Gut microbiota bioactive PDE4 inhibitor precursors

Abstract

This document describes compounds of formula (I), or pharmaceutically acceptable salts thereof, methods for their preparation, and methods for their use in treating or preventing a variety of conditions, including ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, psoriatic arthritis, or psoriasis. #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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. Background Art

[0003] (a) field

[0004] The presently disclosed subject matter generally relates to compounds that are glycoside prodrugs of phosphodiesterase 4 (PDE4) inhibitors. In particular, the present invention relates to compounds that are glycoside prodrugs of (a) β-D-glucuronide, (b) α-D-glucuronide, (c) β-D-glucopyranoside, (d) α-D-glucopyranoside, (e) β-D-galactoside, (f) α-D-galactoside, (g) β-D-mannopyranoside, (h) α-D-mannopyranoside, (i) N-acetyl-β-D-glucosaminide, (j) N-acetyl-α-D-glucosaminide, (k) N-acetyl-β-D-galactosaminide, (l) N-acetyl-α-D-galactosaminide, (m) β-D-glucosaminide, (n) α-D-glucosaminide, (o) β-D-aminogalactoside, (p) α-D-aminogalactoside, (q) β-D-fucopyranoside, (r) α-L-fucopyranoside, (s) α-L-rhamnoside, (t) α-L-arabinofuranoside, (u) β-D-ribofuranoside, (v) polysaccharides such as β-D-cellobioside or α-D-cellobioside or β-N,N-diacetylchitobioside, (w) D-xylopyranoside, (x) D-xylopyranoside, (y) diaryl-substituted ethanepyridones to which a β-D-galactosiduronic acid or (z) α-D-galactosiduronic acid moiety is bound, which are colon-specific prodrugs of PDE4 inhibitors.

[0005] (b) Related existing technologies

[0006] Cyclic adenosine monophosphate (3', 5'-cyclic adenosine monophosphate, "cAMP" or "cyclic AMP") is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, adrenocorticotropic hormone, 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.

[0007] Phosphodiesterases ("PDEs") are a family of enzymes that metabolize 3', 5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cAMP second messenger activity. One particular 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 different 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 inhibiting PDE4, particularly specific PDE4 isoforms that produce adverse reactions, can beneficially affect allergic and inflammatory symptoms. It is desirable to provide new compounds and compositions that inhibit PDE4 activity.

[0008] Tumor necrosis factor alpha (TNF-α) is a cytokine that is primarily released by mononuclear phagocytes in response to immune stimuli. TNFα is able to enhance most cellular processes, such as differentiation, recruitment, proliferation, and proteolytic degradation. At low levels, TNF-α provides protection against infectious agents, tumors, and tissue damage. However, TNF-α also plays a role in many diseases. 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 uncontrolled TNF-α production has been associated with many diseases and medical conditions, such as cancers, such as solid tumors and blood-borne tumors; cardiac diseases, such as congestive heart failure; and viral, genetic, inflammatory, allergic, and autoimmune diseases.

[0009] 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 common problematic diseases. TNF-α plays a central role in the inflammatory response, and administration of its antagonists can block both chronic and acute responses in animal models of inflammatory diseases.

[0010] Pharmaceutical compounds that can block the activity or inhibit the production of certain cytokines, including TNF-α, such as PDE4 inhibitors, may be beneficial therapies for treating or preventing inflammatory diseases associated with TNF-α.

[0011] Ulcerative colitis is a relapsing, chronic inflammatory bowel disease that affects the lining of the colon and rectum. Current treatments include 5-aminosalicylate, corticosteroids, immunomodulators, and TNF-α inhibitors such as infliximab (Remicade). TM), adalimumab (Humira TM ), golimumab (Simponi TM ) and “α4β7 integrin inhibitors, such as vedolizumab (Entyvio TM ).

[0012] PDE4 inhibitors are known to inhibit the synthesis of the proinflammatory cytokine TNF-α, which plays a key role in the pathogenesis of ulcerative colitis. The demonstrated efficacy of TNF-α inhibitors in the treatment of ulcerative colitis further supports the utility of PDE4 inhibitors as an alternative therapy.

[0013] One of the first drugs used to treat ulcerative colitis was a prodrug called sulfasalazine. The sulfonamide moiety acts as a carrier to deliver the active ingredient, 5-aminosalicylic acid (5-ASA, also known as mesalamine or mesalamine), to the colon. Specific bacterial action in the colonic microbiome is responsible for cleavage of the diazo bond in sulfasalazine.

[0014] The oral topical corticosteroid budesonide, as a colon-specific controlled-release formulation (Uceris™), reduces systemic exposure and effectively controls ulcerative colitis with minimal side effects (Sandborn et al., Gastroenterology 2012, 143, 1218).

[0015] The primary rationale for topical treatment of ulcerative colitis is that it directly treats the inflamed colonic mucosa while minimizing systemic side effects.

[0016] In the oral drug disposition of active substances in vivo, it is known that during intrahepatic recirculation, various drug glucuronide conjugates that undergo biliary excretion are reabsorbed in the gastrointestinal tract and hydrolyzed by colonic β-glucuronidase to release the parent active ingredient.

[0017] Bacteria that colonize the mammalian gut possess a large repertoire of carbohydrate processing enzymes, such as but not limited to glycoside hydrolases (glycosidases), polysaccharide lyases, and carbohydrate esterases with degradative and metabolic capabilities (Flint et al., Gut Microbes, 2012, 3(4), 289).

[0018] Many companies have invested in the development of specific PDE4 inhibitors as anti-inflammatory agents, two of which, roflumilast (Daliresp TM , Takeda, COPD) and apremilast (Otezla TM, Celgene, psoriasis / psoriatic arthritis) have been approved by regulatory agencies and entered the market. In a Phase 2 clinical trial, Apremilast also demonstrated its ability to induce and maintain clinical remission in patients with moderate to severe ulcerative colitis for up to 52 weeks (Danese, S. et al., Clin. Gastroenterol. Hepato. 2020, 18 (11), 2526-2534). Regardless of the indication, common side effects of these treatments are headaches and gastrointestinal disorders such as nausea, vomiting, and diarrhea.

[0019] Therefore, there is a need for PDE4 inhibiting compounds that reduce or alleviate the disadvantages of compounds known in the art.

[0020] Therefore, there is a need for PDE4 inhibitory compounds that cause little or no headache, nausea, vomiting, and / or diarrhea. Summary of the Invention

[0021] The present invention relates to compounds that are glycoside prodrugs of phosphodiesterase 4 (PDE4) inhibitors. In particular, the present invention relates to compounds that are glycoside prodrugs of (a) β-D-glucuronide, (b) α-D-glucuronide, (c) β-D-glucopyranoside, (d) α-D-glucopyranoside, (e) β-D-galactoside, (f) α-D-galactoside, (g) β-D-mannopyranoside, (h) α-D-mannopyranoside, (i) N-acetyl-β-D-glucosaminide, (j) N-acetyl-α-D-glucosaminide, (k) N-acetyl-β-D-galactosaminide, (l) N-acetyl-α-D-galactosaminide, (m) β-D-glucosaminide, (n) α-D-glucosaminide, (o) β-D-aminogalactoside, (p) α-D-aminogalactoside, (q) β-D-fucopyranoside, (r) α-L-fucopyranoside, (s) α-L-rhamnoside, (t) α-L-arabinofuranoside, (u) β-D-ribofuranoside, (v) polysaccharides such as β-D-cellobioside or α-D-cellobioside or β-N,N-diacetylchitobioside, (w) D-xylopyranoside, (x) D-xylopyranoside, (y) diaryl-substituted ethanepyridones to which a β-D-galactosiduronic acid or (z) α-D-galactosiduronic acid moiety is bound, which are colon-specific prodrugs of PDE4 inhibitors.

[0022] According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0023]

[0024] wherein X is β-D-glucuronide, α-D-glucuronide, β-D-glucopyranoside, α-D-glucopyranoside, β-D-galactoside, α-D-galactoside, 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-amino Glucoside, α-D-aminoglucosidoside, β-D-aminogalactosidoside, α-D-galactosidoside, β-D-fucopyranoside, α-L-fucopyranoside, α-L-rhamnoside, α-L-arabinofuranoside, β-D-ribofuranoside, β-D-cellobioside, α-D-cellobioside, β-N,N-diacetylchitobioside, D-xylopyranoside, D-xylofuranoside, β-D-galactosiduronic acid, or α-D-galactosiduronic acid; R 1 and R 2 Each independently is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, any one of which is unsubstituted or substituted by 1-6 independent halogens;

[0025] R 3 and R 4 Each independently is H, or -C 1-6 alkyl;

[0026] R 5 、R 6 and R 7 are each independently H, halogen, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl or CN;

[0027] Ar 1 Independently selected from the group consisting of:

[0028] (a)6-R 8 -3-pyridyl or 6-R 9 -3-pyridyl,

[0029] (b)2-R 8 -5-thiazolyl or 5-R 8 -2-thiazolyl,

[0030] (c)2-R 8 -5-pyrimidinyl or 2-R 9 -5-pyrimidinyl,

[0031] (d)6-R 8 -3-pyridazinyl or 6-R 9 -3-pyridazinyl,

[0032] (e)5-R8 -2-furyl,

[0033] (f)5-R 8 -2-thienyl,

[0034] (g)2-R 8 -5-oxazolyl or 5-R 8 -2-oxazolyl,

[0035] (h)5-R 8 -3-isoxazolyl or 3-R 8 -5-isoxazolyl,

[0036] (i)5-R 8 -3-isothiazolyl or 3-R 8 -5-isothiazolyl, and

[0037] (j) For-R 8 -phenyl;

[0038] R 8 Selected from the group consisting of H, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 Alkyl Ar 2 、Ar 2 、C 1-6 Alkoxy, C 1-6 Alkylthio, CN, -C(R 10 )(R 11 )OH、-C(R 10 )(R 11 )OC 1-6 Alkyl, -C(R 10 )(R 11 )OAr 2 、-CO2H、-CO2C 1-6 Alkyl, -C(O)NR 12 R 13 、-SO2NHC(O)Ar 2 、-C(O)C 1-6 Alkyl and -C(O)Ar 2 ;

[0039] R 9 Selected from the group consisting of: -NR 12 R 13 、-NR 12 C(O)R 13 、-NR 12 C(O)NHR 13 、-NR 12 SO2Ar 2 , and -NR 12 CO2Ar2 ;

[0040] R 10 and R 11 Each independently represents H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl or Ar 2 ;

[0041] Or when R 10 and R 11 -C 1-6 When alkyl groups are present, they can be 1-3 Alkyl groups are linked together to form C 3-6 Cycloalkyl;

[0042] R 12 and R 13 Each independently represents H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -C 1-6 Alkyl Ar 2 ;

[0043] Or when R 12 and R 13 -C 1-6 When alkyl groups are present, they can be 1-3 Alkyl groups are linked together to form C 3-6 heterocycloalkyl;

[0044] Ar 2 selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl;

[0045] Each Ar 2 is unsubstituted or substituted by 1-3 members selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, CN, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(R 10 )(R 11 )OH, -CO2H, -CO2C1 -6 Alkyl, -C(O)NR 12 R 13 and -SO2CH3.

[0046] The β-D-glucuronide is β-D-glucuronic acid, β-D-glucuronic acid methyl ester, 2,3,4-tri-O-acetyl-β-D-glucuronic acid methyl ester, 2,3,4-tri-O-acetyl-β-D-glucuronic acid ethyl ester, β-D-glucuronic acid ethyl ester, β-D-glucuronic acid isopropyl ester, β-D-glucuronic acid tert-butyl ester or methyl β-D-glucuramide.

[0047] 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.

[0048] The β-D-galactoside is β-D-galactopyranosyl or 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl.

[0049] The α-D-mannopyranoside is α-D-mannopyranosyl or 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl.

[0050] The β-D-aminoglucosides are β-D-glucosamine groups or α-D-glucosamine groups.

[0051] The N-acetyl-β-D-glucosaminyl 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.

[0052] The β-D-cellobioside is β-D-cellobiosyl or 2,3,6,2',3',4',6'-heptyl-O-acetyl-β-D-cellobiosyl.

[0053] The Ar 1 Can be 6-R 8 -3-pyridyl or 2-R 8 -5-thiazolyl.

[0054] The Ar 1 Can be 6-R 8 -3-pyridyl.

[0055] The R 3 and R 4 They can each be H.

[0056] The R 5 、R 6 and R 7 They can each be H.

[0057] The R 8Can be -C(R 10 )(R 11 )OH.

[0058] The β-D-glucuronide may be a β-D-glucuronic acid.

[0059] The β-D-glucuronic acid group may be methyl glucuronide.

[0060] The compound of formula (I) may be one of the following compounds or a pharmaceutically acceptable salt thereof:

[0061]

[0062]

[0063]

[0064] The compound of formula (I) can be represented as

[0065]

[0066] or a pharmaceutically acceptable salt thereof.

[0067] The compound of formula (I) can be represented as

[0068]

[0069] or a pharmaceutically acceptable salt thereof.

[0070] The compound of formula (I) can be represented as

[0071]

[0072] or a pharmaceutically acceptable salt thereof.

[0073] The present invention also provides a pharmaceutical composition comprising an effective amount of a novel diaryl-substituted ethane pyridone glycoside conjugate and a pharmaceutically acceptable carrier.

[0074] According to another embodiment, a pharmaceutical composition is provided, 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.

[0075] The therapeutically effective amount may 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 the compound of formula (I).

[0076] The composition may be at least one of an immediate release formulation, a sustained release formulation, or a delayed release formulation, or a combination thereof.

[0077] The composition may be in the form of a lotion or a liquid.

[0078] The pharmaceutical composition may further comprise a leukotriene receptor antagonist, a leukotriene biosynthesis inhibitor, an M2 / M3 antagonist, a corticosteroid, an H1 receptor antagonist, a β2 adrenergic receptor agonist, a selective COX-2 inhibitor, an NSAID, an immunomodulator, 5-ASA, a 5-ASA prodrug, a janus kinase inhibitor, or a combination thereof.

[0079] The present invention also provides a method of treatment in a mammal.

[0080] According to another embodiment, a method is provided for treating, in mammals, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granulomas, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related diseases 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, animal chronic obstructive pulmonary disease, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial recurrence, and the like. Stenosis, atherosclerosis, 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 atrophy, depression, memory impairment, tumor growth, cancerous invasion of normal tissue, osteoporosis and bone loss, by administering an effective amount of a novel diaryl-substituted ethane pyridone glycoside conjugate, which is a colon-specific PDE4 prodrug.

[0081] According to another embodiment, there is provided a composition for treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, excessive gastric acid secretion, sepsis or septic shock, endotoxin shock, endotoxin shock-related conditions, spinal cord trauma, head injury, neurogenic inflammation, pain, brain reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, allergic rhinitis, A method for treating 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 invasion 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, comprising administering a therapeutically effective amount or a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present invention.

[0082] According to another embodiment, a method for treating or preventing ulcerative colitis, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis is provided, comprising administering a therapeutically effective amount or a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition of the present invention.

[0083] In the methods of the present invention, administration can be systemic, oral, topical, or a combination thereof.

[0084] According to another embodiment, there is provided a compound of formula (I) or a composition of the present invention for use in the preparation of a composition for treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, excessive gastric acid secretion, sepsis or septic shock, endotoxin shock, endotoxin shock-related diseases, spinal cord trauma, head injury, neurogenic inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, The invention also provides a novel method for treating inflammatory bowel disease, osteoarthritis, chronic tissue degeneration mediated by inflammation and cytokines, 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, cancer invasion of normal tissue, diabetes insipidus, osteoporosis, arterial restenosis, atherosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, transplant rejection, graft-versus-host disease and cachexia.

[0085] According to another embodiment, there is provided use of a compound of formula (I) or a composition of the present invention in the preparation of a medicament for treating or preventing ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis, or psoriasis.

[0086] According to another embodiment, a compound of formula (I) or a composition of the present invention is provided for treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, gastric acid hypersecretion, sepsis or septic shock, endotoxin shock, endotoxin shock-related conditions, spinal cord trauma, head injury, neurogenic inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, Spondylitis, osteoarthritis, inflammatory 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 invasion 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.

[0087] According to another embodiment, there is provided a compound of formula (I) or a composition of the present invention for use in treating or preventing ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis, or psoriasis.

[0088] According to another embodiment, there is provided a compound of formula (I) or a composition of the present invention for treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, excessive gastric acid secretion, sepsis or septic shock, endotoxin shock, endotoxin shock-related conditions, spinal cord trauma, head injury, neurogenic inflammation, pain, cerebral reperfusion injury, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylosis. The invention also relates to the treatment of inflammatory bowel disease, osteoarthritis, inflammatory 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, cancer invasion 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.

[0089] According to another embodiment, provided is a use of a compound of formula (I) or a composition of the present invention in treating or preventing ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis or psoriasis.

[0090] The features and advantages of the present subject matter will become more apparent from the following detailed description of selected embodiments, as illustrated in the accompanying drawings. As will be appreciated, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. The drawings and description are, therefore, to be regarded as illustrative in nature and not restrictive, with the full scope of the subject matter being set forth in the claims.

[0091] Details

[0092] In embodiments, compounds are disclosed that are inactive precursors of PDE4 inhibiting compounds that are believed to cause little or no nausea, vomiting, and / or diarrhea.

[0093] In an embodiment, disclosed is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0094]

[0095] wherein X is β-D-glucuronide, α-D-glucuronide, β-D-glucopyranoside, α-D-glucopyranoside, β-D-galactoside, α-D-galactoside, 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-amino Glucoside, α-D-aminoglucosidoside, β-D-aminogalactosidoside, α-D-galactosidoside, β-D-fucopyranoside, α-L-fucopyranoside, α-L-rhamnoside, α-L-arabinofuranoside, β-D-ribofuranoside, β-D-cellobioside, α-D-cellobioside, β-N,N-diacetylchitobioside, D-xylopyranoside, D-xylofuranoside, β-D-galactosiduronic acid, or α-D-galactosiduronic acid; R 1 and R 2 Each independently is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, any one of which is unsubstituted or substituted by 1-6 independent halogens;

[0096] R 3 and R 4 Each independently is H, or -C 1-6 alkyl;

[0097] R 5 、R 6 and R 7 are each independently H, halogen, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl or CN;

[0098] Ar 1 Independently selected from the group consisting of:

[0099] (a)6-R 8 -3-pyridyl or 6-R 9 -3-pyridyl,

[0100] (b)2-R 8 -5-thiazolyl or 5-R 8 -2-thiazolyl,

[0101] (c)2-R 8 -5-pyrimidinyl or 2-R 9 -5-pyrimidinyl,

[0102] (d)6-R 8 -3-pyridazinyl or 6-R 9 -3-pyridazinyl,

[0103] (e)5-R8 -2-furyl,

[0104] (f)5-R 8 -2-thienyl,

[0105] (g)2-R 8 -5-oxazolyl or 5-R 8 -2-oxazolyl,

[0106] (h)5-R 8 -3-isoxazolyl or 3-R 8 -5-isoxazolyl,

[0107] (i)5-R 8 -3-isothiazolyl or 3-R 8 -5-isothiazolyl, and

[0108] (j) For-R 8 -phenyl;

[0109] R 8 Selected from the group consisting of H, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 Alkyl Ar 2 、Ar 2 、C 1-6 Alkoxy, C 1-6 Alkylthio, CN, -C(R 10 )(R 11 )OH、-C(R 10 )(R 11 )OC 1-6 Alkyl, -C(R 10 )(R 11 )OAr 2 、-CO2H、-CO2C 1-6 Alkyl, -C(O)NR 12 R 13 、-SO2NHC(O)Ar 2 、-C(O)C 1-6 Alkyl and -C(O)Ar 2 ;

[0110] R 9 Selected from the following group: –NR 12 R 13 ,–NR 12 C(O)R 13 ,–NR 12 C(O)NHR 13 ,–NR 12 SO2Ar 2 , and -NR 12 CO2Ar2 ;

[0111] R 10 and R 11 Each independently represents H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl or Ar 2 ;

[0112] Or when R 10 and R 11 -C 1-6 When alkyl groups are present, they can be 1-3 Alkyl groups are linked together to form C 3-6 Cycloalkyl;

[0113] R 12 and R 13 Each independently represents H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 Alkyl Ar 2 ;

[0114] Or when R 12 and R 13 -C 1-6 When alkyl groups are present, they can be 1-3 Alkyl groups are linked together to form C 3-6 heterocycloalkyl;

[0115] Ar 2 selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl;

[0116] Each Ar 2 is unsubstituted or substituted by 1-3 members selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, CN, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(R 10 )(R 11 )OH, -CO2H, -CO2C1 -6 Alkyl, -C(O)NR 12 R 13 and -SO2CH3.

[0117] In one aspect of the present invention, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0118] The β-D-glucuronide is β-D-glucuronic acid, β-D-glucuronic acid methyl ester, 2,3,4-tri-O-acetyl-β-D-glucuronic acid methyl ester, β-D-glucuronic acid ethyl ester, 2,3,4-tri-O-acetyl-β-D-glucuronic acid ethyl ester, β-D-glucuronic acid isopropyl ester, β-D-glucuronic acid tert-butyl ester, methyl β-D-glucuronamide;

[0119] 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;

[0120] The β-D-galactoside is β-D-galactopyranosyl or 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl;

[0121] The α-D-mannopyranoside is α-D-mannopyranosyl or 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl;

[0122] The β-D-aminoglucosides are β-D-glucosamine and α-D-glucosamine;

[0123] The N-acetyl-β-D-glucosaminyl is N-acetyl-β-D-glucosaminyl, 3,4,6-tri-O-acetyl-N-acetyl-β-D-glucosaminyl, N,N,N-trimethyl-β-D-glucosaminyl, N,N-dimethyl-β-D-glucosaminyl; and

[0124] The β-D-cellobioside is β-D-cellobiosyl, or 2,3,6,2',3',4',6'-heptyl-O-acetyl-β-D-cellobiosyl;

[0125] R 1 and R 2 Each independently is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, any one of which is optionally substituted with 1-6 independent halogens;

[0126] R 3 and R 4 Each independently is H, or -C 1-6 alkyl;

[0127] R 5 、R 6 and R 7 are each independently H, halogen, -C1-6 Alkyl, or CN;

[0128] Ar 1 Independently selected from the group consisting of 6-R 8 -3-pyridyl or 2-R 8 -5-thiazolyl;

[0129] R 8 Selected from the group consisting of H, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 Alkyl Ar 2 、Ar 2 、C 1-6 Alkoxy, C 1-6 Alkylthio, CN, -C(R 10 )(R 11 )OH、-C(R 10 )(R 11 )OC 1-6 Alkyl, -C(R 10 )(R 11 )OAr 2 、-CO2H、-CO2C 1-6 Alkyl, -C(O)NR 12 R 13 、-SO2NHC(O)Ar 2 、-C(O)C 1-6 Alkyl and -C(O)Ar 2 ;

[0130] R 9 Selected from the group consisting of: -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 ;

[0131] R 10 and R 11 Each independently represents H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl or Ar 2 ;

[0132] Or when R 10 and R 11 -C 1-6 When alkyl groups are present, they can be1-3 Alkyl groups are linked together to form C 3-6 Cycloalkyl;

[0133] R 12 and R 13 Each independently represents H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -C 1-6 Alkyl Ar 2 ;

[0134] Or when R 12 and R 13 -C 1-6 When alkyl groups are present, they can be 1-3 Alkyl groups are linked together to form C 3-6 heterocycloalkyl;

[0135] Ar 2 selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl;

[0136] Each Ar 2 It may be unsubstituted or substituted by 1-3 members selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, CN, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(R 10 )(R 11 )OH, -CO2H, -CO2C1

[0137] -6 Alkyl, -C(O)NR 12 R 13 and -SO2CH3.

[0138] In another embodiment of the present invention, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0139] R 1 and R 2 Each independently is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, any one of which is unsubstituted or substituted by 1-6 independent halogens;

[0140] R 3 and R 4 Each is H;

[0141] R 5 、R 6 and R 7 Each is H;

[0142] Ar 1 It is 6-R 8 -3-pyridyl;

[0143] R 8 Selected from the following group: -C 1-6 Alkyl Ar 2 、-C(R 10 )(R 11 )OH, -C(O)C 1-6 Alkyl and -C(O)Ar 2 ;

[0144] R 10 and R 11 Each independently represents H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-6 Cycloalkyl or Ar 2 ;

[0145] R 12 and R 13 Each independently represents H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -C 1-6 Alkyl Ar 2 ;

[0146] Or when R 12 and R 13 -C 1-6 When alkyl groups are present, they can be 1-3 Alkyl groups are linked together to form C 3-6 heterocycloalkyl;

[0147] Ar 2 It is phenyl.

[0148] According to another embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0149] X is methyl β-D-glucuronide;

[0150] R 1 and R 2 Each independently is -C 1-6 Alkyl or -C 3-6 Cycloalkyl, any one of which is optionally substituted with 1-6 independent halogens;

[0151] R 3 and R4 Each is H;

[0152] R 5 、R 6 and R 7 Each is H;

[0153] Ar 1 It is 6-R 8 -3-pyridyl;

[0154] R 8 Yes-C(R 10 )(R 11 )OH;

[0155] R 10 and R 11 Each independently is -C 1-6 alkyl.

[0156] According to another embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the β-D-glucuronide is a β-D-glucuronyl group, preferably methyl glucuronide.

[0157] According to another embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, which is one of the following compounds or a pharmaceutically acceptable salt thereof:

[0158]

[0159]

[0160]

[0161]

[0162] According to another embodiment, the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof can be

[0163]

[0164] or a pharmaceutically acceptable salt thereof.

[0165] According to another embodiment, the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof can be

[0166]

[0167] or a pharmaceutically acceptable salt thereof.

[0168] According to another embodiment, the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof can be

[0169]

[0170] or a pharmaceutically acceptable salt thereof.

[0171] Orally inactive PDE4 inhibitor glycosides are thought to bypass triggers of vomiting in the upper gastrointestinal tract and reduce the emetic potential of such drugs. Compared with the parent PDE4 inhibitor, the enhanced hydrophilicity of the glycoside prodrug may improve the ability of the delivery system to evenly distribute and release the active ingredient throughout the colon, where drug dissolution is limited by low water content, irregular motility, and the absence of bile salts.

[0172] It is believed that the PDE4 inhibitor glycoside delivered to the colon is enzymatically hydrolyzed by colon-specific glycosidases to release the biologically active diaryl-substituted ethanepyridone PDE4 inhibitor, thereby exerting a local anti-inflammatory effect on the colonic mucosa. Although this system has never been used in humans, it is believed that it may advantageously represent a means of slowly releasing active agents specifically to the colon by properly selecting the glycoside / glycosidase system and the administered dose to minimize systemic exposure.

[0173] By appropriately selecting the dosage, PDE4 inhibitor glycosides specifically release bioactive diaryl-substituted ethanepyridine PDE4 inhibitors in the colon and are considered a systemic controlled-release system. Colonic residence time is significantly longer than small intestinal transit time, which ranges from 2 to 5 hours, with transit times of 5 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 72 hours. This allows for slow and sustained absorption of the active ingredient, prolonging the duration of effect while minimizing peak plasma concentrations that could trigger adverse reactions.

[0174] As used herein, "alkyl" and other groups with the prefix "alk", such as alkoxy, alkanoyl, alkenyl, alkynyl, etc., refer to carbon chains that can be straight or branched, or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, and the like. "Alkenyl," "alkynyl," and other similar terms include carbon chains that contain at least one unsaturated C-C bond.

[0175] The term "haloalkyl" refers to an alkyl group to which 1 to 9 halo groups are attached. Examples include -CH2F, -CHF2, -CF3, -CH2CH2F, -CHFCH2F, -CF2CH2F, -CF2CHF2, and -CF2CF3.

[0176] The term "cycloalkyl" refers to a carbocyclic ring containing no heteroatoms, including monocyclic, bicyclic, and tricyclic saturated carbocyclic rings, as well as fused ring systems. Such fused ring systems can include a partially or fully unsaturated ring, such as a benzene ring, to form a fused ring system, such as a benzo-fused carbocyclic ring. Cycloalkyl includes fused ring systems such as spiro-fused ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl, adamantyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, and the like. Similarly, "cycloalkenyl" refers to a carbocyclic ring containing no heteroatoms and at least one non-aromatic C-H double bond, including monocyclic, bicyclic, and tricyclic partially saturated carbocyclic rings, as well as benzo-fused cycloalkenyls. Examples of cycloalkenyl groups include cyclohexenyl, indenyl, and the like.

[0177] Unless specifically stated otherwise, the term "cycloalkoxy" includes cycloalkyl groups attached to an oxygen linking atom.

[0178] Unless otherwise stated, the term "alkoxy" includes an alkyl group attached to an oxygen linking atom.

[0179] Unless specifically stated otherwise, the term "aryl" includes polycyclic ring systems as well as single ring systems, for example phenyl or naphthyl.

[0180] Unless specifically stated otherwise, the term "aryloxy" includes polycyclic ring systems as well as monocyclic ring systems connected to the point of attachment through an oxygen linking atom, such as phenyl or naphthyl.

[0181] The term C0-C6 alkyl includes alkyl groups containing 6, 5, 4, 3, 2, 1 or no carbon atoms. When the alkyl group is a terminal moiety, the alkyl group having no carbon atoms is a hydrogen atom substituent. When the alkyl group is a bridging moiety, the alkyl group having no carbon atoms is a direct bond.

[0182] Unless otherwise specified, the term "hetero" includes one or more O, S or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems containing one or more O, S or N atoms in the ring, including mixtures of these atoms. Heteroatoms replace ring carbon atoms. Thus, for example, heterocyclo C5 alkyl is a five-membered ring containing 5 to no carbon atoms. Examples of heteroaryl include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

[0183] Unless otherwise specifically stated, the term "heteroaryloxy" describes a heteroaryl group attached to the attachment site via an oxygen linking atom. 1-6Examples of alkyl groups include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridylmethyl, pyridylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolylmethyl, isoquinolylmethyl, and quinoxalinylmethyl. 3-7 Examples of alkyl groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepine, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

[0184] The term N-heterocyclic C 4-7 Alkyl describes non-aromatic heterocyclic compounds having 3-6 carbon atoms and one nitrogen atom forming a ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepine. Aryl (C 1-6 Examples of alkyl groups include, for example, phenyl (C 1-6 ) alkyl and naphthyl (C 1-6 ) alkyl. Heterocyclic C 3- Alkylcarbonyl (C 1-6 Examples of alkyl groups include azetidinylcarbonyl (C 1-6 ) alkyl, pyrrolidinylcarbonyl (C 1-6 ) alkyl, piperidinylcarbonyl (C 1-6 ) alkyl, piperazinylcarbonyl (C 1-6 )alkyl, morpholinylcarbonyl (C 1-6 )alkyl and thiomorpholinylcarbonyl (C 1-6 )alkyl.

[0185] Unless specifically stated otherwise, the term "amine" includes primary, secondary and tertiary amines.

[0186] Unless otherwise indicated, the term carbamoyl is used to include -NHC(O)OC1-C4alkyl and -OC(O)NHC1-C4alkyl.

[0187] The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

[0188] The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl may represent a pentafluorophenyl group or a phenyl ring. In addition, substitution may be made at any group. For example, substituted aryl (C 1-6 )Alkyl includes substitution on aryl as well as substitution on alkyl.

[0189] The term "oxide" of a heteroaryl group is used in its generally recognized chemical sense and includes, for example, N-oxides of nitrogen heteroatoms.

[0190] The compounds described herein contain one or more double bonds and may therefore give rise to cis / trans isomers and other conformational isomers. The present invention includes all such possible isomers and mixtures of such isomers.

[0191] The compounds described herein may contain one or more asymmetric centers and may therefore produce diastereomers and optical isomers. The present invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above formula (I) does not have a clear stereochemical representation at certain positions. The present invention includes all stereoisomers of formula (I) and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included.

[0192] During the course of synthetic procedures used to prepare such compounds, or using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0193] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid or a eutectic former. The crystalline form can exist in the form of a salt, solvate, hydrate or inclusion compound. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. Salts derived from these inorganic bases include salts such as aluminum, ammonium, calcium, copper (ions and copper), iron, ferrous, lithium, magnesium, manganese (ions and manganese), potassium, sodium, zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable organic non-toxic bases or co-crystals that can form salts or co-crystals include ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0194] When the compound of the present invention is alkaline, 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.

[0195] Structural modifications such as removal or substitution of hydroxyl or carboxyl groups of naturally occurring glycosides have an effect on the binding interaction between the glycosidase and the substrate sugar moiety. This may result in changes in the kinetics of the enzymatic hydrolysis process, which can be advantageously used to accelerate or slow the release rate of the parent PDE4 aglycone in the large intestine.

[0196] According to another embodiment, a pharmaceutical composition comprising a compound represented by 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 can be prepared. These additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) β2 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 compositions include those suitable for oral, aerosol (including inhaler, intranasal spray), rectal, topical (including mucosal, ocular, buccal, otic, transdermal or transcutaneous) and parenteral (including ocular, subcutaneous, intramuscular, intraarterial and intravenous) administration, although the most appropriate route in any given case will depend on the particular host, and the nature and severity of the condition to which the active ingredient is to be administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any 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 capsules (including any chemically modified capsules for targeted delivery), cachets, tablets, lozenges; dispersions; or any 3D printed solid dosage form, oral mucosal film, suppositories; powders; aerosols (including pMDI or similar pulmonary delivery systems); gels; liquid dosage forms suitable for oral or mucosal administration to patients, 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; transdermal or transdermal formulations in eye drops or other ophthalmic preparations, ointments, lotions, creams suitable for topical administration directly or by intradermal device or injection or needle-free device or microneedle patch; mouthwashes and mouth rinses are included within the scope of topical use for the purposes of this invention, as well as sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a patient; formulations that may delay the release of the active ingredient or control the release of the active ingredient as this is delivered in the GIT are also contemplated.

[0197] According to another embodiment, the pharmaceutical composition 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).

[0198] The colonic absorption of a drug in the systemic circulation depends primarily on its permeability and solubility (Tannergren et al., Mol. Pharmacol. 2009, 6(1), 60). Therefore, a portion of the diaryl-substituted ethanepyridone PDE4 inhibitors absorbed by the colonic mucosa may reach the bloodstream for systemic absorption. Therefore, according to another embodiment, a dose that exerts a local anti-inflammatory effect and minimizes systemic exposure to the active agent is needed to reduce the likelihood of headache, nausea, vomiting, and diarrhea reportedly caused by drugs such as rolipram, cilomilast, roflumilast, and apremilast.

[0199] According to another embodiment, colonic absorption of a diaryl-substituted ethanepyridone PDE4 inhibitor into the systemic circulation may be desirable if preclinical or clinical evidence indicates that it is better tolerated than known drugs in the same class, such as cilomilast, roflumilast, and apremilast. Bypassing local triggers of vomiting in the upper gastrointestinal tract by inactive PDE4 inhibitor glycosides is desirable and is considered a benefit in terms of improved tolerability. Slow absorption associated with a longer transit time in the large intestine is also considered a benefit because it reduces the maximum peak plasma concentration that may trigger side effects such as headache, nausea, vomiting, or diarrhea.

[0200] According to another embodiment, systemic exposure to diaryl-substituted ethanepyridone PDE4 inhibitors via colonic absorption can be used to treat inflammatory diseases including ulcerative colitis.

[0201] The dosage level is about 0.0001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 100 mg / kg, or about 0.01 mg / kg to about 100 mg / kg, or about 0.1 mg / kg to about 100 mg / kg, or 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 / kg to about 1 mg / kg, or about 0.001 mg / kg to about 1 mg / kg, or about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, 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, about 0.0001 mg / kg to about 0.01 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg.001 mg / kg body weight / day can be used to treat conditions such as i) pulmonary diseases such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, and ii) gastrointestinal diseases such as ulcerative colitis, Crohn's disease, gastric acid hypersecretion, diverticulitis and irritable bowel syndrome, iii) infectious diseases such as sepsis or septic shock caused by bacteria, fungi or viruses, endotoxin shock (and related diseases such as laminitis and colic in horses) and septic shock, iv) nervous system diseases such as spinal cord trauma, head injury, neurogenic 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 diseases , such as depression, memory impairment and unipolar depression, viii) neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, 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 invasion of normal tissue, xi) metabolic diseases, such as diabetes insipidus, xii) bone diseases, such as osteoporosis, xiii) cardiovascular diseases, such as arterial restenosis stenosis, atherosclerosis, myocardial reperfusion injury, and xiv) other diseases such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease and cachexia - which respond to PDE4 inhibition, 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 0.07 g per patient per day. For example, inflammation can be effectively treated by administering a dose of about 0.0001 mg to 100 mg, 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 g, or about 1 mg to 10 mg, or about 0.0001 mg to 1 mg, or about 0.001 mg to 1 mg, or about 0.01 mg to 1 mg, or about 0.1 mg to 1 mg, or about 0.0001 mg to 0.1 mg, or about 0.001 mg to 0.1 mg, or about 0.01 mg to 10. mg, or about 0.0001 mg to 0.01 mg, or about 0.001 mg to 0.01 mg, or about 0.0001 mg to 0.001 mg of compound per kilogram of body weight per day, 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 0.07 g per patient per day. In addition, it should be understood that the PDE4 inhibitor glycoside prodrug compounds of the present invention can be administered at prophylactically effective dosage levels to prevent the specific conditions mentioned above.

[0202] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the target of treatment and the particular mode of administration. For example, a formulation intended for oral administration to humans can conveniently 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 from about 50 mg to about 500 mg, or from about 500 mg to about 5 g of active agent, formulated with appropriate and acceptable amounts of generally recognized as safe ("GRAS") materials, which can comprise from about 5% to about 95% of the total composition. Unit dosage forms typically 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 1000 mg to about 1000 mg, or from about 0.001 mg to about 100 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 1000 mg to about 1000 mg. In some embodiments, the dosage form may be from about 0.01 mg to about 10 mg, or from about 0.01 mg to about 10 mg, or from about 0.1 mg to about 10 mg, or from about 1 mg to about 10 mg, or from about 0.001 mg to about 1 mg, or from about 0.01 mg to about 1 mg, or from about 0.1 mg to about 1 mg, or from about 0.001 mg to about 0.1 mg, or from about 0.01 mg to about 0.1 mg, or from about 0.001 mg to about 0.01 mg of active ingredient, 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 therebetween.

[0203] However, it will be understood that the specific dosage level for any particular patient will depend upon a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.

[0204] The composition, shape and type of the dosage forms provided herein will generally vary depending on their use. For example, a dosage form for the acute treatment of a disease may comprise a large amount of one or more active ingredients comprising formula (I) compared to a dosage form for the chronic treatment of the same disease. Similarly, a parenteral dosage form may comprise a smaller amount of one or more active ingredients comprising formula (I) compared to an oral dosage form for the treatment of the same disease. These and other ways in which the specific dosage forms provided herein differ from each other will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton, Pennsylvania (2000). In practice, according to conventional pharmaceutical compounding techniques, the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salt / co-crystal may be closely mixed with a pharmaceutical excipient, carrier or diluent as an active ingredient. The carrier can take a variety of forms, depending on the form of formulation required for administration, such as oral, mucosal (e.g., nasal, sublingual, vaginal, inhalation, cystic, rectal, eye, cheek or ear), parenteral (including intravenous), intradermal, subcutaneous, bolus, intramuscular or intraarterial) or topical (e.g., transdermal, percutaneous, eye drops or other ophthalmic preparations). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules (coated or uncoated polymers, such as sustained release or enteric coating or modified for targeted delivery), sachets or tablets (coated or uncoated or double layer or slow release or delayed release, including microencapsulation) or tablets containing spray-dried intermediates, each intermediate containing a predetermined amount of active ingredient. Additionally, the composition can be as a powder, granules, coated slow-release granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion, liposomes, nanosuspensions. In addition to the common dosage forms listed above, the compound represented by formula (I) or its pharmaceutically acceptable salt or co-crystal can also be administered by controlled release or modified release formulations and / or delivery devices. The composition can be prepared by any pharmaceutical method. Generally, such methods include the step of combining the active ingredient with an excipient or carrier constituting one or more essential ingredients. Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier / excipient or a finely divided solid carrier / excipient or both. The product can then be easily shaped into the desired appearance.

[0205] According to another embodiment, glycosidic bonds are known to hydrolyze under acidic conditions. Therefore, as part of the formulation of the compounds of the present invention, PDE4 glycoside prodrugs may include excipients or coatings to prevent premature hydrolysis in the stomach or any other part of the gastrointestinal tract where the pH is below 5.

[0206] Therefore, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier / excipient and a compound of formula (I) or a pharmaceutically acceptable salt / co-crystal. The compound of formula (I) or a pharmaceutically acceptable salt / co-crystal thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0207] The pharmaceutical carrier used can be, for example, used to form oral solid preparations such as powders, capsules and tablets, including fillers such as talc, calcium carbonate, microcrystalline cellulose, kaolin, mannitol, silicic acid, sorbitol, starch and mixtures thereof. Binders, such as colli as. Disintegrants, such as cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch, gum and other starches and mixtures thereof. Lubricants, such as calcium stearate, magnesium stearate, SYLOID silica gel, mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talcum powder, hydrogenated vegetable oils (such as peanut oil, sesame oil, corn oil or soybean oil), ethyl oleate agar or other lipid preparation lubricants and mixtures thereof. Due to being easy to administer, tablets and capsules are preferred oral dosage units, in which solid pharmaceutical carriers are used. Each solid oral dosage unit can further be coated with a special polymer that can delay release or sustained release dosage unit content. Formula (I) can be administered in a delayed release or sustained release manner or by a delivery device well known to those skilled in the art. Non-limiting examples of delayed release or sustained release include those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 5,059,595. Such dosage forms can be used to provide slow or controlled release of one or more ingredients, for example using polymers such as hydroxypropyl methylcellulose, typically in the form of a matrix such as a gel, a permeable membrane, a microemulsion, an osmotic system, a liposome, a microsphere, or a combination thereof. Controlled-release formulations can be used to protect dosage units from exposure to the gastric environment; delay the release of active ingredients to the lower digestive tract, such as the colon; or slow the release of active ingredients, thereby reducing the blood concentration of the drug and affecting the occurrence of side effects.

[0208] Examples of gaseous carriers include carbon dioxide and nitrogen.

[0209] In preparing oral liquid compositions for oral dosage forms, any convenient pharmaceutical media may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs, and solutions.

[0210] A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.

[0211] Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Moulded tablets can be prepared by moulding 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 100 mg to about 1000 mg, or from about 0.001 mg to about 100 mg, or from about 0.01 mg to about 1000 mg. g 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 active ingredient and each cachet or capsule preferably contains about 0.001 mg to about 5000 mg of the active ingredient.

[0212] Pharmaceutical compositions of the present invention suitable for parenteral administration (including intravenous, intramuscular, subcutaneous, ophthalmic and intra-arterial) 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 carriers include Water for Injection USP; Dextrose Injection; Sodium Chloride Injection and Lactated Ringer's Injection. Suitable surfactants, such as polysorbate 80, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, ethanol, polypropylene glycol, and mixtures thereof in non-aqueous carriers such as oils (e.g., corn oil, sesame oil, isopropyl myristate). An antioxidant, such as vitamin C palmitate, helps stabilize the formulation. In addition, preservatives may be included to prevent the harmful growth of microorganisms.

[0213] In addition, the composition may be in the form of a sterile powder for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, non-irritating when a tonicity agent is added, and must be an effective fluid for easy injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it should preferably be preserved to prevent contaminating microorganisms such as bacteria and fungi, such as benzalkonium chloride, chlorobutanol, methylparaben, propylparaben, disodium edetate, sorbic acid, or other agents known to those skilled in the art. The pharmaceutical composition 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 an aerosol, patch, cream, ointment, lotion, dusting powder, emulsion, or the like. Possible routes of application include nasal, sublingual, vaginal, rectal, ophthalmic, buccal, or aural. In addition, the composition may be in a form suitable for transdermal or intradermal microneedle devices. These preparations can be prepared using a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof by conventional processing methods. For example, lotion, emulsifiable concentrate or ointment can be prepared by mixing a hydrophilic material and water and a compound of about 5wt% to about 30wt%, to prepare an emulsifiable concentrate, lotion or ointment with required consistency. The example of a typical excipient comprises water, acetone, ethanol, ethylene glycol, propylene glycol, isopropyl myristate, mineral oil and composition thereof. If desired, wetting agents such as sealants, wetting agents, emollients can also be added to pharmaceutical compositions and dosage forms. The pH of pharmaceutical compositions or dosage forms can also be regulated to improve the delivery of formula (I). The dosage form that is applicable to the treatment of oral mucosal tissue can be mixed with mouthwash or oral gel.

[0214] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid or liquid or spray. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be easily formed by first mixing the composition with a softened or melted carrier, then cooling and shaping in a mold.

[0215] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may include one or more additional carrier components, such as diluents, buffers, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like, as appropriate. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compound described by formula (I) or pharmaceutically acceptable salts thereof can also be prepared in the form of powders or liquid concentrates. The addition of preservatives (such as antioxidants) is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine properties such as shelf life or the stability of the preparation over time (see, for example, Jens T. Carstensen, Drug Stability: Principles and Practice. 2nd Edition, Marcel Dekker, New York, NY. 1995, pp. 379-80).

[0216] It has been found that the compounds and pharmaceutical compositions of the present invention exhibit biological activity as PDE4 inhibitors when activated locally in the colon. Thus, another aspect of the present invention is the treatment of mammals for, for example, 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 diseases such as ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, and gastric acid hypersecretion, iii) infectious diseases such as sepsis or septic shock caused by bacteria, fungi, or viruses, endotoxin shock (and related diseases such as laminitis and colic in horses), and septic shock, iv) neurological diseases such as spinal cord trauma, head injury, neurogenic 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, 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 invasion of normal tissue, xi) metabolic diseases such as diabetes insipidus, xii) bone diseases such as osteoporosis, xiii) cardiovascular diseases such as arterial restenosis, atherosclerosis, myocardial reperfusion injury, and xiv) other diseases such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease, and cachexia - diseases that can be ameliorated by the administration of an effective amount of a compound of the present invention by inhibiting the PDE4 isoenzyme and the resulting increase in cAMP levels. The term "mammal" includes humans and other animals such as dogs, cats, horses, pigs and cattle. Thus, it will be understood that treatment of mammals other than humans is treatment of those clinically relevant diseases to those listed above in relation to the human diseases.

[0217] In addition, as described above, the compounds of the present invention can be used in combination with other therapeutic compounds. In particular, the PDE4 inhibitory 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) combined 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.

[0218] Thus, for example, lung diseases such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, and infant respiratory distress syndrome can be conveniently treated using capsules, cachets, or tablets, each 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 a compound of the present application, or a pharmaceutically acceptable salt thereof, as an active ingredient, administered once, twice, or three times daily.

[0219] Gastrointestinal disorders, such as ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome, and gastric acid hypersecretion, can be conveniently treated with capsules, cachets, or tablets, each 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 invention, or a pharmaceutically acceptable salt thereof, for administration once, twice, or three times daily.

[0220] Infectious diseases, such as bacterial, fungal, or viral sepsis or septic shock, endotoxic shock (and related diseases such as laminitis and colic in horses), and septic shock can be conveniently treated using capsules, cachets, or tablets, each 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 a compound of the present invention, or a pharmaceutically acceptable salt thereof, as the active ingredient, for administration once, twice, or three times daily.

[0221] Neurological diseases such as spinal cord trauma, head injury, neurogenic inflammation, pain and cerebral reperfusion injury can be conveniently treated with capsules, cachets or tablets, each 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 invention or a pharmaceutically acceptable salt thereof, for administration once, twice or three times daily.

[0222] 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, each 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, for administration once, twice or three times daily.

[0223] Allergic diseases, such as allergic rhinitis, allergic conjunctivitis and eosinophilic granuloma, can be conveniently treated with capsules, cachets or tablets or nasal sprays, each tablet 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, for administration once, twice or three times daily.

[0224] Psychiatric disorders such as depression, memory impairment and unipolar depression can be conveniently treated with capsules, cachets or tablets or injections, each 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, for administration once, twice or three times daily.

[0225] Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, can be conveniently treated with capsules, cachets or tablets or injections, each 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, for administration once, twice or three times daily.

[0226] Skin diseases 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, each dose 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 invention or a pharmaceutically acceptable salt thereof, for administration once, twice or three times daily.

[0227] Neoplastic diseases such as cancer, tumor growth, and cancerous invasion of normal tissues can be conveniently treated with capsules, cachets, or tablets or parenteral formulations, each 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 invention, or a pharmaceutically acceptable salt thereof, for administration once, twice, or three times daily.

[0228] Metabolic diseases such as diabetes insipidus can be conveniently treated with capsules, cachets or tablets or injections, each 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.

[0229] Bone diseases such as osteoporosis, cardiovascular diseases such as arterial restenosis, atherosclerosis, myocardial reperfusion injury, and other diseases such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft-versus-host disease and cachexia can be conveniently treated with capsules, cachets or tablets, each 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 invention or a pharmaceutically acceptable salt thereof, for administration once, twice or three times daily.

[0230] Example 1

[0231] Synthesis method

[0232] The compounds of formula (I) of the present invention can be prepared according to the proposed synthetic routes outlined in the following schemes 1-7. The schemes describe glycosidation reactions for coupling racemic pyridones, but it will be apparent to those skilled in the art that the same reactions are applicable to optically pure or optically enriched pyridones III. Unless otherwise defined, the substituents are the same as in formula (I). 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).

[0233] Glucopyranosides of formula Ia-c can be prepared in a multistep sequence from the desired pyridone III and a suitable glucosyl donor IV, as shown in Scheme 1 below. The requisite pyridone III can be synthesized by rearranging pyridine-N-oxide II in the presence of an activating agent such as trifluoroacetic anhydride or tosyl anhydride, in the presence of a tertiary amine such as triethylamine or N,N-diisopropylethylamine, in a solvent such as toluene, chlorobenzene, THF, diethyl ether, 1,4-dioxane, dichloromethane, or a mixture of toluene and 2-methyl-THF, at temperatures ranging from 0°C to room temperature. Once the rearrangement is complete, 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 terminal functional group, Z, which can be activated under appropriate conditions with an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercuric salt. When Z = OH, coupling can be accomplished using the Mitsunobu reaction. In one method, pyridone III will be coupled with 1-halogenated α-glucopyranosides (α-IV, Z = Cl, Br, I) under standard Koenigs-Knorr reaction conditions known to those skilled in the art to provide protected β-glucopyranosides Ia (P = P'). According to Saad et al. (Curr. Org. Synth. 2012, 9 (3), 413), another procedure is used in which pyridone III is coupled with bromo-α-glucopyranosides (α-IV, Z = Br) in the presence of a base such as K2CO3 in an aprotic polar solvent such as DMF. In another method, pyridone III is coupled with 1-O-trichloroacetimidate-α-glucopyranosides (α-IV, Z = OC(NH)CCl3) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane. In another method, pyridone III is coupled with 1-O-acetyl-β-glucopyranoside (β-IV, Z═OAc) in the presence of a catalytic amount of a Lewis acid such as BF3 Et2O in a suitable solvent such as benzene at controlled temperature such as room temperature to give protected β-glucopyranoside Ia according to the procedure described by Sokolov et al. (Russian J. General Chem. 2002, 72(5), 806). In another method, pyridone III is coupled with α-IV (Z═I), wherein P═acetyl and P′═iodoacetyl, according to the method described by Ko et al. (Org. Lett. 2009, 11(3), 609), in the presence of a silver salt such as AgOTf in a solvent such as nitromethane or dichloromethane at ambient temperature. When P and P' are alkyl / aryl esters, the alcohol protecting groups P and P' of β-glucopyranoside Ia can be removed in the presence of a basic agent such as sodium methoxide, LiOH, NaOH, KOH or K2CO3 in a suitable solvent such as methanol or ethanol to give β-glucopyranoside Ib.If P and P' are benzyl groups, deprotection can be accomplished under standard conditions known to those skilled in the art, such as hydrogenolysis with H2 using Pd / C as a catalyst in a solvent such as methanol to give β-glucopyranoside Ib. In the case where 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 according to the procedure of Ko et al. (Org. Lett. 2009, 11(3), 609) to give partially protected 2-hydroxy-β-glucopyranoside 1c.

[0234] Option 1

[0235]

[0236] Glucuronides of formula Id-f can be prepared in a multi-step sequence from the requisite pyridone III and a suitable glucuronyl donor V, as shown in Scheme 2 below. The glucuronyl donor is characterized by a terminal functional group Z, which can be activated under appropriate conditions with an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercuric salt. When Z = OH, the coupling can be accomplished under the Mitsunobu reaction. In one method, according to the procedure described by Zhang et al. (Tetrahedron, 2012, 68, 4194), pyridone III is coupled with 1-O-trichloroacetimidate-α-glucuronide (α-V, Z = OC(NH)CCl3) 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 provide the protected β-glucuronide Id. In another method, pyridinone III is coupled with 1-O-acetyl-α-glucuronide (α-IV, Z═OAc) in the presence of a Lewis acid such as BF 3 Et 2 O in a suitable solvent such as dichloromethane at a controlled temperature such as 0° C. to room temperature to give protected β-glucuronide Id according to the procedure described by Arewang et al. (Carbohydr. Res. 2007, 342(7), 970). In another method, pyridinone III is initially deprotonated with a base such as LiOH and coupled with 1-bromo-α-glucuronide (α-V, Z═Br) in a solvent such as ethanol at room temperature according to the procedure described by Berrang et al. (Synth. Commun. 1975, 5, 231). In an alternative method using 1-bromo-α-glucuronide (α-V, Z = Br), pyridone III will be coupled according to the method of WO 2011 / 147926 by deprotonating the pyridone with a hydride such as NaH in a solvent such as dichloromethane and then adding bromide in the presence of a silver salt such as AgNO 3. Protected β-glucuronide Id can also be obtained under standard Koenigs-Knorr conditions known to those skilled in the art, such as the method described by Friend et al. (J. Med. Chem.. 1985, 28, 51), in which pyridone III will be coupled with 1-bromo-α-glucuronide (α-V, Z = Br) in a solvent such as CHCl 3 or toluene in the presence of a silver salt such as Ag 2 CO 3 or Ag 2 O. When P is an alkyl / aryl ester, removal of the alcohol protecting group P of β-glucuronide Id can be accomplished in the presence of an alkaline reagent such as LiOH, NaOH, KOH, or KCO to afford β-glucuronide Ie in a suitable solvent such as methanol / water or ethanol / water. If the alkyl group of Id is methyl 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. If P = benzyl, deprotection can be accomplished under standard conditions known to those skilled in the art, such as hydrogenolysis with H using Pd / C as a catalyst in a solvent such as methanol to afford β-glucuronide Ie.The acid function of glucuronide Ie or the corresponding salt can be selectively reacted with a reagent such as diazomethane or trimethylsilyldiazomethane in a solvent such as methanol to give the methyl ester glucuronide If (alkyl = methyl). In another method, If can be prepared by treating Ie or its corresponding carboxylate with an alcohol such as methanol, ethanol or isopropanol and a coupling agent such as DCC or EDC in a solvent such as DMF in the presence of DMAP. In another method, If (alkyl = tert-butyl) can be prepared by reacting Ie or its corresponding carboxylate with tert-butyl trichloroacetimidate and a Lewis acid such as BF3 Et2O in a suitable solvent such as dichloromethane.

[0237] Option 2

[0238]

[0239] Glucosamine of formula Ig can be prepared in a multi-step sequence from the necessary pyridone III and a glycosyl donor such as VI, as shown in Scheme 3 below. Glycosyl donor VI (X = Cl) can be synthesized according to the method of St-Pierre et al. (Synthesis 2016, 48, 3575). Glycosyl azide VII can be obtained as a mixture of anomers by coupling pyridone III and glycosyl donor VI (X = Cl) in the presence of a silver salt such as Ag2O in a solvent such as toluene under reflux conditions. Hydrolysis of the ester functional group of the protected glycosyl azide VII can be completed in the presence of an alkaline reagent such as sodium methoxide, LiOH, NaOH, KOH or K2CO3 in a suitable solvent such as methanol. The 2-azido functional group can be reduced to a 2-amino functional group under an H2 atmosphere in the presence of a catalyst such as Pd / C in a solvent such as methanol to provide a mixture of anomers of glucosamine Ig. The anomer mixture can be separated by chromatography methods known to those skilled in the art to obtain α-glucosamine α-Ig and β-glucosamine β-Ig. Alternatively, a single glucosamine isomer of formula β-Ig can be prepared in a multi-step sequence from the necessary pyridone III and a glycosyl donor, such as VIII, as shown in Scheme 4 below. Glycosyl donor VIII can be synthesized according to the method of Morais et al. (Carbohydr. Res. 2003, 338, 1369). Glucosamine IX can be obtained by coupling pyridone III and glycosyl donor VIII under reflux conditions in a solvent such as toluene in the presence of a silver salt such as Ag2O. Hydrolysis of the ester function of the protected glucosamine IX can be accomplished in the presence of an alkaline reagent such as sodium methoxide, LiOH, NaOH, KOH or K2CO3 in a suitable solvent such as methanol. The benzyloxycarbonyl (CBZ) protecting group can be hydrogenolyzed to the 2-amino function under H2 atmosphere in the presence of a catalyst such as Pd / C in a solvent such as methanol to provide glucosamine β-Ig.

[0240] Option 3

[0241]

[0242] Option 4

[0243]

[0244] As described above in Scheme 4, glucosamine β-Ig can be further derivatized to obtain glucosamines of Formula Im, In, Io, and Ip. Polyacetylated glucosamines of Formula Im can be prepared by the action of an acetyling agent, such as acetic anhydride, on intermediate β-Ig in a solvent such as pyridine at room temperature. Alternatively, β-Ig can be treated with an acetyling agent, such as acetic anhydride, in the presence of a base, such as triethylamine, in a solvent such as methanol at 0°C to provide the monoacetylated glucosamines of Formula In. Alternatively, β-Ig can be treated with an excess of an alkylating agent, such as methyl iodide, in a solvent such as THF in the presence of a base, such as i-Pr2NEt, at room temperature to provide the quaternary ammonium salt Io. Alternatively, glucosamines 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.

[0245] The galactosides of formula Ii and Ij can be prepared in a multi-step sequence according to the requisite pyridone III and a suitable glycosyl donor X as shown in Scheme 5 below. The glycosyl donor X is characterized by a functional group Z in the heteroterminal position, which can be activated under appropriate conditions with an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercuric salt. When Z = Cl, Br, or I, the coupling can be accomplished under standard Koenigs-Knorr conditions known to those skilled in the art to obtain polyacetate β-galactoside Ii. In another method, pyridone III is coupled with 1-O-trichloroacetimidate-α-galactoside (Z = OC(NH)CCl3) 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-galactoside Ii can be accomplished 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 obtain β-galactoside Ij.

[0246] Plan 5

[0247]

[0248] Mannopyranosides of formula Ik and II can be prepared in a multi-step sequence from the requisite pyridone III and a suitable glycosyl donor XI, as shown in Scheme 6 below. The glycosyl donor XI is characterized by a functional group Z in the heteroterminal position, which can be activated under appropriate conditions with an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercuric salt. When Z = Cl, Br, or I, the coupling can be accomplished under standard Koenigs-Knorr conditions known to those skilled in the art to obtain the polyacetate β-galactoside Ik. In another approach, the pyridone III will be coupled with 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. The acetyl protecting group of β-mannopyranoside Ik can be removed 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 obtain β-galactoside II.

[0249] Plan 6

[0250]

[0251] Cellobiosides of formula Iq and Ir can be prepared in a multi-step sequence from the desired pyridone III and a suitable glycosyl donor XII, as shown in Scheme 7 below. The glycosyl donor XII is characterized by a functional group Z in the heteroterminal position, which can be activated under appropriate conditions with an activating agent such as a protic acid, a Lewis acid, a silver salt, or a mercuric salt. When Z = Cl, Br, or I, the coupling can be accomplished under standard Koenigs-Knorr conditions known to those skilled in the art to obtain the polyacetate β-cellobioside Iq. In another approach, the pyridone III will be coupled with 1-O-trichloroacetimidate-mannopyranoside (Z = OC(NH)CCl) in the presence of a Lewis acid such as BF3Et2O in a suitable solvent such as dichloromethane. The acetyl protecting group of β-cellobioside Iq can be removed 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 obtain β-cellobioside Ir.

[0252] Option 7

[0253]

[0254] Compounds 1-31 are summarized in Table 1 below:

[0255] Table 1

[0256]

[0257] wherein X is selected from the group consisting of (a) β-D-glucopyranoside, (b) β-D-glucuronide, (c) β-D-galactoside, (d) α-D-mannopyranoside, (e) α / β-D-aminoglucosidoside, (f) β-D-cellobioside, and Ar 1 Selected from (a) 2-(hexafluoro-isopropanol)-5-thiazolyl and (b) 6-(2-hydroxy-propan-2-yl)-3-pyridyl.

[0258]

[0259]

[0260]

[0261] Compound 1: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-triacetate

[0262]

[0263] Compound 1 was prepared by the following procedure: Step 1: (S)-5-(2-(3-cyclopropyloxy-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-cyclopropyloxy-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 is cooled to 0 ℃, triethylamine (0.73mL, 5.25mmol) is added, and trifluoroacetic anhydride (0.74mL, 5.25mmol) is then added dropwise. Once the addition is complete, the reaction is warmed to room temperature and stirred for 30 minutes. The reaction is then cooled to 0 ℃ and 20mL saturated sodium bicarbonate aqueous solution is added. The resulting solution is stirred for 15 minutes, then diluted with 20mL EtOAc and separated. The organic layer is then washed with saturated sodium bicarbonate aqueous solution (10mL), water (10mL) and salt solution (10mL). The organic layer is dried over magnesium sulfate, concentrated, and purified by reverse phase column chromatography using 10-60% MeCN ammonium bicarbonate buffer. The pure fractions are then combined and concentrated to obtain the desired pyridone IIIa as a pale solid.

[0264] Step 2: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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) in toluene (0.2 M) were added silver oxide (1.5 eq) and 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside (1.5 eq). The resulting suspension was stirred at 110°C for 1.5 hours. 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, and lyophilized to afford the desired glucopyranoside as a white solid: 1H NMR (400MHz, acetone-d6) δ7.98(d,J=2.3Hz,1H),7.85(s,1H),7.62(dd,J=8.5,2.4Hz,1H),7.41(d,J=2.0Hz,1H),7.10(d,J=8.2Hz ,1H),7.01–6.57(m,3H),6.26(d,J=8.3Hz,1H),5.42(t,J=9.6Hz,1H),5.20–5.06(m,2H),4.80(dd,J=9.3,6.7Hz,1H),4.27(d d,J=12.3,4.6Hz,1H),4.11(ddd,J=10.0,4.5,2.4Hz,1H),4.03(dd,J=12.3,2.3Hz,1H),3.91–3.84(m,1H),3.54(dd,J=13.8, 6.6Hz,1H),3.44(dd,J"=13.8,9.5Hz,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).

[0265] Compound 2: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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

[0266]

[0267] Compound 2 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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. To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester (10 mg, 0.01 mmol) in THF / water (1:1, 0.1 M) was added LiOH (15 equiv). The solution was stirred at room temperature for 30 min and loaded directly onto a C-18 column (12 g) and purified using a 0-40% MeCN / ammonium bicarbonate gradient. The desired glycoside was obtained as a white solid after lyophilization: 1 H NMR (400 MHz, acetone-d6) δ7.98 (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. 9Hz,1H),4.88–4.73(m,1H),3.94–3.85(m,1H),3.77(dd,J=11.7,2.6Hz,1H),3.65 (dd,J=11.8,4.8Hz,1H),3.57–3.36(m,6H),0.86–0.69(m,3H),0.68–0.59(m,1H).

[0268] Compound 3: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate

[0269]

[0270] Compound 3 was prepared by the following steps: Step 1: (S)-5-(2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one. (S)-3-(2-(3-cyclopropyloxy-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 is cooled to 0 ℃, triethylamine (2.46mL, 17.60mmol) is added, and trifluoroacetic anhydride (1.48mL, 8.80mmol) is then added dropwise. Once the addition is complete, the reaction is warmed to room temperature and stirred for 30 minutes. The reaction is then cooled to 0 ℃ and 20mL saturated sodium bicarbonate aqueous solution is added. The resulting solution is stirred for 2 hours. The solution is then diluted with 200mL EtOAc and the layers are separated. The organic layer is then washed with saturated sodium bicarbonate aqueous solution (10mL), water (10mL) and salt solution (10mL). The organic layer is dried over magnesium sulfate, concentrated, and purified by reverse phase column chromatography using 0-40% MeCN ammonium bicarbonate buffer. The pure fractions are then combined and concentrated to obtain the desired pyridone IIIb as a white solid.

[0271] Step 2: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate. To a solution of (S)-5-(2-(3-cyclopropyloxy-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 (0.2 M) were 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 hours. 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. The desired glycoside was obtained after lyophilization as a white solid: 1H NMR (500MHz, acetone-d6) δ8.53(d,J=1.9Hz,1H),8.01(d,J=2.0Hz,1H), 7.87(dd,J=8.2,2.3Hz,1H), 7.65(dd,J=8.4,2.5Hz,1H), 7.60(d,J=8.1H z,1H), 7.45(d,J=2.0Hz,1H), 7.08(d,J=8.2Hz,1H), 7.00(dd,J=8.3,2.1Hz,1H), 6.93-6.56(m,2H), 6.27(d,J=8.3Hz,1H), 5.42(t,J=9.6Hz, 1H), 5.21-5.09(m,2H), 4.49(t,J=8.1Hz,1H), 4.28(dd,J=12.3,4.6Hz,1H), 4.12(ddd,J=10.0,4.6,2.4Hz,1H), 4.04(dd,J=12.3,2.5Hz,1H ), 3.90(tt,J=6.0,2.8Hz,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).

[0272] Compound 4: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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

[0273]

[0274] Compound 4 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate triester (15 mg, 0.02 mmol) in THF / water (1:1, 0.1 M) was added LiOH (15 equiv). The solution was stirred at room temperature for 30 min and loaded directly onto a C-18 column (12 g) and purified using a 0-40% MeCN / ammonium bicarbonate gradient. The desired glycoside was obtained as a white solid after lyophilization: 1 H 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=8.0Hz,1H), 4.35(t,J=8.1Hz,1H), 3.78(tt,J=6.0,2.9Hz,1H), 3.64(d,J=9.3Hz,1H ), 3.52(dd,J=11.6,4.7Hz,1H), 3.42-3.24(m,6H), 1.33(s,6H), 0.75-0.64(m,2H), 0.62-0.50(m,2H).

[0275] Compound 5: (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-5-hydroxytetrahydro-2H-pyran-3,4-diacetic acid diester

[0276]

[0277] Compound 5 was prepared by the following steps: Step 1: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-diacetic acid diester. To a solution of (S)-5-(2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (5 equiv) in dichloromethane (0.2 M) was added AgOTf (1.2 equiv) at 0°C. The solution was stirred at 0°C for 1 hour. 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 slowly warmed 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. The desired glycoside was obtained after lyophilization as a white solid.

[0278] Step 2: (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-5-hydroxytetrahydro-2H-pyran-3,4-diacetic acid diester. To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-diacetic acid diester (18 mg, 0.02 mmol) in MeOH (0.05 M) was added thiourea (1 equivalent). The solution was stirred at room temperature for 40 minutes. The solution was concentrated under reduced pressure and purified by reverse phase column chromatography (12 g column, 10-80% MeCN in ammonium bicarbonate). The desired glucopyranoside was obtained as a white solid after lyophilization: 1H NMR (500MHz, acetone-d6) δ8.39(d,J=2.0Hz,1H), 7.89(d,J=2.1Hz,1H), 7.73(dd,J=8.2,2.3Hz,1H), 7.49-7.44(m,2H), 7.33(d,J= 2.1Hz,1H), 6.95(d,J=8.2Hz,1H), 6.87(dd,J=8.3,2.1Hz,1H), 6.79-6.44(m,2H), 5.89(d,J=8.1Hz,1H), 5.12(t,J=9.5Hz,1H ), 4.86 (dd, J = 11.9, 7.3Hz, 1H), 4.35 (t, J = 8.1Hz, 1H), 4.18-4.08 (m, 1H), 3.91-3.83 (m, 2H), 3.77 (tt, J = 6.1, 2.9Hz, 1H), 3.6 8–3.58(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).

[0279] Compound 6: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester.

[0280]

[0281] Compound 6 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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 (0.18 M) were added silver oxide (1.1 equiv) and methyl 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronate (1.1 equiv). The resulting suspension was stirred at 110 °C for 1 hour. The suspension was then cooled to room temperature, filtered through celite, concentrated, and purified by reverse phase chromatography (20-80% MeCN in ammonium formate). The desired product was obtained after lyophilization as a white solid. 1 H NMR (400MHz, CDCl3) δ7.80 (d, J = 2.2Hz, 1H), 7.58 (s, 1H), 7.24-7.18 (m, 1H), 7.10 (d, J = 8.2Hz, 1H), 7.01(d,J=2.1Hz,1H), 6.76(dd,J=8.3,2.1Hz,1H), 6.69-6.29(m,2H), 6.20(d,J=7.7Hz,1H), 5.78(s ,1H), 5.42-5.23(m,3H), 4.38(dd,J=8.8,6.7Hz,1H), 4.23(d,J=9.6Hz,1H), 3.74-3.64(m,4H), 3.36 (dd,J=13.8,6.6Hz,1H), 3.24(dd,J=13.8,9.1Hz,1H), 2.04(m,6H), 1.97(s,3H), 0.85-0.59(m,4H).

[0282] Compound 7: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0283]

[0284] Compound 7 was prepared by the following steps: Step 1: lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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 solution of (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester (85 mg, 0.1 mmol) in THF / water (1:1, 0.1 M) was added LiOH (15 equiv). The solution was stirred at room temperature for 30 min and loaded directly onto a C-18 column (12 g) and purified using a 0-40% MeCN / ammonium bicarbonate gradient. The desired lithium glucuronic acid salt was obtained after lyophilization as a white solid.

[0285] Step 2: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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 solution of lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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 (0.1 M) was added TMS-diazomethane (5 equiv) at 0°C, and the solution was stirred at 0°C for 1 hour. The reaction was concentrated under reduced pressure and purified by reverse phase column chromatography eluting with 0-50% MeCN in ammonium bicarbonate. The desired methyl glucuronide was obtained as a white solid after lyophilization. 1H 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=7.7Hz,1H), 3.98(dd,J=9.5,2.9Hz,1H), 3.93-3.82(m,1H), 3.70-3.63(m,4H), 3.58(td ,J=8.7,2.8Hz,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).

[0286] Compound 8: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester.

[0287]

[0288] Compound 8 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester. A black suspension of (S)-5-(2-(3-cyclopropyloxy-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 methyl 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid (9.42 g, 23.0 mmol). The mixture was heated at reflux for 1.5 hours, cooled to room temperature, filtered through celite, washed with ethyl acetate (2 x 30 mL), and concentrated to a dark solid (m ~ 18 g). Purification by flash chromatography using a SNAP Ultra 200 g column and eluting with a gradient mixture of ethyl acetate / hexanes gave the desired glucuronic acid as a light brown solid as follows: 1H NMR (400MHz, CDCl3) δ8.42(d,J=1.7Hz,1H), 7.82(d,J=2.1Hz,1H), 7.59(dd,J=8.3,1.7Hz,1H), 7.35(d,J=8.2Hz,1H), 7.29 -7.24(m,1H), 7.07(d,J=8.2Hz,1H), 7.02(d,J=2.0Hz,1H), 6.76(dd,J=8.3,2.1Hz,1H ), 6.68-6.65(m,1H), 6.46(t,J=75.1Hz,1H), 6.20(d,J=7.7Hz,1H), 5.41-5.24(m,3H) , 4.24(d,J=9.5Hz,1H), 4.18(t,J=7.9Hz,1H), 3.72-3.67(m,1H), 3.67(s,3H), 3.30(d ,J=7.9Hz,2H), 2.05(s,3H), 2.04(s,3H), 1.98(s,3H), 1.54(s,6H), 0.82-0.63(m,4H).

[0289] Compound 9: Lithium (2S,3S,4S,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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

[0290]

[0291] Compound 9 was prepared by the following procedure: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester (600 mg, 0.77 mmol) was added lithium hydroxide (285 mg, 11.6 mmol) to a mixture of THF (3 mL), MeOH (1 mL) and water (1 mL). The reaction was stirred at room temperature for 30 minutes and concentrated. Purification by flash chromatography using a SNAP C18 30 g column and eluting with a gradient mixture of acetonitrile and water gave the desired lithium salt as a white solid after freeze drying. 1HNMR (400MHz, DMSO-d6) δ8.47 (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), 7.4 2(d,J=1.9Hz,1H), 7.04(d,J=8.2Hz,1H), 6.96(dd,J=8.3,2.0Hz,1H), 6.93(t,J=74.7Hz,1H), 6.70(d,J=8.5Hz,1H), 5.55 (d,J=7.8Hz,1H), 5.14(s,1H), 5.10-5.04(m,1H), 4.94-4.86(m,1H), 4.39(t,J=8.1Hz,1H), 3.92(tt,J=6.0,2.9Hz,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).

[0292] Compound 10: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0293]

[0294] Compound 10 was prepared by the following steps: Step 1: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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-triacetic acid triester (9.40 g, 12.2 mmol) in MeOH (95 mL) was added 25 wt% (1 mL) of sodium methoxide. The solution was stirred at room temperature for 10 minutes, neutralized to pH 6-7 by the addition of NH4Cl (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 give the desired methyl ester as a light beige solid after freeze drying: 1 H NMR (400MHz, CDCl3) δ8.33(d,J=1.2Hz,1H), 7.85(s,1H), 7.54(dd,J=8.3,1.8Hz,1H), 7.32(d,J=8.2Hz, 1H), 7.21(d,J=8.6Hz,1H), 7.07(d,J=1.5Hz,1H), 7.04(d,J=8.1Hz,1H), 6.77(dd,J=8.4,1.3Hz,1H), 6. 68(d,J=8.4Hz,1H), 6.46(t,J=75.1Hz,1H), 5.76(d,J=6.5Hz,1H), 4.18(t,J=7.8Hz,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).

[0295] Compound 11: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate

[0296]

[0297] Compound 11 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6S)-2-((5-((S)-2-(3-cyclopropyloxy-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-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (100 mg, 0.11 mmol) in toluene (0.2 M) was added silver oxide (1.5 eq) and ethyl 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronate (1.5 eq), prepared according to Baddeley et al. (J. Chem. Crystallogr. 2013, 33, 33.). The resulting suspension was stirred at 110° C. for 1.5 hours. The reaction was filtered through celite, concentrated under reduced pressure, and purified by normal phase column chromatography, eluting with 20-100% EtOAc / CHCl. ​​The desired ethyl glucuronate was obtained as a beige solid after lyophilization. 1 H NMR (400MHz, CDCl3) δ8.39(d,J=2.1Hz,1H), 7.82(d,J=2.1Hz,1H), 7.53(t,J=2.4Hz,1H), 7.31(dd,J=8.2,0.7Hz,1H), 7.2 8-7.22(m,1H), 7.05(d,J=6.2Hz,1H), 7.01(d,J=2.1Hz,1H), 6.76(dd,J=8.3,2.1Hz,1H), 6.67-6.64(m,1H), 6.45(t,J=75 .1Hz,1H), 6.20(d,J=7.5Hz,1H), 5.41-5.23(m,3H), 4.78(s,1H), 4.21(d,J=6.0Hz,1H), 4.20-4.05(m,3H)), 3.73-3.65(m ,1H), 3.29(d,J=7.9Hz,2H), 2.04(s,3H),2.03(s,3H), 1.97(s,3H), 1.51(s,6H), 1.22(t,J=7.5Hz,3H), 0.82-0.63(m,4H).

[0298] Compound 12: (2S,3S,4S,5R,6S)-ethyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0299]

[0300] Compound 12 was prepared by the following steps: Step 1: (2S,3S,4S,5R,6S)-ethyl 6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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) in DMF (0.2 mL) 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 under vacuum. 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 ethyl ester as a white solid after freeze-drying: 1 H NMR (400MHz, DMSO-d6) δ8.50 (d, J = 2.1Hz, 1H), 8.01 (d, J = 2.3Hz, 1H), 7.91-7.77 (m, 1H), 7.69-7.53 (m,2H), 7.43(d,J=1.9Hz,1H), 7.23-6.69(m,4H), 5.76(d,J=7.8Hz,1H), 5.50-5.25(m,3H), 5.17(s, 1H), 4.42(q,J=8.0Hz,1H), 4.23-4.02(m,2H), 3.94(tt,J=6.1,3.0Hz,1H), 3.86(d,J=9.3Hz,1H), 3. 54-3.22(m,7H), 1.41(d,J=2.5Hz,6H), 1.21(t,J=7.1Hz,3H), 0.90-0.74(m,2H), 0.72-0.55(m,2H).

[0301] Compound 13: (2S,3S,4S,5R,6S)-isopropyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0302]

[0303] Compound 13 was prepared by the following steps: Step 1: (2S,3S,4S,5R,6S)-isopropyl 6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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 DMF (0.5 mL) and isopropanol (0.5 mL) was added DMAP (63.8 mg, 0.51 mmol). The solution was stirred at room temperature for 16 hours, then more DMAP (63.8 mg, 0.51 mmol) and EDC (37.8 mg, 0.18 mmol) were added. The reaction was stirred for 3 days, concentrated under vacuum and purified by flash chromatography using a SNAP C18 12g column eluting with a solvent mixture of acetonitrile and aqueous ammonium formate to give the desired isopropyl ester as a white solid after freeze drying: 1 H NMR (400MHz, DMSO-d6) δ8.51(t,J=3.9Hz,1H), 8.01(d,J=2.2Hz,1H), 7.84(dt,J=13.0,6.5Hz,1H), 7.68-7.54 (m,2H), 7.43(d,J=1.9Hz,1H), 7.17-6.67(m,4H), 5.75(d,J=7.8Hz,1H), 5.38(dd,J=5.2,3.8Hz,2H), 5.27(d, J=4.8Hz,1H), 5.15(s,1H), 4.92(hept,J=6.3Hz,1H), 4.43(t,J=8.1Hz,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=2.4Hz,6H), 1.21(d,J=6.3Hz,6H), 0.90-0.74(m,2H), 0.74-0.57(m,2H).

[0304] Compound 14: (2S,3S,4S,5R,6S)-tert-Butyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0305]

[0306] Compound 14 was prepared by the following steps: Step 1: (2S,3S,4S,5R,6S)-tert-butyl 6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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 L, 0.313 mmol) in 2 mL of CHCl was added 4 drops of a BF3Et2O stock solution (prepared from 0.1 mL of BF3Et2O in 2 mL of CHCl). After the solution was stirred at room temperature for 16 hours, an additional 4 drops of the BF3Et2O stock solution were added. The reaction was stirred for an additional 24 hours 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, afforded the desired tert-butyl ester as a white solid after freeze-drying: 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=1.9Hz,1H), 7.93(d,J=2.2Hz,1H), 7.78(dd,J=8.4,2.4Hz,1H) , 7.71-7.41(m,2H), 7.35(d,J=1.8Hz,1H), 7.15-6.61(m,4H), 5.66(d,J=7.7Hz,1H), 5.28(dd,J= 11.5,5.5Hz,2H), 5.18(d,J=4.9Hz,1H), 5.09(s,1H), 4.36(t,J=8.2Hz,1H), 3.86(tt,J=5.9,2.9 Hz, 1H), 3.64 (d, J = 9.2Hz, 1H), 3.29 (m, 4H), 1.33 (m, 15H), 0.83-0.67 (m, 2H), 0.66-0.47 (m, 2H).

[0307] Compound 15: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0308]

[0309] Compound 15 was prepared by the following steps: Step 1: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)thiazol-5-yl)ethyl)pyridin-2-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (40 mg, 0.045 mmol) was dissolved in 2M MeNH2 in MeOH (0.1 M). The resulting solution was stirred at room temperature for 20 minutes. The solution was then concentrated and purified by reverse phase purification (0-50% MeCN in ammonium bicarbonate). The desired product was obtained after lyophilization as a white solid: 1 H NMR(400MHz,CD3CN)δ7.91(s,1H),7.76(dd,J=2.5,1.0Hz,1H),7.62–7.45(m,1H) ,7.33(d,J=1.9Hz,1H),7.09(d,J=8.2Hz,1H),6.96–6.88(m,1H),6.76(d,J=8.4H z, 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).

[0310] Compound 16: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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

[0311]

[0312] Compound 16 was prepared by the following procedure: Step 1: (2S,3S,4S,5R,6S)-methyl 6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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 a 2 M solution of methylamine in methanol (0.1 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 2 hours 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-methylformamide as a white solid after freeze-drying: 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=2.0Hz,1H),8.00(d,J=2.1Hz,1H),7.95(q,J=4.5Hz,1H),7.85(dd,J=8.2,2.2 Hz,1H),7.67-7.56(m,2H),7.43(d,J=1.7Hz,1H),7.17-6.67(m,4H),5.77-5.67(m,1H),5.33(d,J=4.1Hz,1H),5 .23(t,J=11.4Hz,2H),5.16(s,1H),4.43(t,J=8.1Hz,1H),4.01-3.88(m,1H),3.67(t,J=7.4Hz,1H),3.49-3.37( m, 3H), 3.28 (t, J = 8.3Hz, 1H), 2.57 (t, d = 4.3Hz, 3H), 1.41 (d, J = 2.3Hz, 6H), 0.90-0.76 (m, 2H), 0.72-0.60 (m, 2H).

[0313] Compound 17: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate

[0314]

[0315] Compound 17 was prepared by the following steps: Step 1: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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 (0.16 M) was added 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-galactoside (1.5 equiv) and silver oxide (1.5 equiv). The solution was stirred at 110°C for 1 hour. 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. The desired compound was obtained after lyophilization as a white solid. 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),7.82(d,J=2.3Hz,1H),7.64(d,J=8.2Hz,1H),7.39(d,J=8.4Hz,1H),7.29-7.24(m,1H) ,7.07(d,J=8.2Hz,1H),7.01(d,J=2.0Hz,1H),6.75(dd,J=8.3,2.0Hz,1H),6.68(d,J=8.4Hz,1H),6.46(t,J=75.0Hz,1H) ,6.09(d,J=8.3Hz,1H),5.53-5.42(m,2H),5.14(dd,J=10.4,3.4Hz,1H),4.19(t,J=7.9Hz,1H),4.16-4.07(m,3H),3.72- 3.65(m,1H),3.30(d,J=7.9Hz,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).

[0316] Compound 18: (2S,3R,4S,5R,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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

[0317]

[0318] Compound 18 was prepared by the following steps: Step 1: (2S,3R,4S,5R,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl

[0319] To a solution of tetrahydro-2H-pyran-3,4,5-triacetic acid triester (10 mg, 0.01 mmol) in THF / water (1:1, 0.06 M) was added lithium hydroxide (5 equivalents). The solution was stirred at room temperature for 10 minutes and loaded directly onto a C18 (12 g) and purified using a 0-50% MeCN / ammonium bicarbonate gradient. The compound was obtained after lyophilization as a white solid. 1 HNMR(400MHz,CD3CN)δ8.46(d,J=2.0Hz,1H),7.93(d,J=2.2Hz,1H),7.77(dd,J=8.3,2.2Hz,1H),7.54(dd,J= 8.5,2.4Hz,1H),7.50(d,J=8.2Hz,1H),7.35(d,J=2.0Hz,1H),7.06(d,J=8.3Hz,1H),6.92(dd,J=8.3,2.0Hz,

[0320] 1H),6.73(d,J=8.4Hz,1H),6.81-6.38(m,1H),5.69(d,J=7.8Hz,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

[0321] (m,3H),3.19(s,1H),2.87(s,1H),1.46(s,6H),0.90-0.60(m,4H).

[0322] Compound 19: (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate

[0323]

[0324] Compound 19 was prepared by the following steps: Step 1: (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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 (0.15 M) was added 1-bromo-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside (1.5 equiv) and silver oxide (1.5 equiv). The solution was stirred at 110°C for 1 hour. 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. The desired compound was obtained after lyophilization as a white solid. 1H NMR (400MHz, CDCl3) δ8.37(d,J=2.1Hz,1H),7.86(d,J=2.2Hz,1H),7.57-7.51(m,1H)),7.35-7.29(m,1H),7.06(dd,J=9 .9,5.2Hz,2H),6.78(dd,J=8.3,2.1Hz,1H),6.70(d,J=8.4Hz,1H),6.66-6.23(m,1H),6.38(d,J=1.8Hz,1H),5.52(dd,J= 10.1,3.4Hz,1H),5.43-5.36(m,2H),4.24(dd,J=12.1,4.6Hz,1H),4.20-4.09(m,2H),4.06(dd,J=12.1,2.5Hz,1H),3.73 -3.66(m,1H),3.29(d,J=7.8Hz,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).

[0325] Compound 20: (2R,3S,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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

[0326]

[0327] Compound 20 was prepared by the following steps: Step 1: (2R,3S,4S,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 of (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate triester (10 mg, 0.01 mmol) in THF / water (1:1, 0.06 M) was added LiOH (5 eq). The solution was stirred at room temperature for 10 minutes and the solution was directly loaded onto C18 (12 g) and purified using a 0-50% MeCN / ammonium bicarbonate gradient. The compound was obtained after lyophilization as a white solid. 1H 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, 8.3 Hz, 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=18.6Hz,3H),1.51-1.41(m,7H),0.87-0.59(m,4H).

[0328] Compound 21: (2R,3S,4R,5R)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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

[0329]

[0330] Compound 21 was prepared by the following steps: Step 1: (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diacetic acid diester. To a solution of (S)-5-(2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one (50 mg, 0.11 mmol) in toluene (0.2 M) was added silver oxide (1.5 eq) and 1-chloro-2-azido-3,4,6-tri-O-acetyl-α-D-glucopyranoside (1.5 eq), prepared according to the procedure of St-Pierre et al. (Synthesis 2016, 48, 3575). The resulting suspension was stirred at 110 ° C for 1.5 hours. 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. The desired azidoglycoside anisomeric mixture was obtained as a white solid after lyophilization.

[0331] Step 2: (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropyloxy-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 solution of (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diacetic acid diester (18 mg, 0.02 mmol) in THF / water (1:1, 0.1 M) was added LiOH (15 equiv). The solution was stirred at room temperature for 30 min and loaded directly onto a C-18 column (12 g) and purified using a 10-50% MeCN / ammonium bicarbonate gradient. The desired deacetylated azido glycoside was obtained as a white solid after lyophilization.

[0332] Step 3: (2R,3S,4R,5R)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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 solution of (2R,3S,4R,5R)-5-azido-6-((5-((S)-2-(3-cyclopropyloxy-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 methanol (0.1 M) was added Pd / C (2 mg, 25% w / w). The suspension was bubbled with hydrogen for 10 minutes and stirred under a hydrogen atmosphere for 24 hours. 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. A mixture of α- and β-D-glucosamine prodrugs was obtained as a white solid after lyophilization: 1H NMR(500MHz,CD3CN)δ8.45(d,J=2.1Hz,1H),7.99-7.93(m,1H),7.77(dd,J=8.3,1.9Hz,1H),7.57-7.52(m,1H),7.50(d ,J=8.2Hz,1H), 7.36-7.34(m,1H), 7.07(d,J=8.2Hz,1H), 6.94-6.92(m,1H), 6.79-6.72(m,1H), 6.61(t,J=75.4Hz,1H), 6.22(d,J=3.5Hz,0.5H), 5.62(d,J=8.3Hz,0.25H), 4.41(t,J=8.2Hz,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=9.9,3.6Hz,0.78H), 1.46(s,6H), 0.85-0.80(m,2H), 0.71-0.65(m,2H).

[0333] Compound 22: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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

[0334]

[0335] Compound 22 was prepared by the following steps: Step 1: (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropyloxy-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-diacetic acid diester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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 (0.1 M) was added silver oxide (1.5 equiv) and (2R,3S,4R,5R,6R)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-chlorotetrahydro-2H-pyran-3,4-diacetic acid diester (1.5 equiv). The solution was stirred at 110° C. for 1 hour. The reaction was cooled to room temperature, filtered through celite, concentrated, and purified by reverse phase chromatography (20-80% MeCN in ammonium formate). The desired product was obtained as a beige solid after lyophilization.

[0336] Step 2: Benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 solution of (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropyloxy-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-diacetic acid diester (69 mg, 0.08 mmol) in THF / water (1:1, 0.1 M) was added LiOH (12 equiv). 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. The desired compound was obtained after lyophilization as a white solid.

[0337] Step 3: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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 solution of benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 (0.1 M) was added Pd / C (20% wt), and the solution was stirred under a hydrogen atmosphere for 16 hours. The solution was filtered through celite, concentrated, and purified by reverse phase chromatography (0-50% MeCN in ammonium bicarbonate). The desired glucosamine was obtained as a white solid after lyophilization. 1 H NMR (400MHz, CD3CN) δ7.91(d,J=2.3Hz,1H),7.73(s,1H),7.50(dd,J=8.5,2.5Hz,1H),7.32(d,J=2.1H z,1H),7.08(d,J=8.2Hz,1H),6.91(dd,J=8.3,2.1Hz,1H),6.73(d,J=8.4Hz,1H),6.85-6.41(m,1H),5. 63(d,J=8.3Hz,1H),4.73-4.61(m,1H),3.89-3.79(m,1H)),3.76-3.68(m,1H),3.60(dd,J=11.8,4.8H z,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).

[0338] Compound 23: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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

[0339]

[0340] Compound 23 was prepared by the following steps: Step 1: (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diacetic acid diester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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 (0.1 M) was added silver oxide (1.5 equiv) and (2R,3S,4R,5R,6R)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-chlorotetrahydro-2H-pyran-3,4-diacetic acid diester (1.5 equiv). The solution was stirred at 110°C for 1 hour. The reaction was cooled to room temperature, filtered through celite, concentrated, and purified by reverse phase chromatography (20-80% MeCN in ammonium formate). The desired product was obtained as a beige solid after lyophilization.

[0341] Step 2: Benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 solution of (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-5-(((benzyloxy)carbonyl)amino)-6-((5-((S)-2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2-yl)oxy)tetrahydro-2H-pyran-3,4-diacetic acid diester (23 mg, 0.03 mmol) in THF / water (1:1, 0.1 M) was added LiOH (12 equiv). 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. The desired compound was obtained after lyophilization as a white solid.

[0342] Step 3: (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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 solution of benzyl ((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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 (14 mg, 0.02 mmol) in MeOH (0.1 M) was added Pd / C (20% wt) 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). The desired glucosamine was obtained as a white solid after lyophilization. 1 H NMR (400MHz, CD3CN) δ8.46(d,J=1.9Hz,1H),7.92(d,J=2.0Hz,1H),7.77(dd,J=8.3,2.2Hz,1H),7.55(dd,J=8.5,2.4Hz,1H ),7.50(d,J=8.2Hz,1H),7.35(d,J=1.9Hz,1H),7.06(d,J=8.2Hz,1H),6.92(dd,J=8.3,2.0Hz,1H),6.72(d,J=8.5Hz,1H),6 .82-6.37(m,1H),5.61(d,J=8.2Hz,1H),4.40(t,J=8.3Hz,1H),4.29(s,1H),3.85(tt,J=6.0,2.8Hz,1H),3.70(d,J=11.8H z,1H),3.59(d,J=8.7Hz,1H),3.43–3.23(m,5H),2.71(t,J=8.7Hz,2H),1.45(s,6H),0.92-0.74(m,2H),0.76-0.61(m,2H).

[0343] Compound 24: (2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-diacetic acid diester

[0344]

[0345] Compound 24 was prepared by the following steps: Step 1: (2R,3S,4R,5R,6S)-5-acetylamino-2-(acetoxymethyl)-6-((5-((S)-2-(3-cyclopropyloxy-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-diacetic acid diester. To a solution of (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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) in pyridine (0.2 M) was added acetic anhydride (4 eq) and the resulting solution was stirred at room temperature overnight. The solution was directly loaded onto a c-18 column (40 g) and purified using 20-80% MeCN in ammonium formate. The desired product was obtained after lyophilization as a white solid. 1 H NMR(400MHz,CD3CN)δ7.88(d,J=2.2Hz,1H),7.80-7.74(m,1H),7.57-7.46(m,1 H),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).

[0346] Compound 25: N-((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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

[0347]

[0348] Compound 25 was prepared by the following steps: Step 1: N-((2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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) at 0°C was added EtN (3 eq) followed by acetic anhydride (3 eq). The solution was stirred at room temperature for 5 minutes. The solution was concentrated and purified by reverse phase chromatography (0-100% MeCN in water). The desired product was obtained after lyophilization as a white solid. 1 H NMR(500MHz,CD3CN)δ7.88(d,J=2.1Hz,1H),7.76(d,J=0.8Hz,1H),7.52(dd,J=8.5,2.5Hz,1H),7.31(d ,J=2.1Hz,1H),7.09(d,J=8.3Hz,1H),6.92(dd,J=8.3,2.1Hz,1H),6.68(d,J=8.4Hz,1H),6.82-6.45(m ,2H),5.89(d,J=8.8Hz,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 ,4.9Hz,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).

[0349] Compound 26: (2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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-iodine

[0350]

[0351] Compound 26 was prepared by the following steps: Step 1: (2S,3R,4R,5S,6R)-2-((5-((S)-2-(3-cyclopropyloxy-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-iodinated amine. To a solution of (2R,3S,4R,5R,6S)-5-amino-6-((5-((S)-2-(3-cyclopropyloxy-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 (0.05 M) was added MeI (5 equiv) followed by (iPr)2NEt (5 equiv). The reaction was stirred at room temperature overnight. The solution was concentrated and purified by reverse phase chromatography (0-100% MeCN in ammonium formate). The desired quaternary amine was obtained as a white solid after lyophilization. 1H NMR (400MHz, CD3CN) δ8.35(s,1H),7.94(d,J=2.2Hz,1H),7.68(s,1H),7.55(dd,J=8.5,2.4Hz,1H),7.36(d,J=2. 0Hz,1H),7.10(d,J=8.2Hz,1H),6.93(dd,J=8.3,2.0Hz,1H),6.78(d,J=8.4Hz,1H),6.85-6.40(m,1H),6.60(d,J= 3.4Hz,1H),4.74-4.59(m,1H),4.04(t,J=8.1Hz,1H),3.94(t,J=9.1Hz,1H),3.88-3.80(m,1H),3.71-3.59(m,3H ), 3.56 (dd, J=11.1, 5.5Hz, 1H), 3.40 (qd, J=14.0, 8.2Hz, 2H), 3.25 (s, 9H), 0.88-0.69 (m, 3H), 0.67-0.59 (m, 1H).

[0352] Compound 27: (2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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

[0353]

[0354] Compound 27 was prepared by the following steps: Step 1: (2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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-cyclopropyloxy-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) was added formaldehyde (10 eq) followed by sodium cyanoborohydride (3 eq) and 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. The desired N,N-dimethylglucamine was obtained as a white solid after freeze drying. 1 H NMR (400MHz, acetone-d6) δ7.97(s,1H),7.84(dd,J=1.9,0.4Hz,1H),7.58(dd,J=8.4,2.5Hz,1H),7.43(d,J=2.2Hz,1H),7.10(dd,J=8.2,2.5 Hz,1H),7.04-6.54(m,3H),6.12(dd,J=8.7,2.7Hz,1H),4.80(t,J=7.9Hz,1H),3.88(dt,J=8.9,3.0Hz,1H),3.75(d,J=11.6Hz,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).

[0355] 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-cyclopropyloxy-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-triacetate.

[0356]

[0357] Compound 28 was prepared by the following steps: 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-cyclopropyloxy-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-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-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-triacetate triester (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 x 20 mL) and concentrated to a dark solid.Purification by flash chromatography using a SNAP C18 12 g column eluting with a solvent mixture of acetonitrile and water gave the desired disaccharide polyacetate as a brown solid: 1H NMR (400 MHz, 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=74.9Hz,1H),6.06(d,J=8.2Hz,1H),5.84(s,1H),5.30(t,J=9.1Hz,1 H),5.25-5.04(m,3H),4.95(t,J=8.5Hz,1H),4.53(d,J=7.9Hz),4.51-4.45(m,1H),4.43 -4.35(m,2H),4.12(dd,J=12.2,4.4Hz,),4.07(dd,J=12.4,H1.8Hz,1H),3.91(t,J=9.3Hz,1H),3.84-3.76(m,1H),3.74-3.61(m,2H),3.36(dd,J= 14.0,6.7Hz,1H),3.26(dd,J=13.8,8.9Hz,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).

[0358] Compound 29: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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

[0359]

[0360] Compound 29 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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. 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-cyclopropyloxy-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-triacetate triester (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 and concentrated under reduced pressure. Purification by flash chromatography using a SNAP C18 12 g column, eluting with a solvent mixture of acetonitrile and water, gave the desired disaccharide as a white solid: 1 H NMR (400MHz, DMSO-d6) δ7.92(s,1H),7.60(bs,1H),7.55(dd,J=8.7,1.9Hz,1H),7.32(s,J=11.7Hz,1H),7.0 3(d,J=8.0Hz,1H),6.95(t,J=74.6Hz,1H),6.88(d,J=7.4Hz,1H),6.70(d,J=8.4Hz,1H),5.69(d,J=8.1Hz,1H ),5.58-5.07(m,2H),5.03-4.87(m,1H),4.82-4.55(m,3H),4.29(d,J=7.7Hz,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).

[0361] 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-cyclopropyloxy-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-triacetate

[0362]

[0363] Compound 30 was prepared by the following steps: 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-cyclopropyloxy-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-triacetate triester. To a solution of (S)-5-(2-(3-cyclopropyloxy-4-(difluoromethoxy)phenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)ethyl)pyridin-2(1H)-one IIIb (85 mg, 0.19 mmol) in toluene (0.16 mmol) 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-triacetate triester (1.5 equiv) and silver oxide (1.5 equiv). The resulting suspension was stirred at 110° C. for 1.5 hours. 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 to afford the desired product as a white solid after lyophilization. 1H NMR (400MHz, CDCl3) δ8.39(d,J=2.1Hz,1H),7.79(d,J=2.1Hz,1H),7.55(d,J=8.3Hz,1 H),7.33(d,J=8.2Hz,1H),7.23(dd,J=8.5,2.4Hz,1H),7.07(d,J=8.2Hz,1H),7.01(d,J =2.1Hz,1H),6.76(dd,J=8.3,2.1Hz,1H),6.64(s,1H),6.45(t,J=70.5Hz,1H),6.04(d, J=8.1Hz,1H),5.32-5.25(m,1H),5.22-5.03(m,3H),4.94(dd,J=9.1,8.0Hz,1H),4.51( d,J=7.9Hz,1H),4.46(dd,J=12.1,1.9Hz,1H),4.38(dd,J=12.5,4.4Hz,1H),4.20-4.0 8(m,2H),4.05(dd,J=12.4,2.2Hz,1H),3.94-3.85(m,1H),3.80(ddd,J=9.8,4.3,2.0Hz ,1H),3.67(tdd,J=6.7,5.0,2.8Hz,2H),3.28(d,J=7.9Hz,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).

[0364] Compound 31: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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

[0365]

[0366] Compound 31 was prepared by the following steps: Step 1: (2S,3R,4S,5S,6R)-2-(((2R,3S,4R,5R,6S)-6-((5-((S)-2-(3-cyclopropyloxy-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. 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-cyclopropyloxy-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-triacetate triester (50 mg, 0.05 mmol) in THF / water (1 / 1, 0.1 M) was added lithium hydroxide (15 eq). The resulting solution was stirred at room temperature for 1 hour. The solution was then loaded directly onto a C18 column (30 g) and purified using a 10-60% MeCN in ammonium bicarbonate gradient. The desired disaccharide was obtained after lyophilization as a white solid. 1 H NMR(400MHz,CD3CN)δ8.45(d,J=1.9Hz,1H),7.93(d,J=2.1Hz,1H),7.76(dd,J=8.3,2.3Hz,1H), 7.54(dd,J=8.4,2.3Hz,1H),7.50(d,J=8.2Hz,1H),7.35(d,J=2.0Hz,1H),7.06(d,J=8.2Hz,1H), 6.92(dd,J=8.3,2.0Hz,1H),6.72(d,J=8.5Hz,1H),6.81-6.39(m,1H),5.80(d,J=8.1Hz,1H),4.4 1(dd,J=8.0,4.3Hz,2H),3.90-3.16(m,21H),1.45(s,6H),0.90-0.77(m,2H),0.75-0.59(m,2H).

[0367] Example 2

[0368] Tests to demonstrate biological activity

[0369] Assay Protocol for Measuring Inhibitory Potency Against PDE4 Isozymes The following protocol was used to measure the potency of compounds that inhibit the hydrolysis of cAMP to AMP by type IV cAMP-specific phosphodiesterase (IC 50): First, serial dilutions of the test compound were made in 100% DMSO. Each intermediate compound dilution (in 100% DMSO) was then diluted 10-fold into assay buffer to obtain 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. The enzymatic reaction was 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 the test compound. After the enzymatic reaction, 100 μl of binding solution (binder diluted 1:100 with 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 wavelength of 470 nm and an emission wavelength of 528 nm. PDE activity was determined in duplicate at each concentration. Fluorescence intensity was converted to fluorescence polarization using Tecan Magellan 6 software. Fluorescence polarization data were analyzed using Graphpad Prism. Fluorescence polarization in the absence of compound (FP) was calculated for each data set. t ) is defined as 100% activity. In the absence of PDE and the compound, the fluorescence polarization value (FP) in each data set b ) is defined as 0% activity. The percentage activity in the presence of the compound was calculated according to the following equation: % activity = (FP-FP b ) / (FP t -FP b ) × 100%, where FP = fluorescence polarization in the presence of compound. Nonlinear regression analysis was then used to plot the % activity against a range of compound concentrations using the formula Y = B + (TB) / 1 + 10 ((LogEC50-X)×Hill Slope) Sigmoidal dose-response curves were generated 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. 50 Values ​​were determined as the concentration that gave a percentage of half-maximal activity. Parent PDE4 inhibitor IC 50 The values ​​should be less than about 1000 nM, preferably less than about 100 nM, and even more preferably less than about 10 nM. The IC values ​​of the parent PDE4 inhibitor compounds IIIa and IIIb were determined for the isozymes PDE4A1A, PDE4B1, and PDE4D2. 50 The IC value of the PDE4 inhibitor glycoside represented by formula (I) is less than 10 nM. 50 The value should be the IC value of the corresponding parent PDE4 inhibitor. 50The value is 10 times or more, preferably the IC value of the corresponding parent PDE4 inhibitor. 50 100-fold higher than the IC values ​​of their corresponding parent PDE4 inhibitors 50 The IC value of compound 22 was 1000 times higher than that of compound 22. 50 The value, even if it is contaminated with 0.17% of IIIa, exceeds 100 nM. Based on the potency of IIIa and mathematical prediction (100 / 0.17X the IC of IIIa 50 ), this contamination accounted for 100% of the recorded potency of compound 22.

[0370] TNFα Inhibition Assay Protocol. The following protocol was used to measure the efficacy of PDE4 inhibitors in the LPS-induced TNFα assay in human whole blood: Fresh blood was collected from healthy human volunteers (male and female) in heparinized tubes by venipuncture. These subjects should not have overt inflammatory conditions, symptoms of bacterial / viral infection, fever, and should not have taken any NSAIDs for at least 1 week prior to blood collection. Blood from each donor was dispensed into 96-deep-well plates, 500 μL per well. Blood was pre-incubated with 2 μL of vehicle (DMSO) or test compound at 37°C / 5% CO2 for 15 minutes. Then, 10 μL of lipopolysaccharide from E. coli serotype 0111:B4 (LPS, Sigma-Aldrich, Saint-Louis, MO, USA) diluted in 0.1% bovine serum albumin fraction V (BSA, Sigma-Aldrich, Saint-Louis, MO, USA) in phosphate-buffered saline (PBS) was added for 24 hours at 37°C / 5% CO2 to a final concentration of 1 μg / mL. Each inhibitor concentration was incubated in duplicate with blood from each donor. Appropriate PBS (without LPS) was used as a blank control (4 wells), while blood samples stimulated with LPS control (without PDE4 inhibitor) served as a positive control (4 wells). After incubation, samples were centrifuged at 1500×g for 10 minutes at 4°C. Plasma (approximately 200 μL per well) was recovered and stored at -80°C for ELISA analysis. Plasma TNFα was quantified by ELISA (Invitrogen, Frederick, MD, USA) according to the manufacturer's instructions. In each case, the positive control value from the same patient on the same plate was used to calculate the percentage inhibition. From each blood analysis sample, 4 μL of plasma was diluted in 196 μL of dilution buffer (1:50 dilution), which provided the optical density value (OD) within the linear portion of the standard curve (data not shown). The assay plates were read at 450 nm on an Infinite F200PRO-Tecan microplate reader. The absorbance values ​​were converted to percentage inhibition based on the positive and negative control values ​​on each plate, and the resulting percentage inhibition data were fitted to a four-parameter logistic by nonlinear regression using GraphPad Prism (Version 6.00, GraphPad Software, Inc., La Jolla, California, USA). The reported IC 50 The values ​​are those derived from a four-parameter fit, providing the concentration of the tested inhibitor that gave half-maximal inhibition of TNFα. The mean IC values ​​for compounds IIIa and IIIb were determined using blood from 12 healthy volunteers. 50 The value was less than 50 nM.

[0371] In vitro glycoside prodrug permeability assessment. The permeability of glycoside prodrugs was measured using a bidirectional Caco-2 assay. Caco-2 cells were seeded onto permeable polycarbonate supports in 12-well Costar 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 (top: HBSS containing 25mM MES, 0.25% BSA, pH 6.0; basolateral: HBSS containing 25mM HEPES, 0.25% BSA, pH 7.4) and the plate was incubated at 37°C for 30 minutes before TEER (transepithelial electrical resistance) measurement. The buffer in the donor chamber (apical side for A-to-B assay, basolateral side for B-to-A assay) was removed and replaced with working solution (10 μM test article in transport buffer). The plate was then placed at 37°C with gentle agitation. At designated time points (30, 60, and 90 minutes); an aliquot of transport buffer was removed from the receiving chamber and replenished with fresh transport buffer. The samples were quenched with ice-cold CH3CN containing an internal standard and then centrifuged to precipitate the protein. The resulting supernatant was further diluted with 50 / 50 ACN / H2O (H2O was used only for atenolol) and submitted to LC / MS / MS analysis. The reported apparent permeability (Papp) represents the average of 2 determinations. Atenolol and propranolol were tested as low and medium permeability references. Bidirectional transport of digoxin was assessed to demonstrate P-gp activity / expression. The apparent permeability (Papp) of the compounds was 0.05. app , in cm / s) is determined according to the following formula:

[0372]

[0373] Where dQ / dt is the net appearance rate in the receiving chamber, and A is the area of ​​the Transwell in cm 2 (1.12cm 2 ) is used as the unit, C0 is the initial concentration of the compound added to the donor compartment, and 60 is the conversion factor from minutes to seconds. Since the glycoside prodrug is intended to deliver the active PDE4 inhibitor to the colonic compartment of the gastrointestinal tract (GIT), it is desirable to have a compound of formula (I) that is minimally absorbed from the upper GIT. Since Caco-2 P app The correlation between intestinal absorption and in vivo absorption has been confirmed (Artursson P.; Karlsson J.1991Biochem.Biophys.Res.Commun.175(3),880), through A-to-BP appThe measured permeability of the glycoside prodrug should be lower than that of the corresponding parent PDE4 inhibitor, preferably the measured P app Less than 1X10 -6 cm / sec, even more preferably less than 0.1X10 -6 cm / sec. The glycoside prodrugs of formula (I) were found to have lower Caco-2Papp than their corresponding PDE4 inhibitors III (Table 2).

[0374] Table 2

[0375]

[0376] In vitro rate of hydrolysis of glycoside prodrugs. The metabolic stability of prodrug candidates that release the parent PDE4 inhibitor can be assessed in vitro according to, but not limited to, the following protocol: Feces are collected overnight on a mixture of dry ice and wet ice in a metabolic cage. Ten volumes (v / w; 30 mL) of 100 mM phosphate buffer (pH 6.5) are added to 3 g of freshly collected rodent feces. The mixture is homogenized using a Stomacher Circulator 400 (2 x 1 minute cycles at 225 rpm). The mixture is transferred to a 50 mL tube, centrifuged at 10,000 x g for 10 minutes (4°C), and the supernatant is passed through a 0.45 μm filter. In a 96-deep-well plate, 198 μL of fecal supernatant is aliquoted into two wells per compound. Each compound, including the positive control, is tested in duplicate. 2 μL of a 10 mM stock solution of each test compound was then spiked into each well (in duplicate) at a final concentration of 100 μM, and the samples were then sealed and mixed using a vortexer at 1000 rpm for 30 seconds. The samples were incubated in a thermomixer at 37°C for the desired time while continuously stirring (300 rpm). At the desired time point, 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 incubations were mixed and centrifuged at 21,000 x g for 10 minutes at 4°C. 22.5 μL of fecal supernatant was added to 225 μL of ice-cold quenching solution (acetonitrile + 0.1% (v / v) formic acid) to generate a true t o(No metabolism, 100% total recovery of unchanged prodrug). 2.5 μL of a 1 mM solution of each test compound was then added, sealed, mixed thoroughly, and centrifuged at 21,000 x 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 the corresponding prodrug remaining. A 100% recovery standard was set as the target, where the sum of the percentage of prodrug remaining and the percentage of parent PDE4 inhibitor released should be 100%, with an experimental error tolerance of ±20%. When the prodrug represented by formula (I) was incubated with mouse, rat, and dog feces for 24 hours under the above conditions, the glycoside prodrug was hydrolyzed to release the corresponding parent PDE4 inhibitor III (Table 3). As a negative control, when compounds 4, 10 and 21 were incubated for 24 hours under the above conditions but in the absence of enzyme activity, the supernatant of mouse fecal extract in which the supernatant was boiled for 10 minutes to inactivate the supernatant was used, and 100% of the prodrug was recovered unchanged. As a positive control, when compounds 9 and 10 were incubated at 37°C for 24 hours in the presence of β-D-glucuronidase (50 U / mL) in phosphate buffer (pH 6.5), 85% and 37% of IIIb were released, respectively, and 2% of compound 9 and 64% of compound 10 were recovered unchanged.

[0377] Table 3

[0378]

[0379]

[0380] In vivo glycoside prodrug bioactivation. In vivo pharmacokinetic experiments were performed using preclinical species (such as, but not limited to, mice and rats). Following oral administration of a PDE4 inhibitor glycoside of Formula (I), the distribution of the prodrug and the corresponding parent PDE4 inhibitor over time was assessed in tissues such as the blood and intestine. The amount of prodrug and the corresponding parent excreted in feces was also measured. This will enable researchers to assess the in vivo bioactivation of the glycoside prodrug to release the parent PDE4 inhibitor and the degree of colon specificity of the glycoside prodrug delivery system. Advantageously, the parent PDE4 inhibitor should not be released before reaching the colonic compartment of the GIT, and the prodrug should not be absorbed in the upper part of the GIT. More advantageously, the local exposure of the parent PDE4 inhibitor measured in feces and / or colon should be superior to the parent systemic exposure measured in the blood. When compound 10 was orally administered to rats as an aqueous suspension, the prodrug or its corresponding metabolite, compound 9, was not detected in the blood within 24 hours. In the same study, the corresponding PDE4 inhibitor IIIb was not detected in the blood before T = 2 hours, representing the orocecal transit time. Within 24 hours, the extent of prodrug bioactivation, as measured by the ratio of parent PDE4 inhibitor IIIb to residual prodrug 10 in excreted feces, was 96%. When compound 10 was orally administered to C57Bl / 6 mice as a labrasol / 5% glucose solution, the extent of prodrug bioactivation (measured in excreted feces) was >98% within 48 hours, 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, the measured exposure (AUC0-24) of released parent PDE4 inhibitor IIIb in colonic tissue (proximal and distal colon) was 200-fold higher than the exposure measured in the blood.

[0381] The emetic threshold of a PDE4 inhibitor glycoside can be assessed as a measure of improved tolerability compared to the corresponding parent PDE4 inhibitor. In this observational model, animals, such as, but not limited to, dogs, ferrets, or non-human primates, are administered a PDE4 inhibitor glycoside or its corresponding parent PDE4 inhibitor at equal doses, and vomiting is recorded. Improved tolerability is defined as a ratio of the emetic dose of the PDE4 inhibitor glycoside to the emetic dose of the corresponding parent PDE4 inhibitor >3, advantageously >10, and even more advantageously >30.

[0382] Although the preferred embodiment has been described above and shown in the accompanying drawings, it is obvious to those skilled in the art that modifications can be made without departing from the present disclosure. Such modifications are considered to be possible variations within the scope of the present disclosure.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, in, X is β-D-glucuronide, α-D-glucuronide, β-D-glucopyranoside, α-D-glucopyranoside, β-D-galactoside, α-D-galactoside, β-D-mannopyranoside, α-D-mannopyranoside, N-acetyl-β-D-glucosaminyl, 3,4,6-tri-O-acetyl-N-acetyl-β-D-glucosaminyl, N,N-dimethyl-β-D-glucosaminyl, N-acetyl-α-D-glucosaminyl, N-acetyl-β-D-galactosaminyl, N-acetyl-α-D-galactosaminyl, β-D-glucosaminyl, α-D-glucosaminyl, β-D-glucosaminyl, α-D-glucosaminyl, β-D-galactosaminyl, α-D-galactosaminyl, β-D-cellobioside, or α-D-cellobioside; R 1 is -C1 alkyl, and the -C1 alkyl is substituted by 1-3 halogens independently selected from F or Cl; R 2 -C 3-6 Cycloalkyl; R 3 and R 4 Each independently is H; R 5 、R 6 and R 7 Each independently is H; Ar 1 Independently selected from the group consisting of: (a)6-R 8 -3-pyridyl, (b)2-R 8 -5-thiazolyl, (c)2-R 8 -5-pyrimidinyl, (d)6-R 8 -3-pyridazinyl, (e)5-R 8 -3-isothiazolyl or 3-R 8 -5-isothiazolyl; R 8 -C(R 10 )(R 11 )OH; R 10 and R 11 Each independently represents H, -C 1-6 Alkyl, or -C 1-6 Halogenated alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The β-D-glucuronide is β-D-glucuronic acid, β-D-glucuronic acid methyl ester, 2,3,4-tri-O-acetyl-β-D-glucuronic acid methyl ester, 2,3,4-tri-O-acetyl-β-D-glucuronic acid ethyl ester, β-D-glucuronic acid ethyl ester, β-D-glucuronic acid isopropyl ester, β-D-glucuronic acid tert-butyl ester or methyl β-D-glucuramide.

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

5. 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. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The β-D-aminoglucosides are β-D-glucosamine groups or α-D-glucosamine groups.

7. 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'-heptyl-O-acetyl-β-D-cellobiosyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Ar 1 6-R 8 -3-pyridyl or 2-R 8 -5-thiazolyl.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Ar 1 6-R 8 -3-pyridyl.

10. The compound according to claim 1, wherein The β-D-glucuronide is a β-D-glucuronic acid group.

11. The compound according to claim 10, wherein The β-D-glucuronic acid group is methyl glucuronide.

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

13. The compound according to claim 1, wherein The compound of formula (I) is represented by the following formula or a pharmaceutically acceptable salt thereof 14. The compound according to claim 1, wherein the compound of formula (I) is represented by the following formula or a pharmaceutically acceptable salt thereof 15. The compound according to claim 1, wherein the compound of formula (I) is represented by the following formula or a pharmaceutically acceptable salt thereof 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent.

18. The pharmaceutical composition according to claim 16, comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 16, wherein The therapeutically effective amount is 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 the compound of formula (I).

20. The pharmaceutical composition according to claim 16, wherein The composition is at least one of an immediate release formulation, a sustained release formulation, or a delayed release formulation, or a combination thereof.

21. The pharmaceutical composition according to claim 16, wherein The composition is in liquid form.

22. The pharmaceutical composition according to claim 16, wherein The composition is in the form of a lotion.

23. The pharmaceutical composition of claim 16, further comprising a leukotriene receptor antagonist, a leukotriene biosynthesis inhibitor, an M2 / M3 antagonist, a corticosteroid, a H1 receptor antagonist, a β2 adrenergic receptor agonist, a selective COX-2 inhibitor, an NSAID, an immunomodulator, 5-ASA, a 5-ASA prodrug, a janus kinase inhibitor, or a combination thereof.

24. The method of claim 1 for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, irritable bowel syndrome, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, depression, memory impairment, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, cancer, cancerous invasion of normal tissue, and atherosclerosis.

25. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 15 in the preparation of a medicament for treating or preventing ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis, or psoriasis.

26. Use of a pharmaceutical composition as described in any one of claims 16 to 23 in the preparation of a medicament for treating or preventing asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, irritable bowel syndrome, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, depression, memory impairment, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign proliferative skin diseases, malignant proliferative skin diseases, atopic dermatitis, cancer, cancerous invasion of normal tissue, and atherosclerosis.

27. Use of the pharmaceutical composition of any one of claims 16 to 23 in the preparation of a medicament for treating or preventing ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), psoriatic arthritis, or psoriasis.

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