WO2022178215A1 - Amino amide tetrahydro imidazo pyridines as jak inhibitors - Google Patents

Amino amide tetrahydro imidazo pyridines as jak inhibitors Download PDF

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Publication number
WO2022178215A1
WO2022178215A1 PCT/US2022/016925 US2022016925W WO2022178215A1 WO 2022178215 A1 WO2022178215 A1 WO 2022178215A1 US 2022016925 W US2022016925 W US 2022016925W WO 2022178215 A1 WO2022178215 A1 WO 2022178215A1
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alkyl
group
compound
pharmaceutically
acceptable salt
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PCT/US2022/016925
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French (fr)
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Robert Murray Mckinnell
Tom M. LAM
Cameron Smith
Paul R. Fatheree
Lan Jiang
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Theravance Biopharma R&D Ip, Llc
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Publication of WO2022178215A1 publication Critical patent/WO2022178215A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • asthma An estimated 300 million people worldwide suffer from asthma and it is estimated that the number of people with asthma will grow by more than 100 million by 2025. In the United States, asthma afflicts about 6 % to 8 % of the population, making it one of the most common chronic diseases in the country. Although most patients can achieve control of asthma symptoms with the use of inhaled corticosteroids that may be combined with a leukotriene modifier and/or a long acting beta agonist, there remains a subset of patients with severe asthma whose disease is not controlled by conventional therapies. Severe persistent asthma is defined as disease that remains uncontrolled on high doses of inhaled corticosteroids.
  • Cytokines are intercellular signaling molecules which include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor. Cytokines are critical for normal cell growth and immunoregulation but also drive immune-mediated diseases and contribute to the growth of malignant cells. Elevated levels of many cytokines have been implicated in the pathology of asthma inflammation. For example, antibody-based therapies targeted at interleukins (IL)-5, and 13 have been shown to provide clinical benefit in subsets of severe asthma patients.
  • IL interleukins
  • cytokines implicated in asthma inflammation many act through signaling pathways dependent upon the Janus family of tyrosine kinases (JAKs), which signal through the Signal Transducer and Activator of Transcription (STAT) family of transcription factors.
  • Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon- ⁇ (IFN ⁇ ) and granulocyte-macrophage colony- stimulating factor (GM-CSF).
  • TSLP thymic stromal lymphopoietin
  • IFN ⁇ interferon- ⁇
  • GM-CSF granulocyte-macrophage colony- stimulating factor
  • the JAK family comprises four members, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Binding of cytokine to a JAK-dependent cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the JAK kinase, effecting JAK activation. Phosphorylated JAKs, in turn, bind and phosphorylate various STAT proteins which dimerize, internalize in the cell nucleus and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease.
  • the JAKs usually associate with cytokine receptors in pairs as homodimers or heterodimers. Specific cytokines are associated with specific JAK pairings.
  • Each of the four members of the JAK family is implicated in the signaling of at least one of the cytokines associated with asthma inflammation. Consequently, a chemical inhibitor with pan-activity against all members of the JAK family could modulate a broad range of pro-inflammatory pathways that contribute to severe asthma. However, the broad anti-inflammatory effect of such inhibitors could suppress normal immune cell function, potentially leading to increased risk of infection. Evidence of increased infection risk has been observed with the JAK inhibitor tofacitinib, which is dosed orally for the treatment of rheumatoid arthritis. In asthma, inflammation is localized to the respiratory tract. Inflammation of the airways is characteristic of other respiratory diseases in addition to asthma.
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • pneumonitis interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, and sarcoidosis are also respiratory tract diseases in which the pathophysiology is believed to be related to JAK-signaling cytokines.
  • Local administration of a JAK inhibitor to the lungs by inhalation offers the potential to be therapeutically efficacious by delivering a potent anti-cytokine agent directly to the site of action, limiting systemic exposure and therefore limiting the potential for adverse systemic immunosuppression.
  • JAK-signaling cytokines also play a major role in the activation of T cells, a sub-type of immune cells that is central to many immune processes.
  • Pathological T cell activation is critical in the etiology of multiple respiratory diseases.
  • autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also termed COS). Similar to COS the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipient’s T cells by the transplanted donor lung.
  • Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD).
  • CLAD was previously known as bronchiolitis obliterans (BO) but now is considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction.
  • Chronic lung allograft dysfunction (CLAD) is a major challenge in long-term management of lung transplant recipients as it causes a transplanted lung to progressively lose functionality (Gauthier et al., Curr. Transplant.
  • JAK inhibition has been shown to be effective in kidney transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors have the potential to be effective in treating or preventing lung transplant rejection and CLAD. Similar T cell activation events as described as the basis for lung transplant rejection also are considered the main driver of lung graft-versus-host disease (GVHD) which can occur post hematopoietic stem cell transplants. Similar to CLAD, lung GVHD is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved.
  • JAK inhibitors having good solubility in aqueous solution permitting the development of liquid compositions suitable for nebulized delivery to the lungs.
  • present disclosure provides novel compounds having activity as Janus kinase inhibitors.
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered monocyclic cycloalkyl group, a 4 to 7 membered monocyclic heterocyclic group, -C 1- 6 alkyl-aryl, and -C 1-6 alkyl-heteroaryl, wherein the 3 to 7 membered monocyclic cycloalkyl group, and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO 2 R 3 , -CONR 3 R 4 , OH, SH, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NR 3 R 4 , -OC(O)NR 3 R 4 , -NR 3 C(O)
  • the present disclosure also provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier.
  • the present disclosure also provides a method of treating respiratory disease, in particular, asthma and lung rejection, in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure.
  • the present disclosure also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy, as well as the use of such compound in the manufacture of a formulation or medicament for a treating respiratory disease in a mammal (e.g. a human).
  • the present disclosure provides compounds having activity as a Janus kinase inhibitor. Accordingly, the present disclosure provides a compound of formula (I): or a pharmaceutically-acceptable salt thereof, wherein: R 1 is selected from the group consisting of H, C 1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered monocyclic cycloalkyl group, a 4 to 7 membered monocyclic heterocyclic group, -C 1- 6 alkyl-aryl, and -C 1-6 alkyl-heteroaryl, wherein the 3 to 7 membered monocyclic cycloalkyl group, and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO 2 R 3 , -CONR 3 R 4 , OH, SH, -O-C 1-6 alkyl, -S-C 1-6 al
  • R 2 is C 1-3 alkyl or C 1-3 alkyl-OH or R 1 and R 2 taken together form a 4 to 6 membered monocyclic cycloalkyl group optionally substituted with 1 to 2 substituents independently selected from the group consisting of CN, -CONR 3 R 4 , OH, -O-C 1-3 alkyl, -S-C 1-3 alkyl, and -NR 3 R 4 .
  • R 2 is -CH 3 or -CH 2 -OH or R 1 and R 2 taken together form a cyclopentyl group.
  • the compound, or a pharmaceutically-acceptable salt thereof has the formula (II): In some embodiments, the compound, or a pharmaceutically-acceptable salt thereof, has the formula (III):
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, aryl, a 3 to 5 membered monocyclic cycloalkyl, -CR a R b -heteroaryl, -CR a R b -aryl, and -CR a R b - heterocyclyl, wherein R a and R b are each independently selected from the group consisting of H and C1-4 alkyl, wherein the heterocyclyl is a 5 or 6 membered monocyclic heterocyclic group; wherein the 3 to 5 membered monocyclic cycloalkyl and the -CR a R b -heterocyclyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen,
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, phenyl, a 3 to 5 membered monocyclic cycloalkyl, -CR a R b -heteroaryl, -CR a R b -phenyl, and -CR a R b - heterocyclyl; wherein R a and R b are each independently selected from the group consisting of H and C 1-2 alkyl; wherein the heterocyclyl is a 5 or 6 membered monocyclic heterocyclic group containing 1 or 2 oxygen atoms; wherein the C 1-6 alkyl is optionally substituted with 1 substituent selected from the group consisting of CN, -CONR 3 R 4 , OH, -O-C 1-3 alkyl, -S-C 1-3 alkyl, and -NR 3 R 4 , wherein the phenyl, -CR a R b -phenyl and -CR a R b
  • R 1 is selected from the group consisting of H, C1-4 alkyl, phenyl, - CH 2 -pyrimidinyl, -CH 2 -pyridinyl, -CH 2 -thiophenyl, -CH 2 -imidazolyl, -CH 2 -indolyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 -dioxolanyl, -CH 2 -tetrahydropyranyl, and -CH 2 - phenyl, wherein the C 1-4 alkyl is optionally substituted with 1 substituent selected from the group consisting of CN, OH, SMe, OMe, NH 2 , NMe 2 , and CONH 2 , wherein the imidazolyl is optionally substituted with Me, and wherein the -CH 2 -phenyl is optionally substituted with 1 substituent selected from the group consisting of F, Cl
  • a compound of formula 1 or a pharmaceutically-acceptable salt thereof.
  • a compound of formula 2 or a pharmaceutically-acceptable salt thereof.
  • a compound of formula 3 or a pharmaceutically-acceptable salt thereof.
  • the compounds of the present disclosure may contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like.
  • Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated.
  • the depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated stereochemistry with the understanding that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.
  • the compounds of the present disclosure may also contain several basic groups (e.g., amino groups) and therefore, such compounds can exist as the free base or in various salt forms, such a mono-protonated salt form, a di-protonated salt form, a tri-protonated salt form, etc or mixtures thereof. All such forms are included within the scope of this present disclosure, unless otherwise indicated.
  • This present disclosure also includes isotopically-labeled compounds of formula (I), (II) and (III), i.e., compounds of formula (I), (II) and (III) where one or more atom has been replaced or enriched with an atom having the same atomic number but an atomic mass different from the atomic mass that predominates in nature.
  • isotopes that may be incorporated into a compound of formula (I), (II) and (III) include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, and 18 O.
  • compounds of formula (I), (II) and (III) enriched in tritium or carbon-14 which compounds can be used, for example, in tissue distribution studies.
  • alkyl means a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms.
  • alkyl groups include, by way of example, methyl (Me), ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl (n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t-Bu) or (tBu), n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2- methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like.
  • C 1-3 alkyl means an alkyl group having from 1 to 3 carbon atoms wherein the carbon atoms are in any chemically- acceptable configuration, including linear or branched configurations.
  • amino protecting group means a protecting group suitable for preventing undesired reactions at an amino nitrogen.
  • amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl and tri- fluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), p-nitrobenzyloxycarbonyl (PNZ), 2,4-dichlorobenzyloxycarbonyl, and 5-benzisoxazolylmethoxycarbonyl; arylmethyl groups, such as benzyl (Bn), 4-methoxybenzyl, trityl (Tr), and 1,1-di-(4’-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), [2-(
  • aryl means an aromatic hydrocarbon group having a single ring (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, by way of example, phenyl (i.e., a benzene ring), naphthyl (i.e., a naphthalene ring), and the like. As used herein, the term aryl includes monovalent, divalent or multivalent aryl groups.
  • cycloalkyl means a monovalent saturated carbocyclic group which may be monocyclic or multicyclic.
  • cycloalkyl groups typically contain from 3 to 10 carbon atoms.
  • Representative cycloalkyl groups include, by way of example, cyclopropyl (cPr), cyclobutyl (cBu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • halo means fluoro, chloro, bromo or iodo.
  • heteroaryl means an aromatic group having a single ring or two fused rings and containing in a ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur (i.e., a heteroaromatic group). Unless otherwise defined, such heteroaryl groups typically contain from 1 to 9 carbon atoms and from 3 to 10 total ring atoms.
  • heteroaryl groups include, by way of example, mono-, di- or multivalent species of benzimidazole, benzofuran, benzothiazole, benzothiophene, furan, imidazole, indole, isoquinoline, isothiazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiazole, thiophene, triazole, triazine and the like, where the point or points of attachment are at any available carbon or nitrogen ring atom.
  • heteroaryl includes monovalent, divalent or multivalent heteroaryl groups.
  • heterocyclyl means a monovalent saturated or partially unsaturated cyclic non-aromatic group, having from 3 to 10 total ring atoms, wherein the ring contains from 2 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Heterocyclic groups may be monocyclic or multicyclic (i.e., fused or bridged).
  • heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl, 2-imidazolinyl, tetrahydropyranyl, 1,2,3,4-tetrahydroisoquinolin-2- yl, quinuclidinyl, 7-azanorbornanyl, nortropanyl, and the like, where the point of attachment is at any available carbon or nitrogen ring atom.
  • such groups may alternatively be referred to as a non-valent species, i.e.
  • pharmaceutically acceptable salt means a salt that is acceptable for administration to a patient or a mammal, such as a human (e.g., salts having acceptable mammalian safety for a given dosage regime).
  • Representative pharmaceutically acceptable salts include salts of acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6- disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and xinafoic acid, and the like.
  • terapéuticaally effective amount means an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treating or “treatment” means preventing, ameliorating or suppressing the medical condition, disease or disorder being treated (e.g., a respiratory disease) in a patient (particularly a human); or alleviating the symptoms of the medical condition, disease or disorder.
  • salt thereof means a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the cation can be a protonated form of a compound of formula (I), (II) or (III), i.e. a form where one or more amino groups have been protonated by an acid.
  • the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • General Synthetic Procedures Compounds of the present disclosure, and intermediates thereof, can be prepared according to the following general methods and procedures using commercially-available or routinely-prepared starting materials and reagents.
  • the substituents and variables (e.g., R 1 , R 2 , etc.) used in the following schemes have the same meanings as those defined elsewhere herein unless otherwise indicated.
  • compounds having an acidic or basic atom or functional group may be used or may be produced as a salt unless otherwise indicated (in some cases, the use of a salt in a particular reaction will require conversion of the salt to a non-salt form, e.g., a free base, using routine procedures before conducting the reaction).
  • a particular embodiment of the present disclosure may be shown or described in the following procedures, those skilled in the art will recognize that other embodiments or aspects of the present disclosure can also be prepared using such procedures or by using other methods, reagents, and starting materials known to those skilled in the art.
  • compounds of the present disclosure may be prepared by a variety of process routes in which reactants are combined in different orders to provide different intermediates en route to producing final products.
  • a general method of preparing final compounds of the present disclosure is illustrated in the following scheme.
  • Compound (I) can be formed by reacting compound I-17 with the appropriate carboxylic acid reactant under amide coupling conditions.
  • the amino portion of the carboxylic acid reactant may optionally be protected with an amino protecting group such as Boc, in which case the amide coupling is followed by deprotection of the amino group, for example using a strong acid such as TFA or HCl.
  • Compound (I-17), the carboxylic acid reactant (1 to 5 equivalents, for example 1.5 equivalents), and a base such as DIPEA or TEA (1 to 10 equivalents, for example 3 equivalents) are dissolved in a solvent such as ACN, DMA, DMSO or DMF at a 0.05-0.1 M concentration of I-17.
  • an amide coupling reagent such as HBTU, EDC + HOBt, or HATU (1 to 5 equivalents, for example 1.5 equivalents) is added and the reaction mixture is stirred at between 15 and 30 °C, for example at room temperature, typically between 2 and 24 hours, or until the reaction is substantially complete.
  • HATU hydrazine (2 to 10 equivalents, for example 5 equivalents) can then be added to cleave undesired byproducts, and the reaction mixture is concentrated. Typical isolation conditions can be used to isolate the product.
  • compositions are typically used in the form of a pharmaceutical composition or formulation. Such pharmaceutical compositions may advantageously be administered to a patient by inhalation.
  • compositions may be administered by any acceptable route of administration including, but not limited to, oral, rectal, nasal, topical (including transdermal) and parenteral modes of administration. Accordingly, in one of its compositions aspects, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically-acceptable carrier or excipient and a compound of formula (I), (II) or (III), where, as defined above, "compound of formula (I), (II) or (III)" means a compound of formula (I), (II) or (III) or a pharmaceutically-acceptable salt thereof.
  • such pharmaceutical compositions may contain other therapeutic and/or formulating agents if desired. In some embodiments, such pharmaceutical compositions further comprise one or more other therapeutic agents.
  • the one or more other therapeutic agents are useful for treating a respiratory disease in a mammal (e.g. a human).
  • a mammal e.g. a human
  • the “compound of the present disclosure” may also be referred to herein as the "active agent”.
  • the term “compound of the present disclosure” is intended to include all compounds encompassed by formula (I) as well as the species embodied in formula (I) and pharmaceutically-acceptable salts thereof
  • the pharmaceutical compositions of the present disclosure typically contain a therapeutically effective amount of a compound of the present disclosure.
  • a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount.
  • such pharmaceutical compositions will contain from about 0.01 to about 95% by weight of the active agent; including, for example, from about 0.05 to about 30% by weight; and from about 0.1 % to about 10% by weight of the active agent.
  • pharmaceutical compositions contain from 0.1 mg to 100 mg of the active agent; including, for example, from 1 mg to 20 mg of the active agent including, for example, from 1 mg to 10 mg of the active agent.
  • any conventional carrier or excipient may be used in the pharmaceutical compositions of the present disclosure.
  • the choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the carriers or excipients used in the pharmaceutical compositions of the present disclosure are commercially-available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C.
  • compositions which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and
  • compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharmaceutically-acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills and the like using conventional procedures and equipment.
  • the pharmaceutical composition is suitable for inhaled administration.
  • Pharmaceutical compositions for inhaled administration are typically in the form of an aerosol or a powder.
  • Such compositions are generally administered using inhaler delivery devices, such as a dry powder inhaler (DPI), a metered-dose inhaler (MDI), a nebulizer inhaler, or a similar delivery device.
  • the pharmaceutical composition is administered by inhalation using a dry powder inhaler.
  • Such dry powder inhalers typically administer the pharmaceutical composition as a free-flowing powder that is dispersed in a patient's air-stream during inspiration.
  • the therapeutic agent is typically formulated with a suitable excipient such as lactose, starch, mannitol, dextrose, polylactic acid (PLA), polylactide-co-glycolide (PLGA) or combinations thereof.
  • the therapeutic agent is micronized and combined with a suitable carrier to form a composition suitable for inhalation.
  • a representative pharmaceutical composition for use in a dry powder inhaler comprises lactose and a compound of the present disclosure in micronized form.
  • Such a dry powder composition can be made, for example, by combining dry milled lactose with the therapeutic agent and then dry blending the components. The composition is then typically loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. Dry powder inhaler delivery devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available.
  • representative dry powder inhaler delivery devices or products include Aeolizer (Novartis); Airmax (IVAX); ClickHaler (Innovata Biomed); Diskhaler (GlaxoSmithKline); Diskus/Accuhaler (GlaxoSmithKline); Ellipta (GlaxoSmithKline); Easyhaler (Orion Pharma); Eclipse (Aventis); FlowCaps (Hovione); Handihaler (Boehringer Ingelheim); Pulvinal (Chiesi); Rotahaler (GlaxoSmithKline); SkyeHaler/Certihaler (SkyePharma); Twisthaler (Schering- Plough); Turbuhaler (AstraZeneca); Ultrahaler (Aventis); and the like.
  • the pharmaceutical composition is administered by inhalation using a metered-dose inhaler.
  • metered-dose inhalers typically discharge a measured amount of a therapeutic agent using a compressed propellant gas.
  • pharmaceutical compositions administered using a metered-dose inhaler typically comprise a solution or suspension of the therapeutic agent in a liquefied propellant.
  • Any suitable liquefied propellant may be employed including hydrofluoroalkanes (HFAs), such as 1,1,1,2- tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA 227); and chlorofluorocarbons, such as CCl 3 F.
  • the propellant is hydrofluoroalkanes.
  • the hydrofluoroalkane formulation contains a co- solvent, such as ethanol or pentane, and/or a surfactant, such as sorbitan trioleate, oleic acid, lecithin, and glycerin.
  • a representative pharmaceutical composition for use in a metered-dose inhaler comprises from about 0.01% to about 5% by weight of a compound of the present disclosure; from about 0% to about 20% by weight ethanol; and from about 0% to about 5% by weight surfactant; with the remainder being an HFA propellant.
  • compositions are typically prepared by adding chilled or pressurized hydrofluoroalkane to a suitable container containing the therapeutic agent, ethanol (if present) and the surfactant (if present). To prepare a suspension, the therapeutic agent is micronized and then combined with the propellant. The composition is then loaded into an aerosol canister, which typically forms a portion of a metered-dose inhaler device.
  • Metered-dose inhaler devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available.
  • representative metered-dose inhaler devices or products include AeroBid Inhaler System (Forest Pharmaceuticals); Atrovent Inhalation Aerosol (Boehringer Ingelheim); Flovent (GlaxoSmithKline); Maxair Inhaler (3M); Proventil Inhaler (Schering); Serevent Inhalation Aerosol (GlaxoSmithKline); and the like.
  • the pharmaceutical composition is administered by inhalation using a nebulizer inhaler.
  • nebulizer devices typically produce a stream of high velocity air that causes the pharmaceutical composition to spray as a mist that is carried into the patient's respiratory tract.
  • the therapeutic agent when formulated for use in a nebulizer inhaler, can be dissolved in a suitable carrier to form a solution.
  • the therapeutic agent can be micronized or nanomilled and combined with a suitable carrier to form a suspension.
  • a representative pharmaceutical composition for use in a nebulizer inhaler comprises a solution or suspension comprising from about 0.05 ⁇ g/mL to about 20 mg/mL of a compound of the present disclosure and excipients compatible with nebulized formulations.
  • the solution has a pH of about 3 to about 8.
  • Nebulizer devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available.
  • representative nebulizer devices or products include the Respimat Softmist Inhalaler (Boehringer Ingelheim); the AERx Pulmonary Delivery System (Aradigm Corp.); the PARI LC Plus Reusable Nebulizer (Pari GmbH); and the like.
  • the pharmaceutical compositions of the present disclosure may alternatively be prepared in a dosage form intended for oral administration.
  • Suitable pharmaceutical compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
  • the pharmaceutical compositions of the present disclosure will typically comprise the active agent and one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate.
  • such solid dosage forms may also comprise: fillers or extenders, binders, humectants, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, coloring agents, and buffering agents. Release agents, wetting agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the pharmaceutical compositions of the present disclosure.
  • Alternative formulations may also include controlled release formulations, liquid dosage forms for oral administration, transdermal patches, and parenteral formulations. Conventional excipients and methods of preparation of such alternative formulations are described, for example, in the reference by Remington, supra. The following non-limiting examples illustrate representative pharmaceutical compositions of the present disclosure.
  • Dry Powder Composition A micronized compound of formula (I) (1 g) is blended with milled lactose (25 g). This blended mixture is then loaded into individual blisters of a peelable blister pack in an amount sufficient to provide between about 0.1 mg to about 4 mg of the compound of formula (I) per dose. The contents of the blisters are administered using a dry powder inhaler. Dry Powder Composition A micronized compound of formula (I) (1 g) is blended with milled lactose (20 g) to form a bulk composition having a weight ratio of compound to milled lactose of 1:20. The blended composition is packed into a dry powder inhalation device capable of delivering between about 0.1 mg to about 4 mg of the compound of formula (I) per dose.
  • Metered-Dose Inhaler Composition A micronized compound of formula (I) (10 g) is dispersed in a solution prepared by dissolving lecithin (0.2 g) in demineralized water (200 mL). The resulting suspension is spray dried and then micronized to form a micronized composition comprising particles having a mean diameter less than about 1.5 ⁇ m. The micronized composition is then loaded into metered-dose inhaler cartridges containing pressurized 1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 0.1 mg to about 4 mg of the compound of formula (I) per dose when administered by the metered dose inhaler.
  • Nebulizer Composition A compound of formula (I) (25 mg) is dissolved in a solution containing 1.5-2.5 equivalents of hydrochloric acid, followed by addition of sodium hydroxide to adjust the pH to 3.5 to 5.5 and 3% by weight of glycerol. The solution is stirred well until all the components are dissolved. The solution is administered using a nebulizer device that provides about 0.1 mg to about 4 mg of the compound of formula (I) per dose.
  • the JAK inhibitors of the present disclosure have been designed for the treatment of inflammatory and fibrotic disease of the respiratory tract. In particular, the compounds have been designed to enable delivery of a potent anti-cytokine agent directly to the site of action of respiratory disease in the lung while limiting systemic exposure.
  • the compounds tested also have the property of being quickly metabolized by the liver which further reduces the risk of potential systemic effects.
  • the compounds also possess adequate solubility for formulation in liquid solution for nebulized delivery to the lungs.
  • Assays 1-2 and Table 1 the compounds of the present disclosure have been shown to be potent inhibitors of the JAK family of enzymes: JAK1, JAK2, JAK3, and TYK2. It has been recognized that the broad anti-inflammatory effect of JAK inhibitors could suppress normal immune cell function, potentially leading to increased risk of infection.
  • the present compounds have therefore been optimized to limit absorption from the lung into the plasma, thus minimizing the risk of immunosuppression. As described in the experimental section below, the absorption and distribution of select compounds have been profiled in preclinical assays.
  • Compounds 1-3, 9, 34, and 41 were tested in mice, in Assay 6, and showed at 5 hours post-dosing high concentration in lung tissue and low absorption into plasma.
  • Compounds 1-3, 9, 12, 22, 27, 34, 37, 41, and 45 have been shown to inhibit an effect of the pro-inflammatory cytokine IL-13 in mouse lung tissue.
  • the compounds have demonstrated inhibition of IL-13-induced phosphorylation of STAT6 in lung tissue which provides evidence of local lung JAK target engagement in vivo. This effect has been observed when the pro-inflammatory cytokine IL-13 is administered 4 hours after administration of the test compound, providing further evidence of significant retention in the lung.
  • the compounds tested also have the property of being quickly metabolized by the liver which further reduces the risk of potential systemic effects.
  • Assay 4 and Table 1 the compounds possess adequate solubility for formulation in liquid solution for nebulized delivery to the lungs.
  • the anti-inflammatory activity of JAK inhibitors has been robustly demonstrated in preclinical models of asthma (Malaviya et al., Int. Immunopharmacol., 2010, 10, 829,-836; Matsunaga et al., Biochem. and Biophys. Res. Commun., 2011, 404, 261-267; Kudlacz et al., Eur. J. Pharmacol, 2008, 582, 154-161).
  • Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon- ⁇ (IFN ⁇ ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Accordingly, the compounds of the present disclosure are expected to be useful for the treatment of inflammatory respiratory disorders, in particular, asthma.
  • TSLP thymic stromal lymphopoietin
  • IFN ⁇ interferon- ⁇
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • Inflammation and fibrosis of the lung is characteristic of other respiratory diseases in addition to asthma such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • pneumonitis interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.
  • the present compounds are also expected to be useful for the treatment of chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.
  • Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low (Kuruvilla et al, Clin Rev Allergy Immunol, 2019, 56(2), 219–233). Based on their mechanism of action, the compounds of the disclosure have the potential to treat both endotypes, T2-high and T2-low.
  • Eosinophilic airway inflammation is a characteristic feature of diseases collectively termed eosinophilic lung diseases (Cottin et al., Clin. Chest. Med., 2016, 37(3), 535-56). Eosinophilic diseases have been associated with IL-4, IL-13 and IL-5 signaling.
  • Eosinophilic lung diseases include infections (especially helminthic infections), drug-induced pneumonitis (induced for example by therapeutic drugs such as antibiotics, phenytoin, or l-tryptophan), fungal-induced pneumonitis (e.g. allergic bronchopulmonary aspergillosis), hypersensitivity pneumonitis and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome).
  • Eosinophilic lung diseases of unknown etiology include idiopathic acute eosinophilic pneumoni, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, and Löffler syndrome.
  • a polymorphism in the IL-6 gene has been associated with elevated IL-6 levels and an increased risk of developing pulmonary arterial hypertension (PAH) (Fang et al., J. Am. Soc. Hypertens., 2017, 11(3), 171-177).
  • PAH pulmonary arterial hypertension
  • Corroborating the role of IL-6 in PAH inhibition of the IL-6 receptor chain gp130 ameliorated the disease in a rat model of PAH (Huang et al., Can. J. Cardiol., 2016, 32(11), 1356.e1-1356.e10).
  • Cytokines such as IFN ⁇ , IL-12 and IL-6 have been implicated in a range of non-allergic lung diseases such as sarcoidosis, and lymphangioleiomyomatosis (El-Hashemite et al., Am. J. Respir. Cell. Mol. Biol., 2005, 33, 227-230, and El-Hashemite et al., Cancer Res., 2004, 64, 3436-3443).
  • Bronchiectasis and infiltrative pulmonary diseases are diseases associated with chronic neutrophilic inflammation.
  • Pathological T cell activation is critical in the etiology of multiple respiratory diseases.
  • bronchiolitis obliterans organizing pneumonia also termed COS. Similar to COS the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipients T cells by the transplanted donor lung. Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but now is considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction.
  • BO Primary Graft Dysfunction
  • OP organizing pneumonia
  • AR acute rejection
  • LB lymphocytic bronchiolitis
  • CLAD Chronic Lung Allograft Dysfunction
  • Chronic lung allograft dysfunction is a major challenge in long- term management of lung transplant recipients as it causes a transplanted lung to progressively lose functionality (Gauthier et al., Curr Transplant Rep., 2016, 3(3), 185–191).
  • CLAD is poorly responsive to treatment and therefore, there remains a need for effective compounds capable of preventing or treating this condition.
  • JAK-dependent cytokines such as IFN ⁇ and IL-5 are up-regulated in CLAD and lung transplant rejection (Berastegui et al, Clin. Transplant. 2017, 31, e12898).
  • lung GVHD is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved.
  • systemic JAK inhibition is associated with serious adverse events and a small therapeutic index, the need remains for an inhaled lung-directed, non-systemic JAK inhibitor to prevent and/or treat lung transplant rejection or lung GVHD.
  • the compounds of the present disclosure have the characteristics required to meet this need.
  • the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction.
  • the lung transplant rejection is acute lung transplant rejection.
  • the lung transplant rejection is chronic lung allograft dysfunction.
  • the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung allograft dysfunction, and neutrophilic allograft dysfunction.
  • the present disclosure provides a method of treating a respiratory disease in a mammal (e.g., a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a mammal e.g., a human
  • the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonitis, cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, or sarcoidosis.
  • the respiratory disease is asthma or chronic obstructive pulmonary disease.
  • the Asthma is T2-high Asthma. In some embodiments, the Asthma is T2-low Asthma.
  • the respiratory disease is a lung infection, an eosinophilic disease, a helminthic infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, an infiltrative pulmonary disease, drug-induced pneumonitis, fungal induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler syndrome, bronchiolitis obliterans organizing pneumonia, acute and chronic lung transplant rejections (including PGD, OP, LB, AR and CLAD, BO, restrictive CLAD and neutrophilic allograft dysfunction), lung graft-versus-host disease, or immune-checkpoint-inhibitor induced pneumonitis.
  • lung infection an eosinophilic disease
  • the present disclosure further provides a method of treating asthma in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a mammal e.g. a human
  • the compounds of the present disclosure will typically be administered in a single daily dose or in multiple doses per day, although other forms of administration may be used.
  • the amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the present disclosure further provides a method of treating a respiratory disease (including but not limited to the disease described herein) in a mammal (e.g. a human), the method comprising administering to the mammal (or human), a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure When used to treat a respiratory disease (including but not limited to the disease described herein), the compounds of the present disclosure will typically be administered in a single daily dose or in multiple doses per day, although other forms of administration may be used.
  • the amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • Human coronavirus is a common respiratory pathogen and typically induces mild upper respiratory disease.
  • SARS-CoV-1 Severe Acute Respiratory Syndrome associated- Coronavirus
  • MERS-CoV Middle East Respiratory Syndrome-associated Coronavirus
  • a subgroup of patients with COVID-19 appears to have a hyperinflammatory “cytokine storm” resulting in acute lung injury and acute respiratory distress syndrome (ARDS). This cytokine storm may also spill over into the systemic circulation and produce sepsis and ultimately, multi-organ dysfunction syndrome.
  • the dysregulated cytokine signaling that appears in COVID-19 is characterized by increased expression of interferons (IFNs), interleukins (ILs), and chemokines, resulting in ALI and associated mortality.
  • IFNs interferons
  • ILs interleukins
  • chemokines resulting in ALI and associated mortality.
  • This hyperinflammatory response can potentially be modulated and treated by a lung-selective pan-Janus Kinase (JAK) inhibitor.
  • JNK pan-Janus Kinase
  • Monoclonal antibodies directed against IL-6 appear to be effective in treating patients with ALI from COVID-19 (Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab, 2020, PNAS, https://doi.org/10.1073/pnas.2005615117).
  • JAK inhibitors have also been shown to be beneficial in mouse models of lipopolysaccharide-or ganciclovir- induced ALI (Severgnini et al., Am J Respir Crit Care Med., 2005, 171(8), 858-67; Jin et al., Am J Physiol-Lung Cell Mol Physiol., 2018, 314(5), L882–92).
  • baricitinib a JAK inhibitor
  • EUA emergency use authorization
  • the present disclosure provides a method of treating a mammal (or patient) infected with a coronavirus such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, or the symptoms thereof, the method comprising administering to the mammal (or patient) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a coronavirus such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV
  • the present disclosure also provides a method of treating ALI and/or ARDS in a mammal (or a patient) caused by a coronavirus infection (such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV), the method comprising administering to the mammal (or patient) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a coronavirus infection such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV
  • JAK inhibitors The mechanism of action of JAK inhibitors has been linked to the treatment of nasal inflammatory diseases (Therapeutic Effects of Intranasal Tofacitinib on Chronic Rhinosinusitis with Nasal Polyps in Mice, Joo et al., The Laryngoscope, 2020, https://doi.org/10.1002/lary.29129). Further, Dupilumab, which acts by blocking the IL-4 and IL-13 signaling pathways, has been approved for the treatment of chronic rhinosinusitis with nasal polyps. Therefore, also provided herein is a method of treating nasal inflammatory diseases in a mammal (e.g.
  • the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the nasal inflammatory disease is selected from the group consisting of chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, and rhinitis (non- allergic, allergic, perenial, and vasomotor rhinitis).
  • the compounds of the present disclosure may also be useful for a variety of other diseases.
  • the compounds of the present disclosure may be useful for a variety of gastrointestinal inflammatory indications that include, but are not limited to, inflammatory bowel disease, ulcerative colitis (proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis), Crohn’s disease, collagenous colitis, lymphocytic colitis, Behcet’s disease, celiac disease, immune checkpoint inhibitor induced colitis, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis. Ulcerative colitis (Reimund et al., J. Clin.
  • PD-1- or PD-L1-inhibitor-induced colitis are characterized by elevation of certain pro-inflammatory cytokine levels.
  • pro-inflammatory cytokines signal via JAK activation
  • compounds described in this application may be able to alleviate the inflammation and provide symptom relief.
  • the compounds of the present disclosure may be useful for the induction and maintenance of remission of ulcerative colitis, and for the treatment of Crohn's disease, immune checkpoint inhibitor induced colitis, and the gastrointestinal adverse effects in graft versus host disease.
  • the present disclosure provides a method of treating a gastrointestinal inflammatory disease in a mammal (e.g., a human), the method comprising administering to the mammal a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • a mammal e.g., a human
  • Atopic dermatitis and other inflammatory skin diseases have been associated with elevation of proinflammatory cytokines that rely on the JAK-STAT pathway.
  • the compounds of the present disclosure may be beneficial in a number of dermal inflammatory or pruritic conditions that include, but are not limited to atopic dermatitis, alopecia areata, vitiligo, psoriasis, dermatomyositis, cutaneous T cell lymphoma (Netchiporouk et al., Cell Cycle 2014; 13, 3331-3335) and subtypes (Sezary syndrome, mycosis fungoides, pagetoid reticulosis, granulomatous slack skin, lymphomatoid papulosis, pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, CD30+ cutaneous T-cell lymphoma, secondary cutaneous CD30+ large cell lymphoma, non-mycosis fungoides CD30 ⁇ cutaneous large T-cell lymphoma, pleomorphic
  • atopic dermatitis (Bao et al., JAK-STAT, 2013, 2, e24137), alopecia areata (Xing et al., Nat. Med. 2014, 20, 1043-1049), vitiligo (Craiglow et al, JAMA Dermatol. 2015, 151, 1110-1112), prurigo nodularis (Sonkoly et al., J. Allergy Clin. Immunol. 2006, 117, 411-417), lichen planus (Welz- Kubiak et al., J. Immunol. Res. 2015, ID:854747), primary localized cutaneous amyloidosis (Tanaka et al., Br. J.
  • the present disclosure provides a method of treating an inflammatory skin disease in a mammal (e.g., a human), the method comprising applying a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier to the skin of the mammal.
  • a mammal e.g., a human
  • the inflammatory skin disease is atopic dermatitis.
  • Many ocular diseases have been shown to be associated with elevations of proinflammatory cytokines that rely on the JAK-STAT pathway.
  • the compounds of the present disclosure may be useful for the treatment of a number of ocular diseases that include, but are not limited to, uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, and atopic keratoconjunctivitis.
  • ocular diseases include, but are not limited to, uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, and atopic keratoconjunctivitis.
  • uveitis Horai and Caspi, J. Interferon Cytokine Res., 2011, 31, 733-744
  • diabetic retinopathy Abcouwer, J. Clin. Cell.
  • the present disclosure provides a method of treating an ocular disease in a mammal (e.g. a human), the method comprising administering a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically-acceptable salt thereof and a pharmaceutical carrier to the eye of the mammal (or human).
  • a mammal e.g. a human
  • the ocular disease is uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, or atopic keratoconjunctivitis.
  • the method comprises administering the compound of the present disclosure, or a pharmaceutically acceptable salt thereof by intravitreal injection.
  • Compounds of the present disclosure, or a pharmaceutically acceptable salt thereof may also be used in combination with one or more compound useful to ocular diseases.
  • the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof may also be useful to treat other diseases such as other inflammatory diseases, autoimmune diseases or cancers.
  • the compounds of the present disclosure may be useful to treat one or more of cytokine release syndrome (CRS), arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, transplant rejection, xerophthalmia, psoriatic arthritis, diabetes, insulin dependent diabetes, motor neurone disease, myelodysplastic syndrome, pain, sarcopenia, cachexia, septic shock, systemic lupus erythematosus, leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, ankylosing spondylitis, myelofibrosis, B-cell lymphoma, hepatocellular carcinoma, Hodgkins disease, breast cancer, Multiple myeloma, melanoma, non- Hodgkin lymphoma, non-small-cell lung cancer, ovarian clear cell carcinoma, ova
  • CRS cytokine release
  • Combination therapy Compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used in combination with one or more agents which act by the same mechanism or by different mechanisms to treat a disease.
  • the different agents may be administered sequentially or simultaneously, in separate compositions or in the same composition.
  • agents for combination therapy include, but are not limited to, a beta 2 adrenoceptor agonist, a muscarinic receptor antagonist, a glucocorticoid agonist, a G-protein coupled receptor-44 antagonist, a leukotriene D4 antagonist, a muscarinic M3 receptor antagonist, a histamine H1 receptor antagonist, an immunoglobulin E antagonist, a PDE 4 inhibitor, an IL-4 antagonist, a muscarinic M1 receptor antagonist, a histamine receptor antagonist, an IL-13 antagonist, an IL-5 antagonist, a 5-Lipoxygenase inhibitor, a beta adrenoceptor agonist, a CCR3 chemokine antagonist, a CFTR stimulator, an immunoglobulin modulator, an interleukin 33 ligand inhibitor, a PDE 3 inhibitor, a phosphoinositide-3 kinase delta inhibitor, a thromboxane A2 antagonist, an elasta
  • JAK inhibitor compounds include, but are not limited to rosiptor acetate, umeclidinium bromide, secukinumab, metenkefalin acetate, tridecactide acetate, fluticasone propionate, alpha-cyclodextrin-stabilized sulforaphane, tezepelumab, mometasone furoate, BI-1467335, dupilumab, aclidinium, formoterol, AZD-1419, HI-1640V, rivipansel, CMP-001, mannitol, ANB-020, omalizumab, tregalizumab, Mitizax, benralizumab, golimumab, roflumilast, imatinib, REGN-3500, masitinib, apremilast, RPL-554, Actimmune, adalim
  • a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents.
  • the therapeutic agent may be selected from the class of agents specified above and from the list of specific agents described above.
  • the pharmaceutical composition is suitable for delivery to the lungs.
  • the pharmaceutical composition is suitable for inhaled or nebulized administration.
  • the pharmaceutical composition is a dry powder or a liquid composition.
  • the present disclosure provides a method of treating a disease or disorder in a mammal (e.g. a human) comprising administering to the mammal (or human) a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents.
  • the agents When used in combination therapy, the agents may be formulated in a single pharmaceutical composition, or the agents may be provided in separate compositions that are administered simultaneously or at separate times, by the same or by different routes of administration. Such compositions can be packaged separately or may be packaged together as a kit. The two or more therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration.
  • EXAMPLES The following synthetic and biological examples are offered to illustrate the disclosure, and are not to be construed in any way as limiting the scope of the disclosure. In the examples below, the following abbreviations have the following meanings unless otherwise indicated. Abbreviations not defined below have their generally accepted meanings.
  • ACN acetonitrile
  • DCM dichloromethane
  • DIPEA N,N-diisopropylethylamine
  • DMA Dimethylacetamide
  • DMSO Dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • EtOAc ethyl acetate
  • HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate
  • HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate
  • IPA isopropyl alcohol
  • Pd(PPh3)4
  • reaction mixtures were worked up as described specifically in each reaction; commonly they were purified by extraction and other purification methods such as temperature-, and solvent-dependent crystallization, and precipitation.
  • reaction mixtures were routinely purified by column chromatography or by preparative HPLC, typically using C18 or BDS column packings and conventional eluents. Typical preparative HPLC conditions are described below. Characterization of reaction products was routinely carried out by mass and 1 H-NMR spectrometry.
  • the resulting reaction mass was stirred at room temperature for 15 minutes, followed by the addition of benzyl bromide (24.0 mL, 204 mmol) in drop wise manner. The resulting reaction mixture was stirred for 6 hours at room temperature. After completion of the reaction (TLC monitoring), the resulting reaction mass was poured into water (1.0 L) followed by the extraction of compound with EtOAc (2 x 2L). The combined organics were washed with cold water, brine solution and dried over sodium sulfate, filtered and evaporated under reduced pressure.
  • the resulting reaction mixture was heated up to 80°C for next 16h. After completion of the reaction (TLC monitoring), the reaction mass was filtered through celite bed and mother liquor was evaporated under reduced pressure to obtain the crude product. Crude residue was purified by column chromatography over silica gel (100-200M) by using eluents 1% EtOAc in hexane to get the desired product (I-4) as a light yellow oily compound (32.0 g, 66%).
  • reaction mixture was then cooled to 0 °C and 1N HCl was added until the solution reached pH ⁇ 1.
  • the reaction was extracted by ethyl acetate (2x200 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the desired product as an off white solid (21.0 g, 91.3% yield).
  • reaction mixture was quenched with cold water (200 mL) and extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with brine (300 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by silica gel column chromatography (15% EtOAc in heptane) to afford the desired product (10.0 g, 48.5% yield).
  • Boc-protected intermediate was dissolved in dioxane (2.5 ml) and water (0.5 ml), then HCl, 4 M in dioxane (2.5 ml, 10.00 mmol) was added and the reaction mixture was stirred at room temperature until judged complete by LCMS (3 hours).
  • HATU 11.53 g, 30.3 mmol
  • Hydrazine 3.96 ml, 126 mmol
  • the solution was then dripped into 500 mL of water with stirring to precipitate out the product as a white solid, which was then collected by filtration and dried under vacuum.
  • Example 5 2-amino-3-(1,3-dioxolan-2-yl)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H- indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)propan-1-one
  • the general procedure was followed on a 0.042 mmol scale, using 2-([(tert-butoxy) carbonyl] amino)-3-(1,3-dioxolan-2-yl)propanoic acid (16 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (7.3 mg, 28% yield).
  • Biochemical JAK Kinase Assays A panel of four LanthaScreen JAK biochemical assays (JAK1, 2, 3 and Tyk2) were carried in a common kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , and 1 mM EGTA). Recombinant GST-tagged JAK enzymes and a GFP-tagged STAT1 peptide substrate were obtained from Life Technologies.
  • Results were expressed as pIC50 (negative logarithm of IC 50 ) and subsequently converted to pK i (negative logarithm of dissociation constant, Ki) using the Cheng-Prusoff equation. Test compounds having a lower Ki value or higher pKi value in the four JAK assays show greater inhibition of JAK activity.
  • Assay 2 Cellular JAKI Potency Assay The JAKI cellular potency assay was carried out by measuring inhibition of interleukin- 13 (IL-13, R&D Systems) induced STAT6 phosphorylation in BEAS-2B human lung epithelial cells (ATCC).
  • IL-13 interleukin- 13
  • ATCC human lung epithelial cells
  • BEAS-2B cells were grown at 37°C in a 5% CO 2 humidified incubator in 50% DMEM/50% F-12 medium (Life Technologies) supplemented with 10% FBS (Hyclone), 100 U/mL penicillin, 100 ⁇ g/mL streptomycin (Life Technologies), and 2 mM GlutaMAX (Life Technologies). On day 1 of the assay, cells were seeded at a 7,500 cells/well density in white poly-D-lysine-coated 384-well plates (Corning) with 25 ⁇ L medium and were allowed to adhere overnight in the incubator.
  • assay buffer Hank's Balanced Salt Solution/HBSS, 25mM HEPES, and 1 mg/ml bovine serum albumin/BSA
  • test compounds were serially diluted in DMSO and then diluted another 1000-fold in media to bring the final DMSO concentration to 0.1%.
  • Cells were incubated with test compounds at 37°C for 1 h and followed by the addition of 12 ⁇ l of pre-warmed IL-13 (80 ng/mL in assay buffer) for stimulation.
  • the assay buffer (containing compound and IL-13) was removed, and 10 ⁇ L of cell lysis buffer (25 mM HEPES, 0.1 % SDS, 1 % NP-40, 5 mM MgCl2, 1.3 mM EDTA, 1 mM EGTA, supplemented with Complete Ultra mini protease inhibitors and PhosSTOP from Roche Diagnostics).
  • cell lysis buffer 25 mM HEPES, 0.1 % SDS, 1 % NP-40, 5 mM MgCl2, 1.3 mM EDTA, 1 mM EGTA, supplemented with Complete Ultra mini protease inhibitors and PhosSTOP from Roche Diagnostics.
  • the plates were shaken at ambient temperature for 30min before the addition of detection reagents.
  • Levels of pSTAT6 were measured using the AlphaLISA SureFire Ultra pSTAT6 (Tyr641) assay kit from PerkinElmer. For dose-response analysis, percent inhibition data were plotted
  • liver microsomes Human Liver Microsome Assay The objective of this assay was to assess the metabolic stability of test compounds in an in vitro human liver subcellular fraction, known as liver microsomes. Liver microsomes are obtained from the endoplasmic reticulum of hepatic cells and are a rich source of drug metabolizing enzymes.
  • Test compounds or control compounds (10 mM stock solution in DMSO) were diluted in DMSO, acetonitrile and cofactor solution containing NADPH to yield final incubation concentrations of 0.1 mg/mL microsomal protein, 0.1 ⁇ M test compound, 1 mM NADPH, 0.0001% DMSO (v/v) and 0.1% acetonitrile (v/v).
  • Controls used in this assay were 7-ethoxycoumarin and propranolol for CYP P450 enzyme activity, and benfluorex and trandolapril for esterase enzyme activity.
  • Assay 4 Aqueous Solubility Assay The purpose of this assay was to quantify the solubility of test compounds in pH 4 and pH 7.4 PBS buffers. The assay required 40 ⁇ L of 10 mM DMSO test compound solution per desired buffer in addition to 20 ⁇ L required to make a test standard. For example, to test a compound in both buffers, 100 ⁇ L (2 * 40 ⁇ L + 20 ⁇ L) of 10 mM DMSO compound stock solution was required.
  • the standard was created by diluting 20 ⁇ L of 10 mM DMSO compound stock solution into 180 ⁇ L of methanol and was shaken for five minutes to ensure solution uniformity.
  • the resulting solution had a concentration of 1 mM, or 1,000 ⁇ M, of the test compound.
  • This 1,000 ⁇ M solution was run on an Agilent 1260 LC-MS system by injecting 2 ⁇ L in order to obtain the peak area.
  • 40 ⁇ L of 10 mM DMSO compound stock solution, per PBS buffer condition were dried down into a powder overnight. Once in powder form, 400 ⁇ L of the desired PBS buffer was added to the powder and allowed to shake vigorously for four hours. The maximum theoretical concentration for this sample solution was 1,000 ⁇ M.
  • A represents a pK i value ⁇ 10 (K i ⁇ 0.1 nM)
  • B represents a pK i value between 9 and 10 (K i between 1 nM and 0.1 nM)
  • C represents a pK i value between 8 and 9 (K i between 10 nM and 1 nM)
  • D represents a pKi value between 7 and 8 (Ki between 100 nM and 10 nM)
  • E represents a pKi value of 7 or below (K i of 100 nM or above).
  • A represents a pIC50 value ⁇ 7.5 (IC50 ⁇ 32 nM)
  • B represents a pIC50 value between 7 (included) and 7.5
  • C represents a pIC50 value between 6.5 (included) and 7
  • D represents a pIC50 value between 6.0 (included) and 6.5.
  • A represents a value between 1500 and 2000
  • B represents a value between 1000 and 1500
  • C represents a value between 500 and 1000
  • D represents a value between 100 and 500.
  • A represents a value between 500 and 1000
  • B represents a value between 250 and 500
  • C represents a value between 100 and 250
  • D represents a value between 50 and 100
  • E represents a value between 20 and 50.
  • Table 1 Assay 5 Murine (Mouse) model of IL-13 induced pSTAT6 induction in lung tissue IL-13 binds to cell surface receptors activating members of the Janus family of kinases (JAK) which then phosphorylate STAT6 and subsequently activates further transcription pathways.
  • a dose of IL-13 was delivered locally into the lungs of mice to induce the phosphorylation of STAT6 (pSTAT6) which is then measured as the endpoint.
  • lungs were collected for both pSTAT6 detection using an AlphaLISA Immunoassay (PerkinElmer) and analyzed for total drug concentration. Selected compounds of the present disclosure were tested in the assay. Activity in the model is evidenced by a decrease in the level of pSTAT6 present in the lungs of treated animals at 5 hours compared to the vehicle treated, IL-13 challenged control animals. The difference between the control animals which were vehicle- treated, IL-13 challenged and the control animals which were vehicle-treated, vehicle challenged dictated the 0% and 100% inhibitory effect, respectively, in any given experiment. Exemplary compounds were tested in the assay and exhibited inhibition of STAT6 phosphorylation at 4 hours after IL-13 challenge as documented below. In the following table, A represents between 80 % and 100 % inhibition, B represents between 60 % and 80 % inhibition and C represents between 40 % and 60 % inhibition. Table 2: pSTAT6 Inhibition
  • Assay 6 Pharmacokinetics in Plasma and Lung in Mouse After Oral Aspiration Administration of Test Compounds Plasma and lung concentrations of test compounds were quantified and pharmacokinetic parameters were calculated in the following manner. Male CD1 mice from Charles River Laboratories were used in the pharmacokinetic studies. Test compounds were individually formulated in 20% propylene glycol in pH 4 citrate buffer at a concentration of 0.2 mg/mL. Test compounds were administered in two, 25 ⁇ L increments introduced into the trachea of each mouse by oral aspiration using a calibrated pipette once the animal was anesthetized using isoflurane. Blood samples were collected as terminal collections via cardiac puncture at 0.167, 1, 4, 8, and 24 hr post-dosing.
  • Plasma and lung concentrations of test compounds were determined by LC-MS/MS analysis against analytical standards constructed into a standard curve in the test matrix.
  • the pharmacokinetic parameters of test compounds were determined by non-compartmental analysis. For concentrations below the limit of quantification, zero was used for mean calculations. Mean values were not reported if more than 50% of the samples were below the limit of quantification at a timepoint, or if more than 50% of a calculated pharmacokinetic parameter was not reportable.
  • AUC(0-inf) AUC(0-t) + Clast / k
  • AUC(0-t) the area under the concentration-time curve from the time of dosing to the last measurable concentration calculated by the linear trapezoidal rule
  • C last is the last measurable concentration
  • k the first order rate constant associated with the terminal elimination phase, estimated by linear regression of time versus log concentration.
  • AUC(0-inf) values were not reported if percent extrapolated was >20% or r 2 was ⁇ 0.8, or if ⁇ 3 measurable points past T max were available, where T max .is the time to maximal concentration.
  • the lung-to-plasma AUC ratio was determined as the ratio of the lung AUC(0-inf) in ⁇ g*hr/g to the plasma AUC(0-inf) in ⁇ g*hr/mL.
  • Plasma AUC(0-inf) was not reported for compound 3, therefore plasma and lung AUC(0-t) with T last being 24h in plasma and lung were used for this compound
  • B denotes a value between 0.5 and 1.
  • B denotes a value between 50 and 100
  • C denotes a value between 15 and 50.
  • A denotes a ratio 300-400
  • B denotes a ratio between 200 and 300
  • C denotes a ratio between 100 and 200
  • D denotes a ratio between 50 and 100.
  • Table 3 Plasma and Lung Exposure in Mice Following Oral Aspiration Administration of Test Compounds Assay 7: Cytotoxicity Assay A CellTiter-Glo luminescent cell viability/cytotoxicity assay was carried out in BEAS- 2B human lung epithelial cells (ATCC) under the normal growth condition.

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Abstract

Provided herein are compounds of formula (I): where the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are Janus kinases inhibitors. Also provided herein are pharmaceutical compositions comprising such compounds and methods of using such compounds to treat respiratory diseases.

Description

AMINO AMIDE TETRAHYDRO IMIDAZO PYRIDINES AS JAK INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to United States Provisional Application No. 63/200,178, filed February 19, 2021, which is hereby incorporated by reference in its entirety. BACKGROUND Field Provided herein are compounds useful as Janus kinase inhibitors. Also provided herein are pharmaceutical compositions comprising such compounds and methods of using such compounds to treat respiratory diseases. State of the Art Asthma is a chronic disease of the airways for which there are no preventions or cures. The disease is characterized by inflammation, fibrosis, hyper-responsiveness, and remodeling of the airways, all of which contribute to airflow limitation. An estimated 300 million people worldwide suffer from asthma and it is estimated that the number of people with asthma will grow by more than 100 million by 2025. In the United States, asthma afflicts about 6 % to 8 % of the population, making it one of the most common chronic diseases in the country. Although most patients can achieve control of asthma symptoms with the use of inhaled corticosteroids that may be combined with a leukotriene modifier and/or a long acting beta agonist, there remains a subset of patients with severe asthma whose disease is not controlled by conventional therapies. Severe persistent asthma is defined as disease that remains uncontrolled on high doses of inhaled corticosteroids. While severe asthmatics are estimated to account for approximately 5 % of all asthma sufferers, they have a high risk of morbidity and mortality and are responsible for a disproportionate share of health care resource utilization among asthmatics. There remains a need for novel therapies to treat these patients. Cytokines are intercellular signaling molecules which include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor. Cytokines are critical for normal cell growth and immunoregulation but also drive immune-mediated diseases and contribute to the growth of malignant cells. Elevated levels of many cytokines have been implicated in the pathology of asthma inflammation. For example, antibody-based therapies targeted at interleukins (IL)-5, and 13 have been shown to provide clinical benefit in subsets of severe asthma patients. Among the cytokines implicated in asthma inflammation, many act through signaling pathways dependent upon the Janus family of tyrosine kinases (JAKs), which signal through the Signal Transducer and Activator of Transcription (STAT) family of transcription factors. Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon-γ (IFNγ) and granulocyte-macrophage colony- stimulating factor (GM-CSF). The JAK family comprises four members, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Binding of cytokine to a JAK-dependent cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the JAK kinase, effecting JAK activation. Phosphorylated JAKs, in turn, bind and phosphorylate various STAT proteins which dimerize, internalize in the cell nucleus and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease. The JAKs usually associate with cytokine receptors in pairs as homodimers or heterodimers. Specific cytokines are associated with specific JAK pairings. Each of the four members of the JAK family is implicated in the signaling of at least one of the cytokines associated with asthma inflammation. Consequently, a chemical inhibitor with pan-activity against all members of the JAK family could modulate a broad range of pro-inflammatory pathways that contribute to severe asthma. However, the broad anti-inflammatory effect of such inhibitors could suppress normal immune cell function, potentially leading to increased risk of infection. Evidence of increased infection risk has been observed with the JAK inhibitor tofacitinib, which is dosed orally for the treatment of rheumatoid arthritis. In asthma, inflammation is localized to the respiratory tract. Inflammation of the airways is characteristic of other respiratory diseases in addition to asthma. Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, and sarcoidosis are also respiratory tract diseases in which the pathophysiology is believed to be related to JAK-signaling cytokines. Local administration of a JAK inhibitor to the lungs by inhalation offers the potential to be therapeutically efficacious by delivering a potent anti-cytokine agent directly to the site of action, limiting systemic exposure and therefore limiting the potential for adverse systemic immunosuppression. The need remains for a potent JAK inhibitor suitable for local administration to the lungs for treatment of respiratory disease. JAK-signaling cytokines also play a major role in the activation of T cells, a sub-type of immune cells that is central to many immune processes. Pathological T cell activation is critical in the etiology of multiple respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also termed COS). Similar to COS the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipient’s T cells by the transplanted donor lung. Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but now is considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction. Chronic lung allograft dysfunction (CLAD) is a major challenge in long-term management of lung transplant recipients as it causes a transplanted lung to progressively lose functionality (Gauthier et al., Curr. Transplant. Rep., 2016, 3(3), 185–191). CLAD is poorly responsive to treatment and therefore, there remains a need for effective compounds capable of preventing or treating this condition. Several JAK-dependent cytokines such as IFNγ and IL-5 are up-regulated in CLAD and lung transplant rejection (Berastegui et al, Clin. Transplant. 2017, 31, e12898). Moreover, high lung levels of CXCR3 chemokines such as CXCL9 and CXCL10 which are downstream of JAK-dependent IFN signaling, are linked to worse outcomes in lung transplant patients (Shino et al, PLOS One, 2017, 12 (7), e0180281). Systemic JAK inhibition has been shown to be effective in kidney transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors have the potential to be effective in treating or preventing lung transplant rejection and CLAD. Similar T cell activation events as described as the basis for lung transplant rejection also are considered the main driver of lung graft-versus-host disease (GVHD) which can occur post hematopoietic stem cell transplants. Similar to CLAD, lung GVHD is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved. A retrospective, multicenter survey study of 95 patients with steroid- refractory acute or chronic GVHD who received the systemic JAK inhibitor ruxolitinib as salvage therapy demonstrated complete or partial response to ruxolitinib in the majority of patients including those with lung GVHD (Zeiser et al, Leukemia, 2015, 29, 10, 2062-68). As systemic JAK inhibition is associated with serious adverse events and a small therapeutic index, the need remains for an inhaled lung-directed, non-systemic JAK inhibitor to prevent and/or treat lung transplant rejection or lung GVHD. There is also a need for JAK inhibitors that can be quickly metabolized by the liver to further prevent systemic effects. Finally, there is also a need for JAK inhibitors having good solubility in aqueous solution permitting the development of liquid compositions suitable for nebulized delivery to the lungs. SUMMARY In one aspect, the present disclosure provides novel compounds having activity as Janus kinase inhibitors. Accordingly, the present disclosure provides a compound of formula (I):
Figure imgf000005_0001
or a pharmaceutically-acceptable salt thereof, wherein: R1 is selected from the group consisting of H, C1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered monocyclic cycloalkyl group, a 4 to 7 membered monocyclic heterocyclic group, -C1- 6 alkyl-aryl, and -C1-6 alkyl-heteroaryl, wherein the 3 to 7 membered monocyclic cycloalkyl group, and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, wherein the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, a 3 to 7 membered monocyclic cycloalkyl group, and a 4 to 7 membered monocyclic heterocyclic group, wherein the 3 to 7 membered monocyclic cycloalkyl group and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R6, -CONR6R7, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, - NR6R7, -OC(O)NR6R7, -NR6C(O)R7, -NR6C(O)2R7, -NR6-C(O)NR7R8, -C1-6 alkyl-OR6, -C1-6 alkyl-NR6R7, and -C1-6 alkyl-CO2R6, wherein the aryl, heteroaryl, -C1-6 alkyl-aryl, and -C1-6 alkyl-heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, - OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl- NR3R4, and -C1-6 alkyl-CO2R3, R2 is H or C1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R9, -CONR9R10, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, - NR9R10, -OC(O)NR9R10, -NR9C(O)R10, -NR9C(O)2R10, -NR9-C(O)NR10R11, or R1 and R2 taken together form a 3 to 7 membered monocyclic cycloalkyl group or a 4 to 7 membered monocyclic heterocyclic group, wherein the 3 to 7 membered monocyclic cycloalkyl group and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, - CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, - NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl- CO2R3, and R3, R4, R5, R6, R7, R8 , R9, R10, and R11 are each independently selected from the group consisting of H and C1-6 alkyl. The present disclosure also provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier. The present disclosure also provides a method of treating respiratory disease, in particular, asthma and lung rejection, in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure. The present disclosure also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy, as well as the use of such compound in the manufacture of a formulation or medicament for a treating respiratory disease in a mammal (e.g. a human). DETAILED DESCRIPTION In one aspect, the present disclosure provides compounds having activity as a Janus kinase inhibitor. Accordingly, the present disclosure provides a compound of formula (I):
Figure imgf000006_0001
or a pharmaceutically-acceptable salt thereof, wherein: R1 is selected from the group consisting of H, C1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered monocyclic cycloalkyl group, a 4 to 7 membered monocyclic heterocyclic group, -C1- 6 alkyl-aryl, and -C1-6 alkyl-heteroaryl, wherein the 3 to 7 membered monocyclic cycloalkyl group, and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, wherein the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, a 3 to 7 membered monocyclic cycloalkyl group, and a 4 to 7 membered monocyclic heterocyclic group, wherein the 3 to 7 membered monocyclic cycloalkyl group and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R6, -CONR6R7, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, - NR6R7, -OC(O)NR6R7, -NR6C(O)R7, -NR6C(O)2R7, -NR6-C(O)NR7R8, -C1-6 alkyl-OR6, -C1-6 alkyl-NR6R7, and -C1-6 alkyl-CO2R6, wherein the aryl, heteroaryl, -C1-6 alkyl-aryl, and -C1-6 alkyl-heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, - OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl- NR3R4, and -C1-6 alkyl-CO2R3, R2 is H or C1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R9, -CONR9R10, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, - NR9R10, -OC(O)NR9R10, -NR9C(O)R10, -NR9C(O)2R10, -NR9-C(O)NR10R11, or R1 and R2 taken together form a 3 to 7 membered monocyclic cycloalkyl group or a 4 to 7 membered monocyclic heterocyclic group, wherein the 3 to 7 membered monocyclic cycloalkyl group and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, - CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, - NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, and R3, R4, R5, R6, R7, R8, R9, R10, and R11 are each independently selected from the group consisting of H and C1-6 alkyl. In some embodiments, R2 is C1-3 alkyl or C1-3 alkyl-OH or R1 and R2 taken together form a 4 to 6 membered monocyclic cycloalkyl group optionally substituted with 1 to 2 substituents independently selected from the group consisting of CN, -CONR3R4, OH, -O-C1-3 alkyl, -S-C1-3 alkyl, and -NR3R4. In some embodiments, R2 is -CH3 or -CH2-OH or R1 and R2 taken together form a cyclopentyl group. In some embodiments, the compound, or a pharmaceutically-acceptable salt thereof, has the formula (II):
Figure imgf000008_0001
In some embodiments, the compound, or a pharmaceutically-acceptable salt thereof, has the formula (III):
Figure imgf000008_0002
In some embodiments, R1 is selected from the group consisting of H, C1-6 alkyl, aryl, a 3 to 5 membered monocyclic cycloalkyl, -CRaRb-heteroaryl, -CRaRb-aryl, and -CRaRb- heterocyclyl, wherein Ra and Rb are each independently selected from the group consisting of H and C1-4 alkyl, wherein the heterocyclyl is a 5 or 6 membered monocyclic heterocyclic group; wherein the 3 to 5 membered monocyclic cycloalkyl and the -CRaRb-heterocyclyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, - OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl- NR3R4, and -C1-6 alkyl-CO2R3, wherein the C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, and -NR3-C(O)NR4R5, wherein the aryl, -CRaRb-aryl, and -CRaRb-heteroaryl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, - CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, - NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, and R3, R4, and R5 are each independently selected from the group consisting of H and C1-6 alkyl. In some embodiments, R1 is selected from the group consisting of H, C1-6 alkyl, phenyl, a 3 to 5 membered monocyclic cycloalkyl, -CRaRb-heteroaryl, -CRaRb-phenyl, and -CRaRb- heterocyclyl; wherein Ra and Rb are each independently selected from the group consisting of H and C1-2 alkyl; wherein the heterocyclyl is a 5 or 6 membered monocyclic heterocyclic group containing 1 or 2 oxygen atoms; wherein the C1-6 alkyl is optionally substituted with 1 substituent selected from the group consisting of CN, -CONR3R4, OH, -O-C1-3 alkyl, -S-C1-3 alkyl, and -NR3R4, wherein the phenyl, -CRaRb-phenyl and -CRaRb-heteroaryl are optionally substituted with 1 substituent independently selected from the group consisting of halogen, OH, C1-4 alkyl, and O-C1-4 alkyl, and R3 and R4, are each independently selected from the group consisting of H and C1-3 alkyl. In some embodiments, R1 is selected from the group consisting of H, C1-4 alkyl, phenyl, - CH2-pyrimidinyl, -CH2-pyridinyl, -CH2-thiophenyl, -CH2-imidazolyl, -CH2-indolyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-dioxolanyl, -CH2-tetrahydropyranyl, and -CH2- phenyl, wherein the C1-4 alkyl is optionally substituted with 1 substituent selected from the group consisting of CN, OH, SMe, OMe, NH2, NMe2, and CONH2, wherein the imidazolyl is optionally substituted with Me, and wherein the -CH2-phenyl is optionally substituted with 1 substituent selected from the group consisting of F, Cl, OH, OMe, and Me. In some embodiments, R1 is selected from the group consisting of H,
Figure imgf000009_0001
Figure imgf000010_0001
. Also provided is a compound of formula 1:
Figure imgf000010_0002
or a pharmaceutically-acceptable salt thereof. Also provided is a compound of formula 2:
Figure imgf000010_0003
or a pharmaceutically-acceptable salt thereof. Also provided is a compound of formula 3:
Figure imgf000010_0004
or a pharmaceutically-acceptable salt thereof. Chemical structures are named herein according to IUPAC conventions as implemented in ChemDraw software (PerkinElmer, Inc., Cambridge, MA). Furthermore, the imidazo portion of the tetrahydroimidazopyridine moiety exists in tautomeric forms, illustrated below for a fragment of the compounds of the present disclosure.
Figure imgf000011_0001
According to the IUPAC convention, these representations give rise to different numbering of the atoms of the imidazole portion: (1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine (structure A) vs. (1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (structure B). It will be understood that although structures are shown, or named, in a particular form, the present disclosure also includes the tautomer thereof. The compounds of the present disclosure may contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like. Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated. The depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated stereochemistry with the understanding that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer. The compounds of the present disclosure may also contain several basic groups (e.g., amino groups) and therefore, such compounds can exist as the free base or in various salt forms, such a mono-protonated salt form, a di-protonated salt form, a tri-protonated salt form, etc or mixtures thereof. All such forms are included within the scope of this present disclosure, unless otherwise indicated. This present disclosure also includes isotopically-labeled compounds of formula (I), (II) and (III), i.e., compounds of formula (I), (II) and (III) where one or more atom has been replaced or enriched with an atom having the same atomic number but an atomic mass different from the atomic mass that predominates in nature. Examples of isotopes that may be incorporated into a compound of formula (I), (II) and (III) include, but are not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, and 18O. Of particular interest are compounds of formula (I), (II) and (III) enriched in tritium or carbon-14, which compounds can be used, for example, in tissue distribution studies. Also of particular interest are compounds of formula (I), (II) and (III) enriched in deuterium especially at a site of metabolism, which compounds are expected to have greater metabolic stability. Additionally, of particular interest, are compounds of formula (I), (II) and (III) enriched in a positron emitting isotope, such as 11C, 15O and 13N, which compounds can be used, for example, in Positron Emission Tomography (PET) studies. Definitions When describing this present disclosure including its various aspects and embodiments, the following terms have the following meanings, unless otherwise indicated. The term "alkyl" means a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example, methyl (Me), ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl (n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t-Bu) or (tBu), n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2- methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like. When a specific number of carbon atoms are intended for a particular term, the number of carbon atoms is shown preceding the term. For example, the term “C1-3 alkyl” means an alkyl group having from 1 to 3 carbon atoms wherein the carbon atoms are in any chemically- acceptable configuration, including linear or branched configurations. The term "amino protecting group" means a protecting group suitable for preventing undesired reactions at an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl and tri- fluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), p-nitrobenzyloxycarbonyl (PNZ), 2,4-dichlorobenzyloxycarbonyl, and 5-benzisoxazolylmethoxycarbonyl; arylmethyl groups, such as benzyl (Bn), 4-methoxybenzyl, trityl (Tr), and 1,1-di-(4’-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), [2-(trimethylsilyl)ethoxy]methyl (SEM); and the like. The term “aryl” means an aromatic hydrocarbon group having a single ring (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, by way of example, phenyl (i.e., a benzene ring), naphthyl (i.e., a naphthalene ring), and the like. As used herein, the term aryl includes monovalent, divalent or multivalent aryl groups. The term "cycloalkyl" means a monovalent saturated carbocyclic group which may be monocyclic or multicyclic. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl (cPr), cyclobutyl (cBu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like. The term “halo” means fluoro, chloro, bromo or iodo. The term “heteroaryl” means an aromatic group having a single ring or two fused rings and containing in a ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur (i.e., a heteroaromatic group). Unless otherwise defined, such heteroaryl groups typically contain from 1 to 9 carbon atoms and from 3 to 10 total ring atoms. Representative heteroaryl groups include, by way of example, mono-, di- or multivalent species of benzimidazole, benzofuran, benzothiazole, benzothiophene, furan, imidazole, indole, isoquinoline, isothiazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiazole, thiophene, triazole, triazine and the like, where the point or points of attachment are at any available carbon or nitrogen ring atom. As used herein, the term heteroaryl includes monovalent, divalent or multivalent heteroaryl groups. The term "heterocyclyl", "heterocycle", "heterocyclic", or "heterocyclic ring" means a monovalent saturated or partially unsaturated cyclic non-aromatic group, having from 3 to 10 total ring atoms, wherein the ring contains from 2 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic groups may be monocyclic or multicyclic (i.e., fused or bridged). Representative heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl, 2-imidazolinyl, tetrahydropyranyl, 1,2,3,4-tetrahydroisoquinolin-2- yl, quinuclidinyl, 7-azanorbornanyl, nortropanyl, and the like, where the point of attachment is at any available carbon or nitrogen ring atom. Where the context makes the point of attachment of the heterocyclic group evident, such groups may alternatively be referred to as a non-valent species, i.e. pyrrolidine, piperidine, piperazine, imidazole, tetrahydropyran etc. The term “pharmaceutically acceptable salt” means a salt that is acceptable for administration to a patient or a mammal, such as a human (e.g., salts having acceptable mammalian safety for a given dosage regime). Representative pharmaceutically acceptable salts include salts of acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6- disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and xinafoic acid, and the like. The term “therapeutically effective amount” means an amount sufficient to effect treatment when administered to a patient in need of treatment. The term “treating” or “treatment” means preventing, ameliorating or suppressing the medical condition, disease or disorder being treated (e.g., a respiratory disease) in a patient (particularly a human); or alleviating the symptoms of the medical condition, disease or disorder. The term “salt thereof” means a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. For example, the cation can be a protonated form of a compound of formula (I), (II) or (III), i.e. a form where one or more amino groups have been protonated by an acid. Typically, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. General Synthetic Procedures Compounds of the present disclosure, and intermediates thereof, can be prepared according to the following general methods and procedures using commercially-available or routinely-prepared starting materials and reagents. The substituents and variables (e.g., R1, R2, etc.) used in the following schemes have the same meanings as those defined elsewhere herein unless otherwise indicated. Additionally, compounds having an acidic or basic atom or functional group may be used or may be produced as a salt unless otherwise indicated (in some cases, the use of a salt in a particular reaction will require conversion of the salt to a non-salt form, e.g., a free base, using routine procedures before conducting the reaction). Although a particular embodiment of the present disclosure may be shown or described in the following procedures, those skilled in the art will recognize that other embodiments or aspects of the present disclosure can also be prepared using such procedures or by using other methods, reagents, and starting materials known to those skilled in the art. In particular, it will be appreciated that compounds of the present disclosure may be prepared by a variety of process routes in which reactants are combined in different orders to provide different intermediates en route to producing final products. A general method of preparing final compounds of the present disclosure is illustrated in the following scheme.
Figure imgf000015_0001
Compound (I) can be formed by reacting compound I-17 with the appropriate carboxylic acid reactant under amide coupling conditions. The amino portion of the carboxylic acid reactant may optionally be protected with an amino protecting group such as Boc, in which case the amide coupling is followed by deprotection of the amino group, for example using a strong acid such as TFA or HCl. Compound (I-17), the carboxylic acid reactant (1 to 5 equivalents, for example 1.5 equivalents), and a base such as DIPEA or TEA (1 to 10 equivalents, for example 3 equivalents) are dissolved in a solvent such as ACN, DMA, DMSO or DMF at a 0.05-0.1 M concentration of I-17. Then, an amide coupling reagent such as HBTU, EDC + HOBt, or HATU (1 to 5 equivalents, for example 1.5 equivalents) is added and the reaction mixture is stirred at between 15 and 30 °C, for example at room temperature, typically between 2 and 24 hours, or until the reaction is substantially complete. When using HATU, hydrazine (2 to 10 equivalents, for example 5 equivalents) can then be added to cleave undesired byproducts, and the reaction mixture is concentrated. Typical isolation conditions can be used to isolate the product. If an acid labile amino protecting group such as Boc is used on the protected amino reactant, the crude product is then dissolved in TFA (for example in a volume equal to the solvent’s volume used in the previous step) to remove the Boc protection. After about 10 minutes to 1 hour, the reaction mixture is concentrated, and the crude product can be purified using typical methods, for example by using a preparative HPLC (5-70% ACN/water gradient with 0.05% TFA, C18 column for example). Pharmaceutical Compositions The compounds of the present disclosure and pharmaceutically-acceptable salts thereof are typically used in the form of a pharmaceutical composition or formulation. Such pharmaceutical compositions may advantageously be administered to a patient by inhalation. In addition, pharmaceutical compositions may be administered by any acceptable route of administration including, but not limited to, oral, rectal, nasal, topical (including transdermal) and parenteral modes of administration. Accordingly, in one of its compositions aspects, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically-acceptable carrier or excipient and a compound of formula (I), (II) or (III), where, as defined above, "compound of formula (I), (II) or (III)" means a compound of formula (I), (II) or (III) or a pharmaceutically-acceptable salt thereof. Optionally, such pharmaceutical compositions may contain other therapeutic and/or formulating agents if desired. In some embodiments, such pharmaceutical compositions further comprise one or more other therapeutic agents. In some embodiments, the one or more other therapeutic agents are useful for treating a respiratory disease in a mammal (e.g. a human). When discussing compositions and uses thereof, the "compound of the present disclosure" may also be referred to herein as the "active agent". As used herein, the term "compound of the present disclosure" is intended to include all compounds encompassed by formula (I) as well as the species embodied in formula (I) and pharmaceutically-acceptable salts thereof The pharmaceutical compositions of the present disclosure typically contain a therapeutically effective amount of a compound of the present disclosure. Those skilled in the art will recognize, however, that a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount. Typically, such pharmaceutical compositions will contain from about 0.01 to about 95% by weight of the active agent; including, for example, from about 0.05 to about 30% by weight; and from about 0.1 % to about 10% by weight of the active agent. In some embodiments, pharmaceutical compositions contain from 0.1 mg to 100 mg of the active agent; including, for example, from 1 mg to 20 mg of the active agent including, for example, from 1 mg to 10 mg of the active agent. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the present disclosure. The choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the carriers or excipients used in the pharmaceutical compositions of the present disclosure are commercially-available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999). Representative examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical compositions. Pharmaceutical compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharmaceutically-acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills and the like using conventional procedures and equipment. In one aspect, the pharmaceutical composition is suitable for inhaled administration. Pharmaceutical compositions for inhaled administration are typically in the form of an aerosol or a powder. Such compositions are generally administered using inhaler delivery devices, such as a dry powder inhaler (DPI), a metered-dose inhaler (MDI), a nebulizer inhaler, or a similar delivery device. In a particular embodiment, the pharmaceutical composition is administered by inhalation using a dry powder inhaler. Such dry powder inhalers typically administer the pharmaceutical composition as a free-flowing powder that is dispersed in a patient's air-stream during inspiration. In order to achieve a free-flowing powder composition, the therapeutic agent is typically formulated with a suitable excipient such as lactose, starch, mannitol, dextrose, polylactic acid (PLA), polylactide-co-glycolide (PLGA) or combinations thereof. Typically, the therapeutic agent is micronized and combined with a suitable carrier to form a composition suitable for inhalation. A representative pharmaceutical composition for use in a dry powder inhaler comprises lactose and a compound of the present disclosure in micronized form. Such a dry powder composition can be made, for example, by combining dry milled lactose with the therapeutic agent and then dry blending the components. The composition is then typically loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device. Dry powder inhaler delivery devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available. For example, representative dry powder inhaler delivery devices or products include Aeolizer (Novartis); Airmax (IVAX); ClickHaler (Innovata Biomed); Diskhaler (GlaxoSmithKline); Diskus/Accuhaler (GlaxoSmithKline); Ellipta (GlaxoSmithKline); Easyhaler (Orion Pharma); Eclipse (Aventis); FlowCaps (Hovione); Handihaler (Boehringer Ingelheim); Pulvinal (Chiesi); Rotahaler (GlaxoSmithKline); SkyeHaler/Certihaler (SkyePharma); Twisthaler (Schering- Plough); Turbuhaler (AstraZeneca); Ultrahaler (Aventis); and the like. In another particular embodiment, the pharmaceutical composition is administered by inhalation using a metered-dose inhaler. Such metered-dose inhalers typically discharge a measured amount of a therapeutic agent using a compressed propellant gas. Accordingly, pharmaceutical compositions administered using a metered-dose inhaler typically comprise a solution or suspension of the therapeutic agent in a liquefied propellant. Any suitable liquefied propellant may be employed including hydrofluoroalkanes (HFAs), such as 1,1,1,2- tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA 227); and chlorofluorocarbons, such as CCl3F. In a particular embodiment, the propellant is hydrofluoroalkanes. In some embodiments, the hydrofluoroalkane formulation contains a co- solvent, such as ethanol or pentane, and/or a surfactant, such as sorbitan trioleate, oleic acid, lecithin, and glycerin. A representative pharmaceutical composition for use in a metered-dose inhaler comprises from about 0.01% to about 5% by weight of a compound of the present disclosure; from about 0% to about 20% by weight ethanol; and from about 0% to about 5% by weight surfactant; with the remainder being an HFA propellant. Such compositions are typically prepared by adding chilled or pressurized hydrofluoroalkane to a suitable container containing the therapeutic agent, ethanol (if present) and the surfactant (if present). To prepare a suspension, the therapeutic agent is micronized and then combined with the propellant. The composition is then loaded into an aerosol canister, which typically forms a portion of a metered-dose inhaler device. Metered-dose inhaler devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available. For example, representative metered-dose inhaler devices or products include AeroBid Inhaler System (Forest Pharmaceuticals); Atrovent Inhalation Aerosol (Boehringer Ingelheim); Flovent (GlaxoSmithKline); Maxair Inhaler (3M); Proventil Inhaler (Schering); Serevent Inhalation Aerosol (GlaxoSmithKline); and the like. In another particular aspect, the pharmaceutical composition is administered by inhalation using a nebulizer inhaler. Such nebulizer devices typically produce a stream of high velocity air that causes the pharmaceutical composition to spray as a mist that is carried into the patient's respiratory tract. Accordingly, when formulated for use in a nebulizer inhaler, the therapeutic agent can be dissolved in a suitable carrier to form a solution. Alternatively, the therapeutic agent can be micronized or nanomilled and combined with a suitable carrier to form a suspension. A representative pharmaceutical composition for use in a nebulizer inhaler comprises a solution or suspension comprising from about 0.05 µg/mL to about 20 mg/mL of a compound of the present disclosure and excipients compatible with nebulized formulations. In one embodiment, the solution has a pH of about 3 to about 8. Nebulizer devices suitable for administering therapeutic agents by inhalation are described in the art and examples of such devices are commercially available. For example, representative nebulizer devices or products include the Respimat Softmist Inhalaler (Boehringer Ingelheim); the AERx Pulmonary Delivery System (Aradigm Corp.); the PARI LC Plus Reusable Nebulizer (Pari GmbH); and the like. In yet another aspect, the pharmaceutical compositions of the present disclosure may alternatively be prepared in a dosage form intended for oral administration. Suitable pharmaceutical compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of a compound of the present disclosure as an active ingredient. When intended for oral administration in a solid dosage form, the pharmaceutical compositions of the present disclosure will typically comprise the active agent and one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate. Optionally or alternatively, such solid dosage forms may also comprise: fillers or extenders, binders, humectants, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, coloring agents, and buffering agents. Release agents, wetting agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the pharmaceutical compositions of the present disclosure. Alternative formulations may also include controlled release formulations, liquid dosage forms for oral administration, transdermal patches, and parenteral formulations. Conventional excipients and methods of preparation of such alternative formulations are described, for example, in the reference by Remington, supra. The following non-limiting examples illustrate representative pharmaceutical compositions of the present disclosure. Dry Powder Composition A micronized compound of formula (I) (1 g) is blended with milled lactose (25 g). This blended mixture is then loaded into individual blisters of a peelable blister pack in an amount sufficient to provide between about 0.1 mg to about 4 mg of the compound of formula (I) per dose. The contents of the blisters are administered using a dry powder inhaler. Dry Powder Composition A micronized compound of formula (I) (1 g) is blended with milled lactose (20 g) to form a bulk composition having a weight ratio of compound to milled lactose of 1:20. The blended composition is packed into a dry powder inhalation device capable of delivering between about 0.1 mg to about 4 mg of the compound of formula (I) per dose. Metered-Dose Inhaler Composition A micronized compound of formula (I) (10 g) is dispersed in a solution prepared by dissolving lecithin (0.2 g) in demineralized water (200 mL). The resulting suspension is spray dried and then micronized to form a micronized composition comprising particles having a mean diameter less than about 1.5 μm. The micronized composition is then loaded into metered-dose inhaler cartridges containing pressurized 1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 0.1 mg to about 4 mg of the compound of formula (I) per dose when administered by the metered dose inhaler. Nebulizer Composition A compound of formula (I) (25 mg) is dissolved in a solution containing 1.5-2.5 equivalents of hydrochloric acid, followed by addition of sodium hydroxide to adjust the pH to 3.5 to 5.5 and 3% by weight of glycerol. The solution is stirred well until all the components are dissolved. The solution is administered using a nebulizer device that provides about 0.1 mg to about 4 mg of the compound of formula (I) per dose. Utility The JAK inhibitors of the present disclosure have been designed for the treatment of inflammatory and fibrotic disease of the respiratory tract. In particular, the compounds have been designed to enable delivery of a potent anti-cytokine agent directly to the site of action of respiratory disease in the lung while limiting systemic exposure. The compounds tested also have the property of being quickly metabolized by the liver which further reduces the risk of potential systemic effects. The compounds also possess adequate solubility for formulation in liquid solution for nebulized delivery to the lungs. As shown in Assays 1-2 and Table 1, the compounds of the present disclosure have been shown to be potent inhibitors of the JAK family of enzymes: JAK1, JAK2, JAK3, and TYK2. It has been recognized that the broad anti-inflammatory effect of JAK inhibitors could suppress normal immune cell function, potentially leading to increased risk of infection. The present compounds have therefore been optimized to limit absorption from the lung into the plasma, thus minimizing the risk of immunosuppression. As described in the experimental section below, the absorption and distribution of select compounds have been profiled in preclinical assays. Compounds 1-3, 9, 34, and 41 were tested in mice, in Assay 6, and showed at 5 hours post-dosing high concentration in lung tissue and low absorption into plasma. Compounds 1-3, 9, 12, 22, 27, 34, 37, 41, and 45 have been shown to inhibit an effect of the pro-inflammatory cytokine IL-13 in mouse lung tissue. Specifically, the compounds have demonstrated inhibition of IL-13-induced phosphorylation of STAT6 in lung tissue which provides evidence of local lung JAK target engagement in vivo. This effect has been observed when the pro-inflammatory cytokine IL-13 is administered 4 hours after administration of the test compound, providing further evidence of significant retention in the lung. As shown in Assay 3 and Table 1, the compounds tested also have the property of being quickly metabolized by the liver which further reduces the risk of potential systemic effects. As shown in Assay 4 and Table 1, the compounds possess adequate solubility for formulation in liquid solution for nebulized delivery to the lungs. The anti-inflammatory activity of JAK inhibitors has been robustly demonstrated in preclinical models of asthma (Malaviya et al., Int. Immunopharmacol., 2010, 10, 829,-836; Matsunaga et al., Biochem. and Biophys. Res. Commun., 2011, 404, 261-267; Kudlacz et al., Eur. J. Pharmacol, 2008, 582, 154-161). Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon-γ (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Accordingly, the compounds of the present disclosure are expected to be useful for the treatment of inflammatory respiratory disorders, in particular, asthma. Inflammation and fibrosis of the lung is characteristic of other respiratory diseases in addition to asthma such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis. The present compounds, therefore, are also expected to be useful for the treatment of chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis. Further, Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low (Kuruvilla et al, Clin Rev Allergy Immunol, 2019, 56(2), 219–233). Based on their mechanism of action, the compounds of the disclosure have the potential to treat both endotypes, T2-high and T2-low. The compounds of the present disclosure possess biological activity involved in the inhibition of cytokines associated with inflammation. Therefore, the compounds of the present disclosure are expected to be useful for the treatment of certain specific respiratory diseases, as detailed below. Eosinophilic airway inflammation is a characteristic feature of diseases collectively termed eosinophilic lung diseases (Cottin et al., Clin. Chest. Med., 2016, 37(3), 535-56). Eosinophilic diseases have been associated with IL-4, IL-13 and IL-5 signaling. Eosinophilic lung diseases include infections (especially helminthic infections), drug-induced pneumonitis (induced for example by therapeutic drugs such as antibiotics, phenytoin, or l-tryptophan), fungal-induced pneumonitis (e.g. allergic bronchopulmonary aspergillosis), hypersensitivity pneumonitis and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). Eosinophilic lung diseases of unknown etiology include idiopathic acute eosinophilic pneumoni, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, and Löffler syndrome. A polymorphism in the IL-6 gene has been associated with elevated IL-6 levels and an increased risk of developing pulmonary arterial hypertension (PAH) (Fang et al., J. Am. Soc. Hypertens., 2017, 11(3), 171-177). Corroborating the role of IL-6 in PAH, inhibition of the IL-6 receptor chain gp130 ameliorated the disease in a rat model of PAH (Huang et al., Can. J. Cardiol., 2016, 32(11), 1356.e1-1356.e10). Cytokines such as IFNγ, IL-12 and IL-6 have been implicated in a range of non-allergic lung diseases such as sarcoidosis, and lymphangioleiomyomatosis (El-Hashemite et al., Am. J. Respir. Cell. Mol. Biol., 2005, 33, 227-230, and El-Hashemite et al., Cancer Res., 2004, 64, 3436-3443). Bronchiectasis and infiltrative pulmonary diseases are diseases associated with chronic neutrophilic inflammation. Pathological T cell activation is critical in the etiology of multiple respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also termed COS). Similar to COS the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipients T cells by the transplanted donor lung. Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but now is considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction. Chronic lung allograft dysfunction (CLAD) is a major challenge in long- term management of lung transplant recipients as it causes a transplanted lung to progressively lose functionality (Gauthier et al., Curr Transplant Rep., 2016, 3(3), 185–191). CLAD is poorly responsive to treatment and therefore, there remains a need for effective compounds capable of preventing or treating this condition. Several JAK-dependent cytokines such as IFNγ and IL-5 are up-regulated in CLAD and lung transplant rejection (Berastegui et al, Clin. Transplant. 2017, 31, e12898). Moreover, high lung levels of CXCR3 chemokines such as CXCL9 and CXCL10 which are downstream of JAK-dependent IFN signaling, are linked to worse outcomes in lung transplant patients (Shino et al, PLOS One, 2017, 12 (7), e0180281). Systemic JAK inhibition has been shown to be effective in kidney transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors have the potential to be effective in treating or preventing lung transplant rejection and CLAD. Similar T cell activation events as described as the basis for lung transplant rejection also are considered the main driver of lung graft-versus-host disease (GVHD) which can occur post hematopoietic stem cell transplants. Similar to CLAD, lung GVHD is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved. A retrospective, multicenter survey study of 95 patients with steroid-refractory acute or chronic GVHD who received the systemic JAK inhibitor ruxolitinib as salvage therapy demonstrated complete or partial response to ruxolitinib in the majority of patients including those with lung GVHD (Zeiser et al, Leukemia, 2015, 29, 10, 2062-68). As systemic JAK inhibition is associated with serious adverse events and a small therapeutic index, the need remains for an inhaled lung-directed, non-systemic JAK inhibitor to prevent and/or treat lung transplant rejection or lung GVHD. The compounds of the present disclosure have the characteristics required to meet this need. Therefore, provided herein is a method of treating lung transplant rejection in a human in need thereof comprising administering to the human a compound of Formula (I), or a pharmaceutically-acceptable salt thereof. In some embodiments, the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction. In some embodiments, the lung transplant rejection is acute lung transplant rejection. In some embodiments, the lung transplant rejection is chronic lung allograft dysfunction. In some embodiments, the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung allograft dysfunction, and neutrophilic allograft dysfunction. More recently, immune-checkpoint inhibitor induced pneumonitis, another T cell mediated lung disease emerged with the increased use of immune-checkpoint inhibitors. In cancer patients treated with these T cell stimulating agents, fatal pneumonitis can develop. The compounds of the disclosure possess biological activity allowing inhibition of IFNγ secretion. In one aspect, therefore, the present disclosure provides a method of treating a respiratory disease in a mammal (e.g., a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonitis, cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, or sarcoidosis. In another aspect, the respiratory disease is asthma or chronic obstructive pulmonary disease. In some embodiments, the Asthma is T2-high Asthma. In some embodiments, the Asthma is T2-low Asthma. In one aspect, the respiratory disease is a lung infection, an eosinophilic disease, a helminthic infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, an infiltrative pulmonary disease, drug-induced pneumonitis, fungal induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler syndrome, bronchiolitis obliterans organizing pneumonia, acute and chronic lung transplant rejections (including PGD, OP, LB, AR and CLAD, BO, restrictive CLAD and neutrophilic allograft dysfunction), lung graft-versus-host disease, or immune-checkpoint-inhibitor induced pneumonitis. The present disclosure further provides a method of treating asthma in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. When used to treat asthma, the compounds of the present disclosure will typically be administered in a single daily dose or in multiple doses per day, although other forms of administration may be used. The amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. The present disclosure further provides a method of treating a respiratory disease (including but not limited to the disease described herein) in a mammal (e.g. a human), the method comprising administering to the mammal (or human), a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. When used to treat a respiratory disease (including but not limited to the disease described herein), the compounds of the present disclosure will typically be administered in a single daily dose or in multiple doses per day, although other forms of administration may be used. The amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. Human coronavirus is a common respiratory pathogen and typically induces mild upper respiratory disease. The two highly pathogenic viruses, Severe Acute Respiratory Syndrome associated- Coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome-associated Coronavirus (MERS-CoV), caused severe respiratory syndromes resulting in more than 10% and 35% mortality, respectively (Assiri et al., N Engl J Med., 2013, 369, 407–1). The recent emergence of Coronavirus Disease 2019 (COVID-19 and subsequent pandemic has created a global health care emergency. Similar to SARS-CoV-1 and MERS-CoV, a subset of patients (about 16%) can develop a severe respiratory illness manifested by acute lung injury (ALI) leading to ICU admission (about 5%), respiratory failure (about 6.1%) and death (Wang et al., JAMA, 2020, 323, 11, 1061-1069; Guan et al., N Engl J Med., 2020, 382, 1708-1720; Huang et al., The Lancet, 2020. 395 (10223), 497–506; Chen et al., The Lancet, 2020, 395(10223), 507– 13). A subgroup of patients with COVID-19 appears to have a hyperinflammatory “cytokine storm” resulting in acute lung injury and acute respiratory distress syndrome (ARDS). This cytokine storm may also spill over into the systemic circulation and produce sepsis and ultimately, multi-organ dysfunction syndrome. The dysregulated cytokine signaling that appears in COVID-19 is characterized by increased expression of interferons (IFNs), interleukins (ILs), and chemokines, resulting in ALI and associated mortality. This hyperinflammatory response can potentially be modulated and treated by a lung-selective pan-Janus Kinase (JAK) inhibitor. Monoclonal antibodies directed against IL-6 (tocilizumab and sarilumab) appear to be effective in treating patients with ALI from COVID-19 (Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab, 2020, PNAS, https://doi.org/10.1073/pnas.2005615117). Though in-vivo models of COVID-19 have yet to be published, infection with mouse adapted strains of the 2003 SARS-CoV-1 and 2012 MERS- CoV, as well as a transgenic mouse expressing the human SARS-CoV-1 receptor hACE2 infected with human SARS-CoV-1, demonstrate elevations of JAK-dependent cytokines, such as IFNγ, IL-6, and IL-12, and downstream chemokines, such as chemokine (C-C motif) ligand 10 (CCL10), CCL2, and CCL7 (McCray et al., J Virol., 2007, 81(2), 813–21; Gretebeck et al., Curr Opin Virol. 2015, 13, 123–9.; Day et al., Virology. 2009, 395(2), 210–22. JAK inhibitors have also been shown to be beneficial in mouse models of lipopolysaccharide-or ganciclovir- induced ALI (Severgnini et al., Am J Respir Crit Care Med., 2005, 171(8), 858-67; Jin et al., Am J Physiol-Lung Cell Mol Physiol., 2018, 314(5), L882–92). Finally, based on the results of clinical trials, baricitinib, a JAK inhibitor, has received an emergency use authorization (EUA) in combination with remdesivir, for the treatment of COVID-19 in patients requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda- authorizes-drug-combination-treatment-covid- 19#:~:text=Today%2C%20the%20U.S.%20Food%20and,or%20older%20requiring%20supplem ental%20oxygen%2C). In a clinical trial of hospitalized patients with COVID-19, baricitinib, in combination with remdesivir, was shown to reduce time to recovery within 29 days after initiating treatment compared to patients who received a placebo with remdesivir. Therefore, compounds of formula (I), which are lung-selective inhaled pan-JAK inhibitors, could be uniquely suited to dampen the cytokine storm associated with COVID-19. By delivering to the lung and avoiding systemic immunosuppression, additional infections that lead to worsened mortality may also be avoided. This is particularly true in those patients requiring ventilatory support. As major causes of death in subjects with COVID-19 appear to be comorbidities and superinfection, an inhaled medication may be a way to avoid systemic immunosuppression that would pre-dispose patients to these risks. Therefore, the present disclosure provides a method of treating a mammal (or patient) infected with a coronavirus such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, or the symptoms thereof, the method comprising administering to the mammal (or patient) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating ALI and/or ARDS in a mammal (or a patient) caused by a coronavirus infection (such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV), the method comprising administering to the mammal (or patient) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. The mechanism of action of JAK inhibitors has been linked to the treatment of nasal inflammatory diseases (Therapeutic Effects of Intranasal Tofacitinib on Chronic Rhinosinusitis with Nasal Polyps in Mice, Joo et al., The Laryngoscope, 2020, https://doi.org/10.1002/lary.29129). Further, Dupilumab, which acts by blocking the IL-4 and IL-13 signaling pathways, has been approved for the treatment of chronic rhinosinusitis with nasal polyps. Therefore, also provided herein is a method of treating nasal inflammatory diseases in a mammal (e.g. a human), the method comprising administering to the mammal (or human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the nasal inflammatory disease is selected from the group consisting of chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, and rhinitis (non- allergic, allergic, perenial, and vasomotor rhinitis). As JAK inhibitors, the compounds of the present disclosure may also be useful for a variety of other diseases. The compounds of the present disclosure may be useful for a variety of gastrointestinal inflammatory indications that include, but are not limited to, inflammatory bowel disease, ulcerative colitis (proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis), Crohn’s disease, collagenous colitis, lymphocytic colitis, Behcet’s disease, celiac disease, immune checkpoint inhibitor induced colitis, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis. Ulcerative colitis (Reimund et al., J. Clin. Immunology, 1996, 16, 144-150), Crohn’s disease (Woywodt et al., Eur. J. Gastroenterology Hepatology, 1999, 11, 267-276), collagenous colitis (Kumawat et al., Mol. Immunology, 2013, 55, 355-364), lymphocytic colitis (Kumawat et al., 2013), eosinophilic esophagitis (Weinbrand-Goichberg et al., Immunol. Res., 2013, 56, 249-260), graft versus host disease-related colitis (Coghill et al., Blood, 2001, 117, 3268-3276), infectious colitis (Stallmach et al., Int. J. Colorectal Dis., 2004, 19, 308–315), Behcet’s disease (Zhou et al., Autoimmun. Rev., 2012, 11, 699-704), celiac disease (de Nitto et al., World J. Gastroenterol., 2009, 15, 4609- 4614), immune checkpoint inhibitor induced colitis (e.g., CTLA-4 inhibitor-induced colitis; (Yano et al., J. Translation. Med., 2014, 12, 191), PD-1- or PD-L1-inhibitor-induced colitis), and ileitis (Yamamoto et al., Dig. Liver Dis., 2008, 40, 253-259) are characterized by elevation of certain pro-inflammatory cytokine levels. As many pro-inflammatory cytokines signal via JAK activation, compounds described in this application may be able to alleviate the inflammation and provide symptom relief. In particular, the compounds of the present disclosure may be useful for the induction and maintenance of remission of ulcerative colitis, and for the treatment of Crohn's disease, immune checkpoint inhibitor induced colitis, and the gastrointestinal adverse effects in graft versus host disease. In one aspect, therefore, the present disclosure provides a method of treating a gastrointestinal inflammatory disease in a mammal (e.g., a human), the method comprising administering to the mammal a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Atopic dermatitis and other inflammatory skin diseases have been associated with elevation of proinflammatory cytokines that rely on the JAK-STAT pathway. Therefore, the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be beneficial in a number of dermal inflammatory or pruritic conditions that include, but are not limited to atopic dermatitis, alopecia areata, vitiligo, psoriasis, dermatomyositis, cutaneous T cell lymphoma (Netchiporouk et al., Cell Cycle 2014; 13, 3331-3335) and subtypes (Sezary syndrome, mycosis fungoides, pagetoid reticulosis, granulomatous slack skin, lymphomatoid papulosis, pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, CD30+ cutaneous T-cell lymphoma, secondary cutaneous CD30+ large cell lymphoma, non-mycosis fungoides CD30− cutaneous large T-cell lymphoma, pleomorphic T-cell lymphoma, Lennert lymphoma, subcutaneous T-cell lymphoma, angiocentric lymphoma, blastic NK-cell lymphoma), prurigo nodularis, lichen planus, primary localized cutaneous amyloidosis, bullous pemphigoid, skin manifestations of graft versus host disease, pemphigoid, discoid lupus, granuloma annulare, lichen simplex chronicus, vulvar/scrotal/perianal pruritus, lichen sclerosus, post herpetic neuralgia itch, lichen planopilaris, and foliculitis decalvans. In particular, atopic dermatitis (Bao et al., JAK-STAT, 2013, 2, e24137), alopecia areata (Xing et al., Nat. Med. 2014, 20, 1043-1049), vitiligo (Craiglow et al, JAMA Dermatol. 2015, 151, 1110-1112), prurigo nodularis (Sonkoly et al., J. Allergy Clin. Immunol. 2006, 117, 411-417), lichen planus (Welz- Kubiak et al., J. Immunol. Res. 2015, ID:854747), primary localized cutaneous amyloidosis (Tanaka et al., Br. J. Dermatol. 2009, 161, 1217-1224), bullous pemphigoid (Feliciani et al., Int. J. Immunopathol. Pharmacol. 1999, 12, 55-61), and dermal manifestations of graft versus host disease (Okiyama et al., J. Invest. Dermatol. 2014, 134, 992-1000) are characterized by elevation of certain cytokines that signal via JAK activation. Accordingly, compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be able to alleviate associated dermal inflammation or pruritus driven by these cytokines. In particular, compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be expected to be useful for the treatment of atopic dermatitis and other inflammatory skin diseases. In one aspect, therefore, the present disclosure provides a method of treating an inflammatory skin disease in a mammal (e.g., a human), the method comprising applying a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier to the skin of the mammal. In one aspect, the inflammatory skin disease is atopic dermatitis. Many ocular diseases have been shown to be associated with elevations of proinflammatory cytokines that rely on the JAK-STAT pathway. The compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, therefore, may be useful for the treatment of a number of ocular diseases that include, but are not limited to, uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, and atopic keratoconjunctivitis. In particular, uveitis (Horai and Caspi, J. Interferon Cytokine Res., 2011, 31, 733-744), diabetic retinopathy (Abcouwer, J. Clin. Cell. Immunol., 2013, Suppl 1, 1- 12), diabetic macular edema (Sohn et al., American Journal of Opthamology, 2011, 152, 686- 694), dry eye disease (Stevenson et al, Arch. Ophthalmol., 2012, 130, 90-100), and age-related macular degeneration (Knickelbein et al, Int. Ophthalmol. Clin., 2015, 55(3), 63-78) are characterized by elevation of certain pro-inflammatory cytokines that signal via the JAK-STAT pathway. Accordingly, compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be able to alleviate the associated ocular inflammation and reverse disease progression or provide symptom relief. In one aspect, therefore, the present disclosure provides a method of treating an ocular disease in a mammal (e.g. a human), the method comprising administering a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically-acceptable salt thereof and a pharmaceutical carrier to the eye of the mammal (or human). In one aspect, the ocular disease is uveitis, diabetic retinopathy, diabetic macular edema, dry eye disease, age-related macular degeneration, or atopic keratoconjunctivitis. In one aspect, the method comprises administering the compound of the present disclosure, or a pharmaceutically acceptable salt thereof by intravitreal injection. Compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may also be used in combination with one or more compound useful to ocular diseases. The compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may also be useful to treat other diseases such as other inflammatory diseases, autoimmune diseases or cancers. The compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be useful to treat one or more of cytokine release syndrome (CRS), arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, transplant rejection, xerophthalmia, psoriatic arthritis, diabetes, insulin dependent diabetes, motor neurone disease, myelodysplastic syndrome, pain, sarcopenia, cachexia, septic shock, systemic lupus erythematosus, leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, ankylosing spondylitis, myelofibrosis, B-cell lymphoma, hepatocellular carcinoma, Hodgkins disease, breast cancer, Multiple myeloma, melanoma, non- Hodgkin lymphoma, non-small-cell lung cancer, ovarian clear cell carcinoma, ovary tumor, pancreas tumor, polycythemia vera, Sjoegrens syndrome, soft tissue sarcoma, sarcoma, splenomegaly, T-cell lymphoma, and thalassemia major. Combination therapy Compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used in combination with one or more agents which act by the same mechanism or by different mechanisms to treat a disease. The different agents may be administered sequentially or simultaneously, in separate compositions or in the same composition. Useful classes of agents for combination therapy include, but are not limited to, a beta 2 adrenoceptor agonist, a muscarinic receptor antagonist, a glucocorticoid agonist, a G-protein coupled receptor-44 antagonist, a leukotriene D4 antagonist, a muscarinic M3 receptor antagonist, a histamine H1 receptor antagonist, an immunoglobulin E antagonist, a PDE 4 inhibitor, an IL-4 antagonist, a muscarinic M1 receptor antagonist, a histamine receptor antagonist, an IL-13 antagonist, an IL-5 antagonist, a 5-Lipoxygenase inhibitor, a beta adrenoceptor agonist, a CCR3 chemokine antagonist, a CFTR stimulator, an immunoglobulin modulator, an interleukin 33 ligand inhibitor, a PDE 3 inhibitor, a phosphoinositide-3 kinase delta inhibitor, a thromboxane A2 antagonist, an elastase inhibitor, a Kit tyrosine kinase inhibitor, a leukotriene E4 antagonist, a leukotriene antagonist, a PGD2 antagonist, a TNF alpha ligand inhibitor, a TNF binding agent, a complement cascade inhibitor, an eotaxin ligand inhibitor, a glutathione reductase inhibitor, an histamine H4 receptor antagonist, an IL-6 antagonist, an IL2 gene stimulator, an immunoglobulin gamma Fc receptor IIB modulator, an interferon gamma ligand, an interleukin 13 ligand inhibitor, an interleukin 17 ligand inhibitor, a L-Selectin antagonist, a leukocyte elastase inhibitor, a leukotriene C4 antagonist, a Leukotriene C4 synthase inhibitor, a membrane copper amine oxidase inhibitor, a metalloprotease-12 inhibitor, a metalloprotease-9 inhibitor, a mite allergen modulator, a muscarinic receptor modulator, a nicotinic acetylcholine receptor agonist, a nuclear factor kappa B inhibitor, a p-Selectin antagonist, a PDE 5 inhibitor, a PDGF receptor antagonist, a phosphoinositide-3 kinase gamma inhibitor, a TLR-7 agonist, a TNF antagonist, an Abl tyrosine kinase inhibitor, an acetylcholine receptor antagonist, an acidic mammalian chitinase inhibitor, an ACTH receptor agonist, an actin polymerization modulator, an adenosine A1 receptor antagonist, an adenylate cyclase stimulator, an adrenoceptor antagonist, an adrenocorticotrophic hormone ligand, an alcohol dehydrogenase 5 inhibitor, an alpha 1 antitrypsin stimulator, an alpha 1 proteinase inhibitor, an androgen receptor modulator, an angiotensin converting enzyme 2 stimulator, an ANP agonist, a Bcr protein inhibitor, a beta 1 adrenoceptor antagonist, a beta 2 adrenoceptor antagonist, a beta 2 adrenoceptor modulator, a beta amyloid modulator, a BMP10 gene inhibitor, a BMP15 gene inhibitor, a calcium channel inhibitor, a cathepsin G inhibitor, a CCL26 gene inhibitor, a CCR3 chemokine modulator, a CCR4 chemokine antagonist, a cell adhesion molecule inhibitor, a chaperonin stimulator, a chitinase inhibitor, a collagen I antagonist, a complement C3 inhibitor, a CSF-1 antagonist, a CXCR2 chemokine antagonist, a cytokine receptor common beta chain modulator, a cytotoxic T-lymphocyte protein-4 stimulator, a deoxyribonuclease I stimulator, a deoxyribonuclease stimulator, a dipeptidyl peptidase I inhibitor, a DNA gyrase inhibitor, a DP prostanoid receptor modulator, an E-Selectin antagonist, an EGFR family tyrosine kinase receptor inhibitor, an elastin modulator, an Endothelin ET-A antagonist, an Endothelin ET-B antagonist, an epoxide hydrolase inhibitor, a FGF3 receptor antagonist, a Fyn tyrosine kinase inhibitor, a GATA 3 transcription factor inhibitor, a Glucosylceramidase modulator, a Glutamate receptor modulator, a GM-CSF ligand inhibitor, a Guanylate cyclase stimulator, a H+ K+ ATPase inhibitor, an hemoglobin modulator, an Heparin agonist, an Histone deacetylase inhibitor, an Histone deacetylase-2 stimulator, an HMG CoA reductase inhibitor, an I-kappa B kinase beta inhibitor, an ICAM1 gene inhibitor, an IL-17 antagonist, an IL-17 receptor modulator, an IL-23 antagonist, an IL-4 receptor modulator, an Immunoglobulin G modulator, an Immunoglobulin G1 agonist, an Immunoglobulin G1 modulator, an Immunoglobulin epsilon Fc receptor IA antagonist, an Immunoglobulin gamma Fc receptor IIB antagonist, an Immunoglobulin kappa modulator, an Insulin sensitizer, an Interferon beta ligand, an Interleukin 1 like receptor antagonist, an Interleukin 18 ligand inhibitor, an Interleukin receptor 17A antagonist, an Interleukin-1 beta ligand inhibitor, an Interleukin-5 ligand inhibitor, an Interleukin-6 ligand inhibitor, a KCNA voltage-gated potassium channel-3 inhibitor, a Kit ligand inhibitor, a Laminin-5 agonist, a Leukotriene CysLT1 receptor antagonist, a Leukotriene CysLT2 receptor antagonist, a LOXL2 gene inhibitor, a Lyn tyrosine kinase inhibitor, a MARCKS protein inhibitor, a MDR associated protein 4 inhibitor, a Metalloprotease-2 modulator, a Metalloprotease-9 modulator, a Mineralocorticoid receptor antagonist, a Muscarinic M2 receptor antagonist, a Muscarinic M4 receptor antagonist, a Muscarinic M5 receptor antagonist, a Natriuretic peptide receptor A agonist, a Natural killer cell receptor modulator, a Nicotinic ACh receptor alpha 7 subunit stimulator, a NK cell receptor modulator, a Nuclear factor kappa B modulator, an opioid growth factor receptor agonist, a P-Glycoprotein inhibitor, a P2X3 purinoceptor antagonist, a p38 MAP kinase inhibitor, a Peptidase 1 modulator, a phospholipase A2 inhibitor, a phospholipase C inhibitor, a plasminogen activator inhibitor 1 inhibitor, a platelet activating factor receptor antagonist, a PPAR gamma agonist, a prostacyclin agonist, a protein tyrosine kinase inhibitor, a SH2 domain inositol phosphatase 1 stimulator, a signal transduction inhibitor, a sodium channel inhibitor, a STAT-3 modulator, a Stem cell antigen-1 inhibitor, a superoxide dismutase modulator, a T cell surface glycoprotein CD28 inhibitor, a T-cell surface glycoprotein CD8 inhibitor, a TGF beta agonist, a TGF beta antagonist, a thromboxane synthetase inhibitor, a thymic stromal lymphoprotein ligand inhibitor, a thymosin agonist, a thymosin beta 4 ligand, a TLR-8 agonist, a TLR-9 agonist, a TLR9 gene stimulator, a Topoisomerase IV inhibitor, a Troponin I fast skeletal muscle stimulator, a Troponin T fast skeletal muscle stimulator, a Type I IL-1 receptor antagonist, a Type II TNF receptor modulator, an ion channel modulator, a uteroglobin stimulator, and a VIP agonist. Specific agents that may be used in combination with the present JAK inhibitor compounds include, but are not limited to rosiptor acetate, umeclidinium bromide, secukinumab, metenkefalin acetate, tridecactide acetate, fluticasone propionate, alpha-cyclodextrin-stabilized sulforaphane, tezepelumab, mometasone furoate, BI-1467335, dupilumab, aclidinium, formoterol, AZD-1419, HI-1640V, rivipansel, CMP-001, mannitol, ANB-020, omalizumab, tregalizumab, Mitizax, benralizumab, golimumab, roflumilast, imatinib, REGN-3500, masitinib, apremilast, RPL-554, Actimmune, adalimumab, rupatadine, parogrelil, MK-1029, beclometasone dipropionate, formoterol fumarate, mogamulizumab, seratrodast, UCB-4144, nemiralisib, CK-2127107, fevipiprant, danirixin, bosentan, abatacept, EC-18, duvelisib, dociparstat, ciprofloxacin, salbutamol HFA, erdosteine, PrEP-001, nedocromil, CDX-0158, salbutamol, enobosarm, R-TPR-022, lenzilumab, fluticasone furoate, vilanterol trifenatate, fluticasone propionate, salmeterol, PT-007, PRS-060, remestemcel-L, citrulline, RPC-4046, nitric oxide, DS-102, gerilimzumab, Actair, fluticasone furoate, umeclidinium, vilanterol, AG- NPP709, Gamunex, infliximab, Ampion, acumapimod, canakinumab, INS-1007, CYP-001, sirukumab, fluticasone propionate, mepolizumab, pitavastatin, solithromycin, etanercept, ivacaftor, anakinra, MPC-300-IV, glycopyrronium bromide, aclidinium bromide, FP-025, risankizumab, glycopyrronium, formoterol fumarate, Adipocell, YPL-001, tiotropium bromide, glycopyrronium bromide, indacaterol maleate, andecaliximab, olodaterol, esomeprazole, dust mite vaccine, mugwort pollen allergen vaccine, vamorolone, gefapixant, revefenacin, gefitinib, ReJoin, tipelukast, bedoradrine, SCM-CGH, SHP-652, RNS-60, brodalumab, BIO-11006, umeclidinium bromide, vilanterol trifenatate, ipratropium bromide, tralokinumab, PUR-1800, VX-561, VX-371, olopatadine, tulobuterol, formoterol fumarate, triamcinolone acetonide, reslizumab, salmeterol xinafoate, fluticasone propionate, beclometasone dipropionate, formoterol fumarate, tiotropium bromide, ligelizumab, RUTI, bertilimumab, omalizumab, glycopyrronium bromide, SENS-111, beclomethasone dipropionate, CHF-5992, LT-4001, indacaterol, glycopyrronium bromide, mometasone furoate, fexofenadine, glycopyrronium bromide, azithromycin, AZD-7594, formoterol, CHF-6001, batefenterol, OATD-01, olodaterol, CJM-112, rosiglitazone, salmeterol, setipiprant, inhaled interferon beta, AZD-8871, plecanatide, fluticasone, salmeterol, eicosapentaenoic acid monoglycerides, lebrikizumab, RG-6149, QBKPN, Mometasone, indacaterol, AZD-9898, sodium pyruvate, zileuton, CG-201, imidafenacin, CNTO-6785, CLBS-03, mometasone, RGN-137, procaterol, formoterol, CCI- 15106, POL-6014, indacaterol, beclomethasone, MV-130, GC-1112, Allergovac depot , MEDI- 3506, QBW-251, ZPL-389, udenafil, GSK-3772847, levocetirizine, AXP-1275, ADC-3680, timapiprant, abediterol, AZD-7594, ipratropium bromide, salbutamol sulfate, tadekinig alfa, ACT-774312, dornase alfa, iloprost, batefenterol, fluticasone furoate, alicaforsen, ciclesonide, emeramide, arformoterol, SB-010, Ozagrel, BTT-1023, Dectrekumab, levalbuterol, pranlukast, hyaluronic acid, GSK-2292767, Formoterol, NOV-14, Lucinactant, salbutamol, prednisolone, ebastine, dexamethasone cipecilate, GSK-2586881, BI-443651, GSK-2256294, VR-179, VR- 096, hdm-ASIT+, budesonide, GSK-2245035, VTX-1463, Emedastine, dexpramipexole, levalbuterol, N-6022, dexamethasone sodium phosphate, PIN-201104, OPK-0018, TEV-48107, suplatast, BI-1060469, Gemilukast, interferon gamma, dalazatide, bilastine, fluticasone propionate, salmeterol xinafoate, RP-3128, bencycloquidium bromide, reslizumab, PBF-680, CRTH2 antagonist, Pranlukast, salmeterol xinafoate, fluticasone propionate, tiotropium bromide monohydrate, masilukast, RG-7990, Doxofylline, abediterol, glycopyrronium bromide, TEV- 46017, ASM-024, fluticasone propionate, glycopyrronium bromide, salmeterol xinafoate, salbutamol, TA-270, Flunisolide, sodium chromoglycate, Epsi-gam, ZPL-521, salbutamol, aviptadil, TRN-157, Zafirlukast, Stempeucel, pemirolast sodium, nadolol, fluticasone propionate + salmeterol xinafoate, RV-1729, salbutamol sulfate, carbon dioxide + perfluorooctyl bromide, APL-1, dectrekumab + VAK-694, lysine acetylsalicylate, zileuton, TR-4, human allogenic adipose-derived mesenchymal progenitor cell therapy, MEDI-9314, PL-3994, HMP-301, TD- 5471, NKTT-120, pemirolast, beclomethasone dipropionate, trantinterol, monosodium alpha luminol, IMD-1041, AM-211, TBS-5, ARRY-502, seratrodast, recombinant midismase, ASM-8, deflazacort, bambuterol, RBx-10017609, ipratropium + fenoterol, fluticasone + formoterol, epinastine, WIN-901X, VALERGEN-DS,OligoG-COPD-5/20, tulobuterol, oxis Turbuhaler, DSP-3025, ASM-024, mizolastine, budesonide + salmeterol, LH-011, AXP-E, histamine human immunoglobulin, YHD-001, theophylline, ambroxol + erdosteine, ramatroban, montelukast, pranlukast, AG-1321001, tulobuterol, ipratropium + salbutamol, tranilast, methylprednisolone suleptanate, colforsin daropate, repirinast, and doxofylline. Also provided, herein, is a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. The therapeutic agent may be selected from the class of agents specified above and from the list of specific agents described above. In some embodiments, the pharmaceutical composition is suitable for delivery to the lungs. In some embodiments, the pharmaceutical composition is suitable for inhaled or nebulized administration. In some embodiments, the pharmaceutical composition is a dry powder or a liquid composition. Further, in a method aspect, the present disclosure provides a method of treating a disease or disorder in a mammal (e.g. a human) comprising administering to the mammal (or human) a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. When used in combination therapy, the agents may be formulated in a single pharmaceutical composition, or the agents may be provided in separate compositions that are administered simultaneously or at separate times, by the same or by different routes of administration. Such compositions can be packaged separately or may be packaged together as a kit. The two or more therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration. EXAMPLES The following synthetic and biological examples are offered to illustrate the disclosure, and are not to be construed in any way as limiting the scope of the disclosure. In the examples below, the following abbreviations have the following meanings unless otherwise indicated. Abbreviations not defined below have their generally accepted meanings. ACN = acetonitrile DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMA = Dimethylacetamide DMSO = Dimethyl sulfoxide DMF = N,N-dimethylformamide EtOAc = ethyl acetate h = hour(s) HATU= N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HBTU = N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate IPA = isopropyl alcohol MeOH= methanol min = minute(s) Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0) RT = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran bis(pinacolato)diboron = 4,4,5,5,4',4',5',5'-octamethyl- [2,2']bi[[1,3,2]dioxaborolanyl] Reagents and solvents were purchased from commercial suppliers (Aldrich, Fluka, Sigma, etc.), and used without further purification. Progress of reaction mixtures was monitored by thin layer chromatography (TLC), analytical high performance liquid chromatography (anal. HPLC), and mass spectrometry. Reaction mixtures were worked up as described specifically in each reaction; commonly they were purified by extraction and other purification methods such as temperature-, and solvent-dependent crystallization, and precipitation. In addition, reaction mixtures were routinely purified by column chromatography or by preparative HPLC, typically using C18 or BDS column packings and conventional eluents. Typical preparative HPLC conditions are described below. Characterization of reaction products was routinely carried out by mass and 1H-NMR spectrometry. For NMR analysis, samples were dissolved in deuterated solvent ( such as CD3OD, CDCl3, or d6-DMSO), and 1H-NMR spectra were acquired with a Varian Gemini 2000 instrument (400 MHz) under standard observation conditions. Mass spectrometric identification of compounds was performed by an electrospray ionization method (ESMS) with an Applied Biosystems (Foster City, CA) model API 150 EX instrument or a Waters (Milford, MA) 3100 instrument, coupled to autopurification systems. Preparative HPLC Conditions Column: C18, 5 µm. 21.2 x 150 mm or C18, 5 µm 21 x 250 or C14, 5 µm 21x150 mm Column temperature: Room Temperature Flow rate: 20.0 mL/min Mobile Phases: A = Water + 0.05 % TFA B = ACN + 0.05 % TFA, Injection volume: (100-1500 µL) Detector wavelength: 214 nm Crude compounds were dissolved in 1:1 water:acetic acid at about 50 mg/mL . A 4 minute analytical scale test run was carried out using a 2.1 x 50 mm C18 column followed by a 15 or 20 minute preparative scale run using 100 µL injection with the gradient based on the % B retention of the analytical scale test run. Exact gradients were sample dependent. Samples with close running impurities were checked with a 21 x 250 mm C18 column and/or a 21 x 150 mm C14 column for best separation. Fractions containing desired product were identified by mass spectrometric analysis. Preparation of 2-(4-(benzyloxy)-2-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (I-4)
Figure imgf000036_0001
1-(benzyloxy)-3-ethylbenzene (I-2) To a stirred solution of 3-ethylphenol (I-1) (25.0 g, 204.0 mmol) in ACN (250 mL, 10 vol) was added potassium carbonate (42.0 g, 306 mmol) at room temperature. The resulting reaction mass was stirred at room temperature for 15 minutes, followed by the addition of benzyl bromide (24.0 mL, 204 mmol) in drop wise manner. The resulting reaction mixture was stirred for 6 hours at room temperature. After completion of the reaction (TLC monitoring), the resulting reaction mass was poured into water (1.0 L) followed by the extraction of compound with EtOAc (2 x 2L). The combined organics were washed with cold water, brine solution and dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was then purified by column chromatography over silica gel (100-200M) by using eluents 2% EtOAc in hexane to get the desired product (I-2) as a light yellow oily compound (35.0 g, 81%). 1H NMR (400 MHz, chloroform-d) δ 7.46-7.44 (m, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.34-7.31 (m, 1H), 7.21 (t, J = 7.6 Hz), 6.86-6.80 (m, 3H), 5.07 (s, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). 4-(benzyloxy)-1-bromo-2-ethylbenzene (I-3) To an ice cold stirred solution of 1-(benzyloxy)-3-ethylbenzene (I-2) (35.0 g, 164 mmol) in ACN (525 mL, 15 vol) was added N-bromosuccinimide (32.0 g 181 mmol) in portions over a period of 15 minutes. The resulting reaction mixture was stirred for next 1 hour at room temperature. After completion of reaction (TLC monitoring), the resulting reaction mass was poured into ice cold water (1.50 L) followed by the extraction of compound with EtOAc (2 x 1L). The combined organics were washed with water and dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude product. n-Hexane (250 mL) was added to the crude material, resulting in a slurry, followed by filtration through a sintered funnel. Mother liquor was evaporated under reduced pressure to obtain the desired product I-3 as a light yellow oily compound (42.0 g, 87%). 1H NMR (400 MHz, chloroform-d) δ 7.52-7.29 (m, 7H), 6.88 (s, 1H), 6.68 (d, J = 6.0 Hz, 1H), 5.04 (s, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H). 2-(4-(Benzyloxy)-2-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-4) A stirred solution of 4-(benzyloxy)-1-bromo-2-ethylbenzene (I-3) (42.0 g, 144 mmol), bis(pinacolato) diboron (44.0 g, 173 mmol), and potassium acetate (28 g, 288 mmol) in dioxane (440 mL) was degassed by purging N2 (g) for 15 min followed by addition of PdCl2(dppf).DCM complex (11.0 g, 15 mmol). The resulting reaction mixture was heated up to 80°C for next 16h. After completion of the reaction (TLC monitoring), the reaction mass was filtered through celite bed and mother liquor was evaporated under reduced pressure to obtain the crude product. Crude residue was purified by column chromatography over silica gel (100-200M) by using eluents 1% EtOAc in hexane to get the desired product (I-4) as a light yellow oily compound (32.0 g, 66%). 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.4 Hz, 1H), 7.45-7.36 (m, 5H), 6.84-6.78 (m, 2H), 5.08 (s, 2H), 2.91 (q, J = 7.6 Hz), 1.33 (s, 12H), 1.19 (t, J = 7.6 Hz, 3H).
Preparation of tert-butyl 1-benzyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate (I-8)
Figure imgf000038_0001
4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (I-6) To a stirred solution of 2-(1H-imidazol-5-yl)ethan-1-amine (I-5) (50.0 g, 271.73 mmol) in 0.01M HCl (500 mL) was added diethoxymethane (68.19 mL, 543.47 mmol). The resulting solution was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under vacuum and the resulting residue was triturated with ACN followed by diethyl ether and dried to afford the desired product as the dihydrochloride salt as a crude, off-white solid (57.0 g) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 2H), 8.98 (s, 1H), 4.28 (s, 2H), 3.61 (s, 2H), 3.41 (t, J = 6.1 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H). (m/z): [M+H]+ calcd for C6H10N3124.08 found 124.05. tert-Butyl 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (I-7) To a stirred solution of I-6 (57 g, 290.81 mmol) in methanol (500 mL) was added DIPEA (130.5 mL, 727.04 mmol) followed by addition of di-tert-butyl dicarbonate (155.3 mL, 727.04 mmol). The resulting solution was allowed to stir at room temperature. After stirring for 16 hours, NH4OH solution (100 mL) was added and allowed to stir overnight at room temperature for 16 hours. The solvent was removed and the gummy material was diluted with water (500 mL) and extracted in 5% MeOH-DCM (3x500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product (41.0 g) which was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 4.32 (s, 2H), 3.60 (t, J = 5.8 Hz, 2H), 2.56 (t, J = 5.7 Hz, 2H), 1.41 (s, 9H). (m/z): [M+H]+ calcd for C11H18N3O2224.14 found 224.10. tert-Butyl 1-benzyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (I-8) To a stirred solution of I-7 (31.0 g, 139.01 mmol) in DMF (200 mL) at 0 °C was added NaH (8.34 g, 208.5 mmol) and the mixture was stirred for 30 minutes. Benzylbromide (18.15 mL, 152.9 mmol) was then added to the reaction mixture and it was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography by using eluents 5% MeOH in DCM to obtain the desired product (21.0 g, 48% yield). The product was isolated as a mixture of benzyl isomers and used as is in the subsequent step. Major Diastereomer: 1H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.38-7.34 (m, 3H), 7.19 (m, 2H), 5.12 (s, 2H), 4.26 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.42 (t, J = 5.8 Hz, 2H), 1.38 (s, 9H). (m/z): [M+H]+ calcd for C18H24N3O2314.18 found 314.14. Preparation of 4'-(benzyloxy)-2'-ethyl-3-fluoro-[1,1'-biphenyl]-4-carboxylic acid (I-
Figure imgf000039_0001
Methyl 4-bromo-2-fluorobenzoate (I-10) To a stirred solution of I-9 (30.0 g, 138.24 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL, 276.48 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was heated to reflux. After 3 hours, the reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3x300 mL). The combined organic layers were further washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced vacuum to obtain the crude desired product (34 g) that was used directly in the subsequent step without further purification. 1H NMR (400 MHz, Chloroform-d) δ 7.87 – 7.78 (m, 1H), 7.40 – 7.31 (m, 2H), 3.93 (s, 3H). Methyl 4'-(benzyloxy)-2'-ethyl-3-fluoro-[1,1'-biphenyl]-4-carboxylate (I-11) To a stirred solution of I-10 (20.0 g, 86.58 mmol) in a dioxane:water mixture (180:20 mL) was added I-4 (29.28 g, 86.58 mmol) and K3PO4 (45.94 g, 216.45 mmol). The reaction mixture was purged with argon for 10 minutes, after which Pd(PPh3)4 (10.0g, 8.65mmol) was added to the reaction mixture and the reaction was heated to 110 °C and stirred for 16 hours under an argon atmosphere. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was filtered through a Celite pad and the filtrate was diluted with water and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (10% EtOAc in hexanes) to obtain the desired product (24.0 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.31 – 7.21 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 8.5, 2.7 Hz, 1H), 5.15 (s, 2H), 3.88 (s, 3H), 2.55 (q, J = 9.2, 8.3 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H). (m/z): [M+H]+ calcd for C23H21FO3365.15 found 365.17. 4'-(benzyloxy)-2'-ethyl-3-fluoro-[1,1'-biphenyl]-4-carboxylic acid (I-12) To a stirred solution of I-11 (24.0 g, 65.93 mmol) in a THF:H2O mixture (200:200 mL) was added lithium hydroxide monohydrate (14.14 g, 329.67 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 hours (monitored by TLC). The reaction mixture was then cooled to 0 °C and 1N HCl was added until the solution reached pH ~1. The reaction was extracted by ethyl acetate (2x200 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the desired product as an off white solid (21.0 g, 91.3% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.22 (dd, J = 9.5, 4.9 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.92 (dd, J = 8.5, 2.7 Hz, 1H), 5.15 (s, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H). (m/z): [M+H]+ calcd for C22H20FO3354.14 found 351.17. Preparation of 3-ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H- indazol-6-yl)phenol (I-17)
Figure imgf000040_0001
tert-Butyl 1-benzyl-2-(4'-(benzyloxy)-2'-ethyl-3-fluoro-[1,1'-biphenyl]-4-carbonyl)- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (I-14) To a stirred solution of I-12 (13.5 g, 38.52 mmol) in DCM (100 mL) was added oxalyl chloride (68 mL) drop wise at 0 °C followed by DMF (0.2 mL). The resulting reaction mixture was allowed to stir at 50 °C for 2 hours. After completion of reaction (by TLC monitoring, checked by quenching in MeOH), the reaction mixture was evaporated under nitrogen to obtain crude I-13. To a stirred solution of I-8 (10.0 g, 31.90 mmol) in ACN (50 mL) was added Et3N (22.4 mL, 159.54 mmol). Compound I-13 (14.20 g, 38.28 mmol) was separately dissolved in ACN (30 mL) and was added to the reaction mixture dropwise at room temperature. The resulting solution was stirred at room temperature for 30 minutes (monitored by TLC and LCMS). The reaction mixture was quenched with cold water (200 mL) and extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with brine (300 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by silica gel column chromatography (15% EtOAc in heptane) to afford the desired product (10.0 g, 48.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.68 (q, J = 7.1 Hz, 1H), 7.48 (d, J = 7.5 Hz, 2H), 7.45 – 7.26 (m, 6H), 7.26 – 7.11 (m, 5H), 7.01 (d, J = 2.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.71 (d, J = 7.9 Hz, 2H), 5.16 (s, 2H), 4.44 (s, 1H), 4.37 (s, 1H), 3.65 (dd, J = 12.7, 6.5 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.58 (q, J = 7.3 Hz, 2H), 1.39 (s, 9H), 1.07 (t, J = 7.4 Hz, 3H). (m/z): [M+H]+ calcd for C40H41FN3O4646.30 found 646.36. tert-Butyl 1-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-1H-indazol-3-yl)-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (I-15) To a stirred solution of I-14 (10.0 g, 15.48 mmol) in DMSO (70 mL) was added hydrazine hydrate (7.5 mL, 154.8 mmol). The reaction mixture was heated to 90 °C and stirred for 3 hours. Progress of the reaction was monitored by TLC and LCMS. The resulting reaction mixture was poured into ice water and extracted with ethyl acetate (2x200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude mixture was then purified by silica gel column chromatography (25% EtOAc in heptane) to obtain the desired product (8.1 g, 81.8 % yield). 1H NMR (400 MHz, DMSO-d6) δ 13.22 (d, J = 5.5 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.38 – 7.28 (m, 4H), 7.30 – 7.19 (m, 1H), 7.19 – 7.10 (m, 4H), 7.01 (d, J = 2.7 Hz, 1H), 6.92 (dd, J = 8.5, 2.8 Hz, 1H), 5.86 (d, J = 5.6 Hz, 2H), 5.15 (s, 2H), 4.44 (s, 1H), 4.32 (s, 1H), 3.64 (q, J = 5.2 Hz, 2H), 2.66 (s, 1H), 2.61 – 2.51 (m, 3H), 1.41 (s, 9H), 1.04 (t, J = 7.4 Hz, 3H). (m/z): [M+H]+ calcd for C40H41N5O3640.32 found 640.32. tert-Butyl 2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate (I-16) To a stirred solution of I-15 (8.1 g, 12.60 mmol) in a IPA:THF mixture (70:30 mL) was added 10% Pd/C (8.0 g). The reaction mixture was sealed and subjected to hydrogenation using a H2 balloon and allowed to stir at room temperature for two days. Progress of the reaction was monitored by TLC. The reaction mixture was filtered on a Celite pad and the filtrate was concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (5% MeOH in DCM) to afford the desired product as an off-white solid (3.4 g, 58.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 12.47 (s, 1H), 9.39 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 7.12 – 7.02 (m, 2H), 6.75 (d, J = 2.5 Hz, 1H), 6.67 (dd, J = 8.2, 2.5 Hz, 1H), 4.43 (s, 2H), 3.67 (t, J = 5.7 Hz, 2H), 2.66 (s, 2H), 2.53 (q, J = 7.5 Hz, 2H), 1.44 (s, 9H), 1.03 (t, J = 7.5 Hz, 3H). (m/z): [M+H]+ calcd for C26H30N5O3460.23 found 460.32. 3-Ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (I-17) To a stirred solution of I-16 (3.4 g, 7.40 mmol) in DCM (40 mL) was added TFA (35 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 2 hours. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was evaporated under vacuum and the residual solid was triturated with diethyl ether to afford the desired product as an off white solid (3.75 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.20 (dd, J = 8.4, 1.4 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 6.68 (dd, J = 8.2, 2.6 Hz, 1H), 4.31 (s, 2H), 3.50 (t, J = 6.1 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.47 (d, J = 7.4 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H). (m/z): [M+H]+ calcd for C21H22N5O 360.18 found 360.19.
Example 1: (S)-2-amino-1-[2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl]-3-hydroxy-3-methylbutan-1-one (1)
Figure imgf000043_0001
3-Ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6- yl)phenol, HCl (I-17) (0.25 g, 0.631 mmol), Boc-(S)-2-amino-3-hydroxy-3-methylbutanoic acid (0.177 g, 0.758 mmol), and DIPEA (0.276 ml, 1.579 mmol) were dissolved in DMF (5 ml), then HATU (0.288 g, 0.758 mmol) was added and the reaction mixture was stirred at room temperature until judged complete by LCMS (22 hours). Hydrazine (0.099 ml, 3.16 mmol) was and the reaction mixture was dripped in 50 mL of water to precipitate out the product. The resulting solid was then collected by filtration and dried under vacuum to provide 189 mg of the Boc-protected intermediate I-18. The Boc-protected intermediate was dissolved in dioxane (2.5 ml) and water (0.5 ml), then HCl, 4 M in dioxane (2.5 ml, 10.00 mmol) was added and the reaction mixture was stirred at room temperature until judged complete by LCMS (3 hours). The reaction mixture was then frozen and lyophilized, and the resulting solid was purified by preparative HPLC (5-70% ACN/water, C18 column) to provide the TFA salt of the title compound (150 mg, 40% yield). (m/z): [M+H]+ calcd for C26H30N6O3475.24 found 475.2. 1H NMR (600 MHz, Methanol-d4) δ 8.08 (t, J = 9.2 Hz, 1H), 7.44 (d, J = 4.5 Hz, 1H), 7.22 (dd, J = 8.4, 6.0 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.98 (d, J = 16.4 Hz, 1H), 4.87 (s, 1H), 4.64 (d, J = 16.4 Hz, 1H), 4.48 (d, J = 22.3 Hz, 1H), 4.15 – 4.06 (m, 1H), 3.97 – 3.91 (m, 1H), 3.01 – 2.79 (m, 2H), 2.46 (q, J = 7.5 Hz, 2H), 1.27 (dd, J = 19.9, 5.7 Hz, 6H), 0.96 (t, J = 7.5 Hz, 3H). Example 2: (S)-2-amino-1-[2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl]-3-phenylpropan-1-one (2)
Figure imgf000044_0001
3-Ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6- yl)phenol, HCl (I-17) (0.50 g, 1.263 mmol), Boc-Phe-OH (0.402 g, 1.516 mmol), and DIPEA (0.662 ml, 3.79 mmol) were dissolved in DMF (8.0 ml), then HATU (0.576 g, 1.516 mmol) was added and the reaction mixture was stirred at room temperature until judged complete by LCMS (24 hours). Hydrazine (0.198 ml, 6.31 mmol) was added, then the reaction mixture was dripped into 75 mL of water to precipitate out the product. The product was collected by filtration, washed with water, then dried under vacuum to provide 639 mg of the crude Boc-protected intermediate I-19. The intermediate was dissolved in 8 mL of TFA and the reaction mixture was stirred at room temperature until judged complete by LCMS (1 hour). The reaction mixture was concentrated, then the crude product was purified by reverse phase chromatography (5-70% ACN/Water, 150 g C18aq column) to provide the TFA salt of the title compound (486 mg, 76% yield). (m/z): [M+H]+ calcd for C30H30N6O2507.25 found 507.2. 1H NMR (600 MHz, Methanol-d4) δ 8.02 (dd, J = 8.5, 4.3 Hz, 1H), 7.41 (d, J = 15.3 Hz, 1H), 7.25 – 7.12 (m, 4H), 7.03 (t, J = 7.5 Hz, 1H), 6.95 (dd, J = 11.8, 8.2 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.67 (dd, J = 6.4, 2.4 Hz, 1H), 6.58 (ddd, J = 8.4, 6.2, 2.4 Hz, 1H), 4.62 (d, J = 16.3 Hz, 1H), 4.40 (dt, J = 13.2, 4.6 Hz, 1H), 4.29 (d, J = 15.6 Hz, 1H), 3.98 (d, J = 15.6 Hz, 1H), 3.59 – 3.52 (m, 1H), 3.44 – 3.28 (m, 1H), 3.18 – 3.02 (m, 1H), 2.92 (dd, J = 12.9, 10.6 Hz, 1H), 2.68 – 2.59 (m, 2H), 2.49 – 2.40 (m, 2H), 2.04 – 1.98 (m, 1H), 0.95 (dt, J = 10.9, 7.6 Hz, 3H). Example 3: (S)-2-amino-1-[2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl]-3-methoxypropan-1-one (3)
Figure imgf000045_0001
3-Ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6- yl)phenol, HCl (I-17) (10 g, 25.3 mmol), Boc-Ser(Me)-OH (6.65 g, 30.3 mmol), and DIPEA (11.03 ml, 63.1 mmol) were dissolved in DMF (100 ml), then the reaction flask was placed in a water bath to blunt any exotherm. HATU (11.53 g, 30.3 mmol) was then added and the reaction mixture was stirred at room temperature until judged complete by LCMS (3 hours). Hydrazine (3.96 ml, 126 mmol) was added, followed by the addition of 10 mL of methanol to better solubilize a thick slurry that formed. The solution was then dripped into 500 mL of water with stirring to precipitate out the product as a white solid, which was then collected by filtration and dried under vacuum. The Boc-protected intermediate I-20 was dissolved in dioxane (70 ml) and water (14 ml), then HCl, 4 M in dioxane (70 ml, 280 mmol) was added and the reaction mixture was stirred at room temperature until judged complete by LCMS (5 hours). The reaction mixture was then frozen and lyophilized, and the resulting solid was purified by reverse phase chromatography (5-70% ACN/water, 150 g C18aq column, 7 batches) to provide the TFA salt of the title compound (7.88 g, 54% yield). (m/z): [M+H]+ calcd for C25H28N6O3461.23 found 461.3.1H NMR (600 MHz, Methanol-d4) δ 8.20 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 8.3, 2.4 Hz, 1H), 5.05 – 4.76 (m, 5H), 4.10 – 3.98 (m, 1H), 3.96 – 3.70 (m, 2H), 3.46 (d, J = 22.5 Hz, 3H), 3.16 – 2.90 (m, 2H), 2.58 (q, J = 7.6 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H). General Procedure for the Preparation of Compounds
Figure imgf000046_0001
3-ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol, HCl (I-17) (1 eq), a carboxylic acid reactant (1.5 eq), and DIPEA (3 eq) were dissolved in DMF at a 0.05-0.1 M concentration of I-17, then HATU (1.5 eq) was added and the reaction mixture was stirred at room temperature until judged complete by LCMS (2 to 24 hours). Hydrazine (5 eq) was then added, and the reaction mixture was concentrated. The crude product was then dissolved in TFA (equal to the volume of DMF previously used). After the reaction was judged complete by LCMS (10 minutes to 1 hour) the reaction mixture was concentrated, then the crude product was purified by preparative HPLC (5-70% ACN/water gradient with 0.05% TFA, C18 column). Example 4: (S)-2,6-diamino-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)hexan-1-one
Figure imgf000046_0002
The general procedure was followed on a 0.042 mmol scale, using Boc-Lys(Boc)-OH as the carboxylic acid reactant (22 mg, 0.063 mmol), to provide the TFA salt of the title compound (17.6 mg, 59% yield). (m/z): [M+H]+ calcd for C27H33N7O2488.27 found 488.3. Example 5: 2-amino-3-(1,3-dioxolan-2-yl)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H- indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)propan-1-one
Figure imgf000046_0003
The general procedure was followed on a 0.042 mmol scale, using 2-([(tert-butoxy) carbonyl] amino)-3-(1,3-dioxolan-2-yl)propanoic acid (16 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (7.3 mg, 28% yield). (m/z): [M+H]+ calcd for C27H30N6O4503.24 found 503.2. Example 6: (S)-2-amino-3-(dimethylamino)-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H- indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)propan-1-one
Figure imgf000047_0001
The general procedure was followed on a 0.042 mmol, using Boc-aza-L-leucine (15 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (13.6 mg, 46% yield). (m/z): [M+H]+ calcd for C26H31N7O2474.26 found 474.3. Example 7: (S)-2-amino-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-3-hydroxypropan-1-one
Figure imgf000047_0002
The general procedure was followed on a 0.042 mmol scale, using Boc-Ser-OH (13 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (12.6 mg, 54% yield). (m/z): [M+H]+ calcd for C24H26N6O3447.21 found 447.2. Example 8: (S)-3-amino-4-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-4-oxobutanamide
Figure imgf000047_0003
The general procedure was followed on a 0.042 mmol scale, using Boc-Asn-OH (15 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (11 mg, 45% yield). (m/z): [M+H]+ calcd for C25H27N7O3474.22 found 474.2. Example 9: (S)-3-amino-4-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-4-oxobutanenitrile
Figure imgf000048_0001
The general procedure was followed on a 0.076 mmol scale, using Boc-beta-cyano-L- alanine (24 mg, 0.114 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (19.5 mg, 45% yield). (m/z): [M+H]+ calcd for C25H25N7O2456.21 found 456.2. Example 10: (S)-2-amino-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-3-(1H-imidazol-4-yl)propan-1-one
Figure imgf000048_0002
The general procedure was followed on a 0.042 mmol scale, using Boc-His-OH (16 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (15 mg, 49% yield). (m/z): [M+H]+ calcd for C27H28N8O2497.24 found 497.3. Example 11: (S)-2-amino-2-cyclopropyl-1-(2-(6-(2-ethyl-4-hydroxyphenyl)-1H- indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethan-1-one
Figure imgf000048_0003
The general procedure was followed on a 0.042 mmol scale, using Boc-L- cyclopropylglycine (14 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (9.9 mg, 41% yield). (m/z): [M+H]+ calcd for C26H28N6O2457.23 found 457.2. Example 12: (1-aminocyclopentyl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3- yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone
Figure imgf000049_0001
The general procedure was followed on a 0.042 mmol scale, using aminocyclopentanecarboxylic acid (14 mg, 0.063 mmol) as the carboxylic acid, to provide the TFA salt of the title compound (9.8 mg, 40% yield), with the exception to the general procedure that the use of TFA was not needed, as no Boc protecting group was present. (m/z): [M+H]+ calcd for C27H30N6O2471.25 found 471.3. The compounds in the following Table were prepared using similar synthetic methods and the appropriate reactants.
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Biological Assays The compounds of the present disclosure have been characterized in one or more of the following biological assays. Assay 1: Biochemical JAK Kinase Assays A panel of four LanthaScreen JAK biochemical assays (JAK1, 2, 3 and Tyk2) were carried in a common kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl2, and 1 mM EGTA). Recombinant GST-tagged JAK enzymes and a GFP-tagged STAT1 peptide substrate were obtained from Life Technologies. Serially diluted compounds were pre-incubated with each of the four JAK enzymes and the substrate in white 384-well microplates (Corning) at ambient temperature for 1h. ATP was subsequently added to initiate the kinase reactions in 10 µL total volume, with 1% DMSO. The final enzyme concentrations for JAK1, 2, 3 and Tyk2 are 4.2 nM, 0.1 nM, 1 nM, and 0.25 nM respectively; the corresponding Km ATP concentrations used are 25 µM, 3 µM, 1.6 µM, and 10 µM; while the substrate concentration is 200 nM for all four assays. Kinase reactions were allowed to proceed for 1 hour at ambient temperature before a 10 μL preparation of EDTA (10mM final concentration) and Tb-anti-pSTAT1 (pTyr701) antibody (Life Technologies, 2 nM final concentration) in TR-FRET dilution buffer (Life Technologies) was added. The plates were allowed to incubate at ambient temperature for 1h before being read on the EnVision reader (Perkin Elmer). Emission ratio signals (520nm/495nm) were recorded and utilized to calculate the percent inhibition values based on DMSO and background controls. For dose-response analysis, percent inhibition data were plotted vs. compound concentrations, and IC50 values were determined from a 4-parameter robust fit model with the Prism software (GraphPad Software). Results were expressed as pIC50 (negative logarithm of IC50) and subsequently converted to pKi (negative logarithm of dissociation constant, Ki) using the Cheng-Prusoff equation. Test compounds having a lower Ki value or higher pKi value in the four JAK assays show greater inhibition of JAK activity. Assay 2: Cellular JAKI Potency Assay The JAKI cellular potency assay was carried out by measuring inhibition of interleukin- 13 (IL-13, R&D Systems) induced STAT6 phosphorylation in BEAS-2B human lung epithelial cells (ATCC). BEAS-2B cells were grown at 37°C in a 5% CO2 humidified incubator in 50% DMEM/50% F-12 medium (Life Technologies) supplemented with 10% FBS (Hyclone), 100 U/mL penicillin, 100 µg/mL streptomycin (Life Technologies), and 2 mM GlutaMAX (Life Technologies). On day 1 of the assay, cells were seeded at a 7,500 cells/well density in white poly-D-lysine-coated 384-well plates (Corning) with 25µL medium and were allowed to adhere overnight in the incubator. On day 2 of the assay, the medium was removed and replaced with 12 µL of assay buffer (Hank's Balanced Salt Solution/HBSS, 25mM HEPES, and 1 mg/ml bovine serum albumin/BSA) containing dose-responses of test compounds. Compounds were serially diluted in DMSO and then diluted another 1000-fold in media to bring the final DMSO concentration to 0.1%. Cells were incubated with test compounds at 37°C for 1 h and followed by the addition of 12 μl of pre-warmed IL-13 (80 ng/mL in assay buffer) for stimulation. After incubating at 37°C for 30 min, the assay buffer (containing compound and IL-13) was removed, and 10 μL of cell lysis buffer (25 mM HEPES, 0.1 % SDS, 1 % NP-40, 5 mM MgCl2, 1.3 mM EDTA, 1 mM EGTA, supplemented with Complete Ultra mini protease inhibitors and PhosSTOP from Roche Diagnostics). The plates were shaken at ambient temperature for 30min before the addition of detection reagents. Levels of pSTAT6 were measured using the AlphaLISA SureFire Ultra pSTAT6 (Tyr641) assay kit from PerkinElmer. For dose-response analysis, percent inhibition data were plotted vs. compound concentrations, and IC50 values were determined from a 4-parameter robust fit model with the Graphpad Prism software. Results are expressed as the negative logarithm of the IC50 value, pIC50. Test compounds having a lower IC50 value or higher pIC50 value in this assay show greater inhibition of IL-13 induced STAT6 phosphorylation. Assay 3: Human Liver Microsome Assay The objective of this assay was to assess the metabolic stability of test compounds in an in vitro human liver subcellular fraction, known as liver microsomes. Liver microsomes are obtained from the endoplasmic reticulum of hepatic cells and are a rich source of drug metabolizing enzymes. Human liver microsomes obtained from Sekisui XenoTech (Kansas City, KS)) were thawed on ice and diluted into 0.5 mM potassium phosphate buffer pH 7.4 (Corning, NY). Test compounds or control compounds (10 mM stock solution in DMSO) were diluted in DMSO, acetonitrile and cofactor solution containing NADPH to yield final incubation concentrations of 0.1 mg/mL microsomal protein, 0.1 µM test compound, 1 mM NADPH, 0.0001% DMSO (v/v) and 0.1% acetonitrile (v/v). Incubations were conducted at 37°C and 15 µL sampling aliquots were taken at 0, 5, 15, 30,45, and 60 minutes. Each aliquot was crashed into 55 µL acetonitrile containing 1 µM internal standard, followed by mixing and centrifugation for 5 min at approximately 2074 x g at 4°C. Volumes of 20 µL of supernatant per sample were transferred to wells each containing 50 µL water with 0.1% formic acid (v/v) for injection onto an LC-MS/MS system for analysis. For each incubation, the peak area of the analytes in each t=0 aliquot was set to 100% and the peak areas from subsequent time point aliquots were converted to percentage of parent compound remaining relative to t=0. The percentage of parent compound remaining was converted to natural log scale and plotted versus time in minutes. A linear regression analysis was performed for the initial decline of the parent disappearance profile and a formula for the best-fit line was determined. The slope of the resultant line was normalized to protein concentration in mg/mL protein and CLint was calculated as follows for liver microsomes: CLint (µL/min/mg microsomal protein) = (Slope x 1000)/ [Protein Concentration in mg/mL] An assay was considered valid if the intrinsic clearance for assay controls was within 2 standard deviations of the historic mean CLint value. Controls used in this assay were 7-ethoxycoumarin and propranolol for CYP P450 enzyme activity, and benfluorex and trandolapril for esterase enzyme activity. Assay 4: Aqueous Solubility Assay The purpose of this assay was to quantify the solubility of test compounds in pH 4 and pH 7.4 PBS buffers. The assay required 40 µL of 10 mM DMSO test compound solution per desired buffer in addition to 20 µL required to make a test standard. For example, to test a compound in both buffers, 100 µL (2 * 40 µL + 20 µL) of 10 mM DMSO compound stock solution was required. The standard was created by diluting 20 µL of 10 mM DMSO compound stock solution into 180 µL of methanol and was shaken for five minutes to ensure solution uniformity. The resulting solution had a concentration of 1 mM, or 1,000 µM, of the test compound. This 1,000 µM solution was run on an Agilent 1260 LC-MS system by injecting 2 µL in order to obtain the peak area. For the test solutions, 40 µL of 10 mM DMSO compound stock solution, per PBS buffer condition, were dried down into a powder overnight. Once in powder form, 400 µL of the desired PBS buffer was added to the powder and allowed to shake vigorously for four hours. The maximum theoretical concentration for this sample solution was 1,000 µM. After four hours of shaking, the samples were centrifuged for 10 minutes at 3,000 RPM before injecting 2 µL on the same Agilent 1260 LC-MS system to obtain the peak area. Once the peak areas for the standard and the test solution were determined, the ratio of sample area to standard area * 1,000 yielded the µM solubility of the test compound solution, with a maximum upper limit of 1,000 µM. Table 1 summarizes the results obtained. In Vitro Assay Results The compounds were tested in the four JAK enzyme assays; JAK1, JAK2, JAK3, and Tyk2, and the BEAS-2B cellular potency assay described above. Select compounds were tested in the HLM Clint and solubility assays. In the Table below, for the JAK1, JAK 2, JAK3, and TYK2 enzyme assays, A represents a pKi value ≥ 10 (Ki ≤ 0.1 nM), B represents a pKi value between 9 and 10 (Ki between 1 nM and 0.1 nM), C represents a pKi value between 8 and 9 (Ki between 10 nM and 1 nM), D represents a pKi value between 7 and 8 (Ki between 100 nM and 10 nM), and E represents a pKi value of 7 or below (Ki of 100 nM or above). For the BEAS2B Potency assay, A represents a pIC50 value ≥ 7.5 (IC50 ≤ 32 nM), B represents a pIC50 value between 7 (included) and 7.5, C represents a pIC50 value between 6.5 (included) and 7, and D represents a pIC50 value between 6.0 (included) and 6.5. For the HLM Clint assay, A represents a value between 1500 and 2000, B represents a value between 1000 and 1500, C represents a value between 500 and 1000, and D represents a value between 100 and 500. For the Solubility assays, A represents a value between 500 and 1000, B represents a value between 250 and 500, C represents a value between 100 and 250, and D represents a value between 50 and 100, and E represents a value between 20 and 50. Table 1
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Assay 5: Murine (Mouse) model of IL-13 induced pSTAT6 induction in lung tissue IL-13 binds to cell surface receptors activating members of the Janus family of kinases (JAK) which then phosphorylate STAT6 and subsequently activates further transcription pathways. In the described model, a dose of IL-13 was delivered locally into the lungs of mice to induce the phosphorylation of STAT6 (pSTAT6) which is then measured as the endpoint. Adult balb/c mice from Harlan were used in the assay. On the day of study, animals were lightly anesthetized with isoflurane and administered either vehicle or test compound (0.5 mg/mL, 50 µL total volume over several breaths) via oral aspiration. Animals were placed in lateral recumbency post dose and monitored for full recovery from anesthesia before being returned to their home cage. Four hours later, animals were once again briefly anesthetized and challenged with either vehicle or IL-13 (0.03 µg total dose delivered, 50 µL total volume) via oral aspiration before being monitored for recovery from anesthesia and returned to their home cage. One hour after vehicle or IL-13 administration, lungs were collected for both pSTAT6 detection using an AlphaLISA Immunoassay (PerkinElmer) and analyzed for total drug concentration. Selected compounds of the present disclosure were tested in the assay. Activity in the model is evidenced by a decrease in the level of pSTAT6 present in the lungs of treated animals at 5 hours compared to the vehicle treated, IL-13 challenged control animals. The difference between the control animals which were vehicle- treated, IL-13 challenged and the control animals which were vehicle-treated, vehicle challenged dictated the 0% and 100% inhibitory effect, respectively, in any given experiment. Exemplary compounds were tested in the assay and exhibited inhibition of STAT6 phosphorylation at 4 hours after IL-13 challenge as documented below. In the following table, A represents between 80 % and 100 % inhibition, B represents between 60 % and 80 % inhibition and C represents between 40 % and 60 % inhibition. Table 2: pSTAT6 Inhibition
Figure imgf000060_0002
Figure imgf000061_0001
Assay 6: Pharmacokinetics in Plasma and Lung in Mouse After Oral Aspiration Administration of Test Compounds Plasma and lung concentrations of test compounds were quantified and pharmacokinetic parameters were calculated in the following manner. Male CD1 mice from Charles River Laboratories were used in the pharmacokinetic studies. Test compounds were individually formulated in 20% propylene glycol in pH 4 citrate buffer at a concentration of 0.2 mg/mL. Test compounds were administered in two, 25 µL increments introduced into the trachea of each mouse by oral aspiration using a calibrated pipette once the animal was anesthetized using isoflurane. Blood samples were collected as terminal collections via cardiac puncture at 0.167, 1, 4, 8, and 24 hr post-dosing. Following inhalation with CO2, a direct cardiac puncture was performed while avoiding puncturing the lung and blood was immediately transferred into K2EDTA tubes and placed on wet ice. Blood samples were centrifuged (Eppendorf centrifuge, 5804R) for 4 minutes at approximately 12,000 rpm at 4°C to collect plasma. Intact lungs were also excised from these mice using the same timepoints (0.167, 1, 4, 8, and 24 hr). Lungs were washed with sterile water to remove any blood residue and were patted dry, weighed, and homogenized in 0.1% formic acid in water at a dilution of 1:3 (lung:water, weight/volume). Plasma and lung concentrations of test compounds were determined by LC-MS/MS analysis against analytical standards constructed into a standard curve in the test matrix. The pharmacokinetic parameters of test compounds were determined by non-compartmental analysis. For concentrations below the limit of quantification, zero was used for mean calculations. Mean values were not reported if more than 50% of the samples were below the limit of quantification at a timepoint, or if more than 50% of a calculated pharmacokinetic parameter was not reportable. The area under the concentration-time curve extrapolated to infinity (AUC(0-inf)) was calculated as follows: AUC(0-inf) = AUC(0-t) + Clast / k, where AUC(0-t) is the area under the concentration-time curve from the time of dosing to the last measurable concentration calculated by the linear trapezoidal rule, Clast is the last measurable concentration, and k is the first order rate constant associated with the terminal elimination phase, estimated by linear regression of time versus log concentration. AUC(0-inf) values were not reported if percent extrapolated was >20% or r2 was <0.8, or if <3 measurable points past Tmax were available, where Tmax .is the time to maximal concentration. The lung-to-plasma AUC ratio was determined as the ratio of the lung AUC(0-inf) in µg*hr/g to the plasma AUC(0-inf) in µg*hr/mL. Plasma AUC(0-inf) was not reported for compound 3, therefore plasma and lung AUC(0-t) with Tlast being 24h in plasma and lung were used for this compound In the following table, for Plasma AUC(0-24), A denotes a value below 0.5, and B denotes a value between 0.5 and 1. For the Lung Tissue AUC(0-24), A denotes a value between 100 and 200, B denotes a value between 50 and 100, and C denotes a value between 15 and 50. For the ratio of lung exposure to plasma exposure (Assay 3), A denotes a ratio 300-400, B denotes a ratio between 200 and 300, and C denotes a ratio between 100 and 200, and D denotes a ratio between 50 and 100. Table 3: Plasma and Lung Exposure in Mice Following Oral Aspiration Administration of Test Compounds
Figure imgf000062_0001
Assay 7: Cytotoxicity Assay A CellTiter-Glo luminescent cell viability/cytotoxicity assay was carried out in BEAS- 2B human lung epithelial cells (ATCC) under the normal growth condition. Cells were grown at 37°C in a 5% CO2 humidified incubator in 50% DMEM/50% F-12 medium (Life Technologies) supplemented with 10% FBS (Hyclone), 100 U/mL penicillin, 100 µg/mL streptomycin (Life Technologies), and 2 mM GlutaMAX (Life Technologies). On day 1 of the assay, cells were seeded at a 500 cells/well density in white 384-well tissue culture plates (Corning) with 25 µL medium and were allowed to adhere overnight in the incubator. On day 2 of the assay, 5 µL of medium containing dose-responses of test compounds was added and incubated at 37°C for 48 h. 30 µL of CellTiter-Glo detection solution (Promega) was subsequently added, mixed on an orbital shaker for 5 min, and incubated for additional 10 min before being read on the EnVision reader. Luminescence signals were recorded and percent DMSO control values were calculated. For dose-response analysis, percent DMSO control data were plotted vs. compound concentrations to derive dose-response curves by line connecting each data point. The concentration at which each curve crosses the 15 % inhibition threshold is defined as CC15. Results are expressed as the negative logarithm of the IC15 value, pIC15. It is expected that test compounds exhibiting a lower pCC15 value in this assay have less likelihood to cause cytotoxicity and/or growth inhibition. Table 4: Comparative Data (HLM Clearance, Cytotoxicity and BEAS2B Cellular Potency Data)
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Compounds C-1 to C-4 were disclosed in US Application No. 15/341,226 published as US/2017/0121327 and were prepared using similar chemistry. Compounds C-5 and C-6 were disclosed in WO/2020/173400 and prepared using similar chemistry. Compound C-7 was disclosed in Jones et al., J. Med. Chem., 2017, 60, 767-786. Compared to compound C-1, compound 2 has much higher HLM Clint and therefore is much more readily metabolized by the liver which reduces the risk of potential systemic effects. The compound also has higher potency in the BEAS2B assay. Compared to compounds C-2 to C-7, compounds 1 and 3 have much higher HLM Clint and therefore are much more readily metabolized by the liver which reduces the risk of potential systemic effects. Compounds 1 and 3 also have significantly lower pCC15 cytotoxicity values than compounds C-2 to C-4 and compound C-7. While the present disclosure has been described with reference to specific aspects or embodiments thereof, it will be understood by those of ordinary skilled in the art that various changes can be made or equivalents can be substituted without departing from the true spirit and scope of the disclosure. Additionally, to the extent permitted by applicable patent statutes and regulations, all publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety to the same extent as if each document had been individually incorporated by reference herein.

Claims

WHAT IS CLAIMED IS: 1. A compound of formula (I):
Figure imgf000066_0001
or a pharmaceutically-acceptable salt thereof, wherein: R1 is selected from the group consisting of H, C1-6 alkyl, aryl, heteroaryl, a 3 to 7 membered monocyclic cycloalkyl group, a 4 to 7 membered monocyclic heterocyclic group, -C1- 6 alkyl-aryl, and -C1-6 alkyl-heteroaryl, wherein the 3 to 7 membered monocyclic cycloalkyl group, and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, wherein the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, a 3 to 7 membered monocyclic cycloalkyl group, and a 4 to 7 membered monocyclic heterocyclic group, wherein the 3 to 7 membered monocyclic cycloalkyl group and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R6, -CONR6R7, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, - NR6R7, -OC(O)NR6R7, -NR6C(O)R7, -NR6C(O)2R7, -NR6-C(O)NR7R8, -C1-6 alkyl-OR6, -C1-6 alkyl-NR6R7, and -C1-6 alkyl-CO2R6, wherein the aryl, heteroaryl, -C1-6 alkyl-aryl, and -C1-6 alkyl-heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, - OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl- NR3R4, and -C1-6 alkyl-CO2R3, R2 is H or C1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, -CO2R9, -CONR9R10, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, - NR9R10, -OC(O)NR9R10, -NR9C(O)R10, -NR9C(O)2R10, -NR9-C(O)NR10R11, or R1 and R2 taken together form a 3 to 7 membered monocyclic cycloalkyl group or a 4 to 7 membered monocyclic heterocyclic group, wherein the 3 to 7 membered monocyclic cycloalkyl group and the 4 to 7 membered monocyclic heterocyclic group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of -CN, - CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, - NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, and R3, R4, R5, R6, R7, R8 , R9, R10, and R11 are each independently selected from the group consisting of H and C1-6 alkyl. 2. The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R2 is C1-3 alkyl or C1-3 alkyl-OH or wherein R1 and R2 taken together form a 4 to 6 membered monocyclic cycloalkyl group optionally substituted with 1 to 2 substituents independently selected from the group consisting of CN, -CONR3R4, OH, -O-C1-3 alkyl, -S-C1-3 alkyl, and - NR3R4. 3. The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein R2 is -CH3 or -CH2-OH or wherein R1 and R2 taken together form a cyclopentyl group. 4. The compound of claim 1, or a pharmaceutically-acceptable salt thereof, having the formula (II):
Figure imgf000067_0001
.
5. The compound of claim 1, or a pharmaceutically-acceptable salt thereof, having the formula (III):
Figure imgf000068_0001
. 6. The compound of any one of claims 1 to 5, or a pharmaceutically-acceptable salt thereof, wherein R1 is selected from the group consisting of H, C1-6 alkyl, aryl, a 3 to 5 membered monocyclic cycloalkyl, -CRaRb-heteroaryl, -CRaRb-aryl, and -CRaRb-heterocyclyl, wherein Ra and Rb are each independently selected from the group consisting of H and C1-4 alkyl, wherein the heterocyclyl is a 5 or 6 membered monocyclic heterocyclic group; wherein the 3 to 5 membered monocyclic cycloalkyl and the -CRaRb-heterocyclyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, -CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, - OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl- NR3R4, and -C1-6 alkyl-CO2R3, wherein the C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of CN, -CO2R3, -CONR3R4, OH, SH, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, -NR3C(O)R4, -NR3C(O)2R4, and -NR3-C(O)NR4R5, wherein the aryl, -CRaRb-aryl, and -CRaRb-heteroaryl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, -CN, -CO2R3, - CONR3R4, OH, SH, C1-6 alkyl, -O-C1-6 alkyl, -S-C1-6 alkyl, -NR3R4, -OC(O)NR3R4, - NR3C(O)R4, -NR3C(O)2R4, -NR3-C(O)NR4R5, -C1-6 alkyl-OR3, -C1-6 alkyl-NR3R4, and -C1-6 alkyl-CO2R3, and R3, R4, and R5 are each independently selected from the group consisting of H and C1-6 alkyl. 7. The compound of any one of claims 1 to 5, or a pharmaceutically-acceptable salt thereof, wherein R1 is selected from the group consisting of H, C1-6 alkyl, phenyl, a 3 to 5 membered monocyclic cycloalkyl, -CRaRb-heteroaryl, -CRaRb-phenyl, and -CRaRb-heterocyclyl; wherein Ra and Rb are each independently selected from the group consisting of H and C1-2 alkyl; wherein the heterocyclyl is a 5 or 6 membered monocyclic heterocyclic group containing 1 or 2 oxygen atoms; wherein the C1-6 alkyl is optionally substituted with 1 substituent selected from the group consisting of CN, -CONR3R4, OH, -O- C1-3 alkyl, -S-C1-3 alkyl, and -NR3R4, wherein the phenyl, -CRaRb-phenyl and -CRaRb-heteroaryl are optionally substituted with 1 substituent independently selected from the group consisting of halogen, OH, C1-4 alkyl, and O-C1-4 alkyl, and R3 and R4, are each independently selected from the group consisting of H and C1-3 alkyl. 8. The compound of any one of claims 1 to 5, or a pharmaceutically-acceptable salt thereof, wherein R1 is selected from the group consisting of H, C1-4 alkyl, phenyl, -CH2- pyrimidinyl, -CH2-pyridinyl, -CH2-thiophenyl, -CH2-imidazolyl, -CH2-indolyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-dioxolanyl, -CH2-tetrahydropyranyl, and -CH2-phenyl, wherein the C1-4 alkyl is optionally substituted with 1 substituent selected from the group consisting of CN, OH, SMe, OMe, NH2, NMe2, and CONH2, wherein the imidazolyl is optionally substituted with Me, and wherein the -CH2-phenyl is optionally substituted with 1 substituent selected from the group consisting of F, Cl, OH, OMe, and Me. 9. The compound of any one of claims 1 to 5, or a pharmaceutically-acceptable salt thereof, wherein R1 is selected from the group consisting of H,
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
or a pharmaceutically-acceptable salt thereof.
Figure imgf000077_0002
1 or a pharmaceutically-acceptable salt thereof. 12. A compound of formula 2:
Figure imgf000077_0003
2 or a pharmaceutically-acceptable salt thereof.
13. A compound of formula 3:
Figure imgf000078_0001
3 or a pharmaceutically-acceptable salt thereof. 14. A pharmaceutical composition comprising a compound of any one of claims 1 to 13, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier. 15. The pharmaceutical composition of claim 14, further comprising one or more other therapeutic agents. 16. A compound of any one of claims 1 to 13, or a pharmaceutically-acceptable salt thereof, for use in the treatment of a respiratory disease in a mammal. 17. The compound, or pharmaceutically-acceptable salt thereof, of claim 16, wherein the respiratory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, an eosinophilic disease, a helminthic infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, an infiltrative pulmonary disease, drug-induced pneumonitis, fungal induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler syndrome, bronchiolitis obliterans organizing pneumonia, lung graft-versus- host disease, COVID-19, SARS, MERS, chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, rhinitis, and immune-checkpoint-inhibitor induced pneumonitis. 18. The compound, or pharmaceutically-acceptable salt thereof, of claim 16, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.
19. A compound of any one of claims 1 to 13, or a pharmaceutically-acceptable salt thereof, for use in the treatment of lung transplant rejection in a mammal. 20. The compound, or pharmaceutically-acceptable salt thereof, of claim 19, wherein the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction. 21. The compound, or pharmaceutically-acceptable salt thereof, of claim 19, wherein the lung transplant rejection is acute lung transplant rejection. 22. The compound, or pharmaceutically-acceptable salt thereof, of claim 19, wherein the lung transplant rejection is chronic lung allograft dysfunction. 23. The compound, or pharmaceutically-acceptable salt thereof, of claim 19, wherein the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung allograft dysfunction, and neutrophilic allograft dysfunction. 24. Use of a compound of any one of claims 1 to 13, or a pharmaceutically- acceptable salt thereof, for the manufacture of a medicament for the treatment of a respiratory disease in a mammal. 25. The use of claim 24, wherein the respiratory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, an eosinophilic disease, a helminthic infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, an infiltrative pulmonary disease, drug-induced pneumonitis, fungal induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler syndrome, bronchiolitis obliterans organizing pneumonia, lung graft-versus-host disease, COVID-19, SARS, MERS, chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, rhinitis, and immune- checkpoint-inhibitor induced pneumonitis.
26. The use of claim 24, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease. 27. Use of a compound of any one of claims 1 to 13, or a pharmaceutically- acceptable salt thereof, for the manufacture of a medicament for the treatment of lung transplant rejection in a mammal. 28. The use of claim 27, wherein the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction. 29. The use of claim 27, wherein the lung transplant rejection is acute lung transplant rejection. 30. The use of claim 27, wherein the lung transplant rejection is chronic lung allograft dysfunction. 31. The use of claim 27, wherein the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung allograft dysfunction, and neutrophilic allograft dysfunction. 32. A method of treating a respiratory disease in a human in need thereof comprising administering to the human a compound of any one of claims 1 to 13, or a pharmaceutically- acceptable salt thereof. 33. The method of claim 32, wherein the respiratory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, an eosinophilic disease, a helminthic infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, an infiltrative pulmonary disease, drug-induced pneumonitis, fungal induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler syndrome, bronchiolitis obliterans organizing pneumonia, lung graft-versus-host disease, COVID-19, SARS, MERS, chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, rhinitis, and immune- checkpoint-inhibitor induced pneumonitis. 34. The method of claim 32, wherein the respiratory disease is asthma. 35. The method of claim 32, wherein the respiratory disease is chronic obstructive pulmonary disease. 36. A method of treating lung transplant rejection in a human in need thereof comprising administering to the human a compound of any one of claims 1 to 13, or a pharmaceutically-acceptable salt thereof. 37. The method of claim 36, wherein the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction. 38. The method of claim 36, wherein the lung transplant rejection is acute lung transplant rejection. 39. The method of claim 36, wherein the lung transplant rejection is chronic lung allograft dysfunction. 40. The method of claim 36, wherein the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung allograft dysfunction, and neutrophilic allograft dysfunction.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023230236A1 (en) * 2022-05-26 2023-11-30 Theravance Biopharma R&D Ip, Llc Process for preparing jak inhibitors and intermediates thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170121327A1 (en) 2015-11-03 2017-05-04 Theravance Biopharma R&D Ip, Llc JAK Kinase Inhibitor Compounds for Treatment of Respiratory Disease
WO2018165395A1 (en) * 2017-03-09 2018-09-13 Theravance Biopharma R&D Ip, Llc Fused imidazo-piperidine jak inhibitors
WO2020173400A1 (en) 2019-02-25 2020-09-03 河南迈英诺医药科技有限公司 Jak inhibitor compound and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170121327A1 (en) 2015-11-03 2017-05-04 Theravance Biopharma R&D Ip, Llc JAK Kinase Inhibitor Compounds for Treatment of Respiratory Disease
WO2017079205A1 (en) * 2015-11-03 2017-05-11 Theravance Biopharma R&D Ip, Llc Jak kinase inhibitor compounds for treatment of respiratory disease
WO2018165395A1 (en) * 2017-03-09 2018-09-13 Theravance Biopharma R&D Ip, Llc Fused imidazo-piperidine jak inhibitors
WO2020173400A1 (en) 2019-02-25 2020-09-03 河南迈英诺医药科技有限公司 Jak inhibitor compound and use thereof

Non-Patent Citations (53)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS & WHITE
ABCOUWER, J. CLIN. CELL. IMMUNOL., 2013, pages 1 - 12
ASSIRI ET AL., N ENGL J MED., vol. 369, 2013, pages 407 - 1
BAO ET AL., JAK-STAT, vol. 2, 2013, pages e24137
BERASTEGUI ET AL., CLIN. TRANSPLANT., vol. 31, 2017, pages el2898
COGHILL ET AL., BLOOD, vol. 117, 2001, pages 3268 - 3276
COTTIN ET AL., CLIN. CHEST. MED., vol. 37, no. 3, 2016, pages 535 - 56
CRAIGLOW ET AL., JAMA DERMATOL., vol. 151, 2015, pages 1110 - 1112
DAY ET AL., VIROLOGY, vol. 395, no. 2, 2009, pages 210 - 22
DE NITTO ET AL., WORLD J. GASTROENTEROL., vol. 15, 2009, pages 4609 - 4614
EL-HASHEMITE ET AL., AM. J. RESPIR. CELL. MOL. BIOL., vol. 33, 2005, pages 227 - 230
EL-HASHEMITE ET AL., CANCER RES., vol. 64, 2004, pages 3436 - 3443
FANG ET AL., J. AM. SOC. HYPERTENS., vol. 11, no. 3, 2017, pages 171 - 177
FELICIANI ET AL., INT. J. IMMUNOPATHOL. PHARMACOL., vol. 12, 1999, pages 55 - 61
GAUTHIER ET AL., CURR TRANSPLANT REP., vol. 3, no. 3, 2016, pages 185 - 191
GAUTHIER ET AL., CURR. TRANSPLANT. REP., vol. 3, no. 3, 2016, pages 185 - 191
GRETEBECK ET AL., CURR OPIN VIROL., vol. 13, 2015, pages 123 - 9
GUAN ET AL., NENGL J MED., vol. 382, 2020, pages 1708 - 1720
HORAICASPI, J. INTERFERON CYTOKINE RES., vol. 31, 2011, pages 733 - 744
HUANG ET AL., CAN. J. CARDIOL., vol. 32, no. 11, 2016, pages e1 - e10
HUANG ET AL., THE LANCET, vol. 395, no. 10223, 2020, pages 507 - 506
JIN ET AL., AM J PHYSIOL-LUNG CELL MOL PHYSIOL., vol. 314, no. 5, 2018, pages L882 - 92
JONES ET AL., J. MED. CHEM., vol. 60, 2017, pages 767 - 786
JOO ET AL.: "Therapeutic Effects of Intranasal Tofacitinib on Chronic Rhinosinusitis with Nasal Polyps in Mice", THE LARYNGOSCOPE, 2020, Retrieved from the Internet <URL:https://doi.org/10.1002/lary.29129>
KNICKELBEIN ET AL., INT. OPHTHALMOL. CLIN., vol. 55, no. 3, 2015, pages 63 - 78
KUDLACZ ET AL., EUR. J. PHARMACOL, vol. 582, 2008, pages 154 - 161
KUMAWAT ET AL., MOL. IMMUNOLOGY, vol. 55, 2013, pages 355 - 364
KURUVILLA ET AL., CLIN REV ALLERGY IMMUNOL, vol. 56, no. 2, 2019, pages 219 - 233
MALAVIYA ET AL., INT. IMMUNOPHARMACOL., vol. 10, 2010, pages 829 - 836
MATSUNAGA ET AL., BIOCHEM. AND BIOPHYS. RES. COMMUN., vol. 404, 2011, pages 261 - 267
MCCRAY ET AL., J VIROL., vol. 81, no. 2, 2007, pages 813 - 21
NETCHIPOROUK ET AL., CELL CYCLE, vol. 13, 2014, pages 3331 - 3335
OKIYAMA ET AL., J. INVEST. DERMATOL., vol. 134, 2014, pages 992 - 1000
PETER JONES ET AL: "Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 2, 4 January 2017 (2017-01-04), US, pages 767 - 786, XP055468539, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01634 *
REIMUND ET AL., J. CLIN. IMMUNOLOGY, vol. 16, 1996, pages 144 - 150
SEVERGNINI ET AL., AM J RESPIR CRIT CARE MED., vol. 171, no. 8, 2005, pages 858 - 67
SHINO ET AL., PLOS ONE, vol. 12, no. 7, 2017, pages e0180281
SOHN ET AL., AMERICAN JOURNAL OF OPTHAMOLOGY, vol. 152, 2011, pages 686 - 694
SONKOLY ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 117, 2006, pages 411 - 417
STALLMACH ET AL., INT. J. COLORECTAL DIS., vol. 19, 2004, pages 308 - 315
STEVENSON ET AL., ARCH. OPHTHALMOL., vol. 130, 2012, pages 90 - 100
TANAKA ET AL., BR. J. DERMATOL., vol. 161, 2009, pages 1217 - 1224
VICENTI ET AL., AMERICAN JOURNAL OF TRANSPLANTATION, vol. 12, 2012, pages 2446 - 56
WANG ET AL., JAMA, vol. 323, no. 11, 2020, pages 1061 - 1069
WEINBRAND-GOICHBERG ET AL., IMMUNOL. RES., vol. 56, 2013, pages 249 - 260
WELZ-KUBIAK ET AL., J. IMMUNOL. RES., 2015
WOYWODT ET AL., EUR. J. GASTROENTEROLOGY HEPATOLOGY, vol. 11, 1999, pages 267 - 276
XING ET AL., NAT. MED., vol. 20, 2014, pages 1043 - 1049
XU XHAN MLI TSUN WWANG DFU B ET AL.: "Effective Treatment of Severe COVID-19 Patients with Tocilizumab", PNAS, 2020, Retrieved from the Internet <URL:https://doi.org/10.1073/pnas.2005615117>
YAMAMOTO ET AL., DIG. LIVER DIS., vol. 40, 2008, pages 253 - 259
YANO ET AL., J. TRANSLATION. MED., vol. 12, 2014, pages 191
ZEISER ET AL., LEUKEMIA, vol. 29, no. 10, 2015, pages 2062 - 68
ZHOU ET AL., AUTOIMMUN. REV., vol. 11, 2012, pages 699 - 704

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023230236A1 (en) * 2022-05-26 2023-11-30 Theravance Biopharma R&D Ip, Llc Process for preparing jak inhibitors and intermediates thereof

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