPEA (N,N-diisopropylethylamine, i.e., Hunig's base) (367 mL, 2.10 mmol, 1.2 equiv) under nitrogen. The reaction mixture was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and then evaporated. The crude residue was purified by column chromatography (Hex: EtOAc) to give E117-K in 67% yield (299 mg, 1.18 mmol). [ka]

[0148] E117-K (100 mg, 0.39 mmol, 1.0 equiv) under nitrogen was charged with 1 mL of dry acetonitrile and DBU (58 mL, 0.39 mmol, 1 equiv). To this solution was added piperidine (41 mL, 0.41 mmol, 1.05 equiv). The reaction mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCl. ​​The combined organics were dried over sodium sulfate, filtered, and then evaporated. The crude residue was purified by column chromatography (Hex:EtOAc) to give E117-L in 62% yield (82 mg, 0.24 mmol). [ka]

[0149] E117-L (82 mg, 0.24 mmol, 1.0 equiv) under nitrogen was charged with 2-methylisoindoline-5-amine hydrochloride (29 mg, 0.25 mmol, 1.05 equiv), palladium(II) acetate (2.2 mg, 0.01 mmol, 5 mol%), BINAP (22 mg, 0.04 mmol, 15 mol%) and potassium carbonate (133 mg, 0.96 mmol, 4.0 equiv), followed by dioxane and tert-butyl alcohol (4 mL, 1:1). The reaction mixture was heated at 120° C. overnight. The reaction mixture was poured into saturated sodium bicarbonate / saturated sodium chloride and CHCl. ​​The organic layer was separated and the aqueous layer was extracted with CHCl. ​​The combined organic layers were dried over sodium sulfate, then filtered and evaporated. The crude residue was purified by column chromatography (Hex:EtOAc, then CH2Cl2:MeOH) to give E65 in 80% yield (80 mg, 0.19 mmol). [ka]

[0150] E65 (70 mg, 0.17 mmol, 1.0 equiv) in 2 mL of dry dioxane was charged dropwise with lithium aluminum hydride (1 M in THF, 0.21 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and then at room temperature for 1 h. The reaction mixture was quenched by dropwise addition of 1:1 EtOAc:H2O and then filtered through Celite. The filtrate was evaporated and purified by column chromatography (CH2Cl2:MeOH) to give E66 in 78% yield (51.5 mg, 0.13 mmol). [ka]

[0151] To a solution of E66 (50 mg, 0.13 mmol, 1.0 equiv) and triethylamine (30 mL, 0.39 mmol, 3 equiv) in 4 mL of dry dioxane was added methanesulfonyl chloride (30 mL, 0.19 mmol, 1.5 equiv) dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated and the crude E117-M was carried on to the next step without further purification. [ka]

[0152] To a solution of E117-M (35 mg, 75 mmol, 1.0 equiv) in 1 mL of dry DMSO was charged KCN (15 mg, 0.23 mmol, 3.0 equiv). The reaction mixture was heated to 80° C. and allowed to stir overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and then evaporated. The crude residue was purified via column chromatography (CH2Cl2:MeOH) to give E117-N (7 mg, 18 mmol) in 25% yield. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7] [Table 18-8] [Table 18-9] [Table 18-10] [Table 18-11] [Table 18-12] [Table 18-13] [Table 18-14] [Table 18-15]

[0153] Using essentially the same procedures as described above, with appropriate modifications, compounds E118a-E150a can be prepared. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] Scheme 7. [ka]

[0154] Preparation of 2-(3-((7R,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E152): Preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((7R,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)azetidin-3-yl)acetonitrile under nitrogen 4-Amino-1-methylpyrazole hydrochloride (79 mg, 0.46 mmol, 1.05 equiv.), palladium(II) acetate (4.9 mg, 0.012 mmol, 5 mol%), BINAP (41 mg, 0.07 mmol, 15 mol%) and potassium carbonate (243 mg, 1.76 mmol, 4.0 equiv.) were charged to 4-amino-1-methylpyrazole hydrochloride (79 mg, 0.46 mmol, 1.05 equiv.), palladium(II) acetate (4.9 mg, 0.012 mmol, 5 mol%), BINAP (41 mg, 0.07 mmol, 15 mol%) and potassium carbonate (243 mg, 1.76 mmol, 4.0 equiv.) followed by dioxane and tert-butyl alcohol (4 mL, 1:1). The reaction mixture was heated at 120° C. overnight. The reaction mixture was poured into saturated sodium bicarbonate / saturated sodium chloride and CHCl. ​​The organic layer was separated and the aqueous layer was extracted with CHCl. ​​The combined organic layers were dried over sodium sulfate, then filtered and evaporated. The crude residue was purified by column chromatography (Hex: EtOAc, then CH2Cl2: MeOH) to give methyl 2-(1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)-3-(piperidin-1-yl)azetidin-3-yl)acetate in 33% yield (61 mg, 0.14 mmol).

[0155] Using the same general technique, the following compounds in Table 20 were synthesized: [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 21-1] [Table 21-2] General Scheme 2. Preparation of aryl and heteroaryl compounds [ka] Scheme 8. [ka]

[0156] Preparation of 2-(3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-1-(5-methyl-2-((2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E202). To 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)azetidin-3-yl)acetonitrile (E201), 58 mg, 0.16 mmol, 1.0 equiv. under nitrogen was charged 2-methyl-2,3-dihydro-1H-isoindol-5-amine dihydrochloride (37 mg, 0.17 mmol, 1.05 equiv.), palladium(II) acetate (2.2 mg, 0.01 mmol, 5 mol%), BINAP (15 mg, 0.02 mmol, 15 mol%) and potassium carbonate (231 mg, 0.63 mmol, 4.0 equiv.), followed by dioxane and tert-butyl alcohol (1.6 mL, 1:1). The reaction mixture was heated at 100° C. overnight. The reaction mixture was poured into saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3:1 CHCl / isopropyl alcohol (IPA). The combined organic layers were dried over sodium sulfate, then filtered and evaporated. The crude residue was purified by column chromatography (hexane:EtOAc, then CHCl:EtOH) to give 2-(3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-1-(5-methyl-2-((2-methylisoindolin-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile in 33% yield (E202, 25 mg, 0.05 mmol).

[0157] Using procedures to those shown above for Schemes 1-3, substituting the appropriate starting materials, compounds E203-E218 (Table 22) were synthesized. E219-E268 (Table 23) can be synthesized. [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5] [Table 23-1] [Table 23-2] [Table 23-3] Scheme 9. [ka]

[0158] Preparation of tert-butyl ((1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)methyl)carbamate (E269). To 2,4-dichloro-5-methylpyrimidine (196 mg, 1.2 mmol) in DMF (3.9 mL) was added tert-butyl ((3-methylazetidin-3-yl)methyl)carbamate hydrochloride (1.05 equiv.) and DIPEA (2 equiv.) and the solution was heated to 50° C. After 2 h, the solution was cooled and extracted with EtOAc and NaHCO3. The organics were dried (Na2SO4), filtered and evaporated. Column chromatography (0-100% EtOAc-hexanes) afforded pure tert-butyl ((1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)methyl)carbamate (E269, 89%).

[0159] Preparation of tert-butyl ((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate (E270). To tert-butyl ((1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)methyl)carbamate (E269, 104 mg, 0.32 mmol) in dioxane (6.9 mL) in a pressure tube was added 3-methylisothiazol-5-amine (37.5 mg, 0.33 mmol), BINAP (39.8 mg, 0.06 mmol), Cs2CO3 (156 mg, 0.48 mmol) and Pd(OAc)2 (7.1 mg, 0.03 mmol)) and the mixture was sparged with N2 for 1 min. The pressure tube was capped and heated to 129 °C for 1.5-2 h, cooled, and the mixture was extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered, and evaporated. Column chromatography (0-5% MeOH-CH2Cl2) afforded pure tert-butyl ((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate (E270, 51%).

[0160] Preparation of N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E271). To tert-butyl ((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate (270, 67 mg, 0.17 mmol) in CHCl (0.9 mL) was added HCl (4N in dioxane, 0.33 mL, 1.33 mmol) and the solution was stirred for 3 h and evaporated. The compound was taken up in water and 2-methyl-THF. NaHCO3 (sat) and K2CO3 were added until pH 10 (pH paper) and the aqueous solution was extracted with 2-methyl-THF. NaCl was added and the mixture was further extracted with 2-methyl-THF. Column chromatography (0-90% (EtOH / 10% 2N NH3-MeOH)-CH2Cl2) afforded pure N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E271, 39 mg, 75%).

[0161] Preparation of N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)ethanesulfonamide (E272). To N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E271, 17 mg, 0.06 mmol) in CHCl (4 mL) and DMF (0.2 mL) was added DIPEA (9.7 μL, 0.06 mmol) and the reaction was cooled to 0° C. Ethanesulfonyl chloride was added and the reaction was allowed to warm to room temperature. The reaction was extracted with EtOAc, dried (NaSO), filtered and evaporated. Column chromatography (0-10% MeOH-CH2Cl2) afforded pure N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)ethanesulfonamide (272, 15.1 mg, 68%). Scheme 10. [ka] Preparation of (S)-2,2-difluoro-N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)cyclopropane-1-carboxamide (E273). To N-(4-(3-(aminomethyl)-3-methylazetidin-1-yl)-5-methylpyrimidin-2-yl)-3-methylisothiazol-5-amine (E271, 20.4 mg, 0.07 mmol) in DMF (0.35 mL) was added (S)-2,2-difluorocyclopropane-1-carboxylic acid (9.8 mg, 0.08 mmol), EDC (22 mg, 0.11 mmol), DMAP (1.6 mg, 0.01 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was poured into EtOAc / NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (0-10% MeOH-CH2Cl2) afforded pure (S)-2,2-difluoro-N-((3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methyl)cyclopropane-1-carboxamide (E273, 11.5 mg, 43%). Scheme 11. [ka]

[0162] Preparation of tert-butyl (S)-3-(2,2-difluorocyclopropane-1-carboxamide)-3-methylazetidine-1-carboxylate (E275). To tert-butyl 3-amino-3-methylazetidine-1-carboxylate (E274, 400 mg, 2.1 mmol) in DMF (7 mL) was added (S)-2,2-difluorocyclopropane-1-carboxylic acid (313 mg, 2.6 mmol), EDC (659 mg, 3.4 mmol) and DMAP (52 mg, 0.4 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was poured into EtOAc and HCL (1N), extracted with EtOAc, dried (Na2SO4) and filtered. Column chromatography (0-50% EtOAc-hexanes) afforded pure tert-butyl (S)-3-(2,2-difluorocyclopropane-1-carboxamide)-3-methylazetidine-1-carboxylate (E275, 519 mg, 84%).

[0163] Preparation of (S)-2,2-difluoro-N-(3-methylazetidin-3-yl)cyclopropane-1-carboxamide trifluoroacetate (E276). To tert-butyl (S)-3-(2,2-difluorocyclopropane-1-carboxamide)-3-methylazetidine-1-carboxylate (E275, 519 mg, 1.79 mmol) in CHCl (13 mL) was added TFA (2 mL) and the solution was stirred overnight. The solvent was evaporated and the residue was azeotroped with toluene to give (S)-2,2-difluoro-N-(3-methylazetidin-3-yl)cyclopropane-1-carboxamide trifluoroacetate (E276, 492 mg, 90%).

[0164] Preparation of N-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (E277). To (S)-2,2-difluoro-N-(3-methylazetidin-3-yl)cyclopropane-1-carboxamide trifluoroacetate (E276, 492 mg, 1.6 mmol) in DMF (5.2 mL) was added DIPEA (0.57 mL, 3.2 mmol) and 2,4-dichloro-5-methylpyrimidine (264 mg, 1.6 mmol) and the solution was heated to 30° C. overnight. The reaction mixture was cooled, poured into EtOAc and NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Automated column (0-80% EtOAc-hexane) afforded pure N-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-methylazetidin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (E277, 315 mg, 61%).

[0165] Preparation of 2,2-difluoro-N-(3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E278). To 2,2-difluoro-N-(3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E277, 73 mg, 0.23 mmol) in dioxane (4.9 mL) was added 3-methylisothiazol-5-amine (27.4 mg, 0.24 mmol), BINAP (28.4 mg, 0.05 mmol), CsCO (111 mg, 0.34 mmol) and Pd(OAc) (5.1 mg, 0.02 mmol)) in a pressure tube and the mixture was bubbled with N for 1 min. The pressure tube was capped and heated to 129 °C for 1.5-2 h, cooled, and the mixture was extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered, and evaporated. Column chromatography (0-5% MeOH-CH2Cl2) afforded pure 2,2-difluoro-N-(3-methyl-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)cyclopropane-1-carboxamide (E278, 50 mg, 56%).

[0166] Using Schemes S1-S4 above, with appropriate modifications, the following compounds were synthesized: [Table 24] Scheme 12. [ka]

[0167] Preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((4-methoxybenzyl)amino)azetidin-3-yl)acetonitrile (E287). To 2-(1-(2-chloro-5-methylpyrimidin-4-yl)azetidin-3-ylidene)acetonitrile (E6, 250 mg, 1.1 mmol) in DMF (3.7 mL) was added 4-methoxybenzylamine (163 μL, 1.25 mmol) and DIPEA (177 μL, 1.0 mmol) and the solution was stirred at room temperature overnight. Additional 4-methoxybenzylamine (146 μL, 1.1 mmol) and DIPEA (78 μL, 0.46 mmol) were added in two portions and stirring was continued for 30 h. The reaction was extracted with EtOAc and NaHCO3(sat), then washed with NaCl(sat), dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 12 g gold cartridge, 0-5% MeOH-CH2Cl2) afforded pure 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((4-methoxybenzyl)amino)azetidin-3-yl)acetonitrile (E287, 69%).

[0168] Preparation of 2-(3-((4-methoxybenzyl)amino)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E288). To 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((4-methoxybenzyl)amino)azetidin-3-yl)acetonitrile (E287, 279 mg, 0.78), 3-methylisothiazol-5-amine (120 mg, 1.1 mmol), Cs2CO3 (381 mg, 1.17 mmol), BINAP (97 mg, 0.16 mmol) and Pd(OAc)2 (17.5 mg, 0.08 mmol) in a pressure tube was added 1,4 dioxane (10.4 mL) and the sealed tube was heated to 105 °C for 4 h. The reaction was cooled and extracted with EtOAc and water. The organics were then extracted with NaCl (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 12 g gold cartridge, 0–8% MeOH-CH2Cl2) afforded pure 2-(3-((4-methoxybenzyl)amino)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E288, 239 mg, 70%).

[0169] Preparation of 2-(3-amino-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E289). To 2-(3-((4-methoxybenzyl)amino)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E288, 239 mg, 0.56 mmol) in CHCl (3.4 mL) was added TFA (2.7 mL) and the solution was heated at 50° C. overnight. The solvent was evaporated and azeotroped with toluene. The residue was extracted with 2-methylTHF and NaHCO (sat), dried (NaSO), filtered and evaporated. Column chromatography (Teledyne, 4 g cartridge, 0–20% MeOH—CH2Cl2) afforded pure 2-(3-amino-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E289, 92 mg, 53%).

[0170] Preparation of (S)-N-(3-(cyanomethyl)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (E290). To 2-(3-amino-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E289, 26 mg, 0.08 mmol) in DMF (0.35 mL) was added EDC*HCl (26 mg, 0.13 mmol), DMAP (2 mg, 0.016 mmol) and (S)-2,2-difluorocyclopropane-1-carboxylic acid (12 mg, 0.099 mmol) and the solution was stirred at room temperature overnight. The reaction mixture was extracted with NaHCO3 (sat) and EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 4 g cartridge, 0-10% MeOH-CH2Cl2) afforded pure (S)-N-(3-(cyanomethyl)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (E290, 25.1 mg, 72%). Scheme 13. [ka]

[0171] Preparation of N-(3-(cyanomethyl)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methanesulfonamide (E291). To 2-(3-amino-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E289, 27 mg, 0.08 mmol) in pyridine (0.5 mL) was added methanesulfonyl chloride (7.1 μL, 0.092 mmol) and the solution was stirred at room temperature. Further methanesulfonyl chloride was added (6.5 μL) and the reaction mixture was stirred at room temperature. The reaction was extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 4 g gold cartridge, 0–10% MeOH-CH2Cl2) afforded pure N-(3-(cyanomethyl)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)methanesulfonamide (E291, 4.6 mg, 14%) and the by-product E292. Scheme 14. [ka]

[0172] Preparation of 1-(3-(cyanomethyl)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)-3-(2,2,2-trifluoroethyl)urea (E293). To 2-(3-amino-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E289, 25 mg, 0.08 mmol) in CHCl (0.3 mL) and pyridine (0.2 mL) was added DMAP (1-2 mg, 0.006 mmol) and 1,1,1-trifluoro-2-isocyanatoethane (11.9 mg, 0.095 mmol) and the reaction was stirred at room temperature. After 2.5 h, additional 1,1,1-trifluoro-2-isocyanatoethane (30.6 mg, portionwise) was added and the solution was stirred at room temperature. The reaction was extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 4 g, 0-10% MeOH-CH2Cl2) afforded 1-(3-(cyanomethyl)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)-3-(2,2,2-trifluoroethyl)urea (E293, 22.4 mg, 64%). Scheme 15. [ka]

[0173] Preparation of 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((2,4-difluorobenzyl)amino)azetidin-3-yl)acetonitrile (E294). To 2-(1-(2-chloro-5-methylpyrimidin-4-yl)azetidin-3-ylidene)acetonitrile (E6, 131 mg, 0.59 mmol) in MeOH (1.8 mL) and DMF (0.5 mL) was added (2,4-difluorophenyl)methanamine (180 mg, 1.25 mmol) and DIPEA (113 μL, 0.65 mmol) and the solution was stirred at 50° C. overnight. The reaction was cooled to room temperature and extracted with EtOAc and NaHCO3 (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 12 g gold cartridge, 0–5% MeOH-CH2Cl2) afforded 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((2,4-difluorobenzyl)amino)azetidin-3-yl)acetonitrile (E294, 94.3 mg, 44%).

[0174] Preparation of 2-(3-((2,4-difluorobenzyl)amino)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E295). To 2-(1-(2-chloro-5-methylpyrimidin-4-yl)-3-((2,4-difluorobenzyl)amino)azetidin-3-yl)acetonitrile (E294, 68 mg, 0.19 mmol), 3-methylisothiazol-5-amine (32 mg, 0.28 mmol), Cs2CO3 (91 mg, 0.28 mmol), BINAP (23 mg, 0.04 mmol) and Pd(OAc)2 (4.2 mg, 0.02 mmol) in a pressure tube was added 1,4 dioxane (2.5 mL) and the solution was sparged with N2 (1 min), then sealed and heated to 105 °C for 4 h. The reaction was cooled and extracted with EtOAc and water. The organics were then extracted with NaCl (sat), dried (Na2SO4), filtered and evaporated. Column chromatography (Teledyne, 12 g gold cartridge, 0–100% EtOAc-hexanes) afforded pure 2-(3-((2,4-difluorobenzyl)amino)-1-(5-methyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acetonitrile (E295, 44 mg, 53%).

[0175] Using the techniques outlined in the schemes above, with appropriate modifications, the compounds in Table 25 and Table 26 have been made, or can be made. [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5] [Table 25-6] [Table 26-1] [Table 26-2] [Table 26-3] [Table 26-4]

[0176] Additional compounds prepared according to the procedures described herein include the compounds in Table 27, or a pharma- ceutically acceptable salt thereof. [Table 27-1] [Table 27-2]

[0177] Additional compounds that may be prepared according to the procedures described herein include the compounds in Table 28, or a pharma- ceutically acceptable salt thereof. [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4]

[0178] Additional compounds that may be prepared according to the procedures described herein include the compounds in Table 29, or a pharma- ceutically acceptable salt thereof. [Table 29] Isomers

[0179] The compounds described herein may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational or anomeric forms, including, but not limited to, cis and trans forms; E and Z forms; c, t and r forms; endo and exo forms; R, S and meso forms; D and L forms; d and l forms; (+) and (-) forms; keto, enol and enolate forms; syn and anti forms; synclinal and anticlinal forms; alpha and beta forms; axial and equatorial forms; boat, chair, twisted, envelope and half-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0180] In one embodiment, the compounds described herein can be enantiomerically enriched isomers of the stereoisomers described herein.For example, the compounds can have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.Enantiomer, as used herein, refers to any of a pair of chemical compounds whose molecular structures have a mirror image relationship to each other.

[0181] In one embodiment, a preparation of a compound disclosed herein is enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter. For example, the compound has a purity of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% corresponding to a compound having the selected stereochemistry at a selected stereocenter.

[0182] In one embodiment, the compositions described herein include preparations of compounds disclosed herein that are enriched in one or more structures at a selected stereocenter with a selected stereochemistry, e.g., R or S. Exemplary R / S configurations can be those provided in the examples described herein.

[0183] "Enriched preparation", as used herein, is enriched in a selected configuration of one, two, three or more selected stereocenters in a target compound. Exemplary selected stereocenters and exemplary configurations thereof can be selected from those provided herein, for example, from the examples described herein. Enriched means, for example, that at least 60% of the molecules of the compound in the preparation have the selected stereochemistry of the selected stereocenter. In one embodiment, at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%. Enriched refers to the level(s) of target molecules and does not imply a process limitation unless specified.

[0184] The compounds can be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or resolution. The compounds can be resolved into their component enantiomers or diastereomers, for example, by standard techniques, such as the formation of stereoisomeric pairs by salt formation with optically active bases, followed by fractional crystallization and regeneration of the free acid. The compounds can also be resolved by the formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using chiral chromatographic columns. Enantiomers can also be obtained from the kinetic resolution of the racemates of the corresponding esters using lipase enzymes.

[0185] Except as described below for tautomeric forms, structural or constitutional isomers (i.e., isomers that differ not only in the spatial position of the atoms, but rather in the bonding states between the atoms) are specifically excluded from the term "isomer" as used herein. For example, a reference to a methoxy group, -OCH3, should not be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structural isomeric forms within that class (e.g., C3-alkyl or propyl includes n-propyl and iso-propyl; C4-alkyl or butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

[0186] The above exclusion does not relate to tautomeric forms, e.g., keto, enol and enolate forms, such as, for example, the following tautomeric pairs: keto / enol, imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo and nitro / aci-nitro.

[0187] It should be noted that specifically included within the term "isomer" are compounds that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3 H can be in any isotopic form, including T; C can be in any isotopic form, including T; 12 C. 13 C and 14 It can be in any isotopic form, including C; O is 16 O and 18 It can be any isotopic form containing O, etc.

[0188] Thus, the compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced with an atom having the same atomic number but a different atomic mass or mass number than that found predominantly in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 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 In some embodiments, isotopically labeled compounds are useful for drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium confers greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet another embodiment, 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process in which an appropriate isotopically labeled reagent is substituted for a non-isotopically labeled reagent in another process.

[0189] 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. salt

[0190] The compounds described herein may be in the form of a salt, e.g., a pharma- ceutically acceptable salt. The term "pharma- ceutically acceptable salt" includes salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, e.g., solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this disclosure. Examples of pharma- ceutically acceptable salts are discussed in Berge et al, 1977, "Pharmaceutically Acceptable Salts." J. Pharm. Sci. Vol. 66, pp. 1-19. In one embodiment, the compound is present in the form of a monosalt. In an embodiment, the compound is present in the form of a di-salt.

[0191] For example, the compound is anionic or has a functional group that can become anionic (e.g., -COOH becomes -COO - In the case of cations such as cations, salts can be formed with suitable cations. Examples of suitable inorganic cations include alkali metal ions, such as Na + and K. + , alkaline earth cations, e.g. Ca 2+ and Mg 2+ , as well as other cations. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NH3R1 + , NH2R2 + , NHR3 + , NR4 + Examples of some suitable substituted ammonium ions include, but are not limited to, the following: ethylamine, diethylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from dibasic amino acids such as lysine and arginine.

[0192] The compound is cationic or has a functional group that can become cationic (e.g., -NH2 becomes -NH3 + In the case where the cation can be an aryl group, salts can be formed with suitable anions. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: boric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0193] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, p-toluenesulfonic, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0194] Unless otherwise specified, a reference to a particular compound also includes its salt forms. Chemically protected forms

[0195] It may be convenient or desirable to prepare, purify, and / or handle active compounds in a chemically protected form. The term "chemically protected form" is used herein in its conventional chemical sense to refer to a compound in which one or more reactive functional groups are protected from undesired chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, etc.). In practice, well-known chemical methods are utilized to reversibly inactivate otherwise reactive functional groups under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of protected or protective groups (also known as masked or blocked groups). By protecting reactive functional groups, reactions involving other non-protected reactive functional groups can be carried out without affecting the protected groups, and the protective groups can usually be removed in a subsequent step without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). Unless otherwise specified, a reference to a particular compound also includes chemically protected forms thereof.

[0196] A wide variety of such "protecting", "blocking" or "masking" methods are widely used and well known in organic synthesis. For example, a compound with two non-equivalent reactive functional groups, both of which are reactive under specified conditions, can be derivatized under specified conditions to make one of the functional groups "protected" and therefore inactive. Thus protected, the compound can be used as a reactant with, in effect, only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group can be "deprotected" to return to its original functionality.

[0197] Hydroxyl groups can be protected as ethers (-OR) or esters (-OC(O)R), for example, as t-butyl ethers; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ethers; trimethylsilyl or t-butyldimethylsilyl ethers; or acetyl esters (-OC(O)CH, -OAc).

[0198] The aldehyde or ketone group may be protected as an acetal (RCH(OR)2) or ketal (R2C(OR)2), respectively, where the carbonyl group (R2C=O) is converted to a diether (R2C(OR)2), for example, by reaction with a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

[0199] Amine groups can be, for example, as amides (-NRC(O)R) or urethanes (-NRC(O)OR), e.g., as methylamides (-NHC(O)CH3); benzyloxyamides (-NHC(O)OCH2C6H5, -NH-Cbz); tert-butoxyamides (-NHC(O)OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamides (-NHCO(O)C(CH3)2C6H4C6H5, -NH-Bpoc), 9-fluorenylmethoxyamides (- NH-Fmoc), as 6-nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichloroethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), as 2(-phenylsulfonyl)ethyloxyamide (-NH-Psec); or, in appropriate cases (e.g., cyclic amines), as a nitroxide radical (>NO<<).

[0200] Carboxylic acid groups can be protected as esters, for example, alkyl esters (e.g., methyl esters; t-butyl esters); haloalkyl esters (e.g., haloalkyl esters); trialkylsilylalkyl esters; or arylalkyl esters (e.g., benzyl esters; nitrobenzyl esters); or as amides, for example, methylamides.

[0201] Thiol groups can be protected as thioethers (-SR), for example, as a benzylthioether; as an acetamidomethyl ether (-S-CH2NHC(O)CH3). Prodrugs and Other Modifications

[0202] In addition to salt forms, the present disclosure may also provide compounds in prodrug form.Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to provide the compounds described herein.Prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with or without suitable enzymes or chemical reagents.

[0203] The compounds described herein can also be modified by providing appropriate functionalities to improve selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, modify metabolism, and / or modify the rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycol, derivatization with pivalate or fatty acid substituents, conversion to carbamate, hydroxylation of aromatic rings, and substitution of heteroatoms on aromatic rings. Uses and Activity

[0204] The compounds disclosed herein and compositions comprising them have kinase inhibitory activity and are therefore useful for modulating the action of kinases and treating and / or preventing diseases or conditions affected by kinases. The compounds and compositions described above can be used to modulate (e.g., affect or inhibit) the action of kinases in either cells in vitro or cells in an organism in vivo. Specifically, in one embodiment, a method is provided for modulating the action of kinases, comprising applying an effective inhibitory amount of a compound as disclosed herein to a medium such as an assay medium or contacting a cell, either in vitro or in vivo. In another embodiment, a method is provided for inhibiting the action of kinases, comprising applying an effective inhibitory amount of a compound as disclosed herein to a medium such as an assay medium or contacting a cell, either in vitro or in vivo. In one embodiment, the kinase to be inhibited is JAK (e.g., JAK2) kinase.

[0205] JAK inhibitors are useful for treating various JAK-related diseases or conditions.Examples of JAK-related diseases include diseases and conditions involving immune system, including organ transplant rejection (e.g., allograft rejection and graft-versus-host disease).Further examples of JAK-related diseases or conditions include autoimmune diseases, such as alopecia areata, alopecia universalis, 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, chronic obstructive pulmonary disease (COPD), etc.In some embodiments, the autoimmune disease is arthritis.

[0206] Further examples of JAK-associated diseases or conditions include allergic conditions, such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic eczema) and rhinitis. Further examples of JAK-associated diseases or conditions include viral diseases, such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1, varicella-zoster virus (VZV) and human papillomavirus (HPV).

[0207] Further examples of JAK-related diseases or conditions include those characterized by solid tumors (e.g., prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyoma, melanoma, etc.), blood cancers (e.g., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or multiple myeloma), and skin cancers, such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Exemplary CTCLs include Sézary syndrome and mycosis fungoides. Other examples of JAK-related diseases or conditions include pulmonary arterial hypertension.

[0208] Other examples of JAK-associated diseases or conditions include inflammation-associated cancer. In some embodiments, the cancer is associated with 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-associated cancer is colitis-associated cancer. In some embodiments, the inflammation-associated 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, blood cancer, or rectal cancer.

[0209] The compounds of the present disclosure have use in methods of inhibiting kinases in cells, tissues, or subjects, such as humans, comprising contacting a cell with one or more of the compounds of the present disclosure in an amount effective to modulate, and in particular inhibit, the activity of the kinase. In one embodiment, the compound is administered in a pharma- ceutically acceptable composition, e.g., in or with a pharma- ceutically acceptable carrier.

[0210] In another embodiment, a compound of the present disclosure is used in a method for modulating the action of a kinase in a cell, comprising contacting a cell with one or more compounds of the present disclosure in an amount effective to modulate the action of the kinase in the cell. In one embodiment, a compound of the present disclosure is administered in a pharma- ceutically acceptable composition, e.g., in or with a pharma- ceutically acceptable carrier.

[0211] Treatment or prevention of ocular diseases or conditions for which the disclosed compounds may be useful include any disease or condition associated with kinase activity or affected by kinases. Examples of these types of diseases or conditions include inflammatory diseases, autoimmune diseases, ocular inflammatory conditions such as non-infectious uveitis, chorioretinitis, iritis, sterile conjunctivitis, keratitis, episcleritis, xerophthalmia, meibomian gland dysfunction, allergic conjunctivitis, MGD, injury-related ocular inflammation or dry eye syndrome, primary and secondary Sjogren's syndrome, redness, blepharitis, keratoconjunctivitis sicca, ocular hyperemia, macular degeneration (wet and dry), diabetic retinopathy, DME, RVO, posterior uveitis, retinal inflammation, inflammation caused by gene therapy vectors (e.g., viral vectors), graft versus host disease, Thygeson's superficial punctate keratitis (TSPK) or combinations thereof, neurodegenerative diseases or conditions such as Alzheimer's disease; ocular diseases such as diabetic eye disease, wet or dry age-related macular degeneration, inflammatory eye diseases, retinal degeneration and glaucoma; cardiovascular diseases; and cancer. Additional examples include bone conditions, obesity, liver disease, kidney disease, pancreatitis, stomach disorders, hypertension, birth control, hair growth conditions, nasal congestion, neurogenic bladder conditions, gastrointestinal conditions, skin conditions and respiratory indications.

[0212] In some embodiments, the compound of the present disclosure is administered together with one or more additional therapeutic agents.Suitable classes of additional therapeutic agents include, but are not limited to, corticosteroids, other JAK inhibitors, IKK inhibitors, ROCK inhibitors, beta blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotics or cholinergic agents, epinephrine compounds, or neuroprotective or other anti-inflammatory compounds.The administration of the compound of the present disclosure together with one or more additional therapeutic agents can be co-administered as a mixture in a single pharmaceutical composition, or the compound of the present disclosure and one or more additional therapeutic agents can be chemically conjugated to each other directly or through a linker, so that the conjugate of the two therapeutic agents is cleaved upon exposure to physiological conditions.

[0213] Beta-blockers. These compounds are believed to lower intraocular pressure (IOP) by reducing the production of aqueous humor. Examples include levobunolol (BETAGAN™), timolol (BETIMOL™, TIMOPTIC™), betaxolol (BETOPTIC™) and metipranolol (OPTIPRANOLOL™).

[0214] Alpha agonists. These compounds are believed to lower IOP by decreasing aqueous humor production and increasing drainage. Examples include apraclonidine (IOPIDINE™) and brimonidine (ALPHAGAN™).

[0215] Carbonic anhydrase inhibitors. These compounds are believed to lower IOP by also reducing aqueous humor production. Examples include dorzolamide (TRUSOPT™) and brinzolamide (AZOPT™).

[0216] Prostaglandin-like compounds. These compounds are believed to lower IOP primarily by increasing the outflow of aqueous humor via the uveoscleral pathway. Examples include AR-102, latanoprost (XALATAN™), bimatoprost (LUMIGAN™), tafluprost (ZIOPTAN™), and travoprost (TRAVATAN™).

[0217] Miotics or cholinergic agents. These agents are thought to work by causing the pupil to constrict. Examples include pilocarpine (ISOPTO CARPINE™, PILOPINE™) and carbachol (ISOPTO CARBACHOL™).

[0218] Epinephrine and Norepinephrine Compounds. These compounds, such as dipivefrin (PROPINE™), are believed to work by both reducing aqueous humor outflow and increasing fluid drainage.

[0219] Neuroprotective or anti-inflammatory compounds. These compounds, such as aflibercept (EYLEA™), are treatments for retinal conditions such as macular degeneration, and are designed as anti-VEGF treatments or have similar types of anti-growth or anti-inflammatory activity.

[0220] Corticosteroids. These compounds, such as dexamethasone, are thought to function by reducing inflammatory mediators through nuclear transcription.

[0221] Thus, provided herein is a method of treating an ophthalmic condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, composition, or pharmaceutical composition provided herein.

[0222] Also provided herein is a method of reducing ocular inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, composition, or pharmaceutical composition provided herein.

[0223] In one aspect, provided herein is a method of treating an ophthalmic condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0224] In some embodiments, the eye disease or condition is dry eye.

[0225] In some embodiments, the ocular disease or condition is meibomian gland dysfunction (MGD).

[0226] In some embodiments, the ocular disease or condition is uveitis.

[0227] In some embodiments, the eye disease or condition is blepharitis.

[0228] In another aspect, provided herein is a method of reducing inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0229] In some embodiments of these aspects, the compound or pharmaceutical composition is administered locally to the eye of the subject.

[0230] In some embodiments, provided herein is a method of treating an ophthalmic disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of one of the formulas provided herein, or a pharma- ceutically acceptable salt thereof.

[0231] In some embodiments, provided herein is a method of treating an ophthalmic disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided in any one of the tables herein, or a pharma- ceutically acceptable salt thereof.

[0232] In some embodiments, provided herein is a method of alleviating a sign or symptom of dry eye disease (DED) or meibomian gland dysfunction (MGD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of one of the formulas provided herein, or a pharma- ceutical acceptable salt thereof.

[0233] In some embodiments, provided herein are methods of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound set forth in the various Tables, or a pharma- ceutically acceptable salt thereof.

[0234] Some embodiments of the method of the present disclosure further comprise 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, alpha agonists, carbonic anhydrase inhibitors, prostaglandins or prostaglandin-like compounds, miotics or cholinergic agents, epinephrine compounds, or neuroprotective or anti-inflammatory compounds. In some embodiments, the one or more additional therapeutic agents are prostaglandins or prostaglandin-like compounds. In some embodiments, the prostaglandin-like compounds are AR-102, latanoprost, bimatoprost, tafluprost or travoprost. In another embodiment, the additional therapeutic agent is another JAK inhibitor or a corticosteroid. As explained above, the administration of the compounds of the present disclosure can be simultaneous as a mixture in a single pharmaceutical composition, or can be chemically conjugated to each other directly or through a linker.

[0235] Also provided herein is a method of treating an autoimmune disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, composition, or pharmaceutical composition provided herein.

[0236] In some embodiments, provided herein is a method of treating an autoimmune disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of one of the formulas provided herein, or a pharma- ceutically acceptable salt thereof.

[0237] In some embodiments, provided herein is a method of treating an autoimmune disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided in any one of the tables herein, or a pharma- ceutically acceptable salt thereof.

[0238] 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. Compositions and Administration

[0239] The additional therapeutic agent(s) can be administered simultaneously or sequentially with the compound of the present disclosure. Sequential administration includes administration before and after the compound of the present disclosure. In some embodiments, the additional therapeutic agent(s) can be administered in the same composition as the compound of the present disclosure. In other embodiments, there can be a time interval between administration of the additional therapeutic agent and the compound of the present disclosure.

[0240] In some embodiments, administration of an additional therapeutic agent with a compound of the present disclosure allows for lower doses of the other therapeutic agent to be administered for a longer period of time.

[0241] Also provided herein is a composition comprising a compound provided herein, or a pharma- ceutically acceptable salt thereof. In one embodiment, the composition provided herein is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier.

[0242] The pharmaceutical composition for use according to the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.Thus, the compounds and their physiologically acceptable salts and solvates can be formulated for example, solid dosage, drops, topical oily formulations, injection (including injection of drug-eluting devices into either the whole body or specific tissues of the eye), inhalation (through either the mouth or nose), administration by implant, or oral, buccal, parenteral or rectal administration.Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, PA).

[0243] The route of administration of the compound of the present disclosure (component A) and the form of the composition determine the type of carrier (component B) used. The composition can be in various forms suitable for administration, for example, by systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant or parenteral), or intraocular injection into one of the chambers of the eye, for example, subconjunctival, subretinal, retrobulbar, intravitreal injection, intracameral injection or injection into the aqueous humor, or topical administration, for example, by topical application to the skin, including the eyelid, or to the eye, using a solution, suspension, nanosuspension, ocular liposomal delivery system, or iontophoresis.

[0244] Carriers for systemic administration typically include at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, combinations thereof, etc. All carriers are optionally present in systemic compositions.

[0245] Component a) is a diluent. Suitable diluents for solid dosage forms include sugars such as glucose, lactose, dextrose and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of component a) in the systemic or topical composition is typically about 50% to about 90%.

[0246] Component b) is a lubricant.Suitable lubricants for solid dosage forms are exemplified by solid lubricants, including silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants, such as polyethylene glycol and vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and Theobroma oil.The amount of component b) in the systemic or topical composition is typically about 5 to about 10%.

[0247] Component c) is a binder. Suitable binders for solid dosage forms include polyvinylpyrrolidone; magnesium aluminum silicate; starches, such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose and sodium carboxymethylcellulose. The amount of component c) in systemic compositions is typically about 5 to about 50%, and in ophthalmic solid dosage forms, it is up to 99%.

[0248] Component d) is a disintegrant. Suitable disintegrants for solid dosage forms include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays and ion exchange resins. The amount of component d) in the systemic or topical composition is typically about 0.1 to about 10%.

[0249] Ingredient e) for solid dosage forms is a colorant, such as an FD&C dye. If used, the amount of ingredient e) in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0250] Ingredient f) for solid dosage forms is a flavoring such as menthol, peppermint, and fruit flavors. The amount of ingredient f) in a systemic or topical composition, if used, is typically about 0.1 to about 1.0%.

[0251] Ingredient g) for solid dosage forms are sweeteners such as aspartame and saccharin. The amount of ingredient g) in a systemic or topical composition is typically from about 0.001 to about 1%.

[0252] Ingredient h) is an antioxidant such as butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT") and vitamin E. The amount of ingredient h) in a systemic or topical composition is typically from about 0.1 to about 5%.

[0253] Ingredient j) is a preservative such as benzalkonium chloride, methylparaben, and sodium benzoate. The amount of ingredient j) in a systemic or topical composition is typically about 0.01 to about 5%.

[0254] Ingredient k) for solid dosage forms is a glidant such as silicon dioxide. The amount of ingredient k) in a systemic or topical composition is typically about 1 to about 5%.

[0255] Ingredient m) is a solvent, such as water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffer solutions. The amount of ingredient m) in a systemic or topical composition is typically from about 0 to about 100%.

[0256] Ingredient n) is a suspending agent. Suitable suspending agents include Avicel® RC-591 (FMC Corporation, Philadelphia, PA) and sodium alginate. The amount of ingredient n) in a systemic or topical composition is typically about 1 to about 8%.

[0257] Ingredient o) is a surfactant or penetration enhancer, such as lecithin, polysorbate 80 and sodium lauryl sulfate, and TWEEN® from Atlas Powder Company, Wilmington, Delaware. Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of ingredient o) in the systemic or topical composition is typically about 0.1% to about 5%.

[0258] The amounts of components A and B in a systemic composition will vary depending on the systemic composition being prepared, the particular derivative selected for component A, and the type of component B ingredient, but generally, a systemic composition will contain 0.01%-50% component A and 50-99.99% component B.

[0259] A composition for parenteral administration typically comprises A) 0.1-10% of a compound of the present disclosure and B) 90-99.9% of a carrier, including a) a diluent and m) a solvent. In one embodiment, component a) comprises propylene glycol, and m) comprises ethanol or ethyl oleate.

[0260] Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of component A), usually at least about 5%, more specifically about 25% to about 50%. Oral administration compositions further contain about 50% to about 95% of component B), more specifically about 50% to about 75%.

[0261] Tablets can be compressed, can be molded tablets, can be enteric coated, can be sugar coated, can be film coated, or can be multiple compressed. Tablets typically include component A and component B, which is a carrier that includes a component selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain g) sweeteners, such as aspartame and saccharin, or f) flavors, such as menthol, peppermint, fruit flavors, or combinations thereof.

[0262] Capsules (including implants, time release and sustained release formulations) typically comprise component A and a carrier comprising one or more a) diluents as disclosed above in a capsule comprising gelatin. Granules typically comprise component A, and preferably further comprise k) glidants, such as silicon dioxide, which improve flow properties. Implants can be of biodegradable or non-biodegradable type. Implants can be prepared using any known biocompatible formulation.

[0263] The selection of ingredients in the carrier for oral compositions depends on secondary considerations such as taste, cost, and shelf stability, which are not critical for the purposes of this disclosure. Those skilled in the art will know how to select appropriate ingredients without undue experimentation.

[0264] The solid compositions can also be coated by conventional methods, typically with a pH or time dependent coating, so that Component A is released into the gastrointestinal tract in the vicinity of the desired application or at various points and times that extend the desired effect. The coating typically comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Rohm & Haas GMBH, Darmstadt, Germany), waxes and shellac.

[0265] Compositions for oral administration can also have liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. Orally administered liquid compositions typically include component A and component B, i.e., carriers that include components selected from the group consisting of a) diluents, e) colorants, f) flavorants, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants. Oral liquid compositions preferably include one or more components selected from the group consisting of e) colorants, f) flavorants, and g) sweeteners.

[0266] Other compositions useful for obtaining systemic delivery of target compound include injection, sublingual, buccal and nasal dosage forms.Such compositions typically comprise soluble filler material, such as a) diluent, including sucrose, sorbitol and mannitol; and c) binder, such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.Such compositions may further comprise b) lubricant, e) colorant, f) flavor, g) sweetener, h) antioxidant and k) glidant.

[0267] In one embodiment of the present disclosure, the compound of the present disclosure is administered topically.The topical composition that can be applied topically to the eye can be in any form known in the art, including, but not limited to, solubilized in eye drops, suspension or nanosuspension, emulsion or nanoemulsion, administered as solid, gellable droplets, spray, ointment, or sustained or non-sustained release unit that is placed in the conjunctival cul-du-sac or another suitable location of the eye.

[0268] The topical composition that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on-rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. The topical composition comprises component A, which is the compound described above, and component B, which is a carrier. The carrier of the topical composition preferably aids in the penetration of the compound into the eye. Component B may further comprise one or more optional components.

[0269] The effective amount of the compound according to the present disclosure will vary depending on factors such as the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of the concomitant therapy, the route of administration, the particular pharma- ceutically acceptable carrier being utilized, and within the knowledge and expertise of the attending physician. For example, an effective amount of the compound of the present disclosure for systemic administration is about 0.01 to about 1000 μg / kg body weight per day, preferably about 0.1 to about 100 μg / kg body weight, and most preferably about 1 to about 50 μg / kg body weight. Transdermal dosages are designed to obtain similar serum or plasma levels based on techniques known to those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 ng / mL, more preferably 0.05 to 50 ng / mL, and most preferably 0.1 to 10 ng / mL. While these dosage amounts are based on daily administration rates, the compounds of the present disclosure may also be administered at other intervals, such as twice daily, twice weekly, once weekly, or once monthly. Those skilled in the art will be able to calculate appropriate effective amounts for other administration intervals.

[0270] The compounds of the present disclosure are useful in the method of alleviating or reducing ocular inflammation.The compounds of the present disclosure can be administered to the subject in need of treatment in an amount effective to alleviate irritation or inflammation.Therefore, these compounds are useful for treating meibomian gland dysfunction (MGD).The preferred route of administration for treating inflammation is topical.

[0271] The exact amount of each component of the topical composition depends on a variety of factors. The amount of component A added to the topical composition is determined by the IC 50 It depends on the concentration of the drug and is typically expressed in nanomolar (nM) units. For example, the IC 50 When the IC of the drug is 1 nM, the amount of component A is about 0.001 to about 0.3%. 50 When the IC of the drug is 10 nM, the amount of component A) is about 0.01 to about 1%. 50 When the IC is 100 nM, the amount of component A is about 0.1 to about 10%. If the amount of component A is outside the range specified above (i.e., low), the efficacy of the treatment may be reduced. 50 Understand how to calculate and understand the remainder of the composition, up to 100%, is component B.

[0272] The amount of carrier utilized together with component A is sufficient to provide a practical amount of the composition for administration per unit dose of pharmaceutical. Techniques and compositions for making dosage forms useful in the methods of the present disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2 nd Ed., (1976).

[0273] Component B may comprise a single component or a combination of two or more components. In topical compositions, component B comprises a topical carrier. Suitable topical carriers include one or more components selected from the group consisting of phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetric alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, and symmetric alcohol.

[0274] The topical composition carrier may further comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.

[0275] Component q) is an emollient. The amount of component q) in a skin topical composition is typically about 5 to about 95%. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, sebacic acid, and the like. Examples of emollients include di-n-butyl, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof.Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane.

[0276] Component r) is a propellant. The amount of component r) in the topical composition is typically about 0 to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.

[0277] Ingredient s) is a solvent. The amount of ingredient s) in the topical composition is typically about 0 to about 95%. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohol.

[0278] Ingredient t) is a humectant. The amount of ingredient t) in the topical composition is typically 0-95%. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin.

[0279] Component u) is a thickening agent. The amount of component u) in a topical composition is typically from about 0 to about 95%.

[0280] Component v) is a powder. The amount of component v) in the topical composition is typically 0-95%. Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. For ophthalmic application, specific powders include beta-cyclodextrin, such as betadex sulfobutylether sodium, hydroxypropyl cyclodextrin, such as (2-hydroxypropyl)-beta-cyclodextrin, and sodium polyacrylate. For gel dosing of ophthalmic formulations, sodium polyacrylate may be used. Powders may function as penetration enhancers or solubilizers or stabilizers.

[0281] Component w) is a fragrance. The amount of component w) in a topical composition is typically about 0 to about 1.5%, particularly about 0.001 to about 0.1%. For application to the eye, fragrances are typically not used.

[0282] Component x) is a pigment. Suitable pigments for skin application include inorganic pigments, organic lake pigments, pearlescent pigments and their mixtures. Inorganic pigments useful in the present disclosure include those selected from the group consisting of rutile or anatase titanium dioxide, which is coded by color index with reference CI 77,891; black, yellow, red and brown iron oxides, which are coded by reference CI 77,499, 77,492 and 77,491; manganese violet (CI 77,742); ultramarine blue (CI 77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); and ferric blue (CI 77,510), and mixtures thereof.

[0283] Organic pigments and lakes useful in this disclosure include D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No.13(CI 15,630), D&C Red No.7(CI 15,850), D&C Red No.6(CI 15,850), D&C Yellow No.5(CI 19,140), D&C Red No.36(CI 12,085), D&C Orange No.10(CI 45,425), D&C Yellow No.6(CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), dyes or lakes based on cochineal carmine (CI 75,570), and mixtures thereof.

[0284] Pearlescent pigments useful in the present disclosure include those selected from the group consisting of white pearlescent pigments, such as mica coated with titanium oxide, bismuth oxychloride, colored pearlescent pigments, such as titanium mica with iron oxide, titanium mica with ferric blue, titanium mica with chromium oxide, and other organic pigments of the types mentioned above, and those based on bismuth oxychloride, and mixtures thereof. The amount of pigment in topical compositions is typically about 0 to about 10%. For ocular applications, pigments are typically not used.

[0285] In particularly preferred embodiments of the present disclosure, a topical pharmaceutical composition for administration to the eye is prepared, typically comprising components A and B (carriers), e.g., purified water, and one or more ingredients selected from the group consisting of y) sugars or sugar alcohols, e.g., dextrans, particularly mannitol and dextran 70, z) cellulose or derivatives thereof, aa) salts, bb) disodium EDTA (disodium edetate), and cc) pH adjusting additives.

[0286] Examples of z) cellulose derivatives suitable for use in topical pharmaceutical compositions for administration to the eye include sodium carboxymethylcellulose, ethylcellulose, methylcellulose and hydroxypropyl-methylcellulose, in particular hydroxypropyl-methylcellulose.

[0287] Examples of aa) salts suitable for use in topical pharmaceutical compositions for administration to the eye include borates, mono-, di- and trisodium phosphates, sodium chloride, potassium chloride, and combinations thereof.

[0288] cc) Examples of pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of a topical pharmaceutical composition for administration to the eye to within the range of 4.5 to 7.5 pH units.

[0289] Component A may be included in a kit that includes a compound described herein, a systemic or topical composition as described above, or both; and information, instructions, or both, that the use of the kit provides treatment for cosmetic and medical conditions in mammals (especially humans). The information and instructions may be in the form of words, drawings, or both, and the like. Additionally or alternatively, the kit may include a medicament, composition, or both, preferably with the benefit of treating or preventing cosmetic or medical conditions in mammals (e.g. humans); and information, instructions, or both, about the method of application of the medicament or composition.

[0290] The present disclosure is further illustrated by the following illustrative examples, which are considered non-limiting. EXAMPLES

[0291] Example 1 ROCK and JAK assays. ROCK kinase inhibition assay. All compounds were initially prepared as 10 mM stocks in anhydrous dimethyl sulfoxide (DMSO). A 20 μL aliquot of the 10 mM solution was transferred to each well in column 1 of a 96-well polypropylene microtiter plate (Corning #3363) and diluted in DMSO to give a final compound concentration of 4 mM. Test compounds were then serially diluted 1:5 in DMSO for an 11-point concentration response and further diluted in assay buffer to give a final range of all compound concentrations from 100 μM to 10 pM in 2.5% DMSO. Assays were performed in white 96-well, flat-bottom, half-area, non-binding assay plates (Corning #3642) in assay buffer consisting of 20 mM HEPES (pH 7.5), 10 mM MgCl2·6H2O, 100 μM sodium orthovanadate, 0.05% CHAPS and 0.1% bovine serum albumin. A 10 μL aliquot of compound from each well of the intermediate dilution plate and 20 μL of 2× substrate / enzyme solution containing receptor substrate (800 nM RSK2 peptide KRRRLSSLRA (SEQ ID NO: 1)), ROCK2 enzyme (10 nM) or ROCK1 enzyme, and 1,4-dithiothreitol (DTT, 2 uM) were added to all wells. The reaction was initiated by adding 10 μL of 4× undiluted ATP (2 μM). The reaction was mixed thoroughly by hand, covered, and incubated at room temperature for 75 minutes. Protein kinase activity was quantified using Promega's KINASE-GLO™ Luminescent Kinase Assay Kit according to the manufacturer's instructions. The ATP concentration remaining in the test wells after termination of the enzyme reaction was compared to control wells (CTRL) containing an equivalent amount of DMSO without inhibitor. ATP concentrations in both test and CTRL wells were normalized to background (BKG) ATP concentrations in wells containing a concentration of inhibitor that completely inhibited the protein kinase under investigation (i.e., a concentration that prevented any consumption of ATP over the course of incubation). Percent of control (POC) values ​​were determined for each concentration of compound tested according to the equation: POC = ((Test well value - BKG) / (CTRL - BKG)) x 100 I C 50 Values ​​were calculated using the following four-parameter logistic curve-fitting algorithm: f(x)=(A+((BA) / (1+((x / C)^D)))) I C 50 The value of K is calculated using the Cheng-Prusoff equation: i Converted to value: K i =IC 50 / (1+([ATP] / Km ATP])) JAK kinase assay.

[0292] Compounds were prepared in exactly the same manner as described in the ROCK kinase assay, except for the substrate and enzyme. JAK 2x substrate / enzyme solution consisted of the receptor substrate (800nM Abl peptide EAIYAAPFAKKK (SEQ ID NO:2)), JAK1, TYK2, JAK2 or JAK3 enzyme (10nM) and DTT (2uM). All other steps and solutions remained the same as in the ROCK kinase assay above. The results are shown above through the table. Example 2 PTM-HTM assay

[0293] Pig trabecular meshwork cells (PTM) were isolated from freshly obtained excised pig eyes. Immortalized human trabecular meshwork cells (TM-1) were obtained as a kind gift from Donna Peters, Department of Ophthalmology and Visual Sciences, University of Wisconsin. Cells were plated on fibronectin-coated glass-bottom 96-well plates and allowed to attach overnight. Media was removed and replaced with test compounds in media containing 1% fetal bovine serum and incubated for various times. After incubation, cells were formaldehyde fixed, triton solubilized, and stained. PTM cells were stained with Alexa Fluor® 488 phalloidin (F-actin) and Hoechst 33342 (nuclei). TM-1 cells were stained with anti-paxillin followed by Alexa Fluor® 488 goat-anti-mouse IgG (focal adhesions) and Hoechst 33342 (nuclei). All staining reagents were obtained from Invitrogen. Images were collected on an INCell 2200 imager using a 20x objective. Actin fiber length and total area of ​​focal adhesions were analyzed using custom algorithms developed with the INCell Developer Toolbox, v1.9.3. Collected data were converted to percent of control (untreated cells). Curves were fitted to the data in GraphPad Prizm using a sigmoidal dose-response, with upper and lower bounds constrained to 100% and 0%, respectively. Example 3

[0294] Topical ophthalmic pharmaceutical compositions for treating inflammation are prepared by conventional methods and formulated as shown in Table 29. [Table 29-1]

[0295] Provided herein is a compound used as azetidine.When the composition is applied topically to the eye once a day, the composition reduces the ocular inflammation of the subject suffering from MGD or DED. Example 4 Reference Example 1. Pharmacological activity for glaucoma assays.

[0296] Pharmacological activity against glaucoma can also be demonstrated using assays designed to test the ability of the subject compounds to reduce intraocular pressure. Examples of such assays are found in the following references: C. Liljebris, G. Selen, B. Resul, J. Stjernschantz, and U. Hacksell, "Derivatives of 17-phenyl-18, 19, 20-trinorprostaglandin F 2α Isopropyl Ester: Potential Anti-glaucoma Agents", Journal of Medicinal Chemistry 1995, 38 (2): 289-304, incorporated herein by reference.

[0297] Although the present disclosure has been described in detail and with reference to specific embodiments thereof, 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 disclosure.

[0298] The groupings of alternative elements or embodiments disclosed herein may be referred to and claimed individually or in any combination with other members of the group or other elements found herein.

[0299] The contents of all cited documents (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art.

[0300] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the subject matter described herein which equivalents are intended to be encompassed by the following claims.

Claims

Claim 1 A compound having the formula: 【Chemical Formula 53】 or a pharmaceutically acceptable salt thereof: [In the formula, J 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; A is C ６～１６ aryl or C ２～１５ heterocyclyl, each of which is 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) and may be substituted with one or two groups independently selected therefrom; J ３ is CN, OH, NH ２ , C １～６ alkyl, C2-6 alkynyl, C ３～７ cycloalkyl, (C １～３ alkylene)-CN, (C １～３ alkylene)-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 aryl), N(H)C(O)-(C １～３ alkylene)-(C ６～１０ aryl), 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 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(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 １～６ 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 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 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 substituted with 1, 2, 3 or 4 groups independently selected therefrom; and, R ４ is 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 heterocycloalkyl; Or, J. ３ and R ４ combine with the atoms to which they are attached to form C ３～７ Cycloalkyl, C ２～８ Heterocycloalkyl, CC(H)-(C ０～６ alkylene)CN, halogen or (C １～６ C substituted with 1 or 2 groups independently selected from alkylene)CN ３～７ Cycloalkyl, or halogen or (C １～６ C substituted with 1 or 2 groups independently selected from alkylene)CN ２～８ forming a heterocycloalkyl. Claim 2 A compound having the formula: 【Chemical 54】 or a pharmaceutically acceptable salt thereof: [In the formula, R １ is H, F, Cl, Br, I, CN, NH ２ , OH, OCF ３ , OCH ２ CF ３ , C １～６ alkyl, C ３～６ cycloalkyl or C １～６ haloalkyl, and R ２ and R ３ are C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ２ and R ３ are combined to form a heteroalkyl or polycyclic ring having at least 4 and at most 12 constitutive atoms, R ４ is C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, -CH ２ CN, -CH ２ CH ２ CN, -CH ２ CH ２ CH ２ CN, alkylene cycloalkyl, alkylene cyclopropyl or hydroxyl, and A is phenyl or a monocyclic C having 1 to 3 heteroatoms ３～５ heteroaryl, and each heteroatom is independently N, O or S]. Claim 3 A is a monocyclic C having 1 to 3 heteroatoms ３～５ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein each heteroatom is independently N, O or S and is a heteroaryl Claim 4 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula: 【Chemical Formula 55】 or a pharmaceutically acceptable salt thereof: [In the formula, R1 is H, F, Cl, Br, I, CN, NH2, OH, OCF3, OCH2CF3, C1-6 alkyl, C3-6 cycloalkyl or C1-6 haloalkyl; R ２ and R ３ are C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ２ and R ３ combine to form a heteroalkyl or polycyclic ring having at least 4 and at most 10 constituent atoms, R4 is H, OH, C1-6 alkyl, (C1-6 alkylene)-OH, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 halocycloalkyl, (C1-3 alkylene)-(C3-7 cycloalkyl), (C1-6 alkylene)CN, (C1-6 alkylene)-C(O)O-(C1-6 alkyl), (C1-6 alkylene)-OC(O)-(C1-6 alkyl) or C2-8 heterocycloalkyl; and R ５ is C １～１２ alkyl, C １～１２ heteroalkyl or C １～１２ haloalkyl, CH ２ OH, CH ２ CH ２ OH, CH ２ CH ２ CH ２ OH, alkylene cycloalkyl, alkylene cyclopropyl or methoxy]. Claim 5 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula: 【Chemical 56】 or a pharmaceutically acceptable salt thereof: [In the formula, R1 is H, F, Cl, Br, I, CN, NH2, OH, OCF3, OCH2CF3, C1-6 alkyl, C3-6 cycloalkyl or C1-6 haloalkyl; R ２ and R ３ are C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ２ and R ３ combine to form a heteroalkyl or polycyclic ring having at least 4 and at most 8 constituent atoms, R4 is H, OH, C1-6 alkyl, (C1-6 alkylene)-OH, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 halocycloalkyl, (C1-3 alkylene)-(C3-7 cycloalkyl), (C1-6 alkylene)CN, (C1-6 alkylene)-C(O)O-(C1-6 alkyl), (C1-6 alkylene)-OC(O)-(C1-6 alkyl) or C2-8 heterocycloalkyl; R ６ is C １～１２ alkyl, C １～１２ heteroalkyl or C １～１２ haloalkyl, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ CH ２ CH ２ OH, -(CH ２ ) ｎ -COOR １０ , alkylene cycloalkyl, alkylene cyclopropyl or methoxy, and n is an integer between 1 and 10; R １０ is hydrogen, alkyl, cycloalkyl or heteroalkyl]. Claim 6 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula: 【Chemical 57】 or a pharmaceutically acceptable salt thereof: [In the formula, R1 is H, F, Cl, Br, I, CN, NH2, OH, OCF3, OCH2CF3, C1-6 alkyl, C3-6 cycloalkyl or C1-6 haloalkyl, R ２ and R ３ are C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ２ and R ３ combine to form a heteroalkyl ring having at least 4 and at most 8 constituent atoms, R4 is H, OH, C1-6 alkyl, (C1-6 alkylene)-OH, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 halocycloalkyl, (C1-3 alkylene)-(C3-7 cycloalkyl), (C1-6 alkylene)CN, (C1-6 alkylene)-C(O)O-(C1-6 alkyl), (C1-6 alkylene)-OC(O)-(C1-6 alkyl) or C2-8 heterocycloalkyl, X is CH or N, and R ７ and R ８ are, independently, H, C １～１２ alkyl, C １～１２ heteroalkyl or C １～１２ haloalkyl, CH ２ OH, CH ２ CH ２ OH, CH ２ CH ２ CH ２ OH, alkylene cycloalkyl, alkylene cyclopropyl or methoxy, or R ７ and R ８ combine to form a heteroalkyl ring having at least 4 and at most 8 constitutive atoms].

7. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: 【Chemical Formula 58】 A compound, or a pharmaceutically acceptable salt thereof, which is a compound of: [wherein, R １ is H, Cl, C １～６ alkyl, C ３～６ cycloalkyl or C １～３ haloalkyl, and R ２ and R ３ are C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ２ and R ３ combine to form a heteroalkyl ring having at least 4 and at most 8 constituent atoms, R4 is H, OH, C1-6 alkyl, (C1-6 alkylene)-OH, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 halocycloalkyl, (C1-3 alkylene)-(C3-7 cycloalkyl), (C1-6 alkylene)CN, (C1-6 alkylene)-C(O)O-(C1-6 alkyl), (C1-6 alkylene)-OC(O)-(C1-6 alkyl) or C2-8 heterocycloalkyl, and R ５ is C １～６ alkyl, C ３～５ cycloalkyl, CH ２ OH, CH ２ CH ２ OH, CH ２ CH ２ CH ２ OH, alkylene cycloalkyl, alkylene cyclopropyl or methoxy].

8. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: 【Chemical 59】 A compound, or a pharmaceutically acceptable salt thereof, which is a compound of: [wherein, R １ is H, F, Cl, OCF ３ , OCH ２ CF ３ , C １～６ alkyl, C ３～６ cycloalkyl or C １～６ haloalkyl, and R ２ and R ３ are C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ２ and R ３ combine to form a heteroalkyl ring having at least 4 and at most 8 constituent atoms, R4 is H, OH, C1-6 alkyl, (C1-6 alkylene)-OH, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 halocycloalkyl, (C1-3 alkylene)-(C3-7 cycloalkyl), (C1-6 alkylene)CN, (C1-6 alkylene)-C(O)O-(C1-6 alkyl), (C1-6 alkylene)-OC(O)-(C1-6 alkyl) or C2-8 heterocycloalkyl, R ６ is C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ CH ２ CH ２ OH, -(CH ２ ) ｎ -COOR １０ and is alkylene cyclopropyl or methoxy, n is an integer between 1 and 10, and R １０ is hydrogen, alkyl, cycloalkyl or heteroalkyl].

9. A compound, or a pharmaceutically acceptable salt thereof, 【Chemical Formula 60】 【Chemical Formula 61】 【Chemical Formula 62】 【Chemical Formula 63】 【Chemical Formula 64】 【Chemical Formula 65】 【Chemical Formula 66】 【Chemical 67】 selected from, a compound, or a pharmaceutically acceptable salt thereof.

10. A compound, or a pharmaceutically acceptable salt thereof, having the formula: 【Chemical Formula 68】 A compound, or a pharmaceutically acceptable salt thereof, having the following: [wherein, R １ is H, F, Cl, Br, I, CN, OCF ３ , OCH ２ CF ３ , C １～３ alkyl, C ３～６ cycloalkyl or C １～６ haloalkyl, and R ４ is C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, CH ２ CN, CH ２ CH ２ CN, CH ２ CH ２ CH ２ CN, alkylene cycloalkyl, alkylene cyclopropyl or hydroxyl, and R ９ is C １～６ alkyl, C １～６ heteroalkyl or C １～６ haloalkyl, or R ４ and R ９ combine to form a carbocyclic, polycyclic or heteroalkyl ring having at least 4 and at most 8 constituent atoms, and A is phenyl or a monocyclic C having 1 to 3 heteroatoms ３～５ heteroaryl, and each heteroatom is independently N, O, or S].

11. A compound, or a pharmaceutically acceptable salt thereof, selected from 【Chemical Formula 69】 【Chemical 70】 A compound, or a pharmaceutically acceptable salt thereof, selected from the following.

12. A compound, or a pharmaceutically acceptable salt thereof, having the formula: 【Chemical 71】 [wherein, A is J ５ is H, S(O) ２ CH ３ or S(O) ２ CH ２ CH ３ and; R １ is H, CH ３ , CH ２ CH ３ , cyclopropyl, OCH ３ , F, Cl or CN; ; 【Chemical Formula 72】 【Chemical Formula 73】 ; and forms J ３ is CN, OH, NH ２ , 【Chemical 74】 【Chemical 75】 【Chemical 76】 【Chemical Formula 77】 【Chemical 78】 【Chemical Formula 79】 . R ４ is 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-fluorocyclobut-1-yl, tetrahydro-2H-pyran-4-yl, CH ２ C(O)OCH ３ or CH ２ OC(O)CH ３ ; Alternatively, J ３ and R ４ combine with the atoms to which they are attached to form 【Chemical 80】

13. A compound, or a pharmaceutically acceptable salt thereof, selected from A compound, or a pharmaceutically acceptable salt thereof, selected from the following. 【Chemical 83】 【Chemical 84】 【Chemical Formula 85】 The compound according to claim 12, or a pharmaceutically acceptable salt thereof, selected from

14. 【Chemical Formula 86】 【Chemical 87】 【Chemical 88】 【Chemical 89】 【Chemical Formula 90】 【Chemical Formula 91】 【Chemical Formula 92】 【Chemical Formula 93】 【Chemical Formula 94】 【Chemical Formula 95】 【Chemical Formula 96】 【Chemical 97】 【Chemical Formula 98】 【Chemical Formula 99】 【Chemical 100】 【Chemical 101】 【Chemical 102】 【Chemical Formula 103】 【Chemical 104】 【Chemical 105】 【Chemical 106】 【Chemical 107】 【Chemical 108】 【Chemical 109】 【Chemical 110】 【Chemical 111】 【Chemical 112】 【Chemical 113】 【Chemical 114】 【Chemical 115】 【Chemical 116】 【Chemical 117】 【Chemical Formula 118】 【Chemical 119】 【Chemical 120】 【Chemical 121】 【Chemical 122】 【Chemical 123】 【Chemical 124】 【Chemical 125】 【Chemical 126】 【Chemical 127】 【Chemical 128】 【Chemical Formula 129】 【Chemical 130】 【Chemical 131】 The compound according to claim 12, or a pharmaceutically acceptable salt thereof, which is

15. 【Fig. 132】

16. A compound, or a pharmaceutically acceptable salt thereof, which is A compound, or a pharmaceutically acceptable salt thereof, which is 【Chemical 133】

17. A compound, or a pharmaceutically acceptable salt thereof, which is A compound, or a pharmaceutically acceptable salt thereof, which is 【Chemical 134】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

18. 【Fig. 135】 【Chemical 136】

19. A compound, or a pharmaceutically acceptable salt thereof, selected from

20. 【Chemical 137】 【Chemical 138】 【Chemical 139】 A composition comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. The composition according to claim 20, wherein the composition is a pharmaceutical composition.

22. The composition according to claim 21, wherein the composition further comprises a pharmaceutically acceptable carrier.

23. A composition for use in a method of treating a disease or condition associated with JAK kinase activity, or a disease or condition affected by JAK kinase, in a subject in need thereof, wherein the composition comprises the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and the method comprises administering the composition to the subject. ​ ​ **Claim 24** The composition according to claim 23, wherein the method is a method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, and the disease or condition is a neurodegenerative disease or condition, an eye disease or condition, a cardiovascular disease or condition, cancer, blood cancer, a myeloproliferative condition, acute myeloid leukemia, lymphoma, or a combination thereof. **Claim 25** The method is as follows: A method for treating an eye disease or condition associated with JAK kinase activity in a subject in need of treating an eye disease or condition associated with JAK kinase activity; A method for treating an eye disease or condition associated with JAK kinase activity in a subject in need of treating an eye disease or condition associated with JAK kinase activity, wherein the eye disease or condition is non-infectious uveitis, choroiditis, iritis, aseptic conjunctivitis, keratitis, episcleritis, dry eye, meibomian gland dysfunction, allergic conjunctivitis, injury-related ocular inflammation or dry eye syndrome, primary Sjögren's syndrome, secondary Sjögren's syndrome, redness, blepharitis, dry keratoconjunctivitis, ocular hyperemia, Thygeson superficial punctate keratitis, or a combination thereof; A method for treating an eye disease or condition associated with JAK kinase activity in a subject in need of treating an eye disease or condition associated with JAK kinase activity, wherein the eye disease or condition is wet age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, posterior uveitis, retinal inflammation, inflammation due to a gene therapy vector, graft-versus-host disease, blepharitis, or a combination thereof; A method for treating an autoimmune disease or condition associated with JAK kinase activity in a subject in need of treating an autoimmune disease or condition associated with JAK kinase activity; A method for treating an autoimmune disease or condition associated with JAK kinase activity in a subject in need of treating an autoimmune disease or condition associated with JAK kinase activity, wherein the autoimmune disease or condition is alopecia areata, alopecia totalis, polycythemia vera, vitiligo, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus erythematosus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid condition, chronic obstructive pulmonary disease or a combination thereof; A method for treating an autoimmune disease or condition associated with JAK kinase activity in a subject in need of treating an autoimmune disease or condition associated with JAK kinase activity, wherein the autoimmune disease or condition is organ transplant rejection; A method for treating an autoimmune disease or condition associated with JAK kinase activity in a subject in need of treating an autoimmune disease or condition associated with JAK kinase activity, wherein the autoimmune disease or condition is allograft rejection or graft-versus-host disease; A method for treating an autoimmune disease or condition associated with JAK kinase activity in a subject in need of treating an autoimmune disease or condition associated with JAK kinase activity, wherein the autoimmune disease or condition is arthritis; A method for treating an allergic condition associated with JAK kinase activity in a subject in need of treating an allergic condition associated with JAK kinase activity, wherein the allergic condition is asthma, food allergy, eczematous dermatitis, contact dermatitis, atopic dermatitis or rhinitis; A method for treating a viral disease associated with JAK kinase activity in a subject in need of treating a viral disease associated with JAK kinase activity, wherein the viral disease is Epstein-Barr virus, hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus or human papillomavirus; A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is 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's disease, uterine leiomyoma, melanoma, blood cancer or skin cancer; A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is lymphoma or leukemia; A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is acute lymphoblastic leukemia, acute myeloid leukemia or multiple myeloma; A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma; A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is Sézary syndrome or mycosis fungoides; A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is pulmonary arterial hypertension; or, A method for treating a disease or condition associated with JAK kinase activity in a subject in need of treating a disease or condition associated with JAK kinase activity, wherein the disease or condition is cancer associated with colitis, colon cancer, colorectal cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, adenocarcinoma, small intestine cancer, blood cancer or rectal cancer The composition according to claim 23, selected from

26. The composition according to claim 23, wherein the administration is local administration to the eye of the subject or local administration to the eyelid of the subject.

27. The composition according to claim 23, wherein the administration is by intravitreal injection into the eye of the subject.

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