Novel compound

Abstract

Disclosed herein are novel C-mannoside compounds and compositions and their application as pharmaceuticals for the treatment of human diseases. Methods for inhibiting the activity of FimH in a human subject are also provided for the treatment of diseases, such as urinary tract infections.

Description

[Technical field]

[0001] Disclosed herein are novel C-mannoside compounds and compositions and their application as pharmaceuticals for the treatment of human diseases. Methods for inhibiting the activity of FimH in a human subject are also provided for the treatment of diseases, such as urinary tract infections. [Background technology]

[0002] Urinary tract infections (UTIs) are one of the most common infectious diseases in women. Morbidity and economic impact are significant, with more than $2.5 billion spent annually on treatment. Furthermore, recurrent infections remain a significant problem despite appropriate antibiotic therapy for the first infectious episode. Women who present with a first episode of acute UTI have a 25-44% chance of developing a second episode and a 3% chance of experiencing a third episode within 6 months of the first UTI. Furthermore, resistance to antibiotics commonly prescribed to treat or prevent UTIs is spreading rapidly among urinary tract pathogens, highlighting the need for novel therapies that allow for antibiotic sparing.

[0003] More than 85% of UTIs are caused by uropathogenic Escherichia coli (UPEC). Gram-negative bacteria, such as UPEC, are causative agents of a variety of acute and chronic infectious diseases. Many of these infections are initiated by a crucial interaction between a host ligand (often a polysaccharide moiety) and a bacterial adhesin (often expressed at the distal tip of a polymeric pilus filament assembled by the chaperone-usher pathway). Animal models of UTI have revealed that the mannose-binding FimH adhesin of type 1 fimbriae is important for colonization and invasion of the bladder epithelium by UPEC and other uropathogenic bacteria of the Enterobacteriaceae family, such as Klebsiella, Enterobacter and Citrobacter species.

[0004] Type 1 pili are anchored to the bacterial outer membrane and consist primarily of repeated FimA protein subunits that form a helically wound cylinder containing a thick pilus rod. The distal FimH adhesin proteins are connected by a flexible tip fibrillum composed of one copy each of FimF and FimG. The adhesin tip protein FimH contains a pilin domain (FimH) that allows incorporation into the pilus. P ) and a lectin domain (FimH) containing a conserved mannose-binding pocket. L FimH is a two-domain protein composed of a mannose-binding domain and a mannose-binding domain. The X-ray crystal structure of mannose-bound FimH showed that mannose binds to a negatively charged pocket in FimH. The mannose-binding site is highly conserved, as it is invariant in 300 fimH genes sequenced from clinical UPEC strains. It is the interaction of FimH with mannosylated host proteins that is thought to mediate colonization of the lower urinary tract by UPEC and other Enterobacteriaceae during UTI.

[0005] To elucidate the molecular details of UPEC pathogenesis, several murine infection models have been established, recapitulating many of the clinical manifestations commonly seen in humans. These models include acute UPEC infections, chronic and / or recurrent infections, and catheter-associated UTIs. In all these models, the adhesin FimH has been shown to play an essential role in pathogenesis and has emerged as an excellent therapeutic target. The fundamental interaction between FimH and the host is thought to occur by binding to high mannose-containing glycans that cover the luminal surface of the bladder, such as uroplakins and other proteins expressed on the surface of bladder epithelial cells. This initial binding promotes bacterial colonization of the bladder epithelium and bacterial invasion of bladder epithelial cells. Once internalized, single bacteria can escape into the host cell cytoplasm and rapidly replicate and grow to form biofilm-like intracellular bacterial communities (IBCs). As these communities reach maturity, they can disperse and escape the cell, undergoing fibrosis to avoid neutrophil phagocytosis. These filamentous bacteria then infect neighboring cells, reinitiating the IBC formation and pathogenicity cycle. Importantly, evidence of IBCs and bacterial filaments has been observed in the urine of women with acute UTI, supporting the validity of the mouse model in recapitulating human disease.

[0006] In contrast to UTIs, which are primarily mediated by bacterial pathogens, the disease manifesting in patients suffering from idiopathic inflammatory bowel diseases (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is the result of a complex interplay between a genetically susceptible host, a dysfunctional immune system, and microbial components. Examination of biopsy tissues from patients suffering from CD and UC highlighted an increased abundance of Escherichia coli associated with the intestinal mucosa. Analysis of these bacteria led to the discovery of distinct pathotypes known as entero-adhesive invasive E. coli (AIEC), although some of these strains appear to be genomically similar to UPEC. The identification of AIEC and their putative role in CD and UC led to several follow-up studies by several independent groups investigating the gut microbiota of IBD patients. This work provides substantial evidence for the overgrowth of AIEC in patients with ileal CD, together with less convincing data on other IBD subtypes, e.g., UC, colonic CD, and ileocolonic CD. Analysis of ileal enterocytes isolated from CD patients confirmed abnormal expression of the host receptor carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6). CEACAM6 is highly mannosylated and has been demonstrated to promote the binding of AIEC to these cells via type 1 fimbriae. Interestingly, adhesion and invasion of AIEC to intestinal epithelial cells leads to increased expression of the receptor CEACAM6, suggesting that AIEC can promote their own colonization in the ileum of CD patients. Utilizing transgenic mice expressing the human CEA family gene cluster, including CEACAM6, increased colonization of AIEC and recapitulated many of the clinical symptoms of CD, e.g., severe colitis, weight loss, and reduced survival in this model. Moreover, these symptoms could be completely abolished by administration of anti-CEACAM6 antibodies or genetic deletion of FimH in the bacterial strain, indicating a direct link between the recognition of CEACAM6 by FimH and the progression of the disease. Thus, therapies targeting FimH among AIEC may be of great benefit in alleviating symptoms in CD patients. Summary of the Invention

[0007] Novel compounds and pharmaceutical compositions have been discovered that are found to inhibit FimH, along with methods of synthesizing the compounds and methods of using the compounds, including methods of administering the compounds to treat FimH-mediated diseases in a patient.

[0008] More specifically, in one embodiment, the present invention provides a compound of formula I: [ka] [In the formula, Z is [ka] and n is 1 to 3; Q is CF3, CH3 or Cl; R is C 1-3 Alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 Alkynyl, phenyl, -(CH2) m -OH, optionally substituted cyclopropyl or optionally substituted vinyl; R 1 , R 2 and R 3 are independently H, F, Cl, Br, C 3-6 Cycloalkyl, OR', -N(C 1-6 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl (up to 7 fluorine atoms, up to 1 hydroxyl, up to 1 -N(C 1-6 alkyl)2 and up to 1 -OC 1-6 alkyl), up to one -(CO)-NH-CH3 or up to one cyano, provided that not all R2 are simultaneously H; R 4 is H or F, R' is independently H or C 1-6 alkyl (optionally substituted with up to 7 fluorine atoms); Y is independently CH, N, or CR1 if permitted by the structure of Z, provided that not all Y are simultaneously CH; m is 1 to 3. or a pharma- ceutically acceptable salt thereof.

[0009] In one embodiment, the present invention provides a compound of formula I: [ka] [In the formula, Z is [ka] and n is 1 to 3; Q is CF3, CH3 or Cl; R is C 1-3 Alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 Alkynyl, phenyl, -(CH2) m -OH, optionally substituted cyclopropyl or optionally substituted vinyl; R 1 , R 2 and R 3 are independently H, F, Cl, Br, C 3-6 Cycloalkyl, OR', -N(C 1-6 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl (up to 7 fluorine atoms, up to 1 hydroxyl, up to 1 -N(C 1-6 alkyl)2 and up to 1 -OC 1-6 alkyl), up to one -(CO)-NH-CH3 or up to one cyano, with the proviso that all R2 are not simultaneously H; R 4 is H or F, R' is independently H or C 1-6 alkyl (optionally substituted with up to 7 fluorine atoms); Y is independently C, CH, or N, with the proviso that all Y's are not simultaneously CH; m is 1 to 3. or a pharma- ceutically acceptable salt thereof.

[0010] For the avoidance of doubt, the compound has the following general formula (I): [ka] can also be expressed as follows: [ka]

[0011] To avoid any misunderstanding, the substituent R 1 , R 2 and R 3 are H, F, Cl, Br, and C. 3-6 Cycloalkyl, OR', -N(C 1-6 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CO)-NH-CH3, cyano and C 1-6 C may be independently selected from the list consisting of alkyl. 1-6 Alkyl may contain up to seven fluorine atoms, up to one hydroxyl, and up to one -N(C 1-6 alkyl)2 and up to 1 -OC 1-6 may be substituted with alkyl, provided that at least one R 2 The group is not H, but one R 2 The only group may be -(CO)-NH-CH3 or cyano.

[0012] In one embodiment, R is C 1-3 Alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 Alkynyl, phenyl, -(CH2) m -OH, optionally substituted cyclopropyl or optionally substituted vinyl.

[0013] In one embodiment, R is C 1-3 Alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 Alkynyl, phenyl, -(CH2) m -OH, cyclopropyl or vinyl.

[0014] In one embodiment, R is C 1-3 Alkyl, phenyl, -(CH2) m -OH, cyclopropyl, ethynyl or vinyl.

[0015] In one embodiment, R is methyl, ethyl, isopropyl, phenyl, -(CH2) m -OH, cyclopropyl, ethynyl or vinyl.

[0016] In one embodiment, R is methyl or vinyl.

[0017] In one embodiment, R is methyl.

[0018] In one embodiment, Q is CF3 or CH3. In one embodiment, Q is CH3. In one embodiment, R 4 is H.

[0019] In one embodiment, Q is CH3 and R 4 is H, or Q is CF3, and R 4 is H. In one embodiment, Q is CH3 and R 4 is H.

[0020] In one embodiment, R 1 is F, cyclopropyl, -CF or cyano. 1 is cyclopropyl, -CF or cyano. 1 is -CF3.

[0021] In one embodiment, R 2are independently -CF3, -F, -Cl, -Br, cyano, -(CO)-NH-CH3, -CH2-CH2-OH, hydrogen, or cyclopropyl, provided that all R 2 and are never simultaneously hydrogen.

[0022] In one embodiment, R 2 is independently -F, -Cl, cyano, or -(CO)-NH-CH. 2 is F or Cl.

[0023] In one embodiment, R 3 is F, Cl or Br. In one embodiment, R 3 is F.

[0024] In one embodiment, Z is [ka] [In the formula, Y1 is N or CR 1B and Y2 and Y3 are selected from the group consisting of N or CH, with the proviso that at least one of Y1, Y2, and Y3 is N; R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B are H, F, Cl, Br, and C. 3-6 Cycloalkyl, OR', -N(C 1-6 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CO)-NH-CH3, cyano and C 1-6 alkyl, C 1-6 Alkyl may contain up to seven fluorine atoms, up to one hydroxyl, and up to one -N(C 1-6 alkyl)2 and up to 1 -OC 1-6 Optionally, Y is substituted with alkyl, provided that CR 1B If R 1A and R 1BOne of them is H and the other is R 3A and R 3B One of them is H and the other is R 2A , R 2B and R 2C At least one of them is not H, but R. 2A , R 2B and R 2C Only one of may be -(CO)-NH-CH3 or cyano. It is.

[0025] In one embodiment, R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B is independently selected from the group consisting of H, F, Cl, CF3, cyclopropyl, -(CO)-NH-CH3, and cyano, provided that Y is CR 1B If R 1A and R 1B One of them is H and the other is R 3A and R 3B One of them is H and the other is R 2A , R 2B and R 2C At least one of them is not H, but R. 2A , R 2B and R 2C Only one of may be -(CO)-NH-CH3 or cyano.

[0026] In one embodiment, Z is [ka] where Y1, Y2, Y3, R 1A , R 2A , R 2B and R 2C is as defined herein.

[0027] In one embodiment, Z is [ka] where Y1, Y2, Y3 and R 1A is as defined herein.

[0028] In one embodiment, Y1 and Y3 are N and Y2 is CH. In certain embodiments where Y1 and Y3 are N and Y2 is CH, R 1A is selected from the group consisting of F, cyclopropyl, -CF3, or cyano. 1A is cyclopropyl or CF. In one embodiment, R 1A is -CF3.

[0029] In an alternative embodiment, Y3 is N, Y2 is CH and Y1 is CR 1B Y3 is N, Y2 is CH, and Y1 is CR 1B In certain embodiments, R 1A and R 1B One of R is H and the other is selected from the group consisting of F, cyclopropyl, -CF3, or cyano. 1A and R 1B One of R is H and the other is selected from the group consisting of -CF3 or cyano. 1A is H and R 1B is -CF3. In another embodiment, R 1A is -CF3, R 1B is H.

[0030] In a further embodiment, Y3 is CH, Y2 is N and Y1 is CR 1B and R 1A and R 1B One of R is H and the other is selected from the group consisting of F, cyclopropyl, -CF3, or cyano. 1A and R 1B One of R is H and the other is selected from the group consisting of F, -CF3, or cyano. 1A is selected from the group consisting of F, -CF3 or cyano; R1B is H.

[0031] In one embodiment, Y2 and Y3 are N and Y1 is CR 1B and R 1A and R 1B One of R is H and the other is selected from the group consisting of F, cyclopropyl, -CF3, or cyano. 1A and R 1B One of R is H and the other is selected from the group consisting of F, -CF3, or cyano. 1A and R 1B One of R is H and the other is -CF. In one embodiment, R 1A is -CF3, R 1B is H.

[0032] In one embodiment, Z is [ka] where R 2A , R 2B and R 2C is as defined herein.

[0033] In one embodiment, R 2A , R 2B and R 2C is independently selected from the group consisting of H, F, Cl, CF, cyclopropyl, -(CO)-NH-CH, and cyano, with the proviso that R 2A , R 2B and R 2C At least one of them is not H, but R. 2A , R 2B and R 2C Only one of may be -(CO)-NH-CH3 or cyano.

[0034] In one embodiment, R 2A is selected from the group consisting of H, F, CN, and -(CO)-NH-CH3; R 2B is selected from the group consisting of H, CN and Cl; R2C is selected from the group consisting of F and H, with the proviso that R 2A , R 2B and R 2C At least one of them is not H, but R. 2A , R 2B and R 2C Only one of may be cyano.

[0035] In one embodiment, R 2A is F or CN, and R 2B is selected from the group consisting of H and Cl; R 2C is selected from the group consisting of F and H. In more particular embodiments, R 2A is F and R 2B is selected from the group consisting of H and Cl; R 2C is selected from the group consisting of F and H. In more particular embodiments, R 2A is F and R 2B is selected from the group consisting of H and Cl; R 2C is F. In a more particular embodiment, R 2A is F and R 2B is Cl, and R 2C is F.

[0036] In one embodiment, Z is [ka] It is.

[0037] In one embodiment, Z is [ka] [In the formula, R 3A and R 3B One of them is H and the other is F, Cl, Br, C 3-6 Cycloalkyl, OR', -N(C 1-6 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CO)-NH-CH3, cyano and C 1-6independently selected from the group consisting of alkyl, C 1-6 Alkyl may contain up to seven fluorine atoms, up to one hydroxyl, and up to one -N(C 1-6 alkyl)2 and up to 1 -OC 1-6 It may be substituted with alkyl. It is.

[0038] In one embodiment, R 3A and R 3B One of R is H and the other is independently selected from the group consisting of F, Cl, and CF. 3A is H and R 3B is independently selected from the group consisting of F, Cl, and CF. 3A is H and R 3B is CF3.

[0039] In another embodiment, the present invention relates to a compound of formula I above, wherein Z is [ka] and n is 1 to 3; Q is CF3 or CH3; R is C 1-3 Alkyl, phenyl, -(CH2) m -OH, cyclopropyl or vinyl; R 1 is cyclopropyl, -CF3 or cyano, R 2 are independently -CF3, -F, -Cl, -Br, cyano, -(CO)-NH-CH3, -CH2-CH2-OH, hydrogen or cyclopropyl, provided that not all R2 are simultaneously hydrogen; R3 is -F, -Cl or Br; R4 is H or F; Y is independently C, CH, or N, provided that not all Y are simultaneously CH; m is 1 to 3.

[0040] In another embodiment, the present invention relates to a compound of formula I above, wherein Z is [ka] and Y1 is N or CR 1B and Y2 and Y3 are selected from the group consisting of N or CH, with the proviso that at least one of Y1, Y2, and Y3 is N; R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B is independently selected from the group consisting of H, F, Cl, CF, cyclopropyl, -(CO)-NH-CH, and cyano, with the proviso that Y is CR 1B If R 1A and R 1B One of them is H and the other is R 3A and R 3B One of them is H and the other is R 2A , R 2B and R 2C At least one of them is not H, but R. 2A , R 2B and R 2C only one of may be -(CO)-NH-CH3 or cyano; R is methyl or vinyl; Q is CH3 and R 4 is H, or Q is CF3, and R 4 is H.

[0041] In a more particular embodiment, Q is CH3 and R 4 is H.

[0042] In a more particular embodiment, R is methyl.

[0043] In one embodiment, the present invention provides a compound selected from the group consisting of the following compounds, or a pharma- ceutically acceptable salt thereof: (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)allyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-((S)-1-(4'-chloro-3',5'-difluoro-3-methyl-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

[0044] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0045] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0046] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0047] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0048] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0049] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)allyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0050] In one embodiment, the present invention provides a compound which is (2R,3S,4R,5S,6R)-2-((S)-1-(4'-chloro-3',5'-difluoro-3-methyl-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, or a pharma- ceutically acceptable salt thereof.

[0051] In another embodiment, the present invention provides the use of a compound of formula I or a pharma- ceutically acceptable salt as a medicine.

[0052] In one embodiment, the invention provides a compound of formula I or a pharma- ceutically acceptable salt thereof for use in therapy.

[0053] In another embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or condition ameliorated by inhibition of the function or activity of FimH. In a more particular embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or condition ameliorated by inhibition of the function or activity of FimH.

[0054] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition ameliorated by inhibition of the function or activity of FimH. In a more particular embodiment, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition ameliorated by inhibition of the function or activity of FimH.

[0055] In another embodiment, the present invention provides a method for the treatment of a FimH mediated disease, comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof to a human patient in need thereof.

[0056] In one embodiment, the disease or condition is a bacterial infection, Crohn's disease (CD) or inflammatory bowel disease (IBD).

[0057] In one embodiment, the bacterial infection is an antibiotic-resistant bacterial infection.

[0058] In one embodiment, the disease is Crohn's disease.

[0059] In one embodiment, the disease is inflammatory bowel disease.

[0060] In one embodiment, the bacterial infection is a urinary tract infection (UTI), such as cystitis infection and pyelonephritis infection.

[0061] In one embodiment, the urinary tract infection is recurrent.

[0062] In one embodiment, the urinary tract infection is chronic.

[0063] In another embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment or prophylaxis of UTI.In another embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of UTI.

[0064] In another embodiment, the invention provides the use of a compound of formula I or a pharma- ceutically acceptable salt in the manufacture of a medicament for the treatment or prophylaxis of UTI.In another embodiment, the invention provides the use of a compound of formula I or a pharma- ceutically acceptable salt in the manufacture of a medicament for the treatment of UTI.

[0065] In another embodiment, the present invention provides a method for treating a urinary tract infection (UTI), comprising administering a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt to a human patient in need thereof.

[0066] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharma- ceutically acceptable salt, in association with a pharma- ceutically acceptable carrier.

[0067] In one embodiment, the pharmaceutical composition is formulated for oral (PO) administration.

[0068] In one embodiment, the pharmaceutical composition is selected from a tablet and a capsule.

[0069] In one embodiment, the pharmaceutical composition is formulated for topical administration.

[0070] In another embodiment, the present invention provides a method of treating a FimH-mediated disease, comprising the steps of administering (a) a therapeutically effective amount of a compound of formula I, or a pharma-ceutically acceptable salt thereof, and (b) another therapeutic agent.

[0071] In another embodiment, the invention provides a combination of a compound of formula I, or a pharma- ceutically acceptable salt, and another therapeutic agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] definition As used herein alone or in combination, "C 1-6 The term "alkyl" refers to a straight or branched chain alkyl radical containing 1 to 6 carbon atoms. 1-6 Examples of alkyl radicals include methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, and the like.

[0073] As used herein alone or in combination, "C 3-6The term "cycloalkyl" refers to a saturated monocyclic alkyl group containing from 3 to 6 carbon atom ring members in each cyclic moiety. Examples include cyclopropyl (cPr), cyclopentyl (cPe), cyclobutyl (cBu) and cyclohexyl (cHex).

[0074] As used herein, "C 2-6 The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 6 carbon atoms and at least one carbon-carbon double bond. Examples include ethenyl (or ethylene) and propenyl (or propylene).

[0075] As used herein, "C 2-6 The term "alkynyl" refers to a straight or branched hydrocarbon chain containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond. Examples include ethynyl (or ethylene) and propynyl (or propylene).

[0076] The term "heteroaryl" as used herein alone or in combination refers to a 3-15 membered unsaturated heteromonocyclic ring or a fused monocyclic, bicyclic or tricyclic ring system containing at least one atom selected from N, O and S, in which at least one of the fused rings is aromatic. In certain embodiments, a heteroaryl contains 1-4 heteroatoms as ring members. In further embodiments, a heteroaryl contains 1-2 heteroatoms as ring members. In certain embodiments, a heteroaryl contains 5-7 atoms. The term also encompasses fused polycyclic groups in which a heterocycle is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0077] The term "aryl" as used herein alone or in combination means a carbocyclic aromatic system containing one, two or three rings, such polycyclic systems being fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthryl.

[0078] The term "optionally substituted" means that the preceding group may be substituted or unsubstituted. If an optionally substituted group is not specifically recited, the substituents of the "optionally substituted" group may be 1 to 3 substituents independently selected from the following groups: 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 It may include the specifically specified set of groups selected from alkyl, phenyl, cyano, chloro, fluoro, bromo, amido, nitro, -SH, SCH3, -C(O)CH3, -CO2H, aryl or heteroaryl.

[0079] Asymmetric centers exist in compounds of formula I. It is to be understood that the present invention includes compounds of the absolute configuration shown in formula I.

[0080] Due to their potential use in medicine, the salts of the compounds of formula I are preferably pharma-ceutically acceptable salts.Thus, references to salts are to pharma-ceutically acceptable salts."Pharmaceutically acceptable" refers to compounds (including salts), materials, compositions and dosage forms that are suitable for use in contact with human and animal tissues without undue toxicity, irritation or other problems and complications, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. Suitable pharma- ceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19, or those described in PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley- VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0081] If the compound of the invention is a base (containing a basic moiety), the desired salt form can be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid such as acetic acid; trifluoroacetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an α-hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like. Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanate, propiolate, oxalate, succinate, malonate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenate, and the like. These include benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutorate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, mandelate and sulfonates (xylene sulfonate, methane sulfonate, propane sulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate).

[0082] If a basic compound of the invention is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base that has a higher pKa than the free base form of the compound.

[0083] If the compound of the invention is an acid (containing an acidic moiety), the desired salt can be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (e.g., glycine and arginine); ammonia; primary, secondary and tertiary amines; and cyclic amines (e.g., ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0084] Certain compounds of the present invention may form salts with an equivalent or greater amount of an acid (if the compound contains a basic moiety) or base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0085] Since the compounds of the present invention may contain both acidic and basic moieties, pharma- ceutically acceptable salts can be prepared by treating these compounds with alkaline or acidic reagents, respectively. Thus, the present invention also provides the conversion of one pharma- ceutically acceptable salt of a compound of the present invention, such as a hydrochloride salt, to another pharma- ceutically acceptable salt of a compound of the present invention, such as a sodium salt or disodium salt.

[0086] Since the compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, for example 60% or greater purity, more suitably 75% or greater purity, preferably 85% or greater purity, and especially 98% or greater purity (% being weight by weight). Impure preparations of the compounds may be used to prepare the purer forms used in the pharmaceutical compositions.

[0087] The term "combination" refers to the administration of two or more therapeutic agents to treat a condition or disorder described in this disclosure. Such administration includes methods in which these therapeutic agents are administered substantially simultaneously, such as in a single capsule having a fixed ratio of active ingredients, or in multiple separate capsules for each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen provides the beneficial effects of the combination of agents in the treatment of a condition or disorder described herein.

[0088] "FimH inhibitors" or "FimH antagonists" are used herein to refer to compounds that exhibit an HAI (hemagglutination inhibition assay) potency or EC>90 with respect to FimH function / activity, as measured in a FimH hemagglutination assay (HA) generally described herein, of about 100 mM or less, more typically about 50 mM or less. An "HAI potency or EC>90" is the concentration of a FimH inhibitor / antagonist that reduces bacterial agglutination of guinea pig red blood cells by more than 90%. Certain compounds disclosed herein have been found to exhibit this inhibition of FimH function / activity. When measured in the FimH assay described herein, in certain embodiments, the compounds exhibit an EC>90 with FimH of about 10 μM or less, in further embodiments, the compounds exhibit an EC>90 with FimH of about 1 μM or less, in yet other embodiments, the compounds exhibit an EC>90 with FimH of about 250 nM or less, in yet other embodiments, the compounds exhibit an EC>90 with FimH of about 100 nM or less, in yet other embodiments, the compounds exhibit an EC>90 with FimH of about 50 nM or less, and in yet other embodiments, the compounds exhibit an EC>90 with FimH of about 10 nM or less.

[0089] The term "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or disorder or the amount of active ingredient used to affect a clinical endpoint.

[0090] As used herein, "treating" with respect to a condition means (1) ameliorating or preventing the condition or one or more biological symptoms of the condition; (2) (a) interfering with one or more points in the biological cascade leading to or contributing to the condition, or (b) one or more biological symptoms of the condition; (3) alleviating one or more symptoms or effects associated with the condition; or (4) slowing the progression of the condition or one or more biological symptoms of the condition.

[0091] In one embodiment, "treating" with respect to a condition means (1) ameliorating the condition or one or more biological symptoms of the condition; (2) (a) interfering with one or more points in the biological cascade leading to or causing the condition, or (b) one or more biological symptoms of the condition; (3) alleviating one or more symptoms or effects associated with the condition; or (4) slowing the progression of the condition or one or more biological symptoms of the condition.

[0092] As used herein, reference to "prevention" of a patient is intended to include prophylaxis. Prevention of a disease may include complete protection from the disease, such as in the case of prevention of infection by a pathogen, or may include prevention of the progression of the disease. For example, prevention of a disease may not mean completely suppressing the effects associated with the disease at any level, but instead may mean preventing the symptoms of the disease to a clinically significant or detectable level. Prevention of a disease may also mean preventing the disease from progressing to a later stage of the disease.

[0093] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans; livestock animals, such as cows, goats, sheep, pigs, and rabbits; companion animals, such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0094] While it may be possible to administer the compounds of the present invention as the raw chemical, they can also be provided as pharmaceutical formulations (or alternatively referred to as pharmaceutical compositions). Thus, provided herein are pharmaceutical formulations that include one or more of the specific compounds disclosed herein, or one or more pharma- ceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharma- ceutically acceptable carriers thereof and, optionally, one or more therapeutic ingredients. The carrier or carriers must be "therapeutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Appropriate formulations will vary depending on the route of administration chosen. Any of the well-known techniques, carriers, and excipients are suitable and can be used as understood in the art. The pharmaceutical compositions disclosed herein can be prepared by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0095] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, inhalation, intranasal and topical (including cutaneous, buccal, sublingual and ocular) administration, although the most suitable route will vary, for example, depending on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association the compound of the invention or a pharma-ceutically acceptable salt, ester, amide, prodrug or solvate thereof (the "active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0096] As used herein, the term "compound(s) of the invention" refers to a compound of formula I in any form, i.e., any salt or non-salt form (e.g., free acid or free base form, or as a pharma- ceutically acceptable salt thereof), and in any of its physical forms (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, particular polymorphic forms, solvates including hydrates (e.g., monohydrate, dihydrate, hemihydrate)), and mixtures of various forms.

[0097] Formulations of the compounds disclosed herein suitable for oral administration can be presented as discrete units, each containing a predetermined amount of the active ingredient, such as capsules, cachets, or tablets; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary, or paste.

[0098] Orally usable pharmaceutical preparations include tablets, push fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). Tablets can be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, e.g., powder or granules, optionally mixed with a binder, inert diluent, lubricant, surfactant or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredients mixed with fillers (e.g., lactose), binders (e.g., starches), and / or lubricants (e.g., talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of doses of the active compounds.

[0099] The compounds can be prepared for parenteral administration by injection, for example, bolus injection or continuous infusion. The preparations for injection can be provided in unit dosage form (e.g., ampoules) or in multi-volume containers with the addition of a preservative. The compositions can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain compounding agents, for example, suspending, stabilizing and / or dispersing agents. The preparations can be provided in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier (e.g., saline or sterile pyrogen-free water) immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

[0100] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active ingredient, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides), or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing the preparation of highly concentrated solutions.

[0101] In addition to the above-mentioned preparations, compound can also be prepared as depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, compound can be prepared with suitable polymeric or hydrophobic materials (for example, as an emulsion in acceptable oil) or ion exchange resin, or compound can be prepared as poorly soluble derivative, for example, poorly soluble salt.

[0102] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner.Such compositions may comprise the active ingredient in a flavored base, for example, sucrose and acacia or tragacanth.

[0103] The compounds can also be formulated in rectal compositions such as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides).

[0104] Certain compounds disclosed herein can be administered by local administration, i.e., non-systemic administration. This includes external application of the compounds disclosed herein to the epidermis or buccal cavity, as well as instillation of such compounds into the rectum, lungs, vaginal cavity, ears, eyes, and nose, such that the compounds do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0105] Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may be, for example, 0.001% w / w to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may be up to 10% w / w. In other embodiments, the active ingredient may be less than 5% w / w. In certain embodiments, the active ingredient may be 2% w / w to 5% w / w. In other embodiments, the active ingredient may be 0.1% w / w to 1% w / w of the formulation.

[0106] For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound of the present invention can take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, for example, lactose or starch. The powder composition can be presented in unit dosage form, for example, in the form of capsules, cartridges, gelatin, or blister packs from which the powder can be administered by an inhaler or insufflator.

[0107] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0108] It will be appreciated that the formulations may include, in addition to the ingredients specifically mentioned above, other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0109] The compounds can be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units may conveniently contain one or more compounds in such amounts or multiples thereof that are effective, for example, a unit containing 5 mg to 500 mg, usually about 10 mg to 200 mg. In one embodiment, the compounds of the invention are administered at about 150 mg qd (once a day) or bid (twice a day).

[0110] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0111] The compound can be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient is the responsibility of the attending physician. The specific dose level of a particular patient depends on various factors, such as the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, the exact disorder being treated, and the severity of the indication or condition being treated. The administration route may also vary depending on the condition and severity.

[0112] In certain instances, it may be appropriate to administer one or more of the compounds described herein (or a pharma- ceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if hypertension is one of the side effects experienced by a patient when one of the compounds described herein is administered, it may be appropriate to administer an antihypertensive drug in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself, the adjuvant has minimal therapeutic effect, but in combination with another therapeutic agent, the therapeutic effect on the patient as a whole is enhanced). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a treatment regimen) that also has a therapeutic benefit. By way of example only, in the treatment of a urinary tract infection that includes administration of one of the compounds described herein, an increased therapeutic effect may be provided by also providing the patient with another therapeutic agent for the urinary tract infection. In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be merely additive or may be a synergistic benefit of the two therapeutic agents.

[0113] In either case, the two or more therapeutic agents (one or more of which is a compound disclosed herein) may be administered in any order, or simultaneously. If simultaneously, the two or more therapeutic agents may be provided in a single unified form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be administered multiple times, or both may be administered multiple times. If not simultaneously, the timing between the multiple administrations may be anywhere from a few minutes to four weeks.

[0114] Thus, in another aspect, certain embodiments provide a method for treating a FimH-mediated disorder in a human or animal subject in need of such medical care, comprising administering to the subject an amount of a compound disclosed herein in combination with one or more additional agents for the treatment of the disorder known to those of skill in the art, effective to reduce or prevent the disorder in the subject. In a related aspect, certain embodiments provide a therapeutic composition comprising one or more compounds disclosed herein in combination with one or more additional agents for the treatment of a FimH-mediated disorder.

[0115] Particular diseases that may be treated by the compounds, compositions and methods disclosed herein include bacterial infections, Crohn's disease and irritable bowel syndrome (IBS). In certain embodiments, the bacterial infection is a urinary tract infection.

[0116] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals. More preferred animals include horses, dogs and cats. EXAMPLES

[0117] General synthetic scheme for compounds of the present invention The compounds of the present invention can be prepared according to the synthetic method described in WO2017 / 156508 or its obvious variations. However, without limiting the present invention in any way, the following description also provides reaction methods that can be used to prepare the compounds of the present invention for illustrative purposes only. The synthesis of C-mannoside ketone intermediates followed the route shown in Scheme A. Benzyl-protected methyl mannoside is allylated with allyltrimethylsilane to form α-allyl mannoside as the major isomer. The terminal double bond is then isomerized to an internal double bond with (PhCN)2PdCl2. A two-step procedure involving dihydroxylation of the double bond and cleavage with sodium periodate produces an aldehyde that is used without further purification (see Wong, CH et. al. Small Molecules as Structural and Functional Mimics of Sialyl Lewis X in Selectin Inhibition: A Remarkable Enhancement of Inhibition by Additional Negative Charge and / or Hydrophobic Group. J. Amer. Chem. Soc. (1997) 119 (35) 8152-8158). This aldehyde intermediate is reacted with an aryl iodide A1 and n-butyllithium species and oxidized with Dess-Martin periodinane to form the ketone A2.

[0118] General synthesis of core mannoside ketones (Scheme A) Scheme A [ka]

[0119] The boronate or bromide coupling partners B through E can be synthesized according to the scheme shown below. 1-3 Alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 Alkynyl, phenyl, -(CH2) mIn the case of -OH or an optionally substituted vinyl, intermediate B can be prepared by reaction of RLi or RMgBr (or R-TMS, e.g., R=trifluoromethyl, if organometallic reagents are not suitable) with ketone A2 as shown in Scheme B, followed by reduction of the tertiary alcohol with triethylsilane.

[0120] R=methyl, Q=CF3 and R=C when removal of tertiary alcohols with triethylsilane is an issue. 4 As seen in Example 3 for =CF3, scheme C can be used instead. The organometallic CH3MgBr was reacted with ketone A2, followed by elimination of the tertiary alcohol with thionyl chloride. The resulting double bond was reduced with Pd on carbon to give intermediate C.

[0121] Depicted in Scheme D are alternative routes to the formation of benzyl vinyl intermediates D and E, which may be modified to provide access to optionally substituted vinyl derivatives or further derivatized to provide access to R groups consisting of optionally substituted cyclopropyl, hydroxyalkyl, propargyl or alkynyl derivatives. A functionalized phenylallylsilane is reacted with methylmannose using a Lewis acid, e.g., TMS-triflate. The phenyl bromide intermediate D can then be converted to a boronic ester using a palladium catalyst and bis(pinacolato)diboron to provide intermediate E.

[0122] Synthesis schemes for aryl bromide / heteroaryl bromide intermediates or boronic acid intermediates Scheme B [ka]

[0123] Scheme C [ka]

[0124] Scheme D [ka]

[0125] Two general schemes for Suzuki coupling are illustrated in Schemes E and F below. All examples utilize Suzuki coupling between a halide and a boronate. The mannoside is protected with a benzyl group. The benzyl group can be removed with BCl3 or by hydrogenolysis with Pd / C. The R group can be further functionalized using reactions known in the art. For example, if the R group contains a double bond, the double bond can be hydroxylated using hydroboration. Alternatively, the double bond can be dihydroxylated with OsO4 and NMO. The diol can be cleaved with NaIO4 to form an aldehyde, which can then be reduced with DIBAL.

[0126] Two general schemes for Suzuki coupling and deprotection Scheme E [ka]

[0127] Scheme F [ka]

[0128] General procedure for Suzuki coupling reaction To a solution of mannoside (1.0 equiv.) in dioxane / water (V / V=5 / 1), arylboronic acid (or boronate) or aryl halide (approx. 1.1 equiv.), cesium carbonate (approx. 3 equiv.) and tetrakis(triphenylphosphine)palladium (approx. 0.05 equiv.) are added at room temperature. The resulting mixture is degassed three times. The flask is then placed in an oil bath preheated to 80° C. and stirred for a specified time (usually 30 min to 2 h). The reaction mixture is then cooled to room temperature and the solvent is evaporated under reduced pressure. The crude residue is then purified by silica gel chromatography. The product is then deprotected by a deprotection protocol.

[0129] Deprotection Protocol B Unless otherwise stated, the benzyl ether is deprotected by adding 1M BCl3 (8.0 equiv.) in DCM to a solution of the partially purified mannoside from the Suzuki reaction (10 mL) at -78°C. The reaction is stirred at -78°C for the specified time. The reaction is then quenched with MeOH at -78°C. The reaction is then warmed to room temperature and concentrated under reduced pressure to give the debenzylated compound.

[0130] Example 1 [ka]

[0131] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol [ka]

[0132] [ka] (4-Bromo-2-methylphenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone To a solution of (R)-(4-bromo-2-methylphenyl)((2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanol (2 g, 2.76 mmol) and pyridine (660 mg, 8.35 mmol) in DCM (20 mL) was added Dess-Martin periodinane (2.34 g, 5.52 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. After completion, the reaction was quenched with water (20 mL), extracted with DCM (20 mL × 3), the organic phases were combined, washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give the residue (2 g) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+Na] + Calc'd for (C 42 H41 BrO6Na + ) 743.22, found, 743.15.

[0133] [ka] 1-(4-bromo-2-methylphenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethanol To a solution of (4-bromo-2-methylphenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (2 g, 2.77 mmol) in THF (20 mL) was added methylmagnesium bromide (2.8 mL, 8.4 mmol, 3M Et2O solution) at -78 °C. The reaction mixture was stirred at 25 °C for 4 h. After completion, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel using a gradient of 0-25% ethyl acetate in petroleum ether as eluent to give the title product (2 g, 98% yield) as a yellow oil. ESI-MS [M+H] + Calc'd for (C 43 H 45 BrO6Na + ) 759.25, found, 759.15

[0134] [ka] (2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(1-(4-bromo-2-methylphenyl)ethyl)tetrahydro-2H-pyran To a solution of 1-(4-bromo-2-methylphenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethanol (2 g, 2.71 mmol) in DCM (30 mL) was added EtSiH (1.57 g, 13.5 mmol) and CFCOOH (3.09 g, 27.1 mmol) at -78 °C. The reaction mixture was warmed to 25 °C and stirred for 12 min. After completion, the reaction was quenched with water (20 mL) and extracted with DCM (20 mL x 3), the organic phases were combined, washed with brine (20 mL), dried over NaSO and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel using a gradient of 0-30% ethyl acetate in petroleum ether as eluent to afford the title product (1.8 g, 92% yield) as a yellow oil. ESI-MS [M+Na] + Calc'd for (C 43 H 45 BrO5Na + ) 743.25, found, 743.24.

[0135] [ka] 4,4,5,5-Tetramethyl-2-(3-methyl-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-1,3,2-dioxaborolane A mixture of (2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(1-(4-bromo-2-methylphenyl)ethyl)tetrahydro-2H-pyran (1.8 g, 2.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (953 mg, 3.75 mmol), potassium acetate (735 mg, 7.5 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II).CHCl (204 mg, 0.25 mmol) in 1,4-dioxane (20 mL) was heated at 80° C. with stirring for 12 hours. Upon completion, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of 0-30% ethyl acetate in petroleum ether as eluent to afford the title product (1.6 g, 83% yield) as a light brown solid. ESI-MS [M+Na] + Calc'd for (C 49 H 57 BO7Na + ) 791.13, found, 791.16.

[0136] [ka] 2-(3-methyl-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-5-(trifluoromethyl)pyrazine A mixture of 4,4,5,5-tetramethyl-2-(3-methyl-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-1,3,2-dioxaborolane (1.6 g, 2.08 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (457 mg, 2.5 mmol), cesium carbonate (2.03 g, 6.25 mmol) and tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 80° C. for 40 minutes. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give a residue that was purified by column chromatography on silica gel using a gradient of 0-17% ethyl acetate in petroleum ether as eluent to give the title product (1.4 g, 85% yield) as a yellow oil. ESI-MS [M+Na] + Calc'd for (C 48 H 47 F3N2O5Na + ) 811.34, found, 811.16

[0137] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol To a solution of 2-(3-methyl-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-5-(trifluoromethyl)pyrazine (1.4 g, 1.78 mmol) in DCM (20 mL) was added BCl3 (1N solution in DCM, 14.2 mL, 14.2 mmol) dropwise at -78 °C. The resulting solution was stirred at -78 °C for 40 min. Upon completion, the reaction was quenched with MeOH (12 mL) and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 column 30×150mm 5μm; Mobile phase A: water (10mmol / L NH4HCO3); Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 25% B to 45% B in 9 min; 220nm; Rt:7.82 minutes; Injection volume: 2mL; Runs:3; The mixture was purified by preparative chiral chromatography under the following conditions: Column: CHIRALPAK IF, 2×25cm, 5μm; Mobile phase A: Hex(8mmol / L NH3MeOH)-HPLC; Mobile phase B: EtOH-HPLC; Flow rate: 20mL / min; Gradient: 30B to 30B in 18 minutes; 254 / 220nm; Injection volume: 1mL; Runs:12; Further separation at RT=9.25 min with MS signal of the desired product was collected and concentrated in vacuo to give the title product (200 mg, 26% yield) as a white solid. Formula:C 20 H 23 F3N2O5 Exact mass: 428.16 Molecular weight: 428.41 Analytical data: 11H NMR (300 MHz, methanol-d4) δ 9.28 (d, J = 1.5 Hz, 1H), 9.08 - 8.99 (m, 1H), 8.02-8.00 (m, 2H), 7.57 (d, J = 8.9 Hz, 1H), 4.24 (dd, J = 10.1 Hz, 2.7 Hz, 1H), 4.10 (t, J = 3.0 Hz, 1H), 3.82 (dd, J = 8.6 Hz, 3.2 Hz, 1H), 3.73 (t, J = 8.5 Hz, 1H), 3.58-3.51 (m, 2H), 3.40 (dd, J = 11.7 Hz, 2.9 Hz, 1H), 3.24-3.19 (m, 1H), 2.52 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H). ESI-MS [M+Na] + Calc’d for (C 20 H 23 F3N2O5Na + ) 451.15, found, 451.10.

[0138] Example 2 (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol

Chem.

[0139]

Chem.

[0140] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol and (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((S)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol To a solution of 2-(3-methyl-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-4-(trifluoromethyl)pyridine (630 mg, 0.800 mmol) in DCM (10 mL) at -78°C under N2 was added BCl3 (1N solution in DCM, 6.40 mL, 6.40 mmol). The reaction mixture was stirred at -78°C for 1 h under N2. The reaction mixture was quenched with MeOH (5 mL) and concentrated on a rotary evaporator to give a residue. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column 30×150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3); Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B in 7 min; 254 nm; Rt:6.77 minutes; Injection volume: 1.40mL; Number of runs: 5 The mixture was purified by chiral HPLC under the following conditions: Column: CHIRALPAK IG, 20×250mm, 5μm; Mobile phase A:Hex(8mmol / L NH 3. MeOH)-HPLC; Mobile phase B: EtOH-HPLC; Flow rate: 20mL / min; Gradient: 25B to 25B in 16 minutes; 220 / 254nm; RT1: 10.423 min; RT2: 12.47 min; Injection volume: 0.5mL; Number of runs: 14 was further separated.

[0141] The faster eluting isomeric fractions were collected and concentrated under reduced pressure to give (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol (88 mg, 25.8% yield, R isomer, assumed) as a white solid. Formula:C 21 H 24 F3NO5 Exact mass: 427.16 Molecular weight: 427.42 Analytical data: 1 H NMR (400 MHz, methanol-d4) δ 8.85 (d, J = 5.1 Hz, 1H), 8.09 (s, 1H), 7.87-7.86 (m, 2H), 7.60 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 4.23 (dd, J = 10.2 Hz, 2.6 Hz, 1H), 4.11 (t, J = 2.9 Hz, 1H), 3.82 (dd, J = 8.6 Hz, 3.2 Hz, 1H), 3.72 (t, J = 8.6 Hz, 1H), 3.56-3.52 (m, 2H), 3.40 (dd, J = 11.6 Hz, 2.8 Hz, 1H), 3.23-3.19 (m, 1H), 2.52 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H). ESI-MS [M+Na] + Calc'd for (C 21 H 24 F3NO5Na + ) 450.15, found, 450.10.

[0142] The slower eluting isomeric fractions were collected and concentrated under reduced pressure to give (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((S)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol (7 mg, 2.05% yield, S isomer, assumed) as a white solid. Formula:C21 H 24 F3NO5 correct mass: 427.16 Molecular weight: 427.42 Analysis: 1 H NMR (400 MHz, メタノール-d4) δ 8.87 (d, J = 5.2 Hz, 1H), 8.11 (s, 1H), 7.93-7.92 (m, 2H), 7.60 (d, J = 5.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 4.14 - 4.05 (dd, J = 11.4 Hz, 2.6 Hz, 1H), 3.91 (dd, J = 11.8 Hz, 2.4 Hz, 1H), 3.78 - 3.72 (m, 2H), 3.69 - 3.49 (m, 4H), 2.52 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). ESI-MS [M+H] + Calc'd for (C 21 H 24 F3NO5H + ) 428.17, found, 428.15.

[0143] Example 3

change

[0144] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol

change

[0145]

change

[0146] [ka] 1-(4-Bromo-2-(trifluoromethyl)phenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol To a solution of (4-bromo-2-(trifluoromethyl)phenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone (5.3 g, 6.83 mmol) in tetrahydrofuran (THF) (50 mL) was added methylmagnesium bromide (34.2 mL, 34.2 mmol) at -78 °C. The reaction mixture was then warmed to 25 °C and stirred for 12 h. A sample was taken from the reaction mixture, diluted with MeOH, and subjected to LCMS analysis, which showed the reaction was complete. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue. The residue was dissolved in DCM (40 mL), pre-adsorbed onto silica gel by evaporation, and then purified by silica gel chromatography, eluting with EtOAc in petroleum ether (17%). Fractions with the MS signal of the desired product were collected and concentrated in vacuo to give 1-(4-bromo-2-(trifluoromethyl)phenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (4.8 g, 5.68 mmol, 83% yield) as an orange oil. ESI-MS [M+Na] + Calc'd for (C 43 H 42 BrF3O6Na + ) 813.20, found, 813.

[0147] [ka] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol To a solution of 1-(4-bromo-2-(trifluoromethyl)phenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (3.8 g, 4.80 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.463 g, 5.76 mmol) and potassium acetate (1.413 g, 14.40 mmol) in 1,4 dioxane (40 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.392 g, 0.480 mmol). The reaction mixture was stirred at 80 °C for 16 h, then LCMS analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with brine (40 mL) and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was dissolved in ethyl acetate and pre-adsorbed onto silica gel (4 grams) by evaporation, then the residue was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in petroleum ether as eluent to give the title product. Fractions with the same MS signal were collected and concentrated to give the product 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (3.80 g, 4.00 mmol, 83% yield) as an orange oil. ESI-MS [M+Na] + Calc'd for (C 49 H 54 BF3O8Na + ) 861.38, found 861.

[0148] [ka] 4,4,5,5-Tetramethyl-2-(3-(trifluoromethyl)-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)vinyl)phenyl)-1,3,2-dioxaborolane To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)-1-((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (3.2 g, 3.82 mmol) and TEA (2.127 mL, 15.26 mmol) in DCM (30 mL) was added SOCl3 (0.557 mL, 7.63 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min and LCMS showed the reaction to be complete. The reaction was quenched with water (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product (3.2 g, brown oil). The residue was dissolved in DCM (50 mL), preabsorbed onto silica gel (7 g) by evaporation, loaded onto a column, and then purified by chromatography on silica gel eluting with EtOAc (17%) in petroleum. Fractions with the MS signal of the desired product were collected and concentrated in vacuo to give 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)vinyl)phenyl)-1,3,2-dioxaborolane (2.5 g, 62.4% yield, partially hydrolyzed to the boronic acid) as an orange oil. ESI-MS [M+Na] + Calc'd for (C 49 H 52 BF3O7Na + ) 843.37, found 843.

[0149] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol A mixture of 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)-4-(1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)vinyl)phenyl)-1,3,2-dioxaborolane (2.4 g, 2.92 mmol) and palladium on carbon (1.5 g, 1.410 mmol) in MeOH (15 mL) was stirred at 25° C. The resulting mixture was degassed with hydrogen three times and then stirred under hydrogen (approximately 3 atm) at 25° C. for 11 h. The reaction was monitored by LCMS. LCMS indicated that the benzyl group had been removed but the double bond was still present. The reaction was quenched and resubmitted to the reaction conditions for an additional 12 h. LCMS indicated the reaction was complete. The reaction mixture was filtered through Celite and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title product (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol (1.1 g, 1.071 mmol, 36.6% yield) as a colorless oil. ESI-MS [M+Na] + Calc'd for (C 21 H 30 BF3O7Na + ) 485.19, found, 485.

[0150] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol To a solution of (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol (600 mg, 1.298 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (284 mg, 1.558 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(Ph3P)4 (150 mg, 0.130 mmol) and Cs2CO3 (1269 mg, 3.89 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h. A sample was taken directly from the reaction mixture, diluted with MeOH, and then submitted for LC-MS analysis. LC-MS showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with water (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue. The residue was dissolved in MeOH (3 mL) and then purified by TLC to give the residue (350 mg) as a yellow solid. The solid was then purified by preparative chiral HPLC using: Column: Lux 5 μm Cellulose-4, 5×25 cm, 5 μm; Mobile phase A:; Mobile phase B:; Flow rate: 150 mL / min; Gradient: 0B to 0B (min); 220 nm; RT1: 6.5; RT2: 8.1; Injection volume: 4 mL; Runs: 10 to give (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol (73 mg, 0.150 mmol, 11.54% yield) as a white solid. Formula:C 20 H 20 F6N2O5 Exact mass: 482.13, Molecular weight: 482.38 Analytical data: 1H NMR (400 MHz, CD3OD) δ ppm: 9.36 (s, 1H), 9.09(s, 1H), 8.52(s, 1H), 8.42(d, J = 10Hz, 1H), 7.88(d, J = 8.4Hz, 1H), 4.30(d, J = 10Hz, 1H), 4.10 - 4.11(m, 1H),3.61 - 3.75(m, 3H), 3.47 - 3.53(m, 1H), 3.34(d, J = 2.8Hz, 1H), 3.12 - 3.20(m, 1H), 1.33 (d, J = 6.4Hz, 3H). ESI-MS [M+H] + Calc’d for (C 20 H 20 F6N2O5H + ) 483.14, found, 483.14.

[0151] Example 4 (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol

Chem.

[0152]

Chem.

[0153] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol To a solution of 3-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)phenyl)-5-(trifluoromethyl)pyridine (110 mg, 0.140 mmol) in DCM (5 mL) at -78°C under N2 was added BCl3 (1N solution in DCM, 1.117 mL, 1.117 mmol). The reaction mixture was stirred at -78°C for 1 h under N2. The reaction mixture was quenched with MeOH (5 mL) and concentrated on a rotary evaporator to give a residue. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 30 × 150 mm 5 μm; Mobile phase A: water (10mmol / L NH4HCO3); Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 15B to 38B in 12 minutes; 254 nm; RT1: 11.60; Injection volume: 2.4mL; Number of runs: 2 to afford the title product (25 mg, 0.058 mmol, 42% yield) as a white solid. Formula:C 21 H 24 F3NO5 Exact mass: 427.16 Molecular weight: 427.42 Analytical data: 1H NMR (400 MHz, メタノール-d4) δ 9.08 (d, J = 2.1 Hz, 1H), 8.91 - 8.78 (m, 1H), 8.34 (t, J = 2.2 Hz, 1H), 7.61 - 7.47 (m, 3H), 4.22 (dd, J = 10.2 Hz, 2.6 Hz, 1H), 4.10 (t, J = 3.0 Hz, 1H), 3.82 (dd, J = 8.6 Hz, 3.2 Hz, 1H), 3.72 (t, J = 8.6 Hz, 1H), 3.60-3.52 (m, 2H), 3.42 (dd, J = 11.6 Hz, 2.8 Hz, 1H), 3.24-3.20 (m, 1H), 2.51 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H). ESI-MS [M+H] + Calc'd for (C 21 H 24 F3NO5H + ) 428.17, found, 428.05.

[0154] Example 5

change

[0155] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol

change

[0156]

change

[0157] [ka] (2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-((R)-1-(4-bromo-2-methylphenyl)allyl)tetrahydro-2H-pyran To a solution of (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran (52 g, 93.7 mmol) in ACN (400 mL) was added (3-(4-bromo-2-methylphenyl)allyl)trimethylsilane (53 g, 187 mmol) and TMSOTf (31.2 g, 140.4 mmol) at 25° C. The resulting solution was stirred at 25° C. for 16 h. After completion, the reaction was quenched with water (150 mL). The organic layer was separated. The aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of 0-30% ethyl acetate in petroleum ether as eluent to give the mixture (20 g) as a yellow oil. The mixture was purified by preparative SFC under the following conditions: Column: Phenomenex Lux 5μ Cellulose-3, 5×25 cm, 5 μm; Mobile phase A:CO2:50; Mobile phase B: MeOH-preparative: 50; Flow rate: 150mL / min; 220nm; Further separation at RT=10.32 min with MS signal of the desired product was collected and concentrated in vacuo to give the title compound (5.5 g, 8% yield, minor isomer) as a yellow oil. ESI-MS [M+NH4] + Calc'd for (C 44 H 45 BrO5NH4 + ) 750.28, found, 752.25. 1H NMR (300 MHz, chloroform-d) δ 7.42-7.23 (m, 23 H), 5.76-5.65 (m, 1 H), 4.97 (d, J = 12.0 Hz, 1H), 4.87 - 4.82 (m, 1H), 4.72-4.35 (m, 9H), 3.90-3.84 (m, 4H), 3.76-3.72 (m, 2H), 3.63-3.57 (m, 1H), 2.22 (s, 3H).

[0158] [ka] 4,4,5,5-Tetramethyl-2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)allyl)phenyl)-1,3,2-dioxaborolane To a solution of (2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-((R)-1-(4-bromo-2-methylphenyl)allyl)tetrahydro-2H-pyran (470 mg, 0.64 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (195 mg, 0.77 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2.CH2Cl2 (52 mg, 0.064 mmol), KOAc (188 mg, 1.92 mmol) at 25° C. The reaction mixture was stirred at 80° C. for 16 h. After completion, the reaction mixture was concentrated to give a residue. The residue was dissolved in ethyl acetate, pre-adsorbed onto silica gel by evaporation, loaded onto a column and then purified by silica gel chromatography eluting with EtOAc (17%) in petroleum to give the title product (350 mg, 70% yield) as a yellow oil. ESI-MS [M+Na] + Calc'd for (C 50 H 57 BO7Na + ) 803.42, found, 803.42

[0159] [ka] 4,4,5,5-Tetramethyl-2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)propyl)phenyl)-1,3,2-dioxaborolane To a solution of 4,4,5,5-tetramethyl-2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)allyl)phenyl)-1,3,2-dioxaborolane (1.25 g, 1.6 mmol) in MeOH (30 mL) was added Pd / C (1.25 g) at 25° C. The reaction mixture was then stirred under H2 at 25° C. for 3 h. After completion, the reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was dissolved in DCM (10 mL), pre-adsorbed onto silica gel by evaporation, loaded onto a column, and then purified by silica gel chromatography eluting with a petroleum solution of EtOAc (17%) to give the title product (800 mg, 64% yield) as a colorless oil in 79% purity. ESI-MS [M+Na] + Calc'd for (C 50 H 59 BO7Na + ) 805.44, found, 805.44.

[0160] [ka] 2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)propyl)phenyl)-5-(trifluoromethyl)pyrazine To a solution of 4,4,5,5-tetramethyl-2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)propyl)phenyl)-1,3,2-dioxaborolane (200 mg, 0.26 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added 2-chloro-5-(trifluoromethyl)pyrazine (47 mg, 0.26 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol) and Cs2CO3 (167 mg, 0.51 mmol) at 25 °C. The reaction mixture was then stirred at 80 °C for 1 h under N2. After completion, the reaction was cooled to room temperature and the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with ethyl acetate (19%) in petroleum ether to give the title product (150 mg, 72% yield) as a yellow oil. ESI-MS [M+H] + Calc'd for (C 49 H 49 F3N2O5H + ) 803.36,found, 803.94.

[0161] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol To a solution of 2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)propyl)phenyl)-5-(trifluoromethyl)pyrazine (130 mg, 0.16 mmol) in DCM (5 mL) was added BCl3 (1N in DCM, 1.3 mL, 1.3 mmol) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with MeOH (5 mL) and concentrated to give a residue. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Prep C18 OBD column 19×150mm 5μm; Mobile phase A: water (10mmol / L NH4HCO3); Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 30% B to 45% B in 8 min; 254 nm; Rt:7.87 minutes to afford the desired product (40 mg, 57% yield) as a white solid. Formula:C 21 H 25 F3N2O5 Exact mass: 442.17 Molecular weight: 442.44 Analytical data: 1 H NMR (400 MHz, methanol-d4) δ 9.28 (d, J = 1.5 Hz, 1H), 9.13 - 8.99 (m, 1H), 8.03-8.01 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 4.19 (dd, J = 8.8 Hz, 3.6 Hz, 1H), 3.99-3.98 (m, 1H), 3.84 - 3.69 (m, 2H), 3.63 (dd, J = 11.7 Hz, 5.5 Hz, 1H), 3.50 - 3.35 (m, 2H), 3.28-3.24 (m, 1H), 2.53 (s, 3H), 1.93-1.86 (m, 1H), 1.73-1.65 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H). ESI-MS [M+Na] + Calc'd for (C 21 H 25 F3N2O5Na + ) 465.17, found, 465.

[0162] Example 6 (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)allyl)tetrahydro-2H-pyran-3,4,5-triol [ka]

[0163] [ka] 2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)allyl)phenyl)-5-(trifluoromethyl)pyrazine To a solution of 4,4,5,5-tetramethyl-2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)allyl)phenyl)-1,3,2-dioxaborolane (250 mg, 0.32 mol) in 1,4-dioxane (8 mL) and water (2 mL) was added 2-chloro-5-(trifluoromethyl)pyrazine (59 mg, 0.32 mmol), Pd(PPh3)4 (37 mg, 0.032 mmol) and Cs2CO3 (209 mg, 0.64 mmol) at 25 °C. The reaction mixture was then stirred at 80 °C for 1 h under N2. After completion, the reaction was cooled to 25° C. and the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with ethyl acetate in petroleum ether (14%) to give the title product (250 mg, 97.5% yield) as a yellow oil. ESI-MS [M+Na] + Calc'd for (C 49 H 47 F3N2O5Na + ) 823.33,found, 823.94.

[0164] [ka] (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)allyl)tetrahydro-2H-pyran-3,4,5-triol To 2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)allyl)phenyl)-5-(trifluoromethyl)pyrazine (230 mg, 0.29 mmol) was added BCl3 (1N solution in DCM, 2.3 mL, 2.3 mmol) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with MeOH (5 mL) and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column 30×150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3.H2O); Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 25% B to 51% B in 9 min; 220nm; Rt:7.47 minutes to afford the title product (82 mg, 64% yield) as a white solid. Formula:C 21 H 23 F3N2O5 Exact Mass: 440.16 Molecular Weight: 440.42 Analytical data: 1H NMR (300 MHz, メタノール-d4) δ 9.28 (d, J = 1.4 Hz, 1H), 9.04 (d, J = 1.4 Hz, 1H), 8.06-8.03 (m, 2H), 7.64 - 7.54 (m, 1H), 5.98-5.87 (m, 1H), 5.30 - 5.09 (m, 2H), 4.42 (dd, J = 10.8 Hz, 2.0 Hz, 1H), 4.25 - 4.07 (m, 2H), 3.89 (dd, J = 9.0 Hz, 3.3 Hz, 1H), 3.74 (t, J = 9.1 Hz, 1H), 3.57 (dd, J = 11.7 Hz, 4.8 Hz, 1H), 3.41 (dd, J = 11.7 Hz, 2.8 Hz, 1H), 3.23-3.18 (m, 1H), 2.52 (s, 3H). ESI-MS [M+H] + Calc'd for (C 21 H 23 F3N2O5H + ) 441.16, found, 441.20.

[0165] Example 7

change

[0166] (2R,3S,4R,5S,6R)-2-((S)-1-(4'-chloro-3',5'-difluoro-3-methyl-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

change

[0167]

change

[0168] [ka] (S)-2-(4-bromo-2-methylphenyl)-2-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol To a solution of (S)-3-(4-bromo-2-methylphenyl)-3-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)propane-1,2-diol (125 mg, 0.16 mmol) in THF (1.5 mL) and water (0.6 mL) was added NaIO4 (87 mg, 0.41 mmol). The reaction mixture was stirred at 25 °C for 2 h. After completion, the reaction was quenched with ice water (5 mL) and extracted with DCM (5 mL x 3), the organic phases were combined, washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo (without heating) to give the aldehyde intermediate as a syrup. ESI-MS [M+Na] + Calc'd for (C 43 H 44 BrO6Na + ) 758.22, found, 759.1. After drying, the crude aldehyde was dissolved in DCM (1 mL) under N2 and cooled to 0 °C. DIBAL (1M in hexanes; 0.24 mL, 0.24 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 30 min and then warmed to room temperature overnight. After completion, the reaction mixture was diluted with DCM (5 mL) and carefully quenched by addition of ice. The reaction mixture was washed with [1N] aqueous HCl (5 mL x 3), followed by brine (5 mL x 1), then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of 0-50% ethyl acetate in hexanes as eluent to give the title product (68.3 mg, 56.8% yield). ESI-MS [M+Na] + Calc'd for (C 43 H 45 BrO6Na + ) 759.23, found, 759.1.

[0169] [ka] (S)-2-(4'-chloro-3',5'-difluoro-3-methyl-[1,1'-biphenyl]-4-yl)-2-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol A flask under N2 was charged with a solution of (S)-2-(4-bromo-2-methylphenyl)-2-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (68 mg, 0.093 mol) in 1,4 dioxane (5 mL) and water (1 mL), followed by the sequential addition of (4-chloro-3,5-difluorophenyl)boronic acid (35.6 mg, 0.19 mmol), Cs2CO3 (75.4 mg, 0.23 mmol), and Pd(PPh3)4 (16.0 mg, 0.013 mmol). The reaction was purged with N2 three times and then placed in an oil bath at 80 °C. The reaction mixture was stirred at 80 °C for 2 h. Upon completion, the reaction was cooled to room temperature and concentrated under reduced pressure to give a residue which was partially purified by column chromatography on silica gel using a gradient of 0-50% ethyl acetate in hexanes as eluent to give the title product (72.1 mg, 96.2% yield) as a yellow syrup. ESI-MS [M+Na] + Calc'd for (C 49 H 47 ClF2O6Na + ) 827.29, found, 827.3.

[0170] [ka] (2R,3S,4R,5S,6R)-2-((S)-1-(4'-chloro-3',5'-difluoro-3-methyl-[1,1'-biphenyl]-4-yl)-2-hydroxyethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol To a solution of (S)-2-(4'-chloro-3',5'-difluoro-3-methyl-[1,1'-biphenyl]-4-yl)-2-((2R,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (72.1 mg, 0.90 mmol) and pentamethylbenzene (199 mg, 1.34 mmol) in DCM (1 mL) was added BCl3 (1N solution in DCM, 1.34 mL, 1.34 mmol) dropwise at -78 °C. The resulting solution was stirred at -78 °C for 1 h. Upon completion, the reaction was quenched with MeOH (0.5 mL), brought to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions: Column: Teledyne Isco RediSep Prep C18 column, 20 × 150 mm, 5 μm; Mobile phase A: water (0.05%TFA); Mobile phase B: ACN (0.05%TFA); Flow rate: 18.9mL / min; Gradient: 10% B to 39% B in 35 min; 254 / 214nm; Purification at Rt: 33 min afforded the title compound (16.3 mg, 51.2%) as a white solid. Formula:C 21 H 23 ClF2O6 Exact mass: 444.12 Molecular weight: 444.86 Analytical data: 1 H NMR (400 MHz, methanol-d4) δ 7.60 (d, J = 8.2 Hz, 1H), 7.47-7.36 (m, 4H), 4.34 (t, J = 6.7 Hz, 1H), 3.95-3.78 (m, 4H), 3.74-3.63 (m, 2H), 3.62-3.54 (m, 1H), 3.47-3.40 (m, 2H), 2.48 (s, 3H). ESI-MS [M+H] + Calc'd for (C 21 H 23 ClF2O6Na +) 467.10, found, 467.0.

[0171] Table 1 shows the compounds prepared and the biological and pharmacokinetic data (rats) when tested.

[0172] [Table 1] TIFF0007628506000061.tif209170TIFF0007628506000062.tif218170TIFF0007628506000063.tif209170TIFF0007628506000064.tif208170 [Table 2]

[0173] Protocols Used to Evaluate Compounds of the Invention The activity of the compounds of Examples 1-34 above as FimH antagonists / inhibitors was measured by the following assays and the results are shown in Table 1. No results are shown means that the activity has not yet been tested.

[0174] Hemagglutination Inhibition Assay (HAI) Hemagglutination inhibition (HAI) assays were performed using UTI89 bacteria and guinea pig red blood cells as previously described (SJ Hultgren, WR Schwan, AJ Schaeffer, JL Duncan Infect. Immun. 1986, 54, 613-620 and Jarvis, C.; Han, Z.; Kalas, V.; Klein, R.; Pinkner, JS; Ford, B.; Binkley, J.; Cusumano, CK; Cusumano, Z.; Mydock-McGrane, L.; Hultgren, SJ; Janetka, JW, ChemMedChem 2016, 11, 367-373). Results are shown in Table 1. Values ​​not listed were not tested.

[0175] A common assay to obtain AUC(oral)h μM, %F and Ue%PO values 1.1.Animals Male Wistar Han rats were purchased from Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). The animals were approximately 6-8 weeks old and weighed 200-300 g on the day of dosing. The animals were housed in a 12-h light / 12-h dark cycle environment and had free access to food and water. All animals were fed prior to dosing. The study was approved by the Pharmaron Institutional Animal Care and Use Committee (IACUC).

[0176] Study Design Male Wistar Han rats (n=3 per dose group) were assigned to groups as shown in the table below. Test articles were administered via intravenous infusion at 5 mL / kg / h for 1 hour (1 mg / kg). After 48 hours, animals received a single oral dose (5 mg / kg, free form) at a dose of 10 mL / kg each. Blood samples were taken at various time points after IV infusion and PO administration. Urine samples were taken (for some compounds) at various time points after IV infusion and PO administration.

[0177] [Table 3]

[0178] 1.3. Preparation of Formulations Preparation of Drug Dosage for IV Infusion Administration (1 mg / kg) The test article was dissolved in DMSO by vortexing and sonication to obtain a stock solution, and an aliquot of the stock solution was mixed with 10% HR-β-CD saline solution with vortexing to obtain a solution of the test article at a concentration of 0.2 mg / mL.

[0179] Preparation of Dosage Form for PO Administration (5 mg / kg) The test article was added to 1% methylcellulose, vortexed and sonicated to obtain a homogenous suspension of test article at a concentration of 0.5 mg / mL.

[0180] 1.4.Sample Collection Blood samples For IV infusion (1 mg / kg) dosing, blood samples were taken from each animal at 0, 0.25, 0.5, 0.75, 1, 1.08, 1.25, 1.5, 1.75, 2, 3, 5, 8, 12, and 24 hours after dosing.

[0181] For PO (5 mg / kg) dosing, blood samples were taken from each animal at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing.

[0182] Blood samples (50 μL) were taken from each animal via the jugular vein. These blood samples were placed in tubes containing K2EDTA. Whole blood was mixed with an equal volume of water and inverted several times. Blood samples were stored at -75±15°C until analysis.

[0183] Urine sample For IV infusion (1 mg / kg) administration, urine samples were collected from each animal at 0–4, 4–8, 8–12, and 12–24 hours after dosing.

[0184] For PO (5 mg / kg) dosing, urine samples were collected from each animal (for some compounds) at 0–4, 4–8, 8–12, and 12–24 hours after dosing.

[0185] Urine samples were collected continuously at intervals outlined below into containers kept on dry ice and stored at −80°C prior to analysis.

[0186] 1.5. Preparation of standard solutions for LC-MS / MS analysis The 10 mg / mL test article stock was diluted in DMSO to give a 1 mg / mL standard stock solution (free form).

[0187] Calibration standard solutions at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10000 ng / mL were prepared by serial dilution of the standard stock solution with 50% acetonitrile in water. Quality control standard solutions at concentrations of 10, 500, and 8000 ng / mL were prepared by serial dilution of the standard stock solution with 50% acetonitrile in water. These QC samples were prepared on the day of analysis in the same manner as the calibration standard solutions.

[0188] 1.6. Sample Processing 5 μL of each of the calibration standard solutions (5, 10, 20, 50, 100, 500, 1000, 5000 and 10000 ng / mL) was added to 50 μL of blank Wistar Han blood (blank blood: water = 1:1). Alternatively, in the case of urine, calibration standard solutions of 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) were used in a total volume of 55 μL. Quality control (QC) samples of 1 ng / mL (low), 50 ng / mL (medium), and 800 ng / mL (high) were prepared for blood or urine separately from the samples used for the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standard solutions.

[0189] 55 μL of standard solution, 55 μL of QC sample or 55 μL of unknown sample (50 μL of blood or urine and 5 μL of 50% acetonitrile) were mixed with 200 μL of acetonitrile containing IS (dexamethasone) to precipitate proteins. The samples were then vortexed for 30 s. After centrifugation at 4700 rpm for 30 min at 4 °C, 5 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis.

[0190] 1.7. Pharmacokinetic Analysis Blood and urinary concentrations of the test article for each animal following 1 mg / kg IV infusion and 5 mg / kg PO were used to calculate pharmacokinetic parameters by non-compartmental analysis (Phoenix™ WinNonlin® 7.0). A linear trapezoidal algorithm was used to calculate the AUC. AUC(oral)h μM: Area under the curve of blood drug concentration vs. time after oral administration (AUC: area under the curve) (unit: h μM) %F: oral bioavailability (%) derived from the ratio of dose-normalized AUC after PO and IV administration Ue%PO: Percentage of the oral dose excreted unchanged in urine, or an estimate of that parameter generated using the percentage of the iv dose excreted in urine multiplied by the oral bioavailability

[0191] From the above description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to adapt the present invention to various usages and conditions without departing from the spirit and scope thereof.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, Z is, 【Chemistry 2】 and Q is CF ３ , C.H. ３ or Cl, R is C １－３ is alkyl or vinyl; R ４ is H or F, Y 1 is N or CR 1B , Y 2 and Y 3 are selected from the group consisting of N or CH, with the proviso that at least one of Y 1 , Y 2 and Y 3 is N; R 1A and R 1B are independently selected from the group consisting of H, F, Cl, CF 3 , cyclopropyl, --(CO)--NH--CH 3 and cyano, with the proviso that when Y 1 is CR 1B , then one of R 1A and R 1B is H. or a pharma- ceutically acceptable salt thereof.

2. Y １ and Y ３ is N, Y ２ is CH, R １Ａ is cyclopropyl or -CF ３ 2. The compound of claim 1, wherein:

3. Y ３ is N, Y ２ is CH, Y １ is CR １Ｂ and R １Ａ and R １Ｂ One of the groups is H and the other is -CF ３ or cyano, or a pharma- ceutically acceptable salt thereof.

4. Q is CH ３ and R ４ is H or Q is CF ３ and R ４ or H. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. Q is CH ３ and R ４ or a pharma- ceutically acceptable salt thereof.

6. 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein R is methyl or vinyl.

7. 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R is methyl.

8. The following compound: (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol; and (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)allyl)tetrahydro-2H-pyran-3,4,5-triol 2. The compound of claim 1, selected from the group consisting of:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

11. 11. A medicament according to claim 9 or a pharmaceutical composition according to claim 10 for use in the treatment of bacterial infections, Crohn's disease (CD) and inflammatory bowel disease (IBD).

12. The medicament or pharmaceutical composition according to claim 11, wherein the bacterial infection is an antibiotic-resistant bacterial infection.

13. 12. The medicament or pharmaceutical composition according to claim 11, wherein the bacterial infection is a urinary tract infection (UTI).

14. 14. The medicament or pharmaceutical composition of claim 13, wherein the urinary tract infection is recurrent.

15. 14. The medicament or pharmaceutical composition of claim 13, wherein the urinary tract infection is chronic.

16. Use of a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament or pharmaceutical composition according to any one of claims 9 to 15.

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