WO2022178215A1 - Tétrahydro-imidazo-pyridines de type amino-amide utiles en tant qu'inhibiteurs de jak - Google Patents

Tétrahydro-imidazo-pyridines de type amino-amide utiles en tant qu'inhibiteurs de jak 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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English (en)
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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/fr

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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

La présente invention concerne des composés de formule (I), dans laquelle les variables sont définies dans la description, ou un sel pharmaceutiquement acceptable de ceux-ci, qui sont des inhibiteurs de Janus kinases. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés et des procédés d'utilisation de tels composés pour traiter des maladies respiratoires.
PCT/US2022/016925 2021-02-19 2022-02-18 Tétrahydro-imidazo-pyridines de type amino-amide utiles en tant qu'inhibiteurs de jak WO2022178215A1 (fr)

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WO2023230236A1 (fr) * 2022-05-26 2023-11-30 Theravance Biopharma R&D Ip, Llc Procédé de préparation d'inhibiteurs de jak et d'intermédiaires de ceux-ci

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