WO2022081872A1 - Janus kinase inhibitors - Google Patents

Abstract

Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein X, Q, Ak, L1, L2, R1, R2, R3 and n are as defined herein. Also provided are compositions comprising such compounds, processes for their preparation, and methods relating to their use for treating diseases, disorders and conditions associated with kinase function.

Description

JANUS KINASE INHIBITORS

FIELD OF THE INVENTION

[0001] The present invention relates generally to Janus Kinase (JAK) inhibitors, pharmaceutical compositions comprising them, processes for preparing them and uses of such inhibitors to treat or prevent diseases, disorders and conditions associated with kinase function.

BACKGROUND

[0002] The Janus Kinases are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines implicated in the pathogenesis of inflammatory diseases and are critical to both innate and adaptive immunities.

[0003] The family comprises four members, JAK1, JAK2 and TYK2 - which are expressed ubiquitously - and JAK3, found only in hematopoietic cells. These enzymes show high sequence homology and are constitutively bound to the cytoplasmic tail of cytokine receptors. When a cytokine binds to its receptor, multimerization (dimerization or higher order complexes) of receptor subunits occurs, bringing the JAK enzymes associated with each subunit proximal to one another. JAK family members then auto- and/or trans-phosphorylate, which triggers a series of phosphorylation events resulting ultimately in the phosphorylation and activation of signal transducers and activators of transcription (STAT) proteins. A phosphorylated STAT dimer then translocates to the nucleus of the cell where it binds to target genes to modulate their expression and alter cellular function. Importantly, there are no known compensatory pathways around JAK/STAT signaling and, as such, the JAK enzymes are essential in regulating the cytokines that signal through these pathways.

[0004] JAK kinases function as homo or heterodimers dimers which are specific to cytokine receptor subunits. For example, JAK1-JAK3 heterodimers associate with the y-common chain of receptors to control signaling associated with IL2, IL4, IL7, IL9, IL15 and IL21, cytokines predominantly associated with adaptive immune functions. JAK1, however, also functions as a heterodimer with JAK2 and TYK2 to regulate signaling through a wide array of cytokine receptors. In this manner, JAK1 modulates the signaling of several proinflammatory cytokines associated with the innate immune response, such as IL6 and the type I interferons. JAK2 is the only member of the JAK family that can operate as a homodimer. In this combination, JAK2 controls the signaling of various cytokines and growth factors, such as IL3, IL5, granulocyte macrophage colony-stimulating factor, erythropoietin and thrombopoietin.

[0005] JAKs are also thought to play role in numerous forms of cancer. Mutations in JAK1 and JAK3, as well as other rare mutations in JAK2, have been associated with T-cell acute lymphoblastic leukemia (T-ALL). Similarly, JAK1 mutations were found in 9% cases of hepatocellular carcinoma; in particular, the S703I mutation is likely responsible for the loss of JAK1 auto-inhibition ability. Ruxolitinib has been evaluated against several forms of cancer. Clinical study have examined ruxolitinib in the treatment of Hodgkin's disease (HD) and the combination of ruxolitinib with ibrutinib (an approved BTK inhibitor) for treatment of chronic lymphocytic leukemia (CLL). The combination of ruxolitinib and paclitaxel leads to a greater reduction of tumor growth compared to single treatment of either agent in a tumor mouse model that represents late stage ovarian cancer (Han et al, "Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer" Oncotarget. 2018; 9(36), 24304- 24319.)

[0006] The JAK1/2 blockade has also been considered for the treatment of AIDS. For example, ruxolitinib showed significant results in controlling the levels of reservoir T-cells in HIV-l patients.

[0007] JAKs are under investigation for the treatment of COVID-19, wherein JAK inhibition may play a role in placating the cytokine storm responsible for the severe acute respiratory syndrome associated with COVID-19 .

[0008] JAK enzymes have emerged as significant drug discovery targets, particularly for autoimmune diseases, and several JAK inhibitors that have received regulatory approval. However, many of the JAKi drugs can cause serious side effects. For example, Ruxolitinib carries safety warnings and can cause serious side effects, including low blood counts (platelet, red blood cell, or white blood cell), infection, skin cancers and increases in cholesterol. Baricitinib has been associated with serious side effects such as infections, including tuberculosis (TB), shingles, and others caused by bacteria, fungi, or viruses, cancer and immune system problems, blood clots and tears in the stomach or intestines.

[0009] There is thus a need for new JAK inhibitors that are potent, selective inhibitors of Janus kinases with appropriate metabolic stability and pharmacokinetic properties. There is a particular need for selective JAK inhibitors exhibiting minimal or no side effects. BRIEF SUMMARY

[0010] Described herein are compounds having the structure of formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein X, Ak, n, Q, L¹, L², R¹, R² and R³ are as defined below.

[0011] In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.

[0012] In one embodiment, a method of modulating a JAK enzyme is provided comprising contacting the JAK enzyme with an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

[0013] In one embodiment, a method for treating a JAK dependent condition is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

[0014] In one embodiment, the use of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is provided, in the manufacture of a medicament.

DETAILED DESCRIPTION

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0016] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.

[0017] Reference in the specification to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.

[0018] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about lOOpL" means "about lOOpL" and also "lOOpL." In some embodiments, about means within 5% of the value. Hence, "about lOOpL" means 95-105pL. Generally, the term "about" includes an amount that would be expected to be within experimental error.

[0019] In embodiment, compounds are provided having the structure of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:

X is F or Cl;

Ak is Ci-6 alkyl optionally substituted by 1, 2 or 3 fluorine atoms; n is 1 or 2;

Q is a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms;

L¹ is C(O), S(O)₂, CH₂ or a bond; L² is a bond, Ci-6 alkylene, C3-6 cycloalkylene, C4-6 heterocycle containing 1 N or C4-9 heterospirocycle containing 1 N;

R¹ is H, C1-3 alkyl, OH, OMe, NH₂, NMe or NMe₂;

R² is H or Me;

R³ is H or Me; or R² and R³ together with a C atom to which they are both attached form a C3-4 cycloalkyl.

[0020] As used herein, "alkyl" means a straight chain or branched saturated hydrocarbon group. "Lower alkyl" means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, /so-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0021] "Alkenyl" groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -CH=CH₂, -CH=CH(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, -CH=CHCH₂CH₃, -CH=CH(CH₂)₂CH₃, -CH=CH(CH₂)₃CH₃, -CH=CH(CH₂)₄CH₃, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

[0022] "Alkynyl" groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C^CH, -C^CfCHs), -C=C(CH₂CH3), -CH₂C=CH, -CH₂C=C(CH₃), and -CH₂C=C(CH₂CH₃), among others.

[0023] As used herein, "alkylene" means a divalent alkyl group. Examples of straight chain lower alkylene groups include, but are not limited to, methylene (i.e., -CH₂-), ethylene (i.e., -CH₂CH₂-), propylene (i.e., -CH₂CH₂CH₂-), and butylene (i.e., -CH₂CH₂CH₂CH₂-). As used herein, "heteroalkylene" is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P.

[0024] "Alkoxy" refers to an alkyl as defined above joined by way of an oxygen atom (i.e., — O— a Ikyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0025] The terms "carbocyclic" and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic. Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0026] "Cycloalkyl" groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0027] "Aryl" groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6- 14 carbons in the ring portions of the groups. The terms "aryl" and "aryl groups" include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0028] "Carbocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle. Examples of carbocyclealkyl groups include, but are not limited to, benzyl and the like.

[0029] As used herein, "heterocycle" or "heterocyclyl" groups include aromatic and nonaromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. A heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. In some embodiments, heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzodioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocycle groups within the meaning herein. A heterocycle group designated as a C2-heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a Czi-heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms.

[0030] "Heteroaryl" groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C2-heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a Czi-heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, qui nolinyl, isoqui nolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl groups" include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl.

[0031] "Heterocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle. Examples of heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like.

[0032] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0033] "Haloalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, “CHzCFs, and the like.

[0034] "Haloalkoxy" refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkoxy groups include, but are not limited to -OCF3, -OCH2CF3, and the like.

[0035] "Hydroxyalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with -OH. Examples of lower hydroxyalkyl groups include, but are not limited to -CH2OH, -CH2CH2OH, and the like.

[0036] As used herein, the term "optionally substituted" refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to -OR^a, -NR^aR^b, -S(O)2R^a or -S(O)2OR^a, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R^a and R^b is, independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or R^a and R^b, together with the atom to which they are attached, form a 3-8 membered carbocycle or heterocycle.

[0037] In further embodiments of Formula (I), the various substituents (i.e., X, Ak, n, Q, L¹, L², R¹, R² and R³) are as more specifically defined below.

[0038] In some embodiments X is F.

[0039] In some embodiments Ak is methyl or ethyl.

[0040] In other embodiments X is F and Ak is ethyl.

[0041] In some embodiments n is 1. [0042] In other embodiments n is 2.

[0043] In some embodiments L¹ is C(O).

[0044] In other embodiments L¹ is S(O)2.

[0045] In other embodiments L¹ is CH2.

[0046] In other embodiments L¹ is a bond.

[0047] In some embodiments Q is a 6-membered heteroaromatic ring containing 1 nitrogen atom.

[0048] In other embodiments Q is a 6-membered heteroaromatic ring containing 2 nitrogen atoms.

[0049] In other embodiments Q is a 6-membered heteroaromatic ring containing 3 nitrogen atoms.

[0050] In some embodiments Q is pyridine, pyridazine, pyrimidine, pyrazine or triazine.

[0051] In some embodiments Q is pyrazine.

[0052] In some embodiments L¹ and the 1,4-diazepane are positioned meta to each other.

[0053] In some embodiments L¹ and the 1,4-diazepane are positioned para to each other.

[0054] In some embodiments Q is pyrazine and L¹ and the 1,4-diazepane are positioned meta to each other.

[0055] In other embodiments Q is pyrazine and L¹ and the 1,4-diazepane are positioned para to each other.

[0056] In some embodiments Q is pyrazine, L¹ is C(O), and L¹ and the 1,4-diazepane are positioned meta to each other.

[0057] In other embodiments Q is pyrazine, L¹ is C(O), and L¹ and the 1,4-diazepane are positioned para to each other.

[0058] In some embodiments L² is methylene, ethylene, n-propylene or /-propylene.

[0059] In some embodiments L² is methylene, ethylene, n-propylene or /-propylene and

R¹ is H.

[0060] In some embodiments L² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0061] In some embodiments L² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and

R¹ is H. [0062] In some embodiments L² is azetidine, pyrrolidine or piperidine.

[0063] In some embodiments L² is azetidine, pyrrolidine or piperidine and R¹ is H or Me.

[0064] In some embodiments C4-6 heterospirocycle containing 1 N.

[0065] In some embodiments R¹ is H or Me and L² is:

[0066] In some embodiments R¹ is H or C1-3 alkyl.

[0067] In some embodiments R¹ is Me. In some embodiments R¹ is OH, OMe, NH2, NMe or NMez.

[0068] In some embodiments R² is H and R³ is H.

[0069] In some embodiments R² is H and R³ is Me. In some embodiments R² is Me and

R³ is Me.

[0070] In some embodiments R² and R³ together with the C atom to which they are attached form cyclopropyl or cyclobutyl.

[0071] In another embodiment, compounds are provided having the structure of formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:

L¹ is C(O) or CH₂;

L² is a bond, C1-6 alkylene, C3-6 cycloalkylene, C4-6 heterocycle containing 1 N or

C4-9 heterospirocycle containing 1 N; and

R¹ is H, C1-3 alkyl, OH, OMe, NH₂, NMe or NMe₂.

[0072] In further embodiments of Formula (II), the various substituents (i.e., L¹, L² and

R¹) are as more specifically defined below.

[0073] In some embodiments L¹ is C(O). [0074] In some embodiments L¹ is CH2.

[0075] In some embodiments L² is a bond.

[0076] In some embodiments R¹ is H or C1-3 alkyl.

[0077] In some embodiments R¹ is Me.

[0078] Representative compounds of Formula (I) and/or (II), as applicable, include the compounds listed in Table 1 below, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

Table 1

Representative Compounds

Structure Name

Structure Name

Structure Name

Structure Name

Structure Name

[0079] In some embodiments, the compound has the following structure, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof:

(Compound 1).

[0080] In some embodiments, the compound has the following structure, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof:

[0081] In some embodiments, the compound has the following structure, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof:

(Compound 3).

[0082] In some embodiments the compound is a pharmaceutically acceptable salt of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1.

[0083] As used in the context of the compounds disclosed herein, the following terms have the meanings set forth below.

[0084] "Isomer" is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. The term isomer may also be referred to as a stereioisomer, to distinguish it from a position isomer (which is not encompassed by the term isomer). Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S).

[0085] "Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight. [0086] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0087] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).

[0088] A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

[0089] A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

[0090] "Isotope" refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formulas (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has several isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formulas (I) includes, but not limited to, compounds of Formulas (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19.

[0091] "Tautomer" refers to one of two (or more) structural isomers that exist in equilibrium, and readily converted from one isomeric form to another. With regard to the compounds of Formula (I), this conversion may result in the migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds (e.g., in the context of an imidazole group). Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on a number of factors, including temperature, solvent and pH. While the compounds of the present disclosure may be depicted in a single tautomeric form, it should be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the chemical naming and structural depiction used herein is not intended to exclude other tautomeric forms. It should also be understood that a certain tautomeric form of a compound may have preferred characteristics over another tautomeric form. Accordingly, all tautomeric forms of the disclosed compounds are within the scope of this disclosure.

[0092] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts."

[0093] The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).

[0094] Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0095] Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, salicylic, -galactaric, and galacturonic acid.

[0096] Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of the compounds described herein, for example in their purification by recrystallization.

[0097] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the compound (also referred to as the "active compound") will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0098] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form; for topical administration, in particular by inhalation; for intravenous administration; or in any other formulation described herein.

[0099] The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment.

[0100] Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient's body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.

[0101] As used herein, the term "administering" or "administration" refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.

[0102] As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.

[0103] As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or underdevelopment of a myelin sheath, e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or one at risk of developing the condition. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

[0104] As used herein, the term "effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.

[0105] As used herein, the terms "modulate" or "modulating" refer to the ability to increase or decrease the activity of one or more protein kinases. Accordingly, compounds of the invention can be used in methods of modulating a protein kinase by contacting the protein kinase with any one or more of the compounds or compositions described herein. In some embodiments, the compounds can act as inhibitors of one or more protein kinases. In some embodiments, the compounds can act to stimulate the activity of one or more protein kinases. In further embodiments, the compounds of the invention can be used to modulate activity of a protein kinase in an individual in need of modulation of the receptor by administering a modulating amount of a compound as described herein. [0106] As used herein, the term "JAK-mediated" or JAK-modulated or "JAK-dependent" diseases or disorders means any disease or other deleterious condition in which JAK, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which JAK, or a mutant thereof, is known to play a role. In particular, the present application relates to a method of treating or lessening the severity of a lung disease or condition, wherein said method comprises administering to a patient in need thereof a compound of Formula (I) or a composition according to the present application.

[0107] Also described herein are methods of inhibiting one or more JAK enzymes, comprising contacting the JAK enzyme with an effective amount of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

[0108] Also described herein are methods of treating or preventing an inflammatory disease, comprising administering an effective amount of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

[0109] In some embodiments the inflammatory disease is cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis, COPD, chronic bronchitis, emphysema, asthma, pediatric asthma, atopic dermatitis, allergic dermatitis, contact dermatitis or psoriasis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, diabetic retinopathy, macular oedema, diabetic macular oedema, central retinal vein occlusion (CRVO), dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, uveitis (including posterior, anterior and pan uveitis), corneal graft and limbal cell transplant rejection, gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease, Crohn's disease or ulcerative colitis.

[0110] Also described herein are methods of sensitizing a subject to the antiinflammatory effects of a corticosteroid, comprising administering to the subject an effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments the subject is refractory to the anti-inflammatory effects of a corticosteroid. In some embodiments the subject is under responsive or unresponsive to the anti-inflammatory effects of a corticosteroid.

[0111] Also described herein are uses of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, in the manufacture of a medicament. In some embodiments the medicament is for the treatment of an inflammatory disease.

[0112] JAK enzymes are important drug discovery targets, and a number of JAK inhibitors have received regulatory approval, including the following for the indications noted:

Tofacitinib (XEUANZ®), a pan-JAK inhibitor, approved for treatment of Rheumatoid Arthritis, Psoriatic Arthritis and Ulcerative Colitis;

Ruxolitinib (JAKAFI®), a selective JAK1/JAK2 inhibitor, approved for the treatment of myelofibrosis polycythemia and acute graft-versus-host disease (GVHD);

Upadacitinib (RINVOQ™), a JAK1 inhibitor exhibiting selectivity over JAK2 (74- fold), JAK3 (58-fold) and TYK2, approved for the treatment of moderate to severe rheumatoid arthritis;

Baricitinib (OLUMIANT®), a JAK1 and JAK2 selective inhibitor, approved for treatment of RA and showed promising results against moderate-to-severe atopic dermatitis (AD) , systemic lupus erythematosus (SLE) and diabetic kidney disease (DKD);

Filgotinib (GLPG0634), a JAK1 inhibitor exhibiting 30-fold selectivity for JAK1 over JAK2, having undergone investigation for the treatment of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and Crohn's disease;

Fedratinib (I N REBIC®), a selective JAK2 inhibitor, approved for treatment of myelofibrosis (MF); and

Upadacitinib (RINVOQ®), a selective JAK1 inhibitor, approved for the treatment of rheumatoid arthritis and being investigated for Crohn's disease, ulcerative colitis, atopic dermatitis, psoriatic arthritis, axial SpA and Giant Cell Arteritis and Takayasu Arteritis.

[0113] Other JAK inhibitors in phase 2/3 clinical trials include Peficitinib (ASP015K) for treatment of Rheumatoid Arthritis; Deucravacitinib (BMS-986165) for treatment of Psoriasis; Pacritinib (SB1518) for treatment of Myelofibrosis; Abrocitinib (PF-04965842) for treatment of Psoriasis; R348 for treatment of GvHD-associated ocular surface disease; and Itacitinib (INCB039110) for treatment of Myelofibrosis.

[0114] According, JAK inhibitors are believed to have utility in the treatment of a range of inflammatory diseases. Compounds which have a broad inhibitory activity across the range of Janus kinases, in particular, are likely to have a potent anti-inflammatory effect. However, such a selectivity profile can also lead to undesirable side-effects in systemically circulating compounds, particularly anemia and neutropenia associated with JAK 2 inhibition. There is thus a need to provide new JAK inhibitors that are potent, selective inhibitors of Janus kinases with appropriate metabolic stability and pharmacokinetic properties.

[0115] Described herein are methods of treating a disease in a mammal in need thereof comprising administering to the mammal, a therapeutically effective amount of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments the disease is a JAK mediated disease. In some embodiments the disease is an autoimmune disease, an inflammatory disease or cancer. In some embodiments the disease is a lung disease.

[0116] Also described herein are methods of treating a disease treatable by inhibition of one or more JAK enzymes, in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments the disease is an autoimmune disease, an inflammatory disease or cancer. In some embodiments the disease is a lung disease.

[0117] Also described herein are compounds of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof for use as a medicament. In some embodiments the medicament is useful for treating an autoimmune disease, an inflammatory disease or cancer. In some embodiments the disease is a lung disease. [0118] Also described herein are compounds of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, useful in the manufacture of a medicament for treating a JAK- mediated disease in a mammal. In some embodiments the medicament is useful for treating an autoimmune disease, an inflammatory disease or cancer. In some embodiments the disease is a lung disease.

[0119] Also described herein are compounds of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, useful in the manufacture of a medicament for treating a disease in a mammal in which JAK contributes to the pathology and/or symptoms of the disease.

[0120] In some embodiments, the disease or condition is an allergic or respiratory condition such as allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary disease (COPD), chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airways hyperreactivity consequent to other drug therapy, pulmonary vascular disease (including pulmonary arterial hypertension), acute lung injury, bronchiectasis, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis or atopic dermatitis, particularly asthma or chronic obstructive pulmonary disease, most particularly chronic obstructive pulmonary disease.

[0121] Types of asthma include atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, bronchitic asthma, emphysematous asthma, exercise induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoa l, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis. The treatment of asthma includes palliative treatment for the symptoms and conditions of asthma such as wheezing, coughing, shortness of breath, tightness in the chest, shallow or fast breathing, nasal flaring (nostril size increases with breathing), retractions (neck area and between or below the ribs moves inward with breathing), cyanosis (gray or bluish tint to skin, beginning around the mouth), runny or stuffy nose, and headache.

[0122] Many JAK dependent cytokines play key roles in the pathology of COPD which involves the interplay of multiple inflammatory cells such as T lymphocytes, neutrophils, macrophages and lung epithelium. For example, the JAK 1/JAK 3 heterodimer plays a key role in T lymphocyte survival and activation whereas JAK 2 is thought to be critical for regulation of neutrophil activation and apoptosis. JAK 1 and JAK 2 play an important role in IL-13 mediated inflammatory signaling in macrophages, which is thought to link acute inflammatory events to chronic progressive disease. JAK 1, JAK 2 and TYK 2 play an important role in signaling mediated by I FNy, a cytokine associated with the chronic inflammation observed in COPD, which modulates the activity of T cells, epithelium and macrophages whilst not being modulated by corticosteroids.

[0123] Macrophage phagocytosis of bacteria is impaired in the lungs of COPD patients, potentially in part due to high local I FNy levels. In vitro studies with isolated patient cells have shown that JAK inhibitors increase phagocytotic rate in the presence of I FNy. Consequently, as well as exerting a direct anti-inflammatory effect, JAK inhibitors may also increase the ability of the lung to maintain a sterile environment.

[0124] JAK inhibitors therefore have utility in the treatment of a range of inflammatory diseases, including lung diseases such as COPD, asthma and pulmonary vascular disease. Compounds which have a broad inhibitory activity across the range of Janus kinases, in particular, are likely to have a potent anti-inflammatory effect. However, such a selectivity profile can also lead to undesirable side-effects in systemically circulating compounds, particularly anemia and neutropenia associated with JAK 2 inhibition. For the treatment of lung diseases, it is therefore particularly favorable to provide JAK inhibitors which can be administered by inhalation and which inhibit Janus kinases locally in the lung without having a significant systemic exposure.

[0125] There is thus a need to provide new JAK inhibitors that are potent, selective inhibitors of Janus kinases with appropriate metabolic stability and pharmacokinetic properties, particularly compounds which can be administered by inhalation and are active in lung tissue whilst having poor systemic penetration or high systemic lability. [0126] In other embodiments, the disease and/or condition is inflammation (including neuroinflammation), arthritis (including rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous arthritis, osteoarthritis and gouty arthritis), pain, fever, pulmonary sarcoisosis, silicosis, cardiovascular disease (including atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury), cardiomyopathy, stroke, ischemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (including type 1 and type 2 diabetes), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis and sunburn.

[0127] In other embodiments, the disease is an inflammatory disease, e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. In another embodiment, the mammal is suffering from inflammatory skin disease which includes, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring psoriatic lesions in the skin, joints, or other tissues or organs. In another embodiment, the inflammatory disease is asthma or dermatitis.

[0128] In other embodiments, the disease and/or condition is an autoimmune disease, e.g., inflammatory bowel disease, arthritis, lupus including Lupus Nephritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, granulomatosis with polyangiitis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, dry eye (including Sjogren's dry eye and non-Sjogren's dry eye), multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, pemphigus such as pemphigus vulgaris and/or foliaceus, bullous pemphigoid, age-related macular degeneration (wet and dry), diabetic macular edema, corneal transplantation, abdominal aortic aneurysm, mucous membrane pemphigoid, or vulvodynia.

[0129] In other embodiments, the disease is a hetero-immune condition or disease, e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis. In another embodiment, the disease is atopic dermatitis.

[0130] In other embodiments, the disease is acute inflammatory and/or autoimmune disease, where corticosteroid therapy is used as the first- or second-line therapy or first- or second-line maintenance therapy.

[0131] In other embodiments, the disease is acute necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia areata, alopecia universalis, amyloidosis, ankylosing spondylitis, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS), antiphospholipid antibody syndrome, aplastic anemia, arthritis, autoimmune angioedema, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, autoimmune hemolytic anemia, axonal & neuronal neuropathies, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, coeliac disease, Cogans syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, Crohn's disease, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), diabetes, discoid lupus, Dressier's syndrome, dry eye, dysautonomia, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, experimental allergic encephalomyelitis, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, lgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, interstitial cystitis, juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), lupus including lupus nephritis, lyme disease, chronic, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), mooren's ulcer, Mucha-Habermann disease, mucous membrane pemphigoid, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyotonia, neutropenia, ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, osteoarthritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, pemphigus such as pemphigus vulgaris, pemphigus foliaceus, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis, psoriaticarthritis, pure red cell aplasia, pyoderma gangrenosum, raynauds phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, stiff person syndrome, Still's disease, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/Giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, Type I, II, & III autoimmune polyglandular syndromes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, vulvodynia, or lupus.

[0132] In other embodiments, the disease is cancer. In some embodiments, the cancer is a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, chromic myleogenous leukemia, B-cell acute lymphoblastic leukemia (B-ALL), Philadelphia chromosome positive B- ALL, B-cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B- cell non-Hodgkin lymphoma, lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis.

[0133] In general, the compounds of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In one embodiment, the dosage level will be about 0.1 to about 250 mg/kg per day. In another embodiment the dosage level will be about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 1000 mg of the active ingredient, particularly about 1.0g, 5.0g, 10g, 15g, 20g, 25g, 50g, 75g, 100g, 150g, 200g, 250g, 300g, 400g, 500g, 600g, 750g, 800g, 900g, and 1000g of the active ingredient. The actual amount of the compound, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.

[0134] The amount of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, in a formulation may vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %.

[0135] Compounds of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, may be administered as pharmaceutical compositions by any suitable route of administration, including, but not limited to oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous), topical (e.g. to the lung, eye or intestines), and the like.

[0136] In some embodiments pharmaceutical formulations are adapted for topical administration. Such formulations include those in which the excipients (including any adjuvant, diluent and/or carrier) are topically acceptable.

[0137] Topical administration to the lung may be achieved by use of an aerosol formulation. Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (H FC). Suitable CFC propellants include trichloromonofluoromethane (propellant 11), dichlorotetrafluoroethane (propellant 114), and dichlorodifluoromethane (propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (H FC-227). The propellant typically comprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalation composition. The formulation may comprise excipients including co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Other possible excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine and the like. Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari).

[0138] Topical administration to the lung may also be achieved by use of a nonpressurized formulation such as an aqueous solution or suspension. This may be administered by means of a nebulizer e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable). The formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents. Suspension liquid and aerosol formulations (whether pressurized or unpressurised) will typically contain the compound of the invention in finely divided form, for example with a Dsoof 0.5-10 pm e.g. around 1-5 pm. Particle size distributions may be represented using Dio, Dso and D90 values. The D50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half. The measurement derived from laser diffraction is more accurately described as a volume distribution, and consequently the D50 value obtained using this procedure is more meaningfully referred to as a Dvso value (median for a volume distribution). As used herein Dv values refer to particle size distributions measured using laser diffraction. Similarly, Dioand D90 values, used in the context of laser diffraction, are taken to mean Dvio and DV90 values and refer to the particle size whereby 10% of the distribution lies below the Dw value, and 90% of the distribution lies below the D90 value, respectively.

[0139] Topical administration to the lung may also be achieved by use of a dry-powder formulation. A dry powder formulation will contain the compound of the disclosure in finely divided form, typically with a mass mean aerodynamic diameter (MMAD) of 1-10 pm or a Dsoof 0.5-10 pm e.g. around 1-5 pm. Powders of the compound of the invention in finely divided form may be prepared by a micronization process or similar size reduction process. Micronization may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument). The formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), usually of large particle size e.g. an MMAD of 50 pm or more, e.g. 100 pm or more or a D50 of 40-150 pm. As used herein, the term "lactose" refers to a lactose-containing component, including a-lactose monohydrate, P-lactose monohydrate, a-lactose anhydrous, -lactose anhydrous and amorphous lactose. Lactose components may be processed by micronization, sieving, milling, compression, agglomeration or spray drying. Commercially available forms of lactose in various forms are also encompassed, for example Lactohale® (inhalation grade lactose; DFE Pharma), lnhaLac®70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose® (sieved inhalation grade lactose; DFE Pharma) products. In one embodiment, the lactose component is selected from the group consisting of a-lactose monohydrate, a-lactose anhydrous and amorphous lactose. Preferably, the lactose is a-lactose monohydrate.

[0140] Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate.

[0141] A dry powder formulation is typically delivered using a dry powder inhaler (DPI) device. Examples of dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. Further examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

[0142] In one embodiment a compound of formula (I), or of a compound of formula (II), or of any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, is provided in a micronized dry powder formulation, for example further comprising lactose of a suitable grade optionally together with magnesium stearate, filled into a single dose device such as AEROLISER or filled into a multi dose device such as DISKUS.

[0143] The compounds disclosed herein can be synthesized using standard synthetic techniques known to those of skill in the art. For example, compounds of the present disclosure can be synthesized using the general synthetic procedures set forth in Schemes 1-4.

[0144] Modifications to these methods will be apparent to one skilled in the art. To this end, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation^] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed.

[0145] Unless otherwise indicated, conventional methods of mass spectroscopy (MS), liquid chromatography-mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March's Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-lnterscience. (2006). All starting materials and reagents are commercially available or readily prepared.

[0146] In some embodiments, compound of formula (I) wherein LI is C(O) are synthesized according to Scheme 1.

Scheme 1

[0147] In some embodiments, treatment of Al with a carboxylic acid derivative Bl using standard amide coupling conditions (e.g. involving a coupling agent such as HATU or T3P, optionally in the presence of a base such as DIEPA or TEA, and in a suitable solvent such as DMF or THF) will directly afford amide derivative DI. Alternatively, the OH of Bl may first be converted to a suitable leaving group (LG) such as a halogen or sulfonate, to give Cl. Subsequent reaction of Cl with Al in the presence of a base (such as TEA, DIEA, NaHCOs, or K2CO3) and in the presence of a suitable solvent (such as DCM, THF, or DMF), with or without an activating agent (such as DMAP), and with or without heating will afford DI. Alternatively, treatment of Al with El (wherein LG represents a leaving group which is displaced preferentially before leaving group LG¹) in the presence of a base (such as TEA or DIEA) and in the presence of a suitable solvent (such as DCM, THF, or DMF), with or without an activating agent (such as DMAP), and with or without heating will afford amide-derivative Fl. Subsequent conversion of Fl to DI may be achieved via treatment with 1,4-diazepane derivative G1 using a variety of conditions, for example (i) a typical SuAr reaction in the presence of a suitable base (such as TEA or DIEA) and in a suitable solvent (such as THF, DMF, or DMSO), with or without an activating agent (such as DMAP), and with or without heating, or (ii) a Buchwald-Hartwig coupling employing a suitable transition metal catalyst (such as palladium), a suitable ligand (such as BINAP, dppf, or BrettPhos), in a suitable solvent (such as THF or toluene) and in the presence of a base (such as sodium tert-butoxide or potassium tert-butoxide, with heating (J. Am. Chem. Soc. 2008, 130, 13552 - 13554).

[0148] In some embodiments, compound of formula (I), wherein L¹ is S(O)2, are synthesized according to Scheme 2.

Scheme 2

[0149] In some embodiments, treatment of Al with B2 in the presence of a base (such as TEA, DIEA, NaHCCh, or K2CO3) and in the presence of a suitable solvent (such as DCM, THF, or DMF), with or without an activating agent (such as DMAP), and with or without heating will afford sulfonamide derivative C2. Alternatively, treatment of Al with D2 (wherein the chloride of sulfonyl chloride is displaced preferentially before leaving group LG¹) in the presence of a base (such as TEA or DIEA) and in the presence of a suitable solvent (such as DCM, THF, or DMF), with or without an activating agent (such as DMAP), and with or without heating will afford amide-derivative E2. Subsequent conversion of E2 to C2 may be achieved via treatment with 1,4-diazepane derivative G1 using a variety of conditions, as previously described above (Scheme 1).

[0150] In some embodiments, compound of formula (I), wherein L¹ is CH2, are synthesized according to Scheme 3.

[0151] In some embodiments, treatment of Al with aldehyde derivative B3 in the presence of a suitable reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride), in a suitable solvent (such as THF, DMF, or 1,2-dichloroethane), and optionally in the presence of acetic acid, will afford D3. Alternatively, treatment of Al with C3 (wherein LG represents a leaving group such as halogen or sulfonate) in the presence of a base (such as TEA or DIEA), in a suitable solvent (such as DCM, THF, or DMF), with or without an activating agent (such as DMAP), and with or without heating will afford D3. Alternatively, D3 may be prepared as follows. Treatment of Al with aldehyde E3 in the presence of a suitable reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride), in a suitable solvent (such as THF, DMF, or 1,2-dichloroethane), and optionally in the presence of acetic acid, will afford F3. Subsequent conversion of F3 to D3 may be achieved via treatment with 1,4-diazepane derivative G1 using a variety of conditions, as previously described above (Scheme 1).

[0152] In some embodiments, compound of formula (I), wherein L¹ is a bond, are synthesized according to Scheme 4. Scheme 4

[0153] In some embodiments, treatment of Al with B4 (wherein Z = Cl, Br, I, or OTf) via a Buchwald-Hartwig coupling, employing a suitable transition metal catalyst (such as palladium), a suitable ligand (such as BINAP, dppf, or BrettPhos), in a suitable solvent (such as THF or toluene) and in the presence of a base (such as sodium tert-butoxide or potassium tert- butoxide, with heating affords C4.

[0154] The invention is further illustrated by the following examples. The examples below are non-limiting are merely representative of various aspects of the invention. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated. The following examples were prepared according to the methods described in Schemes 1 through 4 using the appropriately substituted or modified intermediates.

EXAMPLE 1

Synthesis of [2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-lH-indazol-3-yl]-3,4,6,7- tetrahydroimidazo[4,5-c]pyridin-5-yl]-[5-(4-methyl-l,4-diazepan-l-yl)pyrazin-2-yl] methanone (Compound 1)

Compound 1

Step 1: Methyl 5-(4-methyl-l,4-diazepan-l-yl)pyrazine-2-carboxylate

[0155] To a stirred solution of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and l-methyl-l,4-diazepane (728 mg, 6.37 mmol) in DMF (20 mL) at rt, was added TEA (2.42 mL, 17.38 mmol). The mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was purified (CombiFlash reverse-phase chromatography; eluting with a mixture of MeOH and water) to afford methyl 5-(4-methyl-l,4- diazepan-l-yl)pyrazine-2-carboxylate (1.18 g, 77%) as a yellow solid. ¹H NMR (300 MHz, DMSO- d₆) 6 8.64 (s, 1H), 8.22 (s, 1H), 3.71 - 3.81 (m, 7H), 2.61 - 2.64 (m, 2H), 2.48 - 2.50 (m, 2H), 2.25 (s, 3H), 1.83 - 1.91 (m, 2H); LCMS (ESI) m/z = 251.1 (M+H). Step 2: 5-(4-methyl-l,4-diazepan-l-yl)pyrazine-2-carboxylic acid

[0156] To a stirred solution of methyl 5-(4-methyl-l,4-diazepan-l-yl)pyrazine-2- carboxylate (1.18 g, 4.71 mmol) in THF (30 mL) and water (10 mL) was added lithium hydroxide (339 mg, 14.14 mmol). The mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and the pH was adjusted to 3 - 4 with IN hydrochloric acid. Methanol (5 mL) was added and the resulting solution was purified (CombiFlash reverse-phase chromatography; eluting with 5% acetonitrile in water) to afford 5-(4-methyl-l,4-diazepan-l- yl)pyrazine-2-carboxylic acid (2.20 g, 98%) as a yellow oil. ^TH NMR (300 MHz, DMSO-de) 6 8.66 (s, 1H), 8.25 (s, 1H), 3.95 - 4.05 (m, 2H), 3.73 - 3.77 (m, 2H), 2.93 - 3.07 (m, 4H), 2.60 (s, 3H), 2.13 - 2.23 (m, 2H); LCMS (ESI) m/z = 237.1 (M+H).

Step 3: [2-[6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-lH-indazol-3-yl]-3,4,6,7- tetrahydroimidazo [4,5-c]pyridin-5-yl]-[5-(4-methyl-l,4-diazepan-l-yl)pyrazin-2- yllmethanone (Compound 1)

Compound 1

[0157] To a stirred solution of 5-(4-methyl-l,4-diazepan-l-yl)pyrazine-2-carboxylic acid (571 mg, 2.42 mmol), HATU (345 mg, 906 irnol) and DIEA (316 L, 1.81 mmol) in DMF (10 mL) at rt under an inert atmosphere, was added 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-3H- imidazo[4,5-c]pyridin-2-yl)-lH-indazol-6-yl]phenol (prepared according to procedures described in WO2013/014567) (272 mg, 604 pmol). The mixture was stirred at rt for 3 h. The reaction mixture was filtered, and the filtrate purified (Reverse-phase preparative HPLC; eluting with acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) to afford Compound 1 (97 mg, 26%) as an off-white solid. ¹H NMR (400 MHz, MeOH-cU) 6 8.46 (s, 1H), 8.17 - 8.30 (m, 1H), 8.13 (s, 1H), 7.39 (s, 1H), 7.10 - 7.20 (m, 1H), 6.86 - 6.91 (m, 2H), 4.80 - 4.90 (m, 2H), 4.01 - 4.12 (m, 2H), 3.90 - 3.93 (m, 2H), 3.77 - 3.81 (m, 2H), 2.89 - 2.99 (m, 2H), 2.78 - 2.80 (m, 2H), 2.64 - 2.67 (m, 2H), 2.48 - 2.54 (m, 2H), 2.39 (s, 3H), 2.01 - 2.08 (m, 2H), 1.05 (t, 3H); LCMS (ESI) m/z = 596.2 (M+H).

EXAMPLE 2

Synthesis of 5-ethyl-2-fluoro-4-[3-[5-[[5-(4-methyl-l,4-diazepan-l-yl)pyrazin-2-yl]methyl]-

3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl]-lH-indazol-6-yl]phenol (Compound 2)

Compound 2

Step 1: (5-chloropyrazin-2-yl)methanol

0 °C

[0158] To a stirred solution of methyl 5-chloropyrazine-2-carboxylate (20 g, 116 mmol) in methanol (240 mL) at 0 °C, was added sodium borohydride (8.77 g, 232 mmol) in portions. The resulting mixture was stirred at 0 °C for 1 h. Water (50 mL) was added dropwise and the resulting mixture was extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified (silica gel; eluting with petroleum ether/ethyl acetate, 7:3) to afford (5-chloropyrazin-2-yl)methanol (8.70 g, 52%) as a light yellow solid. ^TH NMR (400 MHz, DMSO-d₆) 6 8.20 (s, 1H), 8.51 (s, 1H), 5.68 (t, J = 8.0 Hz, 1H), 4.62 (d, J = 8.0 Hz, 1H); LCMS (ESI) m/z = 145.2 (M+H).

Step 2: 5-chloropyrazine-2-carbaldehvde

DMP

RT

[0159] To a stirred solution of (5-chloropyrazin-2-yl)methanol (10.4 g, 71.94 mmol) in dichloromethane (100 mL) at rt, was added Dess-Martin periodinane (61.03 g, 143.89 mmol). After stirring for 2 h at rt, water (50 mL) was added dropwise. The resulting mixture was extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified (silica gel; eluting with petroleum ether/ethyl acetate, 7:3) to afford 5- chloropyrazine-2-carbaldehyde (5.96 g, 58%) as a yellow solid. ¹H NMR (400 MHz, DMSO-de) 6 10.05 (s, 1H), 9.02 (s, 1H), 8.96 (s, 1H).

Step 3: 4-[3-[5-[(5-chloropyrazin-2-yl)methyl1-3,4,6,7-tetrahvdroimidazo[4,5-c1pyridin-2- yl]-lH-indazol-6-yl]-5-ethyl-2-fluoro-phenol

[0160] To a stirred suspension of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-3H- imidazo[4,5-c]pyridin-2-yl)-lH-indazol-6-yl]phenol (prepared according to the procedures described in WO2013/014567) (3.87 g, 8.60 mmol) in DMF (30 mL), were added DIEA (1.63 mL, 9.35 mmol), 5-chloropyrazine-2-carbaldehyde (2.00 g, 14.03 mmol) and acetic acid (535 pL, 9.35 mmol). After stirring at room temperature for 1 h, sodium triacetoxyborohydride (5.95 g, 28.06 mmol) was added in portions over a period of 1 hr. The reaction mixture was stirred for another 15 h at rt. Water (50 mL) was added dropwise and the resulting mixture was extracted with ethyl acetate (x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified (silica gel; eluting with DCM/Methanol, 4:1) to afford 4-[3-[5-[(5-chloropyrazin-2-yl)methyl]- 3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl]-lH-indazol-6-yl]-5-ethyl-2-fluoro-phenol (3.70 g, 78%) as a yellow solid. ^XH NMR (400 MHz, DMSO-d₆) 6 13.16 (s, 1H), 12.36 (brs, 1H), 9.84 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.28 - 8.34 (m, 1H), 7.37 (s, 1H), 6.99 - 7.08 (m, 2H), 6.88 - 6.91 (m, 1H), 4.62 (s, 1H), 4.08 - 4.12 (m, 1H), 3.91 (s, 2H), 3.15 (s, 2H), 2.82 - 2.86 (m, 2H), 2.65 - 2.71 (m, 2H), 0.97 - 1.02 (m, 3H); LCMS (ESI) m/z = 504 (M+H).

Step 4: 5-ethyl-2-fluoro-4-[3-[5-[[5-(4-methyl-l,4-diazepan-l-yl)pyrazin-2-yl]methyl]- 3,4,6,7-tetrahvdroimidazo[4,5-c]pyridin-2-yl]-lH-indazol-6-yl]phenol (Compound 2)

[0161] To a solution of 4-[3-[5-[(5-chloropyrazin-2-yl)methyl]-3,4,6,7-tetrahydroimidazo- [4,5-c]pyridin-2-yl]-lH-indazol-6-yl]-5-ethyl-2-fluoro-phenol (200 mg, 397 pmol) in NMP (5 mL) under an inert atmosphere, were added l-methyl-l,4-diazepane (68 mg, 595 pmol) and DIEA (207 pL, 1.19 mmol). The resulting mixture was stirred at 120 °C for 18 h. After cooling to rt, water (50 mL) was added. The mixture was extracted with ethyl acetate (x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by trituration with methanol/acetonitrile and further purified (CombiFlash reverse-phase chromatography; eluting with acetonitrile/water) to afford Compound 2 (101 mg, 38%) as a light yellow solid. ^TH NMR (300 MHz, DMSO-d₆) 6 13.16 (s, 1H), 12.23 - 12.34 (m, 1H), 9.85 (brs, 1H), 8.28 - 8.34 (m, 1H), 8.09 (s, 2H), 7.36 (s, 1H), 6.90 - 7.10 (m, 3H), 3.61 - 3.76 (m, 6H), 3.48 - 3.53 (m, 2H), 2.80 - 2.92 (m, 2H), 2.59 - 2.70 (m, 4H), 2.37 - 2.50 (m, 4H), 2.26 (s, 3H), 1.88 - 1.95 (m, 2H), 1.01 (t, 3H); LCMS (ESI) m/z = 582.0 (M+H). EXAMPLE 3

Synthesis of 5-ethyl-2-fluoro-4-[3-[5-[[6-(4-methyl-l,4-diazepan-l-yl)pyrazin-2-yl]methyl]- 3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl]-lH-indazol-6-yl]phenol (Compound 3)

Compound 3

Step 1: (6-chloropyrazin-2-yl)methanol

0 °C

[0162] A suspension of methyl 6-chloropyrazine-2-carboxylate (1.5 g, 2.90 mmol) in water (10 mL) was cooled to 0 °C. Sodium borohydride (548 mg, 14.49 mmol) was added in portions. The mixture was allowed to warm to rt and stirred for a further 16 h. Water (50 mL) was added dropwise and the mixture was extracted with ethyl acetate (x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified (silica gel; eluting with petroleum ether/ethyl acetate, 4:1) to afford compound 3-b (137 mg, 33%) as a light yellow solid. ^XH NMR (400 MHz, DMSO-d₆) 6 8.70 (s, 2H), 5.75 (brs, 1H), 4.60 (s, 2H); LCMS (ESI) m/z = 145.2 (M+H).

Step 2: 6-chloropyrazine-2-carbaldehvde

CHCI₃ reflux

[0163] To a solution of (6-chloropyrazin-2-yl)methanol (2.40 g, 16.60 mmol) in chloroform (10 mL) at rt, was added MnCh (11.55 g, 132.82 mmol) in one portion and the mixture stirred for 20 h at 75 °C (maintaining gentle reflux). After cooling to room temperature, DCM (50 mL) was added and the resulting mixture filtered. The filtrate was concentrated under reduced pressure and purified (silica gel; eluting with petroleum ether/ethyl acetate, 9:1) to afford 6-chloropyrazine-2-carbaldehyde (1.30 g, 51%) as a yellow oil. ^TH NMR (300 MHz, DMSO- d₆) 6 10.00 (s, 1H), 9.15 (s, 2H).

Step 3: 4-[3-[5-[(6-chloropyrazin-2-yl)methyl1-3,4,6,7-tetrahvdroimidazo[4,5-c1pyridin-2- yl]-lH-indazol-6-yl]-5-ethyl-2-fluoro-phenol

2) Na(OAc)₃BH, RT, overnight

[0164] To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-lH-indazol-6-yl]phenol (prepared according to the procedures described in WO2013/014567) (2.57 g, 5.70 mmol) in DMF (20 mL) at rt, were added DIEA (993 pL, 5.70 mmol), acetic acid (326 pL, 5.70 mmol) and 6-chloropyrazine-2-carbaldehyde (3-c) (1.30 g, 9.12 mmol). The mixture was stirred at rt for 1 h. Sodium triacetoxyborohydride (3.62 g, 17.10 mmol) was added, and the resulting mixture was stirred for 17 h at rt. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue purified (silica gel; eluting with DCM/MeOH, 9:1) to afford 4-[3-[5-[(6-chloropyrazin-2-yl)methyl]-3,4,6,7-tetrahydroimidazo- [4,5-c]pyridin-2-yl]-lH-indazol-6-yl]-5-ethyl-2-fluoro-phenol (2.10 g, 68%) as a light yellow solid. ^TH NMR (300 MHz, DMSO-d₆) 6 13.18 (s, 1H), 12.39 (brs, 1H), 9.84 (s, 1H), 8.69 - 8.77 (m, 2H), 8.30 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 12.0 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 3.94 (s, 2H), 3.61 (s, 2H), 3.82 - 3.90 (m, 2H), 3.70 - 3.76 (m, 2H), 2.44 - 2.50 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

Step 4: 5-ethyl-2-fluoro-4-[3-[5-[[6-(4-methyl-l,4-diazepan-l-yl)pyrazin-2-yl]methyl]-

3,4,6,7-tetrahvdroimidazo[4,5-c]pyridin-2-yl]-lH-indazol-6-yl]phenol (Compound 3)

Compound 3

[0165] To a solution of 4-[3-[5-[(6-chloropyrazin-2-yl)methyl]-3,4,6,7-tetrahydroimidazo- [4,5-c]pyridin-2-yl]-lH-indazol-6-yl]-5-ethyl-2-fluoro-phenol (250 mg, 496 pmol), l-methyl-1,4- diazepane (141 mg, 1.24 mmol) in NMP (2 mL) at rt and under an inert atmosphere, was added DIEA (259 pL, 1.49 mmol). The resulting mixture was stirred for 40 h at 120 °C. After cooling to rt, water (10 mL) was added. The solids were collected by filtration, triturated with methanol (20 mL) and then filtered. The filtrate was concentrated under reduced pressure to give Compound 3 (136 mg, 41%) as a light-brown solid. ¹H NMR (400 MHz, DMSO-de) 6 13.16 (s, 1H), 12.28 - 12.35 (m, 1H), 9.84 (brs, 1H), 8.31 (m, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.36 (s, 1H), 7.00 - 7.08 (m, 2H), 6.91 (d, 1H), 3.55 - 3.76 (m, 8H), 2.82 - 2.86 (m, 2H), 2.60 - 2.68 (m, 4H), 2.47 - 2.51 (m, 4H), 2.26 (s, 3H), 1.80 - 1.90 (m, 2H), 0.92 - 1.03 (m, 3H); LCMS (ESI) m/z = 582.0 (M+H). EXAMPLES 4-27

[0166] Compounds 4-27 listed in Table 2 below may be prepared according to the methods described in Schemes 1 through 4, and Examples 1 through 3, as shown herein using the appropriately substituted or modified intermediates.

Table 2

No. Structure Name

c]pyridin-5-yl)methanone No. Structure Name

(2-(6-(2- th l-5-fl -4-h d h l)-

No. Structure Name

No. Structure Name

BIOLOGICAL ASSAYS

[0167] The compounds described herein were tested in various assays as described below. Compound PF06263276 (see Coe, et al, WO2013/014567 and Jones, et al, J. Med. Chem. 2017, 60, 767 - 786) was used as a comparative reference (Ref).

Reference Compound (Ref)

EXAMPLE 28

Human JAK1, JAK2, JAK3, and TYK2 Biochemical Inhibition Assays

[0168] Compounds described herein were tested for the ability to inhibit activity of human JAK1, JAK2, JAK3, and TYK2 which was achieved using TR-FRET assays. Briefly, the Kinases (JAK1, JAK2, JAK3 and TYK2) were incubated with a series of concentrations of the test compound for 30 min at RT. ATP solution was added to start the reaction, and incubated for 80 min at RT. The reaction was stopped by adding detection buffer and incubated for a further 60 min at RT. The samples were analyzed using Envision to calculate % inhibition at each of the series of concentrations of the test compound. The I Cso value of the compounds for each of the kinases were calculated using XLFit software and is shown in table 3. Table 3

ICso (nM)

Cpd. No. JAK1 JAK2 JAK3 TYK2

Ref 0.2 0.12 0.16 0.68

1 0.02 0.01 0.02 0.09

2 0.03 0.01 0.02 0.23

3 0.04 0.02 0.02 0.88

EXAMPLE 29

Human Primary Cell Assays

[0169] Compounds described herein were tested for inhibition activity in the following cellular assays; the results are shown in Table 4.

Inhibition of pSTAT5 from IL-2 Stimulated Human PBMC Cells

[0170] Inhibition of IL-2 induced phosphorylation of STAT5 in human PBMCs was measured using FACS analysis. Briefly, human PBMCS (isolated from Leukopaks) were seeded in 96 well plates in completed RPMI media (Gibco, Cat#11875-093). Cells were treated with a series of concentrations of the test compound for 60 min at 37 °C. The cells were then stimulated with recombinant human IL-2 (RnD systems; Cat#202-IL/CF) at 5ng/ml for 15 min at 37 °C. The cells were fixed using fixation buffer (Biolegend, Cat#420801) and washed, followed by permeabilization using Perm Buffer III (BD Bioscience, #558050) treatment for 30 min at 4 °C. Cells were washed with FACS buffer and treated with Fc block (Biolegend, Cat#422302), pSTAT5 antibody (BD Biosciences, Cat#612598) and CD3 antibody (BD Biosciences, Cat#336412) overnight at 4 °C. The phosphorylation of STAT5 was measured using FACS analysis. The pSTAT5 signal was normalized to control and plotted vs log dose, to calculate the IC50 value of the compound.

Inhibition of pSTAT5 from TPO Stimulated Human Platelet Cells

[0171] Inhibition of TPO induced phosphorylation of STAT5 in human platelets was measured using FACS analysis. Briefly, human Platelets (AllCells, CA) were seeded in 96 well plates in completed RPMI media (Gibco, Cat#11875-093). Cells were treated with a series of concentrations of the test compound for 60 min at 37 °C. The cells were then stimulated with recombinant human TPO (PeproTECH; Cat#300-18) at 2ng/ml for 15 min at 37 °C. The cells were fixed using fixation buffer (Biolegend, Cat#420801) and washed, followed by permeabilization using Perm Buffer III (BD Bioscience, #558050) treatment for 30 min at 4 °C. Cells were washed with FACS buffer and stained with a cocktail of with Fc block (Biolegend, Cat#422302), pSTAT5- AF488 antibody (BD, Cat#612598) and CD61-APC antibody (Biolegend, Cat#336412) for 30 min at 4 °C. The phosphorylation of STAT5 was measured using FACS analysis. The pSTAT5 signal was normalized to control and plotted vs log dose, to calculate the IC50 value of the compound.

Inhibition of pSTATl from IFNa Stimulated Human PBMC Cells

[0172] Inhibition of IFNa induced phosphorylation of STAT1 in human PBMCs was measured using FACS analysis. Briefly, human PBMCs (isolated from Leukopaks) were seeded in 96 well plates in completed RPMI media (Gibco, Cat#11875-093). Cells were treated with a series of concentrations of the test compound for 60 min at 37 °C. The cells were then stimulated with recombinant human IFNa (PBL Assay Science, Cat#11101-l) at lng/ml for 15 min at 37 °C. The cells were fixed using fixation buffer (Biolegend, Cat#420801) and washed, followed by permeabilization using Perm Buffer III (BD Bioscience, #558050) treatment for 30 min at 4 °C. Cells were washed with FACS buffer and stained with a cocktail of Fc block (Biolegend, Cat#422302), pSTATl- AF488 antibody (BD Biosciences, Cat#612596) and CD45 APC antibody (Biolegend, Cat#368512) for 30 min at RT. The phosphorylation of STAT1 was measured using FACS analysis. The pSTATl signal was normalized to control and plotted vs log dose, to calculate the IC50 value of the compound.

Inhibition of pSTATl from IFNg Stimulated Human PBMC Cells

[0173] Inhibition of IFNg induced phosphorylation of STAT1 in human PBMCs was measured using FACS analysis. Briefly, human PBMCs (isolated from Leukopaks) were seeded in 96 well plates in completed RPMI media (Gibco, Cat#11875-093). Cells were treated with a series of concentration of the test compound for 60 min at 37 °C. The cells were then stimulated with recombinant human IFNg (RnD Systems, Cat#285/IF/CF) at lOng/ml for 15 min at 37 °C. The cells were fixed using fixation buffer (Biolegend, Cat#420801) and washed, followed by permeabilization using Perm Buffer III (BD Bioscience, #558050) treatment for 30 min at 4 °C. Cells were washed with FACS buffer and stained with a cocktail of with Fc block (Biolegend, Cat#422302), pSTATl- AF488 antibody (BD Biosciences, Cat#612596), CD45 PB antibody (Invitroge, Cat#MHCD4528) and CD14 (Biolegend, Cat#367114) for 30 min at RT. The phosphorylation of ST ATI was measured using FACS analysis. The pSTATl signal was normalized to control and plotted vs log dose, to calculate the IC50 value of the compound.

Table 4

Human Primary Cell Activity IC50 (nM)

Cpd. PBMCIL-2: Platelet TPO: PBMC IFNa: PBMC IFNg:

No. pSTAT5 pSTAT5 pSTATl pSTATl

Ref 17 11 10 3.0

1 6.5 6.1 5.4 1.2

2 6.7 8.2 3.6 3.5

3 85 6.2 6.8 6.1

EXAMPLE 30

Determination of in vivo Pharmacokinetic Parameters

[0174] Studies were conducted to investigate both lung and plasma pharmacokinetics and total lung tissue distribution of compounds of the present invention, following inhaled administration to fifteen BALB/C mice (N=3 per time point). Briefly, male BALB/c mice were treated with the nebulized test compound via nose only passive inhalation for 30 min using CH technologies rodent inhalation tower. Blood (for plasma) and lung tissue were harvested at 1 and 4 hours post inhalation treatment. Animals were anesthetized by isoflurane at each time point. The blood samples were collected from mice via cardiac puncture in labeled micro centrifuge tube containing K2EDTA as anticoagulant. Plasma samples were separated by centrifuge at 4°C at 10,000 RPM for 10 minutes and stored below -70°C until bioanalysis. Animals were then euthanized via cervical dislocation to collect lung tissue. Lungs were not perfused for Compound 1 or the Reference Compound). These samples were used to determine concentrations in both plasma and lung tissue. Compound 1 and the Reference Compound were separately formulated as a solution in 2.5% Solutol HS15/2.5% 2-pyrrolidone in DI water. Aerosol concentration and PSD was measured during dosing using a 7-stage Mercer impactor. Samples were processed for analysis by protein precipitation using acetonitrile and analyzed with a fit-for-purpose LC-MS/MS method. The results are shown in Tables 5 and 6.

Table 5

Target aerosol concentrations and dose levels

„ , . ... _P Aerosol Expected Dose Expected Dose

Cpd. No. MMAD „ ,, ,

Cone mg/kg body weight mg/kg Lung

1 2.7 pm 12.8 pg/L 0.4 3.00

Ref 2.7 pm 9.5 pg/L 0.3 3.00t

Table 6

PK Parameters in mice post 30 min inhaled administration

EXAMPLE 31

Solubility Determination

[0175] Studies were conducted to investigate the aqueous solubility of compounds of the present invention. To 5 mg of compound, 0.1 mL of water containing 0.002% tyloxapol as a wetting agent was added, followed by 1 molar ratio of 1 N HCI, the mixture was mixed and sonicated in a sonicator bath to evaluate solubility. If the compound did not dissolve, an additional 1 mol ratio of 1 N HCI was added (no further acid was added if compound did not dissolve). Then an additional 0.1 mL of water containing 0.002% tyloxapol was added and pH adjusted to ~ 5-6 with 1 N NaOH and solubility was assessed visually to ensure no precipitation or cloudiness was observable. Table ?

Solubility (mg/mL) at indicated pH

Cpd. No. Solubility mg/mL Ref <1 (pH 4-7)

1 > 15 (pH 5)

2 > 20 (pH 5)

3 < 5 (pH 5)

[0176] The various embodiments described herein may be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the abovedetailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:

X is F or Cl;

Ak is Ci-6 alkyl optionally substituted by 1, 2 or 3 fluorine atoms; n is 1 or 2;

Q is a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms;

L¹ is C(O), S(O)₂, CH₂ or a bond;

L² is a bond, Ci-6 alkylene, C3-6 cycloalkylene, C4-6 heterocycle containing 1 N or

C4-9 heterospirocycle containing 1 N;

R¹ is H, C1-3 alkyl, OH, OMe, NH₂, NMe or NMe₂;

R² is H or Me;

R³ is H or Me; or R² and R³ together with a C atom to which they are both attached form a

C3-4 cycloalkyl.

2. The compound of claim 1, wherein X is F.

3. The compound of claim 1, wherein Ak is methyl or ethyl.

4. The compound of claim 2, wherein Ak is ethyl.

5. The compound of claim 1, wherein n is 1.

6. The compound of claim 1, wherein n is 2.

7. The compound of claim 1, wherein Q is a 6-membered heteroaromatic ring containing 2 nitrogen atoms.

8. The compound of claim 1, wherein Q is pyrazine.

9. The compound of claim 8, wherein L¹ and the 1,4-diazepane are positioned meta to each other.

10. The compound of claim 8, wherein L¹ and the 1,4-diazepane are positioned para to each other.

11. The compound of claim 1, wherein L¹ is C(O).

12. The compound of claim 1, wherein L² is methylene, ethylene, n-propylene or /-propylene.

13. The compound of claim 12, wherein R¹ is H.

14. The compound of claim 1, wherein L² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

15. The compound of claim 14, wherein R¹ is H.

16. The compound of claim 1, wherein L² is azetidine, pyrrolidine or piperidine.

17. The compound of claim 16, wherein R¹ is H or Me.

57

18. The compound of claim 1, wherein L² is C4-6 heterospirocycle containing 1

N atom.

19. The compound of claim 1, wherein R¹ is H or Me and L² is

20. The compound of claim 1, wherein R¹ is H or C1-3 alkyl.

21. The compound of claim 1, wherein R¹ is Me.

22. The compound of claim 1, wherein R¹ is OH, OMe, NH2, NMe or NMez.

23. The compound of claim 1, wherein R² is H and R³ is H.

24. The compound of claim 1, wherein R² is H and R³ is Me.

25. The compound of claim 1, wherein R² is Me and R³ is Me.

26. The compound of claim 1, wherein R² and R³ together with the C atom to which they are both attached form cyclopropyl or cyclobutyl.

28. A compound, having the structure:

29. A compound, having the structure:

30. A compound having the structure of formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:

L¹ is C(O) or CH₂;

L² is a bond, C1-6 alkylene, C3-6 cycloalkylene, C4-6 heterocycle containing 1 N or

C4-9 heterospirocycle containing 1 N; and

R¹ is H, C1-3 alkyl, OH, OMe, NH₂, NMe or NMe₂.

31. The compound of claim 30, wherein L¹ is C(O).

32. The compound of claim 30, wherein L¹ is CH2.

33. The compound of claim 30, wherein R¹ is H or C1-3 alkyl.

34. The compound of claim 30, wherein R¹ is Me.

35. A compound having a structure listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

36. A pharmaceutically acceptable salt of a compound of any one of claims 1- 35.

37. A pharmaceutical composition comprising a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

38. The pharmaceutical composition of claim 37, further comprising a pharmaceutically acceptable carrier, adjuvant or vehicle.

39. A method of inhibiting one or more JAK enzymes, comprising contacting the JAK enzyme with an effective amount of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

40. A method of treating or preventing an inflammatory disease, comprising administering an effective amount of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

41. The method of claim 40, wherein the inflammatory disease is cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis, COPD, chronic bronchitis, emphysema, asthma, paediatric asthma, atopic dermatitis, allergic dermatitis, contact dermatitis or psoriasis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, diabetic retinopathy, macular oedema, diabetic macular oedema, central retinal vein occlusion (CRVO),

60 dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, uveitis (including posterior, anterior and pan uveitis), corneal graft and limbal cell transplant rejection, gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease, Crohn's disease or ulcerative colitis.

42. A method of sensitizing a subject to the anti-inflammatory effects of a corticosteroid, comprising administering to the subject an effective amount of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

43. The method of claim 42, wherein the subject is refractory to the antiinflammatory effects of a corticosteroid.

44. Use of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, in the manufacture of a medicament, particularly for treatment of an inflammatory disease.