Novel compounds

Abstract

Disclosed herein are novel C-mannoside compounds and compositions and their use as medicaments for the treatment of human diseases. Also provided are methods of inhibiting FimH activity in a human subject to treat diseases such as urinary tract infections.

Description

[0001] This application is a divisional application based on a patent application with an application date of May 6, 2020, application number 202080034020.4 (PCT / EP2020 / 062501), and invention name: "New Compounds". Technical Field

[0002] Disclosed herein are novel C-mannoside compounds and compositions and their use as medicaments for treating human diseases. Also provided are methods of inhibiting FimH activity in human subjects for treating diseases (eg, urinary tract infections). Background Art

[0003] Urinary tract infection (UTI) is one of the most common infectious diseases in women. The morbidity and economic impact are huge, with more than $2.5 billion spent on treatment each year. In addition, despite appropriate antibiotic therapy for patients with initial infection, recurrent infection remains a major problem. Women presenting with an initial episode of acute UTI have a 25-44% chance of developing a second episode within six months of the initial UTI, and a 3% chance of experiencing a third episode. In addition, resistance to antibiotics that are commonly prescribed for the treatment or prevention of UTIs is spreading rapidly among urinary tract pathogens, which exacerbates the need for new restrained antibiotic therapies and new effective antibiotic-enabling therapies.

[0004] 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 critical interaction between host ligands (usually polysaccharide moieties) and bacterial adhesins (usually expressed at the distal tip of polymeric fimbriae fibers assembled via the chaperone-usher pathway). Animal models of UTI have revealed that the mannose-binding FimH adhesin of type 1 fimbriae is essential for colonization and invasion of UPEC and other uropathogenic members of the Enterobacteriaceae family (such as Klebsiella species, Enterobacter species, and Citrobacter species) into the bladder epithelium.

[0005] Type 1 pili are anchored to the outer membrane of the bacterium and are composed mostly of repeating FimA protein subunits that form a helically wound cylinder containing a thick pilus shaft. The distal FimH adhesin protein is connected to the pilus shaft by a flexible top fiber composed of one copy each of FimF and FimG. The adhesin tip protein FimH is a two-domain protein consisting of a pilin domain (FimH) that allows it to bind to the pilus. P) and a lectin domain containing a conserved mannose-binding pocket (FimH L ). The X-ray crystal structure of FimH bound to mannose shows that mannose is bound in a negatively charged pocket on FimH. The mannose binding site is highly conserved as it is invariant in 300 fimH genes sequenced from clinical UPEC strains. It is believed that it is the interaction of FimH with mannosylated host proteins that mediates colonization of the lower urinary tract by UPEC and other Enterobacteriaceae during UTI.

[0006] In order to elucidate the molecular details of UPEC pathogenesis, several murine infection models that reproduce many of the clinical manifestations commonly seen in humans have been established. These models include acute UPEC infection, chronic and / or recurrent infection, and UTI associated with indwelling urinary catheters. In all of these models, the adhesin FimH has been shown to play an integral role in pathogenesis, highlighting its potential as a good therapeutic target. The fundamental interaction between FimH and the host is thought to occur through binding to high-mannose-containing glycans such as urolysin and other proteins expressed on the surface of bladder epithelial cells that coat the luminal surface of the bladder. This initial binding facilitates bacterial colonization in the bladder epithelium and invasion into bladder epithelial cells. Once internalized, individual bacteria that escape into the host cytoplasm can rapidly replicate and develop into biofilm-like intracellular bacterial communities (IBCs). Once these communities mature, they are able to spread and escape from the cell, forming filaments to evade phagocytosis by neutrophils. These filamentous bacteria can then proceed to infect neighboring cells, restarting the IBC formation and pathogenicity cycle. Importantly, evidence of IBC and bacterial filament formation has been observed in the urine of women with acute UTI, supporting the validity of the described mouse model in recapitulating human disease.

[0007] In contrast to UTIs, which are primarily mediated by bacterial pathogens, disease symptoms in patients with idiopathic inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), are the result of a complex interaction between a genetically susceptible host, a dysregulated immune system, and microbial components. Biopsies from patients with CD and UC clearly demonstrate an increased abundance of Escherichia coli associated with the intestinal mucosa. Analysis of these bacteria has revealed a distinct pathotype termed adherent-invasive E. coli (AIEC), although a subset of these strains appear genomically similar to UPEC. The identification of AIEC and its putative role in CD and UC has prompted a number of follow-up studies by several independent groups that have examined the gut microbiota in patients with IBD. This work has provided substantial evidence for the overgrowth of AIEC in patients with ileal CD, but less convincing data are available for other IBD subtypes, including UC, colonic CD, and ileocolonic CD. Analysis of ileal enterocytes isolated from CD patients identified aberrant expression of the host receptor carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which is highly mannosylated and has been shown to promote AIEC binding to these cells via type 1 fimbriae. Interestingly, AIEC adhesion to and invasion into enterocytes resulted in increased expression of the receptor CEACAM6, suggesting that AIEC are able to promote their own ileal colonization in CD patients. The use of transgenic mice expressing the human CEA family gene cluster, including CEACAM6, resulted in increased AIEC colonization, which reproduced many of the clinical symptoms of CD, including severe colitis, weight loss, and reduced survival in this model. Furthermore, these symptoms were completely abolished by administration of anti-CEACAM6 antibodies or by genetic deletion of FimH in bacterial strains, demonstrating a direct link between FimH recognition of CECAM6 and disease progression. Therefore, therapies targeting FimH in AIEC may be of great benefit in alleviating symptoms in CD patients. Summary of the invention

[0008] Novel compounds and pharmaceutical compositions that inhibit FimH have been discovered, as well as methods of synthesizing and using these compounds, including methods of treating FimH-mediated diseases in patients by administering the compounds.

[0009] More specifically, in one embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in

[0012] Z is

[0013]

[0014] n = 1 to 3;

[0015] Q is CF3, CH3 or Cl;

[0016] 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;

[0017] 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 (optionally substituted with up to 7 fluorine atoms, up to 1 hydroxyl group, up to 1 -N(C 1-6 alkyl)2, and up to 1 -OC 1-6 alkyl), up to 1 -(CO)-NH-CH3, or up to 1 cyano; provided that R 2 It cannot all be H at the same time;

[0018] R 4 is H or F;

[0019] R' is independently H or C 1-6 Alkyl (optionally substituted with up to 7 fluorine atoms);

[0020] Y is independently CH, N, or, if the structure of Z permits, CR1, provided that all Y cannot be CH at the same time; and

[0021] m=1 to 3.

[0022] In one embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:

[0023]

[0024] in

[0025] Z is

[0026]

[0027] n = 1 to 3;

[0028] Q is CF3, CH3 or Cl;

[0029] 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;

[0030] 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 (optionally substituted with up to 7 fluorine atoms, up to 1 hydroxyl group, up to 1 -N(C 1-6 alkyl)2, and up to 1 -OC 1-6 alkyl), up to 1 -(CO)-NH-CH3, or up to 1 cyano; provided that R 2 It cannot all be H at the same time;

[0031] R 4 is H or F;

[0032] R' is independently H or C 1-6 Alkyl (optionally substituted with up to 7 fluorine atoms);

[0033] Y is independently C, CH or N, provided that all Y cannot be CH at the same time; and

[0034] m=1 to 3.

[0035] For the avoidance of doubt, the following general formula (I):

[0036]

[0037] It can also be expressed as follows

[0038]

[0039] Furthermore, for the avoidance of doubt, the substituent R 1 , R 2 and R 3 Can be independently selected from: H, 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 1-6 Alkyl, wherein the C1-6 The alkyl group is optionally substituted with up to 7 fluorine atoms, up to 1 hydroxyl group, up to 1 -N(C 1-6 alkyl)2, and up to 1 -OC 1-6 Alkyl, provided that at least one R2 group is not H, and provided that only one R2 group may be -(CO)-NH-CH3 or cyano.

[0040] 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.

[0041] 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.

[0042] In one embodiment, R is C 1-3 Alkyl, phenyl, -(CH2) m -OH, cyclopropyl, ethynyl, or vinyl.

[0043] In one embodiment, R is methyl, ethyl, isopropyl, phenyl, -(CH2) m -OH, cyclopropyl, ethynyl, or vinyl.

[0044] In one embodiment, R is methyl or vinyl.

[0045] In one embodiment, R is methyl.

[0046] In one embodiment, Q is CF3 or CH3. In one embodiment, Q is CH3. In one embodiment, R 4 For H.

[0047] 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 For H.

[0048] In one embodiment, R 1 is F, cyclopropyl, -CF3 or cyano. In one embodiment, R 1 is cyclopropyl, -CF3 or cyano. In one embodiment, R 1 It is -CF3.

[0049] In one embodiment, R 2 are independently -CF3, -F, -Cl, -Br, cyano, -(CO)-NH-CH3, -CH2-CH2-OH, hydrogen or cyclopropyl; provided that R 2 It can't be all hydrogen at the same time.

[0050] In one embodiment, R 2 is independently -F, -Cl, cyano or -(CO)-NH-CH3. In one embodiment, R 2 is F or Cl.

[0051] In one embodiment, R 3 is F, Cl or Br. In one embodiment, R 3 For F.

[0052] In one embodiment, Z is:

[0053]

[0054] Where Y1 is N or CR 1B , and Y2 and Y3 are selected from N or CH, provided that at least one of Y1, Y2 and Y3 is N; and

[0055] Where R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B Independently selected from: H, 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 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with up to 7 fluorine atoms, up to 1 hydroxyl group, up to 1 -N(C 1-6 alkyl)2, and up to 1 -OC 1-6 Alkyl, provided that:

[0056] When Y1 is CR 1B When R 1A and R 1B One of them is H;

[0057] R 3A and R 3B One of them is H;

[0058] R 2A , R2B and R 2C At least one of is not H; and

[0059] R 2A , R 2B and R 2C Only one of them can be -(CO)-NH-CH3 or cyano.

[0060] In one embodiment, R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B are independently selected from: H, F, Cl, CF3, cyclopropyl, -(CO)-NH-CH3 and cyano, provided that:

[0061] When Y1 is CR 1B When R 1A and R 1B One of them is H;

[0062] R 3A and R 3B One of them is H;

[0063] R 2A , R 2B and R 2C At least one of is not H; and

[0064] R 2A , R 2B and R 2C Only one of them can be -(CO)-NH-CH3 or cyano.

[0065] In one embodiment, Z is:

[0066]

[0067] Among them, Y1, Y2, Y3, R 1A , R 2A , R 2B and R 2C As defined herein.

[0068] In one embodiment, Z is:

[0069]

[0070] Among them, Y1, Y2, Y3 and R 1A As defined herein.

[0071] In one embodiment, Y1 and Y3 are N, and Y2 is CH. In a specific embodiment, when Y1 and Y3 are N and Y2 is CH, R 1A is selected from F, cyclopropyl, -CF3 or cyano. In one embodiment, R 1A is cyclopropyl or -CF3. In one embodiment, R 1A It is -CF3.

[0072] In an alternative embodiment, Y3 is N, Y2 is CH, and Y1 is CR 1B In a specific embodiment, when Y3 is N, Y2 is CH, and Y1 is CR 1B When R 1A and R 1B One of them is H, and the other is selected from F, cyclopropyl, -CF3 or cyano. In one embodiment, R 1A and R 1B One of them is H, and the other is selected from cyclopropyl, -CF3 or cyano. In one embodiment, R 1A and R 1B One of them is H, and the other is selected from -CF3 or cyano. In one embodiment, R 1A is H, and R 1B In another embodiment, R 1A is -CF3, and R 1B For H.

[0073] In another embodiment, Y3 is CH, Y2 is N, and Y1 is CR 1B , R 1A and R 1B One of them is H, and the other is selected from F, cyclopropyl, -CF3 or cyano. In one embodiment, R 1A and R 1B One of them is H, and the other is selected from F, -CF3 or cyano. In one embodiment, R 1A is selected from F, -CF3 or cyano, and R 1B For H.

[0074] In one embodiment, Y2 and Y3 are N, and Y1 is CR 1B , R 1A and R 1B One of them is H, and the other is selected from F, cyclopropyl, -CF3 or cyano. In one embodiment, R 1A and R 1B One of them is H, and the other is selected from F, -CF3 or cyano. In one embodiment, R 1A and R 1BOne of them is H, and the other is -CF3. In one embodiment, R 1A is -CF3, and R 1B For H.

[0075] In one embodiment, Z is:

[0076]

[0077] Where R 2A , R 2B and R 2C As defined herein.

[0078] In one embodiment, R 2A , R 2B and R 2C are independently selected from: H, F, Cl, CF3, cyclopropyl, -(CO)-NH-CH3 and cyano, provided that R 2A , R 2B and R 2C At least one of them is not H, and the condition is R 2A , R 2B and R 2C Only one of them can be -(CO)-NH-CH3 or cyano.

[0079] In one embodiment: R 2A is selected from the group consisting of: H, F, CN and -(CO)-NH-CH3; R 2B is selected from H, CN and Cl; and R 2C Selected from F and H; provided that R 2A , R 2B and R 2C At least one of them is not H, and the condition is R 2A , R 2B and R 2C Only one of them can be cyano.

[0080] In one embodiment: R 2A F or CN, R 2B is selected from H and Cl, and R 2C is selected from F and H. In a more specific embodiment, R 2A For F, R 2B is selected from H and Cl, and R 2C is selected from F and H. In a more specific embodiment, R 2A For F, R 2B is selected from H and Cl; and R 2C In a more specific embodiment, R 2A For F, R 2B is Cl, and R 2C For F.

[0081] In one embodiment, Z is:

[0082]

[0083] In one embodiment, Z is:

[0084]

[0085] Where R 3A and R 3B One of them is H, and the other is independently selected from 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 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with up to 7 fluorine atoms, up to 1 hydroxyl group, up to 1 -N(C 1-6 alkyl)2, and up to 1 -OC 1-6 alkyl.

[0086] In one embodiment, R 3A and R 3B One of them is H, and the other is independently selected from F, Cl, CF3. In one embodiment, R 3A is H, and R 3B In one embodiment, R 3A is H, and R 3B In another embodiment, the present invention relates to a compound of formula I

[0087] in

[0088] Z is

[0089]

[0090] n = 1 to 3;

[0091] Q is CF3 or CH3;

[0092] R is C 1-3 Alkyl, phenyl, -(CH2) m -OH, cyclopropyl, ethynyl or vinyl;

[0093] R 1 is cyclopropyl, -CF3 or cyano;

[0094] R 2are independently -CF3, -F, -Cl, -Br, cyano, -(CO)-NH-CH3, -CH2-CH2-OH, hydrogen or cyclopropyl; provided that R 2 It cannot be all hydrogen at the same time;

[0095] R 3 is -F, -Cl or -Br;

[0096] R 4 is H or F;

[0097] Y is independently C, CH or N, provided that all Y cannot be CH at the same time; and

[0098] m is 1 to 3.

[0099] In another embodiment, the present invention relates to a compound of formula I

[0100] Where Z is:

[0101]

[0102] Where Y1 is N or CR 1B , and Y2 and Y3 are selected from N or CH, provided that at least one of Y1, Y2 and Y3 is N; and

[0103] Where R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B are independently selected from: H, F, Cl, CF3, cyclopropyl, -(CO)-NH-CH3 and cyano, provided that:

[0104] When Y1 is CR 1B When R 1A and R 1B One of them is H;

[0105] R 3A and R 3B One of them is H;

[0106] R 2A , R 2B and R 2C At least one of is not H; and

[0107] R 2A , R 2B and R 2C Only one of them may be -(CO)-NH-CH3 or cyano; and

[0108] wherein R is methyl or vinyl; and

[0109] Q is CH3, and R 4 is H, or Q is CF3, and R 4 For H.

[0110] In a more specific embodiment, Q is CH3, and R 4 For H.

[0111] In a more specific embodiment, R is methyl.

[0112] In one embodiment, the present invention provides a compound selected from the group consisting of:

[0113] (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;

[0114] (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;

[0115] (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;

[0116] (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;

[0117] (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;

[0118] (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;

[0119] (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;

[0120] or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0122] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0123] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0124] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0125] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0126] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0127] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which compound 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.

[0128] In another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt as a medicament.

[0129] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy.

[0130] In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing a disease or condition improved by inhibiting the function or activity of FimH. In a more specific embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or condition improved by inhibiting the function or activity of FimH.

[0131] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or condition improved by inhibiting the function or activity of FimH. In a more specific embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition improved by inhibiting the function or activity of FimH.

[0132] In another embodiment, the present invention provides a method of treating a FimH-mediated disease, comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, the disease or disorder is a bacterial infection, Crohn's disease (CD), or inflammatory bowel disease (IBD).

[0134] In one embodiment, the bacterial infection is an antibiotic resistant bacterial infection.

[0135] In one embodiment, the disease is Crohn's disease.

[0136] In one embodiment, the disease is inflammatory bowel disease.

[0137] In one embodiment, the bacterial infection is a urinary tract infection (UTI), including cystitis and pyelonephritis infections.

[0138] In one embodiment, the urinary tract infection is recurrent.

[0139] In one embodiment, the urinary tract infection is chronic.

[0140] In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing UTI. In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating UTI.

[0141] In another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt in the preparation of a medicament for treating or preventing UTI. In another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt in the preparation of a medicament for treating UTI.

[0142] In another embodiment, the present invention provides a method of treating a urinary tract infection (UTI) comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0143] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0144] In one embodiment, the pharmaceutical composition is formulated for oral (PO) administration.

[0145] In one embodiment, the pharmaceutical composition is selected from the group consisting of tablets and capsules.

[0146] In one embodiment, the pharmaceutical composition is formulated for topical administration.

[0147] In another embodiment, the present invention provides a method for treating a FimH-mediated disease, the method comprising the step of administering:

[0148] a. a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and

[0149] b. Another therapeutic agent.

[0150] In another embodiment, the present invention provides a combination of a compound of formula I or a pharmaceutically acceptable salt and another therapeutic agent. DETAILED DESCRIPTION OF THE INVENTION

[0152] definition

[0153] The term "C 1-6 "Alkyl", as used herein alone or in combination, refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms. 1-6Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like.

[0154] The term "C 3-6 "Cycloalkyl", as used herein, alone or in combination, refers to a saturated monocyclic alkyl group, wherein each ring portion contains 3 to 6 ring carbon atom members. Examples are cyclopropyl (cPr), cyclopentyl (cPe), cyclobutyl (cBu) and cyclohexyl (cHex).

[0155] The term "C 2-6 "Alkenyl," as used herein, 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).

[0156] The term "C 2-6 "Alkynyl," as used herein, 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 acetylene) and propynyl (or propyne).

[0157] As used herein, the term "heteroaryl", used alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic or tricyclic ring system, wherein at least one fused ring is aromatic, comprising at least one atom selected from N, O and S. In certain embodiments, the heteroaryl will comprise 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl will comprise 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl will comprise 5 to 7 atoms. The term also includes fused polycyclic groups, wherein a heterocyclic ring is fused to an aromatic ring, wherein a heteroaromatic ring is fused to other heteroaromatic rings, wherein a heteroaromatic ring is fused to a heterocycloalkyl ring, or wherein a heteroaromatic ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolyl, tetrazolopyridazinyl, tetrahydroisoquinolyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0158] The term "aryl" as used herein, alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings, wherein such multiple ring systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthrenyl.

[0159] The term "optionally substituted" means that the preceding group may be substituted or unsubstituted. When the optionally substituted group is not specifically named, the substituents of the "optionally substituted" group may include one to three substituents independently selected from the following groups or selected from the following specific designated groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, phenyl, cyano, chloro, fluoro, bromo, amido, nitro, -SH, SCH3, -C(O)CH3, -CO2H, aryl or heteroaryl.

[0160] Asymmetric centers exist in the compounds of Formula I. It is to be understood that the present invention encompasses compounds having the absolute configuration shown in Formula I.

[0161] Due to their potential use in medicine, the salts of the compounds of formula I are preferably pharmaceutically acceptable salts. Therefore, the salts mentioned are pharmaceutically acceptable salts. "Pharmaceutically acceptable" refers to compounds (including salts), materials, compositions and dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation or other problems or complications within the scope of reasonable medical judgment, and they have a reasonable benefit / risk ratio. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse in J. Pharm. Sci (1977) 66, pp 1-19 or those listed in Handbook of Pharmaceutical Salts edited by PHStahl and CG Wermuth; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html ).

[0162] When the compound of the present invention is a base (contains a basic moiety), the desired salt form can be prepared by any suitable method known in the art, including treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or treating the free base with 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, pyranosidic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propionates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetate, phenylpropionate, phenylbutyrate, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and naphthalene-2-sulfonates.

[0163] If a basic compound of the invention is isolated as a salt, the corresponding free base form of the compound may be prepared by any suitable method known in the art comprising treating the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound.

[0164] When the compound of the present invention is an acid (contains an acidic moiety), the desired salt can be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines (such as ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine and piperazine); and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0165] Some of the compounds of the present invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0166] Because the compounds of the present invention can contain both acid and base moieties, pharmaceutically acceptable salts can be prepared by treating these compounds with alkaline agents or acid reagents, respectively. Therefore, the present invention also provides a pharmaceutically acceptable salt (e.g., hydrochloride) of the compounds of the present invention converted into another pharmaceutically acceptable salt (e.g., sodium salt or disodium salt) of the compounds of the present invention.

[0167] Because the compounds of the present invention are intended for use in pharmaceutical compositions, it will be readily appreciated that each of them is preferably provided in a substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, preferably at least 85% pure, especially at least 98% pure (% on a weight / weight basis). Such impure preparations of the compounds may be used to prepare more pure forms for use in pharmaceutical compositions.

[0168] The term "combination" refers to the administration of two or more therapeutic agents to treat the conditions or disorders to be treated as described herein. The administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients or in a plurality of separate capsules for each active ingredient. In addition, the administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen provides a beneficial effect of the drug combination in treating the conditions or disorders described herein.

[0169] As used herein, "FimH inhibitor" or "FimH antagonist" refers to a compound that has an HAI (hemagglutination inhibition assay) titer or EC>90 for FimH function / activity of no greater than about 100 μM, and more typically no greater than about 50 μM, as measured in the FimH hemagglutination assay (HA) generally described herein. "HAI titer or EC>90" is the concentration of FimH inhibitor / antagonist that can reduce bacterial agglutination of guinea pig erythrocytes by more than 90%. It has been found that certain compounds disclosed herein exhibit inhibition of the FimH function / activity. In certain embodiments, the compounds exhibit an EC>90 of no more than about 10 μM for FimH; in further embodiments, the compounds exhibit an EC>90 of no more than about 1 μM for FimH; in additional embodiments, the compounds exhibit an EC>90 of no more than about 250 nM for FimH; in additional embodiments, the compounds exhibit an EC>90 of no more than about 100 nM for FimH; in additional embodiments, the compounds exhibit an EC>90 of no more than about 50 nM for FimH; in additional embodiments, the compounds exhibit an EC>90 of no more than about 10 nM for FimH, as measured in the FimH assay described herein.

[0170] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or condition or to produce a clinical endpoint.

[0171] As used herein, "treating" with respect to a disorder means: (1) ameliorating or preventing the disorder or one or more biological manifestations of the disorder, (2) interfering with: (a) one or more points in the biological cascade leading to the disorder or causing the disorder; or (b) one or more biological manifestations of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

[0172] In one embodiment, the term "treating" with respect to a disorder means: (1) ameliorating the disorder or one or more biological manifestations of the disorder, (2) interfering with: (a) one or more points in the biological cascade leading to the disorder or causing the disorder; or (b) one or more biological manifestations of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

[0173] Prevention of a disease may involve complete freedom from the disease, such as in the case of preventing infection with a pathogen, or may involve prevention of progression of the disease. For example, prevention of a disease may not mean complete elimination of any effects associated with any level of the disease, but may mean preventing 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.

[0174] The term "patient" is generally synonymous with the term "subject" and includes all mammals (including humans). Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and pets (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0175] Although the compounds of the present invention may be administered as raw chemicals, they may also be presented in the form of pharmaceutical preparations (or alternatively referred to as pharmaceutical compositions). Therefore, pharmaceutical preparations are provided herein, which contain one or more compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides or solvates thereof, and one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. In terms of being compatible with the other ingredients of the preparation and harmless to the recipient, the carrier must be "therapeutically acceptable". Appropriate preparations depend on the selected route of administration. Any of any of the known techniques, carriers and excipients may be used appropriately as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or tableting methods.

[0176] 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 skin, buccal, sublingual and intraocular) administration, but the most suitable route may depend on, for example, the condition and disorder of the recipient. The formulations can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical art. Generally, these methods include the step of combining the compound of the present invention or its pharmaceutically acceptable salt, ester, amide, prodrug or solvate ("active ingredient") with a carrier constituting one or more auxiliary ingredients. Generally, the formulation is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0177] As used herein, the term "compound of the present invention" refers to a compound of Formula I in any form, i.e., any salt or non-salt form thereof (e.g., as a free acid or base form, or a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms) and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi-hydrates)), as well as mixtures of various forms.

[0178] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; 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 may also be presented as a bolus, electuary or paste.

[0179] Pharmaceutical preparations that can be used orally include tablets, push fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). The tablets can be made by compression or molding, optionally containing one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, an inert diluent or lubricant, a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets can be optionally coated or scored, and can be formulated so that the active ingredient therein can be slowly or controlled released. All oral formulations should be in a dosage suitable for such administration. The push-in capsules can contain active ingredients mixed with fillers (such as lactose), binders (such as starches) and / or lubricants (such as talc or magnesium stearate) and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added. The lozenge core has a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally include gum arabic, talcum powder, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. Dye or pigment can be added to tablets or lozenge coatings to identify or characterize the different combinations of active compound dosage.

[0180] The compound can be formulated for parenteral administration by injection (e.g., push injection or continuous infusion). Injectable preparations can be present in unit dosage form, for example, in ampoules with preservatives added or in multi-dose containers. The composition can take the form of a suspension, solution or emulsion such as in an oily or aqueous vehicle, and can include preparatons, such as suspending agents, stabilizers and / or dispersants. The preparation can be present in unit dose or multi-dose containers (e.g., sealed ampoules and vials), and can be stored in powder form or stored under freeze drying (lyophilization) conditions (only sterile liquid carriers (e.g., saline or sterile pyrogen-free water) need to be added immediately before use). Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the aforementioned types.

[0181] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions (which may include 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 a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a highly concentrated solution.

[0182] In addition to the preparations described previously, the compound can also be formulated into a depot preparation. Such a long-acting preparation can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or formulated as a slightly soluble derivative, for example, as a slightly soluble salt.

[0183] For buccal or sublingual administration, the composition may be formulated in conventional manner in the form of tablets, lozenges, pastilles or gels. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0184] The compounds may 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.

[0185] Certain compounds disclosed herein can be administered topically, i.e., by non-systemic administration. This includes applying a compound disclosed herein externally to the epidermis or oral cavity and instilling the compound into the rectum, lungs, vaginal cavity, ears, eyes, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0186] Preparations suitable for topical application include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for application to eyes, ears or noses. The active ingredient for topical application can account for, for example, from 0.001% to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient can account for up to 10% w / w. In other embodiments, it can account for less than 5% w / w. In certain embodiments, the active ingredient can account for from 2% w / w to 5% w / w. In other embodiments, it can account for from 0.1% to 1% w / w of the preparation.

[0187] For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack or other convenient delivery device for delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present invention may take the form of a dry powder composition, such as a powder mixture of the compound and a suitable powder base (such as lactose or starch). The powder composition may be presented in a unit dosage form, such as a capsule, cartridge, gelatin or blister pack, from which the powder can be administered by means of an insufflator or insufflator.

[0188] Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.

[0189] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0190] The compound can be administered orally or by injection at a dosage of 0.1 to 500 mg / kg per day. The dosage range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units can conveniently contain a certain amount of one or more compounds, which are effective at this dosage or multiple dosages, for example, comprising 5 mg to 500 mg, typically a unit of 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).

[0191] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0192] The compound can be administered in various ways, for example, orally, topically or by injection. The exact amount of the compound administered to the patient is determined by the attending physician. The specific dosage level for any particular patient will depend on a variety of factors, including 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 treated, and the severity of the indication or condition treated. Similarly, the administration route may vary depending on the condition and its severity.

[0193] In some cases, at least one compound described herein (or a pharmaceutically acceptable salt, ester or prodrug thereof) may be appropriately administered in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds herein is hypertension, an antihypertensive agent may be appropriately administered in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant itself has only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit brought to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit. By way of example only, in the treatment of urinary tract infection involving the administration of one of the compounds described herein, the increased therapeutic benefit may also be obtained by providing the patient with another therapeutic agent for urinary tract infection. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be a simple sum of the two therapeutic agents, or the patient may experience a synergistic benefit of the two therapeutic agents.

[0194] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms (as a single pill or as two separate pills, by way of example only). One of the therapeutic agents can be administered in multiple doses, or both can be administered in multiple doses. If not administered simultaneously, the time interval between multiple doses can be any duration from a few minutes to four weeks.

[0195] Thus, in another aspect, certain embodiments provide a method of treating a FimH-mediated disorder in a human or animal subject in need of such treatment, the method comprising administering to the subject an amount of a compound disclosed herein in combination with at least one additional drug, wherein the amount of the compound disclosed herein is effective to reduce or prevent the disorder in the subject, the additional drug being a drug known in the art for treating the disease. In a related aspect, some embodiments provide a therapeutic composition comprising a combination of at least one compound disclosed herein and one or more additional drugs for treating a FimH-mediated disorder.

[0196] Specific diseases 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.

[0197] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be used in veterinary treatment of companion animals, exotic animals, and livestock, including mammals, etc. More preferred animals include horses, dogs, and cats.

[0198] General Synthesis Scheme of Compounds of the Invention

[0199] The compounds of the present invention can be prepared according to the synthesis method described in WO2017 / 156508 or its obvious variants. However, without limiting the present invention in any way, the following description also provides a reaction method that can be used to prepare the compounds of the present invention, for illustrative purposes only. The synthesis of C-mannoside ketone intermediate follows the route shown in Scheme A. Benzyl-protected methyl mannoside is allylated with allyltrimethylsilane to form α-allyl mannoside as the main isomer. The terminal double bond is then isomerized to an internal double bond with (PhCN)2PdCl2. The two-step operation of dihydroxylation of the double bond and cleavage with sodium periodate generates an aldehyde which can be used without further purification (see Wong, CH et al. Small Molecules as Structural and Functional Mimics of Sialyl Lewis X in Select in Inhibition: A Remarkable Enhancement of Inhibition by Additional Negative Charge and / or Hydrophobic Group. J. Amer. Chem. Soc. (1997) 119 (35) 8152-8158). The aldehyde intermediate reacts with an aryl iodide compound A1 and n-butyl lithium and is oxidized with a Dess-Martin reagent to form a ketone A2.

[0200] General Synthesis of Core Mannoside Ketones (Scheme A)

[0201] Plan A

[0202]

[0203] Boronate or bromide coupling ligands BE can be synthesized by the scheme shown below. 1-3 Alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 Alkynyl, phenyl, -(CH2) m -OH, or an optionally substituted vinyl group, intermediate B can be prepared by reacting RLi or RMgBr (or R-TMS for situations where organometallic reagents are not feasible, such as R = trifluoromethyl) with ketone A2, followed by reduction of the tertiary alcohol with triethylsilane, as shown in Scheme B.

[0204] As in Example 3 (when Q = CF3 and R 4 =CF3), if removal of the tertiary alcohol by triethylsilane is problematic, then Scheme C can be used alternatively for the case where R = methyl. The organometallic CH3MgBr reacts with the ketone A2, followed by removal of the tertiary alcohol with thionyl chloride. The resulting double bond is reduced with palladium / carbon to give intermediate C.

[0205] An alternative route to the formation of benzyl vinyl intermediates D and E, which can be modified to give optionally substituted vinyl derivatives or further derivatized to give R groups consisting of optionally substituted cyclopropyl, hydroxyalkyl, propargyl or alkynyl derivatives, is described in Scheme D. Functionalized phenylallylsilanes are reacted with methylmannose using a Lewis acid such as TMS-triflate. Phenyl bromide intermediate D can then be converted to a boronate ester using a palladium catalyst and bis(pinacolato)diboron to give intermediate E.

[0206] Synthesis scheme of aryl / heteroaryl bromide or boronic acid intermediates

[0207] Plan B

[0208]

[0209] Plan C

[0210]

[0211] Plan D

[0212]

[0213] Two general schemes for Suzuki coupling are described in Schemes E and F below. All examples utilize Suzuki coupling between halides and boronates. Mannosides are protected with benzyl groups. The benzyl groups can be removed with BCl3 or by hydrogenolysis with Pd / C. The R groups can be further functionalized using reactions known in the art. For example, if the R group contains a double bond, it can be hydroxylated using hydroboration. Alternatively, the double bond can be dihydroxylated using OsO4 and NMO. The diol can be cleaved with NaIO4 to form an aldehyde, which can then be reduced with DIBAL.

[0214] Two general protocols for Suzuki coupling and deprotection

[0215] Plan E

[0216]

[0217] Plan F

[0218]

[0219] General procedure for Suzuki coupling reaction: To a solution of mannoside (1.0 equiv) in dioxane / water (V / V=5 / 1) was added arylboronic acid (or boronate) or aryl halide (~1.1 equiv), cesium carbonate (~3 equiv) and tetrakis(triphenylphosphine)palladium (~0.05 equiv) at room temperature. The resulting mixture was degassed three times. The flask was then placed in an oil bath preheated to 80°C and stirred for the indicated time (usually 30 minutes to 2 hours). The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The crude residue was then purified by silica gel chromatography. The product was then deprotected by a deprotection protocol.

[0220] Deprotection scheme Benzyl ether was deprotected by adding BCl3 (8.0 equivalents, 1M in DCM) to a solution of partially purified mannoside in DCM (10 mL) from the Suzuki reaction at -78°C unless otherwise noted. The reaction was stirred at -78°C for a specified time. After completion, the reaction was quenched with MeOH (1 mL) at -78°C. The reaction was then heated to room temperature and concentrated under reduced pressure to obtain the debenzylated compound.

[0221] Example 1

[0222]

[0223] (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

[0224]

[0225] (4-Bromo-2-methylphenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone

[0226] 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) at 0°C was added Dess-Martin periodinane (2.34 g, 5.52 mmol). The reaction mixture was stirred at 25°C for 2 hours. Upon completion, the reaction was quenched with water (20 mL), extracted with DCM (20 mL×3), and the organic phases were combined, washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a residue (2 g) as a yellow oil, which was used in the next step without further purification. ESI-MS [M+Na] + (C 42 H 41 BrO6Na + )Calculated value: 743.22, measured value: 743.15.

[0227]

[0228] 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

[0229] 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 in Et2O) at -78°C. The reaction mixture was stirred at 25°C for 4 hours. Upon completion, the reaction was quenched with water (20 mL), 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. The residue was purified by silica gel column chromatography using a gradient of 0-25% ethyl acetate in petroleum ether as the eluent to give the title product (2 g, 98% yield) as a yellow oil. ESI-MS [M+H] + (C 43 H 45 BrO6Na + ) Calculated value: 759.25, Measured value: 759.15

[0230]

[0231] (2R,3R,4R,5R,6R)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-(1-(4-bromo-2-methylphenyl)ethyl)tetrahydro-2H-pyran

[0232] 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 Et3SiH (1.57 g, 13.5 mmol) and CF3COOH (3.09 g, 27.1 mmol) at -78°C. The reaction mixture was warmed to 25°C and stirred for 12 hours. Upon completion, the reaction was quenched with water (20 mL), extracted with DCM (20 mL×3), and 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 silica gel column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether as eluent to give the title product (1.8 g, 92% yield) as a yellow oil. ESI-MS [M+Na] + (C 43 H 45 BrO5Na + )Calculated value: 743.25, measured value: 743.24.

[0233]

[0234] 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

[0235] A stirred 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'-bis(1,3,2-dioxaborolane) (953 mg, 3.75 mmol), potassium acetate (735 mg, 7.5 mmol) and (1.1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II).CH2Cl2 (204 mg, 0.25 mmol) in 1,4-dioxane (20 mL) was heated at 80° C. for 12 hours. Upon completion, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether as eluent to give the title product (1.6 g, 83% yield) as a light brown solid. ESI-MS [M+Na] + (C 49 H 57 7Nb + )Calculated value: 791.13, measured value: 791.16.

[0236]

[0237] 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

[0238] 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. The residue was purified by silica gel column chromatography 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]+ (C 48 H 47 F3N2O5Na + ) Calculated value: 811.34, measured value: 811.16

[0239]

[0240] (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

[0241] 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 (1 N 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 by MeOH (12 mL) and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC using the following conditions: column: XBridge Prep OBD C18 column 30×150 mm 5 um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B, 9 minutes; 220 nm; Rt: 7.82 minutes; injection volume: 2 ml; number of runs: 3; a mixture (300 mg) was obtained. The mixture was further separated by Prep-Chiral using the following conditions: Column: CHIRALPAK IF, 2*25cm, 5um; Mobile phase A: Hex (8mmol / L NH3.MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20mL / min; Gradient: 30B to 30B, 18 minutes; 254 / 220nm; Injection volume: 1ml; Number of runs: 12; Fractions with RT=9.25 minutes (with MS signal of the desired product) were collected and concentrated in vacuo to give the title product (200mg, 26% yield) as a white solid.

[0242] Formula: C 20 H 23 F3N2O5 accurate mass: 428.16 molecular weight: 428.41.

[0243] Analyze the data: 1H NMR(300MHz, methanol-d4)δ9.28(d,J=1.5Hz,1H),9.08–8.99(m,1H),8.02-8.00(m,2H),7 .57(d,J=8.9Hz,1H),4.24(dd,J=10.1Hz,2.7Hz,1H),4.10(t,J=3.0Hz,1H),3.82(d d,J=8.6Hz,3.2Hz,1H),3.73(t,J=8.5Hz,1H),3.58-3.51(m,2H),3.40(dd,J=11.7H z,2.9Hz,1H),3.24-3.19(m,1H),2.52(s,3H),1.29(d,J=6.8Hz,3H).ESI-MS[M+Na] + (C 20 H 23 F3N2O5Na + ) Calculated value: 451.15, measured value: 451.10.

[0244] Example 2

[0245] (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

[0246]

[0247] 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

[0248] 2-Chloro-4-(trifluoromethyl)pyridine (189 mg, 1.041 mmol), tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.104 mmol), and Cs2CO3 (678 mg, 2.081 mmol) were added to a solution 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 (800 mg, 1.041 mmol) in 1,4-dioxane (8 mL) and water (2.0 mL). The resulting solution was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x3), dried over Na2SO4 and filtered. The filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography using a petroleum ether solution with a gradient of 0 to 18% ethyl acetate. The fractions with the MS signal of the desired product were combined and concentrated in vacuo to give the title product (630 mg, 0.8 mmol, 77% yield) as a yellow oil. ESI-MS [M+Na] + (C 49 H 48 F3N2O5Na + )Calculated value: 810.34, measured value: 810.0.

[0249]

[0250] (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

[0251] 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) was added BCl (1 N in DCM, 6.40 mL, 6.40 mmol) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 1 hour under N2. The reaction mixture was quenched with MeOH (5 mL) and concentrated by rotary evaporator to give a residue. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18OBD column 30*150mm, 5um; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 23% B to 43% B, 7 minutes; 254nm; Rt: 6.77 minutes; Injection volume: 1.40ml; Number of runs: 5, to obtain a mixture (190mg mixture of two isomers) as a white solid. The mixture was further separated by chiral-HPLC using the following conditions: column: CHIRALPAK IG, 20*250 mm, 5 um; mobile phase A: Hex (8 mmol / L NH3.MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 25B to 25B, 16 minutes; 220 / 254 nm; RT1: 10.423 minutes; RT2: 12.47 minutes; injection volume: 0.5 ml; number of runs: 14;

[0252] 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.

[0253] Formula: C 21 H 24 F3NO5 accurate mass: 427.16 molecular weight: 427.42.

[0254] Analyze the data: 1H NMR (400MHz, methanol-d4) δ8.85 (d, J=5.1Hz, 1H), 8.09 (s, 1H), 7.87-7.86 (m, 2H), 7.60 (d, J= 5.1Hz,1H),7.52(d,J=8.6Hz,1H),4.23(dd,J=10.2Hz,2.6Hz,1H),4.11(t,J=2.9Hz,1H) ,3.82(dd,J=8.6Hz,3.2Hz,1H),3.72(t,J=8.6Hz,1H),3.56-3.52(m,2H),3.40(dd,J=1 1.6Hz,2.8Hz,1H),3.23-3.19(m,1H),2.52(s,3H),1.29(d,J=6.8Hz,3H).ESI-MS[M+Na] + (C 21 H 24 F3NO5Na + )Calculated value: 450.15, measured value: 450.10.

[0255] 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.

[0256] Formula: C 21 H 24 F3NO5 accurate mass: 427.16 molecular weight: 427.42.

[0257] Analyze the data: 1 H NMR (400MHz, methanol-d4) δ8.87(d,J=5.2Hz,1H),8.11(s,1H),7.93-7.92(m,2H),7.60(d,J=5.4Hz,1H),7.46(d,J=8.0Hz,1H),4.14-4.05(dd,J= 11.4Hz,2.6Hz,1H),3.91(dd,J=11.8Hz,2.4Hz,1H),3.78-3.72(m,2H),3.69-3.49(m,4H),2.52(s,3H),1.35(d,J=6.8Hz,3H).ESI-MS[M+H] + (C 21 H 24 F3NO5H + )Calculated value: 428.17, measured value: 428.15.

[0258] Example 3

[0259]

[0260] (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

[0261]

[0262] (4-Bromo-2-(trifluoromethyl)phenyl)((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanone

[0263] To a solution of (S)-(4-bromo-2-(trifluoromethyl)phenyl)((2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methanol (5.45 g, 7.01 mmol) in DCM (50 mL) was added pyridine (1.700 mL, 21.02 mmol), Dess-Martin reagent (5.94 g, 14.02 mmol) at 0°C. The reaction mixture was then stirred at 0°C for 2 hours. A sample was removed from the reaction mixture and diluted with MeOH, and LCMS analysis indicated that the reaction was complete. The reaction mixture was quenched with 10% Na2S2O3(aq) (50 mL) / saturated NaHCO3(aq) (50 mL), and then extracted with DCM (10 mLx3). The organic layers were combined, washed with saturated NaHCO3(aq) (100 mL), dried over MgSO4, and filtered. The filtrate was concentrated to give 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, 98% yield) (orange oil), which was used in the next step without further purification. ESI-MS [M+Na] + (C 42 H 38 BrF3O6Na + )Calculated value: 797.17, measured value: 797.

[0264]

[0265] 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

[0266] Methylmagnesium bromide (34.2 mL, 34.2 mmol) was added 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) at -78°C. The reaction mixture was then warmed to 25°C and stirred for 12 hours. A sample was removed from the reaction mixture and diluted with MeOH, and LCMS analysis indicated that 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] + (C 43 H 42 BrF3O6Na + )Calculated value: 813.20, measured value: 813.

[0267]

[0268] 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

[0269] 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'-bis(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 hours, after which LCMS analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture is quenched with water (50mL), and extracted with ethyl acetate (40mL x 3). The organic phase merged is washed with salt water (40mL), and through Na2SO4 dry. The mixture is filtered, and the filtrate is concentrated in vacuo to obtain residue. Residue is dissolved in ethyl acetate, and is pre-adsorbed on silica gel (4 grams) by evaporation, then the petroleum ether solution that uses gradient is 0~20% ethyl acetate as the silica gel column chromatography purification of eluent, obtains 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] + (C 49 H 54 BF3O8Na + )Calculated value: 861.38, measured value: 861.

[0270]

[0271] 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

[0272] 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) at 0°C was added SOCl2 (0.557 mL, 7.63 mmol) dropwise. The reaction was stirred at 0°C for 30 minutes, at which time LCMS showed that the reaction was 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), pre-adsorbed onto silica gel (7 g) by evaporation, and loaded onto a column, 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 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 boronic acid) as an orange oil. ESI-MS [M+Na] + (C 49 H 52 BF3O7Na + )Calculated value: 843.37, measured value: 843.

[0273]

[0274] (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

[0275] 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 at 25°C for 11 hours under a hydrogen atmosphere (~3 atm). The reaction was monitored by LCMS. LCMS showed that the benzyl group was removed but the double bond was still present. The reaction was stopped and continued for another 12 hours under the reaction conditions. LCMS showed that 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] + (C 21 H 30 BF3O7Na + ) Calculated value: 485.19, measured value: 485.

[0276]

[0277] (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

[0278] 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) at 25°C was added Pd(Ph3P)4 (150 mg, 0.130 mmol) and Cs2CO3 (1269 mg, 3.89 mmol). The reaction mixture was stirred at 80°C for 2 hours. A sample was taken directly from the reaction mixture and diluted with MeOH and then used for LC-MS analysis. LC-MS showed complete consumption of the starting material. The reaction mixture is cooled to room temperature.The reaction mixture is quenched with water (10mL), and then extracted with ethyl acetate (3x 10mL).Merge organic layer, wash with water (10mL), through Na2SO4 dry and filter.The filtrate is concentrated to obtain residue.Residue is dissolved in MeOH (3mL), then by TLC purification, obtain residue (350mg), be yellow solid. The solid was then purified by Prep-chiral HPLC (column: Lux 5um Cellulose-4, 5*25cm, 5um; mobile phase A: , mobile phase B: ; flow rate: 150mL / min; gradient: 0B to 0B, min; 220nm; RT1: 6.5; RT2: 8.1; injection volume: 4ml; number of 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 (73mg, 0.150mmol, 11.54% yield) as a white solid.

[0279] Formula: C 20 H 20 F6N2O5. Accurate mass: 482.13, molecular weight: 482.38

[0280] Analytical data: 1H NMR (400MHz, CD3OD) δppm: 9.36 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.42 (d, J = 10 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 10 Hz, 1H), 4.10-4.11 (m, 1H), 3.61-3.75 (m, 3H), 3.47-3.53 (m, 1H), 3.34 (d, J = 2.8 Hz, 1H), 3.12-3.20 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H). ESI-MS [M+H] + (C 20 H 20 F6N2O5H + )Calculated value: 483.14, Measured value: 483.14.

[0281] Example 4

[0282] (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

[0283]

[0284] 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

[0285] 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)ethyl)phenyl)-1,3,2-dioxaborolane (150 mg, 0.195 mmol) in water (1 mL) and 1,4-dioxane (4.0 mL) was added 3-bromo-5-(trifluoromethyl)pyridine (44.1 mg, 0.195 mmol), tetrakis(triphenylphosphine)palladium(0) (22.55 mg, 0.020 mmol) and Cs2CO3 (127 mg, 0.390 mmol) at 25° C. The reaction mixture was stirred at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), dried over Na2SO4 and filtered. The filtrate was concentrated to give a residue. The residue was dissolved in DCM (5 mL) and then purified by Prep-TLC (ethyl acetate-petroleum ether = 1: 4). The bands with Rf = 0.5 were combined and washed with ethyl acetate. The appropriate fractions were combined and concentrated in vacuo to give the title compound (110 mg, 72% yield) as a yellow oil. ESI-MS [M + H] + (C 49 H 48 F3NO5H + )Calculated value: 788.36, measured value: 788.0.

[0286]

[0287] (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

[0288] 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) was added BCl (1 N in DCM, 1.117 mL, 1.117 mmol) under N at -78 °C. The reaction mixture was stirred at -78 °C under N for 1 hour. The reaction mixture was quenched with MeOH (5 mL) and concentrated by rotary evaporator to give a residue. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15B to 38B, 12 minutes; 254 nm; RT1: 11.60; Injection volume: 2.4 ml; Number of runs: 2; The title product (25 mg, 0.058 mmol, 42% yield) was obtained as a white solid.

[0289] Formula: C 21 H 24 F3NO5 accurate mass: 427.16 molecular weight: 427.42.

[0290] Analyze the data: 1 H NMR(400MHz, methanol-d4)δ9.08(d,J=2.1Hz,1H),8.91-8.78(m,1H),8.34(t,J=2.2Hz,1 H),7.61-7.47(m,3H),4.22(dd,J=10.2Hz,2.6Hz,1H),4.10(t,J=3.0Hz,1H),3.82( dd,J=8.6Hz,3.2Hz,1H),3.72(t,J=8.6Hz,1H),3.60-3.52(m,2H),3.42(dd,J=11.6 Hz,2.8Hz,1H),3.24-3.20(m,1H),2.51(s,3H),1.28(d,J=6.8Hz,3H).ESI-MS[M+H] + (C 21 H 24 F3NO5H + )Calculated value: 428.17, measured value: 428.05.

[0291] Example 5

[0292]

[0293] (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

[0294]

[0295] (3-(4-Bromo-2-methylphenyl)allyl)trimethylsilane

[0296] To a solution of Ph3PCH3Br (65 g, 182 mmol) in THF (200 mL) at 0°C was added nBuLi (80.5 mL, 201.3 mmol. 2.5 M in hexane). The resulting solution was warmed and stirred at 25°C for 1 hour. The solution was cooled to 0°C and a solution of TMS-CH2I (47 g, 219.5 mmol) in THF (200 mL) was added. The reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was cooled to 0°C and a solution of nBuLi (66.5 mL, 166.3 mmol, 2.5 M in hexane) was added. The reaction mixture was kept at 0°C for 1 hour and then cooled to -78°C. 4-Bromo-2-methylbenzaldehyde (30 g, 150.7 mmol) was added at -78°C and the reaction mixture was then warmed to room temperature and stirred for 3 hours. Upon completion, the reaction was quenched with aqueous NH4Cl (200 mL). The organic layer was separated. The aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using petroleum ether as eluent to give the title product (34.9 g, 81.8% yield, mixture of isomers) as a colorless oil. ESI-MS [M+H] + (C 13 H 19 BnS + )Calculated value: 283.25, Measured value: no mass.

[0297]

[0298] (2R,3R,4R,5R,6R)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-((R)-1-(4-bromo-2-methylphenyl)allyl)tetrahydro-2H-pyran

[0299] To a solution of (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran (52g, 93.7mmol) in ACN (400mL) was added (3-(4-bromo-2-methylphenyl)allyl)trimethylsilane (53g, 187mmol) and TMSOTf (31.2g, 140.4mmol) at 25°C. The resulting solution was stirred at 25°C for 16 hours. After completion, the reaction was quenched with water (150mL). The organic layer was separated. The aqueous phase was extracted with ethyl acetate (100mLx 3). The combined organic layers were washed with brine (100mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether as eluent to give a mixture (20 g) as a yellow oil. The mixture was further separated by Prep-SFC using the following conditions: Column: Phenomenex Lux 5u Cellulose-3, 5*25cm, 5um; Mobile phase A: CO2: 50, Mobile phase B: MeOH-----Preparative: 50; Flow rate: 150mL / min; 220nm; Fractions with MS signal of the desired product at RT = 10.32 minutes were collected and concentrated in vacuo to give the title compound (5.5g, 8% yield, minor isomer) as a yellow oil. ESI-MS [M+NH4] + (C 44 H 45 BrO5 NH4 + )Calculated value: 750.28, measured value: 752.25. 1 H NMR (300MHz, chloroform-d) δ7.42-7.23(m,23H),5.76-5.65(m,1H),4.97(d,J=12.0Hz,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).

[0300]

[0301] 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

[0302] 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'-bis(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 hours. 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 and loaded onto a column, then purified by silica gel chromatography eluting with EtOAc in petroleum ether (17%) to give the title product (350 mg, 70% yield) as a yellow oil. ESI-MS [M+Na] + (C 50 H 57 7Nb + )Calculated value: 803.42, Measured value: 803.42

[0303]

[0304] 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

[0305] 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 hours. Upon 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 and loaded onto a column, then purified by silica gel chromatography eluting with EtOAc in petroleum ether (17%) to give the title product (800 mg, 64% yield) as a colorless oil with 79% purity. ESI-MS [M+Na] + (C50 H 59 BO7 + )Calculated value: 805.44, measured value: 805.44.

[0306]

[0307] 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

[0308] 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) at 25° C. 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). The reaction mixture was then stirred at 80° C. for 1 hour 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 x 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 eluted with a petroleum ether solution of ethyl acetate (19%) to give the title product (150 mg, 72% yield) as a yellow oil. ESI-MS [M + H] + (C 49 H 49 F3N2O5H + ) Calculated value: 803.36, measured value: 803.94.

[0309]

[0310] (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

[0311] 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 BCl (1 N in DCM, 1.3 mL, 1.3 mmol) under N at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched with MeOH (5 mL) and concentrated to give a residue. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD column 19×150mm 5um; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 30% B to 45% B, 8 minutes; 254nm; Rt: 7.87 minutes to give the desired product (40mg, 57% yield) as a white solid.

[0312] Formula: C 21 H 25 F3N2O5 accurate mass: 442.17, molecular weight: 442.44

[0313] Analyze the 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=11.7Hz,5.5Hz,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=7.4Hz,3H).ESI-MS[M+Na] + (C 21 H 25 F3N2O5Na + )Calculated value: 465.17, measured value: 465.

[0314] Example 6

[0315] (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

[0316]

[0317] 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

[0318] To a solution of 4,4,5,5-tetramethyl-2-(3-methyl-4-((R)-1-((2R,3R,4R,5R,6R)-3,4,5-tri(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) at 25° C. 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). The reaction mixture was then stirred at 80° C. for 1 hour under N2. After completion, the reaction was cooled to 25°C and the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 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] + (C 49 H 47 F3N2O5Na + )Calculated value: 823.33, measured value: 823.94.

[0319]

[0320] (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

[0321] 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)allyl)phenyl)-5-(trifluoromethyl)pyrazine (230 mg, 0.29 mmol) in DCM (5 mL) was added BCl (1 N in DCM, 2.3 mL, 2.3 mmol) under N at -78°C. The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with MeOH (5 mL) and concentrated in vacuo to give a residue. The residue was purified by Prep-HPLC using the following conditions: column: XBridge Shield RP18 OBD column 30*150mm, 5um; 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, 9 minutes; 220nm; Rt: 7.47 minutes to give the title product (82mg, 64% yield) as a white solid.

[0322] Formula: C 21 H 23 F3N2O5 accurate mass: 440.16 molecular weight: 440.42

[0323] Analyze the data: 1 H NMR (300 MHz, methanol-d4) δ9.28 (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), 4.2 5-4.07(m,2H),3.89(dd,J=9.0Hz,3.3Hz,1H),3.74(t,J=9.1Hz,1H),3.57(dd,J=11.7Hz, 4.8Hz,1H),3.41(dd,J=11.7Hz,2.8Hz,1H),3.23-3.18(m,1H),2.52(s,3H).ESI-MS[M+H] + (C 21 H 23 F3N2O5H + )Calculated value: 441.16, measured value: 441.20.

[0324] Example 7

[0325]

[0326] (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

[0327]

[0328] (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

[0329] 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 (600 mg, 0.82 mmol) in THF (10 mL) and water (5 mL) was added N-methylmorpholine-N-oxide (384 mg, 3.28 mmol) under N2. Osmium tetroxide (2.5% wt. in t-BuOH; 2.92 g, 0.29 mmol) was added dropwise and the reaction was stirred at 25°C for 24 hours. Upon completion, saturated Na2S2O3 (aq.) was added and the reaction mixture was stirred until a black precipitate formed. The reaction mixture was then extracted with ethyl acetate (30 mL x 4). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-50% ethyl acetate in hexane as the eluent, wherein the two separable isomers were collected together to give the title product (557.3 mg, 88.5% yield, mixture of isomers) as a colorless syrupy substance. ESI-MS [M+NH] + (C 44 H 47 B7H + ) Calculated value: 789.24, measured value: 789.2.

[0330]

[0331] (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

[0332] 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 hours. After completion, the reaction was quenched with ice water (5 mL), extracted with DCM (5 mL×3), and 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 syrupy substance. ESI-MS [M+Na] + (C 43 H 44 BrO6Na + ) Calculated value: 758.22, found value: 759.1. After drying, the crude aldehyde was dissolved in DCM (1 mL) under N2 and cooled to 0°C. DIBAL (1M in hexane; 0.24 mL, 0.24 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 30 minutes and then warmed to room temperature overnight. Upon completion, the reaction mixture was diluted with DCM (5 mL) and carefully quenched by adding ice. The reaction mixture was washed with [1N] HCl (aq.) (5 mL x 3), followed by brine (5 mL x 1), then dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-50% ethyl acetate in hexane as the eluent to give the title product (68.3 mg, 56.8% yield). ESI-MS [M+Na] + (C 43 H 45 BrO6Na + ) Calculated value: 759.23, measured value: 759.1.

[0333]

[0334] (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

[0335] Under N2, 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) was added to a flask, followed by (4-chloro-3,5-difluorophenyl)boric 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 3 times and then placed in an oil bath at 80°C. The reaction mixture was stirred at 80°C for 2 hours. After completion, the reaction was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was partially purified by silica gel column chromatography 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] + (C 49 H 47 ClF2O6Na + ) Calculated value: 827.29, measured value: 827.3.

[0336]

[0337] (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

[0338] 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 (1 N in DCM, 1.34 mL, 1.34 mmol) dropwise at -78°C. The resulting solution was stirred at -78°C for 1 hour. Upon completion, the reaction was quenched with MeOH (0.5 mL), warmed to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC using the following conditions: Column: Teledyne Isco RediSep Prep C18 column, 20×150 mm, 5 um; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN (0.05% TFA); Flow rate: 18.9 mL / min; Gradient: 10% B to 39% B, 35 minutes; 254 / 214 nm; Rt: 33 minutes) to give the title compound (16.3 mg, 51.2%) as a white solid.

[0339] Formula: C 21 H 23 ClF2O6 accurate mass: 444.12 molecular weight: 444.86

[0340] Analyze the data: 1 H NMR (400 MHz, methanol-d4) δ7.60 (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] + (C 21 H 23 ClF2O6Na + )Calculated value: 467.10, measured value: 467.0.

[0341] Table 1 provides the prepared compounds and their biological and pharmacokinetic data (rat), if tested.

[0342] Table 1

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352] Description of Table 1

[0353]

[0354] HAI

[0355] <50 "++++"

[0356] 50-200 "+++"

[0357] 201-1000 "++"

[0358] >1000 “+”

[0359] Protocols for evaluating compounds of the invention

[0360] The activity of the compounds of Examples 1-34 above as FimH antagonists / inhibitors was obtained by the following assay and the results are provided in Table 1. Results not provided indicate that the compound has not been tested for activity.

[0361] Hemagglutination inhibition assay (HAI)

[0362] As previously described, the hemagglutination inhibition (HAI) assay was performed using UTI89 bacteria and guinea pig erythrocytes (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). The results are listed in Table 1. Values ​​not listed indicate that they were not tested.

[0363] Obtain AUC oral h* μ Routine determination of m, %F and Ue%PO values

[0364] 1.1. Animals

[0365] 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 caged in an environment with a 12-hour light / 12-hour dark cycle with free access to food and water. All animals were fed before dosing. The study was approved by the Pharmaron Laboratory Animal Care and Use Committee (IACUC).

[0366] Study design

[0367] As shown in the table below, male Wistar Han rats (n=3 per dose group) were divided into 1 group. Test articles were administered by intravenous infusion at a rate of 5 mL / kg / h for 1 hour (1 mg / kg). After 48 hours, the animals each received a single oral dose (5 mg / kg, free form) at a dose volume of 10 mL / kg. Blood samples were collected at various time points after IV infusion and PO administration. Urine samples (for some compounds) were collected at various time points after IV infusion and PO administration.

[0368]

[0369] 1.3. Preparation of formulations

[0370] Preparation of IV infusion dose (1 mg / kg):

[0371] The test article was dissolved in DMSO by vortexing and sonication to obtain a stock solution. An aliquot of this stock solution was mixed with 10% HP-β-CD in saline by vortexing to obtain a solution with a test article concentration of 0.2 mg / mL.

[0372] Preparation of PO dose (5 mg / kg):

[0373] The test article was added to 1% methylcellulose by vortexing and sonication to obtain a homogenous suspension with a test article concentration of 0.5 mg / mL.

[0374] 1.4 Sample collection

[0375] Blood samples:

[0376] For IV infusion (1 mg / kg) dosing, blood samples were collected 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, 24 hours after dosing.

[0377] For PO (5 mg / kg) dosing, blood samples were collected from each animal at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours after dosing.

[0378] Blood samples (50 μL) were collected from each animal via the jugular vein. These blood samples were placed in tubes containing K2EDTA. All blood was mixed with an equal volume of water and inverted several times. The blood samples were stored at -75±15°C until analysis.

[0379] Urine sample:

[0380] For IV infusion (1 mg / kg) dosing, urine samples were collected from each animal at 0-4, 4-8, 8-12, 12-24 hours after dosing.

[0381] For PO (5 mg / kg) dosing, urine samples were collected from each animal at 0-4, 4-8, 8-12, 12-24 hours post-dose (for some compounds).

[0382] Urine samples were collected serially at time intervals as described above, placed in containers maintained at temperature with dry ice, and stored at -80°C prior to analysis.

[0383] 1.5 Preparation of standard solutions for LC-MS / MS analysis

[0384] A 10 mg / mL stock solution of the test article was diluted with DMSO to obtain a 1 mg / mL standard stock solution (free form).

[0385] Calibration standard working solutions were prepared at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10000 ng / mL by serial dilution of the standard stock solution in 50% acetonitrile in water. Quality control working solutions were prepared at concentrations of 10, 500, and 8000 ng / mL by serial dilution of the standard stock solution in 50% acetonitrile in water. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0386] 1.6 Sample processing

[0387] 5 μL of each calibration standard working solution (5, 10, 20, 50, 100, 500, 1000, 5000 and 10000 ng / mL) was added to 50 μL of blank Wistar Han rat blood (blank blood: water = 1: 1) or urine to obtain 55 μL of 0.5-1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) calibration standards. For samples used for calibration curves, quality control (QC) samples of blood or urine of 1 ng / mL (low), 50 ng / mL (middle), 800 ng / mL (high) were prepared respectively. These QC samples were prepared in the same manner as the calibration standards on the day of analysis.

[0388] 55 μL of standard, 55 μL of QC sample or 55 μL of unknown sample (50 μL of blood or urine containing 5 μL of 50% acetonitrile) was mixed into 200 μL of acetonitrile containing IS (dexamethasone) to precipitate protein. The sample was then vortexed for 30 seconds. After centrifugation at 4700 rpm for 30 minutes at 4°C, 5 μL of supernatant was injected into the LC-MS / MS system for quantitative analysis.

[0389] 1.7 Pharmacokinetic analysis

[0390] After IV infusion of 1 mg / kg and PO at 5 mg / kg, the test article blood and urine concentrations in each animal were analyzed by non-compartmental analysis (Phoenix TM 7.0) Calculate pharmacokinetic parameters. The linear trapezoidal algorithm was used for AUC calculation.

[0391] AUC oral h*uM: area under the blood drug concentration-time (unit: h*μM) curve (AUC) after oral administration

[0392] %F: Oral bioavailability (%) derived from the ratio of dose-normalized AUC after PO and IV administration

[0393] Ue%PO: The percentage of the oral dose eliminated unchanged in the urine or an estimate of the parameter generated by multiplying the percentage of the intravenous dose eliminated in the urine by the oral bioavailability

[0394] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope of the present invention, can make various changes and modifications to the invention to adapt it to various usages and conditions.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in Z is n = 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 (optionally substituted with up to 7 fluorine atoms, up to 1 hydroxyl group, up to 1 -N(C 1-6 alkyl)2, and up to 1 -OC 1-6 alkyl), up to 1 -(CO)-NH-CH3, or up to 1 cyano; provided that R 2 It cannot all be H at the same time; 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, if the structure of Z permits, CR1, provided that all Y cannot be CH at the same time; and m=1 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is: Where Y1 is N or CR 1B , and Y2 and Y3 are selected from N or CH, provided that at least one of Y1, Y2 and Y3 is N; and R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B are independently selected from: H, F, Cl, CF3, cyclopropyl, -(CO)-NH-CH3 and cyano, provided that: When Y1 is CR 1B When R 1A and R 1B One of them is H; R 3A and R 3B One of them is H; R 2A , R 2B and R 2C At least one of is not H; and R 2A , R 2B and R 2C Only one of them can be -(CO)-NH-CH3 or cyano.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Z is:

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Z is:

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein Y1 and Y3 are N, and Y2 is CH; and R 1A It is cyclopropyl or -CF3.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein: Y3 is N, Y2 is CH, and Y1 is CR 1B ;and R 1A and R 1B One of them is H, and the other is selected from: -CF3 or cyano.

7. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Z is:

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein 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; and R 2C Selected from F and H; provided that R 2A , R 2B and R 2C At least one of them is not H, and the condition is R 2A , R 2B and R 2C Only one of them can be cyano.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 2A For F, R 2Bis selected from H and Cl; and R 2C For F.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Q is CH3 and R 4 is H, or Q is CF3 and R 4 For H.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein Q is CH3 and R 4 For H.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R is methyl or vinyl.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

14. A compound according to claim 1, selected from: (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; and (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 pharmaceutically acceptable salt thereof.

15. A compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in therapy.

16. A compound as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of bacterial infections, Crohn's disease (CD) and inflammatory bowel disease (IBD).

17. A compound as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the prevention or treatment of bacterial infection, Crohn's disease (CD) and inflammatory bowel disease (IBD).

18. A method of treating bacterial infection, Crohn's disease (CD) or inflammatory bowel disease (IBD), the method comprising administering to a human patient in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

19. A compound for use according to claim 16 or a pharmaceutically acceptable salt thereof, the use according to claim 17 or the method according to claim 18, wherein the bacterial infection is an antibiotic resistant bacterial infection.

20. A compound for use according to claim 16 or a pharmaceutically acceptable salt thereof, the use according to claim 17 or the method according to claim 18, wherein the bacterial infection is a urinary tract infection (UTI).

21. A compound for use, or a pharmaceutically acceptable salt thereof, use or method according to claim 20, wherein the urinary tract infection is recurrent.

22. A compound for use, or a pharmaceutically acceptable salt thereof, use or method according to claim 20, wherein the urinary tract infection is chronic.

23. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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