Bioactivatable PDE4 inhibitor precursors in the gut microbiota

Abstract

This document describes a compound of formula (I): [Formula 1] This invention describes a compound represented by TIFF2023528397000067.tif37170, or a pharmaceutically acceptable salt thereof, methods for preparing them, and methods for using them to treat or prevent a number of diseases, including ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, psoriatic arthritis, or psoriasis.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 031,023, filed May 28, 2020, the specification of which is incorporated herein by reference in its entirety.

[0002] The disclosed subject matter generally relates to compounds that are glycoside prodrugs of phosphodiesterase 4 (PDE4) inhibitors. In particular, the present invention provides colon-specific prodrugs of PDE4 inhibitors, including (a) β-D-glucuronides, (b) α-D-glucuronides, (c) β-D-glucopyranosides, (d) α-D-glucopyranosides, (e) β-D-galactopyranosides, (f) α-D-galactopyranosides, (g) β-D-mannopyranosides, (h) α-D-mannopyranosides, (i) N-acetyl-β-D-glucosaminides, (j) N-acetyl-α-D-glucosaminides, (k) N-acetyl-β-D-galactosaminides, (l) N-acetyl-α-D-galactosaminides, and (m) β-D-glucosaminides. (n) α-D-glucosaminide, (o) β-D-galactosaminide, (p) α-D-galactosaminide, (q) β-D-fucopyranoside, (r) α-L-fucopyranoside, (s) α-L-rhamnopyranoside, (t) α-L-arabinofuranoside, (u) β-D-ribofuranoside, (v) a polysaccharide such as β-D-cellobioside or α-D-cellobioside or β-N,N-diacetylchitobioside, (w) a D-xylopyranoside, (x) a D-xylofuranoside, (y) β-D-galacturonide or (z) a diaryl-substituted ethane pyridone linked to an α-D-galacturonide moiety. [Background technology]

[0003] Cyclic adenosine monophosphate (adenosine 3',5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known to be a second messenger for hormones, including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.

[0004] Phosphodiesterases ("PDEs") are a family of enzymes that metabolize 3',5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cAMP second messenger activity. A specific phosphodiesterase, phosphodiesterase-4 ("PDE4," also known as "PDE-IV"), is a high-affinity, cAMP-specific, type IV PDE that has attracted interest as a potential target for the development of novel anti-inflammatory compounds. PDE4 is known to exist as at least four isoenzymes (A, B, C, and D), each encoded by a separate gene. Each of the four known PDE4 gene products is believed to play a different role in allergic and / or inflammatory responses. Therefore, it is believed that inhibition of PDE4, particularly specific PDE4 isoforms that produce adverse responses, can beneficially affect allergic and inflammatory symptoms. It is desirable to provide novel compounds and compositions that inhibit PDE4 activity.

[0005] Tumor necrosis factor alpha (TNF-α) is a cytokine released primarily by mononuclear phagocytes in response to immune stimulants. TNFα can enhance most cellular processes, including differentiation, recruitment, proliferation, and proteolysis. At low levels, TNF-α confers protection against infectious agents, tumors, and tissue damage. However, TNF-α is also involved in many It also has a role in disease. When administered to mammals or humans, TNF-α causes or exacerbates inflammation, fever, cardiovascular effects, bleeding, coagulation, and acute phase responses similar to those seen in acute infections and shock states. Enhanced or unregulated TNF-α production has been implicated in many diseases and conditions, including cancers such as solid tumors and blood-borne tumors, heart diseases such as congestive heart failure, and viral, genetic, inflammatory, allergic, and autoimmune diseases.

[0006] Inflammatory diseases, such as arthritis, related arthritic conditions (e.g., osteoarthritis and rheumatoid arthritis), inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), sepsis, psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, chronic obstructive pulmonary disease, and chronic inflammatory lung disease, are also prevalent and problematic. TNF-α plays a central role in the inflammatory response, and administration of its antagonists blocks chronic and acute responses in animal models of inflammatory disease.

[0007] Pharmaceutical compounds, such as PDE4 inhibitors, that can block the activity or inhibit the production of certain cytokines, including TNF-α, may be valuable therapeutic agents for treating or preventing inflammatory diseases involving TNF-α.

[0008] Ulcerative colitis is a recurring chronic inflammatory bowel disease that affects the lining of the colon and rectum. Current treatments include 5-aminosalicylic acid, corticosteroids, immunomodulatory agents, and infliximab (Remicade). TM ), adalimumab (Humira TM ), golimumab (Simpony TM ), and vedolizumab (Entyvio TM ) and TNF-α inhibitors such as α4β7 integrin inhibitors.

[0009] PDE4 inhibitors are well known to suppress the synthesis of the proinflammatory cytokine TNF-α, which plays an important role in the pathogenesis of ulcerative colitis. The demonstrated efficacy of TNF-α inhibitors in the treatment of ulcerative colitis further supports the usefulness of PDE4 inhibitors as an alternative therapy.

[0010] One of the first drugs used to treat ulcerative colitis was a prodrug called sulfasalazine. The sulfonamide moiety functions as a carrier to deliver the active ingredient, 5-aminosalicylic acid (5-ASA, also known as mesalazine or mesalamine), to the colon. Specific bacterial activity of the colonic microflora is responsible for cleavage of the diazo bond of sulfasalazine.

[0011] Colon-specific controlled-release formulation (Eucelis TM The topical corticosteroid budesonide, administered orally as a topical anticoagulant, reduces systemic exposure and is effective in managing ulcerative colitis with minimal side effects (Sandborn et al., Gastroenterology 2012,143,1218).

[0012] The primary rationale for topical therapy in the treatment of ulcerative colitis is to directly treat the inflamed colonic mucosa while minimizing systemic side effects.

[0013] It is known that during intrahepatic recirculation, various drug glucuronide conjugates undergo biliary excretion, are reabsorbed in the gastrointestinal tract, and hydrolyzed by colonic β-glucuronidase to release the parent active principle.

[0014] Bacteria that colonize the mammalian gut contain, but are not limited to, glycoside hydrolases (glycosidases), polysaccharide lyases, and carbohydrate esterases that are capable of degrading and metabolizing They have a large repertoire of carbohydrate-processing enzymes, including esterases (Flint et al. al. Gut Microbes, 2012, 3(4), 289).

[0015] Many companies are investing in the development of specific PDE4 inhibitors as anti-inflammatory drugs, two of which are roflumilast (Dalisprenil). TM , Takeda, COPD) and apremilast (Otezla TM , Celgene Corporation, psoriasis / psoriatic arthritis) have received regulatory approval and are on the market. Apremilast also demonstrated the ability to induce and maintain clinical remission for up to 52 weeks in patients suffering from moderate to severe ulcerative colitis in a phase 2 clinical trial (Danese, S. et al. Clin. Gastroenterol. Hepato. 2020, 18(11), 2526-2534). Regardless of the symptoms, common side effects of these treatments were headache and gastrointestinal disturbances such as nausea, vomiting, and diarrhea.

[0016] Thus, there is a need for PDE4 inhibitor compounds that reduce or alleviate the shortcomings of compounds known in the art.

[0017] Therefore, there is a need for PDE4 inhibitor compounds that cause little or no headache, nausea, vomiting and / or diarrhea. [Prior art documents] [Non-patent literature]

[0018] [Non-Patent Document 1] Sandborn et al.Gastroenterology 2012,143,1218 [Non-patent document 2] Flint et al.Gut Microbes,2012,3(4),289 [Non-patent document 3] Danese,S.et al.Clin.Gastroenterol.Hepato.2020,18(11),2526-2534 Summary of the Invention

[0019] The present invention relates to compounds that are glycoside prodrugs of phosphosiderase 4 (PDE4) inhibitors. In particular, the present invention relates to colon-specific prodrugs of PDE4 inhibitors, including (a) β-D-glucuronides, (b) α-D-glucuronides, (c) β-D-glucopyranosides, (d) α-D-glucopyranosides, (e) β-D-galactopyranosides, (f) α-D-galactopyranosides, (g) β-D-mannopyranosides, (h) α-D-mannopyranosides, (i) N-acetyl-β-D-glucosaminides, (j) N-acetyl-α-D-glucosaminides, (k) N-acetyl-β-D-galactosaminides, (l) N-acetyl-α-D-galactosaminides, and (m) β-D-glucosaminides. (n) α-D-glucosaminide, (o) β-D-galactosaminide, (p) α-D-galactosaminide, (q) β-D-fucopyranoside, (r) α-L-fucopyranoside, (s) α-L-rhamnopyranoside, (t) α-L-arabinofuranoside, (u) β-D-ribofuranoside, (v) a polysaccharide such as β-D-cellobioside or α-D-cellobioside or β-N,N-diacetylchitobioside, (w) a D-xylopyranoside, (x) a D-xylofuranoside, (y) β-D-galacturonide, or (z) a diaryl-substituted ethane pyridone linked to an α-D-galacturonide moiety.

[0020] According to one embodiment, a compound of formula (I): [ka] (In the formula, X is β-D-glucuronide, α-D-glucuronide, β-D-glucopyranoside, α-D-glucopyranoside, β-D-galactopyranoside, α-D-galactopyranoside, β-D-mannopyranoside, α-D-mannopyranoside, N-acetyl-β-D-glucosaminide, N-acetyl-α-D-glucosaminide, N-acetyl-β-D-galactosaminide, N-acetyl-α-D-galactosaminide, β-D-glucosaminide D-glucosaminide, β-D-galactosaminide, α-D-galactosaminide, β-D-fucopyranoside, α-L-fucopyranoside, α-L-rhamnopyranoside, α-L-arabinofuranoside, β-D-ribofuranoside, β-D-cellobioside, α-D-cellobioside, β-N,N-diacetylchitobioside, D-xylopyranoside, D-xylofuranoside, β-D-galacturonide or α-D-galacturonide; R 1 and R 2 are independently -C 1-6 Alkyl group, -C 3-6 cycloalkyl groups, any of which is unsubstituted or substituted with 1 to 6 independent halogen atoms; R 3 and R 4 are, independently of each other, H or -C 1-6 represents an alkyl group, R 5 , R 6 and R 7 are independently H, halogen atoms, -C 1-6 Alkyl group, -C(O)C 1-6 represents an alkyl group or CN, Ar 1 is, independently, (a)6-R 8 -3-pyridyl group or 6-R 9 -3-pyridyl group, (b)2-R 8 -5-thiazolyl group or 5-R 8 -2-thiazolyl group, (c)2-R 8 -5-pyrimidinyl group or 2-R 9 -5-pyrimidinyl group, (d)6-R 8 -3-pyridazinyl group or 6-R 9 a 3-pyridazinyl group, (e)5-R 8 -2-furyl group, (f)5-R 8 -2-thienyl group, (g)2-R 8 -5-oxazolyl group or 5-R 8 -2-oxazolyl group, (h)5-R 8 -3-isoxazolyl group or 3-R 8 -5-isoxazolyl group, (i)5-R 8 -3-isothiazolyl group or 3-R 8 -5-isothiazolyl group, and (j) pR 8 -phenyl group, is selected from the group consisting of R 8 is H, halogen atom, -C 1-6 Alkyl group, -C 3-6 Cycloalkyl groups, -C 1-6 Alkyl Ar 2 , Ar 2 , C 1-6 Alkoxy group, C 1-6 Alkylthio groups, CN, -C(R 10 )(R 11 )OH, -C(R 10 )(R 11 )OC 1-6 Alkyl group, -C(R 10 )(R 11 )OAr 2 , -CO2H, -CO2C 1-6 Alkyl group, -C(O)NR 12 R 13 , -SO2NHC(O)Ar 2 , -C(O)C 1-6 Alkyl groups and -C(O)Ar 2 is selected from the group consisting of R 9 is -NR 12 R 13 , -NR 12 C(O)R 13 , -NR 12 C(O)NHR13 , -NR 12 SO2Ar 2 , and -NR 12 CO2Ar 2 is selected from the group consisting of R 10 and R 11 are, independently of each other, H, -C 1-6 Alkyl group, -C 1-6 Haloalkyl group, -C 3-6 Cycloalkyl group, or Ar 2 represents, or R 10 and R 11 Ga-C 1-6 When alkyl groups are represented, they are C 1-3 C bonded together through alkyl groups 3-6 may form a cycloalkyl group, R 12 and R 13 are H,-C independently of each other. 1-6 Alkyl group, -C 3-6 Cycloa alkyl group, or -C 1-6 Alkyl Ar 2 represents or R 12 and R 13 Ga-C 1-6 When alkyl groups are represented, they are -C 1-3 C bonded together through alkyl groups 3-6 may form a heterocycloalkyl group, Ar 2 is selected from the group consisting of phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl; Each Ar 2 is unsubstituted or a halogen atom, -C 1-6 Alkyl group, -C1-6 Haloalkyl groups, CN, -C 1-6 Alkoxy group, -C 1-6 Alkylthio group, -C(R 10 )(R 11 )OH, -CO2H, -CO2C 1-6 Alkyl group, -C(O)NR 12 R 13 and -SO2CH3, or a pharmaceutically acceptable salt thereof.

[0021] The β-D-glucuronide can be β-D-glucuronic acid, methyl β-D-glucuronidate, methyl 2,3,4-tri-O-acetyl-β-D-glucuronidate, ethyl 2,3,4-tri-O-acetyl-β-D-glucuronidate, ethyl β-D-glucuronidate, i-propyl β-D-glucuronidate, tert-butyl β-D-glucuronidate, or methyl β-D-glucuronamide.

[0022] The β-D-glucopyranoside can be β-D-glucopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl, or 3,4,6-tri-O-acetyl-β-D-glucopyranosyl.

[0023] The β-D-galactopyranoside can be β-D-galactopyranosyl or 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl.

[0024] The α-D-mannopyranoside can be α-D-mannopyranosyl or 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl.

[0025] The β-D-glucosaminide can be β-D-glucosaminyl or α-D-glucosaminyl.

[0026] The N-acetyl-β-D-glucosaminide can be N-acetyl-β-D-glucosaminyl, 3,4,6-tri-O-acetyl-N-acetyl-β-D-glucosaminyl, N,N,N-trimethyl-β-D-glucosaminyl, or N,N-dimethyl-β-D-glucosaminyl.

[0027] The β-D-cellobioside can be β-D-cellobiosyl or 2,3,6,2',3',4',6'-hepta-O-acetyl-β-D-cellobiosyl.

[0028] Ar 1 is 6-R 8 -3-pyridyl group, or 2-R 8 It may be a -5-thiazolyl group. Ar 1 is 6-R 8 It may be a -3-pyridyl group.

[0029] R 3 and R 4 can each be H.

[0030] R 5 , R 6 and R 7 can each be H.

[0031] R 8 is -C(R 10 )(R 11 )OH.

[0032] The β-D-glucuronide can be β-D-glucuronyl.

[0033] The β-D-glucuronyl may be methyl glucuronate.

[0034] The compound of formula (I) can be one of the following compounds, or a pharmaceutically acceptable salt thereof: [Table 1] TIFF0007762168000003.tif242170TIFF0007762168000004.tif189170

[0035] The compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof.

[0036] The compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof.

[0037] The compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof.

[0038] The present invention also provides pharmaceutical compositions comprising an effective amount of the novel diaryl-substituted ethane pyridone glycoside conjugates and a pharmaceutically acceptable carrier.

[0039] According to another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent or excipient.

[0040] A therapeutically effective amount can be about 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of a compound of Formula (I).

[0041] The composition may be at least one of an immediate release formulation, an extended release formulation, or a delayed release formulation, or a combination thereof.

[0042] The composition may be in the form of a lotion or liquid.

[0043] The pharmaceutical composition may further comprise a leukotriene receptor antagonist, a leukotriene biosynthesis inhibitor, an M2 / M3 antagonist, a corticosteroid, an HI receptor antagonist, a beta2 adrenergic receptor agonist, a selective COX-2 inhibitor, an NSAID (NSAID), an immunomodulator, 5-ASA, a 5-ASA prodrug, a Janus kinase inhibitor, or a combination thereof.

[0044] The present invention further provides a method of treatment in a mammal.

[0045] In another embodiment, administration of an effective amount of a novel diaryl-substituted ethane pyridone glycoside conjugate that is a colon-specific PDE4 prodrug is effective to treat conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatosis, psoriasis and other benign or malignant proliferative skin diseases, endotoxin shock (and related conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, and other conditions in animals. In one embodiment, methods are provided for treating chronic obstructive pulmonary disease, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft-versus-host disease, gastric acid hypersecretion, bacterial, fungal or viral sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumor growth, cancerous invasion of normal tissues, osteoporosis, bone loss, and the like in a mammal.

[0046] According to another embodiment, there is provided a method for treating asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, gastric acid hypersecretion, sepsis or septic shock, endotoxic shock, endotoxic shock-related conditions, spinal cord trauma, head trauma, neurological inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spinal cord, rheumatoid arthritis, ankylosing spinal cord, psoriatic arthritis, rheumatoid arthritis, ankylosing spinal cord, rheumatoid arthritis ... Methods are provided for the treatment or prevention of spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergic conjunctivitis, eosinophilic granuloma, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, cancerous infiltration of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, and cachexia.

[0047] According to another embodiment, there is provided a method for the treatment or prevention of ulcerative colitis, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis, comprising the step of administering a therapeutically or prophylactically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present invention.

[0048] In the methods of the present invention, administration can be systemic, oral, topical, or a combination thereof.

[0049] In another embodiment, the present invention relates to the treatment of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, hypersecretion of gastric acid, sepsis or septic shock, endotoxic shock, endotoxic shock-related conditions, spinal cord trauma, head trauma, neurological inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergic conjunctivitis. In another aspect of the present invention, there is provided use of a compound of formula (I) or a composition of the invention in the manufacture of a medicament for the treatment or prevention of inflammatory bowel disease, eosinophilic granuloma, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, cancerous infiltration of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexia.

[0050] According to another embodiment, a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis Uses of the compounds or compositions of the invention are provided.

[0051] In another embodiment, the present invention relates to a method for treating asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, hypersecretion of gastric acid, sepsis or septic shock, endotoxic shock, endotoxic shock-related conditions, spinal cord trauma, head trauma, neurological inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergies, and the like. The present invention provides a compound of formula (I) or a composition of the present invention for use in the treatment or prevention of inflammatory conjunctivitis, eosinophilic granuloma, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, local tissue without cancer infiltration, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, and cachexia.

[0052] According to another embodiment, there is provided a compound of formula (I) or a composition of the invention for use in the treatment or prevention of ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis.

[0053] In another embodiment, the present invention relates to a method for treating asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, hypersecretion of gastric acid, sepsis or septic shock, endotoxic shock, endotoxic shock-related conditions, spinal cord trauma, head trauma, neurological inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergies, and the like. Use of a compound of formula (I) or a composition of the invention in the treatment or prevention of inflammatory conjunctivitis, eosinophilic granuloma, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, local tissue without cancer infiltration, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, and cachexia is provided.

[0054] In another embodiment, there is provided the use of a compound of formula (I) or a composition of the invention in the treatment or prevention of ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis.

[0055] The features and advantages of the present subject matter will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying drawings. As will be understood, all of the subject matter disclosed and claimed can be modified in various respects without departing from the scope of the claims. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive, with the full scope of the subject matter being set forth in the claims.

[0056] Detailed Description In embodiments, compounds are disclosed that are inactive precursors of PDE4 inhibitor compounds that are believed to cause little or no nausea, vomiting and / or diarrhea.

[0057] In an embodiment, the compound of formula (I): [ka] (In the formula, X is β-D-glucuronide, α-D-glucuronide, β-D-glucopyranoside, α-D-glucopyranoside, β-D-galactopyranoside, α-D-galactopyranoside, β-D-mannopyranoside, α-D-mannopyranoside, N-acetyl-β-D-glucosaminide, N-acetyl-α-D-glucosaminide, N-acetyl-β-D-galactosaminide, N-acetyl-α-D-galactosaminide, β-D-glucosaminide D-glucosaminide, β-D-galactosaminide, α-D-galactosaminide, β-D-fucopyranoside, α-L-fucopyranoside, α-L-rhamnopyranoside, α-L-arabinofuranoside, β-D-ribofuranoside, β-D-cellobioside, α-D-cellobioside, β-N,N-diacetylchitobioside, D-xylopyranoside, D-xylofuranoside, β-D-galacturonide or α-D-galacturonide; R 1 and R 2 are independently -C 1-6 Alkyl group, -C 3-6 cycloalkyl groups, any of which is unsubstituted or substituted with 1 to 6 independent halogen atoms; R 3 and R 4 are, independently of each other, H or -C 1-6 represents an alkyl group; R 5 , R 6 and R 7 are independently H, halogen atoms, -C 1-6 Alkyl group, -C(O)C 1-6 represents an alkyl group or CN, Ar 1 is independent (a)6-R 8 -3-pyridyl group or 6-R 9 -3-pyridyl group, (b)2-R 8 -5-thiazolyl group or 5-R 8 -2-thiazolyl group, (c)2-R 8 -5-pyrimidinyl group or 2-R 9 -5-pyrimidinyl group, (d)6-R 8 -3-pyridazinyl group or 6-R 9 a 3-pyridazinyl group, (e)5-R 8 -2-furyl group, (f)5-R 8 -2-thienyl group, (g)2-R 8 -5-oxazolyl group or 5-R 8 -2-oxazolyl group, (h)5-R 8 -3-isoxazolyl group or 3-R 8 -5-isoxazolyl group, (i)5-R 8 -3-isothiazolyl group or 3-R 8 -5-isothiazolyl group, and (j)pR 8 -phenyl group, is selected from the group consisting of R 8 is H, halogen atom, -C 1-6 Alkyl group, -C 3-6 Cycloalkyl groups, -C 1-6 Alkyl Ar 2 , Ar 2 , -C 1-6 Alkoxy group, -C 1-6 Alkylthio groups, CN, -C(R 10 )(R 11 )OH, -C(R 10 )(R 11 )OC 1-6 Alkyl group, -C(R 10 )(R 11 )OAr 2 , -CO2H, -CO2C 1-6 Alkyl group, -C(O)NR 12 R 13 , -SO2NHC(O)Ar 2 , -C(O)C 1-6 Alkyl groups and -C(O)Ar 2 is selected from the group consisting of R9 is -NR 12 R 13 , -NR 12 C(O)R 13 , -NR 12 C(O)NHR 13 , -NR 12 SO2Ar 2 , and -NR 12 CO2Ar 2 is selected from the group consisting of R 10 and R 11 are, independently of each other, H, -C 1-6 Alkyl group, -C 1-6 Haloalkyl group, -C 3-6 Cycloalkyl group, or Ar 2 represents or R 10 and R 11 Ga-C 1-6 When alkyl groups are represented, they are -C 1-3 C bonded together through alkyl groups 3-6 may form a cycloalkyl group, R 12 and R 13 are H,-C independently of each other. 1-6 Alkyl group, -C 3-6 Cycloa alkyl group, or -C 1-6 Alkyl Ar 2 represents or R 12 and R 13 Ga-C 1-6 When alkyl groups are represented, they are C 1-3 C bonded together through alkyl groups 3-6 may form a heterocycloalkyl group, Ar 2is selected from the group consisting of phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl; Each Ar 2 is unsubstituted or a halogen atom, -C 1-6 Alkyl group, -C 1-6 Haloalkyl groups, CN, C 1-6 Alkoxy group, C 1-6 Alkylthio group, -C(R 10 )(R 11 )OH, -CO2H, -CO2C 1-6 Alkyl group, -C(O)NR 12 R 13 and -SO2CH3, or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment of the present invention, the compound of the present invention has formula (I), wherein the β-D-glucuronide can be β-D-glucuronic acid, methyl β-D-glucuronidate, methyl 2,3,4-tri-O-acetyl-β-D-glucuronidate, ethyl β-D-glucuronidate, ethyl 2,3,4-tri-O-acetyl-β-D-glucuronidate, i-propyl β-D-glucuronidate, tert-butyl β-D-glucuronidate, methyl β-D-glucuronamide; The β-D-glucopyranosides may be β-D-glucopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl, 3,4,6-tri-O-acetyl-β-D-glucopyranosyl; the β-D-galactopyranosides may be β-D-galactopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl; the α-D-mannopyranosides may be α-D-mannopyranosyl, 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl, and the β-D-glucopyranosyl The glucosaminide may be β-D-glucosaminyl or α-D-glucosaminyl; the N-acetyl-β-D-glucosaminide may be N-acetyl-β-D-glucosaminyl, 3,4,6-tri-O-acetyl-N-acetyl-β-D-glucosaminyl, N,N,N-trimethyl-β-D-glucosaminyl or N,N-dimethyl-β-D-glucosaminyl; the β-D-cellobioside may be β-D-cellobiosyl or 2,3,6,2',3',4',6'-hepta-O-acetyl-β-D-cellobiosyl; R 1 and R 2 are, independently of each other, -C 1-6 Alkyl group, -C 3-6 cycloalkyl groups, any of which is optionally substituted with 1 to 6 independent halogen atoms; R 3 and R 4 are, independently of each other, H or -C 1-6 represents an alkyl group; R 5 , R 6 and R 7 are independently H, halogen atoms, -C 1-6 represents an alkyl group or CN, Ar 1 independently, 6-R 8 -3-pyridyl group or 2-R 8 -5-thiazolyl groups, R 8 is H, halogen atoms, -C 1-6 Alkyl group, -C 3-6 Cycloalkyl groups, -C 1-6 Alkyl Ar 2 , Ar2 , C 1-6 Alkoxy group, C 1-6 Alkylthio groups, CN, -C(R 10 )(R 11 )OH, -C(R 10 )(R 11 )OC 1-6 Alkyl group, -C(R 10 )(R 11 )OAr 2 , -CO2H, -CO2C 1-6 Alkyl group, -C(O)NR 12 R 13 , -SO2NHC(O)Ar 2 , -C(O)C 1-6 Alkyl groups and -C(O)Ar 2 is selected from the group consisting of R 9 is -NR 12 R 13 , -NR 12 C(O)R 13 , -NR 12 C(O)NHR 13 , -NR 12 SO2Ar 2 , and -NR 12 CO2Ar 2 is selected from the group consisting of R 10 and R 11 are, independently of each other, H, -C 1-6 Alkyl group, -C 1-6 Hello alkyl group, -C 3-6 Cycloalkyl group, or Ar 2 represents or R 10 and R 11 Ga-C 1-6 When alkyl groups are represented, they are C 1-3 C bonded together through alkyl groups 3-6 may form a cycloalkyl group, R 12 and R 13 are independently H, -C 1-6 Alkyl group, -C 3-6 Cycloalkyl group, or -C 1-6 Alkyl Ar 2 represents or R 12 and R 13 Ga-C 1-6 When alkyl groups are represented, they are C 1-3 C bonded together through alkyl groups 3-6 may form a heterocycloalkyl group, Ar 2 is selected from the group consisting of phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl; Each Ar 2 is unsubstituted or a halogen atom, -C 1-6 Alkyl group, -C 1-6 Haloalkyl groups, CN, C 1-6 Alkoxy group, C 1-6 Alkylthio group, -C(R 10 )(R 11 )OH, -CO2H, -CO2C 1-6 Alkyl group, -C(O)NR 12 R 13 and -SO2CH3, or a pharmaceutically acceptable salt thereof.

[0059] In another embodiment of the present invention, the compound of the present invention has formula (I), 1 and R 2 are, independently of each other, -C 1-6 Alkyl group, -C 3-6 cycloalkyl groups, any of which is unsubstituted or substituted with 1 to 6 independent halogen atoms; R 3 and R 4 respectively represent H, R 5 , R 6 and R7 respectively represent H, Ar 1 is 6-R 8 represents a 3-pyridyl group, R 8 -C 1-6 Alkyl Ar 2 , -C(R 10 )(R 11 )OH, -C(O)C 1-6 Alkyl groups, and -C(O)Ar 2 is selected from the group consisting of R 10 and R 11 are, independently of each other, H, -C 1-6 Alkyl group, -C 1-6 Haloalkyl group, -C 3-6 Cycloalkyl group, or Ar 2 represents R 12 and R 13 are, independently of each other, H, -C 1-6 Alkyl group, -C 3-6 Cycloalkyl group, or -C 1-6 Alkyl Ar 2 represents or R 12 and R 13 Ga-C 1-6 When alkyl groups are represented, they are C 1-3 C bonded together through alkyl groups 3-6 may form a heterocycloalkyl group, Ar 2 represents a phenyl group.) or a pharmaceutically acceptable salt thereof.

[0060] According to another embodiment, the compound of the present invention has formula (I): (Wherein, X represents methyl β-D-glucuronidate, R 1 and R 2 are, independently of each other, -C 1-6 Alkyl group or -C 3-6 cycloalkyl groups, any of which is optionally substituted with 1 to 6 independent halogen atoms; R 3 and R4 respectively represent H, R 5 , R 6 and R 7 respectively represent H, Ar 1 is 6-R 8 represents a 3-pyridyl group, R 8 is -C(R 10 )(R 11 )OH, R 10 and R 11 are independent of each other -C 1-6 represents an alkyl group.) or a pharmaceutically acceptable salt thereof.

[0061] According to another embodiment of the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof, the β-D-glucuronide is β-D-glucuronyl, preferably methyl glucuronate.

[0062] According to another embodiment of the compound of the present invention represented by formula (I), or a pharmaceutically acceptable salt thereof, the compound is one of the following compounds or a pharmaceutically acceptable salt thereof: [Table 2] TIFF0007762168000010.tif236170TIFF0007762168000011.tif184170

[0063] According to another embodiment, the compound of the present invention represented by formula (I), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0064] According to another embodiment, the compound of the present invention represented by formula (I), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0065] According to another embodiment, the compound of the present invention represented by formula (I), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0066] Orally administered inactive PDE4 inhibitor glycosides are believed to avoid triggering upper gastrointestinal vomiting and reduce the emetogenicity of such drugs. The enhanced hydrophilic properties of glycoside prodrugs compared to the parent PDE4 inhibitors may improve the ability of the delivery system to distribute and release the active ingredient uniformly throughout the colon when drug dissolution is limited by low water content, irregular motility, and a lack of bile salts.

[0067] It is believed that the PDE4 inhibitor glycoside delivered to the colon is enzymatically hydrolyzed by colon-specific glycosidases, releasing the biologically active diaryl-substituted ethane pyridone PDE4 inhibitor and providing local anti-inflammatory effects to the colonic mucosa. Although this system has not been used in humans, in embodiments, it is believed that by appropriately selecting the glycoside / glycosidase system and the dosage administered to minimize systemic exposure, it can advantageously represent a method for slowly releasing the active agent, particularly in the colon.

[0068] PDE4 inhibitor glycosides, which specifically release biologically active diaryl-substituted ethanepyridone PDE4 inhibitors in the colon, may function as a systemic controlled-release system when the dosage is appropriately selected. In contrast to the small intestinal transit time of 2-5 hours, colonic residence times are significantly longer, with transit times of 5-12 hours, 12-24 hours, 24-36 hours, and 36-72 hours. This allows for slow, sustained absorption of the active agent, prolonging the duration of effect while minimizing peak plasma concentrations that may cause undesirable side effects.

[0069] As used herein, "alkyl group" and other groups having the prefix "alk," such as alkoxy, alkanoyl, alkenyl, alkynyl, etc., refer to carbon chains that may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, etc. "Alkenyl group," "alkynyl group," and other similar terms include carbon chains that include at least one unsaturated C-C bond.

[0070] The term "haloalkyl group" refers to an alkyl group having one to nine halo groups attached thereto. Examples include -CHF, -CHF, -CF, -CHCHF, -CHFCHF, -CFCHF, -CFCHF, -CFCF, and the like.

[0071] The term "cycloalkyl group" refers to a carbocycle containing no heteroatoms and includes monocyclic, bicyclic, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can contain one ring that is partially or fully unsaturated, such as a benzene ring, forming a fused ring system such as a benzofused carbocycle. Cycloalkyl groups include fused ring systems such as spirofused ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like. Similarly, "cycloalkenyl group" refers to a carbocycle containing no heteroatoms and at least one non-aromatic C-C double bond, and includes monocyclic, bicyclic, and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl groups include cyclohexenyl, indenyl, and the like.

[0072] The term "cycloalkyloxy group", unless otherwise specified, includes a cycloalkyl group attached to the oxy connecting atom.

[0073] The term "alkoxy group", unless otherwise specified, includes an alkyl group connected to the oxy connecting atom.

[0074] The term "aryl group", unless otherwise specified, includes monocyclic ring systems such as, for example, phenyl or naphthyl groups, as well as polycyclic ring systems.

[0075] The term "aryloxy group," unless otherwise specified, includes single ring systems, such as phenyl or naphthyl, as well as multiple ring systems, connected to the connecting site through the oxy connecting atom.

[0076] The term "C0-C6 alkyl group" includes alkyl groups containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl group with no carbon atoms is a hydrogen atom substituent when the alkyl group is a terminal moiety. An alkyl group with no carbon atoms is a direct bond when the alkyl group is a bridging moiety.

[0077] The term "hetero," unless otherwise specified, includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl groups include ring systems containing one or more O, S, or N atoms in the ring, as well as ring systems containing mixtures of such atoms. Heteroatoms replace ring carbon atoms. Thus, for example, a heterocycloC5 alkyl group is a five-membered ring containing from 5 to 0 carbon atoms. Examples of heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, and indazolyl groups. , oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, benzimidazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, and tetrazolyl group.

[0078] The term "heteroaryloxy group," unless otherwise stated, refers to a heteroaryl group attached through the oxy connecting atom to the connecting site. 1-6Examples of alkyl groups include a furylmethyl group, a furylethyl group, a thienylmethyl group, a thienylethyl group, a pyrazolylmethyl group, an oxazolylmethyl group, an oxazolylethyl group, an isoxazolylmethyl group, a thiazolylmethyl group, a thiazolylethyl group, an imidazolylmethyl group, an imidazolylethyl group, a benzimidazolylmethyl group, an oxadiazolylmethyl group, an oxadiazolylethyl group, a thiadiazolylmethyl group, a thiadiazolylethyl group, a triazolylmethyl group, a triazolylethyl group, a tetrazolylmethyl group, a tetrazolylethyl group, a pyridinylmethyl group, a pyridinylethyl group, a pyridazinylmethyl group, a pyrimidinylmethyl group, a pyrazinylmethyl group, a quinolinylmethyl group, an isoquinolinylmethyl group, and a quinoxalinylmethyl group. 3-7 Examples of alkyl groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl groups.

[0079] "N-heterocyclo C 4-7 The term "alkyl group" refers to a non-aryl heterocyclic compound having 3-6 carbon atoms and one nitrogen atom forming a ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl groups. Aryl (C 1-6 Examples of alkyl groups include phenyl (C 1-6 ) alkyl groups, and naphthyl (C 1-6 ) alkyl groups. Heterocyclo C 3- Alkylcarbonyl (C 1-6 Examples of alkyl groups include azetidinylcarbonyl (C 1-6 ) alkyl group, pyrrolidinylcarbonyl (C 1-6 ) alkyl group, piperidinyl carbonyl (C 1-6 ) alkyl group, piperazinyl carbonyl (C 1-6 ) alkyl group, morpholinylcarbonyl (C 1-6 ) alkyl group, and thiomorpholinylcarbonyl (C1-6 ) alkyl groups.

[0080] The term "amine" includes primary, secondary, and tertiary amines unless otherwise specified.

[0081] Unless otherwise specified, the term "carbamoyl group" is used to include -NHC(O)OC1-C4 alkyl groups and -OC(O)NHC1-C4 alkyl groups.

[0082] The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

[0083] The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, an optionally substituted aryl group can represent a pentafluorophenyl group or a phenyl ring. Furthermore, substitution can occur on any group. For example, a substituted aryl (C 1-6 ) The alkyl group includes substitution on the aryl group and substitution on the alkyl group.

[0084] The term "oxide" of a heteroaryl group is used in its normal, well-known chemical sense and includes, for example, the N-oxide of a nitrogen heteroatom.

[0085] The compounds described herein may contain one or more double bonds and may occur as cis / trans isomers and other conformational isomers. The present invention includes all such possible isomers, as well as mixtures of such isomers.

[0086] The compounds described herein may contain one or more asymmetric centers and may therefore give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers, as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above formula (I) is shown without definitive stereochemistry at specific positions. The present invention includes all stereoisomers of formula (I) and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included.

[0087] During the course of the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0088] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids or co-crystal formers. Crystalline forms can exist as salts, solvates, hydrates, or clathrates. When a compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper(II) and copper(I)), ferric, ferrous, lithium, magnesium, manganese (manganese(III) and manganese(II)), potassium, sodium, zinc, and the like salts. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as salts of cyclic amines and substituted amines, including naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable organic non-toxic bases or co-crystals with which salts or co-crystals can be formed include, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and other ion exchange resins.

[0089] When the compound of the present invention is basic, its corresponding salt or co-crystal can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Particularly preferred are benzenesulfonic acid, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0090] Structural modifications, such as removal or substitution of hydroxyl or carboxyl groups of naturally occurring glycosides, affect the binding interactions between glycosidases and substrate glycones. This may result in a change in the kinetics of the enzymatic hydrolysis process that can be advantageously used to accelerate or slow down the rate at which the parent PDE4 aglycone is released in the large intestine.

[0091] According to another embodiment, pharmaceutical compositions may be prepared comprising a compound of Formula (I) (or a pharmaceutically acceptable salt or co-crystal thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients may include, for example, i) a leukotriene receptor antagonist, ii) a leukotriene biosynthesis inhibitor, ii) corticosteroids, iv) HI receptor antagonists, v) beta2 adrenergic receptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) nonsteroidal anti-inflammatory drugs (“NSAIDs”), ix) M2 / M3 antagonists, x) 5-ASA and 5-ASA prodrugs, xi) azathioprine, xii) cyclosporine, and xiii) methotrexate. The most suitable route of administration in any given case will depend on the particular host, as well as the nature and severity of the condition for which the active ingredient is being administered; however, compositions include those suitable for oral, aerosol (including inhalers and intranasal sprays), rectal, topical (mucosal, ophthalmic, buccal, otic, transdermal or transcutaneous), and parenteral (including ophthalmic, subcutaneous, intramuscular, intraarterial and intravenous) administration. Pharmaceutical compositions are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Non-limiting examples of dosage forms include tablets; caplets; capsules such as soft elastic gelatin capsules, HPMC or any common hard gelatin capsule (including any chemically modified capsules for targeted delivery), cachets, troches, lozenges, etc.; dispersions; or any 3D printed solid dosage form, buccal mucosal films, suppositories; powders; air liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, elixirs, liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations, transdermal or transdermal formulations of ointments, lotions, creams suitable for topical administration via direct or intradermal devices or injections, needle-free or needle-free devices, or microneedle patches; mouthwashes and gargles fall within the scope of topical use for the purposes of the present invention, as well as sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient; formulations that may delay or control the release of the active ingredient delivered in the GIT are also contemplated.

[0092] According to another embodiment, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier / excipient, a compound of formula (I) or a pharmaceutically acceptable salt / co-crystal, and the corresponding parent PDE4 inhibitor of the compound of formula (I).

[0093] Colonic absorption of a drug into the systemic circulation is primarily determined by its permeability and solubility (Tannergren et al. Mol. Pharmacol. 2009, 6(1), 60). Therefore, some of the diaryl-substituted ethane pyridone PDE4 inhibitors absorbed by the colonic mucosa can reach the bloodstream and be absorbed systemically. Therefore, according to another embodiment, a dose that exerts a local anti-inflammatory effect and minimizes systemic exposure to the active agent is desired to reduce the possibility of headache, nausea, vomiting, and diarrhea, which have been reported for drugs such as rolipram, cilomilast, roflumilast, and apremilast.

[0094] In another embodiment, colonic absorption of diaryl-substituted ethane pyridone PDE4 inhibitors into the systemic circulation may be desirable if preclinical or clinical evidence suggests that they are better tolerated than known drugs of the same class, such as cilomilast, roflumilast, and apremilast. Avoiding the local triggering of vomiting in the upper gastrointestinal tract caused by inactive PDE4 inhibitor glycosides is desirable and considered an advantage in improving tolerability. Slow absorption due to the long colonic transit time is also considered an advantage, as it reduces the maximum peak plasma concentration, which may cause adverse effects such as headache, nausea, vomiting, and diarrhea.

[0095] According to another embodiment, systemic exposure to diaryl-substituted ethanepyridone PDE4 inhibitors via colonic absorption may be indicated for the treatment of inflammatory diseases, including ulcerative colitis.

[0096] From about 0.0001 mg / kg to about 100 mg / kg of body weight per day, or from about 0.001 mg / kg to about 100 mg / kg, or from about 0.01 mg / kg to about 100 mg / kg, or from about 0.1 mg / kg to about 100 mg / kg, or from about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 100 mg / kg, or about 0.0001 mg / kg to about 10 mg / kg, or about 0.001 mg / kg to about 10 mg / kg, or about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 10 mg / kg, or about 0.0001 mg / kg to about 1 mg / kg, or about 0.001 mg / kg to about 1 mg / kg g, or about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.0001 mg / kg to about 0.1 mg / kg, or about 0.001 mg / kg to about 0.1 mg / kg, or about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg, or about 0.001 mg / kg to about 0.01 mg / kg, or about 0.0001 mg / kg to about 0.The 0.01 mg / kg dose level is intended for use in i) pulmonary diseases such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, and chronic obstructive pulmonary disease in animals; ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, gastric hypersecretion, diverticulitis, and irritable bowel syndrome; and iii) bacterial, fungal, or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and colic in horses). iv) neurological disorders such as spinal cord trauma, head trauma, neurological inflammation, pain, and cerebral reperfusion injury; v) inflammatory diseases such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation, and cytokine-mediated chronic tissue degeneration; vi) allergic diseases such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma; vii) psychiatric disorders such as depression, memory impairment, and unipolar depression; viii) neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and acute and chronic multiple sclerosis; ix) skin diseases such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria; x) neoplastic diseases such as cancer, tumor proliferation, and cancerous invasion of normal tissue; xi) metabolic disorders such as diabetes insipidus; xii) bone disorders such as osteoporosis; xiii) cardiovascular disorders such as arterial restenosis, atherosclerosis, and myocardial reperfusion injury; and xiv) chronic It may be useful in treating conditions such as glomerulonephritis, vernal conjunctivitis, transplant rejection, graft-versus-host disease, cachexia, and other diseases that respond to PDE4 inhibition, where dosage levels are from about 0.007 mg to about 7 g, or from about 0.07 mg to about 7 g, or from about 0.7 mg to about 7 g, or from about 0.007 mg to about 0.7 g, or from about 0.07 mg to about 0.7 g, or from about 0.007 mg to about 0.07 g per patient per day. For example, inflammation may be controlled by administering about 0.0001 mg to 100 mg of compound per kilogram of body weight per day, or about 0.001 mg to 100 mg, or about 0.01 mg to 100 mg, or about 0.1 mg to 100 mg, or about 1 mg to 100 mg, or about 10 mg to 100 mg, or about 0.0001 mg to 10 mg, or about 0.001 mg to 10 mg, or about 0.01 mg to 10 mg, or about 0.1 mg to 10 mg, or about 1 mg to 10 mg, or about 0.0001 mg to 1 mg, or about 0.or about 0.007 mg to about 7 g, or about 0.07 mg to about 7 g, or about 0.7 mg to about 7 g, or about 0.007 mg to about 0.7 g, or about 0.07 mg to about 0.7 g, or about 0.007 mg to about 0.7 g, or about 0.007 mg to about 0.0 ... .

[0097] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form can vary depending on the target being treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g, or from about 0.5 mg to about 500 mg, or from about 0.5 mg to about 50 mg, or from about 0.5 mg to about 5 mg, or from about 5 mg to about 5 g, or from about 5 mg to about 500 mg, or from about 5 mg to about 50 mg, or from about 50 mg to about 5 g, or may conveniently contain from about 50 mg to about 500 mg, or from about 500 mg to about 5 g, of active agent, and may be formulated using appropriate and acceptable amounts of generally recognized as safe ("GRAS") materials, which may vary from about 5 to about 95% of the total composition. Unit dosage forms generally contain from about 0.001 mg to about 5000 mg, or from about 0.01 mg to about 5000 mg, or from about 0.1 mg to about 5000 mg, or from about 1 mg to about 5000 mg, or from about 10 mg to about 5000 mg, or from about 100 mg to about 5000 mg, or from about 1000 mg to about 5000 mg, or from about 0.001 mg to about 1000 mg, or from about 0.01 mg to about 1000 mg, or from about 0.1 mg to about 1000 mg, or from about 1 mg to about 1000 mg, or from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg, or from about 0.001 mg to about 100 mg, or from about 0.01 mg to about 100 mg, or from about 0.1 mg to about 100 mg, or from about 1 mg to about 10 or about 10 mg to about 100 mg, or about 0.001 mg to about 10 mg, or about 0.01 mg to about 10 mg, or about 0.1 mg to about 10 mg, or about 1 mg to about 10 mg, or about 0.001 mg to about 1 mg, or about 0.01 mg to about 1 mg, or about 0.1 mg to about 1 mg, or about 0.001 mg to about 0.1 mg, or about 0.01 mg to about 0.1 mg, or about 0.001 mg to about 0.01 mg, typically 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 5.0 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 3000 mg, 5000 mg or any dose in between.

[0098] However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0099] The composition, shape, and type of dosage forms provided herein typically vary depending on their intended use. For example, a dosage form used for the acute treatment of a disease may contain a larger amount of one or more active ingredients comprising Formula (I) than a dosage form used for the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients comprising Formula (I) than an oral dosage form used to treat the same disease. These and other ways in which specific dosage forms provided herein vary from one another will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing, Easton, PA (2000). In practice, the compound of Formula (I) of the present invention, or a pharmaceutically acceptable salt / cocrystal thereof, can be combined as an active ingredient intimately admixed with pharmaceutical excipients, carriers, or diluents according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, mucosal (e.g., nasal, sublingual, vaginal, inhalation, cyst, rectal, ocular, buccal, or otic), parenteral (including intravenous, intradermal, subcutaneous, bolus injection, intramuscular, or intraarterial), or topical (e.g., transdermal, transcutaneous, eye drops, or other ophthalmic formulations). Thus, pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration such as capsules (coated or uncoated with polymers, for targeted delivery, as sustained release, or enteric coated, or modified), sachets, or tablets (coated or uncoated, or sustained or delayed release, including bilayers or microencapsulation), or tablets each comprising a spray-dried intermediate containing a predetermined amount of the active ingredient. Further, the composition may be presented as a powder, granules, coated sustained-release particles, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion, liposomes, nanosuspension. In addition to the common dosage forms set out above, the compounds of formula (I), or pharmaceutically acceptable salts or co-crystals thereof, may also be administered in controlled or modified release formulations and / or delivery devices.The compositions can be prepared by any of the methods of pharmacy. Generally, such methods require the addition of one or more active ingredients. The method includes combining the active ingredient with the excipient or carrier that constitutes the active ingredient. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier / excipient or a finely divided solid carrier / excipient, or both. The product can then be conveniently shaped into the desired presentation.

[0100] According to another embodiment, glycosidic bonds are known to be hydrolyzable under acidic conditions, and therefore, as part of a compound formulation of the present invention, the PDE4 glycoside prodrug may include an excipient or coating to prevent premature hydrolysis in the stomach or other parts of the gastrointestinal tract where the pH is below 5.

[0101] Thus, pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier / excipient and a compound of Formula (I) or a pharmaceutically acceptable salt / co-crystal thereof. The compound of Formula (I), or a pharmaceutically acceptable salt / co-crystal thereof, may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0102] The pharmaceutical carriers used can form oral solid dosage forms such as powders, capsules, and tablets, containing fillers such as talc, calcium carbonate, microcrystalline cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, and mixtures thereof. Binders such as Kollidon. Disintegrants such as croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, gums and other starches, and mixtures thereof. Lubricants such as calcium stearate, magnesium stearate, syloid silica gel, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, sesame oil, corn oil, or soybean oil), ethyl oleate agar, or other lipid-formulated lubricants, and mixtures thereof. Because of their ease of administration, tablets and capsules are preferred oral dosage units, and solid pharmaceutical carriers are used. Each solid oral dosage unit can be further coated with a special polymer that can delay or sustain the release of the contents of the dosage unit. Formula (I) can be administered by delayed-release or sustained-release means or by delivery devices known to those skilled in the art. Non-limiting examples of delayed-release or sustained-release formulations include those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; and 5,059,595. Such dosage forms can be used to provide sustained or controlled release of one or more ingredients, usually in the form of a matrix such as a gel, permeable membrane, microemulsion, osmotic system, liposome, microsphere, or combination thereof, using a polymer such as hydroxypropylmethylcellulose. Controlled-release formulations can be used to protect the dosage unit from exposure to the gastric environment; delay release of the active ingredient into the lower gastrointestinal tract, such as the colon; or delay release of the active ingredient, which can reduce blood levels of the drug and affect the occurrence of side effects.

[0103] Examples of gaseous carriers include carbon dioxide and nitrogen.

[0104] In preparing oral liquid compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used to form oral liquid preparations such as suspensions, elixirs, and solutions.

[0105] A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.

[0106] Compressed tablets are prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.001 mg to about 5000 mg, or from about 0.01 mg to about 5000 mg, or from about 0.1 mg to about 5000 mg, or from about 1 mg to about 5000 mg, or from about 10 mg to about 5000 mg, or from about 100 mg to about 5000 mg, or from about 1000 mg to about 5000 mg, or from about 0.001 mg to about 1000 mg, or from about 0.01 mg to about 1000 mg, or from about 0.1 mg to about 1000 mg, or from about 1 mg to about 1000 mg, or from about 10 mg to about 1000 mg, or from about 0.001 mg to about 100 mg, or from about 0.01 mg to about 100 mg, or about 0.1 mg to about 100 mg, or about 1 mg to about 100 mg, or about 10 mg to about 100 mg, or about 0.001 mg to about 10 mg, or about 0.01 mg to about 10 mg, or about 0.1 mg to about 10 mg, or about 1 mg to about 10 mg, or about 0.001 mg to about 1 mg, or about 0.01 mg to about 1 mg, or about 0.1 mg to about 1 mg, or about 0.001 mg to about 0.1 mg, or about 0.01 mg to about 0.1 mg, or about 0.001 mg to about 0.01 mg of the active ingredient, and each cachet or capsule preferably contains from about 0.001 mg to about 5000 mg of the active ingredient.

[0107] Pharmaceutical compositions of the present invention suitable for parenteral administration (including intravenous, intramuscular, subcutaneous, ocular, and intraarterial) can be prepared as solutions or suspensions of the active compound in an injectable component. Parenteral dosage forms are preferably sterile or can be sterilized before administration to a patient. Non-limiting examples of suitable vehicles include water for injection, USP; dextrose injection; sodium chloride injection; and lactated Ringer's injection. A suitable surfactant, such as polysorbate 80, can be included. Dispersions can also be prepared in non-aqueous vehicles such as oils (e.g., corn oil, sesame oil, isopropyl myristate), with glycerol, liquid polyethylene glycol, ethyl alcohol, polypropylene glycol, and mixtures thereof. Antioxidants, such as vitamin C palmitate, can be used to stabilize the formulation. Additionally, preservatives can be included to prevent the detrimental growth of microorganisms.

[0108] Furthermore, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, non-irritating with the addition of an isotonicity agent, and substantially fluid for easy injection. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be preserved against the contaminating action of microorganisms, such as bacteria and fungi, using agents such as benzalkonium chloride, chlorobutanol, methylparaben, propylparaben, edetate disodium, sorbic acid, or other agents known to those skilled in the art. The pharmaceutical compositions of the present invention may be in a form suitable for topical application to the skin and its appendages or various mucous membranes, such as, for example, an aerosol, patch, cream, ointment, lotion, dusting powder, emulsion, etc. Possible administration routes include nasal, sublingual, vaginal, rectal, ocular, oral, or otic. Furthermore, the compositions may be in a form suitable for use in transdermal or intradermal microneedle devices. These formulations may be prepared by conventional processing methods using the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof. For example, to produce a cream, lotion, or ointment with a desired consistency, the lotion, cream, or ointment is prepared by mixing a hydrophilic material and water together with about 5% to about 30% by weight of the compound. Typical examples of excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, isopropyl myristate, mineral oil, and mixtures thereof. If necessary, moisturizers such as occlusive agents, humectants, and emollients may also be added to the pharmaceutical composition and dosage form. The pH of the pharmaceutical composition or dosage form may also be adjusted to improve delivery of Formula (I). Dosage forms suitable for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels.

[0109] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, where the carrier is solid, liquid, or spray.Preferably, the mixture forms unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by first mixing the composition with the softened or melted carrier, followed by cooling and shaping in molds.

[0110] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical formulations may optionally contain one or more additional carrier components such as diluents, buffers, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof may also be prepared in powder or liquid concentrate form. The addition of preservatives such as antioxidants is widely accepted in the pharmaceutical industry as a means of simulating long-term storage to determine properties such as the shelf life and stability of formulations over time (see, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice. 2nd Ed. Marcel Dekker, NY, NY. 1995, pp. 379-80).

[0111] It has been found that the compounds and pharmaceutical compositions of the present invention, when locally activated in the colon, exhibit the biological activity of PDE4 inhibitors.Therefore, another aspect of the present invention is that by administering an effective amount of the compounds of the present invention, the diseases that are susceptible to the inhibition of PDE4 isoenzyme and the resulting increase in cAMP level are improved, for example: i) pulmonary diseases such as animal asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough and animal chronic obstructive pulmonary disease; ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, gastric acid hypersecretion; iii) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxin shock (and related conditions such as laminitis and colic in horses) and septic shock; iv) neurological diseases such as spinal cord trauma, head trauma, neurogenic inflammation, pain, cerebral reperfusion injury; v) psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation. and cytokine-mediated chronic tissue degeneration; vi) allergic diseases such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma; vii) psychiatric disorders such as depression, memory impairment, and unipolar depression; viiii) neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and acute and chronic multiple sclerosis; ix) skin diseases such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria; x) neoplastic diseases such as cancer, tumor growth, and cancerous infiltration of normal tissue; xi) metabolic disorders such as diabetes insipidus; xii) bone disorders such as osteoporosis; xiii) cardiovascular disorders such as arterial restenosis, atherosclerosis, and myocardial reperfusion injury; and xiv) other diseases such as chronic glomerulonephritis, vernal conjunctivitis, graft rejection, graft-versus-host disease, and cachexia. The term "mammal" includes humans and other animals, such as dogs, cats, horses, pigs, and cows. Thus, it is understood that the treatment of mammals other than humans is the treatment of afflictions that are clinically relevant to the above-listed examples of human afflictions.

[0112] Furthermore, as mentioned above, the compounds of the present invention can be used in combination with other therapeutic compounds.In particular, the combination of PDE4 inhibitor compounds of the present invention can be advantageously used in combination with: i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2 / M3 antagonists, vii) corticosteroids, viiii) HI (histamine) receptor antagonists, ix) β2 adrenergic receptor agonists, x) 5-ASA and 5ASA prodrugs, xi) azathioprine, xii) cyclosporine, xiii) methotrexate, and xiv) Janus kinase (JAK) inhibitors.

[0113] Thus, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory Pulmonary diseases such as chronic obstructive pulmonary disease (COPD), infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, and infant respiratory distress syndrome can be conveniently treated with capsules, cachets, or tablets containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of a compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0114] Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, and gastric acid hypersecretion may be conveniently treated with capsules, cachets, or tablets containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of a compound of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0115] Infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and colic in horses), and septic shock can be conveniently treated with capsules, cachets or tablets containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg, respectively, of the active ingredient of a compound of the present application or a pharmaceutically acceptable salt thereof administered once, twice, or three times daily.

[0116] Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and cerebral reperfusion injury can be conveniently treated with capsules, cachets, or tablets containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of the compounds of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0117] Inflammatory diseases such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation, and cytokine-mediated chronic tissue degeneration can be conveniently treated with capsules, cachets, or tablets or topical formulations containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of the compounds of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0118] Allergic diseases such as allergic rhinitis, allergic conjunctivitis, eosinophilic granulomas, etc. may be conveniently treated with capsules, cachets, or tablets or nasal sprays containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of a compound of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0119] Psychiatric disorders such as depression, memory impairment, and unipolar depression may be conveniently treated with capsules, cachets, or tablets or injections containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of the compounds of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0120] Neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis may be conveniently treated with capsules, cachets or tablets or injections containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of the compounds of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0121] Skin disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria can be conveniently treated with capsules, cachets, or tablets or topical delivery systems containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of a compound of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0122] Neoplastic disorders such as cancer, tumor growth, cancerous invasion of normal tissues, etc. may be conveniently treated with capsules, cachets, or tablets or parenteral formulations containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of the compounds of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0123] Metabolic disorders such as diabetes insipidus may be conveniently treated with capsules, cachets, or tablets or injections containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg of the active ingredient of a compound of the present application or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.

[0124] Bone disorders such as osteoporosis, cardiovascular disorders such as arterial restenosis, atherosclerosis, myocardial reperfusion injury, and other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, and cachexia can be conveniently treated with capsules, cachets, or tablets containing 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 10 mg, 50 mg, 250 mg, or 1000 mg, respectively, of the active ingredient of the compounds of the present application or a pharmaceutically acceptable salt thereof administered once, twice, or three times daily. [Example]

[0125] Synthesis method The compounds of formula (I) of the present invention can be prepared according to the proposed synthetic routes outlined in Schemes 1-7 below. Although the glycosidation reaction is described for the coupling of racemic pyridones, it will be apparent to those skilled in the art that the same reaction applies to optically pure or optically enriched pyridone III. The substituents are the same as in formula (I) unless otherwise defined. The PDE4 inhibitor pyridine-N-oxide II can be prepared using procedures such as those described in Friesen et al. (J. Med. Chem. 2003, 46(12), 2413) and / or O'Shea et al. (J. Org. Chem. 2005, 70, 3021).

[0126] Glucopyranosides of Formula Ia-c can be prepared in a multistep sequence from the required pyridone III and an appropriate glucosyl donor IV, as shown in Scheme 1 below. The required pyridone III can be synthesized by rearrangement of pyridine-N-oxide II in the presence of a tertiary amine such as triethylamine or Hunig's base and an activating agent such as trifluoroacetic anhydride or tosyl anhydride in a solvent such as toluene, chlorobenzene, THF, diethyl ether, 1,4-dioxane, dichloromethane, or a mixture of solvents such as toluene and 2-methyl-THF, at temperatures such as 0°C to room temperature. Upon completion of the rearrangement, the resulting mixture can be further treated with a base such as LiOH, NaOH, or NaHCO3 to afford pyridone III. The glucosyl donor IV is characterized by a functional group Z at the anomeric position, which can be activated under appropriate conditions using an activating agent such as a protic acid, Lewis acid, silver salt, or mercury salt. When Z represents OH, coupling can be achieved via the Mitsunobu reaction. In one method, pyridone III is coupled with a 1-halogeno-α-glucopyranoside (α-IV, Z = Cl, Br, I) under standard König-Knorr conditions known to those skilled in the art to give the protected β-glucopyranoside Ia (P = P'). Another procedure by Saad et al. (Curr. Org. Synth. 2012, 9(3), 413) can be used to obtain pyridone III. Pyridone III is coupled to bromo-α-glucopyranoside (α-IV, Z = Br) in the presence of a base such as KCO in an aprotic polar solvent such as DMF. Alternatively, pyridone III is coupled to 1-O-trichloroacetimidate α-glucopyranoside (α-IV, Z = OC(NH)CCl) in the presence of a Lewis acid such as BFEtO in a suitable solvent such as dichloromethane. Alternatively, following the procedure described by Sokolov et al. (Russian J. General Chem. 2002, 72(5), 806), pyridone III is coupled to 1-O-acetyl-β-glucopyranoside (β-IV, Z = OAc) in the presence of a catalytic amount of a Lewis acid such as BFEt in a suitable solvent such as benzene at a controlled temperature, such as room temperature, to give the protected β-glucopyranoside Ia. Alternatively, following the procedure described by Ko et al. (Org. Lett. 2009, 11(3), 609.), pyridone III is coupled to α-IV (Z=1) (where P=acetyl and P'=iodoacetyl) in the presence of a silver salt such as AgOTf in a solvent such as nitromethane or dichloromethane at ambient temperature. Removal of the alcohol protecting groups P and P' of β-glucopyranoside Ia, when P and P' are alkyl / aryl esters, is achieved in the presence of a basic reagent such as sodium methoxide, LiOH, NaOH, KOH, or KCO in a suitable solvent such as methanol or ethanol to give β-glucopyranoside Ib. When P and P' are benzyl groups, deprotection is achieved under standard conditions known to those skilled in the art, such as H hydrogenolysis using Pd / C as a catalyst in a solvent such as methanol, to give β-glucopyranoside Ib. If the ester protecting group P is different from the ester protecting group P', the protecting group P' can be selectively hydrolyzed using a reagent such as thiourea to give the partially protected 2-hydroxy-β-glucopyranoside 1c, according to the procedure of Koh et al. (Org. Lett. 2009, 11(3), 609.). [ka]

[0127] Glucuronides of formula Id-f can be prepared in a multi-step sequence from the requisite pyridone III and an appropriate glucuronyl donor V, as shown in Scheme 2 below. Glucuronyl donors are characterized by a functional group Z at the anomeric position, which can be activated under appropriate conditions using an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercury salt. When Z = OH, conjugation can be achieved via a Mitsunobu reaction. In one method, following the procedure described by Chang et al. (Tetrahedron, 2012, 68, 4194), pyridone III is coupled to 1-O-trichloroacetimidate-α-glucuronide (α-V, Z = OC(NH)CCl) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane at a controlled temperature such as -20 °C, to give the protected β-glucuronide Id. In another method following the procedure described by Arewang et al. (Carbohydr. Res. 2007, 342(7), 970), pyridone III is coupled to 1-O-acetyl-α-glucuronide (α-V, Z=OAc) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane at a controlled temperature such as 0°C to room temperature to give the protected β-glucuronide Id. In another method following the procedure described by Arewang et al. (Synth. Commun. 1975, 5, 231), pyridone III is first deprotonated with a base such as LiOH and then dissolved in a suitable solvent such as ethanol. In another procedure using 1-bromo-α-glucuronide (α-V, Z=Br), pyridone III is coupled by deprotonation of the pyridone with a hydride such as NaH in a solvent such as dichloromethane, followed by addition of bromide in the presence of a silver salt such as AgNO, according to the procedure of WO 2011 / 147296. Protected β-glucuronides Id can also be obtained under standard König-Knorr conditions known to those skilled in the art, such as the procedure described by Friend et al. (J. Med. Chem. 1985, 28, 51), in which pyridone III is coupled to 1-bromo-α-glucuronide (α-V, Z=Br) in a solvent such as CHCl or toluene in the presence of a silver salt such as AgCO or AgO. When P is an alkyl / aryl ester, removal of the alcohol protecting group P of β-glucuronide Id can be achieved in the presence of a basic reagent such as LiOH, NaOH, KOH, or KCO in a suitable solvent such as methanol / water or ethanol / water to give β-glucuronide Ie. When the alkyl group of Id is a methyl group and P is an alkyl ester such as acetate, If can be prepared by treating Id with a methanolic alkoxide such as sodium methoxide in a suitable solvent such as methanol. When P = benzyl, deprotection can be achieved under standard conditions known to those skilled in the art, such as H hydrogenolysis using Pd / C as a catalyst in a solvent such as methanol, to give β-glucuronide Ie. The acid functionality or the corresponding salt of glucuronide Ie can be selectively reacted with a reagent such as diazomethane or trimethylsilyldiazomethane in a solvent such as methanol to give the methyl ester β-glucuronide If (alkyl group = methyl). Alternatively, If can be prepared by treating Ie or its corresponding carboxylate salt with an alcohol such as methanol, ethanol, or i-propanol in a solvent such as DMF in the presence of DMAP and a coupling agent such as DCC or EDC.In an alternative procedure, If (Alkyl = tert-butyl group) can be prepared by reacting Ie or its corresponding carboxylate with tert-butyl trichloroacetimidate and a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane. [ka]

[0128] Glucosamines of formula Ig can be prepared in a multi-step sequence from glycosyl donors such as the requisite pyridones III and VI, as shown in Scheme 3 below. Glycosyl donor VI (X=Cl) can be prepared as described by Saint-Pierre et al. (Synthesis 2016) Glycosyl azides VII can be synthesized according to the procedure of [Illegible Text] (48, 3575). Glycosyl azides VII can be obtained as a mixture of anomers by coupling pyridone III with glycosyl donor VI (X = Cl) in the presence of a silver salt such as AgO in a solvent such as toluene under reflux conditions. Hydrolysis of the ester function of protected glycosyl azides VII can be achieved in the presence of a basic reagent such as sodium methoxide, LiOH, NaOH, KOH, or KCO in a suitable solvent such as methanol. The 2-azido function can be reduced to a 2-amino function in the presence of a catalyst such as Pd / C under an H atmosphere in a solvent such as methanol, affording an anomeric mixture of glucosamine Ig. The anomeric mixture can be separated by chromatographic methods known to those skilled in the art to afford α-glucosamine α-Ig and β-glucosamine β-Ig. Alternatively, a single glucosamine isomer represented by formula β-Ig can be prepared in a multistep sequence from the required glycosyl donors, such as pyridones III and VIII, as shown in Scheme 4 below. Glycosyl donor VIII can be synthesized according to the procedure of Morais et al. (Carbohydr. Res. 2003, 338, 1369). Glucosamine IX could be obtained by coupling pyridone III with glycosyl donor VIII in the presence of a silver salt, such as AgO, in a solvent, such as toluene, under reflux conditions. Hydrolysis of the ester functionality of the protected glucosamine IX can be achieved in the presence of a basic reagent, such as sodium methoxide, LiOH, NaOH, KOH, or KCO, in a suitable solvent, such as methanol. The benzyloxycarbonyl (CBZ) protecting group can be hydrogenolyzed to the 2-amino functionality under an H atmosphere in the presence of a catalyst, such as Pd / C, in a solvent, such as methanol, to afford glucosamine β-Ig. [ka] [ka]

[0129] As illustrated in Scheme 4 above, glucosamine β-Ig can be further derivatized to give glucosamines of formulas Im, In, Io, and Ip. Polyacetylated glucosamine of formula Im can be prepared by treating intermediate β-Ig with an acetylating agent such as acetic anhydride in a solvent such as pyridine at room temperature. Alternatively, β-Ig can be treated with an acetylating agent such as acetic anhydride in the presence of a base such as triethylamine in a solvent such as methanol at 0°C to give monoacetylated glucosamine of formula In. Alternatively, β-Ig can be treated with an excess of an alkylating agent such as methyl iodide in the presence of a base such as i-PrNEt in a solvent such as THF at room temperature to give the quaternary ammonium salt Io. Alternatively, glucosamine of formula Ip can be prepared by subjecting β-Ig to reductive alkylation conditions using formaldehyde and a reducing agent such as sodium cyanoborohydride in methanol at room temperature.

[0130] Galactopyranosides of formula Ii and Ij may be prepared in a multi-step sequence from the required pyridone III and an appropriate glycosyl donor X, as shown in Scheme 5 below. The glycosyl donor X is characterized by an anomeric functional group Z, which can be activated under appropriate conditions with an activating agent such as a protic acid, Lewis acid, silver salt, or mercury salt. When Z=Cl, Br, or I, the coupling can be carried out using standard Könning chemistry known to those skilled in the art. This can be accomplished under Hicknol conditions to give polyacetate β-galactopyranoside Ii. Alternatively, pyridone III is coupled with 1-O-trichloroacetimidate-α-galactopyranoside (Z = OC(NH)CCl) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane. Removal of the acetyl protecting group of β-galactopyranoside Ii can be achieved in the presence of a basic reagent such as sodium methoxide, LiOH, NaOH, KOH, or K2CO3 in a suitable solvent such as methanol or a mixture of solvents such as THF / water to give β-galactopyranoside Ij. [ka]

[0131] Mannopyranosides of formulae Ik and Il can be prepared in a multistep sequence from the requisite pyridone III and an appropriate glycosyl donor XI, as shown in Scheme 6 below. The glycosyl donor XI is characterized by an anomeric functional group Z, which can be activated under appropriate conditions using an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercury salt. When Z = Cl, Br, or I, coupling is achieved under standard König-Knorr conditions known to those skilled in the art to give polyacetate β-galactopyranoside Ik. Alternatively, pyridone III is coupled to 1-O-trichloroacetimidate-α-mannopyranoside (Z = OC(NH)CCl) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane. Removal of the acetyl protecting group of β-mannopyranoside Ik can be achieved in the presence of a basic reagent such as sodium methoxide, LiOH, NaOH, KOH, or K2CO3 in a suitable solvent such as methanol or a mixture of solvents such as THF / water to give β-galactopyranoside Il. [ka]

[0132] Cellobiosides represented by formulae Iq and Ir can be prepared in a multistep sequence from the required pyridone III and an appropriate glycosyl donor XII, as shown in Scheme 7 below. The glycosyl donor XII is characterized by an anomeric functional group Z, which can be activated under appropriate conditions using an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercury salt. When Z = Cl, Br, or I, coupling can be achieved under standard König-Knorr conditions known to those skilled in the art to give polyacetate β-cellobiosides Iq. Alternatively, pyridone III can be coupled to 1-O-trichloroacetimidate-α-mannopyranoside (Z = OC(NH)CCl) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane. Removal of the acetyl protecting group of β-cellobioside Iq can be achieved in the presence of a basic reagent such as sodium methoxide, LiOH, NaOH, KOH, or K2CO3 in a suitable solvent such as methanol or a solvent mixture such as THF / water to give β-cellobioside Ir. [ka]

[0133] Compounds 1-31 are summarized in Table 1 below: Table 1 [ka] wherein X is selected from (a) β-D-glucopyranoside, (b) β-D-glucuronide, (c) β-D-galactopyranoside, (d) α-D-mannopyranoside, (e) α / β-D-glucosaminide, (f) β-D-cellobioside, and Ar 1 is selected from (a) 2-(hexafluoro-i-propanol)-5-thiazolyl and (b) 6-(2-hydroxy-propan-2-yl)-3-pyridyl. [Table 3] TIFF0007762168000024.tif81170

[0134] Compound 1: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] Compound 1 was prepared according to the following procedure: Step 1: (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2(1H)-one. (S)-3-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridine 1-oxide IIa (1.00 g, 1.75 mmol), prepared according to O'Shea et al. (J. Org. Chem. 2005, 70, 3021), was dissolved in toluene (8.77 mL, 0.2 M). The solution was cooled to 0° C., and triethylamine (0.73 mL, 5.25 mmol) was added, followed by the dropwise addition of trifluoroacetic anhydride (0.74 mL, 5.25 mmol). Upon complete addition, the reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was then cooled to 0° C., and 20 mL of saturated aqueous sodium bicarbonate solution was added. The resulting solution was stirred for 15 minutes, then diluted with 20 mL of EtOAc, and the layers were separated. The organic layer was then washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, concentrated, and diluted with 10-60% MeCN in ammonium bicarbonate buffer. The pure fractions were then combined and concentrated to give the desired pyridone IIIa as an off-white solid. Step 2: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a toluene solution (0.2 M) of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2(1H)-one IIIa (101 mg, 0.18 mmol) was added silver oxide (1.5 equiv.) and 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside (1.5 equiv.). The resulting suspension was stirred at 110° C. for 1.5 h. The reaction was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 20-80% MeCN in ammonium formate to give the desired glucopyranoside as a white solid after lyophilization: 1 H NMR (400 MHz, Acetone-d6) δ 7.98 (d, J = 2.3 Hz, 1H), 7.85 (s, 1H), 7.62 (dd, J = 8.5, 2.4 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.01 - 6.57 (m, 3H), 6.26 (d, J = 8.3 Hz, 1H), 5.42 (t, J = 9.6 Hz, 1H), 5.20 - 5.06 (m, 2H), 4.80 (dd, J = 9.3, 6.7 Hz, 1H), 4.27 (dd, J = 12.3, 4.6 Hz, 1H), 4.11 (ddd, J = 10.0, 4.5, 2.4 Hz, 1H), 4.03 (dd, J = 12.3, 2.3 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.54 (dd, J= 13.8, 6.6 Hz, 1H), 3.44 (dd, J = 13.8, 9.5 Hz, 1H), 2.01 (s, 3H), 1.97 - 1.95 (m, 6H), 1.89 (s, 3H), 0.86 - 0.69 (m, 3H), 0.62 - 0.52 (m, 1H).

[0135] Compound 2: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] Compound 2 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran To a solution (0.1 M) of 3,4,5-triyltriacetate (10 mg, 0.01 mmol) in THF / water (1:1), LiOH (15 equiv.) was added. The solution was stirred at room temperature for 30 min. The solution was then loaded directly onto a C18 column (12 g) and purified using a gradient of 0-40% MeCN in ammonium bicarbonate. After lyophilization, the desired glucoside was obtained as a white solid. 1 H NMR (400 MHz, Acetone-d6) δ 7.98 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.57 (dd, J = 8.5, 2.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.03 - 6.54 (m, 3H), 5.82 (d, J = 7.9 Hz, 1H), 4.88 - 4.73 (m, 1H), 3.94 - 3.85 (m, 1H), 3.77 (dd, J = 11.7, 2.6 Hz, 1H), 3.65 (dd, J = 11.8, 4.8 Hz, 1H), 3.57 - 3.36 (m, 6H), 0.86 - 0.69 (m, 3H), 0.68 - 0.59 (m, 1H).

[0136] Compound 3: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka]

[0137] Compound 3 was prepared according to the following procedure: Step 1: (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one. (S)-3-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridine 1-oxide IIb (1.00 g, 2.20 mmol), prepared according to Friesen et al. (J. Med. Chem. 2003, 46(12), 2413), was dissolved in toluene (10 mL) and tetrahydrofuran (1 mL) (10:1 mixture, 0.2 M). The solution was cooled to 0° C., and triethylamine (2.46 mL, 17.60 mmol) was added, followed by the dropwise addition of trifluoroacetic anhydride (1.48 mL, 8.80 mmol). Upon complete addition, the reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was then cooled to 0° C., and 20 mL of saturated aqueous sodium bicarbonate solution was added. The resulting solution was stirred for 2 hours. The solution was then diluted with 200 mL of EtOAc, and the layers were separated. The organic layer was then washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, concentrated, and purified by reverse-phase column chromatography using 0-40% MeCN in ammonium bicarbonate buffer. Pure fractions were then combined and concentrated to afford the desired pyridone IIIb as a white solid. Step 2: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate Tate. To a 0.2 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (50 mg, 0.11 mmol) in toluene, silver oxide (1.5 equiv.) and 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside (1.5 equiv.) were added. The resulting suspension was stirred at 110 °C for 1.5 h. The reaction was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 20–80% MeCN in ammonium formate. After lyophilization, the desired glucoside was obtained as a white solid. 1 H NMR (500 MHz, Acetone-d6) δ 8.53 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.2, 2.3 Hz, 1H), 7.65 (dd, J = 8.4, 2.5 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.08 (d, J= 8.2 Hz, 1H), 7.00 (dd, J = 8.3, 2.1 Hz, 1H), 6.93 - 6.56 (m, 2H), 6.27 (d, J = 8.3 Hz, 1H), 5.42 (t, J = 9.6 Hz, 1H), 5.21 - 5.09 (m, 2H), 4.49 (t, J = 8.1 Hz, 1H), 4.28 (dd, J = 12.3, 4.6 Hz, 1H), 4.12 (ddd, J = 10.0, 4.6, 2.4 Hz, 1H), 4.04 (dd, J = 12.3, 2.5 Hz, 1H), 3.90 (tt, J = 6.0, 2.8 Hz, 1H), 3.54 - 3.43 (m, 2H), 2.02 (s, 3H), 1.97 (s, 6H), 1.90 (s, 3H), 1.46 (s, 6H), 0.87 - 0.70 (m, 3H), 0.67 - 0.60 (m, 1H).

[0138] Compound 4: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan)-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] Compound 4 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To a solution (0.1 M) of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (15 mg, 0.02 mmol) in THF / water (1:1), LiOH (15 equiv.) was added. The solution was stirred at room temperature for 30 min. The solution was directly loaded onto a C18 column (12 g) and purified using a gradient of 0-40% MeCN in ammonium bicarbonate. After lyophilization, the desired glucoside was obtained as a white solid. 1H NMR (500 MHz, Acetone-d6) δ 8.39 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.3, 2.3 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.35 (d, J= 2.0 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 8.3, 2.0 Hz, 1H), 6.79 - 6.44 (m, 2H), 5.68 (d, J = 8.0 Hz, 1H), 4.35 (t, J= 8.1 Hz, 1H), 3.78 (tt, J = 6.0, 2.9 Hz, 1H), 3.64 (d, J = 9.3 Hz, 1H), 3.52 (dd, J = 11.6, 4.7 Hz, 1H), 3.42 - 3.24 (m, 6H), 1.33 (s, 6H), 0.75 - 0.64 (m, 2H), 0.62 - 0.50 (m, 2H).

[0139] Compound 5: (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-5-hydroxytetrahydro-2H-pyran-3,4-diyl diacetate [ka] Compound 5 was prepared according to the following procedure: Step 1: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-5-(2-iodoacetoxy)tetrahydro-2H-pyran-3,4-diyl diacetate. To a 0.2 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (5 equiv.) in dichloromethane was added AgOTf (1.2 equiv.) at 0 °C. The solution was stirred at 0 °C for 1 h. 1-Iodo-2-O-iodoacetyl-3,4,6-tetra-O-acetyl-α-D-glucopyranoside (30 mg, 0.05 mmol), prepared according to Ko et al. (Org. Lett. 2009, 11(3), 609), was then added, and the reaction was allowed to warm slowly to room temperature overnight. The solution was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 5–80% MeCN in ammonium formate. After lyophilization, the desired glucoside was obtained as a white solid. Step 2: (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-5-hydroxytetrahydro-2H-pyran-3,4-diyl diacetate. To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-5-(2-iodoacetoxy)tetrahydro-2H-pyran-3,4-diyl diacetate (18 mg, 0.02 mmol) in MeOH (0.05 M) was added thiourea (1 equiv.). The solution was stirred at room temperature for 40 min. The solution was concentrated under reduced pressure and purified by reverse-phase column chromatography (12 g column, 10–80% MeCN in ammonium bicarbonate). After lyophilization, the desired glucopyranoside was obtained as a white solid. 1H NMR (500 MHz, Acetone-d6) δ 8.39 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.33 (d, J = 2.1Hz, 1H ), 6.95 (d, J = 8.2 Hz, 1H), 6.87 (dd, J = 8.3, 2.1 Hz, 1H), 6.79 - 6.44 (m, 2H), 5.89 (d, J = 8.1 Hz, 1H), 5.12 (t, J = 9.5 Hz, 1H), 4.86 (dd, J = 11.9, 7.3 Hz, 1H), 4.35 (t, J = 8.1 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.91 - 3.83 (m, 2H), 3.77 (tt, J = 6.1, 2.9 Hz, 1H), 3.68 - 3.58 (m, 1H), 3.41 - 3.26 (m, 2H), 1.87 (s, 3H), 1.86 (s, 3H), 1.82 (s, 3H), 1.33 (s, 6H), 0.75 - 0.62 (m, 2H), 0.62 - 0.49 (m, 2H).

[0140] Compound 6: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate. [ka] Compound 6 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a 0.18 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2(1H)-one IIIa (100 mg, 0.18 mmol) in toluene, silver oxide (1.1 equiv.) and methyl 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronate (1.1 equiv.) were added. The resulting suspension was stirred at 110 °C for 1 h. The suspension was then cooled to room temperature, filtered through Celite, concentrated, and purified by reverse-phase chromatography (20–80% MeCN in ammonium formate). After lyophilization, the desired product was obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J= 2.2 Hz, 1H), 7.58 (s, 1H), 7.24 - 7.18 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 8.3, 2.1 Hz, 1H), 6.69 - 6.29 (m, 2H), 6.20 (d, J = 7.7 Hz, 1H), 5.78 (s, 1H), 5.42 - 5.23 (m, 3H), 4.38 (dd, J = 8.8, 6.7 Hz, 1H), 4.23 (d, J = 9.6 Hz, 1H), 3.74 - 3.64 (m, 4H), 3.36 (dd, J = 13.8, 6.6 Hz, 1H), 3.24 (dd, J= 13.8, 9.1 Hz, 1H), 2.04 (m, 6H), 1.97 (s, 3H), 0.85 - 0.59 (m, 4H).

[0141] Compound 7: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate [ka] Compound 7 was prepared according to the following procedure: Step 1: Lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. To a 0.1 M solution of (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (85 mg, 0.1 mmol) in THF / water (1:1), LiOH (15 equiv.) was added. The solution was stirred at room temperature for 30 min, and then loaded directly onto a C18 column (12 g) and purified using a gradient of 0-40% MeCN in ammonium bicarbonate. After lyophilization, the desired lithium glucuronide salt was obtained as a white solid. Step 2: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. To a 0.1 M solution of lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (50 mg, 0.07 mmol) in MeOH at 0 °C, TMS-diazomethane (5 equiv.) was added, and the solution was stirred at 0 °C for 1 h. The reaction was concentrated under reduced pressure and purified by reverse-phase column chromatography eluting with 0–50% MeCN in ammonium bicarbonate. After lyophilization, the desired methyl glucuronate was obtained as a white solid. 1 H NMR (400 MHz, Acetone-d6) δ 7.98 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.12 - 7.05 (m, 1H), 7.02 - 6.55 (m, 2H), 6.68 (dd, J = 8.4, 3.3 Hz, 1H), 5.93 (dd, J = 7.7, 3.1 Hz, 1H), 4.79 (t, J = 7.7 Hz, 1H), 3.98 (dd, J = 9.5, 2.9 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.70 - 3.63 (m, 4H), 3.58 (td, J = 8.7, 2.8 Hz, 1H), 3.55 - 3.47 (m, 2H), 3.47 - 3.38 (m, 1H), 0.87 - 0.68 (m, 3H), 0.67 - 0.58 (m, 1H).

[0142] Compound 8: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6- (Methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate. [ka] Compound 8 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a black suspension of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (7.00 g, 15.3 mmol) and silver oxide (5.38 g, 23.0 mmol) in toluene (105 mL) was added methyl 1-bromo-2,3,4-tri-O-acetyl-α-d-glucuronate (9.42 g, 23.0 mmol). The mixture was heated to reflux for 1.5 h, cooled to room temperature, filtered through Celite, washed with ethyl acetate (2 × 30 mL), and concentrated to a dark solid (~18 g). Purification by flash chromatography using a SNAP Ultra 200 g column eluting with a gradient mixture of ethyl acetate and hexane afforded the desired glucuronate as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 8.3, 1.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.3, 2.1 Hz, 1H), 6.68 - 6.65 (m, 1H), 6.46 (t, J = 75.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 5.41 - 5.24 (m, 3H), 4.24 (d, J = 9.5 Hz, 1H), 4.18 (t, J = 7.9 Hz, 1H), 3.72 - 3.67 (m, 1H), 3.67 (s, 3H), 3.30 (d, J = 7.9 Hz, 2H), 2.05 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.54 (s, 6H), 0.82 - 0.63 (m, 4H).

[0143] Compound 9: Lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate [ka] Compound 9 was prepared according to the following procedure: Step 1: To a solution of (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (600 mg, 0.77 mmol) in a mixture of THF (3 mL), MeOH (1 mL) and water (1 mL) was added lithium hydroxide (285 mg, 11.6 mmol). The reaction was stirred for 30 minutes at room temperature and concentrated. Purification by flash chromatography using a SNAP C18 30 g column eluting with a gradient mixture of acetonitrile and water gave the desired lithium salt as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.9 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.3, 2.3 Hz, 1H), 7.61 - 7.52 (m, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.96 (dd, J = 8.3, 2.0 Hz, 1H), 6.93 (t, J = 74.7 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.55 (d, J = 7.8 Hz, 1H), 5.14 (s, 1H), 5.10 - 5.04 (m, 1H), 4.94 - 4.86 (m, 1H), 4.39 (t, J = 8.1 Hz, 1H), 3.92 (tt, J = 6.0, 2.9 Hz, 1H), 3.43 - 3.33 (m, 1H), 3.25 - 3.10 (m, 3H), 3.09 - 3.00 (m, 1H), 1.38 (s, 3H), 1.37 (s, 1H), 0.87 - 0.73 (m, 2H), 0.70 - 0.56 (m, 2H).

[0144] Compound 10: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate [ka] Compound 10 was prepared according to the following procedure: Step 1: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate . To a solution of (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9.40 g, 12.2 mmol) in MeOH (95 mL) was added 25% by weight sodium methoxide (1 mL). The solution was stirred at room temperature for 10 min, neutralized to pH 6-7 by addition of NHCl (5 mL), and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using a SNAP C18 Ultra 220 g column eluting with a solvent mixture of acetonitrile and aqueous ammonium formate to afford the desired methyl ester as a light beige solid after lyophilization. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.2 Hz, 1H), 7.85 (s, 1H), 7.54 (dd, J = 8.3, 1.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.77 (dd, J = 8.4, 1.3 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.46 (t, J = 75.1 Hz, 1H), 5.76 (d, J = 6.5 Hz, 1H), 4.18 (t, J = 7.8 Hz, 1H), 4.11 (d, J = 9.1 Hz, 1H), 3.84 - 3.68 (m, 4H), 3.67 (s, 3H), 3.33 - 3.17 (m, 2H), 1.50 (s, 3H), 1.49 (s, 3H), 0.80 - 0.62 (m, 4H).

[0145] Compound 11: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] Compound 11 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(ethoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a 0.2 M toluene solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (100 mg, 0.11 mmol) was added silver oxide (1.5 equiv.) and ethyl 1-bromo-2,3,4-tri-O-acetyl-α-d-glucuronate (1.5 equiv.), prepared according to Baddeley et al. (J. Chem. Crystallogr. 2013, 33, 33.). The resulting suspension was stirred at 110 °C for 1.5 h. The reaction was filtered through Celite, concentrated under reduced pressure, and purified by normal-phase column chromatography eluting with 20–100% EtOAc in CHCl. ​​After lyophilization, the desired ethyl glucuronate was obtained as a beige solid. 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.1 Hz, 1H), 7.82 (d, J= 2.1 Hz, 1H), 7. 53 (t, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.2, 0.7 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.05 (d, J= 6.2 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 8.3, 2.1 Hz, 1H), 6.67 - 6.64 (m, 1H), 6.45 (t, J= 75.1 Hz, 1H), 6.20 (d, J = 7.5 Hz, 1H), 5.41 - 5.23 (m, 3H), 4.78 (s, 1H), 4.21 (d, J = 6.0 Hz, 1H), 4.20 - 4.05 (m, 3H), 3.73 - 3.65 (m, 1H), 3.29 (d, J = 7.9 Hz, 2H), 2.04 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.51 (s, 6H), 1.22 (t, J = 7.5 Hz, 3H), 0.82 - 0.63 (m, 4H).

[0146] Compound 12: (2S,3S,4S,5R,6S)-ethyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate [ka] Compound 12 was prepared according to the following procedure: Step 1: (2S,3S,4S,5R,6S)-ethyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. Lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (25 mg, 0.039 mmol) and EDC (17.2 mg, 0.086 mmol) 1674691448618_0 To a mixture of 1,2-dimethyl-3-(2-methyl-2-propanol)-2-propanol (1,2-diol) and ethanol (0.2 mL) was added DMAP (24.2 mg, 0.196 mmol). The solution was stirred at room temperature for 16 hours and concentrated in vacuo. Purification by flash chromatography using a SNAP C18 12 g column eluting with a solvent mixture of acetonitrile and aqueous ammonium formate afforded the desired ethyl ester as a white solid after lyophilization. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.91 - 7.77 (m, 1H), 7.69 - 7.53 (m, 2H), 7.43 (d, J= 1.9 Hz, 1H), 7.23 - 6.69 (m, 4H), 5.76 (d, J = 7.8 Hz, 1H), 5.50 - 5.25 (m, 3H), 5.17 (s, 1H), 4.42 (q, J = 8.0 Hz, 1H), 4.23 - 4.02 (m, 2H), 3.94 (tt, J = 6.1, 3.0 Hz, 1H), 3.86 (d, J = 9.3 Hz, 1H), 3.54 - 3.22 (m, 7H), 1.41 (d, J = 2.5 Hz, 6H), 1.21 (t, J = 7.1 Hz, 3H), 0.90 - 0.74 (m, 2H), 0.72 - 0.55 (m, 2H).

[0147] Compound 13: (2S,3S,4S,5R,6S)-i-propyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate [ka] Compound 13 was prepared according to the following procedure: Step 1: (2S,3S,4S,5R,6S)-i-Propyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. To a solution of lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (110 mg, 0.17 mmol) and EDC (37.8 mg, 0.18 mmol) in a mixture of DMF (0.5 mL) and i-propyl alcohol (0.5 mL) was added DMAP (63.8 mg, 0.51 mmol). The solution was stirred at room temperature for 16 hours, followed by the addition of additional DMAP (63.8 mg, 0.51 mmol) and EDC (37.8 mg, 0.18 mmol). The reaction was stirred for 3 days, concentrated in vacuo, and purified by flash chromatography using a SNAP C18 12 g column eluting with a solvent mixture of acetonitrile and aqueous ammonium formate to give the desired i-propyl ester as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (t, J = 3.9 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.84 (dt, J = 13.0, 6.5 Hz, 1H), 7.68 - 7.54 (m, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.17 - 6.67 (m, 4H), 5.75 (d, J = 7.8 Hz, 1H), 5.38 (dd, J = 5.2, 3.8 Hz, 2H), 5.27 (d, J = 4.8 Hz, 1H), 5.15 (s, 1H), 4.92 (hept, J = 6.3 Hz, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.00 - 3.87 (m, 1H), 3.81 (d, J= 9.3 Hz, 1H), 3.42 - 3.21 (m, 5H), 1.41 (d, J = 2.4 Hz, 6H), 1.21 (d, J= 6.3 Hz, 6 H), 0.90 - 0.74 (m, 2H), 0.74 - 0.57 (m, 2H).

[0148] Compound 14: (2S,3S,4S,5R,6S)-tert-butyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate [ka] Compound 14 was prepared according to the following procedure: Step 1: (2S,3S,4S,5R,6S)-tert-butyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. To a solution of lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (25 mg, 0.031 mmol) and tert-butyl 2,2,2-trichloroacetimidate (57 μL, 0.313 mmol) in 2 mL of CHCl was added four drops of a stock solution of BF·EtO (prepared from 0.1 mL of BF·EtO in 2 mL of CHCl). The solution was stirred at room temperature for 16 h, and four more drops of the BF·EtO stock solution were added. The reaction was stirred for an additional 24 h and concentrated under reduced pressure. Purification by flash chromatography using a SNAP C18 12 g column eluting with a solvent mixture of acetonitrile and aqueous ammonium formate gave the desired tert-butyl ester as a white solid after lyophilization. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.71 - 7.41 (m, 2H), 7.35 (d, J = 1.8 Hz, 1H), 7.15 - 6.61 (m, 4H), 5.66 (d, J = 7.7 Hz, 1H), 5.28 (dd, J = 11.5, 5.5 Hz, 2H), 5.18 (d, J = 4.9 Hz, 1H), 5.09 (s, 1H), 4.36 (t, J = 8.2 Hz, 1H), 3.86 (tt, J = 5.9, 2.9 Hz, 1H), 3.64 (d, J = 9.2 Hz, 1H), 3.29 (m, 4H), 1.33 (m, 15 H), 0.83 - 0.67 (m, 2H), 0.66 - 0.47 (m, 2H).

[0149] Compound 15: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamide [ka] Compound 15 was prepared according to the following procedure: Step 1: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamide. (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-Cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (40 mg, 0.045 mmol) was dissolved in 2 M MeNH in MeOH (0.1 M). The resulting solution was stirred at room temperature for 20 min. The solution was then concentrated and purified by reverse phase (0-50% MeCN in ammonium bicarbonate). After lyophilization, the desired product was obtained as a white solid. 1 H NMR (400 MHz, CD3CN) δ 7.91 (s, 1H), 7.76 (dd, J = 2.5, 1.0 Hz, 1H), 7.62 - 7.45 (m, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.96 - 6.88 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.87 - 6.41 (m, 2H), 5.88 - 5.79 (m, 1H), 4.74 - 4.62 (m, 1H), 3.88 - 3.77 (m, 2H), 3.58 - 3.29 (m, 6H), 2.72 - 2.63 (m, 3H), 0.89 - 0.68 (m, 3H), 0.63 (d, J = 6.0 Hz, 1H).

[0150] Compound 16: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamide [ka] Compound 16 was prepared according to the following procedure: Step 1: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamide. To a solution of lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (170 mg, 0.26 mmol) and HATU (114 mg, 0.29 mmol) in 1.5 mL of DMF was added 2 M methylamine in methanol (0.1 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 2 h and purified by flash chromatography using a SNAP C18 30 g column eluting with a solvent mixture of acetonitrile and aqueous ammonium formate to give the desired N-methylcarboxamide as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.95 (q, J = 4.5 Hz, 1H), 7.85 (dd, J = 8.2, 2.2 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.43 (d, J = 1.7 Hz, 1H), 7.17 - 6.67 (m, 4H), 5.77 - 5.67 (m, 1H), 5.33 (d, J = 4.1 Hz, 1H), 5.23 (t, J = 11.4 Hz, 2H), 5.16 (s, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.67 (t, J = 7.4 Hz, 1H), 3.49 - 3.37 (m, 3H), 3.28 (t, J = 8.3 Hz, 1H), 2.57 (t, d = 4.3 Hz, 3H), 1.41 (d, J = 2.3 Hz, 6H), 0.90 - 0.76 (m, 2H), 0.72 - 0.60 (m, 2H).

[0151] Compound 17: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] Compound 17 was prepared according to the following procedure: Step 1: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a 0.16 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (30 mg, 0.07 mmol) in toluene, 1-bromo-2,3,4,6-tetra-O-acetyl-α-d-galactopyranoside (1.5 equiv.) and silver oxide (1.5 equiv.) were added. The solution was stirred at 110 °C for 1 h. The solution was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 30–100% MeCN in ammonium formate. After lyophilization, the desired compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.3, 2.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.46 (t, J = 75.0 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 5.53 - 5.42 (m, 2H), 5.14 (dd, J = 10.4, 3.4 Hz, 1H), 4.19 (t, J = 7.9 Hz, 1H), 4.16 - 4.07 (m, 3H), 3.72 - 3.65 (m, 1H), 3.30 (d, J = 7.9 Hz, 2H), 2.17 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 1.96 (s, 3H), 1.56 (s, 6H), 0.82 - 0.62 (m, 4H).

[0152] Compound 18: (2S,3R,4S,5R,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] Compound 18 was prepared according to the following procedure: Step 1: (2S,3R,4S,5R,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To a solution (0.06 M) of (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 mg, 0.01 mmol) in THF / water (1:1), lithium hydroxide (5 equiv.) was added. The solution was stirred at room temperature for 10 min. The solution was directly loaded onto a C18 column (12 g) and purified using a gradient of 0-50% MeCN in ammonium bicarbonate. After lyophilization, the compound was obtained as a white solid. 1 H NMR (400 MHz, CD3CN) δ 8.46 (d, J = 2.0 Hz, 1H), 7.93 (d, J= 2.2 Hz, 1H), 7.77 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (dd, J = 8.5, 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 8.3, 2.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.81 - 6.38 (m, 1H), 5.69 (d, J = 7.8 Hz, 1H), 4.40 (t, J = 8.2 Hz, 1H), 4.28 (s, 1H), 3.88 - 3.80 (m, 2H), 3.71 - 3.54 (m, 5H), 3.49 (s, 1H), 3.43 - 3.32 (m, 3H), 3.19 (s, 1H), 2.87 (s, 1H), 1.46 (s, 6H), 0.90 - 0.60 (m, 4H).

[0153] Compound 19: (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] Compound 19 was prepared according to the following procedure: Step 1: (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a 0.15 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (30 mg, 0.07 mmol) in toluene, 1-bromo-2,3,4,6-tetra-O-acetyl-α-d-mannopyranoside (1.5 equiv.) and silver oxide (1.5 equiv.) were added. The solution was stirred at 110 °C for 1 h. The solution was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 30–100% MeCN in ammonium formate. After lyophilization, the desired compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 2.1 Hz, 1H), 7.86 (d, J= 2.2 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.35 - 7.29 (m, 1H), 7.06 (dd, J = 9.9, 5.2 Hz, 2H), 6.78 (dd, J = 8.3, 2.1 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.66 - 6.23 (m, 1H), 6.38 (d, J = 1.8 Hz, 1H), 5.52 (dd, J = 10.1, 3.4 Hz, 1H), 5.43 - 5.36 (m, 2H), 4.24 (dd, J = 12.1, 4.6 Hz, 1H), 4.20 - 4.09 (m, 2H), 4.06 (dd, J= 12.1, 2.5 Hz, 1H), 3.73 - 3.66 (m, 1H), 3.29 (d, J = 7.8 Hz, 2H), 2.19 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H) 1.52 (s, 6H), 0.81 - 0.66 (m, 4H).

[0154] Compound 20: (2R,3S,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] Compound 20 was prepared according to the following procedure: Step 1: (2R,3S,4S,5S,6R)-2-((5-((S)-2-(3- Cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To a solution (0.06 M) of (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 mg, 0.01 mmol) in THF / water (1:1), LiOH (5 equiv.) was added. The solution was stirred at room temperature for 10 min. The solution was directly loaded onto a C18 column (12 g) and purified using a gradient of 0-50% MeCN in ammonium bicarbonate. After lyophilization, the compound was obtained as a white solid. 1 H NMR (400 MHz, acetone) δ 8.50 (s, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.03 (dd, J = 32.2, 8.3Hz, 2H), 6.95 - 6.53 (m, 2H), 6.32 (s, 1H), 4.63 (s, 1H), 4.47 (t, J = 7.7 Hz, 1H), 4.15 (s, 1H), 3.98 - 3.87 (m, 2H), 3.88 - 3.73 (m, 2H), 3.72 - 3.56 (m, 3H), 3.42 (t, J= 18.6 Hz, 3H), 1.51 - 1.41 (m, 7H), 0.87 - 0.59 (m, 4H).

[0155] Compound 21: (2R,3S,4R,5R)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol [ka] Compound 21 was prepared according to the following procedure: Step 1: (2R,3S,4R,5R)-5-Azido-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diyl diacetate. To a 0.2 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one (50 mg, 0.11 mmol) in toluene, silver oxide (1.5 equiv.) and 1-chloro-2-azido-3,4,6-tri-O-acetyl-α-d-glucopyranoside (1.5 equiv.), prepared according to the procedure of Saint-Pierre et al. (Synthesis 2016, 48, 3575.), were added. The resulting suspension was stirred at 110 °C for 1.5 h. The reaction was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 20–80% MeCN in ammonium formate. After lyophilization, the anomeric mixture of the desired azidoglucosides was obtained as a white solid. Step 2: (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy (iii)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol. To a solution (0.1 M) of (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diyl diacetate (18 mg, 0.02 mmol) in THF / water (1:1), LiOH (15 equiv.) was added. The solution was stirred at room temperature for 30 min. The solution was then loaded directly onto a C18 column (12 g) and purified using a gradient of 10–50% MeCN in ammonium bicarbonate. After lyophilization, the desired deacetylated azidoglucoside was obtained as a white solid. Step 3: (2R,3S,4R,5R)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol. To a 0.1 M solution of (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (8 mg, 0.01 mmol) in MeOH was added Pd / C (2 mg, 25% w / w). The suspension was bubbled with hydrogen for 10 min and stirred under a hydrogen atmosphere for 24 h. The solution was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography eluting with 0–40% MeCN in ammonium bicarbonate. After lyophilization, a mixture of α- and β-D-glucosamine prodrugs was obtained as a white solid. 1H NMR (500 MHz, CD3CN) δ 8.45 (d, J = 2.1 Hz, 1H), 7.99-7.93 (m, 1H), 7.77 (dd, J = 8.3, 1.9 Hz, 1H), 7.57-7.52 (m, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.36-7.34 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.94-6.92 (m, 1H), 6.79 - 6.72 (m, 1H), 6.61 (t, J = 75.4 Hz, 1H), 6.22 (d, J = 3.5 Hz, 0.5H), 5.62 (d, J = 8.3 Hz, 0.25H), 4.41 (t, J = 8.2 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.67-3.63 (m, 0.25H), 3.59 - 3.50 (m, 3H), 3.44-3.31 (m, 3H), 2.70 (dd, J = 9.9, 3.6 Hz, 0.78H), 1.46 (s, 6H), 0.85 - 0.80 (m, 2H), 0.71-0.65 (m, 2H).

[0156] Compound 22: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol [ka] Compound 22 was prepared according to the following procedure: Step 1: (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3 ,3-Hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate. To a 0.1 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2(1H)-one IIIa (100 mg, 0.18 mmol) in toluene, silver oxide (1.5 equiv.) and (2R,3S,4R,5R,6R)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-chlorotetrahydro-2H-pyran-3,4-diyl diacetate (1.5 equiv.) were added, and the solution was stirred at 110 °C for 1 h. The reaction was cooled to room temperature, filtered through Celite, concentrated, and purified by reverse-phase chromatography (20–80% MeCN in ammonium formate). After lyophilization, the desired product was obtained as a beige solid. Step 2: Benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate. To a 0.1 M solution of (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate (69 mg, 0.08 mmol) in THF / water (1:1), LiOH (12 equiv.) was added. The solution was stirred at room temperature for several minutes. The solution was directly loaded onto a C18 column (12 g) and purified using a gradient of 10–70% MeCN in ammonium bicarbonate. After lyophilization, the desired compound was obtained as a white solid. Step 3: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol. To a 0.1 M solution of benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (108 mg, 0.12 mmol) in MeOH, Pd / C (20% by weight) was added, and the solution was stirred under a hydrogen atmosphere for 16 h. The solution was filtered through Celite, concentrated, and purified by reverse-phase chromatography (0–50% MeCN in ammonium bicarbonate). After lyophilization, the desired glucosamine was obtained as a white solid. 1 H NMR (400 MHz, CD3CN) δ 7.91 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.50 (dd, J = 8.5, 2.5 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.08 (d, J= 8.2 Hz, 1H), 6.91 (dd, J = 8.3, 2.1 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.85 - 6.41 (m, 1H), 5.63 (d, J= 8.3 Hz, 1H), 4.73 - 4.61 (m, 1H), 3.89 - 3.79 (m, 1H), 3.76 - 3.68 (m, 1H), 3.60 (dd, J = 11.8, 4.8 Hz, 1H), 3.51 - 3.39 (m, 1H), 3.39 - 3.27 (m, 4H), 2.78 - 2.70 (m, 1H), 0.94 - 0.67 (m, 3H), 0.67 - 0.55 (m, 1H).

[0157] Compound 23: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2 -Hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol [ka] Compound 23 was prepared according to the following procedure: Step 1: (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate. To a 0.1 M solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (25 mg, 0.05 mmol) in toluene, silver oxide (1.5 equiv.) and (2R,3S,4R,5R,6R)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-chlorotetrahydro-2H-pyran-3,4-diyl diacetate (1.5 equiv.) were added, and the solution was stirred at 110 °C for 1 h. The reaction was cooled to room temperature, filtered through Celite, concentrated, and purified by reverse-phase chromatography (20–80% MeCN in ammonium formate). After lyophilization, the desired product was obtained as a beige solid. Step 2: Benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate. To a 0.1 M solution of (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate (23 mg, 0.03 mmol) in THF / water (1:1), LiOH (12 equiv.) was added. The solution was stirred at room temperature for several minutes. The solution was directly loaded onto a C18 column (12 g) and purified using a gradient of 10–70% MeCN in ammonium bicarbonate. After lyophilization, the desired compound was obtained as a white solid. Step 3: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol. Benzyl((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-4 To a solution of 5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (14 mg, 0.02 mmol) in MeOH (0.1 M), Pd / C (20% by weight) was added, and the solution was stirred under a hydrogen atmosphere for 2 hours. The solution was filtered through Celite, concentrated, and purified by reverse-phase chromatography (0-50% MeCN in ammonium bicarbonate). After lyophilization, the desired glucosamine was obtained as a white solid. 1H NMR (400 MHz, CD3CN) δ 8.46 (d, J = 1.9 Hz, 1H), 7.92 (d, J= 2.0 Hz, 1H), 7.77 (dd, J = 8.3, 2.2 Hz, 1H), 7.55 (dd, J = 8.5, 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 8.3, 2.0 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.82 - 6.37 (m, 1H), 5.61 (d, J = 8.2 Hz, 1H), 4.40 (t, J = 8.3 Hz, 1H), 4.29 (s, 1H), 3.85 (tt, J = 6.0, 2.8 Hz, 1H), 3.70 (d, J = 11.8 Hz, 1H), 3.59 (d, J = 8.7 Hz, 1H), 3.43 - 3.23 (m, 5H), 2.71 (t, J = 8.7 Hz, 2H), 1.45 (s, 6H), 0.92 - 0.74 (m, 2H), 0.76 - 0.61 (m, 2H).

[0158] Compound 24: (2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate [ka] Compound 24 was prepared according to the following procedure: Step 1: (2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate. To a pyridine solution (0.2 M) of (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (169 mg, 0.23 mmol), acetic anhydride (4 equiv.) was added, and the resulting solution was stirred at room temperature overnight. The solution was directly loaded onto a C18 column (40 g) and purified using 20–80% MeCN in ammonium formate. After lyophilization, the desired product was obtained as a white solid. 1 H NMR (400 MHz, CD3CN) δ 7.88 (d, J = 2.2 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.57 - 7.46 (m, 1H), 7.32 - 7.24 (m, 1H), 7.12 - 7.04 (m, 1H), 6.97 - 6.86 (m, 1H), 6.85 - 6.39 (m, 3H), 6.21 - 6.09 (m, 1H), 5.36 - 5.26 (m, 1H), 5.10 - 4.98 (m, 1H), 4.73 - 4.62 (m, 1H), 4.24 - 4.17 (m, 1H), 4.17 - 4.06 (m, 1H), 4.05 - 3.98 (m, 1H), 3.95 - 3.87 (m, 1H), 3.86 - 3.78 (m, 1H), 3.50 - 3.40 (m, 1H), 3.40 - 3.30 (m, 1H), 2.01 - 1.99 (m, 3H), 1.99 - 1.93 (m, 6H), 1.77 - 1.71 (m, 3H), 0.88 - 0.67 (m, 3H), 0.56 (s, 1H).

[0159] Compound 25: N-((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide [ka] Compound 25 was prepared according to the following procedure: Step 1: N-((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide. To a solution of (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (76 mg, 0.10 mmol) in MeOH (0.1 M) was added EtN (3 equiv.) followed by acetic anhydride (3 equiv.) at 0 °C. The solution was stirred at room temperature for 5 min. The solution was concentrated and purified by reverse-phase chromatography (0–100% MeCN in water). After lyophilization, the desired product was obtained as a white solid. 1H NMR (500 MHz, CD3CN) δ 7.88 (d, J = 2.1 Hz, 1H), 7.76 (d, J= 0.8 Hz, 1H), 7.52 (dd, J = 8.5, 2.5 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 8.3, 2.1 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.82 - 6.45 (m, 2H), 5.89 (d, J = 8.8 Hz, 1H), 4.74 - 4.64 (m, 1H), 3.87 - 3.80 (m, 2H), 3.76 - 3.71 (m, 1H), 3.61 (dd, J = 11.9, 4.9 Hz, 1H), 3.56 - 3.50 (m, 1H), 3.47 - 3.32 (m, 4H), 1.81 (s, 3H), 0.88 - 0.69 (m, 3H), 0.66 - 0.56 (m, 1H).

[0160] Compound 26: (2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)-N,N,N-trimethyltetrahydro-2H-pyran-3-aminium iodide [ka] Compound 26 was prepared according to the following procedure: Step 1: (2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)-N,N,N-trimethyltetrahydro-2H-pyran-3-aminium iodide. To a 0.05 M solution of (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (4 mg, 0.01 mmol) in THF, MeI (5 equiv.) was added, followed by (iPr)2NEt (5 equiv.). The reaction was stirred overnight at room temperature. The solution was concentrated and purified by reverse-phase chromatography (0–100% MeCN in ammonium formate). After lyophilization, the desired quaternary amine was obtained as a white solid. 1 H NMR (400 MHz, CD3CN) δ 8.35 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.68 (s, 1H), 7.55 (dd, J = 8.5, 2.4 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.3, 2.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.85 - 6.40 (m, 1H), 6.60 (d, J = 3.4 Hz, 1H), 4.74 - 4.59 (m, 1H), 4.04 (t, J = 8.1 Hz, 1H), 3.94 (t, J = 9.1 Hz, 1H), 3.88 - 3.80 (m, 1H), 3.71 - 3.59 (m, 3H), 3.56 (dd, J = 11.1, 5.5 Hz, 1H), 3.40 (qd, J = 14.0, 8.2 Hz, 2H), 3.25 (s, 9H), 0.88 - 0.69 (m, 3H), 0.67 - 0.59 (m, 1H).

[0161] Compound 27: (2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-5-(dimethylamino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol [ka] Compound 27 was prepared according to the following procedure: Step 1: (2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-5-(dimethylamino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol. To a solution of (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (84 mg, 0.11 mmol) in MeOH (0.1 M), formaldehyde (10 equiv.) was added, followed by sodium cyanoborohydride (3 equiv.). The resulting solution was stirred at room temperature overnight. The solution was concentrated and purified by reverse-phase chromatography using 10–50% MeCN in ammonium bicarbonate. After lyophilization, the desired N,N-dimethylglucosamine was obtained as a white solid. 1 H NMR (400 MHz, Acetone-d6) δ 7.97 (s, 1H), 7.84 (dd, J = 1.9, 0.4 Hz, 1H), 7.58 (dd, J = 8.4, 2.5 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.2, 2.5 Hz, 1H), 7.04 - 6.54 (m, 3H), 6.12 (dd, J = 8.7, 2.7 Hz, 1H), 4.80 (t, J = 7.9 Hz, 1H), 3.88 (dt, J = 8.9, 3.0 Hz, 1H), 3.75 (d, J = 11.6 Hz, 1H), 3.70 - 3.27 (m, 6H), 2.54 - 2.43 (m, 1H), 2.44 - 2.37 (m, 6H), 0.88 - 0.67 (m, 3H), 0.67 - 0.55 (m, 1H).

[0162] Compound 28: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] Compound 28 was prepared according to the following procedure: Step 1: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate. To a solution of (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2(1H)-one IIIa (152 mg, 0.27 mmol) in 5.4 mL of toluene was added (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (280 mg, 0.4 mmol) and silver oxide (185 mg, 0.8 mmol). The resulting black suspension was refluxed for 2 h, cooled to room temperature, filtered through Celite, washed with ethyl acetate (2 × 20 mL), and concentrated to a dark solid, which was purified by flash chromatography on a SNAP C18 12 g column eluted with a solvent mixture of acetonitrile and water to give the desired disaccharide polyacetate as a brown solid. 1H NMR (400MHz, CDCl3) δ 7.78 (d, J = 2.4 Hz, 1H), 7.57 (s, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.78 (dd, J = 8.2, 1.9 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.50 (t, J = 74.9 Hz, 1H), 6.06 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 5.30 (t, J = 9.1 Hz, 1H), 5.25 - 5.04 (m, 3H), 4.95 (t, J = 8.5 Hz, 1H), 4.53 (d, J = 7.9 Hz), 4.51 - 4.45 (m, 1H), 4.43 - 4.35 (m, 2H), 4.12 (dd, J= 12.2, 4.4 Hz), 4.07 (dd, J = 12.4, H 1.8 Hz, 1H), 3.91 (t, J = 9.3 Hz, 1H), 3.84 - 3.76 (m, 1H), 3.74 - 3.61 (m, 2H), 3.36 (dd, J= 14.0, 6.7 Hz, 1H), 3.26 (dd, J= 13.8, 8.9 Hz, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 2.05 (s, 6H), 2.02 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 0.90 - 0.59 (m, 4H).

[0163] Compound 29: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] Compound 29 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethacrylate) oxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (56 mg, 0.047 mmol) in THF / MeOH / water (0.9 / 0.3 / 0.3 mL) was added lithium hydroxide (31.2 mg, 0.71 mmol). The resulting solution was stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified by flash chromatography using a SNAP C18 12 g column eluting with a solvent mixture of acetonitrile and water to give the desired disaccharide as a white solid. 1H NMR (400MHz, DMSO-d6) δ 7.92 (s, 1H), 7.60 (bs, 1H), 7.55 (dd, J = 8.7, 1.9 Hz, 1H), 7.32 (s, J = 11.7 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 74.6 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 8.1 Hz, 1H), 5.58 - 5.07 (m, 2H), 5.03 - 4.87 (m, 1H), 4.82 - 4.55 (m, 3H), 4.29 (d, J = 7.7 Hz, 1H), 3.94 - 3.81 (m, 1H), 3.74 - 3.55 (m, 3H), 3.50 - 3.15 (m, 12H), 3.12 - 2.96 (m, 2H), 0.86 - 0.70 (m, 2H), 0.70 - 0.61 (m, 1H), 0.59 - 0.49 (m, 1H).

[0164] Compound 30: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ka] Compound 30 was prepared according to the following procedure: Step 1: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate. (S)-5-(2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin To a solution of dizin-2(1H)-one IIIb (85 mg, 0.19 mmol) in toluene (0.16 mmol), (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.5 equiv.) was added, followed by silver oxide (1.5 equiv.). The resulting suspension was stirred at 110 °C for 1.5 h. The reaction was filtered through Celite, concentrated under reduced pressure, and purified by reverse-phase column chromatography, eluting with 20–70% MeCN in ammonium formate. After lyophilization, the desired product was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.23 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 8.3, 2.1 Hz, 1H), 6.64 (s, 1H), 6.45 (t, J = 70.5 Hz, 1H), 6.04 (d, J = 8.1 Hz, 1H), 5.32 - 5.25 (m, 1H), 5.22 - 5.03 (m, 3H), 4.94 (dd, J= 9.1, 8.0 Hz, 1H), 4.51 (d, J = 7.9 Hz, 1H), 4.46 (dd, J = 12.1, 1.9 Hz, 1H), 4.38 (dd, J = 12.5, 4.4 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.05 (dd, J = 12.4, 2.2 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.80 (ddd, J = 9.8, 4.3, 2.0 Hz, 1H), 3.67 (tdd, J = 6.7, 5.0, 2.8 Hz, 2H), 3.28 (d, J = 7.9 Hz, 2H), 2.10 (s, 3H), 2.06 (s, 3H), 2.04 (s, 6H), 2.01 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H), 1.52 (s, 6H), 0.80 - 0.63 (m, 4H)。

[0165] Compound 31: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ka] Compound 31 was prepared according to the following procedure: Step 1: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropoxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (50 mg, 0.05 mmol) To a 0.1 M solution of 1H 2 SO 4 in THF / water (1 / 1) was added lithium hydroxide (15 equiv.). The resulting solution was stirred at room temperature for 1 h. The solution was then loaded directly onto a C18 column (30 g) and purified using a gradient of 10-60% MeCN in ammonium bicarbonate. After lyophilization, the desired disaccharide was obtained as a white solid. 1H NMR (400 MHz, CD3CN) δ 8.45 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.3, 2.3 Hz, 1H), 7.54 (dd, J = 8.4, 2.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 8.3, 2.0 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.81 - 6.39 (m, 1H), 5.80 (d, J = 8.1 Hz, 1H), 4.41 (dd, J = 8.0, 4.3 Hz, 2H), 3.90 - 3.16 (m, 21H), 1.45 (s, 6H), 0.90 - 0.77 (m, 2H), 0.75 - 0.59 (m, 2H).

[0166] Example 2 Assays demonstrating biological activity Assay protocol for measuring inhibitory potency against PDE4 isoenzymes. The potency of compounds inhibiting the hydrolysis of cAMP to AMP by type IV cAMP-specific phosphodiesterase (IC 50) was measured using the following protocol: serial dilutions of test compounds were first made in 100% DMSO. Each intermediate compound dilution (in 100% DMSO) was then diluted 10-fold with assay buffer to achieve an intermediate DMSO concentration of 10%. 5 μl of this dilution was added to a 50 μL reaction to obtain 1% DMSO in all reactions. Enzyme reactions were carried out at room temperature for 60 minutes in a 50 μL mixture containing PDE assay buffer, 100 nM FAM-cAMP, PDE enzyme (PDE4A1A 2 ng / reaction, PDE4B1 0.04 ng / reaction, PDE4D2 0.013 ng / reaction), and test compound. After the enzyme reaction, 100 μL of binding solution (1:100 dilution of binding agent in binding agent diluent) was added to each well, and the plate was incubated for an additional 15 minutes. Fluorescence intensity was measured using a Tecan Infinite M1000 microplate reader at an excitation of 470 nm and an emission of 528 nm. PDE activity assays were performed in duplicate at each concentration. Fluorescence intensity was converted to fluorescence polarization using Tecan Magellan 6 software. Fluorescence polarization data were analyzed using computer software GraphPad Prism. Fluorescence polarization in the absence of compound (FP) was measured in each data set. t ) was defined as 100% activity. In the absence of PDE and compound, the fluorescence polarization (FP b ) was defined as 0% activity. Percent activity in the presence of compound was calculated according to the following formula: %Activity=(FP-FP b ) / (FP t -FP b )×100% Here, FP represents fluorescence polarization in the presence of compound. The % activity values ​​for a range of compound concentrations are then calculated using the formula Y=B+(TB) / 1+10 ((LogEC50-X)×ヒルスロープ) (where Y = percent activity, B = minimum percent activity, T = maximum percent activity, X = logarithm of the compound, and Hill slope = slope factor or Hill coefficient.) The sigmoidal dose-response curves generated by the method were plotted using nonlinear regression analysis. 50Values ​​were determined by the concentration of half-maximal percent activity. IC of parent PDE4 inhibitors 50 The IC values ​​should be less than about 1000 nM, preferably less than about 100 nM, and even more preferably less than about 10 nM. Measured IC values ​​for parent PDE4 inhibitor compounds IIIa and IIIb against isoenzymes PDE4A1A, PDE4B1, and PDE4D2 50 The IC values ​​of the PDE4 inhibitor glycosides represented by formula (I) were less than 10 nM. 50 Values ​​are calculated based on the IC of their corresponding parent PDE4 inhibitors. 50 at least 10 times the IC value of its corresponding parent PDE4 inhibitor, preferably 50 100-fold or more of the IC value of the corresponding parent PDE4 inhibitor, and advantageously 50 The IC measured for compound 22 should be 1000 times higher than the 50 The IC value was greater than 100 nM, despite being contaminated with 0.17% of IIIa. The potency of IIIa and the mathematical prediction (100 / 0.17 × IC of IIIa) 50 Such contamination due to HCl ions accounted for 100% of the recorded potency of compound 22. do.

[0167] TNFα Inhibition Assay Protocol. The efficacy of PDE4 inhibitors in the LPS-induced TNFα assay in human whole blood was measured using the following protocol. Fresh blood was collected into heparin tubes by venipuncture from healthy human volunteers (male and female). These subjects had no obvious inflammatory conditions, no symptoms of bacterial / viral infection, no fever, and had not taken NSAIDs for at least one week prior to blood collection. Blood from each donor was dispensed into a 96-deep-well plate at 500 μL per well. The blood was preincubated with either 2 μL of vehicle (DMSO) or test compound for 15 minutes at 37°C / 5% CO2. This was followed by the addition of 10 μL of lipopolysaccharide from Escherichia coli serotype 0111:B4 diluted in 0.1% bovine serum albumin fraction V (BSA, Sigma-Aldrich, St. Louis, MO, USA) in phosphate-buffered saline (PBS) at a final concentration of 1 μg / mL for 24 h at 37°C / 5% CO2. Duplicate, independent incubations were performed for each inhibitor concentration using blood from each donor. Appropriate PBS controls (no LPS) served as blanks (four wells), and blood samples stimulated with LPS controls (no PDE4 inhibitors) served as positive controls (four wells). After incubation, samples were centrifuged at 1500 × g for 10 min at 4°C. Plasma was collected (approximately 200 μL per well) and kept at -80°C for analysis by ELISA. Plasma TNFα was quantified by ELISA (Invitrogen, Frederick, MD, USA) according to the manufacturer's instructions. In each case, a positive control value from the same patient on the same plate was used to calculate percent inhibition. From each blood assay sample, 4 μL of plasma was diluted (1:50) in 196 μL of dilution buffer to obtain optical density (OD) values ​​within the linear portion of the standard curve (data not shown). Assay plates were read at 450 nm on an Infinite F200 Protecan reader.Absorbance values ​​were converted to % inhibition based on the positive and negative control values ​​for each plate, and the resulting % inhibition data were fit to a 4-parameter logistic by nonlinear regression using GraphPad Prism (version 6.00, GraphPad Software, Inc., La Jolla, CA, USA), resulting in reported ICs. 50 Values ​​are from a four parameter fit and are the concentrations of test inhibitors that give half-maximal TNFα inhibition. Mean IC determined for compounds IIIa and IIIb using blood from 12 healthy volunteers. 50 The values ​​were less than 50 nM.

[0168] In vitro glycoside prodrug permeability evaluation. The permeability of glycoside prodrugs was measured using a bidirectional Caco-2 assay. Caco-2 cells were seeded on permeable polycarbonate supports in 12-well coaster transwell plates and allowed to grow and differentiate for 21–25 days. On day 24, the culture medium (DMEM supplemented with 10% FBS, 1% non-essential amino acids, and penicillin / streptomycin) was removed from both sides of the transwell insert, and the cells were rinsed with warm HBSS. After the rinse step, the chamber was filled with warm transport buffer (apical: HBSS containing 25 mM MES, 0.25% BSA, pH 6.0; basolateral: HBSS containing 25 mM HEPES, 0.25% BSA, pH 7.4), and the plate was incubated at 37°C for 30 min before TEER (transepithelial electrical resistance) measurements. The buffer in the donor chamber (apical for A-to-B assays, basolateral for B-to-A assays) was removed and replaced with working solution (10 μM test substance in transport buffer). The plate was then placed at 37°C with gentle agitation. At designated time points (30, 60, and 90 min), aliquots of transport buffer from the receiver chamber were removed and replenished with fresh transport buffer. Samples were quenched with ice-cold CH3CN containing internal standard and then centrifuged to precipitate proteins. The resulting supernatant was diluted 50 / 50. Further dilutions were made with ACN / HO (HO only for atenolol) and subjected to LC / MS / MS analysis. app ) represent the mean of duplicate determinations. Atenolol and propranolol were tested as low and intermediate permeability standards. Bidirectional transport of digoxin was assessed to demonstrate P-gp activity / expression. The apparent permeability (P app , measured in cm / s) was determined according to the following formula: [ka] where dQ / dt represents the net appearance rate in the receiver compartment; A is cm 2 (1.12cm 2 ) represents the area of ​​the Transwell measured in minutes, C0 represents the initial concentration of compound added to the donor chamber, and 60 represents the conversion factor from minutes to seconds. Because glycoside prodrugs are intended to deliver active PDE4 inhibitors to the colonic portion of the gastrointestinal tract (GIT), minimal absorption of the compound represented by formula (I) from the upper GIT is desirable. Caco-2 P app Since a correlation between A-to-B P and in vivo intestinal absorption has been demonstrated (Artursson P.; Karlsson J. 1991 Biochem. Biophys. Res. Commun. 175(3), 880), app The permeability of the glycoside prodrug should be inferior to that of the corresponding parent PDE4 inhibitor, as measured by app is 1 x 10 -6 cm / sec, and even more preferably less than 0.1×10 -6 The glycoside prodrugs of formula (I) exhibited an inferior Caco-2 P activity compared to the corresponding PDE4 inhibitor III. app It was found to have (Table 2). [Table 4]

[0169] In vitro rates of hydrolysis of glucoside prodrugs. The metabolic stability of prodrug candidates releasing parent PDE4 inhibitors could be assessed in vitro according to, but not limited to, the following protocol: Feces were collected overnight on a mixture of dry and wet ice in metabolic cages. Ten volumes (v / w; 30 mL) of 100 mM phosphate buffer (pH 6.5) were added to 3 g of freshly collected rodent feces. The mixture was cycled 2 x 1 min at 225 rpm in a Stomacher Circulator 400. The mixture was homogenized with a 0.45 μm filter. The mixture was transferred to a 50 mL tube and centrifuged at 10,000 × g for 10 minutes (4 °C), and the supernatant was passed through a 0.45 μm filter. In a 96-deep-well plate, 198 μL of fecal supernatant was dispensed into two wells per compound. Each compound, including the positive control, was tested in duplicate. Next, 2 μL of a 10 mM stock solution of each test compound was spiked into individual wells (in duplicate) for a final concentration of 100 μM. The samples were then sealed and mixed using a vortexer at 1000 rpm for 30 seconds. The samples were incubated at 37 °C in a thermomixer with constant agitation (300 rpm) for the desired time. At the desired time points, 25 μL of the reaction mixture was added to 225 μL of ice-cold quenching solution (acetonitrile + 0.1% (v / v) formic acid) to stop bacterial enzyme activity. The quenched culture was mixed and centrifuged at 21,000 × g for 10 minutes at 4 ° C. The actual t0 (100% total recovery of unchanged prodrug without metabolism) was generated by adding 22.5 μL of fecal supernatant to 225 μL of ice-cold quenching solution (acetonitrile + 0.1% (v / v) formic acid). Next, 2.5 μL of a 1 mM solution of each test compound was added, sealed, mixed thoroughly, and centrifuged at 21,000 × g for 10 minutes at 4 ° C. All samples, including analytical standards, were analyzed by LC-MS / MS to measure the concentration of released parent PDE4 inhibitor and the concentration of remaining corresponding prodrug. The set criterion for 100% recovery was aimed for the sum of the remaining prodrug percentage and the released parent PDE4 inhibitor percentage to be 100% with an experimental error margin of ± 20%. When the prodrugs of formula (I) were incubated with mouse, rat, and dog feces under the above conditions for 24 hours, the glycoside prodrugs were hydrolyzed to release the corresponding parent PDE4 inhibitor III (Table 3). As a negative control, when compounds 4, 10, and 21 were incubated with mouse fecal extract supernatants inactivated by boiling the supernatants for 10 minutes under the above conditions (but in the absence of enzyme activity) for 24 hours, 100% of the prodrugs were recovered unchanged.As a positive control, when compounds 9 and 10 were incubated in the presence of β-D-glucuronidase (50 U / mL) at 37°C in phosphate buffer (pH 6.5) for 24 h, 85% and 37%, respectively, of IIIb were released, and 2% of compound 9 and 64% of compound 10 were recovered unchanged. [Table 5]

[0170] Bioactivation of glycoside prodrugs in vivo. In vivo pharmacokinetic studies were conducted using preclinical species, including, but not limited to, mice and rats. Following oral administration of a PDE4 inhibitor glycoside represented by Formula (I), the distribution of the prodrug and the corresponding parent PDE4 inhibitor as a function of time was assessed in tissues such as the blood and intestine. The amounts of the prodrug and the corresponding parent excreted in the feces were also measured. This allows researchers to release the parent PDE4 inhibitor, assess the in vivo bioactivation of the glycoside prodrug, and evaluate the degree of colon specificity for the glycoside prodrug delivery system. Advantageously, the parent PDE4 inhibitor should not be released before reaching the colonic portion of the GIT, and the prodrug should not be absorbed into the upper GIT. More advantageously, the local exposure of the parent PDE4 inhibitor measured in the feces and / or colon should be superior to the systemic exposure of the parent measured in the blood. When compound 10 was orally administered to rats as an aqueous suspension, neither the prodrug nor its corresponding metabolite, compound 9, was detected in the blood over a 24-hour period. In the same study, the corresponding PDE4 inhibitor IIIb was not detected in the blood before T = 2 hours, which represents the gastrointestinal transit time. Over 24 hours, the degree of bioactivation of the prodrug was 96%, as measured in the excreted feces by the ratio of parent PDE4 inhibitor IIIb to the remaining prodrug 10. When compound 10 was orally administered to C57Bl / 6 mice in a Labrasol / 5% dextrose solution, the degree of bioactivation of the prodrug over 48 hours measured in the excreted feces was > 98%, with only trace amounts of unchanged prodrug detected. 81% of the administered dose of compound 10 was excreted in the feces as parent PDE4 inhibitor IIIb. In the same study, in colonic tissue (proximal and distal colon), The measured exposure (AUC 0-24 ) was 200-fold superior to that measured in blood.

[0171] The emetic threshold of PDE4 inhibitor glycoside can be evaluated as a measure of improved tolerance compared with corresponding parent PDE4 inhibitor.In this observation model, animals such as (but not limited to) dogs, ferrets or non-human primates are administered with equivalent doses of PDE4 inhibitor glycoside or its corresponding parent PDE4 inhibitor, and emesis is recorded.Improved tolerance is defined as the ratio of the emetic dose of PDE4 inhibitor glycoside to the emetic dose of corresponding parent PDE4 inhibitor is >3, preferably this ratio is >10, and even more preferably this ratio is >30.

[0172] While preferred embodiments have been described above and illustrated in the accompanying drawings, it will be apparent to those skilled in the art that modifications may be made without departing from this disclosure, and such modifications are considered to be possible modifications within the scope of this disclosure.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, X is β-D-glucuronide, α-D-glucuronide, β-D-glucopyranoside, α-D-glucopyranoside, β-D-galactopyranoside, α-D-galactopyranoside, β-D-mannopyranoside, α-D-mannopyranoside, N-acetyl-β-D-glucosaminide, N-acetyl-α-D-glucosaminide, N-acetyl-β-D-galactosaminide, N-acetyl-α-D-galactosaminide, β-D-glucosaminide amide, α-D-glucosaminide, β-D-galactosaminide, α-D-galactosaminide, β-D-fucopyranoside, α-L-fucopyranoside, α-L-rhamnopyranoside, α-L-arabinofuranoside, β-D-ribofuranoside, β-D-cellobioside, α-D-cellobioside, β-N,N-diacetylchitobioside, D-xylopyranoside, D-xylofuranoside, β-D-galacturonide or α-D-galacturonide; R １ and R ２ are, independently of each other, -C １－６ alkyl group, -C ３－６ represents cycloalkyl groups, any of which is unsubstituted or substituted with 1 to 6 independent halogen atoms; R ３ and R ４ are each independently H or —C １－６ represents an alkyl group, R ５ , R ６ and R ７ are each independently H, a halogen atom, -C １－６ Alkyl group, —C(O)C １－６ represents an alkyl group or CN; Ar １ is independent (a) 6-R ８ -3-pyridyl group or 6-R ９ -3-pyridyl group, (b) 2-R ８ -5-thiazolyl group or 5-R ８ -2-thiazolyl group, (c) 2-R ８ -5-pyrimidinyl group or 2-R ９ -5-pyrimidinyl group, (d) 6-R ８ -3-pyridazinyl group or 6-R ９ -3-pyridazinyl group, (e) 5-R ８ -2-furyl group, (f) 5-R ８ -2-thienyl group, (g) 2-R ８ -5-oxazolyl group or 5-R ８ -2-oxazolyl group, (h) 5-R ８ -3-isoxazolyl group or 3-R ８ -5-isoxazolyl group, (i) 5-R ８ -3-isothiazolyl group or 3-R ８ -5-isothiazolyl group, and (j) p-R ８ -phenyl group, is selected from the group consisting of R ８ is H, halogen atom, -C １－６ alkyl group, -C ３－６ cycloalkyl group, -C １－６ AlkylAr ２ , Ar ２ , C １－６ Alkoxy group, C １－６ Alkylthio group, CN, —C(R １０ ) (R １１ )OH, —C(R １０ ) (R １１ ) O.C. １－６ alkyl group, —C(R １０ ) (R １１ ) OAr ２ , -CO ２ H, -CO ２ C １－６ Alkyl group, —C(O)NR １２ R １３ , -SO ２ NHC(O)Ar ２ , -C(O)C １－６ Alkyl groups and —C(O)Ar ２ is selected from the group consisting of R ９ is -NR １２ R １３ , -NR １２ C(O)R １３ , -NR １２ C(O)NHR １３ , -NR １２ SO ２ Ar ２ , and -NR １２ CO ２ Ar ２ is selected from the group consisting of R １０ and R １１ are independently H, —C １－６ alkyl group, -C １－６ haloalkyl group, —C ３－６ a cycloalkyl group, or Ar ２ represents, or R １０ and R １１ Ga-C １－６ When alkyl groups are represented, they are C １－３ C bonded together via alkyl groups ３－６ may form a cycloalkyl group, R １２ and R １３ are independently H, -C １－６ alkyl group, -C ３－６ a cycloalkyl group, or -C １－６ AlkylAr ２ represents or R １２ and R １３ Ga-C １－６ When alkyl groups are represented, they are C １－３ C bonded together via alkyl groups ３－６ may form a heterocycloalkyl group, Ar ２ is selected from the group consisting of phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl; Each Ar ２ is unsubstituted or a halogen atom, —C １－６ alkyl group, -C １－６ Haloalkyl groups, CN, C １－６ Alkoxy group, C １－６ alkylthio group, —C(R １０ ) (R １１ ) OH, —CO ２ H, -CO ２ C １－６ Alkyl group, —C(O)NR １２ R １３ , and -SO ２ CH ３ or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the β-D-glucuronide is β-D-glucuronic acid, methyl β-D-glucuronidate, methyl 2,3,4-tri-O-acetyl-β-D-glucuronidate, ethyl 2,3,4-tri-O-acetyl-β-D-glucuronidate, ethyl β-D-glucuronidate, i-propyl β-D-glucuronidate, tert-butyl β-D-glucuronidate, or methyl β-D-glucuronamide.

3. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the β-D-glucopyranoside is β-D-glucopyranosyl, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl, or 3,4,6-tri-O-acetyl-β-D-glucopyranosyl.

4. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the β-D-galactopyranoside is β-D-galactopyranosyl or 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl.

5. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the α-D-mannopyranoside is α-D-mannopyranosyl or 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl.

6. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the β-D-glucosaminide is β-D-glucosaminyl or α-D-glucosaminyl.

7. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the N-acetyl-β-D-glucosaminide is N-acetyl-β-D-glucosaminyl, 3,4,6-tri-O-acetyl-N-acetyl-β-D-glucosaminyl, N,N,N-trimethyl-β-D-glucosaminyl, or N,N-dimethyl-β-D-glucosaminyl.

8. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the β-D-cellobioside is β-D-cellobiosyl or 2,3,6,2',3',4',6'-hepta-O-acetyl-β-D-cellobiosyl.

9. Ar １ But, 6-R ８ -3-pyridyl group, or 2-R ８ 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the aryl group is a 5-thiazolyl group.

10. Ar １ But, 6-R ８ 9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R represents a 3-pyridyl group.

11. R ３ and R ４ and each represent H, or a pharmaceutically acceptable salt thereof.

12. R ５ , R ６ and R ７ and each represent H, or a pharmaceutically acceptable salt thereof.

13. R ８ But -C(R １０ ) (R １１ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R represents 1 or 2;

14. The compound of claim 1, wherein the β-D-glucuronide is β-D-glucuronyl.

15. 15. The compound of claim 14, wherein the β-D-glucuronyl is methyl glucuronate.

16. 2. The compound of claim 1, wherein the compound of formula (I) is one of the following compounds or a pharmaceutically acceptable salt thereof: Table 1

17. The compound represented by formula (I) 【Chemistry 2】 2. The compound of claim 1, wherein the compound is:

18. The compound represented by formula (I) 【Transformation 3】 2. The compound of claim 1, wherein the compound is:

19. The compound represented by formula (I) 【Chemistry 4】 2. The compound of claim 1, wherein the compound is:

20. 20. A pharmaceutical composition comprising a compound of formula (1) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

21. The pharmaceutical composition of claim 20, wherein the therapeutically effective amount of the compound represented by formula (I) is 0.001 mg to 1000 mg.

22. 22. The pharmaceutical composition of any one of claims 20 to 21, wherein the composition is at least one of an immediate release formulation, an extended release formulation, or a delayed release formulation, or a combination thereof.

23. 23. The pharmaceutical composition of any one of claims 20 to 22, wherein the composition is in the form of a lotion or liquid.

24. Furthermore, leukotriene receptor antagonists, leukotriene biosynthesis inhibitors, M2 / M3 antagonists, corticosteroids, HI receptor antagonists, β ２ 24. The pharmaceutical composition of any one of claims 20 to 23, comprising an adrenoceptor agonist, a selective COX-2 inhibitor, an NSAID, an immunomodulator, 5-ASA, a 5-ASA prodrug, a Janus kinase inhibitor, or a combination thereof.

25. Asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, hypersecretion of gastric acid, sepsis or septic shock, endotoxin shock, endotoxin shock-related conditions, spinal cord injury, head injury, neurological inflammation, pain, cerebral reperfusion injury 20. A compound of formula (I), as defined in any one of claims 1 to 19, for use in the manufacture of a medicament for use in a patient suffering from rheumatoid arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergic conjunctivitis, eosinophilic granulomas, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, cancerous invasion of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, or cachexia, or a combination thereof.

26. 20. A compound of formula (I) as defined in any one of claims 1 to 19 for use in the manufacture of a medicament for use in a patient suffering from ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis, or a combination thereof.

27. Asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, gastric hypersecretion, sepsis or septic shock, endotoxic shock, endotoxic shock-related conditions, spinal cord injury, head trauma, neurogenic inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergic conjunctivitis, eosinophilic granuloma 20. A compound of formula (I) as defined in any one of claims 1 to 19 for use in patients suffering from rheumatoid arthritis, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, cancerous invasion of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, or cachexia, or a combination thereof.

28. 20. A compound of formula (I) as defined in any one of claims 1 to 19 for use in patients suffering from ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis, or a combination thereof.

29. Asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, gastric hypersecretion, sepsis or septic shock, endotoxic shock, endotoxic shock-related conditions, spinal cord injury, head trauma, neurogenic inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergic conjunctivitis, eosinophilic granuloma 25. The composition of any one of claims 20 to 24 for use in the manufacture of a medicament for use in patients suffering from depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, cancerous infiltration of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, or cachexia, or a combination thereof.

30. 25. A composition according to any one of claims 20 to 24 for use in a patient suffering from ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis, or a combination thereof.

31. Asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, ulcerative colitis, Crohn's disease, diverticulitis, hypersensitivity bowel syndrome, gastric acid hypersecretion, sepsis or septic shock, endotoxic shock, endotoxic shock-related states, spinal cord injury, head trauma, neurogenic inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, allergic conjunctivitis, eosinophilic granuloma, depression, memory impairment, unipolar depression, Parkinson's disease, Alzheimer's disease, acute and a composition according to any one of claims 20 to 24 for use in patients suffering from chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, urticaria, cancer, tumor growth, cancerous invasion of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, or cachexia, or a combination thereof.

32. 25. A composition according to any one of claims 20 to 24 for use in a patient suffering from ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis, or a combination thereof.

Images